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

Safety

Bone

Equivocal results on bone mineral density (BMD) and osteoporosis risks have been reported in transwomen treated with CHT (Table 2). It is generally accepted that oestrogens have a protective effect on bone health and indeed studies have shown that they play a significant role in maintaining bone health. Areal BMD is well preserved in transwomen receiving CHT over a period of two or more years, regardless of the type of oestrogens used.[40,41] However, some studies have actually shown a decrease in BMD in transwomen, arguing that they may be more prone to osteopenia and osteoporosis than transmen, due to androgen deprivation induced by anti-androgen administration which can also impair muscle mass.[42] Longer term studies have shown that after 8 years of anti-androgen plus oestrogen therapy, transwomen have a reduced areal BMD and a lower volumetric BMD with a smaller bone size, similar to that of natal women.[43,44]

After SRS, continuation of oestrogens is recommended at the lowest effective dose to maintain bone density and to minimize cardiovascular and thrombotic risks. Although transwomen have a greater risk of osteoporosis than men, they maintain a lower risk than women due to a pretreatment increased bone density, a larger volume of bones and the fact that they do not face the loss of bone density typical of menopause. Taking into account these considerations, it can be questioned whether bone densitometric data should be plotted on female or male nomograms. There are no data about long-term fracture risk in transwomen, but in our opinion, the use of male nomograms may increase the probability of overtreatment, while use of female nomograms may carry risks for transwomen noncompliant to the therapy. Evaluation of basal BMD and of its evolution in time is recommended.

Physical exercise and vitamin D supplementation is also recommended as helpful, particularly in transwomen who do not have adequate exposure to sunlight. Van Caenegem et al.[45] reported a high prevalence (72%) of vitamin D deficiency in transwomen attributed to a different lifestyle with less social or outdoor activities.

Sexual Function

There are few studies in the literature about sexual function in transwomen during CHT and before SRS. Sexual function is obviously strongly influenced by the quality of surgery. Transpeople appear to have adequate sexual functioning or high rates of sexual satisfaction following SRS, and most reports indicate moderate to high rates of orgasmic function in transwomen.[46] In several studies, it has been reported that over half of transwomen have a high satisfaction with sexual function in terms of existence, frequency and quality.[16] On the other hand, Weyers et al.[47] reported suboptimal sexual function as assessed through the Female Sexual Function Index (FSFI) when compared with women, specifying impairment in the areas of arousal, lubrication and pain. Profound androgen depletion and the effect of oestrogens on sex hormone-binding globulin (SHBG) production might lead to hypo-active sexual desire disorder due to low levels of free testosterone.[48]

Cardiovascular Safety

In Asscheman et al.[12] current but not previous ethinyl oestradiol use is associated with an independent threefold increased risk of cardiovascular death. Cardiovascular mortality in transwomen treated with anti-androgens and oestrogens is higher than in transmen treated with testosterone.[12] Another report shows a higher prevalence of myocardial infarction in transwomen than in control women, whereas the proportion is similar when compared to control men.[49] In a previous report, cardiovascular problems are observed in six per cent of transwomen after an average 11·3 years of hormonal treatment.[50]

Venous Thromboembolism

Venous thromboembolism (VTE) is the most serious complication in transwomen treated with oestrogens. Dose, route of administration and type of oestrogen have been suggested to affect VTE risk and the contribution of the progestin to this risk should not be overlooked. Significantly, higher incidence of thrombotic events in transwomen treated with ethinyl oestradiol or CEE[29] when compared to other oestrogens such as oestradiol valerate or oestradiol have been reported.[18,50–52] Other studies comparing ethinyl oestradiol to transdermal oestradiol suggest that the transdermal route may be safer than the oral route. The influence of the dose has never been systematically investigated in these subjects; however, in other populations, the risk of VTE seems to be lower when using lower oral oestrogen doses as compared to higher ones.[53] VTE usually occurs during the first year of therapy.[18] The risk of VTE increases with age, and this should be kept in mind in the selection of treatment for elderly transwomen. Discontinuation of oestrogen therapy in cases of prolonged immobilization or before elective surgery is recommended, but in recent years, the use of transdermal oestradiol has lead to a reduction of this complication.[51]

Mortality

Asscheman et al.[12] reported an increased total mortality (51% higher than the general population) due to suicide, acquired immunodeficiency syndrome, cardiovascular disease, drug abuse and other unknown causes in transwomen. Transwomen aged between 25 and 39 have been reported to have an increased risk of suicide.[12,54] For these reasons, careful attention should be paid to the emotional health of these subjects. Wierckx et al.[50] evaluated 50 transwomen on CHT for an average time of 10 years and did not report any cases of death; however, twelve per cent of transwomen had thromboembolic and/or other cardiovascular events during CHT.

Oncological Safety

In Asscheman et al.[12] no increase was observed in total cancer mortality; however, lung and haematological cancer mortality rates were elevated. The increase in mortality rate due to lung cancer may be related to heavier smoking in transpeople, while it is difficult to explain the increased mortality rate due to the variety of haematological cancers. This may be a chance finding or due to the association of non-Hodgkin lymphomas with HIV.[12]

Breast Cancer. One of the concerns of oestrogen therapy is the risk of breast oestrogen sensitive carcinomas.[28] Nine transwomen with breast cancer have been reported in literature.[55] Gooren et al. estimated a rate of breast cancer in transwomen receiving hormonal treatment of 5·9 per 100 000 persons/years, lower than expected for female breast cancer but similar to that expected for male breast cancer.[55,56]

Prostate Cancer. The prostate is not removed during SRS; therefore, risks of benign prostatic hyperplasia and prostate cancer do exist. Prostate cancer is rare, especially in those starting androgen deprivation therapies before the age of 40.[57] Oestrogen therapy is not reported to induce hypertrophy or premalignant changes in the prostate.[58] Benign prostate hypertrophy cases have been reported in transwomen treated for 20–25 years.[59] In a recent report, 51 173 person/years of exposure were evaluated showing an overall incidence of prostate cancer of 0·04% and 0·13% in subjects who had initiated hormonal treatment after the age of 40.[60] Prostate cancer seems to be aggressive in this androgen-deprived population because of hormone receptor negative clone selection; misdiagnosis is a risk because of prostate-specific antigen (PSA) suppression due to androgen deprivation. A few cases of prostate carcinomas (three) have been reported in transwomen who commenced cross-sex therapy after the age of 50, but it is uncertain whether the condition was present before the initiation of hormone treatment.[61–63]

Prolactinoma. Pituitary lactotroph cells have oestrogen receptors, and for this reason, 20% of transwomen using oestrogen may have increased prolactin (PRL) levels.[17] Two transwomen receiving normal doses of oestrogens have been diagnosed with prolactinoma after a long period of treatment with oestrogens.[64] Five cases of prolactinomas have been reported in the literature in transwomen who self-medicated with supraphysiological doses of oestrogens.[51,65] It should be kept in mind that the anti-androgen cyproterone acetate may increase PRL levels.

Meningioma. Two cases of meningioma have been reported after up to 5 years of hormonal treatment with oestrogens and cyproterone acetate[66,67] and one case in a transwoman treated with oestradiol for more than 10 years.[68]

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