Sex Steroids, Sleep, and Metabolic Dysfunction in Women

Not Applicable

Completed

Conditions: Polycystic Ovary Syndrome (PCOS)
Obstructive Sleep Apnea
Obesity

Interventions: Drug: Progesterone
Drug: testosterone
Device: continuous positive airway pressure
Drug: Estrogen
Other: Control
Drug: glucocorticoid

Registration Number: NCT00805207

Lead Sponsor: Washington University School of Medicine

Brief Summary: Increased plasma triglyceride concentration is a common feature of the metabolic abnormalities associated with obesity and a major risk factor for cardiovascular disease. Obesity is a major risk factor for two conditions that appear to be increasing in prevalence in women: the polycystic ovary syndrome (PCOS) and sleep disordered breathing. PCOS affects 5-8% of women. Sleep disordered breathing affects up to 10% of women. Obstructive sleep apnea (OSA) is the most common cause for sleep disordered breathing and particularly prevalent in obese women with PCOS (\~50%). Both PCOS and OSA augment the increase in plasma triglyceride (TG) concentration associated with obesity, and the effects of PCOS and OSA on plasma TG concentration appear to be additive. The mechanisms responsible for the adverse effects on plasma TG metabolism are not known. The primary goal of this project, therefore, is to determine the mechanisms responsible for the increase in plasma TG concentration in obese women with PCOS and OSA. It is our general hypothesis that alterations in the hormonal milieu that are characteristic of these two conditions are, at least in part, responsible for the increase in plasma TG concentration in obese women with the conditions. Furthermore, we hypothesize that the hormonal aberrations characteristic of the two conditions are particularly harmful to obese, compared with lean, women.

The effects of PCOS on skeletal muscle protein metabolism are also not known. However, sex hormones are thought to be important regulators of muscle protein turnover suggesting that muscle protein metabolism is likely to be affected by PCOS. We will examine this by determining the effect of individual sex hormones on muscle protein metabolism and hypothesize that testosterone administration will stimulate muscle protein metabolism while estrogen and progesterone administration will inhibit muscle protein metabolism.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 61

Inclusion Criteria

Women aged 18-75 years and men 45-75 years
Healthy lean, overweight and obese women (BMI 18-40 kg/m2) and obese men (BMI 30-40 kg/m2)
Obese women (BMI 30-40 kg/m2) with OSA or PCOS

Exclusion Criteria

Pregnant, lactating, peri- or postmenopausal women will be excluded from the study because of potential confounding influences of these factors and potential ethical concerns (pregnant women)
Women taking medications known to affect substrate metabolism and those with evidence of significant organ dysfunction (e.g. impaired glucose tolerance, diabetes mellitus, liver disease, hypo- or hyper-thyroidism) other than PCOS and OSA
Severe hypertriglyceridemia (fasting plasma TG concentration >400 mg/dl)
Subjects with OSA who have an apnea-hypopnea index (AHI) score >30 (the total number of obstructive events divided by the total hours of sleep) will be excluded and instructed to seek medical care

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Progesterone - PCOS	Progesterone	Women with obesity and polycystic ovary syndrome
Testosterone - premenopausal women	testosterone	Healthy premenopausal women.
Continuous positive airway pressure	continuous positive airway pressure	Women and men with obesity and obstructive sleep apnea
Estrogen	Estrogen	Postmenopausal women
control	Control	Postmenopausal women - tested before and after no treatment. Duration between before and after testing ranged from 31 to 78 days with an average of 46 days between visits
Glucocorticoid	glucocorticoid	Lean and obese healthy women, and obese men
Progesterone - Postmenopausal women	Progesterone	Postmenopausal women
Testosterone - Postmenopausal women	testosterone	Postmenopausal women

Primary Outcome Measures

Name	Time	Method
Very-Low Density Lipoprotein-Triglyceride (VLDL-TG) Secretion Rate	Before and at the end of interventions	VLDL was isolated from plasma by ultracentrifugation with the tracer-to-tracee (TTR) of free glycerol in plasma and glycerol in VLDL-TG determined by gas chromatography-mass spectrometry. The fractional turnover rates of VLDL-TG was determined by fitting the glycerol TTR time courses in plasma and in VLDL-TG to a multicompartmental model. The hepatic (liver) secretion rates of VLDL-TG was calculated by multiplying the fractional turnover rates of VLDL-TG by the of VLDL-TG concentration.

Secondary Outcome Measures

Name	Time	Method
Very-Low Density Lipoprotein-Triglyceride (VLDL-TG) Concentration	Before and at the end of the interventions	VLDL was isolated from plasma by ultracentrifugation with VLDL-TG concentration measured by using a colorimetric enzymatic kit (Sigma-Aldrich, St. Louis, MO).
VLDL-TG Plasma Clearance Rate (Means)	Before and at the end of the interventions	VLDL was isolated from plasma by ultracentrifugation with the tracer-to-tracee (TTR) of free glycerol in plasma and glycerol in VLDL-TG determined by gas chromatography-mass spectrometry. The fractional turnover rates of VLDL-TG was determined by fitting the glycerol TTR time courses in plasma and in VLDL-TG to a multicompartmental model. The plasma clearance rate of VLDL-TG was calculated by dividing the VLDL-TG secretion rate by the VLDL-TG concentration.
VLDL-TG Plasma Clearance Rate (Medians)	Before and at the end of the interventions	VLDL was isolated from plasma by ultracentrifugation with the tracer-to-tracee (TTR) of free glycerol in plasma and glycerol in VLDL-TG determined by gas chromatography-mass spectrometry. The fractional turnover rates of VLDL-TG was determined by fitting the glycerol TTR time courses in plasma and in VLDL-TG to a multicompartmental model. The plasma clearance rate of VLDL-TG was calculated by dividing the VLDL-TG secretion rate by the VLDL-TG concentration.
Basal, Postabsorptive Fractional Synthesis Rates of Muscle Protein Synthesis	Before and at the end of the intervention	The fractional synthesis rate (FSR) of muscle protein synthesis was determined by assessing the incorporation of \[5,5,5-2H3\]leucine into muscle proteins. \[5,5,5-2H3\]leucine was infused for 5 hours with muscle biopsies obtained from the vastus lateralis muscle in the thigh 2 and 5 hours. The leucine tracer-to-tracee ratio (TTR) in muscle protein and the muscle free leucine pool was determined by gas chromatography-mass spectrometry (GCMS) and the FSR of muscle proteins calculated using a standard precursor-product model. The FSR was calculated as %/h, which reflects the percent of all proteins in the muscle that were synthesized (made) per hour.