hormones

1. H O R M O N E S
Carl Jan M. Ongkingco

2. O B J E C T I V E S
• Discuss the hormones in the adrenal glands
• To illustrate the biosynthesis of these hormones
• Briefly discuss the functions and effects of these hormones
• Give examples of clinical disease related to these hormones

3. R E F E R E N C E S :
• Mark’s Basic Medical Biochemistry; A Clinical Approach 5th edition
• Harper’s Illustrated Biochemistry; 31st edition
• Harrison’s Principles of Internal Medicine, 21st edition

4. H O R M O N E S
1. Cortisol
2. Aldosterone
3. DHEA and androgenic steroids
4. Epinephrine (adrenaline) and Norepinephrine (noradrenaline)

5. C A T E C H O L A M I N E H O R M O N E S
• water-soluble compounds epinephrine (adrenaline) and norepinephrine (noradrenaline) are
catecholamines, named for the structurally related compound catechol
• are synthesized from tyrosine

6. C A T E C H O L A M I N E H O R M O N E S
• produced in the brain and in other neural tissues function as neurotransmitters
• but epinephrine and norepinephrine are also hormones, synthesized and secreted by the adrenal
glands (adrenals)
• catecholamines are highly concentrated in secretory granules and released by exocytosis, and
they act through surface receptors to generate intracellular second messengers

7. C A T E C H O L A M I N E H O R M O N E S
• catecholamines belong to a family of bioamines and are secretory products of the sympathoadrenal system
• are required for the body to adapt to a great variety of acute and chronic stresses
• Epinephrine (80% to 85% of stored catecholamines) is synthesized primarily in the cells of the adrenal medulla,
• whereas norepinephrine (15% to 20% of stored catecholamines) is synthesized and stored not only in the adrenal
medulla but also in various areas of the CNS and in the nerve endings of the adrenergic nervous system

8. C A T E C H O L A M I N E H O R M O N E S - S Y N T H E S I S
• three neurotransmitters dopamine, norepinephrine, and epinephrine are synthesized in a common pathway from the
amino acid L-tyrosine
• Tyrosine is supplied in the diet or is synthesized in the liver from the essential amino acid phenylalanine by
phenylalanine hydroxylase

9. • The first and rate-limiting step in the synthesis of
these neurotransmitters from tyrosine is the
hydroxylation of the tyrosine ring by tyrosine
hydroxylase, a tetrahydrobiopterin (BH4)-requiring
enzyme.
• Tyrosine hydroxylase is found in both soluble and
particle-bound forms only in tissues that synthesize
catecholamines
• The product formed is dihydroxyphenylalanine ( L-
DOPA)
• The phenyl ring with two adjacent –OH groups is a
catechol – catecholamines
1st step: ring hydroxylation

10. • Catecholamines cannot cross the blood–brain barrier hence, in the brain they must be synthesized
locally
• In certain central nervous system diseases (eg, Parkinson disease), there is a local deficiency of
dopamine synthesis
• LDopa, the precursor of dopamine, readily crosses the blood–brain barrier and so is an important
agent in the treatment of Parkinson disease

11. P A R K I N S O N S

12. • The second step in catecholamine synthesis is the
decarboxylation of LDOPA to form dopamine
• This reaction, like many decarboxylation reactions
of amino acids, requires pyridoxal phosphate
• Dopaminergic neurons (neurons that use dopamine
as a neurotransmitter) stop the synthesis at this point
because these neurons do not synthesize the
enzymes required for the subsequent steps
2nd step: decarboxylation

13. • Dopa Decarboxylase Is Present in All Tissues
• This soluble enzyme requires pyridoxal phosphate for the conversion of Ldopa to 3,4-
dihydroxyphenylethylamine (dopamine)
• Compounds that resemble L-dopa, such as α-methyldopa, are competitive inhibitors of this
reaction. α-Methyldopa is effective in treating some kinds of hypertension

14. • Dopamine β-Hydroxylase (DBH) Catalyzes the
Conversion of Dopamine to Norepinephrine
• DBH is a monooxygenase and uses ascorbate as an
electron donor, copper at the active site, and
fumarate as modulator
• DBH is in the particulate fraction of the medullary
cells, probably in the secretion granule; thus, the
conversion of dopamine to norepinephrine occurs
in this organelle
3rd step: side chain hydroxylation

15. • Phenylethanolamine-N-Methyltransferase (PNMT)
Catalyzes the Production of Epinephrine
• PNMT catalyzes the N-methylation of
norepinephrine to form epinephrine in the
epinephrine-forming cells of the adrenal medulla
• Since PNMT is soluble, it is assumed that
norepinephrine-to-epinephrine conversion occurs
in the cytoplasm
• 4th step: N-methylation to form epinephrine

16. • In albinism, either the copper-dependent tyrosine
hydroxylase of melanocytes (which is distinct from
the tyrosine hydroxylase found in the adrenal
medulla) or other enzymes that convert tyrosine to
melanins may be defective
• Individuals with albinism suffer from a lack of
pigment in the skin, hair, and eyes; have vision
problems; and are sensitive to sunlight

