When an infant has external sex organs that are not clearly male or female (ambiguous genitalia) and/or has low or high blood pressure, low blood potassium (hypokalemia), or signs of excess loss of salt (salt wasting); when the most common cause for CAH, a 21-hydroxylase deficiency, has been ruled out; when a teen fails to develop secondary sexual characteristics and/or has delayed puberty
A blood sample drawn from a vein
The healthcare practitioner may or may not request a morning sample and may or may not give an injection such as ACTH to stimulate steroid hormone release.
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.
How is the test used?
Pregnenolone is typically ordered as part of a panel of tests that are used to help diagnose, monitor and/or rule out two of the more rare forms of congenital adrenal hyperplasia (CAH). The test is typically used 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 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), then pregnenolone tests may be ordered among others to detect the rare forms as the cause of a person's symptoms.
When is it ordered?
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 healthcare practitioner suspects that symptoms may be due to a CAH other than 21-hydroxylase deficiency or 11-beta-hydroxylase deficiency and/or wants to rule it out. An affected person may have signs and symptoms that include:
With 3-beta-hydroxysteroid dehydrogenase deficiency
Both males and females may have signs of adrenal insufficiency and "salt wasting."
- 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.
- Female infants usually appear normal but may have some degree of 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 may have ovaries with numerous fluid-filled cysts (polycystic ovaries).
With 17-alpha-hydroxylase deficiency
Both males and females may have high blood pressure (hypertension).
- 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.
- 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).
In a person who has been diagnosed with one of these types of CAH, pregnenolone may be ordered periodically to monitor the condition and treatment.
What does the test result mean?
In general, if there is an enzyme deficiency somewhere in the steroid hormone production process, then there is likely to be a mild to significant increase or decrease in pregnenolone levels. The degree of increase or decrease depends upon the enzyme that is deficient and the severity of the deficiency. Results of pregnenolone need to be interpreted along with other precursor and hormone results.
With 3-beta-hydroxysteroid dehydrogenase deficiency, pregnenolone, 17-hydroxypregnenolone, and DHEA are typically elevated, and 17-OHP may be elevated. If they are measured, cortisol and aldosterone levels are likely to be low.
With 17-alpha-hydroxylase deficiency, pregnenolone and progesterone may be elevated, along with 11-deoxycorticosterone. Other precursors and steroid hormones, if measured, may be low, including:
With Lipoid CAH, all the steroids tested would be low, but ACTH is expected to be elevated.
Is there anything else I should know?
Since deficiencies in 3-beta-hydroxysteroid dehydrogenase and 17-hydroxylase are rare causes of CAH, pregnenolone is much less commonly ordered than 17-OHP, the primary test for 21-hydroxylase deficiency CAH.
Excess facial and body hair in females and the delayed development of sexual characteristics in males and/or females may be due to a number of causes other than CAH. People should consult with their healthcare provider if they have concerns about their child's, or their own, symptoms or development.
Should I tell all of my doctors if I have CAH?
If I have CAH, or my child does, should my family members be tested?
You should talk to your healthcare provider or a genetic counselor about this. Since CAH is caused by an autosomal recessive genetic mutation, both parents must have an altered gene in order for a child to have the condition. If both parents are carriers then each child has a 25% chance of having the condition.
How long will it take for pregnenolone results?
This testing requires specialized equipment and is not offered by every laboratory. It may be necessary to send your blood sample to a reference laboratory and it may be several days to weeks for results to be available.
How can the doctor determine the sex of a baby with sex organs that are not clearly male or female?
Is this test used for other purposes?
Yes, sometimes it may be used to diagnose or follow treatment of neurological and memory issues. Pregnenolone, pregnenolone sulfate, and allopregnanolone have been implicated as neurosteroids largely through studies in rodents. There is limited and conflicting evidence for enhancement of memory in humans when pregnenolone is given as a supplement or drug. A placebo-controlled clinical trial was conducted, which demonstrated some efficacy improving functional capacity in participants with schizophrenia but did not improve cognitive symptoms. Pregnenolone is converted to pregnenolone sulfate and allopregnanolone, which may be the effective steroid to stimulate or suppress activity in various areas of the brain.