nomenclature , strucutres , syntheses of steroidal drugs

1. Steroid Hormones

2. 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
Chemical Classification of
Hormones

3. Mechanism of Hormone
Action
All hormone action is receptor mediated
1. Peptide hormones and catecholamines bind to cell
surface receptors
2. Steroid and thyroid hormones act via intracellular
receptors

4. Steroid Hormone Classes
Progestins
Glucocorticoids
Mineralocorticoids
Androgens
Estrogens
Vitamin D

5. Steroids are lipophilic molecules.
All steroids, except calcitriol, have
cyclopentanoperhydrophenanthrene
structure (sterane).
Structure of Steroid
Hormones
The parental precursor of
steroids - cholesterol

6. Steroid Hormones
 Are not packaged, but synthesized and immediately
released.
 Are all derived from the same parent compound:
cholesterol.
 Enzymes which produce steroid hormones from
cholesterol are located in mitochondria and smooth
ER.
 Steroids are lipid soluble and thus are freely
permeable to membranes so are not stored in cells.

7. Steroid Hormones
 Are not water soluble so have to be carried in the
blood complexed to specific binding globulins.
 Corticosteroid binding globulin carries cortisol.
 Sex steroid binding globulin carries testosterone and
estradiol.
 In some cases a steroid is secreted by one cell and
is converted to the active steroid by the target cell:
(androgen is secreted by the gonad and converted
into estrogen in the brain).

8. Steroid hormones
 Steroid hormones play important roles in:
- carbohydrate regulation (glucocorticoids)
- mineral balance (mineralocorticoids)
- reproductive functions (gonadal steroids)
 Steroids also play roles in inflammatory responses,
stress responses, bone metabolism, cardiovascular
fitness, behavior, cognition, and mood.

9. Adrenal cortex
• Composed of 3 layers (zones):
• outer zone (zona glomerulosa) produces aldosterone
(mineralocorticoid)
• middle zone (zona fasciculata) produces cortisol
(glucocorticoid)
• inner zone (zona reticularis) produces androgens
Corpus luteum and ovary
• produce progesteron and estradiol
Testes
• produces testosterone and dihydrotestosterone (DHT)
Steroid Hormones

10. Cholesterol
Progestins
Glucocorticoids Androgens
Mineralocorticoids Estrogens
Progestins Are the Biosynthetic
Precursors of the All Other Steroid
Hormones

11. Pregnenolone (C-21)
produced directly from cholesterol, the
precursor molecule for all C18, C19 and
C21 steroids

12. • A progestin, produced directly from
pregnenolone.
• Secreted from the corpus luteum.
• Maintains (with estradiol) the uterine
endometrium for implantation.
• Differentiation factor for mammalian
glands.
Progesterone (C-21)
• Female: regulates gonadotrope secretion
in ovarian cycle.
• Maintains (with progesterone) uterine
endometrium.
• Differentiation of mammalian gland.
• Responsible for secondary female sex
characteristics.
•Male: negative feedback inhibitor of Leydig
cell synthesis of testosterone.
Estradiol (C-18)

13. • After conversion to dihydrotestosterone,
production of sperm proteins in Sertoli cells.
• Responsible for secondary male sex
characteristics.
• Produced from progesterone.
Testosterone (C-19)
Dehydroepiandrosterone
• Week androgen, which can be
converted to estrogen.
• Various protective effects. It may play a
role in the aging process.
• Regulates NAD+ coenzymes.

14. Cortisol
(C-21)
• Dominant glucocorticoid in humans,
synthesized from progesterone in the zona
fasciculata of the adrenal cortex.
• Stress adaptation through various cellular
phenotypic expression, stress adaptation.
• Slight elevation of liver glycogen. Numerous
effects on the immune system, killing effect on
certain T cells in high doses.
• Na+ uptake in epithelia lumen.
Aldosterone (C-21)
• The principal mineralocorticoid.
• Produced from progesterone in the
zona glomerulosa of adrenal cortex.
• Causes sodium ion uptake via
conductance channel.
• Occures in high levels during stress.
Rises blood pressure and fluid volume.

