congenital adrenal hyperplasia

1. CAH

2. 17α: 17α-hydroxylase (P450c17); 17,20: 17,20 lyase which is part of the P450c17 enzyme; 3β: 3β-
hydroxysteroid dehydrogenase; 21: 21-hydroxylase (P450c21); 11β: 11β-hydroxylase; (P450c11); 18
refers to the two-step process of aldosterone synthase (P450c11as), resulting in the addition of an
hydroxyl group that is then oxidized to an aldehyde group at the 18-carbon position; ?: unclear if
pathway functions in vivo; DHEA: dehydroepiandrostenedione; 17KSR: 17-ketosteroid reductase;
and A: aromatase.

4. INTRODUCTION
•Defective conversion of 17-hydroxyprogesterone to 11-
deoxycortisol accounts for more than 90 percent of cases of
congenital adrenal hyperplasia
•this conversion is mediated by 21-hydroxylase, the enzyme
encoded by the CYP21A2 gene.

5. •Patients with "classic" or the most severe form of congenital
adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency
present during the neonatal period and early infancy with
adrenal insufficiency with or without salt losing, or as toddlers
with virilization. Females have genital ambiguity.
•"Nonclassic," or late-onset 21-hydroxylase deficiency, presents
later in life with signs of androgen excess, and without
neonatal genital ambiguity. Clinical features in childhood may
include premature pubarche, and accelerated bone age;
adolescent and adult females may present with hirsutism,
menstrual irregularity, infertility, and acne. Some patients with
nonclassic CAH remain asymptomatic.

6. GENETICS
•The salt-losing form of the disorder is most often associated with large
deletions or intron 2 mutations that affect splicing and result in no
enzyme activity.
Patients with simple virilizing form have low but detectable enzyme
activity (ie, 1 to 2 percent) that supports sufficient aldosterone and
glucocorticoid production.
Women with the nonclassic form may be either compound heterozygotes
(with a classic mutation and a variant allele) or heterozygotes with
two variant alleles, allowing for 20 to 60 percent of normal enzymatic
activity
Patients who are compound heterozygotes for two different CYP21A2
mutations usually have the phenotype associated with the less severe
of the two genetic defects . Heterozygotes may have mild biochemical
abnormalities, but no clinically important endocrine disorder...

8. CLINICAL PRESENTATION
•The clinical spectrum of disease ranges from the most severe to
mild forms, depending on the degree of 21-hydroxylase
deficiency.
•Three main clinical phenotypes have been described:
•classic salt-losing,
•classic non-salt-losing (simple-virilizing)
•and nonclassic (late-onset):

9. Females with the classic form (salt-losing and non-salt-losing) present
with genital ambiguity.
Males with the salt-losing form who are not identified by neonatal
screening present with failure to thrive, dehydration,
hyponatremia, and hyperkalemia typically at 7 to 14 days of life.
Males with the classic non-salt-losing form who are not identified
by neonatal screening typically present at two to four years of
age with early virilization (pubic hair, growth spurt, adult body
odor).
Nonclassic or late-onset 21-hydroxylase deficiency may present as
hirsutism and menstrual irregularity in young women, early
pubarche or sexual precocity in school age children, or there
may be no symptoms.

11. DIAGNOSIS
Classic 21-hydroxylase deficiency results in one of two clinical
syndromes:
a salt-losing form or a non-salt-losing (simple virilizing) form. Girls
with either form present as neonates with ambiguous
genitalia.
Boys present as neonates with a salt-losing adrenal crisis
(hyponatremia, hyperkalemia, and failure to thrive) or as
toddlers with signs of puberty (non-salt-losing form)

12. Classic 21-hydroxylase deficiency — The characteristic biochemical
abnormality in patients with 21-hydroxylase deficiency is an
elevated serum concentration of 17-hydroxyprogesterone, the
normal substrate for 21-hydroxylase.
A very high serum concentration of 17-hydroxyprogesterone in a
randomly timed blood sample is diagnostic of classic 21-
hydroxylase.
Most affected neonates have concentrations greater than 3500
ng/dL (105 nmol/L)

13. The non-salt-losing (simple-virilizing) form of 21-hydroxylase
deficiency cannot be distinguished from the salt-losing form on
the basis of serum 17-hydroxyprogesterone values , However,
patients with the most complete enzyme deficiency typically
have the highest 17-hydroxyprogesterone levels.
To assess borderline cases, the standard high-dose (250 mcg
cosyntropin) test, not the low-dose (1 mcg) test, should be
used.
Genetic testing also can be used to evaluate borderline cases.
Genetic testing detects approximately 90 to 95 percent of
mutant alleles.

14. Patients with the salt-losing form of 21-hydroxylase deficiency have
low serum concentrations of aldosterone and 11-
deoxycorticosterone and increased plasma renin activity.
The mineralocorticoid deficiency can lead to volume depletion,
hyponatremia, and hyperkalemia.
Patients are also at risk for hypoglycemia during an adrenal crisis.

15. Nonclassic CYP21A2 deficiency —
The biochemical findings are less severe in patients with the late-
onset form of the disorder.
Basal serum 17-hydroxyprogesterone concentrations (during the
follicular phase of the menstrual cycle) may be only slightly high,
especially late in the day, but are always greater than 200 ng/dL
(6 nmol/L) in adult women and greater than 82 ng/dL (2.5
nmol/L) in children.
A morning value greater than 200 ng/dL (6 nmol/L) in the early
follicular phase or greater than 82 ng/dL in children strongly
suggests the diagnosis.

16. The diagnosis may be confirmed by a high dose (250 mcg) ACTH
stimulation test. The response to ACTH is exaggerated, and most
patients have values exceeding 1500 ng/dL (43 nmol/L) after
ACTH stimulation
Stimulated values of serum 17-hydroxyprogesterone
concentrations at 60 minutes range between 1000 ng/dL (30
nmol/L) and 10,000 ng/dl (300 nmol/L).

17. Other abnormalities that may be present include high serum
concentrations of 17-hydroxypregnenolone,
dehydroepiandrosterone (DHEA),
dehydroepiandrosterone sulfate (DHEA-S)

19. treatment
Women
Hirsutism and acne in women — Antiandrogen therapy,
including cyproterone acetate may be superior to
glucocorticoids for the treatment of hirsutism.
Oral contraceptives, which suppress ovarian androgens, also
suppress ACTH and adrenal androgens . Given the potential
risks and side effects of glucocorticoids, and the fact that
hirsutism typically requires long-term therapy, oral
contraceptives and/or antiandrogens are reasonable
options for first-line therapy.
Oligomenorrhea – If fertility is not desired, we suggest oral
contraceptive agents rather than glucocorticoid therapy for
menstrual cycle management. Although glucocorticoids
may restore ovulation and regular cycles, they do not
provide contraception, and are associated with important
risks and side effects.

20. Anovulatory infertility – Dexamethasone is generally the initial
treatment for ovulation induction ; clomiphene citrate and other
assisted reproduction techniques may be added if glucocorticoid
therapy alone is ineffective
Treatment may be discontinued when an adult woman no longer
seeks fertility. Hyperandrogenic symptoms persist, and require
ongoing therapy, although not necessarily with glucocorticoids

21. Men — Treatment is not necessary for men unless there are
testicular masses (testicular adrenal rest tumors) or
oligospermia (in a man desiring fertility). The few studies
reporting treatment of testicular rest tumors or infertility in men
initially used dexamethasone (0.75 mg/day), a dose which was
often reduced later because of the development of Cushingoid
features
Surgical extirpation of the masses in eight men with classic CAH did
not normalize sperm count in one study

22. Choice of glucocorticoid — Dexamethasone, given as a bedtime
dose of 0.25 to 0.75 mg, is the preferred treatment for older
adolescents and adults after epiphyseal closure is complete. The
lowest dose that ameliorates the sign or symptom being treated
should be used.
Prednisone (5 to 7.5 mg) also may be given at bedtime

23. We consider bedtime dexamethasone administration to be optimal
because most ACTH secretion occurs between about 2:00 AM
and 10:00 AM. The duration of the biologic action of
dexamethasone taken at bedtime encompasses this period.
Additional doses of dexamethasone increase the risk of
osteoporosis and Cushing's syndrome.
In the United Kingdom, other regimens are popular, including daily
prednisolone (median dose 7 mg/day, range 4 to 10 mg/day),
and single or split dosing of hydrocortisone (median 30 mg/day,
range 15 to 40 mg/day)

25. cases
21-year-old woman is referred by her general practitioner with
deteriorating hirsutism.
Since menarche at the age of 16 she has noted deteriorating facial
and truncal hirsutism. She had been taking the oral
contraceptive pill and had regular withdrawal bleeds up until
one year ago when she stopped the pill due to weight gain.
Since then she has had only one period, three months ago.
On examination her pulse was 82 beats per minute, blood
pressure 128/82 mmHg and she had a BMI of 30.4 kg/m2.
Investigations reveal:

26. Free T4 12.8 pmol/L(10-22)
TSH 1.2 mU/l(0.4-5)
17 Beta-oestradiol 254 pmol/L(130-850)
LH 11.4 mU/L(2-10)
FSH 6.2 mU/l(2-10)
Prolactin 610 mU/L(50-450)
Testosterone 3.2 nmol/L(<3)
Dehydroepiandrostenedione sulphate (DHEAS) 17.2 pmol/L(2-10)
17-Hydroxy progesterone 3.2 pmol/L(2-20)
What is the most likely diagnosis?
(Please select 1 option)
Adrenal carcinoma
Congenital adrenal hyperplasia
Microprolactinoma
Polycystic ovarian syndrome (PCOS)
Pregnancy

27. This patient is obese, has oligomenorrhoea and hirsutism.
Her investigations show a normal oestradiol with increased
luteinising hormone (LH):follicle-stimulating hormone (FSH),
mild hyperprolactinaemia and mildly increased androgens -
typical of PCOS.
Mild hyperprolactinaemia is a typical feature of PCOS and this
picture of normal oestradiol secretion with
hyperandrogenism does not fit with a microprolactinoma.
An elevated 17 OHP would be expected in association with
congenital adrenal hyperplasia (CAH).
A testosterone secreting tumour of either ovarian or adrenal
origin would typically cause a testosterone concentration
above 7 nmol/L and would switch off LH/FSH with
consequent hypo-oestrogenism.
Markedly elevated oestrogen and prolactin would be expected
at 12 weeks gestation and testosterone would be expected
to be normal

28. 22-year-old female presents with a one year history of
secondary amenorrhoea and a five year history of facial
hirsutism.
Examination reveals normal female secondary sexual
characterisitcs with mild facial hair and hair extending up
to the umbilicus and tops of thighs.
Investigations reveal:
Oestradiol concentration 65 pmol/L(130-450)
LH 3.2 mU/L(3-10)
FSH 3.5 mU/L(3-10)
Prolactin 320 mU/L(<450)
Testosterone 3.4 pmol/L (<3)

29. From the following list, select the investigation that may
provide useful diagnostic information.
(Please select 1 option)
A-17 hydroxyprogesterone (17 OHP) concentration This is
the correct answer
B-Dehydroepiandrosterone sulphate (DHEAS) concentration
C-Karyotype
D-Sex hormone binding globulin (SHBG) concentration
E-Transvaginal ovarian ultrasound scan Incorrect answer
selected

30. This patient has hypogonadotrophic hypogonadism, a slightly raised
testosterone concentration and hirsutism.
Non-classical congenital adrenal hyperplasia may account for this picture
and a 17-OHP concentration above 33 nmol/L would be diagnostic.
Cushing's syndrome may also account for this picture and a urine free
cortisol could provide useful information.
This is not a polycystic ovary syndrome (PCOS)/primary ovarian problem
as the normal concentrations of luteinising hormone (LH) and follicle-
stimulating hormone (FSH) with low oestradiol reflect
hypogonadotrophic hypogonadism.
Normal oestradiol would be expected in PCOS.
A high oestradiol with high prolactin would be expected in pregnancy.
An ovarian testosterone secreting tumour would be expected to be
associated with far higher testosterone concentrations.
This patient was found to have non-classical congenital adrenal
hyperplasia (CAH).
CAH is most commonly due to a defect of 21 hydroxylase and may
present variably from birth with salt wasting syndrome and
ambiguous genitalia, through childhood with precocious puberty, to
adulthood with primary or secondary amenorrhoea and hirsutism.

31. A 21-year-old woman comes to the endocrine clinic for
review.
She has a history of hypertension which is managed with a
combination of ramipril and indapamide. Her past medical
history includes 11-beta hydroxylase deficiency diagnosed
shortly after birth when cliteromegaly was identified by the
midwives.
Which of the following is likely to be markedly raised?
(Please select 1 option)
11-Deoxycortisol This is the correct answer
Oestradiol
Oestrone
17-OH progesterone Incorrect answer selected
17-OH pregnenolone

32. 11 Beta-hydroxylase is responsible for conversion of 11-
deoxycorticosterone and 11-deoxycortisol to
corticosterone and cortisol. As this enzyme is not active in
patients with 11-beta hydroxylase deficiency, levels of
these steroids accumulate in patients suffering from the
disorder.
Whilst levels of 17-OH steroids are elevated in those with 11-
beta hydroxylase deficiency, the elevation seen is not as
great as that seen with 21-hydroxylase deficiency,
occasionally an incorrect diagnosis of 21-hydroxylase
deficiency may however be made.
Oestrogens are synthesised by aromatase conversion of
androgens, and as such levels are not markedly elevated.

