Originally summarized by Christine Schroeder, PH.D. and published on INCIID. Update added by INCIID May 2026.

Summarized by Christine Schroeder, Ph.D.

Authors: Vincenzo De Leo, Antonio la Marca, Antonino Ditto, Giuseppe Morgante, and Antonio Cianci, Department of Obstetrics and Gynecology, Universities of Siena and Catania, Italy
Journal: Fertility and Sterility, Volume 72, Number 2, pp. 282-285

About This Article

This page presents Dr. Schroeder’s summary of an early and influential study on metformin use in PCOS patients undergoing FSH treatment. While the study was small and reflected the state of knowledge in the late 1990s, it was among the first to demonstrate that metformin could improve the predictability of ovarian stimulation in PCOS patients resistant to clomiphene. The findings helped shape subsequent research that now spans decades and thousands of patients. A 2026 Update section at the bottom of this page summarizes what current evidence and international guidelines say about metformin’s role today.

Original Summary by Christine M. Schroeder, Ph.D.

Polycystic ovarian syndrome (PCOS) is a common cause of menstrual disruption. PCOS is characterized by elevated androgen, insulin, and luteinizing hormone levels. Patients also frequently present with male pattern hair growth, amenorrhea, and above-normal weight.

Patients with PCOS frequently experience infertility; additionally their cases can present a challenge to the fertility specialist. These individuals will often respond very slowly to stimulation and tend not to develop dominant follicles. As a result, these patients will often ultimately develop a large number of mature follicles and are at increased risk for hyperstimulation.

Metformin is a drug normally used to treat individuals with non-insulin dependent diabetes. It has multiple actions, including reduction of glucose production in the liver and increasing glucose uptake throughout the body. Metformin also decreases hyperinsulinism, reduces plasma levels of luteinizing hormone (LH), and reduces ovarian androgen production.

The insulin, androgen, and LH-related actions of metformin form the basis for its use for patients with PCOS. The normalization of these hormone levels addresses many of the underlying mechanisms of PCOS. As a result, patients should respond to ovarian stimulation in a more predictable and orderly fashion.

The current study examines whether metformin affects the response to FSH therapy among PCOS patients resistant to clomiphene citrate (CC). The researchers defined CC resistance as a failure to ovulate or conceive on CC dosages of up to 150 mg for three cycles or more. Study participants were 20 women with PCOS who had normal blood pressure, prolactin levels, thyroid function, and ACTH response. Patients were not screened for insulin resistance. All male partners had normal semen analyses, and none of the patients had taken ovulatory medications within two cycles of starting the study.

Participants were randomly assigned to two groups. In the first group (“F-M”), patients underwent two cycles of FSH treatment, then one cycle of metformin treatment, and another cycle of metformin and FSH treatment. The second group (“M-F”) received metformin treatment for one cycle, followed by a cycle of metformin and FSH treatment.

Study Structure:

• Group F-M: Cycle One — FSH only / Cycle Two — FSH only / Cycle Three — Metformin only / Cycle Four — FSH + Metformin
• Group M-F: Cycle Three — Metformin only / Cycle Four — FSH + Metformin

The treatment protocol began patients on one vial of urinary-derived FSH per day. The dosage was increased by one vial per day until detection of an ovarian response. The patient was then maintained on that dosage until the hCG shot was given. The criteria for administering the hCG shot were: (1) the presence of at least one follicle of 18 mm or greater and (2) no more than three follicles greater than or equal to 17 mm. The metformin dosage used was 500 mg three times daily.

A preliminary analysis of the results indicated that the two treatment groups did not differ in terms of age, infertility history, body mass index, or hormonal profiles. In the first FSH-only cycle that the F-M group underwent, one of the patients conceived. A second patient conceived in the next cycle of FSH-only treatment. Therefore, only eight of the ten patients in the F-M group went on to take Metrodin.