15. 1, 25-Dihydroxyvitamin D3 (Calcitriol)
• Causes synthesis of Ca2+ transport protein.
• Regulates calcium and phosphorus homeostasis.

16. Biosynthesis of Steroid
Hormones
 Peptide hormones are encoded by specific genes;
steroid hormones are synthesized from the
enzymaticaly modified cholesterol.
 Thus, there is no gene which encodes individual
hormone.
 The regulation of steroidogenesis involves control of
the enzymes which modify cholesterol into the
steroid hormone of interest.

17. Sources of Cholesterol for Steroid
Synthesis
 Cholesterol can be made within the cell from acetyl CoA
(de novo synthesis).
 This is a multistep process, involving many enzymatic
reactions.
 A key rate-limiting enzyme is HMG-CoA reductase.
 There is negative feedback regulation of HMG-CoA
reductase activity by cholesterol, so that high intracellular
cholesterol inhibits de novo synthesis.
acetyl CoA HMG-CoA mevalonate cholesterol
HMG-CoA reductase

18. Sources of Cholesterol for Steroid
Synthesis
 Cholesterol is also taken up by the cell in the form of
low density lipoprotein (LDL).
- LDL is a complex composed of cholesterol,
phospholipids, triglycerides, and proteins (proteins
and phospholipids make LDL soluble in blood).
- LDL is taken into cells via LDL receptors, and
broken down into esterified cholesterol, and then
free cholesterol:

19. • Mitochondrial side chain cleavage enzyme
cholesteroldesmolase initiates the synthesis of
the progestins.
• It hydroxylates C 20 and 22 and involves the
cleavage of a 6-carbon group from cholesterol
(isocaproic aldehyde).
• This reaction require cytochrom P- 450 as an
intermediate electron carrier (integral part of the
inner mitochondrial membrane, a flavoprotein
containing both FAD and FMN).
• Electron pass from the reduced NADPH to FAD,
then to FMN and finally to an O2
22
20
Isocaproic aldehyde

20. Hormonal Stimulation Of Steroid Hormone
Biosynthesis
• Hormone stimulation depends
on the cell type and receptor
(ACTH for cortisol synthesis,
FSH for estradiol synthesis, LH
for testosterone synthesis etc.)
• Hormone binds to cell
membrane receptor and activates
adenylate cyclase mediated by a
stimulatory G protein.
• Receptor, activated by
hormone, may directly stimulate
a calcium channel or indirectly
stimulate it by activating the
phosphatidylinositol (PI) cycle.
•

21. • The increase in cAMP
activates protein kinase
whose phosphorylations cause
increased hydrolysis of
cholesteryl esters from droplet
to free cholesterol and increase
cholesterol transport into the
mitochodrion.
• Elevated Ca 2+ levels and
protein phophorylation bring
about induced levels of the
side chain cleavage reaction.
• Steroid is produced, secreted
into the extracellular space and
circulated to the target tissue in
the bloodstream
Hormonal Stimulation Of Steroid Hormone
Biosynthesis

22. Biosynthesis of Steroid
Hormones
 Critical step is the cell activity in mobilizing
cholesterol stored in a droplets, transport of
cholesterol to mitochondrion.
 The rate-limiting step is the rate of cholesterol side
chain cleavage in mitochondrion by enzymes
known as the cytochrome P450 side chain
cleavage enzyme complex.

23. Steroidogenic Enzymes
Common name „Old“ name Current name
Cholesteroldesmolase
(Side-chain cleavage enzyme)
P450SCC CYP11A1
3b-hydroxysteroid dehydroge-
nase
3 b-DH 3 b-DH
17a-hydroxylase/17,20 lyase P450C17 CYP17
21-hydroxylase P450C21 CYP21A2
11b-hydroxylase P450C11 CYP11B1
Aldosterone synthase P450C11AS CYP11B2
Aromatase P450aro CYP19

24. corticosteroids
 The term corticosteroids refers to steroid hormones secreted by the
adrenal cortex.
 Corticosteroids are involved in a wide range of physiologic systems
such as stress response, immune response, and regulation of
inflammation, carbohydrate metabolism, protein catabolism, blood
electrolyte levels, and behavior.
 Drugs belonging to this class are:
 glucocorticoids :- hydrocortisone, 11-dehydrocorticosterone, corticosterone),
 mineralocorticoids :- aldeosterone, 11-deoxycorticosterone, 11-deoxy-17-
oxycorticosterone)
 sex hormons :- androsterone, androstendion, estrone, progesterone).

