Research reveals that hormone therapy does not increase risk of low bone therapy or cardiovascular events

Spyridoula Maraka, MD, MSc, assistant professor of medicine at the University of Arkansas for Medical Sciences and colleagues evaluated 29 studies to determine the effects of sex steroids on changes in lipids including total, LDL and HDL cholesterol, triglicerides, and cardiovasculat events such as myocardial infarction, transient ischemic attack, strokes and venous thromboembolism events.

The 29 studies had examined 4731 transgender patients (3231 transitioning from male to female and 1500 transitioning from female to male).

Serum triglyceride levels significantly increased at 3 to 6 months and 24 months or longer of therapy compared with baseline in patients transitioning from female to male. Further, serum LDL cholesterol increased at 12 months and 24 months or longer, and HDL cholesterol decreased across all follow-up time periods. There were no changes observed for total serum cholesterol levels at any time.

In patients transitioning from male to female, no significant differences were observed for serum LDL, HDL or total cholesterol levels from baseline to any follow-up period. However, serum triglyceride levels were higher than baseline at 24 months or more.

VTE occurred in 56 of 1,767 patients transitioning from male to female and in one of 771 patients transitioning from female to male. Stroke occurred in eight of 859 patients transitioning from male to female and in none transitioning from female to male. MI occurred in 14 of 1,073 patients transitioning from male to female and one of 478 transitioning from female to male. Mortality occurred in 139 of 1,486 transitioning from male to female and 13 of 651 transitioning from female to male.

Clinicians prescribing cross-sex hormonal therapy need to share with transgender individuals the current uncertainty regarding potential side effects of masculinizing/feminizing hormone therapy and make treatment decisions based on patients’ values, preferences and context.

Future research is needed to ascertain the safety of hormone therapies in transgender individuals. Randomized trials nested within study center cohorts could test the relative safety of different cross-sex hormone regimens. Moreover, the medical centers that provide care to transgender individuals should make it a priority to conduct long-term follow-up studies evaluating patient-important outcomes. In this context, observational studies in which baseline CV risk is assessed and balanced between study groups with proper ascertainment of exposure and outcomes measures are also feasible and urgently needed.

--Dr. Maraka

In a separate study, Naykky Singh Ospina, MD, MSc, assistant professor in the department of medicine at the University of Florida and colleagues evaluated 13 studies to determine the effects of sex steroids on bone health, including Bone Mineral Density at the lumbar spine, femoral neck and total hip and fractures. 639 transgender patients were included in the studies (392 transitioning from male to female and 247 from female to male). Changes in BMD were evaluated in twelve of the studies and the other evaluated fracture rates.

After therapy initiation, no changes were observed in lumbar spine, femoral neck or total hip BMD at 12 and 24 months compared with baseline in patients transitioning from female to male.

In patients transitioning from male to female, BMD significantly increased at the lumbar spine at 12 and 24 months compared with baseline. No significant changes were observed for femoral neck BMD.

In the study evaluating fracture rates, none of the participants experienced a fracture at 12 months of follow-up.

In our analysis of the current literature evaluating the effects of sex steroids on the bone health of transgender individuals, we found a small, statistically significant increase in BMD at the lumbar spine of patients who received estrogen-based therapies (male-to-female individuals) and no statistically significant changes in those who received testosterone-based therapies (female-to-male individuals). These findings suggest that exposure to sex steroids was not associated with a clinically significant worsening of the BMD of transgender individuals. However, there was limited information regarding the effect of these therapies on the fracture risk, which is the most important outcome. Clinicians should discuss with their patients the possible effects on sex steroid therapy on their bone health.

--Dr. Singh Ospina

The meta-analyses regarding the impact of transgender hormone therapy on bone and lipids should be reassuring to clinicians providing care to transgender individuals. Sex steroids are known to play a major role in bone health, and transgender treatment guidelines suggest that monitoring of bone density be considered for hormone-treated transgender individuals. Some have reported lower bone density among transgender women even prior to hormone treatment without an explanation for why that might be so. However, treatment with sex steroids might be predicted to benefit bone density. The meta-analysis concluded that masculinizing HT had no demonstrated impact on bone density, but feminizing HT increased bone density at the lumbar spine in a statistically significant fashion. Studies of transgender health care are few and modest. Therefore, the meta-analysis suffered from depending on inferior studies in the first place, which might compromise the overall conclusions even when viewed in the aggregate. Further, ultimate endpoints like fracture risk and mortality could not be assessed. However, the report does represent the best published data to date that transgender HT does not appear to be harmful to bone. Rather, male-to-female regimens may actually be good for bone health.

Sex steroids are known to play a modest role in lipid profiles with the potential to be of consequence for CV health. Transgender treatment guidelines suggest that monitoring lipid profiles ought to be considered for hormone-treated transgender individuals. Some have reported elevated HDL cholesterol (a good thing) and triglycerides (possibly a bad thing) in response to estrogens. By contrast, androgens are reported to result in a shift in the HDL-to-LDL ratio in a negative way. The meta-analysis concluded that masculinizing HT resulted both in decreased HDL cholesterol and increased triglycerides while feminizing HT increased triglyceride levels without other impact on lipid profiles. Studies of transgender health care are few and modest. Therefore, the meta-analysis suffered from depending on inferior studies in the first place, which might compromise the overall conclusions even when viewed in the aggregate. Further, ultimate endpoints like CV risk and mortality could not be assessed. However, the report does represent the best published data to date that female-to-male hormone regimens may represent modest risk to lipid profiles and that male-to-female regimens may indeed raise triglyceride levels as has been previously suspected.

--Joshua D. Safer, MD, Endocrinologist, Medical Director, Center for Transgender Surgery and Medicine, Boston Medical Center

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