Steroidogenesis:

Hormones are substances secreted by endocrine glands which are transported in the bloodstream to distant
target organs where they elicit specific responses.
Steroid hormones are synthesized from cholesterol. All steroids have this characteristic four ring
structure (3x cyclohexane, 1x cyclopentane).

Adrenal gland:
Mineralocorticoids: Involved in “mineral” (salt/water) balance.
Aldosterone – the principal mineralocorticoid, produced from progesterone in the outer zone (zona
glomerulosa) of adrenal cortex, just beneath capsule.

 Increases Na+ uptake  Raises blood pressure and fluid volume

 Secreted in response to elevated concentrations of angiotensin II or plasma potassium.
Glucocorticoids: Involved in glucose metabolism
Cortisol – dominant glucocorticoid in humans, synthesized from progesterone in the zona fasciculata of
the adrenal cortex.
Functions include:

 Involved in stress adaptation (hypoglycaemia, fear, pain, heavy exercise, infection)

 Elevates blood pressure and Na+ uptake
 Numerous effects on the immune system
Secreted in response in response to adrenocorticotrophic hormone (ACTH) from the anterior pituitary.
Production follows a diurnal pattern – peak in early hours (blunted in obesity).
Sex hormones:
Androstenedione – a weak androgen produced in the zona reticularis of the adrenal gland among other
locations. Can be converted into testosterone.
Testosterone – an androgen produced from progesterone in the testes. Principal male sex hormone →
responsible for secondary male sex characteristics
Oestradiol – an oestrogen produced in the ovary. Principal female sex hormone → responsible for
secondary female sex characteristics.
Other major steroid hormones:
Pregnenolone – produced directly from cholesterol
Progesterone – a progestin, produced directly from pregnenolone and in females is secreted from the
corpus luteum (in the ovary), responsible for changes associated with luteal phase of the menstrual cycle
and is involved in differentiation of the mammary glands.
Cholesterol  pregnenolone  progesterone

Androstenedione (cyp17a1), cortisol (cyp11b1 – 11beta-hydroxylase), aldosterone (cyp11b2 – aldosterone synthase)

Testosterone  17Bestradiol

Steroid hormone synthesis pathways:

Note that adrenal androgens are converted to testosterone, and then to oestrogens by enzymes outside the
adrenal.
How do steroid hormones work?
Steroid hormones work by acting as ligands for nuclear
receptors. Steroid hormone receptors are hormone-
activated transcription factors which have hormone-
binding domains, activation domains and DNA binding
domains.
They bind to specific SHR elements upstream of gene
promotors.
Examples:

 Androgen receptor – testosterone

 Oestrogen receptor – oestrogen
 Progesterone receptor
 Glucocorticoid receptor – cortisol, dexamethasone
 Mineralocorticoid receptor – aldosterone, cortisol
How do we make the mineralocorticoid receptor specific?
Seeing that cortisol binds to both GR and MR, how can we make it

such that the MR is only activated by aldosterone.

An enzyme, 11 β-hydroxysteroid dehydrogenase type 2, plays a crucial role in converting hormonally
active cortisol to inactive cortisone, thereby conferring specificity on the mineralocorticoid receptor.
Certain compounds e.g. glycyrrhetinic acid (in licorice) inhibit this enzyme, allowing greater stimulation
of MR → hypertension, reduced local fat deposition

Disorders of steroid hormones:

Cushing’s syndrome: hypercortisolism
Causes and epidemiology
Affects 1/100 000 people per year – usually adults 20-50. Causes include:

 Pituitary adenoma (most common endogenous cause) → over production of ACTH →

hyperplasia of adrenal cortex and increased cortisol production
Can be treated surgically
 Adrenal tumors
 Steroid containing medications
Steroid medications:
Used in various inflammatory conditions (e.g. asthma,
lupus, Crohn’s etc.) to dampen the immune response (by
inhibiting NF-κB – decreasing cytokine production).
When given in large doses, over a long period, CS may
develop.
Presentation:

 Hypertension
 High blood glucose
 Menstrual irregularities and hirsutism
 Lipdystrophy – irregular fat deposition
 Irritability, psychosis, mania, depression
 Muscle wasting and proximal limb weakness
 Abdominal striae, easy bruising, poor wound healing

Addison’s disease:
A disorder of adrenal insufficiency – affects about 1/100 000 people.
Causes:
Occurs when adrenal glands do not produce enough cortisol (and in some cases aldosterone). Most cases
are caused by gradual autoimmune destruction of the adrenal cortex.
Presentation:

 Weight loss
 Muscle weakness
 Fatigue
 Low blood pressure
Treatment:
Oral glucocorticoids → can produce CS

Male pattern baldness:

Sex hormones:
Adrenal androgens (DHEA, androstenedione), are weak androgens which are converted to more potent
sex hormones (testosterone and oestrogen) in other tissues.
Testosterone and oestrogen are also made de novo in the gonads.
Mechanism:
Overexpression of the enzyme 5α-reductase in the scalp → overproduction of testosterone → baldness.

Congenital adrenal
hyperplasia:
CAH is due to 21-hydoxylase
deficiency. It is seen in roughly
1/15000 births worldwide.
Less commonly, it can be caused
by a deficiency in 11β-
hydroxylase.
Mechanism:
Enzyme deficiency shunts
production towards androgens, resulting in clinical manifestations.

 Glucocorticoid insufficiency
o Hypotension
o Hypoglycaemia
o Impaired response to infection
o Elevated ACTH
 Mineralocorticoid insufficiency
o Hypotension
o Salt-wasting crisis in infancy (life-threatening vomiting and dehydration in the first few
weeks of life)
 Androgen excess
o Virilization (ambiguous genitalia in girls, clitoromegaly)
o Precocious pseudopuberty
o Hirsutism
o Infertility
Androgens are important in determining sexual differentiation – also important in gender identity (in
rats).

XY androgen insensitivity:
Genetically male, but appear female due to a deficiency of androgen receptors.
Believed to exist at a higher prevalence in models.
Steroid hormones in cancer:
Certain types of tumors rely on steroid hormones to survive and grow:
  Oestrogens – some breast, ovarian, uterine cancers
 Androgens – prostate cancers
Hormone therapy cuts the supply of hormones to the cancer → reduced growth.