September 23, 2020
By Kaitlin VanderKolk, MD, MPH

Editor’s Note: This is a review of research[i] published earlier this year in the International Journal ofFertility and Sterility titled, “Medical and Surgical Treatment of Reproductive Outcomes in Polycystic Ovary Syndrome: An Overview of Systematic Reviews.” It was written by Dr. Kaitlin VanderKolk as part of the fertility awareness elective taught by FACTS executive director, Dr. Marguerite Duane, at Georgetown University School of Medicine.

As with the PCOS review we published earlier this month to kick off this 4-week series, no mention was made of fertility awareness-based methods (FABMs) in the research article reviewed this week. This is a strong reminder to us at FACTS that we must continue to educate medical professionals, researchers, program directors, and faculty members at medical schools and residency programs about the use of FABMs to diagnose and treat common women’s health conditions.

Next week, we will wrap up this series to raise awareness about PCOS with another review of research. As knowledge about the practical applications of FABMs in women’s health continues to grow among medical professionals, we hope more women and couples will be offered these safe and effective options for health monitoring, family planning, and general women’s health.

Introduction

Polycystic ovary syndrome (PCOS) is a complex metabolic-endocrine condition affecting an estimated 9-18% of reproductive-aged women. It can present with a variety of clinical symptoms that may include infertility, menstrual irregularities, and metabolic dysfunction often evidenced by insulin resistance and overweight/obesity. PCOS is classically diagnosed by the Rotterdam criteria in which 2 of the 3 following conditions are met: (1) anovulation or oligo-ovulation (irregular cycles) (2) hyperandrogenism (e.g., hirsutism, acne, or confirmatory laboratory tests), and (3) evidence of polycystic ovaries on ultrasound.

Although several medical and surgical treatments are available for the infertility associated with PCOS, a lack of consensus persists in the guidelines regarding the efficacy of these options. Outside of artificial reproductive technology, management options primarily include lifestyle modification, surgical approaches (laparoscopic ovarian drilling), or medications to induce ovulation such as clomiphene, letrozole, metformin, or gonadotropins.

This extensive overview study by Gadalla et al reviewed 44 pertinent systematic reviews of the medical and surgical treatments of PCOS, creating a summary of the best current research trends and recommendations for this condition.

Methods

The authors designed a broad overview study to include any systematic review assessing medical or surgical treatments of PCOS and their reproductive outcomes. The relevant reviews were selected based on well-known protocols and guidelines for conducting systematic reviews. Selection criteria included systematic reviews published from 2009-2017 (time of database search) which had PCOS and reproductive outcomes as their primary focus.

Review Selection

From the initial database search, 831 citations were found after removing duplicates. After screening based on title, abstract, or text as well as whether reproductive outcomes were the primary objective of the review, a total of 44 articles were included for review. The majority of these articles were rated as moderate to high quality.

 

Summary of Most Relevant Results

Although this review presented many different conclusions from the research, some of the most pertinent findings are presented below.

• Letrozole
Six reviews were related to letrozole. These reviews found that for women with PCOS using timed intercourse, letrozole had statistically significant increases in ovulation, pregnancy, and live birth compared to clomiphene citrate. Additionally, 10 days of letrozole resulted in more pregnancies than 5 days.

• Clomiphene citrate
Seventeen reviews evaluated clomiphene citrate. Primary findings from this overview showed that clomiphene did have statistically higher pregnancy and ovulation compared to placebo, but did not perform as well as gonadotropins or letrozole. Interestingly, clomiphene’s efficacy appears to depend on BMI as well. Clomiphene resulted in higher pregnancy rates compared to metformin for women with BMI >30, but metformin was superior to clomiphene in women with a BMI <30. Combining metformin and clomiphene caused increased gastrointestinal (GI) side effects, but the combination was superior to either medication given alone.

• Gonadotropins
Regarding gonadotropins, the meta-analyses showed that for women with clomiphene-resistant PCOS, gonadotropins were superior to laparoscopic ovarian drilling and inferior to letrozole. With the addition of metformin, gonadotropins showed even higher rates of live birth and pregnancy.

