使用青春期阻斷劑的男性在服用雌激素11年以上後，脊椎骨密度Z值仍然偏低

接受青春期抑制及隨後性別肯定荷爾蒙治療的跨性別青少年的骨礦物質密度

Authors: Maria Anna Theodora Catharina van der Loos, Mariska Caroline Vlot, Daniel Tatting Klink, Sabine Elisabeth Hannema, Martin den Heijer, Chantal Maria Wiepjes
Journal: JAMA Pediatrics
Year: 2023
Source: https://doi.org/10.1001/jamapediatrics.2023.4588

Summary

The Amsterdam gender clinic, which pioneered puberty blockers for gender dysphoria (distress about one's sex), followed up adults who took blockers as teenagers and then cross-sex hormones for 9 to 15 years. As earlier studies found, bone density fell behind their peers while puberty was paused. Females given testosterone had caught back up to their starting level by about age 28. Males given estrogen recovered at the hip, but their lower-spine bone density stayed well below where it started and below average for their age. Depending on the comparison used, up to 18% of males had spine density far below normal for their age. The authors call the treatment 'safe' for bone in those taking testosterone. But only half of those eligible took part, people who stopped hormones were left out, there was no untreated comparison group, and broken bones were not measured.

Key findings

研究追蹤了 75 名成人（25 人出生時為男性，50 人出生時為女性），他們在 18 歲前開始使用青春期阻斷劑，隨後平均使用跨性別荷爾蒙約 12 年。
與同齡其他人相比，兩種性別在使用阻斷劑期間骨質密度都落後，如同早期的研究所顯示的。
在給予雌激素的男性中，下脊椎的骨質密度與使用阻斷劑前相比，仍明顯落後於同齡組，也低於平均，而髖部密度則回到起始時的水準。
依據與哪一個性別比較，在約 28 歲時，9% 至 18% 的男性脊椎骨質密度遠低於其年齡的正常範圍。
在給予睪固酮的女性中，脊椎和髖部的骨質密度回到治療前的水準，接近同齡的平均。
143 名符合資格者中只有 75 人（52%）參加：21% 拒絕，19% 聯絡不上，4% 已停用荷爾蒙者被排除。
作者的結論是，阻斷劑後接荷爾蒙，對服用睪固酮者的骨骼是「安全的」，但服用雌激素者需要更好調整的治療和更多研究。

Abstract

IMPORTANCE: Bone mineral density (BMD) z scores in transgender adolescents decrease during puberty suppression with a gonadotropin-releasing hormone (GnRH) agonist. Previous research found that after short-term use of gender-affirming hormones (GAH), pretreatment z scores were not restored. Long-term follow-up studies are lacking.

OBJECTIVE: To assess BMD after long-term GAH treatment in transgender adults who used puberty suppression in adolescence.

DESIGN, SETTING, AND PARTICIPANTS: This single-center cohort study with follow-up duration of 15 years selected participants from a database containing all people visiting a gender identity clinic at an academic hospital in the Netherlands between 1972 and December 31, 2018. Recruitment occurred from March 1, 2020, to August 31, 2021. A total of 75 participants diagnosed with gender dysphoria who had used puberty suppression before age 18 years prior to receiving at least 9 years of long-term GAH were included.

EXPOSURES: Puberty suppression with a GnRH agonist followed by GAH treatment.

MAIN OUTCOMES AND MEASURES: Lumbar spine, total hip, and femoral neck BMD and z scores before the start of puberty suppression, at start of GAH, and at short- and long-term follow-up.

