Biosynthesis of Oxytocin
Oxytocin is a cyclic nona peptide that differs from
vasopressin by only two amino acids. It is synthesized as a
larger precursor molecule in cell bodies of the
paraventricular nucleus, and to a lesser extent, the
supraoptic nucleus in the hypothalamus.
The precursor is rapidly converted by proteolysis to the
active hormone and its neurophysin, packaged into
secretory granules as an oxytocin-neurophysin complex,
and secreted from nerve endings that terminate primarily
in the posterior pituitary gland (neurohypophysis).
• Oxytocin (OT) – from paraventricular nucleus
Target = smooth muscle in uterus and breast
Effect = contraction of muscle (labor, milk ejection,
sexual arousal – “cuddle” hormone.)
Regulation = hormonal changes during pregnancy,
• Clinical summary:
• Oxytocin is used to induce labor or to augment its
progression. After delivery, oxytocin also can be used to
increase uterine tone and diminish postpartum hemorrhage.
• In contrast, the oxytocin receptor antagonist, atosiban, can
be used to suppress uterine contractions in the setting of
premature labor; its precise role relative to other drugs is still
• Stimuli for oxytocin secretion include sensory stimuli arising
from dilation of the cervix and vagina and from suckling at
• Increases in circulating oxytocin in women in labor are
difficult to detect, partly because of the pulsatile nature of
oxytocin secretion and partly because of the activity of
• Nevertheless, increased oxytocin in maternal circulation is
detected in the second stage of labor, likely triggered by
sustained distension of the uterine cervix and vagina.
• Estradiol stimulates oxytocin secretion, whereas the ovarian
polypeptide relaxin inhibits release. The inhibitory effect of
relaxin appears to be the net result of a direct stimulatory
effect on oxytocin-producing cells and an inhibitory action
mediated indirectly by endogenous opioids.
• Physiological Roles of Oxytocin
Uterus. The human uterus has a very low level of motor
activity during the first two trimesters of pregnancy.
• During the third trimester, spontaneous motor activity
increases progressively until the sharp rise that constitutes
the initiation of labor. Oxytocin stimulates the frequency and
force of uterine contractions.
• Uterine responsiveness to oxytocin roughly parallels this
increase in spontaneous activity and is highly dependent on
estrogen, which increases the expression of the oxytocin
• An eightfold increase in uterine sensitivity to oxytocin occurs
in the last half of pregnancy, mostly in the last 9 weeks,
accompanied by a thirtyfold increase in oxytocin receptor
number between early pregnancy and early labor
The finding that the oxytocin antagonist atosiban (TRACTOCILE)
is effective in suppressing preterm labor further supports the
physiological importance of oxytocin in this setting.
• Breast. Oxytocin plays an important physiological role in milk
ejection. Stimulation of the breast through suckling or
mechanical manipulation induces oxytocin secretion, causing
contraction of the myoepithelium that surrounds alveolar
channels in the mammary gland. This action forces milk from
the alveolar channels into large collecting sinuses, where it is
available to the suckling infant.
Mechanism of Action
Oxytocin acts via specific G protein-coupled receptors closely
related to the V1a and V2 vasopressin receptors. In the human
myometrium, these receptors couple to Gq and G11, activating
the PLCb-IP3-Ca2+ pathway and enhancing activation of
voltage-sensitive Ca2+ channels. Oxytocin also increases local
prostaglandin production, which further stimulates uterine
• Clinical Use of Oxytocin
Induction of Labor. Uterine-stimulating agents are used most
frequently to induce or augment labor in selected pregnant
• Indications for induction of labor include situations in which
the risk of continued pregnancy to the mother or fetus is
considered to be greater than the risks of delivery or of
• Such circumstances include premature rupture of the
membranes, isoimmunization, fetal growth restriction, and
uteroplacental insufficiency (as in diabetes, preeclampsia, or
• Oxytocin (PITOCIN, SYNTOCINON) is the drug of choice for
labor induction. It is administered by intravenous infusion of a
diluted solution (typically 10 mIU/mL), preferably by means of
an infusion pump.
• Augmentation of Labor. Because the resulting uterine
hyperstimulation often is too forceful and sustained to be
compatible with the safety of the mother and fetus, oxytocin
generally should not be used to augment labor that is
• To augment hypotonic contractions in dysfunctional labor, it
rarely is necessary to exceed an infusion rate of 10
mIU/minute, and doses of >20 mIU/minute rarely are
effective when lower concentrations fail.
• Third Stage of Labor and Puerperium. Postpartum
hemorrhage is a significant problem in developed nations and
is of even greater importance in underdeveloped countries.
After delivery of the fetus or after therapeutic abortion, a firm,
contracted uterus greatly reduces the incidence and extent of
hemorrhage. Oxytocin (10 IU/minute intramuscularly) often is
given immediately after delivery to help maintain uterine
contractions and tone.
• Oxytocin Challenge Test. In patients whose pregnancy holds
increased risk for maternal or fetal complications (e.g.,
maternal diabetes mellitus or hypertension), an oxytocin
challenge test can be used to assess fetal well-being.
• Oxytocin is infused intravenously, initially at a rate of 0.5
mIU/minute; this rate is increased slowly until 3 uterine
contractions occur in 10 minutes.
• Oxytocin-Receptor Antagonists
Peptide analogs that competitively inhibit the interaction of
oxytocin with its membrane receptor have been developed,
and one such antagonist, atosiban, has been introduced in a
number of countries for the treatment of preterm labor.
• In clinical trials, atosiban decreased the frequency of uterine
contractions and increased the number of women who
remained undelivered, with at least comparable efficacy to b
adrenergic agonists but with a lower incidence of side effects
• Oxytocin is a peptide hormone of the posterior pituitary gland. It
stimulates the contractions of the pregnant uterus, which becomes
much more sensitive to it at term. Patients with posterior pituitary
disease(diabetes insipidus) can, however, go into labour normally.
• Oxytocin is structurally close to vasopressin and it is no surprise that it
also has antidiuretic activity. Serious water intoxication can occur with
prolonged i.v. infusions, especially where accompanied by large
volumes of fluid.
• The association of oxytocin with neonatal jaundice appears to be
due to increased erythrocyte fragility causing haemolysis. Oxytocin
has been supplanted by the Methylergometrine (Methergin®), as the
prime treatment of postpartum haemorrhage.
• Oxytocin is reflexly released from the pituitary following
suckling (also by manual stimulation of the nipple) and causes
almost immediate contraction of the myoepithelium of the
Oxytocin is used i.v. in the induction of labour. It produces,
almost immediately, rhythmic contractions with relaxation
between, i.e. it mimics normal uterine activity.
The decision to use oxytocin requires special skill. It has a t1/2 of
6 min and is given by i.v. infusion using a pump; it must be
closely supervised; the dose is adjusted by the results;
overdose can cause uterine tetany and even rupture.
Atosiban is a modified form of oxytocin that inhibits the action of this
hormone on the uterus, leading to a cessation of contractions. It is
used i.v. as a tocolytic to halt premature labor.
Barusiban is three to four times more potent antagonist than
atosiban with higher affinity and selectivity for the oxytocin receptor
• ADRENOCORTICOTROPIC HORMONE;
Adrenocorticotropic hormone (ACTH, also called
corticotropin) and the steroid hormone products of the
adrenal cortex are considered together because the major
physiological and pharmacological effects of ACTH result from
its action to increase the circulating levels of adrenocortical
• Synthetic derivatives of ACTH are used principally in the
diagnostic assessment of adrenocortical function. Because all
known therapeutic effects of ACTH can be achieved with
corticosteroids, synthetic steroid hormones generally are
used therapeutically instead of ACTH.
• Corticosteroids and their biologically active synthetic
derivatives differ in their metabolic (glucocorticoid) and
electrolyte-regulating (mineralocorticoid) activities. These
agents are employed at physiological doses for replacement
therapy when endogenous production is impaired.
• ACTH is synthesized as part of a larger precursor protein, pro-
opiomelanocortin (POMC), and is liberated from the
precursor through proteolytic cleavage at dibasic residues by
the enzyme prohormone convertase 1 .
• Impaired processing of POMC due to a mutation in
prohormone convertase 1 has been implicated in the
pathogenesis of a human disorder that presents with adrenal
insufficiency, childhood obesity, hypogonadotropic
hypogonadism, and diabetes.
• A number of other biologically important peptides, including
endorphins, lipotropins, and the melanocyte-stimulating
hormones (MSH), also are produced from the same POMC
• The actions of ACTH and the other melanocortins liberated
from POMC are mediated by their specific interactions with
five melanocortin receptor (MCR) subtypes comprising a
distinct subfamily of G protein-coupled receptors
• Actions on the Adrenal Cortex. Acting via MC2R, ACTH
stimulates the adrenal cortex to secrete glucocorticoids,
mineralocorticoids, and the androgen precursor
dehydroepiandrosterone (DHEA) that can be converted
peripherally into more potent androgens.
• The adrenal cortex histologically and functionally can be
separated into three zones that produce different steroid
products under different regulatory influences.
• The outer zona glomerulosa secretes the mineralocorticoid
aldosterone, the middle zona fasciculata secretes the
glucocorticoid cortisol, and the inner zona reticularis secretes
DHEA and its sulfated derivative.
