CC-resistant Polycystic Ovary Syndrome Research Articles

Comparative study of the efficacy of combined metformin–clomiphene citrate versus combined metformin–letrozole in induction of ovulation in overweight women with polycystic ovarian syndrome

Background Polycystic ovary syndrome (PCOS) is the common cause of infertility. Clomiphene citrate (CC) is the first-line treatment in ovulation induction. Metformin biguanide has been used in insulin resistance in PCOS women. Adding metformin to CC in the CC-resistant PCOS was highly effective in achieving ovulation in 68.6–77.7% of patients. Letrozole, aromatase inhibitor, its use in patients with CC-resistant PCOS achieved ovulation 54.6–84.4% of the time. Aim We aimed to compare the efficacy of combined metformin–CC to combined metformin–letrozole in ovulation induction in overweight infertile PCOS women. Patients and methods A prospective randomized study was conducted at Obstetrics & Gynecology Department in Tanta University Hospitals. In total, 40 infertile overweight cases with PCO were included. Cases were randomly allocated in two groups. Results The mean age was 26.40 ± 5.20 years for CC group and 26.50 ± 5.10 years for letrozole group. BMI was 27.50 ± 1.43 for CC group and 27.45 ± 1.36 for letrozole group. The duration of infertility was 2.90 ± 1.40 years for CC group and 2.88 ± 1.21 for letrozole group. There was insignificant difference in both groups as regards the follicles more than 18 mm and endometrial thickness. But, as regards progesterone level, there was a statistically significant increase in letrozole group than CC group (P<0.005). Concerning pregnancy rate, there was insignificant difference between two groups. Conclusion The present investigation demonstrated that both CC and letrozole are similarly viable in treatment of infertility in PCOS patients, when joined with metformin treatment.

Metformin plus Clomiphene Citrate versus Gonadotropins in Clomiphene Citrate- Resistant Polycystic Ovary Syndrome

Introduction: Clomiphene citrate (CC) is the first-line pharmacological therapy for ovulation induction in polycystic ovary syndrome (PCOS). However, 15%-40% of patients show CC-resistance. Different drugs and drug combinations were in trial to overcome resistance.
 Aim of the study: comparison between the metformin plus CC and low dose exogenous follicle stimulating hormone (FSH) in CC-resistant PCOS.
 Subjects and methods: A prospective comparative trial was carried out for a period of 36 months (between June 2019 to June 2022) with ovulation induction period of 3 months. It included 40 patients with CC- resistance. They were divided into 2 groups. The first received metformin plus CC and the second received low dose exogenous FSH for 3 months. The cycles were monitored by transvaginal sonography (TVS), starting on the 11th day of the cycle. The primary outcome was the successful ovulation, and the secondary outcome was the detection of pregnancy sac (clinical pregnancy).
 Results: Metformin plus CC succeeded to produce a higher rate of ovulation. However, gonadotrophins are more effective as it produced a significantly higher rate in the first cycle (45.0% vs. 15%). However, there were no significant differences at the second and third cycles. The overall ovulation rate was 60% and 80.0% in metformin-CC group compared to gonadotrophin group. The clinical pregnancy rate was 25% and 15% in groups I and II, respectively (p value >0.05). Complications were confined to gonadotrophin group (multiple pregnancy and ovarian hyperstimulation syndrome (each in one patient).
 Conclusions: Gonadotrophins are more effective than metformin plus CC in the management of CC-resistant PCOS. However, it was associated with lower clinical pregnancy rate and higher complications rate. But the difference was statistically non-significant.

Correlation of serum leptin and ghrelin levels with endocrine and reproductive parameters in women with clomiphene citrate resistant polycystic ovary syndrome.

