First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis

Abstract

BACKGROUND Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment–covariate interaction analyses and therefore offers an opportunity for personalised medicine. OBJECTIVE AND RATIONALE We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics. SEARCH METHODS We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs. OUTCOMES IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17–1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23–1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38–2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01–1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00–1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00–1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87–1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01–1.06). WIDER IMPLICATIONS In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS.

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

“…Polycystic ovary syndrome (PCOS) is a frequent metabolic disorder, characterized by chronic anovulation, hyperandrogenism, and polycystic ovaries in ultrasonography; PCOS affects 5-10% of women of reproductive age [1][2][3][4][5]. Recent studies show that 50% of women with PCOS fulfill the criteria of metabolic syndrome [6].…”

“…Loss of body weight (BW) and life-style modifications are highly recommended as the first line of treatment in PCOS, especially for obese women [2,[12][13][14][15][16][17][18][19]. A 5-10% loss in BW over a period of six months, regardless of body mass index (BMI), may be associated with improvements in central obesity, hyperandrogenism, and ovulation rate [18,19].…”

“…A 5-10% loss in BW over a period of six months, regardless of body mass index (BMI), may be associated with improvements in central obesity, hyperandrogenism, and ovulation rate [18,19]. For women who desire to become pregnant, clomiphene citrate (CC) has been long considered as the front-line treatment based on its high cost-effectiveness [2,[19][20][21][22][23][24], although recommendations from the international evidence-based guideline for the assessment and management of PCOS favored that letrozole should be considered first line pharmacological treatment for ovulation induction in women with PCOS with anovulatory infertility and no other infertility factors to improve ovulation, pregnancy and liver birth rates [10]. CC is a competitive inhibitor of estrogen that binds to estrogen receptors (ERs), resulting in an increase of the hypothalamic gonadotropin-releasing hormone (GnRH) pulse frequency and circulating concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).…”

“…Most importantly, the cost of CC is very low. CC treatment also has fewer side effects and a lower chance of multiple pregnancies (2-13%) compared to other medical treatments, such as using GnRH agonists or antagonists, aromatase inhibitors (AIs), and gonadotropin stimulation treatments [2,[19][20][21][22][23][24]. The initial dose of CC is 50 mg per day.…”

Identification of the Active Constituents and Significant Pathways of Cangfu Daotan Decoction for the Treatment of PCOS Based on Network Pharmacology

“…In the past few decades, oral contraceptive pills (OCPs) have been widely used in PCOS patients to regulate their menstrual cycles and reduce hyperandrogenism [4]. Clomiphene citrate and letrozole have both been used to induce ovulation in PCOS patients with fertility problems [9][10][11]. However, reports have been coming in regarding the side effects of OCPs in increasing the risk of venous thromboembolism (VTE) [12,13].…”