Hormone agonists, antagonists, or modulatorsHormone agonists, antagonists, or modulators
Treatment of hormone deficiency statesTreatment of hormone deficiency states
Treatment of hormone excessTreatment of hormone excess
Diagnostic tools- challenge/stimulation testsDiagnostic tools- challenge/stimulation tests
Modification of normal endocrine functionModification of normal endocrine function
Treatment of non-endocrine diseases Treatment of non-endocrine diseases
Endocrine PharmacologyEndocrine Pharmacology
Hypothalamic/pituitary control of Hypothalamic/pituitary control of endocrine functionendocrine function
Trophic hormone regulated by:
Growth hormone GRH SRIF
Prolactin TRH Dopamine
LH, FSH GnRH
ACTH CRH
TSH TRH SRIF
Posterior pituitary hormones: Vasopressin & Oxytocin
(Anterior pituitary) (Hypothalamus)
(Hypothalamus)
Growth hormone(hGH; somatropin, somatotropin)
Chemistry:
Single chain191 amino acids2 intramolecular
disulfide bondsSimilar to:
prolactinplacental lactogen hGH-V
Li CH and Graf L, Proc Nat Acad Sci USA 71: 1197-1201, 1974
GH: preparations used clinicallySpecies specificHuman pituitary-derived GH risk of Creutzfeldt- Jakob disease
Recombinant GH preparations used currently: Somatropin
Recombinant human GH (rhGH)Somatrem
Recombinant methionyl GH (met-rhGH)N-terminal Met start signal for transcriptionMore antigenicNearly equal in effectiveness to rhGH
Sustained-release rhGH- 1 to 2 doses/month;Increases compliance
Growth hormone secretion (review)
HypothalamusHypothalamus
Liver, PeripheryLiver, PeripheryIGF-IIGF-I
Anterior PituitaryAnterior Pituitary
GHGH
LL-DOPA, -DOPA, -adrenergic -adrenergic agonists, 5-HTagonists, 5-HT
Low glucoseLow glucose
Sleep, exercise, Sleep, exercise, stressstress
++
GHRHGHRH
++
Gonadal SteroidsGonadal Steroids++
GH secretagogues
ß-adrenergic agonists-
- -
SRIF - -
Actions: synthesis of chondroitin and collagen skeletal growth soft tissue growthUrinary retention of nitrogen, potassium, phosphate
Mechanism of action: Specific membrane receptors - members of the
cytokine receptor superfamily
Growth hormone (review)
Hypersecretion Gigantism in childrenAcromegaly in adults
progressive enlargement of head, face, hands, feet, thorax; heat intolerance, sweating, fatigue, lethargy
Deficiency Postnatal growth retardation
CongenitalAcquired
Adult GH deficiencyAdult-onset pituitary/hypothalamic disease, surgery, radiation therapy, or traumaAge-associated (up to 1/3 of the elderly)
Growth hormone: pathology
Uses of somatropin and somatrem
1) Administered SQ for deficiency in childrenDaily administration more effective than the same
total dose given 3 days per weekEvening administration mimics normal patternDepot preparations: 1 or 2 doses/month
2) To improve growth in very short stature children in absence of deficiency Use IGF-I to treat growth retardation from GH
resistance (receptor defect)3) Administered SQ for adult GH deficiency
Use to treat “somatopause” is controversialImproves lean body mass, skin thickness, cognitive
function, vitality
Half-life : Endogenous GH: 20 to 30 minutes
SQ rhGH peak: 2 - 4 hours duration: up to 36 hours
25 - 30 % bound to GH-binding protein in plasmaAdverse effects
Few in childrenIn adults: peripheral edema, myalgias, arthralgias,
carpal tunnel syndromeHyperglycemia not a frequent side effect
Drug interactionsIncreased cytochrome P450 isoforms increased
clearance of steroids, anticonvulsants, cyclosporine
Uses of somatropin and somatrem
G protein-coupled receptor binding
cAMP production
GH synthesis and secretion
Growth hormone-releasing hormone (GRH or GHRH)
Preparation used clinically: sermorelin acetate
Action and mechanism of action:
Half-life: 50 minutes
+
+
GRH: Clinical usesDiagnostic:
To determine GH secretory reserve:
For treating growth hormone deficiency: children who have growth hormone reserves, i.e. hypothalamic GRH deficiency
Somatostatin (somatotropin release-inhibiting factor, SRIF)
Secreted by hypothalamic anterior region and by cells of the pancreatic islets
Secretion by GH, IGF-I, thyroid hormonesSynthetic analogue: Octreotide
Octreotide
Properties:
Synthetic octapeptide analog used clinically
More potent at inhibiting GH secretion than native SRIF
Less potent at inhibiting insulin secretion
Increased half-life: 1.7 hours (SRIF: 1 to 3 minutes)
Resistant to enzymatic degradation- D-Phe, D-Trp
Rebound hypersecretion lower than for SRIF
Sustained-release form recently approved for use
Somatostatin and octeriotide
Actions:
Inhibits GH secretion but not its synthesis
Inhibits basal and TRH-stimulated TSH secretion
Inhibits secretion of GI peptide hormones:
insulin, glucagon, VIP, gastrin, and others
Mechanism of action:
Gi protein-coupled receptors
Reduces cAMP production and Ca2+
Clinical usesAcromegaly
For excess GH secretion by somatrope adenomas that remains or recurs after irradiation or surgery
Does not induce hyperglycemia
Carcinoid tumorsIntestinal tumors, may secrete physiologically active
substances (5-HT, prostaglandins, etc.)
