Letrozole Significantly Improves Growth Potential in a Pubertal Boy With Growth Hormone Deficiency

Abstract

ABSTRACT. Clinical experience with using an aromatase inhibitor to suppress estrogen production during puberty for improvement of growth potential in adolescents with short stature is limited. This report documents treatment of such a patient with a combination of growth hormone and letrozole, a third-generation aromatase inhibitor. Our case demonstrates a favorable outcome on a short-term basis. E strogen plays a critical role for the pubertal growth spurt, skeletal maturation, and accrual and maintenance of bone mass in females as well as males. [1][2][3][4] It is now evident that gene mutations of aromatase or estrogen receptor that result in impairment of estrogen production or action have similar phenotypes, including abnormally tall stature with eunuchoid proportions, a lack of pubertal growth spurt, unfused epiphyses, and osteopenia. Aromatase, encoded by the CYP19 gene located on chromosome 15q21.2 and expressed in bones, is the key enzyme for estrogen biosynthesis. 2,4 It has been proposed that an aromatase inhibitor (AI) can be used to improve the final adult height in short pubertal boys. The hypothesis is that suppressing estrogen formation after the onset of puberty would delay the closure of the epiphyses, thus allowing for an extended period of growth without affecting the progression of androgenic development. Potential adverse effects of AIs, such as reduced bone mineral density (BMD), metabolic effects including a propensity for insulin resistance and dyslipidemia, and impairment of the hypothalamic-pituitary-gonadal axis, need to be considered. 5 To date, a couple of studies, at least in the short term, indicate that the use of an AI is safe and promising. 6-8 CASE REPORTA white male was first seen for evaluation of short stature at 14 years 8 months old. He was healthy with no other medical problems, and his birth weight and length were reported as normal. Family history was unremarkable. His father's height was 177.8 cm, and his mother's height was 162.5 cm. His midparental target height was 176.7 cm (calculated as the average of parents' heights ϩ 6.55). His initial examination revealed the following: height, 143 cm (Ͻ3rd percentile; z score Ϫ2.94); upper/lower segment ratio, 1.0; weight, 44.5 kg (11th percentile); pubic hair, Tanner II; testicular volume, 4 to 6 mL; bilateral gynecomastia. Growth hormone (GH) deficiency was diagnosed after a standard comprehensive work-up (GH peak: 6.1 ng/mL, poststimulation), and GH treatment (0.3 mg/kg per week) was initiated at 15 years. The patient responded well (Fig 1). After 14 months of GH treatment, his height increased from 144.5 to 158 cm (z score: from Ϫ2.94 to Ϫ2.04), a gain of 13.5 cm (Table 1). However, although his puberty advanced to Tanner stage IV for pubic hair and testicular volume increased to 10 mL (Tanner III), his final adult-height prediction still remained 2 SDs below his target height. Letrozole (2.5 mg/ day) was added at 16 years 2 months, when his bone age was 14 years. He was treated with the combination GH/letrozole for 17 m...

Idiopathic short stature: Management and growth hormone treatment

“…Aromatase inhibition [93,[99][100][101][102] may be an effective means of enhancing growth in boys, with growth stimulated by the continued presence of androgen and bone age advancement slowed by elimination of estrogen. In a double-blind, placebo-controlled trial, the potent aromatase inhibitor, letrozole, was used to slow the rate of skeletal maturation in boys with short stature and delayed puberty who were also receiving testosterone [99,103].…”

Of Mice and Men: The Many Guises of Estrogens

“…In men, AIs have been, or are being, examined as potential therapies for breast cancer (Zabolotny et al 2005), gynecomastia (Plourde et al 2004;Riepe et al 2004;Boccardo et al 2005;Rhoden and Morgentaler 2004), hypogonadism (Dougherty et al 2005;Leder et al 2004;Holbrook and Cohen 2003), short stature and bone metabolism in pubertal boys (Mauras et al 2004;Zhou et al 2005;Dunkel and Wickman 2003;Wickman et al 2003), epilepsy (Harden and MacLusky 2004), infertility (Raman and Schlegel 2003), and androgenindependent prostate carcinoma (Smith et al 2003;Santen et al 2001). …”

Effect of Antiandrogen, Aromatase Inhibitor, and Gonadotropin-releasing Hormone Analog on Adult Height in Familial Male Precocious Puberty

“…The discovery that estrogen mediates epiphyseal fusion has prompted interest in aromatase inhibitor treatment as a potential means to increase AH in other pediatric conditions associated with short stature, such as constitutional delay of growth and adolescence, 26 growth hormone deficiency, 27 and idiopathic short stature. 28–32 Although the improved AH outcome in the current study of boys with FMPP is consistent with this potential, we agree with the recommendation to complete ongoing long-term clinical trials before expanding pediatric aromatase inhibitor treatment to a much wider patient group.…”