Constant vigilance is required for both the patient and the clinicians when treating people with congenital adrenal hyperplasia. Early screening, diligent monitoring, and a holistic approach can ensure that complications are kept at bay and the patients can maintain a high quality of life.
In the quiet exam rooms of specialized endocrine clinics, a high-stakes balancing act plays out every day. It is a clinical tightrope walk where the safety net is made of synthetic hormones and the stakes are measured in lifelong metabolic health. This is the world of congenital adrenal hyperplasia (CAH), a group of rare genetic disorders that transform the adrenal glands — the body’s chemical powerhouses — into sites of profound dysfunction.
The treatment of CAH has evolved from being a childhood disease with high mortality to one where most patients now survive into adulthood. Richard J. Auchus, MD, PhD, professor of internal medicine Division of Metabolism, Endocrinology & Diabetes (MEND) and chief of the Endocrinology & Metabolism Section at the University of Michigan Medical School, Ann Arbor, Mich., points out that although children with CAH have received effective treatment for years, it is only over the past two to three decades that many individuals have reached later adulthood, presenting new challenges in adult care.
“Adults with CAH is somewhat of a new disease,” Auchus says, mentioning that it is only recently that these patients have been able to navigate complications that occur later in life such as infertility, menopause, and osteoporosis. “When the disease is managed properly during childhood, patients tend to experience fewer complications. Problems usually occur if good endocrinology management is inconsistent and control of the disease is lost.”
The Biological Disruption: What is CAH?
At its core, classic (severe) CAH is a breakdown in the body’s internal hormonal manufacturing line. Due to an autosomal recessive genetic defect — most commonly a deficiency in the enzyme 21-hydroxylase, but there are also deficiencies in enzymes like 11β-hydroxylase, 17α-hydroxylase/17,20-lyase, or 3β-hydroxysteroid dehydrogenase — the adrenal glands are unable to produce cortisol, the “stress hormone” essential for maintaining blood pressure, blood sugar, and immune response.
“Adults with CAH is somewhat of a new disease. When the disease is managed properly during childhood, patients tend to experience fewer complications. Problems usually occur if good endocrinology management is inconsistent and control of the disease is lost.” — Richard J. Auchus, MD, PhD, professor of internal medicine, Division of Metabolism, Endocrinology & Diabetes (MEND) and chief of the Endocrinology & Metabolism Section, University of Michigan Medical School, Ann Arbor, Mich.
Because the pituitary gland senses a lack of cortisol, it goes into overdrive, pumping out adrenocorticotropic hormone (ACTH) to stimulate the adrenals. However, since the production line is broken, the building blocks meant for cortisol are diverted into the production of other steroids, most commonly androgens (male sex hormones). This results in a double-edged sword: a dangerous deficiency in vital steroids and a toxic surplus of androgens.
This biochemical imbalance creates a lifelong “Goldilocks” problem:
- Too little medication: Excess androgens lead to rapid bone aging, premature puberty, and virilization.
- Too much medication: Excessive glucocorticoids (GCs) lead to stunted growth, obesity, and cardiovascular disease.
The Pediatric Tightrope: Growth and Puberty
For pediatric endocrinologists, the challenge begins at birth. As mentioned in the 2018 The Endocrine Society Guidelines for CAH, universal newborn screening via 17-hydroxyprogesterone (17-OHP) levels is “the gold standard” for early detection, preventing fatal salt-wasting crises. However, the following years involve a struggle over height and development timing.
“Until we have a medication that more closely mimics the daily secretion patterns of our own adrenal glands, we have to constantly readjust,” says Phyllis Speiser, one of the guideline authors and a pediatric endocrinologist from the Cohen Children’s Medical Center of New York at Northwell Health and Feinstein Institutes for Medical Research, Manhasset, N.Y.
The primary tool for treatment remains GCs like hydrocortisone. However, GCs are potent growth inhibitors. If a child is slightly over-treated to suppress androgens, their linear growth slows. Conversely, if under-treated, the excess androgens cause the “growth plates” (epiphyses) in the bones to fuse too early. The result in both scenarios is the same: a significant loss in final adult height.
Furthermore, the androgen surge in poorly controlled CAH can trigger precocious (early) puberty. This is not just a physical change; it carries immense psychological weight for a young child and further complicates the hormonal milieu, often requiring additional medications like GnRH agonists to “pause” puberty while the adrenal management is refined.
The Cardiometabolic Toll of Treatment
As patients transition into adulthood, the focus shifts from growth to metabolic survival. For decades, the medical community relied on “supraphysiologic” doses of steroids to keep adrenal androgens in check. We now know this comes at a heavy price.
Published in a 2010 JCEM article, the landmark CaHASE study (Congenital Adrenal Hyperplasia Adult Study Executive) in the UK exposed a sobering reality: Many adults with CAH have the metabolic profile of people much older.
