Cortisol Regulation in Polycystic Ovary Syndrome (PCOS)

The purpose of this study is to determine if insulin resistance (how well the body uses insulin and clears sugar) can affect cortisol levels in normal healthy women and women with polycystic ovary syndrome of all body weights.

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.

Pioglitazone will be given to women with PCOS. 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.

Metformin will be given to women with PCOS. 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.

Placebo will be given to women with PCOS. 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.

The comparison of body surface area adjusted cortisol production rate (CPR/BSA) before insulin sensitizing therapy in women with PCOS.

The comparison of body surface area adjusted cortisol production rate (CPR/BSA) after insulin sensitizing therapy in women with PCOS.

Comparisons of 24-hour values for adrenocorticotropic hormone , free-cortisol, and cortisol binding globulin.

Comparisons of 24-hour values for adrenocorticotropic hormone , free-cortisol, and cortisol binding globulin.

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.