Results:

• The daily dose needed to cause a detectable ovarian response was similar in both groups.
• Estradiol levels in FSH-only cycles were significantly higher: 720 pg/mL versus 450 pg/mL.
• Number of follicles in FSH-only cycles was significantly higher: 4.5 versus 2.5.
• Cycles cancelled due to too many follicles: 31.5% in FSH-only cycles versus none in FSH-Metformin cycles.
• Pregnancy rates per cycle: 10.5% (FSH-only) versus 16.6% (FSH-Metformin) — not statistically significant.
• Hyperstimulation after hCG: 26.3% (FSH-only) versus 16.6% (FSH-Metformin) — not statistically significant.

The researchers concluded that metformin pretreatment appears to result in more orderly follicular growth in FSH-treated patients with PCOS. Additionally, because the patients were not screened for insulin resistance, the results are not specific to only insulin-resistant PCOS patients.

Note from Dr. Schroeder: These sample sizes were very small. With a larger sample, it is likely that the pregnancy and hyperstimulation rates between the two groups would have been significantly different.

2026 Update: What Current Evidence and Guidelines Say About Metformin and PCOS/PMOS

Editorial update by INCIID, 2026. All updates reflect current peer-reviewed literature and guidelines from ASRM and the 2023 International Evidence-based Guideline for the Assessment and Management of PCOS/PMOS (ESHRE/ASRM).

The study summarized above was an early and important contribution to understanding how metformin could improve ovarian stimulation outcomes in PCOS/PMOS patients. In the nearly three decades since it was published, metformin has been the subject of extensive clinical trials, Cochrane reviews, and international guideline development. Here is where the evidence stands today.

PCOS/PMOS: A More Complete Picture in 2026

The understanding of PCOS/PMOS has expanded considerably since the late 1990s. PCOS/PMOS is now recognized as the most common endocrine disorder in women of reproductive age, affecting 8 to 13 percent of women globally. It is diagnosed using the Rotterdam Criteria, which require two of three features: oligo-ovulation or anovulation, clinical or biochemical hyperandrogenism, and polycystic ovarian morphology on ultrasound.

PCOS/PMOS is understood today as a heterogeneous condition with reproductive, metabolic, and psychological consequences across a woman’s lifespan — not simply a fertility problem. The psychological burden of PCOS/PMOS, including elevated rates of anxiety, depression, and disordered eating, is now a recognized and prioritized component of care in international guidelines.

A Note on Terminology: PCOS Is Now PMOS

In 2024, The Lancet published a landmark commission recommending that polycystic ovary syndrome be renamed Polycystic Metabolic and Ovarian Syndrome — PMOS. This name change was endorsed by ASRM and reflects a more accurate understanding of the condition as a systemic metabolic disorder, not simply an ovarian one. The new name removes the stigma associated with “cysts” (which are actually follicles, not cysts) and better represents the full spectrum of metabolic, hormonal, and reproductive features involved.

Throughout this article the condition is referred to as PCOS to match the original study and current clinical literature, which has not yet fully transitioned to the new terminology. For a full explanation of the name change and what it means for patients, see INCIID’s PMOS article and INCIID Insights Episode 2 on Spotify — our podcast episode dedicated to this topic.

The Current Role of Metformin: Metabolic First, Fertility Second

The 2023 International Evidence-based Guideline for the Assessment and Management of PCOS/PMOS — jointly endorsed by ASRM and the European Society of Human Reproduction and Embryology (ESHRE) — provides the most comprehensive current guidance on metformin use.

The guidelines confirm that metformin remains a valuable medication for women with PCOS/PMOS, but clarify its primary role: metformin is now recommended primarily for the management of metabolic features of PCOS/PMOS — particularly insulin resistance, elevated glucose levels, and lipid abnormalities — rather than as a first-line fertility treatment on its own.

Specifically, the 2023 guidelines state that metformin alone is not the preferred first-line option for ovulation induction. It may be used alone when other ovulation-inducing agents are not available or appropriate, but patients should be informed that more effective options exist. Metformin is not routinely recommended for use during pregnancy in women with PCOS/PMOS, and patients should be counseled that the long-term effects of metformin on infant health remain an area of ongoing research.

Letrozole Has Replaced Clomiphene as the First-Line Treatment

One of the most significant changes since the study above was published is the shift in first-line therapy for ovulation induction. For most of the history covered by this article, clomiphene citrate (Clomid) was the standard first-line medication for inducing ovulation in women with PCOS/PMOS. That is no longer the case.

