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Endocrinology - Introduction
u Pituitary hormones
– control numerous physiological functions
» direct effects of pituitary hormones
» indirect effects mediated by target gland hormones
– controlled by hypothalamus and feedback from target gland hormones
– the pituitary comprises a posterior and anterior lobe
u Posterior Pituitary
– oxytocin, vasopressin
u Anterior Pituitary
– glycoprotein hormones (LH, FSH, TSH)
– somatomammotropic hormones (GH, prolactin)
– ACTH-related hormones (ACTH, MSH, etc.)
Posterior Pituitary Hormones
u synthesized in hypothalamus, transported to the posterior pituitary and released directly into the
systemic circulation.
u secretion controlled directly by the activity of hypothalamic neurons.
u Oxytocin
– responsible for the milk ‘let-down’ reflex
release regulated through a neuroendocrine reflex arc initiated by suckling
– stimulation of uterine contraction (principal therapeutic use)
u Vasopressin
– controls water reabsorption in the kidney
– release regulated by hypothalamic neurons that sense plasma osmolarity.
Anterior Pituitary Hormones
u glycoprotein, somatomammotropic, ACTH-related hormones
– release controlled by hypothalamic hormones released into portal circulation
– release is episodic, and influenced by diurnal rhythms & developmetal factors
» regulate function of target gland/tissue;
» regulated by target gland hormones (-ve feedback mechanism)
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Posterior Pituitary Hormones
u Vasopressin & Oxytocin
– are nine amino acid peptide hormones
– are synthesized in magnocellular neurons of the paraventricular and supraoptic hypothalamic nuclei.
– are encoded by separate, closely-linked genes that were likely derived from a common ancestral gene.
– are synthesized from larger precursor hormones that also encode a neurophysin, the function of which
is critical to processing of AVP and oxytocin
– are released by exocytosis from axon terminals in the posterior pituitary to reach the systemic
circulation
Vasopressin (Antidiuretic Hormone)
Overview of Physiology & Pharmacology
u physiological role in regulating fluid volume and plasma osmolality, primarily through its ability to
enhance fluid reabsorption from the distal tubule and cortical collecting duct of the kidney.
u disorders of the vasopressinergic system include:
– neurogenic diabetes insipidus
» treated primarily with desmopressin (dDAVP), a synthetic AVP
– nephrogenic diabetes insipidus
» treated with thiazide diuretics
– Syndrome of Inappropriate ADH secretion (SIADH)
» often asymptomatic, but may be treated with demeclocycline, which interferes with AVP action
Vasopressin Physiology
u release of AVP from posterior pituitary is:
– increased with increases in plasma osmolality
– inhibited by increases in blood volume and blood pressure
– enhanced by AngII and inhibited by ANP
– inhibited by alcohol
u AVP has cardiovascular, pituitary and renal effects
– via V1a receptors, coupled to phospholipases, it causes vasoconstriction
– via V1b receptors, also coupled to phospholipases, it enhances ACTH release (synergistically with
CRF)
– via V2 receptors, positively coupled to adenylyl cyclase, it stimulates water reabsorption from the renal
distal tubule and collecting duct and causes excretion of a sparse, concentrated urine
Vasopressin Pharmacology
Vasopressin and analogs
u vasopressin
– short half-life (~20 min); V1 side effects (vasoconstriction)
– not orally available; parenteral and intranasal
u lypressin (pig vasopressin)
– less potent antidiuretic than dDAVP; less pressor activity than AVP
– intranasal
u desmopressin (dDAVP)
– high antidiuretic to pressor activity; long-lasting
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– intranasal
– treatment of choice for neurogenic DI
u vasopressin antagonist (OPC-31260)
Others:
u enhance AVP action
– chlorpropamide (an oral sulfonylurea)
– carbamazepine (related to tricyclic antidepressants)
– clofibrate (a fibric acid derivative)
» can enhance effects of low levels of AVP but have a number of side effects related to their
primary actions
u inhibit AVP action
– demeclocycline and lithium interfere with AVP actions at the kidney
» lithium treatment in particular can lead to nephrogenic DI
Therapeutic Uses of Vasopressin Drugs
u Neurogenic DI
– characterized by AVP levels that are undetectable (or abnormally low given the prevailing plasma
osmolality).
» result is persistent polyuria which can lead to hypertonic dehydration; water balance is maintained
through increased water intake
– desmopressin (dDAVP) is the treatment of choice
» can be treated with lypressin if dDAVP is too potent
» chlorpropamide, carbamazepine and clofibrate may be used if dDAVP and lypressin are not welltolerated
u Nephrogenic DI
– treated with thiazide diuretics; vasopressin analogs are not useful in this indication
u SIADH
– inability to suppress AVP secretion when plasma osmolality decreases
» patients are often asymptomatic
» can lead to hypervolemic hyponatremia and hypoosmolality
» treated by restricting fluid intake and the renal effects of AVP inhibited using demeclocycline (or
Li+, if tetracyclines are contraindicated).
u Nocturnal Enuresis
– bed-wetting can be treated with intranasal desmopressin
u von Willebrand’s Disease
– V2-mediated increase in vWF and factor VIII by desmopressin
u Gastrointestinal Bleeding
– V1-mediated decrease in splanchnic blood flow to decrease blood flow and pressure in splanchnic and
portal vasculature
Side Effects of Vasopressin Drugs
The vasopressin drugs are well-tolerated and have minimal side effects at therapeutic doses
u V1-mediated side effects - smooth muscle
– potential for coronary artery vasoconstriction
u V2-mediated side effects - renal
– water intoxication (esp. do not use in primary polydipsia)
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– increased water load (a problem in individuals with heart problems)
u interactions with other drugs
– chlorpropamide, clofibrate, carbamazepine, NSAIDS enhance effects
– lithium, demeclocycline inhibit effects
Oxytocin
Overview of Physiology & Pharmacology
– endocrine component of neuroendocrine reflex arc that mediates suckling-induced lactation (the milk
‘let-down’ reflex).
» may be used to assist with breast-feeding
– a potent stimulant of uterine contraction and may be involved physiologically in parturition
» oxytocin is used pharmacologically to induce or augment labor or to reduce post-partum bleeding
u other uterine motility agents
– stimulants of utrine motility include prostaglandins and ergot alkaloids
– inhibitors are b2-adrenergic agonists, MgSO4, nifedipine & alcohol
Oxytocin Physiology
u Release of oxytocin is triggered by:
– stimulus of the nipples, as in suckling
– distention of the cervix and vagina during delivery
u Effects of oxytocin are
– mediated by G-protein-coupled receptor, acting via phospholipase C and increases in intracellular
calcium to stimulate smooth muscle contraction (activation of MLCK)
» stimulates contraction of breast myoepithelial cells
» increases force & frequency of uterine contractions
» constricts umbilical arteries and veins
Oxytocin Pharmacology
u General
– available for parenteral administration (usually iv)
– short half-life (5 to 10 minutes)
– metabolized by the liver and kidney
– also can be administered intranasally (less efficient)
u Therapeutic uses
– to induce labor
– to augment dysfunctional labor
» care must be taken to avoid damage to fetus or mother caused by excessively frequent or forceful
contractions or by compromised placental gas/nutrient exchange (umbilical vessel constriction)
– to control post partum bleeding
– to assist with breast feeding
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Uterine Motility Agents - Stimulation
Prostaglandins (E and F type)
– are involved in cervical ‘ripening’ (increasing the compliance of the cervix) and the initiation of labor.
PGE2 (dinoprostone)
» PGF2a (carboprost) and its 15-methyl derivative (carboprost tromethamine)
» A PGE1 analog (misoprostol)
– are used therapeutically for
» midtrimester abortions (dinoprostone, carboprost; intramuscular or intravaginally)
» to evacuate the uterus (as above)
» to induce cervical ripening (dinoprostone; locally applied gel)
» to treat postpartum hemorrhage (carboprost tromethamine)
– side effects are nausea, vomiting & diarrhea
Uterine Motility Agents - Stimulation
Ergot Alkaloids
– Ergot is a poison from a fungus found in edible grains; ergot alkaloids such as ergonovine and
methylergonovine have potent uterotonic effects (via a1-adrenoceptor and 5-HT receptors)
» orally available with a half-life of 0.5 to 2 hours
– Ergot alkaloids should not be given prior to delivery. They are used therapeutically
» to control postpartum bleeding
» to promote uterine involution when delayed
– Side effects include:
» vasoconstriction and hypertension
» can interfere with lactation
Uterine Motility Agents - Inhibition
u b2-adrenoceptor Agonists
– inhibit uterine smooth muscle contractility
– the preferred treatment for premature labor
» ritodrine and terbutaline
– side effects of b2 stimulation include:
» peripheral vasodilation and reflex tachycardia; edema; hyperglycemia
u MgSO4 and nifedipine
– both inhibit uterine contraction by interfering with calcium entry
» Mg2+ interferes with many processes dependent on calcium entry (e.g. neuromuscular
transmission); nifedipine causes peripheral vasodilation
u Ethanol
– decreases oxytocin release at high doses; only used in emergency
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Recapitulation
u Vasopressinergic Agents
– Synthetic vasopressin analogs: vasopressin, lypressin, desmopressin
– Vasopressin potentiators: chlorpropamide, carbamazepine, clofibrate
– Vasopressin inhibitor: demeclocycline, lithium carbonate
u Oxytocin & Uterine Muscle Motility
– Synthetic oxytocin analogs: oxytocin
– Stimulation of uterine motility:
» Prostaglandins: dinoprostone, carboprost, misoprostol
» Ergot Alkaloids: ergonovine, methylergonovine
– Inhibition of uterine motility (tocolytic agents):
» b2-adrenergic agonists: ritodrine, terbutaline
» calcium channel inhibitors: MgSO4, nifedipine
» miscellaneous: ethanol
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Prolactin and Growth Hormone
Prolactin
u Overview of Physiology & Pharmacology
– prolactin is a somatomammotropic pituitary hormone that is required for initiation and support of
lactation
– hyperprolactinemia is the most common hypothalamo-pituitary disorder
» it is a leading cause of infertility and is treated with bromocriptine
Prolactin Physiology
u synthesis and release
– PRL is a 199 amino acid peptide hormone secreted by pituitary lactotropes
» PRL is homologous to GH (a somatomammotropic hormone)
– unique features of the control of PRL secretion
» under primarily negative regulation by the hypothalamus
u dopamine inhibits PRL secretion
» not subject to long-loop feedback as it does not stimulate a target organ hormone
– otherwise PRL release is :
» episodic and peaks during sleep
» enhanced by a number of hypothalamic releasing factors (TRH, VIP, etc.)