The study first exposed the “failure of balance” in adult CAH care, revealing that standard glucocorticoid treatments often resulted in poor metabolic health (e.g., metabolic syndrome, hypertension, and osteopenia/osteoporosis), stunted growth, and impaired fertility (e.g., PCOS and irregular ovulation in females and testicular adrenal rest tumors in men). CaHASE pushed the medical community to move beyond the hyper-reactive 17-OHP biomarker, which often led to overtreatment. This shift directly paved the way for more stable monitoring through androstenedione and, most recently, the adoption of 11-oxygenated androgens (like 11-ketotestosterone). These newer biomarkers are highly adrenal-specific, allowing clinicians to precisely target androgen excess without the collateral damage of excessive steroid use.
The High Cost of Poor Control: A Cautionary Tale
A recent case study highlights the extreme consequences of chronic ACTH overstimulation. Published in JCEM Case Reports, the study details a patient with poorly controlled CAH who developed giant bilateral adrenal myelolipomas — benign tumors composed of mature adipose tissue and hematopoietic elements.
“Even in the case of very large myelolipomas that do not cause any symptoms, I would not see a compelling indication for surgery and would only recommend surgery if the patient absolutely wants it. Of course, the risk of rupture of the giant myelolipoma is not zero, but it is not extremely high either. We must be careful not to make patients who are not ill ‘unnecessarily’ ill.” — Martin Fassnacht, MD, head of Endocrinology and Diabetology at Medical Clinic 1 at the University Hospital, Wurzburg, Germany
While small lesions (under 5 cm) are typically left alone, those exceeding 6 cm are classified as “giant” and often require intervention due to the risk of serious complications. The European Society of Endocrinology (ESE)’s clinical practice guidelines for incidental adrenal masses in 2023 recommended “against adrenal biopsy during workup in any adrenal mass unless there is a history of extra-adrenal malignancy.”
Under the relentless lash of high ACTH levels, the adrenal tissue does not just work harder; it morphs. In this specific case, the masses grew to a staggering 30 cm and 27.5 cm — roughly the size of watermelons — filling the abdominal cavity, displacing the kidneys, and compressing the vena cava.
The decision to undergo a bilateral adrenalectomy (removal of both adrenal glands) is a heavy one. It renders the patient permanently dependent on life-sustaining medication with zero internal backup. However, when a mass is displacing organs or causing chronic pain, surgery becomes the only viable path.
“For me, such symptoms would be a reason for surgery and almost the only clear indication for surgery. Even in the case of very large myelolipomas that do not cause any symptoms, I would not see a compelling indication for surgery and would only recommend surgery if the patient absolutely wants it,” says Martin Fassnacht, MD, head of Endocrinology and Diabetology at Medical Clinic 1 at the University Hospital in Wurzburg, Germany and one of the ESE guideline authors. “Of course, the risk of rupture of the giant myelolipoma is not zero, but it is not extremely high either. We must be careful not to make patients who are not ill ‘unnecessarily’ ill.”
A New Toolkit: Decoupling Treatment
The most exciting development in 2026 is the emergence of therapies that “decouple” the management of adrenal insufficiency from the suppression of androgens. For 70 years, we used one hammer (steroids) for two different nails. Now, we have specialized tools.
1. CRF-1 Antagonists
Drugs like crinecerfont (Crenessity), approved in late 2024 by the U.S. Food and Drug Administration for children as young as four years, block the corticotropin-releasing factor receptor 1 in the pituitary gland. This lowers ACTH production at the source without requiring extra steroids and advances the idea that better control of children with CAH can improve prospects for long-term health.
2. ACTH Antagonists
For patients who do not respond to pituitary blockers, newer agents like atumelnant (CRN04894, currently in Phase 3) block the ACTH receptor on the adrenal gland itself. This provides a “safety valve” to prevent the adrenals from overproducing androgens even if ACTH levels remain high.
3. Chronotherapy
New delayed-release formulations, such as Efmody, are designed to be taken at bedtime. They release cortisol in the early morning hours to mimic the natural human “dawn phenomenon,” suppressing the morning ACTH surge more effectively than traditional tablets.
These new tools are not substitutes but can be used in conjunction with standard medication regimens including hydyrcortisone and fludrocortisone.
“Future guidelines may prioritize non-steroidal adjuncts as first-line therapy for androgen control, fundamentally altering the long-term complication profile of the disease, says Maximilien Rappaport, assistant professor of clinical medicine at the University of South Carolina School of Medicine in Greenville and first author of the JCEM Case Reports study.
A New Era of Care
The journey of a CAH patient is one of resilience. It is a journey that requires constant vigilance from both the patient and a dedicated medical team. The transition from the “brute force” hormone suppression of the past to the “precision management” of today offers hope for better quality of life and fewer surgical complications.
Recent literature offers us clear lessons: We must screen early, monitor precisely, and treat holistically. By integrating the rigorous clinical guideline standards with the multidisciplinary care models advocated by modern researchers, we can ensure that “giant” complications remain a rarity, and that every patient with CAH can live a healthy, balanced life.
Oberst is a freelance writer and former associate editor of Endocrine News. She contributes to the monthly Trends & Insights column.
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