Characterisation of testicular function and spermatogenesis in transgender women

Abstract

STUDY QUESTION Does gender-affirming treatment prevent full spermatogenesis in transgender women (TW)? SUMMARY ANSWER Adequate hormonal therapy (HT) leads to complete suppression of spermatogenesis in most TW, if serum testosterone levels within female reference ranges are obtained. WHAT IS KNOWN ALREADY Gender-affirming treatment in transgender individuals may involve gender-affirming HT. The effects on spermatogenesis in TW remain unclear. In order to add information from a referral centre for transgender care, we wish to compare results of earlier studies with our population of TW who received a standard hormone treatment. STUDY DESIGN, SIZE, DURATION This was a prospective cohort study part of the European Network for the Investigation of Gender Incongruence (ENIGI), conducted between 15 February 2010 and 30 September 2015. There were 162 TW were included in the ENIGI study at the Ghent University Hospital in Belgium. Participants are included in ENIGI when they first start HT, and follow-up visits occur over the next 3 years. PARTICIPANTS/MATERIALS, SETTING METHODS The study included 97 TW who initiated HT with cyproterone acetate (CPA) plus oestrogens and proceeded with gonadectomy at the Ghent University Hospital. Testicular tissue retrieved during gonadectomy was processed and stained for four different germ cell markers by the Biology of the Testis lab at the Vrije Universiteit Brussel. Subsequent immunohistochemical staining was performed for melanoma-associated antigen A4 (MAGE-A4, marker for spermatogonia and early spermatocytes), boule homologue, RNA-binding protein (BOLL, marker for secondary spermatocytes and round spermatids), cAMP-responsive element modulator (CREM, marker for round spermatids) and acrosin (marker for acrosome visualization). Serum levels of sex steroids were measured prior to surgery. MAIN RESULTS AND THE ROLE OF CHANCE Suppressed testosterone levels (<50 ng/dl) were found in 92% of the participants prior to surgery. The mean time between initiation of HT and surgery was 685 days. In 88% (85/97) of the sections, MAGE-A4 staining was positive. Further staining could not reveal complete spermatogenesis in any participant. LIMITATIONS, REASONS FOR CAUTION Testicular function of the participants prior to initiation of HT was not assessed, although all participants presented with cisgender male serum testosterone values before initiation of HT. The current study only reports on people using CPA at a fixed dose and may therefore not be applicable to all TW. WIDER IMPLICATIONS OF THE FINDINGS HT leads to complete suppression of spermatogenesis in most TW, if serum testosterone levels within female reference ranges are obtained. Serum testosterone levels are associated with the sperm maturation rate. It is important to discuss sperm preservation before the start of hormone therapy. If serum testosterone levels remain higher, spermatogenesis may still occur. STUDY FUNDING/COMPETING INTEREST(S) D.V.S. is a post-doctoral fellow of the Fonds Wetenschappelijk Onderzoek (FWO; 12M2819N). Processing of the testis specimens was funded by the Biology of The Testes (BITE) research group (Department of Reproduction, Genetics and Regenerative medicine at Vrije Universiteit Brussel (VUB)). There are no competing interests. TRIAL REGISTRATION NUMBER N/A.

Histological study on the influence of puberty suppression and hormonal treatment on developing germ cells in transgender women

“…This finding was confirmed by Jiang et al (2019) who even observed complete spermatogenesis in 40% of the 72 included transgender women. However, several other recent studies found lower percentages of complete spermatogenesis ranging from 0% to 11% of the study cohort ( Jindarak et al , 2018 ; Kent et al , 2018 ; Matoso et al , 2018 ; Vereecke et al , 2021 ). It must be noted that hormonal and preoperative treatment protocols vary considerably within, and between, the different studies conducted on this topic.…”

“…Since a study performed by Vereecke et al (2021) also adhered strict in- and exclusion criteria that are similar to those in our adult subgroup, their results allow for the most accurate comparison. In addition, their method of analysis using immunohistochemistry to determine the most advanced germ cell type is similar to our study.…”

“…However, none of their orchiectomy specimens showed complete spermatogenesis, as opposed to 4% of orchiectomy specimens in the adult subgroup of our cohort. Vereecke et al (2021) also assessed the relationship between serum hormone levels and spermatogenic state in their cohort. They found that higher serum testosterone levels were associated with more advanced maturation, and higher serum estradiol levels were associated with a lower number of spermatogonia.…”

“…They found that higher serum testosterone levels were associated with more advanced maturation, and higher serum estradiol levels were associated with a lower number of spermatogonia. However, the hormone levels were not measured on the day of gGAS, but at the last visit in the outpatient clinic 91.0 (57.5–152.5) days before surgery ( Vereecke et al , 2021 ). In contrast, Schneider et al (2015) did collect serum and intratesticular testosterone levels on the day of gGAS but did not find an obvious correlation with spermatogenic state.…”

MANAGEMENT OF ENDOCRINE DISEASE: Optimal feminizing hormone treatment in transgender people

“…Importantly, antiandrogen treatment will result in testicular atrophy and azoospermia within few months. After a longer treatment duration (2-3 years), the decrease in fertility is considered, at least partially, irreversible, therefore, sperm cryopreservation should be carefully discussed before the prescription of anti-androgen treatment (21,22). In the case of orchiectomy, anti-androgen treatment can be stopped and spare the patient from the side effects of antiandrogen treatment.…”