Adrenal Hyperplasia (AH) is a collection of genetic conditions affecting the adrenal glands, which produce important hormones. This disorder interferes with the body’s ability to synthesize cortisol, often leading to a compensatory overproduction of other hormones, particularly androgens. While the severe form, Classic Congenital Adrenal Hyperplasia (CAH), is typically identified at birth, the milder, late-onset presentation, Non-Classic Adrenal Hyperplasia (NCAH), often goes undiagnosed until adulthood. NCAH is the focus for adults seeking answers for persistent hormonal symptoms.
Understanding Non-Classic Adrenal Hyperplasia
NCAH is caused by a partial deficiency in the 21-hydroxylase enzyme, encoded by the CYP21A2 gene. This enzyme is required for synthesizing the stress hormone cortisol and the mineral-regulating hormone aldosterone. In NCAH, the gene mutation is mild, leaving patients with approximately 20% to 50% of normal enzyme activity. This partial function is usually enough to prevent the severe salt-wasting crisis and cortisol deficiency seen in the classic form.
The body attempts to overcome the partial enzyme block by increasing the production of adrenocorticotropic hormone (ACTH) from the pituitary gland. This elevated ACTH constantly stimulates the adrenal glands, causing them to enlarge, which is the “hyperplasia” part of the name. Since the 21-hydroxylase enzyme is still partially impaired, the precursor hormones used to make cortisol begin to accumulate.
Specifically, the precursor 17-hydroxyprogesterone (17-OHP) builds up and is then shunted toward the pathway that produces androgens, or male hormones. This excessive production of androgens, such as testosterone and androstenedione, ultimately causes most of the clinical signs and symptoms observed in adults with NCAH. Unlike the classic form, NCAH generally results in sufficient cortisol and aldosterone production, meaning the risk of an adrenal crisis is low unless the patient is undergoing significant physical stress.
Manifestations in Adult Males and Females
The symptoms of Non-Classic Adrenal Hyperplasia primarily stem from the chronic overproduction of androgens and manifest differently between the sexes. Females often experience more pronounced symptoms, leading to a higher rate of diagnosis in this group. A common complaint is hirsutism, which is the growth of excessive, coarse hair in a male pattern on the face, chest, or abdomen.
Women may also struggle with persistent acne that does not respond well to typical dermatological treatments. The excess androgens frequently disrupt the normal ovulatory cycle, resulting in irregular or absent menstrual periods, known as oligomenorrhea or amenorrhea. This hormonal imbalance can also contribute to fertility issues, as it interferes with the predictable release of an egg.
Manifestations in adult males are often more subtle and may be entirely absent, meaning the condition is frequently underdiagnosed in men. Males might exhibit premature balding in a male-pattern distribution or a slightly earlier development of beard hair. A more serious, though less common, complication is the development of benign growths in the testicles called testicular adrenal rest tumors (TARTs). These tumors are essentially adrenal tissue that has migrated to the testes, and they can impair sperm production.
Confirming the Diagnosis
The diagnostic process for Non-Classic Adrenal Hyperplasia involves specific laboratory tests designed to detect the partial enzyme deficiency. The initial screening step is measuring the baseline level of the precursor hormone 17-hydroxyprogesterone (17-OHP) in the morning serum. An elevated baseline 17-OHP level, often greater than 200 ng/dL, serves as a strong indicator that further testing is warranted. However, basal levels alone can sometimes be normal in individuals with NCAH, so a definitive test is required.
The gold standard for confirmation is the ACTH stimulation test, which involves administering a synthetic version of ACTH and then measuring the resulting spike in 17-OHP. This test exaggerates the adrenal gland’s response, revealing the underlying defect that may not be apparent under normal conditions. A stimulated 17-OHP level greater than 30 nmol/L (or approximately 10 ng/mL) is considered diagnostic for NCAH.
The results of the ACTH stimulation test must be interpreted carefully, as a mild elevation can sometimes occur in other conditions or in healthy individuals. Therefore, genetic testing for mutations in the CYP21A2 gene is often used as a confirmatory measure, especially when the biochemical results are borderline. This analysis can identify the specific mutations that cause the partial 21-hydroxylase deficiency.
Treatment and Long-Term Management
The treatment approach for Non-Classic Adrenal Hyperplasia is highly individualized and focuses on suppressing the overproduction of androgens to manage symptoms. The cornerstone of medical management is the use of low-dose glucocorticoids, such as prednisone or dexamethasone. These medications work by providing negative feedback to the pituitary gland, which decreases the release of ACTH and, consequently, reduces the adrenal gland’s excessive androgen production.
For women experiencing hirsutism and irregular menses, this treatment aims to normalize hormone levels, often leading to more regular menstrual cycles. Glucocorticoid therapy is reserved for symptomatic patients, as it carries risks of side effects like reduced bone density or weight gain if over-dosed. Non-glucocorticoid treatments, such as anti-androgen drugs or oral contraceptives, may also be used, particularly to manage skin and hair symptoms.
Long-term management involves regular monitoring of hormone levels, including 17-OHP and androgens, to ensure the treatment is effective without causing overtreatment. For patients seeking pregnancy, therapy is often adjusted to achieve the necessary hormonal balance for successful ovulation and gestation. Treatment is considered a lifelong commitment, with the goal of minimizing hyperandrogenism and improving quality of life while avoiding the complications associated with chronic steroid use.