25. Zona glomerulosa cells lack the P450c17 that converts pregnenolone and progesterone to their
C17 hydroxylated analogs. Thus, the pathways to the glucocorticoids and the androgens are
blocked.
Steroids of the
Adrenal Cortex
http://themedicalbiochemistrypage.org/steroid-hormones.html
Mitochondria

26. Steroid Hormones of the
Gonades
• Hormones that affect the development
of the reproductive organs and sexual
characteristics.

27. Testes
Leydig cells produce:
• Testosterone
Sertoli cells produce:
• dihydrotestosterone (DHT) – but most of conversion of
testosterone to DHT occurs outside the testes.
• 17-b-estradiol – a small amount of testosterone is also
converted into estradiol by aromatization (inhibits testosterone
synthesis)
• inhibin – polypeptide hormone, which inhibits FSH releasing
FSH binds to the Sertoli cells and stimulates the synthesis of
androgen-binding protein (ABP). ABP binds testosterone
(produced by Leydig cells) and transports it to the site of
spermatogenesis.

28. http://themedicalbiochemistrypage.org/steroid-hormones.html
• In a number of target tissues,
testosterone can be converted to
dihydrotestosterone (DHT).
• DHT is the most potent of the male
steroid hormones, with an activity that
is 10 times that of testosterone.
• Because of its relatively lower
potency, testosterone is sometimes
considered to be a prohormone.
Gonadal Steroid Hormones

29. Estrogens are formed by aromatization of androgens.
Aromatase is a complex endoplasmic reticulum enzyme found in the
ovary and in numerous other tissues in both males and females. Its action
involves hydroxylations and dehydrations that culminate in aromatization
of the A ring of the androgens.
Synthesis of Estrogens

30. Ovaries
 17-b-estradiol is the main hormone produced during the
follicular phase of the menstrual cycle.
 After ovulation progesterone is made by follicular cells, which
now constitute the corpus luteum.
Steroid
hormone
Steroid producing
cells
Signal Second
messenger
Signal system
Testosterone Leydig cells LH cAMP Hypothalamic-pituitary
17-b-
Estradiol
Granulosa cells FSH cAMP Hypothalamic-pituitary
Progesterone Corpus luteum LH cAMP Hypothalamic-pituitary
Regulation of Sex Hormones Synthesis

31. Calcitriol - 1,25 (OH)2-D3

32.  1a-hydroxylation is the rate-limiting step in calcitriol
synthesis
Calcitriol
- increases uptake of Ca2+ and phosphate from the
intestine
- stimulates calcium binding protein synthesis
Regulation of 1a-hydroxylase
Activation Inhibition
Hypocalcemia
Parathroid hormone
Hypophosphatemia
Calcitriol
Calcitriol - 1,25 (OH)2-D3

33. Schematic model to describe the action of 1,25-
(OH2)D3 in the intestine in stimulating intestinal
calcium transport.
Copy from Devlin T.M.: Textbook of Biochemistry with Clinical Correlations

34. Transport of Hormones
in the Bloodstream
Steroids are lipophilic molecules  they are
bound to protein carriers in the blood
Protien carriers are
• Albumin
• Corticosteroid binding globulin (CBG) or transcortin
• Sex hormone binding globulin (SHBG)
• Androgen binding protein (ABP)
Only the free fraction is biologically active (usually less than
10%)
Carrier-
bound
hormone
Endocrine
cell
Free
hormone
Hormone
Receptor
Hormone
degradation Biological
effects

35. Hormone half life
Steroids and thyroid hormone, which are
bound to plasma proteins, have a long half life (~
hours)
Peptides and catecholamines are water-
soluble, they are transported dissolved in plasma
generally have a very short half life (~ seconds
to minutes)

36. Transport of Adrenal
Steorid Hormones in the
Bloodstream
CORTISOL
70% is bound to corticosteroid
binding globulin (transcortin)
22% of cortisol is bound to albumin
8% free cortisol
ALDOSTERONE
60% of aldosterone is bound to
albumin
10 % is bound to transcortin
A small amount of aldosterone is
bound to other plasma
proteins
Transcortin is produced in the liver and its synthesis is increased by
estrogens.
Hormone bound to transport proteins are protect from metabolism and
inactivation.
Transport proteins assist in maintaining a level of hormones in circulation.