17. A L B I N I S M

18. C A T H E C H O L A M I N E S - S E C R E T I O N
• Secretion is stimulated by a variety of stresses, including pain, hemorrhage, exercise, hypoglycemia, and hypoxia
• Release is mediated by stress-induced transmission of nerve impulses emanating from adrenergic nuclei in the
hypothalamus
• impulses stimulate the release of the neurotransmitter acetylcholine from preganglionic neurons that innervate the
adrenomedullary cells
• Acetylcholine depolarizes the plasma membranes of these cells, allowing the rapid entry of extracellular calcium
(Ca2+) into the cytosol
• Ca2+ stimulates the synthesis and release of epinephrine and norepinephrine from the chromaffin granules into the
extracellular space by exocytosis

19. C A T E C H O L A M I N E S – P H Y S I O L O G I C E F F E C T S
• act through two major types of receptors on the plasma membrane of target cells, the α-adrenergic and the β-adrenergic
receptors
• actions of epinephrine and norepinephrine in the liver, the adipocyte, the skeletal muscle cell, and the α- and β-cells of
the pancreas directly influence fuel metabolism
• are counterregulatory hormones that have metabolic effects directed toward mobilization of fuels from their storage
sites for oxidation by cells to meet the increased energy requirements of acute and chronic stress
• simultaneously suppress insulin secretion, which ensures that fuel fluxes will continue in the direction of fuel use rather
than storage

20. C A T E C H O L A M I N E S – P H Y S I O L O G I C E F F E C T S
• In addition, norepinephrine works as a neurotransmitter and affects the sympathetic nervous system in the heart,
lungs, blood vessels, bladder, gut, and other organs
• These effects of catecholamines on the heart and blood vessels increase cardiac output and systemic blood pressure,
hemodynamic changes that facilitate the delivery of bloodborne fuels to metabolically active tissues
• Epinephrine has a short half-life in the blood, and to be effective pharmacologically, it must be administered
parenterally
• It may be used clinically to support the beating of the heart, to dilate inflamed bronchial muscles and even to
decrease bleeding from organs during surgery

22. P H E O C H R O M O C Y T O M A
• a neoplasm of the adrenal medulla that is secreting
excessive quantities of epinephrine or norepinephrine
(a pheochromocytoma)
• either the catecholamines themselves (epinephrine,
norepinephrine, and dopamine) or their metabolites
(the metanephrines and vanillylmandelic acid
[VMA]), may be measured in a 24-hour urine
collection, or the level of catecholamines in the blood
may be measured
• patient who has consistently elevated levels in the
blood or urine should be considered to have
pheochromocytoma
• particularly if the patient has signs and symptoms of
catecholamine excess, such as excessive sweating,
palpitations, tremulousness, and hypertension

23. • clinical presentation is so variable that
pheochromocytoma has been termed “the
great masquerader”
• episodes of palpitation, headache, and
profuse sweat-ing are typical, and these
manifestations constitute a classic triad
• dominant sign is hypertension

24. S T E R O I D H O R M O N E S
• Steroid Hormones —corticosteroid
(adrenocortical) hormones and sex hormones—
are synthesized from cholesterol in several
endocrine tissues
• travel to their target cells through the
bloodstream, bound to carrier proteins

25. G L U C O C O R T I C O I D S
• Cortisol (hydrocortisone) is the
major physiologic glucocorticoid
(GC) in humans
• Cortisol is secreted from the adrenal
cortex in response to ACTH

26. G L U C O C O R T I C O I D
S Y N T H E S I S
• Cortisol synthesis requires three hydroxylases located in the
fasciculata and reticularis zones of the adrenal cortex that act
sequentially on the C17, C21, and C11 positions
• The first two reactions are rapid, while C11 hydroxylation is
relatively slow
• If the C11 position is hydroxylated first, the action of 17α-
hydroxylase is impeded, and the mineralocorticoid pathway is
followed (forming corticosterone or aldosterone, depending on
the cell type)
• 17α-Hydroxylase is a smooth endoplasmic reticulum enzyme that
acts on either progesterone or, more commonly, pregnenolone

27. G L U C O C O R T I C O I D
S Y N T H E S I S
• 17α-Hydroxyprogesterone is hydroxylated at C21 to form 11-
deoxycortisol, which is then hydroxylated at C11 to form
cortisol, the most potent natural glucocorticoid hormone in
humans
• 21-Hydroxylase is a smooth endoplasmic reticulum enzyme,
whereas 11β-hydroxylase is a mitochondrial enzyme

28. G L U C O C O R T I C O I D -
S E C R E T I O N
• synthesis and secretion of cortisol are controlled by
a cascade of neural and endocrine signals linked in
tandem in the cerebrocortical–hypothalamic–
pituitary–adrenocortical axis
• Cerebrocortical signals to the midbrain are initiated
in the cerebral cortex by “stressful” signals such as
pain, hypoglycemia, hemorrhage, and exercise
• These nonspecific “stresses” elicit the production of
monoamines in the cell bodies of neurons of the
midbrain