» enhanced during pregnancy, probably by E2
u E2 stimulates lactotrope hyperplasia, PRL expression and secretion
» stimulated by suckling via a neuroendocrine reflex arc
u lactational hyperprolactinemia may contribute to postpartum anovulation and infertility
» enhanced by stress, exercise, sleep, hypoglycemia
u mechanism of action
– effects are mediated by the PRL receptor
» a member of the hematopoeitin receptor family
u mechanism of action of the PRL receptor is incompletely understood
u by analogy with GH, it may involve a tyrosine phosphorylation cascade
u physiological effects
– the breast is the primary target of PRL action
» PRL is required during pregnancy, together with other hormones, to prepare the breast for milk
production (e.g. stimulates expression of milk protein genes)
u E2 inhibits lactation during pregnancy, but lactation is initiated by PRL post partum after E2
levels decrease
– PRL receptors are widespread, but their function in other tissues is not well understood
– at high levels, PRL inhibits gonadotropin release from the pituitary
Prolactin Pharmacology
u Prolactin itself has no known therapeutic value
u To treat hyperprolactinemia
– hyperprolactinemia is associated with infertility
– bromocriptine is a dopamine agonist that inhibits PRL release
» orally available, semi-synthetic ergot alkaloid with a half-life of ~ 3h
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» longer-lasting dopamine agonists with fewer side effects may soon be available (e.g. cabergoline,
quinagolide)
» fertility is restored with bromocriptine
– side effects of bromocriptine
» nausea, dizziness, postural hypotension
» psychotic symptoms such as hallucinations and delusions have been reported
Growth Hormone Axis
u Overview of Physiology & Pharmacology
– GH is a somatomammotropic anterior pituitary hormone responsible for regulating growth
» GH deficiencies are associated with growth failure; GH excess causes gigantism and acromegaly
u It is controlled by GHRH & somatostatin from the hypothalamus and by IGF-1 and IGF-2 that
are produced in response to GH (negative feedback).
» effects of GH on target tissue are either direct or indirect (mediated by IGFs).
– Pharmacological agents that target this axis include
» synthetic GHRH stimulates GH release
» a somatostatin analog, octreotide inhibits GH release
» recombinant human GH (somatropin, somatrem) is used to replace GH in states of deficiency
» recombinant IGF-1 is used to treat GH insensitivity (Laron-type dwarfism).
GHRH Physiology
u synthesis and release
– a 40 or 44 amino acid peptide hormone from larger precursor
– biological activity is contained within the first 29 amino acids
– released from hypothalamic neurons into portal circulation in pulsatile fashion
» release enhanced by clonidine, exercise
u mechanism of action
– acts on pituitary somatotrope via G protein-coupled receptor to increase cAMP and [Ca2+]i and
thereby enhance GH release
» also increases somatostatin release from hypothalamus which, in turn, decreases release of GH
from pituitary (ultra-short loop feedback)
GHRH Pharmacology
u Synthetic human GHRH
– multiple forms have been tested (44, 40 and 29 amino acid forms)
» half-life ~ 7 min
» can be administered iv, sc or intranasally with different potencies (300:30:1)
an additional peptide (GHRP) has been identified and non-peptide orally active mimetics of GHRP are
being tested and may become important therapeutically.
u Uses of GHRH
– therapeutic - has been used experimentally to stimulate GH secretion in GH-deficient patients with
functional somatotropes
» use of pulsatile GHRH to mimic normal patterns
» continuous non-pulsatile delivery may also be effective (depot preparations)
– diagnostic - to test pituitary function in GH-deficient patients
» priming with repeated GHRH challenges may be necessary
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Somatostatin Physiology
u SS is a brain-gut peptide with a widespread distribution
u synthesis and release
– SS exists as a 14 and 28 amino acid peptide
» SS(14) is the more common form
» the two forms have slightly different potencies in different bioassays
– released from hypothalamic neurons into portal circulation in pulsatile fashion
» release of SS is enhanced by GH & IGF-1 which results in diminished GH and IGF-1 production
(-ve feedback inhibition)
» release inhibited by L-dopa, leading to increased GH levels (basis of provocative test)
– SS is also produced in the gut (pancreatic D cells, stomach, intestine)
» released when food is detected in the gut (especially protein and fat)
– SS is differentially distributed throughout the CNS
u mechanism of action and effects
– in general, somatostatin has inhibitory effects on target cells
u multiple somatostatin receptor subtypes (sst1-sst5) have been identified but those which mediate
specific effects of SS are not yet well-defined
» in pituitary somatotropes, GH release is inhibited by SS
u SS decreases adenylyl cyclase and cAMP
u SS also enhances K+ channels and inhibits Ca2+ channels
» in the gut, SS inhibits GI motility and secretions (endocrine and exocrine)
u inhibits insulin and VIP secretion
» in the CNS, somatostatin has inhibitory effects on central neurons
u SS enhances neuronal K+ channels and inhibits Ca2+ channels
u systemically administered SS (or analogs) have no known central effects
Somatostatin Pharmacology
u somatostatin
– not orally active, short half-life (<>
u octreotide
– octapeptide variant of somatostatin
» not orally active but much longer half-life (~ 2 h)
» ratio of GH to insulin suppression is increased ~ 45-fold
– therapeutic uses
» to treat acromegaly (excess GH secretion in adults)
u as an adjunct to surgery, which is rarely 100% effective
u causes decreased GH secretion and may shrink the adenoma
u bromocriptine is also effective in treatment of acromegaly (paradoxical)
» to treat carcinoid and pancreatic tumors (e.g. VIP-secreting)
u FDA approved for relief of symptoms (diarrhea, flushing)
u unlike adenomas, octreotide does not shrink these tumors
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Growth Hormone Physiology
u synthesis and release
– GH activity is predominantly due to a 191 amino acid, 22 kDa protein
» numerous additional forms of GH are also present
– GH release from pituitary somatotropes is:
» episodic and peaks during sleep
» high in children, peaks in puberty and falls to lower levels in adults
» enhanced by GHRH and inhibited by SS and IGF-1
» enhanced by a number of agents that are used in provocative clinical tests
u mechanism of action
– direct effects of GH are mediated by the GH receptor
» a member of the hematopoeitin receptor family
u it is closely associated with a tyrosine kinase activity
» extracellular domain can be cleaved to release a GH binding protein
» receptors are mutated in Laron-type dwarfs
u normal or even elevated levels of GH, but low levels of IGF-1
u GH has direct and indirect effects
u direct effects
– stimulation of IGF-1 and IGF-2
» ‘dual effector model of GH action’ to explain synergistic effects of GH and IGF
u in bone, GH stimulates differentiation of prechondrocytes so that they express IGF receptors
and secrete IGF-1. The IGF-1 then acts in a paracrine fashion to stimulate clonal expansion
and further differentiation
– metabolic effects that are opposite those of insulin
» increased lipolysis, glucose transport
» decreased insulin sensitivity
u this combination of anti-insulin actions can cause increased insulin secretion which, if
prolonged or severe, can lead to b cell “burn-out’ (a so-called ‘diabetogenic’ effect of GH)
u indirect effects
– indirect metabolic effects are insulin-like and are mediated by IGFs
Growth Hormone Pharmacology
u Recombinant human GH (somatropin, somatrem)
– the two forms are equipotent, but somatrem is somewhat more antigenic
» administered daily, either by sc or im injection
» half-life of ~20-30 min, peak of GH at 2-6 h and of IGF-1 at ~20 h
u Therapeutic uses of GH
– to replace GH in children with GH deficiency, gonadal dysgenesis or chronic renal insufficiency
» promotes substantial acceleration in growth in GH deficiency
» synergistic and/or permissive effects of other hormones must be considered
» early diagnosis is important; height normalization is best achieved before puberty
– other uses are controversial
» treatment of short children (constitutional growth delay)
» abused by athletes for its lipolytic and growth promoting effects
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Somatomedin Physiology
u Somatomedin - generic term for peptides like IGF-1 and IGF-2
u general
– IGF-1 is a 70 amino acid protein; IGF-2 is a 67 amino acid protein
» they are highly homologous to proinsulin
u synthesis and release
– IGF-1 is GH-dependent and has major growth promoting effects
» GH is primary secretagogue for IGF-1 release from the liver
u circulating levels of IGF-1 follow those of GH
u levels are high in acromegaly and low in GH deficiency
» nutritional status is the second most important regulator of IGF-1
u malnutrition is the most common cause of growth failure worldwide
» synthesized in target tissue to act locally in paracrine fashion
u often under hormonal control (e.g. GnRH/FSH in gonads)
– IGF-2 is less GH-dependent and has more insulin-like activity
» circulating levels are less variable and ~3-fold higher than IGF-1
u IGF-binding proteins (at least six)
– the effect of the IGF binding proteins is to serve as a reservoir for IGFs and to limit their availability to
target tissues
– most of the IGFs are bound to IGFBP-3 in a ternary complex
» IGFBP-3 is regulated by GH, allowing coordinate changes in IGF-1 and its major binding protein
» IGFs bind to IGFBP-3, which results in a conformational change in IGFBP-3 and allows
interaction with a second subunit (which is in excess)
– other IGFBPs are regulated by metabolic conditions
» their levels are increased at times when insulin is reduced (e.g. fasting)
u this may serve to limit the insulin-like effects of IGFs at times when those effects would be
inappropriate
u mechanism of action
– effects of IGFs are mediated by IGF type I and type II receptors
» the IGF type I receptor is highly homologous to the insulin receptor
u it comprises two a and two b chains, with an extracellular hormone binding domain and an
intracellular tyrosine kinase activity
u the type I receptor mediates most of the known growth promoting effects of both IGF-1
and IGF-2
u binding specificity is IGF-1 > IGF-2 > insulin
u this receptor is regulated in IGF target tissues by many of the same factors that regulate IGF-1
itself (e.g. LH/FSH in gonads)
» the IGF type II receptor is identical to the mannose-6-phosphate receptor
u it has no dissociable subunits and no tyrosine kinase activity; it may be G protein coupled, but
is obviously not a typical 7 TM G protein-coupled receptor
u responses known to be mediated by this receptor are limited
u physiological effects
– the IGFs mediate most of the growth promoting effects of GH
» promote growth of bones via the ‘dual effector model of GH action’
promote growth and differentiation of many cell types
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u IGFs are essential for survival of many cell types in culture
» IGFs act synergistically with other hormones in target tissue
u for example, they potentiate the steroidogenic effects of LH/FSH in gonads by inducing the
cholesterol side chain cleavage enzyme
Somatomedin Pharmacology
u Recombinant human IGF-1
– use in the treatment of GH-deficient patients is experimental
» GH replacement is the treatment of choice
u perhaps useful if the patient develops GH antibodies or if there is concern regarding GHinduced
diabetes mellitus (‘diabetogenic’ effect of GH)
– may be indicated in children with Laron-type dwarfism
» these children have mutations in GH receptor and therefore are not responsive to GH
– Side Effects of IGF-1
» causes a pronounced hypoglycemia (insulin-like effects)
u note that this is not a problem with GH replacement, as GH simultaneously induces IGFBP-3
together with enhancing IGF-1 secretion
GH Deficiency - Differential Diagnosis
u Algorithm for diagnosis of GH deficiency
– check levels of IGF-1 (or IGFBP-3)
