By: Robert Ring
Editor’s Note: For many years, clomiphene citrate was the recommended first-line agent for ovulation induction in women with polycystic ovary syndrome (PCOS). Yet, the 2019 meta-analysis study[i] summarized below provides further evidence that letrozole, or clomiphene plus metformin, can now be recommended as a first-line treatment for ovulation induction in most women with PCOS. The study by Wang et al also supports a personalized approach for the management of anovulatory infertility related to PCOS. Titled, “First-line ovulation induction for polycystic ovary syndrome: An individual participant data meta-analysis,” the study was published in Human Reproduction Update. Robert Ring summarized their findings while on the FACTS elective, and notes how assessing the effect of these medications on cervical mucus secretion in follow-up research could inspire new insights and contribute to a more personalized approach in the care of these women.
Introduction
During the FACTS elective, Dr. Marguerite Duane and Dr. Joseph Stanford led a discussion of a nuanced treatment approach for patients with PCOS based on the predominant clinical phenotype. I was captivated and challenged to learn more about developments in the management of ovulation induction in women with PCOS.
Polycystic ovary syndrome is a common endocrine disorder in women leading to anovulatory subfertility. It may be characterized by a diverse spectrum of clinical presentations including oligomenorrhea, amenorrhea, insulin resistance, obesity, and clinical or biochemical hyperandrogenism. It affects 4 to 8% of women worldwide.[ii] Clomiphene citrate (CC) has been the first-line treatment for ovulation induction for women with PCOS, though 20-25% of women may be treatment-resistant to ovulation induction with CC.[iii] The aromatase inhibitor letrozole has shown promising efficacy for ovulation induction in women with PCOS. However, evidence from clinical trials has yet to reach a clear consensus as to whether letrozole is at least non-inferior to first-line treatment with clomiphene citrate.i
Methodology
This study is an individual participant data (IPD) meta-analysis of randomized control trials (RCTs) completed through December 2018. Included RCTs were identified comparing the following interventions in women diagnosed with PCOS: clomiphene citrate, metformin, CC plus metformin, letrozole, gonadotropins, and tamoxifen. Studies were excluded with treatment-resistant women (classified as a prior treatment failure using CC[iv]). The primary outcome was live birth. Secondary outcomes included clinical pregnancy rate, ovulation rate, and time-to-pregnancy. Individual participant data from 20 RCTs including 3,962 women with PCOS were obtained.
Sources of potential bias were thoroughly evaluated and taken into account in the overall GRADE assessment of final outcome evidence. All analyses were completed with intention-to-treat principles. In the meta-analyses of letrozole versus CC, I2 =0 values demonstrated consistency in individual RCT outcomes. These findings were robust to sensitivity analyses, meaning that no one RCT disproportionately impacted the final outcome.
Results
Letrozole improves live birth rate, clinical pregnancy rate, and time-to-pregnancy rate when compared with CC
Six RCTs compared letrozole and CC in 1,284 women. The primary study outcome compared the relative efficacy of letrozole versus CC on live birth rates. Compared with CC, letrozole was shown to improve live birth rates (3 RCTs, 1,043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17–1.75, moderate-certainty evidence). Meta-analyses of the effect of letrozole vs. CC on live birth 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).
On study secondary outcomes, compared with CC, letrozole also demonstrated improved clinical pregnancy rates (6 RCTs, 1,284 women, RR 1.45, 95% CI 1.23–1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1,235 women, hazard ratio [HR] 1.72, 95% CI 1.38–2.15, moderate-certainty evidence).
No clear difference shown between CC + metformin and CC alone on live birth rate
Eight RCTs compared CC plus metformin to CC alone in 1,039 women. Assessing the primary outcome of live birth rates, there was not clear evidence of a difference between CC plus metformin vs. CC alone (5 RCTs, 907 women, RR 1.08, 95% CI 0.87–1.35, low-certainty evidence). Despite a lack of clear evidence of effect on live birth, meta-analyses showed a slightly 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).
CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1,039 women, RR 1.18, 95% CI 1.00–1.39, low-certainty evidence) and may reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00–1.57, low-certainty evidence). However, the overall grade of evidence was low-certainty.