30. • Glucocorticoids inhibit DNA, RNA, and protein synthesis and stimulate the degradation of these macromolecules
• In response to chronic stress, glucocorticoids act to make fuels available
• When glucocorticoids are elevated, glucose uptake by the cells of many tissues is inhibited, lipolysis occurs in
peripheral adipose tissue, and proteolysis occurs in skin, lymphoid cells, and muscle
• The fatty acids that are released are oxidized by the liver for energy, and the glycerol and amino acids serve in the
liver as substrates for the production of glucose, which is converted to glycogen and stored

32. C U S H I N G S Y N D R O M E
ETIOPATHOGENESIS
• Constellation of clinical features that result from chronic exposure to excess glucocorticoids of
any etiology
• Iatrogenic use of glucocorticoids (for immunosuppression or treatment of inflammatory
disorders) is the most common cause
• Cushing’s disease refers specifically to Cushing’s syndrome caused by a pituitary corticotrope
adenoma

33. C U S H I N G S Y N D R O M E
ACTH-Dependent
• Means that Cushing’s syndrome is due to excess ACTH
Possible sources of ACTH excess:
Pituitary corticotrope adenoma (Cushing’s disease)
Ectopic secretion of ACTH by nonpituitary tumor (paraneoplastic syndrome)
ACTH-Independent
• Means that Cushing’s syndrome is not due to excess ACTH
• Majority of patients with ACTH-independent cortisol excess harbor a cortisol-producing adrenal
adenoma
• Other causes include adrenocortical carcinoma and nodular adrenal hyperplasia

36. M I N E R A L O C O R T I C O I D S
Aldosterone (very potent; accounts for ≈90% of all
mineralocorticoid activity)
Deoxycorticosterone (1/30 as potent as aldosterone, but
very small quantities are secreted)

37. M I N E R A L O C O R T I C O I D
S Y N T H E S I S
• Synthesis of aldosterone follows the mineralocorticoid pathway
and occurs in the zona glomerulosa
• Pregnenolone is converted to progesterone by the action of two
smooth endoplasmic reticulum enzymes, 3β-hydroxysteroid
dehydrogenase (3β-OHSD) and Δ5,4-isomerase
• Progesterone is hydroxylated at the C21 position to form 11-
deoxycorticosterone (DOC), which is an active (Na+-retaining)
mineralocorticoid

38. M I N E R A L O C O R T I C O I D
S Y N T H E S I S
• The next hydroxylation, at C11, produces corticosterone, which
has glucocorticoid activity and is a weak mineralocorticoid (it has
<5% of the potency of aldosterone)
• In the zona glomerulosa, which does not have the smooth
endoplasmic reticulum enzyme 17α-hydroxylase, a
mitochondrial 18-hydroxylase is present
• The 18-hydroxylase (aldosterone synthase) acts on
corticosterone to form 18- hydroxycorticosterone, which is
changed to aldosterone by conversion of the 18-alcohol to an
aldehyde

39. C L I N I C A L F E A T U R E S : M I N E R A L O C O R T I C O I D
E X C E S S
Excess activation of mineralocorticoid receptor leads to:
• Potassium depletion (hypokalemia)
• Increased sodium retention (expansion of extracellular and plasma volume →
hypertension)
• Most common cause is primary hypertension
• Clinical hallmark is hypokalemic hypertension
• Conn’s Syndrome = aldosterone-producing adrenal adenoma

40. A N D R O G E N S Y N T H E S I S
• The major androgen or androgen precursor produced by the
adrenal cortex is dehydroepiandrosterone (DHEA)
• Most 17-hydroxypregnenolone follows the glucocorticoid pathway,
but a small fraction is subjected to oxidative fission and removal of
the two-carbon side chain through the action of 17,20-lyase
• The lyase activity is actually part of the same enzyme (P450c17)
that catalyzes 17α-hydroxylation

41. A N D R O G E N S Y N T H E S I S
• The lyase activity is important in both the adrenals and the gonads
and acts exclusively on 17α-hydroxy-containing molecules
• Adrenal androgen production increases markedly if glucocorticoid
biosynthesis is impeded by the lack of one of the hydroxylases
(adrenogenital syndrome)
• DHEA is really a prohormone since the actions of 3β-OHSD and
Δ5,4-isomerase convert the weak androgen DHEA into the more
potent androstenedione

42. A N D R O G E N S Y N T H E S I S
• Small amounts of androstenedione are also formed in the adrenal
by the action of the lyase on 17α-hydroxyprogesterone
• Reduction of androstenedione at the C17 position results in the
formation of testosterone, the most potent adrenal androgen
• Small amounts of testosterone are produced in the adrenal by this
mechanism, but most of this conversion occurs in the testes

43. A D R E N O G E N I T A L S Y N D R O M E
• The adrenogenital syndrome (AGS) is a relatively common inherited metabolic disease
• generally caused by a deficiency of the adrenocortical enzyme steroid 21-hydroxylase
• results in an insufficient biosynthesis of several important steroid hormones such as cortisol
and aldosterone, on the other hand a strongly increased production of androgens
(testosterone)
• In girls, virilization of the external genitals is usually seen
• severe salt loss occurs shortly after birth, and a life-threatening crisis may develop

45. E N D