The Combined Effect of N-Acetyl Cysteine and Metformin in Polycystic Ovary Syndrome Patients (PCOS)

July 4, 2025 updated by: Marwa Rafat Talat, Cairo University
The study aims to evaluate the effects of combination of metformin with NAC in PCOS on biochemical and hormonal parameters.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Polycystic ovarian syndrome (PCOS) is one of the prevalent endocrine illnesses that affects women in industrialized and developing nations, with a prevalence that ranges from 8% to 13%. The most widely accepted criteria for diagnosing polycystic ovary syndrome (PCOS) are the Rotterdam criteria established in 20032. According to these criteria, a diagnosis is made if a patient meets at least two of the following three criteria:

The Rotterdam criteria

Polycystic ovarian syndrome is diagnosed when 2 out of 3 criteria are met:

  1. Oligo-or/and anovulation
  2. Clinical hyperandrogenism (acne, hirsutism, alopecia) or biochemical hyperandrogenism.
  3. Polycystic ovarian morphology on transvaginal ultrasonography or high antimullerian hormone.

And exclusion of other etiologies (congenital adrenal hyperplasia, androgen-secreting tumors, Cushing's syndrome).

The 2023 International Evidence-based Guideline for the Assessment and Management of PCOS has built on the Rotterdam criteria by emphasizing more comprehensive assessments.

These updates highlight the need to consider a broader range of phenotypes, assess metabolic risks, and prioritize patient-centered, individualized care.

Algorithm: Screening and diagnostic assessment

Step 1:

Irregular Menstrual Cycles + Clinical Hyperandrogenism

• Exclude other causes* = diagnosis.

Step 2:

Irregular Menstrual Cycles Without Clinical Hyperandrogenism • Test for biochemical hyperandrogenism and exclude other causes* = Diagnosis

Step 3:

If Only Irregular Cycles or Only Hyperandrogenism

  1. Adolescents: Ultrasound or AMH is not indicated = considered at risk of PCOS and reassessed later

  2. Adults: Ultrasound for Polycystic Ovarian morphology (PCOM)* OR Anti-Mullerian Hormone (AMH) level, if positive (exclude other causes) * = diagnosis

    • Exclusion of Other Causes = TSH, prolactin, FSH or, if clinically indicated, exclude other causes (e.g. Cushing's syndrome, adrenal tumors, etc.) Irregular menstrual cycles 1 to < 3 years post-menarche: Cycle length is either less than 21 days or more than 45 days.

> 3 years post-menarche until perimenopause: Cycle length is either less than 21 days, more than 35 days, or fewer than 8 cycles per year.

> 1-year post-menarche: Any cycle lasting more than 90 days. Primary amenorrhea: no menstruation by age 15 or more than 3 years after the onset of breast development (thelarche).

Biochemical hyperandrogenism Elevated total or free testosterone, or calculated indices of free testosterone Clinical hyperandrogenism Comprehensive history and physical examination are needed. Adults: acne, female pattern hair loss, and hirsutism. Adolescents: severe acne and hirsutism.

Note the negative psychosocial impact of clinical hyperandrogenism. Standardized visual scales are preferred, including the modified Ferriman Gallway score (mFG), a score of ≥ 4-6 = hirsutism.

Ultrasound and polycystic ovary morphology (PCOM) and anti-mullerian hormone (AMH) Using ultrasound transducers with a frequency bandwidth including 8 MHz, the PCOM threshold is a follicle number per ovary of ≥ 20 and/or an ovarian volume ≥ 10 ml on either ovary, avoiding corpora lutea, cysts or dominant follicles.

Either serum AMH OR ultrasound may be used but not both to avoid overdiagnosis Serum AMH could be used for defining PCOM in adults as an alternative to pelvic or abdominal ultrasound.

People with PCOS often experience various metabolic and reproductive outcomes such as obesity, insulin resistance (IR), oxidative stress (OS), hirsutism, acne, irregular menstruation, and infertility, as well as long-term consequences including cancer and cardiovascular illnesses.

The cause of PCOS is still unknown, despite evidence indicating the pathophysiology of the condition is primarily driven by the production of high quantities of androgen and IR. Additionally, research showed that OS is linked to IR, hyperinsulinemia, hyperandrogenism, persistent inflammatory conditions, abnormalities in fat and carbohydrate metabolism, ovarian dysfunction, and unfavorable pregnancy outcomes. Consequently, antioxidant therapy might be useful in the management of PCOS. Patients with PCOS frequently seek treatment for a variety of symptoms, including menstrual irregularities, heavy menstrual bleeding, acne, hirsutism, and weight management challenges.

