There has been a sharp increase in the visibility and acceptance of transgender and gender diverse (TGD) individuals in Australia and, with that, an increased attendance at health services for assistance, particularly among TGD children (prepubertal) and adolescents. Of Australian adolescents, 1.2 per cent identify as transgender and this prevalence is likely to increase.¹

Subsequently, services have been established throughout health networks that require the development of guidelines to direct provision of these services for TGD individuals.² Gender-affirming treatment is a multidisciplinary practice. After evaluation, education and diagnosis, treatment may include mental healthcare, hormone therapy and/or surgical therapy.

TGD children and adolescents will often commence social transitioning long before they seek gender-affirming hormone treatment or surgery. Australian and international guidelines^{3 4} make the strong recommendation that counselling on the potential loss of fertility as a result of suppression of puberty with GnRH agonist therapy (stage 1 treatment) and gender-affirming hormone therapy (stage 2) is an essential criterion for accessing treatment. The loss of fertility due to surgical transition (stage 3) must also be addressed. It is now the standard of care to offer all TGD children, adolescents and their families the opportunity to discuss the impact of treatment on future fertility and the options for preserving fertility.

Impact of treatment on fertility

The first stage of treatment is puberty suppression and is indicated when adolescents with gender dysphoria experience significant distress with the onset or progression of pubertal development. This is generally done using GnRH agonists. These agonists work by downregulating the GnRH receptor on the pituitary gland and reducing the release of gonadotrophins, therefore impairing spermatogenesis and oocyte maturation. This is considered reversible in both instances, although testicular activity takes longer to recover than ovarian function.

Spermatogenesis can be accomplished by spontaneous gonadotrophin recovery after cessation of GnRH agonists, or by gonadotrophin treatment, and will probably be associated with physical manifestations of testosterone. There are no data published concerning the time required for sufficient spermatogenesis to collect enough sperm for later fertility.⁵ The only comparative population are those being treated for precocious puberty where spermarche is noted 0.7–3 years after cessation of GnRH agonists.⁶ In men with gonadotrophin deficiency (Kallmann syndrome), sperm are noted in seminal fluid after 6–12 months of gonadotrophin treatment, however, it is likely they will not achieve the recognised normative range.⁷ Commencement of GnRH agonist treatment in children may affect testicular volume, spermatogonial proliferation, Sertoli cell numbers and the number and morphology of Leydig cells, possibly hindering the potential of that tissue to develop optimal quality or quantity of sperm at a later date.⁸

Equally, there are no published studies on ovarian activation following cessation of GnRH agonists in TGD individuals. Girls treated for precocious puberty with GnRH agonists have been observed long term, but none of these studies reported on the long-term adverse effects of pubertal suppression on ovarian function after treatment cessation, nor response to ovulation induction following prolonged suppression.^{9 10}

Adolescents will eventually move to gender-affirming hormones, or ‘cross-sex hormones’, oestrogen or testosterone, that they will continue taking for the rest of their lives. This will induce the onset of secondary sexual characteristics of the desired gender. There is no good evidence to provide objective recommendations as to when these hormones should be introduced¹¹ and this tends to be individualised. Gender-affirming hormones are considered to be only partially reversible.

For transgender females (male to female), many different regimes have been established. Often, an anti-androgen, cyproterone acetate, is used followed by oestrogen therapy.6 Studies are not in agreement about the effect of these hormones on testicular structure and function, with some studies suggesting complete involution of spermatogenesis and Leydig cell appearance. Other studies demonstrate unchanged Leydig cell abundance and qualitatively complete spermatogenesis, but functionally inactive tissues. Restoration of spermatogenesis after cessation of prolonged oestrogen treatment has not been studied, however, it is suggested that the endocrine process can be reverted to a male pattern in just a few weeks, whereas the spermatogenic involution will persist for a much longer time.

For transgender males (female to male), the effect of prolonged treatment with exogenous testosterone on ovarian function is uncertain. The time frame for resumption of ovulation and menses after cessation of testosterone is unclear and some studies have reported irreversible amenorrhea.¹² There are reports of an increased incidence of polycystic ovaries, though this is not confirmed by all studies.¹³ Pregnancies using autologous (patient’s own) oocytes have also been reported in transgender males following cessation of androgen treatment.¹⁴ While studies do suggest minimal obstetric impact, there are no studies examining the transgenerational effects of previous testosterone usage in the offspring.

Fertility preservation in the transgender male

Fertility preservation in the adolescent transgender male can be achieved with oocyte cryopreservation (egg freezing). This is a proven technique routinely used in other populations such as oncofertility. It is achieved by controlled ovarian hyperstimulation of the transgender male with recombinant gonadotrophins and surgical collection of oocytes. The oocytes can then be fertilised at a later date via donor sperm or a partner who can provide sperm. The transgender male can carry the pregnancy themselves or use a surrogate. Research has conclusively proven that cryopreserved oocytes perform as well as those in a ‘fresh’ collection and can be stored for many years without deterioration.