• In the absence of the anterior pituitary, the inner zones of the
cortex atrophy, and the production of glucocorticoids and
adrenal androgens is markedly impaired.
Adrenal (suprarenal) glands
• Each is really two endocrine glands
– Adrenal cortex (outer)
– Adrenal medulla (inner)
• Unrelated chemicals but all help with extreme situations
• Persistently elevated levels of ACTH, due either to repeated
administration of large doses of ACTH or to excessive
endogenous production, induce hyperplasia and hypertrophy
of the inner zones of the adrenal cortex, with overproduction
of cortisol and adrenal androgens.
• Adrenal hyperplasia is most marked in congenital disorders of
steroidogenesis, in which ACTH levels are continuously
elevated as a secondary response to impaired cortisol
• Mechanism of Action. ACTH stimulates the synthesis and
release of adrenocortical hormones. As specific mechanisms
for steroid hormone secretion have not been defined and
since steroids do not accumulate appreciably in the gland, it is
believed that the actions of ACTH to increase steroid
hormone production are mediated predominantly at the level
of de novo biosynthesis.
• Extra-Adrenal Effects of ACTH. In large doses, ACTH causes a
number of metabolic changes in adrenalectomized animals,
including ketosis, lipolysis, hypoglycemia (immediately after
treatment), and resistance to insulin (later after treatment).
• Because of the large doses of ACTH required, the
physiological significance of these extra-adrenal effects is
questionable. ACTH also improves learning in experimental
animals; this latter effect appears to be non-endocrine and
mediated via distinct receptors in the central nervous system.
• Regulation of ACTH Secretion. Hypothalamic-Pituitary-
Adrenal Axis. The rate of glucocorticoid secretion is
determined by fluctuations in the release of ACTH by the
pituitary corticotropes. These corticotropes, in turn, are
regulated by corticotropin-releasing hormone (CRH), a
peptide hormone released by CRH neurons of the endocrine
• Central Nervous System. The central nervous system
integrates a number of positive and negative influences on
ACTH secretion that are conveyed by several
• These signals converge on the CRH neurons, which are
clustered largely in the parvocellular region of the
paraventricular hypothalamic nucleus and make axonal
connections to the median eminence of the hypothalamus.
• Arginine Vasopressin. Arginine vasopressin (AVP) also acts as
a secretagogue for corticotropes, significantly potentiating
the effects of CRH. Like CRH, AVP is produced in the
parvocellular neurons of the paraventricular nucleus and
secreted into the pituitary plexus from the median eminence.
• Negative Feedback of Glucocorticoids. Glucocorticoids inhibit
ACTH secretion via direct and indirect actions on CRH neurons
to decrease CRH mRNA levels and CRH release and via direct
effects on corticotropes.
• The Stress Response. Stress overcomes negative feedback
regulation of the HPA axis, leading to a marked rise in
corticosteroid production. Examples of stress signals include
injury, hemorrhage, severe infection, major surgery,
hypoglycemia, cold, pain, and fear.
• Assays for ACTH. Initially, ACTH levels were assessed by
bioassays that measured induced steroid production or the
depletion of adrenal ascorbic acid.
• Radioimmunoassays that subsequently were developed to
quantitate ACTH levels in individual patients were not always
reproducible and did not clearly differentiate between low
and normal levels of ACTH.
• Immunochemiluminescent assays that use two separate
antibodies directed at distinct epitopes on the ACTH molecule
now are widely available.
• Therapeutic Uses and Diagnostic Applications of ACTH.
There are anecdotal reports that selected conditions respond
better to ACTH than to corticosteroids (e.g., multiple
sclerosis), and some clinicians continue to advocate therapy
• Despite this, ACTH currently has only limited utility as a
therapeutic agent. Therapy with ACTH is less predictable and
less convenient than therapy with corticosteroids
• Testing the Integrity of the HPA Axis. The major clinical use
of ACTH is in testing the integrity of the HPA axis. Other tests
used to assess the HPA axis include the insulin tolerance test
and the metyrapone test. Cosyntropin (CORTROSYN,
SYNACTHEN) is a synthetic peptide that corresponds to
residues 1 to 24 of human ACTH.
• CRH Stimulation Test. Ovine CRH (corticorelin [ACTHREL])
and human CRH are available for diagnostic testing of the
• In patients with documented ACTH-dependent
hypercorticism, CRH testing may help differentiate between
a pituitary source (i.e., Cushing's disease) and an ectopic
source of ACTH.
• At the recommended dose, CRH generally is well tolerated,
although flushing may occur, particularly if the dose is
administered as a bolus.
• Patients with Cushing's disease respond to CRH with either
a normal or an exaggerated increase in ACTH, whereas
ACTH levels do not increase in patients with ectopic
sources of ACTH.
• In this test, an inferior petrosal/peripheral ratio of >2.5
supports a pituitary source of ACTH. When performed by a
skilled neuroradiologist, this procedure increases diagnostic
accuracy with a tolerable risk of complications from the
catheterization procedure .
Absorption and Fate. ACTH is readily absorbed from
parenteral sites. The hormone rapidly disappears from the
circulation after intravenous administration; in humans, the
half-life in plasma is about 15 minutes, primarily due to rapid
Toxicity of ACTH. Aside from rare hypersensitivity reactions,
the toxicity of ACTH is primarily attributable to the increased
secretion of corticosteroids. Cosyntropin generally is less
antigenic than native ACTH; thus cosyntropin is the preferred
agent for clinical use.
• Adrenal cortex
– Secretes lipid-based steroid hormones, called
“corticosteroids” – “cortico” as in “cortex”
• MINERALOCORTICOIDS-Aldosterone is the main one
• GLUCOCORTICOIDS-Cortisol (hydrocortisone) is the main
Adrenal medulla:Secretes epinephrine& norepinephrine
Aldosterone (main mineral corticoid)Secreted by adrenal
cortex in response to a decline in either blood volume or
blood pressure (e.g. severe hemorrhage)
– Is terminal hormone in renin-angiotensin mechanism
• Prompts distal and collecting tubules in kidney to reabsorb
more sodium:-Water passively follows
-Blood volume thus increases
Cortisol, the most important glucocorticoid
Glucocorticoid receptors are found in the cells of most vertebrate tissues)
• It is essential for life
• Helps the body deal with stressful situations within minutes
– Physical: trauma, surgery, exercise
– Psychological: anxiety, depression, crowding
– Physiological: fasting, hypoglycemia, fever, infection
• Regulates or supports a variety of important cardiovascular,
metabolic, immunologic, and homeostatic functions
including water balance
People with adrenal insufficiency: these stresses can cause
hypotension, shock and death: must give glucocorticoids,
eg for surgery or if have infection, etc.
• Keeps blood glucose levels high enough to support
– Forces other body cells to switch to fats and amino acids as
• Catabolic: break down protein
• Redirects circulating lymphocytes to lymphoid and
peripheral tissues where pathogens usually are
• In large quantities, depresses immune and inflammatory
– Used therapeutically
– Responsible for some of its side effects
Hormonal stimulation of glucocorticoids
HPA axis (hypothalamic/pituitary/adrenal axis)
• With stress, hypothalamus sends CRH to anterior pituitary
• Pituitary secretes ACTH
• ACTH goes to adrenal cortex where stimulates
– Sympathetic nervous system can also stimulate it
• Adrenal cortex also secretes DHEA
– Converted in peripheral tissues to testosterone and estrogen (also
– Unclear function in relation to stress
Cortex – 80-90%
Derived from mesoderm
Produce over 2 dozen steroid
hormones essential to life
Zona glomerulosa – outer zone
Produces mineralcorticoids – affect Na+ & K+
Aldosterone – 95%
• Acts on kidney tubules
• Causes resorption of Na+ which also increases
resorption of Cl-, HCO3
- & H2O
– adrenocortical steroids
Introduction The adrenal cortex synthesizes two classes of
steroids: the corticosteroids (glucocorticoids and
mineralocorticoids), which have 21 carbon atoms, and the
androgens, which have 19.
The actions of corticosteroids historically were described as
glucocorticoid (carbohydrate metabolism-regulating) and
mineralocorticoid (electrolyte balance-regulating), reflecting
their preferential activities. In humans, cortisol
(hydrocortisone) is the main glucocorticoid and aldosterone is
the main mineralocorticoid
Although the adrenal cortex is an important source of androgen
precursors in women, patients with adrenal insufficiency can
be restored to normal life expectancy by replacement therapy
with glucocorticoids and mineralocorticoids. Nevertheless,
some recent studies have shown that addition of DHEA to the
standard replacement regimen in women with adrenal
insufficiency improved subjective well-being and sexuality
• Physiological Functions and Pharmacological Effects
Physiological Actions. The effects of corticosteroids are
numerous and widespread, and include alterations in
carbohydrate, protein, and lipid metabolism; maintenance of
fluid and electrolyte balance; and preservation of normal
function of the cardiovascular system, the immune system,
the kidney, skeletal muscle, the endocrine system, and the
In addition, corticosteroids endow the organism with the
capacity to resist such stressful circumstances as noxious
stimuli and environmental changes.
