Matti Hero

Treatment with the aromatase inhibitor letrozole during adolescence increases near-final height in boys with constitutional delay of puberty

Objective  We investigated whether inhibition of oestrogen biosynthesis with the aromatase inhibitor, letrozole, during adolescence improves near‐final height in boys with constitutional delay of puberty.

Aromatase inhibitors in pediatrics.

Aromatase, an enzyme located in the endoplasmic reticulum of estrogen-producing cells, catalyzes the rate-limiting step in the conversion of androgens to estrogens in many tissues. The clinical features of patients with defects in CYP19A1, the gene encoding aromatase, have revealed a major role for this enzyme in epiphyseal plate closure, which has promoted interest in the use of inhibitors of aromatase to improve adult height. The availability of the selective aromatase inhibitors letrozole and anastrozole—currently approved as adjuvant therapy for breast cancer—have stimulated off-label use of aromatase inhibitors in pediatrics for the following conditions: hyperestrogenism, such as aromatase excess syndrome, Peutz–Jeghers syndrome, McCune–Albright syndrome and functional follicular ovarian cysts; hyperandrogenism, for example, testotoxicosis (also known as familial male-limited precocious puberty) and congenital adrenal hyperplasia; pubertal gynecomastia; and short stature and/or pubertal delay in boys. Current data suggest that aromatase inhibitors are probably effective in the treatment of patients with aromatase excess syndrome or testotoxicosis, partially effective in Peutz–Jeghers and McCune–Albright syndrome, but probably ineffective in gynecomastia. Insufficient data are available in patients with congenital adrenal hyperplasia or functional ovarian cysts. Although aromatase inhibitors appear effective in increasing adult height of boys with short stature and/or pubertal delay, safety concerns, including vertebral deformities, a decrease in serum HDL cholesterol levels and increase of erythrocytosis, are reasons for caution.

Vertebral morphology in aromatase inhibitor–treated males with idiopathic short stature or constitutional delay of puberty

Aromatase inhibitors (AIs), blockers of estrogen biosynthesis, delay bone maturation and therefore are used increasingly to promote growth in children and adolescents with growth disorders. The effects of treatment on skeletal health are largely unknown. Since estrogen deficiency is associated with various detrimental skeletal effects, we evaluated in this cross‐sectional posttreatment study vertebral body morphology, dimensions and endplates, and intervertebral disks by the use of magnetic resonance imaging (MRI) in two cohorts of males previously treated with the AI letrozole or placebo. Males with idiopathic short stature received treatment with letrozole or placebo for 2 years during prepuberty or early puberty; males with constitutional delay of puberty received letrozole or placebo in combination with low‐dose testosterone for 1 year during early or midpuberty. In males with idiopathic short stature, mild vertebral body deformities were found in 5 of 11 (45%) letrozole‐treated subjects, whereas in the placebo group no deformities were detected (p = .01). In the cohort of males with constitutional delay of puberty, a high prevalence of endplate and intervertebral disk abnormalities was observed in both the letrozole‐ and the placebo‐treated groups. We conclude that AI therapy during prepuberty or early puberty may predispose to vertebral deformities, which probably reflect impaired vertebral body growth rather than impaired bone quality and compression fractures. If AIs are used in growth indications, follow‐up of vertebral morphology is indicated.

Zoledronic acid treatment in children with osteogenesis imperfecta.

Background: Intravenous disodium pamidronate has become an established treatment in osteogenesis imperfecta (OI). Another bisphosphonate, zoledronic acid, has been indicated for the treatment of adult osteoporosis. We studied its efficacy and safety in children with mild OI. Methods: Patients were treated for 1.0–3.2 years with 0.05 mg/kg zoledronic acid intravenously every 6 months as part of their clinical care. They were carefully followed for clinical and biochemical parameters, side effects, bone mineral densities (BMD) and compression fractures. Results: The study included 17 patients (age 1.5–16.8 years) with type I OI. They had sustained altogether 73 fractures; 9 had compression fractures. During the treatment, 6 patients suffered in total 10 new long-bone fractures. The median lumbar spine areal BMD z-score increased from –2.0 to –0.7 during 2 years of treatment. The infusions were associated with a transient decrease in serum calcium and phosphate and a significant increase in serum PTH. Two patients developed symptomatic hypocalcemia. Bone turnover markers decreased during the treatment. Conclusions: Intravenous zoledronic acid is an effective mode of treatment in children with OI. The treatment response is comparable to pamidronate but the infusion protocol is more convenient. Further studies are needed to establish optimal dosing and long-term safety.

Impact of aromatase inhibitor therapy on bone turnover, cortical bone growth and vertebral morphology in pre- and peripubertal boys with idiopathic short stature.

