Pregnenolone Test

About the Test

Pregnenolone tests are blood tests conducted on infants, usually as part of a panel of tests. It is used as a diagnostic tool to help find the underlying cause of CAH in infants. CAH is suspected when an infant has ambiguous external sex organs, signs of adrenal insufficiency, excess loss of sodium and fluids, or low or high blood pressure.

Purpose of the test

Pregnenolone tests are one diagnostic tool doctors use on newborns after the more common causes of CAH have been ruled out.

All newborns are screened for the most common cause of CAH using a test that measures 17-hydroxyprogesterone (17-OHP). If this testing is abnormal, it may be followed by adrenocorticotropic hormone (ACTH) testing and then by groups or panels of precursors and hormones to determine which enzyme deficiencies are present. This includes 11-deoxycorticosterone and 11-deoxycortisol testing to help detect 11-beta-hydroxylase deficiency.

If the two common forms of CAH are ruled out, especially if a baby has external sex organs that are not clearly male or female (ambiguous genitalia), pregnenolone tests may be ordered, among others, to detect the rare forms as the cause of the symptoms.

What does the test measure?

This test measures the amount of pregnenolone in the blood to help detect rare forms of CAH.

CAH is a group of inherited disorders associated with deficiencies in the enzymes required to produce steroid hormones. This 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. 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 (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). This can affect the development of secondary sexual characteristics of both males and females at puberty.

Laboratory tests can measure pregnenolone, several intermediate precursors, and one or more steroid hormones to determine which step is deficient or defective. This is 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 and tests for other precursors may help establish a diagnosis of 3-beta-hydrosteroid dehydrogenase or 17-alpha-hydroxylase or StAR deficiency.

When should I get this test?

Pregnenolone is ordered when an infant has external sex organs that are not clearly male or female (ambiguous genitalia) and/or has signs of adrenal insufficiency, excess loss of sodium and fluids (“salt wasting”), or low or high blood pressure. It is usually ordered following testing for 17-OHP.

This test is primarily ordered when a health care practitioner suspects symptoms may be due to a CAH other than 21-hydroxylase deficiency or 11-beta-hydroxylase deficiency and/or wants to rule it out. If affected, the signs and symptoms include:

With 3-beta-hydroxysteroid dehydrogenase deficiency

Both males and females may have signs of adrenal insufficiency and “salt wasting.”

Males

• Male infants may have sex organs that are not clearly male or female and/or may have an opening of the urethra on the underside of the penis instead of the tip (hypospadias).
• Teen boys may have poor and/or delayed development of secondary sexual characteristics, such as facial hair or deep voice.

Females

• Female infants usually appear normal but may have some abnormal enlargement of the clitoris.
• Girls may have acne and accelerated growth.
• Teen girls may have excess hair on their body and face (hirsutism) and ovaries with numerous fluid-filled cysts (polycystic ovaries).

With 17-alpha-hydroxylase deficiency

Both males and females may have high blood pressure (hypertension).

Males

• Male infants may have entirely female external sex organs and be mistaken for a female, or they may have sex organs that are not clearly male or female.
• Teen boys will have symptoms of delayed puberty, with a lack of development of secondary sexual characteristics.

Females

• Female infants will appear normal.
• Teen girls will have symptoms of delayed puberty, with a lack of development of secondary sexual characteristics and no menstrual periods (amenorrhea).

If a patient has been diagnosed with one of these types of CAH, pregnenolone may be ordered periodically to monitor the condition and treatment.

Some doctors may also use a pregnenolone test to help diagnose and determine the effectiveness of treatment for memory and neurologic illnesses. There is limited and conflicting evidence for memory enhancement in humans when pregnenolone is given as a supplement or drug.

A placebo-controlled clinical trial was conducted, which demonstrated some efficacy in improving functional capacity in participants with schizophrenia but did not improve cognitive symptoms. Pregnenolone is converted to pregnenolone sulfate and allopregnanolone, which may be an effective steroid to stimulate or suppress activity in various brain areas.