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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

Status
Completed
Phases
Phase 2
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT01294319
Enrollment
51
Registered
2011-02-11
Start date
2011-01-24
Completion date
2016-08-10
Last updated
2024-07-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cortisol Resistance, Negative Feedback, ACTH, Mineralcorticoid, Glucocorticoid

Keywords

Cortical Resistance, ACTH, Glucocorticoid, Mifepristone, SPIRONOLACTONE, Exercise, Hypothalamic-Pituitary-Adrenal Axis, Healthy Volunteer, HV

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.

Interventions

DRUGMifepristone
DRUGPlacebo
DRUGSpironolactone
DRUGCombined
DRUGDexamethasone

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Lead SponsorNIH

Study design

Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender
MALE
Age
18 Years to 80 Years
Healthy volunteers
No

Inclusion 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

Design outcomes

Primary

MeasureTime frameDescription
Proportion of Suppressors After Dexamethasonecortisol measured between 8 and 9 after dexamethasone was taken between 11 PM and midnightAll 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.

Secondary

MeasureTime frame
Post-dexamethasone Cortisol LevelCortisol obtained at 8-9 AM after dexamethasone taken between 11 pm and midnight

Countries

United States

Participant flow

Participants by arm

ArmCount
Sedentary Young Adults, SMCP
Spironolactone, Then Mifepristone, Then Combined, Then Placebo, Then Dexamethasone
4
Endurance-trained Young Athletes, SMCP
Spironolactone, Then Mifepristone, Then Combined, Then Placebo, Then Dexamethasone
6
Sedentary Young Adults, MSPC
Mifepristone, Then Spironolactone, Then Placebo, Then Combined, Then Dexamethasone
5
Endurance-trained Young Athletes, MSPC
Mifepristone, Then Spironolactone, Then Placebo, Then Combined, Then Dexamethasone
5
Sedentary Young Adults, CPSM
Combined, Then Placebo, Then Spironolactone, Then Mifepristone, Then Dexamethasone
5
Endurance-trained Young Athletes, CPSM
Combined, Then Placebo, Then Spironolactone, Then Mifepristone, Then Dexamethasone
4
Sedentary Young Adults,PCMS
Placebo, Then Combined, Then Mifepristone, Then Spironolactone, Then Dexamethasone
5
Endurance-trained Young Athletes,PCMS
Placebo, Then Combined, Then Mifepristone, Then Spironolactone, Then Dexamethasone
5
Total39

Baseline characteristics

CharacteristicTotalSedentary Young Adults, SMCPEndurance-trained Young Athletes, SMCPSedentary Young Adults, MSPCEndurance-trained Young Athletes, MSPCEndurance-trained Young Athletes, CPSMSedentary Young Adults,PCMSEndurance-trained Young Athletes,PCMSSedentary Young Adults, CPSM
Age, Continuous24.73 years
STANDARD_DEVIATION 2.87
23.57 years
STANDARD_DEVIATION 0.99
25.01 years
STANDARD_DEVIATION 1.58
24.2 years
STANDARD_DEVIATION 2.33
25.2 years
STANDARD_DEVIATION 1.79
24.5 years
STANDARD_DEVIATION 4.22
27.8 years
STANDARD_DEVIATION 3.06
23.6 years
STANDARD_DEVIATION 4.01
23.3 years
STANDARD_DEVIATION 2.97
Body Mass Index23.53 Kg/m^2
STANDARD_DEVIATION 2.63
23.6 Kg/m^2
STANDARD_DEVIATION 4.33
24.0 Kg/m^2
STANDARD_DEVIATION 3.27
23.7 Kg/m^2
STANDARD_DEVIATION 3.04
22.3 Kg/m^2
STANDARD_DEVIATION 1.89
24.1 Kg/m^2
STANDARD_DEVIATION 1.1
23.4 Kg/m^2
STANDARD_DEVIATION 2.98
22.8 Kg/m^2
STANDARD_DEVIATION 2
24.2 Kg/m^2
STANDARD_DEVIATION 2.75
Fat mass16.61 kg
STANDARD_DEVIATION 5.45
16.28 kg
STANDARD_DEVIATION 8.05
16.73 kg
STANDARD_DEVIATION 5.6
19.13 kg
STANDARD_DEVIATION 4.8
14.70 kg
STANDARD_DEVIATION 3.19
15.13 kg
STANDARD_DEVIATION 3.79
17.64 kg
STANDARD_DEVIATION 4.31
13.69 kg
STANDARD_DEVIATION 4.56
19.21 kg
STANDARD_DEVIATION 8.69
Race
Asian
7 Participants1 Participants1 Participants2 Participants1 Participants1 Participants1 Participants0 Participants0 Participants
Race
Black
4 Participants0 Participants0 Participants0 Participants0 Participants1 Participants1 Participants0 Participants2 Participants
Race
Unknown
11 Participants2 Participants2 Participants1 Participants0 Participants0 Participants1 Participants4 Participants1 Participants
Race
White
17 Participants1 Participants3 Participants2 Participants4 Participants2 Participants2 Participants1 Participants2 Participants
Sex/Gender, Customized
Male
37 Participants4 Participants5 Participants5 Participants5 Participants4 Participants5 Participants5 Participants4 Participants
Sex/Gender, Customized
Unknown
2 Participants0 Participants1 Participants0 Participants0 Participants0 Participants0 Participants0 Participants1 Participants
Total Fat Percent21.33 percent
STANDARD_DEVIATION 5.28
21.1 percent
STANDARD_DEVIATION 6.9
20.2 percent
STANDARD_DEVIATION 5.16
25.2 percent
STANDARD_DEVIATION 5.11
19.5 percent
STANDARD_DEVIATION 1.99
19.7 percent
STANDARD_DEVIATION 5.15
24.4 percent
STANDARD_DEVIATION 5.16
16.8 percent
STANDARD_DEVIATION 4.04
23.2 percent
STANDARD_DEVIATION 5.82

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
0 / 190 / 20
other
Total, other adverse events
0 / 190 / 20
serious
Total, serious adverse events
0 / 190 / 20

Outcome results

Primary

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.

Time frame: cortisol measured between 8 and 9 after dexamethasone was taken between 11 PM and midnight

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Endurance-trained Young AthletesProportion of Suppressors After Dexamethasone0 Participants
Sedentary Young AdultsProportion of Suppressors After Dexamethasone1 Participants
p-value: 0.4872Fisher Exact
Secondary

Post-dexamethasone Cortisol Level

Time frame: Cortisol obtained at 8-9 AM after dexamethasone taken between 11 pm and midnight

ArmMeasureValue (MEAN)Dispersion
Endurance-trained Young AthletesPost-dexamethasone Cortisol Level11.98 mcg/dLStandard Deviation 5.92
Sedentary Young AdultsPost-dexamethasone Cortisol Level9.98 mcg/dLStandard Deviation 5.39
p-value: 0.2786t-test, 2 sided

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026