Discussion
The 2019 meta-analysis by Wang et al demonstrates that, in women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC. Baseline total testosterone levels are also positively associated with effect of letrozole on live birth [RR 1.29]. Therefore, letrozole can be recommended as the preferred first-line treatment for women with PCOS and infertility.
While insufficient evidence currently exists to demonstrate a difference in live birth between CC plus metformin and CC alone, treatment outcome with CC plus metformin on live birth rate is positively affected, albeit to a small degree [RR 1.03], by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenemia and insulin resistance provide further insights into a personalized approach for the management of anovulatory infertility related to PCOS.
Whereas CC has been the first-line agent for ovulation induction, it has approximately 70-80% success in inducing ovulation,ii yet only a 35-40% success in live birth rate.i It may be understandable, in the context of fertility awareness-based methods (FABMs), that CC negatively impacts the production of estrogen-type fertile cervical mucus, which is essential for fertilization. Given the different mechanism of action of letrozole as an aromatase inhibitor while clomiphene citrate is an estrogen-receptor antagonist, letrozole may have a less deleterious effect on the production and quality of cervical mucus. This would make letrozole a superior choice to treat anovulatory infertility in women with PCOS.
With the development of an international consortium of individual participant data studying PCOS, future research could begin by engaging researchers initially unresponsive to the call for data by using this publication’s success as a flagship for new endeavors using the IPD meta-analysis framework. Furthermore, a quantitative analysis of the impact of letrozole vs. CC on cervical mucus secretion would be enlightening for a continued personalized approach to fertility care and individualized treatment with FABMs.
Strengths and limitations of this research study
This study benefits from the robust methodology of individual participant data meta-analysis. It is the first of its kind to analyze subgroup interactions, including time-to-pregnancy, which is a valuable patient-centered metric that is not possible without the IPD meta-analysis study design. Additionally, the inclusion of treatment-naïve women from diverse geographical and cultural settings increases the general applicability and strength of the findings.
The exclusion of treatment-resistant women may limit the magnitude of the most clinically realistic predictions of letrozole’s effect on live birth rate. However, the exclusion of known treatment-resistant women helps to prevent selection bias in favor of letrozole.
Take-home insights
In contrast to a one-size-fits-all solution, a personalized approach using first-line letrozole or CC with metformin for ovulation induction in PCOS is grounded in a sound understanding of endocrine and reproductive physiology. Physicians can empathetically accompany patients along the challenging journey of infertility while maintaining a pursuit of excellence in their understanding of the pathophysiology of PCOS and supporting research into additional effective treatments based on a cogent scientific foundation.
References
[i] Wang R, Li W, Bordewijk EM, et al. First-line ovulation induction for polycystic ovary syndrome: An individual participant data meta-analysis. Hum Reprod Update. 2019;25(6):717-732. doi:10.1093/humupd/dmz029.
[ii] Franik S, Eltrop SM, Kremer JA, Kiesel L, Farquhar C. Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome. Cochrane database Syst Rev. 2018;5(5):CD010287. doi:10.1002/14651858.CD010287.pub3.
[iii] Sachdeva G, Gainder S, Suri V, Sachdeva N, Chopra S. Prediction of responsiveness to clomiphene citrate in infertile women with PCOS. J Reprod Infertil. 2019;20(3):143-150. /pmc/articles/PMC6670260/?report=abstract. Accessed July 5, 2020.
[iv] Wang LL, Qi HB, Baker PN, et al. Altered circulating inflammatory cytokines are associated with anovulatory polycystic ovary syndrome (PCOS) women resistant to clomiphene citrate treatment. Med Sci Monit. 2017;23:1083-1089. doi:10.12659/MSM.901194.
ABOUT THE AUTHOR
Robert Ring
Robert Ring wrote this review as a fourth-year osteopathic medical student at A.T. Still University/Kirksville College of Osteopathic Medicine in Kirksville, MO. He plans to practice rural family medicine with obstetrics, and hopes to pursue further FABM training in residency and beyond. He completed the FACTS online elective and looks forward to sharing the good news of FABMs as a FACTS ambassador. He values how the practice of FABMs thoughtfully cooperates with a person’s natural physiology to restore healthy functioning of body, mind, and spirit—something wholly consistent with his training in osteopathic medicine.
