NonClassical CAH, Congenital Adrenal Hyperplasia
Irregular Menstrual Cycles, Acne, and Hirsutism
by Jeffrey Dach MD
Our nation spends millions of dollars on laser hair removal treatments, and acne skin treatments.(1) Infertile women spend small fortunes on sophisticated in-vitro fertilization techniques. These symptoms can be found in a common genetic disorder called Non-Classic CAH which occurs 3% of certain ethnic groups, and the diagnosis may be missed by the medical system. Curative treatment is an inexpensive tablet costing pennies a day, called Dexamethasone, given at bedtime which restores fertility and cycle regularity, and eliminates the hirsutism (facial hair) and acne.
 An estimated ten percent of Poly Cystic Ovary Syndrome (PCOS) patients may have underlying Non-Classical CAH causing symptoms of irregular menstrual periods, acne, hirsutism (unwanted facial hair) and infertility. Click here for an earlier report on Understanding PCOS, the Hidden Epidemic.(2)
Left Image: Hirsutism, unwanted hair grrowth under chin caused by CAH. Courrtesy of Wikipedia.
What is NonClassical CAH?
Also called: NonClassical Congenital Adrenal Hyperplasia, Non-Classical 21 Hydroxylase Deficiency (NC21OHD)
Non Classical CAH- A Common Genetic Disorder
This chart shows incidence of CAH among various ethnic groups.
Non-Classical CAH is in the central rectangle. Courtesy of Maria New MD(3)
Non-Classical CAH or 21-Hydroxylase Deficiency is the most common genetic disease known, occurring in 1% of New Yorkers, and up to 3% in ethnic groups such as of Ashkenazi Jews, Hispanics, Italians, and Yugoslavs (3).
 Adrenal Gland Enzyme Deficiency, and Reduced Ability to Make Cortisol
The underlying genetic disorder causes an enzyme deficiency in the adrenal gland which reduces the ability of the adrenal to make cortisol. Instead of making cortisol, the adrenal steroid pathways are shunted towards testosterone causing elevated testosterone and the typical symptoms of hair growth (hirsutism), and acne and there may also be menstrual irregularities, anovulation, and infertility.(3)(4)
Left Image: The Adrenal Gkands Courtesy of Wikipedia
What is the 21 Hydroxylase Enzyme?
This is a key enzyme in the adrenal gland involved in the conversion of cholesterol into cortisol. In the Classical form of CAH, the 21 hydroxylase enzyme (21-OH) is severely deficient with resulting low cortisol levels, and high testosterone levels. In the Non-Classical form however, the 21 hydroxylase (21-OH) enzyme is still working fairy well with only a slight reduction in activity, and cortisol levels are usually normal, while testosterone levels may be elevated to a variable degree. The Adrenal Steroid synthesis pathways and the adrenal enzymes involved can be understood on a chart on the Quest web site.(5)
How to Make the Diagnosis of Non-Classical CAH? Use Cortrosyn Stimulation.
The most definitive diagnosis is done with a Cortrosyn Stimulation test (0.25 mg) which measures 17-hydroxyprogesterone (17-OHP) at 0 and 60 minutes after SQ injection of the Cortrosyn (ACTH). This test in simple terms is described here:
First a preliminary (baseline ) blood test is done for various hormones including 17-OHP, this is followed by a subcutaneous injection of 0.25 mg of a drug called Cortrosyn which is a form of ACTH which stimulates the adrenal glands to make more hormones. An hour (60 minutes) after the Cortrosyn injection, a post stimulation blood sample is drawn for lab testing for 17-OHP and other hormones.
