Assoc. Prof. Ivan Lambeve-mail: itlambev@mail.bg

Medical University of Sofia, Faculty of MedicineDepartment of Pharmacology and Toxicology

Hypothalamic hormonesPituitary hormonesParathyroid hormone

Hormones (from Greek hormaein – to set in motion)are chemical substances of intence biological activity. They are secreted by specific endocrine gladns and are transported in the bloodstream to act on theirdistant target organs. Hormones regulate body functions and maintain homeostasis in the face markedly variable external and internal environment.The natural hormones and their synthetic analogues(which in many cases may be more effective), are used as drugs for substitution therapy as well as for pharmacotherapy.In addition, hormone antagonists and hormone syn-thesis release inhibitors have significant therapeuticimportance too.

Classification of hormones

1. Pituitary

a) Anterior Pituitary Growth hormone (GH) Prolactin Adrenocorticotropic hormone (ACTH, Corticotrophin) Thyroid stimulating hormones (TSH, Thyrotrophin) Gonadotrophins

- Follicle stimulating hormone (FSH)- Lutenizing hormone (LH)

b) Posterior Pituitary Oxytocin Antidiuretic hormone (ADH, Vasopressin)

2. ThyroidThyroxine (T4), Triiodthyronine (T3)Calcitonin

3. Parathyroid: Parathormone (PTH)4. Pancreas (Islets of Langerhans): Insulin, Glucagon5. Adrenalsa) Cortex

- Glucocorticoids (GCS): Hydrocortisone, Cortisone- Mineralcorticoids: Aldosterone- Sex steroids: Dehydroepiandrosterone (…Testost.)

b) Medulla: Adrenaline, Noradrenaline6. Gonads

a) Androgens: Testosteroneb) Estrogens: Estradiolc) Progestins: Progesterone

7. Hypothalamic hormones (factors)Thyrotrophin releasing hormone (TRH) – peptideCorticotrophin releasing hormone (CRH) – peptideGonadotrophin releasing hormone

(GnRH – Gonadorelin): LH-RH/FSH-RH – peptide

Growth hormone releasing hormone: GHRH) – peptide

Prolactin releasing factor (PRF): UnknownProlactin release inhibitory hormone (PRIH):

Dopamine (DA)Growth hormone release inhibitory hormone

(GHRIH): Somatostatin – peptide8. Placental hormones

Prolactin, Progesterone, Chorionic gonadotrophin

Mechanisms of hormone action

ACTH, Adrenaline, Calcitonin, Glucagon, FSH, LH, PHT,some hypothalamic RH, TSH, Vasopressin (via V2-rec.)

Alteration of protein kinase A

Regulation of cell function: Ca2+ acting as a third messenger in some situations

1. Action on the cell membrane receptors

a) Through alteration of intracellular cAMP concentration

Oxytocin, Vasopressin (via V1-rec.)

Release of intracelullar Ca2+

and protein kinase C activation

b) Through the IP3 and DAG generation

GH, Insulin, Prolactin

Phosphorilation cascade

Regulation of various enzymes

c) Direct transmembrane activation of tyrosine kinase

2. Action on the intracellular(steroid or thyroid) receptors

EffectorCouplingTime scaleExamples

gene transcriptionvia DNAhoursSteroide hormonesthyroid hormonescalcitriol

a) At cytoplasmic receptors: Steroid hormones, Calcitriol

Rang et al. Pharmacology – 5st Ed. (2003)

b) Directly at nuclear receptors: Thyroid hormones (T3, T4)

T3 or T4 penetrates the nucleus

Combines with their receptors

Alters DNA-RNA mediatedprotein synthesis

Hypothalamic hormonesregulate anterior pituitarytrophic hormones that, inturn, determine target gland secretion. There is aperipheral hormones feed back which regulate hypothalamic and pituitary hormones

Hypothalamic and Pituitary Hormones

Feedbackregulationof endocrineaxes

Neurons that regulate the anterior lobe cluster in themediobasal hypothalamus,including the paraventricular(PVN) and the arcuate (ARC) nuclei secretehypothalamic releasing hormones, which reach the anterior pituitary via the hypothalamic-adenohypo-physeal portal system and stimulate distinct populationsof pituitary cells. These cells,in turn, secrete the trophic hormones, which regulateendocrine organs and othertissues.

Goodman & Gilman's The PharmacologicBasis of Therapeutics - 11th Ed. (2006)

Goodman & Gilman's The PharmacologicBasis of Therapeutics - 11th Ed. (2006)

Corticotrophin releasing hormone (CRH) – corticoliberin, is a hypothalamic polypeptide fordiagnostic use. It increases ACTH secretion inCushing's disease secondary to pituitary ACTH-secreting adenoma. Natural corticotrophin (ACTH) is a 39-amino-acid polypeptide secreted by the anterior pituitary gland, obtained from animal pituitaries. The physiologicalactivity resides in the first 24-amino acids (whichare common to many species) and most immuno-logical activity resides in the remaining 15 amino-acids. The pituitary output of corticotrophin responds rapidly to physiological requirements by the familiar negative-feedback homeostatic mechanism.