Objective:To investigate the changes in serum ghrelin and leptin levels in patients with clomiphene-resistant polycystic ovary syndrome (PCOS).Materials and Methods:Thirty-five patients who could not achieve ovulation or pregnancy despite using 150 mg/day of clomiphene citrate (CC) participated in the study. Thirty-five patients who were compatible with the study group in terms of age and body mass index (BMI) but did not have clinical and laboratory findings of PCOS constituted the control group. On the third day of the cycle, in addition to the basal hormone profile, ghrelin and leptin levels were also measured. Patients in both groups went to IVF/ICSI. Basal hormone values, leptin, ghrelin, metabolic, demographic parameters, and clinical pregnancy rates were correlated.Results:Patients in both groups were recorded to be similar in terms of age (29.4±0.11 vs 28.5±7.30), BMI (24.3±3.07 vs 23.8±1.55), and infertility time (6.14±4.30 vs 6.03±1.28). Serum ghrelin levels of the PCOS group were significantly lower than the control group (0.48±2.21 vs 1.19±4.02) Serum leptin levels of the PCOS group were significantly higher than the control patients (45.6±304 vs 16.5±0.32). Serum leptin levels and BMI (r=0.65, p<0.01) A positive correlation was found between luteinizing hormone (LH) (r=0.53, p<0.02), and insulin resistance (r=0.74, p<0.03). There was a negative (r=-0.76, p<0.03) correlation between serum ghrelin and LH. A positive and significant correlation was found between serum ghrelin, testosterone, mature oocyte, and implantation rates.Conclusion:Serum ghrelin correlates with fertility outcomes in women with CC-resistant PCOS undergoing IVF/ICSI.

Comparison of the efficacy of letrozole stair-step protocol with clomiphene citrate stair-step protocol in the management of clomiphene citrate-resistant polycystic ovary syndrome patients.

We sought to compare the efficacy of the letrozole (LTZ) stair-step protocol with clomiphene citrate (CC) stair-step protocol in the management of 150 mg dose of CC-resistant polycystic ovary syndrome (PCOS) patients. We retrospectively compared a total of 61 patients diagnosed as being resistant to the traditional CC protocol who were subsequently managed using the LTZ stair-step protocol with CC-resistant 56 patients who were treated with CC stair-step protocol. The number of follicles ≥18 mm, endometrial thickness, time to ovulation, clinical pregnancy rates, multiple pregnancy rates, spontaneous abortion rates, live birth rates, and systemic side effects in patients were evaluated. The mean time to ovulation was significantly shorter in the LTZ stair-step group than the CC stair-step group (17.3 ± 7.7 and 22.4 ± 8.1 days, respectively, p < 0.001). The ovulation rate was significantly higher in patients treated with LTZ stair-step protocol than those treated with the CC stair-step protocol (83.6% and 64.2%, respectively, p=0.007). The clinical pregnancy rate was higher in the LTZ stair-step than the CC stair-step group (32.7% and 17.8%, respectively, p=0.015). LTZ stair-step group had a significantly higher live birth rate than that of the CC stair-step group (27.8% and 14.2%, respectively, p=0.012). The LTZ stair-step protocol revealed higher ovulation, clinical pregnancy, and live birth rates with a shorter time to achieve ovulation than the CC stair-step protocol. Increment of the dose in the same cycle in both protocols did not cause any additional severe side effects.

Impact of Cyproterone Acetate and Ethinylestradiol on Clomiphene Resistant PCOS Patient with High Serum AMH level

Background: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. PCOS is characterized by hyperandrogenism and oligomenorrhea, and Polycystic ovary .It is a common cause of female subfertility. Anti-mullerianhormone (AMH) is 2-4 times higher in patients with PCOS compared to normal subfertilety patient.&#x0D; Objective: To assess the impact of metformin and oral contraceptives (OCs) containing cyproterone acetate and ethinyl estradiol on serum anti-Mullerian hormone (AMH) levels, with CC resistant polycystic ovary syndrome (PCOS)&#x0D; Methods: This prospective randomized controlled trial was conducted at Bangabandhu Sheikh Mujib Medical University(BSMMU), Dhaka during the preoid of January 2019 to june 2019. Already diagnosed patients of polycystic ovary syndrome with subfertility with high serum AMH level more than 5 ng/ml attending in the OPD of Reproductive Endocrinology and infertility department at BSMMU are the study population. Total 60 subjects fulfilling rotardum criteria and who are treated with 3 cycle CC with 100mg /day for 5 days from day 2 of menstrual cycle but fail to ovulate were recruited for the current study. Those subjects with tubal, and male factors excluded from the study. .After enrollment of the patients, randomization will be carried out by blocked randomization method to divide them equally into two groups-Group A number of patients 30 ( treated with2mg cyproterone acetate (CPA) and 35 mcg of ethinylestradiol (EE) and Group B number of patients 30 treated with Metformin). Group A patients will receive treatment with 2mg cyproterone acetate (CPA) and 35 mcg of ethinylestradiol (EE) for 6 months and Group B patients will receive treatment with Metformin for 6 months . After enrollment of the patients, base line hormonal assessment basal level of FSH, LH ,thyroid-stimulating hormone (TSH), prolactin (PRL), and testosterone hormones were registered and metabolic assessment included OGTT and fasting insulin level were done, and to identify the changes in clinical and biochemical profile of study population. Clinical evaluation, by history and examination, transvaginal ultrasonography of both group and changes of the above mentioned parameters of both group were recorded after 6 month of completion of treatment.&#x0D; Results: A Changes in clinical parameters (Acne, BMI, Menestrual cycle) was recorded every three monthly for 6 month. Changes of biochemical parameters (serum LH (D2), serum FSH (D2), serum testosterone, OGTT and fasting insulin), serum AMH were recorded every three monthly for 6 month. Changes of sonographic parameters (ovarian volume, Antral follicular count development, was done monthly for 6 cycles. AMH levels are significantly reduced under treatment with OCP containing 35mg ethinylestradiol plus 2 mg cyproteroneacetate than metformin. AMH was significantly decreased after treatment with 35 mg ethinylestradiol plus 2 mg cyproterone acetate ( p &lt; 0.001 at 6 months). and treatment with metformin did not significantly affect serum AMH levels. AMH was significantly decreased after treatment with metformin (p &lt; 0.005). Serum LH was and OGTT was significantly decreased in both treatment p&lt;0.001.&#x0D; Conclusion(s:) AMH serum levels were significantly decreased under treatment with 35mg ethinylestradiol plus 2mg cyproterone acetate, due to decrease in androgens and suppression of gonadotropins(LH).&#x0D; J Shaheed Suhrawardy Med Coll, December 2020, Vol.12(1); 38-44

