Congenital Adrenal Hyperplasia (CAH) For 5th Year Medical Students and Endocrinology Modules and Master and MD Degree Internal Medicine and Endocrinology By Dr Usama Ragab Youssif References: Oxford Handbook of Endocrinology & Diabetes

1. Congenital
Adrenal
Hyperplasia
Usama Ragab Youssif, MD
Lecturer of Medicine
Zagazig University Email: usamaragab@medicine.zu.edu.eg
Slideshare: https://www.slideshare.net/dr4spring/
Mobile: 00201000035863

2. Definition
CAH is an inherited group of disorders (AR) characterized by a
deficiency of one of the enzymes necessary for cortisol biosynthesis.
More than 90% of cases are due to 21α-hydroxylase deficiency.
There is a wide clinical spectrum, from presentation in the neonatal
period with salt wasting and virilization to nonclassic CAH in
adulthood.

4. Epidemiology
Wide racial variations, most common in those
of Jewish, hispanic, Slavic, and Italian origin
Carrier frequency of classic CAH: 1:60 in white
people
Carrier frequency of nonclassic CAH: 19% in
Ashkenazi Jews, 13.5% in Hispanics, 6% in
Italians, and 3% in other Caucasian
populations

5. Pathogenesis & Genetics
CYP21 encodes for the
21α-hydroxylase enzyme,
located on the short arm
of chromosome 6
(chromosome 6p21.3).
21α-Hydroxylase
deficiency results from
gene mutations, partial
gene deletions, or gene
conversions.

6. Pathogenesis & Genetics (cont.)
There is a
correlation
between the
severity of
the
molecular
defect and
the clinical
severity of
the disorder.
Non-classic CAH is usually due to a point
mutation (single base change); missense
mutations result in simple virilizing disease
Classic CAH due to gene conversion or partial
deletion usually results in presentation in
infancy with salt wasting or severe virilization.

7. Steroidogenesis

8. Biochemistry
21α-Hydroxylase deficiency results in aldosterone and
cortisol deficiency.
There is ACTH oversecretion because of the loss of
negative feedback, and this causes adrenocortical
hyperplasia and excessive accumulation of 17-hydroxy
progesterone (17OHP) and other steroid precursors.
These are then shunted into androgen synthesis
pathways, resulting in testosterone and
androstenedione excess.

10. Steroidogenesis

11. A list of enzyme deficiencies in CAH
Enzyme deficiency Substrate Product Androgen Mineralocorticoid % of
CAH
21α-hydroxylase Progesterone Deoxycorticosterone (DOC) ↑ ↓ >90%
17-hydroxy progesterone 11-deoxycortisol
11β-hydroxylase Deoxycorticosterone
(DOC)
Corticosterone ↑ ↑ 5%
Steroidogenic acute
regulatory protein
(sTAR)
-- Necessary for cholesterol
transport into mitochondria
↓ ↓ Rare
3β-hydroxysteroid
dehydrogenase (3β-
HSD)
Pregnenolone, 17-OH
pregnenolone, DHEA
Progesterone, 17-OHP, Δ 4-
androstenedione
↓ ↓ Rare
17α-hydroxylase Pregnenolone 17-OH pregnenolone ↓ ↑ Rare
Progesterone 17-OHP

12. Steroidogenesis

13. A list of enzyme deficiencies in CAH
Enzyme deficiency Substrate Product Androgen Mineralocorticoid % of
CAH
21α-hydroxylase Progesterone Deoxycorticosterone (DOC) ↑ ↓ >90%
17-hydroxy progesterone 11-deoxycortisol
11β-hydroxylase Deoxycorticosterone
(DOC)
Corticosterone ↑ ↑ 5%
Steroidogenic acute
regulatory protein
(sTAR)
-- Necessary for cholesterol
transport into mitochondria
↓ ↓ Rare
3β-hydroxysteroid
dehydrogenase (3β-
HSD)
Pregnenolone, 17-OH
pregnenolone, DHEA
Progesterone, 17-OHP, Δ 4-
androstenedione
↓ ↓ Rare
17α-hydroxylase Pregnenolone 17-OH pregnenolone ↓ ↑ Rare
Progesterone 17-OHP