Pancreatic cell tumors (VIPomas)diarrhea, achlorhydria
Adverse effects
Reduction of bile production, gallbladder contractility
biliary sludge and/or gallstones
GI disturbances
Pain, nausea, diarrhea
Growth hormone analogs: Pegvisomant
Recombinant hGH analog (approved March, 2003) growth hormone antagonistIncreases T1/2 (SQ) to approximately 6 daysReduces immunogenicityReduces binding affinity
Most effective pharmacologic treatment for acromegaly
Well-tolerated
Growth hormone analogs: Pegvisomant
Treatment of growth hormone or prolactin hypersecretion
Ergot-derived Dopamine agonists
Bromocriptine Pergolide Cabergoline
N
S
HN
NH
O
N
N
O
HN
N
HO
N
O N
O
HN
OO
N
HN
H
H
Br
Prolactin (PRL) Secretion: inhibited by dopamine
Binds to a specific receptor, similar to GHR Primary target: mammary gland
development during pregnancyinduces milk protein synthesisinitiates and maintains lactation
Not used clinicallyhypoprolactinemia extremely rare
Inhibits pulsatile GnRH secretion hypogonadism
Female: luteal phase is shortened anovulation, oligomonorrhea, amenorrhea
Male: testosterone synthesis spermatogenesis
Treatment of hyperprolactinemiaTransphenoidal microsurgery: Microadenomas -
85% long term remission Macroadenomas - outcome less satisfactory
Hyperprolactinemia:
Dopamine agonists for GH or prolactin hypersecretion
Given orallyAdverse effects:
nausea, vomiting, dizziness, postural hypotensionStart at reduced doses to minimize adverse effects
Paradoxical inhibitory effect on GH secretion:Somatroph adenomas express receptor
characteristics of lactotrophsMost useful for GH hypersecretion when prolactin
secretion also is elevatedCabergoline is more effective than bromocriptine
Normalizes IGF-I in 35% of patients
Chemistry: Glycoproteins
92 amino acid subunit (identical to that of TSH) ß subunits which confer biological specificity:
Luteinizing hormone (lutropin, LH) - 115 aa
Follicle stimulating hormone (follitropin, FSH)- 115 aa
Chorionic gonadotropin (choriogonadotropin, CG)- 145 aa
Placental, same receptor as LH but longer half-life
Gonadotropins
Mechanism of action: Specific G protein-coupled receptors, activation of adenylate cyclase
LH activity: Human chorionic gonadotropin (hCG)
Equivalent LH and FSH activity:Human menopausal gonadotropin (hMG;
menotropin)
FSH activity:Urofollitropin (uFSH)
Menotropin with LH component removed
Recombinant human FSH (rFSH)
Gonadotropins used clinically
Gonadotropins: ActionsIn the female:
FSH:stimulates development of ovarian follicles
LH stimulates production of estrogen and progesterone, induces ovulation
In the male:
FSH stimulates production of androgen-binding globulinmaintains high testosterone levels in the seminiferous tubules required for spermatogenesis
LH stimulates production of testosterone
Gonadotropins: Clinical uses
Ovarian stimulation
Induction of ovulation for treatment of infertility
DAYS FROM LH PEAK
LH
FSH
10 15 20 25 0 5 10 15
Normal ovarian cycle:FSH stimulates follicle growth
LH surge induces ovulation
Gonadotropins: Clinical uses
Ovarian stimulation1. FSH to stimulate follicle growth
Menotropins or urofollitropin, i.m. or
Highly purified urofollitropin or rFSH, s.c.