Controlled ovarian hyperstimulation with gonadotropins for Clomiphene Citrate resistant Polycystic ovary syndrome leads to a higher risk of ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) caused by controlled ovarian hyperstimulation ,although usually regressingspontaneously, may occasionally occur with clomiphene citrate, typically with gonadotropin, which sometimes results in seriouscomplications. 25-year-old patient was followed up in our hospital due to OHSS. Since our patient was Clomiphene Citrate (CC)resistant Polycystic ovary syndrome (PCOS), follitropin alpha was started. Firstly, treatment started from 75 IU rFSH. Increasedto 150 IU on day 15, if no improvement in the ovaries. Due to the development of two 18 mm follicles on the 21 st day and theE2 value being 773 pg/mL, human chorionic gonadotropin (hCG) was applied and insemination was performed. Patients with CCresistant PCOS represent a challenge for reproductive medicine. We propose a calculated low-dose stimulation strategy with step-up according to ovarian response in gonadotropins protocols. If the treatment period is extended and the dose is increased; Even ifthe follow-up values are normal, the patient should be closely monitored to avoid OHSS.

Molecular Mechanisms of Laparoscopic Ovarian Drilling and Its Therapeutic Effects in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy, characterized by chronic anovulation, hyperandrogenism, and multiple small subcapsular cystic follicles in the ovary during ultrasonography, and affects 5–10% of women of reproductive age. PCOS is frequently associated with insulin resistance (IR) accompanied by compensatory hyperinsulinemia and, therefore, presents an increased risk of type 2 diabetes mellitus (DM). The pathophysiology of PCOS is unclear, and many hypotheses have been proposed. Among these hypotheses, IR and hyperandrogenism may be the two key factors. The first line of treatment in PCOS includes lifestyle changes and body weight reduction. Achieving a 5–15% body weight reduction may improve IR and PCOS-associated hormonal abnormalities. For women who desire pregnancy, clomiphene citrate (CC) is the front-line treatment for ovulation induction. Twenty five percent of women may fail to ovulate spontaneously after three cycles of CC treatment, which is called CC-resistant PCOS. For CC-resistant PCOS women, there are many strategies to improve ovulation rate, including medical treatment and surgical approaches. Among the various surgical approaches, one particular surgical method, called laparoscopic ovarian drilling (LOD), has been proposed as an alternative treatment. LOD results in an overall spontaneous ovulation rate of 30–90% and final pregnancy rates of 13–88%. These benefits are more significant for women with CC-resistant PCOS. Although the intra- and post-operative complications and sequelae are always important, we believe that a better understanding of the pathophysiological changes and/or molecular mechanisms after LOD may provide a rationale for this procedure. LOD, mediated mainly by thermal effects, produces a series of morphological and biochemical changes. These changes include the formation of artificial holes in the very thick cortical wall, loosening of the dense and hard cortical wall, destruction of ovarian follicles with a subsequently decreased amount of theca and/or granulosa cells, destruction of ovarian stromal tissue with the subsequent development of transient but purulent and acute inflammatory reactions to initiate the immune response, and the continuing leakage or drainage of “toxic” follicular fluid in these immature and growth-ceased pre-antral follicles. All these factors contribute to decreasing local and systemic androgen levels, the following apoptosis process with these pre-antral follicles to atresia; the re-starting of normal follicular recruitment, development, and maturation, and finally, the normalization of the “hypothalamus–pituitary–ovary” axis and subsequent spontaneous ovulation. The detailed local and systematic changes in PCOS women after LOD are comprehensively reviewed in the current article.

