NIHR Signal Diabetes drug aids fertility in women with polycystic ovaries

Published on 15 February 2018

The diabetes drug metformin may help women with polycystic ovarian syndrome who are having problems getting pregnant, but it is unclear whether it works better than an alternative fertility drug that stimulates the ovaries.

This study updates a previous review of trials that compare metformin with placebo, no treatment or with the fertility drug clomifene. It summarised results of 48 studies, including 4,451 women. The study found that metformin may work better than placebo or no treatment and helps about six in every hundred women with the condition to achieve a successful pregnancy. But there was insufficient evidence to say whether it worked better than clomifene, or whether the combination worked better than clomifene alone.

The findings reflect the current state of knowledge about treatment of this condition and are aligned with current practice and guidance.

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Why was this study needed?

Polycystic ovarian syndrome is a hormonal disorder which affects between 5 and 15% of women of reproductive age. Ovulation is often suppressed, making it harder for women to get pregnant. Women with polycystic ovaries are often overweight or obese and may have insulin resistance or type 2 diabetes.

Weight loss is often suggested as first-line treatment where required, followed by clomifene, a drug that stimulates ovulation, or metformin, a drug that addresses insulin resistance, helps weight loss and can help control type 2 diabetes. However, it is unclear which treatment is better for helping women to have a successful pregnancy. This study updates a previous review of the evidence, adding four new trials and re-analysing the data.

What did this study do?

This was a systematic review and meta-analysis. Researchers assessed trials comparing insulin-sensitising drugs with no treatment, placebo or the ovulation-stimulating drug clomifene, for women with polycystic ovaries and fertility problems.

The researchers searched the literature and found 48 relevant trials (including 4,451 women), all of which looked at the insulin-sensitising drugs including metformin. The review was an update of a review published in 2012 and identified four new trials.

Researchers presented data about live birth rate and gastro-intestinal side effects. They also included information about pregnancies, miscarriages and ovulation rates, and compared results in women who were obese (BMI of 30 or over) or not obese.

They assessed risk of bias in the individual studies and found that this ranged from very low to moderate.

What did it find?

  • Women were more likely to have a live birth if they took metformin, compared to no treatment, or placebo. Low-quality evidence from four studies (435 women) showed a birth rate of 208 per 1,000 women with metformin (95% confidence interval [CI] 141 to 292) compared to 141 per 1,000 for women taking placebo or no treatment. That suggests a 59% increased chance of live birth for women taking metformin (odds ratio [OR] 1.59, 95% CI 1.00 to 2.51), although the results are only marginally statistically significant.
  • Women taking metformin were more likely to get gastrointestinal side effects (OR 4.76, 95% CI 3.06 to 7.41), based on moderate quality evidence from seven studies (435 women). There was no difference in rates of miscarriage; however (OR 1.08, 95% CI 0.50 to 2.35) based on low-quality evidence from four studies (748 women).
  • It was unclear whether adding metformin to clomifene helped more women to have live births (OR 1.21, 95% CI 0.92 to 1.59), based on low-quality evidence from nine studies (1,079 women).
  • It was unclear whether metformin alone or clomifene alone helped more women to have live births. The results varied depending on the women’s BMI. Women with a BMI of under 30 were more likely to give birth if they had taken metformin (OR 1.71, 95% CI 1.00 to 2.94, based on three studies with 241 women) while women with a BMI of over 30 were more likely to give birth if they had taken clomifene (OR 0.30, 95% CI 0.17 to 0.52 based on two studies with 500 women). However, evidence for both groups was judged of very low quality.

What does current guidance say on this issue?

The NICE guideline on fertility problems published in 2013 recommends: “Offer women with WHO Group II anovulatory infertility (which includes polycystic ovarian syndrome) one of the following treatments, taking into account potential adverse effects, ease and mode of use, the woman's BMI, and monitoring needed: clomifene or metformin or a combination of the above.”

The guideline says women taking metformin should be informed about potential gastrointestinal side effects, and that women with polycystic ovarian syndrome who are obese should be advised that losing weight may restore ovulation.