The management of PCOS is typically tailored to address these specific symptoms, with a range of therapeutic options available depending on the patient's presentation. Menstrual irregularity and heavy bleeding in patients with PCOS can be managed through lifestyle interventions, such as diet and exercise aimed at achieving a weight reduction of 5%-10%8, or by using combined hormonal contraceptives. These may include oral norethindrone acetate (5 mg daily for 7 days every 30-90 days, or 5 mg daily for 3 weeks on and 1 week off), ethinyl estradiol (20-35 mcg of ethinyl estradiol in combination with a progestin), or oral drospirenone (4 mg for 24 days, followed by 4 days of placebo). In cases where hormonal contraceptives are not suitable or effective, metformin (1500-2000 mg daily in divided doses, starting at 500 mg and increasing by 500 mg every 1-2 weeks) may be considered. Inositol supplementation, commonly administered as 4 g of myo-inositol daily, is another option that has been shown to improve menstrual regularity, metabolic disturbances, and reducing weight in patients with PCOS.

For managing acne, hirsutism, or alopecia, first-line treatments include combined hormonal contraceptives to address androgenic symptoms. In addition, topical treatments for hirsutism, such as 13% eflornithine, can help reduce unwanted facial hair. Minoxidil (2% solution, applied twice daily) is commonly used for the treatment of alopecia. Topical or oral acne treatments should follow general dermatological guidelines, depending on the severity of the condition.

Overweight or obesity is commonly addressed through lifestyle interventions. Metformin (1500-2000 mg daily in divided doses, with gradual titration starting at 500 mg) can be used to improve insulin sensitivity and aid in weight management.

For ovulation induction, letrozole (2.5 mg-7.5 mg for 5 days) is considered a first-line treatment for ovulation induction in many guidelines. To confirm successful ovulation, it is recommended to measure serum progesterone levels approximately 3 weeks after initiating letrozole. Metformin (1500-2000 mg daily) can also be used to enhance ovulatory function. Clomiphene is also used to induce ovulation, starting at 50 mg daily for 5 days from days 2-5 of the cycle. If ineffective, the dose may be increased to 100 mg or 150 mg in subsequent cycles for up to 6 cycles.

N-Acetyl Cysteine (NAC) has antioxidant properties and is essential for the body's production of glutathione, and both glutathione and NAC are potent antioxidants. By promoting the synthesis of glutathione synthetase hormone (GSH), NAC helps inhibit OS, preventing hyperinsulinemia-induced IR and protecting insulin receptors from oxidative damage. NAC likely enhances insulin receptor activity, leading to increased glucose consumption, which indicates improved insulin sensitivity. IR, dyslipidemia, and hyperhomocysteinemia are risk factors for ischemic heart disease in women with PCOS. NAC has been utilized as a therapeutic agent to improve homocysteine levels and lipid profiles, which in turn have been shown to affect insulin receptor activity. As a result, the primary cause of PCOS was alleviated and insulin levels fell. The antioxidant properties of NAC have been utilized in multiple clinical trials conducted on infertile PCOS females to increase oocyte quality and ovulation rate.

In this study, the investigators will evaluate and compare the efficacy of metformin and NAC combination versus metformin alone on clinical, metabolic, hormonal, and biochemical aspects in patients with PCOS.

Study Type

Interventional

Enrollment (Estimated)

102

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Egypt
      • Cairo, Egypt
        • Recruiting
        • Kasr El-Ainy hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Female aged 20 to 45 years old.
  2. Confirmed diagnosis with PCOS according to the 2023 International Evidence-based Guideline for the Assessment and Management of PCOS.
  3. Ability to give informed consent.