The actions of corticosteroids are interrelated to those of other
hormones. For example, in the absence of lipolytic hormones,
cortisol has virtually no effect on the rate of lipolysis by
adipocytes. Likewise, in the absence of glucocorticoids,
epinephrine and norepinephrine have only minor effects on
• Corticosteroids are grouped according to their relative
potencies in Na+ retention, effects on carbohydrate
metabolism (i.e., hepatic deposition of glycogen and
gluconeogenesis), and antiinflammatory effects.
• In general, potencies of steroids as judged by their ability to
sustain life in adrenalectomized animals closely parallel those
determined for Na+ retention, while potencies based on
effects on glucose metabolism closely parallel those for
• The effects on Na+ retention and the carbohydrate/
antiinflammatory actions are not closely related and reflect
selective actions at distinct receptors.
• Some steroids that are classified predominantly as
glucocorticoids (e.g., cortisol) also possess modest but
significant mineralocorticoid activity and thus may affect fluid
and electrolyte handling in the clinical setting.
• General Mechanisms for Corticosteroid Effects.
Corticosteroids interact with specific receptor proteins in
target tissues to regulate the expression of corticosteroid-
responsive genes, thereby changing the levels and array of
proteins synthesized by the various target tissues .
• As a consequence of the time required to modulate gene
expression and protein synthesis, most effects of
corticosteroids are not immediate but become apparent after
• The receptors for corticosteroids are members of the nuclear
receptor family of transcription factors that transduce the
effects of a diverse array of small, hydrophobic ligands,
including the steroid hormones, thyroid hormone, vitamin D,
• These receptors share two highly conserved domains: a
region of approximately 70 amino acids forming two zinc-
binding domains, called zinc fingers.
• Glucocorticoid Receptor. The GR resides predominantly in the
cytoplasm in an inactive form until it binds glucocorticoids .
• Steroid binding results in receptor activation and
translocation to the nucleus. The inactive GR is complexed
with other proteins, including heat-shock protein (HSP)
• Regulation of Gene Expression by Glucocorticoids. After
ligand binding, the GR dissociates from its associated proteins
and translocates to the nucleus. There, it interacts with
specific DNA sequences within the regulatory regions of
• The short DNA sequences that are recognized by the
activated GR are called glucocorticoid responsive elements
(GREs) and provide specificity to the induction of gene
transcription by glucocorticoids.90, a member of the heat-
shock family of stress-induced protein.
• The recognition that the metabolic effects of glucocorticoids
generally are mediated by transcriptional activation, while the
antiinflammatory effects largely are mediated by
transrepression, suggests that selective GR ligands may
maintain the antiinflammatory actions while lessening the
metabolic side effects.
• Regulation of Gene Expression by Mineralocorticoids. Like
the GR, MR also is a ligand-activated transcription factor and
binds to a very similar, if not identical, hormone-responsive
• Although its actions have been studied in less detail than the
GR, the basic principles of action appear to be similar; in
particular, the MR also associates with HSP90 and activates
the transcription of discrete sets of genes within target
• Aldosterone exerts its effects on Na+ and K+ homeostasis
primarily via its actions on the principal cells of the distal
renal tubules and collecting ducts, while the effects on H+
secretion largely are exerted in the intercalated cells.
• Receptor-Independent Mechanism for Corticosteroid
Specificity. The availability of cloned genes encoding the GR
and MR led to the surprising finding that aldosterone (a
classic mineralocorticoid) and cortisol (generally viewed as
predominantly glucocorticoid) binds the MR with equal
• Carbohydrate and Protein Metabolism. Corticosteroids
profoundly affect carbohydrate and protein metabolism.
Teleologically, these effects of glucocorticoids on intermediary
metabolism can be viewed as protecting glucose-dependent
tissues (e.g., the brain and heart) from starvation. They
stimulate the liver to form glucose from amino acids and
glycerol and to store glucose as liver glycogen.
• The mechanisms by which glucocorticoids inhibit glucose
utilization in peripheral tissues are not fully understood.
• Glucocorticoids decrease glucose uptake in adipose tissue,
skin, fibroblasts, thymocytes, and polymorphonuclear
leukocytes; these effects are postulated to result from
translocation of the glucose transporters from the plasma
membrane to an intracellular location.
• These peripheral effects are associated with a number of
catabolic actions, including atrophy of lymphoid tissue,
decreased muscle mass, negative nitrogen balance, and
thinning of the skin.
• Lipid Metabolism. Two effects of corticosteroids on lipid
metabolism are firmly established. The first is the dramatic
redistribution of body fat that occurs in settings of
endogenous or pharmacologically induced hypercorticism,
such as Cushing's syndrome.
• Electrolyte and Water Balance. Aldosterone is by far the
most potent endogenous corticosteroid with respect to fluid
and electrolyte balance.
• Thus, electrolyte balance is relatively normal in patients with
adrenal insufficiency due to pituitary disease, despite the loss
of glucocorticoid production by the inner cortical zones.
• Mineralocorticoids act on the distal tubules and collecting
ducts of the kidney to enhance reabsorption of Na+ from the
tubular fluid; they also increase the urinary excretion of K+
• These actions on electrolyte transport, in the kidney and in
other tissues (e.g., colon, salivary glands, and sweat glands),
appear to account for the physiological and pharmacological
activities that are characteristic of mineralocorticoids.
• Thus, the primary features of hyperaldosteronism are positive
Na+ balance with consequent expansion of extracellular fluid
volume, normal or slight increases in plasma Na+
concentration, hypokalemia, and alkalosis.
• Mineralocorticoid deficiency, in contrast, leads to Na+
wasting and contraction of the extracellular fluid volume,
hyponatremia, hyperkalemia, and acidosis.
• Glucocorticoids also exert effects on fluid and electrolyte
balance, largely due to permissive effects on tubular function
and actions that maintain glomerular filtration rate.
• Glucocorticoids play a permissive role in the renal excretion
of free water; the ability to excrete a water challenge was
used at one time to diagnose adrenal insufficiency. In part,
the inability of patients with glucocorticoid deficiency to
excrete free water results from the increased secretion of
AVP, which stimulates water reabsorption in the kidney.
• Cardiovascular System. The most striking effects of
corticosteroids on the cardiovascular system result from
mineralocorticoid-induced changes in renal Na+ excretion, as
is evident in primary aldosteronism.
• The resultant hypertension can lead to a diverse group of
adverse effects on the cardiovascular system, including
increased atherosclerosis, cerebral hemorrhage, stroke, and
• The second major action of corticosteroids on the
cardiovascular system is to enhance vascular reactivity to
other vasoactive substances.
• Conversely, hypertension is seen in patients with excessive
glucocorticoid secretion, occurring in most patients with
Cushing's syndrome and in a subset of patients treated with
synthetic glucocorticoids (even those lacking any significant
Skeletal Muscle. Permissive concentrations of corticosteroids
are required for the normal function of skeletal muscle, and
diminished work capacity is a prominent sign of
In patients with Addison's disease, weakness and fatigue are
frequent symptoms that may reflect an inadequacy of the
circulatory system. Excessive amounts of either
glucocorticoids or mineralocorticoids also impair muscle
• Central Nervous System. Corticosteroids exert a number of
indirect effects on the CNS, through maintenance of blood
pressure, plasma glucose concentrations, and electrolyte
concentrations. Increasingly, direct effects of corticosteroids
on the CNS have been recognized, including effects on mood,
behavior, and brain excitability.
Patients with adrenal insufficiency exhibit a diverse array of
psychiatric manifestations, including apathy, depression, and
irritability; some patients are frankly psychotic.
Formed Elements of Blood. Glucocorticoids exert minor effects
on hemoglobin and erythrocyte content of blood, as
evidenced by the frequent occurrence of polycythemia in
Cushing's syndrome and of normochromic, normocytic
anemia in adrenal insufficiency.
More profound effects are seen in the setting of autoimmune
hemolytic anemia, in which the immunosuppressive effects of
glucocorticoids can diminish the self-destruction of
Antiinflammatory and Immunosuppressive Actions. In addition
to their effects on lymphocyte number, corticosteroids
profoundly alter the immune responses of lymphocytes
• These effects are an important facet of the antiinflammatory
and immunosuppressive actions of the glucocorticoids.
Glucocorticoids can prevent or suppress inflammation in
response to multiple inciting events, including radiant,
mechanical, chemical, infectious, and immunological stimuli.
• Stresses such as injury, infection, and disease result in the
increased production of cytokines, a network of signaling
molecules that integrate actions of macrophages/monocytes,
T lymphocytes, and B lymphocytes in mounting immune
• Among these cytokines, interleukin (IL)-1, IL-6, and tumor
necrosis factor-a (TNF-a) stimulate the HPA axis, with IL-1
having the broadest range of actions.
IL-1 stimulates the release of CRH by hypothalamic neurons,
interacts directly with the pituitary to increase the release of
ACTH, and may directly stimulate the adrenal gland to
• Absorption, Transport, Metabolism, and Excretion
Absorption. Hydrocortisone and numerous congeners,
including the synthetic analogs, are orally effective.
• Certain water-soluble esters of hydrocortisone and its
synthetic congeners are administered intravenously to
achieve high concentrations of drug rapidly in body fluids.
