Timing of Puberty Suppression and Surgical Options for Transgender Youth

Care was conducted according to the (locally adapted) World Professional Association for Transgender Health Standards of Care²  and Endocrine Society guidelines.³  In individuals applying for care, clinical diagnoses and treatment requests were explored in an interdisciplinary setting. Transgender individuals were assessed and supported by a mental health professional before and during somatic treatments. For transgender adolescents, parents were included in these sessions. Following the Endocrine Society guidelines, adolescents diagnosed with gender dysphoria and without substantial interfering psychosocial issues can receive gonadotropin-releasing hormone analogue treatments after the first physical changes of puberty have taken place (minimum Tanner 2) and CSH around the age of 16. At the age of 18, and when having no substantial interfering psychosocial issues, individuals can receive gender-affirming surgeries.

The study was a single-center cohort study using registry and patient record data collected in a retrospective design. Data were reported as part of standardized routine treatment evaluations; they were reported before PS by the pediatrician, before CSH treatment by the endocrinologist, and pre- and postoperatively by the plastic surgeon. Eligible transgender individuals were identified by using local registries. Data were collected standardly on case report forms. Under Dutch law, retrospective studies using clinical data are exempt from requiring ethical permission.

All adolescents who applied for gender-affirming medical interventions between 2006 and 2013 were identified by using local registries (n = 386; Fig 1), and outcome data were collected between application and follow-up in 2018. Individuals were included for analyses when (1) a gender dysphoria diagnosis was confirmed, (2) they were at least 18 at the point of data collection, (3) they were <18 when starting PS, (4) they initiated and continued PS treatment, and (5) they were not lost to follow-up. Of the identified individuals, 200 met the inclusion criteria and were included for analyses. A random sample of clinical controls was identified by using hospital records. These 100 controls were approximately the same age as the PS group at follow-up, received no PS treatment, but did receive CSH and applied for gender-affirming surgery in the same years as the PS cohort. Furthermore, the same inclusion criteria (except initiating and continuing PS treatment) applied to controls.

Participants were included in the cohort when applying for PS (between 2006 and 2013), and data were registered at fixed points during treatments. For the current study, data were collected at 3 time points; before receiving PS (for the PS group only), post-PS, and around surgical treatments. This outcome database was completed retrospectively at follow-up (after CSH and/or surgery) during a 6-month period in 2018. A full overview of the points of data collection and the data collected is displayed in Fig 2.

Data on demographic characteristics were collected through history taking and patient records (eg, gender, age, sexual activity screening question). Standardized information on the onset and type of PS and CSH treatment was collected. Standardized routine physical examinations were conducted by trained pediatric endocrinologists according to clinical guidelines. These included height and weight measurement and Tanner staging of breasts and genitals. Preoperative physical examination by trained specialists included the examination of breasts in transgender men and genitals in transgender women (penile length and testes descended) by using standardized classification and report forms.^9–11  Physical examination of the breasts was conducted according to conventional principles and included visual assessment of the breast cup and combined visual `and manual assessment of breast ptosis (level of breast sagging and nipple position relative to inframammary fold [IMF]) and elasticity (elastic ability of the skin). Lastly, surgical reports were reviewed for the surgical techniques applied by using predefined standardized case report forms.

The sample background characteristics were calculated as means, medians, and frequencies for the Tanner 2/3, Tanner 4/5, and clinical control groups. Physical (sex) characteristics before PS and CSH were presented as descriptive data for the Tanner 2/3 and Tanner 4/5 groups for each gender separately. Data on the sex characteristics before gender-affirming surgery and the surgical techniques performed were calculated as means, medians, and frequencies for the Tanner 2/3, Tanner 4/5, and clinical control groups. Subgroup differences were assessed through analysis of variance and Kruskal-Wallis testing. Effect sizes were calculated via Cohen’s d and likelihood ratios. Outcomes were corrected for multiple testing. All analyses were conducted in SPSS 22 (IBM SPSS Statistics, IBM Corporation).

The total sample included 184 (61.3%) transgender men and 116 (38.7%) transgender women, having an average age of 23 years (SD = 2.9) at follow-up. Clinical characteristics of the study sample are displayed in Table 1. Forty-three (14.3%) participants started with PS at Tanner 2/3 and 157 (52.3%) at Tanner 4/5, whereas the 100 controls (33.3%) received no PS. The Tanner 2/3 group included more transgender women, whereas the Tanner 4/5 group included more transgender men compared with the other groups. The Tanner 2/3 and 4/5 groups were, on average, younger at initial clinical assessment, onset of CSH treatments, and first gender-affirming surgery. When compared with transgender individuals without PS, a lower share reported to be sexually active at the start of CSH (but also being younger when asked).

