Steroid hormones

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Steroid hormones

• by
• Henry Wormser, Ph.D.

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Hormones (introduction)

• hormones are chemical messengers that transport
  signals from one cell to another
• there are 4 major chemical classes of hormones
• steroid hormones - i.e. progesterone
• peptide hormones - i.e. insulin
• amino acid derivatives - epinephrine
• prostaglandins and related compounds

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Three major functional types of hormones

• endocrine
• example steroid hormones
• paracrine
• example prostaglandins
• autocrine
• example interleukin-2

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General characteristics of hormones

• hormones are required in very small quantities
• example 1 molecule of epinephrine --- 1x1011
  molecule of glucose
• they are degraded very rapidly, thus are very
  difficult to study
• concentrations vary from 10-6 to 10-12 M
• from 1 ton of bull testis --- 270 mg of
  testosterone
• modern analytical techniques and chemical
  synthesis are very important

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Steroid Hormones

• Steroid hormone biosynthesis
• common precursor is cholesterol
• first step is degradation of side chain via
  desmolase and formation of pregnenolone (C21)
• pregnenolone can then follow several pathways
• It can be converted to progesterone which can be
  converted into gluco and mineralocorticoids, C21
  (in the adrenal cortex)
• It can also be converted through several steps
  into testosterone (C19) which in turn can be
  aromatized into estradiol (C18)

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Model of steroid hormone action
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Steroid hormone receptor structure
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Steroid hormone classes

• glucocorticoids
• mineralocorticoids
• androgens
• estrogens
• progestins
• vitamin D

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ADRENOCORTICAL HORMONES
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Adrenal cortex

• Composed of 3 layers (zones)
• outer zone (zona glomerulosa)
• produces aldosterone (mineralocorticoid)
• middle zone (zona fasciculata)
• produces cortisol (glucocorticoids)
• inner zone (zona reticularis)
• produces corticosterone and androgens

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Major functions of adrenal steroids

• Glucocorticoids
• increases gluconeogenesis
• increases glycogenesis
• increases protein catabolism
• decreases antibody response
• antiinflammatory response
• antineoplastic response

• Mineralocorticoids
• increase sodium and water retention
• promote potassium loss

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ACTH (adrenocorticotropic hormone)

• Single polypeptide chain 39AA (M.W. 3500)
• produced by basophilic cells of adenohypophysis
• AA 1 thru 24 needed for full activity
• AA 25 - 33 species differences and immunologic
  specificity
• AA 34 - 39 sequence common to all species
• biological half-life is 10 min.
• controlled by CRH (corticotropin releasing
  hormone) from hypothalamus

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ACTH products

• used mainly for diagnostic purposes
• limited therapeutic value in conditions
  responsive to corticosteroids
• products
• Corticotropin Injection (Acthar)
• Repository corticotropin injection (H.P. Acthar
  Gel)
• Cosyntropin (Cortrosyn)

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Actions of ACTH on adrenal cortex

• increase in adrenal weight
• decrease in adrenal lipids
• decrease in adrenal cholesterol
• decrease in adrenal ascorbic acid
• increase in protein synthesis (enzymes which
  hydroxylate steroids)
• increase in oxidative phosphorylation
• increase in rate of glycolysis

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GLUCOCORTICOIDS

• synthesized from cholesterol
• to pregnenolone --------- progesterone
  -----------17-a-hydroxyprogesterone
  ------------------------11-deoxycortisol--------co
  rtisol
• requires hydroxylating enzymes
• 21-beta hydroxylase
• 17-alpha hydroxylase
• 11-beta hydroxylase

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common pathway
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mineralocorticoid pathway
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glucocorticoid pathway
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androgenic pathway
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GLUCOCORTICOIDS

• anti-inflammatory effect
• effect on protein synthesis
• inhibit protein-translation of inducible COX -II
  (which also inhibits PG and thromboxanes)
• promote synthesis of lipocortins which inhibit
  phospholipase A2 (this inhibits production of
  arachidonic acid and hence prostaglandins and
  leukotrienes)
• physiologic effects

