Estrogen use tied to over fivefold increase in venous thromboembolism risk
The use of estrogen therapy in transgender women appears to put them at increased risk for cardiac events, a review of the available scientific literature found.
The analysis found a "definite" increase in venous thromboembolism (VTE) and "probable" increases in both the risk of myocardial infarction (MI) and stroke among transgender women (those born biologically male but identifying as female), according to Michael Irwig, MD, of George Washington University School of Medicine and Health Sciences in Washington.
Among transgender men (those born as female but identifying as male), there appeared to be no increase in stroke or VTE, while the risk of MI is still unknown, as reported in Reviews in Endocrine and Metabolic Disorders.
"In the short term ... over 5 to 10 years, it appears that there are more cases of heart attack and stroke in transgender women who take estrogen than in transgender men who are on testosterone," Irwig told MedPage Today. "So estrogen may have more risks, from a cardiovascular standpoint, than does testosterone."
But he said that more research is needed for those who have been on hormones "for 20, 30, 40 years." And in addition to these long-term data, Irwig said more research is needed on older adults who transition in their 50s, 60s, or 70s, and on routes of administration, type of therapy, and dosing.
The review noted that there is "strong evidence" among the various studies that estrogen therapy increases VTE risk over fivefold in transgender women. Among the studies examined, rates of VTE in a meta-analysis of 10 studies including 1,767 transgender women on estrogen therapy ranged between 0% and 5%. The findings support another recent study that observed a higher likelihood of VTE in these individuals compared with cisgender men or women.
In transgender men, the rates of VTE in a meta-analysis of eight studies that included 771 individuals on testosterone therapy ranged between 0% and 0.34%.
Still, Irwig stressed the importance of being vigilant to the long-term potential for cardiac events even among these individuals. "Although testosterone appears to be safe in the short-term for transgender men, we really don't have the full picture yet," he said.
Joshua Safer, MD, executive director of the Mount Sinai Center for Transgender Medicine and Surgery in New York City, told MedPage Today that the review "accentuates areas where we need more research, and it makes us more confident that even though there are some risks to hormone therapy they're not enormous."
He said that for transgender men, testosterone therapy remains "relatively safe," but that for transgender women, there's a risk of blood clotting with certain estrogen preparations.
"All we seem to know is what we've known for some decades. Ethinyl estradiol is bad and estrogen, in general, seems to increase blood clot risk slightly," Safer said. "The risks that are there are exactly the risks that have been suspected ... they're not enormous, and they will not change most patients' choices regarding taking hormones."
Regarding MI, a meta-analysis of three studies that included 1,073 transgender women on estrogen therapy -- in combination with an anti-androgen when testes were present -- reported 14 cases of MI. And a retrospective study of 816 transgender women -- completed at a time when ethinyl estradiol and cyproterone acetate were standard treatment -- reported 10 such cases and 6 deaths.
By comparison, investigators found just one MI case in a retrospective study of 293 transgender men (over a period of 2,418 patient-years) given testosterone esters IM or oral testosterone undecanoate.
With regard to stroke, Irwig pointed to a meta-analysis of 859 transgender women on estrogen therapy, in which researchers found 8 cases of stroke across two studies; for transgender men, a meta-analysis of 340 individuals on testosterone showed no cases of stroke.
Also, a retrospective study of 324 transgender men and women who completed gender affirmation surgery reported an increased risk of cardiovascular disease-related death compared with matched controls from the general population (adjusted hazard ratio 2.5, 95% CI, 1.2-5.3).
Irwig told MedPage Today that in terms of cardiovascular risk, the estrogen patch appears to be safer than pills, based on literature of pre- and postmenopausal women.
"It's not metabolized by the liver when it goes through the skin," he explained, though he stressed that more studies on the "safest route" of estrogen for transgender women are still needed.
"Nobody's looked at sublingual estrogen. Nobody's looked at injectable estrogen in large numbers. Most of the studies have been done with oral estrogen," Irwig said.
Safer, who was not involved in the review, questioned the assertion that topical hormone preparation may be safer. "We still don't really have conclusive studies demonstrating that," he said, but noted that it is commonly expected and perhaps even likely.
It's also "widely believed" that the higher the dose of estrogen the greater the risk of cardiological events, he continued. However, the type of estrogen and the route of administration may also factor into such risks.
Also evaluated in the review were differences in surrogate markers, such as blood pressure (systolic and diastolic were both increased among transgender men), lipid concentration (LDL increased and HDL decreased in transgender men), hemoglobin and hematocrit levels (increased among transgender men), and triglycerides (increased among transgender men).
Testosterone therapy is known to decrease HDL cholesterol, decreases of which are often linked to heart disease, Irwig explained.
"A lot of studies show that testosterone for trans men can also increase their blood pressure a little bit," he added, but it's still unclear whether this slight bump has clinical implications, such as increasing the risk of heart attack or stroke.
Among transgender women, these markers were more inconsistent -- an observed decrease in hemoglobin and hematocrit levels and either no change or increases in both triglycerides and diastolic blood pressure.
One limitation of the review was the small sample size of many of the studies. "We don't have tens of thousands of patients," said Irwig. He pointed out that better studies on transgender individuals would require "getting a good duration of follow-up and having careful records about which hormones somebody has been on, and for how long."
Reviews in Endocrine and Metabolic Disorders
Source Reference: Irwig MS "Cardiovascular health in transgender people" Rev Endocr Metab Disord 2018; DOI: 10.1007/s11154-018-9454-3.
Read the original article on Medpage Today: Cardiovascular Risks Elevated in Transgender Women