Bone Development in Transgender Adolescents Treated With GnRH Analogues and Subsequent Gender-affirming Hormones

Sebastian E. E. Schagen; Femke M. Wouters; Peggy T. Cohen-Kettenis; Louis J. Gooren; Sabine E. Hannema

Disclosures

J Clin Endocrinol Metab. 2020;105(12) 

In This Article

Results

A total of 54 transgirls and 73 transboys started treatment according to this protocol. For 51 transgirls and 70 transboys, DXA scans were available at the start of GnRHa administration and these individuals were included in the analyses. There were no significant differences between the ages of the transgirls and the transboys at the start of GnRHa administration (Table 1).

A total of 36 transgirls and 42 transboys received gender-affirming hormone treatment in addition to GnRHa treatment. The transboys were slightly but significantly older at start of gender-affirming hormone treatment than the transgirls (Table 1). The ratio of subjects who were in early and in late puberty was not different in the group evaluated for the effects of gender-affirming hormone treatment compared with the group analyzed during GnRHa treatment alone.

Anthropometric data and data on pubertal development of the subjects at baseline are shown in Table 1. All adolescents had sex characteristics typical of the sex assigned at birth and none had signs of a difference/disorder of sex development. None of the adolescents had a bone fracture during the study.

Changes During 2 Years of GnRHa Treatment

Bone Mineral Apparent Density. Changes in aBMD and aBMD z-scores are shown in Table 2. BMAD of the lumbar spine did not change during 2 years of GnRHa treatment in the transgirls or the early pubertal transboys (P = 0.84, P = 0.09, and P = 0.69, respectively) (see Figure 1, Table 2). In the late-pubertal transboys, a small but significant decrease in BMAD of the lumbar spine was found.

Figure 1.

Estimated marginal means and standard error of the mean of BMAD prior to and during 2 years of GnRHa administration in transgirls and transboys. Significant changes during the 2 years of GnRHa administration are indicated by an asterisk. Abbreviations: BMAD: bone mineral apparent density; FM, femoral neck; LS, lumbar spine.

BMAD of the femoral neck showed a significant decrease in the late-pubertal transgirls and in both groups of transboys (P = 0.007, P = 0.015, and P < 0.001, respectively) (see Figure 1, Table 2). The small decrease in the early pubertal transgirls was not significant (P = 0.31).

Bone Mineral Apparent Density Z-scores. At the start, z-scores of the BMAD at both locations were higher in the transboys than in the transgirls. The BMAD z-score of the lumbar spine significantly decreased in all 4 groups (P ≤ 0.001) (see Figure 1, Table 2). The BMAD z-scores of the femoral neck significantly decreased in all groups (P = 0.006, P = 0.002, and P < 0.001) except for the early-pubertal transgirls (P = 0.25). Four transgirls had a z-score of the hip below −2 after 2 years of GnRHa treatment and 3 individuals had a z-score of the lumbar spine below −2. Two transboys had a z-score of the hip below −2 whereas none of the transboys had a z-score of the lumbar spine below −2 after 2 years of GnRHa treatment.

Bone Mineral Density During Prolonged GnRHa Treatment. Because the average age at the start of GnRHa treatment was more than 14 years, most individuals were not treated with GnRHa for more than 2 years before gender-affirming hormone treatment was started. However, a few younger individuals were treated for up to 4 years. The aBMD values of the lumbar spine and hip in 4 transboys and 11 transgirls remained stable during 3 years of GnRHa treatment. The z-scores on the other hand declined (Table 3).

Serum Bone Markers. At baseline, there were no significant differences in serum levels of any of the 4 bone markers (P1NP, P3NP, osteocalcin, 1CTP) between the early- and late-pubertal groups of transgirls (Figure 2). In the transboys, baseline serum levels of all 4 bone markers were significantly higher in those in early puberty compared to those in later puberty.

Figure 2.

Estimated marginal means and negative standard error of the mean of osteocalcin, P1NP, P3NP, and 1CTP prior to and during 2 years of GnRHa administration in transgirls and transboys. Significant changes during the 2 years of GnRHa administration are indicated by asterisk.

After 2 years of GnRHa treatment serum levels of all 4 bone markers showed a significant decrease in both groups of transgirls and in early-pubertal transboys, which was most marked during the first year of treatment (Figure 2). Serum levels of P3NP and 1CTP showed a smaller but significant decrease in late-pubertal transboys whereas serum levels of P1NP and osteocalcin did not change in this group.

Changes During 3 Years of Gender-affirming Hormone Treatment

After an average of 1.89 years (± 1.03 year) of GnRHa administration, gender-affirming hormones were added to the treatment. Both early-pubertal groups were on GnRHa for a significantly longer time (2.5 years in transgirls (n = 7) and 4.0 years in transboys (n = 3)) when compared with both late-pubertal groups (1.5 years in transgirls and 1.7 years in transboys) (P < 0.001).

Bone Mineral Apparent Density. Changes in aBMD and aBMD z-scores are shown in Table 4. A significant increase in BMAD of the lumbar spine was found in all 4 groups (P < 0.001) after 3 years of gender-affirming hormone treatment (Figure 3, Table 4). The BMAD of the femoral neck showed a significant increase in both groups of transgirls and in the early-pubertal transboys (P < 0.05). In the late-pubertal transboys the increase was not significant.

Figure 3.

Estimated marginal means and standard error of the mean of BMAD prior to and during 3 years of GnRHa + gender-affirming treatment in transgirls and transboys. Significant changes during the 3 years of GnRHa + gender-affirming treatment are indicated by an asteriks.

Bone Mineral Apparent Density Z-scores. The BMAD z-scores of the lumbar spine significantly increased in all 4 groups (Figure 3, Table 4). Z-scores of the femoral neck showed a significant increase in both groups of transgirls and in the early pubertal transboys. The increase of the z-score in late-pubertal transboys was not significant.

Three transgirls had a z-score of the femoral neck below −2 and 3 individuals had a z-score of the lumbar spine below −2 after 3 years of gender-affirming hormone treatment. None of the transboys had a z-score below −2 after 3 years of gender-affirming hormone treatment.

Serum Bone Markers. The mean serum levels of the bone markers prior to gender-affirming hormone administration are shown in Figure 4. Serum levels of P1NP, P3NP, and 1CTP were significantly higher in the early pubertal transgirls than in the late-pubertal transgirls. In the transboys, baseline serum levels of P1NP and P3NP were significantly higher in the early pubertal group compared with the late-pubertal group. Levels of all 4 markers changed little in the late-pubertal transboys, whereas in the early pubertal transboys and late-pubertal transgirls, osteocalcin, P1NP, and P3NP showed a pronounced decrease during the first year of gender-affirming hormone treatment, after which levels stabilized. Remarkably, in the early-pubertal transgirls an initial increase in the P1NP, P3NP, and 1CTP levels was found followed by a decrease. After 3 years of gender-affirming hormone treatment, all 4 bone markers had significantly decreased in both early and late-pubertal transgirls. In transboys, osteocalcin, P1NP, and 1CTP significantly decreased. In both early and late-pubertal transboys, serum levels of P3NP did not significantly change.

Figure 4.

Estimated marginal means and standard error of the mean of osteocalcin, P1NP, P3NP, and 1CTP prior to and during 3 years of GnRHa + gender-affirming treatment in transgirls and transboys. Significant changes during the 3 years of GnRHa + gender-affirming treatment are indicated by an asteriks.

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