» if normal, impaired GH secretion is unlikely
» low levels do not necessarily indicate a GH deficiency
– test levels of GH with provocative tests (screening and formal tests)
» screening with exercise test - only 70% of normals respond to this stimulus
u if GH increases after exercise, GH insufficiency is ruled out
u if low, use at least two standard stimulation tests
» formal tests - two are necessary because of ‘false positives’ (~25%)
u if standard stimuli increase GH levels, GH insufficiency is ruled out
u if GH response is below normal in both tests, the patient is GH deficient
– localize the site of the problem - hypothalamus or pituitary - with GHRH test
u if GH increases in response to GHRH, the pituitary somatotropes are OK and the problem is
hypothalamic
u if GH response is below normal, the primary deficit is in the pituitary (recall that some priming
of the somatotropes may be necessary)
Recapitulation
u GHRH
– stimulates GH release (GH deficiency of hypothalamic origin)
u Octreotide (also bromocriptine)
– inhibits GH release (acromegaly)
– for treatment of symptoms of GI tumours
u GH (somatropin, somatrem)
– GH replacement therapy in GH deficient states
u IGF-1
– to stimulate growth in GH deficiency and particularly GH insensitivity (e.g. Laron-type dwarfs)
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Hypothalamic-Pituitary-Gonadal Axis
u GnRH (from the mediobasal hypothalamus)
u LH & FSH (from the anterior pituitary)
u steroid hormones from gonads
– estrogens & progestins (from the ovaries)
– androgens (from the testis)
u Physiological function of this hormonal axis
– development of primary and secondary sexual characteristics
– control of gametogenesis and reproduction
u Pharmacological agents are used for
– contraception, infertility, hormone-dependent disorders (e.g. breast and prostate cancer), hormone
replacement (e.g. menopause) and precocious puberty
Hormones and Development
u three main periods when the axis is active
– midtrimester of fetal period
» male sexual differentiation; folliculogenesis in females
– early neonatal period
» increase in activity following decrease in circulating maternal hormones
– from puberty throughout reproductive years
» initially most active at night (sleep) in both sexes
» males
u elevated levels of testosterone throughout remainder of life
» females
u cyclic activity until menopause
u after menopause - E2 declines (effects on bone, lipids, etc.) while LH/FSH increase
(disinhibition of hypothalamus/pituitary)
Ovulation and the Menstrual Cycle
Major Events
u follicular stage - E2 dominates
– recruitment and growth of ovarian follicles
– growth of endometrium (proliferative phase)
u LH surge & ovulation
– positive feedback from maintained high levels of E2
– stimulates LH surge and ovulation
u luteal phase - progesterone dominates
– formation of corpus luteum and synthesis of high levels of progesterone and E2
– differentiation of endometrium (secretory phase)
u menstruation or pregnancy
– no pregnancy - luteolyis, decreased hormone levels and endometrial sloughing
– pregnancy - hCG from fetus maintains luteal function
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Gonadotropin Releasing Hormone
GnRH controls release of LH &FSH from the anterior pituitary
u therapeutic uses of GnRH agonists
– to mimic effects of GnRH for treatment of infertility
– to block effects of GnRH and cause a reversible ‘chemical castration’
u GnRH neurons are located in the mediobasal hypothalamus
– influenced by neural factors (e.g. stress inhibits GnRH release)
u GnRH release into portal circulation in a pulsatile fashion
– acts via G-protein coupled receptor, linked to phospholipase C
– stimulates release of LH and FSH from pituitary gonadotropes
– release of GnRH and effects on pituitary are influenced by negative feedback from gonadal steroid
hormones
at mid-cycle in females, E2 stimulates GnRH release (+ve feedback)
GnRH Pharmacology
GnRH and synthetic analogs
– for parenteral administration (also intranasally); not orally available
u GnRH
– gonadorelin is short-acting synthetic GnRH
– used to stimulate gonadotropin secretion
» applied in pulsatile fashion in fertility programs
u synthetic analogs
– leuprolide, histrelin, nafarelin, goserelin are longer-acting analogs
» position 6, D-amino acid; position 10, N-ethylamide
– continuous application used to inhibit gonadotropin secretion
» precocious puberty, endometriosis, cancer chemotherapy
– side effects are those of hypogonadism (similar to menopause in women)
» hot flushes, loss of bone mass, etc.
LH & FSH
u glycoprotein family of pituitary hormones
– common a subunit; hormone-specific b subunits
u release from gonadotropes stimulated by pulsatile GnRH
u induce synthesis and release of gonadal steroids
– two-hormone/two cell theory of ovarian steroidogenesis
– LH stimulates testosterone production by Leydig cells
u stimulate follicular maturation/spermatogenesis (esp. FSH)
u negative feedback regulation
– by steroid hormones
– and gonadal peptides
u positive feedback by E2 in midcycle of women
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LH & FSH Pharmacology
Natural preparations of gonadotropins
– not orally available; administered intramuscularly
u Menotropins (hMG, uFSH)
– from urine of menopausal women
» human menopausal gonadotropins (hMG) has both LH and FSH activities
» Urofollitropin (uFSH) is predominantly FSH activity
u human Chorionic Gonadotropin (hCG)
– from urine of pregnant women
» predominantly LH-like activity
u diagnostic and therapeutic uses of gonadotropins
LH & FSH - Diagnostic Uses
immunologic testing for levels of gonadotropins is used to:
u test for pregnancy
– colorimetric detection of urinary hCG; non-prescription
u test for ovulation
– semi-quantitative colorimetric detection of urinary LH; non-prescription
u distinguish gonadal from hypothalamic/pituitary failure
– low levels of gonadal steroid hormones associated with
» high levels of gonadotropins = gonadal failure
» low levels of gonadotropins = hypothalamic or pituitary failure
LH & FSH - Therapeutic Uses
u to treat female infertility
– hMG (or urofollitropin) to stimulate follicular growth
– then hCG to induce ovulation
» major concern: to avoid ovarian hyperstimulation
u to treat male infertility
– hCG to stimulate testosterone synthesis
– then hMG treatment; FSH activity stimulates spermatogenesis and LH activity contributes to
testosterone production
» extended treatment period due to length of time for spermatogenesis
u to treat cryptorchidism
– hCG given to induce testicular descent
» surgical treatment may be necessary if testis again become cryptorchid
» major concern: to avoid precocious sexual development
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Estrogen Physiology & Pharmacology
Overview
u cause development of secondary sex characteristics in females
u important for reproductive process
– positive feedback for the LH surge
– contribute to follicular development and endometrial growth following menses
u therapeutic uses of estrogens
– in contraceptive pills
– in hormone replacement regimens
u Antiestrogens are used for
– treatment of infertility
– breast cancer
Estrogen Physiology
u Natural estrogens
u estradiol (E2), estrone & estriol
– in premenopausal women LH & FSH stimulate ovarian estradiol synthesis
– in men and postmenopausal women, estrone is synthesized predominantly in adipose tissue
– bound in plasma to SHBG and serum albumin
» ‘free’ hormone is active; bound acts as a reservoir
u mechanism of action is genomic
u physiological effects
– development of secondary sexual characteristics
– feedback (-ve and +ve) on gonadotropin release
– proliferation of endometrium and synthesis of PR; follicular growth
– decrease bone resorption; increase HDL:LDL ratio
Estrogen Pharmacology
u Natural estrogens
– estradiol, estrone and estriol are not orally available due to extensive hepatic first-pass metabolism
– transdermal patches of estradiol; slow, sustained release
u Synthetic steroidal estrogens
– estradiol esters (estradiol cypionate, estradiol valerate)
» dissolved in oil; administered intramuscularly
– conjugated estrogens (estrone sulfate, equilin sulfate)
» oral, parenteral and topical; in hormone replacement therapy
– alkyl estrogens (ethinyl estradiol, mestranol)
» most potent; orally available due to C17 ethinyl substitution; used in oral contraceptives;
mestranol is a prodrug of ethinyl estradiol
u Non-steroidal estrogens
– include diethylstilbestrol and environmental estrogens
Side Effects
– hypertension, cholestasis
– cancer
» estrogens alone cause increase incidence of endometrial cancer (with progesterone, the risk is
decreased)
17
» breast cancer - the jury is out
– nausea, vomiting, breast tenderness, edema, migraine headaches
– gynecomastia in males treated with estrogen for prostate cancer
Contraindications
– breast or endometrial cancer, endometriosis, undiagnosed vaginal bleeding
– hepatic disease, incomplete abortion, suspected pregnancy
Estrogen - Therapeutic Uses
u oral contraceptive preparations
u replacement therapy
– postmenopausal women
» alleviate symptoms of estrogen deficiency (hot flushes, osteoporosis)
– hypogonadotropic females
» development of female secondary sex characteristics
– dysfunctional uterine bleeding
» cyclic treatment to restore regular menstrual cycles
u other
– inhibit lactation; prostate cancer; estrogen-dependent breast cancer
Antiestrogens
Estrogen receptor antagonists
u clomiphene and tamoxifen
– orally available, activated metabolically, excreted in feces
– more precisely - they are partial agonists, with agonist efficacy dependent on assay system
– for therapeutic effects they act as antagonists
» clomiphene inhibits E2 action at hypothalamus and pituitary
» tamoxifen inhibits E2 action on breast cancer cells
Estrogen synthesis (aromatase) inhibitors
u aminoglutethimide
– not very potent or specific; also inhibits cholesterol side chain cleavage enzyme
– a more specific aromatase inhibitor, anastrazole (ARIMIDEX) is now available
Antiestrogens - Therapeutic Uses
u Infertility - clomiphene
– decrease negative feedback at pituitary and/or hypothalamus leading to increase FSH and LH and
promoting follicular growth and ovulation
– major concern is ovarian hyperstimulation
» other side effects may include hot flushes, nausea, dry vaginal mucosa
» teratogenic - should not be given to pregnant women
18
Antiestrogens - Therapeutic Uses
u Breast cancer - tamoxifen and aminoglutethimide/anastrazole
– tamoxifen used to treat advanced breast cancer in postmenopausal women
– used together with GnRH analogs in premenopausal women
» side effects include symptoms of menopause (antagonist effects)
» may increase risk of endometrial cancer (agonist effects)
» slows osteoporosis and lowers LDL (agonist effects)
– aminoglutethimide/anastrazole is a second- or third-line therapy (when breast cancer no longer
responds to tamoxifen)
-tamoxifen was found to be highly effective as a preventive treatment in women at high risk for breast
cancer (incidence was decreased by ~45%) in a recent multi-center study funded by NCI
» increased risk of endometrial cancer and blood clots, but lower rate of bone fractures due to
partial agonist effects of tamoxifen
Selective Estrogen Receptor Modulators
u Raloxifene is the prototypical compound in this class
– these compounds are agonists in some contexts and antagonists in others
» acts as an agonist in bone and lipid metabolism
» acts as an antagonist in breast and endometrium
– has FDA approval for treatment of postmenopausal women (instead of estrogen replacement therapy)
» positive effects on bone density and blood lipid profiles without the risks of estrogen treatment
on the breast and endometrium
» does not reduce the hot flashes and can actually increase them
» it remains to be determined if it reproduces the positive effects of estrogen on atrophic vaginitis
or mood/cognition
- a major study will begin this year to compare raloxifene with tamoxifen in prevention of breast cancer
in women at high risk
19
Progesterone Physiology & Pharmacology
Overview
u major physiological effect is to prepare the reproductive tract to support and maintain pregnancy (i.e.
