ENDOCRINE PHARMACOLOGY

• Hypothalamic-Pituitary Hormones• Thyroid Hormones• Gonadal Hormones and Inhibitors• Agents Affecting Bone Homeostasis• Glucocorticoids and Mineralocorticoids• Insulin and Anti-diabetic drugs

HORMONES: Pituitary, Pancreas, Thyroid, Adrenal, Ovarian ,Testicular

1. Gonadotrophins 2. Prostaglandins 3. Progestins 4. Oestrogens 5.Androgens 6. Antiprogestins 7. Antioestrogens 8. Antiandrogens

PITUITARY HORMONES

Hypothalamic Hormones

Growth Hormone-Releasing Hormone (GHRH)

• 44 amino acid peptide• Full biological activity in 1-29

– Structural homologies to GI peptide hormones

• Function– Stimulates synthesis and release of growth

hormone (GH) from the anterior pituitary

• Research purposes only

Growth Hormone-Releasing peptides (GHRPS)

• Group of synthetic peptide analogs that can stimulate GH secretion

• Sermorelin – Synthetic 1-29 terminal end of GHRH– Must have properly functioning pituitary

Somatostatin (Growth Hormone-Inhibiting Hormone,

Somatotropin Release-inhibiting hormone)

• Structure- 14- or 28-amino acid structure

• Function– Inhibits growth hormone release in normal

individuals, thus opposes GHRH– Inhibits the release of glucagon, insulin TSH, LH and

gastrin (GI hormones)– Lowers the rate of gastric empting and reduces smooth

muscle contractions and decreases blood flow the intestine

Octreotide

• Somatostatin analog– Inhibits release of GH from pituitary– 45x more potent than endogenous

peptide • Therapeutic use

– Treatment of a variety of hormone-secreting tumors

– Acromegaly: Excess GH in adults; Usually from a pituitary carcinoma

Gonadotropin-Releasing HormoneLuteinizing hormone-releasing hormone

• Pulsatile GnRH secretion stimulates the gonadotroph cells in the anterior pituitary to produce and release LH,FSH

• Sustained non-pulsatile administration inhibits the release of FSH and LH by the pituitary in both males and females

GnRH AND ANALOGS: GnRH:

Chemistry: single chain 10 amino acid peptide Pyro-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly

• Binds to specific G protein-coupled receptor • Biologic preparation very costly, hence synthetic GnRH

analogs are used. • Hormone preparations used clinically: • Synthetic GnRH (gonadorelin hydrochloride) peptide

analogues: sed for pulsatile administration• Long-acting synth. agonists- Buserelin acetate, Leuprolide acetate, istrelin

acetate ,Nafarelin acetate, Goserelin acetate, fertyilerin, deslorelin

Indications: • Follicular cysts • Endometriosis and Uterine fibroids

– Breast cancer– Prostate cancer– Central precocious puberty– Male and female infertility

• Delayed ovulation, anovulation • Acyclicity- anoestrus, suboestrus, • Improved conception rate after AI • In oestrus synchronisation

Dose:

Buserelin; cow. 10-20µg; horse, 40 µg, IM, IV, SC; • gonadorelin: cow, 0.5mg, IM,SC,IV, Fertilerin, cow, 100 µg,IM

GnRH Antagonists:

Ganirelix acetate, Cetorelix acetate• 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

• Endometriosis and uterine fibroids

Corticotropin-Releasing Hormone

• Secreted in response to stress

• Stimulates corticotropin cells to produce adrenocorticotropic hormone (ACTH)

• Diagnostic use only

Thyrotropin-Releasing Hormone

• Stimulates secretion of thyroid stimulating hormone (TSH) from the anterior pituitary

• Protirelin

• Diagnostic purposes only

Posterior Pituitary Gland Hormones

• ADH is used to treat diabetes insipidus (disease characterized by the inability to concentrate urine due to insufficient amounts of ADH)

• Oxytocin is used to aid in uterine contraction and induce labor in animals at term, expel the placenta, induce milk letdown, and as an adjunct therapy for animals with open pyometra

Anterior Pituitary Hormones

Growth Hormone (Somatotropin)

• Polypeptide hormone, 191 amino acids

• Released from the anterior pituitary in response to GHRH

• Inhibited by GHIH

(somatostatin)

• Recombinant human

growth hormone

Growth Hormone (Somatotropin)

• Induces lipolysis in adipose tissue and growth in skeletal muscle– Binding to its receptor (direct)

• Adipose tissue stimulated to break down triglyceride and stops the uptake of circulating lipids