The physical characteristics of transgender men and women before PS are displayed in Table 2. Transgender men who started PS at Tanner 4/5 showed more advanced breast development, were taller, and had a higher weight, BMI, and hip circumference compared with those who started at Tanner 2/3. Transgender women who started at Tanner 4/5 were also taller and heavier compared with those who started at Tanner 2/3.

At the visit just before initial (breast) surgery, no statistically significant differences were observed n height, weight, and BMI between the Tanner 2/3, 4/5, and no PS control groups (Table 3). Yet, breast development was significantly less in the Tanner 2/3 group compared with the Tanner 4/5 and control groups. Also, breast development was less in the Tanner 4/5 group compared with controls. No statistically significant group differences in breast elasticity, ptosis grade, and chest circumference were observed. As a result of differences in breast development, mastectomy surgery was frequently omitted in the Tanner 2/3 group (in contrast with the other groups; Table 3), and if performed, it was conducted via periareolar approaches with low resection weight. In general, a periareolar approach is used for small-size breasts without ptosis, whereas a more invasive approach via the IMF is used for larger-size breasts. The Tanner 4/5 group was an intermediate group with more frequent IMF mastectomy compared with the Tanner 2/3 group but less frequent than the controls. Phallic reconstructive surgeries were infrequently performed (yet) in all subgroups. No data on future treatment wishes were collected.

Analogous to transgender men, no statistically significant differences in length, weight, and BMI were observed between the Tanner 2/3, 4/5, and control groups (Table 3). Penile length was assessed before genital-affirming surgery and revealed that the onset of PS significantly influences penile development. As a result, the conventional technique used for vaginoplasty (penile inversion) was used less frequently in the PS groups (Tanner 2/3: 21.1%; Tanner 4/5: 73.3%; and controls: 85%; significant for Tanner 2/3 versus controls), whereas vaginoplasty using the intestine was most frequently performed in the Tanner 2/3 group (68.4%). No differences between groups were observed in the frequency of performed penile inversion vaginoplasty with additional full-thickness graft (FTG). All participants applied for vaginoplasty surgery, yet some were still waiting at the time of data collection.

The use of PS had substantial effects on body development and technical approaches to gender-affirming surgeries. Transgender men who initiated PS treatment at Tanner 2/3 developed less breast tissue. For those who underwent mastectomy, on average, 540 g less breast tissue was removed compared with those who did not have PS treatment (d = −2.12). For this reason, they were less likely to undergo an IMF mastectomy. Furthermore, the likelihood of not undergoing mastectomy at all was higher. If PS was initiated at Tanner 4/5, the effects were less pronounced. The majority of this group still applied for a mastectomy. Compared with controls, resected breast tissue was on average 209 g less (d = −0.46), and the surgical technique was less frequently an IMF mastectomy (Table 4).

Penile length was measured before transwomen underwent vaginoplasty. In transwomen who started with PS at Tanner 2/3, this was on average 4.8 cm less compared with controls without PS (d = −1.73). In this group, the likelihood of receiving an intestinal vaginoplasty was 84 times increased. If individuals started with PS at Tanner 4/5, penile length was 2.1 cm shorter than controls (d = −0.83) and the likelihood of requiring an intestinal vaginoplasty was increased as well (9.8 times, all compared with controls; Table 4).

Although PS has become an increasingly important treatment modality in young adolescents experiencing gender dysphoria, little evidence has been produced on the physical development of sex characteristics after PS and the implications for gender-affirming surgeries. Our findings suggest a dependency on the onset or duration of PS treatment; the earlier the onset of PS, the greater the effects on the development of breasts (in transgender men) and penis (in transgender women). Because technical feasibility of various gender-affirming surgical techniques depends on physical characteristics (eg, tissue availability), individuals who used PS may select for different types of surgery.

No statistically significant effects of PS on height, weight, and BMI were observed before surgery in both transgender men and women. In the transgender men, the most significant difference in physical development was observed in breast development, being least in the Tanner 2/3 group, intermediate in the Tanner 4/5 group, and most in the control group. Decrease or even regression of breast tissue development when using PS has previously been reported,^3,8  yet no data on the effect of the onset of PS have been described. As a consequence of the effects on breast development, less mastectomies were performed after PS (Tanner 2/3) and those performed were less invasive mastectomies (Tanner 2/3 and 4/5) compared with controls. This finding is in line with surgical guidelines suggesting which mastectomy technique to perform on the basis of breast size, elasticity, and ptosis grade.¹⁰  Earlier studies revealed that individuals having gone through puberty without PS nearly always require a mastectomy to obtain a more masculine chest.¹⁰  Although PS increases the chance of not requiring mastectomy for chest, this is no guaranteed outcome.

