Hormonal Mechanisms of Sleep Restriction - Axis Study in Older Men and Postmenopausal Women

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

Status and phase: Active, not recruiting; Early Phase 1

Conditions: Sleep Restriction

Treatments: Drug: Corticorelin (also known as Acthrel); Drug: Hydrocortisone Injection (also known as solu-cortef); Drug: Dexamethasone Pill; Drug: Dexamethasone injection; Drug: Cosyntropin Injectable Product; Drug: Ketoconazole Pill (also known as nizoral); Drug: Recombinant Human Luteinizing Hormone (also known as luveris); Drug: Saline Solution; Drug: Gonadorelin (also known as Lutrepulse); Drug: Ganirelix; Drug: Placebo oral tablet; Drug: Saline solution for injection

Study type: Interventional

Funder types: Other

Identifiers

NCT04037605

P31056-01R

Details and patient eligibility

About

The purpose of this study is to 1) determine how hypothalamic-pituitary-adrenal axis (HPA axis) activation occurs with sleep restriction and 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.

Full description

Sleep restriction and its consequences are major public health problems, especially in older adults. Among the more severe physiological sequelae of sleep restriction is the development of insulin resistance. The mechanisms by which sleep restriction leads to increased insulin resistance are unknown, especially in vulnerable older adults; such research informs development of targeted interventions against the sleep loss/insulin resistance link.

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 40 participants can be enrolled. However, participants will be allowed an opportunity to be randomized to all 4 conditions so that as few as 10 participants may be required. We anticipate 5 men and 5 women will be enrolled assuming each undergoes all 4 clamp conditions.

Enrollment: 5 patients

Sex: All

Ages: 60 to 80 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Men or postmenopausal women aged 60-80 years
• Willingness to provide written informed consent
• Stable weight over preceding 6 weeks
• Body Mass index (BMI) 22-28 kg/m2
• Physically and psychologically healthy
• Good habitual sleep with regular bedtimes
• Neither extreme morning- nor extreme evening-type using Horne-Ostberg Morningness-Eveningness criteria

Exclusion criteria

• Medications that interfere with the adrenal or gonadal axis will be excluded
• 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
• Mini- mental state examination (MMSE) < 27

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Triple Blind

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5 participants in 4 patient groups

Control Condition

Experimental group

Description:

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

Treatment:

Drug: Saline solution for injection

Drug: Saline Solution

Drug: Gonadorelin (also known as Lutrepulse)

Drug: Placebo oral tablet

Drug: Corticorelin (also known as Acthrel)

Hypothalamic Condition

Experimental group

Description:

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 blood sample

Treatment:

Drug: Saline solution for injection

Drug: Ganirelix

Drug: Dexamethasone injection

Drug: Gonadorelin (also known as Lutrepulse)

Drug: Placebo oral tablet

Drug: Corticorelin (also known as Acthrel)

Pituitary Condition

Experimental group

Description:

8 am - Saline Solution for Injection 10 am - Ketoconazole Pill 1 pm - Saline Solution for Injection 4 pm - Ketoconazole Pill \& start of hourly blood sampling 7 pm - GnRH and CRH 9 pm - Hydrocortisone Injection and last blood sample

Treatment:

Drug: Saline Solution

Drug: Ketoconazole Pill (also known as nizoral)

Drug: Hydrocortisone Injection (also known as solu-cortef)

Drug: Gonadorelin (also known as Lutrepulse)

Drug: Corticorelin (also known as Acthrel)

Adrenal/Testis Condition

Experimental group

Description:

10 pm - Ganirelix Injection \& Dexamethasone Pills (night before) 8 am - Start of hourly blood sampling 10 am - Dexamethasone Pills 11 am - Last hourly blood sample taken 11:30 am - Start of blood sampling every 10 minutes 1 pm - Recombinant Human Luteinizing Hormone (rhLH) Injection 3 pm - rhLH Injection 5 pm - rhLH Injection 5 pm - Cosyntropin Injectable product 7 pm - GnRH and CRH Injections 9 pm - Last blood sample

Treatment:

Drug: Ganirelix

Drug: Recombinant Human Luteinizing Hormone (also known as luveris)

Drug: Dexamethasone Pill

Drug: Gonadorelin (also known as Lutrepulse)

Drug: Cosyntropin Injectable Product

Drug: Corticorelin (also known as Acthrel)