11-hydroxylase deficiency (11-OHD) is a rare, inherited disorder that primarily affects the adrenal glands, situated above the kidneys. This condition belongs to a group of genetic diseases known collectively as Congenital Adrenal Hyperplasia (CAH). The disorder disrupts the body’s ability to manufacture three necessary steroid hormones: cortisol, aldosterone, and sex hormones. This imbalance leads to the overproduction of male hormones and abnormal blood pressure regulation.
Understanding the Adrenal Gland Pathway
The adrenal glands house a complex pathway of enzymes responsible for converting cholesterol into various steroid hormones. Cortisol and aldosterone are among the most important products of this process. The enzyme 11-hydroxylase (CYP11B1) is responsible for the final steps in the creation of both cortisol and a precursor to aldosterone.
When the gene for this enzyme is mutated, the production line for cortisol and aldosterone is severely blocked. This blockage causes immediate precursors to build up significantly within the adrenal gland cells. The primary precursor that accumulates due to this faulty enzyme is 11-deoxycortisol, also called Compound S.
The severe shortage of cortisol is recognized by the pituitary gland, which responds by releasing large amounts of Adrenocorticotropic Hormone (ACTH). ACTH stimulates the adrenal glands to produce more cortisol, but because the enzyme is defective, the stimulation only causes the gland to enlarge (hyperplasia) and churn out greater quantities of the blocked precursors.
These accumulating precursors are shunted into an alternative branch of the steroid pathway, leading to the excessive production of androgens (male sex hormones). Furthermore, the buildup of 11-deoxycorticosterone (DOC), a precursor in the aldosterone pathway, is significant. DOC possesses potent mineralocorticoid activity, meaning it strongly regulates salt and water balance in the body.
Key Clinical Manifestations: Hormone Imbalance Effects
The dual problem of excess androgens and excess mineralocorticoid precursors results in two distinct, observable health effects: virilization and hypertension. Virilization, the development of male physical characteristics, is the direct result of the adrenal glands overproducing androgens. In female newborns, high exposure to male hormones in the womb can cause the external genitalia to appear ambiguous at birth, such as having an enlarged clitoris or partially fused labia.
Boys with the condition usually appear normal at birth, but both sexes will show signs of premature sexual maturation later in childhood, often between two and four years of age. This includes the appearance of pubic or underarm hair, adult body odor, and accelerated growth velocity. This rapid growth leads to an accelerated maturation of the bones, which can ultimately result in a shorter adult height.
The second major manifestation of 11-OHD is high blood pressure (hypertension), which occurs in approximately two-thirds of individuals with the severe, or classic, form. This is a distinguishing feature of 11-OHD compared to other forms of CAH. The hypertension stems from the accumulated precursor, 11-deoxycorticosterone (DOC), acting on the body’s mineralocorticoid receptors.
The action of DOC causes the kidneys to retain salt and water, which increases the total blood volume and elevates blood pressure. Chronic hypertension can lead to serious complications like left ventricular hypertrophy, where the heart muscle thickens. The salt retention typically suppresses the body’s natural renin levels, which is a useful diagnostic indicator.
Diagnosis and Newborn Screening
Diagnosis of 11-hydroxylase deficiency often begins with the clinical observation of virilization in a female infant or the onset of hypertension in early childhood. Newborn screening programs for CAH primarily measure 17-hydroxyprogesterone (17-OHP), which is not a reliable primary screen for 11-OHD, although some cases may show a slightly elevated 17-OHP.
The most definitive biochemical marker for 11-OHD is the measurement of the precursor 11-deoxycortisol, which is markedly elevated in classic cases. For diagnostic confirmation, blood tests assess the levels of cortisol, ACTH, and adrenal androgens like androstenedione. Suppressed plasma renin activity, alongside elevated 11-deoxycortisol and 11-deoxycorticosterone, strongly indicate the diagnosis.
If initial blood work is inconclusive, an ACTH stimulation test may be used, where a synthetic ACTH is administered to see how the adrenal glands react and which precursor hormones accumulate. Genetic testing confirms the presence of a mutation in the CYP11B1 gene and is important for genetic counseling.
Lifelong Management and Monitoring
The primary goal of managing 11-hydroxylase deficiency is to replace the missing cortisol and suppress ACTH overproduction. This is achieved through lifelong glucocorticoid replacement therapy, typically using oral hydrocortisone. Suppressing ACTH reduces the excessive drive on the adrenal glands, diminishing the production of androgens and the blood pressure-raising DOC.
Glucocorticoid dosage must be carefully balanced. Insufficient treatment allows virilization and hypertension to worsen, while excessive treatment can lead to side effects like weight gain and growth suppression. Because excess DOC provides sufficient mineralocorticoid activity, patients with 11-OHD usually do not require separate mineralocorticoid medication.
Regular monitoring ensures the treatment is effective and balanced. This includes frequent checks of blood pressure and periodic blood tests for 11-deoxycortisol and adrenal androgens. Growth velocity and skeletal maturation are also monitored in children.
An important aspect of management is “stress dosing,” requiring patients to temporarily increase their glucocorticoid dose during periods of physical stress, such as fever or surgery. This proactive increase prevents a life-threatening adrenal crisis, a risk for anyone with chronic adrenal insufficiency.