Randomized controlled open-label study of the effect of vitamin E supplementation on fertility in clomiphene citrate-resistant polycystic ovary syndrome.

To evaluate the effect of vitamin E on ovulation and pregnancy in women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). A prospective, randomized, controlled, open label study was conducted on women with CC-resistant PCOS. Patients were randomized, to either control group (n = 30), who received metformin 500 mg thrice daily, in addition to 150 mg/day CC for 5 days starting from day 3 of menstruation for three menstruation cycles, or vitamin E group (n = 30) who received vitamin E 1500 IU/day for the whole study period in addition to metformin and CC with the same previous regimen. The primary outcome was cumulative ovulation rate, while secondary outcomes were pregnancy rate, serum midluteal progesterone, mean follicular diameter, number of dominant follicles and endometrial thickness. Ovulation was reported in 57 (64.8%) of 88 cycles in the control group and 63 (73.3%) of 86 cycles in the vitamin E group (P = 0.227), while pregnancy was reported in 4 (4.5%) of 88 cycles in the control group and 6 (7%) of 86 cycles in the vitamin E group (P = 0.491).There were nonsignificant differences between groups regarding serum midluteal progesterone, number of dominant follicles and mean follicular diameter. Endometrial thickness was significantly higher in the vitamin E group compared to the control group. The findings of this trial do not support the hypothesis that vitamin E may increase the ovulation and pregnancy rates in women with clomiphene citrate-resistant PCOS.

Does ischaemia-modified albumin level predict clomiphene citrate resistant polycystic ovary syndrome patients?

This study aims to examine the role of ischaemic-modified albumin (IMA) in predicting clomiphene citrate (CC) resistance in patients with CC-resistant and CC-sensitive infertile polycystic ovary syndrome (PCOS). Sixty women patients admitted to the infertility clinic were evaluated. The patients were divided into two groups. Group 1 comprised 30 infertile PCOS patients with CC resistance; group 2 was the control group comprising 30 infertile PCOS patients with CC sensitivity. Serum IMA levels of PCOS patients with CC resistance were significantly higher than CC sensitivity patients (p < .001). The independent variables BMI and age effects were adjusted according to the logistic regression method with groups. Significant differences were observed between the two groups in the levels of IMA (p = .0005), HOMA-IR (p = .0045), insulin (p = .022), free testosterone (p = .0001) and total testosterone (p = .03) values. By using ROC curve analysis for IMA between study and control groups, cut off point of IMA was calculated as 0.505 U/mL, sensitivity was 80% and specificity was 63%. The area under the curve was 0.926. This shows us that more oxidative stress (OS) occurs in the CC-resistant group. As a reflection of OS in the follicular endocrine, microenvironment may be linked with impaired oocyte developmental competence and embryo quality in association with increased IMA, free testosterone, total testosterone, insulin and HOMA-IR levels. Impact statement What is already known on this subject? In previous studies, IMA was compared between PCOS and control groups. In this study, serum IMA levels were measured in infertile PCOS patients resistant to CC for the first time. What the results of this study add? Serum IMA levels were significantly higher in resistant infertile PCOS patients compared to the control group. This shows us that more OS occurs in the CC-resistant group. What the implications are of these findings for clinical practice and/or further research? IMA will be a guide for PCOS management in patients with CC-resistant PCOS.

