Effect of NAE on Polycystic Ovarian Syndrome (PCOS) (NAE-PCOS)

June 2, 2026 updated by: sadaf naeem, Jinnah Sindh Medical University

Effect of Nepeta Adenophyta Hedge Extract and Its Fractions on Polycystic Ovarian Syndrome (PCOS)

Polycystic Ovarian Syndrome (PCOS) is a multifaceted endocrine metabolic condition impacting about 5-10% of women throughout their reproductive lifespan. It is influenced by neuroendocrine dysfunction, insulin resistance, chronic low-grade inflammation, and ovarian oxidative stress. Existing medications, including metformin, clomiphene citrate, and anti-androgens, provide only limited advantages and are frequently restricted by side effects such as gastrointestinal intolerance, teratogenic risks, and weight gain. NAE (family Lamiaceae) is a fragrant perennial herb indigenous to the Himalayan and sub-Himalayan areas of Pakistan and Afghanistan. Phytochemical profiling of this plant has revealed high concentrations of flavonoids (luteolin, apigenin, quercetin), phenolic acids (rosmarinic and caffeic acid), terpenoids (nepetalactones), and glycosides. In a preclinical study lasting 30 days that involved Letrozole induced PCOS in Albino Wistar rats, the oral delivery of crude extract (350 and 500 mg/kg) and its methanol/butanol fractions (64 mg/kg; 12.5mg/kg) significantly restored estrous cyclicity, decreased serum LH and testosterone levels, normalized the LH/FSH ratio, enhanced insulin sensitivity (reduced HOMA IR), corrected dyslipidaemia, and reversed ovarian histopathological alterations. Molecular analysis by qRT PCR showed upregulation of IL 4 and downregulation of AR, CYP-17, TLR4, TNF α, and NF κB. Based on this multi targeted preclinical efficacy and a favourable safety profile, this clinical trial will assess the safety and effectiveness of a standardised NAE in women with PCOS, compared to metformin and combination therapy over 4 months.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Polycystic Ovarian Syndrome indicates an increasing health challenge for women of reproductive age, with global prevalence estimates between 6% and 14%. Individuals affected often experience psychological distress, metabolic issues, and difficulties with fertility. The pathophysiology of PCOS consists of three interrelated axes: (i) heightened GnRH pulse frequency results in an increased LH/FSH ratio and theca cell hyperplasia, driving ovarian hyperandrogenism; (ii) peripheral insulin resistance coupled with compensatory hyperinsulinemia further enhances ovarian androgen production; and (iii) chronic oxidative stress and inflammation, driven by cytokines from adipose tissue (TNF α, IL 6) and reactive oxygen species, which hinder follicular development and exacerbate metabolic dysfunction.

Traditional first-line therapies - metformin (insulin sensitizer), clomiphene citrate (ovulation stimulant), and spironolactone (anti-androgen) - each address only a single facet of the syndrome and have notable drawbacks: metformin can lead to dose-dependent gastrointestinal issues; clomiphene elevates the risk of multiple pregnancies and presents anti-estrogenic side effects; spironolactone is teratogenic and is unsuitable for women attempting to conceive. Additionally, none of these agents concurrently tackle hyperandrogenism, insulin resistance, inflammation, and oxidative stress.

Herbal remedies provide a multifaceted, multi-target strategy that corresponds effectively with the intricate pathophysiology of PCOS. NAE shows considerable potential. Its flavonoid fraction (luteolin, apigenin, quercetin) acts as a free radical scavenger, inhibits lipid peroxidation, enhances endogenous antioxidant enzymes (superoxide dismutase, glutathione peroxidase), and down regulates 17α hydroxylase, thereby reducing ovarian testosterone production. The phenolic acids (caffeic acid, rosmarinic acid) inhibit pro-inflammatory cytokines TNF α and IL 6, while improving insulin sensitivity through the enhancement of GLUT 4 translocation in adipose tissue and skeletal muscle. Terpenoids (nepetalactones) influence the hypothalamic pituitary gonadal axis, aiding in the normalization of the LH/FSH ratio, while also offering anxiolytic effects that might alleviate stress-related hormonal disturbances. Glycosides and reducing sugars enhance insulin receptor signaling, stimulate hepatic glycogen production, and block gluconeogenic enzymes like glucose 6 phosphatase.