progestational)
u therapeutic uses of progestins
– in contraceptive pills
– in hormone replacement regimens (to counter effects of estrogen)
u Antiprogestin
– receptor antagonist is used in therapeutic abortion
Progesterone Physiology
Natural progestins
u progesterone, 17a-hydroxyprogesterone
– synthesized/released from luteinized follicular cells under LH (or hCG) control
– bound in plasma to CBG and serum albumin
» 'free' hormone is active; bound acts as a reservoir
short half-life (5 min); metabolism in liver, excretion in urine
u mechanism of action is genomic
– in many tissues PR is upregulated by estrogen (estrogen-priming)
u physiological effects
– negative feedback at hypothalamus and pituitary, except at mid-cycle
– inhibits E2 synthesis, increases E2 metabolism
– inhibits endometrial proliferation and decreases myometrial contractility
– central effects; respiratory stimulant, thermogenic, depressant/anesthetic
Progesterone Pharmacology
u Natural progestins
– progesterone is not orally available due to extensive hepatic first-pass metabolism
u Synthetic C21 Progestins
– ester substitutions at C17
» MPA and megestrol acetate can be given orally (methyl group at C6)
» MPA used in hormone replacement therapy
u Synthetic C19 Progestins
– derived from C19 nor-testosterone; have more androgenic activity than C21
» ethinyl group at C17 allows oral administration
– gonane compounds are further substituted to reduce androgenic activity and increase
progestational activity
– these are used in most oral contraceptive preparations; also in Norplant
Side Effects
u some are due to androgenic action
– weight gain, acne, hirsutism, libido changes and lower HDL:LDL ratio
u others:
– menstrual irregularities, fluid retention, mood lability, depression
u Contraindications
– hepatic disease, incomplete abortion, suspected pregnancy, undiagnosed vaginal bleeding
20
Progestins - Therapeutic Uses
u oral contraceptive preparations
– this is the most common use of progestational agents
u replacement therapy
– postmenopausal women
» counter effects of estrogen
u dysfunctional uterine bleeding
u to treat endometriosis
– less common than GnRH or danazol
Antiprogestin Pharmacology
Receptor Antagonist
u Mifepristone (RU 486)
– orally available derivative of the 19-nor compound, norethindrone
– its principal use is for first trimester abortion (with a prostaglandin)
» may find use as contraceptive, anticancer drug or in labor induction
Synthesis Inhibitor
– progesterone is early in steroid biosynthetic pathway so that inhibiting its synthesis will have numerous
non-specific effects
Oral Contraceptives - ‘The Pill’
Combination Oral Contraceptives
u the most effective form of hormonal contraception available
– pill taken for 21 days; placebo or no pill for 7 days (withdrawal bleeding)
– mechanism involves primarily inhibition of mid-cycle LH surge
» also alterations in cervical mucus
– many formulations - simple, biphasic or triphasic
intended to lower the total amount of hormone administered and to provide ratios of estrogen and
progestin similar to the menstrual cycle
– choice of formulation guided by:
» desire to use lowest possible steroid concentrations
» estrogenic vs. progestogenic side effects
Combination Oral Contraceptives
Side Effects
u untoward side effects
– estrogenic include:
» hypertension, thromboembolic disorders, gall bladder disease
» nausea, headache, vomiting, breast tenderness, edema
– progestogenic include:
» weight gain, hirsutism, depression, acne, irregular bleeding
u beneficial effects
» decreased incidence of endometrial and ovarian cancer
21
Combination Oral Contraceptives
u Contraindications
– presence or history of thromboembolic disease or cerebrovascular disease
– myocardial infarction, coronary artery disease
– congenital hyperlipidemia
– carcinoma of the breast, reproductive tract, or other hormone-dependent neoplasia
– a bnormal or undiagnosed vaginal bleeding
– pregnancy
– presence or history of liver tumors, impaired liver function
The risk of serious cardiovascular side effects is particularly high among smokers over the age of 35,
for whom even low dose oral contraceptives are contraindicated.
Other Hormonal Contraceptives
Progestin-only formulations
– mechanism of contraception is both feedback suppression of LH and FSH and production of a scant
viscid cervical mucus
u progesterone ‘mini-pill’
– low doses of progesterone taken daily
– useful when estrogens are contraindicated but less effective than combination preparations
– associated with irregular bleeding - leads to non-compliance
u Norplant (subcutaneous implant of levonorgesterol)
– long-lasting contraception (up to five years)
– again irregular bleeding is potentially problematic
» often improves after the first year
u MPA injection (every three months)
Other Hormonal Contraceptives
Post-Coital Contraceptive ‘morning-after pill’
u mechanism of action is unknown, but serious side effects limit use and compliance
u very high dose of estrogen
– for example, 2.5 mg twice daily for 5 days within 72 hours of coitus
– nausea, vomiting, headache, dizziness, breast tenderness, leg and abdominal cramps
u estrogen and progestin combination
– lower doses used result in fewer and less severe side effects
22
Androgen Physiology and Pharmacology
u Anabolic androgenic steroids
– are synthesized and secreted principally by the male gonad
u major physiological effect
– growth promoting (anabolic)
– virilizing (androgenic)
u therapeutic uses of androgens
– in hormone replacement regimens
– to treat hormone-dependent disorders (endometriosis)
– abused by athletes
u Antiandrogens - receptor antagonists & synthesis inhibitors
– to treat hormone-dependent disorders (prostate cancer, prostatic hyperplasia)
– to treat hirsutism
Androgen Physiology
u Testosterone
– synthesized/released from testicular Leydig cells under LH control
» metabolized to 5a-dihydrotestosterone, a more potent androgen
» aromatized to estrogen and mediates effects via the estrogen receptor
– bound in plasma to SHBG (high affinity) and to CBG & serum albumin
» ‘free’ hormone is active (2%); bound acts as a reservoir
short half-life (10 to 20 min); metabolism in liver, excretion in urine
u mechanism of action is genomic
– a single AR mediates androgenic & anabolic effects
u physiological effects of androgens
– induces male phenotype in fetus
– development of secondary sexual characteristics at puberty (growth of muscles, bones)
– negative feedback at hypothalamus and pituitary
– maintain spermatogenesis, increase libido and male sexual behavior
Androgen Pharmacology
u Natural androgens
– testosterone is not orally available due to extensive hepatic first-pass metabolism
– intramuscularly in oil; in transdermal patches
u 17b-Testosterone Esters
– ester substitutions at C17 (testosterone cypionate, testosterone enanthate)
» used as intramuscular injections in an oil vehicle for hormone replacement
» released slowly from the depot, ester groups rapidly removed,
» pharmacokinetics dictated by hydrophobicity of the ester group
u 17a-Testosterone Alkyls
– orally available, but hepatotoxicity limits clinical usefulness
– danazol is a weak androgen used in hereditary angioneurotic edema and together with GnRH analogs
to treat endometriosis.
23
Androgens - Therapeutic Uses
u replacement therapy
– the most clear indication for androgen therapy - hypogonadism
– parenterally administered testosterone esters are the treatment of choice
– FSH treatment is initiated to induce spermatogenesis when pregnancy is desired
u hereditary angioneurotic edema
– danazol is used to increase inhibitor of the first component of complement which is reduced or absent
in this autosomal dominant disorder
u to treat endometriosis
– danazol is used to inhibit hypothalamo-pituitary function, and thereby decrease ovarian function and
estrogen production
u others
– anemia, breast cancer, catabolic states, enhance athletic performance
Androgen Pharmacology
Side Effects
u virilizing
acne, hirsutism and changes in the voice, male pattern baldness, clitoral enlargement, weight gain,
libido changes and lower HDL:LDL ratio
u Feminizing effects
– gynecomastia as testosterone is converted to estrogen
u Toxic effects
– edema and liver disease (jaundice, hepatic carcinoma, peliosis hepatitis)
Antiandrogen Pharmacology
u Androgen Receptor Antagonists
– Flutamide
» orally active androgen receptor antagonist used in treatment of prostate cancer; also need GnRH
agonist to suppress gonadotropin and testosterone secretion
– Cyproterone acetate
» orally active antagonist for treatment of severe hirsutism; investigational
u Androgen Synthesis Inhibitors
– Ketoconazole and Spironolactone
» not widely used but have been tried in prostate cancer and hirsutism
u 5a-Reductase Inhibitor
– Finasteride
» orally active; for treatment of benign prostatic hyperplasia
» also for treatment of male pattern baldness (PROPECIA)
Endocrinology - Introduction
u Pituitary hormones
– control numerous physiological functions
» direct effects of pituitary hormones
» indirect effects mediated by target gland hormones
– controlled by hypothalamus and feedback from target gland hormones
– the pituitary comprises a posterior and anterior lobe
u Posterior Pituitary
– oxytocin, vasopressin
u Anterior Pituitary
– glycoprotein hormones (LH, FSH, TSH)
– somatomammotropic hormones (GH, prolactin)
– ACTH-related hormones (ACTH, MSH, etc.)
