Evaluation of Cortisol Resistance in Young Endurance-trained and Elderly Men

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )
ClinicalTrials.gov Identifier:
NCT01294319
First received: February 10, 2011
Last updated: August 16, 2016
Last verified: August 2016
  Purpose

Background:

  • The adrenal glands, located above the kidneys, produce hormones called glucocorticoids and mineralocorticoids. Glucocorticoids, especially the hormone cortisol, act on nearly all cells in the body with effects that are especially important to the body's stress response. They maintain heart function, blood pressure, and proper blood sugar levels, and help regulate the body's responses to infections and injury. Mineralocorticoids help to regulate salt and water levels in the body.
  • Blood levels of cortisol have a natural day-to-night pattern: the highest levels occur in the morning and the lowest levels occur at night. This pattern is regulated by the hormone ACTH, which is made by the pituitary gland, and causes increased or decreased cortisol levels in response to the levels in the blood. Research has shown that older men have higher ACTH and cortisol levels than younger men, and that endurance-trained athletes have different cortisol levels than more sedentary individuals. Researchers are interested in studying these differences in cortisol levels and their potential effects on health.

Objectives:

- To compare cortisol levels and responses in sedentary young men and endurance-trained male athletes and elderly men.

Eligibility:

  • Healthy men between 18 and 30 years of age who have exercised less than 1 hour each week for the past 3 years.
  • Healthy men between 18 and 30 years of age who have regularly run more than 45 km (28 miles) per week for at least 3 months.
  • Healthy men between 65 and 80 years of age who have exercised less than 1 hour each week for the past 3 years.

Design:

  • Participants will be screened with a full medical history and physical examination, as well as blood and urine samples.
  • Participants will collect saliva and urine samples at home, both for cortisol measurements. Saliva samples should be collected in the evening on 2 separate days, and urine samples should be collected continuously for 12-hour intervals (7 AM to 7 PM and 7 PM to 7 AM) over a single 24-hour period. Participants will provide baseline blood samples at the National Institutes of Health when they drop off the saliva and urine samples.
  • Participants will have four separate evening/overnight tests at the National Institutes of Health. At these tests, participants will take study drugs or a look-alike capsule to block the effects of only glucocorticoid, only mineralocorticoid, both glucocorticoid and mineralocorticoid, or neither. Blood, saliva, and urine samples will be collected regularly from 7 PM to 7 AM the next morning.
  • Participants will have a final clinic test in which they will take dexamethasone late in the evening (11 PM to midnight) and visit the National Institutes of Health by 8 AM the next morning to provide a blood sample.

Condition Intervention Phase
Cortisol Resistance
Negative Feedback
ACTH
Mineralcorticoid
Glucocorticoid
Drug: Mifepristone
Drug: Placebo
Drug: Spironolactone
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Prevention
Official Title: Evaluation of Cortisol Resistance in Young Endurance-Trained and Elderly Men

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Proportion of Suppressors After Dexamethasone [ Time Frame: cortisol measured between 8 and 9 after dexamethasone was taken between 11 PM and midnight ]

Secondary Outcome Measures:
  • Post-dexamethasone Cortisol Level [ Time Frame: Cortisol obtained at 8-9 AM after dexamethasone taken between 11 pm and midnight ]
  • ACTH after taking various study interventions [ Time Frame: 1900h - 2300h at 30 minute intervals ]

Enrollment: 51
Study Start Date: January 2011
Study Completion Date: August 2016
Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: mifepristone and placebo
Mifepristone, 400 mg, given at 1200h and 1700h; placebo given at same times.
Drug: Mifepristone Drug: Placebo
Experimental: spironolactone and placebo
Spironolactone 200mg, given at 1200h and 1700h; placebo given at same times
Drug: Placebo Drug: Spironolactone
Experimental: mifepristone and spironolactone
mifepristone, 400mg and spironolactone 200 mg, given as 1200h and 1700h
Drug: Mifepristone Drug: Spironolactone
Placebo Comparator: Placebo
two placebo capsules given at 1200h and 1900h
Drug: Placebo

