Department of pediatrics and child

health CMHS, Gondar

Yohanes Hailu(MD)
 Adrenal Steroid Biosynthesis
Cholesterol is the starting substrate for all steroid
biosynthesis.
The rate-limiting step of adrenal steroidogenesis is
importation of cholesterol across the mitochondrial outer
and inner membrane.
At the mitochondrial inner membrane, the side chain of
cholesterol is cleaved to yield pregnenolone.
Pregnenolone then diffuses out of mitochondria and
enters the endoplasmic reticulum. The subsequent
reactions that occur depend on the zone of the adrenal
cortex.

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 Cont….
The adrenal gland synthesis and secretes
different steroid hormones at different zones of
the cortex:
Innermost zone (zona reticularis)-androgens
and estrogens
Middle zone (zona fasciculata) -cortisol
Outermost zona( zona glomerulosa)
-aldosterone.

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 Regulation of the hypothalamic-pituitary-
adrenal (HPA) axis.

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 Fig. Steroid biosynthesis and metabolism during gestation. Conversions within the fetal adrenal cortex, fetal liver, male
(i.e., testosterone-exposed) genital skin, and placenta are denoted by arrows; the enzyme mediating each conversion
is also shown. Enzymatic conversions in the adrenal cortex are the same postnatally as prenatally, but cortisol and
aldosterone biosynthesis are more prominent, and normally little testosterone is synthesized.

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 Simplified scheme of adrenal steroidogenesis. Two reactions (dotted arrows) occur primarily
in gonads, not in adrenal gland. Chemical names for enzymes shown above or to right of arrows;
circled numbers refer to traditional names: 1) 20,22-desmolase; 2) 3β−hydroxysteroid dehydrogenase/
isomerase; 3) 21-hydroxylase; 4) 11β−hydroxylase; 5) 17α-hydroxylase; 6) 17,20-lyase; 7)
18-hydroxylase; 8) 18-oxidase; 9) 17β−hydroxysteroid dehydrogenase; 10) aromatase; StAR = steroidogenic
acute regulatory protein; DOC = 11-deoxycorticosterone.

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 Synthetic pathways for adrenal steroid synthesis

17α: 17α-hydroxylase (CYP17, P450c17); 17,20: 17,20 lyase (also mediated by CYP17); 3β: 3β-hydroxysteroid
dehydrogenase; 21: 21-hydroxylase (CYP21A2, P450c21); 11β: 11β-hydroxylase; (CYP11B1, P450c11); 18 refers to
the two-step process of aldosterone synthase (CYP11B2, P450c11as), resulting in the addition of an hydroxyl group
that is then oxidized to an aldehyde group at the 18-carbon position; 17βR: 17β-reductase; 5αR: 5α-reductase; DHEA:
dehydroepiandrosterone; DHEAS: DHEA sulfate; A: aromatase (CYP19); SK: sulfokinase; SL: sulfotransferase.
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 Regulation of the Adrenal Cortex
Regulation of cortisol secretion
Mainly regulated by ACTH (corticotropin).
Cortisol is secreted in a pulsatile rhythm caused
by the varying amplitudes of ACTH pulses. The
highest pulse occurs at about the time of
waking, and the lower is in late afternoon and
evening, and reach their lowest point 1 or 2 hr
after sleep begins.
CRH is the most stimulator of ACTH.

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 Cont….
Regulation of aldosterone secretion
Regulated by the renin–angiotensin system and
by potassium levels, with ACTH having only a
short-term effect.
Angiotensinogen rennin
→→→→
angiotensin
→→→→
I ACE
angiotensin II Aminopeptidase
→→→→ →→→→ →→→
N angiotensin
III
Angiotensins II and III are potent stimulators of
aldosterone secretion; angiotensin II is a more
potent vasopressor agent.

