Role of Insulin Action and Free Fatty Acids in Hyperandrogenism of Women With Polycystic Ovary Syndrome

Role of Insulin Action and Free Fatty Acids in Hyperandrogenism and Role of Metabolism of Inositols in Insulin Resistance of Women With Polycystic Ovary Syndrome

The investigators hypothesis is that free fatty acids (FFA) accumulation in non fatty tissues would lead to insulin resistance and hyperandrogenism in PCOS women. Accordingly, Peroxisome Proliferator-Activated Receptor gamma (PPARγ) agonist (rosiglitazone) would be a great therapeutic option for PCOS as their activation induces transcription factors of gene implicated in fatty acids metabolism.

The aim is to verify if insulin-related hyperandrogenism can be reversed in women having polycystic ovary syndrome following an 8-week treatment with rosiglitazone compared to simple insulin reduction with acarbose.

For the purpose of this study, 14 lean women (BMI ≤ 25 kg/m2) and 36 obese women (BMI 30-39 kg/m2) with PCOS as well as 14 lean and 14 obese control women will be recruited to determine their insulin sensibility (insulin levels, M-value, metabolic clearance rate of glucose)and FFA metabolism (FFA levels, rythm of apparition and disapearance of FFA) during a 75g oral glucose tolerance test and a 2-step insulin-glucose clamp.

Study Overview

• Status: Completed
• Conditions: Polycystic Ovary Syndrome
• Intervention / Treatment: Drug: Rosiglitazone; Drug: Acarbose

Detailed Description

Polycystic ovary syndrome (PCOS) is a very common but complex endocrine disorder affecting 6 to 10% of childbearing age women. To diagnose PCOS, women must display two of these three symptoms: clinical or biochemical hyperandrogenism, oligoamenorrhea, and/or echographycally confirmed polycystic ovary. Many studies have also demonstrated that PCOS women are more insulin resistant than control women when matched for body mass index (BMI). Thus, insulin resistance (IR) and secondary hyperinsulinemia would be important premises in the development of PCOS. In fact, the prevalence of type 2 diabetes (T2D) is tripled in PCOS women.

Higher free fatty acid (FFA) concentrations were also observed in the circulation of PCOS women. As FFA accumulates in liver and muscle instead of fat cells, this could be an important cause of IR according to the theory of lipotoxicity. Some indirect evidences are suggesting that FFA accumulation in androgen secreting cells (ovary and adrenal gland) could enhance their androgen production. Based on these findings, our hypothesis is that FFA accumulation in non fatty tissues would lead to IR and hyperandrogenism in PCOS women. Accordingly, Peroxisome Proliferator-Activated Receptor gamma (PPARγ) agonist (rosiglitazone) would be a great therapeutic option for PCOS as their activation induces transcription factors of gene implicated in fatty acids metabolism.

The aim is to verify if insulin-related hyperandrogenism can be reversed in PCOS women following an 8-week treatment with rosiglitazone compared to simple insulin reduction with acarbose. For the purpose of this study, 14 lean women (BMI ≤ 25 kg/m2) and 36 obese women (BMI 30-39 kg/m2) with PCOS as well as 14 lean and 14 obese control women will be recruited to determine their insulin sensibility (insulin levels, M-value, metabolic clearance rate of glucose)and FFA metabolism (FFA levels, rythm of apparition and disapearance of FFA) during a 75g oral glucose tolerance test and a 2-step insulin-glucose clamp.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Universite de Sherbrooke

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

PCOS :

• Biochemical hyperandrogenism (free testosterone ≥ 50 pmol/l)
• Oligomenorhea (≤ 8 menstrual cycle per year)

Health volunteers :

• Normal menstrual cycle
• Normal levels of free and total testosterone
• No family history with PCOS

Exclusion Criteria:

• Diabetes or glucose intolerance
• Current or past use within 3 months of oral contraceptives
• Current or past use within 3 months of medications known to affect insulin sensitivity (metformin, PPARy agonists, b-blockers, thiazides, calcium channel blockers, glucocorticoids, etc.)
• Pulmonary, cardiac, renal, hepatic, neurologic, psychiatric, infectious or neoplastic disease (other than non-melanoma skin cancer)
• Documented or suspected recent (within one year) history of drug abuse or alcoholism
• Use of any investigational drug within three months prior to study onset

Healthy volunteers :

• History of gestational diabetes
• Positive family history for first-degree relative with diabetes
• Disorders linked to insulin resistance (hypertension, dyslipidemia or acanthosis nigricans)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Rosiglitazone; Lean and obese PCOS women	Drug: Rosiglitazone; 4 mg twice daily for 8 weeks orally; Other Names: Avandia
ACTIVE_COMPARATOR: Acarbose; Obese PCOS women	Drug: Acarbose; 100 mg three times daily for 8 weeks orally; Other Names: Prandase
NO_INTERVENTION: Control; Obese and lean healthy women evaluated only at baseline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Androgen hyper-responsiveness to insulin - Ratio	The calculated ratio of free testosterone to the area under the insulin curve during an OGTT	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Androgen hyper-responsiveness to insulin - Relationship	Determined by the relationship between testosterone and insulin levels during an OGTT.	8 weeks
Insulin sensitivity	Determined by a 2-step insulin-glucose clamp	8 weeks
Insulin secretion	Determined by a 2-step insulin-glucose clamp	8 weeks
Hepatic glucose production	Determined by a 2-step insulin-glucose clamp	8 weeks
Plasma DCI-IPG during euglycemic-hyperinsulinemic clamp	Measured during steady-state	8 weeks

Collaborators and Investigators

• Sponsor: Jean-Patrice Baillargeon
• Collaborators: Canadian Institutes of Health Research (CIHR)

Study record dates

Study Major Dates

• Study Start: August 1, 2006
• Primary Completion (ACTUAL): July 1, 2021
• Study Completion (ACTUAL): July 1, 2021

Study Registration Dates

• First Submitted: November 24, 2009
• First Submitted That Met QC Criteria: November 24, 2009
• First Posted (ESTIMATE): November 25, 2009

Study Record Updates

• Last Update Posted (ACTUAL): January 20, 2022
• Last Update Submitted That Met QC Criteria: January 4, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: PCOS
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Endocrine System Diseases; Disease; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; 46, XX Disorders of Sex Development; Disorders of Sex Development; Urogenital Abnormalities; Adrenogenital Syndrome; Congenital Abnormalities; Polycystic Ovary Syndrome; Hyperandrogenism; Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Glycoside Hydrolase Inhibitors; Rosiglitazone; Acarbose
• Other Study ID Numbers: 06-075