– Insulin-like growth factor-1 (indirect)• Stimulates the liver to release IGF-1 target tissues>produces growth at open

epiphyses

GH Available

• Recombinant human GH• Somatropin

– Identical to natural hGH

• Deficiency– Children Failure to grow conditions

– Kidney disease, Turner’s syndrome

• GH deficiency; genetic or acquired

– Adults Generalized obesity, reduced muscle mass, asthenia and reduces cardiac output

• Widely abused hormone

Growth Hormone Receptor Antagonist

• Binds to GH receptors, blocks GH-stimulated, hepatic production of IGF-1

• Pegvisomant

• Treatment of– Acromegaly

• Increased growth hormone in adults

GONADOTROPINSa)Pituitary Gonadotropins : Luteinizing hormone ( LH) - 115 aa; Follicle stimulating hormone (f FSH)- 115 aa.

Both can be obtained in semipurified form, but expensive

Porcine FSH(pFSH) and recombinant derived FSH are used to induce superovulation in donor cows for embryo transfer.

b) Non Pituitary Gonadotropins: human Chorionic gonadotropin (hCG) Pregnant mare serum gonadotrophin

(PMSG/eCG)

Gonadotropins used clinically

• LH activity:

Human chorionic gonadotropin (hCG)

• Equivalent LH and FSH activity:

Human menopausal gonadotropin (hMG; menotropin)

• FSH activity:

Urofollitropin (uFSH) Pregnant mare serum gonadotrophin (PMSG/equine chorionic gonadotrophin;eCG), Menotropin with LH component removed Recombinant human FSH (rFSH)

Actions In the female: FSH: dev. Of ovarian follicles LH : production of estrogen and progesterone,

induces ovulationIn the male: FSH : • production of androgen-binding globulin• Maint. high testosterone levels in seminiferus

tubules req.for spermatogenesis LH : stimulates production of testosterone

Indications of FSH ( PMSG) • Superovulation in donor cows for embryo

transfer • Impaired spermatogenesis in bulls • Induce oestrus in physiological anoestrus in

bitches • In association with hCG to stimulate onset of

cyclical activity after farrowing in pigs. • In association with intravaginal progestogen

sponges to advance the onset of breeding season in sheep and goats

• Dose: 1500- 300IU, SC or IM,IV(cattle); 500-800IU, SC or IM(sheep and goat); 50-200IU, SC or IM(dog); 1000I U, SC or IM(pig)

Indications of LH (hCG)• Delayed ovulation, anovulation, ovarian

cysts , luteal deficiency• improving conception rate• improving libido in cattle , pigs, sheeps,

goat and horses • To induce ovulation in cats• to curtail prolonged or persistent

prooestrus/oestrus in bitches.• Dose: 1500- 300IU, IV or IM(cattle and horse); 100- 500 IU,

SC or IM(sheep and goat); 100-500 IU, SC or IM(dog); 500-1000I U,

IV or IM(pig), 100-200 IU (cat)

Prolactin

Positive regulation on prolactin release: TRH,GnRH, stimulation of the nipple and mammary gland, and estrogens

Dopamine Agonists

• Decrease prolactin secretion through a dopamine-mimic action

• Bromocriptine , Pergolide

• Cabergoline , Quinagolide• Indications:

– Prolactin secreting adenomas– Acromegaly– pseudo pregnancy in bitches – Mammilitis: excessive lactation

Gonadal Hormones and

Inhibitors

The Female

• Major sex hormones– Estrogens– Progestins

• Function– Development of secondary sex

characteristics– Control pregnancy– Control Ovulatory-Menstrual cycle– Bone Homeostasis

Estrogens

• 17 Beta-Estradiol– Principle ovarian estrogen– Most potent

• Estriol– Principle placental estrogen

• Estrone– Metabolite of 17Beta-estradiol– Major ovarian and post-menopausal estrogen

Progestin

• Progesterone

• Secreted by the – Corpus luteum– Placenta

• Functions– Preparing the body for pregnancy– Maintains pregnancy

Negative Feedback Loops

• Estrogen synthesis and secretion stimulated by FSH

• Progesterone production stimulated by LH

• Inhibin– Ovarian protein– Negatively affects

FSH

Biosynthesis

• Estrogen– Ovary– Other tissues produce significant amounts

• Progesterone– Placenta– Corpus luteum in ovary

Steroidogenesis

• Cholesterol is converted to pregnenolone

• Converted directly to progesterone or to 17alpha-hydroxypregnenolone

• Androgen steroids– Testosterone– Androstenedion

e

Steroidogenesis

• By an AROMATASE

(enzyme), the androgens can be converted to ESTRONE and ESTRADIAL

Estrogen Agents

• Naturally occurring – Rapidly inactivated– Not much value therapeutically – estradiol, estrone, estriol