These mechanistic predictions were confirmed in a carefully regulated animal study. PCOS was established in female Albino Wistar rats through Letrozole (1 mg/kg) given orally dissolved in 0.5% carboxymethylcellulose (CMC) for 21 days. The animals were split into 07 categories, which included untreated control, PCOS control, metformin standard (350 mg/kg), crude NAE (low dose 350 mg/kg, high dose 500 mg/kg), methanol fraction (64 mg/kg), and butanol fraction (12.5 mg/kg), given orally for 30 days. Essential discoveries comprised:

  • Hormonal: Significant reduction in serum LH and total testosterone, with normalisation of the LH/FSH ratio (p < 0.01).
  • Metabolic: Decreased fasting blood sugar, reduced HOMA IR, enhanced lipid profile (lowered total cholesterol, triglycerides, LDL; raised HDL).
  • Ovarian structure: Normal follicular arrangement on H&E staining.
  • Gene expression: qRT PCR of ovarian tissue showed an increase in the anti-inflammatory cytokine IL-4, whereas androgen receptor (AR), toll-like receptor 4 (TLR4), Cytochrome-17 (CYP-17), tumor necrosis factor α (TNF-α), and nuclear factor κB (NF-κB) were significantly decreased.

No mortality or signs of hepatorenal toxicity were observed at any dose. Considering this strong preclinical evidence, the current clinical trial aims to apply these results to human PCOS patients. The research will recruit 116 women diagnosed with PCOS according to Rotterdam criteria and having insulin resistance (HOMA IR > 2.00). Participants will be assigned randomly to three parallel groups: (1) NAE extract 500 mg two times a day; (2) metformin XR 750 mg two times a day; (3) a combination of both. The duration of the treatment is 4 months. The main goal is the reestablishment of normal ovulatory menstrual cycles (21-35 days) verified by ultrasound. Secondary outcomes consist of alterations in serum LH, FSH, testosterone, HOMA IR, HbA1c, Fasting Insulin, Body weight, and quality of life specific to PCOS (PCOSQOL). Safety will be assessed via the recording of adverse events, tests for liver and kidney function, and a comprehensive blood count.

Study Type

Interventional

Enrollment (Estimated)

116

Phase

  • Phase 1

Contacts and Locations

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

Study Locations

  • Pakistan
    • Sindh
      • Karachi, Sindh, Pakistan
        • Jinnah Postgraduate Medical Centre

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:

  • Female subjects of reproductive age (18-40 years).
  • Subjects with a diagnosis of polycystic ovary syndrome (PCOS) confirmed by clinician diagnostic criteria (Rotterdam criteria).
  • Subjects with insulin resistance defined as HOMA-IR > 2.00.

Exclusion Criteria:

  • Pregnant or lactating women.
  • Subjects with known Cushing's syndrome.
  • Subjects with late-onset congenital adrenal hyperplasia.
  • Subjects with androgen-secreting tumors.
  • Subjects with uncontrolled thyroid disease.
  • Subjects with hyperprolactinemia.
  • Subjects with diabetes mellitus.
  • Subjects with uncontrolled hypertension.
  • Subjects with other cardiovascular diseases.
  • Subjects with acute or chronic infections.
  • Subjects with any known malignancy.
  • Subjects with impaired renal function (serum creatinine > 1.5 × ULN).
  • Subjects with impaired liver function (serum ALT ≥ 2.5 × ULN).

