Post on 24-May-2015
transcript
Steroid hormones
by
Henry Wormser, Ph.D.
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
Three major functional types of hormones
• endocrine• example: steroid hormones
• paracrine• example: prostaglandins
• autocrine• example: interleukin-2
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
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)
Model of steroid hormone action
Steroid hormone receptor structure
SH SHSH
SH SH
HS SH
SH SH
SHZn Zn
DNA BINDING SITEHORMONE BINDING SITE
COOH
"ZINC FINGERS"
H3N
TRANSCRIPTIONAL ACTIVATIONELEMENT
Steroid hormone classes
• glucocorticoids
• mineralocorticoids
• androgens
• estrogens
• progestins
• vitamin D
ADRENOCORTICAL ADRENOCORTICAL HORMONESHORMONES
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
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
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
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)
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
GLUCOCORTICOIDS
• synthesized from cholesterol• to pregnenolone --------- progesterone -----------
17-hydroxyprogesterone ------------------------11-deoxycortisol--------cortisol
• requires hydroxylating enzymes• 21-beta hydroxylase
• 17-alpha hydroxylase
• 11-beta hydroxylase
CH3
CH3
H3C
CH3
CH3
HO
HH
H
CH3
CH3
H3C
HO
O
CH3
CH3
H3C
O
O
3--hydroxysteroid dehydrogenase
cholesterol
pregnenoloneprogesterone
P450scc
common pathway
CH3
CH3
H3C
O
O
progesterone
CH3
CH3
O
OHOCH2
desoxycorticosterone
CH3
CH3
HOCH2
O
O
HO
corticosterone18-hydroxycorticosterone
P45021
CH2
CH3
O
CH2OHO
HO
HO
CHO
CH3
HOCH2
O
O
HO
aldosterone
P450aldo
P450aldo
P450aldo
mineralocorticoidpathway
CH3
CH3
H3C
O
O
CH3
CH3
H3C
O
O
OH
CH3
CH3
HOCH2
O
O
OH
progesterone 17--hydroxyprogesterone
11-deoxycortisol
CH3
CH3
HOCH2
O
O
HOOH
cortisol
P45021
P45011
P45017
PREGNENOLONE 17--HYDROXYPREGNENOLONEP45017
glucocorticoidpathway
CH3
CH3
H3C
HO
O
pregnenolone
CH3
CH3
H3C
HO
O
17--hydroxypregnenolone
dehydroepiandrosterone
CH3
CH3
HO
androstenedione
CH3
CH3
O
O
P45017
P45017
3-HSD
HYDROXYPROGESTERONE
P45017 androgenic pathway
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
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
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
Indications for systemic glucocorticoids
• ophthalmic diseases• allergic conjunctivitis
• keratitis
• allergic corneal marginal ulcers
• herpes zoster ophthalmicus
• iritis and iridocyclitis
• optic neuritis
• retrobulbar neuritis
O
CH3
CH3
CH2OH
OH
O
HO
H
H
H
HYDROCORTISONE
O
CH3
CH3
CH2OH
OH
O
HO
H
H
H
PREDNISOLONE
GLUCOCORTICOIDS
hydrocortisone is the most active natural glucocorticoidprednisolone is a delta-1 derivative with greater potency(made synthetically)
O
CH3
CH3
CH2OH
OH
O
HO
F
H
H
CH3
DEXAMETHASONE (DECADRON)
O
CH3
CH3
CH2OH
OH
O
HO
H
H
H
OH
TRIAMCINOLONE
GLUCOCORTICOIDS
these are synthetic glucocorticoid with more potentglucocorticoid activity
O
CH3
CH3
CH2OCOCH2CH3
OCOCH2CH3
O
HO
Cl
H
H
CH3
BECLOMETHASONE DIPROPIONATE (BECLOVENT, VANCERIL)
O
CH3
CH3
CH2OCOC(CH3)3
OH
O
HO
Cl
H
H
F
CH3
CLOCORTOLONE PIVALATE (CLODERM)
GLUCORTICOIDS
O
CH3
CH3
CH2OH
O
O
HO
H
H
H
OC
CH3
CH3
DESONIDE (DESOWEN)
O
CH3
CH3
CH2OH
O
O
HO
F
H
H
OC
CH3
CH3
F
FLUOCINOLONE ACETONIDE (SYNALAR)
GLUCOCORTICOIDS
used in dermatological preparations
O
CH3
CH3
CH2OH
O
O
HO
F
H
H
O
AMCINONIDE (CYCLOCORT) O
CH3
CH3
CH2OH
O
O
HO
F
H
H
OC
CH3
CH3
FLUNISOLIDE (NASALIDE)
GLUCOCORTICOIDS
O
CH3
CH3
CH2OCOCH3
CH3
O
HO
H
H
H
OH
F
PARAMETHASONE ACETATE (HALDRONE)
O
CH3
CH3
CH2Cl
OH
O
HO
F
H
H
CH3
CLOBETASOL (TEMOVATE)
GLUCOCORTICOIDS
O
CH3
CH3
CH2OCOCH3
O
O
HO
H
H
H
OC
CH3
CH3
F
FLUOCINONIDE (LIDEX)
O
CH3
CH3
CH2Cl
O
O
HO
Cl
H
HO
O
CH3
MOMETASONE FUROATE (ELOCON)
GLUCOCORTICOIDS
used in dermatological preparations
O
CH3
CH3
H
O
HO
F
H
OH
F
CH3
OH
DIFLORASONE (PSORCON)
O
CH3
CH3
H
O
HO
H
H
OEt
O
O
OEt
O
PREDNICARBATE (DERMATOP)
O
CH3
CH3
H
O
HO
Cl
H
CH3
OH
F
CLOCORTOLONE (CLODERM)
O
CH3
CH3
H
O
HO
H
H CH3
CH3
CH3
RIMEXOLONE (VEXOL)
O
CH3
CH3
S
H
O
HO
F
H CH3
O
CH2-F
F
C O
Et
FLUTICASONE PROPIONATE (CUTIVATE)
HO
O
CH3
CH3
HH
H
O
OEt
O
OPr n
O