14. Steroidogenesis

15. A list of enzyme deficiencies in CAH
Enzyme deficiency Substrate Product Androgen Mineralocorticoid % of
CAH
21α-hydroxylase Progesterone Deoxycorticosterone (DOC) ↑ ↓ >90%
17-hydroxy progesterone 11-deoxycortisol
11β-hydroxylase Deoxycorticosterone
(DOC)
Corticosterone ↑ ↑ 5%
Steroidogenic acute
regulatory protein
(sTAR)
-- Necessary for cholesterol
transport into mitochondria
↓ ↓ Rare
3β-hydroxysteroid
dehydrogenase (3β-
HSD)
Pregnenolone, 17-OH
pregnenolone, DHEA
Progesterone, 17-OHP, Δ 4-
androstenedione
↓ ↓ Rare
17α-hydroxylase Pregnenolone 17-OH pregnenolone ↓ ↑ Rare
Progesterone 17-OHP

17. Clinical
features
• Classic CAH
-Most patients are
diagnosed in infancy
Women Men
 Sexual dysfunction and
subfertility in women,
particularly in salt wasters.
 Reconstructive genital
surgery is required in most
women
 With improvement of
medical and surgical care,
pregnancy rates have
improved.
 ↑ Androgen → ↓ GN → ↓
testicular function
 ↑ ACTH → TARTs (always
benign but may be
misdiagnosed as testicular
tumors), TARTs can be
destructive, leading to
testicular failure.
 Spermatogenesis is often
low if CAH is poorly
controlled.

18. European Journal of Pediatrics (2008) 168(7):847-9

20. Clinical features (cont.)
• Non-Classic CAH
o Partial deficiency of 21α-hydroxylase.
o Glucocorticoid and aldosterone production are normal, but there is overproduction
of 17OHP and, thus, androgens.
o Patients present with hirsutism (60%), acne (33%), and oligomenorrhea (54%),
often around the onset of puberty.
o Only 13% of women present with subfertility.
o 1/3 of women have polycystic ovaries on US, and adrenal incidentalomas or
hyperplasia is seen in 40%.

21. Laboratory
Investigations

22. Laboratory evaluation
• Diagnosis of non-classic CAH—17OHP measurement
o Timing: Screen in the follicular phase of the menstrual cycle
o 17OHP is produced by the corpus luteum, so false-positive results may occur if
measured in the luteal phase of the cycle.
o Interpretation of result
 <166.7 ng/dL (<5 nmol/L)—normal.
 >500 ng/dL (>15 nmol/L)—CAH.
 166.7–500 ng/dL (5 – 15 nmol/L)— ACTH stimulation test. A fifth will have
non-classic CAH.

24. Laboratory evaluation (cont.)
• ACTH stimulation test
o Measure 17OHP 30 minutes after ACTH administration.
o An exaggerated rise in 17OHP is seen in non-classic CAH.
 17OHP level <1000 ng/dL (<30 nmol/L) post-ACTH excludes the diagnosis.
 Most patients have levels >1500 ng/dL (>45 nmol/L).
 Levels of 1000–1500 ng/dL (30 – 45 nmol/L) suggest heterozygosity or
nonclassic CAH.
o Cortisol response to ACTH stimulation is usually low to normal.

25. Other investigations
Androgen
• In poorly controlled classic CAH
in women, testosterone and
androstenedione levels may be
in the adult male range.
• DHEAS levels are usually only
mildly, and not consistently,
elevated in CAH.
Renin
• Plasma renin levels are markedly
elevated in 75% of patients with
inadequately treated classic CAH
(inadequate fludrocortisone
dose), reflecting deficient
aldosterone production.
• A proportion of women with
non-classic CAH may also have
mildly elevated renin.

