PHARMACOLOGY
ADRENOCORTICOSTEROIDS AND
ADRENOCORTICOTROPIC ANTAGONIST
The corticosteroids are steroid hormones
produced by the adrenal gland cortex. They
consist of 2 major physiological and
pharmacologic groups:
(1) Glucocorticoids - which have important
effects on carbohydrate, fat, and protein
metabolism, catabolism, immune responses
and inflammation.
(2) Mineralocorticoids - regulate sodium
and potassium reabsorption collecting
tubules of the kidney.
Glucocorticoids (G)
Short Acting (8-12 hours):
Hydrocortisone (Cortisol): G with maximum
M activity.
Cortisone: Less potent G
Intermediate Acting (12-36 hours):
 Prednisone: Prodrug
 Prednisolone
 Meprednisone
 Fluprednisone
 Triamcinolone: Acetonide salt is G with
maxium topical activity
 Methylprednisolone
Long acting (36-72 hours)
 Dexamethasone:
 Dexamethasone: Maximum G capacity
 Paramethasome: Maximum G potency
Mineralocorticoids (M)
 Aldosterone: Most Potent M, Maximum M
activity
 Fludrocortisone: M with maximum G
activity
 DOCA: Selective M (Zero G Activity)
USES OF CORTICOSTEROIDS
1. Replacement Use
Acute adrenal Insufficiency: It is an
emergency condition and requires
immediate management with parenteral
administration (i.v.) of hydrocortisone
Chronic Adrenal Insufficiency (Addison’s
disease): It is treated with oral doses of
hydrocortisone. Mineralocorticoids like
fludrocortisone may also be required.
Chronic adrenal insufficiency (Addison’s
disease): It is treated with oral doses of
hydrocortisone. Mineralocorticoids like
fludrocortisone may also be required.
Congenital adrenal hyperplasia(CAH): This
disorder is a result of congenital deficiency
of the enzymes involved in the synthesis of
corticosteroids. Due to decreased adrenal
steroids, there is no feedback inhibition of
pituitary and consequently ACTH secretion
increases. ACTH cannot release
corticosteroids (because they are not
synthesized) but it results in overgrowth of
adrenal glands leading to symptoms. Thus,
treatment if CAG is aimed at reducing ACTH
secretion. Exogenous glucocorticoids like
hydrocortisone cause feedback inhibition of
HPA (hypothalamus-pituitary-adrenal) Axis
and lead to amelioration of symptoms. To
prevent CAH (in pregnant female with
history of baby with CAH), steroids should
be administered at 6 weeks period.
2. Diagnostic Use
Dexamethasone suppression test is used to
test the intactness of HPA axis function and
diagnosis of Cushing’s syndrome.
4. Non-Adrenal Uses
Anti-inflammatory uses: Corticosteroids can
be useful in RA, OA (intraarticular) and
acute gouty arthritis when NSAIDs fail to
provide relief. These are also useflu in
inflammatory conditions of eye like
conjunctivitis, iritis, iridocyclitis and keratitis.
However, stroids are contraindicated in
herpes simplex keratitis.
PHARMACOLOGY
Anti-allergic uses: Corticosteroids are useful
in the management of anaphylaxis (DOC is
adrenaline), urticaria, angioedema and
serum sickness. These are used by
inhalational route in chronic severe asthma
(status asthmaticus). Skin conditions like
pemphigus vulgaris, exfoliative dermatitis
and SJS also require systemic steroid
therapy.
Immunosuppressive uses: High dose of
corticosteroid therapy is required in the
organ transplantation to prevent graft
rejection. They are also useful in
autoimmune diseases (e.g. mysthenia
gravis, hemolytic anemia) and collagen
vascular diseases (SLE, polyarteritis nodosa
and nephrotic syndrome). Steroids are also
useful in patients with ulcerative colitis and
Crohn’s disease who are not responding to
5-aminosalicylic acid.
Anti-cancer uses: Due to prominent
lymphotic action in malignant cells, steroids
are essential component of the combination
therapy of ALL and lymphomas (both
Hodgkin as well as non-Hodgkin). These are
also useful in CLL, multiple myeloma and
breast carcinoma. These can also be used
with antineoplastic agents to decrease
nausea and vomiting.
Other uses:
- Steroids with selective
glucocorticoid action (without
sodium and water retaining activity)
like betamethasone and
dexamethasone are used to
decrease cerebral edema due to
malignancies or TB.
- Steroids are also useful in severe
infective conditions (like TB
meningitis and lepra reaction) to
tide over the acute crisis.