What are the implications?

The study reaffirms the current state of knowledge in treatment of polycystic ovarian syndrome. The updated summary of evidence does not suggest a need to change practice.

The relatively high levels of gastrointestinal side effects found in the studies are a reminder that women should be advised of this risk when considering treatment. The differential findings regarding success of metformin and clomifene for women of different weights reinforces the suggestion in NICE guidelines that clinicians consider a woman’s weight before recommending treatment.

Citation and Funding

Morley LC, Tang T, Yasmin E, et al. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2017;11:CD003053.

No external funding was received.

Bibliography

NICE. Fertility problems: assessment and treatment. CG156. London: National Institute for Health and Care Excellence; 2013.

Why was this study needed?

Polycystic ovarian syndrome is a hormonal disorder which affects between 5 and 15% of women of reproductive age. Ovulation is often suppressed, making it harder for women to get pregnant. Women with polycystic ovaries are often overweight or obese and may have insulin resistance or type 2 diabetes.

Weight loss is often suggested as first-line treatment where required, followed by clomifene, a drug that stimulates ovulation, or metformin, a drug that addresses insulin resistance, helps weight loss and can help control type 2 diabetes. However, it is unclear which treatment is better for helping women to have a successful pregnancy. This study updates a previous review of the evidence, adding four new trials and re-analysing the data.

What did this study do?

This was a systematic review and meta-analysis. Researchers assessed trials comparing insulin-sensitising drugs with no treatment, placebo or the ovulation-stimulating drug clomifene, for women with polycystic ovaries and fertility problems.

The researchers searched the literature and found 48 relevant trials (including 4,451 women), all of which looked at the insulin-sensitising drugs including metformin. The review was an update of a review published in 2012 and identified four new trials.

Researchers presented data about live birth rate and gastro-intestinal side effects. They also included information about pregnancies, miscarriages and ovulation rates, and compared results in women who were obese (BMI of 30 or over) or not obese.

They assessed risk of bias in the individual studies and found that this ranged from very low to moderate.

What did it find?

  • Women were more likely to have a live birth if they took metformin, compared to no treatment, or placebo. Low-quality evidence from four studies (435 women) showed a birth rate of 208 per 1,000 women with metformin (95% confidence interval [CI] 141 to 292) compared to 141 per 1,000 for women taking placebo or no treatment. That suggests a 59% increased chance of live birth for women taking metformin (odds ratio [OR] 1.59, 95% CI 1.00 to 2.51), although the results are only marginally statistically significant.
  • Women taking metformin were more likely to get gastrointestinal side effects (OR 4.76, 95% CI 3.06 to 7.41), based on moderate quality evidence from seven studies (435 women). There was no difference in rates of miscarriage; however (OR 1.08, 95% CI 0.50 to 2.35) based on low-quality evidence from four studies (748 women).
  • It was unclear whether adding metformin to clomifene helped more women to have live births (OR 1.21, 95% CI 0.92 to 1.59), based on low-quality evidence from nine studies (1,079 women).
  • It was unclear whether metformin alone or clomifene alone helped more women to have live births. The results varied depending on the women’s BMI. Women with a BMI of under 30 were more likely to give birth if they had taken metformin (OR 1.71, 95% CI 1.00 to 2.94, based on three studies with 241 women) while women with a BMI of over 30 were more likely to give birth if they had taken clomifene (OR 0.30, 95% CI 0.17 to 0.52 based on two studies with 500 women). However, evidence for both groups was judged of very low quality.

What does current guidance say on this issue?

The NICE guideline on fertility problems published in 2013 recommends: “Offer women with WHO Group II anovulatory infertility (which includes polycystic ovarian syndrome) one of the following treatments, taking into account potential adverse effects, ease and mode of use, the woman's BMI, and monitoring needed: clomifene or metformin or a combination of the above.”

The guideline says women taking metformin should be informed about potential gastrointestinal side effects, and that women with polycystic ovarian syndrome who are obese should be advised that losing weight may restore ovulation.

