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111 INCIDENCE OF TESTICULAR CANCER IN TRANS WOMEN USING GENDER-AFFIRMING HORMONAL TREATMENT 7 INTRODUCTION Testicular cancer mainly occurs in young people; the incidence in the Netherlands is 9.5 per 100.000 men, with a peak incidence of 32.4 per 100.000 men in those between 30-34 years old. 15 Testicular cancers can roughly be divided into sex cord or gonadal stromal tumors and germ-cell tumors, of which the latter most commonly occur. Germ-cell tumors are further classified as seminoma, non-seminoma and mixed germ-cell tumors. Prognosis, depending on histology, location of the primary tumor and metastases, and serum tumor marker levels, is generally better for seminoma compared to non-seminoma. 16 Although the incidence has increased over the past 40 years in most countries, the etiology of testicular cancer and the reasons for this rise remain unclear. Established risk factors for testicular cancer are a history of cryptorchidism, a low sperm count, presence of a contralateral testis tumor or a positive family history among first-grade relatives for testicular cancer. 16 Some theories also suggest that a relative excess of exogenous estrogens during pre- or post-natal life (e.g. diethylstilbestrol, pesticides) may play a causal role in the development of testicular cancer. 17-19 It is hypothesized that, following endocrine disruption, some of the primordial germ cells lose track of their normal development and become premalignant cells that may develop into carcinoma in-situ cells, which in their turn may develop into a complete cancer. 18 An increasing group of birth-assigned males with long-term exposure to exogenous estrogens are people with gender dysphoria. Gender dysphoria refers to the distress that results from a conflict between a person’s assigned sex at birth and one’s gender identity. 70 People assigned male at birth who also identify as male are referred to as cis men, whereas birth-assigned males who identify as female are referred to as trans women. Birth-assigned males who neither identify as male nor female fall under the umbrella term gender queer, non-binary or alternative gender. Birth-assigned males with gender dysphoria desiring to align their physical characteristics with their gender identity can choose to undergo medical treatment, consisting of gender-affirming hormonal treatment (GAHT) and gender-affirming surgery (GAS). The hormonal treatment protocol usually consists of antiandrogens, to suppress serum testosterone concentrations, combined with estrogens, to achieve feminization. For people presenting during adolescence (below the age of 18 years) treatment can be initiated when a person reaches puberty (Tanner stage 2 or higher), and aims to suppress pubertal development by administration of gonadotropin-releasing hormone agonist (GnRHa). After at least six months of puberty suppression and having reached the age of 16 years, treatment can be supplemented with estrogens. GAS can involve facial feminization, breast-augmentation, and bilateral orchiectomy often combined with vaginoplasty. 2 For the sake of clarity, we will refer to birth-assigned males seeking feminizing medical treatment as trans women. Until 2014, a sterilization lawwas in place in the Netherlands,meaning that a gonadectomy was required for legal gender recognition. Therefore, almost all trans women visiting our gender identity clinic underwent this procedure until 2014. However, since this law has changed, an increasing number of people with non-binary identities or less need to confirm to binary cis presentation choose to keep their male gonads. As a consequence, in the future we might be faced with a growing population of young trans women using

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