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Principal Investigator: Breland Crudup
Organization: UNIVERSITY OF MISSISSIPPI MED CTR
Fiscal Year: 2024
Award: $32,974
Funding agency: National Heart Lung and Blood Institute
Transgender individuals comprise roughly 1% of the United States population and include those born one sex
but identify as a gender that does not align with their biological sex. Gender-Affirming Hormone Therapy (GAHT)
is used to treat these individuals to match secondary sex characteristics to their gender identity. GAHT in
transgender females (TGF), individuals born male but who identify as female, involves administration of 17β-
estradiol (E2) with an anti-androgen (AA) or castration (CTX). Although long-term studies in this population are
limited, recent studies suggest that cardiovascular (CV) risk may be elevated in GAHT-treated TGF versus cis-
gender men. However, the mechanisms involved are unknown and potential targets to ameliorate CV risk have
yet to be identified. To address this gap in knowledge, the Alexander laboratory has developed a novel model of
feminizing hormone therapy in the male rat that involves administration of E2 to mimic physiological levels
observed in age-matched female rats in conjunction with androgen suppression. My model mimics the increase
in E2, suppression of testosterone and decrease in body weight and lean mass observed in TGF individuals
indicating clinical relevance for this experimental model of GAHT. My studies will use two different rat strains,
the normotensive Sprague Dawley rat and the spontaneously hypertensive rat. Preexisting chronic disease such
as hypertension is contraindicated in GAHT. Yet, GAHT is integral for the treatment of gender dysphoria. To
date, basic research utilizing experimental models of GAHT are limited to nonexistent. Thus, a critical need
involves the use of innovative animal models to provide reliable risk assessment and in-depth investigation into
mechanisms that contribute to increased CV risk in adult TGF individuals that undergo GAHT. Therefore, my
F31 will test the following hypothesis that shifting the hormonal milieu with cross sex steroid treatment versus
natal sex, elevated estrogen coupled to testosterone suppression in the male, increases susceptibility to target
organ injury and cardiovascular risk that is enhanced with aging and involves an estrogen-induced male-specific
effect on the vasoconstrictor-vasodilator balance of the renin angiotensin system. Aim 1 will test the hypothesis
that the shift in the hormonal milieu in gender affirming hormone therapy in a rodent model of the transfemale
rat is associated with increased end organ damage and cardiovascular risk that is further exacerbated with
preexisting chronic disease. Aim 2 will test the hypothesis that increased end organ damage and cardiovascular
risk in transgender females that undergo gender affirming hormone therapy involves an estradiol induced “male
sex-specific” effect on the renin angiotensin system. This grant will also further my training potential as I learn
“gold-standard” methods for measurement of blood pressure via radiotelemetry, assessment of end organ
damage in response to myocardial ischemia reperfusion with echocardiography by sonography, and ex vivo
vascular function studies. Thus, this application will serve towards enhancing my technical skills in scientific
communication skills, scientific rigor and networking as I train to become an independent physician scientist.
