Metformin vs. Birth Control Pills for Polycystic Ovary Syndrome

(SHK002 Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Chris McCartney, MD

Age: 18 - 65

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Recruiting

Sponsor: University of Virginia

Must not be taking: Anticonvulsants, Rifampicin, Glucocorticoids, others

Disqualifiers: Diabetes, Hypertension, Stroke, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

The goal of this study is to determine the relative desirability of metformin vs. oral combined hormonal contraceptives (OCs) in treating Polycystic Ovary Syndrome (PCOS) in women of later reproductive age. Polycystic Ovary Syndrome Questionnaire (PCOSQ) score will be used as a proxy for patient satisfaction. In light of their respective effects on the classic and metabolic facets of PCOS, metformin will provide non-inferior patient satisfaction compared to OCs in later reproductive age women with PCOS.

Will I have to stop taking my current medications?

Yes, you will need to stop taking any medications that affect the reproductive system, such as birth control pills, metformin, progestins, glucocorticoids, antipsychotics, and mood stabilizers, at least 2 months before screening and 3 months before the study.

What data supports the effectiveness of the drug Metformin for treating polycystic ovary syndrome (PCOS)?

Research shows that Metformin can help improve insulin resistance and support ovulation in women with PCOS, which may lead to better fertility outcomes. Additionally, combining Metformin with oral contraceptives may offer metabolic benefits for women with PCOS. ^{1 2 3 4 5}

Is metformin safe for humans?

Metformin is generally considered safe for humans and is commonly used to treat conditions like diabetes and polycystic ovary syndrome (PCOS). It may also help reduce the risk of miscarriage and diabetes during pregnancy, although more research is needed. ^{4 6 7 8 9}

How does the drug Metformin differ from other treatments for polycystic ovary syndrome (PCOS)?

Metformin is unique because it improves insulin sensitivity, which helps reduce insulin levels and improve the metabolic profile in women with PCOS. Unlike other treatments, it can also increase sex hormone-binding globulin (SHBG), decrease androgen levels, and induce ovulation, making it particularly beneficial for those with insulin resistance. ^{8 10 11 12 13}

Eligibility Criteria

Women aged 40-49 with PCOS, having irregular or infrequent menstrual cycles and signs of high male hormones. They should not be at risk for pregnancy, have a history of severe liver disease, heart problems, stroke, blood clots, certain cancers or uncontrolled cholesterol levels. Participants must avoid medications affecting the reproductive system before the trial.

Inclusion Criteria

I have fewer than 10 periods a year or my cycle is longer than 35 days, but I have a history of irregular periods.

I have PCOS with signs of high male hormones and irregular periods.

I am a woman aged 40-49 with PCOS and irregular or infrequent periods.

Exclusion Criteria

I have a history of heart or brain blood flow problems.

I understand what the study involves and why it's being done.

My hormone levels indicate I am in perimenopause.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase 1

Participants receive either metformin or oral contraceptives for 6 months

6 months

Baseline and every 3 months for safety surveillance

Crossover Treatment Phase

Participants switch to the alternate treatment (metformin or oral contraceptives) for another 6 months

6 months

Baseline and every 3 months for safety surveillance

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Metformin (Biguanides)
• Oral combined hormonal contraceptives (Combined Hormonal Contraceptives)

Trial Overview The study is testing whether metformin or birth control pills (oral contraceptives) are more satisfying for treating symptoms of PCOS in women nearing menopause. Satisfaction will be measured using a questionnaire designed to assess patient contentment with their treatment.

Participant Groups

Group I: Metformin then oral combined hormonal contraceptives Experimental Treatment 2 Interventions

Subjects will take metformin 2000 mg/day for the first 6 months, followed by 6 months of oral combined hormonal contraceptive (OCs) with a combination of ethinyl estradiol 20 mcg/norethindrone acetate 1 mg.

Group II: Oral combined hormonal contraceptives then metformin Active Control 2 Interventions

Subjects will take oral combined hormonal contraceptive (OCs) with a combination of ethinyl estradiol 20 mcg/norethindrone acetate 1 mg for the first 6 months, followed by 6 months of metformin 2000 mg/day.

