Hormonal Mechanisms of Sleep Restriction - Axis Study

Phase 1

Active, not recruiting

• Conditions: Sleep Restriction
• Interventions: Drug: Gonadorelin; Drug: Ganirelix; Drug: Ketoconazole Pill; Drug: Dexamethasone Injection; Drug: Corticorelin; Drug: Hydrocortisone Injection; Drug: Dexamethasone; Drug: Placebo oral capsule; Drug: Cosyntropin Injectable Product; Drug: Saline Solution; Drug: Recombinant Human Luteinizing Hormone; Drug: Saline Solution for Injection

• Registration Number: NCT03142893
• Lead Sponsor: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2017-04-11
• Study First Submitted QC: 2017-05-03
• Study Start: 2017-05-08
• Study First Posted: 2017-05-08
• Primary Completion: 2020-10-30
• Status Verified: 2024-03
• Last Update Submitted: 2024-04-22
• Last Update Posted: 2024-04-23
• Study Completion: 2025-03-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: Male
• Target Recruitment: 80

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Hypothalamic Condition	Dexamethasone Injection	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
Control Condition	Gonadorelin	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
Control Condition	Corticorelin	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
Control Condition	Placebo oral capsule	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
Control Condition	Saline Solution	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
Control Condition	Saline Solution for Injection	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
Hypothalamic Condition	Ganirelix	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
Hypothalamic Condition	Gonadorelin	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
Hypothalamic Condition	Corticorelin	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
Hypothalamic Condition	Placebo oral capsule	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
Hypothalamic Condition	Saline Solution for Injection	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
Pituitary Condition	Ketoconazole Pill	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
Pituitary Condition	Hydrocortisone Injection	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
Pituitary Condition	Gonadorelin	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
Pituitary Condition	Saline Solution	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
Adrenal/Testis Condition	Cosyntropin Injectable Product	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
Adrenal/Testis Condition	Corticorelin	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
Adrenal/Testis Condition	Recombinant Human Luteinizing Hormone	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
Adrenal/Testis Condition	Ganirelix	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
Adrenal/Testis Condition	Dexamethasone	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
Adrenal/Testis Condition	Gonadorelin	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
Pituitary Condition	Corticorelin	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

Primary Outcome Measures

Name	Time	Method
Average Blood Cortisol Concentration	5 days	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.
Average Blood Testosterone Concentration	5 days	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.

Secondary Outcome Measures

Name	Time	Method
Peak Blood Testosterone Concentration	5 days	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.
Peak Blood Cortisol Concentration	5 days	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.
Reaction time on Psychomotor Vigilance Task	5 days	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.
Karolinska Sleepiness Scale	5 days	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.
Two card gambling task	5 days	Computerized neurobehavioral testing to determine how 4 nights of sleep restriction affects participants' decision making. The end point is discriminability index, d'.
Modified Sternberg working memory test	5 days	Computerized neurobehavioral testing to determine how 4 nights of sleep restriction affects reaction time and accuracy.
Caloric Intake	5 days	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.
Hunger Scale	5 days	Hunger scale using Flint visual analogue scale to assess how 4 nights of sleep restriction affects participants' appetite.
Food Cravings	5 days	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.
Trough Blood Cortisol Concentration	5 days	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.
Trough Blood Testosterone Concentration	5 days	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.

Trial Locations

Locations (1)

Los Angeles Biomedical Research Institute; 🇺🇸 Torrance, California, United States