Clomiphene and other antioestrogens for ovulation induction in polycystic ovarian syndrome.

Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction, achievement of pregnancy, and live birth in Asian women with polycystic ovary syndrome: a randomized controlled trial

Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a class of drugs that were introduced for ovulation induction in 2001. Since about 2001 clinical trials have reached differing conclusions as to whether the AI letrozole is at least as effective as the first-line treatment clomiphene citrate (CC). To evaluate the effectiveness and safety of aromatase inhibitors for subfertile women with anovulatory PCOS for ovulation induction followed by timed intercourse or intrauterine insemination (IUI). We searched the following sources from inception to November 2017 to identify relevant randomised controlled trials (RCTs): the Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, Pubmed, LILACS, Web of Knowledge, the World Health Organization (WHO) clinical trials register and Clinicaltrials.gov. We also searched the references of relevant articles. We did not restrict the searches by language or publication status. We included all RCTs of AIs used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS. Two review authors independently selected trials, extracted the data and assessed risks of bias. We pooled studies where appropriate using a fixed-effect model to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for most outcomes, and risk differences (RDs) for ovarian hyperstimulation syndrome (OHSS). The primary outcomes were live birth and OHSS. Secondary outcomes were clinical pregnancy, miscarriage and multiple pregnancy. We assessed the quality of the evidence for each comparison using GRADE methods. This is a substantive update of a previous review. We identified 16 additional studies for the 2018 update. We include 42 RCTs (7935 women). The aromatase inhibitor letrozole was used in all studies.Letrozole compared to clomiphene citrate (CC) with or without adjuncts followed by timed intercourseLive birth rates were higher with letrozole (with or without adjuncts) compared to clomiphene citrate (with our without adjuncts) followed by timed intercourse (OR 1.68, 95% CI 1.42 to 1.99; 2954 participants; 13 studies; I2 = 0%; number needed to treat for an additional beneficial outcome (NNTB) = 10; moderate-quality evidence). There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate (0.5% in both arms: risk difference (RD) -0.00, 95% CI -0.01 to 0.00; 2536 participants; 12 studies; I2 = 0%; high-quality evidence). There is evidence for a higher pregnancy rate in favour of letrozole (OR 1.56, 95% CI 1.37 to 1.78; 4629 participants; 25 studies; I2 = 1%; NNTB = 10; moderate-quality evidence). There is little or no difference between treatment groups in the rate of miscarriage by pregnancy (20% with CC versus 19% with letrozole; OR 0.94, 95% CI 0.70 to 1.26; 1210 participants; 18 studies; I2 = 0%; high-quality evidence) and multiple pregnancy rate (1.7% with CC versus 1.3% with letrozole; OR 0.69, 95% CI 0.41 to 1.16; 3579 participants; 17 studies; I2 = 0%; high-quality evidence). However, a funnel plot showed mild asymmetry, indicating that some studies in favour of clomiphene might be missing.Letrozole compared to laparoscopic ovarian drillingThere is low-quality evidence that live birth rates are similar with letrozole or laparoscopic ovarian drilling (OR 1.38, 95% CI 0.95 to 2.02; 548 participants; 3 studies; I2 = 23%; low-quality evidence). There is insufficient evidence for a difference in OHSS rates (RD 0.00, 95% CI -0.01 to 0.01; 260 participants; 1 study; low-quality evidence). There is low-quality evidence that pregnancy rates are similar (OR 1.28, 95% CI 0.94 to 1.74; 774 participants; 5 studies; I2 = 0%; moderate-quality evidence). There is insufficient evidence for a difference in miscarriage rate by pregnancy (OR 0.66, 95% CI 0.30 to 1.43; 240 participants; 5 studies; I2 = 0%; moderate-quality evidence), or multiple pregnancies (OR 3.00, 95% CI 0.12 to 74.90; 548 participants; 3 studies; I2 = 0%; low-quality evidence).Additional comparisons were made for Letrozole versus placebo, Selective oestrogen receptor modulators (SERMS) followed by intrauterine insemination (IUI), follicle stimulating hormone (FSH), Anastrozole, as well as dosage and administration protocols. There is insufficient evidence for a difference in either group of treatment due to a limited number of studies. Hence more research is necessary. Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory polycystic ovary syndrome, compared to clomiphene citrate. There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate. There is high-quality evidence of no difference in miscarriage rates or multiple pregnancy rates. There is low-quality evidence of no difference in live birth and pregnancy rates between letrozole and laparoscopic ovarian drilling, although there were few relevant studies. For the 2018 update, we added good-quality trials, upgrading the quality of the evidence.

