Hormones Tagged for Sex Differences in HDL-C

A study of gender-affirming therapy in adolescents provided the first direct evidence that differences in high-density lipoprotein (HDL) cholesterol levels between men and women are tied to sex hormones, scientists said.

“The degree to which sex hormones versus sex chromosomes and other factors contribute to this difference is unknown. The gender-affirming treatment of transgender and gender-diverse youth provides a unique opportunity to study the association of sex steroids with cholesterol in different sex-chromosome contexts,” said a research team led by Kate Millington, MD, of Boston Children’s Hospital in Massachusetts.

Reporting online in JAMA Pediatrics, Millington’s team said that after 6 months of estradiol treatment in study participants who were designated male at birth, mean HDL-C levels increased by 11.2 mg/dL (95% CI 8.6-13.8, P<0.001) to within the range for female adolescents in the study.

Additionally, after 6 months of testosterone treatment in participants who were designated female at birth, mean HDL-C levels decreased by 7.2 mg/dL (95% CI 5.3-9.1, P<0 .001) to fall to a level nearly identical to that of the male participants at baseline, the researchers said.

Furthermore, obesity had a significant effect on these outcomes, the study found. Obese participants designated male at birth had lower HDL-C levels at baseline than their non-obese counterparts (36.0 mg/dL versus 46.1 mg/dL, P=0.01), and they demonstrated no significant change in HDL-C levels with estradiol treatment (36.0 mg/dL at baseline versus 41.3 mg/dL post-treatment, 95% CI 35.2-36.8 vs 37.6-45.0, P=0.10).

For participants designated female at birth, baseline mean HDL-C levels were not significantly different between those who were obese and those who were not (48.9 mg/dL vs 53.5 mg/dL, P=0.053). However, the drop in HDL-C levels with testosterone therapy was more pronounced in participants with obesity compared to the rest of the group (−12.1 mg/dL vs −5.5 mg/dL, 95% CI −16.3 to −7.9 vs −7.7 to −3.4, P=0.004), the researchers reported.

“To our knowledge, this is the first report of the modifying association of obesity with changes in HDL-C levels with gender-affirming hormone treatment, exacerbating the decrease in HDL-C levels with testosterone and blunting the benefit of estradiol treatment,” Millington’s group said. “Our results provide direct evidence for the hypothesis that changes in HDL-C levels during puberty and the differences in HDL-C levels between men and women are caused primarily by differences in sex steroids, and that sex steroids work synergistically with other risk factors such as obesity.”

Age, race, and tobacco use did not modify gender-affirming hormone-induced changes in HDL-C levels during the study. And the treatment produced no significant changes in low-density lipoprotein (LDL) cholesterol or triglycerides, Millington’s group said.

Asked about implications of the study, Millington said in an email to MedPage Today, “This study adds to what is known about the role of sex steroids (i.e., estrogen and testosterone) in cholesterol metabolism. It will help doctors better understand the role of these hormones on cholesterol changes in women, men, and in transgender patients. This is an active area of research for us and there is much more research planned in this area.”

The study included 269 transgender and gender-diverse youth. Of these, 83 participants (31%) were designated male at birth, and 186 (69%) were designated female at birth. They had no prior gonadotropin-releasing hormone analog use prior to initiating gender-affirming hormone therapy during the study.

The researchers collected laboratory and anthropometric data as part of participants’ clinical care at baseline, and this data was collected again at 6 months and 12 months after initiating gender-affirming hormone therapy. Obesity was defined as a baseline body mass index (BMI) more than the 95th percentile for participants’ designated sex. For statistical analysis, the researchers used a random mixed-effects model, with a P value less than 0.05 considered significant.