- These can be used as a desperate
measure in the septicemic shock
- Deflazacort is approved for the oral
treatment of Duchenne’s muscular
dystrophy
- Steroids can also be used for
treatment of sarcoidosis
- In thrombocytopenia, prednisolone
is used to decrease bleeding
tendency.
- Significant decrease in neurological
defects have been seen in spinal
cord injury patients treated with
large doses of methylprednisolone
(within 8 hours)
POINTS TO REMEMBER FOR SYSTEMIC
USE OF STEROIDS
- Long term use (for more than 2
weeks) can lead to HPA axis
suppression. Steroids should not be
withdrawn abruptly because it may
precipitate acute renal insufficiency.
Many patients recover from HPA
axis suppression within several
weeks to months but recovery may
take one year or longer in some
patients.
- Large single dose is less harmful
than small doses given for long
periods. Thus 80 mg prednisolone
for 2 days is much less harmful than
20 mg dose for 6 months.
- During condition of stress like
infection or trauma, steroid dose
should be unchanged or increased
(2-10 fold). It should not be
reduced.
- To prevent HPA axis suppression,
steroids can be given on alternate
days but long acting steroids like
betamethasone and
dexamethasone cause HPA axis
suppression even when
administered on alternate days.
GLUCOCORTICOIDS
Mechanism of Action
- Corticosteroids enter the cell and
bind to cytosolic receptors that
transport the steroid into the
nucleus. The steroid-receptor
complex alters gene expression by
binding to glucocorticoid response
elements (GREs) or
mineralocorticoid-specific
elements . Tissue-specific
responses to steroids are made
possible by the presence in each
tissue of different protein regulators
that control the interaction between
the hormone-receptor complex and
particular DNA response elements
PHARMACOLOGY
- Major endogenous glucocorticoid is
hydrocortisone (cortisol). Many of
the effects of glucocorticoids are
dose-dependent whereas some are
permissive effects (without these,
many normal functions become
deficient) e.g. response of vascular
and bronchial smooth muscle to
catecholamines is diminished in the
absence of cortisol.
- Effect on metabolism:
Glucocorticoids are catabolic in
nature and thus casue breakdown
of carbohydrates (hyperglycemia),
proteins (muscle wasting) and fat.
There is redistribution of fat;
depostion over face (moon face),
mouth (fish mouth) and back
(buffalo hump) where as removal
from the extremities is seen.
Glucocorticoids cause negative
calcium balance (by inhibiting
intestinal absorption, enhancing
renal excretion and causing loss of
calcium from the bones) and can
predispose to osteoporosis.
- Effect on CVS and CNS:
Glucocorticoids prevent the
increase in the permeability of
capillaries. These have mild
euphoric effect and high doses can
lower seizure threshold.
- Effect on GIT: These hormones
may aggravate peptic ulcer by
increasing the section of HCl and
pepsin in the stomach.
- Effect on hematopoietic system:
Glucocorticoids cause destruction of
T cells and B cells (less sensitive) in
malignancies whereas little effect is
exerted on normal cells. These
drugs cause sequestration of
lymphocytes, eosinophils, moncytes
and basophils in tissues (and thus
decrease circulating levels of theses
cells) whereas circulating
neutrophils are increased due to
release from bone marrow.
- Effect on inflammatory response:
Glucocorticoids are powerful
antiinflammatory agents. Most
important mechanism is the
inhibition of chemotaxis (recruitment
of cells at the side of inflammation).
These hormones also induce the
production of annexis (preciously
called lipocortins) that are
responsible for the inhibition of
phospholipase A2 (involved in the
production of prostaglandings and
leukotrienes). They also delay the
healing of wounds and scar
formation.
- Effect on immunity: These
hormones suppress cell medicated
immunity more than humoral
immunity. Main effect is due to
inhibition of recruitment of immune
cells, but they also inhibit the
release of interleukin 1 and
interleukin 2. Antibody production is
affected at high doses and
continuous administration of
glucocorticoids can result in
catabolism of IgG..
Immunosupressive effect of
glucocorticoids is the basis of their
use in graft rejection and various
hypersensitivity reactions.
Organ and Tissue Effects
1. Metabolic effects—Glucocorticoids
stimulate gluconeogenesis. As a result,
blood glucose rises, muscle protein is
catabolized, and insulin secretion is
stimulated. Both lipolysis and
lipogenesis are stimulated, with a net
increase of fat deposition in certain
areas (eg, the face and the shoulders
and back).
2. Catabolic effects—Glucocorticoids
cause muscle protein catabolism. In
addition, lymphoid and connective
tissue, fat, and skin undergo wasting
under the influence of high
concentrations of these steroids.
