Polycystic Ovary SyndromePhase 4NCT00203996
Polycystic Ovary Syndrome (PCOS) and Sleep Apnea
A Phase 4 study testing continuous positive airway pressure (CPAP), depot leuprolide plus estrogen/progestin replacement and pioglitazone in people with Polycystic Ovary Syndrome and Obstructive Sleep Apnea, run by University of Chicago at 1 site in United States.
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. Read more about this study
- Who is it for?
- Ages 18 to 40 yearsHealthy volunteers can take part
- Conditions the study is for
- Polycystic Ovary Syndrome, Obstructive Sleep Apnea
- What is being tested?
- continuous positive airway pressure (CPAP), depot leuprolide plus estrogen/progestin replacement and pioglitazone
- Type of treatment
- Pill or oral medicine, Injection or infusion, Medical device, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 37 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2003to Jun 2008
- Phase
- Phase 4
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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).
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Sleep, Metabolic, and Cardiovascular Dysfunction in Polycystic Ovary Syndrome
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.
Read the 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
- Being tested
- continuous positive airway pressure (CPAP), depot leuprolide plus estrogen/progestin replacement, pioglitazone, REM frag, SWS supp
- Keywords
- polycystic ovary syndrome, metabolic syndrome, obstructive sleep apnea, impaired glucose tolerance, insulin resistance
- Medical subject headings
- Polycystic Ovary Syndrome, Sleep Apnea, Obstructive, Metabolic Syndrome, Glucose Intolerance, Insulin Resistance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
continuous positive airway pressure (CPAP)Device
Also called Continuous Positive Airway Pressure
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.
depot leuprolide plus estrogen/progestin replacementDrug
Also called Lupron
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.
pioglitazoneDrug
Also called Actos
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.
REM fragProcedure or surgery
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 suppProcedure or surgery
SWS: Slow wave activity will be suppressed without awakening the subject and REM sleep will be left undisturbed.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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). Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: Procedure: REM frag; Procedure: SWS supp |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 3 nights
Secondary outcomes (8)
Aim 1: Blood Pressure [Baseline]
Blood pressure is the pressure of blood within the arteries, produced primarily by the contraction of the heart muscle.
Measured: baseline (0 weeks)
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.
Measured: 8 weeks
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.
Measured: up to half of an hour
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.
Measured: up to half of an hour
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.
Measured: 10 minutes, over a period of 24 hours
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.
Measured: 10 minutes, over a period of 24 hours
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.
Measured: 15 minutes over a period of 24 hours
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.
Measured: 15 minutes over a period of 24 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Sep 2005 (estimated)
- Study startSep 2003
- Primary completionJun 2008
- Study completionJun 2008
Why it stopped: Did not meet target patient accrual goals
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Polycystic Ovary SyndromeStudies of the same condition, open and under way.
- More trials run by University of ChicagoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Care provider
- Enrolment
- 37 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Chicago
- Sponsor type
- University, hospital or other
- Collaborators
- National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Sponsor
- Investigators
- David A Ehrmann, M.D., Principal investigator, University of ChicagoEsra Tasali, M.D., Study director, University of ChicagoEve Van Cauter, Ph.D., Study director, University of Chicago
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00203996
- Sponsor's protocol ID
- 12861B
- Other IDs
- R01HL075079
- Status last verified
- Feb 2023
- First submitted
- 13 Sep 2005
- Last updated
- 21 Mar 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
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.
PubMed 21123449Tasali 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.
PubMed 18172212Tasali 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.
PubMed 18647805