More prolonged effects are obtained by intramuscular
injection of suspensions of hydrocortisone, its esters, and
• Transport, Metabolism, and Excretion. After absorption, 90%
or more of cortisol in plasma is reversibly bound to protein
under normal circumstances. Only the fraction of
corticosteroid that is unbound can enter cells to mediate
Two plasma proteins account for almost all of the steroid-
binding capacity: corticosteroid-binding globulin (CBG; also
called transcortin), and albumin.
• All of the biologically active adrenocortical steroids and their
synthetic congeners have a double bond in the 4,5 position
and a ketone group at C 3.
• As a general rule, the metabolism of steroid hormones
involves sequential additions of oxygen or hydrogen atoms,
followed by conjugation to form water-soluble derivatives.
• Reduction of the 4,5 double bond occurs at both hepatic and
extrahepatic sites, yielding inactive compounds. Subsequent
reduction of the 3-ketone substituent to the 3-hydroxyl
derivative, forming tetrahydrocortisol, occurs only in the liver.
• Synthetic steroids with an 11-keto substituent, such as
cortisone and prednisone, must be enzymatically reduced to
the corresponding 11b-hydroxy derivative before they are
adrenocortical steroids synthetic analogues.
• Structure-Activity Relationships
Chemical modifications to the cortisol molecule have
generated derivatives with greater separations of
glucocorticoid and mineralocorticoid activity; for a number of
synthetic glucocorticoids, the effects on electrolytes are
minimal even at the highest doses used .
• In addition, these modifications have led to derivatives with
greater potencies and with longer durations of action.
• Changes in chemical structure may alter the specificity and/or
potency due to changes in affinity and intrinsic activity at
corticosteroid receptors, and alterations in absorption,
protein binding, rate of metabolic transformation, rate of
excretion, or membrane permeability
• The 17a-hydroxyl group on ring D is a substituent on cortisol
and on all of the currently used synthetic glucocorticoids.
While steroids without the 17a-hydroxyl group
(e.g., corticosterone) have appreciable glucocorticoid activity,
the 17a-hydroxyl group gives optimal potency.
Introduction of an additional double bond in the 1,2 position
of ring A, as in prednisolone or prednisone, selectively
increases glucocorticoid activity (approximately fourfold
compared to hydrocortisone), resulting in an enhanced
glucocorticoid/mineralocorticoid potency ratio. This
modification also results in compounds that are metabolized
more slowly than hydrocortisone.
Fluorination at the 9a position on ring B enhances both
glucocorticoid and mineralocorticoid activity, possibly related
to an electron-withdrawing effect on the nearby 11b-hydroxyl
group. It is used in mineralocorticoid replacement therapy
and has no appreciable glucocorticoid effect at usual daily
doses of 0.05 mg to 0.2 mg.
• Other Substitutions. 6a Substitution on ring B has somewhat
unpredictable effects. 6a-Methylcortisol has increased
glucocorticoid and mineralocorticoid activity, whereas 6a-
methylprednisolone has somewhat greater glucocorticoid
activity and somewhat less mineralocorticoid activity than
• A number of modifications convert the glucocorticoids to
more lipophilic molecules with enhanced topical/systemic
• Examples include the introduction of an acetonide between
hydroxyl groups at C 16 and C 17, esterification of the
hydroxyl group with valerate at C 17, esterification of hydroxyl
groups with propionate at C 17 and C 21, and substitution of
the hydroxyl group at C 21 with chlorine.
• Toxicity of Adrenocortical Steroids
Two categories of toxic effects result from the therapeutic use
of corticosteroids: those resulting from withdrawal of steroid
therapy and those resulting from continued use at
• The side effects from both categories are potentially life-
threatening and mandate a careful assessment of the risks
and benefits in each patient.
Withdrawal of Therapy. The most frequent problem in
steroid withdrawal is flare-up of the underlying disease for
which steroids were prescribed.
There are several other complications associated with steroid
withdrawal. The most severe complication of steroid
cessation, acute adrenal insufficiency, results from overly
rapid withdrawal of corticosteroids after prolonged therapy
has suppressed the HPA axis
• Continued Use of Supraphysiological Glucocorticoid Doses.
These include fluid and electrolyte abnormalities,
hypertension, hyperglycemia, increased susceptibility to
infection, osteoporosis, myopathy, behavioral disturbances,
cataracts, growth arrest, and the characteristic habitus of
steroid overdose, including fat redistribution, striae, and
Fluid and Electrolyte Handling. Alterations in fluid and
electrolyte handling can cause hypokalemic alkalosis, edema,
and hypertension, particularly in patients with primary
hyperaldosteronism secondary to an adrenal adenoma or in
patients treated with potent mineralocorticoids
Metabolic Changes. Hyperglycemia with glycosuria usually can
be managed with diet and/or insulin, and its occurrence
should not be a major factor in the decision to continue
corticosteroid therapy or to initiate therapy in diabetic
• Immune Responses. Because of their multiple effects to
inhibit the immune system and the inflammatory response,
glucocorticoid use is associated with an increased
susceptibility to infection and a risk for reactivation of latent
• Possible Risk of Peptic Ulcers. There is considerable debate
about the association between peptic ulcers and
glucocorticoid therapy. Most patients who develop
gastrointestinal bleeding while receiving corticosteroids also
received nonsteroidal antiinflammatory agents, which are
known to promote ulceration, such that the pathogenic role
of corticosteroids remains open to debate.
Myopathy. Myopathy, characterized by weakness of proximal
limb muscles, can occur in patients taking large doses of
corticosteroids and also is part of the clinical picture in
patients with endogenous Cushing's syndrome. It can be of
sufficient severity to impair ambulation and is an indication
for withdrawal of therapy.
• Behavioral Changes. Behavioral disturbances are common
after administration of corticosteroids and in patients who
have Cushing's syndrome secondary to endogenous
hypercorticism; these disturbances may take many forms,
including nervousness, insomnia, changes in mood or psyche,
and overt psychosis. Suicidal tendencies are not uncommon.
Cataracts. Cataracts are a well-established complication of
glucocorticoid therapy and are related to dosage and duration
of therapy. Patients on long-term glucocorticoid therapy at
doses of prednisone of 10 to 15 mg/day or greater should
receive periodic slit-lamp examinations to detect
glucocorticoid-induced posterior subcapsular cataracts.
Osteoporosis. A reasonable estimate is that 30% to 50% of all
patients who receive chronic glucocorticoid therapy
ultimately will develop osteoporotic fractures.
Glucocorticoids preferentially affect trabecular bone and the
cortical rim of the vertebral bodies; the ribs and vertebrae are
the most frequent sites of fracture.
• Glucocorticoids decrease bone density by multiple
mechanisms, including inhibition of gonadal steroid
hormones, diminished gastrointestinal absorption of Ca2+,
and inhibition of bone formation due to suppressive effects
on osteoblasts and stimulation of resorption due to effects on
osteoclasts mediated by changes in the production of
osteoprotegerin and RANK ligand. In addition, glucocorticoid
inhibition of intestinal Ca2+ uptake may lead to secondary
increases in parathyroid hormone, thereby increasing bone
Osteonecrosis. Osteonecrosis (also known as avascular or
aseptic necrosis) is a relatively common complication of
glucocorticoid therapy. The femoral head is affected most
frequently, but this process also may affect the humeral head
and distal femur. Joint pain and stiffness usually are the
earliest symptoms, and this diagnosis should be considered in
patients receiving glucocorticoids who abruptly develop hip,
shoulder, or knee pain.
• Regulation of Growth and Development. Growth retardation
in children can result from administration of relatively small
doses of glucocorticoids.
• Therapeutic Uses
With the exception of replacement therapy in deficiency
states, the use of glucocorticoids largely is empirical. Based
on extensive clinical experience, a number of therapeutic
principles can be proposed. Given the number and severity of
potential side effects, the decision to institute therapy with
glucocorticoids always requires a careful consideration of the
relative risks and benefits in each patient.
In an attempt to dissociate therapeutic effects from
undesirable side effects, various regimens of steroid
administration have been utilized. To diminish HPA axis
suppression, the intermediate-acting steroid preparations
(e.g., prednisone or prednisolone) should be given in the
morning as a single dose
• Replacement Therapy. Adrenal insufficiency can result from
structural or functional lesions of the adrenal cortex (primary
adrenal insufficiency or Addison's disease) or from structural or
functional lesions of the anterior pituitary or hypothalamus (2O).
• Acute Adrenal Insufficiency. This life-threatening disease is
characterized by gastrointestinal symptoms (nausea, vomiting, and
abdominal pain), dehydration, hyponatremia, hyperkalemia,
weakness, lethargy, and hypotension
The immediate management of patients with acute adrenal
insufficiency includes intravenous therapy with isotonic sodium
chloride solution supplemented with 5% glucose and
corticosteroids and appropriate therapy for precipitating causes
such as infection, trauma, or hemorrhage. Because cardiovascular
function often is reduced in the setting of adrenocortical
insufficiency, the patient should be monitored for evidence of
volume overload such as rising central venous pressure or
Chronic Adrenal Insufficiency. Patients with chronic adrenal
insufficiency present with many of the same manifestations
seen in adrenal crisis, but with lesser severity.
