Summary

Puberty blockers (drugs that pause puberty) are often called a reversible pause, but little is known about their effect on the testicles. Mayo Clinic researchers examined tissue stored from children having surgery to preserve fertility. All 16 born-male patients with gender dysphoria in their tissue bank had taken puberty blockers. Treated children's tissue showed mild to severe shrinking of the sperm-making tubes; one 12-year-old on a blocker plus oestrogen had 59% of tubes completely shrunken. Detailed cell tests on one 14-year-old after more than four years on blockers found sperm-forming cells stuck at an early stage, and computer models judged the tissue to be like a child's before puberty. The authors say this raises 'a potential concern' about full reversibility. It is an early, unchecked signal: few treated patients, mixed drugs, no follow-up after stopping, no fertility measure.

Key findings

• Dintre cei 87 de pacienți dintr-o bancă de țesut testicular de la copii a Mayo Clinic, 16 (18%) aveau disforie de gen. Toți cei 16 luaseră blocante ale pubertății, iar 9 (56%) le luau în momentul operației de păstrare a fertilității.
• Medicamentele numărate drept „blocante ale pubertății” includeau blocante propriu-zise (leuprolid, histrelin, triptorelină), dar și estrogen și alte medicamente hormonale (medroxiprogesteron, spironolactonă), luate timp de 3 până la 52 de luni. Vârsta medie la operație era de 12,5 ani.
• Toți pacienții cu disforie de gen au ales operația de îndepărtare a țesutului în loc de recoltarea unei probe de spermă, pentru că nu voiau sau nu puteau ejacula. 2 din cei 9 pacienți tratați aveau anomalii testiculare la examinare.
• Analizând aproximativ 50 de tuburi la fiecare donator, la 19 donatori fără cancer, densitatea celulelor din tuburi a crescut cu vârsta la copiii netratați, dar nu a arătat nicio schimbare cu vârsta la copiii tratați. Un copil de 12 ani care lua un blocant plus estrogen de 14 luni avea 59% din tuburi complet micșorate, cu mici depozite de calciu.
• Testele genetice detaliate pe celule individuale de la un tânăr de 14 ani după mai mult de 52 de luni de tratament (11.199 de celule, combinate cu date publice la 130.100 de celule) au găsit peste 90% din celulele care formează spermă blocate într-un stadiu timpuriu și stări neobișnuite în celulele de susținere care hrănesc spermatozoizii în dezvoltare.
• Un model computerizat antrenat pe doar 10 persoane (5 copii înainte de pubertate, 5 tineri adulți) a considerat țesutul tânărului tratat de 14 ani ca fiind asemănător cu cel al unui copil dinaintea pubertății. Autorii înșiși spun că grupul mic de antrenare este o slăbiciune majoră.
• Autorii concluzionează că micșorarea și celulele imature „ridică o posibilă îngrijorare” privind reversibilitatea completă și fertilitatea viitoare. Studiul nu a testat recuperarea după oprire și nu a măsurat fertilitatea.

Abstract

Spermatogonial stem cell (SSC) acquisition of meiotogenetic state during puberty to produce genetically diverse gametes is blocked by drugs collectively referred as 'puberty blocker' (PB). Investigating the impact of PB on juvenile SSC state and function is challenging due to limited tissue access and clinical data. Herein, we report largest clinically annotated juvenile testicular biorepository with all children with gender dysphoria on chronic PB treatment highlighting shift in pediatric patient demography in US. At the tissue level, we report mild-to-severe sex gland atrophy in PB treated children. We developed most extensive integrated single-cell RNA dataset to date (>100K single cells; 25 patients), merging both public and novel (52 month PB-treated) datasets, alongside innovative computational approach tailed for germ cells and evaluated the impact of PB and aging on SSC. We report novel constitutional ranges for each testicular cell type across the entire age spectrum, distinct effects of treatments on prepubertal vs adult SSC, presence of spermatogenic epithelial cells exhibiting post-meiotic-state, irrespective of age, puberty status, or PB treatment. Further, we defined distinct effects of PB and aging on testicular cell lineage composition, and SSC meiotogenetic state and function. Using single cell data from prepubertal and young adult, we were able to accurately predict sexual maturity based both on overall cell type proportions, as well as on gene expression patterns within each major cell type. Applying these models to a PB-treated patient that they appeared pre-pubertal across the entire tissue. This combined with the noted gland atrophy and abnormalities from the histology data raise a potential concern regarding the complete 'reversibility' and reproductive fitness of SSC. The biorepository, data, and research approach presented in this study provide unique opportunity to explore the impact of PB on testicular reproductive health.

Conclusion

The authors report mild-to-severe testicular tubule atrophy in puberty-blocker-treated children and an immature, prepubertal-like profile in the testis of a patient treated for more than 52 months. They conclude that, combined with the gland atrophy and histological abnormalities, this raises 'a potential concern regarding the complete reversibility and reproductive fitness' of spermatogonial stem cells. They also report rare post-meiotic (spermatid-like) cells in prepubertal tissue, irrespective of age, puberty status or treatment. They say the biorepository, data and research approach 'provide unique opportunity to explore the impact of PB on testicular reproductive health.'