75 U/day for 6 to 12 days, beginning early in the cycle
Long-acting GnRH agonist may be used to suppress endogenous LH secretion
Assess number and size of follicles (ultrasound and estradiol levels) to determine duration of treatment
2. LH to induce ovulation
hCG, 5000-10,000 U, i.m. one day after last dose of FSH
3. Ovulation should occur in approximately 36 hours
Gonadotropins: Clinical usesOvarian stimulationAdverse effects:
Multiple birthsOvarian hyperstimulation syndrome (OHSS)
Increase in vascular permeability rapid fluid accumulation in the peritoneal cavity, thorax, pericardium
Monitor patient closely during and after treatment, when symptoms may peak
If ovaries become abnormally enlarged during gonadotropin treatment, hCG is not administered
Male hypogonadism and infertility:
1. LH to stimulate testosterone synthesis
hCG, 5000 U, i.m. three times/week for 4 to 6 months
2. LH and FSH to stimulate spermatogenesis
Menotropins, 75 U LH, 75 U FSH, i.m. 3 times/week; hCG reduced to 2000 U twice a week
> 10 weeks required for development of male germ cells
Cryptorchidism:
hCG, 500 to 5000 U, i.m. 2 to 3 times/week for several weeks between ages 4 and 9
Gonadotropins: Clinical uses
Leydig cell failure - stimulation test with CG
No testosterone response indicates primary failure
Normal testosterone response indicates secondary or tertiary disease
Gonadotropins: Diagnostic uses
Non-hormonal agent for infertility
Structurally-similar to tamoxifen
Clomiphene
Cl
OCH2CH2NCH2CH3
CH2CH3
Mechanism of action:
Selective estrogen receptor modulator
Binds to the estrogen receptor
Competitive inhibitor
Half-life: 5 to 7 days; binds to plasma proteins and accumulates in fat
Induction of ovulation:
Intact hypothalamic-pituitary-ovarian axis required
Reduces estrogen-mediated negative feedback increased gonadotropins
Increases amplitude, but not frequency of pulsatile LH and FSH secretion
Administered orally: clomiphene citrate, 50 mg/day for five days
Ovulation should occur 5 to 10 days after final dose
Clomiphene: Clinical uses
Hormone preparations used clinically:
Synthetic GnRH (gonadorelin hydrochloride)
Used for pulsatile administration
Long-acting synthetic agonists
Leuprolide acetate Histrelin acetate
Nafarelin acetate Goserelin acetate
Chemistry: single chain 10 amino acid peptide
Gonadotropin Releasing Hormone (GnRH, LHRH)
Pyro-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly
Secretion by the hypothalamus is driven by a pulse generator that is regulated by negative feedback of the gonadal hormones
Binds to specific G protein-coupled receptor
Frequency and amplitude of GnRH pulses determines the secretion of each gonadotropin
GnRH
Half-life:
GnRH - 5 to 7 minutes
Insertion of D-amino acids at normal protease cleavage sites produces long-acting agonists
Stimulation of LH (FSH) release i.v. or subcutaneous pulsatile administration
of gonadorelin via infusion pump Dose and schedule adjusted empirically for
each patientUsually 1 to 10 µg/pulse at intervals of 60 to 120
minutes For induction of ovulation single dominant
follicle
Also used for cryptorchidism, hypogonadism, and delayed puberty
GnRH: Clinical uses
Secondary vs. tertiary hypogonadism: Stimulation tests- 100 µg infused i.v. over a period of 15 secondsPlasma LH and FSH measured at 0, 30, 60, and 90 minutesLH should increase 1.3 to 2.6 µg/LFSH response is less markedLong-standing hypothalamic disease and GnRH deficiency may
cause lack of LH responsiveness in the absence of pituitary disease; requires prolonged or intermittent stimulation for a valid assessment
GnRH: Diagnostic uses
Suppression of LH (FSH) release:
Prolonged exposure to long-acting agonists downregulates GnRH receptor number
Used for gonadotropin-dependent precocious puberty, endometriosis, polycystic ovarian syndrome, uterine leimyomas, gonadal steroid-dependant prostate cancer
Used to suppress endogenous LH surges during treatment with exogenous menotropins for induction of ovulation
GnRH agonists: Clinical uses
Long acting agonists induce symptoms of hypogonadism, including detrimental effects on bone mineralization and lipids