These patients require daily treatment with corticosteroids
Standard doses of glucocorticoids often must be adjusted
upward in patients who also are taking drugs that increase
their metabolic clearance (e.g., phenytoin, barbiturates, or
Dosage adjustments also are needed to compensate for the
stress of intercurrent illness, and proper patient education is
essential for the execution of these adjustments. All patients
with adrenal insufficiency should wear a medical alert
bracelet or tag that lists their diagnosis and carries
information about their steroid regimen.
Congenital Adrenal Hyperplasia. This term denotes a group
of genetic disorders in which the activity of one of the several
enzymes required for the biosynthesis of glucocorticoids is
The impaired production of cortisol and the consequent lack
of negative feedback inhibition lead to increased release of
In a subset of patients with classical CAH, the enzymatic
deficiency is sufficiently severe to compromise aldosterone
Such patients are unable to conserve Na+ normally and thus
are called "salt wasters." These patients can present with
cardiovascular collapse secondary to volume depletion.
Therapeutic Uses in Nonendocrine Diseases.
The dosage of glucocorticoids varies considerably depending
on the nature and severity of the underlying disorder.
Rheumatic Disorders. Glucocorticoids are used widely in the
treatment of a variety of rheumatic disorders and are a
mainstay in the treatment of the more serious inflammatory
rheumatic diseases, such as systemic lupus erythematosus,
and a variety of vasculitic disorders, such as polyarteritis
nodosa, Wegener's granulomatosis, Churg-Strauss syndrome,
and giant cell arteritis.
Renal Diseases. Patients with nephrotic syndrome secondary
to minimal change disease generally respond well to steroid
therapy, and glucocorticoids clearly are the first-line
treatment in both adults and children.
Allergic Disease. The onset of action of glucocorticoids in
allergic diseases is delayed, and patients with severe allergic
reactions such as anaphylaxis require immediate therapy with
epinephrine: for adults, 0.3 to 0.5 ml of a 1:1000 solution
intramuscularly or subcutaneously.
Bronchial Asthma and Other Pulmonary Conditions. They
sometimes are employed in chronic obstructive pulmonary
disease (COPD), particularly when there is some evidence of
reversible obstructive disease. Data supporting the efficacy of
corticosteroids are much more convincing for bronchial
asthma than for COPD.
In many patients, inhaled steroids (e.g., beclomethasone
dipropionate [VANCERIL], triamcinolone acetonide
[AZMACORT], fluticasone [FLOVENT], flunisolide [AEROBID],
Infectious Diseases. Although the use of immunosuppressive
glucocorticoids in infectious diseases may seem paradoxical,
there are a limited number of settings in which they are
indicated in the therapy of specific infectious pathogens.
One dramatic example of such beneficial effects is seen in
AIDS patients with Pneumocystis carinii pneumonia and
moderate to severe hypoxia; addition of glucocorticoids to
the antibiotic regimen increases oxygenation and lowers the
incidence of respiratory failure and mortality.
Ocular Diseases. Ocular pharmacology, including some
consideration of the use of glucocorticoids. Glucocorticoids
frequently are used to suppress inflammation in the eye and
can preserve sight when used properly.
Skin Diseases. Glucocorticoids are remarkably efficacious in
the treatment of a wide variety of inflammatory dermatoses.
As a result, a large number of different preparations and
concentrations of topical glucocorticoids of varying potencies
are available. A typical regimen for an eczematous eruption is
1% hydrocortisone ointment applied locally twice daily.
Gastrointestinal Diseases. Glucocorticoid therapy is indicated
in selected patients with inflammatory bowel disease (chronic
ulcerative colitis and Crohn's disease. Patients who fail to
respond to more conservative management (i.e., rest, diet,
and sulfasalazine) may benefit from glucocorticoids; steroids
are most useful for acute exacerbations.
Oral administration of budesonide in delayed-release capsules
(ENTOCORT, 9 mg/day)
Hepatic Diseases. Glucocorticoids clearly are of benefit in
autoimmune hepatitis, where as many as 80% of patients
show histological remission when treated with prednisone (40
to 60 mg daily initially, with tapering to a maintenance dose
of 7.5 to 10 mg daily after serum transaminase levels fall).
Malignancies. Glucocorticoids are used in the chemotherapy
of acute lymphocytic leukemia and lymphomas because of
their anti-lymphocytic effects. Most commonly,
glucocorticoids are one component of combination
chemotherapy administered under scheduled protocols.
Cerebral Edema. Corticosteroids are of value in the reduction
or prevention of cerebral edema associated with parasites
and neoplasms, especially those that are metastatic.
• INHIBITORS OF THE BIOSYNTHESIS AND ACTION OF
Five pharmacologic agents are useful inhibitors of
adrenocortical secretion. Mitotane (o,p'-DDD), an
adrenocorticolytic agent. The other inhibitors of steroid
hormone biosynthesis- metyrapone, aminoglutethimide,
ketoconazole, and trilostane.
• Metyrapone, aminoglutethimide, and ketoconazole inhibit
cytochrome P450 enzymes involved in adrenocorticosteroid
biosynthesis. Differential selectivity of these agents for the
different steroid hydroxylases provides some degree of
specificity to their actions.
• Trilostane is a competitive inhibitor of the conversion of
pregnenolone to progesterone, a reaction catalyzed by 3b-
hydroxysteroid dehydrogenase. In addition, agents that act as
glucocorticoid receptor antagonists (anti-glucocorticoids)
• Aminoglutethimide. Aminoglutethimide (a-ethyl-p-aminophenyl-
glutarimide; CYTADREN) primarily inhibits CYP11A1, which
catalyzes the initial and rate-limiting step in the biosynthesis of all
• As a result, the production of all classes of steroid hormones is
impaired. Aminoglutethimide also inhibits CYP11B1 and the
enzyme aromatase, which converts androgens to estrogens.
• Because of its actions to inhibit aromatase, aminoglutethimide
also has been evaluated as a therapeutic agent for the treatment
of hormonally responsive tumors such as prostate and breast
cancer, although more effective agents such as tamoxifen and the
aromatase inhibitors are preferred.
• ANTI-GLUCOCORTICOIDS :The progesterone receptor antagonist
mifepristone [RU-486; (11b-4-dimethylaminophenyl)-17b-hydroxy-
7a-(propyl-1-ynyl)estra-4,9-dien-3-one] has received considerable
attention because of its use as an antiprogestagen that can
terminate early pregnancy
• Metyrapone. Metyrapone (METOPIRONE) is a relatively
selective inhibitor of CYP11B1 (11b-hydroxylase), which
converts 11-deoxycortisol to cortisol in the terminal reaction
of the glucocorticoid biosynthetic pathway.
• Because of this inhibition, the biosynthesis of cortisol is
markedly impaired, and the levels of steroid precursors (e.g.,
11-deoxycortisol) are markedly increased.
• Metyrapone also is used to diagnose patients with Cushing's
syndrome who respond equivocally to the formal
dexamethasone suppression test. Those with pituitary-
dependent Cushing's syndrome exhibit a normal response,
whereas those patients with ectopic secretion of ACTH exhibit
no changes in ACTH or 11-deoxycortisol levels.
Therapeutically, metyrapone has been used to treat the
hypercorticism resulting from either adrenal neoplasms or
tumors producing ACTH ectopically.
Estrogens and Progestins
• Estrogens and progestins are hormones that produce
many physiological actions
• In women,
–Developmental effects (estrogens are largely
responsible for pubertal changes in girls and
secondary sexual characteristics)
–Neuroendocrine actions involved in: Control of
ovulation and the preparation of the reproductive
tract for fertilization and implantation
–Major Actions on: Minerals, Carbohydrates,
Proteins, and Lipid Metabolism
• In men, effects:
• Estrogens and progestins are endogenous hormones that
produce numerous physiological actions.
• In women, these include developmental effects,
neuroendocrine actions involved in the control of ovulation,
the cyclical preparation of the reproductive tract for
fertilization and implantation, and major actions on mineral,
carbohydrate, protein, and lipid metabolism.
• Estrogens also have important actions in males, including
effects on bone, spermatogenesis, and behavior.
• Estrogens also may be produced from androgens via
aromatase in the central nervous system (CNS) and other
tissues and exert local effects near their production site (e.g.,
in bone they affect bone mineral density).
• A group of steroid hormones that readily diffuse across the
• Inside the cell, they interact with estrogen receptors.