Catabolic effects on bone can lead to
osteoporosis. In children, growth is
reduced
PHARMACOLOGY
3. Immunosuppressive effects—
Glucocorticoids inhibit cell mediated
immunologic functions, especially
those dependent on lymphocytes.
These agents are actively lymphotoxic
and, as such, are important in the
treatment of hematologic cancers. The
drugs do not interfere with the
development of normal acquired
immunity but delay rejection reactions
in patients with organ transplants.
4. Anti-inflammatory effects—
Glucocorticoids have a dramatic
suppressant effect on numerous
inflammatory processes. These drugs
increase neutrophils and decrease
lymphocytes, eosinophils, basophils,
and monocytes. The migration of
leukocytes is also inhibited. The
biochemical mechanisms underlying
these cellular effects include the
induced synthesis of an inhibitor of
phospholipase A2 (Chapter 18),
decreased mRNA for cyclooxygenase
2 (COX-2), decreases in interleukin-2
(IL-2) and IL-3, and decreases in
platelet activating factor (PAF), an
inflammatory cytokine.
5. Other effects—Glucocorticoids such
as cortisol are required for normal
renal excretion of water loads. The
glucocorticoids also have effects on
the CNS. When given in large doses,
these drugs may cause profound
behavioral changes. Large doses also
stimulate gastric acid secretion and
decrease resistance to ulcer formation.
Glucocorticoids are important for fetal
lung development.
Important Glucocorticoids
1. Cortisol—The major natural
glucocorticoid is cortisol
(hydrocortisone). The physiologic
secretion of cortisol is regulated by
adrenocorticotropin (ACTH) and
varies during the day (circadian
rhythm); the peak occurs in the
morning and the trough occurs
about midnight. In the plasma,
cortisol is 95% bound to
corticosteroid-binding globulin
(CBG). Given orally, cortisol is well
absorbed from the gastrointestinal
tract, is cleared by the liver, and has
a short duration of action compared
with its synthetic congeners .
Although it diffuses poorly across
normal skin, cortisol is readily
absorbed across inflamed skin and
mucous membranes. The cortisol
molecule also has a small but
significant salt retaining
(mineralocorticoid) effect. This is an
important cause of hypertension in
patients with a cortisol-secreting
adrenal tumor or a pituitary
ACTHsecreting tumor (Cushing’s
syndrome).
2. Synthetic glucocorticoids—The
mechanism of action of these
agents is identical with that of
cortisol. A large number of synthetic
glucocorticoids are available for
use; prednisone and its active
metabolite, prednisolone,
dexamethasone, and triamcinolone
are representative. Their properties
(compared with cortisol) include
longer half-life and duration of
action, reduced salt-retaining effect,
and better penetration of lipid
barriers for topical activity. Special
glucocorticoids have been
developed for use in asthma and
other conditions in which good
surface activity on mucous
membranes or skin is needed and
systemic effects are to be avoided.
Beclomethasone and budesonide
readily penetrate the airway mucosa
but have very short halflives after
they enter the blood, so that
systemic effects and toxicity are
greatly reduced.
PHARMACOLOGY
Clinical Uses
1. Adrenal disorders—Glucocorticoids
are essential to preserve life in patients
with chronic adrenal cortical
insufficiency (Addison’s disease) and
are necessary in acute adrenal
insufficiency associated with life-
threatening shock, infection, or trauma.
Glucocorticoids are also used in
certain types of congenital adrenal
hyperplasia, in which synthesis of
abnormal forms of corticosteroids are
stimulated by ACTH. In these
conditions, administration of a potent
synthetic glucocorticoid suppresses
ACTH secretion sufficiently to reduce
the synthesis of the abnormal steroids.
2. Nonadrenal disorders—Many
disorders respond to corticosteroid
therapy. Some of these are
inflammatory or immunologic in nature
(eg, asthma, organ transplant
rejection, collagen diseases, rheumatic
disorders). Other applications include
the treatment of hematopoietic
cancers, neurologic disorders,
chemotherapy-induced vomiting,
hypercalcemia, and mountain
sickness. Betamethasone, a
glucocorticoid with a low degree of
protein binding, is given to pregnant
women in premature labor to hasten
maturation of the fetal lungs. The
degree of benefit differs considerably
in different disorders, and the toxicity
of corticosteroids given chronically
limits their use.
Antenatal Use
Betamethasone can be given to accelerate
the fetal lung maturation, if delivery is
anticipated before 43 weeks of gestation.
Antenatal steroids may decrease the
incidence of respiratory distress syndrome,
PDA, necrotizing enterocolitis and
periventricular/intraventricular hemorrhage
Toxicity
Short-term (<2 weeks) therapy is well
tolerated. Longer courses can cause serious
toxicity. Most of the toxic effects of the
glucocorticoids are predictable from the
effects already described.
