Growth-promoting therapies frequently prescribed to counteract the adult height loss associated with classical congenital adrenal hyperplasia (CAH) may provide greater height benefits in boys, according to a large multicenter study recently published in The Journal of Clinical Endocrinology & Metabolism. The findings reveal a gender-dependent difference in how effectively these commonly deployed hormonal interventions preserve a child’s genetic growth potential.
Congenital adrenal hyperplasia is a group of rare, inherited genetic disorders that affect the adrenal glands, which sit atop the kidneys and produce essential life-sustaining hormones. In children born with CAH, a specific genetic mutation impairs the production of cortisol and aldosterone. Because the body cannot synthesize these critical hormones, the pituitary gland overcompensates by continuously stimulating the adrenal glands. This constant overdrive floods the body with excessive amounts of male sex hormones, known as androgens, causing severe hormonal and developmental imbalances from early childhood.
The retrospective, longitudinal study titled “Impact of Growth-promoting Therapies on Puberty, Growth, and Final Height in Classical 21-hydroxylase Deficiency,” tracked 284 patients with genetically confirmed classical 21-hydroxylase deficiency (21-OHD), which represents the leading cause of CAH, who were diagnosed before the implementation of a national newborn screening program. Conducted by a pediatric endocrinology research team at Marmara University and Istanbul University in Türkiye, the study found that growth-promoting therapies appeared to confer greater height benefits in boys than in girls, highlighting a sex-related difference in treatment outcomes.
The primary clinical goal in treating classical 21-OHD is replacing deficient glucocorticoids and mineralocorticoids while simultaneously suppressing excess adrenal androgens. Left unchecked, these elevated androgens accelerate bone maturation and trigger precocious puberty, which ultimately fuses skeletal growth plates early and compromises adult height. To disrupt this premature fusion and buy patients more growing time, pediatric endocrinologists frequently deploy growth-promoting drugs — including gonadotropin-releasing hormone (GnRH) analogs, aromatase inhibitors, and cyproterone acetate — either alone or in combination.
The investigators recommend that clinicians implement highly personalized pubertal monitoring protocols and individualize decisions regarding growth-promoting therapies for girls with the condition based on baseline height prognosis, pubertal progression, and treatment response.
The study evaluated final adult height relative to a patient’s genetic target, known as mid-parental height (MPH). Within the total cohort, 41.1% of the patients received growth-promoting protocols. Among boys, growth-promoting therapies were associated with a smaller gap between final adult height and genetic height potential, improving from −6.7 cm to −2.3 cm. In girls, no comparable benefit was observed, with the corresponding values being −3.7 cm and −6.6 cm, respectively. Researchers suggest that baseline differences in disease severity and height prognosis may have contributed to this finding.
Height outcomes differed by sex, with boys showing greater preservation of genetic height potential. The authors note that this observation may, in part, reflect the use of aromatase inhibitors in boys.
The data further revealed that puberty in classical 21-OHD naturally follows an atypical trajectory. It is characterized by an earlier onset but a significantly slower tempo and a prolonged overall duration. This elongated pubertal window was especially pronounced in female patients, effectively lengthening the timeframe during which their developing skeletons were exposed to complex, fluctuating hormonal treatments.
The researchers noted that the delicate clinical balance between necessary glucocorticoid replacement therapy and androgen suppression remains incredibly difficult for physicians to navigate. Over-treatment with glucocorticoids directly stunts linear growth, while under-treatment fails to curb the adrenal androgens that accelerate skeletal maturation. The authors concluded that a rigid, one-size-fits-all approach to managing growth in classical 21-OHD is ineffective. Moving forward, the investigators recommend that clinicians implement highly personalized pubertal monitoring protocols and individualize decisions regarding growth-promoting therapies for girls with the condition based on baseline height prognosis, pubertal progression, and treatment response.