• Conjugated, esterified or mixed estrogenic substances

Conjugated estrogens

• Estrogens produced by natural source, stallions

• Indications– Menopausal symptoms (HRT)– Prevent osteoporosis – Mismating in bitches

Estrogen Agents

• Chemical alterations: increase oral effectiveness• Steroidal, synthetic

– Ethinyl Estradiol (semisynthetic), mestranol, tibolone, hexestrol, dienestrol, diphenyl ethylene(stilbene), esters like estradiol benzoate, cypionate, propionate, valerate, ethenate

– Quinestrol -Contraception in combos with progestins

• Non-steroidal, synthetic/– Diethylstilbestrol (DES)– Chlorotrianisene

.

Estrogen• Promotes female sex characteristics and stimulates and

maintains the reproductive tract

• Synthetic estrogens are used in dogs to prevent implantation of fertilized ova and to correct urinary incontinence, vaginitis, and dermatitis

• Synthetic estrogens are used in cattle to treat persistent corpus luteum, aid in expulsion of retained placentas and mummified feti, and to promote weight gain

• Synthetic estrogens are used in horses to induce estrus in the nonbreeding season

.

Indications • Endometritis in cattle(contraindicated in acute

toxic metritis), to tone atonic uterus • Prevention of unplanned pregnancy /

mismating in bithches, urinary incontinence in spayed bitches,

• prostatic hyperplasia and adenoma in male dog• to depress hypersexuality in male dog. • Ripening of cervix before oxytocin induced

foaling in horse • To induce artificial lactation in cattle • ( with Progesterone)

Antioestrogens (Nonsteroidal)

• Clomiphene citrate, tamoxifen citrate, centchroman

Primarily indicated in

• conditions of anovulatory oestrus

• low sperm counts in males

• breast cancer in females

Selective Estrogen Receptor Modulators (SERMs)

• Medications that act on estrogen receptors• Action differs tissue to tissue, thereby granting

the possibility to selectively inhibit or stimulate estrogen-like action in various tissues

• Raloxifene, toremifene, bazedoxifene, lasofoxifene, ormeloxifene

• Stereochemically similar to 17beta-estradiol

Progestins/ Natural progesterone Derivatives

Medroxyprogesterone acetate Hydroxy progesterone caproateMegestrol acetate Proligestone Delmadinone acetateChlormadinone acetateNorethisterone acetate • Most closely related to natural progesterone, both

structurally and pharmacologically• Tab.- oral administration, liquid solutions or

suspensions for injection or depot-injection.

Synthetic Progesterones

• better oral effectiveness• some degree of androgenic effects• 19-nortestosterones derivatives

– Levonorgestrel (with estrogen in orla contraceptives)

– Norethindrone – Norgestrel

Indications: Prolonged postponement / Temporary Postponement/Suppression Uterine Hemorrhage, Threatened abortion, Pregnancy Failure, Pseudopregnancy, Lactation, NymphomaniaLevonorgestrel (with estrogen)- as oral contraceptives Side Effects 1. Increased Incidence of Uterine Pathology- High doses/ repeated

or prolonged exposure to moderate doses of progestins - cause cystic endometrial hyperplasia (CEH).

2. Mammary Tumors; Increased Secretion of Prolactin3. Increased Secretion of GH and Acromegalic Changes4. Diabetes Mellitus 6. Adrenocortical suppressionDosages: MPA 2.5 - 3.0 mg/kg IM / 5 months, (dog)2.0 mg/kg

IM/ 5 months(cat). MGA -In 2.5 mg/cat/day.• Proligestone- 100 mg/kg SC at sequential intervals of 3, 4 and 5

months, and at intervals of 5 months thereafter.

PRID:

( Progesterone releasing intravaginal device): • device containing progesterone and estradiol

ester, used for synchronization of oestrous/ ovulation in cows and heifers , in combination with PGF2 α.

• The device is is inserted in to vagina ; kept insiteu for 12 days

• PGF2 α administered 24 hours before removal.

• Oestrus occurs after 2-5 days of withdrawl.

Antiprogestins

synthetic steroids which bind with great affinity to progesterone receptors

Mifepristone (RU 486) Aglepristone (RU 534) • Mifepristone is a progesterone and glucocorticoid

antagonist. • More potent as anti-progestin than as an anti-corticoid.• In the absence of progesterone or cortisol,

mifepristone can have a moderate agonistic effect• To improve its efficacy, used in combination with low

doses of prostaglandin analogs such as misoprostol.

