Congenital Adrenal Hyperplasia – Something to Consider

Adrenal Steroid Pathways (from Wikipedia)
The New York Times this week has a very nice article about Congenital Adrenal Hyperplasia or CAH, as it is called. I thought the article was very well-written, but might be confusing for folks who don’t know the basics about CAH, and might lead some women to over-diagnose themselves with what is a rather uncommon condition. So let me see if I can give you the basics and help you put the article in perspective.

Congenital Adrenal Hyperplasia (CAH)

CAH is caused by a genetic enzyme abnormality in the adrenal gland. In women, this can lead to an over-production of testosterone, which in turn can cause irregular menses, acne, hirsutism (excess hair growth) and infertility.

Clinically, CAH is classified in decreasing order of severity as –

  • Classical salt-wasting CAH (Early onset): Presenting at birth with varying degrees of genital ambiguity in females (normal genitals in males), severe adrenal insufficiency and life-threatening salt wasting (both males and females). It is treated with lifelong steroids. Females have normal internal genital structures and with treatment can have normal menstrual cycles and normal pregnancies. Hirsutism can be problematic but is usually quite treatable. Surgery is usually done to correct the genital abnormalities.
  • Non-classical, virilizing CAH – Enough adrenal steroids are produced to prevent adrenal insufficiency and genitals are normal at birth. Elevated testosterone levels can causes early puberty and in girls, excess hair growth and clitoral enlargement.
  • Late-onset, non-classical CAH – Presents in the late teens and 20’s with menstrual irregularities, severe acne or hirsutism, and sometimes, infertility. Can also cause early puberty, though this is less common. Can have no symptoms at all.
The condition the NY Times article is addressing is late onset or non-classical CAH. So that’s what we’ll be talking about in the rest of this post.

Genetics of CAH

The gene affected in CAH is called CYP21A2, and it codes for the enzyme 21-hydroxylase. This enzyme is part of the adrenal production pathway for cortisol, and catalyzes the conversion of 17-hydroxyprogesterone to 11-deoxycortisol. (It’s the second vertical green bar on the top in the steroid production pathway up there.) If that enzyme is blocked, levels of 17 hydroxyprogesterone build up, and then steroid production tends to preferentially head down the other path towards testosterone.

Think of it as a construction delay at the Manhattan-bound Lincoln Tunnel, with cars backed up all the way to the Jersey Turnpike. Traffic is so hemmed in that you can’t get over to the right lane, and you end up on Rte 3 headed to Secaucus (testosterone) instead of Manhattan (cortisol). Not exactly where you wanted to go, was it?

CYP21A2 is a recessive gene, meaning that an individual usually has to carry two abnormal gene copies to be affected. There are several different known mutations of the gene, some leading to more severe enzyme deficiencies than other, and various combinations of these mutations in an individual can lead to varying degrees of severity of the condition. The correlation between a specific CYP21A2 mutation and clinical presentation is not always predictable, and other genes are thought to influence the phenotypic presentation.

How common is late-onset or non-classical CAH?

The Times article states that CAH is much more common than realized, and not diagnosed or treated as often as it should be.

Dr. New, who has studied the disease among New Yorkers, said she found it in 1 out of 100 people, but more often in certain ethnic groups — 1 in 27 Ashkenazi Jews, for example, and 1 in 40 Hispanics. It is the most common of the autosomal recessive diseases, in which a child inherits two copies of a recessive gene from his parents — a class that includes sickle cell anemia, Tay-Sachs and cystic fibrosis.
Remember that Dr New screens a select population of women and New Yorkers, so those numbers are not necessarily representative of the US population at large. I’ve been screening for late-onset CAH for over 20 years whenever an adolescent or adult woman presents to me with irregular menses and acne or hair growth, and I’ve diagnosed it in maybe 2 or 3 patients. It just is not very common. Be careful also not to confuse the incidence of the gene defect with the clinical condition – not all women who have the gene defect have any symptoms.

As an aside, I’ve probably seen more classic CAH patients in my career than most gynecologists, having done the pelvic exams as part of a long term study of classical CAH patients conducted by Dr New.

Screening for late-onset CAH

The screen for late-onset CAH is a simple blood test for 17 hydroxyprogesterone – that hormone builds up as a result of the mild enzyme block in the adrenals. It should be done whenever a woman presents with menstrual irregularities and signs of excess androgens such as hirsutism or severe acne. (The test has a very low yield in the absence of signs of androgen excess, but may be useful in evaluating infertility if severe menstrual irregularities are present or there is no response to standard treatments.).

