As is currently understood, the use of puberty blockers prior to maturation of the reproductive organs, followed by continuation onto cross-sex hormones without a period of exposure to the natal sex hormone levels they would otherwise experience, prevents the production of viable sperm or oocytes (eggs) and appears to foreclose the possibility of fertility. This issue has been recognized in the literature, including the 7th edition of the WPATH Standards of Care (Coleman et al., 2012):
A special group of individuals are prepubertal or pubertal adolescents who will never develop reproductive function in their natal sex due to blockers or cross gender hormones. At this time there is no technique for preserving function from the gonads of these individuals.
The Endocrine Society’s transgender clinical guidelines acknowledge that use of puberty blockers at an early pubertal stage prevents maturation of gametes, with the only option suggested being the temporary discontinuation of puberty blockers, resulting in the resumption of the undesired natal puberty that blockers were intended to prevent (Hembree et al., 2017):
Treating early pubertal youth with GnRH analogs will temporarily impair spermatogenesis and oocyte maturation. Given that an increasing number of transgender youth want to preserve fertility potential, delaying or temporarily discontinuing GnRH analogs to promote gamete maturation is an option.
By this accounting, trans youth who started puberty blockers at an early stage must choose between either continued effective GnRH treatment to prevent the unwanted masculinization or feminization of their bodies, or preserving their fertility – one, or the other, but not both.
However, a recent report finds that this may not always be the case for trans adolescents who were assigned female. With a treatment protocol adjusting the timing of GnRH treatment and its discontinuation, use of medication for ovarian stimulation, and introduction of testosterone, a trans boy who had been on blockers from the onset of puberty was able to have eggs retrieved while minimizing his exposure to unwanted feminizing hormones (Martin, Lewis, & Omurtag, 2021).
The patient, a 15-year-old boy, had been taking GnRH agonists since age 10 and had remained at Tanner stage 2 of puberty, the earliest stage at which natal puberty begins to occur and puberty blockers can be given. After a final monthly injection of the puberty blocker Lupron in May of 2020, he began the ovarian stimulation protocol in June. Notably, his care team chose to add letrozole during this treatment, an antiestrogen that works to minimize undesired estrogenic effects and has been used for safe and effective fertility preservation in women who had estrogen-responsive breast cancer. This medication was included for the purpose of reducing his exposure to endogenously-produced estrogen, and has previously been used as part of ovarian stimulation protocols in adult trans men to reduce their estrogen exposure as well (Ainsworth, Allyse, & Khan, 2020; Armuand et al., 2017)
His highest recorded estradiol levels were 510.4 pg/mL on the 13th day of the ovarian stimulation protocol, and he experienced a minimal growth of breast tissue during this time as well as a first menstrual period after the ovarian stimulation process had been completed:
Our patient found the minimal degree of breast progression and menstruation distressing; however, he did not report gender dysphoria or suicidal ideation during the stimulation.
The oocyte retrieval procedure took place on the 16th day of treatment, and he began taking testosterone three days later, with his estradiol levels falling to 97.8 pg/mL. Out of 36 oocytes that were retrieved, 22 were found to be mature enough to be cryopreserved, comparable to the number of viable oocytes that were retrieved in other cases of ovarian stimulation in adult trans men who had previously taken testosterone. Menses was halted with Depo-Provera injection, and his remaining breast tissue receded:
Menstrual bleeding has stopped. After being on testosterone for 3 months, his breast tissue was atrophic.
The authors also cite a previous case report where a 16-year-old trans boy who had been on puberty blockers since Tanner stage 2 underwent ovarian stimulation for fertility preservation while his puberty-blocking implant was left in place (Rothenberg, Witchel, & Menke, 2019). In this case, the patient also experienced menstrual bleeding and some breast growth during the process, which afterward “regressed within 3 months”. Only 4 viable oocytes were retrieved from this patient, and the team involved in the more recent case worked with this previous team to modify and optimize the ovarian stimulation protocol:
During the stimulation, a ‘‘low slow’’ approach was used in providing rFSH and HMG. Although the stimulation was successful, only four mature oocytes were obtained. After speaking with that team about their experience, we decided to start with a higher dose of rFSH and HMG. We obtained 22 mature oocytes. This robust response may have been because we removed the histrelin implant and started at a higher dose of rFSH and HMG.
These two reports offer evidence and confirmation that in adolescent trans boys who began puberty blockers at the earliest stage, Tanner 2, preservation of mature oocytes can be successfully performed while minimizing the time required to interrupt transition treatment and any unwanted feminization. In the case of this patient population, a new option has been developed that does allow for the possibility of viable reproductive function. ■