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Classification of CAH depends on 17-OH-Progesterone (17-OHP) values on stimulated test. Normal is lowest circle, non-classical CAH is middle circle, and classical full blown CAH is the upper circle. Courtesy of Maria New MD review article.(3)
Patients with Non Classic 21-OH Deficiency typically show 60-min stimulated 17-OHP values between 1,500 and 10,000 ng/dl. This chart shows how the 17-OHP values cluster at three areas for normal (below 1,500), Non-Classical CAH (1500-10,000) and, and Classical CAH (above 10,000).(6) A useful chart showing the CAH testing algorithm is available.(7)
Genetic Testing for 21-OH Deficiency
Genetic testing is now available and very useful. This Quest Lab test shows whether or not there is a mutation in the CYP21A2 gene coding for the 21-Hydroxylase Enzyme.(8) The CAHDtex test by Esoterix is also useful in showing the exact mutation in the CYP21A2 gene.(9) Once the exact mutation in the CYP21A2 gene is known, refer to this chart to determine the severity of the enzyme defect.(10) Genetic testing of other family members is usually recommended once a sibling is found with the mutation. Dr. Maria New has her own in-house lab in New York which does genetic testing for CAH.(11)
Clinical Presentation in Children
In children, the signs of non-classical CAH include premature onset of puberty, cystic acne, accelerated growth, and advanced bone age. Premature development of pubic hair may occur as early as 6 months of age (due to elevated testosterone). The severe cystic acne may be unresponsive to oral antibiotics and retinoic acid (Accutane). Although the child may be taller than the other kids in early childhood, this early growth spurt finishes early (because of epiphyseal fusion), and final height ends up shorter than usual. Thus, these kids are tall children but short adults. Another feature may be male pattern baldness in a female involving the top of the head and sparing the sides.
Teenagers and Young Adults - Major Cause of Infertility
Teenage girls may present with features of elevated testosterone such as facial hair (hirsutism), acne and menstrual irregularities or anovulation. Young adult females may present with the chief complaint of infertility. It has been generally recognized that infertility of undetermined cause in women may be reversed with glucocorticoid (cortef or prednisone) therapy, which most likely treats an occult Non-Classical CAH Syndrome. William Mc Jefferies MD successfully treated thousands of such cases describerd in his 1976 medical classic, The Safe Uses of Cortisol.(12) Dr. McJefferies speculated correctly that an abnormality in adrenal steroid synthesis was present in many young girls with infertility, and only years later was the exact molecular and genetic basis elucidated. In retrospect, non-classical CAH should be called McJefferies syndrome to give this great clinician credit for his early work.
Treatment of Non Classical CAH with Cortisol Restores Fertility
Oral tablets containing low dose cortisol successfully treat Non-Classical CAH and reverse the symptoms restoring fertility. The cortisol suppresses ACTH and reduces the testosterone production by the adrenal.
 Dr. Maria I New is the present day national expert on non-classical CAH, and she has followed a large group of 400 patients with Non-Classical CAH. Dr. New treats them with 0.25 mg. dexamethasone at the hour of sleep, and notes that it takes about 3 months for reversal of acne and infertility. Hirsutism takes longer to respond, about 30 months. (3)(13)
Left Image Courtesy of Maria I New MD.(13)
The cost for a dexamethasone tablet is $0.50, and the 3-month treatment cost is estimated to be $45. Compare this $45 dollars to the infertility treatment cost of $30,000 for one cycle of in vitro fertilization. Dr. Maria New says that many patients presenting with infertility actually have NonClassical CAH, and fertility could be restored easily with treatment with oral cortisol tablets such as Dexamethasone, Prednisone or even the Cortef recommended by McJefferies.(3) Before spending a fortune on in-vitro fertilization for infertility, it would be prudent to rule out Non-Classical CAH with a simple genetic test.
Safety of Low Dose Cortisol
Low dose Cortef, Prednisone or Dexamethasone treatment is safe without the adverse side effects associated with high dose treatment. However, there is a chance of mild adrenal suppression which could require additional or extra doses of medication under periods of higher stress or illness such as the flu or when undergoing a surgical operation. Therefore McJefferies routinely gave instructions to increase the cortisol dosage when a flu illness is noted coming on or under similar stresses. He also advised his patients to wear a warning bracelet containing the information that the patient has non classical CAH, with cortisol dosage and timing.(12)
Jeffrey Dach MD
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REFERENCES
(1) http://jcem.endojournals.org/cgi/content/full/91/11/4205/T7
TABLE 7. National health care burden for treatment of hyperandrogenic signs associated with NC21OHD. EXTENSIVE CLINICAL EXPERIENCE Nonclassical 21-Hydroxylase Deficiency Maria I. New The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 11 4205-4214
(2) http://jeffreydach.com/2008/02/13/understanding-pcos-the-hidden-epidemic-by-jeffrey-dach-md.aspx Understanding PCOS, the Hidden Epidemic by Jeffrey Dach, M.D.
(3) http://jcem.endojournals.org/cgi/content/full/91/11/4205
EXTENSIVE CLINICAL EXPERIENCE. Nonclassical 21-Hydroxylase Deficiency by Maria I. New MD.The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 11 4205-4214.
