Exaggerated Premature Adrenarche in Boys: Comparative Study of a Therapeutic Intervention With the Aromatase Inhibitor Anastrozole Versus Morning Low Dose Hydrocortisone

Abstract

Abstract Background: In boys, idiopathic premature adrenarche (IPA) is defined as the appearance of pubic or axillary hair/odor before the age of 9 yrs, not due to pathology of the adrenal glands. Exaggerated Adrenarche (EXAD), occurring in 10-15% of children with IPA, is characterized by an elevated >10 DHEA/Δ4 ratio (theoretically indicating reduced 3-β-HSD activity) and accelerated bone age (BA) maturation, continuously increasing the projecting distance from the target height (TH) curve, beyond the one observed in the pattern of Constitutional Advancement of Growth (CAG), eventually leading to short stature (SS). It is traditionally successfully treated with a morning (6-8 am) low dose of hydrocortisone (8 mg/m2) in order to reduce the androgens produced and delay BA progression, similarly to the standard treatment of non-classical (late-onset) CAH. Third generation aromatase inhibitors (AI) have been shown to delay BA by inhibiting the peripheral aromatization of androgens and are being widely used off-label to treat short SS in boys. Aims: To evaluate the effectiveness of the AI anastrozole in delaying BA in boys with EXAD. Methods: 39 boys with advanced BA and a predicted adult height (PAH) <170cm and > -1SDS from TH) were included. Group-A (n=28) received anastrozole 1mg x 1 p.o. and group-B (n=11) low dose (8 mg/m2) hydrocortisone at 6-8 am for at least 3 yrs. All measurements were made on the same height meter by the same examiner. The two groups did not differ in terms of age at intervention onset: 8.6 in group A vs 8.74 yrs in group B, TH: 175.7 vs 175.7 cm, PAH: 168.4 vs 167.8 cm and BA advancement: +2.3 yrs in group A vs +2.4 yrs in group B. A 6-month follow-up included clinical examination, BA assessment, and laboratory tests (general blood, lipid chart, LH, FSH, TESTO, E2, E1, and complete calcium metabolism). Lumbar spine DEXA scan and X-Ray was performed on an annual basis. Results: Both groups had a statistically significant gain in PAH after 3yrs of treatment: Group A +10.3 cm (1.53 SD), p<0.001, and group B +7.1 cm (1.06 SD), p=0.007. Thus, group A exceeded their TH by +3cm (0.45 SDS) and group B reached -0.8cm (-0.11 SDS) from their TH, p=0.03. The reduction of BA advancement was statistically significant in both groups (p<0.05), with superiority of the anastrozole-treated group: at 3yrs in group A BA advancement was +0.48 yrs, and at group B +1.24 yrs (p<0.001). No clinical adverse events or abnormal tests were noted in any of the groups. Bone density and vertebral morphology was not affected within or between groups. Conclusions: Aromatase Inhibitors may have a place in managing exaggerated adrenarche in boys, showing superiority to traditional low-dose hydrocortisone in improving predicted adult height and delaying bone age maturation, but notably by overcoming quality of life and compliance issues associated with hydrocortisone therapy (mandatory 6-8 am).