• Metformin
A number of insulin sensitizers, including metformin, were studied in 30 of the reviews. Overall, metformin resulted in higher live births and pregnancy, and also improved menstrual frequency. During pregnancy, metformin intake for women with PCOS also improved birth outcomes.

• Laparoscopic Ovarian Drilling
Regarding laparoscopic ovarian drilling, meta-analyses found that while it resulted in lower multiple pregnancy rates, it had inferior reproductive outcomes compared to clomiphene, letrozole, and gonadotropins.

Discussion

One of the more notable findings of this paper is the positive findings of letrozole’s efficacy compared to clomiphene citrate. These results are important, given that some guidelines still suggest clomiphene as a first-line treatment while letrozole remains an off-label option for ovulation induction. Thus, for anovulatory women with PCOS, the authors recommend letrozole as first-line treatment and gonadotropins as second-line treatment, since both appear to result in higher live birth and pregnancy rates than clomiphene. From a surgical perspective, laparoscopic ovarian drilling resulted in lower multiple pregnancy rates but, in general, resulted in fewer live births than medical treatment. Future studies will need to elucidate the differences in treatment outcomes for the various subtypes of PCOS.

Editor’s Note: It is worth emphasizing that, in line with current guidelines, this exhaustive review reaffirms lifestyle modification as the first step in management of PCOS before treatment with medications is pursued, particularly in women with BMI > 30. To learn more about PCOS diagnosis, treatment, and FABM applications for this common condition, you may follow the links below.

Polycystic Ovary Syndrome: A Review of Diagnosis and Treatment

Way Beyond Family Planning: FABM Helps Diagnose PCOS

The Role of Cervical Mucus in PCOS-Related Infertility: A Review of Research Findings

Fertility Awareness in PCOS: A Choice Aligned with Future Goals

Beyond Family Planning: Using FABMs for PCOS

 

References

[i] Gadalla MA, Norman RJ, Tay CT, Hiam DS, Melder A, Pundir J, Thangaratinam S, Teede HJ, Mol BWJ, Moran LJ. Medical and surgical treatment of reproductive outcomes in polycystic ovary syndrome: an overview of systematic reviews. Int J Fertil Steril. 2020; 13(4): 257-270.

Author Bio: Kaitlin VanderKolk, MD, MPH is a family medicine resident at Memorial Hospital in South Bend, Indiana. She completed her undergraduate training in biology at the University of Notre Dame, a Masters in Public Health at Saint Louis University, followed by medical school at the University of Colorado Anschutz Medical Campus. She completed this research review as a fourth-year medical student while on the FACTS elective. Thanks to her experience as a FACTS ambassador, she’s excited to integrate her FABM learning into her future practice.

Last Chance to Register!
FACTS 2-Day Virtual CME Conference  |  October 2-3, 2020

Modern Fertility Awareness for Women’s Health and Family Planning

As interest in FABMs increases, it is important that YOU are well-equipped with the latest research to inform women. Join us to expand your toolbox and be better prepared to counsel women about FABMs so they may make more informed healthcare choices. Join us on Friday, October 2 and Saturday October 3, 2020. Can’t make it on these days?! Not to worry – Your registration will also allow access to these presentations through the end of 2020!

Conference highlights will include:

• FABM overview and their applications for:
– Achieving and Preventing Pregnancy
– Infertility
– Adolescence
– Peri Menopause
– Irregular Cycles and Abnormal Uterine Bleeding
• Fertility Apps and Fem Tech
• The Female Cycle as the 5th Vital Sign
• Extensive Q&A with our expert panels
CME Credit*
*The AAFP has reviewed Modern Fertility Awareness for Family Planning and Women’s Health and deemed it acceptable for up to 12.00 Online Only, Live AAFP Prescribed credit. Term of Approval is from 10/02/2020 to 10/03/2020. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

We are looking forward to this event as an opportunity to connect with one another, learn more about fertility awareness, and to share all we have accomplished together!

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