Some are life threatening and include
metabolic effects (growth inhibition,
diabetes, muscle wasting, osteoporosis),
salt retention, reduced wound healing, and
psychosis. Methods for minimizing these
toxicities include local application (eg,
aerosols for asthma), alternate-day therapy
(to reduce pituitary suppression), and
tapering the dose soon after achieving a
therapeutic response. To avoid adrenal
insufficiency in patients who have had long-
term therapy, additional “stress doses” may
need to be given during serious illness or
before major surgery. Patients who are
being withdrawn from glucocorticoids after
prolonged use should have their doses
tapered slowly, over the course of several
months, to allow recovery of normal adrenal
function.
PHARMACOLOGY
MINERALOCORTICOIDS
- Major endogenous
mineralocorticoid is aldosterone. It
acts on the distal convoluted
tubules of the kidney to cause
reabsorption of sodium and
excretion of potassium and
hydrogen. Thus, excess of
mineralocorticoids can lead to
retention of sodium and water
(hypertension and edema),
hypokalemia and alkalosis whereas
Addison’s disease(deficiency of
adrenal corticoids) is characterized
by hyperkalemia, acidosis and
hypotension.
- Aldosterone is also involved in
causing myocardial remodeling
associated with CHF and the drugs
blocking this effect (spironolactone,
ACEIs, ARBs and BBs) decrease
mortality in patients with CHF.
- Other Mineralocorticoids: Other
mineralocorticoids include
deoxycorticosterone, the naturally
occurring precursor of aldosterone,
and fludrocortisone, which also has
significant glucocorticoid activity.
Because of its long duration of
action, fludrocortisone is favored for
replacement therapy after
adrenalectomy and in other
conditions in which
mineralocorticoid therapy is needed.
GLUCOCORTICOID SYNTHESIS
INHIBITORS
- Synthesis Inhibitors:
Several drugs inhibit adrenal steroid
synthesis. The most important of these
drugs are ketoconazole, aminoglutethimide,
metyrapone, and etomidate. Ketoconazole
(an antifungal drug) inhibits the cytochrome
P450 enzymes necessary for the synthesis
of all steroids and is used in a number of
conditions in which reduced steroid levels
are desirable (eg, adrenal carcinoma,
hirsutism, breast and prostate cancer).
Aminoglutethimide blocks the conversion of
cholesterol to pregnenolone and also
inhibits synthesis of all hormonally active
steroids. It can be used in conjunction with
other drugs for treatment of steroid-
producing adrenocortical cancer.
Metyrapone inhibits the normal synthesis of
cortisol but not that of cortisol precursors;
the drug can be used in diagnostic tests of
adrenal function. Etomidate (a general
anesthetic) inhibits 11β-hydroxylase and
can be used in Cushing’s syndrome.
CORTICOSTEROID RECEPTOR
ANTAGONIST
Receptor Antagonists
Spironolactone and eplerenone, antagonists
of aldosterone at its receptor. Mifepristone
(RU-486) is a competitive inhibitor of
glucocorticoid receptors as well as
progesterone receptors and has been used
in the treatment of Cushing’s syndrome.
PHARMACOLOGY
GONADAL HORMONES
- The gonadal hormones include the
steroids of the ovary (estrogens and
progestins) and testis (chiefly testosterone).
Because of their extensive use as
contraceptives and replacement therapy,
many synthetic estrogens and progestins
have been produced. These include
synthesis inhibitors, receptor antagonists,
and some drugs with mixed effects (ie,
agonist effects in some tissues and
antagonist effects in other tissues).
- Mixed agonists with estrogenic effects are
called selective estrogen receptor
modulators (SERMs). Synthetic androgens,
including those with anabolic activity, are
also available for clinical use. A diverse
group of drugs with antiandrogenic effects is
used in the treatment of prostate cancer and
benign prostatic hyperplasia in men and
androgen excess in women.
I. Ovarian Hormones
- The ovary is the primary source of gonadal
hormones in women during the childbearing
years (ie, between puberty and
menopause). When properly regulated by
follicle-stimulating hormone (FSH) and
luteinizing hormone (LH) from the pituitary,
each menstrual cycle consists of the
following events: A follicle in the ovary
matures, secretes increasing amounts of
estrogen, releases an ovum, and is
transformed into a progesterone-secreting
corpus luteum. If the ovum is not fertilized
and implanted, the corpus luteum
degenerates; the uterine endometrium,
which has proliferated under the stimulation
of estrogen and progesterone, is shed as
part of the menstrual flow, and the cycle
repeats. The mechanism of action of both
estrogen and progesterone involves entry
into cells, binding to cytosolic receptors, and
translocation of the receptor–hormone dimer
into the nucleus, where it modulates gene
expression.
