Polycystic Ovary Syndrome (PCOS) and Sleep Apnea
Polycystic Ovary Syndrome (PCOS) and Sleep Apnea
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.
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, rapid eye movement (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. Results were not reported for Aim 3 since no devices or drugs were tested in
 this aim.
Inclusion Criteria:

 -  PCOS subjects will be recruited from the Endocrinology Clinics of the University of
 Chicago. All will be at least 2 years post-menarche 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).

 Exclusion Criteria:

 -  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.