37. Transport of Sex Hormones in
the Bloodstream
Testosterone & estradiol bind to sex hormone binding globulin
(SHBG).
Progesterone binds to transcortin.
Affinity of SHBG for testosterone is higher than for estradiol.
• Before puberty - the level of SHBG is about the same in males and
females .
• At the puberty - there is a small decrease in the level of circulating
SHBG in females and larger decrease in males, insuring relatively
greater amount of the unbound, biologically active sex hormones.
• In adults, males have half of the amount of SHBG than females.
• Testosterone lowers SHBG levels in blood, whereas estradiol raises
SHBG levels.

38. Mechanism of Steroid
Hormone Action
• Steroid hormones are soluble
in the plasma membrane and
readily enter the cytosol.
• Steroids bind to intracellular
receptor either in the cytosol
or in the nucleus.
• The hormone-receptor
complex acts as a
transcription factor which
turns on / turns off the genes.
Copy from Devlin T.M.: Textbook of Biochemistry with Clinical Correlations

39. • Messenger RNA is
transcribed, leaves the
nucleus, and is translated into
a specific protein by ribosome.
• The specific proteins then
carry out function in the target
cell.
• Because steroid hormones
initiate protein synthesis their
effects are produced more
slowly, but are more long-
lasting than those produced by
other hormones.
Mechanism of Steroid
Hormone Action

40. Hormone Catabolism and
Excretion
• Inactivation of steroids involves
reductions and conjugation to
glucuronides or sulfate to increase
their water solubility.
• Most are catabolized by the liver and
kidneys.
• 70% of the conjugated steroids are
excreted in the urine, 20 % leave in
feces and rest exit through the skin.
3
estron-3sulfate

41. Structure-Activity Relationships
Natural Corticosteroids
 4,5 double bond and a 3-ketone group are must for typical steroid
activity.
 A hydroxyl group on C11 is needed for glucocorticoid activity
(corticosterone) but is not required for sodium-retaining activity
(desoxycorticosterone).
 The addition of a hydroxyl group on C17, (which converts
corticosterone to cortisol,) also increases glucocorticoid activity.

42. Synthetic Corticosteroids
Ring A
 double bond at the 1,2 position increases the ratio of carbohydrate
to sodium-retaining potency.
Ring B
 The inclusion of methyl group in position 6 of prednisolone will yield
6--methylprednisolone, a compound with slightly greater
glucocorticoid potency.
 It also greatly diminishes the binding of methylprednisolone to
transcortin.
Structure-Activity Relationships

43. Ring C
 The addition of a fluoride group on the 9 position of cortisol to give
9--fluorocortisol will greatly increase all biological activity.
Ring D
 Hydroxylation or methylation at the 16 position of -
fluoroprednisolone to give triamcinolone, dexamethasone, or
betamethasone increases antiinflammatory potency and drastically
diminishes sodium-retaining activity.
Structure-Activity Relationships

44. The major therapeutic classes of steroids are the following:
• Anti-infl ammatory agents: Cortisone
• Sex hormones: Estrogen, progesterone, and testosterone
• Oral contraceptives: Norethisterone
• Cardiac steroids: Digitoxigenin
• Diuretics: Spironolactone
• Antibiotics: Fusidic acid
• Neuromuscular blockers: Pancuronium chloride
• Vitamin D precursor: Ergosterol

45. Synthesis of cortisone

47. Synthesis of prednisolone
 sy

48. Synthesis of dexamethasone

49. Synthesis of dexamethasone continued

50.  Progestogens could be broadly classified into
two major classes:
 1. Progesterone derivatives
 2. 19-Nor testosterone derivatives

