Endocrine Care of Transpeople Part II

A Review of Cross-sex Hormonal Treatments, Outcomes and Adverse Effects in Transwomen

Maria Cristina Meriggiola; Giulia Gava

Disclosures

Clin Endocrinol. 2015;83(5):607-615. 

In This Article

Most Commonly Used Formulations and Doses

Oestrogens

In addition to suppressing endogenous androgen secretion, exogenous oestrogens must be given to induce female secondary sexual characteristics (Table 1). There is a wide range of oestrogens available. Oral ethinyl oestradiol has been shown to carry a higher risk of venous thromboembolism in transwomen.[11,12] Ethinyl oestradiol and conjugated equine oestrogens (CEE) cannot be monitored through blood measurements, and levels are highly variable both between subjects and within the same subject at different times, making optimization of dosages difficult.[13,14] For these reasons, these formulations should be avoided.[9,15,16]

Oestrogens can be administered using various routes (intramuscular, transdermal and oral). Intramuscular oestradiol valerate can be administered at the dose of 2–10 mg i.m. every week.[9] This formulation is not routinely recommended because it can take a long time to reach a steady state and because of the high potential for abuse or overdose.[17] Transdermal oestrogens are available as patches or gel. Patches are sometimes rejected by transwomen due to possible skin reactions or adhesion problems, making gel preparations a better option. The administration of oestradiol via the transdermal route guarantees a slow and prolonged release of the hormone, together with more constant distribution and systemic blood levels than those obtained with oral doses. Unlike oral administration, transdermal oestradiol is not immediately subjected to hepatic metabolism and reaches the liver via the portal circulation in small quantities. This leads to a more favourable lipidic, inflammatory and coagulative profile.[12,18] The transdermal route of administration may be more favourable for transwomen at risk of thrombosis, especially in those over 40 years of age, smokers, and those with liver disease or diabetes mellitus.[9,19] Preliminary observations suggest that there is no significant difference across oestrogen formulations in breast development, body fat distribution and bone metabolism.[20] Oral oestrogens should be avoided also in patients with familial hypertriglyceridaemia. Recommended doses and formulations are reported in Table 1.

Cyproterone Acetate

Cyproterone acetate (CPA) is the most widely used anti-androgen outside the USA, where it is not available. It has both progestogenic and anti-androgenic activities working on suppression of gonadotrophins and thereby testicular androgen secretion and in competition with androgens for binding to the androgen receptor. The recommended dose of CPA for transwomen is 50–100 mg/day,[9] but even lower doses may effectively induce a profound suppression of gonadotrophins due to its accumulation in the subcutaneous tissue. CPA is reported to have a weak glucocorticoid activity that may lead to weight gain. Cases of hepatotoxicity[21] and dose-dependent sedative effects[20] have been reported. CPA has been associated to higher risk of meningioma[22] and it has been associated with an increased incidence of depression, particularly in the early stages of therapy.

GnRH Agonists

GnRH agonists are used in long-acting monthly or three monthly injections to inhibit gonadotropin secretion and, as result, induce profound suppression of testicular testosterone production. GnRH analogues are increasingly prescribed although the cost of long-acting GnRH agonists often prohibits their use in this population.

In countries where the CPA is not available or in patients who cannot afford GnRH agonists, spironolactone or other anti-androgens (such as finasteride, dutasteride or flutamide) are otherwise available but are second choice options.

Spironolactone

This is an aldosterone antagonist which exerts its anti-androgenic activity through blocking the androgen receptor, suppressing androgen biosynthesis, increasing the metabolism of testosterone, inhibiting 5-alpha reductase activity and testicular steroidogenesis.[23,24] Spironolactone is also an oestrogen receptor agonist resulting, especially at the doses used in transpeople, in additional oestrogenic effects. Absorption after oral administration is widely variable due to its poor water solubility. It may cause hyperkalaemia, especially in persons with renal impairment. The use of spironolactone has been also associated with increased risk of upper gastrointestinal bleeding.[25] Spironolactone has been associated with a higher need for breast augmentation if compared to other anti-androgens or GnRH agonists,[20] and this can be due to a poorer breast outcome consequent to the excessive oestrogenic action.[20] The recommended dose of spironolactone is 100–200 mg/day.[9]

Other Anti-androgens

Other potential options are finasteride, dutasteride or flutamide, which are nonsteroidal anti-androgens. The routine use of finasteride is not recommended because it blocks only one of the two 5-alpha reductase isoenzymes and thus exerting only minor anti-androgenic activity. Finasteride is usually administered at 2·5–5 mg/day, while dutasteride is used at the dose of 0·5 mg/day, and evidence of their efficacy is limited in this population.[26] Flutamide is a potent competitive inhibitor of the binding of androgens to the androgen receptor; however, it does not lower serum testosterone levels which, in fact, increase during its administration. At higher doses, it may lead to severe liver toxicity.[9,27]

Progestins

Medroxyprogesterone acetate at a dose of 5–10 mg/day and dydrogesterone at a dose of 20 mg/day have also been used as strategies for suppressing gonadotrophins and thereby testosterone secretion. The role of progestins in inducing development of breast tissue is unclear, and their routine use cannot be recommended because of potential increased breast cancer risk.[28–30] Use of progestins is not suggested also in consideration of the increased cardiovascular risk when used in combination with oestrogens. Indeed, the Women's Health Initiative reported an increased risk of coronary heart disease, thromboembolic events and stroke in postmenopausal women treated with combined oestrogen and progestin.[30] These data have not been replicated in transwomen, but the increased risk cannot be excluded in transwomen. Other adverse effects have been reported in association with progestin use such as depression, weight gain and lipid changes.[26] In consideration of these risks and lack of data on effectiveness, progestins are not recommended.

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