A. Estrogens
- The major ovarian estrogen in women is
estradiol. Estradiol has low oral
bioavailability but is available in a
micronized form for oral use. It can also be
administered via transdermal patch, vaginal
cream, or intramuscular injection. Long-
acting esters of estradiol that are converted
in the body to estradiol (eg, estradiol
cypionate) can be administered by
intramuscular (IM) injection. Mixtures of
conjugated estrogens from biologic sources
(eg, Premarin) are used orally for hormone
replacement therapy (HRT). Synthetic
estrogens with high bioavailability (eg,
ethinyl estradiol, mestranol) are used in
hormonal contraceptives.
1. Effects:
Estrogen is essential for normal female
reproductive development. It is responsible
for the growth of the genital structures
(vagina, uterus, and uterine tubes) during
childhood and for the appearance of
secondary sexual characteristics and the
growth spurt associated with puberty.
Estrogen has many metabolic effects:
- It modifies serum protein levels and
reduces bone resorption.
- It enhances the coagulability of blood and
increases plasma triglyceride levels while
reducing low-density lipoprotein(LDL)
cholesterol and increasing highdensity
lipoprotein (HDL) cholesterol. Continuous
administration of estrogen, especially in
combination with a progestin, inhibits the
secretion of gonadotropins from the anterior
pituitary.
2. Clinical use:
Estrogens are used in the treatment of
hypogonadism in young females. Another
use is as HRT in women with estrogen
deficiency resulting from premature ovarian
failure, menopause, or surgical removal of
the ovaries. HRT ameliorates hot flushes
and atrophic changes in the urogenital tract.
It is effective also in preventing bone loss
and osteoporosis. The estrogens are
components of hormonal contraceptives
(see later discussion).
PHARMACOLOGY
3. Toxicity:
In hypogonadal girls, the dosage of
estrogen must be adjusted carefully to
prevent premature closure of the epiphyses
of the long bones and short stature. When
used as HRT, estrogen increases the risk of
endometrial cancer; this effect is prevented
by combining the estrogen with a progestin.
Estrogen use by postmenopausal women is
associated with a small increase in the risk
of breast cancer and cardiovascular events
(myocardial infarction, stroke). Dose-
dependent toxicity includes nausea, breast
tenderness, increased risk of migraine
headache, thromboembolic events (eg,
deep vein thrombosis), gallbladder disease,
hypertriglyceridemia, and hypertension.
- Because significant amounts of estrogens
and their active metabolites are excreted in
the bile and reabsorbed from the intestine,
orally administered estrogens will have a
high ratio of hepatic to peripheral effects.
The hepatic effects include increased
synthesis of clotting factors. The hepatic
effects of estrogen can be minimized by
routes that avoid first-pass liver exposure,
ie, vaginal, transdermal, or injection.
- Diethylstilbestrol (DES), a nonsteroidal
estrogenic compound, is associated with
infertility, ectopic pregnancy, and vaginal
adenocarcinoma in the daughters of women
who were treated with the drug during
pregnancy in a misguided attempt to
prevent recurrent spontaneous abortion.
These effects appear to be restricted to
DES because there is no evidence that the
estrogens and progestins in hormonal
contraceptives have similar effects or other
teratogenic effects.
B. Progestins
- Progesterone is the major progestin in
humans. A micronized form is used orally
for HRT, and progesterone-containing
vaginal creams are also available. Synthetic
progestins (eg, medroxyprogesterone) have
improved oral bioavailability. The 19-
nortestosterone compounds differ primarily
in their degree of androgenic effects. Older
drugs (eg, L-norgestrel and norethindrone)
are more androgenic than the newer
progestins (eg, norgestimate, desogestrel).
1. Effects:
Progesterone induces secretory changes in
the endometrium and is required for the
maintenance of pregnancy. The other
progestins named above also stabilize the
endometrium but do not support pregnancy.
Progestins do not significantly affect
plasma proteins, but they do affect
carbohydrate metabolism and stimulate the
deposition of fat. High doses suppress
gonadotropin secretion and often cause
anovulation in women.
2. Clinical use:
Progestins are used as contraceptives,
either alone or in combination with an
estrogen. They are used in combination
with an estrogen in HRT to prevent
estrogen-induced endometrial cancer,
though this combination may increase the
risk of breast cancer. Progesterone is used
in assisted reproductive technology
methods to promote and maintain
pregnancy.
3. Toxicity:
The toxicity of progestins is low. However,
they may increase blood pressure and
decrease HDL. Long-term use of high
doses in premenopausal women is
associated with a reversible decrease in
bone density (a secondary effect of ovarian
suppression and decreased ovarian
production of estrogen) and delayed
resumption of ovulation after termination of
therapy.
