Hormone therapy starts and the first practical question in the clinic arrives immediately: by which route? The answer is not just a matter of convenience. The route through which estradiol is given strongly conditions the risk of thrombosis. It is one of the conclusions pulled together by a review published in Annales d’Endocrinologie by F. Bonnet, P. Vaduva and A. Dosda, which surveys the cardiovascular and thromboembolic risk of sex hormone therapy from contraception through to the care of transgender people.
The progestin, not the “generation” of the pill
In contraception the classic finding is well known: combined oral contraceptives raise the risk of venous thromboembolism. The review insists on a nuance that is often lost: what decides is not the generation of the pill but the residual androgenic activity of the progestin, which modulates the hepatic effect of the oestrogen. That is why the risk is higher with desogestrel, gestodene, drospirenone or cyproterone acetate than with levonorgestrel, and why it rises with the dose of ethinylestradiol. Age over 35, obesity, smoking and a family history of thrombosis amplify the effect.
Pills based on a native oestrogen have a more limited hepatic impact and rank below most ethinylestradiol combinations in current cohorts. The authors warn, however, that their clinical safety is not demonstrated and that there are no comparative outcome data for estetrol or for drospirenone.
What the data show in trans people
In trans women, observational data describe an increased risk of stroke and venous thromboembolism, particularly with oral estradiol and cyproterone acetate. Hence a concrete recommendation: prefer transdermal estradiol in feminising hormone therapy. The review also recalls that androgenicity is not a general marker of venous safety: injectable depot medroxyprogesterone acetate, given alone at supraphysiological doses, is associated with more risk.
In trans men the picture is different. Recent large-scale data show no excess of major cardiovascular events with testosterone, and haematocrit should guide the dose and the route of administration of the androgen. In cisgender men, testosterone deficiency is associated with higher cardiovascular risk and randomised and real-world data support the safety of transdermal replacement, although more pulmonary embolisms and more atrial fibrillation have been observed.
Menopause: the route rules
In menopause hormone therapy the venous thromboembolic risk also increases, especially during the first year, and the route of administration is the main determinant. Transdermal estradiol with micronised progesterone appears as the safest option in that setting.
Practical consequences
- No combined contraceptive is acceptable after a venous thromboembolic event, with a thrombogenic mutation or with migraine with aura, including pills based on a native oestrogen.
- Transdermal estradiol should be preferred both in menopause and in feminising hormone therapy.
- Haematocrit should guide the dose and the route of testosterone.
It is worth being precise about what this paper is and is not: it is a review, not new data from a trial. Its value lies in ordering the available evidence and translating it into concrete decisions for the clinic. For people receiving gender-affirming hormone therapy, and for the teams that prescribe it, the central message is that the route of administration is not a minor detail: it can change the thrombotic risk profile of the whole treatment.
The article does not address the origin of gender identity or the cause of dysphoria. It does examine the treatment that many trans people receive to relieve it, and the cardiovascular precautions that current evidence supports.
Source: Cardiovascular and thromboembolic risks of sex hormone therapy: from contraception to transgender care. Bonnet F, Vaduva P, Dosda A. Annales d’Endocrinologie 2026;103115. DOI: 10.1016/j.ando.2026.103115.
Article published at dosier.es. Image generated with artificial intelligence (marta ai → marta.syf.es).
