National PCOS Awareness Month
Spironolactone and Metformin in PCOS Management: A Review of Research
By: Melanie Kasaris, DO
Director’s Note: To mark Polycystic Ovary Syndrome (PCOS) Awareness Month, we are highlighting research that assessed the efficacy of combining low-dose spironolactone and metformin in the management of PCOS. The research was summarized by Dr. Melanie Kasaris, a former FACTS elective participant. The 2013 study published by Ganie et al in The Journal of Clinical Endocrinology & Metabolism sheds light on treatment options for women diagnosed with PCOS and shows improved outcomes of combined treatments compared to sole agents. It is important to note that fertility awareness-based methods (FABMs) may also be a valuable complement to conventional approaches in the diagnosis and management of PCOS. To learn more about PCOS and other common women’s health concerns, sign up for Parts D and E of our online CME course, Medical Applications of FABMs.
Polycystic ovary syndrome is a common endocrine disorder associated with anovulatory infertility and metabolic imbalances. Comorbidities may include hyperandrogenism, obesity, type 2 diabetes mellitus, dyslipidemia, hypertension, and cardiovascular disease. As the underlying cause of PCOS is not fully understood, most of the treatment efforts focus on management of symptoms. Spironolactone, a steroid synthesis inhibitor, is a frequent choice to manage symptoms of hyperandrogenism such as hirsutism and acne. Metformin, an insulin sensitizer, is often used in PCOS to manage insulin resistance. Other treatment options previously attempted include other oral antidiabetic agents, oral contraceptive pills (OCPs), and clomiphene citrate. Ganie et al published the first study to determine the efficacy of combined low-dose spironolactone and metformin compared to either dose alone to treat women with PCOS. 
“Spironolactone, a steroid synthesis inhibitor, is a frequent choice to manage symptoms of hyperandrogenism such as hirsutism and acne. Metformin, an insulin sensitizer, is often used in PCOS to manage insulin resistance.”
In the study, 204 women met the Androgen Excess-PCOS 2006 criteria for PCOS and consented to participate. Of these women, 198 were randomized into three groups to receive metformin (1000 mg/day), low-dose spironolactone (50 mg/day) or a combination of both medications for six months. The women received the randomly assigned medication, standard diet counseling, activity advice, and medication compliance checks at the initial and follow up visits. Outcome measures included menstrual cycle tracking, body mass index (BMI), blood pressure (BP), waist-hip ratio (WHR), and the Ferriman-Gallwey (FG) score used to assess level of hirsutism. Lab levels monitored included oral glucose tolerance test (OGTT), insulin levels, LH, FSH, prolactin, and total testosterone (T). Data was collected at baseline, and three and six months following the intervention.
At baseline, 6 out of 204 subjects were excluded due to abnormal biochemical testing. An additional 29 women were excluded from final analysis due to dropouts or adverse events (10 in metformin group, 15 in spironolactone group, and 4 in combination group). For the final analysis, 169 women remained in the study (metformin, n=56; spironolactone, n=51; combination, n=62).
The findings for each treatment group were as follows:
- The metformin group showed significant improvements in menstrual cycle frequency, hirsutism, serum total testosterone, 2-hour glucose, and plasma insulin levels during OGTT at three and six months of treatment.
- The low-dose spironolactone group had significant improvements in menstrual cycle frequency, serum total T levels, and FG score at three and six months. Post OGTT glucose levels and several OGTT insulin sensitivity indices showed significant improvement at 6 months.
- For the combination group, significant improvements were made in menstrual cycle frequency, FG score, serum total T, and plasma insulin levels at three and six months. OGTT results showed significant decrease in all glucose levels by six months. The combination of low-dose spironolactone and metformin resulted in significant improvements in glucose and insulin sensitivity markers compared to either drug alone.
“The combination of low-dose spironolactone and metformin resulted in significant improvements in glucose and insulin sensitivity markers compared to either drug alone.”
The study findings demonstrate a clear improvement in efficacy with combination spironolactone and metformin compared to sole agents in the management of PCOS. This is important because at least five million women in the United States are affected by PCOS, and more women likely remain undiagnosed. Long-term sequelae of PCOS include serious conditions such as diabetes, heart disease, sleep apnea, and stroke. More than half of women with PCOS will develop diabetes by age 40.