Comparison of pregnancy outcomes in CC resistance PCOS patients undergoing CC plus letrozole and intra uterine insemination treatment with different follicular diameters

Aim: Using Clomiphene citrate (CC) plus letrozole combination to determine the effect of follicular diameter on pregnancy outcomes in CC resistance Polycystic ovary syndrome (PCOS) patients during intra uterine insemination cycles. Material and Methods: The records of infertile patients who presented to the outpatient clinic were retrospectively analysed. PCOS was diagnosed in 536 (23%) patients, 71 (18%) of whom had CC-resistant PCOS using CC plus letrozole. The patients were divided into two groups; follicular diameter 17-19 mm (group 1, n = 31) and 20-22 mm (group 2, n = 40).Results: The pregnancy rate in group 1 was 20% (6/30), the abortion rate was 17% (1/6), and the multiple pregnancy rate was 17% (1/6). In group 2, the pregnancy rate was 17% (7/41), the abortion rate was 14% (1/7) and the multiple pregnancy rate was 14% (1/7). There was no statistically significant between-group difference in the pregnancy (p =0.3), abortion (p = 0.8) or multiple pregnancy rates (p =0.8).Conclusion: In PCOS patients with CC plus letrozole and intra uterine insemination ovulation induction, pregnancy rate is not related to follicular size between 17-22 mm on hCG day. Although there was no direct relationship between follicular size and endometrial thickness, it was found that delaying HCG was not significant for better results.

Medical and Surgical Treatment of Reproductive Outcomes in Polycystic Ovary Syndrome: An Overview of Systematic Reviews.

Polycystic ovary syndrome (PCOS) is a common, complex condition that affects up to 18% of reproductive- aged women, causing reproductive, metabolic and psychological dysfunctions. We performed an overview and appraisal of methodological quality of systematic reviews that assessed medical and surgical treatments for reproductive outcomes in women with PCOS. Databases (MEDLINE, EMBASE, CINAHL PLUS and PROSPERO) were searched on the 15th of September 2017. We included any systematic review that assessed the effect of medical or surgical management of PCOS on reproductive, pregnancy and neonatal outcomes. Eligibility assessment, data extraction and quality assessment by the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool were performed in duplicate. We identified 53 reviews comprising 44 reviews included in this overview; the majority were moderate to high quality. In unselected women with PCOS, letrozole was associated with a higher live birth rate than clomiphene citrate (CC), while CC was better than metformin or placebo. In women with CC-resistant PCOS, gonadotrophins were associated with a higher live birth rate than CC plus metformin, which was better than laparoscopic ovarian drilling (LOD). LOD was associated with lower multiple pregnancy rates than other medical treatments. In women with PCOS undergo- ing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI), the addition of metformin to gonadotro- phins resulted in less ovarian hyperstimulation syndrome (OHSS), and higher pregnancy and live birth rates than gonadotrophins alone. Gonadotrophin releasing hormone (GnRH) antagonist was associated with less OHSS, gonadotrophin units and shorter stimulation length than GnRH agonist. Letrozole appears to be a good first line treatment and gonadotrophins, as a second line treatment, for anovulatory women with PCOS. LOD results in lower multiple pregnancy rates. However, due to the heterogeneous nature of the included popula- tions of women with PCOS, further larger scale trials are needed with more precise assessment of treatments according to heterogeneous variants of PCOS.

The Prevalence of Incidental Endometriosis in Women Undergoing Laparoscopic Ovarian Drilling for Clomiphene-Resistant Polycystic Ovary Syndrome: A Retrospective Cohort Study and Meta-Analysis.

To evaluate the incidence of endometriosis in polycystic ovary syndrome (PCOS) patients who did not present with any endometriosis symptoms and underwent laparoscopic ovarian drilling (LOD) for clomiphene citrate (CC) resistance, 225 and 630 women with CC-resistant PCOS without classic endometriosis symptoms were included in a retrospective study and a meta-analysis, respectively. All women underwent LOD. The main outcome parameter was the prevalence of incidental endometriosis. Laparoscopy revealed endometriosis in 38/225 (16.9%) women (revised American Fertility Society (rAFS) stage I: 33/38, 86.8%; rAFS stage II: 5/38, 13.2%). When women with CC-resistant PCOS without endometriosis were compared, lower body mass index (BMI) and lower 25-hydroxy-vitamin D levels were associated with the presence of endometriosis at laparoscopy (odds ratios (OR): 0.872, 95% confidence intervals (95%CI): 0.792–0.960; p = 0.005 and OR: 0.980, 95%CI: 0.962–0.999; p = 0.036; respectively). The inclusion criteria for the meta-analysis were fulfilled by 4/230 reports about LOD. After correction for study heterogeneity, the pooled prevalence of incidental endometriosis was 7.7% in women with CC-resistant PCOS. In conclusion, the rate of incidental endometriosis in women with CC-resistant PCOS might reflect the prevalence of asymptomatic endometriosis. All cases were affected by minimal or mild disease. Since the literature lacks reports on associated clinical outcomes, the relevance of this entity in such patients should be the subject of further studies.

