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

Sponsor

Jean-Patrice Baillargeon (Other)

Overall Status

Completed

CT.gov ID

NCT01019356

Collaborator

Canadian Institutes of Health Research (CIHR) (Other)

Enrollment

Location

Arms

179

Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Polycystic Ovary Syndrome	Drug: Rosiglitazone Drug: Acarbose	N/A

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 Design

Study Type:

Interventional

Actual Enrollment :

52 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Basic Science

Official Title:

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

Study Start Date :

Aug 1, 2006

Actual Primary Completion Date :

Jul 1, 2021

Actual Study Completion Date :

Jul 1, 2021

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Androgen hyper-responsiveness to insulin - Ratio [8 weeks]
The calculated ratio of free testosterone to the area under the insulin curve during an OGTT

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 40 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

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)