Sex Steroids, Sleep, and Metabolic Dysfunction in Women

NCT00805207 | Completed Results

• 2 other identifiers: 07-0692NIH P50 HD057796
• Study Type: interventional
• Target: 61
• Locations: 1 country
• Sites: 1

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.

Conditions

Polycystic Ovary Syndrome (PCOS); Obstructive Sleep Apnea; Obesity

Keywords

sleep apnea; obese; Very-low density lipoprotein (VLDL) metabolism; isotope tracer; women

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Very-Low Density Lipoprotein-Triglyceride (VLDL-TG) Concentration

  Before and at the end of the interventions

• VLDL-TG Plasma Clearance Rate (Means)

  Before and at the end of the interventions

• VLDL-TG Plasma Clearance Rate (Medians)

  Before and at the end of the interventions

• Basal, Postabsorptive Fractional Synthesis Rates of Muscle Protein Synthesis

  Before and at the end of the intervention

Study Arms (9)

Progesterone - PCOS

EXPERIMENTAL

Women with obesity and polycystic ovary syndrome

Drug: Progesterone

Testosterone - premenopausal women

EXPERIMENTAL

Healthy premenopausal women.

Drug: testosterone

Continuous positive airway pressure

EXPERIMENTAL

Women and men with obesity and obstructive sleep apnea

Device: continuous positive airway pressure

Glucocorticoid

EXPERIMENTAL

Lean and obese healthy women, and obese men

Drug: glucocorticoid

Estrogen

EXPERIMENTAL

Postmenopausal women

Drug: Estrogen

control

OTHER

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

control - baseline testing only

NO INTERVENTION

Healthy men and women

Progesterone - Postmenopausal women

EXPERIMENTAL

Postmenopausal women

Drug: Progesterone

Testosterone - Postmenopausal women

EXPERIMENTAL

Postmenopausal women

Drug: testosterone

Interventions

Progesterone DRUG

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.

Also known as: Endometrin

Progesterone - PCOS; Progesterone - Postmenopausal women

testosterone DRUG

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.

Also known as: 1% AndroGel

Testosterone - Postmenopausal women; Testosterone - premenopausal women

glucocorticoid DRUG

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.

Glucocorticoid

continuous positive airway pressure DEVICE

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.

Continuous positive airway pressure

Estrogen DRUG

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.

Also known as: Estradiol Patch, Mylan Pharmaceuticals Inc.

Estrogen

Control OTHER

No treatment with studies performed 31 to 72 days apart

control

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (4)

• Wang X, Magkos F, Patterson BW, Reeds DN, Kampelman J, Mittendorfer B. Low-dose dexamethasone administration for 3 weeks favorably affects plasma HDL concentration and composition but does not affect very low-density lipoprotein kinetics. Eur J Endocrinol. 2012 Aug;167(2):217-23. doi: 10.1530/EJE-12-0180. Epub 2012 May 22.

  PMID: 22619349 RESULT

• Wang X, Smith GI, Patterson BW, Reeds DN, Kampelman J, Magkos F, Mittendorfer B. Testosterone increases the muscle protein synthesis rate but does not affect very-low-density lipoprotein metabolism in obese premenopausal women. Am J Physiol Endocrinol Metab. 2012 Mar 15;302(6):E740-6. doi: 10.1152/ajpendo.00533.2011. Epub 2012 Jan 17.

  PMID: 22252942 RESULT

• Smith GI, Reeds DN, Okunade AL, Patterson BW, Mittendorfer B. Systemic delivery of estradiol, but not testosterone or progesterone, alters very low density lipoprotein-triglyceride kinetics in postmenopausal women. J Clin Endocrinol Metab. 2014 Jul;99(7):E1306-10. doi: 10.1210/jc.2013-4470. Epub 2014 Apr 2.

  PMID: 24694337 RESULT

• Smith GI, Yoshino J, Reeds DN, Bradley D, Burrows RE, Heisey HD, Moseley AC, Mittendorfer B. Testosterone and progesterone, but not estradiol, stimulate muscle protein synthesis in postmenopausal women. J Clin Endocrinol Metab. 2014 Jan;99(1):256-65. doi: 10.1210/jc.2013-2835. Epub 2013 Dec 20.

  PMID: 24203065 RESULT

MeSH Terms

Conditions

Polycystic Ovary Syndrome; Sleep Apnea, Obstructive; Obesity; Sleep Apnea Syndromes

Interventions

Progesterone; Testosterone; Glucocorticoids; Continuous Positive Airway Pressure; Estrogens

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; Apnea; Respiration Disorders; Respiratory Tract Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Corpus Luteum Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progesterone Congeners; Gonadal Steroid Hormones; Androstenols; Androstenes; Androstanes; Testosterone Congeners; Adrenal Cortex Hormones; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Positive-Pressure Respiration; Respiration, Artificial; Airway Management; Therapeutics; Respiratory Therapy

Results Point of Contact

• Title: Gordon Smith, PhD
• Organization: Washington University in St Louis

gsmith@wustl.edu

314-362-4375

Study Officials

• Bettina Mittendorfer, PhD

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 5, 2008
• First Posted: December 9, 2008
• Study Start: September 1, 2007
• Primary Completion: March 1, 2013
• Study Completion: March 1, 2013
• Last Updated: August 1, 2018
• Results First Posted: August 1, 2018

Record last verified: 2018-07

Locations

US (1)