Metformin vs. Birth Control Pills for Polycystic Ovary Syndrome

(SHK002 Trial)

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}

Research Team

Chris McCartney, MD

Principal Investigator

University of Virginia

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 Canada, Japan, China, Switzerland for the following indications:

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

Who Is Running the Clinical Trial?

University of Virginia

Lead Sponsor

Trials

802

Recruited

1,342,000+

James E. Ryan

University of Virginia

Chief Executive Officer since 2018

J.D. from Harvard Law School

Nikki Hastings

University of Virginia

Chief Medical Officer since 2018

Ph.D. in Biomedical Engineering from University of Virginia

Findings from Research

In a study of 119 women with polycystic ovary syndrome (PCOS), persistence rates for oral contraceptive pills (OCPs) and metformin were similar at 3 months (57.1% for OCPs vs. 57.8% for metformin), indicating both treatments are equally accepted initially.

However, persistence with both treatments significantly declined over time, with only 21.7% continuing OCPs and 31.2% continuing metformin at 12 months, highlighting a challenge in long-term adherence to treatment for PCOS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Persistence with oral contraceptive pills versus metformin in women with polycystic ovary syndrome. Karjane, NW., Cheang, KI., Mandolesi, GA., et al.[2022]

Targeting insulin resistance in women with PCOS can lead to significant improvements in hormonal balance, metabolism, and ovulation, which may enhance fertility.

The treatment approach for PCOS should be personalized based on individual factors such as age, degree of androgen excess, presence of obesity, and fertility desires, with options including lifestyle changes, insulin sensitizers like metformin, and hormonal therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting insulin sensitivity in the treatment of polycystic ovary syndrome. Pasquali, R., Gambineri, A.[2013]

In a systematic review of 14 randomized controlled trials involving 707 nonobese women with PCOS, the combination of oral contraceptives (OCs) and metformin significantly improved fasting glucose and insulin levels compared to OCs alone.

While the combination treatment enhanced glucose metabolism, it did not show significant differences in other metabolic markers like cholesterol or insulin resistance, suggesting that metformin specifically benefits glucose regulation in this population.

NCBI (Pubmed)

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. Wu, L., Liu, Y., Huang, X., et al.[2023]

In a study of 204 obese women with PCOS and insulin resistance, high-dose metformin (1,500 mg/day) significantly improved weight loss and menstrual patterns after 6 months, making it a recommended treatment for these patients.

Rosiglitazone, either alone or in combination with low-dose metformin, was more effective in reducing total cholesterol and triglyceride levels, suggesting it may be better for women with abnormal lipid profiles.

NCBI (Pubmed)

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. Li, Y., Tan, J., Wang, Q., et al.[2020]

Metformin significantly improved insulin resistance and reduced androgen levels in infertile women with polycystic ovary syndrome (PCOS) over a 3-month treatment period.

While metformin combined with clomiphene citrate showed higher ovulation and pregnancy rates compared to clomiphene alone, these differences were not statistically significant, indicating that while metformin has beneficial effects on insulin and androgens, it may not significantly enhance fertility outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of metformin on insulin resistance, clomiphene-induced ovulation and pregnancy rates in women with polycystic ovary syndrome. Sahin, Y., Yirmibeş, U., Keleştimur, F., et al.[2022]

In a study of 29 non-obese women with PCOS, switching from a gestodene to a drospirenone oral contraceptive while on low-dose flutamide-metformin therapy led to significant reductions in total and abdominal fat, along with an increase in lean body mass over 6 months.

The results suggest that drospirenone may enhance the lipolytic effects of flutamide-metformin, making it a more effective co-therapy for managing body composition in women with hyperinsulinaemic hyperandrogenism associated with PCOS.

NCBI (Pubmed)

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. Ibáñez, L., De Zegher, F.[2013]

In a study involving 40 female rats, both metformin and letrozole were found to significantly affect endometrial thickness compared to a control group, indicating potential benefits for uterine health.