In transgender women, PS was found to have significant effect on penile development. Penile development was less in the Tanner 2/3 group when compared with the other 2 groups, and it was also less in the Tanner 4/5 group compared with controls. The penile length is of importance for vaginoplasty surgery because the penile skin is typically used to create the vaginal lining. In individuals with a small penis size, the penoscrotal skin is not sufficient to reconstruct both a vulva (requiring sufficient prepuce and scrotal skin) and sufficient neovaginal length (requiring sufficient penile skin).¹¹  In these individuals, an alternative vaginoplasty technique is required (eg, by using intestinal tissue or FTG). The effects of PS on the type of vaginoplasty performed are reflected by data from an earlier study¹¹  as well as the data in the current study. We observed a dependency on the onset of PS; standard penile inversion vaginoplasty was generally possible in the control group, whereas this was less frequently possible in Tanner 4/5 and infrequently in Tanner 2/3. Intestinal vaginoplasty was performed as an alternative method in most transgender women who started PS in Tanner 2/3.

We are aware that PS treatment includes many other aspects that need consideration besides its effect on physical development and the implications for surgery. We included no data on the development of other physical characteristics (eg, hair and voice) nor on the adolescents’ well-being. Nevertheless, transgender youth, parents, and prescribing professionals should be aware of the long-term (surgical) consequences of PS treatments when individuals wish to continue medical transition to gender-affirming surgery. For transgender men, less breast development corresponds with an increased likelihood of not requiring mastectomy (52.9% of the Tanner 2/3 group). Noticeably, the favorable effects of PS on breast growth were not only observed for the Tanner 2/3 group but also for adolescents starting at Tanner 4/5. For transgender women, reduced genital development after PS treatment may result in penoscrotal hypoplasia and an increased likelihood of requiring more invasive vaginoplasty approaches (84 times increased in Tanner 2/3 and 9.8 times in Tanner 4/5). If transgender women with penoscrotal hypoplasia wish to have satisfactory vaginal depth, a vaginal cavity may be created by using intestine, adding an extra risk of a colorectal surgery to the procedure. Also, an intestinal vaginoplasty can result in a more moist vagina, which requires more self-care and extensive clinical follow-up.¹¹ 

Clinicians should counsel transgender youth and their parents in making informed decisions when starting PS. Counseling consists of informing about the possible surgical consequences when puberty is suppressed and that these techniques may not be available in general transgender care facilities. Long-term (surgical) risks can be considered along with anticipated psychological gains, other pubertal developments, and so forth.

Regarding health care facilities, service providers should be aware that when pediatricians prescribe PS to transgender youth, this will have “downstream” consequences on the demand for technically complex gender-affirming surgery. For example, plastic surgeons will have to be skilled in minimally invasive mastectomy techniques and more extensive vaginoplasty approaches. Sufficient infrastructure to collaborate with colorectal surgeons and mental health professionals is inevitable to provide this care. Generally, referring physicians should be aware that early referrals to specialized pediatric care can positively impact pubertal development and surgical treatments (along with mental health).

Some limitations can be defined for the current study, including the sample size of some subgroups, reducing statistical power. Secondly, the included sample consisted of approximately two-thirds of the eligible candidates. Because no follow-up data of the remaining third were collected, a selection bias cannot be ruled out. Resulting from the retrospective design, some outcome variables suffered from missing data, leaving some information unreported (eg, breast development in those who did not apply for breast surgery) and creating possible selection bias (eg, control transgender men applying for mastectomy specifically were compared with all transgender men receiving PS, leaving control transgender men with little breast growth out of scope). Lastly, some possibly influential data were not reported (eg, scrotal development). Hence, future research ideally should include multicenter standardized prospective data collection, including patient-reported outcomes, to put the clinical findings into perspective.

Our findings indicate that PS effectively reduces the physical development of sex characteristics. As a result, transgender adolescents who received PS often qualify for different gender-affirming surgical techniques. In transgender men, early PS treatment is associated with no or less invasive chest surgery, whereas in transgender women, it is associated with more invasive genital surgery. Transgender youth and their parents should be aware of these long-term consequences when initiating PS. This asks for a multidisciplinary approach at an early stage. Transgender girls and women, especially, should be informed that they might require more extensive, centralized surgical care with long-term aftercare.

CSH

cross-sex hormone

FTG

full-thickness graft

IMF

inframammary fold

PS

puberty suppression