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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Cortisol Resistance, Negative Feedback, ACTH, Mineralcorticoid, Glucocorticoid

Intervention / Treatment
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* Drug: Mifepristone
* Drug: Placebo
* Drug: Spironolactone
* Drug: Combined
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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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 | Measure Description | Time Frame |
| --- | --- | --- |
| Post-dexamethasone Cortisol Level |  | Cortisol obtained at 8-9 AM after dexamethasone taken between 11 pm and midnight | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HV, Cortical Resistance, ACTH, Glucocorticoid, Mifepristone, SPIRONOLACTONE, Exercise, Hypothalamic-Pituitary-Adrenal Axis, Healthy Volunteer