2009 - Describe the major steps involved in the synthesis of adrenal cortical hormones (40%).

How can abnormalities in this pathway cause disease (60%)?

Introduction

Steroid hormones are synthesised primarily from cholesterol in the adrenal glands and gonads. The
adrenal cortex can be divided into three distinct layers of tissue based on their organisation, each
layer producing a different primary product:

 Zona glomerulosa  Mineralocorticoids (Aldosterone) – secreted in response to renin-

angiotensin system
 Zona fasiculata  Glucocorticoids (Cortisol) – secreted in response to stress through ACTH
 Zona reticularis  Androgens (Dehydroepiandrosterone, DHEA) – controlled by ACTH
secretion

Steroid synthesis

Adrenal steroid synthesis involves a complex sequence of enzymatic steps within the cytoplasm and
mitochondria of the adrenal cell. The initial rate-limiting step, steroidogenesis, is the conversion of
cholesterol to pregnenolone.

In most cases cholesterol is made available from the circulation in the form of LDL. The initial rate-
limiting step, the transport of intracellular cholesterol to sites of steroidogenesis (into
mitochondria), is mediated by steroidogenic acute regulatory protein (StAR) and regulated by ACTH.

Cholesterol is first converted to pregnenolone by cholesterol 20,22 lyase. Pregnenolone then

undergoes a number of reactions to form either aldosterone, via progesterone, cortisol, via 17-OH
progesterone, or the androgens, via DHEA:
Defects in steroid synthesis

Most disorders of steroidogenesis result from enzyme mutations in the cholesterol pathways.
Conditions usually present in childhood and the majority lead to disorders of sex development. The
clinical effects arise from deficiency or excess of the actions of hormonal steroids.

 Cortisol  Deficiency = Hypoglycaemia; Excess = Cushings

 Aldosterone  Deficiency = Salt wasting; Excess = HT
 Progesterone  Deficiency = Infertility
 Oestradiol  Deficiency = Lack of secondary sexual characteristics
 Testosterone and Dihydrotestosterone  Deficiency = Lack of secondary sexual
characteristics; Excess = virilisation

Mutations in StAR cause congenital lipoid adrenal hyperplasia. An absence of all steroids can be
caused by a defect in the conversion of cholesterol to pregnenolone (cholesterol 20, 22 lyase defect,
StAR protein defect). Addison’s disease can also cause a lack of adrenal androgens usually through
autoimmune destruction of the adrenal cortex.

Defects in cortisol synthesis

 CAH – any gene mutation that results in deficiency of an enzyme involved in steroid
biosynthesis. This causes inability to secrete adequate cortisol, increased ACTH and
increased steroid precursors prior to the malfunctioning enzyme. In common forms of the
condition, androgens also raised causing virilisation in females.
 Eg. 21-hydroxylase deficiency-95% of CAH - increased 17α-hydroxyprogesterone. Renal salt
losing crisis.
11b-hydroxylase deficiency - increased 11-deoxycortisol. Hypertension.
Others very rare: 17a-hydroxylase deficiency, 3b-hydroxysteroid dehydrogenase deficiency.

Defects in sex hormone synthesis

 CAH: 17-hydroxysteroid dehydrogenase deficiency – impaired testosterone synthesis
5a-reductase deficiency (partial androgen insensitivity) – failure to synthesis active
testosterone form

Defects in mineralocorticoid synthesis

 Aldosterone synthase deficiency.

Tests

If ambiguous genitalia/primary gonadal failure: do karyotyping (46XY / 46XX) as need to know

whether undervirilised male or virilised female.
Also: cortisol, synacthen test, 17α-hydroxyprogesterone, 11-deoxycortisol, urinary steroid profile.

Conclusion

A defect in any stage of the adrenal steroid synthesis pathway can cause a clinical manifestation.
Some disorders are severe and will be picked up at birth (21OH), others may be diagnosed at
puberty (5a-reductase) and others later in adulthood (fertility issues).