medwireNews: Some children with congenital adrenal hyperplasia (CAH) could benefit from treatment with the aromatase inhibitor anastrozole to optimise their growth potential, US researchers suggest.
“Hyperandrogenemia resulting in estrogen-mediated accelerated bone maturation and early growth plate fusion contributes to short stature” in children with 21-hydroxylase deficiency (21OHD) CAH, but aromatase inhibitor use may “slow epiphyseal closure and allow for a longer duration of growth”, explain Kyriakie Sarafoglou (University of Minnesota Medical School, Minneapolis) and co-workers.
To investigate, the team reviewed the medical records of 60 children with 21OHD CAH and a bone age at least 2 standard deviations above their chronological age who were given off-label anastrozole 1 mg/day to block androgen conversion to oestrogen. The children were treated at a single centre between 2003 and 2024.
The children (56.7% boys) were diagnosed with CAH at an average age of 2.1 years overall, and average ages of 1.6, 1.9 and 2.9 years in those with the salt wasting (n=32), nonclassic (n=8) and simple virilizing (n=20) forms of CAH, respectively. The children continued standard hydrocortisone therapy with fludrocortisone as indicated and 53.3% were also given a gonadotropin-releasing hormone (GnRH) analogue to suppress puberty.
The boys and girls began anastrozole treatment at an average age of 8.0 and 7.3 years, respectively, and were treated until bone age reached 16.0 and 14.0 years, respectively. Fifty-seven children completed 1 year of anastrozole, 53 completed 2 years, 32 completed 4 years and 19 children completed 6 years of treatment.
The mean bone age z-score decreased significantly during treatment with anastrozole, indicating that the degree of bone age advance versus chronological age reduced, with longer duration of treatment having a greater impact. Two years before treatment began, the bone age z-score was 2.0, increasing to 4.2 at baseline of anastrozole treatment and falling to 3.7, 3.0, 2.0 and 1.3 after 1, 2, 4 and 6 years of therapy, respectively.
In turn, the predicted adult height z-score increased significantly during anastrozole therapy, with a correlation between benefit and duration of therapy. The value increased from a baseline of –2.1 to –0.45 and 0.18 after 4 and 6 years of treatment, respectively. The corresponding values for height z-scores after correction for bone age were –1.7, –0.33 and 0.18.
The researchers report that none of the patients or their parents reported an increase in androgen excess symptoms during anastrozole treatment, such as hair growth, acne or virilisation.
The majority (87%) of patients had one or more dual-energy X-ray absorptiometry scans during anastrozole treatment and no significant alterations were detected in total body or lumbar bone mineral density (BMD) z-scores. After taking into consideration height z-scores, a significant increase of 0.44 in total body (but not lumbar) BMD z-scores was detected.
Twenty-one of the 26 girls in the study underwent at least one ovarian ultrasound during anastrozole therapy and a simple cyst was detected on the right ovary of one girl aged 12.7 years after 2.8 years of treatment, although her left ovary was unaffected, “suggesting that anastrozole-driven [luteinising hormone] overdrive was not the reason for the cyst”, write Sarafoglou et al.
Liver function testing detected persistent liver enzyme elevations in two patients with a BMI above the 99th percentile for age during anastrozole treatment, with ultrasound findings indicating metabolic dysfunction associated with steatotic liver disease. One patient had normalisation of liver enzymes while continuing anastrozole, the other patient had normalisation following discontinuation with no increases detected after re-initiation of anastrozole; both cases were thought to be triggered by viral infection.
Finally, the team says that the hydrocortisone dose “remained within the recommended range per CAH consensus guidelines” during anastrozole therapy and that receipt of GnRH analogue therapy did not significantly impact the effect of anastrozole on bone age z-score or BMD z-score.
“Our report is the first to provide longitudinal growth and bone maturation outcomes spanning up to an 8-year period, including 2 years prior and 6 years on anastrozole, in a large cohort of children with 21OHD”, Sarafoglou and co-authors summarise in the Journal of Clinical Endocrinology & Metabolism.
They recommend that “a longitudinal randomized clinical trial is needed to assess long-term outcomes”, during which liver function and BMD should be monitored from baseline, as well as ovarian ultrasound assessments conducted where applicable.
Nevertheless, the researchers add: “While our study showed that anastrozole effectively optimizes growth in patients with CAH via inhibition of estrogen-mediated bone age advancement, it does not target other androgen or [adrenocorticotropic hormone]-mediated side effects, such as increased virilization and testicular adrenal rests.
“Emerging nonsteroidal therapies, including CRF1 receptor antagonists, have the potential to decrease [adrenocorticotropic hormone]-driven adrenal androgen excess and its associated comorbidities during childhood even before clinical symptoms develop in patients with CAH.”
By Lynda Williams
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