Terms: <21+ years old><4-O-beta-D-galactopyranosyl-D-glucose><Active Follow-up><Acute><Address><Adult><Adult Human><Age><Aging><Androgen Antagonists><Androgen Suppression><AngII><Angiotensin II><Angiotensins><Animal Model><Animal Models and Related Studies><Anti-Androgen><Anti-Androgen Agents><Anti-androgen Therapy><Anti-androgen Treatment><Aquadiol><BP control><BP homeostasis><BP management><BP regulation><Basic Research><Basic Science><Biological><Birth><Blood Pressure><Blood Vessels><Body Weight><Brain><Brain Nervous System><Brain Vascular Disorders><Cardiac infarction><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Castration><Causality><Cerebrovascular Disease><Cerebrovascular Disorders><Characteristics><Chronic Disease><Chronic Illness><Common Rat Strains><Communication><Complex><Coupled><Creatinine><Data><Dehydrogenases><Development><Dimenformon><Diogyn><Diogynets><Down-Regulation><Echocardiogram><Echocardiography><Echography><Echotomography><Encephalon><Endocrine><Endocrine Therapy><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Equilibrium><Estrace><Estradiol><Estradiol-17 beta><Estradiol-17beta><Estraldine><Estrogens><Etiology><Experimental Models><Exposure to><Female><Feminization><Gender><Gender Identity><General Population><General Public><Goals><Gonadal Steroid Hormones><Grant><Guidelines><Healthcare><Heart><Heart Injuries><Heart Vascular><Hormonal><Hormonal Therapy><Human><Hypertension><Inbred SHR Rats><Individual><Intracranial Vascular Diseases><Intracranial Vascular Disorders><Investigation><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><Kidney><Kidney Urinary System><Kinases><Knowledge><Laboratories><Lactose><Leanness><Learning><Long-Term Effects><Longitudinal Studies><Longterm Effects><Male Castration><Measurement><Mediating><Medical Ultrasound><Methods><Modeling><Modern Man><Myocardial Infarct><Myocardial Infarction><Myocardial Ischemia><ORCHX><Orchidectomy><Orchiectomy><Organ><Outcome><Ovocyclin><Ovocylin><Oxidoreductase><Oxidoreductase Gene><Participant><Parturition><Pathway interactions><Phosphotransferase Gene><Phosphotransferases><Physicians><Physiologic><Physiological><Population><Predisposition><Prevalence><Progynon><Rat><Rat Strains><Rats Mammals><Rattus><Reductases><Renin-Angiotensin System><Reperfusion Therapy><Reporting><Risk><Risk Assessment><Rodent Model><SHR Rats><Scientist><Sex Characteristics><Sex Hormones><Sex Steroid Hormones><Societies><Spirolactone><Spironolactone><Spontaneously Hypertensive Rats><Sprague-Dawley Rats><Steroid therapy><Supplementation><Surgical Castration><Susceptibility><System><Technical Expertise><Testicles><Testing><Testis><Testosterone><Therapeutic Estradiol><Therapeutic Estrogen><Therapeutic Testosterone><Thinness><Training><Trans-Testosterone><Transphosphorylases><Transthoracic Echocardiography><Ultrasonic Imaging><Ultrasonogram><Ultrasonography><Ultrasound Diagnosis><Ultrasound Medical Imaging><Ultrasound Test><United States><Up-Regulation><Upregulation><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vasoactive Agonists><Vasoconstrictor Agents><Vasoconstrictor Drugs><Vasoconstrictors><Vasodilating Agent><Vasodilator Agents><Vasodilator Drugs><Vasodilators><Vasopressor Agents><Verospirone><Weight><active followup><adult youth><adulthood><ages><androgen inhibitor><arm><balance><balance function><biologic><biological sex><blood pressure control><blood pressure homeostasis><blood pressure management><blood pressure regulation><brain vascular disease><brain vascular dysfunction><cardiac damage><cardiac infarct><cardiac injury><cardiac ischemia><cardiovascular disease risk><cardiovascular disorder><cardiovascular disorder risk><cardiovascular health><cardiovascular risk><cardiovascular risk factor><causation><cerebral vascular disease><cerebral vascular dysfunction><cerebrovascular dysfunction><chronic disorder><circulatory system><cis-gender man><cis-male><cis-man><cisgender man><clinical relevance><clinically relevant><cohort><coronary attack><coronary infarct><coronary infarction><coronary ischemia><developmental><diagnostic ultrasound><disease causation><epidemiologic investigation><epidemiology study><follow up><follow-up><followed up><followup><gender affirmation hormone therapy><gender affirmation hormone treatment><gender affirming hormone therapy><gender affirming hormone treatment><gender dysphoria><gender dysphoric><gonadal steroids><health care><heart attack><heart damage><heart infarct><heart infarction><heart ischemia><heart sonography><high blood pressure><hormone therapy><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><injury to organs><innovate><innovation><innovative><intracranial vascular dysfunction><long-term study><longitudinal outcome studies><longterm study><male><male gonadectomy><model of animal><myocardial ischemia/hypoxia><myocardium ischemia><normotensive><novel><organ injury><pathway><regulate BP><regulate blood pressure><renal><reperfusion><response><sex><sex steroid><skills><sonogram><sonography><sound measurement><spontaneous hypertensive rat><technical skills><trans*><trans-women><transgender><transgender women><transwoman><transwomen><ultrasound imaging><ultrasound scanning><vascular><vasopressor><weights><young adult><young adulthood>