33. 22-year-old woman presented with a five year history of hirsutism, having
noticed coarse dark hair under her chin. Being a teacher in a primary school,
these
symptoms are very distressing for her. She has tried local measures such as
shaving
and applying depilatory creams but without lasting success.
Her periods are irregular with oligomenorrhoea. She attained menarche at
the age of
14 years. She has not yet conceived and has had a coil fitted for
contraception. She
takes 5 mg diazepam at night.
On examination, she had a BMI of 24. She had coarse, dark hair over her chin,
lower
back and inner thighs. She does not have galactorrhoea to expression and
there
were no other clinical features to suggest Cushing's.
Investigations during the follicular phase:
Serum androstenedione 10.1 nmol/l (0.6-8.8)
Serum dehydroepiandrosterone sulphate 11.6 µmol/l (2-10)
Serum 17-hydroxyprogesterone 18.6 nmol/ (1-10)
Serum oestradiol 380 pmol/l (200-400)
Serum testosterone 2.6 nmol/l (0.5-3)
Plasma luteinising hormone 3.3 U/l (2.5-10)
Plasma follicle-stimulating hormone 3.6 U/l (2.5-10)

34. What is the next most appropriate investigation?
(Please select 1 option)
a-24 hour urinary free cortisol
b-CT scan of adrenals
c-GnRH test
d-Short Synacthen test with measurement of 17 hydroxy
progesterone(17OHP)
e-Ultrasound scan of ovaries

35. In this case the patient has features that would suggest polycystic
ovary
syndrome (PCOS) yet the 17OHP concentration is elevated and is
compatible
with non-classical congenital adrenal hyperplasia (CAH) yet just
below the
threshold of 33 nmol/l confidently to make the diagnosis.
Thus a short Synacthen test would be the most appropriate
investigation with
measurement of 17OHP.
A rise in 17OHP above 33 nmol/l suggests non-classical CAH

36. 23 year old female presents with worsening acne and a marked
increase in the development of body and facial hair which she
finds very distressing. She is also overweight and is markedly
stressed by her physical appearance and the development of
stretch marks over her abdomen. She has tried multiple hair
removal techniques with only mild success.
On examination she has a body mass index of 28 kg/m², coarse hair
over the anterior and posterior part of her chest and under
her chin. Her Blood Pressure is 135/90mmHg.
Her lab results are as follows:
9:00 am Cortisol 345 nmol/l (170 700 nmol/l)
LH 17 iU/l (1 20 iU/l)
Basal FSH 7.1 iU/l (1.0 8.8 iU/l)
DHEAS 545 µg/dl (31 228 µg/dl)
Prolactin 160 mU/l (<360 mU/l)
17 OH Progesterone 1025 ng/dl (<80 ng/dl)
Testosterone 3.9 nmol/l (0.9 3.1 nmol/l)
Ultrasound abdomen and pelvis reveals two cysts in the right
ovary.

37. •Which of the following is the most appropriate treatment
option for her condition?
•a-Combined oral contraceptive pill
b-Finasteride
c-Surgical resection of the ovarian cysts
d-Reverse circadian rhythm steroids
e-Metformin in combination with spironolactone

38. The diagnosis in this scenario is non-classical congenital adrenal hyperplasia
which manifests in adolescence/adulthood. It is caused by deficiency in the
enzyme 21 hydroxylase in the steroid biosynthetic pathway
The result is a shift in the production of steroid hormones towards the
androgenic pathwa
Since cortisol secretion is reduced, feedback leads to increased ACTH production
and resultant hyperplasia of the adrenals.
The level of the compounds that are formed prior to the action of 21
hydroxylase is increased, therefore levels of 17 hydroxyprogesterone are
elevated. Due to excessive androgen production, there is virilization and
hirsutism.
Treatment involves steroids given in reverse circadian rhythm, i.e. a higher
dosage at night and a lower dose in the morning.
When steroids are given in higher doses at night, ACTH is suppressed and the
normal physiological steroid peak in the morning is also
Cysts in the ovaries are a common finding on routine ultrasound and do not
necessarily represent polycystic ovarian syndrome.