In boys, estrogen deficiency diminishes the pubertal growth
spurt and delays skeletal maturation and epiphyseal closure
so that linear growth continues into adulthood. Estrogen
deficiency in men leads to elevated gonadotropins,
macroorchidism, and increased testosterone levels and also
may affect carbohydrate and lipid metabolism and fertility
in some individuals
Estriol Estradiol Estrone
• Estrogen is produced primarily by developing follicles in
the ovaries, the corpus luteum, and the placenta
• Follicle-stimulating hormone (FSH) and luteinizing
hormone (LH) stimulate the production of estrogen in the
• Some estrogens are also produced in smaller amounts by
other tissues such as the liver, adrenal glands, and the
• The ovaries are the principal source of circulating estrogen
in premenopausal women, with estrodiol being the main
• In postmenopausal women, the principal circulating
estrogen estrone, which is synthesized from
dehydroepiandrosterone and secreted by the adrenals
• The most potent naturally occurring estrogen in humans for
both the Estrogen Receptor alpha- and beta-mediated
actions is 17beta-estradiol, followed by estrone and estriol
• Each estrogen contains a phenolic A ring with a hydroxyl
group at carbon 3 and a beta-OH or ketone in position 17 of
• The phenolic A ring is the principal structural feature
responsible for selective, high-affinity binding to both
• Synthesis of estrogen begins from the synthesis of
androstenedione from cholesterol
• Androstenedione crosses the basal membrane into
surrounding granulosa cells, where its converted to estrone
or estradiol wither immediately or through testosterone
• The conversion is catalyzed by aromatase
• The variety of steroidal estrogens derived from animal
sources, numerous nonsteroidal estrogens have been
• Many phenols are estrogenic, and estrogenic activity
has been identified in such diverse forms of life as
those found in ocean sediments. Estrogen-mimetic
compounds (flavonoids) are found in many plants,
including saw palmetto, and soybeans and other foods.
• During pregnancy, a large amount of estrogen is
synthesized by the fetoplacental unit—consisting of the
fetal adrenal zone, secreting androgen precursor, and
the placenta, which aromatizes it into estrogen. The
estriol synthesized by the fetoplacental unit is released
into the maternal circulation and excreted into the
In general, the hormone undergoes rapid hepatic
biotransformation, with a plasma half-life measured in
minutes.Estradiol is converted primarily by 17b-
hydroxysteroid dehydrogenase to estrone, which undergoes
conversion by 16a-hydroxylation and 17-keto reduction to
estriol, the major urinary metabolite.
A variety of sulfate and glucuronide conjugates also are
excreted in the urine.The 2- and 4-hydroxycatechols are
largely inactivated by catechol-O-methyl transferases
(COMTs).Half life range between 13-26 minutes .
Estrogens also undergo enterohepatic recirculation via (1)
sulfate and glucuronide conjugation in the liver, (2) biliary
secretion of the conjugates into the intestine, and (3)
hydrolysis in the gut (largely by bacterial enzymes) followed
Estrogen Receptors• Estrogens exert their effects by interaction with receptors that are
members of the super family of nuclear receptors
• The two estrogen receptor (ER) genes are located on separate
chromosomes: ESR1 encodes ER-alpha and ESR2 encodes ER-beta
• Both ERs are estrogen-dependent nuclear transcription factors that
have different tissue distributions and transcriptional regulatory
effects on target genes
• Both ERs are ligand-activated transcription factors that increase or
decrease the transcription of target genes
• After entering the cell by passive diffusion through the plasma
membrane, the hormone binds to an ER in the nucleus
• In the nucleus, the ER is present as an inactive monomer bound to
heat-shock proteins, and upon binding estrogen, a change in ER
confirmation dissociates the heat-shock proteins and causes receptor
dimerization, which increases the affinity and the rate of receptor
binding to DNA
• Estrogen and progesterone levels vary daily
– Changes are dependent on the pituitary gonadotropic
hormones FHS and LH
• On day 1 of an average 28-day cycle, secretions of FSH and
LH begin to increase
– This release is caused by a reduction in the blood levels
of estrogen and progesterone, which normally inhibit
• Estrogens are largely responsible for the changes that take place
– Synthetic estrogens can be used for therapy and conception
– The most common side effects of estrogen therapy are nausea
• Other side effects include uterine bleeding, vaginal discharge,
edema, thrombophlebitis, weight gain, and hypertension
• Estrogen therapy may also promote endometrial
carcinoma in postmenopausal women
– This risk may be cancelled out by administration of a
• Effect on oral tissues
• Changes in sex hormone levels are related to
– Gingivitis at puberty
– During pregnancy
– After menopause
• The increase in gingival inflammation may occur
even with a decrease in the amount of plaque
Anti-estrogens and SERMs
– Pure antagonists
– Clomiphene is for
treatment of infertility in
– Fulvestrant is used for the
treatment of breast
• Selective Estrogen Receptor
– Compounds with tissue-
– The goal of these drugs is
to produce beneficial
estrogenic actions in
certain tissues (ex. Brain,
bone, liver) during
– Tamoxifen, Raloxifen,
Tamoxifen is given orally, and peak plasma levels are reached
within 4 to 7 hours after treatment. This drug displays two
elimination phases with half-lives of 7 to 14 hours and 4 to 11
Due to the prolonged half-life, 3 to 4 weeks of treatment are
required to reach steady-state plasma levels. The parent drug
is converted largely to metabolites within 4 to 6 hours after
oral administration. Tamoxifen is metabolized in humans by
multiple hepatic CYPs, some of which it also induces
Raloxifene is adsorbed rapidly after oral administration and
has an absolute bioavailability of about 2%. The drug has a
half-life of about 28 hours and is eliminated primarily in the
feces after hepatic glucuronidation; it does not appear to
undergo significant biotransformation by CYPs.
Clomiphene is well absorbed following oral administration,
and the drug and its metabolites are eliminated primarily in
the feces and to a lesser extent in the urine.
The long plasma half-life (5 to 7 days) is due largely to plasma-
protein binding, enterohepatic circulation, and accumulation
in fatty tissues. Other active metabolites with long half-lives
also may be produced.
Fulvestrant is administered monthly by intramuscular depot
injections. Plasma concentrations reach maximal levels in 7
days and are maintained for a month. Numerous metabolites
are formed in vivo, possibly by pathways similar to
endogenous estrogen metabolism, but the drug is eliminated
primarily (90%) via the feces in humans.
• Progestins include the naturally occurring hormone
progesterone, 17-acetoxyprogesterone derivatives in the
pregnane series, 19-nortestosterone derivatives
(estranges), and norgestrel and related compounds in the
progesterone 17-acetoxyprogesterone 19-nortestosterone
The corpus luteum is the primary source of progesterone
during the normal female sexual cycle
– Progesterone promotes secretory changes in the
endometrium and prepares the uterus for implantation of
the fertilized ovum
• If implantation does not occur, progesterone secretion declines and
• If implantation takes place, the trophoblast secretes chorionic
gonadotropin, which sustains the corpus luteum, maintaining
progesterone and estrogen levels and preventing menstruation
• Progestins are used in a variety of dose forms
– Parenteral medroxyprogesterone (Depo-Provera) is
administered every 3 months as a contraceptive
– Progestin-only “minipills” are used orally
– A progestational agent can be administered as an
intrauterine device (IUD) or implant under the skin of the
Physcical Actions of Progesterone
• In the reproductive tract, progesterone decreases estrogen-
driven endometrial proliferation and leads to the
development of a secretory endometrium
• The abrupt decline in progesterone at the end of the cycle
is the main determinant of the onset of menstruation
• Progesterone is very important for the maintenance of
• It suppresses menstruation and uterine contractility
• The elimination half-life of progesterone is approximately 5
minutes, and the hormone is metabolized primarily in the
liver to hydroxylated metabolites and their sulfate and
glucuronide conjugates, which are eliminated in the urine.
The Progestin Receptor
•Unlike the ER receptor, which requires a phenolic ring for binding,
the PR favors a non-phenolic ring structure
•There is a single gene that encodes two isoforms of the
progesterone receptor (PR): PR-A and PR-B
•Since the ligand-binding domains of the two PR isoforms are
identical, there is no difference in ligand binding
•However, the biological activities of PR-A and PR-B are distinct
and depend on the target gene in question
•PR-B mediates the stimulatory activities of progesterone
•PR-A strongly inhibits this action of PR-B
•Upon binding progesterone, the heat-shock proteins dissociate,
and the receptors are phosphorylated and subsequently form
dimers (homo- and hetero-) that bind with high selectivity to
progesterone response elements located on target genes
• Anti-progestin, first discovered in 1981, is mifepristone,
used to terminate pregnancy
– In the presence of progesterone, mifepristone acts as a
competitive receptor antagonist for both progesterone
• When administered in the early stages of pregnancy,
mifepristone causes decidual breakdown by blocking
uterine progesterone receptors, which leads to detachment
of the blastocyst, decreasing hCG production
Therapeutic Uses and Prospects.
Mifepristone (MIFEPREX), in combination
with misoprostol or other prostaglandins ,
is available for the termination of early
Oral contraceptives are the most common dose forms of
hormonal contraceptives and consist of estrogens and
progestins in various combinations
– These are the most common birth control pills and are more
than 99% effective
• The combination type of oral contraceptive is taken for
21 days of each month
– The seven pills in the fourth week contain no active
• Seasonale is the newest in combination oral
– An extended cycle contraceptive
• The contraceptive vaginal ring is a new dose form that
introduces hormonal contraception into the body
• An injectable contraceptive is also available
• This type is the most frequently used in the United States,
which contain both an estrogen and a progestin
• The theoretical efficacy is 99.9%
• Ethinyl estradiol (a synthetic estrogen) and mestranol are
the estrogens most frequently used
• Levonorgestrel is the most common progestin used
• Currently, this type of contraceptives have lowered doses of
Forms of Combination Contraceptives
• The Pill
• The Patch
• Vaginal Ring
Estrogens are most commonly used to treat vasomotor
disturbances ("hot flashes") in postmenopausal women.
