Anterior pitutary hormones

Hormone

• Secretory products of endocrine glands released directly into circulation in small amounts and transported to specific target cells or organs where they exert physiological, morphological or biochemical responses

Types of cell-to-cell signaling

Endocrine Hormones: travel via bloodstream to target cells

Neurocrine hormones: released from nerve terminals

Paracrine hormones: act on adjacent cells

Autocrine hormones: Released and act on the cell that secreted them.

Intracrine Hormones: act within the cell that produces them.

Classification of hormones

• Depending upon chemical nature – Amines or amino acid derivatives

• Catecholamines, thyroid hormones

– Proteins & polypeptides• Posterior pitutary hormones: oxytocin, vasopressin• Insulin , glucagon, PTH, other anterior pitutary

hormones

– Steroid hormones• Glucocorticoids, mineralocorticoids, sex steroids, Vit D

• Depending on Mechanism of action – Group I & Group II hormones

Depending on MOA

• Group I: bind to intracellular receptors• Group II: Involve second messenger

– A: cyclic AMP: ACTH, ADH, CRH, FSH, LH,TSH, PTH– B: cyclic GMP: Atrial natriuretic factor, NO– C: calcium/PI: AcH, catecholamines 1, gastrin,

oxytocin, TRH, GnRH – D:kinases/phosphatase: erythropoetin, GH,

insulin, IGF, NGF, prolactin

Regulation of hormone secretion

• Feed back control – Negative feed back

• Long loop feed back • Short loop feed back • Ultra short loop feed back

– Positive feed back • Neural control • Chronotrophic control

Negative feed back control

Hypothalamus

Hypophysiotrophic hormone

Anterior pitutary

Pitutary trophic hormone

Target gland

Target gland hormone

Long loop

Short loop

Ultra Short loop

Negative feedback effects of cortisol

Feedback control of insulin by glucose concentrations

Neural control

• Evokes or supresses hormone secretion in response to external & internal stimuli

• External stimuli: visual, auditory, olfactory • Internal stimuli: pain, emotion, fright • Examples of neural control

– Oxytocin : fills milk ducts in response to suckling – Aldosterone: augments circulatory volume in

response to upright posture – Release of melatonin: in response to darkness

Chronotropic control

• Endogenous neuronal rhythmicity• Diurnal rhythms, circadian rhythms (growth

hormone and cortisol), Sleep-wake cycle; seasonal rhythm

• frequency of about one hour—circhoral • An episode of release longer than an hour,

but less than 24 hours: ultradian • If the periodicity is approximately 24 hours,

the rhythm is referred to as circadian – usually referred to as diurnal because the

increase in secretory activity happens at a defined period of the day.

Episodic secretion of hormones

Circadian (chronotropic) control

Circadian Clock

Physiological importance of pulsatile hormone release

• Demonstrated by GnRH infusion • If given once hourly, gonadotropin secretion and

gonadal function are maintained normally • A slower frequency won’t maintain gonad

function • Faster, or continuous infusion inhibits

gonadotropin secretion and blocks gonadal steroid production

Functions of the hormones

• Growth & differentiation • Maintenance of homeostasis • Reproduction• Regulation of biochemical reactions

Role of hypothalamus

• Highest relay centre • Integrates endocrine & ANS and ensures the

smooth coordination by the cerebral cortex • Hypothalamic regulatory hormones

– Releasing hormones • TRH, GnRH, GHRH,CRH, MSH-RF, Prolactin Releasing

factor

– Releasing inhibitory hormones • GH-RIH, MSH-RIF, PIF

Anterior pitutary hormones

Pitutary gland

Anterior pitutary hormones

• Acidophils: – Somatotrophes: Growth hormone– Lactotrophes: Prolactin

• Basophils:– Gonadotrophes: FSH & LH– Thyrotropes: TSH– Corticolipotrohes: ACTH

Growth hormone

• 191 amino acid • 22000 molecular weight • Physiological Functions:

– Growth of organs – Positive nitrogen balance – Direct and indirect actions

Regulation of secretion

• GH Release stimulated by – Dopamine– 5 HT – α2 Agonist

• GH Release inhibited by – IGF-1– Free Fatty Acids– Beta Agonist – GH itself

GHRH & GHIH secreted by hypothalamus

Amplitude of secretory pulses is maximal at night

Provocative stimuli for GH

• Arginine • Glucagon • L-Dopa• Insulin • Clonidine

Syndromes associated with GH

• Deficiency of GH – Dwarfism – Increased CVS Mortality

• Excess GH– Gigantism – Acromegaly

Dwarfism

• Shortness of stature • Growth retardation in all parts of body

proportionately • Normal mental activity • Immature faces • Delicate extremities • Sexual maturity does not occur if associated

with gonadotropin deficiency

Gigantism

• Abnormal height • Large hands and feet• Coarse facial features • Bilateral gynaecomastia • Loss of libido • Hyperglycemia

Acromegaly

• Acromegalic face:– thick lips, macroglossia, prominent eye brows– Broad thick nose, thickened skin

• Prognathism – Protrusion of lower jaw

• Spade like hands, thick wide fingers, large feet• Kyphosis • Organomegaly

Treatment of GH Deficiency

• Cadaveric pitutary growth hormone • Human recombinant preparations

– Somatotropin – Somatotrem – Encapsulated somatotropin – Sermorelin acetate

Somatropin

• Growth hormone preparation whose sequence matches native growth hormone

Somatrem

• Derivative of growth hormone with additional methionine at amino terminus

• Somatropin and somatrem have similar biological action and potencies

• Half life = 20 minutes but biological action lasts 9-17 hrs

• Once daily administration is sufficient

Encapsulated somatropin

• Injected IM once or twice per month

Sermorelin acetate

• A synthetic form of Human GHRH • Peptide of 29 Aminoacids corresponds to first

29 AA of Human GHRH • Has full biological activity • Well tolerated , Less expensive • But less effective will not work in defects of

anterior pitutary

Uses of Growth hormone

• Replacement therapy – 20-40 microgram/ kg Subcutaneously daily

• Turners syndrome – 50 microgram/kg

• Aids associated wasting – 3-4 microgram / kg

Adverse effects

• ↑ ICT with papilloedema • Visual changes• Headache, nausea• Leukemia • ↑ incidence of type 2 DM• Adults:

– Edema, carpal tunnel syndrome, arthralgia, myalgia

Agents used in GH excess

• Somatostatin • Somatostatin analogs

– Octreotide– Lanreotide – Vapreotide – Sandostatin

• Dopamine receptor agonists: bromocriptine• GH antagonist: Pegvisomant

Somatostatin

• GHIH• Non specific

– TSH, insulin, gastrin• Half life = 1-3 min• Rebound increase in GH after its

discontinuation • Not preferred

Octreotide

• More specific for Growth hormone • Less chances of hyperglycemia • Uses

– Carcinoid syndrome – VIP secreting tumors – Gastrinoma – Secretory diarhoea: AIDS, DM– IBS , Esophageal Varices , insulinoma

• Dose: 50 -200 µg TDS subcutaneously

Sandostatin

• Slow releasing form • 20-40 mg IM 4 weekly • Adverse effects of somatostatin analogs

– Abdominal pain – Steathorrea– GB stone – Vit B12 deficiency

Prolactin

• 198 Amino acid peptide hormone • Synthesis and secretion starts in fetal pitutary • ↓ Secretion of prolactin by

– Hypothalamic regulation (D2• ↑ secretion of prolactin by

– Stress, exertion, hypoglycemia– TRH, VIP, prolactin releasing peptide

Regulation of prolactin

Mechanism of action

Physiological effects

• Growth & development of breast • Growth and development of ductal and

lobular epithelium • Induce lactation after birth of baby • Increased prolactin levels supress normal

menstrual cycle

Hyperprolactinemia

• Females:– Galactorrhea and amenorrhoea – Infertility

• Males:– Loss of libido – Infertility

• Drugs causing hyperprolactinemia – Chlorpromazine, haloperidol, metoclopramide– Reserpine , alpha methyl dopa

Treatment of hyperprolactinemia

• Dopaminergic agonists – Bromocriptine – Cabergoline – Pergolide – Quinagolide

Bromocriptine

• Uses – Hyperprolactinemia – Acromegaly – Parkinsonism – Hepatic coma – Supression of lactation