C. Hormonal Contraceptives
Hormonal contraceptives contain either a
combination of an estrogen and a progestin
or a progestin alone. Hormonal
contraceptives are available in a variety of
preparations, including oral pills, longacting
injections, subcutaneous implants,
transdermal patches, vaginal rings, and
intrauterine devices (IUDs). Three types of
oral contraceptives for women are available
in the United States: combination estrogen-
progestin tablets that are taken in constant
dosage throughout the menstrual cycle
(monophasic preparations); combination
preparations (biphasic, triphasic, and
quadriphasic) in which the progestin or
estrogen dosage, or both, changes during
the month (to more closely mimic hormonal
changes in a menstrual cycle); and
progestin-only preparations.
PHARMACOLOGY

The postcoital contraceptives (also known However, the risk of thromboembolism

as “emergency contraception”) prevent
pregnancy if administered within 72 h after
unprotected intercourse. Oral preparations
containing a progestin (L-norgestrel) alone,
estrogen alone, or the combination of an
estrogen and a progestin are effective. The
progestin-only preparation causes fewer
side effects than the estrogen-containing
preparations.
incurred by the use of these drugs is usually
less than that imposed by pregnancy.
b. Breast cancer:
Evidence suggests that the lifetime risk of
breast cancer in women who are current or
past users of hormonal contraceptives is not
changed, but there may be an earlier onset
of breast cancer.

1. Mechanism of action: c. Other toxicities:

The combination hormonal contraceptives
have several actions, including inhibition of
ovulation (the primary action) and effects on
the cervical mucus glands, uterine tubes,
and endometrium that decrease the
likelihood of fertilization and implantation.
Progestinonly agents do not always inhibit
ovulation and instead act through the other
mechanisms listed. The mechanisms of
action of postcoital contraceptives are not
well understood. When administered before
the LH surge, they inhibit ovulation. They
also affect cervical mucus, tubal function,
and the endometrial lining.
The low-dose combined oral and
progestinonly contraceptives cause
significant breakthrough bleeding, especially
during the first few months of therapy. Other
toxicities of the hormonal contraceptives
include nausea, breast tenderness,
headache, skin pigmentation, and
depression. Preparations containing older,
more androgenic progestins can cause
weight gain, acne, and hirsutism. The high
dose of estrogen in estrogencontaining
postcoital contraceptives is associated with
significant nausea.

2. Other clinical uses and beneficial effects:

Combination hormonal contraceptives are
used in young women with primary
hypogonadism to prevent estrogen
deficiency. Combinations of hormonal
contraceptives and progestins are used to
treat acne, hirsutism, dysmenorrhea, and
endometriosis. Users of combination
hormonal contraceptives have reduced risks
of ovarian cysts, ovarian and endometrial
cancer, benign breast disease, and pelvic
inflammatory disease as well as a lower
incidence of ectopic pregnancy, iron
deficiency anemia, and rheumatoid arthritis.

3. Toxicity:
The incidence of dose-dependent toxicity
has fallen since the introduction of the low-
dose combined oral contraceptives.

a. Thromboembolism:

The major toxic effects of the combined

hormonal contraceptives relate to the action
of the estrogenic component on blood
coagulation. There is a well-documented
increase in the risk of thromboembolic
events (myocardial infarction, stroke, deep
vein thrombosis, pulmonary embolism) in
older women, smokers, women with a
personal or family history of such problems,
and women with genetic defects that affect
the production or function of clotting factors.
PHARMACOLOGY
ANTIESTROGENS & ANTIPROGESTINS
A)Selective Estrogen Receptor Modulators
Selective estrogen receptor modulators (SERMs)
are mixed estrogen agonists that have estrogen
agonist effects in some tissues and act as partial
agonists or antagonists of estrogen in other
tissues. This may be due to recruitment of
different regulatory proteins and/or estrogen
receptor (ER) dimers (eg, ERα-ERα, ERα-ERβ,
ERβ-ERβ)
1. Tamoxifen:
Tamoxifen is an SERM that is effective in the
treatment of hormone-responsive breast
cancer, where it acts as an antagonist to
prevent receptor activation by endogenous
estrogens. Prophylactic use of tamoxifen
reduces the incidence of breast cancer in
women who are at very high risk. As an agonist
of endometrial receptors, tamoxifen promotes
endometrial hyperplasia and increases the risk
of endometrial cancer. The drug also causes hot
flushes (an antagonist effect) and increases the
risk of venous thrombosis (an agonist effect).
