Congenital Adrenal Hyperplasia in Adults

OBJECTIVES To review the treatment of classical CAH in adult endocrinology practice To review the diagnosis and treatment of non- classical CAH in adult endocrinology

A bit of Background 1865 Autopsy on G Marzo found: 6 inch penis with hypospadias No testes Normal vagina, uterus, F tubes and ovaries Large adrenal glands  was female at birth, then judged to be male by 4 years of age

Historical case continued Functioned normally in society as a man Suffered episodic vomiting throughout his life Died ~40 yrs old after an episode of vomiting

Some SJHC cases CASE #1 36 yr old woman seen in Dec 2013, cook Diagnosed with CAH at 6 months of age when genital abN found No crises Had been followed by Dr Killinger

CASE #1 Recalls being on steroid at age 10 No reconstructive surgery Menses onset after steroid Noted extra facial hair in teens

CASE #1 Stopped her med in teens due to social stress  No menses Started steroid in early 20’s  menses

CASE #1 At present: On Prednisone 5/2.5 [metformin, T4, NSAID, clonazepam prn] menses Q3 weeks Facial laser in past No acne Not planning any conceptions

CASE #1 Physical Exam: BP 122/81 Weight kg; BMI 46 A few darker facial hairs (had shaved) No striae/bruises/full face

CASE #1 LABS: …………….stay tuned.

CASE #2 25 yr old woman, nurse Onset of menses age 13, always irregular [once/year] Took BCP at age 16, and then had regular monthly “periods”

CASE #2 Age 18 noted hair falling out from head  stopped the BCP as feared it was the cause Menses only 1-2/year Then noted some darker facial and abdominal hair

CASE # 2 Physical Exam Weight 59.1 kg BP 142/85 A few terminal hairs on face Notably thin hair on head (not in male pattern)

CASE #2 Lab tests….stay tuned….

Congenital Adrenal Hyperplasia (CAH) Most common form is 21-hydroxylase deficiency Incidence of classical 21OHD: 1:15000 newborns  therefore carrier incidence is 1/60 Autosomal recessive Rare in African Americans More common in Yupic (Eskimo), Mediterranean peoples Most common cause of genital ambiguity

Traditionally 3 categories: Salt wasting (classical) CAH Simple virilizing CAH Non-classic CAH

Classical CAH in pediatrics: Salt wasting Hypotension (both aldosterone and cortisol lack) Androgen excess

Classial CAH: Peds vs Adults PEDS JOB(s) ONE: Prevention of adrenal crisis Ensuring growth and development

Classical CAH ADULTS: a bit less fragile Less prone to crises Many stop their meds Men may have few--if any--problems for years Women may just learn to deal with the hyperandrogenism “JOB ONE” will depend upon what the patient wants to achieve

Classic CAH So: ADULT GOALS may include: Prevent adrenal crisis (beware concurrent illnesses) Restore fertility Prevent development of adrenal/gonadal hyperplasia and neoplasia Avoid steroid complications

Classic CAH ADULTS: Good to know: Flurinef may no longer be needed  Why? Unknown but speculation: ?High Na content in adult diets ? Perhaps other adrenal pathways begin to function later in life

Classic CAH Flurinef titration: BP lying/standing K concentration Plasma renin

Classic CAH Optimal glucocorticoid regimen is unknown Hydrocortisone mg am/5-10 mg pm  but this may still allow for overnight ACTH rise  hyperandrogenism Alternatives (but with longer ½ lives of course) are prednisone, dexamethasone

Classic CAH Things to watch for in adulthood: Chronic adrenal enlargement  may lead to myelolipomas

Classical CAH HT is more common in adults with CAH despite childhood hypotension BMD may be lower but OP is uncommon

Classic CAH Increased risk for IGT, obesity and dyslipidemia

Classic CAH Good to know pertinent to male health: Testicular atrophy and infertility due to LH/FSH suppression TARTs (testicular adrenal rest tumours)may be present in ~50% if use sensitive US  infertility, pain

Classic CAH: adrenal rests Treatment: increased glucocorticoid replacement Aim for normal testosterone level Exclude cancer if persist Surgical excision can restore LH function, but generally does not restore fertility Yearly US and testicular exam

Classic CAH: goals in Men Lab testGoal Plasma Renin 17-OHP Testosterone Androstenedione LH/FSH Sperm count Normal as possible (but let rise if HT ensues) Suppress if TARTS or infertile Normal Mildly elevated Normal

Classic CAH and women Consider that: Androgen excess Infertility  may require more steroid than just to prevent hypocortisolism

[women can develop ovarian rests]

Classic CAH and women Don’t aim for total suppression of 17OHP and androgens (for fear of steroid excess) unless aim is assisting fertility

Classic CAH: treatment goals in women Lab TestGoal Plasma Renin 17-OHP Testosterone Androstenedione Progesterone Normal as possible (allow rise if HT) Mildly elevated (lower if severe hirsutism, infertile) High normal Mildly elevated Moderately elevated (normalize for fertility)

Classic CAH: good to know Chronic androgen excess in women may result in PCOS picture  therefore hyperandrogenism from ovaries may persist even with ACTH suppression by steroid

Classic CAH  Suboptimal fertility in women WHY? High androgens  oligoanovulation High progesterone  unfavourable endometrial and cervical mucus Endogenous/surgical vaginal difficulties  ~20% attempt a pregnancy