54. Oestrone derivatives

56. Synthesis of Diethylstilbestrol

57. Synthesis of Dienestrol

58. Synthesis of Testosterone

60.  The major pharmacological activities of the glucocorticoids
are anti-inflammation, inhibition of cytokines, and inhibition of
mast cell release of autocoids.
 The anti-inflammatory activity of the glucocorticoids is derived
from their ability to affect protein synthesis. Specifically, they
stimulate the synthesis of lipocortin, a protein that inhibits
phospholipase A2, which is an enzyme that catalyzes the
breakdown of membranes to release arachidonic acid, the
first step in the arachidonic acid cascade that results in the
production of inflammatory prostaglandins and
leukotrienes.Therefore, inhibition of phospholipase A2
ultimately results in the reduction of the inflammatory
prostaglandins and leukotrienes.

61.  A second anti-inflammatory mechanism of glucocorticoids
involves inhibition of IL-1. IL-1 stimulates the
proliferation of T and B lymphocytes that are responsible
for the production of the cytokines and antibodies, which
in turn are important in the inflammatory and immune
responses to antigens.
 The glucocorticoids, by their ability to inhibit IL-1, cause a
decrease in T and B lymphocytes, leading to
immunosuppression, and therefore must be used with caution
in patients with infection.
 A third action of glucocorticoids is to inhibit the synthesis
and release of histamine and other autocoids from mast
cells.

62.  The glucocorticoids, such as hydrocortisone (also known as
cortisol), are biosynthesized and released under the influence
of peptide hormones secreted by the hypothalamus
(corticotropin releasing factor (CRF))and anterior pituitary
(ACTH) (adenohypophysis) to activate the adrenal cortex (the
hypothalamic-pituitary-adrenal [HPA] axis).
 On the other hand, the secretion of the mineralocorticoids,
corticosterone and aldosterone, is under the influence of the
octapeptide, angiotensin II. Angiotensin II is the active
metabolite resulting from the renin-catalyzed proteolytic
hydrolysis of plasma angiotensinogen to angiotensin I in the
blood.

63.  Glucocorticoids bind to cytoplasmic glucocorticoid receptors
containing two subunits of the heat shock protein that belong
to the 90-kDa family.
 The heat shock protein dissociates, allowing rapid nuclear
translocation of the receptor–steroid complex.
 Within the nucleus, the glucocorticoid receptor induces gene
transcription by binding to specific sequences on DNA called
glucocorticoid response elements in the promoter– enhancer
regions of responsive genes .
 In certain cases, the glucocorticoid receptor can interact with
nuclear factor-B and AP-1 to inhibit gene expression activated
by these proinflammatory transcription factors.

64.  The glucocorticoids increase blood glucose and liver glycogen
levels by stimulating gluconeogenesis.
 The source of this augmented carbohydrate production is
protein, and the protein catabolic actions of the
glucocorticoids result in a negative nitrogen balance.
 The inhibition of protein synthesis by glucocorticoids brings
about a transfer of amino acids from muscle and bone to liver,
where amino acids are converted to glucose.

65.  Glucocorticoids not only break down protein but also
stimulate the catabolism of lipids in adipose tissue and
enhance the actions of other lipolytic agents. This occurrence
results in an increase in plasma free fatty acids and an
enhanced tendency to ketosis.
 Glucocorticoids directly stimulate cardiac output and
potentiate the responses of vascular smooth muscle to the
pressor effects of catecholamines and other vasoconstrictor
agents. Such actions on vascular smooth muscle may be
secondary to effects mediated through the central nervous
system or on circulating volume. However, the presence of
steroid receptors on vascular smooth muscle suggests a
direct effect on vasomotor activity

66.  Mineralocorticoids bind to the mineralocorticoid receptor in the
cell cytosol, and are able to freely cross the lipid bilayer of the
cell. This type of receptor becomes activated
upon ligand binding. After a hormone binds to the
corresponding receptor, the newly formed receptor-ligand
complex translocates into the cell nucleus, where it binds to
many hormone response elements (HREs) in
the promoter region of the target genes in the DNA.
 This enzyme, 11-beta hydroxysteroid dehydrogenase type
II (Protein:HSD11B2), catalyzes the deactivation of
glucocorticoids to 11-dehydro metabolites.

