Iris de Nie

128 C H A P T E R 8 Our study is not only relevant for health management of trans women. It also provides a unique insight into the relationship between serum testosterone levels and the occurrence of prostate cancer. A paradox in the current knowledge is that on the one hand, androgen deprivation slows the progression of metastasized or advanced prostate cancer, while on the other hand, higher endogenous serum testosterone or elevating testosterone concentrations in hypogonadal men do not increase prostate cancer risk. 24,25 A proposed theory suggests that the relationship between androgens and prostate cancer follows a saturation curve, as applies to the relation between PSA and testosterone levels. 144 This model states that if all androgen receptors are bound, a further increase of serum androgen concentrations produces no additional biological effects. Below this point of saturation, androgen concentration serves as the rate-limiting step in prostate tissue proliferation. 144 Hereby, the saturation model accounts for the slowed progression of prostate cancer by suppression of androgens below castration levels. As total testosterone concentrations in trans women receiving hormone treatment are generally below 1.7 nmol/L during hormone treatment, the observed low incidence implies that the saturation model might also apply to the initiation and development of prostate cancer. 2 We also have to take the role of estrogen treatment into account which is used by these individuals. One might argue that the incidence of prostate cancer is not only influenced by androgen deprivation but also by the use of estrogens. Estrogens contribute to androgen deprivation through suppression of the hypothalamic-pituitary-gonadal axis and were initially used in prostate cancer treatment before the implementation of luteinizing hormone-releasing hormone agonists. 24 However, some theories also suggest a possible stimulating role of estrogens in the pathogenesis of prostate cancer. 145,146 Estrogen receptors are expressed in the human prostate. With respect to cell-autonomous actions of estrogens in prostate tissue, both pro- and anti-proliferative effects have been reported in the literature. 147 The estrogen receptor alpha has been shown to stimulate prostate cancer growth in preclinical models. Conversely, loss of expression of the estrogen receptor beta has been reported in prostate cancer tissues, implying a role as a tumor suppressor. 146 The exact role of estrogens in the pathogenesis of prostate cancer and its effect on the occurrence of the disease remains unclear and might be an interesting topic for future research. In our cohort, six trans women developed prostate cancer while receiving hormone treatment. It may have been possible that these six individuals harbored small foci of subclinical prostate cancer prior to the start of hormone treatment. Autopsy studies in healthy subjects who died of trauma, have shown microscopic foci of prostate cancer and high-grade prostatic intraepithelial neoplasia from the third decade of life onwards. 148-150 The lesions become more frequent and extensive as age increases. This complements our observation that trans women with prostate cancer had a median age of 47 years at start of hormone treatment. Trans women in previously reported cases of prostate cancer also started hormone treatment at older age. 151 Possibly, androgen deprivation slowed further progression of these carcinogenic foci for many years. The mechanisms of how these foci eventually might have evolved into prostate cancer, despite androgen deprivation, are perhaps similar to proposed mechanisms of the transition from hormone-sensitive to