Pregnenolone is a chemical substance that is a precursor to all steroid hormones. This test measures the amount of pregnenolone in the blood in order to help detect rare forms of congenital adrenal hyperplasia (CAH).
CAH is a group of inherited disorders associated with deficiencies in the enzymes required for the production of the steroid hormones. CAH may be due to:
21-hydroxylase deficiency, the most common cause of CAH (about 90% of cases)
11-beta-hydroxylase deficiency (about 5-8% of cases)
3-beta-hydroxysteroid dehydrogenase and 17-alpha-hydroxylase deficiencies, two rare forms of the disease
Lipoid CAH, also very rare, is most often due to a defect in the StAR gene, which codes for the Steroidogenic acute regulatory protein, which, in turn, regulates the conversion of cholesterol to pregnenolone.
For normal steroid hormone production, cholesterol is converted into pregnenolone in the adrenal glands and then several enzymes complete the production of multiple hormones, including:
Cortisol, which helps metabolize proteins, lipids, and carbohydrates, maintain blood pressure, and regulate the immune system
Aldosterone, which maintains normal sodium and potassium levels in the blood and helps control blood volume and pressure
Sex steroid hormones – including androgens, the "male hormones” such as testosterone, and "female” hormones including estrogen and progesterone, which are responsible for the development and maintenance of male and female secondary sexual characteristics
Because a low level of cortisol causes the level of a pituitary hormone that stimulates adrenal growth and hormone production (adrenocorticotropic hormone, or ACTH) to become elevated, the adrenal gland increases in size. However, the increased size and activity cannot overcome the block in cortisol production. Other substances (such as pregnenolone) that do not need the defective enzyme will be produced in excess.
With CAH, the enzyme deficiency can cause a decrease in cortisol and/or aldosterone and, in some cases, an increase or decrease in androgens. Deficient androgens can cause male newborns to be born with external sex organs that are not clearly male or female (ambiguous genitalia) and can affect the development of secondary sexual characteristics of both males and females at puberty.
Pregnenolone, several of the intermediate precursors, and one or more of the steroid hormones can be measured by laboratory tests to determine which step is deficient or defective, based upon which products have been produced and how much and which precursors are in excess.
If both 21- and 11-hydroxylase deficiencies have been ruled out (the most common forms of CAH), then analysis of pregnenolone, along with tests for other precursors, may be used to help establish a diagnosis of 3-beta-hydrosteroid dehydrogenase or 17-alpha-hydroxylase or StAR deficiency.