Detailed Description:

Adrenocorticotropin (ACTH) secretion is normally exquisitely regulated through endogenous stimulation by corticotrophin-releasing hormone (CRH) and negative feedback inhibition by cortisol, resulting in a circadian rhythm of cortisol. Recent evidence suggests that older men and younger men who are endurance-trained athletes both have reduced sensitivity to negative feedback, and perhaps increased basal levels of cortisol and ACTH. To investigate these possibilities, we propose to examine multiple aspects of the hypothalamic-pituitary-adrenal axis in younger endurance trained and sedentary men, and in older sedentary men.

Subjects will collect saliva during two evenings before additional testing, and will on the same evening collect urine for twelve hours, both for cortisol measurements. Blood samples will be collected to evaluate the function of white blood cells and their responses to dexamethasone. We also will assess ACTH and cortisol responses to medications that reduce negative inhibition of ACTH. This testing will occur in the evening and will include administration of the glucocorticoid antagonist mifepristone, the mineralocorticoid antagonist spironolactone, and/or a look-alike tablet, on four occasions.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Men aged 18 to 30 years of age are required for the young endurance trained and sedentary groups; men aged 65-80 years for the older study group, who will meet criteria for sedentary men below. Women and children are excluded to enhance homogeneity of responses and avoid the influence of menstrual cyclicity on the HPA axis.

Sedentary:

  • Less than one hour physical activity per week for three years
  • No change in exercise anticipated for 6 weeks

Trained:

  • Greater than 45km (28 miles) running per week for at least 3 months
  • No change in exercise anticipated for 6 weeks

For all participants:

  • All races
  • Sleep-wake cycle with sleeping at night, wakening between 5 and 8 AM
  • BMI between 18 and 25 kg/M2
  • Normal TSH and free T4

EXCLUSION CRITERIA:

For all participants:

  • Sleep disorders as assessed by sleep apnea questionnaire
  • Smoking
  • No more than 2 servings of alcohol daily
  • Medications known to affect the HPA axis or steroid metabolism, including narcotics, Glucocorticoids, megace or CYP3A4 modulators
  • History of psychiatric or endocrine disorders
  • Marijuana or other illicit drug use
  • Recent appendicular or skeletal injury
  • Uncontrolled hypertension
  • Chronic pain requiring daily medication
  • Current treatment with medications related to mineralocorticoid function such as potassium, ACE-inhibitors, ARBs, diuretics, spironolactone
  • Frailty score of 4-7 on the Canadian Study of Health and Aging frailty scale (Rockman 2005)
  • Overtraining syndrome will be an exclusion and will be assessed by questionnaire
  • Abnormal creatinine level (greater than 1.2 mg/dl)
  • Liver function tests greater than two fold normal
  • Benzodiazepine use
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01294319

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
Principal Investigator: Lynnette K Nieman, M.D. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  More Information

Additional Information:
Publications:
Responsible Party: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier: NCT01294319     History of Changes
Other Study ID Numbers: 110078  11-CH-0078 
Study First Received: February 10, 2011
Last Updated: August 16, 2016
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Cortical Resistance
ACTH
Glucocorticoid
Mifepristone
SPIRONOLACTONE
Exercise
Hypothalamic-Pituitary-Adrenal Axis
Healthy Volunteer
HV

Additional relevant MeSH terms:
Mifepristone
Spironolactone
Hydrocortisone
Abortifacient Agents, Steroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Contraceptives, Oral, Synthetic
Contraceptives, Oral
Contraceptive Agents, Female
Contraceptive Agents
Contraceptives, Postcoital, Synthetic
Contraceptives, Postcoital
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Luteolytic Agents
Menstruation-Inducing Agents
Mineralocorticoid Receptor Antagonists
Diuretics, Potassium Sparing
Diuretics
Natriuretic Agents
Anti-Inflammatory Agents

ClinicalTrials.gov processed this record on August 22, 2016