PurposeTo evaluate the efficacy of minimal stimulation using discretely administered gonadotropin combined with clomiphene citrate (CC) or letrozole (LTZ) for intrauterine insemination (IUI) cycles.Materials and MethodsTotal 257 IUI cycles from 158 infertile couples were assessed. A CC dose of 100 mg/day (n=126 cycles) or a LTZ dose of 5 mg/day (n=131 cycles) was administered on days 3-5 of the menstrual cycle for 5 days. Each group received human menopausal gonadotropin at a dose of 150 IU by two or three alternative day: CC combined with alternate-day regimen for 2 or 3 days (CC+300, n=37; CC+450, n=89) and LTZ combined with alternate-day regimen for 2 or 3 days (LTZ+300, n=36; LTZ+450, n=95).ResultsThe clinical pregnancy rate was comparable between the CC and LTZ groups (18.3% vs. 13.0%, p=0.243). The clinical pregnancy rate also showed no significant difference among the 4 groups (21.6% vs. 16.9% vs. 11.1% vs. 12.6%, p=0.507). The multiple pregnancy rate was significantly higher in LTZ compared to CC group (37.5% vs. 8.7%, p=0.028) and in the LTZ+450 compared to CC+450 group (50% vs. 13.3%, p=0.038). Overall, there were 15 cases of ovarian hyperstimulation syndrome (OHSS), with the prevalence being significantly lower in the LTZ compared to CC group (1.5% vs. 10.3%, p=0.003). OHSS was more prevalent in the CC+450 compared to the LTZ+450 group (12.4% vs. 1.1%, p=0.002).ConclusionOur findings suggest that minimal stimulation using two alternate-day gonadotropin with LTZ decreases the development of OHSS and multiple pregnancies, while maintaining comparable pregnancy rates in IUI cycles.

Aromatase inhibitors for infertility in polycystic ovary syndrome. The beginning or the end of a new era?

Comparison of efficacy of aromatase inhibitor and clomiphene citrate in induction of ovulation in polycystic ovarian syndrome

Objective To compare the effect of adjunctive use of cabergoline with clomiphene citrate (CC) in infertile polycystic ovarian syndrome (PCOS) patients with normal prolactin level. Study design A randomized clinical trial (NCT 02644304). Setting Assiut University Hospital, Assiut, Egypt. Materials and methods Infertile euprolactinemic PCOS patient were recruited and randomized in a 1:1 ratio to CC plus cabergoline or CC alone. All patients were evaluated by ultrasound examination for number, size of ovarian follicles and they were followed up for 3 consecutive cycles. The primary outcome of the study was the cumulative rate of ovulation in both groups allover the 3 cycles of treatment. The secondary outcomes included clinical pregnancy rate, miscarriage rate, multiple pregnancy rate, ovarian hyperstimulation rate and the rate of adverse effects of the study medications. Results One-hundred thirty patients were included (65 in each group). No statistical difference between both groups regarding the basal criteria. The cumulative ovulation rate in the CC plus cabergoline group was 76.7% versus 58.3% in the CC group (p = .032). Additionally, the largest follicle size in each cycle was significantly more in the CC plus cabergoline group (p Conclusions The use of cabergoline with CC in induction of ovulation in euprolactinemic infertile women with PCOS results in high ovulation rate, high pregnancy rate as compared to use of CC alone.

Use of an aromatase inhibitor in patients with polycystic ovary syndrome: a prospective randomized trial

