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INTRODUCTION Gallstone disease is a common reason for non-gynecologic operations during pregnancy(1,2) and is the major non-obstetric cause for hospitalization in the first year postpartum(3). A significant proportion of women experience biliary disease during pregnancy. Pregnancy may accentuate gallbladder stone formation. Alterations in hepatobiliary function occur during pregnancy to create a lithogenic environment. These changes include secretion of bile with increased amounts of cholesterol and decreased amounts of chenodeoxycholic acid and gallbladder stasis(4). The prevalence of biliary sludge, gallstones, and biliary pancreatitis in pregnancy ranges from 5-36%, 2-11%, and 1/1000-3/10000, respectively(1,5,6,7). In addition to the risks of symptomatic biliary disease on the mother and fetus, treatment approaches including surgery and conservative treatment bring their own risks and restrictions in pregnancy. Though recent guidelines have recommended laparoscopic cholecystectomy (LC) during pregnancy for all symptomatic gallstone disease(8,9), management of symptomatic disease during pregnancy has often been nonsurgical to avoid fetal and maternal harm(10). However, this non-operative management leads to a very high rate of antepartum symptom recurrence(2,8). The aim of the present study was to determine the course and outcomes of pregnant patients with complicated gallstone disease and to reveal the experience of a tertiary center.

l to avoid fetal and maternal harm(10). However, this non-operative management leads to a very high rate of antepartum symptom recurrence(2,8). The aim of the present study was to determine the course and outcomes of pregnant patients with complicated gallstone disease and to reveal the experience of a tertiary center. MATERIALS AND METHODS The written and electronic medical records of 92.567 patients who were admitted to the Emergency Surgery Clinic in İstanbul University İstanbul Faculty of Medicine, between January 2010 and August 2015, were evaluated in this study. The medical records were reviewed using searches for diagnoses with the terms of pregnant, pregnancy, gallstone, cholecystitis, cholangitis, choledocholithiasis, pancreatitis, and endoscopic retrograde cholangiopancreatography (ERCP) in pregnancy in the hospital database. Patients diagnosed as having complicated gallstone disease were included in this study. Complicated gallstone disease was defined as acute cholecystitis, choledocholithiasis, cholangitis, and gallstone pancreatitis(3). All diagnoses were made with a combination of medical history, physical examination, laboratory tests and imaging techniques such as [ultrasonography, and magnetic resonance cholangiopancreatography (MRCP)]. Diagnosis of acute cholecystitis was made when biliary pain was associated with the presence of both gallbladder lithiasis and inflammation. Acute biliary pancreatitis was diagnosed with the presence of gallbladder lithiasis, elevated serum amylase level, and presence of biliary pain. Choledocholithiasis was defined in the presence biliary symptoms, jaundice, abnormal liver function tests, and presence of gallbladder lithiasis. Common bile duct stones were confirmed with either ultrasonography or MRCP; these patients underwent ERCP. Cholangitis was diagnosed in the presence of fever and elevated acute phase reactants. LC and ERCP procedures were performed after explanation of the risks, complications, and alternatives. ERCPs were performed by general surgeons who were experienced with endoscopy using a Fujinon EPX-201 videoendoscope. Double-sided lead shielding was positioned above, below, and on both sides of the patient, covering the abdomen and pelvis in case there was a need for radiation. In all cases, selective cannulation was performed and confirmed by the aspiration and/or direct visualization of the bile. After cannulation of the common bile duct, a guide wire was passed and sphincterotomy was completed.

th sides of the patient, covering the abdomen and pelvis in case there was a need for radiation. In all cases, selective cannulation was performed and confirmed by the aspiration and/or direct visualization of the bile. After cannulation of the common bile duct, a guide wire was passed and sphincterotomy was completed. Stones were extracted using a basket or balloon sweep(11). LC was performed using a standard four-port technique. A hasson trocar was placed, and the abdominal cavity was insufflated with carbon dioxide, with a maximum insufflation pressure of 12 mmHg. Calot’s triangle was identified and the cystic duct and cystic artery were clipped, taking care not to injure the common bile duct. The gallbladder was removed from the liver bed using diathermy. If clear exploration could not be provided using laparoscopy, laparotomic cholecystectomy was performed. Patients with pregnancy-related conditions that may be associated with epigastric pain including severe preeclampsia, hemolysis, elevated liver enzymes, and low platelet count syndrome, acute fatty liver, abruptio placentae, uterine rupture, and intraamniotic infection, and patients with primary sclerosing cholangitis, non-biliary pancreatitis, intrahepatic cholestasis, primary biliary cirrhosis, gallbladder and biliary duct tumors, drug-induced pancreatitis, gastroesophageal reflux, peptic ulcer disease, hepatitis, right-sided pneumonia, and appendicitis were excluded. Attack episode was defined as recurrence of disease after normal physical and laboratory findings. Patients were grouped according to the trimester in which the symptoms developed for the first time. Preterm delivery was defined as birth at <37 weeks of gestation. Low birth weight was defined as a birth weight of a live-born infant of less than 2500 gr. Patients’ age, week of gestation, parity, body mass index (BMI), initial diagnosis at admission, definitive diagnosis, attack episodes, treatment modalities, and obstetric and neonatal complications were evaluated.

of gestation. Low birth weight was defined as a birth weight of a live-born infant of less than 2500 gr. Patients’ age, week of gestation, parity, body mass index (BMI), initial diagnosis at admission, definitive diagnosis, attack episodes, treatment modalities, and obstetric and neonatal complications were evaluated. Statistical Analysis Statistical analysis was performed using SPSS IBM 21 (IBM Co., Armonk, NY, USA). Descriptive analysis was performed including frequency, percentage, means, and standard deviation of the demographic features and disease history. The Shapiro-Wilk test was used to verify normality. The Kruskal-Wallis test was employed to analyze more than two variables in the study. P<0.05 was considered statistically significant. RESULTS Overall, 59 women were diagnosed as having complicated gallstone disease in pregnancy. The demographic features of the patients are shown in Table 1. Thirteen (15.9%) of the patients presented in the first trimester, 25 (30.5%) patients in the second, and 21 (25.6%) patients presented in the third trimester. Table 1 summarizes the distribution of cases throughout pregnancy. Fifty-one (86.4%) of the 59 patients had one attack episode and 6 (10.2%) patients were admitted to hospital twice. Two (3.4%) patients had 3 attack episodes (Table 2). Acute cholecystitis was the most commonly diagnosed complicated gallstone disease in pregnancy; 37 patients were diagnosed as having acute cholecystitis during pregnancy (Table 3).

RESULTS Overall, 59 women were diagnosed as having complicated gallstone disease in pregnancy. The demographic features of the patients are shown in Table 1. Thirteen (15.9%) of the patients presented in the first trimester, 25 (30.5%) patients in the second, and 21 (25.6%) patients presented in the third trimester. Table 1 summarizes the distribution of cases throughout pregnancy. Fifty-one (86.4%) of the 59 patients had one attack episode and 6 (10.2%) patients were admitted to hospital twice. Two (3.4%) patients had 3 attack episodes (Table 2). Acute cholecystitis was the most commonly diagnosed complicated gallstone disease in pregnancy; 37 patients were diagnosed as having acute cholecystitis during pregnancy (Table 3). ERCPs were performed in 4 patients and the procedure was conducted without radiation. Three of the 4 patients opted for laparoscopic surgery. Cholecystectomy was performed in 15 pregnant women; 9 (60%) patients underwent surgery during the second trimester, 1 (6.6%) patient had surgery in the first trimester, and the remainder (n=5) (33.3%) underwent surgery in the third trimester. Laparotomy was performed in 1 patient in the third trimester due to inadequate exploration during laparoscopy.

15 pregnant women; 9 (60%) patients underwent surgery during the second trimester, 1 (6.6%) patient had surgery in the first trimester, and the remainder (n=5) (33.3%) underwent surgery in the third trimester. Laparotomy was performed in 1 patient in the third trimester due to inadequate exploration during laparoscopy. Perinatal outcomes are summarized in Table 4. Four of the 59 pregnant women had preterm delivery. Two of these had undergone surgery and the remainder were treated conservatively. One of 59 pregnant women had a missed abortion (8 weeks of gestation). That patient had been treated conservatively. Five infants had a low birth weight. No gross fetal anomalies were encountered in either the conservatively- or surgically-treated patients. One maternal death was encountered. This patient had severe acute pancreatitis.

t women had a missed abortion (8 weeks of gestation). That patient had been treated conservatively. Five infants had a low birth weight. No gross fetal anomalies were encountered in either the conservatively- or surgically-treated patients. One maternal death was encountered. This patient had severe acute pancreatitis. DISCUSSION Although some pregnant patients experience uncomplicated cholelithiasis, an important proportion develop complicated gallstone disease defined as acute cholecystitis, choledocholithiasis, cholangitis, and gallstone pancreatitis(3). It is widely understood that symptomatic gallstone disease in pregnancy is related with increased mortality risk for both the mother and fetus and may result in complications including spontaneous abortion, fetal abnormalities, preterm labor, and even death(2,5,7). The management of symptomatic biliary disease during pregnancy has often been nonsurgical to avoid fetal and maternal harm(10), but ironically, this results in a high rate of antepartum symptom recurrence(2,8,9). Although laparoscopy is known to be safe in the second trimester, studies have reported the risk of preterm labor or spontaneous abortion with LC(12,13).

during pregnancy has often been nonsurgical to avoid fetal and maternal harm(10), but ironically, this results in a high rate of antepartum symptom recurrence(2,8,9). Although laparoscopy is known to be safe in the second trimester, studies have reported the risk of preterm labor or spontaneous abortion with LC(12,13). There is agreement concerning the security of LC during the second trimester of pregnancy and some physicians also extend the indication to the first and third trimester(12,14,15,16,17). Recent guidelines recommended LC during pregnancy for all symptomatic gallstone disease(8,9) and laparoscopic treatment of acute abdominal disease has the same indications in pregnant and non-pregnant patients(18). Studies reporting uterine injury during trocar placement, increased risk of preterm labor and spontaneous abortion with LC exist, even though they were performed in the second trimester(12,13). The rate of preterm labor is 0-20% for LC(19,20,21,22,23). Fetal mortality rates following LC range from 0 to 5.2%(19,20,21,22,23). In our study, the rate of preterm labor was 3.4% and fetal mortality was not encountered after LC. Symptomatic gallstone disease has been related with increased mortality risk for the mother and fetus, besides the risk of interventions in pregnancy(7). Complications including spontaneous abortion, fetal abnormalities, preterm labor, and even fetal and maternal death may occur. In our study, 1 missed abortion, 1 maternal death, 2 preterm deliveries, 3 low-birth-weight fetuses, and no fetal abnormalities were encountered in conservatively-treated patients. A case series in the literature reported that the most common reasons for biliary surgery during pregnancy were biliary colic in 70% of cases, followed by acute cholecystitis in 20%, choledocholithiasis in 7%, and acute biliary pancreatitis in the remaining 3% of cases(14). In our study, acute cholecystitis was the most commonly diagnosed complicated gallbladder disease in pregnancy; 37 (62.7%) patients were diagnosed as having acute cholecystitis during pregnancy.

ed by acute cholecystitis in 20%, choledocholithiasis in 7%, and acute biliary pancreatitis in the remaining 3% of cases(14). In our study, acute cholecystitis was the most commonly diagnosed complicated gallbladder disease in pregnancy; 37 (62.7%) patients were diagnosed as having acute cholecystitis during pregnancy. There is a very high rate of antepartum symptom recurrence with nonsurgical management of symptomatic biliary disease during pregnancy(2,8,10). It was reported that non-operative management of symptomatic cholelithiasis in pregnancy was associated with frequent hospitalizations(24,25). Recurrence rates after conservative treatment range between 40-92%. Recurrence of biliary pancreatitis was observed in 50% of patients after conservative treatment(24). A higher incidence of preterm labor for patients with conservative versus surgical treatment, with a clear relation with symptom recurrence was reported(22). In our study, 6 (10.2%) patients had 2 attack episodes and 2 (3.4%) were admitted to hospital on three further occasions. ERCP is an important therapeutic option in patients with biliary and pancreatic disease. ERCP is a very effective way to extract common bile duct stones(11). In the literature, it was concluded that ERCP could be performed safely during pregnancy. On the other hand, a lower rate of term pregnancy, higher rate of preterm delivery, and low birth weight were more common when interventions were required during the first trimester(26). In our study, ERCP was performed in 4 patients. Three out of the 4 patients chose LC.

RCP could be performed safely during pregnancy. On the other hand, a lower rate of term pregnancy, higher rate of preterm delivery, and low birth weight were more common when interventions were required during the first trimester(26). In our study, ERCP was performed in 4 patients. Three out of the 4 patients chose LC. We present our clinical experience because the diagnosis, course, and management of complicated gallstone disease is complicated. We aimed to determine the outcomes of pregnant patients. As a new thought, biliary tract screening by sonographic examination may be recommended before pregnancy, and LC prior to pregnancy may be suggested to prevent complications related to gallstones during gestation. It might be especially considered for pregnant patients with a high BMI and a history of multiple small stones in the gallbladder. However, further randomized controlled trials are required before this idea can be fully supported. There are some limitations of this study. This study had a retrospective design and the patient population was small; further studies with greater patient populations will highlight possible missing comments. I would like to express my sincere thanks to all my colleagues and Mr. David F. Chapman for language editing of the manuscript. Ethics: Ethics Committee Approval: Retrospective study, Informed consent: Retrospective study. Peer-review: Externally peer-reviewed.

We present our clinical experience because the diagnosis, course, and management of complicated gallstone disease is complicated. We aimed to determine the outcomes of pregnant patients. As a new thought, biliary tract screening by sonographic examination may be recommended before pregnancy, and LC prior to pregnancy may be suggested to prevent complications related to gallstones during gestation. It might be especially considered for pregnant patients with a high BMI and a history of multiple small stones in the gallbladder. However, further randomized controlled trials are required before this idea can be fully supported. There are some limitations of this study. This study had a retrospective design and the patient population was small; further studies with greater patient populations will highlight possible missing comments. I would like to express my sincere thanks to all my colleagues and Mr. David F. Chapman for language editing of the manuscript. Ethics: Ethics Committee Approval: Retrospective study, Informed consent: Retrospective study. Peer-review: Externally peer-reviewed. Authorship Contribution: Surgical and Medical Practices: Mehmet İlhan, Kayıhan Günay, Cemalettin Ertekin, Concept: Mehmet İlhan, Gülşah İlhan, Kayıhan Günay, Design: Mehmet İlhan, Gülşah İlhan, Kayıhan Günay, Data Collection or Processing: Mehmet İlhan, Ali Fuat Kaan Gök, Analysis or Interpretation: Mehmet İlhan, Gülşah İlhan, Literature Search: Mehmet İlhan, Gülşah İlhan, Writing: Mehmet İlhan, Gülşah İlhan. Conflict of Interest: No conflict of interest was declared by the authors.

Authorship Contribution: Surgical and Medical Practices: Mehmet İlhan, Kayıhan Günay, Cemalettin Ertekin, Concept: Mehmet İlhan, Gülşah İlhan, Kayıhan Günay, Design: Mehmet İlhan, Gülşah İlhan, Kayıhan Günay, Data Collection or Processing: Mehmet İlhan, Ali Fuat Kaan Gök, Analysis or Interpretation: Mehmet İlhan, Gülşah İlhan, Literature Search: Mehmet İlhan, Gülşah İlhan, Writing: Mehmet İlhan, Gülşah İlhan. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study received no financial support. Table 1 Demographic features of the patients and distribution of cases throughout pregnancy Table 2 Attack episodes Table 3 Distribution of patients according to diagnosis and surgical intervention Table 4 Perinatal outcomes of the cases

INTRODUCTION Hysterectomy is one of the most common gynecologic operations performed in developed countries and is usually performed for benign disorders(1,2). Sexual function and the quality of life have been the focus of many recent studies. Investigation of the effects of hysterectomy performed for benign indications on sexual function and postoperative quality of life have led to varied results. Hysterectomy may cause sexual dysfunction in the postoperative period(3,4). On the other hand, abnormal uterine bleeding, endometriosis, and adnexal or uterine pathologies can lead to sexual problems, and pain reduce quality of life(5). The rapid progress made in laparoscopic surgery over the past 20 years has been a crucial development in gynecologic surgery and plays a role in the determination of treatment(6). The most significant benefits of laparoscopic surgery include decreased blood loss, lower risk of surgical site infections, shorter hospital stays, and rapid return to normal daily activities in laparoscopy compared with laparotomy(7). However, studies investigating postoperative psychological effects and effects on sexual function are limited. In the present study, we conducted a prospective cohort trial investigating the advantages and potential drawbacks regarding the sexual function of patients who underwent laparoscopic and abdominal hysterectomy. Our goal was to investigate whether there were any differences in the quality of sexual function postoperatively.

e present study, we conducted a prospective cohort trial investigating the advantages and potential drawbacks regarding the sexual function of patients who underwent laparoscopic and abdominal hysterectomy. Our goal was to investigate whether there were any differences in the quality of sexual function postoperatively. MATERIALS AND METHODS The present prospective cohort study was conducted in Zeynep Kamil Training and Research Hospital, which is one of the largest tertiary teaching hospitals in Turkey. All patients provided informed consent. Approval from the local ethics committee was acquired. Preoperatively, all patients underwent gynecologic examination, transvaginal ultrasounds, medical histories were obtained, and routine laboratory tests were performed.

one of the largest tertiary teaching hospitals in Turkey. All patients provided informed consent. Approval from the local ethics committee was acquired. Preoperatively, all patients underwent gynecologic examination, transvaginal ultrasounds, medical histories were obtained, and routine laboratory tests were performed. Patients for whom hysterectomy without concurrent unilateral or bilateral adnexectomy was indicated for a benign gynecologic condition, who had a stable heterosexual relationship for at least 1 year, and who had no psychiatric disorders were included in the study. The exclusion criteria were suspicion of malignancy, a previous lower midline incision, the need for simultaneous interventions such as prolapse repair, the need for intraoperatively diagnosed adnexal pathology requiring subsequent unilateral or bilateral oophorectomy, having preoperative or postoperative hormone-therapy, and an inability to communicate in Turkish. In addition, patients with psychiatric disorders, vaginismus, lack of orgasm, a history of endometriosis, partners with sexual dysfunction, those who refused the interview, lost to follow-up, loss of sexual interest, psychological and physiological problems with partner’s relationship, and in postmenopausal period were excluded from the study. The patients and their physician had decided to the route of hysterectomy. The patients were included in the study if they were scheduled for abdominal or laparoscopic hysterectomy. Patients were divided into two groups according to the surgical treatment: the total abdominal hysterectomy (TAH) group and the total laparoscopic hysterectomy (TLH) group. The demographic characteristics (age, marital status, education, and occupation) were recorded. The sexual function and quality of life were assessed 1 day preoperatively on admission to our hospital. Both of the groups’ patients were contacted 6 months postoperatively and interviewed again. All questionnaires were coded with an identifying number, and women could not view their previous answers. We confirmed that all of the patients had had sexual intercourse again six months after surgery. All data were recorded and analyzed by another researcher who was blinded to the group assignments.

terviewed again. All questionnaires were coded with an identifying number, and women could not view their previous answers. We confirmed that all of the patients had had sexual intercourse again six months after surgery. All data were recorded and analyzed by another researcher who was blinded to the group assignments. Operating procedures All patients underwent general anesthesia and received preoperative antibiotic prophylaxis as well as anticoagulants during immobilization. Laparoscopic hysterectomies were all intentionally TLHs(8) and TAH was performed using the standard extrafascial technique by means of clamps and suture ligation(9). The technical aspects of both types of hysterectomy were discussed with each patient, and the appropriate hysterectomy type was selected through mutual discussion. Questionnaires Sexual dysfunction and quality of sexual life, psychological health status, and self-esteem were assessed preoperatively and 6 months postoperatively using standardized validated questionnaires: the Arizona Sexual Experiences Scale (ASEX), the Symptom Checklist-90-Revised (SCL-90-R), and the Rosenberg Self-Esteem Scale (RSES).

ysfunction and quality of sexual life, psychological health status, and self-esteem were assessed preoperatively and 6 months postoperatively using standardized validated questionnaires: the Arizona Sexual Experiences Scale (ASEX), the Symptom Checklist-90-Revised (SCL-90-R), and the Rosenberg Self-Esteem Scale (RSES). Arizona Sexual Experiences Scale The patients’quality of sexual life was measured using the ASEX scale. The ASEX is a five-item scale with six different levels of answers that measure sexual function. The questionnaire enquires about sex drive, arousal, vaginal lubrication, ability to reach orgasm, and satisfaction with orgasm. The female and male versions of the ASEX differ on the sex-specific question 3, which addresses erection/lubrication. A total ASEX score of ≥19, any one item with an individual score of 5 or 6, and three or more items with individual scores of 4 have all been found highly correlated with physician-diagnosed sexual dysfunction(10). Patients whose partners had sexual dysfunction were eliminated from the study. We used the Turkish version of the inventory, which has been proven valid and reliable by a recent study (Cronbach’s alpha=0.91)(11). Symptom Checklist-90-Revised Scale SCL-90-R was used to evaluate the psychological health status of the patients. The SCL-90-R includes items about psychosomatic symptoms of the patient and covers nine scales: 1. Somatization; 2. Obsessive-compulsive behavior; 3. Interpersonal sensitivity; 4. Depression; 5. Anxiety; 6. Hostility; 7. Phobic anxiety; 8. Paranoid ideation; 9. Psychoticism(12,13).

Symptom Checklist-90-Revised Scale SCL-90-R was used to evaluate the psychological health status of the patients. The SCL-90-R includes items about psychosomatic symptoms of the patient and covers nine scales: 1. Somatization; 2. Obsessive-compulsive behavior; 3. Interpersonal sensitivity; 4. Depression; 5. Anxiety; 6. Hostility; 7. Phobic anxiety; 8. Paranoid ideation; 9. Psychoticism(12,13). Stressful personality, depression, anxiety, and somatization are generally measured using five-point scales (sores between 0-4)(14). Increasing scores generally indicate that the patient is anxious about the symptoms and signs. We used the Turkish version of the inventory, which has been proven valid and reliable by a recent study (Cronbach’s alpha=0.83)(15). Rosenberg Self-Esteem Scale RSES consists of 10 items for assessing levels of self-esteem. The items are answered on a four-point scale using anchors of strongly agree (0) and strongly disagree. Its reliability and validity in Turkish were confirmed in 1986 by Çuhadaroğlu(16) and the first 10 items of the test, which assess self-esteem, were used. The subjects achieve scores between 0 and 6 according to the self-assessment system of the scale. A score of 0-1 is considered high self-esteem, a score of 2-4 is considered moderate self-esteem, and a score of 5-6 is considered low self-esteem. A high score indicates low self-esteem, whereas a low score indicates high self-esteem.

achieve scores between 0 and 6 according to the self-assessment system of the scale. A score of 0-1 is considered high self-esteem, a score of 2-4 is considered moderate self-esteem, and a score of 5-6 is considered low self-esteem. A high score indicates low self-esteem, whereas a low score indicates high self-esteem. Statistical Analysis Statistical analysis was performed using SPSS version 21.0 for Windows. Values are expressed as mean ± standard deviation. The Kolmogorov-Smirnov test was performed to assess the distribution of data. A comparison of two groups was performed using Student’s t-test or Mann-Whitney U test for continuous variables, and the chi-square test for categorical variables. Comparisons of preoperative and postoperative scores were performed using the paired-samples t-test and Wilcoxon test. A p value of <0.05 was considered to indicate statistical significance. RESULTS The patient flow chart is listed in detail in Figure 1. Out of 150 eligible patients, 84 completed the study. The demographic and clinical data of the two groups are summarized in Table 1. There were no statistically significant differences in the pre-and postoperative SCL-90-R scores between the groups (p>0.05) (Table 2).

