Cortisol Regulation in Polycystic Ovary Syndrome (PCOS)

PCOS is a common clinical problem affecting young women, characterized by oligomenorrhea and
hyperandrogenism. Central obesity and insulin resistance are also prominent features of
PCOS, and in addition are important risk factors for development of hypertension,
hyperlipidemia and atherosclerotic heart disease. Previous studies have suggested that
cortisol is dysregulated in PCOS, primarily through increased hypothalamic-pituitary-adrenal
(HPA) axis activity and enhanced cortisol secretion. Increased adrenocorticotropic hormone
(ACTH) secretion could also potentially lead to elevated adrenal androgen production in
PCOS. Techniques used in previous studies have been inconsistent, however, and a link
between increased HPA axis activity and the phenotypic changes in PCOS has not been clearly
demonstrated. Cortisol is also produced from cortisone in peripheral adipose tissue by the
enzyme 11beta-hydroxysteroid dehydrogenase type 1 (HSD 1), suggesting another potential
point of dysregulation that may contribute to central obesity and insulin resistance in
PCOS. Further investigation of both central and peripheral regulation of cortisol is
necessary to better understand the pathophysiology of PCOS.

Specific Aim 1: To perform a cross-sectional study of women with PCOS and normal controls
matched for age and body mass index, and measure insulin sensitivity and visceral fat, as
well as (a) 24-hour CPR, ACTH, free cortisol, and cortisol binding globulin (CBG), (b)
adipocyte, liver, and whole body HSD 1 activity, and (c) androgen levels.

Specific Aim 2: To prospectively administer pioglitazone or metformin to women with PCOS in
a placebo-controlled trial, and after one month and six months of therapy measure (a)
24-hour CPR, ACTH, free cortisol, and CBG, (b) adipocyte, liver, and whole body HSD 1
activity, and (c) insulin sensitivity, visceral fat, and androgen levels.

Inclusion Criteria (Healthy controls):

- Healthy

- At lifetime maximal weight

- Weight stable for at least 6 months prior to study entry

- Willing to commit to not making significant changes to their diet or daily activities
while enrolled.

- Premenopausal

- Have regular menstrual cycles

- No evidence of hirsutism

Additional Inclusion Criteria (Subjects with PCOS):

- Clinical findings of amenorrhea or oligomenorrhea dating from menarche

- Clinical and/or biochemical evidence of hyperandrogenism

- Exclusion of related disorders

Exclusion Criteria (Healthy controls):

- Less than 18 years of age

- Exercise > 30 minutes/day, 3 times a week

- Smokers

- Heavy alcohol drinkers (> 2 drinks/day)

- Type 2 diabetes

- Medical diagnoses including heart disease and cancer

- Psychiatric illness (i.e.depression, psychosis, bipolar, schizophrenia)

- Body weight > 136 kg

- Pregnant

- Endocrine diseases affecting body composition or androgen levels

Additional Exclusion Criteria (Subjects with PCOS):

- Laboratory evidence of hyperprolactinemia, thyroid dysfunction, or
21-hydroxylase-deficient nonclassic CAH

- Contraindication to pioglitazone (i.e. CHF, impaired liver function, anemia,
depressed leukocyte counts, pulmonary disease, known sensitivity to
thiazolidinediones.