HYDROCORTISONE PROBUTATE (PANDEL)
O
CH3
CH3
CH2OH
O
O
HO
H
H
H
OC
CH3
CH3
F
FLURANDRENOLIDE (CORDRAN)
O
CH3
CH3
CH2OH
H
O
HO
H
H CH3
DESOXIMETASONE (TOPICORT)
GLUCOCORTICOIDS
used in dermatological products
O
CH3
CH3
CH2Cl
O
O
HO
F
H
H
OC
CH3
CH3
HALCINONIDE (HALOG)
O
CH3
CH3
CH2OCOC2H5
OCOC2H5
O
HO
H
H
H
CH3
Cl
ALCLOMETASONE DIPROPIONATE (ACLOVATE)
GLUCOCORTICOIDS
O
CH3
CH3
CH2F
F
O
HO
F
H
H
O
CH3
COC2H5
FLUTICASONE (FLONASE)
O
CH3
CH3
CH2OH
O
O
HO
H
H
H
OC
CH2CH2CH3
H
BUDESONIDE (RHINOCORT)
GLUCORTICOIDS
used in inhalation products for asthma and allergies
O
CH3
CH3
OO
O
H H
H
Cl
OEt
O
HO
LOPREDNOL ETABONATE (LOTEMAX, ALREX)this
Typical glucocorticoid inhalers
Products for enteric inflammations
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
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
Indications for systemic glucocorticoids
• allergic states• seasonal or perennial allergic rhinitis
• bronchial asthma
• contact dermatitis
• atopic dermatitis
• serum sickness
• drug hypersensitivity reactions
Indications for systemic glucocorticoids
• Dermatological diseases• pemphigus
• bullous dermatitis herpetiformis
• severe erythema multiforme (Stevens-Johnson)
• exfoliative dermatitis
• mycosis fungoides
• severe psoriasis
Indications for systemic glucocorticoids
• respiratory diseases• symptomatic sarcoidosis
• berylliosis
• disseminated pulmonary tuberculosis
• pulmonary emphysema
• aspiration pneumonitis
• diffuse interstitial pulmonary fibrosis
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
Indications for systemic glucocorticoids
• miscellaneous• ulcerative colitis (via rectal enemas)
• trichinosis
• dental inflammatory reactions
• tuberculous meningitis
Indications for systemic mineralocorticoids
• replacement therapy for primary and secondary insufficiency in Addison’s disease
• treatment of salt-losing adrenogenital syndrome
• most common agents: aldosterone, desoxycorticosterone and fludrocortisone (Fluorinef) (most commonly used)
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
Adrenocortical insufficiency
• Chronic adrenocortical insufficiency– Addison’s 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
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)
Mineralocorticoid pathway
cholesterol ----- pregnenolone -----progesterone --------11-deoxycorticosterone ------corticosterone --------aldosterone
corticosterone and aldosterone both have mineralocorticoid activity, however are not used therapeutically
Aldosterone is the most powerful agent
FLUDROCORTISONE
C
HF
OH
O
H
CH2OH
O
HO
FLUDROCORTISONE (FLORINEF)
a potent steroid with both glucocorticoid andmineralocorticoid activity. Used mainly forits mineralocorticoid activity in Addison’sdisease
dose: 0.1 mg 2- 7 X weekly
Adrenocortical overactivity
• Cushing’s syndrome or adrenal hyperfunction• Cushing’s 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
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
C
C
CH3
H2N NH2
CH3
O
AMPHENONE B
N
C C
N
CH3
CH3O
METYRAPONE
glucocorticoid antagonists
amphenone B block hydroxylation at 11, 17 and 21 position. metyrapone is more selective in blocking beta 11-hydroxylationat low doses. Used more commonly in testing adrenal function.
C
CH
H
ClCl
Cl
Cl
MITOTANE
N
C2H5
OO
H
NH2
AMINOGLUTETHIMIDE
glucocorticoid antagonists
mitotane and aminoglutethimide both interfer with thebiosynthesis of glucocorticoids. Aminoglutethimide is alsoan aromatase inhibitor involved in estrogen biosynthesis
O
O
N NC O
CH2
NCl
Cl
N
H
H3C
O
KETOCONAZOLE (NIZORAL)
O
O S C CH3
O
O
HH
H
SPIRONOLACTONE (ALDACTONE)
spironolactone is a mineralocorticoid antagonist
ketoconazole is a non-specificinhibitor of adrenal and gonadalsteroid biosynthesis
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.)
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
CH3
CH3
O
O
O
SCOCH3
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)
Eplerenone
• a selective aldosterone receptor antagonist (acts on the mineralocorticoid receptor)
• chemical similarity to aldosterone
• used in the management of hypertension
Eplerenone (Inspra)
O
O
O
CH3
CH3
O
OEt
O
EPLERENONE (INSPRA)