Novel Treatment of Delayed Male Puberty with Aromatase Inhibitors

Abstract

Background: As the evidence for the role of oestrogens in epiphyseal closure appears unequivocal, we hypothesized that boys with constitutional delay of puberty would attain greater adult height if oestrogen action was suppressed. Methods: We conducted a randomized, double-blind, placebo-controlled study in which we treated boys with constitutional delay of puberty with testosterone plus placebo or testosterone plus a potent fourth-generation aromatase inhibitor, letrozole. Findings: Letrozole effectively inhibited oestrogen synthesis. The 17β-oestradiol concentrations increased in the untreated group and in the testosterone/placebo-treated group, but in the testosterone/letrozole-treated group no such increase was observed until letrozole treatment was discontinued. Testosterone concentrations were threefold higher in the testosterone/letrozole-treated group than in the other groups. Within 18 months, bone age had advanced by 1.1 ± 0.3 years in the untreated group and by 1.7 ± 0.3 years in the testosterone/placebo-treated group, but only by 0.9 ± 0.2 years in the testosterone/letrozole-treated group (p = 0.02 between treatment groups). Predicted adult height did not change significantly in the untreated group and in the testosterone/placebo-treated group, whereas in the testosterone/letrozole-treated group the increase was 5.1 ± 1.2 cm (p = 0.004). Conclusions: Our findings suggest that, if oestrogen action is inhibited in growing adolescents, adult height will increase. This observation provides a rationale for studies aimed at delaying bone maturation in several growth disorders.

Effects of Testosterone Undecanoate Administered Alone or in Combination with Letrozole or Dutasteride in Female to Male Transsexuals

“…E has important effects on bone metabolism because of the presence of aromatase and E receptors [40]. The inhibition of aromatase by L has been shown to negate the effects of E on pubertal epiphysial fusion, resulting in increased adult growth height [41,42], and although rare, cases of aromatase deficiency in men are linked with low BMD and persistent linear growth [43,44]. In women, bone mineral loss and the associated risk of osteoporosis is a well‐documented consequence of the postmenopausal decrease in E. Furthermore, L and anastrozole monotherapies are associated with an increase in bone loss problems when administered as aromatase inhibitory breast cancer treatments [45,46].…”

The Role of Pro‐Inflammatory Cytokines in Inflammatory Bowel Disease Growth Retardation

“…In girls, low levels of oestrogen promote growth but high levels of oestrogen have the opposing effect (66). The effect of testosterone via GH in puberty for boys seems to be mediated via the aromatisation of testosterone to oestrogen (67). Dihydrotestosterone, a non‐aromatisable androgen is not capable of increasing GH levels.…”

Alfacalcidol prevents aromatase inhibitor (Letrozole)-induced bone mineral loss in young growing female rats

“…Aromatase inhibitor (Letrozole, L) is an emerging therapeutic tool that can be of great hope for those children (Dunkel & Wickman 2001, Shulman et al 2008. When children start their early puberty, estrogen has a major role in shaping and dictating future bone health through initiation of modeling that includes all stages of mineral acquisition, linear growth of long bone, and growth plate closure.…”

“…L causes depletion of estrogen via suppression of testosterone conversion to E 2 (Buzdar & Howell 2001, Buzdar 2003). This effect is utilized to increase the predicted adult height, in children with ISS and CGDP (MacGillivray et al 1998, Dunkel & Wickman 2001, Shulman et al 2008. CGDP is reported in literature to be associated with reduced bone mineral acquisition, and reduced bone mass in adult life (Finkelstein et al 1992, Bonjour 1998.…”

“…CGDP is reported in literature to be associated with reduced bone mineral acquisition, and reduced bone mass in adult life (Finkelstein et al 1992, Bonjour 1998. The population of children with CGDP may utilize the L to improve the predicted adult height, and the induction of an estrogen deficienct state after the treatment may further compromise the bone mineral acquisition (Carani et al 1997, MacGillivray et al 1998, Dunkel & Wickman 2001.…”