Testing for 17 hydroxy-progesterone is best done fasting and in the latter part of the menstrual cycle. If the result is abnormally high, then a confirmatory test is done called an ACTH stimulation test. The patient is given a hormone that stimulates the adrenal gland to make more steroids, leading to more back up behind the enzyme block and a further rise in 17 hydroxy progesterone. (Think of the ACTH stim test as causing rush hour traffic in the analogy I gave above.)

How is CAH Treated?

Treatment of late-onset CAH depends on the desired outcome and severity of symptoms. If the menstrual cycles are fairly regular and hirsute symptoms mild, then no treatment is necessarily needed. Birth control pills are the mainstay of treatment for mild forms of the condition, especially in sexually active women who want to prevent pregnancy. More severe forms will respond to steroids with or without oral contraceptives. Women who want to conceive may be treated with steroids or not depending again on how severe the condition is and how well she responds to standard ovulation induction.

What about Genetic Testing?

Because the CYP21A2 gene is recessive, individuals who carry the gene may not be aware of it. If two carriers have a child, there is a 25% chance they will have a child with the more severe classical form of the disorder.

Which leads of course to the question – who should be screened for the CAH gene defect?

I’d recommend screening if anyone in your immediate family has CAH – you could be a gene carrier. If you are, then your husband can be screened before you get pregnant to determine if you are at risk for having a child with the classical form of CAH. Given the incidence of CAH in Ashkenazi Jews, I suspect at some point we may start offering CAH testing along with Tay Sachs and other genetic prenatal screens. Right now, however, it is not a recommended routine test in this population.

For more information on CAH

35 Responses to Congenital Adrenal Hyperplasia – Something to Consider

  1. Hmmm. You call it rather uncommon; the NYT called it common ("She suffered from a common yet often overlooked condition…"). They cite a rate of 1:100 people (higher in certain groups as you know) and say it's the most common autosomal recessive disease. So, what do you think? Is it truly uncommon? Just curious how one defines "common" in the statistcal medical sense here…

    Reply

  2. Good question – I'd call it uncommon, expecially as compared to Polycystic ovarian syndrome, which is seen in up to 10% of women and can also impact fertility.

    And as I said, the incidence of the genetic defect is not the same as the incidence of the condition.

    More important, and I think the point of the NYT article, is that docs keep this diagnosis in mind when caring for women with menstrual irregularities or infertility.

    Thanks for reading!

    Reply

  3. It is important to note the more serious health risks associated with hyperandrogenism (high testosterone levels) in females. One such risk is metabolic syndrome (obesity, insulin resistance, hypertension, and hyperlipidemia). Another is the increased risk for breast or ovarian cancer, and after these types of cancers, doctors will not prescribe the hormones that are normally used to treat CAH. That leaves spironolactone as perhaps the only option for lowering testosterone after cancer. There is also an increased risk for miscarriage. The myth that Melatonin lowers testosterone levels has been proven untrue.

    Reply

  4. How much do the blood test for 17 hydroxyprogesterone and the ACTH stimulation test typically cost without insurance?

    I ask because I've been diagnosed with hirsutism and excess androgens for several years, and was never given an explanation other than, "well, we checked for PCOS and it's not that." Which is nice to know, but not a real answer as such. The NY Times article caught my attention because most of my symptoms are identical to those of the woman in the article.

    Reply

  5. Anonymous – You will need to check with your lab and your insurer re costs. Try calling quest labs or lab corp – they are big national klabs and they can probably quote you a price. You don't need an ACTH stim test if the 17 oh progesterone is normal.

    Good luck!

    Reply

  7. The article suggests that the Virilising form of CAH is non-classical. This is not true.
    It is considered as being Classical CAH in severity, but without overt salt wasting.

    CAH is on a continuum of severity, determined largely by the genetic mutations inherited. The primary genetic mutation for 21OHD Virilising CAH is I172N and in vivo this has only about 2% activity, as opposed to nonclassical mutations which have anywhere between 15 – 50% activity.

    The non-classical form is the late onset type also with very specific genetic mutations, such as, V281L (for 21OHD) and of commensurate lesser severity.

    Reply

  8. Lea-

    Oh dear- we are getting into CAH terminology, which is fraught with variability and confusion and which was beyond the scope of this article, which I really wrote to focus on the late-onset variety that I see and treat in my practice.