Metformin is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

🇪🇺 Approved in European Union as Glucophage for:

• Type 2 diabetes

🇺🇸 Approved in United States as Glucophage for:

• Type 2 diabetes

🇨🇦 Approved in Canada as Glucophage for:

• Type 2 diabetes

🇯🇵 Approved in Japan as Glucophage for:

• Type 2 diabetes

🇨🇳 Approved in China as Glucophage for:

• Type 2 diabetes

🇨🇭 Approved in Switzerland as Glucophage for:

• Type 2 diabetes

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of Virginia Charlottesville, VA

Who Is Running the Clinical Trial?

University of Virginia Lead Sponsor

References

1. United States pubmed.ncbi.nlm.nih.gov

Persistence with oral contraceptive pills versus metformin in women with polycystic ovary syndrome. [2022] We studied patient persistence with oral contraceptive pills (OCPs) compared to metformin for treatment of polycystic ovary syndrome (PCOS) in an urban university clinic population.

2. England pubmed.ncbi.nlm.nih.gov

Targeting insulin sensitivity in the treatment of polycystic ovary syndrome. [2013] Targeting insulin resistance may result in a list of benefits for women with PCOS, including hormonal, metabolic and ovulatory (and fertility) improvements. The therapeutic strategy to treat PCOS should however depend on the clinical situation, the phenotype, the degree of androgen excess, age, the presence of infertility and the woman's desire to conceive, the presence of obesity and, finally, the spectrum of metabolic abnormalities and the need to treat or prevent long-term associated comorbidities. According to the needs, therapeutic options include, alone or in combination, lifestyle management, particularly in the presence of obesity, the use of insulin sensitizers, metformin and thiazolidinediones, antiandrogens or estro-progestins.

3. England pubmed.ncbi.nlm.nih.gov

Oral contraceptives (OCs) in combination with metformin versus OCs alone on metabolism in nonobese polycystic ovary syndrome: A meta-analysis and systematic review of randomized controlled trials. [2023] To compare OCs(oral contraceptives) + metformin and OCs alone for metabolic effects in nonobese polycystic ovary syndrome (PCOS) patients.

4. United States pubmed.ncbi.nlm.nih.gov

Comparing the individual effects of metformin and rosiglitazone and their combination in obese women with polycystic ovary syndrome: a randomized controlled trial. [2020] To compare the effects of metformin, rosiglitazone, and their combination in obese polycystic ovary syndrome (PCOS) patients with insulin resistance.

5. Ireland pubmed.ncbi.nlm.nih.gov

The effects of metformin on insulin resistance, clomiphene-induced ovulation and pregnancy rates in women with polycystic ovary syndrome. [2022] To evaluate the effects of metformin on insulin resistance, ovarian androgen production, and clomiphene-induced ovulation and pregnancy rates in infertile women with polycystic ovary syndrome (PCOS).

6. England pubmed.ncbi.nlm.nih.gov

Flutamide-metformin plus an oral contraceptive (OC) for young women with polycystic ovary syndrome: switch from third- to fourth-generation OC reduces body adiposity. [2013] Low-dose flutamide-metformin has been developed as a background therapy for non-obese adolescents and young women with hyperinsulinaemic hyperandrogenism, a variant of polycystic ovary syndrome (PCOS). We verified whether the lipolytic efficacy of flutamide-metformin in women with PCOS is enhanced by giving an oral contraceptive (OC) co-therapy that contains drospirenone, instead of gestodene, as progestin.

7. England pubmed.ncbi.nlm.nih.gov

The effects of metformin and letrozole on endometrium and ovary in a rat model. [2018] The effects of metformin and letrozole on endometrium and ovarian reserve were studied in a rat model.

8. New Zealand pubmed.ncbi.nlm.nih.gov

Management of infertility in women with polycystic ovary syndrome : a practical guide. [2019] The management of infertility in women with polycystic ovary syndrome (PCOS) centers around options for inducing ovulation. This is an evidence-based review of the management of PCOS, which includes a MEDLINE search of publications between 1986 and May 2005 and a search of the Cochrane Database. Weight loss, exercise, and metformin will induce ovulation in many insulin-resistant women and obese women with PCOS, and should always be the first-line treatment. Ovulation induction has been performed with clomiphene citrate (clomifene) as the first-line treatment, but the use of aromatase inhibitors has been shown to be as successful. The strategies for reducing the risks of gonadotropin therapy such as low-dose follicle-stimulating hormone (FSH) stimulation and the addition of metformin are discussed. Both gonadotropin releasing-hormone agonists and antagonists are equally effective in in vitro fertilization stimulation in conjunction with FSH therapy. Metformin may have a benefit in pregnancy in reducing the risks of miscarriage and diabetes mellitus; however, prospective trials are still lacking.

