Clinical trial NCT01019356: Role of Insulin Action and Free Fatty Acids in Hyperandrogenism of Women With Polycystic Ovary Syndrome
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Polycystic Ovary Syndrome
Keywords: PCOS
Lead sponsor: Université de Sherbrooke
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
First posted: 2009-11-25
Enrollment: 52
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Androgen hyper-responsiveness to insulin - Ratio
timeFrame: 8 weeks
Secondary outcomes:
measure: Androgen hyper-responsiveness to insulin - Relationship
timeFrame: 8 weeks
measure: Insulin sensitivity
timeFrame: 8 weeks
measure: Insulin secretion
timeFrame: 8 weeks
measure: Hepatic glucose production
timeFrame: 8 weeks
measure: Plasma DCI-IPG during euglycemic-hyperinsulinemic clamp
timeFrame: 8 weeks
Other outcomes:
Locations:
city: Sherbrooke
country: Canada
facility: Université de Sherbrooke
state: Quebec
Study officials:
affiliation: Université de Sherbrooke
name: Jean-Patrice Baillargeon, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References: