3β-Hydroxysteroid Dehydrogenase Deficient NCAH: A Myth or Reality

In contrast to classic adrenal hyperplasia (CAH), which cause symptoms that are evident either at or immediately after birth, the nonclassic adrenal hyperplasias are a series of inherited disorders that cause symptoms generally near or after puberty. Signs and symptoms associated with nonclassic adrenal hyperplasia (NCAH) include signs of premature puberty, including early growth of pubic and underarm hair and advanced bone age. More commonly, post-pubertal women develop excessive facial and body hair, irregular periods, acne, and scalp hair loss (androgenic alopecia). Some women with NCAH have difficulty conceiving due to irregular ovulation as well as the very high levels of circulating progesterones, hormones made in the adrenal glands and ovaries, which causes the lining of the uterus to be unreceptive to a pregnancy.

The most common cause of NCAH is 21- hydroxylase (21-OH) deficiency, due to a genetic defect of the gene CYP21. In fact, well over 90 percent of all CAH and NCAH cases are due to genetic mutations of this gene. There are two other theoretical causes of NCAH including genetic defects of the genes CYP11B1 (determining 11β-hydroxylase [11-OH] activity) and HSD3B2, (determining 3β-hydroxysteroid dehydrogenase [3β-HSD] activity). To date, few subjects have been found to be affected with 11- OH deficient NCAH, the vast majority of them are children, and no patient with genetically confirmed 11-OH deficient NCAH has been diagnosed in adulthood.

Previous reports have suggested that 3β-HSD deficient NCAH is one of the most common causes of androgen (male hormone) excess in women. This assumption was based on the finding that many hyperandrogenic patients had elevated levels of 17-hydroxypregnenolone and DHEA; both of these steroids are immediate precursors to the 3β-HSD enzyme. However, others and we have demonstrated that the elevations in 17-hydroxypregnenolone and DHEA present in hyperandrogenic women are relatively mild, generally not exceeding two-fold the upper normal limit found in healthy women. In contrast, the level of 17-hydroxyprogesterone (17-OHP), the immediate precursor to the 21-OH enzyme, is 3-fold to 10-fold greater than the upper normal limit in NCAH patients. In addition, a number of investigators, including ourselves, have noted that between 25 percent and 40 percent of women with the polycystic ovary syndrome (PCOS), another fairly common cause of androgen excess in women, have elevated levels of DHEA and DHEA sulfate (DHEAS), suggesting that the adrenal may be overactive in patients with PCOS, not related to the presence of a genetic mutation.

This data indicates that we were over-diagnosing patients with 3β-HSD deficient NCAH, and that many of these women simply have PCOS with a hyper-reactive adrenal, similar to the hyper-reactive ovary also observed in PCOS. More recently, Dr. Songya Pang and colleagues have done very careful genetic studies of patients with supposedly 3β-HSD deficient NCAH and observed that the patients who had genetic defects of the 3β-HSD gene had 17-hydroxypregnenolone values that were at least 20-50 standard deviations above age-matched controls (at least 10-fold the upper normal limit), and all of these presented in childhood. In fact, to date, there has been no patient with 3β-HSD deficient NCAH who presented as a hyperandrogenic adult woman. These and other investigators have also observed that the vast majority of individuals who have elevated or exaggerated 17-hydroxypregnenolone or DHEA values following ACTH stimulation actually have a form of PCOS and do not have NCAH.

What is the difference? Patients with PCOS generally have insulin resistance and, while they have a genetic basis that underlies the disorder, the genetic cause is a complex mixture of various genes and the environment. Furthermore, the use of glucocorticoids (dexamethasone, prednisone and hydrocortisone) in patients with PCOS is generally not recommended since it can worsen the insulin resistance. Alternatively, patients with true NCAH may often (but not always) benefit from glucocorticoids and should also be counseled carefully regarding their chance of having a child who is also affected with NCAH or CAH. Consequently, making and treating the true diagnosis that underlies a patient’s hyperandrogenic symptoms is very important.

In summary, the 3β-HSD deficient NCAH has been woefully over-diagnosed, particularly considering modern studies which are able to determine whether a patient actually has a genetic defect of the 3β-HSD gene. In fact, to date, no woman presenting with hyperandrogenism in her adulthood (or even adolescence) has been confirmed to have 3β-HSD NCAH. The vast majority (if not all) of women with an exaggerated (above normal) 17-hydroxypregnenolone or DHEA levels have PCOS. This should be a relief to many patients who are being inappropriately treated with glucocorticoids based on older criteria.

Patients should not be surprised at the general change in diagnostic criteria for 3β-HSD deficient NCAH, since it is difficult to establish the presence of adrenal hyperplasia without proper genetic tools, only made available to us in the past decade and often only in research laboratories. As these genetic tools become more widely available for clinical use, it is highly likely that the reported incidence of “3β-HSD deficient NCAH” (and “11-OH deficient NCAH”) will drop dramatically.

The level of 17-OHP in patients with confirmed NCAH is 3-fold to 10-fold greater than the upper normal limit.

Patients with confirmed genetic defects of 3β-HSD have been shown to have 17-hydroxypregnenolone values of at least 10-fold the upper normal limit.

To date, there has been no patient with 3β-HSD NCAH who was first diagnosed as an adult woman with androgen excess.

Fall 2006 CARES Foundation, Inc.

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3β-Hydroxysteroid Dehydrogenase Deficient NCAH:
A Myth or Reality?
by Ricardo Azziz, M.D., M.P.H., M.B.A.