For prepubertal transgender males, ovarian tissue preservation is the only option. This is where part of the ovarian tissue is removed surgically and, using similar techniques as for oocyte cryopreservation, the tissue is frozen. Despite its global usage, this technique is considered experimental,¹⁵ with births from ovarian tissue preservation limited to specialised centres, and very few births reported from prepubertal cryopreserved tissue.

Fertility preservation in the transgender female

For adolescent transgender females, fertility preservation can be achieved through retrieving and cryopreserving sperm. Retrieval of sperm can be achieved through masturbation, vibratory stimulation or surgically (testicular biopsy) in those unable to achieve erection and ejaculation. Sperm can later be used in assisted reproduction technology (ART) with a donor egg and a woman who acts as a surrogate, or via ART with a partner who is able to produce oocytes and carry a pregnancy.

For prepubertal transgender females, testicular tissue preservation has been suggested as an option, however, this is highly experimental and has not been proven safe or efficacious outside of an animal model. Some centres in Australia currently offer testicular tissue preservation under the banner of ‘novel technologies’, citing that these tissues are unlikely to be required for 10–20 years and that research and technology will be significantly advanced in that time, potentiating safe use of these tissues for future fertility.

There are limited studies examining transgender people’s desire to become parents, particularly with their own genetic eggs or sperm. It is suggested that about half of transgender people without children would like to have them in the future. Reports suggest the process of fertility preservation is perceived traumatic to TGD individuals, with ‘sperm’ and ‘eggs’ seen as engendering and that loss of fertility is rarely seen as a reason to delay transitioning. It is also interesting to note that, although there is low uptake of fertility preservation among TGD children and adolescents, the perception is one of improved awareness and competence in informed decision-making. Significantly more research is required into optimal timing of counselling, fertility desires and potential regret, as well as the barriers (physical, social and psychological) to successful fertility preservation for TGD individuals.

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2. Telfer MM, Tollit MA, Pace CC, Pang KC. Australian standards of care and treatment guidelines for transgender and gender diverse children and adolescents. Med J Aust. 2018;209(3):132-6.
3. Telfer MM, Tollit MA, Pace CC, Pang KC. Australian standards of care and treatment guidelines for transgender and gender diverse children and adolescents. Med J Aust. 2018;209(3):132-6.
4. Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine treatment of gender-dysphoric/gender-incongruent persons: An endocrine society clinical practice guideline. Endocr Pract. 2017;23(12):1437.
5. Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine treatment of gender-dysphoric/gender-incongruent persons: An endocrine society clinical practice guideline. Endocr Pract. 2017;23(12):1437.
6. Bertelloni S, Baroncelli GI, Ferdeghini M, et al. Final height, gonadal function and bone mineral density of adolescent males with central precocious puberty after therapy with gonadotropin-releasing hormone analogues. Eur J Pediatr. 2000;159(5):369-74.
7. Buchter D, Behre HM, Kliesch S, Nieschlag E. Pulsatile GnRH or human chorionic gonadotropin/human menopausal gonadotropin as effective treatment for men with hypogonadotropic hypogonadism: a review of 42 cases. Eur J Endocrinol. 1998;139(3):298-303.
8. Schneider F, Kliesch S, Schlatt S, Neuhaus N. Andrology of male-to-female transsexuals: influence of cross-sex hormone therapy on testicular function. Andrology 2017;5(5):873-80.
9. Pasquino AM, Pucarelli I, Accardo F, et al. Long-term observation of 87 girls with idiopathic central precocious puberty treated with gonadotropin-releasing hormone analogs: impact on adult height, body mass index, bone mineral content, and reproductive function. J Clin Endocrinol Metab. 2008;
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10. Magiakou MA, Manousaki D, Papadaki M, et al. The efficacy and safety of gonadotropin-releasing hormone analog treatment in childhood and adolescence: a single center, long-term follow-up study. J Clin Endocrinol Metab. 2010;95(1):109-17.
11. Telfer MM, Tollit MA, Pace CC, Pang KC. Australian standards of care and treatment guidelines for transgender and gender diverse children and adolescents. Med J Aust. 2018;209(3):132-6.
12. Light AD, Obedin-Maliver J, Sevelius JM, Kerns JL. Transgender men who experienced pregnancy after female-to-male gender transitioning. Obstet Gynecol. 2014;124(6):1120-7.
13. Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine treatment of gender-dysphoric/gender-incongruent persons: An endocrine society clinical practice guideline. Endocr Pract. 2017;23(12):1437.
14. Light AD, Obedin-Maliver J, Sevelius JM, Kerns JL. Transgender men who experienced pregnancy after female-to-male gender transitioning. Obstet Gynecol. 2014;124(6):1120-7.
15. Martinez F. Update on fertility preservation from the Barcelona International Society for Fertility Preservation-ESHRE-ASRM 2015 expert meeting: indications, results and future perspectives. Hum Reprod. 2017;32(9):1802-11.