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GLUCOCORTICOIDS

• antiinflammatory effects
• physiologic effects
• negative effect on lymphocytes, monocytes and
  macrophages
• inhibit the release of IL-1, IL-2 and IL-6 and
  TNF-alpha
• reduced migration of inflammatory cells to site
  of injury
• decreased lymphocyte production
• impairment of delayed-type hypersensitivity

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GLUCOCORTICOIDS

• permissive effects (glucocorticoids required for
  certain actions)
• tissue effects
• inhibit fibroblasts (connective tissue loss)
• negative calcium balance (osteoporosis)
• negative nitrogen balance (catabolism)
• CNS euphoria, behavioral changes, psychosis
• GI increase stomach acid and pepsin production
• cardiovascular effects (inc. BP, heart rate)
• uptake of fat by fat cells
• gluconeogenesis
• insulin release and glycogen deposition

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Indications for systemic glucocorticoids

• ophthalmic diseases
• allergic conjunctivitis
• keratitis
• allergic corneal marginal ulcers
• herpes zoster ophthalmicus
• iritis and iridocyclitis
• optic neuritis
• retrobulbar neuritis

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GLUCOCORTICOIDS
hydrocortisone is the most active natural
glucocorticoid prednisolone is a delta-1
derivative with greater potency (made
synthetically)
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GLUCOCORTICOIDS
these are synthetic glucocorticoid with more
potent glucocorticoid activity
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GLUCORTICOIDS
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GLUCOCORTICOIDS
used in dermatological preparations
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GLUCOCORTICOIDS
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GLUCOCORTICOIDS
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GLUCOCORTICOIDS
used in dermatological preparations
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GLUCOCORTICOIDS
used in dermatological products
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GLUCOCORTICOIDS
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GLUCORTICOIDS
used in inhalation products for asthma and
allergies
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this
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Typical glucocorticoid inhalers
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Products for enteric inflammations
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Indications for systemic glucocorticoids

• endocrine disorders
• primary or secondary adrenocortical
  insufficiency
• congenital adrenal hyperplasia
• nonsuppurative thyroiditis
• hypercalcemia associated with cancer
• shock unresponsive to conventional therapy

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Indications for systemic glucocorticoids

• rheumatic disorders
• rheumatoid arthritis
• ankylosing spondylitis
• acute and subacute arthritis
• acute nonspecific tenosynovitis
• collagen diseases
• systemic lupus erythematosus
• acute rheumatic carditis
• systemic dermatomyositis

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Indications for systemic glucocorticoids

• allergic states
• seasonal or perennial allergic rhinitis
• bronchial asthma
• contact dermatitis
• atopic dermatitis
• serum sickness
• drug hypersensitivity reactions

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Indications for systemic glucocorticoids

• Dermatological diseases
• pemphigus
• bullous dermatitis herpetiformis
• severe erythema multiforme (Stevens-Johnson)
• exfoliative dermatitis
• mycosis fungoides
• severe psoriasis

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Indications for systemic glucocorticoids

• respiratory diseases
• symptomatic sarcoidosis
• berylliosis
• disseminated pulmonary tuberculosis
• pulmonary emphysema
• aspiration pneumonitis
• diffuse interstitial pulmonary fibrosis

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Indications for systemic glucocorticoids

• neoplastic diseases
• leukemias and lymphomas in adults
• acute leukemia of childhood
• hematological disorders
• idiopathic and secondary thrombocytopenia in
  adults
• acquired (autoimmune) hemolytic anemia

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Indications for systemic glucocorticoids

• miscellaneous
• ulcerative colitis (via rectal enemas)
• trichinosis
• dental inflammatory reactions
• tuberculous meningitis

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Indications for systemic mineralocorticoids

• replacement therapy for primary and secondary
  insufficiency in Addisons disease
• treatment of salt-losing adrenogenital syndrome
• most common agents aldosterone,
  desoxycorticosterone and fludrocortisone
  (Fluorinef) (most commonly used)

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Adrenocortical insufficiency

• Acute adrenocortical insufficiency
• adrenal crisis (Waterhouse-Friderichsen syndrome)
• weakness, dehydration
• abdominal pain, high fever
• vomiting and diarrhea
• low blood pressure and eosinophilia
• increased skin pigmentation
• low sodium, high potassium serum levels