RESULTS: Among 75 participants, 25 were assigned male at birth, and 50 were assigned female at birth. At long-term follow-up, the median (IQR) age was 28.2 (27.0-30.8) years in participants assigned male at birth and 28.2 (26.6-30.6) years in participants assigned female at birth. The median (IQR) duration of GAH treatment was 11.6 (10.1-14.7) years among those assigned male at birth and 11.9 (10.2-13.8) years among those assigned female at birth. The z scores decreased during puberty suppression. In individuals assigned male at birth, the mean (SD) z score after long-term GAH use was -1.34 (1.16; change from start of GnRH agonist: -0.87; 95% CI, -1.15 to -0.59) at the lumbar spine, -0.66 (0.75; change from start of GnRH agonist: -0.12; 95% CI, -0.31 to 0.07) at the total hip, and -0.54 (0.84; change from start of GnRH agonist: 0.01; 95% CI, -0.20 to 0.22) at the femoral neck. In individuals assigned female at birth, after long-term GAH use, the mean (SD) z score was 0.20 (1.05; change from start of GnRH agonist: 0.09; 95% CI, -0.09 to 0.27) at the lumbar spine, 0.07 (0.91; change from start of GnRH agonist: 0.10; 95% CI, -0.06 to 0.26) at the total hip, and -0.19 (0.94; change from start of GnRH agonist: -0.20; 95% CI, -0.26 to 0.06) at the femoral neck.

CONCLUSIONS AND RELEVANCE: In this cohort study, after long-term use of GAH, z scores in individuals treated with puberty suppression caught up with pretreatment levels, except for the lumbar spine in participants assigned male at birth, which might have been due to low estradiol concentrations. These findings suggest that treatment with GnRH agonists followed by long-term GAH is safe with regard to bone health in transgender persons receiving testosterone, but bone health in transgender persons receiving estrogen requires extra attention and further study. Estrogen treatment should be optimized and lifestyle counseling provided to maximize bone development in individuals assigned male at birth.

Conclusion

In this cohort study, after long-term use of GAH, z scores in individuals treated with puberty suppression caught up with pretreatment levels, except for the lumbar spine in participants assigned male at birth, which might have been due to low estradiol concentrations. These findings suggest that treatment with GnRH agonists followed by long-term GAH is safe with regard to bone health in transgender persons receiving testosterone, but bone health in transgender persons receiving estrogen requires extra attention and further study. Estrogen treatment should be optimized and lifestyle counseling provided to maximize bone development in individuals assigned male at birth.

Methodological limitations

No untreated comparison group: There was no group of teenagers with gender dysphoria who did not get blockers. The authors admit males already had below-average bone density before treatment, so the effect of the drugs cannot be separated from other factors.
Almost half didn't take part: Of 143 eligible people, only 75 took part. Thirty (21%) said no, 27 (19%) could not be reached, and others were left out. People with worse results may be under-represented.
Only people who stayed on hormones: To be included, people had to have used hormones for at least 9 years without stopping, and the 6 who had stopped were left out. People who detransitioned, or stopped because of side effects, are missing.
Few males: Only 25 people born male were included, and spine scans were available for 22. Results for the group with the worst bone health are uncertain, and the test of whether low estrogen levels were to blame was too small to show anything clear.
Indirect measure, no broken bones: The study measured bone density on scans, not broken bones, bone strength or diagnoses of brittle bones (osteoporosis). The 'safe' conclusion rests on a stand-in measure.
Most started blockers late in puberty: Few people started blockers early in puberty, and results could not be split by puberty stage. Females usually started after breast development had begun and had built more bone. The results may not apply to children given blockers at the very start of puberty.
Choice of comparison group matters: Change over time was measured against people of their birth sex, but the authors note most people were in the normal range compared with their identified gender. Different comparisons give different answers on how many have low bone density.
Old scans and changing machines: Earlier scans came from medical records over 2001–2018 and used three generations of scanner, adjusted to match each other. Hormone blood tests also changed over time and needed conversion.
Missing data: Scans were not available for everyone at every time point. Statistical methods were used to handle this, but the gaps may not be random.
Peak bone strength not known: The typical age at follow-up was 28, and the authors say they could not tell whether peak bone mass was permanently reduced or only delayed.
Clinic judging its own approach: The study was run by the Amsterdam clinic that developed the Dutch approach to blocking puberty. One author reported fees from Pfizer (unrelated), and no funding was reported.

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Summary

Key findings

Abstract

Conclusion