RESULTS The patient flow chart is listed in detail in Figure 1. Out of 150 eligible patients, 84 completed the study. The demographic and clinical data of the two groups are summarized in Table 1. There were no statistically significant differences in the pre-and postoperative SCL-90-R scores between the groups (p>0.05) (Table 2). Both groups exhibited a statistically significant decrease in the postoperative RSES scores compared with the preoperative scores (p<0.05). However, there were no statistically significant differences between the groups (p>0.05) (Table 3). Evaluations of sexual function are summarized in Table 4. No differences were observed between the two groups preoperatively. Postoperative decreases in ASEX scores (improvement in sexual function) were observed in both groups. Improvement in sex drive score and psychological arousal scores were better in the laparoscopic hysterectomy group compared with the abdominal group (p<0.01).

rences were observed between the two groups preoperatively. Postoperative decreases in ASEX scores (improvement in sexual function) were observed in both groups. Improvement in sex drive score and psychological arousal scores were better in the laparoscopic hysterectomy group compared with the abdominal group (p<0.01). DISCUSSION In the present study, decreased ASEX scores were observed 6 months postoperatively in both groups. This was more remarkable in the laparoscopy group compared with the laparotomy group. Both groups showed improvement in RSES scores; however, no significant difference was observed. Regarding the psychiatric evaluation, there were no significant differences between the groups preoperatively and 6 months postoperatively. The effects of hysterectomy on women’s sexuality are controversial, and sexual function in the post-hysterectomy period is a complicated and uncertain issue by means of its results(17,18,19,20,21). Hysterectomy may increase the quality of life in patients who did not respond to conservative therapy by relieving symptoms(22). Nevertheless, patients preparing for hysterectomy may experience fear and anxiety of sexual function loss(23). Hysterectomy is a loss because the uterus is an organ to which women are connected psychologically. Psychosexual problems after hysterectomy are usually related to marital issues and poor body image, which are exacerbated with hysterectomy. Age, biologic and psychological factors, relationships and social and cultural circumstances affect a woman’s sexuality(2,24). Therefore, women’s sexuality needs to be assessed through many independent factors. On the other hand, preoperative sexual function and psychological status are also important determinants of sexual dysfunction postoperatively. In our study, essential factors affecting sexuality such as self-respect and psychological status were evaluated. We observed no statistically significant changes in psychiatric scores in either group; however, amelioration of self-respect was observed postoperatively, and in our opinion, this may be a substantial factor affecting sexual improvement. In order to ensure a homogenous study population, we excluded patients with high preoperative psychiatric scores. Thus, we aimed to assess the effect of the operation on sexual life and also on the patient’s psychology.

postoperatively, and in our opinion, this may be a substantial factor affecting sexual improvement. In order to ensure a homogenous study population, we excluded patients with high preoperative psychiatric scores. Thus, we aimed to assess the effect of the operation on sexual life and also on the patient’s psychology. Following hysterectomy, elimination of pain, discomfort, resistant menometrorrhagia associated with present disease, and risk of cancer and unwanted pregnancy may result in higher frequency of orgasms and a more satisfying sexual life(25). Farrell and Kieser(26) claimed in their study that improvement in quality of life and no negative effects on sexuality were observed. The most important factor they emphasized was that there were many factors influencing sexual life and that these should be assessed in unity. Ayoubi et al.(2) compared three types of hysterectomy (vaginal, abdominal, and laparoscopic) and found no differences in the effects on orgasm, frequency of sexual intercourse and sexual desire between groups; however, poorer body image was observed less in the TLH group compared with the TAH group. Another important finding of this study was that adverse psychological effects were observed less in the laparoscopy group. The absence of abdominal scars in the laparoscopy group and less postoperative pain may explain these findings.

r, poorer body image was observed less in the TLH group compared with the TAH group. Another important finding of this study was that adverse psychological effects were observed less in the laparoscopy group. The absence of abdominal scars in the laparoscopy group and less postoperative pain may explain these findings. A study that compared 5 different hysterectomy procedures conducted by Lermann et al.(27) reported that women in the laparoscopic supracervical hysterectomy (LASH) and TLH groups had more favorable results. However, the difference between TLH and LASH groups was not statistically significant. The study of Lermann et al.(27) was a long-term and broad study but the retrospective study design and lack of sexual evaluation before surgery were important limitations of the study. Although statistical significant differences between the groups were not encountered, the conclusion of less invasive methods had more favorableresults was compatible with our results.

nd broad study but the retrospective study design and lack of sexual evaluation before surgery were important limitations of the study. Although statistical significant differences between the groups were not encountered, the conclusion of less invasive methods had more favorableresults was compatible with our results. Gutl et al.(28) compared vaginal hysterectomy (VH) and TAH groups. The authors assessed patients 3 months and 2 years postoperatively and observed improvement on sexual function in both groups; more pain and poor self-image were observed in the TAH group, which may be associated with abdominal scar appearance. In addition, the recovery period was longer compared with the VH group. Hehenkamp et al.(29) randomly assigned patients to undergo uterine artery embolization and hysterectomy for the treatment uterine fibroids, then assessed sexual activity and body image scales in both groups. Improvement was more apparent in the uterine artery embolization group. Less invasive methods of surgery appear to have a positive impact on quality of life and patient comfort. This favorable change in self-body image and quality of life also has indirect positive repercussions on sexual life. Both TLH and TAH groups showed decreased postoperative ASEX scores. In comparison with abdominal operations, sexual drive scores and arousal scores decreased more in the TLH group, which indicated improvement in sexual function. TLH appears to have advantages for women who require total hysterectomy for benign indications, particularly with regard to sexual functions. The main strengths of our study were the prospective observational design and the patients were chosen homogeneously. However, the small number of the study group and short follow-up period (6 months postoperatively) were the main limitations of the study.

nign indications, particularly with regard to sexual functions. The main strengths of our study were the prospective observational design and the patients were chosen homogeneously. However, the small number of the study group and short follow-up period (6 months postoperatively) were the main limitations of the study. CONCLUSION In conclusion, laparoscopic surgery should be performed on suitable patients considering that it is less invasive, has a shorter recovery period, and has positive effects on sexual function and quality of life. We think that further research with a prospective long-term follow-up design is necessary to identify a surgical option associated with maximum preservation of sexual function during hysterectomy procedures. Ethics: Ethics Committee Approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Approval number: 127/2013, Informed Consent: Informed consent was obtained from all individual participants included in the study. Peer-review: Internally peer-reviewed.

Ethics: Ethics Committee Approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Approval number: 127/2013, Informed Consent: Informed consent was obtained from all individual participants included in the study. Peer-review: Internally peer-reviewed. Authorship Contributions: >Surgical and Medical Practices: Meryem Kürek Eken, Ateş Karateke, Concept: Meryem Kürek Eken, Gülşah İlhan, Evrim Erbek Çelik, Design: Ateş Karateke, Meryem Kürek Eken, Evrim Erbek Çelik, Data Collection or Processing: Meryem Kürek Eken, Dilşad Herkiloğlu, Evrim Erbek Çelik, Analysis or Interpretation: Meryem Kürek Eken, Gülşah İlhan, Osman Temizkan, Literature Search: Osman Temizkan, Evrim Erbek Çelik, Dilşad Herkiloğlu, Writing: Meryem Kürek Eken, Gülşah İlhan, Osman Temizkan. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study received no financial support. Table 1 Patients’ sociodemographic variables and medical characteristics prior to surgery Table 2 Comparison of Symptom Checklist-90-Revised preoperative and postoperative 6th month Table 3 Comparison of Rosenberg Self-Esteem Scale preoperative and postoperative 6th month Table 4 Comparison of Arizona Sexual Experiences Scale score preoperative and postoperative Figure 1 Flow chart of study design SCL-90-R: Symptom Checklist-90-Revised

INTRODUCTION Window of implantation is defined as the period of an optimal synchronization between the embryo and the endometrium. In physiological menstrual cycles, this period corresponds to the menstrual days of 21-24 days in a women with regular 28 days of cycles. In other words, implantation can be achieved in a period of 4-7 days to next expected cycle. This period of implantation is determined by the sensitive balanced stimulation of steroids hormones of estrogen and progesterone secreted through the cycle(1,2,3)">(1,2,3). However; in stimulated cycles, it was reported that endometrial maturation can be 3 days early compared to unstimulated cycles(4). In the current practice, window of implantation was tried to be predicted indirectly by endometrial thickness measurement. Cut off value for the endometrial thickness for successful implantation was reported to be 6 mm(5,6,7). However according to our experience and the reports from literature, 50% of patients with optimal endometrial thickness and high grade embryos fail to conceive. Endometrial receptivity is determined by several factors and these factors were reported to be under the effect of gonadal hormones, so it is expected to see a change in receptive period with changing endocrine milieu. In ovarian stimulation cycles gonadal hormones are secreted in high levels compared to physiological states so this may change the implantation period.

actors and these factors were reported to be under the effect of gonadal hormones, so it is expected to see a change in receptive period with changing endocrine milieu. In ovarian stimulation cycles gonadal hormones are secreted in high levels compared to physiological states so this may change the implantation period. The aim of this study was to assess whether the time from the menstrual day at embryo transfer to expected menstrual cycle (TETEMC) is associated with the implantation in women with regular cycles or not.

actors and these factors were reported to be under the effect of gonadal hormones, so it is expected to see a change in receptive period with changing endocrine milieu. In ovarian stimulation cycles gonadal hormones are secreted in high levels compared to physiological states so this may change the implantation period. The aim of this study was to assess whether the time from the menstrual day at embryo transfer to expected menstrual cycle (TETEMC) is associated with the implantation in women with regular cycles or not. MATERIALS AND METHODS Between January 2014 and December 2015, women with regular cycles who underwent artificial reproduction in the in vitro fertilization (IVF)/intra-cytoplasmic sperm injection unit of Zeynep Kamil Women and Children’s Health Training and Research Hospital were recruited from prospectively collected database. Age, body mass index matched groups of women with (n=40) and without (n=40) successful implantation after grade 1 embryo transfer were randomly selected and compared in terms of some demographic and clinical characteristics including TETEMC, endometrial thickness at embryo transfer and duration of regular cycles. Embryo grading was determined according to the review by Alpha Scientists in Reproductive Medicine and European Society of Reproduction and Embryology Special Interest Group of Embryology(8). All the participants had regular menstrual cycles, as well as normal serum prolactin levels and without hormone treatment within three months. The patients’ ages ranged from 24 to 39 years. In all patients artificial reproductive techniques (ART) were indicated for unexplained infertility. Unexplained infertility was diagnosed when a patient was infertile with normal ovulatory and tubal functions along with a normal sperm count for her partner. These were determined by the regularity of menstrual cycles, hysterosalphingography, and semen analysis, respectively. Women with low ovarian reserve, irregular cycles, polycystic ovarian syndrome and the endometriosis were excluded from the study.

ry and tubal functions along with a normal sperm count for her partner. These were determined by the regularity of menstrual cycles, hysterosalphingography, and semen analysis, respectively. Women with low ovarian reserve, irregular cycles, polycystic ovarian syndrome and the endometriosis were excluded from the study. Antagonist protocol was used in all cases; on the second day of the menstrual cycle, recombinant follicle stimulating hormone (rFSH), depending on patient’s response, were administered and follicular growth was monitored using transvaginal sonography. The dosage of rFSH was adjusted from day 5 of stimulation according to the ovarian response. Antagonist Cetrorelix (Merk-Sereno, Geneva, Switzerland) 0.25 mg/day was administered when the follicular size was 12 mm. After the follicular size reached >18 mm, recombinant human chorionic gonadotropin (HCG) 250 µg was administered, and follicular puncture was performed after 34-36 hours. Then we started the application of 8% vaginal progesterone gel twice/daily. Serum HCG level was measured two weeks later, and if serum HCG level was more than or equal to normal level, we performed ultrasonography to detect the pulse of fetus to confirm clinical pregnancy. TETEMC was divided into 4 groups as group 1: 0-4 days, group 2: 5-8 days, group 3: 9-13 days, group 4: >14 days. Groups were compared in terms of successful implantation. TETEMC was the number of days from the day at embryo transfer to the first day of expected menstrual cycle determined from regular cycles.

Antagonist protocol was used in all cases; on the second day of the menstrual cycle, recombinant follicle stimulating hormone (rFSH), depending on patient’s response, were administered and follicular growth was monitored using transvaginal sonography. The dosage of rFSH was adjusted from day 5 of stimulation according to the ovarian response. Antagonist Cetrorelix (Merk-Sereno, Geneva, Switzerland) 0.25 mg/day was administered when the follicular size was 12 mm. After the follicular size reached >18 mm, recombinant human chorionic gonadotropin (HCG) 250 µg was administered, and follicular puncture was performed after 34-36 hours. Then we started the application of 8% vaginal progesterone gel twice/daily. Serum HCG level was measured two weeks later, and if serum HCG level was more than or equal to normal level, we performed ultrasonography to detect the pulse of fetus to confirm clinical pregnancy. TETEMC was divided into 4 groups as group 1: 0-4 days, group 2: 5-8 days, group 3: 9-13 days, group 4: >14 days. Groups were compared in terms of successful implantation. TETEMC was the number of days from the day at embryo transfer to the first day of expected menstrual cycle determined from regular cycles. Statistical Analyses Data was analyzed using SPSS 15.0 for Windows. Pearson’s correlation analysis or Spearman’s correlation analysis was performed to assess the correlation between different variables and ovarian response and the correlation between one variable and another as appropriate. Student t test was used to compare continuous variables between the groups. Multivariate regression analyses were used to assess the adjusted associations. Receiver operating characteristic (ROC) analyses were used to assess the predictive value of the test and to calculate sensitivity and specificity. P value <0.05 was accepted to be statistically significant.

us variables between the groups. Multivariate regression analyses were used to assess the adjusted associations. Receiver operating characteristic (ROC) analyses were used to assess the predictive value of the test and to calculate sensitivity and specificity. P value <0.05 was accepted to be statistically significant. RESULTS Group comparisons Comparison of groups with and without successful implantation revealed significant differences in between groups with regard to TETEMC and menstrual period (Table 1). There were 11 three day embryo transfers where as the number of five day embryo transfer was 69 (p>0.05). Correlation analyses Correlation analyses revealed significant correlations in between the successful implantation and TETEMC, duration of menstruation and the age (Table 2). Multivariate regression analyses Multivariate analysis revealed significant association in between the TETEMC and clinical pregnancy after adjustment for age and the duration of menstruation (Table 3). Receiver operating characteristic analyses In ROC analyses both the TETEMC (AUC=0.824, p<0.001) and the menstrual period (AUC=0.797, p<0.001, Figure 1) were significant predictors for clinical pregnancy. Cut off value for the menstrual cycle was found to be 27.5 days with 82.6% sensitivity and 65% specificity. Cut off value for TETEMC was 11.5 with 75% sensitivity and 63.2% specificity.

ETEMC (AUC=0.824, p<0.001) and the menstrual period (AUC=0.797, p<0.001, Figure 1) were significant predictors for clinical pregnancy. Cut off value for the menstrual cycle was found to be 27.5 days with 82.6% sensitivity and 65% specificity. Cut off value for TETEMC was 11.5 with 75% sensitivity and 63.2% specificity. Subgroup comparisons Comparison of groups with TETEMC ≤11.5 and >11.5 days for successful implantation revealed a significant difference indicating higher rates in group with TETEMC ≤11.5 (75.9% vs. 35.3%, p<0.05, Table 4). Comparison of groups with duration from the menstrual period ≤27.5 and >28 days for successful implantation revealed a significant difference indicating higher rates in group with menstrual period ≤27.5 (82.6% vs. 36.8%, p<0.05, Table 5). Comparison of successful implantation among the group with 4 different TETEMC revealed 100% implantation rate in group with TETEMC ≤8 days (Table 6).

Subgroup comparisons Comparison of groups with TETEMC ≤11.5 and >11.5 days for successful implantation revealed a significant difference indicating higher rates in group with TETEMC ≤11.5 (75.9% vs. 35.3%, p<0.05, Table 4). Comparison of groups with duration from the menstrual period ≤27.5 and >28 days for successful implantation revealed a significant difference indicating higher rates in group with menstrual period ≤27.5 (82.6% vs. 36.8%, p<0.05, Table 5). Comparison of successful implantation among the group with 4 different TETEMC revealed 100% implantation rate in group with TETEMC ≤8 days (Table 6). DISCUSSION In this study, we tried to assess the effect of menstrual day at embryo transfer on the implantation rates in ovarian stimulation cycles. Our data revealed an early maturation of endometrium, however more sooner transfers especially 11.5 days before the next expected menstruation was associated with unsuccessful implantation with 75% sensitivity and 63.2% specificity. Besides estrogen and the progesterone, gonadotropin-releasing hormone (GnRH) receptors were shown in extra pituitary tissue including the endometrium(9,10,11), studies reported the presence of GnRH mRNA gene expression in the endometrium throughout the menstrual cycle, with a significant increase in the secretory phase. These data indicate the possible physiological role of GnRH in the early stages of implantation via paracrine/autocrine pathways. Due to this physiological effect, clinicians have become suspicious for the possible negative effect of GnRH antagonists in combination with gonadotropin on the assisted reproductive technology success(12,13). Some evidence showed detrimental effects of GnRH antagonist that may interfere with the embryo implantation. Consequently(14), high dosages of GnRH antagonist (1 or 2 mg once daily) were found to be associated with low implantation rate (8.8 and 1.5%, respectively) in fresh cycles. Due to this data, in order to prevent ovarian hyper stimulation syndrome and for more receptive endometrium, freeze all policies were introduced and the review on this issue indicated reduced risk of ovarian hyper stimulation syndrome and improved outcomes with frozen embryo transfer(15).

respectively) in fresh cycles. Due to this data, in order to prevent ovarian hyper stimulation syndrome and for more receptive endometrium, freeze all policies were introduced and the review on this issue indicated reduced risk of ovarian hyper stimulation syndrome and improved outcomes with frozen embryo transfer(15). Reduced implantation rates in IVF cycles were shown in some studies compared to natural ones(16), however, there is still some controversy regarding this issue. A large retrospective analysis, showed similar implantation rates between donor and recipient IVF patients(17). In IVF cycles, the day of oocyte retrieval was thought to be the equivalent to day 14 in a natural cycle in women with 28 days regular cycles(18,19). However, in ovarian stimulation cycles, an advanced endometrial maturation has been shown in some studies, this advancement was reported to be around 2±4 days(20) and seen in 45.5%(21) of cycles. As a consequence, an early and increased progesterone concentrations were blamed for early secretory transformation(22) and followed by mid-luteal glandular maturation arrest(23). High serum estradiol concentrations in stimulated cycles were also thought to result in glandular ± stromal dyssynchrony that may interfere with the endometrial receptivity(24). Another data showed the direct effect of HCG that might lead to the advanced endometrial maturation(25,26). Finally, studies showed that ovarian stimulation changed the luteal phase endometrial development.

so thought to result in glandular ± stromal dyssynchrony that may interfere with the endometrial receptivity(24). Another data showed the direct effect of HCG that might lead to the advanced endometrial maturation(25,26). Finally, studies showed that ovarian stimulation changed the luteal phase endometrial development. Luteal phase support was thought to significantly improve clinical outcomes in in-vitro fertilization cycles by the correction of these detrimental effects of ovulation induction(27). There is a consensus on the detrimental effect of ovarian stimulation on the endometrial receptivity and some measures have been introduced to overcome this issue like luteal phase support however, we hypothesized that despite advanced endometrial maturation, earlier transfers may be the main problem that lead to failed implantation, therefore timing of embryo transfer may be the cornerstone of this problem.

ceptivity and some measures have been introduced to overcome this issue like luteal phase support however, we hypothesized that despite advanced endometrial maturation, earlier transfers may be the main problem that lead to failed implantation, therefore timing of embryo transfer may be the cornerstone of this problem. Study assessed the histological features of endometrium both at the 6th day after luteinising hormone (LH) surge and the 10 days after LH surge. Study revealed similar histological features with regard to endometrial maturation(28), in another study, pinopodes were observed at 20th day of menstruation and indicated period of implantation window started to open at days of 22-23 in women with 28 day regular cycles(29), as we mentioned above there is two to four days maturation advancement in stimulated cycles. Our data also showed some advancement in endometrial maturation but more sooner embryo transfers failed to implant. Significant predictive value of longer menstrual cycles also confirm this argument which increase possibility of high TETEMC. A cochrane review on the comparison of ART success between the cases with two different embryo transfer days revealed significant difference in live birth rates in favour of blastocyst transfer (day 5 to 6) compared to cleavage stage transfer (day 2 to 3)(30). This data supports our arguments that three days delay in timing of embryo transfer seem to increase success rate.

een the cases with two different embryo transfer days revealed significant difference in live birth rates in favour of blastocyst transfer (day 5 to 6) compared to cleavage stage transfer (day 2 to 3)(30). This data supports our arguments that three days delay in timing of embryo transfer seem to increase success rate. Recently published well designed study showed a suboptimal endometrial development in ART cycles, and indicated a altered regulation of specific endometrial receptors compared to the the natural cycle. Similar to our end point authors concluded to modify ovarian stimulation not only to yield the optimal number of oocytes, but also to achieve serum hormonal levels that promote an optimal endometrial development and better pregnancy outcomes with fresh cycles. In addition to this study proposed cancellation of fresh embryo transfer and vitrification of embryos and postponing the transfer to more suitable endometrial development such as reached during natural cycles or controlled endometrial maturation(31). Our data showed that TETEMC lower than eight days resulted in 100% implantation where as there were 62.7% successful implantation in groups with TETEMC between the 9-13 days. The rate was 4.5% in group with TETEMC >13 days, we thought that this group of cases may be the appropriate candidates for freeze all policy.

1). Our data showed that TETEMC lower than eight days resulted in 100% implantation where as there were 62.7% successful implantation in groups with TETEMC between the 9-13 days. The rate was 4.5% in group with TETEMC >13 days, we thought that this group of cases may be the appropriate candidates for freeze all policy. Expression of HOXA10 varies in the human endometrium throughout the menstrual cycle, rising dramatically in the luteal phase at the time of implantation(32). This pattern of expression suggests a role for HOXA10 in the process of cyclic endometrial development and endometrial receptivity. We thought that there is a sensitive gene expression regulation during menstrual cycle that determines the duration of menstruation and the time of implantation window, with ovarian stimulation, it seems that this regulated gene expression is not easily adapt this new microenvironment, previous study indicated the minimum period required to achieve a new level is directly proportional to product half-lives because rates of decay control the ratio between the rate of synthesis and the concentration of gene products at steady state(33). Endometrial receptivity array have recently been introduced to assess the endometrial receptivity via genetic evaluation(34), however this test needs invasive procedures. CONCLUSION In conclusion, longer menstrual cycle and the TETEMC seem to be associated with the implantation failure. According to this data it is reasonable to take account the duration of regular menstruation and TETEMC to determine the candidates for freeze all policy.

Endometrial receptivity array have recently been introduced to assess the endometrial receptivity via genetic evaluation(34), however this test needs invasive procedures. CONCLUSION In conclusion, longer menstrual cycle and the TETEMC seem to be associated with the implantation failure. According to this data it is reasonable to take account the duration of regular menstruation and TETEMC to determine the candidates for freeze all policy. Ethics: Ethics Committee Approval: The study were approved by Zeynep Kamil Training and Research Hospital Local Ethics Committee, Informed Consent: Study was approved by institutional review board and inform constent was obtained by each participant. Peer-review: Internal peer-reviewed. Authorship Contributions: Surgical and Medical Practices: İlhan Şanverdi, Enis Özkaya, Tayfun Kutlu, Yavuz Şahin, Concept: Enis Özkaya, Tayfun Kutlu, Ateş Karateke, Design: Enis Özkaya, İlhan Şanverdi, Data Collection or Processing: Taylan Şenol, Munip Akalın, Eda Sayar Akalın, Analysis or Interpretation: Enis Özkaya, Taylan Şenol, Literature Search: Enis Özkaya, Taylan Şenol, Writing: Enis Özkaya, Taylan Şenol. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support.

Authorship Contributions: Surgical and Medical Practices: İlhan Şanverdi, Enis Özkaya, Tayfun Kutlu, Yavuz Şahin, Concept: Enis Özkaya, Tayfun Kutlu, Ateş Karateke, Design: Enis Özkaya, İlhan Şanverdi, Data Collection or Processing: Taylan Şenol, Munip Akalın, Eda Sayar Akalın, Analysis or Interpretation: Enis Özkaya, Taylan Şenol, Literature Search: Enis Özkaya, Taylan Şenol, Writing: Enis Özkaya, Taylan Şenol. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Table 1 Comparison of some demographic and clinical characteristics between groups Table 2 Summary of correlation analyses between successful implantation and some variables Table 3 Multivariate regression analyses for successful implantation Table 4 Comparison of implantation rates between groups with high and low transfer to expected menstrual cycle Table 5 Comparison of implantation rates between groups with long and short menstrual period Table 6 Comparison of implantation rates among groups with different transfer to expected menstrual cycle intervals Figure 1 Receiver operating characteristic curve of transfer to expected menstrual cycle and menstrual period to predict implantation ROC: Receiver operating characteristic

INTRODUCTION There is a necessity to evaluate the endometrial cavity in many different gynecologic conditions. Pre and post-menopausal bleeding, endometrial lesions found with ultrasound, and evaluation of endometrial cavity before performing hysterectomy are some indications that may require saline infusion sonography (SIS)(1,2). The specificity and sensitivity of SIS for detecting endometrial pathology were 81-100% and 85-100%, respectively. For detecting submucosal myoma, it has sensitivity of 57-100% and specificity of 96-100%. For detecting endometrial hyperplasia or cancer it has sensitivity of 29-80% and specificity of 82-100%(3). In sum, SIS is a valuable and indispensable method in gynecology practice. Unfortunately, SIS may cause pain and discomfort depending on the technique and methods of anesthesia. Grasping the cervix with a tenaculum, movement of cannulas in the uterus, and distention of the uterine cavity with saline may cause pain in the procedure. Hence, active cooperation of patients is highly desirable to obtain maximum efficacy, and effective anesthesia becomes very important. Paracervical block (PCB) is the most frequently used method to prevent pain in the procedure. Previous reports showed that intrauterine lidocaine (IUL) is also a safe and effective method for preventing pain in outpatient gynecologic procedures(4,5,6,7,8,9). We designed a randomized controlled trial to compare the efficacy of PCB vs. IUL, and also with placebo.