GnRH: Adverse effects
Ganirelix acetate, Cetorelix acetate
GNRH analogs
competitive antagonists of the GnRH receptor
LH secretion > than FSH
Used to inhibit premature LH surges during the early to mid-follicular phase in women undergoing controlled ovarian stimulation for treatment of infertility
A low dose is given SQ beginning on day 5 or 6 and continued daily until the day of hCG administration
Do not induce a transient increase in gonadotropins
GnRH Antagonists
Vasopressinarginine vasopressin (AVP) antidiuretic hormone (ADH)
Chemistry:
Nonapeptide which differs from oxytocin by only 2 amino acids
Clinical preparations:synthetic arginine vasopressin (human form)desmopressin (1-deamino-8-D-arginine vasopressin,
DDAVP), synthetic analog with longer duration of action and selective activity for renal effects
Phe - Tyr - Cys Glu - Asn - Cys - Pro - Arg - Gly - NH2
Vasopressin secretionStimulated by:
Increasing extracellular fluid osmolality
Falling blood pressure
Decreased extracellular fluid volume without change in osmolality (as in hemorrhage)
The renin-angiotensin II system
Vasopressin secretionOther stimulatory factors: FYIacetylcholine cholecystokinin prostaglandins
histamine neuropeptide Y
dopamine substance P
glutamine VIP
Inhibitory factors: FYI stress: atrial natriuretic factor (ANF)
pain GABAhypoxia opioid peptides nausea
Stimulators:nicotineepinephrinevincristine (antimitotic)cyclophosphamide
(antineoplastic agent)morphine (at high doses)
tricyclic antidepressantsimipramine
lithium Stimulates secretion but inhibits renal response
Inhibitors:ethanolglucocorticoidsphenytoin
morphine (at low doses)butorphanol, oxilorphan (K
agonists)antipsychotics
tricyclic phenothiazineschlorpromazine
butyrophenones haloperidol
AVP secretion: Pharmacological agents (FYI)
AVP: Mechanism of action
Three specific G-protein -coupled receptors:
V1a binding
phospholipase C
IP3, Ca2+
contraction of
vascular and GI smooth muscle
+
+
+
V1b binding
phospholipase C
IP3, Ca2+
potentiation of ACTH secretion
by anterior pituitary
+
+
+
V2 binding
adenylate cyclase
cAMP
insertion of
aquaporin into luminal membrane of
renal medullary collecting ducts
+
+
+
AVP Actions
V2-mediated effects occur at much lower concentrations than those mediated by V1
V1 pressor effects may be most important in maintainting arterial pressure in the face of extreme hypovolemia and hypotension
Vasopressin half-life
AVP circulates unbound in the plasma
Half-life is approximately 15 minutes
Desmopressin
2-compartment disappearance curve
half-lives of 6.5 to 9 and 30-117 minutes
Duration of action of 12 to 24 hours
Vasopressin: Clinical uses
Treatment of central Diabetes Insipidusreduced water permeability and polyuria
Causes of DI:AVP deficiency
Central = neurogenic = pituitary D.I.May be congenital or acquired
Impaired renal response to AVPnephrogenic D.I.
Vasopressin: Clinical uses
Replacement therapy for central DI:
Use desmopressin
V2 effects much greater than V1 effects
10 µg once or twice a day using aqueous solution as metered nasal spray
or
1 to 2 µg once or twice a day s.c.
Vasopressin: Clinical uses
G.I. Applications
Based on V1-mediated contraction of GI smooth muscle: for post-operative ileus and to dispel intestinal gas before abdominal imaging
Based on V1-mediated contraction of vascular smooth muscle: for emergency treatment of bleeding esophageal varices (varicose veins) and for acute hemorrhagic gastritis
DDAVP is not appropriate for these uses.
Vasopressin: Clinical uses
Diagnostic: To differentiate central and nephrogenic D.I.
Challenge with 1 µg desmopressin s.c., i.m., or i.v. following water deprivation
One hour after treatment, urine osmolality should increase > 50 % if cause is AVP deficiency
Vasopressin: Adverse effects
Primarily a result of unwanted V1 effects:
constriction of blood vessels
coronary vessels
stimulation of GI muscle
Cross-reaction with the oxytocin receptor
stimulation of uterine muscle
Adverse effects rare:
V2-mediated effects at lower doses than V1-mediated effects
Other agents for D.I.