Tamoxifen has more agonist than antagonist
action on bone and thus prevents osteoporosis
in postmenopausal women. Toremifene is
structurally related to tamoxifen and has similar
properties, indications, and toxicitylective
Estrogen Receptor Modulators Selective
estrogen receptor modulators (SERMs) are
mixed estrogen agonists that have estrogen
agonist effects in some tissues and act as partial
agonists or antagonists of estrogen in other
tissues. This may be due to recruitment of
different regulatory proteins and/or estrogen
receptor (ER) dimers (eg, ERα-ERα, ERα-ERβ,
ERβ-ERβ)
2. Raloxifene:
Raloxifene, approved for prevention and
treatment of osteoporosis in postmenopausal
women, has a partial agonist effect on bone.
Like tamoxifen, raloxifene has antagonist effects
in breast tissue and reduces the incidence of
breast cancer in women who are at very high
risk. Unlike tamoxifen, the drug has no
estrogenic effects on endometrial tissue.
Adverse effects include hot flushes (an
antagonist effect) and an increased risk of
venous thrombosis (an agonist effect).
Bazedoxifene, a newer SERM, is approved for
treatment of menopausal symptoms and
prophylaxis of postmenopausal osteoporosis in
combination with conjugated estrogens.
3. Clomiphene:
Clomiphene is a partial agonist at estrogen
receptors. It is used to induce ovulation in
anovulatory women who wish to become
pregnant. By selectively blocking estrogen
receptors in the pituitary, clomiphene reduces
negative feedback and increases FSH and LH
output. The increase in gonadotropins
stimulates ovulation.
B)Pure Estrogen Receptor Antagonists
Fulvestrant is a pure estrogen receptor
antagonist (in all tissues). It is used in the
treatment of women with breast cancer
resistant to tamoxifen.
C)Synthesis Inhibitors
1. Aromatase inhibitors—Anastrozole and
related compounds (eg, letrozole) are
nonsteroidal competitive inhibitors of
aromatase, the enzyme required for the last
step in estrogen synthesis. Exemestane is an
irreversible aromatase inhibitor. These drugs
are used in the treatment of breast cancer.
2. Danazol—Danazol inhibits several
cytochrome P450 enzymes involved in gonadal
steroid synthesis and is a weak partial agonist of
progestin, androgen, and glucocorticoid
receptors. The drug is sometimes used in the
treatment of endometriosis and fibrocystic
disease of the breast.
D)Gonadotropin-Releasing Hormone Analogs
and Antagonists
PHARMACOLOGY
The continuous administration of gonadotropin-
releasing horm one (GnRH) agonists (eg,
leuprolide) suppresses gonadotropin secretion
and thereby inhibits ovarian production of
estrogens and progesterone.
The GnRH agonists are used in combination
with other agents in controlled ovarian
hyperstimulation and are also used for
treatment of precocious puberty in children and
short-term (<6 mo) treatment of endometriosis
and uterine fibroids in women. Treatment
beyond 6 mo in premenopausal women can
result in decreased bone density. The GnRH
receptor antagonists ganirelix and cetrorelix are
used for controlled ovarian hyperstimulation.
E)Antiprogestins
Mifepristone (RU 486) is an orally active steroid
antagonist of progesterone and glucocorticoids
(Chapter 39). Its major use is as an abortifacient
in early pregnancy (up to 49 days after the last
menstrual period). The combination of
mifepristone and the prostaglandin E analog
misoprostol achieves a complete abortion in
over 95% of early pregnancies. The most
common complication is failure to induce a
complete abortion. Side effects, which are
primarily due to the misoprostol, include
nausea, vomiting, and diarrhea plus the
cramping and bleeding associated with passing
the pregnancy. Rarely, patients who used
mifepristone and misoprostol for medical
abortion have experienced serious infection,
sepsis, and even death due to unusual infection
(eg, Clostridium sordellii).
ANDROGENS
Testosterone and related androgens are
produced in the testis, the adrenal, and, to a
small extent, the ovary. Testosterone is
synthesized from progesterone and
dehydroepiandrosterone (DHEA). In the plasma,
testosterone is partly bound to sex hormone-
binding globulin (SHBG), a transport protein.
The hormone is converted in several organs (eg,
prostate) to dihydrotestosterone (DHT), which is
the active hormone in those tissues. Because of
rapid hepatic metabolism, testosterone given
orally has little effect. It may be given by
injection in the form of long-acting esters or
transdermal patch. Orally active variants are
also available.
Many androgens have been synthesized in an
effort to increase the anabolic effect (see
Effects, discussed later) without increasing
androgenic action. Oxandrolone and stanozolol
are examples of drugs that, in laboratory
testing, have an increased ratio ofanabolic-
androgenic action. However, all the so-called
anabolic steroids have full androgenic agonist
effects when used in humans.