What are the implications?

The study reaffirms the current state of knowledge in treatment of polycystic ovarian syndrome. The updated summary of evidence does not suggest a need to change practice.

The relatively high levels of gastrointestinal side effects found in the studies are a reminder that women should be advised of this risk when considering treatment. The differential findings regarding success of metformin and clomifene for women of different weights reinforces the suggestion in NICE guidelines that clinicians consider a woman’s weight before recommending treatment.

Citation and Funding

Morley LC, Tang T, Yasmin E, et al. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2017;11:CD003053.

No external funding was received.

Bibliography

NICE. Fertility problems: assessment and treatment. CG156. London: National Institute for Health and Care Excellence; 2013.

Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility

Published on 29 November 2017

Morley, L. C.,Tang, T.,Yasmin, E.,Norman, R. J.,Balen, A. H.

Cochrane Database Syst Rev Volume 11 , 2017

BACKGROUND: Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia occurs secondary to insulin resistance and is associated with increased risk of cardiovascular disease and diabetes mellitus. Insulin-sensitising agents such as metformin may be effective in treating PCOS-related anovulation. OBJECTIVES: To evaluate the effectiveness and safety of insulin-sensitising drugs in improving reproductive and metabolic outcomes for women with PCOS undergoing ovulation induction. SEARCH METHODS: We searched the following databases from inception to January 2017: Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. We searched registers of ongoing trials and reference lists from relevant studies. SELECTION CRITERIA: We included randomised controlled trials of insulin-sensitising drugs compared with placebo, no treatment, or an ovulation-induction agent for women with oligo and anovulatory PCOS. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility and bias. Primary outcomes were live birth rate and gastrointestinal adverse effects. Secondary outcomes included other pregnancy outcomes, menstrual frequency and metabolic effects. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I(2) statistic and reported quality of the evidence for primary outcomes using GRADE methodology. MAIN RESULTS: We assessed the interventions metformin, clomiphene citrate, metformin plus clomiphene citrate, D-chiro-inositol, rosiglitazone and pioglitazone. We compared these with each other, placebo or no treatment. We included 48 studies (4451 women), 42 of which investigated metformin (4024 women). Evidence quality ranged from very low to moderate. Limitations were risk of bias (poor reporting of methodology and incomplete outcome data), imprecision and inconsistency. Metformin versus placebo or no treatmentThe evidence suggests that metformin may improve live birth rates compared with placebo (OR 1.59, 95% CI 1.00 to 2.51, 4 studies, 435 women, I(2) = 0%, low-quality evidence). The metformin group experienced more gastrointestinal side effects (OR 4.76, 95% CI 3.06 to 7.41, 7 studies, 670 women, I(2) = 61%, moderate-quality evidence) but had higher rates of clinical pregnancy (OR 1.93, 95% CI 1.42 to 2.64, 9 studies, 1027 women, I(2) = 43%, moderate-quality evidence), ovulation (OR 2.55, 95% CI 1.81 to 3.59, 14 studies, 701 women, I(2) = 58%, moderate-quality evidence) and menstrual frequency (OR 1.72, 95% CI 1.14 to 2.61, 7 studies, 427 women, I(2) = 54%, low-quality evidence). There was no clear evidence of a difference in miscarriage rates (OR 1.08, 95% CI 0.50 to 2.35, 4 studies, 748 women, I(2) = 0%, low-quality evidence). Metformin plus clomiphene citrate versus clomiphene citrate alone There was no conclusive evidence of a difference between the groups in live birth rates (OR 1.21, 95% CI 0.92 to 1.59, 9 studies, 1079 women, I(2) = 20%, low-quality evidence), but gastrointestinal side effects were more common with combined therapy (OR 3.97, 95% CI 2.59 to 6.08, 3 studies, 591 women, I(2) = 