9. Germany pubmed.ncbi.nlm.nih.gov

Effect of metformin and exenatide on pregnancy rate and pregnancy outcomes in overweight or obese infertility PCOS women: long-term follow-up of an RCT. [2022] The majority of Polycystic ovary syndrome (PCOS) are overweight or obese with increased infertility and high risk of pregnancy complications. We aim to compare efficacy of metformin and exenatide on spontaneous pregnancy rate, overall pregnancy rate after assisted reproductive technology treatment (ART) and pregnancy outcomes in overweight or obese infertility PCOS.

10. Switzerland pubmed.ncbi.nlm.nih.gov

Current approaches to the diagnosis and treatment of polycystic ovarian syndrome in youth. [2022] Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in reproductive-age women. It often presents during late adolescence but in some cases certain features are evident even before menarche. PCOS is a spectrum of disorders with any combination of oligo/anovulation, clinical and/or biochemical evidence of androgen excess, obesity, insulin resistance and polycystic ovaries on ultrasound. The pathogenesis is unknown; however, it is a complex multigenetic disorder where disordered gonadotropin release, dysregulation of steroidogenesis, hyperinsulinism and insulin resistance play a role. The diagnosis is based on a typical physical exam (acne, hirsutism, obesity, and acanthosis nigricans) and laboratory evidence of hyperandrogenism, such as elevated free testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS), decreased sex hormone-binding globulin (SHBG) and increased luteinizing hormone (LH). An ovarian ultrasound may detect the multiple cysts. Secondary causes of PCOS need to be excluded. There are several classes of medications correcting different parameters of PCOS that can be used alone or in combination. Oral contraceptive therapy is used to reduce androgen and LH levels with resultant improvement in acne and hirsutism, and the induction of regular menses. Antiandrogens are usually required for a substantial improvement in hirsutism score. Insulin sensitizers such as metformin are a new class of drugs utilized in treatment of PCOS. By improving insulin sensitivity and decreasing insulin levels, they improve the unfavorable metabolic profile of patients with PCOS. Metformin also helps to increase SHBG, decrease androgen levels and induce ovulation. Despite all the available medications, life-style changes are the mainstay of therapy as weight loss and exercise improve all parameters of PCOS without the potential side effects of medication.

11. England pubmed.ncbi.nlm.nih.gov

Metformin versus oral contraceptive pill in polycystic ovary syndrome: a Cochrane review. [2022] The object of this review was to compare metformin versus oral contraceptive pill (OCP) treatment in polycystic ovary syndrome.

12. England pubmed.ncbi.nlm.nih.gov

Clinical outcomes of ovulation induction with metformin, clomiphene citrate and human menopausal gonadotrophin in polycystic ovary syndrome. [2017] This pilot study evaluated the effects of coadministration of metformin with clomiphene citrate (CC) and human menopausal gonadotrophin (HMG) in women with CC-resistant polycystic ovary syndrome (PCOS). Sixty women with PCOS were randomly assigned to receive 3 months' treatment with metformin or placebo together with CC and HMG. Transvaginal ultrasound was used to monitor follicular development and ovulation was induced by human chorionic gonadotrophin (HCG). The number of dominant follicles, the oestradiol level on the day HCG was given and the amount of HMG required were significantly lower in the metformin group than in the placebo group, whereas the mono-ovulatory rate and pregnancy rate in the third cycle were significantly higher. The cumulative pregnancy rate in the metformin group (43.3%) was higher than in the placebo group (20.0%), but this difference did not reach statistical significance. In conclusion, coadministration of metformin with CC and HMG reduced the amount of HMG required and increased the mono-ovulatory rate and pregnancy rate.

13. England pubmed.ncbi.nlm.nih.gov

Effects of metformin and ethinyl estradiol-cyproterone acetate on clinical, endocrine and metabolic factors in women with polycystic ovary syndrome. [2013] Polycystic ovary syndrome (PCOS) is a major endocrine abnormality that affects women of reproductive age. Oral contraceptive pills are usually the first choice of treatment for PCOS when fertility is not desired. Metformin, an insulin-sensitizing drug, has been shown to improve such metabolic abnormality. Aim. To compare the effects of a contraceptive pill in combination with metformin on the clinical, endocrine and metabolic parameters in obese and non-obese patients with PCOS.