26. What about ACTH?
Greatly elevated in poorly
controlled classic CAH
Usually, normal levels in
nonclassic CAH

27. Management

28. Aim of
treatment
To maintain normal energy levels and weight
and avoid adrenal crises in all patients
To minimize hyperandrogenism and to restore
regular menses and fertility in women
Avoid over-replacement of CS
Follow sick-day guidelines in case of stress

30. CCAH - Prednisolone
Total dose 5–7.5mg/day. Given in two divided doses, with one-third of the total
dose given on waking (about 7 a.m.) and two-thirds of the dose on evening. The
aim is to suppress the early morning peak of ACTH and thus androgen secretion.
The optimum dose is the minimum dose required to normalize serum
androgens.
Occasional patients who are not controlled on prednisolone may be optimally
treated with nocturnal dexamethasone instead (0.25–0.5mg).

31. CCAH – Other therapies
Mineralocorticoids: 3/4 of patients are salt wasters and
thus require mineralocorticoid replacement therapy.
Fludrocortisone in a dose of 50–200 mcg/ day is given as a
single daily dose.
Bilateral adrenalectomy: may very occasionally be
considered in patients with severe virilization resistant to
conventional therapy or intractable infertility in females.

32. NCCAH
Oligo- and amenorrhea are treated with glucocorticoid therapy—e.g.,
nocturnal dexamethasone 0.25–0.5 mg or prednisone 2.5–5 mg/day, maybe
used. Slightly higher doses may be required to normalize ovulatory function.
If fertility is not desired, symptoms may be treated with OCPs and
antiandrogen.
Hirsutism and acne may be treated using OCPs (see PCOS).

33. NCCAH (cont.)
Spironolactone should be avoided because of the potential risk of
salt wasting and thus hyperreninemia.
If the plasma renin level is elevated, then fludrocortisone given in a
dose sufficient to normalize renin concentrations may improve
adrenal hyperandrogenism.
Men do not usually require treatment. The occasional man may
need glucocorticoids to treat subfertility.

34. Monitoring of treatment
Annual follow-up is
usually adequate in
adults.
Clinical assessment:
• Look for evidence of hyperandrogenism and glucocorticoid
excess.
• Amenorrhea in women usually suggests inadequate therapy.
• Measure BP and weight.
17OHP
• Suppressed levels of 17OHP, testosterone (T), and renin
are an indication for reduced dose of steroid.
• Aim for a mildly elevated level (about 2–4xnormal).

35. Monitoring of treatment (cont.)
Plasma
rennin
Aim: for renin in mid-normal range.
Why: Hyperandrogenism will be difficult to control if the patient is
mildly salt depleted (ACTH production stimulated by hypovolemia).
Androgens Aim: to normalize serum testosterone/androstenedione taken
before A.M. steroids.
Consider bone density, which may be reduced by supraphysiological
steroid doses.

36. Monitoring of therapy (cont.)
Testicular function
• It requires special attention.
• Low LH is a sign of raised adrenal androgens.
• Raised FSH may follow adrenal rests as a sign of testicular
failure, testicular adrenal rest tumors may develop (up to 94%),
and their detection may prevent infertility later.
• US testis every 3–5 years.
• Consider sperm count/storage if adrenal rests are present.

37. Prognosis
Adults with treated CAH have
a normal life expectancy.
Improvement in medical and
surgical care has also
improved quality of life (QoL)
for most sufferers.

38. Unresolved issues

39. Issues
Height
• Despite optimal treatment in
childhood, patients with CAH
are, on average, significantly
shorter than their predicted
genetic height.
• Studies suggest that this may be
due to overtreatment with
glucocorticoids during infancy.
Fertility
• Women: Fertility remains
reduced particularly in salt
wasters, from factors including
inadequate vaginal introitus and
anovulation secondary to both ↑
androgen and ↑ 17OHP levels.
• Men: fertility may be affected
with poorly controlled classic
CAH, and adrenal rests.

40. Unresolved Issues (cont.)
Adrenal incidentalomas and testicular
adrenal rest tumors
• Benign adrenal adenomas have
been reported in up to 50% of
patients with classic CAH.
• Men with CAH may develop
adrenal rests. These are ACTH-
responsive and should be
treated by optimizing
glucocorticoid therapy.
Psychosexual issues
• Gender dysphoria common in
females.
• A significant number of females
with classic CAH, despite
adequacy of vaginal
reconstruction, are not sexually
active.

42. Thanks