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Adrenocortical insufficiency

• Chronic adrenocortical insufficiency
• Addisons disease
• weakness and anorexia
• nausea, vomiting and diarrhea
• hypotension
• sparce axillary hair
• increased skin pigmentation of creases, nipples
  and pressure areas (due to ACTH production)
• eosinophilia and lymphocytosis

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Tests for adrenal insufficiency

• ACTH test
• give ACTH and measure cortisol (helps to
  distinguish between primary and secondar adrenal
  insufficiency)
• primary insufficiency cortisol levels remain low
• secondary insufficiency cortisol levels increase
• metyrapone test
• confirmatory test for secondary adrenal
  insufficiency
• metyrapone inhibits 11-beta hydroxylation and
  thus cortisol synthesis
• should result in high ACTH levels (if not, we
  know the problem is secondary)

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Mineralocorticoid pathway

• cholesterol ----- pregnenolone -----progesterone
  --------11-deoxycorticosterone ------corticosteron
  e --------aldosterone
• corticosterone and aldosterone both have
  mineralocorticoid activity, however are not used
  therapeutically
• Aldosterone is the most powerful agent

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FLUDROCORTISONE
a potent steroid with both glucocorticoid
and mineralocorticoid activity. Used mainly
for its mineralocorticoid activity in
Addisons disease
dose 0.1 mg 2- 7 X weekly
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Adrenocortical overactivity

• Cushings syndrome or adrenal hyperfunction
• Cushings disease or pituitary basophilism
• buffalo obesity (moon face and buffalo hump)
• easy bruisability (ecchymoses)
• purple striae
• impotence or amenorrhea
• osteoporosis
• hypertension, glucosuria
• low serum potassium
• low eosinophils and lymphopenia

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Toxicity of adrenocorticoids

• pituitary-adrenal suppression (adrenal
  insufficiency)
• fluid and electrolyte disturbances
• hyperglycemia and glucosuria
• increased susceptibility to infections
• peptic ulceration
• myopathy (weakness of muscles of arms and legs)
• osteoporosis and vertebral compression fractures
• posterior subcapsular cataracts

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glucocorticoid antagonists
amphenone B block hydroxylation at 11, 17 and 21
position. metyrapone is more selective in
blocking beta 11-hydroxylation at low doses. Used
more commonly in testing adrenal function.
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glucocorticoid antagonists
mitotane and aminoglutethimide both interfer with
the biosynthesis of glucocorticoids.
Aminoglutethimide is also an aromatase inhibitor
involved in estrogen biosynthesis
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ketoconazole is a non-specific inhibitor of
adrenal and gonadal steroid biosynthesis
spironolactone is a mineralocorticoid antagonist
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Mineralocorticoid receptor antagonists

• compounds or drugs which interfer with the action
  of aldosterone
• currently 2 such drugs are available in the U.S.
  spironolactone (Aldactone) and eplerenone
  (Inspra)
• other drugs canrenone, potassium carenoate (not
  available in the U.S.)

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SPIRONOLACTONE(Aldactone)

• a competitive antagonist of aldosterone
• action occurs in the distal portion of tubule
• only effective if sufficient sodium reaches the
  distal tubule and if excess aldosterone is
  present
• has demonstrated tumorigenic action in rodents
  not humans
• causes occasional hormonal problems, i.e.
  gynecomastia in males
• has gradual onset activity peaks in 2 - 3 days
• 80 is metabolized to canrenone

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Spironolactone (Aldactone)

• useful in patients with gout or diabetes, since
  it causes no hyperuricemia or impairment of
  glucose tolerance
• do not administer potassium supplement -
  hyperkalemia
• effective in the management of primary and
  secondary aldosteronism
• dosage 10 mg/day initially for edema for
  essential hypertension 100 - 400 mg
• frequently combined with HCTZ ( Aldactazide)

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Eplerenone

• a selective aldosterone receptor antagonist (acts
  on the mineralocorticoid receptor)
• chemical similarity to aldosterone
• used in the management of hypertension

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Eplerenone (Inspra)
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