Classic Congenital Adrenal Hyperplasia (CAH) is the most common rare disease affecting
the adrenal glands. It is characterized by primary adrenal insufficiency due to
congenital enzymatic defects, which impair glucocorticoid synthesis. As a result,
patients require lifelong glucocorticoid replacement therapy, often combined with
mineralocorticoid supplementation in the salt-wasting form of the disease. Standard
treatment involves short-acting, immediate-release glucocorticoids (such as
hydrocortisone or cortisone acetate) administered two or three times daily. Although
lifesaving, chronic glucocorticoid therapy is associated with increased cardiometabolic
risk, altered glucose and lipid metabolism, weight gain, osteoporosis, higher infection
susceptibility, and reduced life expectancy, even at replacement-level doses.
In CAH, supraphysiologic doses and reverse circadian timing of glucocorticoid
administration are often employed to suppress androgen excess. This approach, however,
may exacerbate side effects related to glucocorticoid overexposure. A dose-dependent
impact of glucocorticoid therapy has been observed on cardiovascular risk, bone mineral
density, body composition, and immune function. Despite these known effects, reproductive
and sexual health outcomes remain under-investigated, representing a significant unmet
need in the comprehensive management of CAH.
In male patients, reproductive dysfunction is frequently observed and is often attributed
to the development of testicular adrenal rest tumors (TARTs), which can impair fertility.
Current medical approaches to TARTs include high-dose, long-acting glucocorticoid
therapy, with variable effects on tumor regression and semen quality. However, this
strategy is associated with additional metabolic and cardiovascular risks. Furthermore,
uncontrolled androgen excess may be converted to estrogens and, together with elevated
progestogen levels, suppress the hypothalamic-pituitary-gonadal axis, contributing to
hypogonadotropic hypogonadism.
Female patients with CAH may present with menstrual disturbances, anovulation,
biochemical and clinical hyperandrogenism, and infertility. Additionally, non-hormonal
factors such as anatomical variations and psychological distress may impact sexual health
and reproductive intentions.
Recent advances in CAH therapy include the development of novel glucocorticoid
formulations that aim to better replicate the circadian rhythm of cortisol secretion.
Dual-release hydrocortisone and non-glucocorticoid therapeutic options have shown promise
in improving metabolic, immunological, and hormonal parameters, and may allow a
decoupling of glucocorticoid replacement from androgen suppression. However, real-world
data on the long-term cardiometabolic outcomes of these newer treatments remain limited,
and reproductive parameters-such as semen quality, pregnancy rates, and menstrual cycle
normalization-require further clinical investigation.
The aim of this observational prospective study is to evaluate the impact of hormonal
alterations and treatment strategies on reproductive and sexual health in individuals
with CAH. The study will adopt a multidimensional clinical-translational approach,
integrating clinical assessments with advanced profiling techniques such as steroidomics,
microRNA analysis, and gene expression profiling. These precision medicine tools are
expected to identify novel biomarkers and mechanistic pathways involved in reproductive
dysfunction, ultimately supporting the development of targeted therapeutic strategies.
Following screening based on inclusion and exclusion criteria, eligible participants will
provide informed consent and undergo baseline evaluations. Follow-up assessments will be
conducted after significant modifications in therapy or lifestyle interventions,
typically within 3 to 6 months. In the absence of changes, at least one follow-up
evaluation will be scheduled within a 3- to 12-month timeframe, as appropriate for each
participant. Study evaluations will be integrated into routine clinical care without
altering standard management protocols.