Randomized controlled trial of N-acetylcysteine versus l-carnitine among women with clomiphene-citrate-resistant polycystic ovary syndrome.

To compare clinical and metabolic profiles between N-acetylcysteine and l-carnitine among women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). A randomized trial at Zagazig University between January 2017 and March 2018. Women with CC-resistant PCOS were allocated randomly to receive CC plus N-acetylcysteine or CC plus l-carnitine. The primary outcome was clinical pregnancy rate; secondary outcomes were ovulation rate and metabolic changes. Overall, 162 women completed the study (N-acetylcysteine group, n=82; l-carnitine group, n=80). After 3months, there was no difference in pregnancy (P=0.15), ovulation (P=0.21), or spontaneous abortion (P=0.11) rates between the two groups. There was no significant decrease in BMI in either group (both P>0.05). There were improvements in menstrual pattern, follicle-stimulating hormone, luteinizing hormone, free testosterone, and insulin resistance markers in both groups (all P<0.05). An improvement in lipid profile was observed only in the l-carnitine group (P<0.001). N-Acetylcysteine treatment led to significantly greater improvement in free testosterone and insulin resistance parameters as compared with l-carnitine (all P<0.05). Both N-acetylcysteine and l-carnitine were equally effective in improving pregnancy and ovulation rates among women with CC-resistant PCOS. However, N-acetylcysteine was superior in ameliorating insulin resistance and only l-carnitine improved lipid profile. ClinicalTrials.gov: NCT03164421.

Comparison of Clinical, Metabolic, Hormonal, and Ultrasound Parameters among the Clomiphene Citrate-Resistant and Clomiphene Citrate-Sensitive Polycystic Ovary Syndrome Women.

Objective:The objective of the study is to compare the clinical, metabolic, hormonal, and ultrasound parameters among the clomiphene citrate (CC)-sensitive and CC-resistant polycystic ovary syndrome (PCOS) women.Materials and Methods:This was a prospective observational study.Setting:The study was conducted at the infertility outpatient department in a government hospital.Sample Size:A total of 164 women with PCOS-related infertility were included.Intervention:Incremental dose of CC from 50 mg/day to 100 mg/day to 150 mg/day over three cycles was given.Response:Ovulation was the outcome. Those who failed to ovulate with 150 mg CC were CC resistant.Results:Of the total 164 PCOS women, 88 (53.7%) were CC resistant and 76 (46.3%) were CC sensitive. Of the 76 PCOS women who ovulated, maximum, i.e., 37 (22.6%) women ovulated with 100 mg CC. The most common diagnostic feature of PCOS in this study was hyperandrogenism (96.3%). CC-resistant PCOS women had significantly higher weight, waist circumference, waist-hip ratio, and body mass index (BMI). Significantly longer menstrual cycles and hyperandrogenism were significantly more common in CC-resistant group. CC-resistant group had a significantly higher ovarian reserve (ovarian volume, antral follicle count, and anti-Müllerian hormone values). Baseline luteinizing hormone (LH) values and LH-follicle stimulating hormone ratio were significantly higher in the CC-resistant group.Conclusion:Clomiphene-resistant PCOS women have significantly higher hyperandrogenism, longer cycles, more deranged metabolic profile, higher BMI, and ovarian reserve. These differences should be kept in mind while deciding the ovulation induction protocol.

Impact of Ultrasound-Guided Transvaginal Ovarian Needle Drilling Versus Laparoscopic Ovarian Drilling on Ovarian Reserve and Pregnancy Rate in Polycystic Ovary Syndrome: A Randomized Clinical Trial