Synthetic corticotrophin tetracosactide has theadvantage that they are shorter amino acid chains (devoid of amino acids 25–39) and so are less likelyto cause serious allergy, though this can happen. In addition they are not contaminated by animal proteins which are potent allergens. It consists of the biologically active first 24 amino acids of naturalcorticotrophin (from man or animals) and so it hassimilar properties, e.g. t1/2 10 min.

Corticotrophin stimulates the synthesis of cortico-steroids (of which the most important is hydro-cortisone) and to a lesser extent of androgens, bythe cells of the adrenal cortex. It has only a minoreffect on aldosterone production.The release of natural corticotrophin by thepituitary gland is controlled by the hypothalamusvia corticotrophin releasing hormone (cortico-liberin), production of which is influenced bystress as well as by the level of circulating hydrocortisone.

High plasma concentration of any steroid with glucocorticoid effect prevents release of cortico-trophin releasing hormone and so of ACTH, lack ofwhich in turn results in adrenocortical hypofunction.This is the reason why catastrophe may follow sud-den withdrawal of steroid therapy in the chronicallytreated patient who has an atrophied cortex.The effects of corticotrophin are those of the steroids(hydrocortisone, androgens) liberated by its actionon the adrenal cortex. Prolonged heavy dosagecauses the clinical picture of Cushing's syndrome.

Corticotrophin is usedprincipally in diagnosisand rarely in treatment. It is inactive if taken orally and has to be injected like other peptidehormones.

Rang et al. Pharmacology –5st Ed. (2003)

Rang et al. Pharmacology –5st Ed. (2003)

Diagnostic use: as a test of the capacity of theadrenal cortex to produce cortisol; with the shorttest, the plasma cortisol (hydrocortisone) concen-tration is measured before and after an i.m.injection of tetracosactide (Synacthen®).Therapeutic use of ACTH is seldom appropriatebecause the peptide hormone has to be injected;selective glucocorticoid action (without mineralo-corticoid effect) cannot be obtained, and clinical results are irregular.

Thyrotrophin releasing hormone (TRH) – protirelin, is a tripeptide formed in the hypo-thalamus and controlled by free plasma T4and T3 concentration. It has been synthesizedand can be used in diagnosis to test the capacity of the pituitary to release thyroidstimulating hormone, e.g. to determinewhether hypothyroidism is due to primarythyroid gland failure or is secondary to pituitarydisease or to a hypothalamic lesion. TRH isalso a potent prolactin-releasing factor.

Thyroid stimulating hormone (TSH) thyro-trophin, a glycoprotein of the anterior pituitary,controls the synthesis and release of thyroid hor-mone from the gland, and also the uptake of iodide. There is a negative feedback of thyroidhormones on both the hypothalamic secretion of TRH and pituitary secretion of TSH.

Sermorelin is an analogue of the hypothalamicgrowth hormone releasing hormone (somatorelin);it is used in a diagnostic test for growth hormonesecretion from the pituitary.

Two hypothalamic factors, growthhormone-releasing hormone (GHRH) and somatostatin (SST),act on the somatotropes in theanterior pituitary to regulategrowth hormone secretion. SST also inhibits GHRH release.Growth hormone exerts direct effects on target tissues and indirect effects mediated by stimulating the release of insulin-like growth factor-1 (IGF-1).

The gastric peptide ghrelin enhances growth hormone release, directly by actions at the anterior pituitary and indirectly by multipleactions on the hypothalamus. IGF-1 feeds back at the anterior pituitary to inhibit growth hormone secretion and also to inhibit furtherGHRH release by the hypothalamus.

Goodman & Gilman's The PharmacologicBasis of Therapeutics - 11th Ed. (2006)

Growth hormone (GH), one of the peptide hormones produced by the anterior pituitary, is required duringchildhood and adolescence for attainment of normaladult size and has important effects throughout post-natal life on lipid and carbohydrate metabolism, and on body mass. Its effects are primarily mediated viainsulin-like growth factor 1 (IGF-1)and to a lesser extent both directly and through insulin-like growth factor 2 (IGF-2). Individuals withcongenital or acquired deficiency in GH during child-hood or adolescence fail to reach their predicted adultheight and have disproportionately increased body fatand decreased muscle mass. Adults with GH defi-ciency also have disproportionately small body mass.

GH is a 191-amino-acid peptide. Its structure closelyresembles that of prolactin. Two types ofrecombinant human growth hormone (rhGH)are approved for clinical use: Somatrophin (identical with the native form of human GH) and Somatrem (with 191 amino acids of GH plus an extra methionineresidue at the amino terminal end). The drugs are used in children with growth hormonedeficiency, while the bone epiphyses are still open,to prevent dwarfism (underdevelopment of the body)and provide normal growth. Treatment improvesexercise performance and increases lean bodymass. It may improve overall quality of life.

