Evaluation of Cortisol Resistance in Young Sedentary and Endurance-Trained Men

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

This study proposes to examine multiple aspects of the hypothalamic-pituitary-adrenal axis in younger endurance trained and sedentary men, and in older sedentary men.

Study Overview

• Status: Completed
• Conditions: ACTH; Glucocorticoid; Cortisol Resistance; Negative Feedback; Mineralcorticoid
• Intervention / Treatment: Drug: Placebo; Drug: Dexamethasone; Drug: Mifepristone; Drug: Spironolactone; Drug: Combined

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 response 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.

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sedentary young adults, SMCP; Spironolactone, Then Mifepristone, Then Combined, Then Placebo (SMCP), Then Dexamethasone	Drug: Placebo; Drug: Dexamethasone; Other Names: Dexamethasone 0.25 mg; Drug: Mifepristone; Other Names: Mifepristone 400 MG; Drug: Spironolactone; Other Names: Spironolactone 200 MG; Drug: Combined; Other Names: Mifepristone 400 MG and Spironolactone 200 MG
Experimental: Endurance-trained young athletes, SMCP; Spironolactone, Then Mifepristone, Then Combined, Then Placebo (SMCP), Then Dexamethasone	Drug: Placebo; Drug: Dexamethasone; Other Names: Dexamethasone 0.25 mg; Drug: Mifepristone; Other Names: Mifepristone 400 MG; Drug: Spironolactone; Other Names: Spironolactone 200 MG; Drug: Combined; Other Names: Mifepristone 400 MG and Spironolactone 200 MG
Experimental: Sedentary young adults, MSPC; Mifepristone, Then Spironolactone, Then Placebo, Then Combined (MSPC), Then Dexamethasone	Drug: Placebo; Drug: Dexamethasone; Other Names: Dexamethasone 0.25 mg; Drug: Mifepristone; Other Names: Mifepristone 400 MG; Drug: Spironolactone; Other Names: Spironolactone 200 MG; Drug: Combined; Other Names: Mifepristone 400 MG and Spironolactone 200 MG
Experimental: Endurance-trained young athletes, MSPC; Mifepristone, Then Spironolactone, Then Placebo, Then Combined (MSPC), Then Dexamethasone	Drug: Placebo; Drug: Dexamethasone; Other Names: Dexamethasone 0.25 mg; Drug: Mifepristone; Other Names: Mifepristone 400 MG; Drug: Spironolactone; Other Names: Spironolactone 200 MG; Drug: Combined; Other Names: Mifepristone 400 MG and Spironolactone 200 MG
Experimental: Sedentary young adults, CPSM; Combined, Then Placebo, Then Spironolactone, Then Mifepristone (CPSM), Then Dexamethasone	Drug: Placebo; Drug: Dexamethasone; Other Names: Dexamethasone 0.25 mg; Drug: Mifepristone; Other Names: Mifepristone 400 MG; Drug: Spironolactone; Other Names: Spironolactone 200 MG; Drug: Combined; Other Names: Mifepristone 400 MG and Spironolactone 200 MG
Experimental: Endurance-trained young athletes, CPSM; Combined, Then Placebo, Then Spironolactone, Then Mifepristone (CPSM), Then Dexamethasone	Drug: Placebo; Drug: Dexamethasone; Other Names: Dexamethasone 0.25 mg; Drug: Mifepristone; Other Names: Mifepristone 400 MG; Drug: Spironolactone; Other Names: Spironolactone 200 MG; Drug: Combined; Other Names: Mifepristone 400 MG and Spironolactone 200 MG
Experimental: Sedentary young adults,PCMS; Placebo, Then Combined, Then Mifepristone, Then Spironolactone (PCMS), Then Dexamethasone	Drug: Placebo; Drug: Dexamethasone; Other Names: Dexamethasone 0.25 mg; Drug: Mifepristone; Other Names: Mifepristone 400 MG; Drug: Spironolactone; Other Names: Spironolactone 200 MG; Drug: Combined; Other Names: Mifepristone 400 MG and Spironolactone 200 MG
Experimental: Endurance-trained young athletes,PCMS; Placebo, Then Combined, Then Mifepristone, Then Spironolactone (PCMS), Then Dexamethasone	Drug: Placebo; Drug: Dexamethasone; Other Names: Dexamethasone 0.25 mg; Drug: Mifepristone; Other Names: Mifepristone 400 MG; Drug: Spironolactone; Other Names: Spironolactone 200 MG; Drug: Combined; Other Names: Mifepristone 400 MG and Spironolactone 200 MG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Suppressors After Dexamethasone	All subjects will take 0.25mg dexamethasone as an outpatient between 2300 and 2400h and will then report to the clinic by 0800h next day for the final visit. At the final visit, cortisol response to dexamethasone suppression was assessed. The cortisol response was dichotomized (suppression vs. non-suppression, using 1.8 ug/dL as the cutoff point) and compared between the two groups,Sedentary Young Adults and Endurance-trained Young Athletes.	cortisol measured between 8 and 9 after dexamethasone was taken between 11 PM and midnight

Secondary Outcome Measures

Outcome Measure	Time Frame
Post-dexamethasone Cortisol Level	Cortisol obtained at 8-9 AM after dexamethasone taken between 11 pm and midnight

Collaborators and Investigators

• Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Publications and helpful links

General Publications

• Bauer ME. Stress, glucocorticoids and ageing of the immune system. Stress. 2005 Mar;8(1):69-83. doi: 10.1080/10253890500100240.
• Bertagna X, Bertagna C, Luton JP, Husson JM, Girard F. The new steroid analog RU 486 inhibits glucocorticoid action in man. J Clin Endocrinol Metab. 1984 Jul;59(1):25-8. doi: 10.1210/jcem-59-1-25.
• Booth CK, Probert B, Forbes-Ewan C, Coad RA. Australian army recruits in training display symptoms of overtraining. Mil Med. 2006 Nov;171(11):1059-64. doi: 10.7205/milmed.171.11.1059.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start: January 24, 2011
• Primary Completion (Actual): August 10, 2016
• Study Completion (Actual): August 10, 2016

Study Registration Dates

• First Submitted: February 10, 2011
• First Submitted That Met QC Criteria: February 10, 2011
• First Posted (Estimate): February 11, 2011

Study Record Updates

• Last Update Posted (Actual): November 21, 2017
• Last Update Submitted That Met QC Criteria: October 19, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Exercise; HV; Healthy Volunteer; Mifepristone; ACTH; Glucocorticoid; Hypothalamic-Pituitary-Adrenal Axis; Cortical Resistance; SPIRONOLACTONE
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Natriuretic Agents; Diuretics; Hormone Antagonists; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Abortifacient Agents; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Luteolytic Agents; Abortifacient Agents, Steroidal; Contraceptives, Postcoital, Synthetic; Contraceptives, Postcoital; Menstruation-Inducing Agents; Dexamethasone; Dexamethasone acetate; BB 1101; Spironolactone; Mifepristone
• Other Study ID Numbers: 110078; 11-CH-0078 (Other Identifier: National Institutes of Health)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No