71. Name
Glucocorticoid
potency
Mineralocorticoid
potency
Terminal half-
life (hours)
Cortisoll(hydrocortisone) 1 1 8
Cortisone 0.8 0.8 8
Prednisone 3.5–5 0.8 16–36
Prednisolone 4 0.8 16–36
Methylprednisolone 5–7.5 0.5 18–40
Dexamethasone 25–80 0 36–54
Betamethasone 25–30 0 36–54
Triamcinolone 5 0 12–36
Fludrocortisone acetate 15 200 24
Deoxycorticosterone
acetate
0 20 -

72. Adverse drug reactions
 glucocorticoid-induced adrenocortical insufficiency,
glucocorticoid-induced osteoporosis, and generalized protein
depletion
 Although side effects and toxicities vary with the drug and,
sometimes, with the patient, facial mooning, flushing,
sweating, acne, thinning of the scalp hair, abdominal
distention, and weight gain are observed with most
glucocorticoids.
 Protein depletion (with osteoporosis and spontaneous
fractures), myopathy (with weakness of muscles of the thighs,
pelvis, and lower back), and aseptic necrosis of the hip and
humerus are other side effects.
 These drugs can cause psychological disturbances,
headache, vertigo, and peptic ulcer, and they can suppress
growth in children.

73. SEX STEROIDS
The sex steroids are comprised of three classes:
estrogens, progestins, and androgens
The principal class of the male sex steroid hormone is the androgens
The two principal classes of female sex steroid hormones are estrogens
and progestins

74. ANDROGENS ’ physiological
effects
 Androgens are needed for the development of secondary sex
characteristics. The male voice deepens because of thickening of the
laryngeal mucosa and lengthening of the vocal cords.
 In both men and women, they play a role first in stimulating the
growth of hair on the face, arms, legs, and pubic areas and later in
the recession of the male hairline.
 The fructose content of human semen and both the size and the
secretory capacity of the sebaceous glands also depend on the levels
of testosterone.

75.  The actions of androgen in the reproductive tissues, including
prostate, seminal vesicle, testis, and accessory structures, are
known as the androgenic effects,
 Nitrogen-retaining effects of androgen in muscle and bone are
known as the anabolic effects.

78. SAR of Androgens
 Oxygen functional groups normally occurring at positions 3 and 17
of the steroid ring system are not essential for androgenic activity.
 Generally, ring expansion or ring contraction significantly reduces
or destroys the androgenic and anabolic activities.
 Introduction of a 3-ketone function or a 3a-OH group enhances
androgenic activity.
 A hydroxyl group in the 17a-position of androstane contributes no
androgenic or anabolic activity.
 The 17b-oxygen atom is important for attachment to the receptor
site, while 17a-alkyl groups are important for preventing metabolic
changes at this position.

79. SAR of Androgens
 Such 17a-substituents render the compounds orally active.
Increasing the length of the alkyl side chain at the 17a-position,
however, resulted in decreased activity, and the incorporation of
other substituents, such as the 17a-ethynyl group, produced
compounds with useful progestational activity (progestins), such as
ethisterone.
 Attaching an isoxazole ring to ethisterone produced danazol
(Danatrol, Danocrine), which exhibited potent antigonadotropic
properties, weak androgen and anabolic properties, and no estrogen
or progestin activity

80. SAR of Androgens
 Several modifications of 17a-methyltestosterone lead to potent,
orally active anabolic agents. Two hydroxylated analogs include
oxymesterone (Fig. 40.9) and oxymetholone These drugs have at
least three times the anabolic and half the androgenic activity of
testosterone
 Halogen substitution produces compounds with decreased activity
except when inserted into positions 4 or 9 (e.g., fluoxymesterone).
 Replacement of a carbon atom in position 2 by oxygen has produced
the only clinically successful heterocyclic steroid (oxandrolone)
among a number of azasteroids and oxasteroids. Some of the 2-
oxasteroids are potent anabolic agents.

