Polycystic Ovary Syndrome (PCOS) and Sleep Apnea

NCT00203996 | Terminated Phase 4 Results

• 2 other identifiers: 12861BR01HL075079
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 1

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.

Conditions

Polycystic Ovary Syndrome; Obstructive Sleep Apnea

Keywords

polycystic ovary syndrome; metabolic syndrome; obstructive sleep apnea; impaired glucose tolerance; insulin resistance

Outcome Measures

Primary Outcomes (8)

• 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

• 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

• 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)

• 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

• 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)

• 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

• 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

• 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 Outcomes (8)

• Aim 1: Blood Pressure [Baseline]

  baseline (0 weeks)

• Aim 1: Blood Pressure [After Treatment]

  8 weeks

• Aim 1: Visceral Adiposity [Baseline]

  up to half of an hour

• Aim 1: Visceral Adiposity [After Treatment]

  up to half of an hour

• Aim 2: Mean Cortisol Levels Over 24 Hours, Per Patient [Baseline]

  10 minutes, over a period of 24 hours

Study Arms (10)

Aim 1: Placebo

NO INTERVENTION

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

Aim 1: Pioglitazone

EXPERIMENTAL

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

Drug: pioglitazone

Aim 1: Leuprolide + Estrogen/Progestin

EXPERIMENTAL

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

Aim 2: PCOS + SDB

EXPERIMENTAL

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)

Aim 2: Matched Controls

EXPERIMENTAL

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)

Aim 3: REM frag - SWS supp - Baseline

EXPERIMENTAL

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; Procedure: SWS supp

Aim 3: REM frag - Baseline - SWS supp

EXPERIMENTAL

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; Procedure: SWS supp

Aim 3: Baseline - REM frag - SWS supp

EXPERIMENTAL

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; Procedure: SWS supp

Aim 3: SWS supp - REM frag - Baseline

EXPERIMENTAL

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; Procedure: SWS supp

Aim 3: Baseline - SWS supp - REM frag

EXPERIMENTAL

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; Procedure: SWS supp

Interventions

continuous positive airway pressure (CPAP) 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.

Also known as: Continuous Positive Airway Pressure

Aim 2: Matched Controls; Aim 2: PCOS + SDB

depot leuprolide plus estrogen/progestin replacement 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.

Also known as: Lupron

Aim 1: Leuprolide + Estrogen/Progestin

pioglitazone 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.

Also known as: Actos

Aim 1: Pioglitazone

REM frag 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.

Aim 3: Baseline - REM frag - SWS supp; Aim 3: Baseline - SWS supp - REM frag; Aim 3: REM frag - Baseline - SWS supp; Aim 3: REM frag - SWS supp - Baseline; Aim 3: SWS supp - REM frag - Baseline

SWS supp 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; Aim 3: Baseline - SWS supp - REM frag; Aim 3: REM frag - Baseline - SWS supp; Aim 3: REM frag - SWS supp - Baseline; Aim 3: SWS supp - REM frag - Baseline

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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
• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Chicago: lead
• National Institutes of Health (NIH): collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

University of Chicago

Chicago, Illinois, 60637, United States

Location

Related Publications (3)

• 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.

  PMID: 21123449 RESULT

• 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.

  PMID: 18172212 RESULT

• 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.

  PMID: 18647805 DERIVED

MeSH Terms

Conditions

Polycystic Ovary Syndrome; Sleep Apnea, Obstructive; Metabolic Syndrome; Glucose Intolerance; Insulin Resistance

Interventions

Continuous Positive Airway Pressure; Estrogens; Leuprolide; Pioglitazone

Condition Hierarchy (Ancestors)

Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases; Sleep Apnea Syndromes; Apnea; Respiration Disorders; Respiratory Tract Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Hyperglycemia

Intervention Hierarchy (Ancestors)

Positive-Pressure Respiration; Respiration, Artificial; Airway Management; Therapeutics; Respiratory Therapy; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

No participants were randomized to any of the 3 study arms in Aim 1. Also, the recruitment of control subjects for Aim 2 was hindered by the difficulty in finding subjects who met both inclusion and exclusion criteria.

Results Point of Contact

• Title: David A. Ehrmann, MD
• Organization: The University of Chicago

dehrmann@medicine.bsd.uchicago.edu

(773) 702-6138

Study Officials

• David A Ehrmann, M.D.

  University of Chicago

  PRINCIPAL INVESTIGATOR

• Esra Tasali, M.D.

  University of Chicago

  STUDY DIRECTOR

• Eve Van Cauter, Ph.D.

  University of Chicago

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 13, 2005
• First Posted: September 20, 2005
• Study Start: September 1, 2003
• Primary Completion: June 1, 2008
• Study Completion: June 1, 2008
• Last Updated: March 21, 2023
• Results First Posted: July 16, 2013

Record last verified: 2023-02

Locations

US (1)