Exclusion Criteria:

  1. Hypersensitivity to either metformin or NAC.
  2. Consumption of medications affecting carbohydrate metabolism, such as insulin, sulfonylureas, and taking hormonal analogues two months prior to enrollment.
  3. Hyperprolactinemia, defined as a prolactin level above laboratory reference range.
  4. Diabetes mellitus.
  5. Thyroid dysfunction, subjects with elevated or low TSH level.
  6. Renal impairment where creatinine clearance (CrCl) less than 30 ml/min.
  7. Severe hepatic impairment, defined as significant biochemical abnormalities, including hypoalbuminemia and abnormal serum concentration (2-3 times the upper limit of normal), of at least two of the following liver function markers: total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or gamma-glutamyl transferase (GGT).
  8. Active alcohol abuse.
  9. History of lactic acidosis during metformin therapy.
  10. Active peptic ulcer.
  11. Congenital adrenal hyperplasia.
  12. Cushing's syndrome.
  13. Androgen secreting neoplasia.
  14. Patients who were using spironolactone, other anti-androgens, or any form of hormone therapy for the treatment of hirsutism at least 3 months before enrollment in the study.
  15. Decompensated heart failure.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Group-MN
Group-MN, constituting 51 cases, will receive N-acetyl cysteine and metformin (600 mg three times daily of acetyl cysteine and 500 mg once daily for one week, then 500 mg twice daily for one week, and 500 mg three times daily thereafter of metformin)
Drug: N-acetyl cysteine
N-Acetyl Cysteine (NAC) has antioxidant properties and is essential for the body's production of glutathione, and both glutathione and NAC are potent antioxidants.
Other Names:
  • NAC
Drug: Metfomin
metformin is commonly used for managing polycystic ovary syndrome (PCOS) due to its benefits in addressing several underlying features of the condition. While it is not officially approved by regulatory agencies like the FDA for PCOS, it is widely recognized and recommended in clinical practice guidelines as an off-label treatment for PCOS, particularly in women with insulin resistance and metabolic dysfunction.
Experimental: Group-M
Group-M, constituting 51 cases, will receive treatment with metformin (starting with 500 mg once daily for one week, then 500 mg twice daily for one week, and 500 mg three times daily thereafter)
Drug: Metfomin
metformin is commonly used for managing polycystic ovary syndrome (PCOS) due to its benefits in addressing several underlying features of the condition. While it is not officially approved by regulatory agencies like the FDA for PCOS, it is widely recognized and recommended in clinical practice guidelines as an off-label treatment for PCOS, particularly in women with insulin resistance and metabolic dysfunction.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Primary outcome will be change in LH/FSH levels.
Time Frame: 3 months
change in LH/FSH ratio
3 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
improvement in hormonal levels in patients with PCOS
Time Frame: 3 months

Hormonal profile change in:

Total testosterone levels (ng/dL) Free testosterone levels (ng/dL) Free testosterone to total testosterone (FT/TT) ratio, calculated from the measured values.
3 months
improvement in clinical features in patients with PCOS
Time Frame: 3 months
improvement in clinical features: Menstrual irregularities: improvement in oligomenorrhea or amenorrhea, assessed based on The 2023 International Evidence-based Guideline for the Assessment and Management of PCOS Hirsutism: Assessed using the modified Ferriman-Gallwey (mFG) score Acne: Evaluated using the Investigator Global Assessment (IGA) scale technique.
3 months
improvement in biochemical parameters in patients with PCOS
Time Frame: 3 months
biochemical parameters change in: Fasting insulin levels (µIU/mL). Fasting blood glucose (FBG) levels (mg/dL). Glucose/insulin ratio, calculated using fasting glucose and insulin levels. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), calculated using the standard formula.
3 months
improvement in metabolic parameters in patients with PCOS
Time Frame: 3 months
weight in kilograms, height in meters Body mass index (BMI) (kg/m2), calculated as weight (kg) divided by height (m2).
3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Cairo University

Investigators

  • Study Director: Samar F Farid, PhD, Professor and Head of Clinical Pharmacy Department, Faculty of Pharmacy, Cairo University
  • Study Director: Eglal A Mostafa Bassiouny, PhD, Lecturer of Clinical Pharmacy Faculty of Pharmacy, Cairo University
  • Study Director: Amr Z Abdelhamid, PhD, Obstetrics and Gynaecology Lecturer Kasr Al-Ainy School of Medicine, Cairo University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 1, 2025

Primary Completion (Estimated)

February 1, 2026

Study Completion (Estimated)

May 1, 2026

Study Registration Dates

First Submitted

January 30, 2025

First Submitted That Met QC Criteria

February 14, 2025

First Posted (Actual)

February 20, 2025

Study Record Updates

Last Update Posted (Actual)

July 9, 2025

Last Update Submitted That Met QC Criteria

July 4, 2025

Last Verified

July 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Acetylcysteine in PCOS

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Polycystic Ovary Syndrome

Clinical Trials on N-acetyl cysteine

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Angola

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe