It has been known that both estrogen and testosterone are the major sex steroids regulating bone metabolism and other physiological changes in both male and female, respectively. In postmenopausal women, osteoporosis is a major concern secondary to the lack of estrogen. These patients also experience a number of physiological changes that affect their life permanently to include hot flashes, irritability, difficulty concentrating, depression and mental confusion. In hypogonadal men, testosterone deficiency could lead to higher prevalence of depression, osteoporosis, fracture and frailty. Given the new military policy starting to support treatment for gender identity dysphoria military personnel, the number of transgender patients in our Endocrinology clinic has been slowly increasing over the past several months. These patients will require either testosterone replacement therapy or estrogen therapy to achieve their desired sexual characteristics. However, as mentioned above, the lack of estrogen or testosterone in female and male, respectively, could cause several issue in their body composition, cognitive function and quality of life. We designed this prospective case-control study to include patients with hypogonadism and the transgendered populations to learn about the long-term effects of these hormonal replacement therapies on bone density, fractures, memory/cognitive function and quality of life. This is a repetitive measures study taken at baseline, 6-months, and 12-months for three groups consisting of at least 75 subjects. The study will involve 3 arms, i.e. Group 1 primary/secondary untreated hypogonadism, Group 2 male-to female (MTF), and Group 3 female-to-male (FTM) participants that are planning to start hormone replacement therapy as per standard clinical guidelines.

The Endocrine Society defines male hypogonadism as a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone (androgen deficiency) and the normal number of spermatozoa caused by disruption of one or more levels of the hypothalamic-pituitary-gonadal (HPG) axis. It is characterized by low serum testosterone/ high LH/high FSH concentrations (primary hypogonadism) or low testosterone/low LH/low FSH (secondary hypogonadism). The main constellation of signs and symptoms may include erectile dysfunction , decreased libido and volume of ejaculation, decreased lean body mass with increased body fat, loss of body and facial hair, weakness, fatigue, anemia and decreased bone density. There is only little data from large cross-sectional studies that address the impact of hypogonadism on morbidity. However, some small studies have concluded that testosterone deficiency could lead to a higher prevalence of depression, osteoporosis, fracture and frailty . Hypogonadism defined as serum total testosterone level <300 ng/dl has been shown to be related to decreased bone mineral density (BMD). Further review of the literature found various epidemiological studies in men that showed the associations between testosterone and estradiol levels and BMD. They found that estrogen has a major role in regulating bone resorption but both estrogen and testosterone play a role in maintaining bone formation. A recent published trial in 2017 also showed that testosterone replacement therapy in older men was associated with significant greater improvements in stair-climbing power, muscle mass and power. Similar studies found that deficiency of testosterone would lead to decrease in lean mass, muscle size and strength. Given that these two sex steroid hormones, testosterone and estrogen, play an important role in men and women, respectively, we also study their long-term effects in the transgender population once they were started on the opposite gender hormone and lack of their own endogenous production.

Inclusion Criteria:

• Male and female DoD health care beneficiaries
• Ages 18-65
• Diagnosed with primary hypogonadism or transgender treatment for at least 6 months
• Under care for gender identity dysphoria
• On stable dose of sex steroid hormonal therapy for at least 6 months prior to enrolling
• Must be living in the Washington, D.C. area for at least 12 months following enrollment

Exclusion Criteria:

• Pregnancy, plan for pregnancy in the next 12 months
• Cardiac disease, especially coronary artery disease
• Malabsorption disorder
• Gastrointestinal surgeries
• Significant renal or liver dysfunction
• Seizure disorders
• recent orders to move out of the geographic area
• Age less than 18 years old or older than 65 years old
• Scheduled for deployment

Patients (male and female health care beneficiaries of the military system) between the ages of 18 to 65 who have been diagnosed with primary hypogonadism and/or under the care for gender identity dysphoria and have been on a stable dose of sex hormonal therapy

The study findings will be generalized to patients ages of 18 to 65 who are planning to be placed on sex steroid hormone either for hypogonadism or transgender treatment as per clinical guidelines.