A. Mechanism of Action:
Like other steroid hormones, androgens enter
cells and bind to cytosolic receptors. The
hormone-receptor complex enters the nucleus
and modulates the expression of target genes.
B. Effects:
Testosterone is necessary for normal
development of the male fetus and infant and is
responsible for the major changes in the male at
puberty (growth of penis, larynx, and skeleton;
development of facial, pubic, and axillary hair;
darkening of skin; enlargement of muscle mass).
After puberty, testosterone acts to maintain
secondary sex characteristics, fertility, and
libido. It also acts on hair cells to cause male-
pattern baldness. The major effect of
androgenic hormones, in addition to
development and maintenance of normal male
characteristics, is an anabolic action that
involves increased muscle size and strength and
increased red blood cell production. Excretion
of urea nitrogen is reduced, and nitrogen
balance becomes more positive. Testosterone
also helps maintain normal bone density.
C. Clinical Use:
The primary clinical use of the androgens is for
replacement therapy in hypogonadism.
Androgens have also been used to stimulate red
blood cell production in certain anemias and to
promote weight gain in patients with wasting
syndromes (eg, AIDS patients). The anabolic
effects have been exploited illicitly by athletes
to increase muscle bulk and strength and
perhaps enhance athletic performance.
D. Toxicity:
Use of androgens by females results in
virilization (hirsutism, enlarged clitoris,
PHARMACOLOGY

deepened voice) and menstrual irregularity. In testosterone. This can be effectively

women who are pregnant with a female fetus,
exogenous androgens can cause virilization of
the fetus’s external genitalia. Paradoxically,
excessive doses in men can result in
feminization (gynecomastia, testicular
shrinkage, infertility) as a result of feedback
inhibition of the pituitary and conversion of the
exogenous androgens to estrogens. In both
sexes, high doses of anabolic steroids can cause
cholestatic jaundice, elevation of liver enzyme
levels, and possibly hepatocellular carcinoma.
ANTIANDROGENS
Reduction of androgen effects is an important
mode of therapy for both benign and malignant
prostate disease, precocious puberty, hair loss,
and hirsutism. Drugs are available that act at
different sites in the androgen pathway.
A. Receptor Inhibitors:
Flutamide and related drugs (eg, bicalutamide,
nilutamide, and enzalutamide) are nonsteroidal
competitive antagonists of androgen receptors.
These drugs are used to decrease the action of
endogenous androgens in patients with
prostate carcinoma. Spironolactone, a drug
used principally as a potassium-sparing diuretic,
also inhibits androgen receptors and is used in
the treatment of hirsutism in women.
B. 5`-Reductase Inhibitors:
Testosterone is converted to DHT by the
enzyme 5α-reductase. Some tissues, most
notably prostate cells and hair follicles, depend
on DHT rather than testosterone for androgenic
stimulation. This enzyme is inhibited by
finasteride, a drug used to treat benign
prostatic hyperplasia and, at a lower dose, to
prevent hair loss in men. Because the drug does
not interfere with the action of testosterone, it
is less likely than other antiandrogens to cause
impotence, infertility, and loss of libido.
Dutasteride is a newer 5α-reductase inhibitor
with a much longer half-life than that of
finasteride.
accomplished with longacting depot
preparations of leuprolide or similar
gonadotropin-releasing hormone (GnRH)
agonists. These analogs are used in prostatic
carcinoma. During the first week of therapy, an
androgen receptor antagonist (eg, flutamide) is
added to prevent the tumor flare that can
result from the surge in testosterone synthesis
caused by the initial agonistic action of the
GnRH agonist. Within several weeks,
testosterone production falls to low levels. The
GnRH receptor antagonists abarelix and
degarelix are approved for advanced prostate
cancer.
D. Combined Hormonal Contraceptives:
Combined hormonal contraceptives are used in
women with androgeninduced hirsutism. The
estrogen in the contraceptive acts in the liver to
increase the production of sex hormone-
binding globulin, which in turn reduces the
concentration of the free androgen in the blood
that is causing the male-pattern hair growth
characteristic of hirsutism.
E. Inhibitors of Steroid Synthesis:
Ketoconazole, an antifungal drug, inhibits
gonadal and adrenal steroid synthesis. The drug
has been used to suppress adrenal steroid
synthesis in patients with steroid-responsive
metastatic prostate cancer.

C. Gonadotropin-Releasing Hormone Analogs

and Antagonists:
Suppression of gonadotropin secretion,
especially LH, reduces the production of
PHARMACOLOGY