While both treatments showed a tendency to enhance total follicle count, they did not significantly change the ovarian reserve, suggesting that their effects on ovarian follicles are comparable and may not impact fertility negatively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of metformin and letrozole on endometrium and ovary in a rat model. Oner, G., Ozcelik, B., Ozgun, MT., et al.[2018]

Weight loss, exercise, and metformin are effective first-line treatments for inducing ovulation in women with PCOS, particularly those who are insulin-resistant or obese.

Clomiphene citrate remains a standard treatment for ovulation induction, but aromatase inhibitors have shown comparable success, highlighting multiple effective options for managing infertility in PCOS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of infertility in women with polycystic ovary syndrome : a practical guide. Stadtmauer, L., Oehninger, S.[2019]

In a study of 160 overweight or obese women with PCOS, those treated with exenatide for 12 weeks had a higher spontaneous pregnancy rate (29.2%) compared to those treated with metformin (14.7%), suggesting that exenatide may be more effective in promoting natural conception.

Overall pregnancy rates after assisted reproductive technology (ART) were similar between the two groups (79.2% for exenatide and 76% for metformin), indicating that while exenatide improved spontaneous pregnancies, it did not provide additional benefits for pregnancies achieved through ART.

NCBI (Pubmed)

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. Li, R., Mai, T., Zheng, S., et al.[2022]

Polycystic ovary syndrome (PCOS) is a complex disorder affecting reproductive-age women, characterized by symptoms like irregular menstruation, excess androgens, and insulin resistance, with diagnosis based on clinical and laboratory findings.

While medications like oral contraceptives and metformin can help manage symptoms and improve metabolic profiles, lifestyle changes such as weight loss and exercise are crucial for effectively treating PCOS without the side effects associated with drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current approaches to the diagnosis and treatment of polycystic ovarian syndrome in youth. Harwood, K., Vuguin, P., DiMartino-Nardi, J.[2022]

A systematic review of four randomized controlled trials involving 104 subjects found that metformin was less effective than oral contraceptive pills (OCP) in improving menstrual patterns and reducing testosterone levels, but more effective in lowering fasting insulin levels.

Both treatments showed no significant differences in their effects on hirsutism, acne, or the risk of developing type 2 diabetes, indicating that OCP may not pose additional metabolic risks compared to metformin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin versus oral contraceptive pill in polycystic ovary syndrome: a Cochrane review. Costello, MF., Shrestha, B., Eden, J., et al.[2022]

In a pilot study involving 60 women with clomiphene citrate-resistant PCOS, the addition of metformin to clomiphene citrate and human menopausal gonadotrophin significantly reduced the amount of HMG needed for treatment and increased the mono-ovulatory rate.

The cumulative pregnancy rate was higher in the metformin group (43.3%) compared to the placebo group (20.0%), suggesting that metformin may enhance fertility outcomes in women with PCOS, although this difference was not statistically significant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcomes of ovulation induction with metformin, clomiphene citrate and human menopausal gonadotrophin in polycystic ovary syndrome. Cheng, J., Lv, J., Li, CY., et al.[2017]

In a study of 60 women with PCOS, the combination of the contraceptive pill Diane35 and metformin was more effective in reducing hyperandrogenemia and insulin levels compared to metformin alone, suggesting a synergistic effect in managing PCOS symptoms.

Diane35 restored menstrual regularity in all patients, while metformin significantly reduced body mass index and waist-to-hip ratio in obese patients, highlighting the distinct benefits of each treatment approach.

NCBI (Pubmed)

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. Wu, J., Zhu, Y., Jiang, Y., et al.[2013]

References

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

Persistence with oral contraceptive pills versus metformin in women with polycystic ovary syndrome. [2022]

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

Targeting insulin sensitivity in the treatment of polycystic ovary syndrome. [2013]

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]

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]

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]

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]

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

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

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

Management of infertility in women with polycystic ovary syndrome : a practical guide. [2019]

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]

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

Current approaches to the diagnosis and treatment of polycystic ovarian syndrome in youth. [2022]

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

Metformin versus oral contraceptive pill in polycystic ovary syndrome: a Cochrane review. [2022]

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]

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]