Study ObjectiveTo compare the impact of ultrasound-guided transvaginal ovarian needle drilling (TND) versus laparoscopic ovarian drilling (LOD) on ovarian reserve and pregnancy rate in patients with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). DesignA randomized clinical trial (Canadian Task Force classification I). SettingA university hospital. PatientsOf 644 patients who presented at an infertility clinic, 246 with CC-resistant PCOS were randomized for treatment. InterventionsPatients were randomly allocated to ultrasound-guided TND (n = 124) and LOD (n = 122). Measurements and Main ResultsOvarian reserve parameters (serum antimüllerian hormone [AMH] and antral follicle count [AFC]) and pregnancy rate at 3 and 6 months were evaluated. At 3 months, patients in the LOD group experienced a significantly lower AMH (p < .001) and a higher ovulation rate (p < .05) with comparable AFC and pregnancy rate to patients in the TND group (p > .05) and a significant decrease in AMH and AFC within each individual group when compared with baseline (p < .001). At 6 months, patients in the LOD group experienced a significantly lower AMH (p < .001), lower AFC (p < .001), higher ovulation rate (p < .001) and higher pregnancy rate (p < .001) when compared with patients in the TND group. This effect started to diminish between the fourth and sixth month with an increase of AMH and AFC compared with baseline values (p < .05). ConclusionsAlthough TND is simple, safe, and less invasive than LOD, its effect on ovarian reserve appears to be transient and diminishes at 6 months. Multicenter studies are warranted to confirm efficacy as a second-line treatment in patients with CC-resistant PCOS.

Effects of clomiphene citrate for prevention of premature luteinizing hormone surge in those undergoing intrauterine insemination outcome: A randomized, double-blind, placebo-controlled trial.

The objective of the study is to determine the effects of clomiphene citrate (CC) on preventing premature luteinizing hormone (LH) surge in infertile patients with polycystic ovary syndrome (PCOS) undergoing intrauterine insemination (IUI). This was a randomized clinical trial being performed at Shiraz Mother and Child Hospital. We included 162 women with PCOS selected for IUI cycles. Patients were randomly allocated to receive 150 mg/day CC from the 8th of the cycle though the day of human chorionic gonadotropin (hCG) injection (n = 81) or nothing in the same period (n = 81). Main outcomes included the incidence of premature LH surge, pregnancy rate, abortion and ongoing pregnancy rates, number of maturing follicles, and endometrial thickness. The incidence of premature LH surge was significantly lower in those who received CC (3.0% vs. 14.9%; P = 0.021). The pregnancy rate was 10 (15.1%) and 6 (8.9%) in CC and control groups, respectively (P = 0.342). The ongoing pregnancy rate found to be comparable between two study groups (12.1% vs. 5.9%; P = 0.068). Serum level of estradiol (E2) level at the time of hCG administration was significantly higher in those who were treated with CC when compared to control (1153.5 ± 326.4 vs. 943.2 ± 215.3; P < 0.001). Patients who received CC also had higher number of mature follicles >18 mm when compared to controls (3.85 ± 1.3 vs. 2.94 ± 1.01; P < 0.001). Administration of CC from the 8th day of the cycle to the day of hCG injection in combination with Gonal-f in infertile patients with CC-resistant PCOS undergoing IUI cycles is associated with decreased incidence of premature LH surge, higher E2levels, and higher number of mature ovarian follicles. This protocol is safe and simple and could be considered to be cost-effective.

Short term effects of laparoscopic ovarian drilling in clomiphene citrate resistant patients with polycystic ovary syndrome

Abstract Objective The study aims to assess the effect of laparoscopic ovarian drilling (LOD) in clomiphene citrate resistant patients with polycystic ovary syndrome (PCO) on the changes occurred in ovarian reserve. Study design A prospective cohort study. Setting Sohag University Hospital, Sohag, Egypt. Materials and methods Thirty-seven patients with PCO were enrolled in the study. We evaluated the effect of LOD on the ovarian reserve using hormonal assay (measuring FSH, LH, AMH, Testosterone, SHBG, E2 and FAI) and sonographic markers (including ovarian volume, antral follicle count (AFC) and ovarian stromal blood flow). Results Amongst the 37 patients underwent LOD, regulation of the cycle occurred in 20 patients after 6 months (54.06%) (p = 0.001). Occurrence of pregnancy occurred in 4 patients after three months and in 18 patients after 6 months. As regard the hormonal profile, LOD has reducing effect on the serum levels of FSH, LH, AMH, SHBG, Testosterone and free androgen index. This reduction is of statistically significance in case of LH, AMH, testosterone and FAI especially after 6 months (p = 0.01, 0.001, 0.05, 0.05 respectively). The deleterious effect of LOD was statistically significant in the AFC which was reduced from 18.1 ± 2.7 to 11.5 ± 1.8 after 6 months (p = 0.05). Also, the ovarian blood flow indices were reduced with p = 0.01 for all indices. Conclusions Using the AMH and AFC as reliable markers of the ovarian reserve and measuring them for women with anovulatory PCO undergoing LOD may provide a useful tool in evaluating the outcome of LOD as the gold standard treatment for CC resistant PCO women.

