Effects of Suppression of Estrogen Action by the P450 Aromatase Inhibitor Letrozole on Bone Mineral Density and Bone Turnover in Pubertal Boys

Wickman, Sanna; Kajantie, Eero; Dunkel, Leo

doi:10.1210/jc.2002-021643

Cited by 63 publications

(35 citation statements)

References 46 publications

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“…The effect was attributed to delayed bone maturation by inhibition of estrogen synthesis and action (26). Although letrozole tended to decrease the activation of bone metabolism as indicated by the serum PINP and ICTP levels, 1-year treatment did not adversely affect bone mass accretion (27). Letrozole reduced the fasting insulin levels and decreased high density lipoprotein (HDL) cholesterol.…”

Section: Discussionmentioning

confidence: 99%

Letrozole once a week normalizes serum testosterone in obesity-related male hypogonadism

Loves¹,

Ruinemans-Koerts²,

Boer³

2008

European Journal of Endocrinology

123

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Objective: Isolated hypogonadotropic hypogonadism (IHH) is frequently observed in severely obese men, probably as a result of increased estradiol (E 2 ) production and E 2 -mediated negative feedback on pituitary LH secretion. Aromatase inhibitors can reverse this process. This study evaluates whether letrozole once a week can normalize serum testosterone in severely obese men and maintain its long term effect. Design: Open, uncontrolled 6-month pilot study in 12 severely obese men (body mass indexO 35.0 kg/m 2 ) with obesity-related IHH and free testosterone levels !225 pmol/l, treated with 2.5 mg letrozole once a week for 6 months. Results: Six weeks of treatment reduced total E 2 from 123G11 to 58G7 pmol/l (P!0.001, meanG S.E.M.), and increased serum LH from 4.4G0.6 to 11.1G1.5 U/l (P!0.001). Total testosterone rose from 5.9G0.5 to 19.6G1.4 nmol/l (P!0.001), and free testosterone from 163G13 to 604G 50 pmol/l (P!0.001). Total testosterone rose to within the normal range in all subjects, whereas free testosterone rose to supraphysiological levels in 7 out of 12 men. The testosterone and E 2 levels were stable throughout the week and during the 6-month treatment period. Conclusion: Letrozole 2.5 mg once a week produced a sustained normalization of serum total testosterone in obese men with IHH. However, free testosterone frequently rose to supraphysiological levels. Therefore, a starting dose !2.5 mg once a week is recommended.European Journal of Endocrinology 158 741-747

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Section: Discussionmentioning

confidence: 99%

Letrozole once a week normalizes serum testosterone in obesity-related male hypogonadism

Loves¹,

Ruinemans-Koerts²,

Boer³

2008

European Journal of Endocrinology

123

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“…Short-term follow-up (2-3 years) of boys treated with aromatase inhibitors has not shown significant adverse effects on areal bone density (Wickman et al 2003), body composition (Hero et al 2006a) or spermatogenesis (Mauras et al 2005). However, these studies are limited by small sample size and short duration of follow-up.…”

Section: Introductionmentioning

confidence: 99%

Peripubertal aromatase inhibition in male rats has adverse long-term effects on bone strength and growth and induces prostatic hyperplasia

Bajpai¹,

Simm²,

McPherson³

et al. 2010

Journal of Endocrinology

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Aromatase inhibitors have been increasingly used in boys with growth retardation to prolong the duration of growth and increase final height. Multiple important roles of oestrogen in males point to potential adverse effects of this strategy. Although the deleterious effects of aromatase deficiency in early childhood and adulthood are well documented, there is limited information about the potential long-term adverse effects of peripubertal aromatase inhibition. To address this issue, we evaluated short-term and long-term effects of peripubertal aromatase inhibition in an animal model. Peripubertal male Wistar rats were treated with aromatase inhibitor letrozole or placebo and followed until adulthood. Letrozole treatment caused sustained reduction in bone strength and alteration in skeletal geometry, lowering of IGF1 levels, inhibition of growth resulting in significantly lower weight and length of treated animals and development of focal prostatic hyperplasia. Our observation of adverse long-term effects after peripubertal male rats were exposed to aromatase inhibitors highlights the need for further characterisation of long-term adverse effects of aromatase inhibitors in peripubertal boys before further widespread use is accepted. Furthermore, this suggests the need to develop more selective oestrogen inhibition strategies in order to inhibit oestrogen action on the growth plate, while beneficial effects in other tissues are preserved.

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“…Current data involving the use of AIs in growth disorders have been generally promising with respect to safety profiles. 7,9,11,12 However, additional studies are required to establish the long-term side effects of treatment with AIs in this patient group, including the evaluation of their impact on later fertility, lipid profiles, and bone mineral density.…”

Section: Discussionmentioning

confidence: 99%

Growth Hormone With Aromatase Inhibitor May Improve Height in CYP11B1 Congenital Adrenal Hyperplasia

et al. 2017

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With an estimated prevalence of 1 in 100 000 births, 11β-hydroxylase deficiency is the second most common form of congenital adrenal hyperplasia (CAH) and is caused by mutations in CYP11B1. Clinical features include virilization, early gonadotropin-independent precocious puberty, hypertension, and reduced stature. The current mainstay of management is with glucocorticoids to replace deficient steroids and to minimize adrenal sex hormone overproduction, thus preventing virilization and optimizing growth. We report a patient with CAH who had been suboptimally treated and presented to us at 6 years of age with precocious puberty, hypertension, tall stature, advanced bone age, and a predicted final height of 150 cm. Hormonal profiles and genetic analysis confirmed a diagnosis of 11β-hydroxylase deficiency. In addition to glucocorticoid replacement, the patient was commenced on growth hormone and a third-generation aromatase inhibitor, anastrozole, in an attempt to optimize his growth. After the initiation of this treatment, the patient’s growth rate improved significantly and bone age advancement slowed. The patient reached a final height of 177.5 cm (0.81 SD score), 11.5 cm above his mid-parental height. This patient is only the second reported case of the use of an aromatase inhibitor in combination with growth hormone to optimize height in 11β-hydroxylase-deficient CAH. This novel treatment proved to be highly efficacious, with no adverse effects. It may therefore provide a promising option to promote growth in exceptional circumstances in individuals with 11β-hydroxylase deficiency presenting late with advanced skeletal maturation and consequent short stature.

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Effects of Suppression of Estrogen Action by the P450 Aromatase Inhibitor Letrozole on Bone Mineral Density and Bone Turnover in Pubertal Boys

Cited by 63 publications

References 46 publications

Letrozole once a week normalizes serum testosterone in obesity-related male hypogonadism

Letrozole once a week normalizes serum testosterone in obesity-related male hypogonadism

Peripubertal aromatase inhibition in male rats has adverse long-term effects on bone strength and growth and induces prostatic hyperplasia

Growth Hormone With Aromatase Inhibitor May Improve Height in CYP11B1 Congenital Adrenal Hyperplasia

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