(4) http://www.mcg.edu/pediatrics/pedsendo/21.pdf
Consensus Statement on Treatment of 21-Hydroxylase Deficiency. JCEM 87(9):4048-4053, 2002.
(5) http://www.questdiagnostics.com/hcp/intguide/EndoMetab/Gen_Misc/TG_CAH/TG_CAH_Fig1.pdf
Adrenal Steroid Pathways chart Quest Labs
(6) http://jcem.endojournals.org/cgi/content/full/91/11/4205/F5
FIG. 5. Nomogram relating baseline to ACTH-stimulated serum concentrations of 17-OHP. From Maria New article.
(7) http://www.questdiagnostics.com/hcp/intguide/jsp/showintguidepage.jsp?fn=EndoMetab/Gen_Misc/TG_CAH/TG_CAH.htm
Congenital Adrenal Hyperplasia Test Guide Quest Labs
(8) http://www.questdiagnostics.com/hcp/intguide/EndoMetab/EndoManual_AtoZ_PDFs/CAH_Common.pdf
Quest Lab Test Code 14755X - a genetic test for the common mutations for CAH 21 hydroxylase deficiency
(9) http://www.esoterix.com/files/ss_cah.pdf
DNA TESTING FOR 21-HYDROXYLASE DEFICIENCY. Esoterix introduces a new DNA test to identify deficiency in the 21-hydroxylase gene, the most common cause of congenital adrenal hyperplasia (CAH). CAHDetx evaluates the CYP21 gene, detecting mutations and gene deletion/conversions that account for approximately 90% to 95% of all CAH cases.
(10) http://jcem.endojournals.org/cgi/content-nw/full/91/11/4205/T1
TABLE 1. Common gene mutations of the 21-hydroxylase gene CYP21A2 from MAria New
(11) http://www.marianew.com/Laboratory.html
CONGENITAL ADRENAL HYPERPLASIA DNA TESTING FOR 21-HYDROXYLASE DEFICIENCY FACT SHEET. MAria New MD Laboratory
(12) http://www.amazon.com/review/R2IPB7XGMO20NE/ref=cm_cr_rdp_perm
Safe Use of Cortisol is a Unique Medical Classic, December 7, 2007 By Jeffrey Dach MD
(13) http://www.marianew.com/index.html
Dr. Maria I. New is one of the world's leading pediatric endocrinologists and children's advocates. Professor of Pediatrics, Director, Adrenal Steroid Disorders Program, Mount Sinai School of Medicine1 Gustave L. Levy Place, Box 1198, New York, NY 10029-6574
PCOS ICD-9 256.4 Amenorrhea ICD-9 626.0 CAH 255.2
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Link to original article here:
http://jeffreydach.com/2008/02/27/a-commonly-missed-cause-of-infertility-nonclassical-cah-by-jeffrey-dach-md.aspx
Disclaimer: The reader is advised to discuss the comments on these pages with his/her personal physicians and to only act upon the advice of his/her personal physician Also note that concerning an answer which appears as an electronically posted question, I am NOT creating a physician -- patient relationship. Although identities will remain confidential as much as possible, as I can not control the media, I can not take responsibility for any breaches of confidentiality that may occur. Finally, the material produced by myself may be reproduced for personal use, provided that appropriate credit and a link is given.
Copyright (C) 2008 All Rights Reserved Jeffrey Dach MD
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Dear Dr. Dach
I learned of your practice & website through a review of Dr. William Jefferies book - Safe Uses of Cortisol. and your subsequent comments regarding Nonclassical 21-Hydroxylase Deficiency.
Harvard recently published a study titled, "Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome",and I was hoping you might be to offer some insight on whether bioidentical hormone options might be available based on the variances they've found in these related pathways.
http://www.ncbi.nlm.nih.gov/pubmed/18308097
I've also included below some comments from one of the study's authors Jordan Dimitrakov, MD, PHD ~ an open-minded researcher who often contributes to the newsgroup of chronic prostatitis.com.
If you would prefer I set up a phone consultation, I would be more than happy to do so.
Thanks in advance for your time and thoughts.
