Official Title: “Sleep, Metabolic, and Cardiovascular Dysfunction in Polycystic Ovary Syndrome”

Polycystic ovary syndrome (PCOS) affects 5-10% of women in the United States. Its onset is usually at the time of puberty with manifestations of menstrual irregularity, hirsutism, and obesity. Women with PCOS suffer at an early stage of adulthood from all of the components of the metabolic syndrome, a syndrome that typically has its peak in mid-life in other subject populations. Women with PCOS are more insulin resistant than weight-matched control women and have exceptionally high rates of early-onset impaired glucose tolerance and type 2 diabetes, as well as a substantially elevated risk for hypertension, dyslipidemia, coronary, and other vascular diseases. While recent evidence indicates that the prevalence of sleep-disordered breathing (SDB) is 30-40 fold higher in PCOS than in weight-matched control women, the possible role of SDB in causing the increased metabolic and cardiovascular risks of PCOS has not been evaluated. The overall objective of the proposed study is to analyze the direction of causality between sleep disturbances and markers of the metabolic syndrome in PCOS.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver), Placebo Control, Parallel Assignment, Efficacy Study

Study Primary Completion Date: June 2010

Polycystic ovary syndrome (PCOS) affects 5-10% of women and may be viewed as the combination of hyperandrogenism with the classical features of the metabolic syndrome in young women.

PCOS presents a unique opportunity to dissect the relationship between metabolic and cardiovascular risk and sleep disordered breathing (SDB) in a population where intrinsic effects of aging have not yet developed. Because a relationship between obstructive sleep apnea, insulin resistance and elevated testosterone levels has also been observed in men and in women without PCOS, insights gained from studies in PCOS will have broad implications.

The Specific Aims of the present application are:

Specific Aim 1: to test the hypothesis that sleep disturbances are caused by hyperandrogenemia and hyperinsulinemia that characterize PCOS. Following a detailed baseline evaluation of sleep, hormonal, metabolic and cardiovascular parameters, women with PCOS will be randomized to an 8-week treatment phase with pioglitazone or depot leuprolide plus estrogen/progestin replacement or placebo. Pioglitazone will reduce insulin levels, and consequently androgen levels, in PCOS. We will compare the effects of androgen reduction alone (depot leuprolide plus estrogen/progestin) to those of insulin plus androgen reduction achieved with pioglitazone. Primary comparisons will be the change in sleep parameters from baseline between: placebo & pioglitazone; placebo & leuprolide/estrogen/progestin; pioglitazone & leuprolide/estrogen/progestin.

Specific Aim 2: to test the hypothesis that sleep disturbances cause the hormonal, metabolic and cardiovascular alterations seen in women with PCOS. PCOS women with SDB and matched control women with SDB will be evaluated at baseline and following 8 weeks of CPAP treatment.

The primary comparison will be between baseline and post-treatment parameters in PCOS women.

The secondary comparison will be the post-treatment change from baseline between PCOS and control women to test the hypothesis that for the same degree in improvement in SDB, the magnitude of change in metabolic and cardiovascular measures will be greater in PCOS than in controls.

Specific Aim 3: to test the hypothesis that in normal young women, experimental manipulation of sleep that recapitulates the sleep disturbances characteristic of women with PCOS will result in metabolic, hormonal, and cardiovascular alterations that are typical of the metabolic syndrome. A group of healthy young women will be studied twice using a randomized cross-over design. In one study, REM sleep will be fragmented by experimentally induced microarousals for 3 consecutive nights and non-REM sleep will be left undisturbed. In the other, slow wave activity will be suppressed without awakening the subject and REM sleep will be left undisturbed. Each study will be preceded by 2 nights of baseline sleep.