Posterior Pituitary Hormones
u synthesized in hypothalamus, transported to the posterior pituitary and released directly into the
systemic circulation.
u secretion controlled directly by the activity of hypothalamic neurons.
u Oxytocin
– responsible for the milk ‘let-down’ reflex
release regulated through a neuroendocrine reflex arc initiated by suckling
– stimulation of uterine contraction (principal therapeutic use)
u Vasopressin
– controls water reabsorption in the kidney
– release regulated by hypothalamic neurons that sense plasma osmolarity.
Anterior Pituitary Hormones
u glycoprotein, somatomammotropic, ACTH-related hormones
– release controlled by hypothalamic hormones released into portal circulation
– release is episodic, and influenced by diurnal rhythms & developmetal factors
» regulate function of target gland/tissue;
» regulated by target gland hormones (-ve feedback mechanism)
2
Posterior Pituitary Hormones
u Vasopressin & Oxytocin
– are nine amino acid peptide hormones
– are synthesized in magnocellular neurons of the paraventricular and supraoptic hypothalamic nuclei.
– are encoded by separate, closely-linked genes that were likely derived from a common ancestral gene.
– are synthesized from larger precursor hormones that also encode a neurophysin, the function of which
is critical to processing of AVP and oxytocin
– are released by exocytosis from axon terminals in the posterior pituitary to reach the systemic
circulation
Vasopressin (Antidiuretic Hormone)
Overview of Physiology & Pharmacology
u physiological role in regulating fluid volume and plasma osmolality, primarily through its ability to
enhance fluid reabsorption from the distal tubule and cortical collecting duct of the kidney.
u disorders of the vasopressinergic system include:
– neurogenic diabetes insipidus
» treated primarily with desmopressin (dDAVP), a synthetic AVP
– nephrogenic diabetes insipidus
» treated with thiazide diuretics
– Syndrome of Inappropriate ADH secretion (SIADH)
» often asymptomatic, but may be treated with demeclocycline, which interferes with AVP action
Vasopressin Physiology
u release of AVP from posterior pituitary is:
– increased with increases in plasma osmolality
– inhibited by increases in blood volume and blood pressure
– enhanced by AngII and inhibited by ANP
– inhibited by alcohol
u AVP has cardiovascular, pituitary and renal effects
– via V1a receptors, coupled to phospholipases, it causes vasoconstriction
– via V1b receptors, also coupled to phospholipases, it enhances ACTH release (synergistically with
CRF)
– via V2 receptors, positively coupled to adenylyl cyclase, it stimulates water reabsorption from the renal
distal tubule and collecting duct and causes excretion of a sparse, concentrated urine
Vasopressin Pharmacology
Vasopressin and analogs
u vasopressin
– short half-life (~20 min); V1 side effects (vasoconstriction)
– not orally available; parenteral and intranasal
u lypressin (pig vasopressin)
– less potent antidiuretic than dDAVP; less pressor activity than AVP
– intranasal
u desmopressin (dDAVP)
– high antidiuretic to pressor activity; long-lasting
3
– intranasal
– treatment of choice for neurogenic DI
u vasopressin antagonist (OPC-31260)
Others:
u enhance AVP action
– chlorpropamide (an oral sulfonylurea)
– carbamazepine (related to tricyclic antidepressants)
– clofibrate (a fibric acid derivative)
» can enhance effects of low levels of AVP but have a number of side effects related to their
primary actions
u inhibit AVP action
– demeclocycline and lithium interfere with AVP actions at the kidney
» lithium treatment in particular can lead to nephrogenic DI
Therapeutic Uses of Vasopressin Drugs
u Neurogenic DI
– characterized by AVP levels that are undetectable (or abnormally low given the prevailing plasma
osmolality).
» result is persistent polyuria which can lead to hypertonic dehydration; water balance is maintained
through increased water intake
– desmopressin (dDAVP) is the treatment of choice
» can be treated with lypressin if dDAVP is too potent
» chlorpropamide, carbamazepine and clofibrate may be used if dDAVP and lypressin are not welltolerated
u Nephrogenic DI
– treated with thiazide diuretics; vasopressin analogs are not useful in this indication
u SIADH
– inability to suppress AVP secretion when plasma osmolality decreases
» patients are often asymptomatic
» can lead to hypervolemic hyponatremia and hypoosmolality
» treated by restricting fluid intake and the renal effects of AVP inhibited using demeclocycline (or
Li+, if tetracyclines are contraindicated).
u Nocturnal Enuresis
– bed-wetting can be treated with intranasal desmopressin
u von Willebrand’s Disease
– V2-mediated increase in vWF and factor VIII by desmopressin
u Gastrointestinal Bleeding
– V1-mediated decrease in splanchnic blood flow to decrease blood flow and pressure in splanchnic and
portal vasculature
Side Effects of Vasopressin Drugs
The vasopressin drugs are well-tolerated and have minimal side effects at therapeutic doses
u V1-mediated side effects - smooth muscle
– potential for coronary artery vasoconstriction
u V2-mediated side effects - renal
– water intoxication (esp. do not use in primary polydipsia)
4
– increased water load (a problem in individuals with heart problems)
u interactions with other drugs
– chlorpropamide, clofibrate, carbamazepine, NSAIDS enhance effects
– lithium, demeclocycline inhibit effects
Oxytocin
Overview of Physiology & Pharmacology
– endocrine component of neuroendocrine reflex arc that mediates suckling-induced lactation (the milk
‘let-down’ reflex).
» may be used to assist with breast-feeding
– a potent stimulant of uterine contraction and may be involved physiologically in parturition
» oxytocin is used pharmacologically to induce or augment labor or to reduce post-partum bleeding
u other uterine motility agents
– stimulants of utrine motility include prostaglandins and ergot alkaloids
– inhibitors are b2-adrenergic agonists, MgSO4, nifedipine & alcohol
Oxytocin Physiology
u Release of oxytocin is triggered by:
– stimulus of the nipples, as in suckling
– distention of the cervix and vagina during delivery
u Effects of oxytocin are
– mediated by G-protein-coupled receptor, acting via phospholipase C and increases in intracellular
calcium to stimulate smooth muscle contraction (activation of MLCK)
» stimulates contraction of breast myoepithelial cells
» increases force & frequency of uterine contractions
» constricts umbilical arteries and veins
Oxytocin Pharmacology
u General
– available for parenteral administration (usually iv)
– short half-life (5 to 10 minutes)
– metabolized by the liver and kidney
– also can be administered intranasally (less efficient)
u Therapeutic uses
– to induce labor
– to augment dysfunctional labor
» care must be taken to avoid damage to fetus or mother caused by excessively frequent or forceful
contractions or by compromised placental gas/nutrient exchange (umbilical vessel constriction)
– to control post partum bleeding
– to assist with breast feeding
5
Uterine Motility Agents - Stimulation
Prostaglandins (E and F type)
– are involved in cervical ‘ripening’ (increasing the compliance of the cervix) and the initiation of labor.
PGE2 (dinoprostone)
» PGF2a (carboprost) and its 15-methyl derivative (carboprost tromethamine)
» A PGE1 analog (misoprostol)
– are used therapeutically for
» midtrimester abortions (dinoprostone, carboprost; intramuscular or intravaginally)
» to evacuate the uterus (as above)
» to induce cervical ripening (dinoprostone; locally applied gel)
» to treat postpartum hemorrhage (carboprost tromethamine)
– side effects are nausea, vomiting & diarrhea
Uterine Motility Agents - Stimulation
Ergot Alkaloids
– Ergot is a poison from a fungus found in edible grains; ergot alkaloids such as ergonovine and
methylergonovine have potent uterotonic effects (via a1-adrenoceptor and 5-HT receptors)
» orally available with a half-life of 0.5 to 2 hours
– Ergot alkaloids should not be given prior to delivery. They are used therapeutically
» to control postpartum bleeding
» to promote uterine involution when delayed
– Side effects include:
» vasoconstriction and hypertension
» can interfere with lactation
Uterine Motility Agents - Inhibition
u b2-adrenoceptor Agonists
– inhibit uterine smooth muscle contractility
– the preferred treatment for premature labor
» ritodrine and terbutaline
– side effects of b2 stimulation include:
» peripheral vasodilation and reflex tachycardia; edema; hyperglycemia
u MgSO4 and nifedipine
– both inhibit uterine contraction by interfering with calcium entry
» Mg2+ interferes with many processes dependent on calcium entry (e.g. neuromuscular
transmission); nifedipine causes peripheral vasodilation
u Ethanol
– decreases oxytocin release at high doses; only used in emergency
6
Recapitulation
u Vasopressinergic Agents
– Synthetic vasopressin analogs: vasopressin, lypressin, desmopressin
– Vasopressin potentiators: chlorpropamide, carbamazepine, clofibrate
– Vasopressin inhibitor: demeclocycline, lithium carbonate
u Oxytocin & Uterine Muscle Motility
– Synthetic oxytocin analogs: oxytocin
– Stimulation of uterine motility:
» Prostaglandins: dinoprostone, carboprost, misoprostol
» Ergot Alkaloids: ergonovine, methylergonovine
– Inhibition of uterine motility (tocolytic agents):
» b2-adrenergic agonists: ritodrine, terbutaline
» calcium channel inhibitors: MgSO4, nifedipine
» miscellaneous: ethanol
7
Prolactin and Growth Hormone
Prolactin
u Overview of Physiology & Pharmacology
– prolactin is a somatomammotropic pituitary hormone that is required for initiation and support of
lactation
– hyperprolactinemia is the most common hypothalamo-pituitary disorder
» it is a leading cause of infertility and is treated with bromocriptine
Prolactin Physiology
u synthesis and release
– PRL is a 199 amino acid peptide hormone secreted by pituitary lactotropes
» PRL is homologous to GH (a somatomammotropic hormone)
– unique features of the control of PRL secretion
» under primarily negative regulation by the hypothalamus
u dopamine inhibits PRL secretion
» not subject to long-loop feedback as it does not stimulate a target organ hormone
– otherwise PRL release is :
» episodic and peaks during sleep
» enhanced by a number of hypothalamic releasing factors (TRH, VIP, etc.)