Study question Does Letrozole have better offerings while being compared to Clomiphene citrate as an Ovulation inducing agent in infertile women? Summary answer Compared to clomiphene, Letrozole - an aromatase inhibitor, is associated with higher live-birth and ovulation rates among infertile women. What is known already Anovulatory dysfunction is a common problem and is responsible for about 40% of female infertility and among causes; PCOS (polycystic ovarian syndrome) is the leading cause. Clomiphene citrate has been traditionally used as the drug of choice for treatment of women with anovulatory infertility. In the last decade, an aromatase inhibitor, letrozole, has emerged as an alternative ovulation induction agent among anovulatory women with polycystic ovarian syndrome. Letrozole has a definitive role in anovulatory women who have not responded to clomiphene citrate therapy, as confirmed by literature. Study design, size, duration Randomized double-blind study. Total 100 women were randomly assigned and divided into 2 groups of 50 patients each. The 2 groups were well matched at baseline. Study participants are of age 20 to 39 years. Study began in October 2019 and was completed in October 2021. Participants/materials, setting, methods Group 1: Clomiphene citrate (100 mg daily) and group 2: letrozole (5 mg daily), started from any day between 3-5 of the menstrual cycle and continued up to 5 consecutive days. Both groups have received Estradiol Valerate 4 mg on the 12th day of menstruation until 16th day of menstruation. All patients had USG monitoring of follicular and endometrium size with perifollicular flow and uterine scoring system for reproduction (USSR) score with timed intercourse. Main results and the role of chance Women who received letrozole as compared to those who received clomiphene citrate had more cumulative live births (36 of 50 [72%] vs. 28 of 50 [56%]). Number of women ovulated in Letrozole group was – 42 (84%) while in Clomiphene citrate (CC) Group it was 39 (78%). The ovulation rate was significantly higher with letrozole than with clomiphene citrate. Among the study participants who ovulated, there was a significantly greater chance of singleton pregnancy with letrozole compared to clomiphene citrate. The mean number of dominant follicles (18 mm) was 1.40 ± 0.58 for letrozole and 1.10 ± 0.86 for clomiphene citrate (P-value = <0.05). The size of follicular development by day 14 was 17.6 ± 2.92 mm in Letrozole group while in Clomiphene citrate group it was 15.8 ± 3.84 mm (P-value = <0.05). The mean endometrial thickness by day 14 was 7.2 ± 0.77 mm for Letrozole and 6.8 ± 0.92 mm for clomiphene citrate (P-value = <0.05). Limitations, reasons for caution In our study, we have not considered lifestyle intervention before enrolment; although such interventions are recommended by experts, but there is currently no evidence from high quality clinical trials that they improve pregnancy outcomes in obese women. Wider implications of the findings Although Letrozole has still not gained universal acceptance as an ovulating agent for a variety of reasons, emerging evidences suggests that Letrozole could be an effective option and is non inferior to clomiphene citrate as an ovulating agent especially, in patients with non- responders to Clomiphene citrate and PCOS women. Trial registration number Not applicable

Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a novel class of drugs that were introduced for ovulation induction in 2001. Over the last ten years clinical trials have reached differing conclusions as to whether the AI letrozole is at least as effective as the first-line treatment clomiphene citrate (CC). To evaluate the effectiveness and safety of aromatase inhibitors for subfertile women with anovulatory PCOS. We searched the following sources from inception to 24/10/2013 to identify relevant randomised controlled trials (RCTs): the Menstrual Disorders and Subfertility Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO, Pubmed, LILACS, Web of Knowledge, the World Health Organisation (WHO) clinical trials register and Clinicaltrials.gov. Furthermore, we manually searched the references of relevant articles.The search was not restricted by language or publication status. We included all RCTs of aromatase inhibitors used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS. Two review authors independently selected trials, extracted the data and assessed trial quality. Studies were pooled where appropriate using a fixed effect model to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs) for most outcomes and risk differences (RDs) for ovarian hyperstimulation syndrome (OHSS). The primary outcomes were live birth and OHSS. Secondary outcomes were pregnancy, miscarriage and multiple pregnancy. The quality of the evidence for each comparison was assessed using GRADE methods. We included 26 RCTs (5560 women). In all studies the aromatase inhibitor was letrozole. Live birth (12 RCTs) One RCT compared letrozole with placebo in women who were clomiphene resistant and the results were inconclusive (OR 3.17, 95% CI 0.12 to 83.17, n=36)Nine RCTs compared letrozole with clomiphene citrate (with or without adjuncts) followed by timed intercourse. The birth rate was higher in the letrozole group (OR 1.63, 95% CI 1.31 to 2.03, n=1783, I²=3%)Two RCTs compared letrozole with laparoscopic ovarian drilling. There was no evidence of a difference between the groups in live birth rate (OR 1.19, 95% CI 0.76 to 1.86, n=407, I²=0%) OHSS (16 RCTs) There was no evidence of a difference in OHSS rates when letrozole was compared with placebo (one RCT, n=36), clomiphene citrate (with or without adjuncts) followed by timed intercourse (nine RCTs, n=2179), clomiphene citrate (with or without adjuncts) followed by intrauterine insemination (IUI) (two RCTs, n=1494), laparoscopic ovarian drilling (one RCT, n=260) or anastrozole (one RCT, n=220). Events were absent or very rare, and no study had more than 2 cases of OHSS. Clinical pregnancy (25 RCTs) One RCT compared letrozole versus placebo in women who were clomiphene resistant and the results were inconclusive (OR 3.17, 95% CI 0.12 to 83.17, n=36)Fourteen RCTs compared letrozole versus clomiphene citrate (with or without adjuncts) followed by timed intercourse. The pregnancy rate was higher in the letrozole group (OR 1.32, 95% CI 1.09 to 1.60, n=2066, I²=25%)Three RCTs compared letrozole versus clomiphene citrate (with or without adjuncts) followed by IUI. The pregnancy rate was higher in the letrozole group (OR 1.71, 95% CI 1.30 to 2.25, n=1597)Three RCTs compared letrozole versus laparoscopic ovarian drilling. There was no evidence of a difference in the clinical pregnancy rate (OR 1.14, 95% CI 0.80 to 1.65, n=553, I²=0%)Two RCTs compared letrozole versus anastrozole, one RCT compared a five day versus a 10 day administration protocol for letrozole and another RCT compared 5 mg of letrozole versus 7.5 mg of letrozole. There was no evidence of a difference in the clinical pregnancy rate in these comparisons.The quality of the evidence was rated as low for live birth and pregnancy outcomes. The reasons for downgrading the evidence were poor reporting of study methods, possible publication bias and the tendency for studies that reported live birth to report higher clinical pregnancy rates in the letrozole group than studies that failed to report live birth (suggesting that results might be somewhat less favourable to letrozole if all studies reported live birth). Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory PCOS, compared to clomiphene citrate. The quality of this evidence is low and findings should be regarded with some caution. There appears to be no difference in effectiveness between letrozole and laparoscopic ovarian drilling, though there were few relevant studies. OHSS was a very rare event, with no occurrences in most studies.