Other important benefits are amelioration of the effects of
urogenital atrophy, a decreased incidence of colon cancer,
and prevention of bone loss.
Estrogens have proven efficacy for prevention of bone
fractures at all sites in normal women, although when used
solely for this purpose they should not be considered first-line
because of possible untoward side effects including breast
cancer, stroke, and coronary heart disease (CHD).
• Pharmacologic Effects
• MECHANISM OF ACTION:The combinations of estrogens&
progestins exert their contraceptive effect largely through
selective inhibition of pituitary fxn hence inhibition of
• The combination agents also produce a change in the
cervical mucus, in the uterine endometrium, and in motility
and secretion in the uterine tubes, all of which decrease
the likelihood of conception and implantation.
• The continuous use of progestins alone does not always
inhibit ovulation. The other factors mentioned, therefore,
play a major role in the prevention of pregnancy when
these agents are used.
Estrogens tend to increase excitability in the brain, whereas
progesterone tends to decrease it. The thermogenic action of
progesterone and some of the synthetic progestins is also
thought to occur in the central nervous system.
• Combined contraceptives
Mechanism of Action
– Act by preventing ovulation
– Measurements of plasma hormone levels indicate that LH
and FSH levels are suppressed
– The mid-cycle surge of LH is absent
– Endogenous steroid levels are diminished
– Thus, ovulation does not occur
– The multiple actions of estrogens and progestins on the
hypothalamic-pituitary-ovarian axis during the menstrual
cycle and the efficacy of these agents all contribute to the
blockade of ovulation
Progestin-Only Contraceptives:Progesterone is rapidly
absorbed following administration by any route. Its half-life in
the plasma is approximately 5 minutes, and small amounts
are stored temporarily in body fat. It is almost completely
metabolized in one passage through the liver, and for that
reason it is quite ineffective when the usual formulation is
• They contain progestins only, termed “mini pills”
• Slightly less effective, with 99% efficacy
• Their effectiveness is thought to be due largely to a
thickening of cervical mucus, which decreases
sperm penetration and impairs implantation
Medroxyprogesterone acetate, 10–20 mg orally twice
weekly—or intramuscularly in doses of 100 mg/m2 every 1–2
weeks—will prevent menstruation, but it will not arrest
accelerated bone maturation in children with precocious
• Emergency Contraceptives :Multiple mechanisms are likely to
contribute to the efficacy of these agents, however, the exact
mechanism is unknown
• These mechanisms include:
– Ovulation is inhibited or delayed, alterations in endometrial
receptivity for implantation
– Interference with functions of the corpus luteum that maintain
– Production of a cervical mucus that decreases sperm penetration
– Alterations in tubular transport of sperm, egg, or embryo
– Effects on fertilization
• Emergency contraceptives do not interrupt pregnancy after
• The FDA has approved two preparations
• PLAN-B includes 2 doses of levonorgestrel separated by 12
• PREVEN is a 2 pill dose of a high-dose oral contraceptive
(levonorgestrel and ethinyl estradiol) separated by 12 hours
• The first dose of these drugs should be taken 72 hours after
Hormonal contraceptives are associated with a significant
increase in the frequency of dry sockets after
• Contraindications for use of oral contraceptives include
thromboembolitic disorders, significant dysfunction of
the liver, known or suspected carcinoma of the breast
or other estrogen-dependent neoplasm, and
undiagnosed genital bleeding
• Certain antibiotics have been said to reduce the
effectiveness of hormonal contraceptives
– They are thought to do so by indirectly suppressing the
intestinal flora and thus diminishing the availability of
hydrolytic enzymes to regenerate the parent steroid
– Consequently, plasma concentrations of steroids are said to
be abnormally low, and the steroid is cleared more rapidly
from the body than under normal circumstances
• Beneficial Effects of Oral Contraceptives:Treatment with
oral contraceptives has also been shown to be associated
with many benefits unrelated to contraception.
• These include a reduced risk of ovarian cysts, ovarian and
endometrial cancer, and benign breast disease. There is a
lower incidence of ectopic pregnancy. Iron deficiency and
rheumatoid arthritis are less common, and premenstrual
symptoms, dysmenorrhea, endometriosis, acne, and
hirsutism may be ameliorated with their use
• Estrogens enhance the coagulability of blood. Many
changes in factors influencing coagulation have been
reported, including increased circulating levels of factors II,
VII, IX, and X and decreased antithrombin III, partially as a
result of the hepatic effects
• MILD ADVERSE EFFECTS
• 1. Nausea, mastalgia, breakthrough bleeding, and edema are
related to the amount of estrogen in the preparation. These
effects can often be alleviated by a shift to a preparation
containing smaller amounts of estrogen or to agents containing
progestins with more androgenic effects.
• 2. Changes in serum proteins and other effects on endocrine
function must be taken into account when thyroid, adrenal, or
pituitary function is being evaluated. Increases in sedimentation
rate are thought to be due to increased levels of fibrinogen.
• 3. Headache is mild and often transient. However, migraine is
often made worse and has been reported to be associated with an
increased frequency of cerebrovascular accidents. When this
occurs or when migraine has its onset during therapy with these
agents, treatment should be discontinued.
• 4. Withdrawal bleeding sometimes fails to occur—most often with
combination preparations—and may cause confusion with regard
to pregnancy. If this is disturbing to the patient, a different
preparation may be tried or other methods of contraception used
• MODERATE ADVERSE EFFECTS
• Any of the following may require discontinuance of oral contraceptives:
1. Breakthrough bleeding is the most common problem in using
progestational agents alone for contraception..
2. Weight gain is more common with the combination agents
containing androgen-like progestins..
3. Increased skin pigmentation may occur, especially in dark-skinned
4. Acne may be exacerbated by agents containing androgen-like
progestins , whereas agents containing large amounts of estrogen
usually cause marked improvement in acne.
5. Hirsutism may also be aggravated by the "19-nortestosterone"
derivatives, and combinations containing nonandrogenic
progestins are preferred in these patients.
6. Ureteral dilation similar to that observed in pregnancy has been
reported, and bacteriuria is more frequent.
7. Vaginal infections are more common and more difficult to treat in
patients who are receiving oral contraceptives.
8. Amenorrhea occurs in some patients.
• SEVERE ADVERSE EFFECTS
• Vascular Disorders,VENOUS THROMBOEMBOLIC DISEASE
• MYOCARDIAL INFARCTION, CEREBROVASCULAR DISEASE,
• Many cases of cholestatic jaundice have been reported in
patients taking progestin-containing drugs.
• Other: These include alopecia, erythema multiforme,
erythema nodosum, and other skin disorders.
• Contraindications & Cautions: thrombophlebitis,
thromboembolic phenomena, and cardiovascular and
• They should not be used to treat vaginal bleeding when the
cause is unknown. They should be avoided in patients with
known or suspected tumors of the breast or other
Other Agents that Affect Sex Hormone
• Clomiphene has the ability to induce ovulation in
some anovulatory women
• Leuprolide is used in the management of
endometriosis and to treat infertility
• Tamoxifen is indicated in the palliative treatment
of breast cancer in postmenopausal women
• Danazol is used to treat endometriosis and
fibrocystic disease in women
• Aromatase inhibitors reduce almost the entire
amount of estrogen made in the bodies of
(1) Development of the male sexual apparatus and secondary sex
(2) Necessary for normal spermatogenesis
(3) Increasing protein anabolism
(4) Promoting growth of blood cells in bone marrow, especially for red
blood cells (EPO )
(5)Other effects: immune regulation, antiinflammation effects,CVS
(1) Replacement therapy in men: hypogonadism
(2)Female disorders: dysfunctional uterine bleeding, endometriosis,
advanced breast and ovarian cancers
(3) Anemia: aplastic or other anemia (largely replaced by recombinant
(4) Infirmity: anabolic steroids
(5) Others: male contraception, osteoporosis(either alone or in
conjunction with estrogens. Replaced by bisphosphonates) etc.
A. Androgens and antiandrogens
Male Sex Hormones
• Testosterone, the main androgen, has both androgenic and
• Androgens are responsible for the development of
secondary male sex characteristics
• Androgens are used illicitly for muscle mass gain
– Androgenic steroids are schedule III controlled
substances because of their abuse
• Side effects of androgenic steroids include nausea,
cholestatic jaundice, hepatocellular neoplasms, increased
serum cholesterol, habituation, and depression and
- due largely to their masculinizing actions and are most noticeable in
women and prepubertal children.
(1) Sex dysfunction:
• virilisation in female(hirsutism, acne, amenorrhea, clitoral enlargement, and
deepening of the voice, testosterone> 200–300 mg of per month)
• increased libido in male
(2) Hepatic toxicity
• occurs early in the course of treatment, the degree is proportionate to the dose.
bilirubin levels ↑
1. pregnant women, infants and young children (somatotropin is more
appropriate to produce a growth spurt).
2. male patients with carcinoma of the prostate or breast.
3. renal or cardiac disease predisposed to edema
• Caution: Several cases of hepatocellular carcinoma have been
reported in patients with aplastic anemia treated with androgen
anabolic therapy. Erythropoietin and colony-stimulating factors should
be used instead.