47%, moderate-quality evidence). However, the combined therapy group had higher rates of clinical pregnancy (OR 1.59, 95% CI 1.27 to 1.99, 16 studies, 1529 women, I(2) = 33%, moderate-quality evidence) and ovulation (OR 1.57, 95% CI 1.28 to 1.92, 21 studies, 1624 women, I(2) = 64%, moderate-quality evidence). There was a statistically significant difference in miscarriage rate per woman, with higher rates in the combined therapy group (OR 1.59, 95% CI 1.03 to 2.46, 9 studies, 1096 women, I(2) = 0%, low-quality evidence) but this is of uncertain clinical significance due to low-quality evidence, and no clear difference between groups when we analysed miscarriage per pregnancy (OR 1.30, 95% CI 0.80 to 2.12, 8 studies; 400 pregnancies, I(2) = 0%, low-quality evidence). Metformin versus clomiphene citrateWhen all studies were combined, findings for live birth were inconclusive and inconsistent (OR 0.71, 95% CI 0.49 to 1.01, 5 studies, 741 women, I(2) = 86%, very low-quality evidence). In subgroup analysis by obesity status, obese women had a lower birth rate in the metformin group (OR 0.30, 95% CI 0.17 to 0.52, 2 studies, 500 women, I(2) = 0%, very low-quality evidence), while data from the non-obese group showed a possible benefit from metformin, with high heterogeneity (OR 1.71, 95% CI 1.00 to 2.94, 3 studies, 241 women, I(2) = 78%, very low-quality evidence). Similarly, among obese women taking metformin there were lower rates of clinical pregnancy (OR 0.34, 95% CI 0.21 to 0.55, 2 studies, 500 women, I(2) = 0%, very low-quality evidence) and ovulation (OR 0.29, 95% CI 0.20 to 0.43 2 studies, 500 women, I(2) = 0%, low-quality evidence) while among non-obese women, the metformin group had more pregnancies (OR 1.56, 95% CI 1.05 to 2.33, 5 studies, 490 women, I(2) = 41%, very low-quality evidence) and no clear difference in ovulation rates (OR 0.81, 95% CI 0.51 to 1.28, 4 studies, 312 women, low-quality evidence, I(2)=0%). There was no clear evidence of a difference in miscarriage rates (overall: OR 0.92, 95% CI 0.50 to 1.67, 5 studies, 741 women, I(2) = 52%, very low-quality evidence). D-chiro-inositol (2 studies), rosiglitazone (1 study) or pioglitazone (1 study) versus placebo or no treatmentWe were unable to draw conclusions regarding other insulin-sensitising drugs as no studies reported primary outcomes. AUTHORS' CONCLUSIONS: Our updated review suggests that metformin alone may be beneficial over placebo for live birth, although the evidence quality was low. When metformin was compared with clomiphene citrate, data for live birth were inconclusive, and our findings were limited by lack of evidence. Results differed by body mass index (BMI), emphasising the importance of stratifying results by BMI. An improvement in clinical pregnancy and ovulation suggests that clomiphene citrate remains preferable to metformin for ovulation induction in obese women with PCOS.An improved clinical pregnancy and ovulation rate with metformin and clomiphene citrate versus clomiphene citrate alone suggests that combined therapy may be useful although we do not know whether this translates into increased live births. Women taking metformin alone or with combined therapy should be advised that there is no evidence of increased miscarriages, but gastrointestinal side effects are more likely.

Expert commentary

Polycystic ovarian syndrome, the most common endocrinopathy in women of reproductive age, is associated with a spectrum of symptoms including subfertility. Considering insulin resistance as the central feature, metformin is commonly prescribed to improve menstrual cyclicity and fertility.

The evidence, based on the meta-analysis of randomised controlled trials supporting the use of metformin to improve natural conception compared with placebo, provides a pragmatic and safe treatment option that can be offered in the community level albeit its potential gastrointestinal side-effects.

Kanna Jayaprakasan, Subspecialist & Honorary Associate Professor in Reproductive Medicine, Royal Derby Hospital, Derby & University of Nottingham; IVF Consultant, CARE Fertility, Nottingham