BD from SC
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Dr. Dimitrakov's comments:
- The punchline of the paper really is that there appears to be a lack of a specific substance (an enzyme) in two adrenal pathways which lead to the production of aldosterone and cortisol, and this could explain the systemic symptoms that CPPS patients experience. The substance that appears to be missing is called CYP21A2. The bottom-line is that men with CPPS, based on our findings, have either a variable degree of inborn or acquired CYP21A2 deficit. This finding deserves to be studied further in larger patient populations. Good news is that the ones that are found to have the CYP21A2 mutation can benefit from targeted treatments and the test we describe can be used to guide such treatments. Low cortisol levels ARE the initial stimulus which sets the system in motion.
- The way the body works is that CORTISOL levels feed onto the hypothalamus and the pituitary. When cortisol is low (as has been documented in several IC and CPPS studies), the low cortisol signals to the hypothalamus and the pituitary. The hypothalamus releases CRH (corticotrophin releasing hormone) which causes the release of ACTH from the pituitary. That ACTH signal drives the adrenal crazy (in an attempt to make more cortisol) which is impossible due to a block at the level of CYP21A2. Therefore, all substances before the block increase and those after the block decrease.
Is it inborn or acquired? As we state in the article, "CYP21A2 defects traditionally have been described in patients with congenital adrenal hyperplasia (CAH). The hormonal defects in our CP/CPPS population suggest that some might ....
Dear BD from SC,
Thanks for bringing this information to my attention, as I was unaware of the connection bewtween chronic prostatitis and non-classical CAH, with its attendant adrenal hormone defect until your email pointed it out. Given the fact that the prostate in the male is the homolog of the female uterus both of which are hormonally responsive, it is not surprising that underlying hormonal abnormalities are associated with chronic prostatitis. Just as hormonal imbalance cause structural changes in the uterus with fibroids, adenomyosis, endometriosis, etc, medical science has so far ignored the homologous prostate abnormalities relating to hormonal imbalance. Perhaps this would be a fruitful area for research.
If the connection is valid, then I would expect correction of the hormonal abnormality to be curative. McJefferies used low dose cortisol (or dexamethasone) to correct the enzyme abnormality in females with infertility and irregular cycles. This is also effective in males with CAH and its variants. Would low dose cortisol be beneficial in males with chronic prostatitis, or would some other hormonal manipulation be required? This would be a good topic for an NIH grant proposal.
What about the population of males known to have non-classical CAH? Do they have a higher incidence of chronic prostatitis than the general male population? Answering this question would be another good topic for an NIH grant proposal.
Here is the abstract you mentioned:
Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome. Dimitrakov J, Joffe HV, Soldin SJ, Bolus R, Buffington CA, Nickel JC.
Harvard Urological Diseases Research Center, Children's Hospital Boston, Boston, Massachusetts 02115, USA. Urology. 2008 Feb;71(2):261-6.
OBJECTIVES: To identify adrenocortical hormone abnormalities as indicators of endocrine dysfunction in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: We simultaneously measured the serum concentrations of 12 steroids in patients with CP/CPPS and controls, using isotope dilution liquid chromatography, followed by atmospheric pressure photospray ionization and tandem mass spectrometry. RESULTS: We evaluated 27 patients with CP/CPPS and 29 age-matched asymptomatic healthy controls. In the mineralocorticoid pathway, progesterone was significantly greater, and the corticosterone and aldosterone concentrations were significantly lower, in the patients with CP/CPPS than in the controls. In the glucocorticoid pathway, 11-deoxycortisol was significantly lower and the cortisol concentrations were not different between the patients and controls. In the sex steroid pathway, the androstenedione and testosterone concentrations were significantly greater in those with CP/CPPS than in the controls. The estradiol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate concentrations were not different between the patients and controls. The National Institutes of Health-Chronic Prostatitis Symptom Index total and pain domain scores correlated positively with the 17-hydroxyprogesterone and aldosterone (P <0.001) and negatively with the cortisol (P <0.001) concentrations. CONCLUSIONS: Our results suggest reduced activity of CYP21A2 (P450c21), the enzyme that converts progesterone to corticosterone and 17-hydroxyprogesterone to 11-deoxycortisol. Furthermore, these results provide insights into the biologic basis of CP/CPPS. Follow-up studies should explore the possibility that patients with CP/CPPS meet the diagnostic criteria for nonclassic congenital adrenal hyperplasia and whether the hormonal findings improve or worsen in parallel with symptom severity.
Clinical Trial: http://clinicaltrials.gov/ct2/show/NCT00672087
warmest regards,
Jeffrey Dach MD
www.drdach.com
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