Unfortunately, SIS may cause pain and discomfort depending on the technique and methods of anesthesia. Grasping the cervix with a tenaculum, movement of cannulas in the uterus, and distention of the uterine cavity with saline may cause pain in the procedure. Hence, active cooperation of patients is highly desirable to obtain maximum efficacy, and effective anesthesia becomes very important. Paracervical block (PCB) is the most frequently used method to prevent pain in the procedure. Previous reports showed that intrauterine lidocaine (IUL) is also a safe and effective method for preventing pain in outpatient gynecologic procedures(4,5,6,7,8,9). We designed a randomized controlled trial to compare the efficacy of PCB vs. IUL, and also with placebo. MATERIALS AND METHODS We conducted this study between March 2011 and August 2011 in a tertiary reference center. The study was approved by our ethical committee. All participants gave their written informed consent for the study. We included 120 women who underwent SIS for various reasons. We excluded women with severe systemic medical conditions such as heart failure and uncontrolled severe hypertension, and cervical stenosis, acute cervicitis and/or vaginitis, and lidocaine allergy. The remaining 96 women were randomized into three groups: saline controls (group 1), PCB (group 2), and PCB + IUL (group 3); randomization was performed using computer-generated random number tables.

e and uncontrolled severe hypertension, and cervical stenosis, acute cervicitis and/or vaginitis, and lidocaine allergy. The remaining 96 women were randomized into three groups: saline controls (group 1), PCB (group 2), and PCB + IUL (group 3); randomization was performed using computer-generated random number tables. We collected data about patient characteristics including age, gravidity, parity, history of abortion, any known allergy, current drug use, and medical and gynecologic history from patient records.

e and uncontrolled severe hypertension, and cervical stenosis, acute cervicitis and/or vaginitis, and lidocaine allergy. The remaining 96 women were randomized into three groups: saline controls (group 1), PCB (group 2), and PCB + IUL (group 3); randomization was performed using computer-generated random number tables. We collected data about patient characteristics including age, gravidity, parity, history of abortion, any known allergy, current drug use, and medical and gynecologic history from patient records. All women underwent a bimanual pelvic examination to determine the size and position of the uterus. The cervix was exposed using a bivalve speculum and washed with povidone-iodine solution. In the PCB group, 2 mL 2% lidocaine (Iekaine Ampoule, IE Ulagay, İstanbul, Turkey) was injected into the cervix at 4- and 8 o’clock positions at a depth of 2-3 cm after confirming the tip of needle was not inside a vessel lumen. Five minutes were allowed to pass to ensure the anesthetic effect of lidocaine had started. In the PCB + IUL group, an 18-gauge intravenous catheter was gently inserted into the cervical canal up to the internal os. Two milliliters of 2% lidocaine was injected into the uterine cavity. Again, 5 minutes were allowed to pass to ensure that the anesthetic effect of the lidocaine had begun. All forms of anesthetic methods were applied before grasping the cervix with a tenaculum. We used no anesthetic in the control group. Two milliliters of 0.9% saline solution was injected into the cervix at 4- and 8 o’clock positions instead of lidocaine. Five minutes were allowed to pass to create similar circumstances with the other groups. The cervix was grasped with a tenaculum at 11- and 1 o’clock positions. A number 4 carmen cannula was inserted in the uterine cavity. The uterine cavity was filled with 50 mL of normal saline solution. The same operator performed all SIS procedures in the same way with help of the same nurse. Therefore, other variables that may affect pain score were controlled. A tenaculum was used in all patients in the standard procedure technique. Difficulty during passing the cervix and SIS findings were not recorded in our study.

e same operator performed all SIS procedures in the same way with help of the same nurse. Therefore, other variables that may affect pain score were controlled. A tenaculum was used in all patients in the standard procedure technique. Difficulty during passing the cervix and SIS findings were not recorded in our study. We evaluated pain scores using a 10-cm visual analogue scale (VAS), where 0 cm represented no pain and 10 cm represented worst pain imaginable. We evaluated pain scores at three different points: Immediately after installation of normal saline, at the end of the procedure, and 30 minutes after the procedure. All patients were prescribed 500 mg azithromycin as prophylaxis. Statistical calculations were performed using the Statistics Package for the Social Sciences (SPSS) for Windows version 13.0. Descriptive data are presented as mean ± standard deviation or standard error. One-way ANOVA and Post-hoc Tukey tests were used to compare parametric variables and to compare differences between groups, respectively. A value of p<0.05 was accepted as statistically significant. RESULTS The ages of the 96 patients who participated in the study ranged from 23 to 62 years. The mean age of group 1 was 38.38±7.48 years, group 2 was 35.25±8.08 years, group 3 was 37.03±7.27 years. There was no statistically significant difference between the mean ages of the groups (p>0.05).

Statistical calculations were performed using the Statistics Package for the Social Sciences (SPSS) for Windows version 13.0. Descriptive data are presented as mean ± standard deviation or standard error. One-way ANOVA and Post-hoc Tukey tests were used to compare parametric variables and to compare differences between groups, respectively. A value of p<0.05 was accepted as statistically significant. RESULTS The ages of the 96 patients who participated in the study ranged from 23 to 62 years. The mean age of group 1 was 38.38±7.48 years, group 2 was 35.25±8.08 years, group 3 was 37.03±7.27 years. There was no statistically significant difference between the mean ages of the groups (p>0.05). Of the patients included in the study, 16 were postmenopausal and 80 were premenopausal; group 1 (n=32) 26 premenopausal, 6 postmenopausal patients; group 2 (n=32) 27 premenopausal, 5 postmenopausal; and group 3 (n=32) 27 premenopausal, 5 postmenopausal patients. The median scores of the groups were gravida (2, 3, 3), living child (2, 2, 2), abortion (0, 0, 0), and curettage (0, 0, 0) respectively. It has been found to disperse in accordance with the average of all these groups. We found significant differences between groups at tenaculum placement. We used the Post-hoc Tukey test to determine which group had the statistically significant score. We found that pain scores were significantly higher in the control group (p=0.002), but there was no significant difference between either study group (p=0.596).

gnificant differences between groups at tenaculum placement. We used the Post-hoc Tukey test to determine which group had the statistically significant score. We found that pain scores were significantly higher in the control group (p=0.002), but there was no significant difference between either study group (p=0.596). After the injection of sterile saline solution, the control group had significantly increased pain scores, different from both study groups (p=0.045). We found no significant difference between either study group at this point (p=0.835). During tenaculum use, the mean pain in the group 1 was 27.40±25.58, group 2 was 21.74±23.25, and group 3 was 11.74±11.54 (Graphic 1). During saline infusion, the mean pain in the group 1 was 25.20±27.66, group 2 was 29.12±14.56, and group 3 was 20.63±19.50 (Graphic 2) (Table 1, 2, 3). DISCUSSION Patients experience pain in gynecologic outpatient diagnostic interventions. We aimed to determine whether it was correct to use different anesthetic methods in daily clinical practice, and thus we compared PCB and PCB + IUL with placebo.

After the injection of sterile saline solution, the control group had significantly increased pain scores, different from both study groups (p=0.045). We found no significant difference between either study group at this point (p=0.835). During tenaculum use, the mean pain in the group 1 was 27.40±25.58, group 2 was 21.74±23.25, and group 3 was 11.74±11.54 (Graphic 1). During saline infusion, the mean pain in the group 1 was 25.20±27.66, group 2 was 29.12±14.56, and group 3 was 20.63±19.50 (Graphic 2) (Table 1, 2, 3). DISCUSSION Patients experience pain in gynecologic outpatient diagnostic interventions. We aimed to determine whether it was correct to use different anesthetic methods in daily clinical practice, and thus we compared PCB and PCB + IUL with placebo. In the study of Guney et al.(5), IUL that was applied just after buccal misoprostol was found effective preventing pain. IUL failed to prevent pain in procedures such as endometrial biopsy or hysterosalpingograhy in other studies(6,7). Guney et al.(5) attributed this difference to the combined use of lidocaine with other drugs. Though there was no significant difference between study groups, we also find that lidocaine decreased pain with statistical significance. The reason of this result may be the limited local effect of lidocaine. Patients feel pain the most at the time of grasping the cervix with a tenaculum and the insertion of a carmen cannula. Lidocaine shows its anesthetic effect through free nerve endings as described in previous studies. Guney et al.(5) found that pain was decreased in their IUL group during endometrial curettage. We did not perform endometrial biopsy, instead only the uterine cavity was distended in our study. We found no significant differences, probably because we performed a less painful procedure than that of Guney et al.(5).

ies. Guney et al.(5) found that pain was decreased in their IUL group during endometrial curettage. We did not perform endometrial biopsy, instead only the uterine cavity was distended in our study. We found no significant differences, probably because we performed a less painful procedure than that of Guney et al.(5). PCB and PCB + IUL were effective at preventing pain in all premenopausal women in our study. The same effect could not be shown in postmenopausal women. To our knowledge, no studies have compared pain scores of women according to their menopausal status. Only Guney et al.(5) noted that combined use of IUL and misoprostol was effective at preventing pain in premenopausal women, whereas it was not effective in postmenopausal women. More randomized studies are warranted to determine which anesthetic method would be appropriate for postmenopausal women in outpatient gynecologic procedures. Van den Bosch et al.(8) compared gel infusion sonography with SIS in their study of 2009. They found both methods were similar in use but pain caused by the procedure was heightened in SIS. They attributed this difference to the lubricant effect of gel, which made it easier to pass the instrument through the cervix. In their second study, they compared gel infusion sonography alone with gel infusion sonography plus IUL. The authors could not show significant differences in the mean VAS scores. Performing SIS is much easier than gel infusion sonography in outpatient settings. Moreover, the long-term effect of gel use remains unknown(9).

eir second study, they compared gel infusion sonography alone with gel infusion sonography plus IUL. The authors could not show significant differences in the mean VAS scores. Performing SIS is much easier than gel infusion sonography in outpatient settings. Moreover, the long-term effect of gel use remains unknown(9). The effect of different anesthetic methods on endometrial curettage, hysterosalpingograhy, and hysteroscopy has been extensively studied. The results are conflicting because of the different natures of the procedures. We think our study will help those who need an effective method to prevent pain in SIS. CONCLUSION In conclusion, paracervical block is effective at preventing pain in premenopausal women undergoing SIS. The addition of IUL to PCB does not decrease pain but increases both the time and cost of the procedure. Ethics: Ethics Committee Approval: The study were approved by the Dr. Lütfi Kırdar Training and Research Hospital Local Ethics Committee, Informed Consent: Consent form was filled out by all participants. Peer-review: External and Internal peer-reviewed. Authorship Contributions: Surgical and Medical Practices: Sadullah Özkan, Aylin Onan Yılmaz, Yaren Tuba Bektaş, Concept: Sadullah Özkan, Bülent Kars, Design: Sadullah Özkan, Bülent Kars, Data Collection or Processing: Sadullah Özkan, Aylin Onan Yılmaz, Yaren Tuba Bektaş, Analysis or Interpretation: Sadullah Özkan, Önder Sakin, Halim Ömer Kaşıkçı, Literature Search: Sadullah Özkan, Önder Sakin, Writing: Sadullah Özkan, Önder Sakin, Halim Ömer Kaşıkçı.

n, Bülent Kars, Design: Sadullah Özkan, Bülent Kars, Data Collection or Processing: Sadullah Özkan, Aylin Onan Yılmaz, Yaren Tuba Bektaş, Analysis or Interpretation: Sadullah Özkan, Önder Sakin, Halim Ömer Kaşıkçı, Literature Search: Sadullah Özkan, Önder Sakin, Writing: Sadullah Özkan, Önder Sakin, Halim Ömer Kaşıkçı. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Table 1 Demographic characteristics of the groups Table 2 The visual analogue scale scores of all patients during tenaculum use during saline infusion sonogram Table 3 Visual analogue scale scores of all patients during saline infusion into the uterine cavity Graphic 1 Graph showing the mean ± standard deviation D values of pain visual analogue scale scores during tenaculum application SIS: Saline infusion sonography, VAS: Visual analogue scale, TENAC: Tenaculum Graphic 2 The graph showing the mean ± standard deviation values of pain visual analogue scale scores during saline infusion into the uterine cavity SIS: Saline infusion sonography, VAS: Visual analogue scale

PRECIS: Significant drops in estradiol concentrations after ovulation trigger are associated with intrauterine insemination cycle treatment failure. INTRODUCTION Monofollicular development should be the main goal in intrauterine insemination (IUI) cycles. Controlled ovarian stimulation (COH) was found associated with supraphysiologic estradiol levels and might affect endometrial implantation. Also, some data showed increased success rates with high peak estradiol levels, which were presumed to be indirect evidence for oocyte quality, whereas some studies showed poorer outcomes due to the detrimental effect of high estrogen on endometrial receptivity(1,2,3,4). Although we do not expect to observe estradiol in concentrations so high in IUI cycles that they would be detrimental to endometrial receptivity, it may be used as a reflection of oocyte quality. Progesterone is thought to be the dominant hormone during the luteal phase of the cycle and the endometrial window of implantation is mainly regulated by progesterone and progesterone- induced gene regulations; this effect is strictly regulated. Data showed that increased mid luteal serum progesterone levels were not associated with a higher clinical pregnancy rate in women who underwent COH with IUI. However, a lower mid luteal progesterone level was proposed to be a predictor for treatment failure(5). Other data from in vitro fertilization (IVF) cycles showed a detrimental effect of increased progesterone concentrations (>2.0 ng/mL) before ovulatiovn trigger on oocyte quality and therefore embryo quality(6). In another study, a 10% reduction in estradiol concentrations after ovulation trigger was associated with 40-50% lower clinical pregnancy and live birth rates in IVF cycles(7). Although serum estradiol concentrations are one of the main parameters in the assessment of the response to controlled ovarian stimulation, the predictive value of estradiol levels before or after ovulation trigger is still not known. Some data showed a poor predictive value of serum estradiol concentration alone on the day of recombinant-HCG in IVF outcomes(8). A recently published study proposed the use of the post-recombinant-human chorionic gonadotropin (HCG) estradiol level as an additional component to predict the outcome of an IVF cycle just before oocyte pick-up.

r predictive value of serum estradiol concentration alone on the day of recombinant-HCG in IVF outcomes(8). A recently published study proposed the use of the post-recombinant-human chorionic gonadotropin (HCG) estradiol level as an additional component to predict the outcome of an IVF cycle just before oocyte pick-up. The authors indicated the necessity for further studies to clarify the underlying mechanisms that might result in a decrease in postrecombinant-HCG estradiol levels, so that physicians may be able modify following IVF cycles accordingly(7). The aim of this study was to assess the relationship between estrogen-progesterone alterations after the ovulation trigger and treatment success in IUI cycles.

g mechanisms that might result in a decrease in postrecombinant-HCG estradiol levels, so that physicians may be able modify following IVF cycles accordingly(7). The aim of this study was to assess the relationship between estrogen-progesterone alterations after the ovulation trigger and treatment success in IUI cycles. MATERIALS AND METHODS In this cross-sectional study, we included 251 IUI cycles performed in the infertility clinic of Zeynep Kamil Women and Children’s Health Training and Research Hospital between 2012 and 2014. This study was approved by the Institutional Review Board of the Zeynep Kamil Women and Children’s Health Training and Research Hospital. All participants gave signed informed consent. All couples had attempted to conceive for at least one year prior to undergoing COH+IUIs. A self-administered questionnaire was used to collect data about demographic, menstrual, and obstetric characteristics. The study population comprised all couples who were candidates for COH+IUI. Indications for IUI included subfertile male infertility, polycystic ovary syndrome, mild or minimal endometriosis or unexplained infertility and various ovulatory disorders. Subfertile male infertility was defined as per the criteria outlined by Molinaro et al.(9). The Initial evaluation included the cycle’s day 3 hormone profile, and tubal patency as determined using hysterosalpingogram and/or laparoscopy. Exclusion criteria were hydrosalpinx, anatomic abnormalities, infection, and systemic disease before intervention. Ovarian Stimulation Protocol

MATERIALS AND METHODS In this cross-sectional study, we included 251 IUI cycles performed in the infertility clinic of Zeynep Kamil Women and Children’s Health Training and Research Hospital between 2012 and 2014. This study was approved by the Institutional Review Board of the Zeynep Kamil Women and Children’s Health Training and Research Hospital. All participants gave signed informed consent. All couples had attempted to conceive for at least one year prior to undergoing COH+IUIs. A self-administered questionnaire was used to collect data about demographic, menstrual, and obstetric characteristics. The study population comprised all couples who were candidates for COH+IUI. Indications for IUI included subfertile male infertility, polycystic ovary syndrome, mild or minimal endometriosis or unexplained infertility and various ovulatory disorders. Subfertile male infertility was defined as per the criteria outlined by Molinaro et al.(9). The Initial evaluation included the cycle’s day 3 hormone profile, and tubal patency as determined using hysterosalpingogram and/or laparoscopy. Exclusion criteria were hydrosalpinx, anatomic abnormalities, infection, and systemic disease before intervention. Ovarian Stimulation Protocol Transvaginal ultrasonography was performed for each participant on day 3 of the menstrual cycle and daily 75-100 IU recombinant FSH (Gonal-F; Merck Serono, İstanbul, Turkey; and Puregon; MSD, İstanbul, Turkey) injection was started. The ovarian response and endometrial thickness was started to be assessed by transvaginal ultrasound starting from the 5th day of stimulation. If the leading follicle’s diameter was  <10 mm on the 8th day of stimulation, the dose of gonadotropin was increased by 50%. The gonadotropin dose remained the same until the day of recombinant-HCG trigger after the leading follicle reached 12 mm in diameter. Cycles were triggered with 250 μcg recombinant-HCG (Ovitrelle; Merck Serono, İstanbul, Turkey) when the dominant follicle became 18 mm in diameter. Cycles were cancelled if there were more than three dominant follicles and/or estradiol levels >1500 pg/mL to prevent ovarian hyperstimulation syndrome and multiple pregnancies. IUI was performed 36 h after recombinant-HCG administration with a disposable IUI catheter (Embryon; Rocket Medical, Washington, Tyne and Wear, U.K.) by two of the authors. The patient was recommended to rest in a supine position for 15 min after the procedure. Luteal phase progesterone support was started following insemination and continued until a pregnancy test was performed. Luteal phase progesterone support was administered in the form of 90 mg (8%) vaginal gel (Crinone, Merck Serono; İstanbul, Turkey). β-HCG was tested on the 15th day of the post insemination day sample. Luteal phase support was continued until 12 weeks of gestation.

on and continued until a pregnancy test was performed. Luteal phase progesterone support was administered in the form of 90 mg (8%) vaginal gel (Crinone, Merck Serono; İstanbul, Turkey). β-HCG was tested on the 15th day of the post insemination day sample. Luteal phase support was continued until 12 weeks of gestation. RESULTS There were 34 (13.5%) women with a positive pregnancy test following controlled ovarian stimulation and IUI cycle. Estradiol and progesterone levels on the trigger day and the day of IUI were compared within groups with and without positive pregnancy test. The comparison revealed significantly increased levels of progesterone after trigger in both groups; however, although there were drops in estradiol levels, the drop in the group with a negative pregnancy test was statistically significant (Tables 1 and 2). The groups were compared in terms of some demographic and hormonal concentrations, the results of which are summarized in Table 3. Estradiol/progesterone at trigger, estradiol/progesterone at IUI, progesterone/estradiol at trigger, and progesterone/estradiol at IUI, all these ratios failed to predict treatment success (p>0.05, Figure 1).

pared in terms of some demographic and hormonal concentrations, the results of which are summarized in Table 3. Estradiol/progesterone at trigger, estradiol/progesterone at IUI, progesterone/estradiol at trigger, and progesterone/estradiol at IUI, all these ratios failed to predict treatment success (p>0.05, Figure 1). DISCUSSION In this study, we assessed the effect of estrogen and progesterone alterations before and after ovulation trigger on IUI cycle outcomes. Our data revealed that a significant drop in estradiol levels after ovulation trigger leads to unfavorable results in IUI cycles. A progesterone rise was not found to have a significant impact on cycle outcome and progesterone levels on trigger day were not significant predictors of cycle outcome. According to our literature search, although there are some data for IVF/intracytoplasmic sperm injection (ICSI) cycles, hormonal alterations during the periovulatory period were not investigated in IUI cycles in detail. Consistent with our result, previous study on 1712 IVF cycles revealed similar results and indicated estradiol drop >10% after trigger was associated with lower pregnancy rates(7). The mean estradiol drop was 21% in the group with negative implantation and was 11% in successful cycles in our study population. A study showed a significant association between serum estradiol level on trigger day with the pregnancy rates following ovarian stimulation and intrauterine insemination(10). Our data analyses revealed no relationship between the estradiol level on the trigger day and pregnancy rates.

Consistent with our result, previous study on 1712 IVF cycles revealed similar results and indicated estradiol drop >10% after trigger was associated with lower pregnancy rates(7). The mean estradiol drop was 21% in the group with negative implantation and was 11% in successful cycles in our study population. A study showed a significant association between serum estradiol level on trigger day with the pregnancy rates following ovarian stimulation and intrauterine insemination(10). Our data analyses revealed no relationship between the estradiol level on the trigger day and pregnancy rates. Endometrial thickness measurement is the most commonly used parameter to have an indirect idea about endometrial receptivity; an optimal endometrial thickness is required for favorable outcome. However, the use of endometrial thickness alone was found to have high negative predictive value but low positive predictive value with low specificity(11). It is well known that endometrial development requires the combined effect of estrogen and progesterone. This combination effect should be in balance, previous data showed significant predictive value of progesterone/estradiol ratio at the periovulatory phase in estimating the efficacy of the ovulation induction in IUI cycles(12); however, our data showed no association between the progesterone/estradiol ratio either at the trigger or on the day of IUI, which indicates that endometrial receptivity is not under a dominant effect of any of these hormones.

periovulatory phase in estimating the efficacy of the ovulation induction in IUI cycles(12); however, our data showed no association between the progesterone/estradiol ratio either at the trigger or on the day of IUI, which indicates that endometrial receptivity is not under a dominant effect of any of these hormones. Estradiol supplementation has been used to ameliorate endometrial receptivity in IUI cycles. A study on this issue assessed the effect of estradiol supplementation in cycles with luteal phase serum estradiol drop by more than 50% over a 48-hour period within 10 days of recombinant-HCG administration, and the data showed that estradiol supplementation resulted in higher rates of pregnancy (12.6 vs. 20.9%); the difference was more prominent when data were analyzed for patients aged >35 years(13). Consistent with our results, that study also showed a critical role of estradiol during luteal phase. In our study population, ovulation was triggered by recombinant-HCG in all patients. There is evidence about the effect of recombinant-HCG on ovarian endocrine function, a study showed that higher doses of recombinant-HCG administration promoted the secretion of both estradiol and androgens into the follicular fluid, with a shift toward a more androgenic milieu(14). This shows the ovarian endocrine response to recombinant-HCG exposure, which indicates a formation of androgenic state in the ovary. Accordingly, one would expect to observe increased serum sex hormone levels after ovulation trigger; however, our data showed decreased estradiol levels both in the pregnant and non-pregnancy groups, and higher decrements resulted in failure of IUI cycle.

e, which indicates a formation of androgenic state in the ovary. Accordingly, one would expect to observe increased serum sex hormone levels after ovulation trigger; however, our data showed decreased estradiol levels both in the pregnant and non-pregnancy groups, and higher decrements resulted in failure of IUI cycle. Besides the effect of estrogen on the endometrial receptivity, a premature increase in progesterone concentrations in stimulated cycles was found to have a negative impact on pregnancy rates. Although the exact cause of this progesterone concentration elevation is not clear, it was suggested that overstimulation may lead to increased progesterone concentrations at the end of the follicular phase. Furthermore, this premature progesterone elevation was associated with altered gene expression and also reduced endometrial receptivity(15). In our study, we did not see a significant predictive value of progesterone on the trigger day, the mean values were comparable between the groups (0.8 vs. 1.2, p>0.05). A recent study suggested freezing all embryos in IVF/ICSI cycles if the progesterone level was >1.5 on the trigger day(16). A modest elevation of progesterone was observed in our study, this was thought to be due to the mild stimulation protocols specific for COH+IUI cycle.

ble between the groups (0.8 vs. 1.2, p>0.05). A recent study suggested freezing all embryos in IVF/ICSI cycles if the progesterone level was >1.5 on the trigger day(16). A modest elevation of progesterone was observed in our study, this was thought to be due to the mild stimulation protocols specific for COH+IUI cycle. Previous study analyzed the additive value of progesterone level determination 24 hours after recombinant-HCG administration and revealed an improved predictive value compared with a single measurement on the day of recombinant-HCG administration, the authors concluded that the high progesterone levels on both days resulted in low implantation rates compared with normal levels in IVF/ICSI cycles (22% vs. 36%)(17). There is also some evidence that basal progesterone levels may be used to predict premature progesterone elevation in IVF/ICSI cycles(18). In our data, post trigger progesterone levels obtained from the laboratory analyses at 36 hours after trigger were not found to affect cycle outcome.

