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NCT Number: NCT07120815

Optimizing Metformin Use in Polycystic Ovary Syndrome

The goal of this clinical trial is to learn if a metformin dose of 1500 mg or 2250 mg per day is better to treat polycystic ovary syndrome (PCOS) in adults. It will also learn about the adverse effects of metformin. The trial aims to evaluate which metformin dose is better for:

1. improving biochemical and clinical outcomes 2. gastrointestinal side-effects 3. mental health and quality of life

Participants will:

* Be randomized to take metformin at a dose of either 1500mg or 2250mg every day for 6 months * Visit the clinic three times during the trial for checkups and tests * Answer questionnaires on menstrual cyclicity, mental health, quality of life and side-effects

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Key information

Conditions

Polycystic Ovary Syndrome (PCOS) Adnexal Diseases Cysts Endocrine System Diseases Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Genital Diseases Genital Diseases, Female Gonadal Disorders Neoplasms Ovarian Cysts Ovarian Diseases Polycystic Ovary Syndrome Urogenital Diseases

Age range

18 year–37 year

Sex eligibility

Female

Study type

Interventional

Phase

Phase 3

Primary location

The Reproductive Medicine Unit, Helsinki University Hospital

Helsinki, Finland

Location contact

Johanna M Melin, MD

CONTACT

[email protected]

+358505382526

About this study

INTRODUCTION Polycystic ovary syndrome (PCOS) remains a key public health burden as it is one of the most common endocrine and metabolic disorders affecting up to 13% of women globally. The Rotterdam diagnostic criteria were updated and internationally endorsed in the 2023 International PCOS guideline and include a) ovulatory and menstrual dysfunction, b) biochemical and/or clinical hyperandrogenism and c) polycystic ovary morphology (PCOM) at ultra-sound. For a diagnosis in adults two of three criteria are required, with PCOM remaining nonspecific for PCOS in adolescents.

Women with PCOS present with diverse features; metabolic (weight gain, obesity, insulin resistance and diabetes) reproductive (infertility and pregnancy complications), endocrine (hyperandrogenism, hirsutism and acne) and psychosocial (depression, anxiety and poor quality of life).

While lifestyle management is strongly recommended for weight management, for those with higher body mass index (BMI), sustainable efficacy for weight loss can be limited and additional pharmacological treatment may be needed. The 2023 Updated International PCOS Guideline recommends that metformin, in addition to lifestyle, should be considered in adults with PCOS and BMI ≥ 25 kg/m2 for prevention of weight gain and management of weight and metabolic disorders. Metformin may be considered in adults with BMI < 25 kg/m2 and adolescents with PCOS, acknowledging more limited evidence.

The aim of this randomized controlled trial (RCT) is to evaluate whether a metformin dose of 1500 mg is inferior compared to a dose of 2250 mg per day for females 18-37 years of age with PCOS in:

  • improving biochemical and clinical outcomes
  • gastrointestinal side-effects
  • mental health and quality of life

MATERIALS AND METHODS A double-blind, randomized controlled trial, including adults (age 18-37 years) with PCOS and a BMI ≥ 25 kg/m2 will be carried out. The randomization will be computer-generated and performed by the hospital pharmacy with 1:1 allocation in random blocks. Power analysis has indicated that a total number of 184 females (92 in each group) will be needed to reveal a 4 kg weight reduction (equals 5% weight reduction for a person weighting 80 kg) with an 80% power. We estimated a 15% drop-out in our power analysis.

Potential participants for the study will be recruited from females referred to the Reproductive Medicine Unit at Helsinki University Hospital and by advertising via the patient organization for those with PCOS (Korento). The internationally indorsed Rotterdam criteria will be used to diagnose women with PCOS. Pregnant women, women breastfeeding, women with untreated thyroid disease, hyperprolactinemia, other conditions with hyperandrogenism or use of hormonal contraceptive during the last three months will be excluded.

Women willing to participate in the study will be randomized to metformin 1500mg or 2250 mg per day for a 6-month period. Blood samples (on hyperandrogenism and metabolism), clinical examination (anthropometry and hirsutism) and a questionnaire (menstrual cyclicity, mental health, quality of life, side-effects) will be performed before starting the metformin medication, as well as at 3 and 6 months after onset of medication. Polycystic ovary morphology will be evaluated by measuring anti-mullerian hormone levels (AMH) and by vaginal ultrasound.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Diagnosed PCOS (According to the International evidence-based Guideline for PCOS 2023)
  • Age: 18-37 years
  • BMI: ≥ 25 and <40 kg/m2
  • Signed informed consent and willingness to comply with the trial procedures
  • Sufficient skills in the Finnish or Swedish language

Exclusion criteria

  • Not meeting the criteria according to the International evidence-based Guideline for PCOS 2023)
  • Use of hormonal contraceptive during the last 3 months
  • Pregnancy
  • Breastfeeding
  • Untreated diabetes
  • Hypothyroidism
  • Hyperprolactinemia
  • Use of medications for diabetes,
  • Use of medications for high cholesterol
  • Use of medications for obesity
  • Use of medications for cortisone (per oral)
  • Hypersensitivity to metformin
  • Acute metabolic acidosis
  • Renal impairment
  • Hepatic insufficiency
  • Heart- or respiratory failure
  • Serious mental illness
  • Alcoholism
  • Investigator site staff directly involved in the conduct of the study and their family members

Treatment and study plan

Metformin 1500 mg daily

Drug

metformin 500mg tablets, 3 times per day

Metformin 2250 mg daily

Drug

Metformin 750mg, 3 times daily

Primary outcomes

  1. Weight

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    Weight will be measured by a standard scale to an accuracy of +/- 0,1kg.

