Polycystic Ovary Syndrome (PCOS) and Sleep Apnea

This study has been terminated.
(Did not meet target patient accrual goals)
Sponsor:
Collaborators:
Information provided by (Responsible Party):
David Ehrmann, University of Chicago
ClinicalTrials.gov Identifier:
NCT00203996
First received: September 13, 2005
Last updated: July 16, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
Polycystic Ovary Syndrome
Obstructive Sleep Apnea
Device: continuous positive airway pressure (CPAP)
Drug: depot leuprolide plus estrogen/progestin replacement
Drug: pioglitazone
Procedure: REM frag
Procedure: SWS supp
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver)
Primary Purpose: Treatment
Official Title: Sleep, Metabolic, and Cardiovascular Dysfunction in Polycystic Ovary Syndrome

Resource links provided by NLM:


Further study details as provided by University of Chicago:

Primary Outcome Measures:
  • Aim 1: Apnea-Hypopnea Index (AHI) [Baseline] [ Time Frame: baseline ] [ Designated as safety issue: No ]
    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.

  • Aim 1: Apnea-hypopnea Index (AHI) [After Treatment] [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    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.

  • Aim 2: Insulin Sensitivity Index (SI) From Intravenous Glucose Tolerance Test [Baseline] [ Time Frame: baseline (0 weeks) ] [ Designated as safety issue: No ]
    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.

  • Aim 2: Insulin Sensitivity Index (SI) From Intravenous Glucose Tolerance Test [After CPAP] [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    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.

  • Aim 2: Acute Insulin Resistance to Intravenous Glucose (AIRg) [Baseline] [ Time Frame: baseline (0 weeks) ] [ Designated as safety issue: No ]
    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.

  • Aim 2: Acute Insulin Resistance to Intravenous Glucose (AIRg) [After CPAP] [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    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.

  • Aim 3: Insulin Sensitivity Index (SI) From Intravenous Glucose Tolerance Test [Baseline] [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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.

  • Aim 3: Insulin Sensitivity Index (SI) From Intravenous Glucose Tolerance Test [After 3 Nights of SWS Suppression] [ Time Frame: 3 nights ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Aim 1: Blood Pressure [Baseline] [ Time Frame: baseline (0 weeks) ] [ Designated as safety issue: No ]
    Blood pressure is the pressure of blood within the arteries, produced primarily by the contraction of the heart muscle.

  • Aim 1: Blood Pressure [After Treatment] [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Blood pressure is the pressure of blood within the arteries, produced primarily by the contraction of the heart muscle.

  • Aim 1: Visceral Adiposity [Baseline] [ Time Frame: up to half of an hour ] [ Designated as safety issue: No ]
    Visceral adiposity refers to the degree of fat located in the peritoneal cavity (abdominal area) that surrounds the body's internal organs.

  • Aim 1: Visceral Adiposity [After Treatment] [ Time Frame: up to half of an hour ] [ Designated as safety issue: No ]
    Visceral adiposity refers to the degree of fat located in the peritoneal cavity (abdominal area) that surrounds the body's internal organs.

  • Aim 2: Mean Cortisol Levels Over 24 Hours, Per Patient [Baseline] [ Time Frame: 10 minutes, over a period of 24 hours ] [ Designated as safety issue: No ]
    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.

  • Aim 2: Mean Cortisol Levels Over 24 Hours, Per Patient [After Treatment] [ Time Frame: 10 minutes, over a period of 24 hours ] [ Designated as safety issue: No ]
    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.

  • Aim 2: Mean Leptin Levels Over 24 Hours, Per Patient [Baseline] [ Time Frame: 15 minutes over a period of 24 hours ] [ Designated as safety issue: No ]
    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.

  • Aim 2: Mean Leptin Levels Over 24 Hours, Per Patient [After Treatment] [ Time Frame: 15 minutes over a period of 24 hours ] [ Designated as safety issue: No ]
    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.


Enrollment: 37
Study Start Date: September 2003
Study Completion Date: June 2008
Primary Completion Date: June 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: Aim 1: Placebo
One of the 3 treatment arms in Aim 1: Placebo. No subjects were randomized to this arm.
Experimental: Aim 1: Pioglitazone
One of the 3 treatment arms in Aim 1: Pioglitazone. No subjects were randomized to this arm.
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.
Other Name: Actos
Experimental: 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.
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.
Other Name: Lupron
Experimental: 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).
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.
Other Name: Continuous Positive Airway Pressure
Experimental: 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.
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.
Other Name: Continuous Positive Airway Pressure
Experimental: 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.

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

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

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

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

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

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.

  Eligibility

Ages Eligible for Study:   18 Years to 40 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00203996

Locations
United States, Illinois
University of Chicago
Chicago, Illinois, United States, 60637
Sponsors and Collaborators
University of Chicago
Investigators
Principal Investigator: David A Ehrmann, M.D. University of Chicago
Study Director: Esra Tasali, M.D. University of Chicago
Study Director: Eve Van Cauter, Ph.D. University of Chicago
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: David Ehrmann, Professor, University of Chicago
ClinicalTrials.gov Identifier: NCT00203996     History of Changes
Other Study ID Numbers: 12861B, R01HL075079
Study First Received: September 13, 2005
Results First Received: March 5, 2013
Last Updated: July 16, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of Chicago:
polycystic ovary syndrome
metabolic syndrome
obstructive sleep apnea
impaired glucose tolerance
insulin resistance

Additional relevant MeSH terms:
Apnea
Polycystic Ovary Syndrome
Sleep Apnea Syndromes
Sleep Apnea, Obstructive
Respiration Disorders
Respiratory Tract Diseases
Signs and Symptoms, Respiratory
Signs and Symptoms
Ovarian Cysts
Cysts
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Gonadal Disorders
Endocrine System Diseases
Sleep Disorders, Intrinsic
Dyssomnias
Sleep Disorders
Nervous System Diseases
Estrogens
Progestins
Pioglitazone
Leuprolide
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Hypoglycemic Agents
Fertility Agents, Female

ClinicalTrials.gov processed this record on August 28, 2014