Nenhum espermatozoide maduro em mulheres trans que iniciaram bloqueadores cedo na puberdade; só 4,7% de 214 os tinham

Estudo histológico sobre a influência da supressão puberal e do tratamento hormonal nas células germinativas em desenvolvimento em mulheres transgênero

Estudos de coorte e registros Bloqueadores da puberdade Hormônios do sexo oposto

Authors: Iris de Nie, Callista L. Mulder, Andreas Meißner, Yvonne Schut, Elise M. Holleman, Wouter B. van der Sluis, Sabine E. Hannema, Martin den Heijer, et al.
Journal: Human Reproduction
Year: 2022
Source: https://doi.org/10.1093/humrep/deab240

Summary

Amsterdam researchers examined testicle tissue removed during genital surgery from 214 trans women. They wanted to see whether usable sperm, or cells that make sperm, were left after puberty blockers (drugs that pause puberty) and/or estrogen with testosterone-blocking drugs. Only 10 people (4.7%) had any mature sperm, and all had started treatment in late puberty or as adults. None of the 29 who started blockers in early puberty had mature sperm; their tissue held only immature cells. Most people (88%) had only immature cells, which cannot be used to have a child today and would depend on experimental lab methods for growing sperm. Stopping hormones for 4 weeks before surgery made no difference. The authors present this hopefully. Put plainly, it shows that people who start blockers in early puberty currently have no way to have biological children from this tissue.

Key findings

O tecido testicular removido durante a cirurgia de 214 mulheres trans operadas no hospital universitário de Amsterdã entre 2006 e 2018 foi examinado ao microscópio.
Espermatozoides maduros foram encontrados em apenas 10 pessoas (4,7%), todas as quais começaram o tratamento médico no fim da puberdade ou depois (10% das que começaram no fim da puberdade e 4% das que começaram adultas).
Nenhuma das 29 pessoas que começaram bloqueadores da puberdade no início da puberdade tinha espermatozoides maduros; todas tinham apenas células imaturas produtoras de esperma.
88% de todas as amostras de tecido continham apenas células imaturas, que só poderiam ser usadas se métodos experimentais de cultivo de esperma em laboratório se tornarem disponíveis.
7% não tinham nenhuma célula produtora de esperma (11% das que começaram adultas); todas iniciaram o tratamento na idade adulta, muitas com o medicamento bloqueador de testosterona acetato de ciproterona.
Parar os hormônios por 4 semanas antes da cirurgia e o tempo de tratamento não fizeram nenhuma diferença mensurável.
Os autores observam que a fertilização in vitro com esperma obtido cirurgicamente leva a um nascimento vivo em cerca de 22% das vezes por tentativa, e que congelar o sêmen antes do tratamento ainda é a melhor opção.

Abstract

STUDY QUESTION: Can transgender women cryopreserve germ cells obtained from their orchiectomy specimen for fertility preservation, after having used puberty suppression and/or hormonal treatment?

SUMMARY ANSWER: In the vast majority of transgender women, there were still immature germ cells present in the orchiectomy specimen, and in 4.7% of transgender women-who all initiated medical treatment in Tanner stage 4 or higher-mature spermatozoa were found, which would enable cryopreservation of spermatozoa or testicular tissue after having used puberty suppression and/or hormonal treatment.

WHAT IS KNOWN ALREADY: Gender affirming treatment (i.e. puberty suppression, hormonal treatment, and subsequent orchiectomy) impairs reproductive function in transgender women. Although semen cryopreservation is generally offered during the transition process, this option is not feasible for all transgender women (e.g. due to incomplete spermatogenesis when initiating treatment in early puberty, in case of inability to masturbate, or when temporary cessation of hormonal treatment is too disruptive). Harvesting mature spermatozoa, or testicular tissue harboring immature germ cells, from orchiectomy specimens obtained during genital gender-affirming surgery (gGAS) might give this group a chance of having biological children later in life. Previous studies on spermatogenesis in orchiectomy specimens showed conflicting results, ranging from complete absence of germ cells to full spermatogenesis, and did not involve transgender women who initiated medical treatment in early- or late puberty.

STUDY DESIGN, SIZE, DURATION: Histological and immunohistochemical analyses were performed on orchiectomy specimens from 214 transgender women who underwent gGAS between 2006 and 2018. Six subgroups were identified, depending on pubertal stage at initiation of medical treatment (Tanner stage 2-3, Tanner stage 4-5, adult), and whether hormonal treatment was continued or temporarily stopped prior to gGAS in each of these groups.

