STEROIDS HORMONES

1. STEROIDS HORMONSE
PRESENTED BY
Dr. Shweta Verma
PHARMACY ACADEMY
IFTM UNIVERSITY
MORADABAD-244001

2. 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)

3. Model of steroid hormone action

4. Steroid hormone receptor
structure
SH SH
SH
SH SH
HS SH
SH SH
SH
Zn Zn
DNA BINDING SITE
HORMONE BINDING SITE
COOH
"ZINC FINGERS"
H3N
TRANSCRIPTIONAL ACTIVATION
ELEMENT

7. Steroid hormone classes
• glucocorticoids
• mineralocorticoids
• androgens
• estrogens
• progestins
• vitamin D

8. ADRENOCORTICAL
HORMONES

9. 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

12. 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

13. GLUCOCORTICOIDS
• synthesized from cholesterol
• to pregnenolone --------- progesterone -----------
17-a-hydroxyprogesterone ------------------------
11-deoxycortisol--------cortisol
• requires hydroxylating enzymes
• 21-beta hydroxylase
• 17-alpha hydroxylase
• 11-beta hydroxylase

15. CH3
CH3
H3C
CH3
CH3
HO
H
H
H
CH3
CH3
H3C
HO
O
CH3
CH3
H3C
O
O
3--hydroxysteroid dehydrogenase
cholesterol
pregnenolone
progesterone
P450scc
common pathway

16. CH3
CH3
H3C
O
O
progesterone
CH3
CH3
O
O
HOCH2
desoxycorticosterone
CH3
CH3
HOCH2
O
O
HO
corticosterone
18-hydroxycorticosterone
P45021
CH2
CH3
O
CH2OH
O
HO
HO
CHO
CH3
HOCH2
O
O
HO
aldosterone
P450aldo
P450aldo
P450aldo
mineralocorticoid
pathway

17. CH3
CH3
H3C
O
O
CH3
CH3
H3C
O
O
OH
CH3
CH3
HOCH2
O
O
OH
progesterone 17-a-hydroxyprogesterone
11-deoxycortisol
CH3
CH3
HOCH2
O
O
HO
OH
cortisol
P45021
P45011
P45017a
PREGNENOLONE 17-a-HYDROXYPREGNENOLONE
P45017a
glucocorticoid
pathway

18. CH3
CH3
H3C
HO
O
pregnenolone
CH3
CH3
H3C
HO
O

17-a-hydroxypregnenolone
dehydroepiandrosterone
CH3
CH3
HO

androstenedione
CH3
CH3
O
O
P45017a
P45017a
3-HSD
HYDROXYPROGESTERONE
P45017a
androgenic pathway

19. 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

20. 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

21. 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

22. Indications for systemic
glucocorticoids
• ophthalmic diseases
• allergic conjunctivitis
• keratitis
• allergic corneal marginal ulcers
• herpes zoster ophthalmicus
• iritis and iridocyclitis
• optic neuritis
• retrobulbar neuritis

23. 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 glucocorticoid
prednisolone is a delta-1 derivative with greater potency
(made synthetically)

24. 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 potent
glucocorticoid activity

25. O
CH3
CH3
CH2OCOCH2CH3
OCOCH2CH3
O
HO
Cl
H
H
CH3
BECLOMETHASONE DIPROPIONATE (BECLOVENT, VANCERIL)
O
CH3
CH3
CH2OCOC(CH 3)3
OH
O
HO
Cl
H
H
F
CH3
CLOCORTOLONE PIVALATE (CLODERM)
GLUCORTICOIDS

26. O
CH3
CH3
CH2OH
O
O
HO
H
H
H
O
C
CH3
CH3
DESONIDE (DESOWEN)
O
CH3
CH3
CH2OH
O
O
HO
F
H
H
O
C
CH3
CH3
F
FLUOCINOLONE ACETONIDE (SYNALAR)
GLUCOCORTICOIDS
used in dermatological preparations

27. O
CH3
CH3
CH2OH
O
O
HO
F
H
H
O
AMCINONIDE (CYCLOCORT) O
CH3
CH3
CH2OH
O
O
HO
F
H
H
O
C
CH3
CH3
FLUNISOLIDE (NASALIDE)
GLUCOCORTICOIDS