In this randomized placebo-controlled study we examined the influence of aromatase inhibition on bone turnover, cortical bone growth, and vertebral body morphology in peripubertal boys. Thirty peripubertal boys with idiopathic short stature were treated with the aromatase inhibitor letrozole or placebo for 2 years. During treatment and posttreatment follow-up, dual-energy X-ray absorptiometry (DXA)-assessed bone mineral density, metacarpal index (MCI), and markers of bone turnover were examined. Vertebral morphology was examined by DXA after cessation of treatment. In letrozole-treated boys, the concentrations of the bone resorption marker urine aminoterminal telopeptide of type I collagen initially increased and thereafter slowly declined while the concentrations of the bone formation markers serum aminoterminal propeptide of type I collagen and serum alkaline phosphatase remained unchanged or slightly increased, respectively. In placebo-treated boys, all markers of bone turnover increased significantly during treatment. Among those who progressed into puberty, metacarpal index (MCI) increased more in the letrozole-treated than in the placebo-treated boys during treatment (25 vs. 9%, p = 0.007). The change in MCI correlated with the testosterone-to-estradiol ratio (r = 0.59, p = 0.02). Vertebral deformities were detected in 6 out of 13 boys receiving letrozole and in 4 out of 11 receiving placebo (p = 0.70). Aromatase inhibition suppresses bone turnover, possibly through an androgen-mediated effect. In pubertal boys, treatment stimulates cortical bone growth by increasing the testosterone-to-estradiol ratio.

Anti-tumor necrosis factor treatment in cherubism--clinical, radiological and histological findings in two children.

Cherubism is a rare and disfiguring genetic disorder with excessive bone resorption and multilocular lesions in the mandible and/or maxilla. The disease-causing gain-of-function mutations in the SH3-binding protein 2 (SH3BP2) gene result in increased myeloid cell responses to macrophage colony stimulating factor and RANK ligand, formation of hyperactive osteoclasts (giant cells), and hyper-reactive macrophages that produce excessive amounts of the inflammatory cytokine tumor necrosis factor α (TNF-α). Recent findings in the cherubism mouse model suggest that TNF-α plays a major role in disease pathogenesis and that removal of TNF-α prevents development of the bone phenotype. We treated two children with cherubism with the TNF-α antagonist adalimumab for approximately 2.5 years and collected extensive clinical, radiological and histological follow-up data during the treatment. Histologically the treatment resulted in a significant reduction in the number of multinucleated giant cells and TNF-α staining positivity in both patients. As evaluated by computed tomography and magnetic resonance imaging, the lesions in Patient 1 showed either moderate enlargement (mandibular symphysis) or remained stable (mandibular rami and body, the maxilla). In Patient 2, the lesions in mandibular symphysis showed enlargement during the first 8 months of treatment, and thereafter the lesions remained unchanged. Bone formation and resorption markers remained unaffected. The treatment was well tolerated. Based on our findings, TNF-α antagonist may decrease the formation of pathogenic giant cells, but does not result in lesion regression or prevent lesion expansion in active cherubism. TNF-α modulator treatment thus does not appear to provide sufficient amelioration for patients suffering from cherubism.

Bone mineral density, body composition and bone turnover in patients with congenital hypogonadotropic hypogonadism

Patients with congenital hypogonadotropic hypogonadism (HH) may have reduced peak bone mass in early adulthood, and increased risk for osteoporosis despite long-term hormonal replacement therapy (HRT). To investigate the relationship between HRT history and measures of bone health in patients with HH, we recruited 33 subjects (24 men, nine women; mean age 39.8 years, range: 24.0-69.1) with congenital HH (Kallmann syndrome or normosmic HH). They underwent clinical examination, were interviewed and medical charts were reviewed. Twenty-six subjects underwent dual-energy X-ray absorptiometry for evaluation of BMD of lumbar spine, hip, femoral neck and whole body; body composition and vertebral morphology were evaluated in 22 and 23 subjects, respectively. Circulating PINP, ICTP and sex hormone levels were measured. HRT history clearly associated to bone health: BMDs of lumbar spine, femoral neck, hip and whole body were lower in subjects (n = 9) who had had long (≥5 years) treatment pauses or low dose testosterone (T) treatment as compared to subjects without such history (n = 17; all p-values < 0.05). In addition, fat mass and body mass index (BMI) were significantly higher in men with deficient treatment history (median fat mass: 37.5 vs. 23.1%, p = 0.005; BMI: 32.6 vs. 25.2 kg/m(2), p < 0.05). Serum PINP correlated with ICTP (r(s) = 0.61; p < 0.005) in men, but these markers correlated neither with circulating T, nor with serum estradiol levels in women. In conclusion, patients with congenital HH require life-long follow-up to avoid inadequate HRT, long treatment pauses and further morbidity.