» enhanced during pregnancy, probably by E2
u E2 stimulates lactotrope hyperplasia, PRL expression and secretion
» stimulated by suckling via a neuroendocrine reflex arc
u lactational hyperprolactinemia may contribute to postpartum anovulation and infertility
» enhanced by stress, exercise, sleep, hypoglycemia
u mechanism of action
– effects are mediated by the PRL receptor
» a member of the hematopoeitin receptor family
u mechanism of action of the PRL receptor is incompletely understood
u by analogy with GH, it may involve a tyrosine phosphorylation cascade
u physiological effects
– the breast is the primary target of PRL action
» PRL is required during pregnancy, together with other hormones, to prepare the breast for milk
production (e.g. stimulates expression of milk protein genes)
u E2 inhibits lactation during pregnancy, but lactation is initiated by PRL post partum after E2
levels decrease
– PRL receptors are widespread, but their function in other tissues is not well understood
– at high levels, PRL inhibits gonadotropin release from the pituitary
Prolactin Pharmacology
u Prolactin itself has no known therapeutic value
u To treat hyperprolactinemia
– hyperprolactinemia is associated with infertility
– bromocriptine is a dopamine agonist that inhibits PRL release
» orally available, semi-synthetic ergot alkaloid with a half-life of ~ 3h
8
» longer-lasting dopamine agonists with fewer side effects may soon be available (e.g. cabergoline,
quinagolide)
» fertility is restored with bromocriptine
– side effects of bromocriptine
» nausea, dizziness, postural hypotension
» psychotic symptoms such as hallucinations and delusions have been reported
Growth Hormone Axis
u Overview of Physiology & Pharmacology
– GH is a somatomammotropic anterior pituitary hormone responsible for regulating growth
» GH deficiencies are associated with growth failure; GH excess causes gigantism and acromegaly
u It is controlled by GHRH & somatostatin from the hypothalamus and by IGF-1 and IGF-2 that
are produced in response to GH (negative feedback).
» effects of GH on target tissue are either direct or indirect (mediated by IGFs).
– Pharmacological agents that target this axis include
» synthetic GHRH stimulates GH release
» a somatostatin analog, octreotide inhibits GH release
» recombinant human GH (somatropin, somatrem) is used to replace GH in states of deficiency
» recombinant IGF-1 is used to treat GH insensitivity (Laron-type dwarfism).
GHRH Physiology
u synthesis and release
– a 40 or 44 amino acid peptide hormone from larger precursor
– biological activity is contained within the first 29 amino acids
– released from hypothalamic neurons into portal circulation in pulsatile fashion
» release enhanced by clonidine, exercise
u mechanism of action
– acts on pituitary somatotrope via G protein-coupled receptor to increase cAMP and [Ca2+]i and
thereby enhance GH release
» also increases somatostatin release from hypothalamus which, in turn, decreases release of GH
from pituitary (ultra-short loop feedback)
GHRH Pharmacology
u Synthetic human GHRH
– multiple forms have been tested (44, 40 and 29 amino acid forms)
» half-life ~ 7 min
» can be administered iv, sc or intranasally with different potencies (300:30:1)
an additional peptide (GHRP) has been identified and non-peptide orally active mimetics of GHRP are
being tested and may become important therapeutically.
u Uses of GHRH
– therapeutic - has been used experimentally to stimulate GH secretion in GH-deficient patients with
functional somatotropes
» use of pulsatile GHRH to mimic normal patterns
» continuous non-pulsatile delivery may also be effective (depot preparations)
– diagnostic - to test pituitary function in GH-deficient patients
» priming with repeated GHRH challenges may be necessary
9
Somatostatin Physiology
u SS is a brain-gut peptide with a widespread distribution
u synthesis and release
– SS exists as a 14 and 28 amino acid peptide
» SS(14) is the more common form
» the two forms have slightly different potencies in different bioassays
– released from hypothalamic neurons into portal circulation in pulsatile fashion
» release of SS is enhanced by GH & IGF-1 which results in diminished GH and IGF-1 production
(-ve feedback inhibition)
» release inhibited by L-dopa, leading to increased GH levels (basis of provocative test)
– SS is also produced in the gut (pancreatic D cells, stomach, intestine)
» released when food is detected in the gut (especially protein and fat)
– SS is differentially distributed throughout the CNS
u mechanism of action and effects
– in general, somatostatin has inhibitory effects on target cells
u multiple somatostatin receptor subtypes (sst1-sst5) have been identified but those which mediate
specific effects of SS are not yet well-defined
» in pituitary somatotropes, GH release is inhibited by SS
u SS decreases adenylyl cyclase and cAMP
u SS also enhances K+ channels and inhibits Ca2+ channels
» in the gut, SS inhibits GI motility and secretions (endocrine and exocrine)
u inhibits insulin and VIP secretion
» in the CNS, somatostatin has inhibitory effects on central neurons
u SS enhances neuronal K+ channels and inhibits Ca2+ channels
u systemically administered SS (or analogs) have no known central effects
Somatostatin Pharmacology
u somatostatin
– not orally active, short half-life (<>
u octreotide
– octapeptide variant of somatostatin
» not orally active but much longer half-life (~ 2 h)
» ratio of GH to insulin suppression is increased ~ 45-fold
– therapeutic uses
» to treat acromegaly (excess GH secretion in adults)
u as an adjunct to surgery, which is rarely 100% effective
u causes decreased GH secretion and may shrink the adenoma
u bromocriptine is also effective in treatment of acromegaly (paradoxical)
» to treat carcinoid and pancreatic tumors (e.g. VIP-secreting)
u FDA approved for relief of symptoms (diarrhea, flushing)
u unlike adenomas, octreotide does not shrink these tumors
10
Growth Hormone Physiology
u synthesis and release
– GH activity is predominantly due to a 191 amino acid, 22 kDa protein
» numerous additional forms of GH are also present
– GH release from pituitary somatotropes is:
» episodic and peaks during sleep
» high in children, peaks in puberty and falls to lower levels in adults
» enhanced by GHRH and inhibited by SS and IGF-1
» enhanced by a number of agents that are used in provocative clinical tests
u mechanism of action
– direct effects of GH are mediated by the GH receptor
» a member of the hematopoeitin receptor family
u it is closely associated with a tyrosine kinase activity
» extracellular domain can be cleaved to release a GH binding protein
» receptors are mutated in Laron-type dwarfs
u normal or even elevated levels of GH, but low levels of IGF-1
u GH has direct and indirect effects
u direct effects
– stimulation of IGF-1 and IGF-2
» ‘dual effector model of GH action’ to explain synergistic effects of GH and IGF
u in bone, GH stimulates differentiation of prechondrocytes so that they express IGF receptors
and secrete IGF-1. The IGF-1 then acts in a paracrine fashion to stimulate clonal expansion
and further differentiation
– metabolic effects that are opposite those of insulin
» increased lipolysis, glucose transport
» decreased insulin sensitivity
u this combination of anti-insulin actions can cause increased insulin secretion which, if
prolonged or severe, can lead to b cell “burn-out’ (a so-called ‘diabetogenic’ effect of GH)
u indirect effects
– indirect metabolic effects are insulin-like and are mediated by IGFs
Growth Hormone Pharmacology
u Recombinant human GH (somatropin, somatrem)
– the two forms are equipotent, but somatrem is somewhat more antigenic
» administered daily, either by sc or im injection
» half-life of ~20-30 min, peak of GH at 2-6 h and of IGF-1 at ~20 h
u Therapeutic uses of GH
– to replace GH in children with GH deficiency, gonadal dysgenesis or chronic renal insufficiency
» promotes substantial acceleration in growth in GH deficiency
» synergistic and/or permissive effects of other hormones must be considered
» early diagnosis is important; height normalization is best achieved before puberty
– other uses are controversial
» treatment of short children (constitutional growth delay)
» abused by athletes for its lipolytic and growth promoting effects
11
Somatomedin Physiology
u Somatomedin - generic term for peptides like IGF-1 and IGF-2
u general
– IGF-1 is a 70 amino acid protein; IGF-2 is a 67 amino acid protein
» they are highly homologous to proinsulin
u synthesis and release
– IGF-1 is GH-dependent and has major growth promoting effects
» GH is primary secretagogue for IGF-1 release from the liver
u circulating levels of IGF-1 follow those of GH
u levels are high in acromegaly and low in GH deficiency
» nutritional status is the second most important regulator of IGF-1
u malnutrition is the most common cause of growth failure worldwide
» synthesized in target tissue to act locally in paracrine fashion
u often under hormonal control (e.g. GnRH/FSH in gonads)
– IGF-2 is less GH-dependent and has more insulin-like activity
» circulating levels are less variable and ~3-fold higher than IGF-1
u IGF-binding proteins (at least six)
– the effect of the IGF binding proteins is to serve as a reservoir for IGFs and to limit their availability to
target tissues
– most of the IGFs are bound to IGFBP-3 in a ternary complex
» IGFBP-3 is regulated by GH, allowing coordinate changes in IGF-1 and its major binding protein
» IGFs bind to IGFBP-3, which results in a conformational change in IGFBP-3 and allows
interaction with a second subunit (which is in excess)
– other IGFBPs are regulated by metabolic conditions
» their levels are increased at times when insulin is reduced (e.g. fasting)
u this may serve to limit the insulin-like effects of IGFs at times when those effects would be
inappropriate
u mechanism of action
– effects of IGFs are mediated by IGF type I and type II receptors
» the IGF type I receptor is highly homologous to the insulin receptor
u it comprises two a and two b chains, with an extracellular hormone binding domain and an
intracellular tyrosine kinase activity
u the type I receptor mediates most of the known growth promoting effects of both IGF-1
and IGF-2
u binding specificity is IGF-1 > IGF-2 > insulin
u this receptor is regulated in IGF target tissues by many of the same factors that regulate IGF-1
itself (e.g. LH/FSH in gonads)
» the IGF type II receptor is identical to the mannose-6-phosphate receptor
u it has no dissociable subunits and no tyrosine kinase activity; it may be G protein coupled, but
is obviously not a typical 7 TM G protein-coupled receptor
u responses known to be mediated by this receptor are limited
u physiological effects
– the IGFs mediate most of the growth promoting effects of GH
» promote growth of bones via the ‘dual effector model of GH action’
promote growth and differentiation of many cell types
12
u IGFs are essential for survival of many cell types in culture
» IGFs act synergistically with other hormones in target tissue
u for example, they potentiate the steroidogenic effects of LH/FSH in gonads by inducing the
cholesterol side chain cleavage enzyme
Somatomedin Pharmacology
u Recombinant human IGF-1
– use in the treatment of GH-deficient patients is experimental
» GH replacement is the treatment of choice
u perhaps useful if the patient develops GH antibodies or if there is concern regarding GHinduced
diabetes mellitus (‘diabetogenic’ effect of GH)
– may be indicated in children with Laron-type dwarfism
» these children have mutations in GH receptor and therefore are not responsive to GH
– Side Effects of IGF-1
» causes a pronounced hypoglycemia (insulin-like effects)
u note that this is not a problem with GH replacement, as GH simultaneously induces IGFBP-3
together with enhancing IGF-1 secretion
GH Deficiency - Differential Diagnosis
u Algorithm for diagnosis of GH deficiency
– check levels of IGF-1 (or IGFBP-3)
» if normal, impaired GH secretion is unlikely
» low levels do not necessarily indicate a GH deficiency
– test levels of GH with provocative tests (screening and formal tests)