/ICSI cycles (22% vs. 36%)(17). There is also some evidence that basal progesterone levels may be used to predict premature progesterone elevation in IVF/ICSI cycles(18). In our data, post trigger progesterone levels obtained from the laboratory analyses at 36 hours after trigger were not found to affect cycle outcome. The estradiol/progesterone ratio on the day of embryo transfer has been used to predict implantation in ICSI cycles. A study on this issue indicated that this ratio was predictive for ICSI success when combined with embryo quality, endometrial thickness, and estradiol levels, and higher ratios were found associated with favorable results(19). This study emphasized the role of estrogen during the luteal phase of the cycle stressing that higher ratios were found to be predictive for desirable outcome. Progesterone plays an important role during the luteal phase for decidualization changes and progression of pregnancy. Premature progesterone elevation is observed in 5 to 30% of treatments despite the use of GnRH analogs in assisted reproduction technique (ART) cycles(20,21,22). Some studies revealed favorable outcomes in cycles with elevated progesterone/estradiol ratios with higher oocyte collection and normal pregnancy rates(20,23,24). In contrast, other data showed low ovarian reserve and reduced oocyte retrieval in patients with high ratios(25).

roduction technique (ART) cycles(20,21,22). Some studies revealed favorable outcomes in cycles with elevated progesterone/estradiol ratios with higher oocyte collection and normal pregnancy rates(20,23,24). In contrast, other data showed low ovarian reserve and reduced oocyte retrieval in patients with high ratios(25). There is no consensus at to whether embryos should be transferred in women with a premature rise in progesterone. There are also no data in the literature regarding optimal stimulation protocols to avoid premature progesterone rises.

roduction technique (ART) cycles(20,21,22). Some studies revealed favorable outcomes in cycles with elevated progesterone/estradiol ratios with higher oocyte collection and normal pregnancy rates(20,23,24). In contrast, other data showed low ovarian reserve and reduced oocyte retrieval in patients with high ratios(25). There is no consensus at to whether embryos should be transferred in women with a premature rise in progesterone. There are also no data in the literature regarding optimal stimulation protocols to avoid premature progesterone rises. We know about the detrimental effect of premature rise in progesterone levels on the ART cycles. However, a study reported a significant correlation between increased progesterone and high estradiol levels and no detrimental effect on the cycle outcome(26). In fact, unfavorable effects of stimulation have been proposed to be observed in the early luteal phase of the cycle and these effects were thought to be corrected during the late luteal phase(27). Consistent with this argument, Elgindy et al.(28) documented different implantation rates between cleavage stage embryo transfer and blastocysts transfer. The authors claimed that the adverse effect of the progesterone/estradiol ratio in stimulated cycles was compensated for by a day 5 embryo transfer(28). The authors of a review on the regulation of steroid production and its function within the corpus luteum concluded that oxytocin and prostaglandin F alpha were found to stimulate estradiol and progesterone release and estradiol itself further stimulated progesterone release. Furthermore, it was also reported that during luteolysis, invading macrophages secrete tumor necrosis factor, which inhibits the luteotropic effects of estradiol and disrupts the intraluteal circuit(29). These data partially explain why we experienced lower rates of pregnancy in women with high estradiol drop after ovulation trigger; an average estrogenic effect is necessary for optimal corpus luteum function. The proposed underlying mechanisms of insufficient function of the corpus luteum included “supraphysiologic estradiol level, decreased luteinizing hormone level, inhibition of the corpus luteum, and asynchronization of estradiol and progesterone”(30,31). A Meta-analyses on estrogen plus progesterone replacement during luteal phase of the cycle showed higher rates of clinical pregnancy compared with progesterone alone in women undergoing IVF(32).

eased luteinizing hormone level, inhibition of the corpus luteum, and asynchronization of estradiol and progesterone”(30,31). A Meta-analyses on estrogen plus progesterone replacement during luteal phase of the cycle showed higher rates of clinical pregnancy compared with progesterone alone in women undergoing IVF(32). According to this and data from our study, an average but not supraphysiologic estrogen function seems to be mandatory during the luteal phase of ovulation induction cycles; significant drops in the estradiol concentrations after ovulation trigger are associated with IUI cycle treatment failure. Ethics: Ethics Committee Approval: The study were approved by the Local Ethics Committee. Zeynep Kamil women and children’s health training and research hospital, Informed Consent: Consent form was filled out by all participants. Peer-review: External and Internal peer-reviewed. Authorship Contributions: Surgical and Medical Practices: Cansu İpekçi, Concept: Tayfun Kutlu, Design: Birsen Konukçu, Data Collection or Processing: Birsen Konukçu, Cansu İpekçi, Analysis or Interpretation: Enis Özkaya, İlhan Şanverdi, Literature Search: Belgin Devranoğlu, Yavuz Şahin, Writing: Enis Özkaya, Tayfun Kutlu, Ateş Karateke. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study received no financial support.

Authorship Contributions: Surgical and Medical Practices: Cansu İpekçi, Concept: Tayfun Kutlu, Design: Birsen Konukçu, Data Collection or Processing: Birsen Konukçu, Cansu İpekçi, Analysis or Interpretation: Enis Özkaya, İlhan Şanverdi, Literature Search: Belgin Devranoğlu, Yavuz Şahin, Writing: Enis Özkaya, Tayfun Kutlu, Ateş Karateke. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study received no financial support. Table 1 Hormone concentrations on the trigger and intrauterine insemination day in the positive pregnancy test group Table 2 Hormone concentrations on the trigger and intrauterine insemination day in the group with negative pregnancy tests Table 3 Comparison of groups with and without positive pregnancy test and demographic and hormonal characteristics Figure 1 Receiver operating characteristic curve of different ratios to predict positive pregnancy test ROC: Receiver operating characteristic, IUI: Intrauterine insemination

INTRODUCTION Polycystic ovary syndrome (PCOS) is a complex disorder and may present in different phenotypes. Previous data included only the classic phenotype characterized by chronic anovulation and hyperandrogenism(1,2,3). However, accumulated data led to the Rotterdam criteria, which allows for different PCOS phenotypes(4). According to the defined criteria, four different phenotypes can be introduced: I. Hyperandrogenism, chronic anovulation, and polycystic ovaries (PCO); II. Hyperandrogenism and chronic anovulation but normal ovaries; III. Hyperandrogenism and polycystic ovaries but ovulatory cycles; and IV. Chronic anovulation and polycystic ovaries but no clinical or biochemical hyperandrogenism. A meta-analysis concluded that unknown intra-or extraovarian abnormalities may interfere with granulosa cell-oocyte interaction, oocyte maturation, and potential embryonic development and result in unsuccessful artificial reproduction techniques in PCOS(5). However, it is not known whether different phenotypes of PCOS have similar results. It is well known that PCOS is associated with elevated adrenal androgens such as dehydroepiandrosterone sulphate (DHEAS) in 20-50% of cases and meta-analyses about the effect of DHEAS supplementation in assisted reproduction revealed improvement of oocyte production and pregnancy rates(6,7,8,9). However, according to the aforementioned data, we know that all PCOS phenotypes do not have hyperandrogenemia or even PCO morphology, so is it possible to generalize all in vitro fertilization (IVF) outcomes in PCOS by assessing a mixture of women with different PCOS phenotypes?

production and pregnancy rates(6,7,8,9). However, according to the aforementioned data, we know that all PCOS phenotypes do not have hyperandrogenemia or even PCO morphology, so is it possible to generalize all in vitro fertilization (IVF) outcomes in PCOS by assessing a mixture of women with different PCOS phenotypes? In this study, we aimed to assess IVF characteristics among different PCOS phenotypes to show whether PCO morphology or hyperandrogenemia would interfere with the results.

production and pregnancy rates(6,7,8,9). However, according to the aforementioned data, we know that all PCOS phenotypes do not have hyperandrogenemia or even PCO morphology, so is it possible to generalize all in vitro fertilization (IVF) outcomes in PCOS by assessing a mixture of women with different PCOS phenotypes? In this study, we aimed to assess IVF characteristics among different PCOS phenotypes to show whether PCO morphology or hyperandrogenemia would interfere with the results. MATERIALS AND METHODS Study population Between 2009 and 2014, among the women referred to the infertility unit of the Department of Obstetrics and Gynecology, Zeynep Kamil Women and Children’s Health Training and Research Hospital, 262 patients who underwent IVF treatment with an indication of unexplained or tubal factor infertility (control group, n=84), ovulatory patients with isolated PCO morphology (group 1, n=85), PCOS phenotype with oligoanovulation and hyperandrogenemia (group 2, n=38), PCOS phenotype with PCO morphology and oligoanovulation (group 3, n=55) were enrolled in the study (Table 1). Sample size was calculated according to the study by Kim et al.(10) with 95% confidence interval (CI) and 80% power. The exclusion criteria were age ≥40 years; body mass index (BMI) >35 kg/m2; basal follicle-stimulating hormone (FSH) level >12 mIU/mL; presence of endometriosis; three or more previous unsuccessful IVF treatment; and systemic illness or endocrine disorders such as hyperprolactinemia, hypothyroidism, Cushing’s syndrome and non-classic congenital adrenal hyperplasia. The groups were compared in terms of basal clinical characteristics and IVF outcomes. PCO morphology was determined based on the data from transvaginal ultrasound showing the presence of 12 or more peripherally-oriented cystic structures in one ultrasonographic plane, each of which measured 2 to 10 mm in diameter(11). Oligo-anovulation was described as progesterone <3 ng/mL (<9.54 nmol/L) on days 18-21 and/or a menstrual cycle of longer than 35 days. Patients with an elevated serum testosterone >60 ng/dL (>2.08 nmol/L) and/or serum Δ4A levels >3.8 ng/mL were considered to have biochemical hyperandrogenemia and subjects with a Ferriman Gallwey score >8 were accepted as having clinical hyperandrogenemia(12). The study protocol was approved by the Local Ethics Committee of Zeynep Kamil Research and Teaching Hospital.

g/dL (>2.08 nmol/L) and/or serum Δ4A levels >3.8 ng/mL were considered to have biochemical hyperandrogenemia and subjects with a Ferriman Gallwey score >8 were accepted as having clinical hyperandrogenemia(12). The study protocol was approved by the Local Ethics Committee of Zeynep Kamil Research and Teaching Hospital. Treatment protocol On cycle day 3, ovarian stimulation was started by daily injection of recombinant FSH (r-FSH) (Gonal-F, Merck Serono, İstanbul, Turkey) with a starting dose specific for cases according to their age, BMI, ovarian reserve, and antral follicle count (AFC). According to the antagonist protocol, gonadotropin-releasing hormone (GnRH) antagonist (Cetrotide; 0.25 mg; Merck Serono, İstanbul, Turkey) injection was started from the 6th day of stimulation. Monitorization of the cycles was based on the ultrasound examination to record the number and size of the follicles and the double-layer endometrial thickness. For each participant on cycle days 2-3, transvaginal ultrasound was performed to determine AFC and screen for ovarian cysts. A repeat examination was performed on day 6 of stimulation and subsequently every 1-3 days as clinically indicated until the criterion for subcutaneous administration of recombinant chorionic gonadotropin alpha 250 mg (Ovitrelle; Merck-Serono, İstanbul, Turkey) was reached; at least two follicles ≥17 mm in diameter. Ovum retrieval was performed 36 h later. In all cases, an intracytoplasmic sperm injection procedure was performed on the same day (day 0) and embryo transfer was performed on day 3, 4 or 5 based on the quality of embryos. From the day of ovum retrieval, the luteal phase was supported by progesterone intravaginally (Crinone 8% gel; Serono, İstanbul, Turkey) twice a day.

s, an intracytoplasmic sperm injection procedure was performed on the same day (day 0) and embryo transfer was performed on day 3, 4 or 5 based on the quality of embryos. From the day of ovum retrieval, the luteal phase was supported by progesterone intravaginally (Crinone 8% gel; Serono, İstanbul, Turkey) twice a day. Assessment of embryo quality Embryo quality was described according to the blastomeres size and number, the degree of fragmentation, and the presence of multinucleated blastomeres. Embryos with 4 or 5 equal- sized blastomeres and less than 10% cytoplasmic fragmentation with no multinucleation were accepted as good quality on day 2. An embryo with 7 or 8 equal-sized blastomeres with less than 10% cytoplasmic fragmentation and no multinucleation was accepted as good quality on day 3. A good quality embryo on day 4 was determined with following characteristics: embryo cavitation with compacted properties without morphologic anomalies such as vacuolation, excessive fragmentation, large number of excluded cells, and self-cavitation of cells(13,14). On day 5, blastocyst quality and expansion were described in accordance with the classification of Gardner and Schoolcraft(15) and good quality embryo was accepted as ≥grade 3AA.

hout morphologic anomalies such as vacuolation, excessive fragmentation, large number of excluded cells, and self-cavitation of cells(13,14). On day 5, blastocyst quality and expansion were described in accordance with the classification of Gardner and Schoolcraft(15) and good quality embryo was accepted as ≥grade 3AA. In vitro fertilization treatment outcomes Chemical pregnancy was defined as positive β-hCG test following embryo transfer. Clinical pregnancy was defined as presence of gestational sac with fetal cardiac activity under ultrasonography. An ongoing pregnancy was defined as a pregnancy ≥12 weeks of gestation confirmed with ultrasonographic examination. Data of pregnancy outcomes were obtained from the hospital database or the pregnant women via phone. The implantation rate was calculated by dividing the number of gestational sacs with fetal cardiac activity by the number of embryos transferred. The primary end-points of the study were the chemical pregnancy rate, the clinical pregnancy rate, and ongoing pregnancy rate. Secondary outcomes evaluated were the total gonadotropin dose used, estradiol (E2) level on the trigger day, peak estradiol level, number of dominant follicles, number of metaphase II (MII) oocytes, MII oocytes rate, and implantation rate.

hemical pregnancy rate, the clinical pregnancy rate, and ongoing pregnancy rate. Secondary outcomes evaluated were the total gonadotropin dose used, estradiol (E2) level on the trigger day, peak estradiol level, number of dominant follicles, number of metaphase II (MII) oocytes, MII oocytes rate, and implantation rate. Statistical analysis Statistical analysis was performed using SPSS version 11.5 software. All data were summarized using descriptive statistics, correlation analyses were used to show associations, multivariate regression was used to show adjusted associations, receiver operating characteric curve analysis was used to calculate predictive value, and the sensitivity and specificity. One-way ANOVA and Pearson’s Chi-square tests were performed where appropriate; p=0.05 was accepted as the degree of significance. Data were given as mean ± standard deviation or percentage.

ations, receiver operating characteric curve analysis was used to calculate predictive value, and the sensitivity and specificity. One-way ANOVA and Pearson’s Chi-square tests were performed where appropriate; p=0.05 was accepted as the degree of significance. Data were given as mean ± standard deviation or percentage. RESULTS The baseline clinical characteristics of all groups are given in Table 2. There were no significant difference in terms of age, BMI, basal FSH, E2 levels, and duration of infertility among all groups. The characteristics of IVF cycles of patients are detailed in Table 2. The total gonadotropin dose was similar between group 2 and the control group, whereas it was significantly lower in groups 1 and 3 than in other groups (p1=0.002, p2<0.001, p3=0.006). Basal FSH level (beta coefficient=0.207, p=0.003), group (beta coefficient=-0.305, p<0.001) and age (beta coefficient=0.311, p<0.001) were significantly associated with the total gonadotropin dose. There was significant correlation between total gonadotropin dose and age (r=0.303, p<0.001), AFC (r=-0.553, p<0.001), basal FSH level (r=0.243, p<0.001), and group (r=-0.243, p<0.001). Age (AUC=0.595, =0.009) and basal FSH level (AUC=0.646, p<0.001) were found as significant predictors for the high gonadotropin dose >1800 IU, detrimented by the median level (Figure 1). The cut-off value for age was 29.5 years with 58% sensitivity and 54% specificity. The cut-off value for basal FSH was 6.2 with 65% sensitivity and 60% specificity. There were significantly higher numbers of oocytes retrieved in groups 1 and 3 when compared with patients in the control group; it was similar among groups 1, 2 and 3. There was no significant difference with respect to the ratio of MII oocytes and implantation rates among all groups. The number of good quality embryos on transfer day was significantly lower in patients in group 1 and 3 than in group 2. pregnancy rates are shown in Table 3. Biochemical, clinical and ongoing pregnancy rates were found similar among all groups.

spect to the ratio of MII oocytes and implantation rates among all groups. The number of good quality embryos on transfer day was significantly lower in patients in group 1 and 3 than in group 2. pregnancy rates are shown in Table 3. Biochemical, clinical and ongoing pregnancy rates were found similar among all groups. DISCUSSION In the present study, we aimed to assess IVF characteristics among PCOS phenotypes with and without hyperandrogenemia or PCO morphology. Analyses of the data showed that IVF has similar success rates in patients with PCOS independent of presence or absence of hyperandrogenemia or PCO morphology. However, as expected, PCO morphology provided stimulation with lower doses and needed lower amounts of total gonadotropin dose. The number of good quality embryos was found to be significantly higher in the PCOS phenotype with oligoanovulation and hyperandrogenemia group. Despite the absence of PCO morphology, the numbers of dominant follicles were found comparable between this group and patients with PCO morphology. Good quality embryos and a comparable number of dominant follicles led us to conclude that hyperandrogenemia may have a favorable effect. However, this group needed a similar total gonadotropin dose when compared with the control group and higher total gonadotropin dose than the groups with PCO morphology. This shows that PCO morphology provides easier stimulation; hyperandrogenemia provides better results in terms of good quality embryos. Jamil et al.(16) compared the clinical and hormonal parameters among four phenotypes of PCOS based on the Rotterdam criteria and with a control group. Women in the oligo-anovulation and PCO group and in the control group had significantly lower levels of luteinizing hormone/FSH ratio, total testosterone, and free androgen index, and higher levels of FSH and sex hormone-binding globulin when compared with women in the oligo-anovulation, PCO and hyperandrogenemia groups(16). In the literature, it was stated that androgens were found to have a favorable effect on follicle maturation, especially during the early stages(17). However, other studies showed a negative effect of androgens on folliculogenesis and embryonic development(18). Androgens have been suggested to have a modulating effect on FSH activity in developing granulosa cells, and studies on PCOS have shown that androgens have a positive and negative effect on folliculogenesis(17).

ever, other studies showed a negative effect of androgens on folliculogenesis and embryonic development(18). Androgens have been suggested to have a modulating effect on FSH activity in developing granulosa cells, and studies on PCOS have shown that androgens have a positive and negative effect on folliculogenesis(17). Despite the changing effects of androgens and PCO morphology among groups, the end point is similar in terms of biochemical, clinical, and ongoing pregnancy rates. A recently published study on the effect of PCO morphology on oocyte quality in intracytoplasmic sperm injection cycles compared with a control group showed neither positive nor negative effects and the MII oocyte number was found to be higher in the group with PCO morphology, whereas the ratio of MII oocyte was similar, the number of top quality embryos was comparable between groups but the implantation and clinical pregnancy rates were found significantly higher in the PCO morphology group(19). The authors tried to assess the effect of PCO morphology alone on oocyte quality so their results were not consistent with ours because of the ignored effect of hyperandrogenemia, which was shown to have a favorable effect in our study. In addition, patients with PCOS had similar IVF outcomes compared with other hyperresponders without PCOS in a study by O’Neill et al.(20) Our study also produced similar end results but our data showed some critical cycle characteristics among different PCOS phenotypes. Ryan et al.(21) showed a negative effect of prolonged stimulation in assisted reproductive technology cycles but the authors claimed that this effect was not observed in patients with PCOS. According to their article, PCOS had a different response to stimulation in a wide range, and to the best of knowledge, different phenotypes were not assessed separately. The effect of basal testosterone levels in IVF cycles of patients without PCOS was evaluated in a study by Sun et al.(22) consistent with our results in PCOS patients, the authors concluded that although basal testosterone did not predict pregnancy outcomes, it was associated with the large follicles on human koryonik gonadotropin day, FSH dosage, and also that lower levels of basal testosterone might be related with poor ovarian response(22). Embryo cleavage kinetics were studied by Wissing et al.(23) with a small sample size.

tosterone did not predict pregnancy outcomes, it was associated with the large follicles on human koryonik gonadotropin day, FSH dosage, and also that lower levels of basal testosterone might be related with poor ovarian response(22). Embryo cleavage kinetics were studied by Wissing et al.(23) with a small sample size. Contrary to our results, their study showed slower development to the 8-cell stage from fertilization in patients with hyperandrogenic PCOS(23). An article published in 2014 compared cumulative live birth rates among groups of patients with PCOS, isolated PCO, and controls; their data revealed higher live birth rates in the group with isolated PCO compared with controls. This favorable outcome was not observed in the PCOS group and the authors claimed that this may be due to unfavorable embryo competence otherwise observed in PCOS(24). Again, in their study a general conclusion was drawn from a mixture of patients with different PCOS phenotypes. The limitations of our study were its retrospective nature and relatively small sample size. The importance of the present study is in the evaluation of assisted reproductive technology (ART) outcomes of different phenotypes of PCOS because there is limited data in the literature that compares subtypes of PCOS in terms of characteristics and outcomes of ART.

trospective nature and relatively small sample size. The importance of the present study is in the evaluation of assisted reproductive technology (ART) outcomes of different phenotypes of PCOS because there is limited data in the literature that compares subtypes of PCOS in terms of characteristics and outcomes of ART. CONCLUSION To the best of our knowledge, this is a unique study assessing IVF outcomes in different PCOS phenotypes in an acceptable number of participants. PCO morphology provides easier stimulation; hyperandrogenemia provides better results in terms of good quality embryos. Multivariate regression analyses showed that easier stimulation is based on basal FSH level, group, and age. However, the end point was similar regarding biochemical, clinical, and ongoing pregnancy rates. Ethics: Ethics Committee Approval: The study protocol was approved by the Local Ethics Committee of Zeynep Kamil Training and Research Hospital, Informed Consent: A consent form was completed by all participants. Peer-review: External and Internal peer-reviewed. Authorship Contributions: Surgical and Medical Practices: Hüseyin Tayfun Kutlu, Belgin Devranoğlu, Concept: Selçuk Selçuk, Enis Özkaya, Design: Selçuk Selçuk, Enis Özkaya, Hüseyin Tayfun Kutlu, Data Collection or Processing: Ahmet Eser, Melda Kuyucu, Analysis or Interpretation: Enis Özkaya, Literature Search: Selçuk Selçuk, Belgin Devranoğlu, Kenan Sofuoğlu, Writing: Selçuk Selçuk, Enis Özkaya. Conflict of Interest: No conflict of interest was declared by the authors.

Authorship Contributions: Surgical and Medical Practices: Hüseyin Tayfun Kutlu, Belgin Devranoğlu, Concept: Selçuk Selçuk, Enis Özkaya, Design: Selçuk Selçuk, Enis Özkaya, Hüseyin Tayfun Kutlu, Data Collection or Processing: Ahmet Eser, Melda Kuyucu, Analysis or Interpretation: Enis Özkaya, Literature Search: Selçuk Selçuk, Belgin Devranoğlu, Kenan Sofuoğlu, Writing: Selçuk Selçuk, Enis Özkaya. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Table 1 Clinical characteristics of patients according to rotterdam criteria in each group Table 2 Comparison of baseline clinical characteristics among all groups Table 3 Comparison of outcomes of IVF cycles among all groups Figure 1 Receiver operating characteric curve of basal follicle stimulating hormone level and age to predict high gonadotropin dose

INTRODUCTION Tubal disease is responsible for approximately 30-40% of female infertility(1). Recently, the incidence of tubal factor has increased and has become a major cause of female infertility. The major risk factor for tubal factor infertility is pelvic inflammatory disease; other possible risk factors are history of tubal surgery and ectopic pregnancy(2). Hysterosalpingography (HSG) and laparoscopy are the most common procedures used in the assessment of the tubal patency. HSG is usually the first preferred clinical tool because laparoscopy is more invasive and more expensive(3). There is no consensus about the optimal management of patients with unilateral tubal occlusion. The assessment of tubal patency through laparoscopic chromotubation, intrauterine insemination with controlled ovarian stimulation (COH), and in vitro fertilization (IVF) are the recommended management options for these patients(4,5,6). In the literature, there are insufficient data regarding the success rates of COH and IUI in the treatment of patients with unilateral tubal occlusion. In the present study, we aimed to evaluate the pregnancy rates of COH/IUI in patients with unilateral tubal occlusion diagnosed under HSG.