However, a bit more encouraging: 21/23 women with classic CAH due to 21OHD conceived and delivered with BID or TID steroid Casteras et al. Clinical Endocrinology 2009; 70:833

And.. Pregnancy outcomes usually normal 20% risk GDM CS may be more common (keeping in mind the surgical reconstruction that may have been done) Steroid doses unlikely to alter in pregnancy Ratio of girls/boys: 3 times more likely to be female offspring  ? cause

Classic CAH: Psychosocial health QoL scores may be lower especially after surgical corrections, but truly variable outcomes Not unexpectedly, women may have more anxiety about sexual contacts/body image

Approach with caution Perhaps women with Classic CAH have More masculinized play behaviour More likely to play outdoor sports (here’s a truly dumb statistic): 14% with classic CAH had a spare time interest in motor cars. Friesen L. JCEM 2009; 94:

NON-CLASSIC CAH Incidence: 1:1000 Study of 220 NC women  11% diagnosed < 10 yrs old (why? Premature pubarche)  80% years old (why? Hirsutism, oligomenorrhea, acne, infertility, alopencia, 1 amenorrhea) C. Moran Am J. Obstet.Gynecol. 183(6), 1468–1474 (2000).

NC CAH:men Asymptomatic Discovered by screening in families

NC CAH: making the diagnosis 17OHP level done acb: suggestive if > 6 nm/l (done in the follicular phase of cycle—1 st 2 weeks after menses) ACTH stimulation [ 250 ug ACTH, 17OHP one hour later]  consistent with NC CAH if>45 nm/l [for context: Classical CAH: >600 nm/l]

Non-classic CAH Potpourri of metabolic concerns 1.Increased risk IR on HOMA 2.Increased leptin 3.Nocturnal HT 4.Increased intima medial thickness % obese

Non-classic CAH:fertility Observational study 190 NC CAH women proven by ACTH stim 187 pregnancies occurred in 85 women  resulted in 141 births

Non-classic CAH:fertility 99 women conceived before diagnosis 88 women conceived after diagnosis: 11 spontaneously, 77 with steroid

Non-classic CAH:fertility Miscarriage rate 26% without steroids 6% with steroid (p<0.01) [steroid: 15-20mg HC or Dex]

Non-classic CAH:fertility Menstrual response to steroid 38 women with oligomenorrhea  27 normal menses 11 amenorrhea  8 normal menses

Non-classic CAH:fertility Most pregnancies occurred within one year of diagnosis or treatment Bidet M. JCEM 2010; 95:

Non-classic CAH:fertility One more: Multicentre observational ACTH stim proven 203 pregnancies 25.4% spontaneous miscarriage before diagnosis 6.2% spontaneous miscarriage after diagnosis Moran C. JCEM 2006; 91:3451-6

Fertility and NC-CAH Risk of a NC CAH mother having a child with Classic CAH : % NC CAH: 14%

Non-Classic CAH and Bone health NC CAH: normal bone health [Most reports show decreased BMD in classical salt-wasting CAH but reports do vary]

NC-CAH treatment Steroid is not the definitive general treatment (despite enthusiasms in 1980s-1990s) Treat as to what the woman perceives is the problem: oligomenorrhea, hirsutism, acne etc [if steroid is used to improve fertility in the short-term, stress dosing is not necessary]

Helpful Summary: Endocrine Society CPGs Speiser PW et al. JCEM Sept 2010; 95:

Back to our CASES CASE #1 CAH diagnosed at 6 months Labs: prolactin: 5 ug/L TSH: 1.22 miu/l Na/K normal 17OHP: 29.9 nm/l Renin 25.9 ng/L (N up to 38.7)

CASE #1 What would you suggest?

CASE #2 25 year old woman with NC CAH Wishes conception Labs: 17OHP >46 nm/l FSH 5; LH 16; prolactin 15 Renin Testosterone 4.1 nM/l (<1.7) DHEAS 24.9 umol/L (<10) Previous US reported mildly increased ovarian size, no cysts Previous adrenal MRI: normal

CASE #2 What would you suggest?

Question for the audience CAH is autosomal dominant autosomal recessive X linked recessive

Question for the audience: Name the 3 categories of CAH

Questions for the audience Making the diagnosis of nonclassical CAH: 1.At what point in the menstrual cycle should the 17OHP be taken? 2.What random 17OHP is suggestive of NC CAH 3.What ACTH stimulated 17OHP is consistent with NC CAH?

Question for the audience: When were glucocorticoids introduced? Answer: 1950’s

References: 1.Auchus RJ. Congenital adrenal hyperplasia in adults. Current opinion in endocrinology, diabetes and obesity 2010; 17: Riesch N, Arlt W, Krone N. Health Problems in congenital adrenal hyperplasia due to 21- hydroxylase deficiency. Horm Res Paediatrics 2011; 76: Falhammar H, Thoren M. Clinical outcomes in the management of congenital adrenal hyperplasia. Endocrine 2012; 41: Trapp CM, Oberfield SE. Recommendations for treatment of nonclassic congenital adrenal hyperplasia (NCCAH): an update. Steroids 2013:10: Nordenstrom A. adult women with 21-hydroxylase deficient congenital adrenal hyperplasia, surgical and psychological aspects. Current Opinion in pediatrics 2011; 23: