The Role of Estrogen and Testosterone in Determining Heart, Lung, and Brain Regulation in Humans

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

NOT_YET_RECRUITING

Clinical Phase

NA

Total Enrollment

50 participants

Study Classification

INTERVENTIONAL

Study Start Date

2026-03-01

Study Completion Date

2027-12-31

Brief Summary

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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.

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Detailed Description

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Aim 1: Women have historically been excluded from research due to sociocultural and gender biases from a lack of understanding of the menstrual cycle and hormone levels. As a result, many diagnoses and treatments are based on male physiology and may not be appropriate or effective for women. Women are at a greater risk for many types of stroke, have higher rates of Alzheimer's disease, and experience higher mortality and worse neurological and functional outcomes from many cardio- and cerebrovascular diseases. It appears that women experience cerebrovascular disease differently than men, including distinct risk factors related to hormone fluctuations (i.e., pregnancy, menopause). In order to better recognize, understand, and treat women in disease, it is important to understand how they differ in basic mechanisms of cerebrovascular regulation. A key regulator in the differences between men and women are sex-specific hormones, particularly estrogen and testosterone. Despite their fundamental role in physiology, there is little evidence in humans in vivo isolating their influence on basic mechanisms of brain blood flow regulation. Females show significantly higher resting cerebral blood flow (CBF) compared to males, with differences throughout the menstrual cycle and with menopause. Further evidence in animal models support a key role of estrogen in both resting CBF and reactivity. Crucially, these findings have not been replicated in humans, due to natural fluctuations in sex hormones. A definitive role of these hormones in brain blood flow regulation remains to be elucidated.

Females have elevated resting CBF, likely a compensatory mechanism due to structural differences and reduced arterial oxygen content stemming from anemia, hormones, and other related factors (e.g., hemoglobin, menses). Following menopause, women experience lower CBF, further suggesting hormone levels contribute to these differences. Indeed, evidence from animal models implicate estrogen in CBF regulation. In addition to resting brain blood flow, changes with menopause alter cerebrovascular responses to carbon dioxide and metabolic fluctuations. Research investigating natural hormonal fluctuations throughout the menstrual cycle and menopause provides conflicting findings, falling short on isolating the specific hormonal influences likely due large interindividual variations in hormone levels and cycle lengths. Thus, there is a gap between animal models and human application in understanding how hormones influence brain blood flow regulation.

Aim 2: Many common diseases are characterized by a lack of oxygen (i.e., hypoxia), such as chronic obstructive pulmonary disease, sleep apnea, and pulmonary fibrosis. With exposure to hypoxia, ventilation increases in attempt to maintain oxygen delivery to the tissue. Males and females may respond differently to hypoxia and/or hypercapnia, through a reflex pathway (i.e., chemoreflex). Indeed, a large body of research illustrates sex differences in control of breathing. Evidence in females during pregnancy and throughout the menstrual cycle support a role of sex hormones in ventilatory responses. Direct manipulations of estrogen and testosterone in animal models show differences in resting ventilation and ventilatory responses to hypoxia and hypercapnia. Limited investigations in humans have begun to describe how estrogen and testosterone influence ventilatory responses, but more work is needed to elucidate the exact influences and mechanisms of sex hormones on ventilation.

Aim 3: During exercise, the body must meet the blood flow demands of the exercising muscle. Functional sympatholysis enables this by increasing blood flow in the exercising tissues despite vasoconstriction and reduced flow to other tissues. Conflicting evidence in functional sympatholysis between males and females suggests females may or may not have a greater response to exercise. This ability for functional sympatholysis appears to diminish with aging, specifically as women go through menopause. Estrogen therapy augments functional sympatholysis in postmenopausal women and estrogen-deficient rats, supporting a role of hormones in this process. In contrast, others have found no difference in sympatholysis between ovariectomized and ovary-intact rats. Currently, there is no consensus on the influence of sex hormones on functional sympatholysis. An understanding of how estrogen and testosterone influence how blood vessels respond to exercise will provide key insights into blood vessel regulation in health and disease.

Aim 4: Biological sex is a key determinant of appetite and dietary intake, which can ultimately impact body weight and health. Sex hormone-energy intake relationships have been primarily studied in the context of the menstrual cycle in healthy premenopausal females. During the mid-luteal phase (characterized by moderate estradiol and high progesterone), levels of orexigenic hormones (e.g., ghrelin), hunger sensations, and energy intake are higher, while anorectic hormones (e.g., peptide-YY) and satiety sensations are lower than the late follicular phase (high estradiol and low progesterone). The influence of testosterone on appetite and energy intake is less understood. Evidence suggests that testosterone supplementation during short-term energy deficits prevents increases in circulating ghrelin in healthy males, although it does not appear to suppress appetite sensations. These findings highlight the role of endogenous sex hormones in energy balance, but the independent effects of estradiol and testosterone on appetite regulation and energy intake remain unexplored. A deeper understanding of the individual and combined effects of sex hormones on specific components of energy balance is essential to refining models of body weight regulation, informing strategies to optimize health and wellness across diverse populations, and driving future mechanistic and applied research.

Aim 5: Despite the overwhelming similarities, there are anatomical differences in the neuromuscular systems of females and males; however, the extent to which these differences affect function is unclear due to conflicting reports in the literature. A source of this ambiguity is that relatively few studies have assessed the role of sex hormones, which could influence neural and contractile properties because there are hormone receptors throughout the nervous system and within skeletal muscles. No previous studies have implemented the blockade and supplementation design of the present investigation, so considerable insight can be gleaned by evaluating neuromuscular function with such a controlled manipulation of estrogen and testosterone. Given the marked increase in neuromuscular research that considers the possibility of sex-based differences, such insights would be invaluable because there would be a definitive stance on whether or not it is necessary to schedule testing for a specific phase of the menstrual cycle.

Aim 6: Despite the known existence of sex-based differences in whole-body and tissue-metabolism, how estrogen and testosterone modulate metabolic process in distinct tissues and cell-types remains poorly understood in humans. Skeletal muscle comprises up to 40% of total body mass and accounts for approximately 30% of resting energy expenditure, with up to 100-fold increases in skeletal muscle energy demand during intense physical activity. Skeletal muscle mitochondria - the primary site of myocellular energy production - abundantly express both the androgen and estrogen receptors, with evidence of direct modulation of mitochondrial gene expression and bioenergetic function by sex hormones in vitro and in pre-clinical rodent models. Comparatively little is known about how sex hormones control mitochondrial profiles in human skeletal muscle tissue, with most available data being associative in nature (e.g., across menstrual cycle phases) or involving pre- vs. post-menopausal females receiving hormone replacement therapy. No previous study has implemented hormonal manipulation in healthy young adults with comprehensive profiling of skeletal muscle mitochondria. Similar to muscle, little is also known about how sex hormones impact immune cell immune cell mitochondrial profiles, despite the importance of mitochondria for immune responses and sex-based difference in innate and adaptive immunity. Characterization of skeletal muscle and immune cell mitochondrial profiles in response to sex hormone manipulation will provide novel unprecedented insights into the endocrine regulation of tissue- and cellular metabolism in humans.

Therefore, the investigators aim to determine the role of estrogen and testosterone on (i) cerebral blood flow regulation and reactivity, (ii) ventilatory responses, (iii) functional sympatholysis, (iv) appetite sensations and dietary intake, (v) neuromuscular responses, and (vi) leukocyte and skeletal muscle mitochondrial profiles. The investigators will employ a method of direct manipulation of hormone production via gonadotropin releasing hormone (GnRH) antagonist and hormone add-back. These experiments will be conducted in compliance with the protocol provided below whilst adhering to the Guidelines for Good Clinical Practice E6(R1).

Conditions

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

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

NONE

Study Groups

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Hormone Manipulation

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.

Group Type EXPERIMENTAL

GnRH antagonist

Intervention Type DRUG

blockade of hormone production

Estradiol (E2)

Intervention Type DRUG

Estrogen add-back in females

Testosterone

Intervention Type DRUG

testosterone add-back in males

Anastrozole (Arimidex)

Intervention Type DRUG

Prevention of testosterone conversion to estrogen in males

Interventions

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GnRH antagonist

blockade of hormone production

Intervention Type DRUG

Estradiol (E2)

Estrogen add-back in females

Intervention Type DRUG

Testosterone

testosterone add-back in males

Intervention Type DRUG

Anastrozole (Arimidex)

Prevention of testosterone conversion to estrogen in males

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

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. All subjects will sign an informed consent form prior to participation.

Exclusion Criteria

Participants will be excluded if they are hypertensive or hypotensive, have any history of cerebrovascular, cardiopulmonary, cardiovascular, neuromuscular, or renal disease, are smokers, or take cardiovascular medications. Individuals with a current eating disorder (\>2 on the 'SCOFF' questionnaire 68 will also be excluded. Females will be excluded if they have an irregular menstrual cycle, any medical conditions that may affect the menstrual cycle, are pregnant, breastfeeding, or planning to conceive within 3 months, or use oral or hormonal birth control (Copper intrauterine devices (IUDs) will be allowed as they do not change systemic hormone levels). Participants who have had brain surgery, have or think they may have epilepsy, have a family history of epilepsy, or have had a recent (\< 6 months) head injury or concussion would be excluded from the portion of the study that involves transcranial magnetic stimulation (TMS).

Minimum Eligible Age

18 Weeks

Maximum Eligible Age

40 Weeks

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes