The efficacy and safety of anti-androgens in the management of hormonal and clinical features of PCOS

By Tarun Sai LomteReviewed by Lily Ramsey, LLMSep 1 2023

A recent study published in the eClinicalMedicine Journal evaluated the safety and efficacy of anti-androgens in managing polycystic ovary syndrome (PCOS).

Study: Efficacy and safety of anti-androgens in the management of polycystic ovary syndrome: a systematic review and meta-analysis of randomised controlled trials. Image Credit: Alena Menshikova/Shutterstock.com

Background

PCOS remains the most common endocrinological disorder in reproductive-aged females. It is diagnosed based on at least two characteristics – menstrual irregularities, biochemical or clinical hyperandrogenism, and ultrasound detection of polycystic ovary morphology, per the Rotterdam criteria.

Hyperandrogenism is considered a fundamental component of PCOS pathophysiology. Metabolic, reproductive, and psychological factors are associated with PCOS.

Lifestyle management is the recommended first-line option to treat PCOS. Nevertheless, pharmacological agents, such as anti-obesity, combined oral contraceptive pills (COCP), anti-androgens, and metformin, could be used if lifestyle management fails.

Anti-androgens, such as cyproterone acetate (CPA), finasteride, flutamide, and spironolactone, are used to treat hyperandrogenism-related symptoms.

Anti-androgens reduce androgen production, competitively inhibit androgen-binding receptors, or inhibit 5-α-reductase in the skin, and could facilitate the hyperandrogenic state of PCOS.

The 2018 international evidence-based PCOS guidelines revealed the lack of evidence for using identified anti-androgens in PCOS. So far, systematic reviews have focused on females with idiopathic hirsutism, and no systematic review has investigated the use of anti-androgens in PCOS management.

About the study

In the present study, researchers systematically reviewed and meta-analyzed the safety and efficacy of anti-androgens on clinical, hormonal, and anthropometric features of PCOS.

Embase, Medline, PsycINFO, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were searched for randomized clinical trials (RCTs) and systematic reviews (to identify eligible trials) written in English from 2017 onwards.

Additionally, the team included studies identified in the 2018 PCOS guidelines. Title/abstract screening and full-text reviews were performed, and each study's risk of bias was assessed.

Data on study details, participants, intervention, comparison, and outcomes were extracted. Meta-analyses were conducted using random effects models. Sensitivity analyses examined how high-risk studies would influence results.

The I-squared statistic was used to determine statistical heterogeneity. Publication bias was examined by inspecting funnel plot asymmetry. The grading of recommendations assessment, development, and evaluation (GRADE) framework prioritized outcomes as critical or important. Critical outcomes were weight, irregular cycles, body mass index (BMI), liver function, quality of life, and hirsutism.

Findings

The team included ten articles from the search and 17 from the 2018 guidelines. Thirteen studies were pooled in the meta-analysis. They did not perform sub-group analyses due to high heterogeneity and fewer studies.

Sample sizes ranged between 11 and 167 participants, and the treatment lasted six to 12 months. Anti-androgens included bicalutamide, flutamide, finasteride, and spironolactone.

Comparators included placebo, COCP, metformin, lifestyle, or their combination. Most studies included adult populations, and two comprised adolescents. Although healthy, overweight, and obese people were included, many studies were on females with a 25 kg/m2 or higher BMI.

Contraception methods included barriers, hormonal contraceptives, or abstinence. Four, nine, and seven studies had low, moderate, and high risk of bias, respectively.

One RCT investigated finasteride in adolescents with PCOS and found lower hirsutism with anti-androgens compared to placebo, with no differences in BMI, androstenedione, sex hormone-binding globulin (SHBG), or testosterone; however, dehydroepiandrosterone sulfate (DHEAS) was higher. One trial tested flutamide compared to placebo in adults with PCOS and found no outcome differences.

Two RCTs compared anti-androgens and lifestyle with placebo and lifestyle in adults with PCOS, and no differences were observed in BMI, SHBG, or hirsutism.

In one of these, anti-androgens and lifestyle reduced body weight, menstruation frequency, DHEAS, fasting insulin levels, triglycerides, and low-density lipoprotein (LDL) cholesterol relative to placebo. Two trials compared finasteride (once daily or every three days) with flutamide (twice daily or every three days).

Daily use of anti-androgens was superior in reducing androstenedione and hirsutism without differences in DHEAS, testosterone, or SHBG. One RCT investigated anti-androgens with or without metformin relative to metformin alone.

There were no differences in hirsutism, testosterone, BMI, SHBG, androstenedione, or DHEAS in either comparison. Four trials compared anti-androgens and lifestyle with metformin and lifestyle.

Anti-androgens and lifestyle interventions reduced fasting glucose-insulin ratio, hirsutism, and fasting insulin but increased high-density lipoprotein (HDL), menstruation frequency, and SHBG relative to metformin and lifestyle.

Three RCTs compared anti-androgens, lifestyle, and metformin with anti-androgens and lifestyle. Anti-androgens and lifestyle increased fasting glucose, with no differences in other outcomes.

In a trial comparing spironolactone with CPA and ethinyl estradiol, hirsutism was lower with the combination treatment.

Six trials compared COCP and anti-androgens with COCP with or without a placebo. Total cholesterol, triglycerides, and LDL were higher with COCP and anti-androgens compared to COCP alone.

One RCT evaluated the combination of anti-androgens and metformin with or without COCP relative to COCP in adolescents and adults.

The combination without COCP resulted in lower triglycerides, LDL, HDL, and SHBG than COCP alone in adults. However, the combination with COCP reduced SHBG in adolescents.

Conclusions

When combined with effective contraception, anti-androgens could benefit clinical hyperandrogenism (hirsutism).

They could be used in cases where COCP and cosmetic options have been sub-optimal for at least six months, poorly tolerated, or contraindicated. This recommendation is based on the best available evidence that remains limited due to substantial heterogeneity.

Overall, COCPs remain the first-line therapy for clinical hyperandrogenism in PCOS until adequately powered high-quality studies show further benefits of anti-androgens in PCOS.