28. 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

29. O
CH3
CH3
CH2OCOCH3
O
O
HO
H
H
H
O
C
CH3
CH3
F
FLUOCINONIDE (LIDEX)
O
CH3
CH3
CH2Cl
O
O
HO
Cl
H
H
O
O
CH3
MOMETASONE FUROATE (ELOCON)
GLUCOCORTICOIDS
used in dermatological preparations

30. O
CH3
CH3
H
O
HO
F
H
OH
F
CH3
OH
DIFLORASONE (PSORCON)
O
CH3
CH3
H
O
HO
H
H
O
Et
O
O
OEt
O
PREDNICARBATE (DERMATOP)

31. 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)

32. O
CH3
CH3
S
H
O
HO
F
H CH3
O
CH2-F
F
C O
Et
FLUTICASONE PROPIONATE (CUTIVATE)
HO
O
CH3
CH3
H
H
H
O
O
Et
O
O
Pr n
O
HYDROCORTISONE PROBUTATE (PANDEL)

33. O
CH3
CH3
CH2OH
O
O
HO
H
H
H
O
C
CH3
CH3
F
FLURANDRENOLIDE (CORDRAN)
O
CH3
CH3
CH2OH
H
O
HO
H
H CH3
DESOXIMETASONE (TOPICORT)
GLUCOCORTICOIDS
used in dermatological products

34. O
CH3
CH3
CH2Cl
O
O
HO
F
H
H
O
C
CH3
CH3
HALCINONIDE (HALOG)
O
CH3
CH3
CH2OCOC2H5
OCOC2H5
O
HO
H
H
H
CH3
Cl
ALCLOMETASONE DIPROPIONATE (ACLOVATE)
GLUCOCORTICOIDS

35. 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
O
C
CH2CH2CH3
H
BUDESONIDE (RHINOCORT)
GLUCORTICOIDS
used in inhalation products for asthma and allergies

36. O
CH3
CH3
O
O
O
H H
H
Cl
OEt
O
HO
LOPREDNOL ETABONATE (LOTEMAX, ALREX)
this

40. Typical glucocorticoid inhalers

43. Products for enteric inflammations

44. 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

45. 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

46. Indications for systemic
glucocorticoids
• allergic states
• seasonal or perennial allergic rhinitis
• bronchial asthma
• contact dermatitis
• atopic dermatitis
• serum sickness
• drug hypersensitivity reactions

47. Indications for systemic
glucocorticoids
• Dermatological diseases
• pemphigus
• bullous dermatitis herpetiformis
• severe erythema multiforme (Stevens-Johnson)
• exfoliative dermatitis
• mycosis fungoides
• severe psoriasis

48. Indications for systemic
glucocorticoids
• respiratory diseases
• symptomatic sarcoidosis
• berylliosis
• disseminated pulmonary tuberculosis
• pulmonary emphysema
• aspiration pneumonitis
• diffuse interstitial pulmonary fibrosis

49. 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

50. Indications for systemic
glucocorticoids
• miscellaneous
• ulcerative colitis (via rectal enemas)
• trichinosis
• dental inflammatory reactions
• tuberculous meningitis

51. 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)

52. 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

53. 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

54. 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)

55. 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

56. FLUDROCORTISONE
C
H
F
OH
O
H
CH2OH
O
HO
FLUDROCORTISONE (FLORINEF)
a potent steroid with both glucocorticoid and
mineralocorticoid activity. Used mainly for
its mineralocorticoid activity in Addison’s
disease
dose: 0.1 mg 2- 7 X weekly

57. 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

58. 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

59. C
C
CH3
H2N NH2
CH3
O
AMPHENONE B
N
C C
N
CH3
CH3
O
METYRAPONE
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.

60. C
CH
H
Cl
Cl
Cl
Cl
MITOTANE
N
C2H5
O
O
H
NH2
AMINOGLUTETHIMIDE
glucocorticoid antagonists
mitotane and aminoglutethimide both interfer with the
biosynthesis of glucocorticoids. Aminoglutethimide is also
an aromatase inhibitor involved in estrogen biosynthesis

61. O
O
N N
C O
CH2
N
Cl
Cl
N
H
H3C
O
KETOCONAZOLE (NIZORAL)
O
O S C CH3
O
O
H
H
H
SPIRONOLACTONE (ALDACTONE)
spironolactone is a mineralocorticoid antagonist
ketoconazole is a non-specific
inhibitor of adrenal and gonadal
steroid biosynthesis

62. 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.)

63. THANK YOU