INTRODUCTION Tubal disease is responsible for approximately 30-40% of female infertility(1). Recently, the incidence of tubal factor has increased and has become a major cause of female infertility. The major risk factor for tubal factor infertility is pelvic inflammatory disease; other possible risk factors are history of tubal surgery and ectopic pregnancy(2). Hysterosalpingography (HSG) and laparoscopy are the most common procedures used in the assessment of the tubal patency. HSG is usually the first preferred clinical tool because laparoscopy is more invasive and more expensive(3). There is no consensus about the optimal management of patients with unilateral tubal occlusion. The assessment of tubal patency through laparoscopic chromotubation, intrauterine insemination with controlled ovarian stimulation (COH), and in vitro fertilization (IVF) are the recommended management options for these patients(4,5,6). In the literature, there are insufficient data regarding the success rates of COH and IUI in the treatment of patients with unilateral tubal occlusion. In the present study, we aimed to evaluate the pregnancy rates of COH/IUI in patients with unilateral tubal occlusion diagnosed under HSG. MATERIALS AND METHODS This retrospective cohort study was conducted in Zeynep Kamil Tertiary Hospital between 2013 and 2015. The study protocol was approved by the Local Research and Ethics Committee of the institution. Demographic and clinical information of patients were abstracted from the hospital’s database. Inclusion criteria were age ≥18 and <40 years, basal follicle-stimulating hormone (FSH) level <15 IU/mL, normal basal luteinizing hormone, body mass index <35 kg/m2, normal semen parameters according to the World Health Organization (WHO) criteria, no presence of endocrine abnormalities, and no uterine cavity abnormalities(7). Patients with unilateral tubal occlusion diagnosed under HSG and who met the inclusion criteria were accepted into the study group. The control group consisted of patients with unexplained infertility, normal HSG findings and those who met the same inclusion criteria. All patients underwent COH/IUI treatment.

ities(7). Patients with unilateral tubal occlusion diagnosed under HSG and who met the inclusion criteria were accepted into the study group. The control group consisted of patients with unexplained infertility, normal HSG findings and those who met the same inclusion criteria. All patients underwent COH/IUI treatment. In the ovarian stimulation protocol, subcutaneous injection of gonadotropins as recombinant FSH (Gonal F, Merck Serono, İstanbul, Turkey) with starting dose of 50-100 IU/day from the 2nd-4th day of the menstrual cycle was administered. Monitoring using transvaginal ultrasonography (TVU) was performed daily after the fifth day of stimulus. When ≥2 follicles reached a diameter of ≥17 mm, subcutaneous injection of recombinant chorionic gonadotropin alpha 250 mg (Ovitrelle; Merck-Serono, İstanbul, Turkey) was administered. A concentrated, washed sperm sample was prepared and IUI was performed 34-36 hours after human chorionic gonadotropin (hCG) injection. Primary outcomes were biochemical, clinical, and ongoing pregnancy rates. The secondary outcome was the spontaneous pregnancy rate. Patients were invited to the infertility clinic to measure the β-hCG value 15 days after IUI. Positive serum β-hCG levels as ≥10 mIU/L were regarded as biochemical pregnancy and presence of a gestational sac on ultrasonography was regarded as clinical pregnancy. Ongoing pregnancy was defined as a pregnancy ≥12 weeks of gestation. Spontaneous pregnancy was accepted as pregnancy without any treatment within one year after unsuccessful IUI.

as ≥10 mIU/L were regarded as biochemical pregnancy and presence of a gestational sac on ultrasonography was regarded as clinical pregnancy. Ongoing pregnancy was defined as a pregnancy ≥12 weeks of gestation. Spontaneous pregnancy was accepted as pregnancy without any treatment within one year after unsuccessful IUI. Statistical Analysis Statistical analysis was performed using SPSS version 15.0 software. Mann-Whitney U test and Pearson’s Chi-square tests were performed where appropriate. A value of p=0.05 was accepted as the degree of significance. Data are given as mean ± standard deviation or percentage.

as ≥10 mIU/L were regarded as biochemical pregnancy and presence of a gestational sac on ultrasonography was regarded as clinical pregnancy. Ongoing pregnancy was defined as a pregnancy ≥12 weeks of gestation. Spontaneous pregnancy was accepted as pregnancy without any treatment within one year after unsuccessful IUI. Statistical Analysis Statistical analysis was performed using SPSS version 15.0 software. Mann-Whitney U test and Pearson’s Chi-square tests were performed where appropriate. A value of p=0.05 was accepted as the degree of significance. Data are given as mean ± standard deviation or percentage. RESULTS Ninety-seven patients who met the inclusion criteria and underwent COH/IUI treatment were included in study. Forty-four patients with unilateral tubal occlusion were included into the study group and 53 patients with unexplained infertility were assigned as the control group. Comparison of baseline clinical characteristics and sperm parameters of the two groups are given in Table 1. There were no significant differences between the study and control groups. In addition, there were no significant differences regarding IUI cycle characteristics of patients when the two groups were compared (Table 1). The biochemical, clinical, and ongoing pregnancy rates of the two groups are given in Table 2. The biochemical, clinical, and ongoing pregnancy rates per cycle of study group were 13.6%, 11.4%, and 11.4%, respectively. The biochemical, clinical, and ongoing pregnancy rates of the control group were 9.4% for all parameters. There were no statistical differences between the two groups. The spontaneous pregnancy rates were found 15.9% and 18.9% for study group and control group, respectively, and there was no statistically significant difference.

mical, clinical, and ongoing pregnancy rates of the control group were 9.4% for all parameters. There were no statistical differences between the two groups. The spontaneous pregnancy rates were found 15.9% and 18.9% for study group and control group, respectively, and there was no statistically significant difference. DISCUSSION In present study, the biochemical, clinical, and ongoing pregnancy rates of COH/IUI treatment were similar between patients with unilateral occlusion and patients with unexplained infertility. In addition, the spontaneous pregnancy rate within one year after unsuccessful IUI treatment was higher in the control group than in the study group but the difference did not reach statistical significance. The management of infertile patients showed differences based on their HSG findings. In general, patients with bilateral tubal occlusion can be referred to IVF treatment or for further evaluation for tubal patency with laparoscopic chromotubation. The management of patients with one-sided tubal occlusion is less clear(1,8). In the literature, the diagnostic accuracy of HSG was evaluated in various studies. Mol et al.(9) conducted a prospective cohort study of 794 patients with the participation of 11 clinics to evaluate the importance of HSG and laparoscopy for the prediction of fertility outcomes. The sensitivity and specificity of HSG was reported as 0.81 and 0.75, respectively, for any form of tubal occlusion at laparoscopic surgery.

nducted a prospective cohort study of 794 patients with the participation of 11 clinics to evaluate the importance of HSG and laparoscopy for the prediction of fertility outcomes. The sensitivity and specificity of HSG was reported as 0.81 and 0.75, respectively, for any form of tubal occlusion at laparoscopic surgery. The authors reported the adjusted fecundity rate ratios (FRR) for unilateral tubal occlusion diagnosed at HSG as 0.80 and for bilateral tubal occlusion as 0.49. Accordingly, the authors concluded that bilateral tubal occlusion significantly impaired fertility outcomes whereas unilateral tubal occlusion mildly reduced fertility outcomes. Diagnosis of occlusion at laparoscopy had a greater worsening effect on fertility outcomes (FRR=0.51 and 0.15 for unilateral and bilateral tubal occlusion, respectively) than those at HSG(9). A retrospective study assessed the fertility prognosis of patients with tubal occlusion detected using HSG. The FRR of unilateral tubal occlusion was 0.81 and that of bilateral tubal occlusion was 0.30(10). The authors suggested that patients with one-sided tubal pathology and patients with normal HSG findings had nearly similar fertility potential, but the presence of bilateral tubal pathology detected on HSG decreased fertility potential significantly. In our study, the spontaneous pregnancy rate of patients with normal HSG findings was higher than patients with one-sided tubal occlusion, but the difference was not found as statistically significant (18.9% vs. 15.9%, p>0.05).

ce of bilateral tubal pathology detected on HSG decreased fertility potential significantly. In our study, the spontaneous pregnancy rate of patients with normal HSG findings was higher than patients with one-sided tubal occlusion, but the difference was not found as statistically significant (18.9% vs. 15.9%, p>0.05). In the literature, the success rates of COH/IUI in patients with diagnosis of unilateral tubal occlusion at HSG were assessed in different studies. In a retrospective study, Lin et al.(2) reported that the pregnancy rates per cycle of COH/IUI treatment for patients with one-sided tubal occlusion on HSG and those with normal HSG findings were 17.3% and 18.9%, respectively. The difference of pregnancy rates between the two groups showed no statistical significance. The authors stated that COH/IUI could be initial treatment options for infertile patients with unilateral tubal occlusion. Farhi et al.(11) assessed the cumulative pregnancy rates for three cycles of COH/IUI treatment among patients diagnosed as having one-sided tubal occlusion compared with patients with unexplained infertility (controls). The cumulative pregnancy rates were reported as 30.9% for the study group and 42.6% for the control group. The authors stated that there was no significant difference between the two groups in terms of cumulative pregnancy rates. Yi et al.(12) evaluated the outcomes of COH/IUI treatment among thirty-seven infertile women (52 cycles) with unilateral tubal occlusion compared with a control group that included patients with unexplained infertility. The pregnancy rate per cycle was 17.3% in patients with unilateral tubal occlusion and 16.5% in the control group without statistical significance. The outcomes of our study are similar with the literature. In the present study, the ongoing pregnancy rate per cycle of study group was 11.4% whereas the ongoing pregnancy rate per cycle of control group was 9.4%. The biochemical, clinical, and ongoing pregnancy rates per cycles did not show a significant difference between the study and control groups.

r with the literature. In the present study, the ongoing pregnancy rate per cycle of study group was 11.4% whereas the ongoing pregnancy rate per cycle of control group was 9.4%. The biochemical, clinical, and ongoing pregnancy rates per cycles did not show a significant difference between the study and control groups. Conflicting results about the clinical importance of the site of tubal occlusion and outcomes of COH/IUI treatment are reported in different studies. Lower pregnancy rates are demonstrated in women with mid-distal or distal tubal occlusion than in women with proximal tubal occlusion(2,11,12). Some authors stated that the site of tubal occlusion should be considered in the management of patients with unilateral tubal occlusion whereas others reported that the site of tubal occlusion had no importance in the management of these patients(2,11,12). The relatively small sample size and retrospective nature of the study were the limitations of the present study. CONCLUSION Infertile patients with one-sided tubal occlusion on HSG can be managed as with patients with unexplained infertility and normal findings on HSG. In addition, COH/IUI may be considered as the first-line treatment option in the management of these patients. Ethics: Ethics Committee Approval: The study protocol was approved by the Local Research and Ethics Committee of the institution, Informed Consent: This retrospective cohort study was conducted in Zeynep Kamil Tertiary Hospital between 2013 and 2015. Peer-review: External and Internal peer-reviwed.

CONCLUSION Infertile patients with one-sided tubal occlusion on HSG can be managed as with patients with unexplained infertility and normal findings on HSG. In addition, COH/IUI may be considered as the first-line treatment option in the management of these patients. Ethics: Ethics Committee Approval: The study protocol was approved by the Local Research and Ethics Committee of the institution, Informed Consent: This retrospective cohort study was conducted in Zeynep Kamil Tertiary Hospital between 2013 and 2015. Peer-review: External and Internal peer-reviwed. Authorship Contributions: Surgical and Medical Practices: Hüseyin Tayfun Kutlu, Concept: Selçuk Selçuk, Çetin Çam, Design: Selçuk Selçuk, Semra Kayataş Eser, Data Collection or Processing: İlter Yenidede, Mehmet Küçükbaş, Analysis or Interpretation: Çetin Çam, Literature Search: Ahmet Eser, Semra Kayataş Eser, Writing: Selçuk Selçuk, Hüseyin Tayfun Kutlu. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study received no financial support. Table 1 Comparison of demographic and clinical characteristics between the two groups Table 2 Comparison of outcomes of intrauterine insemination cycles between two groups

ause of neonatal and maternal injury, the incidence of which is reported to be between 0.6-1.4% in vaginal births(1). Shoulder dystocia may result in a major neonatal injuries including brachial plexus palsies, fractures of the clavicle and humerus, hypoxic ischemic encephalopathy, and in rare cases, neonatal death(1). To overcome this problem, prophylactic ceserean section and health personnel training strategies have been tried for the acute management of shoulder dystocia. Several risk factors have been identified for the selection of appropriate candidates for prohylactic ceserean section; however, none of them reached sufficient sensitivity or specificity(2,3,4). Therefore, to prevent a single case of permanant neonatal injury, very large numbers of prophylactic cesareans are needed, which may result in severe maternal morbidity(4,5). Although training for acute management of shoulder dystocia has been suggested, there has been little objective evidence that this training impacts neonatal and maternal injuries(5). The rate of neonatal brachial plexus injury in the United States and other countries is comparable: 1.5 vs. 1.3 per 1000 total births, respectively. Most of the antepartum or intrapartum factors cannot be used as a guide for selecting patients at high risk for shoulder dystocia with or without brachial plexus injury(6). Previous data showed sequential use of vacuum and forceps to be risk a factor for both neonatal and maternal injury(7). Data suggest that the McRoberts’ maneuver is adequately successful at relieving shoulder dystocia in the majority of cases and may be associated with decreased morbidity compared with other maneuvers. As a consequence, the McRoberts’ maneuver is recommended as the initial technique for disimpaction of the anterior shoulder(8).

INTRODUCTION Shoulder dystocia is an important cause of neonatal and maternal injury, the incidence of which is reported to be between 0.6-1.4% in vaginal births(1). Shoulder dystocia may result in a major neonatal injuries including brachial plexus palsies, fractures of the clavicle and humerus, hypoxic ischemic encephalopathy, and in rare cases, neonatal death(1).

gest that the McRoberts’ maneuver is adequately successful at relieving shoulder dystocia in the majority of cases and may be associated with decreased morbidity compared with other maneuvers. As a consequence, the McRoberts’ maneuver is recommended as the initial technique for disimpaction of the anterior shoulder(8). The aim of this study was to present some features and incidence of cases of brachial plexus injury in deliveries at the Department of Obstetrics and Gynecology of Zeynep Kamil Maternity and Children’s Training and Research Hospital, from January 2010 through December 2014.

gest that the McRoberts’ maneuver is adequately successful at relieving shoulder dystocia in the majority of cases and may be associated with decreased morbidity compared with other maneuvers. As a consequence, the McRoberts’ maneuver is recommended as the initial technique for disimpaction of the anterior shoulder(8). The aim of this study was to present some features and incidence of cases of brachial plexus injury in deliveries at the Department of Obstetrics and Gynecology of Zeynep Kamil Maternity and Children’s Training and Research Hospital, from January 2010 through December 2014. MATERIALS AND METHODS At the Zeynep Kamil Women and Children’s Health Training and Research Hospital, prospectively collected records of labor and delivery, nursery, and neonatal intensive care unit were reviewed and identified from the computer database of all deliveries that included details of the labor, all cases of Erb’s/Duchenne and Klumpke’s palsies and brachial plexus injury confirmed by a pediatric neurologist’s examination. Among all cases of brachial plexus injury, we recorded gravidity, parity, body mass index, maternal diabetes, labor induction, gestational age at delivery, operative deliveries, malpresentations, prolonged second stage of deliveries, shoulder dystocias, clavicle and humerus fructures, estimated fetal weight, biparietal diameter, abdominal circumference, femur length, fetal sex, route of delivery, maternal age, and fetal anomalies. After delivery of the fetal head, shoulder dystocia was considered in cases when there was need for additional obstetric maneuvers in addition to gentle downward traction. Maneuvers used after unsuccessful head traction were identified as follows: McRoberts maneuver, suprapubic pressure, Rubin maneuver, delivery of the posterior shoulder, Woods corkscrew maneuver, Gaskin maneuver (delivery in the maternal knee-chest position), Zavanelli maneuver, and fundal pressure. Prolonged second stage of labor was defined as longer than 2 h and was extended to more than 3 h when regional analgesia was used in nulliparas. For multiparas, 1 h was the limit, but was extended to 2 h with regional analgesia based on deviations from Friedman’s curve (Macrosomia was defined as a birth weight equal to or more than 4000 g(9). Estimated fetal weight deviation was defined as the difference from expected fetal weight for gestational age, expressed as a percentage)(estimated weight) expected weight)/(expected weight) *100)(10). Body mass index (BMI) was calculated (initial weight/height2 (kg/m2). Excessive weight gain during pregnancy was defined as weight gain above 16 kg between the first visit and delivery.

expected fetal weight for gestational age, expressed as a percentage)(estimated weight) expected weight)/(expected weight) *100)(10). Body mass index (BMI) was calculated (initial weight/height2 (kg/m2). Excessive weight gain during pregnancy was defined as weight gain above 16 kg between the first visit and delivery. Head circumference was measured on a transverse view of the fetal head in an axial plane at the level at which the continuous midline echo was broken by the cavum septi pellucidi in the anterior third and derived from measurement of the occipitofrontal diameter and biparietal diameter(11). Abdominal circumference was measured on a transverse plane, just above the level of the cord insertion and computed from orthogonal diameters(12). To measure femur length, a sonographic plane was obtained including the entire femoral diaphysis, with both ends clearly visible and at an angle of  <45° to the horizontal(13). Estimated fetal weight was calculated in all cases using the following formula of Hadlock et al.(14). Data was entered into SPSS version 15. Some clinical and demographic characteristics of the study population were summarized using descriptive statistics. Chi-square cross tables were used to summarize data of categorical variables. P<0.05 was accepted as statistically significant.

lowing formula of Hadlock et al.(14). Data was entered into SPSS version 15. Some clinical and demographic characteristics of the study population were summarized using descriptive statistics. Chi-square cross tables were used to summarize data of categorical variables. P<0.05 was accepted as statistically significant. RESULTS There were 28 (72/100.000) cases of brahial plexus injury among 38.896 deliveries. Some 18.363 (47.21%) of the deliveries were via c-section, whereas there were 20.533 vaginal deliveries in the 6-year study period. Some demographic and clinical parameters of the cases of brachial plexus injury are summarized in Table 1. The data of women who were grouped according to the WHO BMI classification are summarized in Table 2. Some features of the groups summarized in Table 3.

e were 20.533 vaginal deliveries in the 6-year study period. Some demographic and clinical parameters of the cases of brachial plexus injury are summarized in Table 1. The data of women who were grouped according to the WHO BMI classification are summarized in Table 2. Some features of the groups summarized in Table 3. DISCUSSION In this article, we wanted to point out some clinical characteristics of obstetric cases of brachial plexus injury that occurred in our tertiary referral center. Analyses of the data generated from 2010 through 2014 showed that the incidence of obstetric brachial plexus injury was lower our center, which is thought to be the result of increased awareness, experience, and training. Another explanation for this decrement is the increasing rates of ceserean section that has resulted from the increased awareness of parents of the responsibilities of health workers, which can lead to litigation. In the literature, the incidence of brachial plexus injury has been reported to be 1-2 per 1000 births(15). The incidence of obstetric brachial plexus injury in our study population was 0.72 per 1000 births including both vaginal and ceserean deliveries. Shoulder dystocia and brachial plexus injury have an unpredictable nature. A study on risk factors for brachial plexus injury showed that shoulder dystocia, macrosomia, labor dystocia, vacuum delivery and vaginal breech deliveries were significant risk factors for neonatal brachial plexus paralysis. The study found no association between maternal characteristics such as obesity and diabetes. The authors concluded that despite the improved knowledge of risk factors associated with brachial plexus paralysis, unfortunately, this condition cannot be predicted or prevented(16). Moreover, other data showed no reliable factors associated with the brachial plexus palsy(17). The overall incidence of neonatal brachial plexus palsy, both transient and persistent impairment, was reported to be 1.5 per 1000 total births in the American Congress Obstetricians Gynecologists bulletin in 2014. Due to the changes of health policies in Turkey and with increasing health litigations since 2002, ceserean section rates have started to increase. The increased rate of ceserean deliveries (47.21%) is thought to be the major determinant of this low incidence of injury in our population, but we should not disregard the role of trained health workers and well-conducted maneuvers during shoulder dystocia management.

, ceserean section rates have started to increase. The increased rate of ceserean deliveries (47.21%) is thought to be the major determinant of this low incidence of injury in our population, but we should not disregard the role of trained health workers and well-conducted maneuvers during shoulder dystocia management. In a previous study, direct fetal manipulation techniques used to overcome shoulder dystocia were not found to be associated with an increased rate of brachial plexus injury(18). A study conducted in 1997 concluded that the McRoberts’ maneuver was associated with a significant degree of success in relieving shoulder dystocia and may be associated with decreased morbidity compared with other maneuvers(19). Although the Cochrane review concluded that prophylactic maneuvers should not be used to prevent shoulder dystocia, if a recognizable risk factor for shoulder distocia is present in our institution, a prophylactic McRoberts maneuver is used most of the time(20). When the role of sonography is considered in the prevention neonatal injury, a review published in 2004 reported that the true value of ultrasonography in the management of fetal macrosomia may be its ability to rule out the diagnosis. Ultrasound-derived fetal weight estimates alone are not sensitive or specific enough to determine a route of delivery(21). However, since then the quality of sonography equipment and experience in this area has greatly developed. A recently published study concluded that the impact of diabetes as a risk factor has been minimized by the means of improved screening and treatment, and antenatal sonography was thought to be a promising tool; however, its predictive value is still too low to be used alone(22). In conclusion, sonographic fetal weight estimation and clinical examination performed by experienced obstetricians, and active appropriate management of shoulder dystocias with increased rates of ceserean section seemed to attenuate the incidence of brachial plexus injury in the at risk population at our tertiary referral center.

on, sonographic fetal weight estimation and clinical examination performed by experienced obstetricians, and active appropriate management of shoulder dystocias with increased rates of ceserean section seemed to attenuate the incidence of brachial plexus injury in the at risk population at our tertiary referral center. Ethics Committee Approval: Approved from local ethic committee. Informed Consent: It was taken. Peer-review: Externally peer-reviewed. Concept: Meryem Eken, Ateş Karateke, Design: Meryem Eken, Enis Özkaya, Mehmet Çınar, Data Collection or Processing: Taylan Şenol, Meryem Eken, Enis Özkaya, Analysis or Interpretation: Enis Özkaya, Meryem Eken, Literature Search: Enis Özkaya, Meryem Eken, Mehmet Çınar, Taylan Şenol, Writing: Meryem Eken, Ateş Karateke. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Table 1 Maternal demographic characteristics Table 2 Fetal and neonatal characteristics Table 3 Some characteristics of groups established relative to body mass index

PRECIS: Bone is recognized as an endocrine organ. Osteocalcin seems to play a key role in the heterogeneity of polycystic ovary syndrome. INTRODUCTION Polycystic ovary syndrome (PCOS) is a common and heterogeneous disease characterized by anovulation, hyperandrogenism, and/or polycystic ovaries(1,2). Therefore, an important consideration is whether such adipocytokines as adiponectin, a potential mediator of insulin resistance (IR), are also implicated in the pathogenesis of PCOS(3). Levels of adiponectin, an abundant adipocyte-derived cytokine, are strongly correlated with measures of IR(4,5). Gonzalez et al.(6) illustrated that hyperglycemia caused an increase in reactive oxygen species (ROS) generation from peripheral blood mononuclear cells (MNC). ROS-induced oxidative stress is a known activator of nuclear factor B, a proinflammatory transcription factor that promotes tumor necrosis factor (TNF) gene transcription(7). TNF was established as a mediator of IR by Hotamisligil et al.(8). Thus, increased TNF release from MNC in response to hyperglycemia may be an underlying mechanism for IR in PCOS. Previous animal studies showed that osteocalcin stimulated the expression of insulin in islets and of adiponectin in adipocytes with increased insulin secretion and sensitivity(9). Reduced osteocalcin levels have been claimed to be associated with diabetes mellitus (DM) development(10). We aimed to evaluate the correlations of blood osteocalcin, adiponectin, and TNF-α levels with IR in PCOS. Additionally, we evaluated the relationship of these with some hormonal parameters.

on and sensitivity(9). Reduced osteocalcin levels have been claimed to be associated with diabetes mellitus (DM) development(10). We aimed to evaluate the correlations of blood osteocalcin, adiponectin, and TNF-α levels with IR in PCOS. Additionally, we evaluated the relationship of these with some hormonal parameters. MATERIALS AND METHODS A total of 60 women including 44 patients with PCOS and 16 healthy women (control group) were studied at Erciyes University Gynecology Clinic. The diagnosis of PCOS was based on the established guidelines by the PCOS Consensus Workshop Group(1). Ultrasonographic diagnosis of polycystic ovaries was based on the presence of 12 or more follicles in each ovary measuring 2-9 mm in diameter, and/or increased ovarian volume >10 mL on pelvic or vaginal ultrasound examination. Oligomenorrhea was defined as the absence of menstruation for 35 days or more and amenorrhea was defined as the absence of menstruation for 3 months or more(1).

resence of 12 or more follicles in each ovary measuring 2-9 mm in diameter, and/or increased ovarian volume >10 mL on pelvic or vaginal ultrasound examination. Oligomenorrhea was defined as the absence of menstruation for 35 days or more and amenorrhea was defined as the absence of menstruation for 3 months or more(1). All women were examined both clinically and gynecologically including ultrasonography. Body weight, height, and body mass index (BMI) were recorded. The BMI was calculated as weight/(height)2 in kilograms per square meter. The study and control groups were weight matched. Patients with congenital adrenal hyperplasia, androgen-producing tumors, adrenal dysfunction, Cushing’s syndrome, hyperprolactinemia, DM, liver, kidney, heart, and thyroid diseases were excluded from the study. None of the women in study or control group had taken medications known to effect plasma sex steroids for ≥6 months before the study and none of the volunteers was a cigarette smoker. All the women agreed to participate in the present study. The study was approved by the Ethics Committee of Erciyes University Hospital (approval number: 2011-369) and written informed consent was obtained from each woman. Moreover, we obtained an Australian-New Zealand clinical trials registry number: 12613001132730.

