Letrozole shows promise for treating constitutional delay of growth and puberty in boys

medwireNews: Boys with constitutional delay of growth and puberty achieve greater testicular growth during 6 months of treatment with letrozole than with low-dose testosterone, show the findings of a randomised trial.

Testicular volume increased by 7.2 mL in the letrozole group versus 2.2 mL in the testosterone group, which was a significant improvement.

Taneli Raivio (University of Helsinki, Finland) and co-researchers explored use of the aromatase inhibitor letrozole on the grounds that it suppresses oestrogen, resulting in early stimulation of hypothalamic and pituitary gonadotroph activation and gonadotrophin-induced testicular enlargement and testosterone production. This contrasts with low-dose testosterone therapy which “might initially suppress, rather than activate, the hypothalamic–pituitary–gonadal (HPG) axis”.

They therefore anticipated that letrozole would “promote androgenic signs of puberty and testicular growth, increase height and lean mass gain, and minimise epiphyseal maturation.”

In line with this, during 6 months of treatment, the 15 boys (average age 14.8 years) who were randomly assigned to receive oral letrozole 2.5 mg/day had significantly larger increases in serum levels of luteinising hormone, follicle-stimulating hormone, testosterone and inhibin B than the 15 boys (average age 14.9 years) who received low-dose testosterone as an intramuscular injection of approximately 1 mg/kg every 4 weeks.

These differences disappeared during the 6 months after cessation of treatment, the team notes in The Lancet Child & Adolescent Health.

Clinical puberty progression did not differ between the two groups during treatment, and both treatments significantly increased growth velocity, with boys in the testosterone group growing slightly but significantly faster than those in the letrozole group.

The researchers suggest that letrozole might be appropriate for boys who “expect comprehensive physiological changes of puberty, including testicular growth”, whereas “testosterone might be the primary option for boys who prioritise rapid height gain during treatment.”

The majority of adverse events were mild, with the most common being musculoskeletal symptoms (transient back or joint pain), which occurred in three patients in each group. There was one moderate-to-severe treatment-related adverse event; one boy in the low-dose testosterone group had aggressive behaviour for 1 week after each injection.

Boys in the letrozole group had a significantly smaller increase in bone mineral density at the lumber spine at 6 months, and also at the hip by 12 months, but these differences disappeared after accounting for the size of the vertebrae.

“Taken together, these findings suggest that aromatisable androgen (ie, testosterone) expedites bone mineral accrual more efficiently than does treatment with a compound with exclusive androgenic effects (ie, an aromatase inhibitor), but this difference might result from strong stimulation of bone growth or expansion by testosterone rather than impairment of true volumetric bone mineral density by letrozole”, say Raivio and team.

In a linked commentary, Mehul Dattani (Great Ormond Street Hospital for Children and University College London Hospital, UK) notes the potential for vertebral deformities with aromatase inhibitor treatment, as well as for other issues such as lipid abnormalities.

Such issues may not arise during this relatively short-term use, he says, but he advocates cautious use nonetheless. “In view of the benign nature of the condition, the potential benefits of any intervention should be weighed against the potential risks”, Dattani concludes.

By Eleanor McDermid

medwireNews is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group

Lancet Child Adolecs Health 2019; doi:10.1016/S2352-4642(18)30377-8
Lancet Child Adolecs Health 2019; doi:10.1016/S2352-4642(18)30405-X
Martin Savage
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