Clinical trial NCT01294319: Evaluation of Cortisol Resistance in Young Sedentary and Endurance-Trained Men
Official title: Evaluation of Cortisol Resistance in Young Sedentary and Endurance-trained Men and Elderly Sedentary Men
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cortisol Resistance
Negative Feedback
ACTH
Mineralcorticoid
Glucocorticoid
Keywords: Cortical Resistance
ACTH
Glucocorticoid
Mifepristone
SPIRONOLACTONE
Exercise
Hypothalamic-Pituitary-Adrenal Axis
Healthy Volunteer
HV
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2011-02-11
Enrollment: 51
Sex: MALE
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility 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

Primary outcomes:
measure: Proportion of Suppressors After Dexamethasone
timeFrame: cortisol measured between 8 and 9 after dexamethasone was taken between 11 PM and midnight
Secondary outcomes:
measure: Post-dexamethasone Cortisol Level
timeFrame: Cortisol obtained at 8-9 AM after dexamethasone taken between 11 pm and midnight
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Lynnette K Nieman, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bauer ME. Stress, glucocorticoids and ageing of the immune system. Stress. 2005 Mar;8(1):69-83. doi: 10.1080/10253890500100240.
citation: 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.
citation: 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.