Mechanisms of Blood Pressure Dysfunction in Transmen Receiving Testosterone

The purpose of this research is to explore the effects of chronic androgen exposure on sympathetic nervous system activity (SNSA) and baroreflex control of blood pressure responses in transgender men (trans men) taking gender affirming hormone therapy (HT). Blood pressure, baroreflex gain, and frequency of sympathetic responses to changes in blood pressure will be assessed in trans men and a control group of cisgender women. To fully understand HT effects on blood pressure regulation in trans men, it is crucial to understand how both SNSA, and the pattern of SNSA, can be influenced by high levels of androgen exposure in the female cardiovascular system, as well as how the two regulatory components may interact.

The purpose of this research is to study how testosterone affects blood pressure control in trans men. High testosterone levels are detrimental to the female cardiovascular system in that higher levels are associated with increased blood pressure. Humans control blood pressure in the autonomic nervous system via the baroreflex mechanism. The arterial baroreflex is a key autonomic homeostatic mechanism involved in maintaining arterial blood pressure, and gain of the baroreflex is used as a measure of the sensitivity of sympathetic responses that act to restore acute blood pressure fluctuations. This autonomic regulation of blood pressure is also characterized by rhythmic activity (changes in cardiac frequency), which can be observed by recording sympathetic nerve traffic. When the female cardiovascular system is exposed to elevated androgens, baroreflex gain is impaired, and blood control is less efficient during an orthostatic challenge. However, to best understand the effect of a given stimulus on autonomic function, changes in frequency of the SNSA response must also be quantified in addition to the gain. Sympathetic control of arterial blood pressure is most effective in a narrow frequency range, and if this frequency range for responsiveness should narrow further, control of arterial blood pressure becomes less efficient and presents as dysfunction. The central hypothesis for this research is that dysregulation of blood pressure in trans men taking testosterone for gender affirming HT is a function of both reduced baroreflex gain and narrowed frequency-dependent relationship between arterial pressure and peripheral sympathetic vascular responsiveness. Specifically, these studies test the hypothesis that androgen supplementation with HT is associated with 1) lower baroreflex gain during a lower body negative pressure (LBNP) challenge, and 2) a narrowed response frequency range that precedes impaired sympathetic vascular response dynamics in trans men compared to control cisgender women.

Study procedures include an oral glucose tolerance test (OGTT), microneurography of the median nerve in the forearm to assess SNSA, and 2 LBNP challenges designed to examine baroreflex gain during static LBNP and then the frequency of SNSA during oscillating LBNP (OLBNP). Participants complete 3 visits for this study. Visit 1 is for informed consent procedures; Visit 2 is a pre-screening visit to complete the OGTT; Visit 3 is for experimental testing to assess gain and the frequency range. Blood pressure, heart rate and muscle SNSA (MSNA) are measured during LBNP and OLBNP. MSNA is recorded using 2 microelectrodes inserted through the skin of the forearm to record activity (firing) of the median nerve. Blood samples are taken via IV placement to measure insulin and glucose during the OGTT for Visit 2, and then sex hormones and catecholamines during Visit 3. Results from the group of young trans men will be compared to a control group of cisgender women matched for age and body mass index.

Eligibility Criteria:
Inclusion Criteria:

* Both groups (trans men and cisgender women) must be healthy and non-smoking. Control participants must be cisgender women with regular menses every 26-34 days. Trans men participants must be currently receiving testosterone for gender affirming hormone therapy where physiologic doses of exogenous Dihydrotestosterone have been administered (via injection or transdermal application) for at least 3 months as prescribed by their local endocrine provider as part of their clinically indicated hormone therapy. Doses can vary depending on the size and goals of each patient, but blood testosterone will be between 400-1000 ng/dl.

Exclusion Criteria:

* Subjects who smoke, have diabetes, or BP\>140/90 will be excluded.
* Subjects will not be taking medications during the study, including any insulin-sensitizing or cardiovascular medications.
* Subjects are excluded if they have lost \> 5 kg of weight within the past 6 months or perform high-intensity exercise \> 3 times/week.