In contrast to classic adrenal hyperplasia (CAH), which cause symptoms that are evident either at or immediately after birth, the nonclassic adrenal hyperplasias are a series of inherited disorders that cause symptoms generally near or after puberty. Signs and symptoms associated with nonclassic adrenal hyperplasia (NCAH) include signs of premature puberty, including early growth of pubic and underarm hair and advanced bone age. More commonly, post-pubertal women develop excessive facial and body hair, irregular periods, acne, and scalp hair loss (androgenic alopecia). Some women with NCAH have difficulty conceiving due to irregular ovulation as well as the very high levels of circulating progesterones, hormones made in the adrenal glands and ovaries, which causes the lining of the uterus to be unreceptive to a pregnancy. The most common cause of NCAH is 21- hydroxylase (21-OH) deficiency, due to a genetic defect of the gene CYP21. In fact, well over 90 percent of all CAH and NCAH cases are due to genetic mutations of this gene. There are two other theoretical causes of NCAH including genetic defects of the genes CYP11B1 (determining 11β-hydroxylase [11-OH] activity) and HSD3B2, (determining 3β-hydroxysteroid dehydrogenase [3β-HSD] activity). To date, few subjects have been found to be affected with 11- OH deficient NCAH, the vast majority of them are children, and no patient with genetically confirmed 11-OH deficient NCAH has been diagnosed in adulthood. Previous reports have suggested that 3β-HSD deficient NCAH is one of the most common causes of androgen (male hormone) excess in women. This assumption was based on the finding that many hyperandrogenic patients had elevated levels of 17-hydroxypregnenolone and DHEA; both of these steroids are immediate precursors to the 3β-HSD enzyme. However, others and we have demonstrated that the elevations in 17-hydroxypregnenolone and DHEA present in hyperandrogenic women are relatively mild, generally not exceeding two-fold the upper normal limit found in healthy women. In contrast, the level of 17-hydroxyprogesterone (17-OHP), the immediate precursor to the 21-OH enzyme, is 3-fold to 10-fold greater than the upper normal limit in NCAH patients. In addition, a number of investigators, including ourselves, have noted that between 25 percent and 40 percent of women with the polycystic ovary syndrome (PCOS), another fairly common cause of androgen excess in women, have elevated levels of DHEA and DHEA sulfate (DHEAS), suggesting that the adrenal may be overactive in patients with PCOS, not related to the presence of a genetic mutation. This data indicates that we were over-diagnosing patients with 3β-HSD deficient NCAH, and that many of these women simply have PCOS with a hyper-reactive adrenal, similar to the hyper-reactive ovary also observed in PCOS. More recently, Dr. Songya Pang and colleagues have done very careful genetic studies of patients with supposedly 3β-HSD deficient NCAH and observed that the patients who had genetic defects of the 3β-HSD gene had 17-hydroxypregnenolone values that were at least 20-50 standard deviations above age-matched controls (at least 10-fold the upper normal limit), and all of these presented in childhood. In fact, to date, there has been no patient with 3β-HSD deficient NCAH who presented as a hyperandrogenic adult woman. These and other investigators have also observed that the vast majority of individuals who have elevated or exaggerated 17-hydroxypregnenolone or DHEA values following ACTH stimulation actually have a form of PCOS and do not have NCAH. What is the difference? Patients with PCOS generally have insulin resistance and, while they have a genetic basis that underlies the disorder, the genetic cause is a complex mixture of various genes and the environment. Furthermore, the use of glucocorticoids (dexamethasone, prednisone and hydrocortisone) in patients with PCOS is generally not recommended since it can worsen the insulin resistance. Alternatively, patients with true NCAH may often (but not always) benefit from glucocorticoids and should also be counseled carefully regarding their chance of having a child who is also affected with NCAH or CAH. Consequently, making and treating the true diagnosis that underlies a patient’s hyperandrogenic symptoms is very important. In summary, the 3β-HSD deficient NCAH has been woefully over-diagnosed, particularly considering modern studies which are able to determine whether a patient actually has a genetic defect of the 3β-HSD gene. In fact, to date, no woman presenting with hyperandrogenism in her adulthood (or even adolescence) has been confirmed to have 3β-HSD NCAH. The vast majority (if not all) of women with an exaggerated (above normal) 17-hydroxypregnenolone or DHEA levels have PCOS. This should be a relief to many patients who are being inappropriately treated with glucocorticoids based on older criteria. Patients should not be surprised at the general change in diagnostic criteria for 3β-HSD deficient NCAH, since it is difficult to establish the presence of adrenal hyperplasia without proper genetic tools, only made available to us in the past decade and often only in research laboratories. As these genetic tools become more widely available for clinical use, it is highly likely that the reported incidence of “3β-HSD deficient NCAH” (and “11-OH deficient NCAH”) will drop dramatically. Points to Remember: The level of 17-OHP in patients with confirmed NCAH is 3-fold to 10-fold greater than the upper normal limit. Patients with confirmed genetic defects of 3β-HSD have been shown to have 17-hydroxypregnenolone values of at least 10-fold the upper normal limit. To date, there has been no patient with 3β-HSD NCAH who was first diagnosed as an adult woman with androgen excess.

Dr. Azziz is the Helping Hand of Los Angeles Chair in Obstetrics & Gynecology, Director of the Center for Androgen Related Disorders, Chair of the Department of Ob/Gyn at Cedars-Sinai Medical Center, and Professor and Vice-Chair in the Department of Ob/Gyn and Professor in the Department of Medicine at The David Geffen School of Medicine at UCLA.

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