Letrozole induction of ovulation in women with clomiphene citrate–resistant polycystic ovary syndrome may not depend on the period of infertility, the body mass index, or the luteinizing hormone/follicle-stimulating hormone ratio

Editorial group: Cochrane Gynaecology and Fertility Group. Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 11, 2015.

Laparoscopic ovarian drilling with and without medical ovulation induction may decrease the live birth rate in women with anovulatory PCOS and CC resistance compared with medical ovulation induction alone. But the sensitivity analysis restricted to only RCTs at low risk of selection bias suggests there is uncertainty whether there is a difference between the treatments, due to uncertainty around the estimate. Moderate-quality evidence shows that LOD probably reduces the number of multiple pregnancy. Low-quality evidence suggests that there may be little or no difference between the treatments for the likelihood of a clinical pregnancy, and there is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage. LOD may result in less OHSS. The quality of evidence is insufficient to justify a conclusion on live birth, clinical pregnancy or miscarriage rate for the analysis of unilateral LOD versus bilateral LOD. There were no data available on multiple pregnancy.

Letrozole appears to improve live birth rates and pregnancy rates in infertile women with anovulatory PCOS, compared to SERMs, when used for ovulation induction, followed by intercourse. There is high-certainty evidence that OHSS rates are similar with letrozole or SERMs. There was high-certainty evidence of no difference in miscarriage rate and multiple pregnancy rate. We are uncertain if letrozole increases live birth rates compared to LOD. In this update, we added good quality trials and removed trials with concerns over data validity, thereby upgrading the certainty of the evidence base.

Two weeks of metformin improves clomiphene citrate-induced ovulation and metabolic profiles in women with polycystic ovary syndrome

Aim: Recent evidence has shown that Myoinositol (MI), a nutrient belonging to vitamin B family, may improve hormone profile, and the metabolic disorders accompanying polycystic ovary syndrome (PCOS), probably through the amelioration of preexisting insulin resistance. This study aimed to compare the ovulation and pregnancy outcomes of clomiphene citrate (CC) and its combination with MI in obese PCOS women with infertility. Methods: Data concerning 80 obese, PCOS women with infertility who had undergone ovarian induction were retrieved from the institutional digital database. Controlled ovarian stimulation (OS) was performed using CC 100 mg or CC (100mg) + MI (4 g). The primary outcome measure of this study was the difference in the ovulation and the pregnancy rates of the women receiving CC (CC group) or CC+MI (combination group) for ovarian stimulation. There were 40 patients in each group. Results: Endometrial thickness was significantly higher in the combination group than in the CC group (8.4 (1.1) mm vs. 7.7 (1.2) mm, P=0.006) and the number of the follicles>17 mm following OS was significantly higher in the combination group compared to that of the CC group (1.6 (0.5) vs. 1.4 (0.5), P=0.036). However, the rate of ovulation following OS [37 (92%) vs. 37 (92%), P=1.000] and the rate of the pregnancy were similar in CC and combination groups [6 (15%) vs. 11 (27.5%), P=0.172, respectively]. Conclusions: Compared to ovarian stimulation with CC alone, the combination provides a beneficial effect on endometrial thickness and the number of mature follicles. However, ovulation rates are similar with the two regimens. Although not statistically significant, there was a trend towards higher rates of pregnancy on CC+MI combination compared to CC alone. Further prospective and randomized trials are required to clearly address the role of the MI in management of the PCOS women with infertility.