ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Human Reproduction (Oxford, England) vol. 35, 2 (2020): 257–264. doi: https://academic.oup.com/humrep/article/35/2/257/5709207. https://pubmed.ncbi.nlm.nih.gov/31958337/

This randomized controlled trial compares treatment with peroral letrozole or intramuscular low-dose testosterone in boys with constitutional delay of growth and puberty. Gonadotrophin and Sertoli cell marker levels show that letrozole may be beneficial for Sertoli cell proliferation and future spermatogenesis.

Until now, usual approach for constitutional delay of puberty involves watchful waiting or low-dose androgen treatment (1,2). Recently, peroral letrozole, an aromataze inhibitor, was explored as a new treatment for constitutional delayed puberty (3). It appears more efficacious in inducing hypothalamic-pituitary-gonadal (HPG) axis activation and testis growth than testosterone (3). However, men with a history of delayed puberty exhibit decreased sperm count (4) and so far, the concomitant changes in inhibin B and AMH levels (markers of seminiferous epithelium function, essential to future fertility) in boys receiving letrozole or testosterone had not been described.

The aim of this study was to compare the action of oral letrozole versus testosterone injection on AMH, Inhibin B and gonadotrophin serum levels and clinical outcomes in 28 boys. The authors show that AMH levels similarly decrease over time in both treatment groups, suggesting that letrozole does not cause unduly rapid maturation of Sertoli cells and does not have untoward effects on future sperm producing capacity. However, testosterone has been shown to suppress gonadotrophins and inhibin B, whereas letrozole increases these levels (4). Here, treatment-induced changes in circulating gonadotrophin levels were not associated with changes in serum AMH, but they correlated with changes in inhibin B. This supports the idea that inhibin B depends on gonadotrophin-dependent and Sertoli cell mass-related components (5). The authors also measured circulating levels of letrozole in treated boys (Letrozole 2.5 mg/day). Circulating letrozole levels are highly variable and explained by the dose per weight. There was no significant association between Letrozole levels and any markers of HPG axis activity.

This article paves the way for further studies to investigate the minimal efficient letrozole dose per Kg weight and strengthens the hypothesis that Letrozole-induced activation of HPG-axis will protect Sertoli cell proliferation and future spermatogenesis.

References:

1. Palmert MR, Dunkel L. (2012). Clinical practice. Delayed puberty. N Engl J Med. 366(5):443–453.

2. Ashraf T. Soliman, Mohammed M. Abdul Khadir, Maurice Asfour (1995). Testosterone treatment in adolescent boys with constitutional delay of growth and development. Metabolism 44(8):1013–1015.

3. Varimo T, Huopio H, Kariola L, et al. (2019). Letrozole versus testosterone for promotion of endogenous puberty in boys with constitutional delay of growth and puberty: a randomised controlled phase 3 trial. Lancet Child Adolesc Health. 3(2):109–120.

4. Jensen TK, Finne KF, Skakkebæk NE, et al. (2016). Self-reported onset of puberty and subsequent semen quality and reproductive hormones in healthy young men. Hum Reprod. 31(8):1886–1894.

5. Grinspon RP, Urrutia M, Rey RA. (2018). Male Central Hypogonadism in Paediatrics – the Relevance of Follicle-stimulating Hormone and Sertoli Cell Markers. Eur Endocrinol. 14(2):67–71.