    That said, I have seen "Classical" used to describe the type that presents at birth, with or without salt-wasting. Simple virilizing (which tends not to be called classical in most of what I have read, but I have seen classical described as either salt-wasting and simple virilizing without distinguishing whether genitalia are ambiguous or not) usually refers to the form that presents without ambiguous genitalia with precocious puberty or virilization at puberty. I did not mean to imply anything in using the terms I used. If you want, remove the term "non-classical" from in front of virilizing and we can all agree.

    You are correct that as we learn more about the genetics of CAH, we are finding that defects in different genes are involved. In the future we probably won't be using any of these terms, but taking about the genetic defect.

    Thanks for reading

    Reply

  9. Hi Margret,
    Read some on your Cah story and
    Just thought I'd drop you a line, and let you know about the new site.
    I recently had a new baby, and as luck would have it, she is also diagnosed with Congenital Adrenal Hyperplasia (CAH).
    So I put facts, as well as my daily regime, as to what I need to do to keep the girls safe. Also, some great photos!
    Please visit the sweeties at :
    http://giftsofgraceandhope.com/

    All the best,
    Charissa
    PS, The Meds are the same, and new baby takes more. I pray every day, that there will be no accidents. we barely leave the house, because of dangers all around. I'm hoping for some donations, so I can get a Fence, for safety, as my 3 yr old has already met the neighbors across the street . and swingset for the back yard. (The girls NEED to Play-to grow to be heathy well adjusted adults. )Please feel free to share the site address with any and all of your friends, (Chat rooms, Blogs, whatever will help) Thank you , God bless

    Reply

  10. My brother was diagnosed with CAH when he was 5 days old, and losing weight….he almost died and the doctors at that time told us there was no hope, until he was flown to a bigger and better hospital. That was 21 years ago now.

    We were told not to let him play sports because of the dangers and to make sure he didn't get a cold because it could kill him; however my little brother refused to watch life pass, and actually plays goalie in hockey! He went to school with everyone else, and is now doing his apprenticeship for plumbing. He doesn't tell very many people about CAH, and prefers living that way.

    There were frustrations for him growing up, as he aged faster than other kids, getting his wisdom teeth at age 11! He also stopped growing at 5'1, which is his biggest source of frustration.

    We all consider him our miracle…and he is definitely one of the greatest people I know When he was born there seemed to be very little known about CAH.

    I haven't researched it much lately as it isn't a concern in our daily life anymore, however I just found out that I am pregnant! Now I am concerned with having testing done, as I know there is a significant chance that I am a carrier. Does anyone know how testing is done now a days? It seems everything I knew about CAH is old news.

    Reply

  11. Lucky –
    Congrats on your pregnancy, and so glad to hear your brother has done well.

    Indeed there is carrier testing for CAH. Ask your doc to refer you to a genetics counselor.

    If for any reason you can't get it done locally, I do know someone here in NYC who does the screening.

    Reply

  12. What is the first step to genetic screening. I have a great nephew that has CAH diagnosed at birth. I want to know if I am a carrier.

    Reply

  13. Texas – That's a pretty far distant relative to you, with several other families genes mixed in between. You might want to see what the results of others in the family tree are before you get tested. See a genetics counselor who can do a family tree and then take it from there.

    Reply

  14. I also have a great niece diagnosed wuth CAH. She is 4 weeks old. Which means my sister has a carrier daughter, and my brother has a carrier daughter. Yes there are 4 more families involved with my 2 nieces, but what are the odds of that! My son and his wife are 22weeks of gestation with a girl and they are very concerned. What would be a test that would ease their tension for now. What test could she request of her OB/GYN to make sure neither she or my son are carriers or that they will have an affected girl? I still will persue genetic testing for me. I want to rule out any disorder for my descendants.

    Reply

  15. Texas –
    Well, that's quite a pedigree. Yes, there is testing and you could get tested for the gene or your son. YOu need to speak to a genetics counselor to get the test done. Your son's wife's obstetrician can make the referrals.

    Let us know what you find out.

    Reply

  16. Dear Dr. P,

    What a great blog! Thanks so much for the information and for expanding on the NYT article. It was that article that finally brought about a diagnosis in my case.