» screening with exercise test - only 70% of normals respond to this stimulus
u if GH increases after exercise, GH insufficiency is ruled out
u if low, use at least two standard stimulation tests
» formal tests - two are necessary because of ‘false positives’ (~25%)
u if standard stimuli increase GH levels, GH insufficiency is ruled out
u if GH response is below normal in both tests, the patient is GH deficient
– localize the site of the problem - hypothalamus or pituitary - with GHRH test
u if GH increases in response to GHRH, the pituitary somatotropes are OK and the problem is
hypothalamic
u if GH response is below normal, the primary deficit is in the pituitary (recall that some priming
of the somatotropes may be necessary)
Recapitulation
u GHRH
– stimulates GH release (GH deficiency of hypothalamic origin)
u Octreotide (also bromocriptine)
– inhibits GH release (acromegaly)
– for treatment of symptoms of GI tumours
u GH (somatropin, somatrem)
– GH replacement therapy in GH deficient states
u IGF-1
– to stimulate growth in GH deficiency and particularly GH insensitivity (e.g. Laron-type dwarfs)
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Hypothalamic-Pituitary-Gonadal Axis
u GnRH (from the mediobasal hypothalamus)
u LH & FSH (from the anterior pituitary)
u steroid hormones from gonads
– estrogens & progestins (from the ovaries)
– androgens (from the testis)
u Physiological function of this hormonal axis
– development of primary and secondary sexual characteristics
– control of gametogenesis and reproduction
u Pharmacological agents are used for
– contraception, infertility, hormone-dependent disorders (e.g. breast and prostate cancer), hormone
replacement (e.g. menopause) and precocious puberty
Hormones and Development
u three main periods when the axis is active
– midtrimester of fetal period
» male sexual differentiation; folliculogenesis in females
– early neonatal period
» increase in activity following decrease in circulating maternal hormones
– from puberty throughout reproductive years
» initially most active at night (sleep) in both sexes
» males
u elevated levels of testosterone throughout remainder of life
» females
u cyclic activity until menopause
u after menopause - E2 declines (effects on bone, lipids, etc.) while LH/FSH increase
(disinhibition of hypothalamus/pituitary)
Ovulation and the Menstrual Cycle
Major Events
u follicular stage - E2 dominates
– recruitment and growth of ovarian follicles
– growth of endometrium (proliferative phase)
u LH surge & ovulation
– positive feedback from maintained high levels of E2
– stimulates LH surge and ovulation
u luteal phase - progesterone dominates
– formation of corpus luteum and synthesis of high levels of progesterone and E2
– differentiation of endometrium (secretory phase)
u menstruation or pregnancy
– no pregnancy - luteolyis, decreased hormone levels and endometrial sloughing
– pregnancy - hCG from fetus maintains luteal function
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Gonadotropin Releasing Hormone
GnRH controls release of LH &FSH from the anterior pituitary
u therapeutic uses of GnRH agonists
– to mimic effects of GnRH for treatment of infertility
– to block effects of GnRH and cause a reversible ‘chemical castration’
u GnRH neurons are located in the mediobasal hypothalamus
– influenced by neural factors (e.g. stress inhibits GnRH release)
u GnRH release into portal circulation in a pulsatile fashion
– acts via G-protein coupled receptor, linked to phospholipase C
– stimulates release of LH and FSH from pituitary gonadotropes
– release of GnRH and effects on pituitary are influenced by negative feedback from gonadal steroid
hormones
at mid-cycle in females, E2 stimulates GnRH release (+ve feedback)
GnRH Pharmacology
GnRH and synthetic analogs
– for parenteral administration (also intranasally); not orally available
u GnRH
– gonadorelin is short-acting synthetic GnRH
– used to stimulate gonadotropin secretion
» applied in pulsatile fashion in fertility programs
u synthetic analogs
– leuprolide, histrelin, nafarelin, goserelin are longer-acting analogs
» position 6, D-amino acid; position 10, N-ethylamide
– continuous application used to inhibit gonadotropin secretion
» precocious puberty, endometriosis, cancer chemotherapy
– side effects are those of hypogonadism (similar to menopause in women)
» hot flushes, loss of bone mass, etc.
LH & FSH
u glycoprotein family of pituitary hormones
– common a subunit; hormone-specific b subunits
u release from gonadotropes stimulated by pulsatile GnRH
u induce synthesis and release of gonadal steroids
– two-hormone/two cell theory of ovarian steroidogenesis
– LH stimulates testosterone production by Leydig cells
u stimulate follicular maturation/spermatogenesis (esp. FSH)
u negative feedback regulation
– by steroid hormones
– and gonadal peptides
u positive feedback by E2 in midcycle of women
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LH & FSH Pharmacology
Natural preparations of gonadotropins
– not orally available; administered intramuscularly
u Menotropins (hMG, uFSH)
– from urine of menopausal women
» human menopausal gonadotropins (hMG) has both LH and FSH activities
» Urofollitropin (uFSH) is predominantly FSH activity
u human Chorionic Gonadotropin (hCG)
– from urine of pregnant women
» predominantly LH-like activity
u diagnostic and therapeutic uses of gonadotropins
LH & FSH - Diagnostic Uses
immunologic testing for levels of gonadotropins is used to:
u test for pregnancy
– colorimetric detection of urinary hCG; non-prescription
u test for ovulation
– semi-quantitative colorimetric detection of urinary LH; non-prescription
u distinguish gonadal from hypothalamic/pituitary failure
– low levels of gonadal steroid hormones associated with
» high levels of gonadotropins = gonadal failure
» low levels of gonadotropins = hypothalamic or pituitary failure
LH & FSH - Therapeutic Uses
u to treat female infertility
– hMG (or urofollitropin) to stimulate follicular growth
– then hCG to induce ovulation
» major concern: to avoid ovarian hyperstimulation
u to treat male infertility
– hCG to stimulate testosterone synthesis
– then hMG treatment; FSH activity stimulates spermatogenesis and LH activity contributes to
testosterone production
» extended treatment period due to length of time for spermatogenesis
u to treat cryptorchidism
– hCG given to induce testicular descent
» surgical treatment may be necessary if testis again become cryptorchid
» major concern: to avoid precocious sexual development
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Estrogen Physiology & Pharmacology
Overview
u cause development of secondary sex characteristics in females
u important for reproductive process
– positive feedback for the LH surge
– contribute to follicular development and endometrial growth following menses
u therapeutic uses of estrogens
– in contraceptive pills
– in hormone replacement regimens
u Antiestrogens are used for
– treatment of infertility
– breast cancer
Estrogen Physiology
u Natural estrogens
u estradiol (E2), estrone & estriol
– in premenopausal women LH & FSH stimulate ovarian estradiol synthesis
– in men and postmenopausal women, estrone is synthesized predominantly in adipose tissue
– bound in plasma to SHBG and serum albumin
» ‘free’ hormone is active; bound acts as a reservoir
u mechanism of action is genomic
u physiological effects
– development of secondary sexual characteristics
– feedback (-ve and +ve) on gonadotropin release
– proliferation of endometrium and synthesis of PR; follicular growth
– decrease bone resorption; increase HDL:LDL ratio
Estrogen Pharmacology
u Natural estrogens
– estradiol, estrone and estriol are not orally available due to extensive hepatic first-pass metabolism
– transdermal patches of estradiol; slow, sustained release
u Synthetic steroidal estrogens
– estradiol esters (estradiol cypionate, estradiol valerate)
» dissolved in oil; administered intramuscularly
– conjugated estrogens (estrone sulfate, equilin sulfate)
» oral, parenteral and topical; in hormone replacement therapy
– alkyl estrogens (ethinyl estradiol, mestranol)
» most potent; orally available due to C17 ethinyl substitution; used in oral contraceptives;
mestranol is a prodrug of ethinyl estradiol
u Non-steroidal estrogens
– include diethylstilbestrol and environmental estrogens
Side Effects
– hypertension, cholestasis
– cancer
» estrogens alone cause increase incidence of endometrial cancer (with progesterone, the risk is
decreased)
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» breast cancer - the jury is out
– nausea, vomiting, breast tenderness, edema, migraine headaches
– gynecomastia in males treated with estrogen for prostate cancer
Contraindications
– breast or endometrial cancer, endometriosis, undiagnosed vaginal bleeding
– hepatic disease, incomplete abortion, suspected pregnancy
Estrogen - Therapeutic Uses
u oral contraceptive preparations
u replacement therapy
– postmenopausal women
» alleviate symptoms of estrogen deficiency (hot flushes, osteoporosis)
– hypogonadotropic females
» development of female secondary sex characteristics
– dysfunctional uterine bleeding
» cyclic treatment to restore regular menstrual cycles
u other
– inhibit lactation; prostate cancer; estrogen-dependent breast cancer
Antiestrogens
Estrogen receptor antagonists
u clomiphene and tamoxifen
– orally available, activated metabolically, excreted in feces
– more precisely - they are partial agonists, with agonist efficacy dependent on assay system
– for therapeutic effects they act as antagonists
» clomiphene inhibits E2 action at hypothalamus and pituitary
» tamoxifen inhibits E2 action on breast cancer cells
Estrogen synthesis (aromatase) inhibitors
u aminoglutethimide
– not very potent or specific; also inhibits cholesterol side chain cleavage enzyme
– a more specific aromatase inhibitor, anastrazole (ARIMIDEX) is now available
Antiestrogens - Therapeutic Uses
u Infertility - clomiphene
– decrease negative feedback at pituitary and/or hypothalamus leading to increase FSH and LH and
promoting follicular growth and ovulation
– major concern is ovarian hyperstimulation
» other side effects may include hot flushes, nausea, dry vaginal mucosa
» teratogenic - should not be given to pregnant women
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Antiestrogens - Therapeutic Uses
u Breast cancer - tamoxifen and aminoglutethimide/anastrazole
– tamoxifen used to treat advanced breast cancer in postmenopausal women
– used together with GnRH analogs in premenopausal women
» side effects include symptoms of menopause (antagonist effects)
» may increase risk of endometrial cancer (agonist effects)
» slows osteoporosis and lowers LDL (agonist effects)
– aminoglutethimide/anastrazole is a second- or third-line therapy (when breast cancer no longer
responds to tamoxifen)
-tamoxifen was found to be highly effective as a preventive treatment in women at high risk for breast
cancer (incidence was decreased by ~45%) in a recent multi-center study funded by NCI
» increased risk of endometrial cancer and blood clots, but lower rate of bone fractures due to
partial agonist effects of tamoxifen
Selective Estrogen Receptor Modulators
u Raloxifene is the prototypical compound in this class
– these compounds are agonists in some contexts and antagonists in others
» acts as an agonist in bone and lipid metabolism
» acts as an antagonist in breast and endometrium
– has FDA approval for treatment of postmenopausal women (instead of estrogen replacement therapy)
» positive effects on bone density and blood lipid profiles without the risks of estrogen treatment
on the breast and endometrium
» does not reduce the hot flashes and can actually increase them
» it remains to be determined if it reproduces the positive effects of estrogen on atrophic vaginitis
or mood/cognition
- a major study will begin this year to compare raloxifene with tamoxifen in prevention of breast cancer
in women at high risk
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Progesterone Physiology & Pharmacology
Overview
u major physiological effect is to prepare the reproductive tract to support and maintain pregnancy (i.e.