All the women agreed to participate in the present study. The study was approved by the Ethics Committee of Erciyes University Hospital (approval number: 2011-369) and written informed consent was obtained from each woman. Moreover, we obtained an Australian-New Zealand clinical trials registry number: 12613001132730. Fasting state venous blood was collected from the subjects during the midfollicular phase of the menstrual cycle between 08:00 am and 09:00 am. Glucose levels were measured three days after the normal diet and normal daily activity using the oxidase method with Konelab 60-i auto-analyzers (Thermo Clinical Labsystem, Finland). IR in the fasting state was assessed by using homeostasis model assessment (HOMA) and was calculated with the following formula: fasting plasma glucose (mmol/L) × fasting serum insulin (µU/mL) divided by 22.5, as described by Matthews et al.(11). Hormonal analyses included: thyroid stimulating hormone, dehydroepiandrosterone sulfate (DHEAS), prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), 17-hydroxyprogesterone (17-OHP), androstenedione (A), free testosterone (fT), total testosterone (tT), insulin, and sex hormone binding globulin (SHBG) levels. tT and fT (Biosource, Nivelles, Belgium), 17-OHP (DSL-3500, Texas, USA), DHEAS (Immunotech, Marseille, France), A (DSL-3800, Texas, USA) were measured using an immunoradiometric assay and its commercial kit, serum SHBG (Zentech, Angleur, Belgium), insulin (Biosource, Nivelles, Belgium), LH, FSH, P, PRL (ACS:180, Bayer, Germany) were measured using chemiluminescence and a commercial kit. After centrifugation, blood serum was stored at -70 °C until assayed. Adiponectin (Adiponectin kit, Assaypro, UK), TNF-α (TNF-α Invitrogen 96 Tests, UK) and osteocalcin (Gla-type osteocalcin in vitro enzyme immunoassay kit, Takara Bio Inc., UK) were measured using an enzyme-linked immunosorbent assay.

a commercial kit. After centrifugation, blood serum was stored at -70 °C until assayed. Adiponectin (Adiponectin kit, Assaypro, UK), TNF-α (TNF-α Invitrogen 96 Tests, UK) and osteocalcin (Gla-type osteocalcin in vitro enzyme immunoassay kit, Takara Bio Inc., UK) were measured using an enzyme-linked immunosorbent assay. The intra and inter-assay precision coefficients of variation were 2.8% and 4.6% for FSH, 5% and 6.2% for LH, 9.9% and 11.8% for E2, 4.4% and 4.8% for testosterone, 4.3% and 7.8% for fT, 11% and 2.8% and 7% for A, 6.3% and 9.9% for DHEAS, 9.5% and 10.8% for 17-OHP, 5.2% and 5.8% for SHBG, and 1.6% and 6.1% for insulin, respectively. All results are expressed as means ± standard deviation. Statistical Analysis The Shapiro-Wilk test was used to check the normality assumption of the data. Independent samples t-test and Mann-Whitney U tests were used to compare the differences of variables between the groups. Pearson and Spearman analysis were used to examine correlations, and a scatterplot matrix was also produced to display pairwise relationships between variables. To identify independent risk factors of PCOS, univariate and multivariate logistic regression analysis was used and odds ratios were calculated with their 95% confidence intervals. Statistically significant variables in univariate analysis were included in the multivariate logistic model and backward stepwise selection was performed at a stringency level of p<0.10 to determine the independent risk factors of PCOS. Two-sided p values <0.05 were considered statistically significant.

ence intervals. Statistically significant variables in univariate analysis were included in the multivariate logistic model and backward stepwise selection was performed at a stringency level of p<0.10 to determine the independent risk factors of PCOS. Two-sided p values <0.05 were considered statistically significant. RESULTS The study and control groups were weight matched. Hormone levels and baseline characteristics of the groups are illustrated in Table 1. The level of A was significantly high in the PCOS group. There was no statistically significant difference between the groups for age, BMI, DHEAS, FSH, SHBG, LH, fT, tT, and E2. High levels of HOMA-IR, adiponectin, and osteocalcin were detected in the PCOS group. There was no significant difference between the two groups for TNF-α (Table 1). The cut-off value of HOMA-IR was accepted as 2.5(12,13). We detected a strong positive correlation between adiponectin and osteocalcin in the control group. There was positive correlation between osteocalcin and BMI in addition to a negative correlation between osteocalcin and TNF-α in the PCOS group. We found a moderate positive correlation between BMI and HOMA-IR, a moderate negative correlation between TNF-α and osteocalcin, and a mild negative correlation between adiponectin and BMI (Table 2, Figure 1).

een osteocalcin and BMI in addition to a negative correlation between osteocalcin and TNF-α in the PCOS group. We found a moderate positive correlation between BMI and HOMA-IR, a moderate negative correlation between TNF-α and osteocalcin, and a mild negative correlation between adiponectin and BMI (Table 2, Figure 1). DISCUSSION Many of the symptoms appear to be quite heterogeneous, with marked differences in their prevalence and intensity among different groups of women with PCOS. IR was significantly high in the PCOS group. Some studies showed IR only in obese women with PCOS and others demonstrated IR in lean patients with PCOS. Of importance, the studies that failed to demonstrate IR in lean women with PCOS did, however, demonstrate elevated basal insulin levels compared with weight-matched controls without PCOS(14).

in the PCOS group. Some studies showed IR only in obese women with PCOS and others demonstrated IR in lean patients with PCOS. Of importance, the studies that failed to demonstrate IR in lean women with PCOS did, however, demonstrate elevated basal insulin levels compared with weight-matched controls without PCOS(14). The groups in our study were weight matched; therefore, the effect of adipose tissue on TNF-α and adiponectin was eliminated. We found higher levels of adiponectin in PCOS; however, some authors suggested that women with PCOS had lower adiponectin levels(15). Conversely, an increment in plasma adiponectin was obtained by Frystyk et al.(16) in type 1 DM. One way to interpret the present findings is to conclude that high adiponectin levels may be an early predictor of DM development. Unfortunately, 52.7% of patients in the PCOS group had IR. However, the finding can also be interpreted in the opposite way, as elevated adiponectin levels could represent a beneficial compensatory mechanism. Several markers of inflammation are increased in PCOS, which suggests that it is a state of chronic low grade inflammation. Keeping in mind the anti-inflammatory and anti-DM properties of adiponectin, one could hypothesize that increased adiponectin levels serve to protect patients at high risk of the harmful actions of pro-inflammatory and DM agents.

re increased in PCOS, which suggests that it is a state of chronic low grade inflammation. Keeping in mind the anti-inflammatory and anti-DM properties of adiponectin, one could hypothesize that increased adiponectin levels serve to protect patients at high risk of the harmful actions of pro-inflammatory and DM agents. Increased levels of TNF-α were detected in PCOS; however, there was no statistical difference between the groups. Although Vural et al.(17) could not illustrate higher TNF-α levels in PCOS, Xiong et al.(18) suggested that patients with PCOS showed significantly higher serum TNF-α levels. The pathogenic impact of TNF-α in IR is underscored by the effect of the functional polymorphisms in the promoter regions of TNF-α, with different transcription rates(19), or this situation may be related to the balance of anti-inflammatory and inflammatory agents that are secreted by bone and adipose tissue in PCOS.

. The pathogenic impact of TNF-α in IR is underscored by the effect of the functional polymorphisms in the promoter regions of TNF-α, with different transcription rates(19), or this situation may be related to the balance of anti-inflammatory and inflammatory agents that are secreted by bone and adipose tissue in PCOS. More recently, evidence from animal studies suggested that the skeleton may exert an endocrine regulation of glucose metabolism. Lee et al.(20) showed that mice lacking the gene that encodes osteocalcin had an abnormal amount of visceral fat and exhibited glucose intolerance, IR, and impaired insulin secretion compared with wild-type mice. Adami et al.(21) could not illustrate a significant difference between a PCOS group and control group for osteocalcin, but they found normal androgen levels in their PCOS group; additionally, they did not examine patients for IR. In our study, osteocalcin was significantly increased in PCOS; moreover, there was a negative correlation between osteocalcin and TNF-α. Our study is in agreement with Diamanti-Kandarakis et al.(22) who illustrated higher osteocalcin levels in PCOS.

their PCOS group; additionally, they did not examine patients for IR. In our study, osteocalcin was significantly increased in PCOS; moreover, there was a negative correlation between osteocalcin and TNF-α. Our study is in agreement with Diamanti-Kandarakis et al.(22) who illustrated higher osteocalcin levels in PCOS. There was no correlation between serum adiponectin and HOMA-IR. There was a moderate negative correlation between osteocalcin and TNF-α, in addition to a moderate positive correlation between BMI and HOMA-IR in PCOS. Adiponectin secretion is strongly related with IR rather than obesity, and a previous animal study showed that osteocalcin stimulated the expression of insulin in islets and of adiponectin in adipocytes with increased insulin secretion(23). Perhaps increased osteocalcin levels contribute to high HOMA-IR by increased insulin secretion. Our groups were weight matched and the source of adiponectin was adipose tissue. This situation may explain why we did not detect a correlation between serum adiponectin levels and HOMA-IR. TNF-α can be released from MNCs and hyperglycemia causes an increase in ROS generation from MNCs. Osteocalcin is defined in the literature with antidiabetic and anti-inflammatory properties, thus a plausible explanation of these events is that increased osteocalcin levels lead to a decrease in TNF-α.

There was no correlation between serum adiponectin and HOMA-IR. There was a moderate negative correlation between osteocalcin and TNF-α, in addition to a moderate positive correlation between BMI and HOMA-IR in PCOS. Adiponectin secretion is strongly related with IR rather than obesity, and a previous animal study showed that osteocalcin stimulated the expression of insulin in islets and of adiponectin in adipocytes with increased insulin secretion(23). Perhaps increased osteocalcin levels contribute to high HOMA-IR by increased insulin secretion. Our groups were weight matched and the source of adiponectin was adipose tissue. This situation may explain why we did not detect a correlation between serum adiponectin levels and HOMA-IR. TNF-α can be released from MNCs and hyperglycemia causes an increase in ROS generation from MNCs. Osteocalcin is defined in the literature with antidiabetic and anti-inflammatory properties, thus a plausible explanation of these events is that increased osteocalcin levels lead to a decrease in TNF-α. Study Limitations Due to the relatively small sample size, our results display only weight-matched controls in PCOS. There is a need for further, larger scale studies including interactions between other genetic and environmental factors and the development of PCOS. CONCLUSION Osteocalcin levels may have impact on adiponectin, TNF-α, and IR in PCOS. Therefore, osteocalcin may be responsible for PCOS heterogeneity.

Study Limitations Due to the relatively small sample size, our results display only weight-matched controls in PCOS. There is a need for further, larger scale studies including interactions between other genetic and environmental factors and the development of PCOS. CONCLUSION Osteocalcin levels may have impact on adiponectin, TNF-α, and IR in PCOS. Therefore, osteocalcin may be responsible for PCOS heterogeneity. We thank Dr. Faruk Balkaya (English Department of Erciyes University) for his contribution to English terms and language. Erciyes University financially supported this study. Ethics Ethics Committee Approval: The study was approved by the Erciyes University Local Ethics Committee (approval number: 2011-369). Informed Consent: Consent form was filled out by all participants. Peer-review: External and internal peer-reviewed. Authorship Contributions Surgical and Medical Practices: G.E., İ.İ.M., Concept: F.B., İ.İ.M., Design: F.B., İ.İ.M., G.A., Data Collection or Processing: G.E., A.T.T., Analysis or Interpretation: G.E., G.B., Literature Search: F.B., İ.İ.M., Writing: A.T.T., G.A. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study received no financial support.

Surgical and Medical Practices: G.E., İ.İ.M., Concept: F.B., İ.İ.M., Design: F.B., İ.İ.M., G.A., Data Collection or Processing: G.E., A.T.T., Analysis or Interpretation: G.E., G.B., Literature Search: F.B., İ.İ.M., Writing: A.T.T., G.A. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study received no financial support. Table 1 Hormonal levels and baseline characteristics of groups Table 2 Correlation of osteocalcin level with hormonal levels, age, body mass index, homeostasis model assessment-insulin resistance, tumor necrosis factor-alpha, and adiponectin for both groups Figure 1 A scatterplot matrix displaying the relationship among body mass index, homeostasis model assessment-insulin resistance, tumor necrosis factor-alpha, adiponectin, and osteocalcin variables *p<0.05, **p<0.01 HOMA-IR: Homeostasis model assessment-insulin resistance, BMI: Body mass index, TNF-α: Tumor necrosis factor-alpha

PRECIS: This paper investigated the hematological inflammatory markers in mild and severe cases of intrahepatic cholestasis of pregnancy. Mean platelet volume was significantly increased in severe intrahepatic cholestasis of pregnancy. INTRODUCTION Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease seen during pregnancy, with a changing prevalence worldwide(1,2). The etiology and pathogenesis of ICP are multifactorial. Environmental factors, nutritional deficiencies, hormonal changes, and genetic variations have been found to be responsible for ICP(3,4). It presents most often in the form of pruritus in the second and third trimesters of pregnancy, with elevated serum aminotransferases and/or elevated serum bile acid levels (≥10 µmol/L)(5). ICP can be differentiated from other types of liver diseases unique to pregnancy that share similar laboratory abnormalities such as preeclampsia, acute fatty liver of pregnancy, and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome(1,6,7). In addition, other skin diseases that cause high transaminase levels in pregnancy must be excluded. After delivery, the symptoms of ICP usually resolve within 48 hours, with laboratory abnormalities normalizing within 2-8 weeks(8,9).

and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome(1,6,7). In addition, other skin diseases that cause high transaminase levels in pregnancy must be excluded. After delivery, the symptoms of ICP usually resolve within 48 hours, with laboratory abnormalities normalizing within 2-8 weeks(8,9). Bile acid levels can affect perinatal outcomes and are related to an increased risk of iatrogenic preterm delivery, spontaneous preterm delivery, meconium-stained amniotic fluid (MSA), and sudden intrauterine death of the fetus(8,10,11,12). In the severe ICP group, the incidence of complications is higher than in the mild group(8). Unfortunately, ultrasonography, cardiotocography, fetal movements, and Doppler ultrasonography cannot predict fetal death; there is no perfect test or prognostic marker available to predict fetal outcome(8,13,14).

(8,10,11,12). In the severe ICP group, the incidence of complications is higher than in the mild group(8). Unfortunately, ultrasonography, cardiotocography, fetal movements, and Doppler ultrasonography cannot predict fetal death; there is no perfect test or prognostic marker available to predict fetal outcome(8,13,14). Recent studies demonstrated the prognostic role of inflammatory markers in both cardiovascular diseases and malignancies(15,16), but few studies have been performed with ICP. The neutrophil-to-lymphocyte (NLR) ratio, platelet-to-lymphocyte (PLR) ratio, mean platelet volume (MPV), and red blood cell distribution width (RDW) are hematologic inflammatory markers. One important pathogenesis responsible for the occurrence of ICP is inflammation; however, it is not known which mechanism initiates this inflammation(17). Recently, NLR has been found to be a promising diagnostic marker in ICP(18). To the best of our knowledge, no studies have investigated the roles of PLR and RDW in ICP. Therefore, we aimed to evaluate the role of inflammatory markers, which are readily available and easily calculated parameters, in the severity of ICP.

Recently, NLR has been found to be a promising diagnostic marker in ICP(18). To the best of our knowledge, no studies have investigated the roles of PLR and RDW in ICP. Therefore, we aimed to evaluate the role of inflammatory markers, which are readily available and easily calculated parameters, in the severity of ICP. MATERIALS AND METHODS This retrospective case-control study was conducted at Zeynep Kamil Women and Children’s Health Training and Research Hospital, İstanbul. Patients with ICP who delivered their babies in this hospital from January 2013 to January 2016 were enrolled in this study. All data were obtained from hospital files and our computer database. This study was approved by the Zeynep Kamil Women and Children’s Health Training and Research Hospital Local Ethics Committee (approval number: 136). The term ICP was used if the serum bile acid level was ≥10 µmol/L with pruritus that could not be explained by any other condition. A total of 102 women with ICP were enrolled in this study. The exclusion criteria were: patients with incomplete data, fetal congenital anomalies, multiple pregnancies, chronic/acute liver disease (Wilson’s disease, cholecystitis, primary sclerosing cholangitis, primary biliary cirrhosis, alpha-1-antitrypsin deficiency, symptomatic cholelithiasis, cytomegalovirus, Epstein-Barr virus, autoimmune hepatitis, or acute fatty liver of pregnancy), and HELLP syndrome. A total of 84 singleton pregnancies were included in this research.

se, cholecystitis, primary sclerosing cholangitis, primary biliary cirrhosis, alpha-1-antitrypsin deficiency, symptomatic cholelithiasis, cytomegalovirus, Epstein-Barr virus, autoimmune hepatitis, or acute fatty liver of pregnancy), and HELLP syndrome. A total of 84 singleton pregnancies were included in this research. The patients with ICP were categorized into two groups according to their serum bile acid levels: mild (<40 µmol/L, n=53) and severe (≥40 µmol/L, n=31). The control group was selected from age-matched healthy women who had singleton deliveries on the same day as that of patient’s with ICP. All gestational age-matched controls complied with the exclusion criteria (n=145). Serum bile acids were evaluated using an enzymatic assay with intra and inter-assay precisions of 3% and 4%, respectively, [Diazyme Total Bile Acids (TBA) kit; Diazyme Diagnostic Laboratories, USA] and a Cobas C501 (Roche, USA). A blood analyzer (Cell-Dyn 3700; Abbott, USA) was used to determine the complete blood cell count (CBC). The CBC inflammatory markers measured were white blood cell counts (WBC), platelets, NLR, PLR, MPV, and RDW. Perinatal death was defined as mortality from over 24 weeks’ gestation until 7 days postpartum. A low Apgar score was defined as a score of below 7 at 5 minutes. The main outcome of the measures was the association of the inflammatory factors (WBC, NLR, PLR, MPV, and PDW) with the severity of ICP.

Serum bile acids were evaluated using an enzymatic assay with intra and inter-assay precisions of 3% and 4%, respectively, [Diazyme Total Bile Acids (TBA) kit; Diazyme Diagnostic Laboratories, USA] and a Cobas C501 (Roche, USA). A blood analyzer (Cell-Dyn 3700; Abbott, USA) was used to determine the complete blood cell count (CBC). The CBC inflammatory markers measured were white blood cell counts (WBC), platelets, NLR, PLR, MPV, and RDW. Perinatal death was defined as mortality from over 24 weeks’ gestation until 7 days postpartum. A low Apgar score was defined as a score of below 7 at 5 minutes. The main outcome of the measures was the association of the inflammatory factors (WBC, NLR, PLR, MPV, and PDW) with the severity of ICP. Statistical Analysis The statistical analysis was performed using the Statistical Package for the Social Sciences for Windows version 18 (SPSS Inc., Chicago, IL, USA). A p value of less than 0.05 was accepted as being statistically significant, and all measurements were performed within a 95% confidence interval. The results of the study are expressed as means, standard deviations, and percentages. According to the data distribution, comparisons were made using Student’s t-test, ANOVA, or the chi-square (χ2) test, when appropriate. A post-hoc least significant difference test was used after the ANOVA analysis. Relationships between the data were evaluated using Pearson’s correlations.

deviations, and percentages. According to the data distribution, comparisons were made using Student’s t-test, ANOVA, or the chi-square (χ2) test, when appropriate. A post-hoc least significant difference test was used after the ANOVA analysis. Relationships between the data were evaluated using Pearson’s correlations. RESULTS The comparison between the patients with ICP (n=84) and controls (n=145) showed similar ages (28±5.5 vs. 28.1±5.2 years, p>0.05) and gravidities (2.1±1.3 vs. 2.3±1.2, p>0.05). The ICP group showed significantly decreased gestational weeks at delivery (36.2±2.3 vs. 39.1±1.4 weeks, p<0.001) and birth weights (2899±623.3 g vs. 3373±413.9 g, p<0.001) when compared with the healthy controls. The comparison of the characteristic findings of the patients with mild and severe ICP is presented in Table 1. The majority of patients (77.3% mild ICP vs. 74.1% severe ICP) were overweight/obese and aged younger than 35 years (79.2% mild ICP vs. 70.9% severe ICP), respectively. The women with mild and severe ICP exhibited similar characteristics with regard to educational status, chronic disease history, and previous ICP history (p<0.05). Table 2 presents the laboratory findings; with the exception of serum bile acid levels, the women with mild and severe ICP had similar findings.

spectively. The women with mild and severe ICP exhibited similar characteristics with regard to educational status, chronic disease history, and previous ICP history (p<0.05). Table 2 presents the laboratory findings; with the exception of serum bile acid levels, the women with mild and severe ICP had similar findings. Serum bile acids were positively and significantly correlated with PLR (r=0.343, p=0.003), but the correlations of bile acids with WBC (r=-0.062), neutrophils (r=-0.198), lymphocytes (r=-0.112), MPV (r=0.08), RDW (r=-0.174), and NLR (r=-0.110) were statistically non-significant (p>0.05). Serum bile acids were negatively significantly correlated with gestational age at delivery (r=-0.390, p<0.001) and birth weight (r=-0.252, p=0.02), and PLR was negatively correlated with gestational age at delivery (r=-0.254, p=0.003). The comparison of the obstetric outcomes in the women with mild and severe ICP is given in Table 3. The percentages of those having male fetuses, low Apgar scores, fetal distress, MSA, preeclampsia, perinatal/neonatal mortality, gestational diabetes, Rh isoimmunization, and abortus imminence were similar between the women with mild and severe ICP. However, the gestational age at delivery and time of diagnosis were earlier in the severe group (p<0.05). In addition, the cesarean section rate was significantly increased in the severe group (p<0.05).

tational diabetes, Rh isoimmunization, and abortus imminence were similar between the women with mild and severe ICP. However, the gestational age at delivery and time of diagnosis were earlier in the severe group (p<0.05). In addition, the cesarean section rate was significantly increased in the severe group (p<0.05). Table 4 shows the comparison of the inflammatory markers between the normal and ICP groups. Overall, the inflammatory markers were significantly increased in the ICP group, including WBC, MPV, and PLR (p<0.05), and neutrophils, lymphocytes, and RDW were significantly decreased in the ICP group (p<0.05). However, NLRs were similar between the normal and ICP groups. Table 5 presents the comparison of the inflammatory markers in the healthy controls and women with mild and severe ICP. The RDW (p=0.128) and WBC (p=0.535) values were similar between the women with mild and severe ICP. MPV was significantly increased in the severe ICP group when compared with controls and the mild ICP group (p<0.05). Despite the fact that PLR was increased and RDW was decreased in patients with ICP, they were not significantly changed between the mild and severe groups. MPV was the marker that significantly increased in the severe group.

increased in the severe ICP group when compared with controls and the mild ICP group (p<0.05). Despite the fact that PLR was increased and RDW was decreased in patients with ICP, they were not significantly changed between the mild and severe groups. MPV was the marker that significantly increased in the severe group. DISCUSSION ICP is a liver disease of pregnancy that increases fetal mortality; therefore, early diagnosis and assessment of the severity of the disease is an important task. In this study, we aimed to investigate the associations between the readily available, but newly defined, inflammatory markers, NLR, PLR, MPV, and RDW, with the severity of ICP. The present study found that the inflammatory markers were significantly increased in patients with ICP, and that MPV increased with the severity of ICP.

dy, we aimed to investigate the associations between the readily available, but newly defined, inflammatory markers, NLR, PLR, MPV, and RDW, with the severity of ICP. The present study found that the inflammatory markers were significantly increased in patients with ICP, and that MPV increased with the severity of ICP. Fetal distress, premature delivery, perinatal asphyxia, and intrauterine fetal death may all occur in patients with ICP(2,8,19), and increased bile acid levels are thought to be the cause of these complications(20). Consistent with previous studies, we observed lower birth weights and more preterm deliveries among patients with ICP(11,21,22,23). However, there were no significant differences found in maternal age, parity, diabetes history, history of chronic systemic disease, preeclampsia or maternal hepatitis B and C infections in the women with mild and severe ICP, which was consistent with the study by Kawakita et al.(24). Some studies found similar cesarean section rates(12,25,26), in contrast to others(20,27). In our study, cesarean rates were higher with severe ICP. Some authors found an increased MSA risk in the ICP group when compared with controls(8,28,29), but some authors did not support these findings(27). In addition, some previous studies reported an increased MSA risk in the severe ICP group when compared with the mild group(26,27), but conflicting results have been reported(29) in the literature. Also in our study, we didn’t find an increased MSA risk in the severe group when compared with the mild group. Fetal asphyxia in the newborns of patients with ICP has been reported frequently in the literature(30,31). Overall, the characteristics of these patients show wide variations, and the findings are inconsistent in the literature(30).