Non-hormonal drugs for central D.I.
Thiazide diuretics with paradoxical effect
Chlorpropamide (sulfonylurea)
Clofibrate
Carbamazepine
Potentiate effect of residual AVP
Syndrome of Inappropriate ADH Secretion (SIADH)
Impaired water excretion in the presence of hyponatremia and hypoosmolality
Hypotonicity may produce lethargy, anorexia, nausea and vomiting, muscle cramps; may eventually lead to coma, convulsions, and death
From inappropriately high secretion of AVP/ADHEctopic malignant neoplasmsCNS trauma and infectionsEndocrine diseaseDrug interaction
Syndrome of Inappropriate ADH Secretion (SIADH)
Treatment:
water restriction
i.v. hypertonic saline
loop diuretics such as furosemide
demeclocycline, 1 to 2 g/day orally
reduces renal sensitivity to AVP
nephrotoxic: monitor renal function
Vasopressin and cardiac arrestLaboratory studies: vasopressin vs. epinephrine
increased blood flow and delivery of oxygen to brainbetter chance of resuscitationimproved neurological outcome
Wenzel et al. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med. 2004;350:105-113Vasopressin vs. epinephrine
Equally effective for treating ventricular fibrillation and pulseless electrical activity
AVP is superior for treating asystoleCombined treatment may be better than epinephrine alone in
patients with refractory cardiac arrest“Practitioners should perhaps be encouraged to incorporate the use of vasopressin into their resuscitation protocols immediately”
Differs from AVP in only two amino acids
Synthetic oxytocin is used clinically
Oxytocin
Chemistry: Ile - Tyr - Cys Glu - Asn - Cys - Pro - Arg - Gly - NH2
By hypothalamic oxytocinergic neuronsIn response to neural stimulation
Parturition (distention of the cervix and vagina)Suckling
Stimulated by plasma hypertonicity, hemorrhage
Other stimulatory factors: Inhibitory factors: estrogen opioid peptidesangiotensin II severe painVIP, cholycystokinin temperaturenorepinephrinenausea, satietypsychological stress
Oxytocin secretion
Specific G protein-coupled receptors frequency and force of uterine smooth muscle contraction during parturition contraction of mammary myoepithelial cells and milk ejection
Half-life: 5 to 12 minutes
Oxytocin
OT receptor binding
phospholipase C
IP3, Ca2+
contraction of uterine smooth muscle and
mammary myoepithelial cells
+
+
+
Action and mechanism of action
Induction of term labor: drug of choiceInfused as dilute solution at 10 mU/mLBegin at a rate of 1 mU/minuteIncrease gradually to 4 mU/minuteMaintain for 1 hour before increasing rateMonitor uterine activity, fetal heart rate
Adverse effectsUterine ruptureTrauma or death to the infantRisks minimized by conservative protocol
Oxytocin: Clinical uses
Control of postpartum bleeding:
Administered to maintain uterine tone
For increasing milk ejection:
Administered as a nasal spray
2 to 3 minutes before breast-feeding
Oxytocin: Clinical uses
Oxytocin challenge test:For uteroplacental insufficiencyOT infused at 0.5 mU/minute initiallyRate increased until uterine contractions
(once every 3 - 4 minutes)Fetal heart rate used as a measure of distress
Indicates whether placental reserve is sufficient for continuation of a high-risk pregnancy
Oxytocin: Clinical uses
Ergot alkaloids: ergonovine and methylergonovineControl of postpartum uterine bleeding that does not respond to oxytocin
Adverse effects generally not significant in nonhypertensive patients at effective doses
High sensitivity of the gravid uterusContraindicated in the hypertensive patient
Induce peripheral vasoconstriction
Prostaglandins PGE2 (dinoprostone)
for midtrimester elective abortion15-methyl PGF2a (carboprost)
to control of postpartum bleedingalso for elective abortion
Other uterotonic agents
Uterine relaxants used for premature laborß-adrenergic agonists: ritodrine, terbutaline
Adverse effects: cardiovascular and metabolic-tachycardia, cardiac output, fluid balance disturbances, hyperglycemia
Magnesium salts (sulfate and gluconate)Ca2+ channel blockers (nifedipine)Prostaglandin synthesis inhibitors: indomethacin
Only prior to 34th week of gestation to prevent premature closure of the ductus arteriosus
Tocolytics