Altered Circulating Inflammatory Cytokines Are Associated with Anovulatory Polycystic Ovary Syndrome (PCOS) Women Resistant to Clomiphene Citrate Treatment.

BackgroundPolycystic ovary syndrome (PCOS) is a common gynecological disease characterized by chronic oligoanovulation, clinical/biochemical hyperandrogenism, polycystic ovaries, and insulin resistance. Accumulating evidence has shown that PCOS-related ovarian dysfunction is the main cause of anovulatory infertility. Clomiphene citrate (CC) is the first-line therapy for PCOS patients; however, approximately 15–40% PCOS patients are resistant to CC treatment. It has been demonstrated that PCOS is a chronic pro-inflammatory state, as some pro-inflammatory cytokines were elevated in the peripheral circulation of PCOS patients, but whether altered inflammatory cytokines expression in PCOS patients is associated with blunted response to CC remains unknown.Material/MethodsWe recruited 44 CC-resistant PCOS patients, along with 55 age and body mass index (BMI)-matched CC-sensitive PCOS patients. Ovulation was induced by administrating 50–100 mg/day CC on days 5 to 9 of each menstrual cycle. The cytokine profiles were detected by cytokine antibody microarrays and further validated by ELISAs.ResultsCC-resistant patients had higher levels of high-sensitivity C-reactive protein (hsCRP) than the CC-sensitive individuals. A growth factor, angiopoietin-2, was significantly reduced [1.64 (0.93–1.95) vs. 1.08 (0.85–1.34), p<0.05], while a chemokine CXCL-16 was significantly increased (9.10±2.35 vs. 10.41±2.82, p<0.05) in CC-resistant patients compared to the CC-sensitive subjects. CXCL-16 was positively correlated with hsCRP (r=0.33, p<0.01). Logistic regression analysis showed that angiopoietin-2 and CXCL-16 are associated with CC resistance.ConclusionsCirculating cytokines are disturbed in CC-resistant PCOS patients. Altered angiopoietin-2 and CXCL-16 levels might compromise the responsiveness of the ovary to CC through up-regulating angiogenesis and inflammation.

Letrozole versus laparoscopic ovarian drilling in infertile women with PCOS resistant to clomiphene citrate

Abstract Objective To compare the efficacy of letrozole and laparoscopic ovarian drilling (LOD) in the induction of ovulation in women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). Subjects and methods A total of 80 women with CC-resistant PCOS were enrolled and randomly allocated into groups A and B. Group A (n = 40) underwent LOD, and group B (n = 40) received 2.5 mg letrozole from days 3 to 7 of menses for up to six cycles. A 6-month follow-up was performed. Results No statistically significant differences were found in the baseline clinical characteristics and the major serum hormone profiles, women receiving letrozole had a higher rate of ovulation (70 vs. 57.5%) and however, the differences were not statistically significant also there is significant decrease in MAH in group A. The pregnancy rate was 27.5% in group A versus 35% in group B and abortion rate was 18% in group A versus 7% in the other group. Conclusion Letrozole had superior reproductive outcomes compared with LOD in women with CC-resistant PCOS and seems to be a suitable first-line ovulation induction instead of LOD in those patients.

Cost effectiveness of letrozole and purified urinary FSH in treating women with clomiphene citrate-resistant polycystic ovarian syndrome: a randomized controlled trial

We aimed to compare the cost effectiveness of letrozole versus purified urinary follicle stimulating hormone (FSH) in treating patients with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). This was a randomized trial conducted in Cairo University and Beni-Suef University Hospitals, Egypt. A cohort of 140 eligible women was randomized to receive either letrozole 2.5 mg twice daily for five days, or FSH using a graduated regimen starting with a dose of 75 IU. Treatment was repeated for three months if pregnancy did not occur. There were no significant differences between the two treatments in the cumulative clinical pregnancy rate (30% vs. 34%; p = 0.578), cumulative ovulation rate (47% vs. 57%; p = 0.236), miscarriage rate (9% vs. 4%, p > 0.999) or multiple pregnancy rate (0% and 8%, p = 0.491) but the FSH cycles were 4.8 times more expensive. Letrozole and FSH were both effective in treating women with CC-resistant PCOS but letrozole was more cost effective.Study registration number: NCT02304107.