Brain Blood Flow Responses to Stress: Sex Differences

University of Wisconsin (UW)

Status and phase: Completed; Phase 4

Conditions: Cerebrovascular Disorders

Treatments: Drug: Anastrozole; Drug: Estradiol; Drug: Testosterone gel; Drug: Placebo; Drug: Indomethacin; Drug: Orilissa

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT06253702

2023-0548

EDUC/KINESIOLOGY (Other Identifier)

Protocol Version 07/01/2024 (Other Identifier)

1R01HL150361-01 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

Twenty-six otherwise healthy adults between 18-40 years of age composed of 13 males and 13 females will be enrolled in this study to determine how sex and sex hormones influence cerebral blood flow (CBF) control in healthy young adults without confounds of age or disease. Participants can expect to be on study for approximately 16 days.

Full description

Objective: To determine cerebrovascular control mechanisms in humans and provide mechanistic knowledge to offer new sex-specific therapeutic options for cerebrovascular diseases. The current objective is to determine how sex and sex hormones influence CBF control in healthy young adults without confounds of age or disease.

The central hypothesis is men exhibit reduced cerebral vasodilator function due in part to differences in COX signaling compared to women. Comprehensive CBF data from multi-modal MRI indicate the magnitude of sex differences-as well as the vasodilator mechanisms-are regionally distinct.

The investigators will address 2 specific aims:

1. Are cerebral vasodilator responses greater in women across other physiologic stressors? Do all cerebral vessels respond equally, or are there regional differences-by sex?
2. What mechanisms regulate the increase in CBF to stress; do these differ by sex, or brain region?

This study will be conducted in compliance with federal investigational drug regulations (21 CFR 312) and Good Clinical Practice (GCP) guidelines, as well as state law and institutional policies.

Study Population: Phase 2 include 26 total participants 13 men and 13 women invited back from the Study 2020-0336 (NCT04265053) for Aim 3 who are ≥18 - ≤ 40 years old and considered healthy.

Approach: CBF testing will be performed in research-dedicated 3T magnets. Participants will experience one hypoxia and one hypercapnia trial during each visit. S, study design focuses on the use of Indomethacin to test COX as a potential mechanism explaining sex differences in CBF control. To do this, 4 MRI visits in a double-blind placebo controlled design will be conducted. One set of placebo-Indo visits occurs after the first 4-7 days of sex hormone suppression (with Orilissa) and the second set of MRI visits occurs after 12-16 days of Orilissa while supplementing a single sex hormone by sex.

On day 0 participants will start hormone suppression using Orilissa (male subjects will also start an Anastrozole). After day 2, MRI Visit 1 will be scheduled to occur. Prior to the first study visit the order of drug supplementation will be randomized. Options are: placebo for the first MRI visit, then Indomethacin for the second MRI visit or Indomethacin for the first MRI visit, then placebo for the second MRI visit. After MRI visits 1 and 2 are completed, participants will begin sex hormone add-back (males will receive testosterone and females will receive estradiol). Once participants have been on the hormone add-back protocol for 3-4 days MRI Visits 3 and 4 will be scheduled. Prior to MRI visit 3 the order of drug supplementation will be randomized again.

. Added to protocol on 07/01/2024 = Fecal samples will be collected: at baseline (before beginning Orilissa), 4-8 days after taking the first dose of Orilissa, and 12-16 days after taking the first estradiol or testosterone dose. Subjects will provide 3 fecal samples at home throughout the course of their participation and will take the samples to FedEx to be shipped.

Enrollment: 22 patients

Sex: All

Ages: 18 to 40 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Age between ≥18 - ≤40 years inclusive
• Completed Phase 1: Study 2020-0336

Exclusion criteria

• Hypertensive

  • > 125 mmHg systolic blood pressure; or
  • > 80 mmHg diastolic blood pressure

• BMI ≥25 kg/m2

• Fasting blood glucose ≥100 mg/dl

• LDL cholesterol ≥130 mg/dl

• Triglycerides ≥150 mg/dl

• Current diagnosis or history of:

  • peripheral vascular disease
  • hepatic disease
  • renal disease
  • lung disease
  • gastrointestinal disorders/bleeding
  • hematologic disease
  • stroke
  • myocardial infarction
  • coronary heart disease
  • congestive heart failure
  • heart surgery
  • prediabetes
  • diabetes mellitus (type 1, type 2, MODY, or others)
  • sleep apnea
  • hypertension
  • some autoimmune diseases, such as inflammatory bowel disease or systemic lupus erythematosus (exclusion at discretion of reviewing MD)

• Current smoking, defined as the use of tobacco or nicotine products >5 times in the past 30 days.

• Cardiovascular medication use

• NSAID sensitivity

• Magnesium-restricted diet

• Any contraindications of having an MRI

  • (e.g. the requirement of anxiolytics in order to complete an MRI scan)

• Irregular menstrual cycle (females only)

• Medical conditions that can affect the menstrual cycle, such as hyperprolactinemia, prolactinoma, hypercortisolemia, and congenital adrenal hyperplasia (females only)

• Pregnancy, breast feeding, or plans to conceive within the next 3 months (females only)

• Polycystic ovary syndrome (females only)

• Hirsutism defined as unwanted and/or excessive hair growth on the face, chest, or back (females only)

• Levonorgestrel intrauterine device (IUD) (females only)

• Hormonal birth control will not be allowed in women, in order to control for high variability between type, dose, and route of therapy. However, in discussion with Dr. Davis (Co-I) and Dr. Laura Cooney M.D., physician experts in medical and reproductive endocrinology and infertility, there are two broad exceptions to this birth control criteria:

  • Copper intrauterine devices (IUDs) will be allowed as they do not change systemic sex hormone levels).
  • Women currently taking hormonal birth control (i.e. contraceptive pills, patch, ring) for contraception only (not for a medical condition such as those listed in exclusion criteria above) may consider temporarily stopping to become eligible for enrollment. Hormonal birth control must be stopped at least one month prior to Study Visit 1 to provide time for menstruation to resume. Then stoppage continues through the last planned study visit. Screening information will be reviewed by endocrinology physicians to determine eligibility and timing on this issue.

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Double Blind

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22 participants in 4 patient groups

Placebo First: Hormone Suppression

Experimental group

Description:

Participants drug (placebo vs Indo) are randomized prior to first set of MRI visits, while experiencing hormone suppression.

Treatment:

Drug: Orilissa

Drug: Indomethacin

Drug: Placebo

Drug: Estradiol

Indo First: Hormone Suppression

Experimental group

Description:

Participants drug (placebo vs Indo) are randomized prior to first set of MRI visits, while experiencing hormone suppression.

Treatment:

Drug: Orilissa

Drug: Indomethacin

Drug: Placebo

Placebo First: Hormone Add-Back

Experimental group

Description:

Participants drug (placebo vs Indo) are randomized prior to second set of MRI visits, while experiencing hormone add-back.

Treatment:

Drug: Orilissa

Drug: Indomethacin

Drug: Placebo

Drug: Estradiol

Drug: Testosterone gel

Drug: Anastrozole

Indo First: Hormone Add-Back

Experimental group

Description:

Participants drug (placebo vs Indo) are randomized prior to second set of MRI visits, while experiencing hormone add-back.

Treatment:

Drug: Orilissa

Drug: Indomethacin

Drug: Placebo

Drug: Estradiol

Drug: Testosterone gel

Drug: Anastrozole