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