progestational)
u therapeutic uses of progestins
– in contraceptive pills
– in hormone replacement regimens (to counter effects of estrogen)
u Antiprogestin
– receptor antagonist is used in therapeutic abortion
Progesterone Physiology
Natural progestins
u progesterone, 17a-hydroxyprogesterone
– synthesized/released from luteinized follicular cells under LH (or hCG) control
– bound in plasma to CBG and serum albumin
» 'free' hormone is active; bound acts as a reservoir
short half-life (5 min); metabolism in liver, excretion in urine
u mechanism of action is genomic
– in many tissues PR is upregulated by estrogen (estrogen-priming)
u physiological effects
– negative feedback at hypothalamus and pituitary, except at mid-cycle
– inhibits E2 synthesis, increases E2 metabolism
– inhibits endometrial proliferation and decreases myometrial contractility
– central effects; respiratory stimulant, thermogenic, depressant/anesthetic
Progesterone Pharmacology
u Natural progestins
– progesterone is not orally available due to extensive hepatic first-pass metabolism
u Synthetic C21 Progestins
– ester substitutions at C17
» MPA and megestrol acetate can be given orally (methyl group at C6)
» MPA used in hormone replacement therapy
u Synthetic C19 Progestins
– derived from C19 nor-testosterone; have more androgenic activity than C21
» ethinyl group at C17 allows oral administration
– gonane compounds are further substituted to reduce androgenic activity and increase
progestational activity
– these are used in most oral contraceptive preparations; also in Norplant
Side Effects
u some are due to androgenic action
– weight gain, acne, hirsutism, libido changes and lower HDL:LDL ratio
u others:
– menstrual irregularities, fluid retention, mood lability, depression
u Contraindications
– hepatic disease, incomplete abortion, suspected pregnancy, undiagnosed vaginal bleeding
20
Progestins - Therapeutic Uses
u oral contraceptive preparations
– this is the most common use of progestational agents
u replacement therapy
– postmenopausal women
» counter effects of estrogen
u dysfunctional uterine bleeding
u to treat endometriosis
– less common than GnRH or danazol
Antiprogestin Pharmacology
Receptor Antagonist
u Mifepristone (RU 486)
– orally available derivative of the 19-nor compound, norethindrone
– its principal use is for first trimester abortion (with a prostaglandin)
» may find use as contraceptive, anticancer drug or in labor induction
Synthesis Inhibitor
– progesterone is early in steroid biosynthetic pathway so that inhibiting its synthesis will have numerous
non-specific effects
Oral Contraceptives - ‘The Pill’
Combination Oral Contraceptives
u the most effective form of hormonal contraception available
– pill taken for 21 days; placebo or no pill for 7 days (withdrawal bleeding)
– mechanism involves primarily inhibition of mid-cycle LH surge
» also alterations in cervical mucus
– many formulations - simple, biphasic or triphasic
intended to lower the total amount of hormone administered and to provide ratios of estrogen and
progestin similar to the menstrual cycle
– choice of formulation guided by:
» desire to use lowest possible steroid concentrations
» estrogenic vs. progestogenic side effects
Combination Oral Contraceptives
Side Effects
u untoward side effects
– estrogenic include:
» hypertension, thromboembolic disorders, gall bladder disease
» nausea, headache, vomiting, breast tenderness, edema
– progestogenic include:
» weight gain, hirsutism, depression, acne, irregular bleeding
u beneficial effects
» decreased incidence of endometrial and ovarian cancer
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Combination Oral Contraceptives
u Contraindications
– presence or history of thromboembolic disease or cerebrovascular disease
– myocardial infarction, coronary artery disease
– congenital hyperlipidemia
– carcinoma of the breast, reproductive tract, or other hormone-dependent neoplasia
– a bnormal or undiagnosed vaginal bleeding
– pregnancy
– presence or history of liver tumors, impaired liver function
The risk of serious cardiovascular side effects is particularly high among smokers over the age of 35,
for whom even low dose oral contraceptives are contraindicated.
Other Hormonal Contraceptives
Progestin-only formulations
– mechanism of contraception is both feedback suppression of LH and FSH and production of a scant
viscid cervical mucus
u progesterone ‘mini-pill’
– low doses of progesterone taken daily
– useful when estrogens are contraindicated but less effective than combination preparations
– associated with irregular bleeding - leads to non-compliance
u Norplant (subcutaneous implant of levonorgesterol)
– long-lasting contraception (up to five years)
– again irregular bleeding is potentially problematic
» often improves after the first year
u MPA injection (every three months)
Other Hormonal Contraceptives
Post-Coital Contraceptive ‘morning-after pill’
u mechanism of action is unknown, but serious side effects limit use and compliance
u very high dose of estrogen
– for example, 2.5 mg twice daily for 5 days within 72 hours of coitus
– nausea, vomiting, headache, dizziness, breast tenderness, leg and abdominal cramps
u estrogen and progestin combination
– lower doses used result in fewer and less severe side effects
22
Androgen Physiology and Pharmacology
u Anabolic androgenic steroids
– are synthesized and secreted principally by the male gonad
u major physiological effect
– growth promoting (anabolic)
– virilizing (androgenic)
u therapeutic uses of androgens
– in hormone replacement regimens
– to treat hormone-dependent disorders (endometriosis)
– abused by athletes
u Antiandrogens - receptor antagonists & synthesis inhibitors
– to treat hormone-dependent disorders (prostate cancer, prostatic hyperplasia)
– to treat hirsutism
Androgen Physiology
u Testosterone
– synthesized/released from testicular Leydig cells under LH control
» metabolized to 5a-dihydrotestosterone, a more potent androgen
» aromatized to estrogen and mediates effects via the estrogen receptor
– bound in plasma to SHBG (high affinity) and to CBG & serum albumin
» ‘free’ hormone is active (2%); bound acts as a reservoir
short half-life (10 to 20 min); metabolism in liver, excretion in urine
u mechanism of action is genomic
– a single AR mediates androgenic & anabolic effects
u physiological effects of androgens
– induces male phenotype in fetus
– development of secondary sexual characteristics at puberty (growth of muscles, bones)
– negative feedback at hypothalamus and pituitary
– maintain spermatogenesis, increase libido and male sexual behavior
Androgen Pharmacology
u Natural androgens
– testosterone is not orally available due to extensive hepatic first-pass metabolism
– intramuscularly in oil; in transdermal patches
u 17b-Testosterone Esters
– ester substitutions at C17 (testosterone cypionate, testosterone enanthate)
» used as intramuscular injections in an oil vehicle for hormone replacement
» released slowly from the depot, ester groups rapidly removed,
» pharmacokinetics dictated by hydrophobicity of the ester group
u 17a-Testosterone Alkyls
– orally available, but hepatotoxicity limits clinical usefulness
– danazol is a weak androgen used in hereditary angioneurotic edema and together with GnRH analogs
to treat endometriosis.
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Androgens - Therapeutic Uses
u replacement therapy
– the most clear indication for androgen therapy - hypogonadism
– parenterally administered testosterone esters are the treatment of choice
– FSH treatment is initiated to induce spermatogenesis when pregnancy is desired
u hereditary angioneurotic edema
– danazol is used to increase inhibitor of the first component of complement which is reduced or absent
in this autosomal dominant disorder
u to treat endometriosis
– danazol is used to inhibit hypothalamo-pituitary function, and thereby decrease ovarian function and
estrogen production
u others
– anemia, breast cancer, catabolic states, enhance athletic performance
Androgen Pharmacology
Side Effects
u virilizing
acne, hirsutism and changes in the voice, male pattern baldness, clitoral enlargement, weight gain,
libido changes and lower HDL:LDL ratio
u Feminizing effects
– gynecomastia as testosterone is converted to estrogen
u Toxic effects
– edema and liver disease (jaundice, hepatic carcinoma, peliosis hepatitis)
Antiandrogen Pharmacology
u Androgen Receptor Antagonists
– Flutamide
» orally active androgen receptor antagonist used in treatment of prostate cancer; also need GnRH
agonist to suppress gonadotropin and testosterone secretion
– Cyproterone acetate
» orally active antagonist for treatment of severe hirsutism; investigational
u Androgen Synthesis Inhibitors
– Ketoconazole and Spironolactone
» not widely used but have been tried in prostate cancer and hirsutism
u 5a-Reductase Inhibitor
– Finasteride
» orally active; for treatment of benign prostatic hyperplasia
» also for treatment of male pattern baldness (PROPECIA)
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