Hormonal Mechanisms of Sleep Restriction - Axis Study

Study Overview
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Brief Summary
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The purpose of this study is to 1) determine how hypothalamic-pituitary-adrenal axis (HPA axis) activation occurs with sleep restriction 2) evaluate how hypothalamic-pituitary-gonadal axis (HPG axis) deactivation occurs with sleep restriction. The investigator will also examine the cognitive function associated with sleep restriction, including food intake and food cravings.

Detailed Description
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Sleep restriction increases evening cortisol and decreases testosterone. These are the main catabolic and anabolic hormones in men, respectively. This catabolic-anabolic imbalance likely leads to metabolic and reproductive ill-health. The hypothalamic-pituitary-end organ (adrenal or testis) mechanisms that must underpin these changes are unknown. This study will administer drugs to clamp the function of each of these nodes to determine the regulatory changes that have occurred with sleep restriction. Even though the study is randomized order in design, the main comparison is before and after sleep restriction under each of these clamp conditions. Participants are admitted to the chronobiology laboratory where they are given 1 night of 10 hours sleep opportunity, followed by 4 nights of 4 hours sleep opportunity. Up to 80 participants (assuming twenty different participant for each of the 4 clamp conditions) can be enrolled. However, participants will be allowed an opportunity to be randomized to all 4 conditions so that as few as 20 participants may be required. Urn randomization will be used to ensure that 20 different participants are involved in each of the 4 conditions.

Official Title
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Hormonal Mechanisms of Sleep Restriction - Axis Study

Conditions
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Sleep Restriction

Intervention / Treatment
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* Drug: Ketoconazole Pill
* Drug: Ganirelix
* Drug: Dexamethasone
* Drug: Dexamethasone Injection
* Drug: Cosyntropin Injectable Product
* Drug: Recombinant Human Luteinizing Hormone
* Drug: Hydrocortisone Injection
* Drug: Gonadorelin
* Drug: Corticorelin
* Drug: Placebo oral capsule
* Drug: Saline Solution
* Drug: Saline Solution for Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men aged 22-45 years Willingness to provide written informed consent Stable weight over preceding 6 weeks Body Mass index (BMI) 20-28 kg/m2 Exclusion Criteria: Unable or unwilling to provide IRB (Internal Review Board)-approved informed consent Clinical disorders and/or illnesses Current medical or drug treatment, as assessed by questionnaire History of brain injury or of learning disability - Vision or hearing impairment unless corrected back to normal Anemia (Hct <38%) History of psychiatric illness Clinically significant abnormalities in blood and urine, and free of traces of drugs Other endocrine abnormalities including hypothyroidism or adrenal failure; primary gonadal disease as indicated by serum LH (luteinizing hormone) or FSH (follicle stimulating hormone) concentration >10 or >15 IU/L, respectively, hyperprolactinemia indicated by prolactin >25ug/L Type 2 Diabetes (HgbA1C) Current smoker Recent or concurrent drug or alcohol abuse Blood donation in previous eight weeks Travel across time zones within one month of entering the study Sleep or circadian disorder Shift work within three months of entering the study Irregular bedtimes (not between 6 and 10 hours in duration) Unoperated obstructive uropathy, recurrent prostatitis, indeterminate prostatic nodularity, Hx or Suspicion of cancer of the prostate gland or PSA (prostate-specific antigen) >4ng/ml Previous adverse reaction to sleep deprivation or any of the drugs to be administered Concurrent participation in another research study