Intervention(s) in this Clinical Trial

• Device: continuous positive airway pressure (CPAP)
  • CPAP is the most effective treatment available for sleep disordered breathing. CPAP provides a constant, controllable pressure to keep your upper airway open during sleep so that you can breathe normally. The pressure acts much in the same way as a splint and holds the airway open.
• Drug: depot leuprolide plus estrogen/progestin replacement
  • Depot leuprolide is a long-acting, modified version of the natural brain hormone, gonadotropin releasing hormone (GnRH). This study drug will temporarily reduce the pituitary hormones that stimulate the ovaries to make both female (estrogen) and male (testosterone) hormones. The effect of this study drug will last approximately 12 weeks. During this time, your female hormone levels will be brought to normal by the use of a patch that contains estrogen and progesterone. This patch is placed on the skin and is changed twice a week. The subject will continue to wear this patch for 4 weeks after the end of the study, until the effects of the Lupron injection wear off.
• Drug: pioglitazone
  • Pioglitazone (Actos). Pioglitazone is an oral medication approved in the Unites States for the treatment of patients with type 2 diabetes (however it is not approved for studies in this protocol). This is one of a class of drugs known as thiazolidinediones. This class of drugs has been associated with potential beneficial changes in the metabolism (use of glucose by the body) as well as lipids (fats) in the blood.

Primary Measures

• oral glucose tolerance
  • Time Frame: up to 2 hrs.
    Safety Issue?: No
• intravenous glucose tolerance
  • Time Frame: up to 24 hrs.
    Safety Issue?: Yes
• testosterone levels
  • Time Frame: up to 24 hrs.
    Safety Issue?: No
• luteinizing hormone levels
  • Time Frame: 15 minutes over a period of 24 hours (except meals)
    Safety Issue?: No
• sleep apnea events
  • Time Frame: 20 minutes, 5 times @ 2-hr. intervals, over the course of a day
    Safety Issue?: No

Secondary Measures

• left ventricular function
  • Time Frame: up to half of an hour
    Safety Issue?: No
• blood pressure
  • Time Frame: up to 24 hours
    Safety Issue?: No
• leptin levels
  • Time Frame: 15 minutes over a period of 24 hours
    Safety Issue?: No
• ghrelin levels
  • Time Frame: 10 minutes over a period of 24 hours
    Safety Issue?: No
• cortisol levels
  • Time Frame: 10 minutes, over a period of 24 hours
    Safety Issue?: No
• visceral adiposity
  • Time Frame: up to half of an hour
    Safety Issue?: No
• brachial artery reactivity
  • Time Frame: up to half of an hour
    Safety Issue?: No

Inclusion Criteria:

• PCOS subjects will be recruited from the Endocrinology Clinics of the University of Chicago. All will be at least 2 years postmenarche and less than 40 years of age. A diagnosis of PCOS will require:
• the presence of oligo/amenorrhea;
• hyperandrogenemia, defined by a supranormal plasma free testosterone level (> 10 pg/ml);
• hyperandrogenism, as evidenced by infertility, hirsutism, acne, or androgenetic alopecia; and
• exclusion of nonclassic 21-hydroxylase deficiency congenital adrenal hyperplasia, Cushing's syndrome, hypothyroidism, or significant elevations in serum prolactin.
• Thus, all subjects will meet the National Institutes of Health (NIH) consensus criteria for PCOS.
• Control subjects will be matched, as closely as possible, for age, ethnicity, body mass index (BMI), and body fat distribution (as assessed by single cut abdominal computed tomography [CT] scan and dual energy x-ray absorptiometry [DEXA] scan).
• Normal lean (BMI <25 kg/m2) women will be between 18 and 40 years of age, in good health, with normal menstrual cycles, no sleep complaints, no history of endocrine disorder. All studies will be initiated in the early follicular phase (days 2-4).
• For at least 2 months before the study, all subjects (PCOS and control) must not take steroid preparations (including oral contraceptives), medications known to alter insulin secretion and/or action, or medications known to influence sleep.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 40 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: University of Chicago

Overall Clinical Trial Officials and Contacts

David A Ehrmann, M.D. Principal Investigator University of Chicago  

Overall Contact: David A Ehrmann, M.D. 773 702 9653 dehrmann@uchicago.edu

Information obtained from ClinicalTrials.gov on October 15, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00203996

Study ID Number: 12861B

ClinicalTrials.gov Identifier: NCT00203996

Health Authority: United States: Institutional Review Board