The Role of Estrogen and Testosterone in Determining Brain Blood Flow and Metabolic Regulation in Humans

NCT07212712 | Not Yet Recruiting

• 1 other identifier: H25-00385
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Due to historical exclusion of females from research, there are gaps in the understanding of female physiology, how it differs from males, and how sex-specific hormones contribute. As a result, many diagnoses and treatments are based on male physiology and may not be appropriate or effective for females. Females consistently experience greater risk and report worse neurological outcomes in many diseases, including stroke, cardiac arrest, and dementia. As research in females progresses, differences between sexes and changes throughout the lifespan (e.g., puberty, menopause) highlight the importance of understanding the effects of sex and sex-specific hormones on the body. The brain is arguably the most important organ in the body, consuming 20% of the body's total energy. Previous research supports higher blood flow to the brain in females, and research in animals suggests hormones such as estrogen, progesterone, and testosterone are responsible. However, it is extremely difficult to isolate these hormones in humans, due to natural fluctuations (i.e., menstrual cycle). Therefore, the investigators plan to explore the direct role of these sex-specific hormones in regulating blood flow to the brain by blocking hormone production in healthy males and females and giving back testosterone and estrogen, respectively. The investigators will then conduct a range of tests to look at blood flow to the brain at rest and during various stressors. This research will provide crucial insight into how males and females differ in regulation of brain blood flow and inform new treatments and therapies to a wide range of brain injuries and diseases, improving outcomes and reducing the sex disparity in clinical pathways.

Conditions

Vascular; Cerebral Blood Flow; Cerebral Blood Flow Regulation; Sex Differences; Exercise

Outcome Measures

Primary Outcomes (2)

• Cerebral blood flow responses to estrogen and testosterone

  To determine how cerebral blood flow regulation is altered by estrogen and testosterone concentrations. Measured through doppler ultrasonography, and reported in mL/min.

  7 days

• Cerebral metabolic changes with estrogen and testosterone

  Measured as cerebral metabolic rate of oxygen consumption. Determined using arterial and internal jugular vein blood sampling coupled with doppler ultrasound, to determine metabolism directly using the Fick method.

  4 days

Secondary Outcomes (2)

• Hormone influences on appetite sensations

  7 days

• How estrogen and testosterone influence energy intake

  7 days

Study Arms (1)

Hormone Manipulation

EXPERIMENTAL

Participants will act as their own controls, completing the experiment 3 times. First, with no hormone manipulation; second, with blockade of hormone production; third, with hormone add-back.

Drug: GnRH antagonist; Drug: Estradiol (E2); Drug: Testosterone; Drug: Anastrozole (Arimidex)

Interventions

Anastrozole (Arimidex) DRUG

Prevention of testosterone conversion to estrogen in males

Hormone Manipulation

GnRH antagonist DRUG

blockade of hormone production

Hormone Manipulation

Estradiol (E2) DRUG

Estrogen add-back in females

Hormone Manipulation

Testosterone DRUG

testosterone add-back in males

Hormone Manipulation

Eligibility Criteria

• Age: 18 Weeks - 40 Weeks
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• The investigators will recruit healthy young (18-40 years) males (n = 25) and females (n = 25). Females must be naturally cycling (i.e., no oral or hormonal contraceptives), not pregnant, and premenopausal. Participants must be normotensive (\<140/90 mmHg \& \>90/60 mmHg) and have no medical history of cerebrovascular, cardiopulmonary, cardiovascular, neuromuscular, and renal disease assessed by a study questionnaire. A recent physical examination (within 1 year of participation) from a family physician or a completed physical examination by the study doctor is required prior to participation. All subjects will sign an informed consent form prior to participation.
• Participants will be excluded if they meet any of the following criteria:
• Hypertensive (≥140/90 mmHg) or hypotensive (≤90/60 mmHg)
• BMI ≥ 30 kg/m2
• Fasting blood glucose ≥ 100 mg/dL
• Abnormal results on standard blood hematology tests (e.g., complete blood count, comprehensive metabolic panel)
• Males with hypogonadism (total testosterone ≤ 262 ng/dL, per Endocrine Society recommendations)
• Any history of cerebrovascular, cardiopulmonary, cardiovascular, neuromuscular, or renal disease
• Any liver dysfunction or disease
• Taking any cardiovascular medications or medications that would interfere with study medications (e.g., strong organic anion transporting polypeptide 1B1 inhibitors)
• Contraindications or sensitivities to study medications
• Current eating disorder (defined as \>2 on the 'SCOFF' questionnaire 67)
• Current smokers
• Females with an irregular menstrual cycle or any medical conditions affecting the menstrual cycle (normal cycle defined as 21-35 days from menstrual cycle diary)
• Females who are pregnant (assessed with pregnancy test at screening and prior to starting medications), breastfeeding, or planning to conceive within 3 months

Sponsors & Collaborators

• University of British Columbia: lead

Study Sites (1)

University of British Columbia - Okanagan

Kelowna, British Columbia, V1V 1V7, Canada

Location

Related Publications (3)

• Muer JD, Didier KD, Wannebo BM, Sanchez S, Khademi Motlagh H, Haley TL, Carter KJ, Banks NF, Eldridge MW, Serlin RC, Wieben O, Schrage WG. Sex differences in gray matter, white matter, and regional brain perfusion in young, healthy adults. Am J Physiol Heart Circ Physiol. 2024 Oct 1;327(4):H847-H858. doi: 10.1152/ajpheart.00341.2024. Epub 2024 Aug 9.

  PMID: 39120466 BACKGROUND

• Reeves MJ, Bushnell CD, Howard G, Gargano JW, Duncan PW, Lynch G, Khatiwoda A, Lisabeth L. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol. 2008 Oct;7(10):915-26. doi: 10.1016/S1474-4422(08)70193-5. Epub 2008 Aug 21.

  PMID: 18722812 BACKGROUND

• Moreau KL, Hildreth KL, Klawitter J, Blatchford P, Kohrt WM. Decline in endothelial function across the menopause transition in healthy women is related to decreased estradiol and increased oxidative stress. Geroscience. 2020 Dec;42(6):1699-1714. doi: 10.1007/s11357-020-00236-7. Epub 2020 Aug 8.

  PMID: 32770384 BACKGROUND

MeSH Terms

Conditions

Motor Activity

Interventions

LHRH, Ac-Nal(1)-Cpa(2)-Trp(3)-Arg(6)-Ala(10)-; Estradiol; Testosterone; Anastrozole

Condition Hierarchy (Ancestors)

Behavior

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Androstenols; Androstenes; Androstanes; Testosterone Congeners; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Philip Ainslie, PhD

  University of British Columbia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Lauren Maier, MSc

CONTACT

250 878 6171; laurenm7@student.ubc.ca

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: September 24, 2025
• First Posted: October 8, 2025
• Study Start: April 1, 2026
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027
• Last Updated: February 10, 2026

Record last verified: 2026-02

Locations

CA (1)