  2. Homeostatic model assessment for insulin resistance (HOMA-IR)

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    HOMA-IR will be calculated with the formula: fasting plasma glucose (mmol/L) × fasting serum insulin (mU/L) divided by 22.5 (9)

  3. Hirsutism

    Time frame: The investigators will report change from baseline to 14 and 26 weeks.

    Modified Ferriman Gallwey score (mFG) will be measured and a score of 4 or more will be regarded as hirsutism in Caucasian women, whereas a score of 6 or more will be regarded hirsutism for other ethnicities

  4. Total testosterone

    Time frame: The investigators will measure change from baseline to 14 and 26 weeks

    Testosterone nmol/l (liquid chromatography with tandem mass spectrometry (LC-MS/MS). All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.

  5. Appearance of severe of adverse effects

    Time frame: The investigators will measure change from baseline to 14 and 26 weeks

    In our questionnaire the investigators will ask the participants whether they have experienced abdominal pain, reflux, nausea, diarrhoea or loss of appetite during the last two weeks and grade the symptoms from 1-5 (1 being never and 5 being all the time). The investigators will count the scores and give each participant a score between 5-25. A severe adverse effect is defined as a score of 4 or more in one of the questions (indicating a daily experience of abdominal pain, reflux, nausea, diarrhoea or loss of appetite during the last two weeks).

  6. Anti-Mullerian hormone (AMH)

    Time frame: The investigators will measure change from baseline to 14 and 26 weeks

    AMH will be measured in ug/l. All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.

Secondary outcomes

  1. Body mass index (BMI)

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    Weight (kilogram) and height (metre) will be combined to report BMI in kg/m^2

  2. Waist circumference (WC)

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    WC will be measured halfway between the participant's lowest rib and the top of the participant's hipbone

  3. Waist-hip-ratio (WHR)

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    WHR will be calculated as waist measurement divided by hip measurement (W⁄H). Hip circumference is determined as the maximum value over the glottal region, measured to the nearest centimetre.

  4. Body adiposity index (BAI)

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    BAI will be measured using the following equation: hip circumference (cm)/height (m) - 18

  5. Body composition

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    Body composition will be measured with a multi-frequency segmental body composition analyzer (TANITA Health Ware) WHR (Waist-hip-ratio). Will be calculated as waist measurement divided by hip measurement (W⁄H). Hip circumference is determined as the maximum value over the glottal region, measured to the nearest centimetre.

    WC (Waist circumference). Measured halfway between the participant's lowest rib and the top of the participant's hipbone BAI (Body adiposity index). Will be measured using the following equation: hip circumference (cm)/height (m) - 18 BP (blood pressure) (systolic and diastolic) and pulse. Will be measured twice with at least 3 minutes apart after at least 10 min rest from non-dominant upper extremity in a subject in supine position

  6. Blood pressure (BP)

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    BP (systolic and diastolic) will be measured twice with at least 3 minutes apart after at least 10 min rest from non-dominant upper extremity in a subject in supine position

  7. Pulse

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    Pulse will be measured twice with at least 3 minutes apart after at least 10 min rest from non-dominant upper extremity in a subject in supine position

  8. Fasting glucose

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    fasting glucose mmol/l (photometric hexokinase method) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.

  9. Fasting insulin

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    fasting insulin mU/l (immunochemiluminometric assay) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.

  10. HbA1C

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    HbA1C mmol/mol (photometric enzymatic method) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.

  11. Lipids (cholesterol and its subclasses, triglycerides)

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    Total cholesterol, mmol/l and triglycerides mmol/l with an enzymatic photometric method, LDL and HDL mmol/l with a direct enzymatic photometric method All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.

  12. C-reactive protein (CRP)

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    CRP will be measured in mg/l (photometric immunochemical method) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.

  13. 2-hour oral glucose tolerance test (OGTT)

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    2-hour OGTT mmol/l

  14. Alanine Aminotransferase (ALAT)

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    ALAT will be measured in U/l (photometric method according to the International Federation of Clinical Chemistry and Laboratory Medicine recommendation) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.

  15. Gamma-glutamyl transferase (G-GT)

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    G-GT will be measured in U/l (photometric method according to the International Federation of Clinical Chemistry and Laboratory Medicine recommendation) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.

