Cardiovascular and thromboembolic risks of sex hormone therapy: from contraception to transgender care.
Bonnet Fabrice F, Vaduva Patricia P, Dosda Arnaud A
The risk of venous thromboembolism is increased with combined oral contraceptives, rises with the dose of ethinylestradiol, and is higher with desogestrel, gestodene, drospirenone or cyproterone acetate than with levonorgestrel; the determinant is not the generation of the pill but the residual androgen-receptor activity of the progestin, which modulates the hepatic effect of the estrogen. Age over 35 years, obesity, smoking and a family history of thrombosis amplify it. Pills based on a native estrogen have a more limited hepatic impact and rank below most ethinylestradiol combinations in contemporary cohorts, but their clinical safety is not demonstrated and no comparative outcome data exist for estetrol/drospirenone. Androgenicity is not a general marker of venous safety: injectable depot medroxyprogesterone acetate, given alone at supraphysiological doses, carries an increased risk. Myocardial infarction and stroke are also more frequent, but against a very low background - about 21 additional strokes and 10 additional infarctions per 100,000 person-years, four times fewer than the venous excess - and, unlike venous events, independent of progestin type. Menopause hormone therapy increases venous thromboembolic risk, especially in the first year; the route of administration is the main determinant, transdermal estradiol with micronized progesterone appearing safest. In cisgender men, testosterone deficiency carries increased cardiovascular risk, and randomized and real-world data support the safety of transdermal replacement, although more pulmonary embolism and atrial fibrillation have been observed. In trans women, observational data show an increased risk of stroke and venous thromboembolism, particularly with oral estradiol and cyproterone acetate, whereas recent large-scale data show no excess of major cardiovascular events with testosterone in trans men. The practical consequences are specific: no combined pill is acceptable after a venous thromboembolic event, with a thrombogenic mutation or with migraine with aura, native-estrogen pills included; transdermal estradiol should be preferred for menopause and feminising hormone therapy; and haematocrit should guide the dose and route of testosterone.