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

• left ventricular function [ Time Frame: up to half of an hour ] [ Designated as safety issue: No ]
  
• blood pressure [ Time Frame: up to 24 hours ] [ Designated as safety issue: No ]
  
• leptin levels [ Time Frame: 15 minutes over a period of 24 hours ] [ Designated as safety issue: No ]
  
• ghrelin levels [ Time Frame: 10 minutes over a period of 24 hours ] [ Designated as safety issue: No ]
  
• cortisol levels [ Time Frame: 10 minutes, over a period of 24 hours ] [ Designated as safety issue: No ]
  
• visceral adiposity [ Time Frame: up to half of an hour ] [ Designated as safety issue: No ]
  
• brachial artery reactivity [ Time Frame: up to half of an hour ] [ Designated as safety issue: No ]
  

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.

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.