Effects of Cross-Sex Hormone Therapy (CSHT) on Aortic Reactivity and Metabolic Parameters in Gonadectomized Male and Female Rats

Author

Rifat Ara Islam, University of the PacificFollow

Date of Award

2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Roshanak Rahimian

First Committee Member

John Livesey

Second Committee Member

David Thomas

Third Committee Member

James A. Uchizono

Fourth Committee Member

Xiaoyuan Han

Abstract

With the rising awareness, the number of individuals identifying themselves as transgender in the US is increasing over the years. Cross-sex hormone therapy (CSHT) may alter cardiometabolic parameters leading to the increased risk of cardiovascular diseases (CVD) in transgender population. However, the underlying mechanisms of impaired cardiovascular functions in transgender female (male to female, MtF) or transgender male (female to male, FtM) individuals are not well documented. This study was undertaken to examine the effects of 17β-estradiol (E2)- and testosterone propionate (Tes)-treatment on key cardiometabolic parameters and aortic reactivity in castrated (CAS) male and ovariectomized (OVX) female Sprague Dawley (SD) rats, respectively.CAS male rats aged 8-10 weeks were implanted subcutaneously with either 1.5 mg E2 pellets (60-day release) or placebo (PL) pellets. Meanwhile, OVX female rats of the same age received subcutaneous treatments with either 7.5 mg Tes pellets (60-day release) or PL pellets. Age-matched intact male and female rats were also included to the study. The CAS+PL, CAS+E2, and intact male rats were used to study MtF transition, while the OVX+PL, OVX+Tes, and intact females were assigned to the FtM study group. Specific aims of this study were to determine whether 1) CSHT affects the key cardiometabolic parameters in CAS male and OVX female rats and 2) CSHT alters the relative contributions of endothelium-derived relaxing factors (EDRF) in regulating aortic reactivity of gonadectomized rats. We also investigated the potential molecular mechanisms involved in the alteration of metabolic and vascular function following CSHT. In the study of MtF rat model, we observed that E2-treatment resulted in a decrease in body weight and an improvement in HbA1c levels compared to both intact male and CAS+PL rats. E2-treatment also enhanced glucose tolerance in CAS rats compared to CAS+PL group. The improved glucose homeostasis observed in these animals aligns with the E2-induced upregulation of ERα, pAkt/Akt, and Glut-4 expression in white adipose tissue (WAT). Moreover, E2-treatment increased the levels of high-density lipoprotein (HDL) and triglyceride but had no effect on low-density lipoprotein (LDL) level. Furthermore, acetylcholine (ACh)-induced relaxation was reduced, while phenylephrine (PE)-induced contraction was increased in the aorta of E2-treated CAS rats. Western Blot analysis revealed a decrease in G protein-coupled estrogen receptor (GPER or GPR30) expression and an increase in inducible nitric oxide synthase (iNOS) expression in the aorta of CAS+E2 rats. In the study of FtM rat model, we observed that Tes-treatment resulted in an increase in body weight compared to the intact females. Tes-treatment also improved non-fasting blood glucose levels and glucose tolerance in OVX rats compared to intact females. However, OVX+Tes rats exhibited higher plasma triglycerides, with no significant effect on plasma LDL or HDL levels compared to intact female and OVX+PL rats. Moreover, Tes-treatment did not alter aortic relaxation to ACh or the contractile response to PE in OVX rats. Further studies are needed to explore the molecular mechanisms underlying the Tes-induced improvement in glucose homeostasis observed in OVX rats. In conclusion, the current study suggests that CSHT may have beneficial effects on glucose homeostasis in CAS male and OVX female rats, while adversely affecting triglyceride levels in these animals. The vascular reactivity data indicates that, although E2-treatment may potentiate vascular injury, Tes-treatment did not alter vascular function under these conditions. Further studies with varying doses and extended treatment durations are necessary to confirm these findings.

Pages

141

Recommended Citation

Islam, Rifat Ara. (2025). Effects of Cross-Sex Hormone Therapy (CSHT) on Aortic Reactivity and Metabolic Parameters in Gonadectomized Male and Female Rats. University of the Pacific, Dissertation. https://scholarlycommons.pacific.edu/uop_etds/4303