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 Cont….
Regulation of adrenal androgen secretion
It is not completely understood.
Adrenal Steroid Hormone Actions
Action of glucocorticoids
1. Metabolic Effects
Increase glucose production.
Increase free fatty acid levels.
Increase in proteolysis.

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 Cont…
2. Circulatory and Renal Effects
Have positive inotropic influence on the heart,
Have a permissive effect on the actions of
epinephrine and norepinephrine on both the
heart and the blood vessels.
3. Growth
Necessary for normal growth and development.
Accelerate the differentiation and development of
various tissues, including the hepatic and
gastrointestinal systems, as well as the
production of surfactant in the fetal lung.

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 Cont…
4. Immunologic Effects
Inhibit synthesis of glycolipids and prostaglandin
precursors and the actions of bradykinin.
Block secretion and actions of histamine and
proinflammatory cytokines (tumor necrosis factor-α,
interleukin-1, and interleukin-6), thus diminishing
inflammation.
High doses of glucocorticoids deplete monocytes,
eosinophils, and lymphocytes, especially T cells.
Decrease diapedesis, chemotaxis, and phagocytosis
of polymorphonuclear cells.

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 Cont…
5. Effects on Skin, Bone, and Calcium
Inhibit fibroblasts, leading to increased bruising and poor
wound healing through cutaneous atrophy.
Decrease serum calcium level causing osteoporosis in chronic
use.
6. Central Nervous System Effects
Decrease CNS edema.
Stimulate appetite and cause insomnia.
Causes irritability and emotional lability, with an impairment of
memory and ability to concentrate.
Mild to moderate glucocorticoid excess for a limited period
often causes a feeling of euphoria or well-being.

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 Cont….
Action of mineralocorticoid
Maintain intravascular volume by conserving sodium
and eliminating potassium and hydrogen ions
through kidney, gut, and salivary and sweat glands.
Action of the adrenal androgens
Contribute to the physiologic development of pubic
and axillary hair during normal puberty.
Play a major role in the pathophysiology of CAH,
premature adrenarche, adrenal tumors, and Cushing
syndrome.

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 Cont…
Synthetic Corticosteroids
Prednisone and prednisolone are 4-5 times as potent in
anti-inflammatory and carbohydrate activity but have
slightly less effect on retention of water and sodium than
cortisol.
Betamethasone and dexamethasone have 25-40 times
the glucocorticoid potency of cortisol but have little
mineralocorticoid effect.
The anti-inflammatory activity of fludrocortisone is about
15 times that of hydrocortisone, but fludrocortisone is
more than 125 times as active a mineralocorticoid.

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 Adrenal Medulla
The principal hormones are dopamine,
norepinephrine, and epinephrine.
Both epinephrine and norepinephrine raise the
mean arterial blood pressure, but only
epinephrine increases cardiac output.
By increasing peripheral vascular resistance,
norepinephrine increases systolic and diastolic
blood pressures with only a slight reduction in
the pulse rate.
Epinephrine increases the pulse rate and, by
decreasing the peripheral vascular resistance,
decreases the diastolic pressure.

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Congenital Adrenal Hyperplasia and
Related Disorders
Is autosomal recessive disorder.
The clinical manifestation will depend on:
The deficient hormone
The excess hormone
Patients with CAH may present with:
Virilization of the affected female infant and subsequent signs of
androgen excess in both males and females
Incomplete virilization of the male and signs of sex hormone
deficiency at puberty in both males and females
Salt-wasting crisis secondary to aldosterone deficiency, or
Hormonal hypertension secondary to increased
deoxycorticosterone (DOC).
 Congenital Adrenal Hyperplasia

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.
 Congenital Adrenal Hyperplasia

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 Fig. A, A 6-yr-old girl with congenital virilizing adrenal hyperplasia. The height age was 8.5 yr, and the bone age was 13 yr. B, Notice the clitoral
enlargement and labial fusion. C, Her 5-yr-old brother was not considered to be abnormal by the parents. The height age was 8 yr, and the bone
age was 12.5 yr.