When this research was published in 2013, metformin was the gold standard agent in the management of PCOS. The study findings show clear benefits of adding low-dose spironolactone to metformin and suggest a larger role for this medication in PCOS. Further studies could be undertaken to evaluate the clinical significance of tighter glucose control with combination management. This is necessary to determine whether the medications significantly decrease the incidence of long-term sequelae of PCOS, such as diabetes and cardiovascular disease.
“Further studies could be undertaken to evaluate the clinical significance of tighter glucose control … to determine whether the medications significantly decrease the incidence of long-term sequelae of PCOS, such as diabetes and cardiovascular disease.”
By randomizing the assignment of intervention groups, the study authors reduced selection bias and enabled greater generalization of the results. Randomization also enabled the researchers to compare the groups when assessing the impact of interventions. Regarding study limitations, the open-label design could raise concerns about introducing bias, as both parties were aware of the intervention throughout the study. Also, as there was no placebo, it is possible the improvements found were a result of the diet and exercise interventions implemented at each follow up visit.
In 2015, Naderpoor et al’s meta-analysis in Australia showed lifestyle modifications alongside metformin were associated with a reduction in BMI and subcutaneous adipose tissue as well as improved menstrual cycle frequency over six months. This intervention was compared to lifestyle modifications alone.
A meta-analysis from Saudi Arabia by Almalki et al compared the efficacy of statins, metformin, spironolactone, oral combined OCPs, and lifestyle modifications in reducing testosterone levels in women with PCOS. In their study, atorvastatin showed superior reduction in testosterone compared to combined metformin and spironolactone as well as lifestyle modifications and the placebo arm. Based on these findings, it would seem medical treatment is superior to lifestyle modifications alone. Yet, as the meta-analysis by Almalki et al solely looked at testosterone level changes, further studies would need to address lifestyle modifications versus combined treatment with metformin and spironolactone for PCOS. Research that includes a placebo group could help explain the significant improvement in laboratory findings with combination treatment compared to single agents used alone.
PCOS is a complex condition requiring a multifactorial treatment approach to address the various manifestations of this illness. Additional research about individual and combined treatment approaches, including lifestyle interventions, is warranted.
 Ganie MA, Khurana ML, Nisar S, Shah PA, Shah ZA, Kulshrestha B, Gupta N, Zargar MA, Wani TA, Mudasir S, Mir FA, Taing S. Improved efficacy of low-dose spironolactone and metformin combination than either drug alone in the management of women with polycystic ovary syndrome (PCOS): a six-month, open-label randomized study. J Clin Endocrinol Metab. 2013 Sep;98(9):3599-607. doi: 10.1210/jc.2013-1040. Epub 2013 Jul 11. PMID: 23846820.
 Centers for Disease Control and Prevention. (2020, March 24). PCOS (polycystic ovary syndrome) and diabetes. Centers for Disease Control and Prevention. Retrieved November 2, 2022, from https://www.cdc.gov/diabetes/basics/pcos.html
 Lim CY, In J. Randomization in clinical studies. Korean J Anesthesiol. 2019 Jun;72(3):221-232. doi: 10.4097/kja.19049. Epub 2019 Apr 1. Erratum in: Korean J Anesthesiol. 2019 Aug;72(4):396. PMID: 30929415; PMCID: PMC6547231.
 Naderpoor N, Shorakae S, de Courten B, Misso ML, Moran LJ, Teede HJ. Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis. Hum Reprod Update. 2015 Sep-Oct;21(5):560-74. doi: 10.1093/humupd/dmv025. Epub 2015 Jun 9. Erratum in: Hum Reprod Update. 2016 Apr;22(3):408-9. PMID: 26060208.
 Almalki HH, Alshibani TM, Alhifany AA, Almohammed OA. Comparative efficacy of statins, metformin, spironolactone and combined oral contraceptives in reducing testosterone levels in women with polycystic ovary syndrome: a network meta-analysis of randomized clinical trials. BMC Womens Health. 2020 Apr 5;20(1):68. doi: 10.1186/s12905-020-00919-5. PMID: 32248801; PMCID: PMC7132972.
ABOUT THE AUTHOR
Melanie Kasaris, DO
Melanie Kasaris, DO is a first-year Ob-Gyn resident at Cleveland Clinic Akron General in Akron, Ohio. She is a recent graduate of Ohio University Heritage College of Medicine in Cleveland, Ohio and completed her undergraduate degree at Ohio State University in Columbus, Ohio. Dr. Kasaris has a special interest in health education and advocacy and desires to empower her patients to achieve optimal wellness. She enrolled in the FACTS elective to understand family planning better and prepare to educate her patients more effectively.