Polycystic Ovary Syndrome (PCOS) and Sleep Apnea

Obstructive Sleep Apnea Clinical Trial

Official title:

Sleep, Metabolic, and Cardiovascular Dysfunction in Polycystic Ovary Syndrome

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00203996
• Other study ID #: 12861B
• Secondary ID: R01HL075079
• Status: Terminated
• Phase: Phase 4
• Start date: September 2003
• Est. completion date: June 2008

Study information

• Verified date: February 2023
• Source: University of Chicago
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 37
• Est. completion date: June 2008
• Est. primary completion date: June 2008
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 40 Years

Eligibility

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.

Related Conditions & MeSH terms

• Apnea
• Obstructive Sleep Apnea
• Polycystic Ovary Syndrome
• Sleep Apnea Syndromes
• Sleep Apnea, Obstructive
• Syndrome

Intervention

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.
• 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.

Procedure:
• REM frag
Rapid eye movement (REM) sleep will be fragmented by experimentally induced microarousals for 3 consecutive nights and non-REM sleep will be left undisturbed.
• SWS supp
SWS: Slow wave activity will be suppressed without awakening the subject and REM sleep will be left undisturbed.

Locations

Country	Name	City	State
United States	University of Chicago	Chicago	Illinois

Sponsors (3)

Lead Sponsor	Collaborator
University of Chicago	National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

References & Publications (2)

Tasali E, Chapotot F, Leproult R, Whitmore H, Ehrmann DA. Treatment of obstructive sleep apnea improves cardiometabolic function in young obese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2011 Feb;96(2):365-74. doi: 10.1210/jc.2010-1187 — View Citation

Tasali E, Leproult R, Ehrmann DA, Van Cauter E. Slow-wave sleep and the risk of type 2 diabetes in humans. Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):1044-9. doi: 10.1073/pnas.0706446105. Epub 2008 Jan 2. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Aim 1: Apnea-Hypopnea Index (AHI) [Baseline]	Apnea-hypopnea index (AHI) is an index used to assess the severity of sleep apnea based on the total number of complete cessations (apnea) and partial obstructions (hypopnea) of breathing occurring per hour of sleep.	baseline
Primary	Aim 1: Apnea-hypopnea Index (AHI) [After Treatment]	Apnea-hypopnea index (AHI) is an index used to assess the severity of sleep apnea based on the total number of complete cessations (apnea) and partial obstructions (hypopnea) of breathing occurring per hour of sleep.	8 weeks
Primary	Aim 2: Insulin Sensitivity Index (SI) From Intravenous Glucose Tolerance Test [Baseline]	Insulin sensitivity Index (SI) is the increase in net fractional glucose clearance rate per unit change in plasma insulin concentration after an intravenous glucose load. SI quantifies the capacity of insulin to promote glucose disposal.	baseline (0 weeks)
Primary	Aim 2: Insulin Sensitivity Index (SI) From Intravenous Glucose Tolerance Test [After CPAP]	Insulin sensitivity Index (SI) is the increase in net fractional glucose clearance rate per unit change in plasma insulin concentration after an intravenous glucose load. SI quantifies the capacity of insulin to promote glucose disposal.	8 weeks
Primary	Aim 2: Acute Insulin Resistance to Intravenous Glucose (AIRg) [Baseline]	Acute insulin resistance to intravenous glucose (AIRg) is a measure of the secretion of insulin during the first 10 minutes after an intravenous glucose load. AIRg addresses adequacy of insulin secretion.	baseline (0 weeks)
Primary	Aim 2: Acute Insulin Resistance to Intravenous Glucose (AIRg) [After CPAP]	Acute insulin resistance to intravenous glucose (AIRg) is a measure of the secretion of insulin during the first 10 minutes after an intravenous glucose load. AIRg addresses adequacy of insulin secretion.	8 weeks
Primary	Aim 3: Insulin Sensitivity Index (SI) From Intravenous Glucose Tolerance Test [Baseline]	Insulin sensitivity Index (SI) is the increase in net fractional glucose clearance rate per unit change in plasma insulin concentration after an intravenous glucose load. SI quantifies the capacity of insulin to promote glucose disposal.	Baseline
Primary	Aim 3: Insulin Sensitivity Index (SI) From Intravenous Glucose Tolerance Test [After 3 Nights of SWS Suppression]	Insulin sensitivity Index (SI) is the increase in net fractional glucose clearance rate per unit change in plasma insulin concentration after an intravenous glucose load. SI quantifies the capacity of insulin to promote glucose disposal.	3 nights
Secondary	Aim 1: Blood Pressure [Baseline]	Blood pressure is the pressure of blood within the arteries, produced primarily by the contraction of the heart muscle.	baseline (0 weeks)
Secondary	Aim 1: Blood Pressure [After Treatment]	Blood pressure is the pressure of blood within the arteries, produced primarily by the contraction of the heart muscle.	8 weeks
Secondary	Aim 1: Visceral Adiposity [Baseline]	Visceral adiposity refers to the degree of fat located in the peritoneal cavity (abdominal area) that surrounds the body's internal organs.	up to half of an hour
Secondary	Aim 1: Visceral Adiposity [After Treatment]	Visceral adiposity refers to the degree of fat located in the peritoneal cavity (abdominal area) that surrounds the body's internal organs.	up to half of an hour
Secondary	Aim 2: Mean Cortisol Levels Over 24 Hours, Per Patient [Baseline]	This outcome is defined as the average concentration of cortisol (a glucocorticoid produced by the adrenal gland) in the blood, measured repeatedly over a 24 hour period in each patient individually.	10 minutes, over a period of 24 hours
Secondary	Aim 2: Mean Cortisol Levels Over 24 Hours, Per Patient [After Treatment]	This outcome is defined as the average concentration of cortisol (a glucocorticoid produced by the adrenal gland) in the blood, measured repeatedly over a 24 hour period in each patient individually.	10 minutes, over a period of 24 hours
Secondary	Aim 2: Mean Leptin Levels Over 24 Hours, Per Patient [Baseline]	This outcome is defined as the average concentration of leptin (a hormone produced by the fat cells that affects feeding behavior and appetite) in the blood, measured repeatedly over a 24 hour period in each patient individually.	15 minutes over a period of 24 hours
Secondary	Aim 2: Mean Leptin Levels Over 24 Hours, Per Patient [After Treatment]	This outcome is defined as the average concentration of leptin (a hormone produced by the fat cells that affects feeding behavior and appetite) in the blood, measured repeatedly over a 24 hour period in each patient individually.	15 minutes over a period of 24 hours