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 Three virilized females with untreated congenital adrenal hyperplasia.

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 Clitoromegaly in a 46,XX infant with 21-
hydroxylase deficiency.

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 Cont'd

• Causes of CAH:
– LIPOID ADRENAL HYPERPLASIA
– 3β HYDROXYSTEROID (3β HSD)/Δ4,5-ISOMERASE
DEFICIENCY
– 17-HYDROXYLASE/17,20 LYASE DEFICIENCY
– 21-Hydrtoxylase deficiency
– 11β-HYDROXYLASE DEFICIENCY

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 LIPOID ADRENAL HYPERPLASIA

17α: 17α-hydroxylase (CYP17, P450c17); 17,20: 17,20 lyase (also mediated by CYP17); 3β: 3β-hydroxysteroid
dehydrogenase; 21: 21-hydroxylase (CYP21A2, P450c21); 11β: 11β-hydroxylase; (CYP11B1, P450c11); 18 refers to
the two-step process of aldosterone synthase (CYP11B2, P450c11as), resulting in the addition of an hydroxyl group
that is then oxidized to an aldehyde group at the 18-carbon position; 17βR: 17β-reductase; 5αR: 5α-reductase; DHEA:
dehydroepiandrosterone; DHEAS: DHEA sulfate; A: aromatase (CYP19); SK: sulfokinase; SL: sulfotransferase.
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 LIPOID ADRENAL HYPERPLASIA

• caused by deficiency of cholesterol desmolase

activity leading to deficiency of:
– all adrenal hormones: glucocorticoids (cortisol),
mineralocorticoids (aldosterone), and the sex
steroids.
– gonadal steroids.
• is due to mutation in the gene for steroidogenic acute
regulatory protein (StAR) which is expressed in adrenals
and gonads.

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 Cont'd

• Affected infants present with:

– saltwasting crisis (cardiovascular collapse, hyponatremia,
and hyperkalemia).
– Males have phenotypically female external genitalia.
– Females exhibit no genital abnormalities.
– Increased pigmentation, secondary to increased ACTH.
• Diagnosis
– low levels of all steroid hormones
– eleveted ACTH and plasm renin activity(PRA).
– marked enlargement of the adrenals.
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 3β HYDROXYSTEROID (3β HSD)/Δ4,5-ISOMERASE
DEFICIENCY

17α: 17α-hydroxylase (CYP17, P450c17); 17,20: 17,20 lyase (also mediated by CYP17); 3β: 3β-hydroxysteroid
dehydrogenase; 21: 21-hydroxylase (CYP21A2, P450c21); 11β: 11β-hydroxylase; (CYP11B1, P450c11); 18 refers to
the two-step process of aldosterone synthase (CYP11B2, P450c11as), resulting in the addition of an hydroxyl group
that is then oxidized to an aldehyde group at the 18-carbon position; 17βR: 17β-reductase; 5αR: 5α-reductase; DHEA:
dehydroepiandrosterone; DHEAS: DHEA sulfate; A: aromatase (CYP19); SK: sulfokinase; SL: sulfotransferase.
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 3β HYDROXYSTEROID (3β HSD)/Δ4,5-
ISOMERASE DEFICIENCY

• Occurs in <5% of cases.

• Deficiency in 3β HSD/Δ4,5-Isomerase results in
decreased synthesis of cortisol, aldosterone,
and androstenedione.
• In the testes, it results in decreased ability to
form testosterone.
• Increased level of DHEA result in:
– Virilization of the external genitalia in affected
females(clitoromegaly and partial fusion of the labial
folds).
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 Cont'd

• Males presnet with varying degrees of ambiguity of

the external genitalia ranging from hypospadius to
more significant degrees of incomplete virilization
with partial fusion of the scrotal folds.
• Salt wasting crisis.
• Postnatally present with growth acceleration and
the early onset of pubic and/or axillary hair.
• Increased pigmentation of skin creases.
• Diagnosis:
– Eleveted 17-hydroxypregnenolone, and DHEA.
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 17-HYDROXYLASE/17,20 LYASE DEFICIENCY

17α: 17α-hydroxylase (CYP17, P450c17); 17,20: 17,20 lyase (also mediated by CYP17); 3β: 3β-hydroxysteroid
dehydrogenase; 21: 21-hydroxylase (CYP21A2, P450c21); 11β: 11β-hydroxylase; (CYP11B1, P450c11); 18 refers to
the two-step process of aldosterone synthase (CYP11B2, P450c11as), resulting in the addition of an hydroxyl group
that is then oxidized to an aldehyde group at the 18-carbon position; 17βR: 17β-reductase; 5αR: 5α-reductase; DHEA:
dehydroepiandrosterone; DHEAS: DHEA sulfate; A: aromatase (CYP19); SK: sulfokinase; SL: sulfotransferase.
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 17-HYDROXYLASE/17,20 LYASE
DEFICIENCY

• Results defect in the conversion of:

– pregnenolone and progesterone to 17-hydroxypregnenolone and 17-
hydroxyprogesterone, and
– deficiency in the 17,20 lyase reaction results defect in the
conversion of 17-hydroxypregnenolone and 17-hydroxyprogesterone
to DHEA and Δ4-androstenedione, respectively.
• Present with:
– Hypertension & hypokalemia.
– Hyperpigmentation.
– Affected males are incompletely virilized and are phenotypically female
or ambiguous.
– Affected females have normal female external genitalia and may present
with failure of sexual development at adolescence.

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 Cont'd

• Diagnosis:
– Low levels of all 17-hydroxylated steroids
– Poor response to ACTH and HCG
administration.

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 21-Hydrtoxylase deficiency

17α: 17α-hydroxylase (CYP17, P450c17); 17,20: 17,20 lyase (also mediated by CYP17); 3β: 3β-hydroxysteroid
dehydrogenase; 21: 21-hydroxylase (CYP21A2, P450c21); 11β: 11β-hydroxylase; (CYP11B1, P450c11); 18 refers to
the two-step process of aldosterone synthase (CYP11B2, P450c11as), resulting in the addition of an hydroxyl group
that is then oxidized to an aldehyde group at the 18-carbon position; 17βR: 17β-reductase; 5αR: 5α-reductase; DHEA:
dehydroepiandrosterone; DHEAS: DHEA sulfate; A: aromatase (CYP19); SK: sulfokinase; SL: sulfotransferase.
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 21-Hydrtoxylase deficiency
90% of the cases.
Deficiency of cortisol and aldosterone.
Overproduction of the steroids prior to 21-hydroxylation
mainly 17-hydroxyprogesterone.
Overproduction of the adrenal androgens, especially Δ4-
androstenedione, and by peripheral conversion,
testosterone, resulting in virilization.
Increased ACTH
Adrenal hyperplasia
Approx 2/3 of these patients will have aldosterone
deficiency presenting with salt-wasting crisis in the newborn
period, most often between 1 wk and 1 mo of-age.
 Cont'd
Female fetus is exposed to excessive adrenal
androgens resulting in virilization of the external
genitalia ranging from clitoromegaly, with or without
mild degrees of labial fusion, to marked virilization of
the external genitalia.
Due to continued post-natal virilization:
Progressive clitoromegaly and penile enlargement
Rapid growth
Premature development of pubic and/or axillary hair.
Signs of androgen excess secondary to late or inadequate
treatment (acne, delayed menarche or primary amenorrhea,
menstrual irregularity, hirsutism), and
Infertility.
 Cont'd

Diagnosis:
Elevated serum level of 17-OH progesterone.
Elevated 24-h urinary excretion of pregnanetriol
and 17-ketosteroids, the metabolic products of 17-
hydroxyprogesterone and androgens, respectively.
 11β-HYDROXYLASE DEFICIENCY