idn’t find an increased MSA risk in the severe group when compared with the mild group. Fetal asphyxia in the newborns of patients with ICP has been reported frequently in the literature(30,31). Overall, the characteristics of these patients show wide variations, and the findings are inconsistent in the literature(30). Previous studies about ICP and inflammation suggested that ICP was an inflammatory process, and that perinatal outcomes were related to inflammation(18,31,32,33). Bile acids are thought to be related to inflammation, and they directly affect hepatocytes and stimulate the secretion of proinflammatory mediators, which causes neutrophil accumulation, extravasation, and activation(17). Prior studies used the hematologic markers WBC(18), MPV(31,32), and NLR(18) as inflammatory markers in ICP. However, as far as we know, no studies have investigated the relationships between ICP and PLR and RDW. Therefore, to the best of our knowledge, this paper is the first to determine the associations between ICP and all CBC inflammatory markers. The results showed that serum bile acids were positively and significantly correlated with PLR (r=0.343, p=0.003), and the ICP group had a significantly increased PLR and significantly decreased RDW ratio when compared with the controls. Despite the increased PLRs and decreased RDWs in the patients with ICP, they were not significantly changed in severe ICP.

were positively and significantly correlated with PLR (r=0.343, p=0.003), and the ICP group had a significantly increased PLR and significantly decreased RDW ratio when compared with the controls. Despite the increased PLRs and decreased RDWs in the patients with ICP, they were not significantly changed in severe ICP. Kirbas et al.(18) found significantly higher mean WBC and NLR values and a lower lymphocyte count in their severe ICP group than in controls, and NLR was found to be even higher in patients with mild ICP. They also found a significant association between fasting TBA levels and NLR(18). However, we found that neutrophil and lymphocyte counts were significantly decreased in patients with ICP; NLRs were similar between the normal and ICP group.

han in controls, and NLR was found to be even higher in patients with mild ICP. They also found a significant association between fasting TBA levels and NLR(18). However, we found that neutrophil and lymphocyte counts were significantly decreased in patients with ICP; NLRs were similar between the normal and ICP group. Platelets in the blood vary in size, with the granules and adhesion molecules of the platelets increasing when they become larger and play an active role in homeostasis(34). MPV, which is the most frequently used platelet size measurement, is also an index of platelet activation(34). Platelets release thrombin, which plays a role in inflammation(34) and angiogenesis(35), and a high platelet volume allows greater coagulability and fibrinolysis(36). However, there is a limited number of studies about the relationship between MPV and the severity of ICP, and the relationship between MPV and perinatal outcomes, even though an MPV increase can be seen in patients with ICP(31,32). Kebapcilar et al.(31) investigated the relationship between coagulation parameters and low 5-minute Apgar scores in both patients with ICP and normal pregnancies. In addition, Oztas et al.(32) reported higher MPVs in patients with ICP when compared with a control group, with an increased preterm delivery likelihood just after exceeding an MPV of 11.2 fL. In our study, MPV was significantly increased in women with ICP cases compared with healthy controls. Moreover, apart from the PLR and WBC, the MPV levels increased in the severe group.

nts with ICP when compared with a control group, with an increased preterm delivery likelihood just after exceeding an MPV of 11.2 fL. In our study, MPV was significantly increased in women with ICP cases compared with healthy controls. Moreover, apart from the PLR and WBC, the MPV levels increased in the severe group. Study Limitations The main limitation of this study was its retrospective design, but despite this methodologic limitation, this research investigated all of the available hematologic inflammatory parameters. It confirmed prior data that inflammatory markers are significantly increased in patients with ICP. Despite the significant changes in the inflammatory markers in patients with ICP, only MPV was significantly increased with the severity of the disease. These results suggest that MPV may be a valuable marker in patients with severe ICP, but large scale studies are needed to confirm this result. CONCLUSION Based on the results of this study, the inflammatory markers were significantly increased in patients with ICP. PLR, WBC, and MPV were all significantly increased, whereas the RDW was significantly decreased in ICP. MPV was related to the severity of disease and might be a valuable marker for ICP disease severity in the future. Ethics Ethics Committee Approval: This study was approved by the Zeynep Kamil Women and Children’s Health Training and Research Hospital Local Ethics Committee (approval number: 136). Informed Consent: Consent form was filled out by all participants. Peer-review: External and internal peer-reviewed. Authorship Contributions

CONCLUSION Based on the results of this study, the inflammatory markers were significantly increased in patients with ICP. PLR, WBC, and MPV were all significantly increased, whereas the RDW was significantly decreased in ICP. MPV was related to the severity of disease and might be a valuable marker for ICP disease severity in the future. Ethics Ethics Committee Approval: This study was approved by the Zeynep Kamil Women and Children’s Health Training and Research Hospital Local Ethics Committee (approval number: 136). Informed Consent: Consent form was filled out by all participants. Peer-review: External and internal peer-reviewed. Authorship Contributions Surgical and Medical Practices: Ç.Y.A., F.V., O.P., Ç.K., Concept: Ç.Y.A., F.V., Design: Ç.Y.A., F.V., Data Collection or Processing: Ç.Y.A., E.B.E., İ.Y., A.E., O.P., Analysis or Interpretation: Ç.Y.A., F.V., E.B.E., Literature Search: Ç.Y.A., İ.Y., Ç.K., Writing: Ç.Y.A., F.V. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study received no financial support. Table 1 The basal characteristics of mild (n=53) and severe (n=31) intrahepatic cholestasis of pregnancy Table 2 The comparison of the laboratory findings between patients with mild and severe intrahepatic cholestasis of pregnancy Table 3 The comparison of obstetric outcomes in mild (n=53) and severe (n=31) intrahepatic cholestasis of pregnancy Table 4 The comparison of hematologic indices between control and intrahepatic cholestasis of pregnancy group Table 5 The comparison of inflammatory markers

PRECIS: The prevalence of anemia at the time of pregnancy detection was 20% and this is close to the rates of developed countries. INTRODUCTION It has been demonstrated that anemia in pregnancy is one of the main health problems and affects the results of pregnancy negatively(1). The prevalence of anemia is still in question in our country(2). Anemia can be classified as acquired or hereditary. Deficiency anemia (iron, folate, and vitamin B12), anemias depending on blood loss, chronic disease anemias, acquired hemolytic anemias, and aplastic anemia can be considered as acquired anemias, whereas sickle cell anemia, thalassemia, and Fanconi anemias are considered as hereditary anemias(3). Iron-deficiency anemias (IDA) are responsible for more than half of all cases in all regions worldwide (where malaria is not an endemic). In pregnancy, the most frequently encountered anemia is IDA(4).

cquired anemias, whereas sickle cell anemia, thalassemia, and Fanconi anemias are considered as hereditary anemias(3). Iron-deficiency anemias (IDA) are responsible for more than half of all cases in all regions worldwide (where malaria is not an endemic). In pregnancy, the most frequently encountered anemia is IDA(4). Anemia in the 1st and 3rd trimester of pregnancy was defined by the Centers for Disease Control and Prevention in 1989 as hemoglobin (Hb) or hemotocrit less than 11 g/dL or 33%, respectively, and when the level of Hb or hemotocrit is less than 10.5 g/dL or 32%, respectively, in the 2nd trimester of pregnancy(1). According to the World Health Organization (WHO), anemia in pregnancy in any trimester is considered when the level of Hb in less than 11 g/dL(4). This definition was made in 2001 and is still valid today. When the level of Hb is less than 7 g/dL during pregnancy, it is considered as severe anemia and medical treatment is required. It has been revealed that anemia observed in the first trimester of pregnancy enhances the possibility of premature birth and low birth weight, as well as low APGAR scores(5,6). In our study, we aimed to identify the prevalence of anemia in patients at the time of pregnancy detection.

Anemia in the 1st and 3rd trimester of pregnancy was defined by the Centers for Disease Control and Prevention in 1989 as hemoglobin (Hb) or hemotocrit less than 11 g/dL or 33%, respectively, and when the level of Hb or hemotocrit is less than 10.5 g/dL or 32%, respectively, in the 2nd trimester of pregnancy(1). According to the World Health Organization (WHO), anemia in pregnancy in any trimester is considered when the level of Hb in less than 11 g/dL(4). This definition was made in 2001 and is still valid today. When the level of Hb is less than 7 g/dL during pregnancy, it is considered as severe anemia and medical treatment is required. It has been revealed that anemia observed in the first trimester of pregnancy enhances the possibility of premature birth and low birth weight, as well as low APGAR scores(5,6). In our study, we aimed to identify the prevalence of anemia in patients at the time of pregnancy detection. MATERIALS AND METHODS This study is a retrospective cross sectional study that was designed to detect anemia prevalence of 5228 pregnant women who presented because of delayed menstrual periods and were diagnosed as being pregnant between 2012 and 2014. Hb levels of 11 to 9.5 g/dL, from 9.5 to 8 g/dL and less than 8 g/dL were considered as mild, moderate, and severe anemia, respectively(7,8). Pregnants were classified into 4 groups according to their Hb levels as follows; group 1: severe anemia, group 2: moderate anemia, group 3 mild anemia, and group 4 as normal (Hb levels 11 g/dL or higher).

L, from 9.5 to 8 g/dL and less than 8 g/dL were considered as mild, moderate, and severe anemia, respectively(7,8). Pregnants were classified into 4 groups according to their Hb levels as follows; group 1: severe anemia, group 2: moderate anemia, group 3 mild anemia, and group 4 as normal (Hb levels 11 g/dL or higher). The complete blood count of the women was measured using an automated blood analyzer (Beckman-Coulter, USA). The three-year results were evaluated and classified according to their Hb levels. We did not report the risk factors and independent predictors of anemia. This study was approved by the Etimesgut Military Hospital Local Ethics Committee (approval number 8000-11-12) and all women who accepted to take part gave written informed consent before enrollment in the study. Statistical Analysis The collected data were analyzed using the Statistical Package for Social Sciences version 14.0 (SPSS Inc., Chicago, USA). Continuous variables are expressed as mean ± standard deviation, whereas categorical variables are denoted as numbers or percentages where appropriate. RESULTS Groups 1, 2, 3, and 4 comprised 15, 161, 870, and 4182 patients, respectively. The average age was 30.2±4.75 years and the average Hb was 11.8±1.15 g/dL in our population (Table 1) (Figure 1). In groups 1, 2, 3, and 4, the average ages were 30.4±7.14, 30.2±5.42, 30.1±4.4, 30.2±4.7 years, respectively. The respective Hb levels in each group were 7.5±0.35, 9.0±0.34, 10.4±0.4, and 12.3±0.80 g/dL (Table 2).

RESULTS Groups 1, 2, 3, and 4 comprised 15, 161, 870, and 4182 patients, respectively. The average age was 30.2±4.75 years and the average Hb was 11.8±1.15 g/dL in our population (Table 1) (Figure 1). In groups 1, 2, 3, and 4, the average ages were 30.4±7.14, 30.2±5.42, 30.1±4.4, 30.2±4.7 years, respectively. The respective Hb levels in each group were 7.5±0.35, 9.0±0.34, 10.4±0.4, and 12.3±0.80 g/dL (Table 2). In our population, when pregnancy was diagnosed, 16.64% (n=870) were considered as having mild anemia, 3.07% (n=161) had moderate anemia, and 0.28% (n=15) had severe anemia (Table 2). The overall anemia prevalence at the time of pregnancy diagnosis was 20.0% (n=1046). When the Hb levels were considered according to the age interval of the women, anemia prevalence was close to 20% in those aged 25-34 years (Table 3). Of the pregnant women, 7.3%, 21%, 20.5%, 19.9%, and 13.9% had anemia in the age groups 17-19 years, 20-24 years, 25-29 years, 30-34 years, and over 40 years, respectively (Table 3) (Figure 2).

considered according to the age interval of the women, anemia prevalence was close to 20% in those aged 25-34 years (Table 3). Of the pregnant women, 7.3%, 21%, 20.5%, 19.9%, and 13.9% had anemia in the age groups 17-19 years, 20-24 years, 25-29 years, 30-34 years, and over 40 years, respectively (Table 3) (Figure 2). DISCUSSION Anemia in pregnancy is a global public health problem. The prevalence is 18% in developed countries, whereas it is between 35-75% in developing countries(9). In developing countries, it has been estimated that 460 million women of reproductive age are anaemic, 2/3 of whom are in Asia. It is known that prevalence of anemia in pregnancy is 42% worldwide, the lowest being 6% in North America and the highest is 75% in Gambia(3). The prevalence of anemia in pregnancy is 25.1% in Europe, and around 24.1% in America(10). In a study perfomed in China with 88149 pregnant women, the prevelance of anemia in the first trimester was determined as 22%(5).

egnancy is 42% worldwide, the lowest being 6% in North America and the highest is 75% in Gambia(3). The prevalence of anemia in pregnancy is 25.1% in Europe, and around 24.1% in America(10). In a study perfomed in China with 88149 pregnant women, the prevelance of anemia in the first trimester was determined as 22%(5). In our country, in a study performed in 2006 in which 586 pregnant women were included, the prevalence of anemia was determined as 74.1%(2). In that study, the threshold Hb level for anemia was taken as 11 g/dL(2). This level is close to that of underdeveloped countries. The prevalance of anemia in pregnancy in Turkey was determined as 40.2% by the WHO according to data observed before 2000(3). In some Turkish studies, the prevalance of anemia during pregnancy was identified as 29.4% in Afyon, whereas it was 42.4% in Elazığ(11,12). In a study by Karaoglu et al.(13) with 823 pregnants, the prevalence of anemia was detected as 27.1%. The study was performed in Malatya and the Hb level was accepted as 11 g/dL(13). In the present study, the prevalence of anemia in pregnancy was determined as 20% in 5228 pregnant women in Ankara. In the study performed by Karaoglu et al.(13), it was found that 0.48% of the pregnant women had severe anemia (under 8 g/dL); this rate was 0.28% in our study. This may be due to differences between patient populations in Ankara and Malatya.

f anemia in pregnancy was determined as 20% in 5228 pregnant women in Ankara. In the study performed by Karaoglu et al.(13), it was found that 0.48% of the pregnant women had severe anemia (under 8 g/dL); this rate was 0.28% in our study. This may be due to differences between patient populations in Ankara and Malatya. When anemia prevalence was considered according to age intervals, Karaoglu et al.(13) found that the rate was about 30% in pregnant women aged 30-39 years, wheras it was around 20% in our study for women aged 20-39 years. In a study by Pirinçci et al.(12) that included data before 2001 in 465 pregnant women in Elazığ, it was shown that 42.4% (n=197) of patients had anemia (Hb levels below 11 g/dL); 44.8% of these were observed in the first trimester. Beside this, the authors reported the incidence of anemia as 59.4% for patients aged 19 years and below, 40.8% in the 20-29 years age group, 39.5% in the 30-39 years age group, and 25.0% in the >40 years age group(12).

f patients had anemia (Hb levels below 11 g/dL); 44.8% of these were observed in the first trimester. Beside this, the authors reported the incidence of anemia as 59.4% for patients aged 19 years and below, 40.8% in the 20-29 years age group, 39.5% in the 30-39 years age group, and 25.0% in the >40 years age group(12). In our 2011-2015 data, the anemia prevalance was detected as 7.3% in patients aged 19 years and below, 26.1% in the 20-29 years age group, 24.8% in the 30-39 years age group, and 13.9% in the >40 years age group. In our study, the prevalence of anemia “at the time of pregnancy diagnosis” was determined as 20.1% because fertility is higher between the ages of 20-39 years. When our results are compared with those of Pirinçci et al.(12), one might conclude that the prevalence of anemia decreased by half during this 10-year period. The effect of socioeconomic differences between Elazığ and Ankara and the presence of a more conscious pregnant population could also account for this difference. It was revealed that the incidence of anemia during pregnancy increased as pregnancy advanced (1.8% in the first trimester, 8% in the second trimester, and 27% in the third trimester)(14). In the studies mentioned above, the measurements for determining the prevalance of anemia were performed with regard to the number of weeks’ pregnancy. However, in our study, the prevalance of anemia was investigated in pregnant women in the first trimester only, and this could account for the differences between the rates observed in the indicated studies and our study.

determining the prevalance of anemia were performed with regard to the number of weeks’ pregnancy. However, in our study, the prevalance of anemia was investigated in pregnant women in the first trimester only, and this could account for the differences between the rates observed in the indicated studies and our study. Anemia in the first trimester of pregnancy increases the risk of preterm birth, small-for-gestational-age births, and intrauterine growth restriction(15). For mothers, severe anemia is an important risk factor for morbidity and mortality in developing countries. The risk of operative birth and prolonged delivery increases in cases of severe anemia(15). Study Limitations This study has a limitation, the anemia prevalence in pregnancy “at the time of pregnancy diagnosis” was detected as 20% and this was close to the rates of developed countries. However, this rate could be related to the patient population of Ankara where the socioeconomic level is higher in comparison with other regions of our country. CONCLUSION Anemia in pregnancy is a global public health problem and early diagnosis and treatment are both maternally and perinatally important. Detecting patients with anemia in the preconceptional period and/or delaying pregnancy until optimal Hb levels are reached will lower this rate. Ethics Ethics Committee Approval: The study was approved by the Etimesgut Military Hospital Local Ethics Committee (approval number: 8000-11-12). Informed Consent: Consent form was filled out by all participants. Peer-review: External and internal peer-reviewed. Authorship Contributions

CONCLUSION Anemia in pregnancy is a global public health problem and early diagnosis and treatment are both maternally and perinatally important. Detecting patients with anemia in the preconceptional period and/or delaying pregnancy until optimal Hb levels are reached will lower this rate. Ethics Ethics Committee Approval: The study was approved by the Etimesgut Military Hospital Local Ethics Committee (approval number: 8000-11-12). Informed Consent: Consent form was filled out by all participants. Peer-review: External and internal peer-reviewed. Authorship Contributions Surgical and Medical Practices: M.Ö., Ö.Ö., M.U., E.K., T.Ö., A.A., Concept: M.Ö., Ö.Ö., M.U., E.K., Design: M.Ö., Ö.Ö., M.U., E.K., T.Ö., M.Y., A.A., F.F., Data Collection or Processing: M.Ö., Ö.Ö., A.A., F.F., S.B., Analysis or Interpretation: M.Ö., Ö.Ö., M.U., E.K., Literature Search: M.Ö., Ö.Ö., M.U., E.K., T.Ö., M.Y., A.A., F.F., S.B., Writing: M.Ö., Ö.Ö., M.U., E.K., F.F. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study received no financial support. Table 1 Age and hemoglobin parameters of the participants Table 2 Age and hemoglobin parameters of the participants according severity groups Table 3 Distribution of pregnant women with anemia according to age ranges Figure 1 Distrubition of hemoglobin parameters of the pregnant women Figure 2 Distribution of pregnant women according to age and hemoglobin parameters

PRECIS: Vaginally-assisted laparoscopic sacrohysteropexy is a safe, minimally-invasive procedure in uterovaginal prolapse. Twelve months postoperatively, this procedure showed favorable anatomic and functional results.

PRECIS: Vaginally-assisted laparoscopic sacrohysteropexy is a safe, minimally-invasive procedure in uterovaginal prolapse. Twelve months postoperatively, this procedure showed favorable anatomic and functional results. INTRODUCTION Uterovaginal prolapse is a frequently encountered condition especially among older women, which may lead to disability and poor quality of life(1), and it is a major indication for gynecologic surgery. The lifetime risk for a woman to have uterine prolapse surgery is 11%(1). Risk of developing this kind of disorder increases with advancing age(2). Surgery should be performed to restore anatomy with minimal morbidity and the lowest risk of recurrence. Three different approaches have been introduced to repair the pelvic floor such as abdominal, vaginal, and laparoscopic techniques. Hysterectomy is still considered to be the standard procedure for correcting uterovaginal prolapse(3); however, in the majority of cases, hysterectomy does not overcome abnormalities associated with weakened pelvic support structures such as uterosacral and cardinal ligaments(4). Additionally, due to the belief that the uterus plays a role in sexual satisfaction, an increasing number of women avoid undergoing hysterectomy(5). Hysterectomy was shown to be associated with increased morbidity, blood loss, operative time, and influence post-operative recovery time(6). Sacrospinous hysteropexy has been proposed to be an alternative approach for uterine-preserving prolapse surgery(7). Other management alternatives include transvaginal mesh kits(8,9), abdominal sacrohysteropexy using mesh(10), and laparoscopic uterine suspension using a sling(11) or mesh(12). A modified form of uterine-preserving prolapse surgery using a combined vaginal and laparoscopic approach was introduced and a series of 70 women was reported by Fayyad and Siozos(13).

nsvaginal mesh kits(8,9), abdominal sacrohysteropexy using mesh(10), and laparoscopic uterine suspension using a sling(11) or mesh(12). A modified form of uterine-preserving prolapse surgery using a combined vaginal and laparoscopic approach was introduced and a series of 70 women was reported by Fayyad and Siozos(13). In this case series, we describe the safety, feasibility, and outcomes of a modified form of a combined vaginal and laparoscopic approach, vaginally-assisted laparoscopic sacrohysteropexy (VALSH) for treating advanced uterovaginal prolapse. MATERIALS AND METHODS This study is a descriptive prospective case series of 33 women with symptomatic stage 3 or 4 uterine prolapse on the pelvic organ prolapse-quantification (POP-Q) prolapse examination system(14) who underwent VALSH between 2012 and 2015 in Zeynep Kamil Women and Children’s Health Training and Research Hospital. The procedure was approved by the Zeynep Kamil Women and Children’s Health Training and Research Hospital Local Ethics Committee (approval number: 2015/195) and informed consent forms were obtained from each patient. This new alternative of surgical intervention was offered to women with advanced uterine prolapse. Inclusion criteria were as follows: (1) Symptomatic uterine prolapse > stage 3; (2) symptoms of pelvic organ prolapse such as vaginal bulge and heaviness.

MATERIALS AND METHODS This study is a descriptive prospective case series of 33 women with symptomatic stage 3 or 4 uterine prolapse on the pelvic organ prolapse-quantification (POP-Q) prolapse examination system(14) who underwent VALSH between 2012 and 2015 in Zeynep Kamil Women and Children’s Health Training and Research Hospital. The procedure was approved by the Zeynep Kamil Women and Children’s Health Training and Research Hospital Local Ethics Committee (approval number: 2015/195) and informed consent forms were obtained from each patient. This new alternative of surgical intervention was offered to women with advanced uterine prolapse. Inclusion criteria were as follows: (1) Symptomatic uterine prolapse > stage 3; (2) symptoms of pelvic organ prolapse such as vaginal bulge and heaviness. Women were asked to empty their bladder before examination. All examinations were performed while the women were in the lithotomy position. The women were asked to perform a maximum Valsalva maneuver before genital examination. Stages of uterine prolapse were determined according to the POP-Q classification. Preoperatively, all patients underwent POP-Q questionnaires to assess prolapsed-related symptoms(15). After determining the surgical indication and following preoperative preparations, the procedure was performed under general anesthesia with the patient initially in the lithotomy position. Thirty-three women with stage 3 or more uterine prolapse underwent VALSH operations. Patients were followed up over a 12-month period after surgery for mesh-related complications and improvements of symptoms.

ons, the procedure was performed under general anesthesia with the patient initially in the lithotomy position. Thirty-three women with stage 3 or more uterine prolapse underwent VALSH operations. Patients were followed up over a 12-month period after surgery for mesh-related complications and improvements of symptoms. The operation consisted of three sections; 1st laparoscopy, 2nd vaginal, 3rd laparoscopy. Laparoscopic ports were placed; one 10-mm port for umbilical and two or three 5-mm ports for lateral or suprapubic sites based upon conditions in order to achieve optimal surgical site exposure. The peritoneum over the sacral promontory was incised. A small 5-cm tunnel was made underneath the peritoneum from the sacral promontory downward to the cervix. Then, a lightweight type of mesh was placed onto the promontorium surface. Second, the vaginal part of the surgery was performed. A semicircular incision was made at the posterior cervicovaginal junction. Curved ring forceps were placed into the retroperitoneal area via a tunnel established through blunt dissection from the vaginal part towards the promontory. At the same time, the direction of the instrument was visualized via laparoscopy (Figure 1). When the tip of the ring forceps was observed through the incision in the promontorium, the mesh was grasped and pulled downward within the tunnel with the aid of an instrument. The mesh was then fixed onto the posterior face of the uterine cervix using 3-4 non-absorbable sutures via the vaginal route (Figure 2). The vaginal incision was closed by absorbable sutures.

ough the incision in the promontorium, the mesh was grasped and pulled downward within the tunnel with the aid of an instrument. The mesh was then fixed onto the posterior face of the uterine cervix using 3-4 non-absorbable sutures via the vaginal route (Figure 2). The vaginal incision was closed by absorbable sutures. Finally, the uterus was pushed up to the maximum level using a Rubin’s cannula to obtain the required uterine suspension and mesh was tacked/sutured to the anterior longitudinal ligament at the sacral promontory and the peritoneal membrane over the promontory was sutured via the laparoscopic approach. A transobturator tape insertion procedure was applied in patients with stress urinary incontinence diagnosed before the operation through appropriate urogynecologic tests. A post-operative examination was performed in the lithotomy position using the POP-Q system. Mesh complications including mesh exposure were noted. Statistical Analysis Data were analyzed using SPSS version 15.0 for Windows (SPSS Inc., Chicago, Illinois). The pre- and post-operative data were compared using the Wilcoxon t-rank test, and p values of <0.05 were considered significant.