81. SAR of Androgens
 Introduction of a sp2 hybridized carbon atom into the A ring
(methenolone, testolactone renders the ring more planar, and in turn,
this may be responsible for greater anabolic activity.
 The 19-norsteroids (nandrolone) are of interest, because these agents
seem to produce a more favorable ratio of anabolic to androgenic
activity..

82. ESTROGENS’ physiological
effects
 One of the principal actions of the estrogens is to promote the
development of female secondary sex characteristics.
 These feminizing attributes include hair growth, skin softening,
breast growth, and accumulation of fat in the thighs, hips, and
buttocks.
 Estrogen also stimulates the growth and development of the female
reproductive tract, including the uterine oviduct, cervix, and vagina.
 Estrogens play a significant role in breast tissue as well.
Considerable research has focused on understanding breast cancer
and the factors that influence its growth. Estrogens serve as “fuel”
for hormone-dependent mammary carcinoma and cause proliferation
of breast cells.

83. ESTROGENS’ physiological
effects
 They also stimulate gene expression and, therefore, the production
of several proteins, including intracellular proteins important for
breast cell function and growth, as well as proteins that infl uence
tumor growth and metastasis. Some of these intracellular proteins
include the enzymes needed for DNA synthesis, such as DNA
polymerase, thymidine kinase, thymidylate synthetase, and
dihydrofolate reductase

84. PROGESTINS ’ physiological
effects
 The primary physiologic site of action of progesterone is the uterus.
 It acts on both the endometrium (inner mucous lining) and the
myometrium (muscle mass) of the uterus.
 The effect of progesterone on the endometrium, already primed by
estrogens, is to induce the secretory phase of the menstrual cycle.
 During this phase, the endometrial glands grow and secrete large
amounts of carbohydrates that can be used by the fertilized ovum as
an energy source.
 The primary function of progesterone with respect to the
myometrium is to stop spontaneous rhythmic contractions of the
uterus.
 Progesterone often is referred to as the “hormone of pregnancy.”
 For the fi rst trimester, the corpus luteum serves as the primary
source of progesterone, at which point the developing placenta takes
over as the major source of progesterone and estrogen.

85. PROGESTINS ’ physiological
effects
 The high level of progesterone that is produced during pregnancy
sends a signal to the hypothalamus via the negative feedback system
to prevent release of the FSH and LH necessary for the development
of new ova. In general, the nonreproductive effects of progesterone
are fairly insignifi cant.
 Ovarian biosynthesis and secretion of progesterone is controlled by
the release of LH from the anterior pituitary during ovulation. The
LH induces progesterone secretion from the corpus luteum during
the second half of the menstrual cycle.
 If conception does not occur, the corpus luteum degenerates, and
progesterone production decreases. As progesterone levels drop,
endometrial sloughing occurs—otherwise known as menstruation.

88. SAR of PROGESTINS
 Progestin activity is restricted to those molecules with a steroid
nucleus.
 The synthetic progestins generally can be divided into two steroidal
classes: the androstanes (including the 19-norandrostanes), and the
pregnanes (including the 19-norpregnanes) .
 In the androstane series, a 17α substituent, such as ethynyl, methyl,
ethyl, and variations of these, provides oral bioavailability.
 Ethisterone (17β-hydroxy-17α-ethynyl progesterone) the fi rst
androstane found to be effective, has only about one-third the
activity of progesterone when delivered subcutaneously, but is 15-
fold more active than progesterone when administered orally.

89. SAR of PROGESTINS
 Closely related to testosterone, this progestin has significant
androgenic activity.
 Removal of the CH3 group at position 19 leads to norethindrone
(norethisterone; 19-norandrostane) which has 5- to 10-fold more
progestin activity.
 The activity of norethindrone is increased further by the addition of
a chlorine substituent at position 21 (blocks metabolic
hydroxylation) or by the addition of a methyl group at carbon 18
(norgestrel) .
 Ethynodiol diacetate, another 19-norandrostane, is an extremely
potent oral progestin.It is more active when administered orally than
parenterally and, when combined with an estrogen, is effective as an
OC.
 Further unsaturation of the B or C ring of androstane derivatives
usually enhances progestin activity.