17α: 17α-hydroxylase (CYP17, P450c17); 17,20: 17,20 lyase (also mediated by CYP17); 3β: 3β-hydroxysteroid
dehydrogenase; 21: 21-hydroxylase (CYP21A2, P450c21); 11β: 11β-hydroxylase; (CYP11B1, P450c11); 18 refers to
the two-step process of aldosterone synthase (CYP11B2, P450c11as), resulting in the addition of an hydroxyl group
that is then oxidized to an aldehyde group at the 18-carbon position; 17βR: 17β-reductase; 5αR: 5α-reductase; DHEA:
dehydroepiandrosterone; DHEAS: DHEA sulfate; A: aromatase (CYP19); SK: sulfokinase; SL: sulfotransferase.
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11β-HYDROXYLASE DEFICIENCY

Contributes for 5% of the cases.

Results in:
Block in 11-hydroxylation of 11-deoxycortisol to cortisol
and 11-deoxycorticosterone (DOC) to corticosterone.
Overproduction of adrenal androgens.
The excessive DOC secretion results in:
Sodium and water retention and plasma volume
expansion.
Hypertension and hypokalemia.
 Cont'd

Diagnosis:
Elevated serum level of 11-deoxycortisol (1400–4300
ng/dL) and DOC (183–2050 ng/dL).
Increased 24-h urinary excretion of their
metabolites( tetrahydro-11-deoxycortisol and
tetrahydro-11-deoxycorticosterone ) confirms the
diagnosis.
Hypokalemia may also be present
 Postnatal Androgen Excess
Rapid somatic growth and accelerated skeletal
maturation. Thus , they are tall in childhood but
premature closure of the epiphyses causes growth
to stop relatively early, and adult stature is stunted.
Excessive muscular development.
Early secondary sexual characteristic development.
Despite the enlarged penis, testes are usually
prepubertal and small in size .
Although the internal genital structures are female,
breast development and menstruation will not
occur.

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 Laboratory Findings
Hyponatremia , hyperkalemia, metabolic
acidosis, and often hypoglycemia in Patients
with salt-losing disease, but these abnormalities
can take 10-14 days or longer to develop after
birth.
Elevated 17-hydroxyprogesterone ,
androstenedione and testosterone in affected
females.
Low serum cortisol level.
Elevated plasma levels of renin.

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 Cont…..
Diagnosis of 21-hydroxylase deficiency is most
reliably established by measuring 17-
hydroxyprogesterone before and 30 or 60 min
after an IV of 0.125-0.25 mg of cosyntropin
(ACTH 1-24) compared with a nomograms.

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 Prenatal Diagnosis

Analysis of DNA obtained by chorionic villus sampling in

the 1st trimester or by amniocentesis during the 2nd
trimester.
CYP21 gene analysis for frequently occurring
mutations.
Newborn Screening
Analysis of 17-hydroxyprogesterone levels in
dried blood obtained by heel-stick and absorbed
on filter paper cards.

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 Treatment

Glucocorticoid Replacement
Hydrocortisone 15-20 mg/m2/24 hr po tid.
Double or triple doses during periods of stress,
such as infection or surgery.
Testicular MRI, ultrasonography, and color flow
Doppler examination.
Mineralocorticoid Replacement
Fludrocortisone with sodium supplementation
(sodium chloride, 8 mmol/kg)
Flutamide and Aromatase inhibitors not yet
licensed.

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 Cont….
Surgical Management of Ambiguous
Genitals
Significantly virilized females usually undergo
surgery between 2-6 mo of age.
Prenatal Treatment
Dexamethasone20mcg/kg in 2 or 3 divided
doses and it’s continued only if the fetus is an
affected female based on chorionic villus biopsy
.
If started by 6 wk of gestation, it ameliorates
virilization of the affected females.

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