Finally, the uterus was pushed up to the maximum level using a Rubin’s cannula to obtain the required uterine suspension and mesh was tacked/sutured to the anterior longitudinal ligament at the sacral promontory and the peritoneal membrane over the promontory was sutured via the laparoscopic approach. A transobturator tape insertion procedure was applied in patients with stress urinary incontinence diagnosed before the operation through appropriate urogynecologic tests. A post-operative examination was performed in the lithotomy position using the POP-Q system. Mesh complications including mesh exposure were noted. Statistical Analysis Data were analyzed using SPSS version 15.0 for Windows (SPSS Inc., Chicago, Illinois). The pre- and post-operative data were compared using the Wilcoxon t-rank test, and p values of <0.05 were considered significant. RESULTS The mean age, gravidity, and parity of the study population were 46.5 years (range, 25-68 years), 4.3 (1-9), and 2.9 (1-6), respectively (Table 1). The mean operation time was 59.5 min (range, 20-120 min). Pre- and post-operative symptoms are shown in Table 2. The comparison of pre- and post-operative hemoglobin levels with the parameters of POP-Q values are summarized in Table 3. The rates of pre-operative prolapse stages were 4Ba (n=12, 36.3%), stage 4C (n=10, 30.3%), stage 3 Ba (n=3, 9.1%), stage 3C (n=3, 9.1%), stage 4 Bp (n=2, 6.1%), stage 4D (n=2, 6.1%), and stage 3 Bp (n=1, 3%). There were significant differences between the pre- and post-operative values of POP-Q parameters, which were favorable in the latter evaluation (p<0.001); total vaginal length was preserved after surgery (p>0.05). Among 33 women, stress urinary incontinence was determined in 12 patients by prolapse reduction testing (36.4%) managed by combined VALSH and transobturator tape insertion procedures. No perioperative complications were observed. There were five patients with cervical elongation concomitant with the uterine prolapse. At 12 months after surgery, all 33 patients reported cure of their prolapse symptoms with a subjective cure rate of 100%. None of the patients developed de novo urgency, infection or mesh erosion following surgery during the follow-up period. On assessing the patients’ global impression of improvement, all 33 women reported feeling either “very much better” or “much better.” No recurrence or mesh complication was observed after 12 months’ follow-up.

patients developed de novo urgency, infection or mesh erosion following surgery during the follow-up period. On assessing the patients’ global impression of improvement, all 33 women reported feeling either “very much better” or “much better.” No recurrence or mesh complication was observed after 12 months’ follow-up. DISCUSSION In this case series, we wanted to show the feasibility of a new technique of VALSH. Data from our series show this technique to be feasible, safe, and easy to perform. It has several advantages over conventional techniques and recently introduced new vaginal-assisted laparoscopic approaches. There is still no consensus on the optimal management of advanced uterine prolapse. Vaginal hysterectomy has been proposed to be a standard procedure in these cases. In order to avoid removing a healthy organ and increasing morbidity and mortality with the hysterectomy procedure and also preserve fertility, uterine-preserving approaches were introduced a few decades ago(10,11,12).

ed uterine prolapse. Vaginal hysterectomy has been proposed to be a standard procedure in these cases. In order to avoid removing a healthy organ and increasing morbidity and mortality with the hysterectomy procedure and also preserve fertility, uterine-preserving approaches were introduced a few decades ago(10,11,12). With the recent advances in endoscopic surgery, some laparoscopic uterine suspension techniques have been described(16,17,18). According to the accumulated data, independent from the removal of the uterus, apical suspension is the required step for successful outcomes(19). Recent studies showed some advantages of sacrohysteropexy including low recurrence rates, absence of mesh erosion, preserving an adequate vaginal length, and maintaining the proper physiological vaginal axis(3). Additionally, laparoscopic hysteropexy was shown to be associated with better anatomic cure rates of higher than 90% in the majority of the studies. There was an improvement in symptoms, and cure rates of 73-100% among the patients. Reoperation rates and complication rates were generally low(20).

gical vaginal axis(3). Additionally, laparoscopic hysteropexy was shown to be associated with better anatomic cure rates of higher than 90% in the majority of the studies. There was an improvement in symptoms, and cure rates of 73-100% among the patients. Reoperation rates and complication rates were generally low(20). Furthermore, endoscopic approaches have some well-defined advantages including quicker recovery and a reduction in adhesion formation(12,13). Additionally, current laparoscopic techniques provide better and magnified visualization of the anatomy and better hemostasis resulting from intraperitoneal gas pressure(13). In the literature, one of the techniques of laparoscopic ventrosuspension of uterus used the rectus sheath for this purpose. However, according to the reports from the literature, it had unsatisfactory results(21). On the other hand, uterosacral plication and suture hysteropexy were reported to have 80% success rates(19,22). Recently, total laparoscopic hysteropexy by mesh placement from the upper part of the cervix to the sacral promontory was developed(12). In addition, a published cohort study on the long-term outcomes of laparoscopic versus vaginal mesh hysteropexy revealed high satisfaction rates for both procedures(23). Most hysteropexy techniques have been shown to have high satisfaction and low reoperation rates. It was reported that the type of hysteropexy and possible graft configuration may impact reoperation rates for recurrent prolapse. Furthermore, authors claimed that vaginal mesh risks and the possibility of future hysterectomy with mesh-associated risks should also be considered(24). Moreover, relative to conventional laparoscopic sacral hysteropexy, total laparoscopic hysterectomy with laparoscopic sacrocolpopexy procedures were shown to have similar anatomic results, excellent patient satisfaction, and improved quality of life scores(25). Therefore, some modified forms of laparoscopic hysteropexy operations have been introduced.

l laparoscopic sacral hysteropexy, total laparoscopic hysterectomy with laparoscopic sacrocolpopexy procedures were shown to have similar anatomic results, excellent patient satisfaction, and improved quality of life scores(25). Therefore, some modified forms of laparoscopic hysteropexy operations have been introduced. In their series, Fayyad and Siozos(13) aimed to report the results of a novel technique of hysteropexy using vaginal dissection and mesh placement and fixation of mesh to the sacral promontory via a laparoscopic view. It had some advantages as well as efficacy, especially in patients with cervical elongation and the extra-peritoneal attachment of the mesh to the cervix eliminated the risk of compromise of uterine blood flow. On the other hand, the theoretical disadvantage of this technique is that the insertion of the mesh vaginally can result in increased infection and mesh exposure rates(13).

nts with cervical elongation and the extra-peritoneal attachment of the mesh to the cervix eliminated the risk of compromise of uterine blood flow. On the other hand, the theoretical disadvantage of this technique is that the insertion of the mesh vaginally can result in increased infection and mesh exposure rates(13). In their study, Fayyad and Siozos(13) showed that their technique called “VALUES” was free from increased risk of vaginal shortening and narrowing. In addition, the procedure was shown to result in shorter hospital stay and quicker recovery(13). Sacral colpopexy was reported to have a lower risk of recurrent prolapse on examination, redo surgery for prolapse, post-operative stress urinary incontinence, and dyspareunia than a variety of vaginal interventions. However, there is limited evidence to support the use of transvaginal mesh for apical vaginal prolapse repair. There is no consensus on the best access routes for sacral colpopexy. Moreover, there is no clear conclusion on the comparison between uterine-preserving surgery and vaginal hysterectomy for uterine prolapse(26). Recent studies indicated the necessity of randomized controlled studies to show the benefits of laparoscopic sacrocervicopexy with or without supracervical hysterectomy in terms of surgical outcomes and reduced risk of mesh erosion compared with sacrocolpopexy and concomitant total hysterectomy(25,27). Pelvic organ prolapses and stress urinary incontinence were reported to coexist in 80% of patients with pelvic floor dysfunction(28). We detected coexistence of pelvic organ prolapses and stress urinary incontinence in 36.4% of cases, which was managed through transobturator tape insertion.

t total hysterectomy(25,27). Pelvic organ prolapses and stress urinary incontinence were reported to coexist in 80% of patients with pelvic floor dysfunction(28). We detected coexistence of pelvic organ prolapses and stress urinary incontinence in 36.4% of cases, which was managed through transobturator tape insertion. The most difficult part of the procedure during conventional sacrohysteropexy is to dissect the peritoneum down to the cervix. Hemorrhage during this dissection further deteriorates tissue exposure. Furthermore, this partially blinded dissection increases the risk of hypogastric nerve plexus injury. The cervical region in which the mesh is inserted is very close to the rectum, which further makes the procedure difficult. Also, it is difficult to fix the mesh low enough to the cervix in patients with cervical elongation, which results in unsatisfactory results. Study Limitations This study has some limitations, one of them is small sample size and study needs longer follow-up duration. CONCLUSION VALSH is a safe, minimally-invasive procedure in uterovaginal prolapse that preserves the uterus, enables future normal vaginal delivery, and has shown favorable anatomic and functional outcomes at 12 months follow-up including zero recurrence rates. Ethics Ethics Committee Approval: The study was approved by the Zeynep Kamil Women and Children’s Health Training and Research Hospital Local Ethics Committee (approval number: 2015/195). Informed Consent: Consent form was filled out by all participants. Peer-review: External and internal peer-reviewed. Authorship Contributions

Ethics Ethics Committee Approval: The study was approved by the Zeynep Kamil Women and Children’s Health Training and Research Hospital Local Ethics Committee (approval number: 2015/195). Informed Consent: Consent form was filled out by all participants. Peer-review: External and internal peer-reviewed. Authorship Contributions Surgical and Medical Practices: İ.S., M.P., Concept: İ.S., Design: İ.S., Data Collection or Processing: İ.S., Ç.K., M.P., E.Ö., M.D., A.K., Analysis or Interpretation: E.Ö., İ.S., Literature Search: E.Ö., İ.S., Writing: E.Ö., İ.S., M.D., S.G.K. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study received no financial support. Table 1 Summary of some demographic features of the study population Table 2 Summary of pre- and post-operative urogynecologic symptoms of the whole study population Table 3 Comparison summary of pre- and post-operative pelvic organ prolapse-quantification classification parameters Figure 1 Laparoscopic view of curved ring forceps put into the retroperitoneal space via incision performed on the posterior wall of cervix Figure 2 Cervical incision performed on the posterior wall where curved ring forceps are introduced and later mesh is fixed by 2-0 non-absorbable sutures x4

PRECIS: Scar endometriosis is a condition seen in women during their reproductive period, excision is required by obtaining secure margins in the treatment. Introduction Endometriosis is a condition seen in women during their reproductive period in which both the stromal tissue and the functional endometrial glands are observed outside the uterine cavity. It mostly occurs through iatrogenic seeding in the wake of obstetric and gynecologic surgeries. Patients generally present to general surgery clinics(1). Although endometriosis is often found in the pelvic cavity, it may also show localization outside the pelvic region, such as the heart, lungs, liver, kidneys, central nervous system, and the abdominal wall. Even though the endometrium is found in areas outside its normal localization, endometriotic foci still contain normal endometrial tissue. For this reason, they perform a menstrual cycle as an organ functioning within itself. During menstrual periods, thickening, destruction, and menstrual bleeding also occur almost always in these areas, just as in the endometrium. Perhaps the only difference of scar endometriosis from the endometrial tissue inlaid within the uterus is that it fails to drain the blood formed there.

nctioning within itself. During menstrual periods, thickening, destruction, and menstrual bleeding also occur almost always in these areas, just as in the endometrium. Perhaps the only difference of scar endometriosis from the endometrial tissue inlaid within the uterus is that it fails to drain the blood formed there. Though several theories have been reported as to its formation, the theory of direct implantation is the most recognized(2). Ectopic endometriosis foci do not generally show the tendency to become malignant(3). Various broad series in the literature have addressed why the incidence of the disease in question is rare(4). In this study, we aimed to identify the clinical characteristics of our patients who underwent surgery due to scar endometriosis and to discuss the surgical results in light of the literature. Materials and Methods Data of 29 patients who underwent surgery in the Clinic of General Surgery Haseki Training and Research Hospital between January 2012 and June 2016 with preoperative diagnoses of scar endometriosis, which were confirmed by pathology, were retrospectively examined. Of the 29 patients, five were excluded from the study due to a lack of abdominal magnetic resonance imaging (MRI). All the demographic data, symptoms at the time of presentation, imaging reports including both ultrasonography (USG) and MRI, and pathology reports were retrospectively reviewed. The study was approved by the Haseki Training and Research Hospital Local Ethics Committee (approval number: 367). Informed consent was obtained from all subjects.

ta, symptoms at the time of presentation, imaging reports including both ultrasonography (USG) and MRI, and pathology reports were retrospectively reviewed. The study was approved by the Haseki Training and Research Hospital Local Ethics Committee (approval number: 367). Informed consent was obtained from all subjects. Statistical Analysis Data concerning demographic and clinical characteristics were analyzed using descriptive methods (means, minimum-maximum). The statistical software used was SPSS for Windows, version 15.0 (SPSS Inc., Chicago, IL, USA). Results The mean age of the patients was 31 years (range, 21-40 years). Thirteen (54.2%) patients had presented to the general surgery outpatient clinic and 11 (45.8%) had presented to the gynecology clinic. Twenty-one (87.5%) patients had a painful mass in their previous surgery area, and three (12.5%) had pain only in their previous surgery area. The pain was cyclical in 19 (79.2%) of the patients, whereas it was non-cyclical in six (20.8%). The mean duration of symptoms was 19.8 months (range, 9-31 months). The number of previous ceserean sections in the subjects were as follows: one section in nine patients (37.5%), two in 12 patients (50%), and three in three patients (12.5%). The mean greatest diameter of the endometriotic masses was 39.1 mm (range, 21-54 mm) on USG, and 37.5 mm (range, 21-55 mm) on MRI.

9-31 months). The number of previous ceserean sections in the subjects were as follows: one section in nine patients (37.5%), two in 12 patients (50%), and three in three patients (12.5%). The mean greatest diameter of the endometriotic masses was 39.1 mm (range, 21-54 mm) on USG, and 37.5 mm (range, 21-55 mm) on MRI. Endometriosis was detected on the left side of the incisions of 13 patients (54.2%), whereas it was found on the right side of the incisions of 11 (45.8%) patients. A solid heterogeneous mass detected in 22 (91.6%) patients, an incisional hernia was detected in one (4.2%), and a mass sporadically containing a solid area suggestive of an abscess was detected in one (4.2%). Three (12.5%)  patients underwent surgery due to incisional hernia, whereas 21 (87.5%) patients underwent surgery due to the pre-diagnoses of a tumour on the anterior abdominal wall (Figure 1). During the operations of patients with pre-diagnoses of incisional hernia, a hernia sac and masses adhered to the hernia sac were detected. The masses along with the hernia sac were excised. The defects formed as the result of excising the mass were sutured primarily and then repaired. As the result of the pathology examination, it was reported that all lesions were accordant with endometriosis and that the mean weight of the excised lesions was 61.6 g (range, 46-73 g). None of the patients had any post-operative complications. The patients’ mean hospitalizaiton period was 2 days (range, 1-5 days). The mean follow-up period was 22 months (range, 6-51 months), and no recurrence was detected in any patients (Table 1).

t the mean weight of the excised lesions was 61.6 g (range, 46-73 g). None of the patients had any post-operative complications. The patients’ mean hospitalizaiton period was 2 days (range, 1-5 days). The mean follow-up period was 22 months (range, 6-51 months), and no recurrence was detected in any patients (Table 1). Discussion Endometrioma is defined as endometriosis that forms a mass with a smooth boundary. Although scar endometriosisis can be seen after cesarean surgeries, it may also develop after hysterectomy, hysterotomy, tubal surgeries, appendectomy, trocar-site, amniocentesis, and episiotomy(5,6,7). There have been many theories put forward in terms of its etiopathogenesis. Scar endometriosis is accepted to be formed through the iatrogenic auto-transplantation of endometrial cells during surgery(8,9,10). It can be seen in the lungs, liver, kidneys, ureters, central nervous system, abdominal scar tissues, and in the extremities, apart from in pelvic organs(2,4). Even though scar endometriosis may occur months(11) and even years after gynecologic surgery, the mean occurrence period is 30 months. Elabsi et al.(12) reported an abdominal wall endometrioma that occurred in the wake of a cesarean surgery performed 22 years previously. In our series, the postsurgical period of the patients was 19.8 months (range, 9-31 months) on average.

Discussion Endometrioma is defined as endometriosis that forms a mass with a smooth boundary. Although scar endometriosisis can be seen after cesarean surgeries, it may also develop after hysterectomy, hysterotomy, tubal surgeries, appendectomy, trocar-site, amniocentesis, and episiotomy(5,6,7). There have been many theories put forward in terms of its etiopathogenesis. Scar endometriosis is accepted to be formed through the iatrogenic auto-transplantation of endometrial cells during surgery(8,9,10). It can be seen in the lungs, liver, kidneys, ureters, central nervous system, abdominal scar tissues, and in the extremities, apart from in pelvic organs(2,4). Even though scar endometriosis may occur months(11) and even years after gynecologic surgery, the mean occurrence period is 30 months. Elabsi et al.(12) reported an abdominal wall endometrioma that occurred in the wake of a cesarean surgery performed 22 years previously. In our series, the postsurgical period of the patients was 19.8 months (range, 9-31 months) on average. The incidence of scar endometriosis has been reported to be between 0.03% and 1.7%(13). The most frequent finding is cyclical or non-cyclical painful mass(14,15). At the onset of symptoms, patients are often diagnosed as having inguinal hernia, incisional hernia, and abdominal wall tumors, after which they may be exposed to unnecessary interventions. Accordingly, failure to perform the necessary treatment, or any delay in performing the treatment may also cause emotional and physical stress in patients(16). During the definitive diagnosis; lipoma, granuloma, sebaceous cyst, neuroma, hernia, hematoma, lymphadenopathy, lymphoma, desmoid tumors and sarcomas on the abdominal wall must also be considered(2,4,17). In our study, 13 (54.2%) patients presented to general surgery clinics and 11 (45.8%) presented to gynecology outpatient clinics.

initive diagnosis; lipoma, granuloma, sebaceous cyst, neuroma, hernia, hematoma, lymphadenopathy, lymphoma, desmoid tumors and sarcomas on the abdominal wall must also be considered(2,4,17). In our study, 13 (54.2%) patients presented to general surgery clinics and 11 (45.8%) presented to gynecology outpatient clinics. Andolf et al.(18) in their prospective study in which 578.785 patients were incorporated, detected endometriosis in 749 of 130.305 (0.6%) patients who had given birth through cesarean section. In their study, it was reported that there was no difference in terms of the risk of the development of endometriosis between those who underwent cesarean once and those who had a history of more than one cesarean; however, it was also reported that the risk of endometriosis in those who gave birth through cesarean section was twice as much when compared with those who had vaginal birth. In our series, there was a history of cesarean section in all patients, none had had vaginal births.

ho had a history of more than one cesarean; however, it was also reported that the risk of endometriosis in those who gave birth through cesarean section was twice as much when compared with those who had vaginal birth. In our series, there was a history of cesarean section in all patients, none had had vaginal births. In the evaluation of the mass, USG, computed tomography, and MRI are not examinations that establish the final diagnosis, but provide information about the location of the mass as well as its size and volume. USG and MRI are often the preferable methods for diagnosis (Figure 2,3,4). Differences in size in radiologic imaging may vary depending on the day of the menstrual cycle, the ratio of stromal and glandular elements, the amount of bleeding, and the inflammatory response in the peripheral tissue. Though hypoechoic, a vascularized nodule is seen in USG, it can also be seen as cystic, polycystic or heterogeneous echo. The advantage of MRI over USG is its ability to distinguish masses that imitate endometriosis on the abdominal wall.

, the amount of bleeding, and the inflammatory response in the peripheral tissue. Though hypoechoic, a vascularized nodule is seen in USG, it can also be seen as cystic, polycystic or heterogeneous echo. The advantage of MRI over USG is its ability to distinguish masses that imitate endometriosis on the abdominal wall. In general, biopsy is not required because anamnesis, physical examination, and imaging methods are adequate in the diagnosis of endometriosis. Biopsy is only performed under conditions in which malignancy is suspected. The diagnosis-establishing value of fine needle aspiration biopsy is low. Nevertheless, it is still recommended in scar endometriosis due to its convenience. For a final diagnosis, an accurate pathologic analysis is required. The pathologic detection of glandular epithelial cells, spindle or oval stromal cells, and hemosiderin-laden macrophages allows for establishing a diagnosis(19,20) (Figure 5). On the other hand, because incisional biopsy will cause endometriosis to spread even further, some studies have advised against performing this procedure(2,3,4,21). In our study, neither incisional biopsy nor fine needle aspiration was performed. Apart from the fact that there are two types of treatment options in pelvic cases, which involve medical and surgical methods, neither of them is an effective method of treatment on its own. However, surgery in scar endometriosis, as is also seen in our surgical series, is the gold standard treatment approach. Medical treatment, on the other hand, must be reserved for patients who cannot undergo surgery.

h involve medical and surgical methods, neither of them is an effective method of treatment on its own. However, surgery in scar endometriosis, as is also seen in our surgical series, is the gold standard treatment approach. Medical treatment, on the other hand, must be reserved for patients who cannot undergo surgery. Surgical excision with at least a 1 cm margin boundary should be performed to prevent recurrence in surgical treatment, in addition, some part of the neighbouring structures, such as fascia or muscle, also needs to be excisedl. Thus, the recurrence of endometriosis in the wound area will be prevented by means of the transplantation of microscopic endometrial tissue residuals. In the event that the invasion depth into structures of the abdominal wall causes large defects after surgery, a repair with synthetic materials should be performed(22,23). In our case series, a large excision was performed in 5 patients because the masses had invaded the peritoneal surface, and the large defect area formed on the abdominal wall after the operation was supported with Prolene mesh. If no residual tissue is left inside in scar endometriosis, no additional treatment is required. The recurrence rates after total excision is quite low. In our series, no recurrence was seen during follow-up. Study Limitations The small patient population and the retrospective nature of the study are our limitations.

Surgical excision with at least a 1 cm margin boundary should be performed to prevent recurrence in surgical treatment, in addition, some part of the neighbouring structures, such as fascia or muscle, also needs to be excisedl. Thus, the recurrence of endometriosis in the wound area will be prevented by means of the transplantation of microscopic endometrial tissue residuals. In the event that the invasion depth into structures of the abdominal wall causes large defects after surgery, a repair with synthetic materials should be performed(22,23). In our case series, a large excision was performed in 5 patients because the masses had invaded the peritoneal surface, and the large defect area formed on the abdominal wall after the operation was supported with Prolene mesh. If no residual tissue is left inside in scar endometriosis, no additional treatment is required. The recurrence rates after total excision is quite low. In our series, no recurrence was seen during follow-up. Study Limitations The small patient population and the retrospective nature of the study are our limitations. Conclusion The occurrence of endometriosis whose etiopathogenesis has not yet been fully explained is supported by most authors through the theory of iatrogenic implantation. In the patients who visit hospital with symptoms of a mass on the abdominal wall, previous obstetric and gynecologic operations as well as the medical history of a painful mass becoming increasingly severe during menstruation periods must be questioned in full. In the treatment of scar endometriosis, excision is required by obtaining a secure marginal boundary. If diagnosis can be established in advance in scar endometriosis, then the performance of unnecessary surgeries will be prevented. Studies in broad series are needed to be conducted on such diseases that are rarely observed.

treatment of scar endometriosis, excision is required by obtaining a secure marginal boundary. If diagnosis can be established in advance in scar endometriosis, then the performance of unnecessary surgeries will be prevented. Studies in broad series are needed to be conducted on such diseases that are rarely observed. Ethics Ethics Committee Approval: The study was approved by the Haseki Training and Research Hospital Local Ethics Committee (approval number: 367). Informed Consent: Consent form was completed by all participants. Peer-review: External and internal peer-reviewed. Authorship Contributions Surgical and Medical Practices: D.Y., C.T., O.D., T.D., Concept: D.Y., C.T., T.D., R.N.B., Design: C.T., T.D., A.H., M.T., R.N.B., Data Collection or Processing: C.T., O.D., A.H., M.A., M.T., Analysis or Interpretation: C.T., M.A., R.N.B., Literature Search: D.Y., C.T., O.D., A.H., M.A., M.T., Writing: D.Y., C.T., T.D. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study received no financial support. Table 1 Patient’s demographics Figure 1 Excision of scar endometriosis Figure 2 Ultrasonography Figure 3 Magnetic resonance image axial Figure 4 Magnetic resonance image coronar Figure 5 The pathologic detection of glandular epithelial cells, oval stromal cells