Polycystic Ovary Syndrome (PCOS) and Sleep Apnea

NCT ID: NCT00203996

Last Updated: 2023-03-21

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE4
• Total Enrollment: 37 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2003-09-30
• Study Completion Date: 2008-06-30

Brief 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.

Detailed 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.

Conditions

Polycystic Ovary Syndrome; Obstructive Sleep Apnea

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Aim 1: Placebo

One of the 3 treatment arms in Aim 1: Placebo. No subjects were randomized to this arm.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Aim 1: Pioglitazone

One of the 3 treatment arms in Aim 1: Pioglitazone. No subjects were randomized to this arm.

Group Type: EXPERIMENTAL

pioglitazone

Intervention Type: DRUG

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.

Aim 1: Leuprolide + Estrogen/Progestin

One of the 3 treatment arms in Aim 1: depot leuprolide plus estrogen/progestin replacement. No subjects were randomized to this arm.

Group Type: EXPERIMENTAL

depot leuprolide plus estrogen/progestin replacement

Intervention Type: DRUG

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.

Aim 2: PCOS + SDB

One of the 2 study groups in Aim 2: Women with polycystic ovary syndrome (PCOS) and sleep disordered breathing (SDB) were treated with 8 weeks of continuous positive airway pressure (CPAP).

Group Type: EXPERIMENTAL

continuous positive airway pressure (CPAP)

Intervention Type: DEVICE

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.

Aim 2: Matched Controls

One of the 2 study groups in Aim 2: Women who were of similar age to those in the PCOS+SDB group were treated with 8 weeks of continuous positive airway pressure (CPAP). The recruitment of control subjects for this protocol was hindered by the difficulty in finding subjects who met both inclusion and exclusion criteria. As a consequence, the sample size of control subjects was insufficient to allow for any meaningful conclusions to be drawn. Statistical analyses were not possible due to insufficient sample size.

Group Type: EXPERIMENTAL

continuous positive airway pressure (CPAP)

Intervention Type: DEVICE

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.

Aim 3: REM frag - SWS supp - Baseline

Each subject was assessed under three experimental conditions in the following order.

REM fragmentation: Rapid eye movement (REM) sleep will be fragmented by experimentally induced microarousals for 3 consecutive nights and non-REM sleep will be left undisturbed.

Slow wave sleep (SWS) suppression: Slow wave activity will be suppressed without awakening the subject and REM sleep will be left undisturbed.

Baseline: "Baseline" sleep (i.e., with no experimental intervention) assessment is recorded. This assessment may have been recorded as the first, second, or third intervention.

Group Type: EXPERIMENTAL

REM frag

Intervention Type: PROCEDURE

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

Intervention Type: PROCEDURE

SWS: Slow wave activity will be suppressed without awakening the subject and REM sleep will be left undisturbed.

Aim 3: REM frag - Baseline - SWS supp

Each subject was assessed under three experimental conditions in the following order.

REM fragmentation: Rapid eye movement (REM) sleep will be fragmented by experimentally induced microarousals for 3 consecutive nights and non-REM sleep will be left undisturbed.

Baseline: "Baseline" sleep (i.e., with no experimental intervention) assessment is recorded. This assessment may have been recorded as the first, second, or third intervention.

SWS suppression: Slow wave activity will be suppressed without awakening the subject and REM sleep will be left undisturbed.

Group Type: EXPERIMENTAL

REM frag

Intervention Type: PROCEDURE

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

Intervention Type: PROCEDURE

SWS: Slow wave activity will be suppressed without awakening the subject and REM sleep will be left undisturbed.

Aim 3: Baseline - REM frag - SWS supp

Each subject was assessed under three experimental conditions in the following order.

Baseline: "Baseline" sleep (i.e., with no experimental intervention) assessment is recorded. This assessment may have been recorded as the first, second, or third intervention.

REM fragmentation: 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 suppression: Slow wave activity will be suppressed without awakening the subject and REM sleep will be left undisturbed.

Group Type: EXPERIMENTAL

REM frag

Intervention Type: PROCEDURE

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

Intervention Type: PROCEDURE

SWS: Slow wave activity will be suppressed without awakening the subject and REM sleep will be left undisturbed.

Aim 3: SWS supp - REM frag - Baseline

Each subject was assessed under three experimental conditions in the following order.

SWS suppression: Slow wave activity will be suppressed without awakening the subject and REM sleep will be left undisturbed.

REM fragmentation: Rapid eye movement (REM) sleep will be fragmented by experimentally induced microarousals for 3 consecutive nights and non-REM sleep will be left undisturbed.

Baseline: "Baseline" sleep (i.e., with no experimental intervention) assessment is recorded. This assessment may have been recorded as the first, second, or third intervention.

Group Type: EXPERIMENTAL

REM frag

Intervention Type: PROCEDURE

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

Intervention Type: PROCEDURE

SWS: Slow wave activity will be suppressed without awakening the subject and REM sleep will be left undisturbed.

Aim 3: Baseline - SWS supp - REM frag

Each subject was assessed under three experimental conditions in the following order.

Baseline: "Baseline" sleep (i.e., with no experimental intervention) assessment is recorded. This assessment may have been recorded as the first, second, or third intervention.

SWS suppression: Slow wave activity will be suppressed without awakening the subject and REM sleep will be left undisturbed.

REM fragmentation: Rapid eye movement (REM) sleep will be fragmented by experimentally induced microarousals for 3 consecutive nights and non-REM sleep will be left undisturbed.

Group Type: EXPERIMENTAL

REM frag

Intervention Type: PROCEDURE

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

Intervention Type: PROCEDURE

SWS: Slow wave activity will be suppressed without awakening the subject and REM sleep will be left undisturbed.

Interventions

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.

Intervention Type: DEVICE

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.

Intervention Type: 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.

Intervention Type: DRUG

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.

Intervention Type: PROCEDURE

SWS supp

SWS: Slow wave activity will be suppressed without awakening the subject and REM sleep will be left undisturbed.

Intervention Type: PROCEDURE

Other Intervention Names

Continuous Positive Airway Pressure; Lupron; Actos

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

University of Chicago

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David A Ehrmann, M.D.

Role: PRINCIPAL_INVESTIGATOR

University of Chicago

Esra Tasali, M.D.

Role: STUDY_DIRECTOR

University of Chicago

Eve Van Cauter, Ph.D.

Role: STUDY_DIRECTOR

University of Chicago

Locations

University of Chicago

Chicago, Illinois, United States

Countries

United States

References

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. Epub 2010 Dec 1.

Reference Type: RESULT

PMID: 21123449 (View on PubMed)

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.

Reference Type: RESULT

PMID: 18172212 (View on PubMed)

Tasali E, Van Cauter E, Hoffman L, Ehrmann DA. Impact of obstructive sleep apnea on insulin resistance and glucose tolerance in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2008 Oct;93(10):3878-84. doi: 10.1210/jc.2008-0925. Epub 2008 Jul 22.

Reference Type: DERIVED

PMID: 18647805 (View on PubMed)

Other Identifiers

R01HL075079

Identifier Type: NIH

Identifier Source: secondary_id

View Link

12861B

Identifier Type: -

Identifier Source: org_study_id