    I am 36 years old (nearly 37) and for the last 15 years I have been complaining to doctors about histurism, acne and very irregular periods, no one ever suggested that I be tested for late-onset CAH. I was told many times that I had a suspected case of PCOS despite the fact I have never presented cysts on my ovaries.

    My husband and I have been trying to get pregnant for the last 7 years – unsuccessfully. We relocated from New York to his native Brazil because, among other reasons, we could no longer afford our health insurance and couldn’t see how we could raise a family there. (I miss New York like crazy still 🙂 But, I have found the quality of care here in Brazil very good for the most part despite the fact that reproductive endocronology, pairing with fertility treatment does not seem to exist.

    Since moving here in 2005, we have seen a number of fertility specialists and after comprehensive fertility work-up on both of us, including a LAP, we were recommended the same course of treatment given our long-term infertility – clomid and timed-sex then followed by injectibles + IUI. We had done both twice and were about to give up as I now think I would rather adopt than take the next, expensive step towards IVF.

    Then I happened upon the NYT article. I’d never heard of CAH. It was very eye opening. I printed it out, translated it, marched it into the office of an endocrinologist and said please test me for this.

    My initial 17 hydroxyprogesterone test came back slightly elevated, 1.06ng/ml (with the normal cutoff being 1.00 for follicular phase) and was followed by a challenge test. I however did both tests on day five of my cycle, early in the morning, following a 12 hour fast. I’m wondering if it would have appeared even higher if it was done as you recommended at a later stage in my cycle.

    My doctor put me on a course of 0.5 mg of dexamethasone per day, and I have had no side effects. I was just retested (also on day 5) after 4 months of treatment and the results came back for 17 hydroxyprogesterone at .51ng/ml. So I am very excited and encouraged that perhaps we can still get pregnant after all.

    I am now considering, doing another IUI with injectables. But I can’t seem to find any information if this has the possibility of being successful in late-onset CAH undergoing treatment.

    I’m wondering if, because the cycle is forced with medications, the fact that I'm in treatment for CAD will no make a difference. Our health insurance does not cover IUI or IVF, so we are paying out of pocket.

    After 7 long years trying to get pregnant, if the odds of another IUI succeeding are low, I’d rather save the money and just keep our fingers crossed that maybe we’ll still get lucky someday now that I’ve finally been diagnosed and treated. Adoption is still very much in our plans.

    Sorry for such a long detailed comment. I really appreciate your information. I’ve been looking for more clarity and have felt a bit lost as there is relatively little information out there on this cause of infertility and its outcomes.

    Thanks again for the informative post!

    (btw, I have Easter-European Jewish ancestry on my mother’s side, but no one else in my family as far as I know has ever been diagnosed.)

    Best wishes!
    Robyn

    Reply

  17. Robyn – looks as though things are moving along in a positive way. Glad you found the post helpful. Best of luck on the fertility treatments!

    Reply

  18. Ok…I was first diagnosed with PCO and actually had a wedge resection to get pregnant with my first child in 1996 then my RE thought I may have non-classic CAH because I wasn't insulin resistant and my mom is from Ashkanize Jewish decent. Bingo..So I took dexamethosone to get pregnant with my second child. Question: I have not taken any steriods since 1998 and I have been taking Birth Control, and Metfomin since. I am thinking about going off of birth control because my cholesterol is up and I think it might be the cause and I am 44years old. My new dr said I would benifit from taking 2.5 mg of Predisone at night. I remember how I hated Dex and I am not sure if I want to do that. Do I really need it. I am normal weight, and pretty healthy besides the fact I don't menstrate without medication (Birth control pills) Thanks

    Reply

  19. Anonymous –
    I hope you understand that I cannot give personal health advice on this blog. Do discuss your questions and concerns with your doctor.

    Thanks for reading!

    Peggy

    Reply

  20. a cousin of mine has been diagnoised with LOCAH and she is in her early twenties.though her treatment has begun and she is advised to take few tablets per day for a period of 3 to 6 months.
    but she has heard that LOCAH can cause infertility.is that true?

    Reply

  21. I did a DNA test with 23andme and found out I am 1% Ashkenazi Jewish descent I have been sick for 10 years and no one has thought of CAH until now. I’m glad I did the DNA test it answered a lot of health concerns for me. This may be rare disease but coming down with it with only 1% of a gene makes it seem very sensitive to me.