Circulating antimüllerian hormone levels in boys decline during early puberty and correlate with inhibin B

OBJECTIVE To investigate peripheral levels of inhibin B and antimüllerian hormone (AMH) in boys during peripuberty and in patients with congenital hypogonadotropic hypogonadism (HH). DESIGN Randomized, placebo-controlled trial (peripubertal boys); and cross-sectional clinical study (males with HH). SETTING University central hospital. PATIENT(S) Twenty-eight peripubertal boys with idiopathic short stature (ISS), 19 males with Kallmann syndrome. INTERVENTION(S) Letrozole (2.5 mg/day) or placebo in boys with ISS for 2 years. MAIN OUTCOME MEASURE(S) Longitudinal follow-up observation of serum AMH and its relationship with inhibin B during early puberty and the influence of high (letrozole-treated boys) and low (males with HH) gonadotropin exposure on circulating AMH. RESULT(S) In boys with ISS receiving placebo, the decrease in AMH levels and the increase in inhibin B levels were correlated. The serum AMH level had already declined before a clinically significant increase in testis volume or serum testosterone occurred. Letrozole did not appear to modulate the decline in AMH. The AMH levels were lower in boys and young adults with Kallmann syndrome and prepubertal testes (mean: 20.9 ± 4.7 ng/mL, n = 6) as compared with prepubertal ISS boys (102.3 ± 11.9 ng/mL). CONCLUSION(S) The gonadotropin-mediated early pubertal increase in inhibin B is tightly coupled to decrease in AMH levels and may reflect androgen-mediated differentiation of Sertoli cells. Profound gonadotropin deficiency is associated with low AMH levels, suggesting impaired development of the Sertoli cell population.

Cognitive effects of aromatase inhibitor therapy in peripubertal boys.

OBJECTIVE Aromatase inhibitors, blockers of oestrogen biosynthesis, have emerged as a new potential treatment modality for boys with short stature. The cognitive effects of such therapy are unknown. In this study, we explored the effects of aromatase inhibition on cognitive performance in peripubertal boys. DESIGN Prospective, double-blind, randomised, placebo-controlled clinical study. METHODS Twenty-eight boys, aged 9.0-14.5 years, with idiopathic short stature were treated with the aromatase inhibitor letrozole (2.5 mg/day) or placebo, for 2 years. During the treatment, the progression of physical signs of puberty and the concentrations of sex hormones were followed up. A selection of cognitive tests, focusing on memory function, was administered to the participants at entry, at 12 months and at 24 months after the start of the treatment. RESULTS Letrozole effectively inhibited the conversion of androgen to oestrogen, as indicated by high serum testosterone and low serum oestradiol concentrations in letrozole-treated boys who progressed into puberty. In both the groups, there was a gain in performance during the follow-up period in tests of verbal performance, in most of the tests of visuospatial performance and in some tests of verbal memory. No significant differences between the letrozole- and placebo-treated boys in development of cognitive performance were found in any of the tests during the follow-up period. CONCLUSIONS Our results suggest that blockade of oestrogen biosynthesis with an aromatase inhibitor does not influence cognitive performance in peripubertal males.

Congenital hypogonadotropic hypogonadism, functional hypogonadotropism or constitutional delay of growth and puberty? An analysis of a large patient series from a single tertiary center

STUDY QUESTION What diagnoses underlie delayed puberty (DP) and predict its outcome? SUMMARY ANSWER A multitude of different diagnoses underlie DP, and in boys a history of cryptorchidism, small testicular size and slow growth velocity (GV) predict its clinical course. WHAT IS KNOWN ALREADY DP is caused by a variety of underlying etiologies. Hormonal markers can be used in the differential diagnosis of DP but none of them have shown complete diagnostic accuracy. STUDY DESIGN, SIZE, DURATION Medical records of 589 patients evaluated for DP in a single tertiary care center between 2004 and 2014 were retrospectively reviewed. PARTICIPANTS/MATERIALS, SETTING, METHODS Clinical and biochemical data of 174 boys and 70 girls who fulfilled the criteria of DP were included in the analyses. We characterized the frequencies of underlying conditions and evaluated the predictive efficacy of selected clinical and hormonal markers. MAIN RESULTS AND THE ROLE OF CHANCE Thirty etiologies that underlie DP were identified. No markers of clinical value could be identified in the girls, whereas a history of cryptorchidism in the boys was associated with an increase in the risk of permanent hypogonadism (odds ratio 17.2 (95% CI; 3.4-85.4, P < 0.001)). The conditions that cause functional hypogonadotropic hypogonadism were more frequent in boys with a GV below 3 cm/yr than in those growing faster (19% vs 4%, P < 0.05). In this series, the most effective markers to discriminate the prepubertal boys with constitutional delay of growth and puberty (CDGP) from those with congenital hypogonadotropic hypogonadism (CHH) were testicular volume (cut-off 1.1 ml with a sensitivity of 100% and a specificity of 91%), GnRH-induced maximal LH (cut-off 4.3 IU/L; 100%, 75%) and basal inhibin B (INHB) level (cut-off 61 ng/L; 90%, 83%). LIMITATIONS, REASONS FOR CAUTION The main limitation of the study is the retrospective design. WIDER IMPLICATIONS OF THE FINDINGS Prior cryptorchidism and slow GV are two important clinical cues that may help clinicians to predict the clinical course of DP in boys, whereas markers of similar value could not be identified in girls. In prepubertal boys, testicular size appeared as effective as INHB and GnRH-induced LH levels in the differential diagnosis between CHH and CDGP. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Academy of Finland (268356), Foundation for Pediatric Research (7495), Sigrid Juselius Foundation (2613) and the Finnish Medical Foundation (011115). The authors have no competing interests to report. TRIAL REGISTRATION NUMBER Not applicable.