PCOS Awareness Month
Metformin and Gonadotropins for Ovulation Induction in PCOS: A Review of Research
By: Joe Herba, DO
Director’s Note: During PCOS Awareness Month, our discussion on insulin resistance continues with research exploring the use of metformin as an insulin-sensitizing agent in women diagnosed with PCOS. Joe Herba, a former FACTS elective participant, summarized a systematic review published by Palomba et al in Reproductive Biology and Endocrinology. [1] The summary highlights the implications of combining metformin and gonadotropins to improve ovulation and enhance fertility in PCOS.
Introduction
Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects 7-10% of women of childbearing age and is a leading cause of infertility. In the United States alone, this condition affects an estimated 5 to 6 million women. Even when correcting for the increased population, studies suggest the prevalence of PCOS continues to rise. Although the cause behind this rise is not known, genetic predisposition along with increased cases of diabetes—with which PCOS is associated—are hypothesized to be the primary factors.
PCOS is characterized by hormonal imbalances, metabolic disturbances, and reproductive abnormalities with limited understanding of the underlying pathophysiology. Diagnostic criteria include (1) irregular or absent menstrual cycles due to ovulatory dysfunction, (2) clinical or biochemical signs of high androgen levels (i.e. hirsutism, acne or high testosterone levels), and (3) evidence of polycystic ovaries on ultrasound. Clinical manifestations of PCOS may include metabolic disturbances like obesity, dyslipidemia, insulin resistance, impaired glucose tolerance, and an increased risk of type 2 diabetes.
“Clinical manifestations of PCOS may include metabolic disturbances like obesity, dyslipidemia, insulin resistance, impaired glucose tolerance, and an increased risk of type 2 diabetes.”
Restorative reproductive medical (RRM) treatments for PCOS seek to address the metabolic abnormalities and reproductive aspects to improve menstrual regularity, restore fertility, and manage androgen-related symptoms. Common medications used in patients with PCOS include oral contraceptives, anti-androgens, insulin-sensitizing agents such as metformin, and ovulation induction agents (clomiphene, letrozole, gonadotropins).
The study by Palomba et al [1] assessed whether there was a benefit to using combined metformin and gonadotropins to support the return to regular ovulation and increased fertility. Recognizing that metformin aids tissue response to insulin, they hypothesized this sensitization would occur at the ovary itself, enhancing its function at the cellular level. The introduction of gonadotropins would allow the ovary to respond to these hormones more at a physiologic baseline rather than the dysfunctional state of the polycystic ovary in PCOS. This meta-analysis examined multiple studies of patients with infertility to clarify the effects of metformin in combination with gonadotropins and assess their effectiveness to restore normal ovulation.
Methodology
The authors searched for any studies published up to October 2013 without a language restriction and used relevant keywords regarding PCOS, insulin sensitivity, and infertility. The studies included in the analysis had to be randomized controlled trials with crossover study data included, but only before the crossover period to mimic a randomized controlled study. The manuscript reviewers assessed each manuscript to determine if they were pertinent to the study goals. In the end, 7 studies were used in the meta-analysis.
The primary endpoints revolved around successful return to fertility and assessed live-birth and pregnancy rates. Secondary endpoints focused on poor responses to treatment, particularly in the setting of ovarian hyperstimulation.
Statistical assessment employed an Odds Ratio (OR) approach with two possible outcomes of treatment: successful return to fertility or failure to restore fertility. Inconsistency between studies and treatments was analyzed and a scoring plan was implemented to translate the numerical data to the chance of heterogeneity between studies. Anything under 40% under this score (I2) was not considered important. Further, any P value <0.05 or 95% confidence interval (CI) that did not contain unity was considered significant. 
Results
Data analysis showed metformin had a positive impact on live-birth and pregnancy rates. The OR for live birth was 1.94 (95% CI 1.10 to 3.44, P = 0.020), indicating an increased likelihood of live births with metformin treatment. The OR for pregnancy was 2.25 (95% CI, 1.50 to 3.38, P < 0.0001), indicating a higher chance of achieving pregnancy.