    Reply

  22. can 17 hydroxyprogesterone be elevated slightly just above the normal range without it being caused by locah? can pcos cause a slight elevation in 17hydroxyprogesterone? Can carriers of te defective gene show slight elevation in 17-hydroxyprogesterone?

    Reply

  23. Can you kindly tell me what typically happens with nonclassic CAH in menopause – I just went 7 mos w/out a period. Am curious since the excess hair has always been an issue for me with nonclassic CAH – thank you.

    Reply

  24. Melanie –

    An interesting question, there not a whole lot of info out there. Good topic for some research, I’d say. But if asked to predict, I’d say that since over time androgen levels decline with age but not with menopause per se, I would not anticipate a dramatic change at menopause but a gradual decline with age.
    But you’ll tell us..

    The other thing is that no woman is typical. I’ve learned that lesson many times over the years.

    Best to you.

    Peggy

    Reply

  25. I’m from the UK, and delighted to find this forum after months of searching! I want to get in touch with somebody who has None Classical Adrenal Hyperplasia. After coping with unwanted body/facial hair and no menstural cycle naturally (only induced by Dianette)…finally I’m diagnosed,

    I’m taking 10mg and 2.5mg of Hydrocortisone daily (morning and early evening). I’ve only taken this for 2 weeks and hoping it will induce a period and ovulation as I want more than anything to be a mum!

    Is there anyone who can provide me with their experience?

    Thank you so much

    Reply

  26. I was diagnosed with non classical cah after 7 years of trying to conceive. Drs kept thinking I had pcos even though I had no cysts. I was put on .5 dexemethesone for about 4 months and conceived through IVF first go at 42. Felt like a miracle. I’m now 46 and experiencing menopause with the worst aggression and impatience ever. I feel exhausted and very emotional. I stopped taking the dexemethesone when I was four months pregnant after I found out my child was a boy. I’m totally freaking out about menopause and how horrible I have become and how exhausted I am. I’m not sure what type of dr to see or what to test or how to fix this problem. If there is a hormone balancing fix or not? Has anyone else experienced this or can point me in the right direction. My hot flushes are seriously hot and my night sweats like a sauna. That I can deal with but my friends and family and I can’t deal with my aggression and horrible mood. Thanks daisy

    Reply

  27. I have a 19 year old daughter who has been diagnosed with non-Classic CAH. She does not
    get her period and we are working with an endocrinologist. She is on her third birth control. They are all causing acne, weight gain, depression and extended periods (average over 10 days prematurely. She has been on Cresszelle, kelnor, and yazz. We are running out of options supposedly with (low progesterone and estrogen levels) and her hormones are fluctuating like crazy. I cannot anywhere find any information regarding what types of birth control pills help with this problem and her disorder. Have you heard about any holistic approaches to help with this and her condition? We live in the Boston area.

    Reply

  28. I asked two questions and they’re not here anymore? they were short and medical. How does the infertility manifest ie low AMH? And does being on spironolactone skew any test results for NCAH? Why weren’t these answered?

    Reply

  29. I was on birth control for most of the time between ages 15-30. I am now 35 and have had bad acne and other masculinizing aspects like hair loss, oily skin, even changed to my facial features. My testosterone levels always come up normal however. I no loner produce progesterone though. Day 21 progesterone is around 2 or 3. My day 21 17hydroxyprogesterone is 2. My questiom is is it characteritic in late onset CAH to have these low progesterone levels? Is this level of 17hydroxyprogesterone considered above range and is it possible to have these androgenic symptoms without elevated testosterone in blood?

    Reply

  30. My son at 3 months diagnosed with non classical adrenal hyperplasia but specialist said wait until 1 year old to do skeletal test on hand to fully diagnose since babies they still are growing. If he is positive for this gene does this mean I or my husband have this gene? Or are we just carriers? What’s the difference? I’ve heard from the specialist that most people who were born in countries near the Mediterranean Sea are positive for these issues.

    Reply

  31. I have NC-CAH, of a rather more severe type but am well controlled on OCPs and low dose glucocorticoids periodically. Has only with the more symptomatic type been controlled after discontinuing the OCP in menopause?

    Reply

  33. Why, oh why, oh why do doctors rarely look at the 17keto steroids and 17-OH steroids 24h urine chromotography? Bloodwork is a single moment, where the body may be shunting and shifting, but 24h of what has been processed tells the true story of whether the hormones are acting as substrate or final product, and where the ‘kink’ in the hose to the top tier is…

    Reply

Leave a Reply