A. Androgens and antiandrogens
Synthesis of Testosterone. In men, testosterone is the
principal secreted androgen. The Leydig cells synthesize the
majority of testosterone .
In women, testosterone also is probably the principal
androgen and is synthesized both in the corpus luteum and
the adrenal cortex by similar pathways. The testosterone
precursors androstenedione and dehydroepiandrosterone are
weak androgens that can be converted peripherally to
Metabolism of Testosterone to Active and Inactive
Compounds. Testosterone has many different effects in
tissues. One of the mechanisms by which the varied effects
are mediated is the metabolism of testosterone to two other
active steroids, dihydrotestosterone and estradiol.
Physiological and Pharmacological Effects of Androgens
The biological effects of testosterone can be considered by
the receptor it activates and by the tissues in which effects
occur at various stages of life.
Testosterone can act as an androgen either directly, by
binding to the androgen receptor, or indirectly by conversion
to dihydrotestosterone, which binds to the androgen receptor
even more avidly than testosterone. Testosterone also can act
as an estrogen by conversion to estradiol, which binds to the
Other kinds of androgen receptor mutations may explain why
prostate cancer that is treated by androgen deprivation
eventually becomes androgen-independent.
Men tend to have a better sense of spatial relations than do
women and to exhibit behavior that differs in some ways from
that of women, including being more aggressive.
Adulthood. The serum testosterone concentration and the
characteristics of the adult male are largely maintained during
early adulthood and midlife. One change during this time is
the gradual development of male pattern baldness, beginning
with recession of hair at the temples and the vertex.
Two changes that can occur in the prostate gland during
adulthood are of much greater medical significance. One is
the gradual development of benign prostatic hyperplasia,
which occurs to a variable degree in almost all men,
sometimes obstructing urine outflow by compressing the
urethra as it passes through the prostate
The consequences of androgen deficiency depend on the
stage of life during which the deficiency first occurs and on
the degree of the deficiency.
During Fetal Development. Testosterone deficiency in a male
fetus during the first trimester in utero causes incomplete
sexual differentiation. Deficiency of LH secretion because of
pituitary or hypothalamic disease does not result in
testosterone deficiency during the first trimester, presumably
because Leydig cell secretion of testosterone at that time is
regulated by placental hCG.
Before Completion of Puberty. When a boy can secrete
testosterone normally in utero but loses the ability to do so
before the anticipated age of puberty, the result is failure to
After Completion of Puberty. When testosterone secretion
becomes impaired after puberty is completed, regression of
the pubertal effects of testosterone depends on both the
degree and the duration of testosterone deficiency.
In Women. Loss of androgen secretion in women results in a
decrease in sexual hair, but not for many years. Androgens
may have other important effects in women, and the loss of
androgens (especially with the severe loss of ovarian and
adrenal androgens that occurs in panhypopituitarism) would
result in the loss of these effects.
Therapeutic Androgen Preparations
The need for a creative approach to pharmacotherapy with
androgens arises from the fact that ingestion of testosterone
is not an effective means of replacing testosterone deficiency.
Testosterone Esters. Esterifying a fatty acid to the 17a
hydroxyl group of testosterone creates a compound that is
even more lipophilic than testosterone itself. When an ester,
such as testosterone enanthate (heptanoate).
Alkylated Androgens. Consequently, 17a-alkylated androgens
are androgenic when administered orally; however, they are
less androgenic than testosterone itself, and they cause
hepatotoxicity , whereas native testosterone does not.
Transdermal Delivery Systems. Recent attempts to avoid the
first-pass inactivation of testosterone by the liver have
employed novel delivery systems; chemicals called excipients
are used to facilitate the absorption of native testosterone
across the skin in a controlled fashion.
Therapeutic Uses of Androgens
Male Hypogonadism. The best-established indication for
administration of androgens is for the treatment of male
hypogonadism (testosterone deficiency in men). Any of the
transdermal testosterone preparations or testosterone esters
described above can be used to treat testosterone deficiency
Side Effects. All androgens suppress gonadotropin secretion
when taken in high doses and thereby suppress endogenous
testicular function. This results in diminished fertility.
If administration continues for many years, testicular size may
diminish. Testosterone and sperm production usually return
to normal within a few months of discontinuation but may
take longer. doses of androgens also cause erythrocytosis.
• Catabolic and Wasting States. Testosterone, because of its anabolic
effects, has been used in attempts to ameliorate catabolic and
muscle-wasting states, but this has not been generally effective.
Treatment of men with AIDS-related muscle wasting and subnormal
serum testosterone concerations their muscle mass and strength
Angioedema. The disease is caused by hereditary impairment of C1-
esterase inhibitor or acquired development of antibodies against it.
The 17a-alkylated androgens, such as stanozolol and danazol,
stimulate the hepatic synthesis of the esterase inhibitor. In women,
virilization is a potential side effect. In children, virilization and
premature epiphyseal closure prevent chronic use of androgens for
prophylaxis, for to treat acute episodes.
Blood Dyscrasias. Androgens such as danazol still are used
occasionally as adjunctive treatment for hemolytic anemia and
idiopathic thrombocytopenic purpura that are refractory to first-line
Because some effects of androgens are undesirable, at least
under certain circumstances, agents have been developed
specifically to inhibit androgen synthesis or effects. Other
drugs, originally developed for different purposes, have been
accidentally found to be anti-androgens and now are used
intentionally for this indication.
Inhibitors of Testosterone Secretion. Both agonists and
antagonists of the GnRH receptor are used to reduce
testosterone secretion. Analogs of GnRH effectively inhibit
testosterone secretion by inhibiting LH secretion. GnRH
"superactive" analogs, given repeatedly, down-regulate the
GnRH receptor and are available for treatment of prostate
• Inhibitors of Androgen Action :These drugs inhibit the
binding of androgens to the androgen receptor or inhibit 5a-
Androgen Receptor Antagonists. Flutamide, Bicalutamide,
and Nilutamide. These relatively potent androgen receptor
antagonists have limited efficacy when used alone because
the increased LH secretion stimulates higher serum
• They are used primarily in conjunction with a GnRH analog in
the treatment of metastatic prostate cancer. In this situation,
they block the action of adrenal androgens, which are not
inhibited by GnRH analogs.
• Spironolactone. Spironolactone (ALDACTONE)is an inhibitor
of aldosterone that also is a weak antagonist at the androgen
receptor and a weak inhibitor of testosterone synthesis,
apparently inhibiting CYP17.
• When used to treat fluid retention or hypertension in
men, gynecomastia is a common side effect.
• 5a-Reductase Inhibitors. Finasteride (PROSCAR) is an
antagonist of 5a-reductase, especially type II;
dutasteride (AVODART) is an antagonist of types I and
II; both drugs block the conversion of testosterone to
dihydrotestosterone, especially in the male external
• Cyproterone Acetate. Cyproterone acetate is a
progestin and a weak anti-androgen by virtue of
binding to the androgen receptor. It is moderately
effective in reducing hirsutism alone or in combination
with an oral contraceptive
• Antigonizing androgen receptor;
inhibiting hypothalamus-pituitary axis:
LH↓, FSH↓, testosterone↓
• Used for treatment of prostatic cancer,
severe acne and hersulism, and
A. Androgens and antiandrogens
1. Antiandrogenic action gynecomastia (breast growth),
galactorrhea (milk outflow), and erectile dysfunction.
2.Liver toxicity high dose (200–300 mg/day).
3. Increased risk of DVT ( in combination with ethinylestradiol )
4. Other reactions
•Depressive mood changes
•Suppression of adrenal function and reduced response to ACTH
•Osteoporosis- suppresses production of estrogen due to its
B. Drugs used to treat erectile dysfunction
• Acts by inhibiting cGMP-specific
PDE5, an enzyme that delay
degradation of cGMP, which
regulates blood flow in the penis
• The prime treatment for erectile
dysfunction in all settings,
(1) Sexual dysfunction
(2) Pulmonary arterial hypertension (PAH)
• relaxes the arterial wall, leading to decreased pulmonary
arterial resistance and pressure→workload of the right
ventricle ↓, symptoms of right-sided heart failure↑
• acts selectively in the lungs and penis without inducing
vasodilation in other areas of the body →PDE-5 is
primarily distributed within the arterial wall smooth
muscle of the lungs and penis
(3) Altitude sickness
• prevention and treatment of high-altitude pulmonary
edema associated with altitude sickness -such as that
suffered by mountain climbers.
B. Drugs used to treat erectile dysfunction
B. Drugs used to treat erectile dysfunction
1.Headache, flushing, dyspepsia, nasal congestion and impaired
vision, including photophobia and blurred (lead to vision impairment
in rare cases) - the most common adverse effects
• 2. Priapism, severe hypotension, myocardial infarction (heart
attack), ventricular arrhythmias, stroke, increased intraocular
pressure, and sudden hearing loss -rare but serious
1. Administration of nitric oxide donors
2. Recent stroke or heart attack, or in men for whom sexual
intercourse is inadvisable due to cardiovascular risk factors
3. Hypotension (low blood pressure)
4. Severe hepatic/ renal function impairment
5. Hereditary degenerative retinal disorders (including genetic
disorders of retinal phosphodiesterases)