90. SAR of PROGESTINS
 Introduction of a halogen or methyl substituent in the 6α or 7α
positions generally increases hormonal activity.
 Acetylation of the 17β-OH of norethindrone increases the duration
of action of the drug.
 Removal of the 3-keto function of norethindrone allows retention of
potent progestin activity without androgenic effects.
 Activity of the pregnanes and 19-norpregnanes is enhanced by
unsaturation at C6 and C7 and by substitution of a methyl group or a
halogen at C6. This activity

94. Compound Chemical name
Equilin Δ7-Estrone
Equilenin Δ6,8-Estrone
17α-Dihydroequilin Δ7-17α-Estradiol
17β-Dihydroequilin Δ7-17β-Estradiol
17α-Dihydroequilenin Δ6,8-17α-Estradiol
17β-Dihydroequilenin Δ6,8-17β-Estradiol
8,9-Dehydroestrone Δ8-Estrone
8,9-Dehydroestradiol Δ8-17β-Estradiol
Hippulin Δ8-14-Isoestrone
Equine estrogens

95. Estradiol derivatives
Compound Chemical name
Estradiol (E2) Estra-1,3,5(10)-triene-3,17β-diol
2-Hydroxyestradiol 2-Hydroxyestradiol
4-Hydroxyestradiol 4-Hydroxyestradiol
4-Methoxyestradiol 4-Methoxyestradiol
8β-VE2 8β-Vinylestradiol
16α-IE2 16α-Iodoestradiol
16α-LE2 Estradiol 21,16α-lactone?
Cloxestradiol Estradiol 17β-chloral hemiacetal ether
Estradiol sulfate Estradiol 3-sulfate
Estrapronicate Estradiol 3-propionate 17β-nicotinate
Orestrate
Estradiol 3-propionate 17β-(1-cyclohexenyl)
ether
Promestriene Estradiol 3-propyl 17β-methyl diether

96. Compound Chemical name
Cyclodiol 14α,17α-Ethanoestradiol
Estrazinol 8-Aza-17α-ethynylestradiol 3-methyl ether
Estrofurate 17α-(3-Furyl)-δ7-estradiol 3-acetate
Ethinylestradiol (EE) 17α-Ethynylestradiol
Ethinylestradiol sulfonate
(EES)
17α-Ethynylestradiol 3-isopropylsulfonate
Ethylestradiol 17α-Ethylestradiol
Mestranol (EE3ME) 17α-Ethynylestradiol 3-methyl ether
Methylestradiol 17α-Methylestradiol
Moxestrol 11β-Methoxy-17α-ethynylestradiol
Quinestrol 17α-Ethynylestradiol 3-cyclopentyl ether

97. diethylstilbestrol and derivatives
 Diethylstilbesterol
 Dienestrol
 Benzestrol

98. Chemical contraceptive agents
 Monophasic combinations
 Biphasic and triphasic combinations
 Extended oral contraceptive therpay
 Post coital contraceptives

99.  combined estrogen and progestin pills
 progestin-only (levonorgestrel, LNG) pills
 antiprogestin (ulipristal acetate or mifepristone) pills

100. SERMs & ANTIESTROGENS
Name Brand name Approved uses
Anordrin Zi Yun Emergency contraception
Bazedoxifene Duavee Osteoporosis prevention
Broparestrol Acnestrol Dermatology; Breast cancer treatment
Clomifene Clomid Female infertility
Cyclofenil Sexovid Female infertility; Menopausal symptoms
Lasofoxifene Fablyn
Osteoporosis prevention, treatment; Vaginal
atrophy
Ormeloxifene Saheli Hormonal contraception
Ospemifene Osphena Dyspareunia due to vaginal atrophy
Raloxifene Evista
Osteoporosis prevention, treatment; Breast
cancer prevention
Tamoxifen Nolvadex Breast cancer treatment
Toremifene Fareston Breast cancer treatment

101. Tamoxifen
Toremifene
Raloxifene
Clomifene

102. AROMATASE INHIBITORS
Non-selective
 Aminoglutethimide
 Testolactone
Selective
 Anastrozole
 Letrozole
 Exemestane
 Vorozole
 Formestane
 Fadrozole

103. Aminoglutethimide
Testolactone

104. Anastrozole
Exemestane