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

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.

- 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