There was no significant heterogeneity across the studies for both live-birth and pregnancy rates (P = 0.230 and P = 0.710, respectively). This suggests the effect of metformin on live-birth and pregnancy rates was consistent across studies.
Metformin administration also led to a significant reduction in the cancellation rate of treatments (OR = 0.41, 95% CI, 0.24 to 0.72, P = 0.002). Again, there was no significant heterogeneity observed among the studies (P = 0.500), indicating consistent results across studies regarding the reduction in cancellation rate. The influence of metformin on other secondary endpoints varied and showed significant heterogeneity among the studies.
In summary, results showed metformin treatment improved live-birth and pregnancy rates while reducing treatment cancellation rates in patients with infertility and PCOS.
“Results showed metformin treatment improved live-birth and pregnancy rates while reducing treatment cancellation rates in patients with infertility and PCOS.”
Discussion
The systematic review and meta-analysis demonstrated metformin significantly improves pregnancy rates, resulting in a more than two-fold increase. The live-birth rate was also significantly increased by approximately two-fold with metformin administration. A reduction in the cancellation rate of treatment cycles was observed among patients with PCOS receiving metformin, with a higher proportion achieving monofollicular cycles and mono-ovulation. However, the impact of the reduction in cancellation rate on pregnancy and live-birth rates could not be determined with certainty.
Metformin showed potential effects on oocyte quality, endometrial receptivity, intra-ovarian hyperandrogenism, and insulin resistance. There was no significant effect of metformin on the risk of ovarian hyperstimulation syndrome (OHSS) or multiple pregnancies, likely due to the low baseline risk in the studies included.
“Metformin showed potential effects on oocyte quality, endometrial receptivity, intra-ovarian hyperandrogenism, and insulin resistance.”
The review had limitations, including a narrow number of studies and subjects, heterogeneity in PCOS populations, and metformin administration protocols. The findings were preliminary, and further research was deemed necessary to make definitive clinical recommendations.
Study strengths included rigorous inclusion and exclusion criteria, no heterogeneity in primary reproductive outcomes, and the lack of ongoing clinical trials on the topic at the time of publication. Overall, while the results suggested benefits of metformin in improving pregnancy and live-birth rates in patients with PCOS and infertility, more research is required to fully understand the optimal use and potential impact of metformin treatment when combined with gonadotropins.
References
[1] LPalomba S, Falbo A, La Sala GB. Metformin and gonadotropins for ovulation induction in patients with polycystic ovary syndrome: a systematic review with meta-analysis of randomized controlled trials. Reprod Biol Endocrinol. 2014 Jan 3;12:3. doi: 10.1186/1477-7827-12-3. PMID: 24387273; PMCID: PMC3895676
[2] Yang R, Li Q, Zhou Z, Qian W, Zhang J, Wu Z, Jin L, Wu X, Zhang C, Zheng B, Tan J, Hao G, Li S, Tian T, Hao Y, Zheng D, Wang Y, Norman RJ, Li R, Liu P, Qiao J. Changes in the prevalence of polycystic ovary syndrome in China over the past decade. Lancet Reg Health West Pac. 2022 May 31;25:100494. doi: 10.1016/j.lanwpc.2022.100494. PMID: 35669932; PMCID: PMC9162959
ABOUT THE AUTHOR
Joe Herba, DO
Joe Herba, DO earned his medical degree at Des Moines University in Des Moines, Iowa, and completed his undergraduate education at Drake University, also in Des Moines. Before medical school, he earned a master’s degree in cardiovascular sciences at the University of Glasgow in Glasgow, Scotland. Dr. Herba plans to complete residency in internal medicine at the University of Kansas in Kansas City, followed by a fellowship in endocrinology. He enrolled in the FACTS elective to learn more about family planning and the hormonal imbalances that can keep patients from achieving their goals; he hopes to use this knowledge to support and educate patients at his future endocrine practice.
Learn more about PCOS and its effects on the cycle and fertility at our virtual conference next month. Sign up by THIS Saturday and SAVE!