A landmark randomized trial of 750 women with anovulatory PCOS/PMOS reported cumulative live birth rates of 27.5 percent for letrozole compared to 19.1 percent for clomiphene. Based on this and subsequent evidence, the 2023 international guidelines and ASRM now recommend letrozole as the preferred first-line pharmacological treatment for ovulation induction in women with PCOS/PMOS who have no other infertility factors.

Letrozole is an aromatase inhibitor used off-label for ovulation induction. It is typically given orally for five days beginning on day three of the menstrual cycle. It carries a lower risk of multiple gestation than clomiphene and does not appear to increase the risk of birth defects.

Clomiphene citrate, combined with metformin, remains a recognized second-line option — particularly for women who do not respond to letrozole or who have specific clinical circumstances that make letrozole less appropriate.

Where Metformin Fits in the Current Treatment Pathway

Based on the 2023 international guidelines and current evidence, here is how metformin fits into PCOS/PMOS fertility treatment today:

• For metabolic management: Metformin is recommended for adult women with PCOS/PMOS who have a BMI of 25 kg/m² or higher, primarily to address insulin resistance and metabolic features. It is considered more effective than inositol for this purpose.
• For ovulation induction: Metformin alone may improve clinical pregnancy and live birth rates in women with anovulatory PCOS/PMOS, but it is less effective than letrozole or clomiphene as a standalone treatment.
• Combined with clomiphene: Clomiphene combined with metformin is recognized as a second-line option and may be particularly useful in women with clomiphene resistance.
• For IVF: A 2020 Cochrane review of 13 randomized controlled trials (1,132 women with PCOS/PMOS) found metformin as a co-treatment during IVF/ICSI may reduce OHSS incidence and improve pregnancy outcomes.
• For OHSS prevention: Both metformin and letrozole have been shown to reduce OHSS risk when co-administered with gonadotropins in PCOS/PMOS patients, particularly those with high AMH levels.

What Has Not Changed

Several findings from the original study have stood the test of time: Metformin’s mechanism — reducing hyperinsulinism, suppressing LH, and reducing ovarian androgen production — remains well established. The benefit of more orderly follicular development with metformin co-treatment has been confirmed in much larger studies. Metformin’s favorable safety profile — low cost, minimal serious side effects, no demonstrated teratogenicity — continues to be noted in guidelines. The most common side effects are gastrointestinal and can often be reduced by taking metformin with food or using an extended-release formulation.

A Note for Patients

If you have PCOS/PMOS and are working with a fertility specialist, the current treatment pathway looks different from what was available when the original study above was conducted. Letrozole is now the first medication most clinicians will try. Metformin may be part of your treatment plan — particularly if you have metabolic features of PCOS/PMOS such as insulin resistance, elevated blood sugar, or weight-related symptoms — but it is rarely used alone as a fertility treatment today.

If you have been told you are clomiphene-resistant, there are now more options available: letrozole, gonadotropins with careful monitoring, and IVF with OHSS-prevention protocols are all part of the modern toolkit.

The INCIID forum and advisory board are available to help you understand your options and connect with specialists experienced in PCOS/PMOS management.

References

1. De Leo V, la Marca A, Ditto A, Morgante G, Cianci A. Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome. Fertility and Sterility. 1999;72(2):282-285.
2. 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. ESHRE/ASRM.
3. Legro RS, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. New England Journal of Medicine. 2007;356(6):551-566.
4. Legro RS, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. New England Journal of Medicine. 2014;371(2):119-129.
5. Bordewijk EM, et al. Metformin during ovulation induction with gonadotrophins. Cochrane Database of Systematic Reviews. 2017.
6. Tso LO, et al. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews. 2020.
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8. Cleveland Clinic Journal of Medicine. Polycystic ovary syndrome: An update on diagnosis and management. March 2026.
9. ASRM Practice Committee. Role of metformin for ovulation induction in infertile patients with PCOS: a guideline. Fertility and Sterility. 2017.
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