Mifepristone

• In pregnant bitches

• administered after day 30 of gestation/mating

• 2.5 mg/kg, PO, twice a day for 4 to 5 days.

• Pregnancy: terminated without side effects within 3 to 4 days after treatment.

Aglepristone

• for pregnancy termination from mating date until 45 days after mating

Inhibitors of Steroidogenesis

• Aminoglutethimide – Blocks conversion of cholesterol to pregnenolone,

resulting in decreased production of adrenal glucocorticoids, mineralocorticoids, estrogens and androgens

– Blocks several other steps in steroid synthesis, C-11, C-18 and C-21 hydroxylations and aromatase enzymes

• Treatment of– Cushing's syndrome– Breast carcinoma

Letrozole

• Non-steroidal aromatase inhibitor, thus decreasing estrogens• Treatment of breast cancer

Anastrozole• Non-steroidal aromatase inhibitor, thus decreases estrogens• Treatment of breast cancer

– Preferred medical therapy for postmenopausal women

Exemestane

• Irreversible, steroidal aromatase inhibitor, significantly lowers circulating levels of estrogens

• Structurally related to natural androstenedione• Treatment of hormonally-responsive breast cancer

Letrozole

Testosterone

• Stimulates virilization and important in spermatogenesis

• Androgens (in both sexes)– Stimulate hair growth– Bone growth– Muscle development – erythropoiesis

Therapeutic Overview

Androgens Primary testicular insufficiency Hypogonadotropic hypogonadism Constitutional delay of growth in

adolescence Osteoporosis, anemia Male contraception

Anti-androgens and androgen antagonists

Virilization in women Precocious puberty in boys Prostate cancer

Synthesis of Testosterone

Important prostate androgen

Hypothalamic-Pituitary-Testis Axis

Androgens

• Natural– Not used therapeutically

• Synthetic androgens– Testosterone Enanthate

• Slow-acting ester with release time between 8-10 hours

• Injectable; once every week to once every three weeks

• Testosterone Cypionate– Slow-acting ester

• Testosterone Propionate – Fast-acting ester with a release time of 3-4 days

• Fluoxymesterone, Oxymetholone, methyl testosterone

Indications: • infertility and hypogonadism, produce estrus detectors, and

for testosterone-responsive urinary incontinence in dogs. • to treat debilitated aniumals because of their anabolic

effects• used to postpone oestrus in bitches• to overcome behavioural problems associated with

pseudopregnancy.• to reverse feminization associated with SCT. • Severe burns and senile osteoporosis (anabolic effect) • Promote growth in children• Unapproved uses- increase lean body mass, muscle

strength and aggressiveness/DRUGS OF ABUSE Mibolerone: Blocks the release of LH from the anterior pituitary

gland; Used to prevent estrus in adult female dogs and the treatment of false pregnancies

Antiandrogens

These are progestogens, are used to counteract the behavioural actions of endogenous androgens.

• to control hypersexuality in male dogs, • to treat prostatic hyperplasia, prostatitis in dogs • Eg: Delemidinone acetate, danazol, flutamide,

bicalutamide, cyproterone acetate

Flutamide • Potent non-steroidal, anti-androgen• Competitive antagonist at the receptor and inhibits

androgen uptake• Treatment of prostate cancer

Finasteride

• Inhibits 5-reductase, an enzyme responsible for the conversion of testosterone to dihydrotestosterone (DHT)

• Dihydrotestosterone is the ESSENTIAL androgen in the PROSTATE

• Indiacted in Treatment of benign prostate hyperplasia (BPH; reduces size) and male pattern baldness

Prostaglandins and PG analogues: • Natural PGF2 α ( dinoprost, carboprost ) and its synthetic

analogs( Cloprostenol, luprostiol, , tiaprost ) are potent luteolytic agents, except in bitch and cat.

Indications: Cattle:, Horse, sheep and goats– Oetsrus synchronization in cow and heifers – Treatmwent of silent heat/ nonobserved oestrus.– Induction of parturition /foaling/farrowing– Induction of abortion and expulsion of mummified

fetus – Treatment of pyometra and Endometritis – Treatment of luteal cysts , Pseudopregnancy in goats

• Bitches: treatment of open pyometra and termination of pregnancy / mismating in combination with Antiprogestin.

• Dose: Dinoprost, 25-35mg( 5ml)), cattle; 5mg horse, 10mg, pig; 0.25-0.5mg/kg-bitch, all IM. Cloprostenol -250-500µg,IM, 125-250µg, pig,IM; luprostiol- 15mg, cattle, IM