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
Active Comparator: Metformin XR treated group
Metformin XR 750 mg twice daily for 4 months in PCOS patients
Drug: Metformin XR
Metformin XR 750 mg twice daily for 4 months in PCOS patients
Experimental: NAE treated group
NAE 500 mg twice daily for 4 months in PCOS patients
Drug: Herbal Formulation
NAE 500 mg twice daily for 4 months in PCOS patients
Experimental: Adjunct Group
NAE 500 mg and Metformin XR 750 mg twice daily for 4 months in PCOS patients
Drug: Metformin 750 mg and herbal formulation 500 mg
NAE 500 mg and Metformin XR 750 mg twice daily for 4 months in PCOS patients

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants Achieving Menstrual Cycle Normalization After 4 Months of Treatment
Time Frame: Baseline to 4 months
Regular ovulatory cycles lasting from 21 to 35 days achieved after finishing 4 months of treatment. Cycle regularity is recorded through menstrual diaries maintained by participants and validated by transvaginal ultrasound, where ovulation is recognized by the presence of a dominant follicle (≥18 mm) that later either collapses or vanishes, with or without free fluid present in the pouch of Douglas.
Baseline to 4 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Body Weight Changes
Time Frame: Baseline and 4 months
Change in body weight measured using a calibrated weighing scale. Unit: kg
Baseline and 4 months
Serum Follicle-Stimulating Hormone (FSH) Levels
Time Frame: Baseline and 4 months
Change in serum FSH levels assessed by standard laboratory assays, reported in mIU/mL. Reference ranges: Follicular phase 3.5-12.5, Ovulatory phase 4.7-21.5, Luteal phase 1.7-7.7
Baseline and 4 months
Serum Luteinizing Hormone (LH) Levels
Time Frame: Baseline and 4 months
Change in serum LH levels assessed using standard laboratory assays, expressed in mIU/mL. Reference ranges are 1.9-9.2 during the follicular phase, 6.1-49.1 during ovulation, and 1.3-10.8 in the luteal phase
Baseline and 4 months
Serum Testosterone Levels
Time Frame: Baseline and 4 months
Change in serum testosterone levels determined using standard laboratory assays, expressed in ng/mL. Normal reference range for individuals aged 18-49 years is 0.084-0.481 ng/mL.
Baseline and 4 months
Glycated Hemoglobin (HbA1c) Level
Time Frame: Baseline and 4 months
Change in HbA1c (%) measured using standardized laboratory methods. Reference ranges: Normal <5.6%, Prediabetes 5.7-6.4%, Diabetes ≥6.5%
Baseline and 4 months
Fasting Serum Insulin Concentration
Time Frame: Baseline and 4 months
Change in fasting serum insulin levels assessed using standard laboratory assays, expressed in µIU/mL. Normal reference range: 2-25 µIU/mL.
Baseline and 4 months
HOMA-IR
Time Frame: Baseline and 4 months
HOMA-IR will be calculated at baseline and after 4 months using the formula: HOMA-IR = [fasting plasma glucose (mmol/L) × fasting insulin (μU/mL)] ÷ 22.5
Baseline and 4 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Assessment of quality of life via Polycystic Ovary Syndrome Quality of Life scale (PCOSQOL)
Time Frame: Baseline and 4 months
Disease-specific questionnaire assessing 5 domains (Emotions, Body Hair, Weight, Infertility Problems, Menstrual Problems). 26 items, 7-point Likert scale (1=minimum, 7=maximum). Higher scores indicate improved quality of life.
Baseline and 4 months

Collaborators and Investigators

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

Sponsor

Jinnah Sindh Medical 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

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)

April 10, 2025

Primary Completion (Estimated)

May 30, 2026

Study Completion (Estimated)

June 15, 2026

Study Registration Dates

First Submitted

May 18, 2026

First Submitted That Met QC Criteria

May 18, 2026

First Posted (Actual)

May 22, 2026

Study Record Updates

Last Update Posted (Actual)

June 4, 2026

Last Update Submitted That Met QC Criteria

June 2, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NAE-PCOS-2024
  • NO.F.2-81/2024-GENL/101/JPMC (Other Identifier: Jinnah Postgraduate Medical Centre)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Individual participant data will not be shared due to privacy and confidentiality concerns of study participants, and because the study is not funded by external agencies requiring data sharing.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

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.

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