  16. Fatty Liver Index (FLI)

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    FLI will be measured by the following formula:

    FLI = (e^y) / (1 + e^y) * 100 where: y = 0.953 * ln(TG) + 0.139 * BMI + 0.718 * ln(GGT) + 0.053 * WC - 15.745 e is the base of the natural logarithm (approximately 2.718) ln denotes the natural logarithm TG is triglycerides in mg/dL BMI is body mass index in kg/m² GGT is gamma-glutamyltransferase in U/L WC is waist circumference in cm All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.

  17. Matsuda Index

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    Matsuda Index will be measured by the following formula:

    Matsuda Index = 10,000 / √[(fasting glucose (mg/dL) * fasting insulin (µU/mL)) * (mean glucose (mg/dL) * mean insulin (µU/mL) during OGTT) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.

  18. Triglyceride-Glucose (TyG) index

    Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks

    TyG Index will be measured by the following formula:

    TyG Index=fasting triglycerides (mg/dL) * fasting glucose (mg/dL) / 2 All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.

  19. Acne

    Time frame: The investigators will report change from baseline to 14 and 26 weeks

    The investigators will use the PCOS-Q to ask about acne (score 1-7)

  20. Alopecia

    Time frame: The investigators will report change from baseline to 14 and 26 weeks

    The investigators will use the PCOS-Q to ask about alopecia (score 1-7)

  21. Free androgen index (FAI)

    Time frame: The investigators will measure change from baseline to 14 and 26 weeks

    FAI will be calculated with the following formula:

    FAI = 100 X ((Total Testosterone (nmol/L)/SHBG (nmol/L)) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.

  22. Sex hormone binding globulin (SHBG)

    Time frame: The investigators will measure change from baseline to 14 and 26 weeks

    SHBG will be measured in nmol/l (immunochemiluminometric assay) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.

  23. Dehydroepiandrosterone sulfate (DHEAS)

    Time frame: The investigators will measure change from baseline to 14 and 26 weeks

    DHEAS will be measured in nmol/l (immunochemiluminometric assay) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.

  24. Androstenedione

    Time frame: The investigators will measure change from baseline to 14 and 26 weeks

    Androstenedione will be measured in nmol/l (liquid chromatography with tandem mass spectrometry (LC-MS/MS) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.

  25. Free testosterone

    Time frame: The investigators will measure change from baseline to 14 and 26 weeks

    Free calculated testosterone will be measured in pmol/l (by Anderson Formula). All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.

  26. Menstrual regularity

    Time frame: The investigators will measure change from baseline to 14 and 26 weeks

    Questionnaire, where asking if the menstrual cycle is regular (defined as 21 days or more but under 36 days)

  27. Menstrual cycle length

    Time frame: The investigators will measure change from baseline to 14 and 26 weeks

    Questionnaire, where asking how long the two previous cycles were (days)

  28. Appearance of gastrointestinal adverse effects (GI AE)

    Time frame: The investigators will measure change from baseline to 14 and 26 weeks

    In our questionnaire the investigators will ask the participants whether they have experienced abdominal pain, reflux, nausea, diarrhoea or loss of appetite during the last two weeks and grade the symptoms from 1-5 (1 being never and 5 being all the time). The investigators will count the scores and give each participant a score between 5-25. A severe adverse effect is defined as a score of 4 or more in one of the questions (indicating a daily experience of abdominal pain, reflux, nausea, diarrhoea or loss of appetite during the last two weeks).

  29. Quality of life (QoL)

    Time frame: The investigators will measure change from baseline to 14 and 26 weeks

    The PCOS-Q is a questionnaire that was specifically designed to measure quality of life for women with PCOS. Questions on depression, anxiety, fear etc will be given scores from 1-7, depending on severity.

  30. Weight stigma

    Time frame: The investigators will measure change from baseline to 14 and 26 weeks

    In the questionnaire appearance of weight stigma and examples on it will be asked.

  31. Follicle number per ovary (FNPO) and antral follicle count (AFC)

    Time frame: The investigators will measure change from baseline to 14 and 26 weeks.

    Vaginal ultrasound where the investigators measure FNPO and AFC will be performed at any stage of the cycle.

  32. Ovarian volume

    Time frame: The investigators will measure change from baseline to 14 and 26 weeks.

    Vaginal ultrasound where the investigators measure ovarian volume will be performed at any stage of the cycle.

Study contacts

Contact information is provided by the study sponsor or research team.

Johanna M Melin, MD

CONTACT

[email protected]

+358505382526

Sponsors and collaborators

Lead sponsor

Helsinki University Central Hospital

Other

Collaborators

  • Sakari Alhopuro foundation (funding)
  • The Medical Society of Finland (funding)
  • Valtion tutkimusraha (funding)

Registry information

Official study title

Optimizing Metformin Use in Polycystic Ovary Syndrome - A Randomized Controlled Trial

Acronym: MET-PCOS

Important dates

Study start
2025
Primary completion
2027
Study completion
2028
First posted
Aug 13, 2025
Registry last updated
Aug 13, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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