Bromocriptine

• Pharmacokinetics– Only 1/3rd absorbed orally – First pass metabolism present – Half life = 3 hours

• Dose: – Start 1.25 mg HS – After 1 week 1.25 mg can be added in morning – Can be increased to 5 mg BD

Bromocriptine

• Adverse effects– Nausea , vomiting – Postural hypotension – Nasal decongestion– Digital vasospasm – CNS effects: hallucinations, night mares, insomnia

Pergolide

• Ergot derivative • Cheapest Dopamine agonist • Dose= 0.025 mg increased to 0.25 mg

gradually

Cabergoline

• Ergot derivative with longer hlaf life • T ½ = 65 hours • Higher affinity and selectivity to D2 receptors• More effective less toxic • Dose= 0.25 mg twice weekly

Quinagolide

• Non ergot D2 agonist • T ½ = 22 hours dose= 0.1 -0.5 mg /day

Gonadotropins (FSH & LH)

• Hypothalamus releases GnRH in pulses 1-2 hrly

• GnRh regulates FSH & LH • Feed back inhibition of LH>FSH• Estrogen & Progesterone inhibit both FSH &

LH • Inhibin inhibits only FSH • Dopamine Inhibits only LH

Physiological functions

FSH

Females:– Gametogenesis – Follicular development – Estrogen and progesterone

production – Imp role in Menstrual

cycle

Males– Stimulation &

maintainence of spermatogenesis

LH

Females – Ovulation – Corpus luteum

Maintainence – Estrogen & progesterone

production – Imp role in menstrual

cycle Males:

– Testesterone & androgen biosynthesis

Disturbances of gonadotropin secretion

• Excess– Precocious puberty

• Deficiency – Amenorrhoea, infertility– oligospermia

Preparations of gonadotropins

• Menotropin: FSH + LH– Obtained from urine of postmenopausal women

• Urofollitropin: Pure FSH – Preferred in PCOD

• HCG– Obtained From Urine Of Pregnant Females

• DNA recombinant FSH

Uses of gonadotropins

• Infertility in females – When clomiphene fails – Menotropin for 10 days then HCG 10000 IU, IM

• Infertility in males – HCG 1000-2500 IU, IM 3 times in a week – Then menotropin after 3-4 months

• Cryptorchism • To aid Invitro fertilization• Regress AIDS related Kaposis Sarcoma

Adverse effects

• Ovarian hyperstimulation, multiple pregnancies

• Polycystic ovarian disease • Pain in lower abdomen • Edema, headache, depression• Allergic reactions

GnRH & GnRH analogs

Gonadorelin

• Synthetic GnRH • T ½ = 4-6 min • Used for testing pitutary gonadal axis in male

or female hypogonadism • Pulsatile administration IV every 90 min

– Infertility, cryptorchism. & delayed puberty

GnRH agonists

• Goserelin • Buserilin • Leuprolide • Naferiline • Triptoreline

GnRH agonists

• Longer acting 6-12 hours • Initial increase in LH & FSH • But after 1-2 weeks cause desensitization and

decrease FSH & LH secretion • Decrease estrogen and testesterone• They cause pharmacological oopherectomy

and orchiectomy

Uses of GnRH analogs

• Precocious puberty • Prostatic carcinoma • Breast cancer • Contraception: under investigation

Adverse effects

• Hot flushes • Loss of libido • Vaginal dryness • Osteoporosis • Emotional liability

GnRH antagonists Cetrorelix , Granirelix

• Competitive antagonists • Advantage

– No initial increase in gonadotropins – Do not cause histamine release

• Used in endometriosis 3 mg Cetrorelix SC weekly for 2 months

• Uterine Fibroids: cetrorelix twice weekly for 1 month before surgery

Thyroid stimulating hormone

• Stimulates T3 & T4 secretion• Induces hyperplasia and hypertrophy of

thyroid • Promotes oxidation of trapped iodide

ACTH

• Stimulate cortisol synthesis from adrenal cortex

• Corticotropin Regulating Hormone (CRH): secreted by hypothalamus regulates it.

• USES– Diagnosis of pitutary –adrenal axis disorders – Like corticosteroids but unpredictable action