Sex Steroids, Sleep, and Metabolic Dysfunction in Women

Study Overview
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Brief Summary
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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.

Official Title
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Sex Steroids, Sleep, and Metabolic Dysfunction in Women

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

Intervention / Treatment
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* Drug: Progesterone
* Drug: testosterone
* Drug: glucocorticoid
* Device: continuous positive airway pressure
* Drug: Estrogen
* Other: Control


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Progesterone - PCOS<br>Women with obesity and polycystic ovary syndrome | Drug: Progesterone<br>* Micronized progesterone, 100 mg/d vaginally. The intervention lasts 70 days in total and consisted of 14 days on treatment, 14 days off treatment, 14 days on treatment, 14 days off treatment and a final 14 days on treatment. Testing is performed before and at the end of the 70 day intervention.<br>* Other names: Endometrin;|
| Experimental: Testosterone - premenopausal women<br>Healthy premenopausal women. | Drug: testosterone<br>* Testosterone gel 1250 ug/d applied transdermally for a total of 21 days. Testing is performed before and at the end of the 21 day intervention.<br>* Other names: 1% AndroGel;|
| Experimental: Continuous positive airway pressure<br>Women and men with obesity and obstructive sleep apnea | Device: continuous positive airway pressure<br>* Breathe through the mask of a continuous positive airway pressure device every night when sleep, for 6 weeks. Testing is performed before and at the end of the 6 week intervention.<br>|
| Experimental: Glucocorticoid<br>Lean and obese healthy women, and obese men | Drug: glucocorticoid<br>* Dexamethasone 0.013 mg/kg fat-free mass daily taken orally for a total of 21 days. Testing is performed before and at the end of the 21 day intervention.<br>|
| Experimental: Estrogen<br>Postmenopausal women | Drug: Estrogen<br>* Estrogen treatment (100 ug Estradiol daily) administered transdermally by using continuous delivery patches. The intervention lasted 70 days in total and consisted of 14 days on treatment, 14 days off treatment, 14 days on treatment, 14 days off treatment and a final 14 days on treatment.<br>* Other names: Estradiol Patch, Mylan Pharmaceuticals Inc.;|
| Other: control<br>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 | Other: Control<br>* No treatment with studies performed 31 to 72 days apart<br>|
| No Intervention: control - baseline testing only<br>Healthy men and women | |
| Experimental: Progesterone - Postmenopausal women<br>Postmenopausal women | Drug: Progesterone<br>* Micronized progesterone, 100 mg/d vaginally. The intervention lasts 70 days in total and consisted of 14 days on treatment, 14 days off treatment, 14 days on treatment, 14 days off treatment and a final 14 days on treatment. Testing is performed before and at the end of the 70 day intervention.<br>* Other names: Endometrin;|
| Experimental: Testosterone - Postmenopausal women<br>Postmenopausal women | Drug: testosterone<br>* Testosterone gel 1250 ug/d applied transdermally for a total of 21 days. Testing is performed before and at the end of the 21 day intervention.<br>* Other names: 1% AndroGel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Very-Low Density Lipoprotein-Triglyceride (VLDL-TG) Secretion Rate | 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. | Before and at the end of interventions | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Very-Low Density Lipoprotein-Triglyceride (VLDL-TG) Concentration | VLDL was isolated from plasma by ultracentrifugation with VLDL-TG concentration measured by using a colorimetric enzymatic kit (Sigma-Aldrich, St. Louis, MO). | Before and at the end of the interventions | 
| VLDL-TG Plasma Clearance Rate (Means) | 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. | Before and at the end of the interventions | 
| VLDL-TG Plasma Clearance Rate (Medians) | 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. | Before and at the end of the interventions | 
| Basal, Postabsorptive Fractional Synthesis Rates of Muscle Protein Synthesis | 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. | Before and at the end of the intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sleep apnea, obese, Very-low density lipoprotein (VLDL) metabolism, isotope tracer, women