Ages Eligible for Study
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Minimum Age: 22 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Blood is sampled every 10 minutes from 4PM to 9PM for future mathematical deconvolution in order to determine hormone pulse characteristics in response to the clamp conditions. These values are the primary endpoints.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Control Condition<br>8 am - Saline Solution for Injection 10 am - Placebo oral capsule 1 pm - Saline Solution for Injection 4 pm - Placebo oral capsule & start hourly blood sampling 7 pm - Gonadorelin (GnRH) and Corticorelin (CRH) injections 9 pm - Saline Solution for Injection & last blood sample | Drug: Gonadorelin<br>* Gonadorelin IV injection is given twice per Inpatient Stay<br>* Other names: Lutrepulse;Drug: Corticorelin<br>* Corticorelin IV injection is given twice per Inpatient Stay<br>* Other names: Acthrel;Drug: Placebo oral capsule<br>* Placebo for ketoconazole are given 4 times per Inpatient Stay<br>Drug: Saline Solution<br>* Saline Solution (Placebo) for Dexamethasone IV injection or hydrocortisone IV injection given up to four times per Inpatient Stay<br>Drug: Saline Solution for Injection<br>* Saline Solution (placebo) for ganirelix subcutaneous injection<br>|
| Experimental: Hypothalamic Condition<br>8 am - Ganirelix 10 am - Placebo oral capsule 1 pm - Dexamethasone injection 4 pm - Placebo oral capsule and start of hourly blood sampling 7 pm - GnRH and CRH injections 9 pm - Saline Solution for Injection and last sample of blood taken | Drug: Ganirelix<br>* Ganirelix subcutaneous injection is administered twice per Inpatient Stay<br>Drug: Dexamethasone Injection<br>* Dexamethasone IV injection is given twice per Inpatient Stay<br>Drug: Gonadorelin<br>* Gonadorelin IV injection is given twice per Inpatient Stay<br>* Other names: Lutrepulse;Drug: Corticorelin<br>* Corticorelin IV injection is given twice per Inpatient Stay<br>* Other names: Acthrel;Drug: Placebo oral capsule<br>* Placebo for ketoconazole are given 4 times per Inpatient Stay<br>Drug: Saline Solution for Injection<br>* Saline Solution (placebo) for ganirelix subcutaneous injection<br>|
| Experimental: Pituitary Condition<br>8am - Saline Solution for Injection 10am - Ketoconazole Pill 1pm - Saline Solution for Injection 4pm - Ketoconazole Pill & start of hourly blood sampling 7pm - GnRH and CRH 9pm - Hydrocortisone Injection & last blood sample | Drug: Ketoconazole Pill<br>* Ketoconazole pill is taken 4 times per Inpatient Stay<br>* Other names: Nizoral;Drug: Hydrocortisone Injection<br>* Hydrocortisone IV push is given twice per Inpatient Visit<br>* Other names: solu-cortef;Drug: Gonadorelin<br>* Gonadorelin IV injection is given twice per Inpatient Stay<br>* Other names: Lutrepulse;Drug: Corticorelin<br>* Corticorelin IV injection is given twice per Inpatient Stay<br>* Other names: Acthrel;Drug: Saline Solution<br>* Saline Solution (Placebo) for Dexamethasone IV injection or hydrocortisone IV injection given up to four times per Inpatient Stay<br>|
| Experimental: Adrenal/Testis Condition<br>10pm - Ganirelix Injection & Dexamethasone Pills (night before) 8am - start of hourly blood sampling 10am - Dexamethasone Pills 11am - last hourly blood sample taken 11:30am - start of blood sampling every 10 minutes 1pm - Recombinant Human Luteinizing Hormone (rhLH) Injection 3pm - rhLH Injection 5pm - rhLH Injection 5pm - Cosyntropin Injectable product 7pm - GnRH and CRH Injections 9pm - last blood sample taken | Drug: Ganirelix<br>* Ganirelix subcutaneous injection is administered twice per Inpatient Stay<br>Drug: Dexamethasone<br>* Dexamethasone Pills is taken twice per Inpatient Stay<br>Drug: Cosyntropin Injectable Product<br>* cosyntropin injection is given twice per Inpatient Stay<br>Drug: Recombinant Human Luteinizing Hormone<br>* Leutinizing-Releasing Hormone is given 6 IV infusion pulses per Inpatient Visit<br>* Other names: Luveris;Drug: Gonadorelin<br>* Gonadorelin IV injection is given twice per Inpatient Stay<br>* Other names: Lutrepulse;Drug: Corticorelin<br>* Corticorelin IV injection is given twice per Inpatient Stay<br>* Other names: Acthrel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Blood Cortisol Concentration | Cortisol is measured in blood every 10 minutes for a 5 hour period, at the beginning and at the end of 4 nights of sleep restriction. The average cortisol is the parameter of interest. | 5 days | 
| Average Blood Testosterone Concentration | Testosterone is measured in blood every 10 minutes for a 5 hour period, at the beginning and at the end of 4 nights of sleep restriction. The average cortisol is the parameter of interest. | 5 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Blood Cortisol Concentration | This is the single maximal blood cortisol concentration that is measured during the entire 5 hour period, at the beginning and at the end of 4 nights of sleep restriction. | 5 days | 
| Peak Blood Testosterone Concentration | This is the single maximal blood testosterone concentration that is measured during the entire 5 hour period, at the beginning and at the end of 4 nights of sleep restriction. | 5 days | 
| Trough Blood Cortisol Concentration | This is the single minimal blood cortisol concentration that is measured during the entire 5 hour period, at the beginning and at the end of 4 nights of sleep restriction. | 5 days | 
| Trough Blood Testosterone Concentration | This is the single minimal blood testosterone concentration that is measured during the entire 5 hour period, at the beginning and at the end of 4 nights of sleep restriction. | 5 days | 
| Reaction time on Psychomotor Vigilance Task | This is measured by lapses in attention. As the person becomes more sleepy, there are more lapses (reaction time >500 ms), at the beginning and at the end of 4 nights of sleep restriction. | 5 days | 
| Karolinska Sleepiness Scale | Measures how sleepy participants are using a scale of 1 (extremely alert) through 9. This scale will be used to assess changes in sleepiness throughout the day and through 4 nights of sleep restriction. | 5 days | 
| Two card gambling task | Computerized neurobehavioral testing to determine how 4 nights of sleep restriction affects participants' decision making. The end point is discriminability index, d'. | 5 days | 
| Modified Sternberg working memory test | Computerized neurobehavioral testing to determine how 4 nights of sleep restriction affects reaction time and accuracy. | 5 days | 
| Caloric Intake | The food given to participants is weighed. The amount that is not consumed is also weighed. The difference in weight is the amount of calories consumed. | 5 days | 
| Hunger Scale | Hunger scale using Flint visual analogue scale to assess how 4 nights of sleep restriction affects participants' appetite. | 5 days | 
| Food Cravings | Food cravings is measured using Food Cravings Index scale to assess which food groups participants have cravings for and how their cravings change during 4 nights of sleep restriction. | 5 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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testosterone, cortisol