PARTICIPANTS/MATERIALS, SETTING, METHODS: All transgender women used a combination of estrogens and testosterone suppressing therapy. Orchiectomy specimen sections were stained with Mayer's hematoxylin and eosin and histologically analyzed to assess the Johnsen score and the ratio of most advanced germ cell types in at least 50 seminiferous tubular cross-sections. Subsequently, immunohistochemistry was used to validate these findings using spermatogonia, spermatocytes or spermatids markers (MAGE-A3/A4, γH2AX, Acrosin, respectively). Possibilities for fertility preservation were defined as: preservation of spermatozoa, preservation of spermatogonial stem cells or no possibilities (in case no germ cells were found). Outcomes were compared between subgroups and logistic regression analyses were used to assess the association between the duration of hormonal treatment and the possibilities for fertility preservation.

MAIN RESULTS AND THE ROLE OF CHANCE: Mature spermatozoa were encountered in 4.7% of orchiectomy specimens, all from transgender women who had initiated medical treatment in Tanner stage 4 or higher. In 88.3% of the study sample orchiectomy specimens only contained immature germ cells (round spermatids, spermatocytes or spermatogonia, as most advanced germ cell type). In 7.0%, a complete absence of germ cells was observed, all these samples were from transgender women who had initiated medical treatment in adulthood. Cessation of hormonal treatment prior to gGAS did not affect the presence of germ cells or their maturation stage, nor was there an effect of the duration of hormonal treatment prior to gGAS.

LIMITATIONS, REASONS FOR CAUTION: Since data on serum hormone levels on the day of gGAS were not available, we were unable to verify if the transgender women who were asked to temporarily stop hormonal treatment 4 weeks prior to surgery actually did so, and if people with full spermatogenesis were compliant to treatment.

WIDER IMPLICATIONS OF THE FINDINGS: There may still be options for fertility preservation in orchiectomy specimens obtained during gGAS since a small percentage of transgender women had full spermatogenesis, which could enable cryopreservation of mature spermatozoa via a testicular sperm extraction procedure. Furthermore, the vast majority still had immature germ cells, which could enable cryopreservation of testicular tissue harboring spermatogonial stem cells. If maturation techniques like in vitro spermatogenesis become available in the future, harvesting germ cells from orchiectomy specimens might be a promising option for those who are otherwise unable to have biological children.

STUDY FUNDING/COMPETING INTEREST: None.

TRIAL REGISTRATION NUMBER: N/A.

Conclusion

Counseling of transgender women about the effect of medical treatment on fertility and the currently available options for fertility preservation remains essential. The results show that there may still be options for fertility preservation using orchiectomy specimens obtained during genital gender-affirming surgery: in a small percentage who initiated treatment in Tanner stage 4 or higher, spermatozoa could have been harvested, and the vast majority (>85%) could still opt for cryopreservation of testicular tissue harbouring spermatogonial stem cells. Complete absence of germ cells was seen only in 7%, all of whom commenced treatment as adults. Possibilities seem irrespective of preoperative cessation and duration of hormonal treatment. Initiation of medical treatment in early puberty (Tanner 2–3) limits the ability to retrieve mature spermatozoa that can directly be used for assisted reproduction; if maturation techniques like in vitro spermatogenesis become available, harvesting germ cells from orchiectomy specimens might be a promising option.

Methodological limitations

Did not test actual fertility: The study shows which cells could be seen under a microscope, not whether they could lead to a pregnancy. Immature cells have no proven use for having children in humans.
Hopeful framing rests on future science: The claim that "the vast majority" still have fertility options depends on growing sperm in a lab, which the authors themselves call experimental and far from being used in clinics.
Hormone levels at surgery unknown: Blood hormone levels on the day of surgery were not measured, so nobody could check whether people really stopped hormones for 4 weeks, or kept taking them as reported, as the authors admit.
Some people left out: 49 of 263 eligible people (19%) were excluded because no tissue was kept or the slides had no usable testicle tissue, which could skew the results.
Small early-puberty group: Only 29 people started in early puberty, so results are rough for the group that matters most in the puberty blocker debate.
Groups differed in other ways: Teen and adult starters differed in age, smoking, drinking, estrogen dose and which testosterone blocker they took. So differences cannot be put down to puberty stage alone.
Many different estrogen treatments: People used various types of estrogen that changed over time, so the effect of each type could not be studied.
One clinic: Everyone was treated at one Dutch clinic under its own rules. Results may not apply to other treatments, such as spironolactone or estrogen alone, which were excluded.
Clinic studying its own patients: The authors work at the Amsterdam clinic that provides these treatments and openly present the finding as useful in debates about restricting teen access, which may explain the hopeful framing.

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Summary

Key findings

Abstract

Conclusion