Possibilities of abuse have also arisen, e.g. creationof “super” sports people. Less dubious, but not yeta licensed indication of GH, is the potential for accelerated wound healing reported in childrenwith large cutaneous burns. GH is a popular compo-nent of anti-aging programs. Serum levels of GH normally decline with aging. GH is one of the drugsbanned by the Olympic Committee.In acromegaly, excess GH causes diabetes, hyperten-sion and arthritis. Surgery is the treatment of choice. GH secretion is reduced by octreotide and othersomatostatin analogues and to a lesser degree by bromocriptine.

Somatostatin (growth hormone release inhibitinghormone) occurs in other parts of the brain as wellas in the hypothalamus, and also in some peri-pheral tissues, e.g. pancreas, stomach. It inhibitssecretion of thyrotrophin, insulin, gastrin and 5-HT.Radiolabelled somatostatin is used tolocalise metastases from neuroendocrine tumourswhich often bear somatostatin receptors.Octreotide is a synthetic analogue of somatostatinhaving a longer action (t1/2 1.5 h). Lanreotide is much longer acting, and is admini-stered only twice a month. Uses include acromegaly/gigantism, carcinoid (serotonin secreting) tumours and other rare tumours of the GIT.

A 22-year-old man with gigantism due to excess growth hormoneis shown to the left of his identical twin. The increased height and prognathism (A) and enlarged hand (B) and foot (C) of the affected twin are apparent. Their clinical features began to diverge at the age of approximately 13 years.

Transsphenoidal resectionof pituitary tumour mass viathe endonasal approach.

Gonadorelin (gonadotrophin releasing hormone – GnRH) releases luteinising hormone (LH) andfollicle-stimulating hormone (FSH). It hasuse in assessment of pituitary function. Intermittentpulsatile administration evokes secretion ofgonadotrophins (LH and FSH) and is used to treatinfertility. But continuous use evokes tachyphylaxisdue to down-regulation of its receptors, i.e. gonado-trophin release and therefore gonadal secretions arereduced. Longer-acting analogues of GnRH (buserelin,goserelin, nafarelin, deslorelin and leuprorelin) areused to suppress androgen secretion in prostaticcarcinoma.

The regulation of gonadotrophin release from theanterior pituitary by endogenouse GnRH and drugs

Rang et al. Pharmacology –5st Ed. (2003)

Rang et al. Pharmacology –5st Ed. (2003)

Other uses may include endometriosis,precocious puberty and contraception. All thesedrugs need to be administered by a parenteralroute, by i.m. injection or intranasally.Follicle stimulating hormone (FSH) stimulatesdevelopment of ova and of spermatozoa. It is prep-ared from the urine of postmenopausal women.Urofollitrophin (Metrodin®) contains FSH.Menotrophins (Pergonal®) contains FSH and LH. These drugs are used in female and male hypopituitary infertility.Chorionic gonadotrophin (human chorionic gona-dotrophin – hCG) is secreted by the placenta andis obtained from the urine of pregnant women.

The predominant action of hCG is that of LH.It induces progesterone production by the corpusluteum and, in the male – gonadal testosteroneproduction. It is used in hypopituitary anovular andother infertility in both sexes. It is also usedfor cryptorchidism in prepubertal boys (6 years ofage; if it fails to induce testicular descent, there istime for surgery before puberty to provide maximalpossibility of a full functional testis). It may alsoprecipitate puberty in men where this is delayed.

Prolactin is secreted by the lactotroph cells of theanterior pituitary gland. Its control is by tonichypothalamic inhibition through prolactin inhibitoryfactor (PIF), probably dopamine, opposed by aprolactin releasing factor (PRF) in both women andmen and, despite its name, it influences numerousbiological functions. Prolactin secretion iscontrolled by an inhibitory dopaminergic path. Hyper-prolactinaemia may be caused by drugs (with anti-dopaminergic actions e.g. metoclopramide), hypo-thyroidism, or prolactin secreting adenomas. Medicaltreatment is with bromocriptine, cabergoline, or quinagolide at bedtime.

Goodman & Gilman's The PharmacologicBasis of Therapeutics - 11th Ed. (2006)

Goodman & Gilman's The PharmacologicBasis of Therapeutics - 11th Ed. (2006)

In hypopituitarism there is a partial or completedeficiency of hormones secreted by the anteriorlobe of the pituitary. The posterior lobe hormonesmay also be deficient in a few cases, e.g.when a tumour has destroyed the pituitary. Patientssuffering from hypopituitarism may present incoma, in which case treatment is as for a severeacute adrenal insufficiency. Maintenance therapy isrequired, using hydrocortisone, thyroxine, oestradioland progesterone (in women) and testosterone (inmen) or GH analogues (somatrophin or somatrem).

Hypothalamic neurons in the supraoptic (SON)and paraventricular (PVN)nuclei synthesize argininevasopressin (AVP) oroxytocin (OXY).

Most of their axons projectdirectly to the posterior pituitary, from which AVPand OXY are secreted intothe systemic circulation to regulate their target tissues.Goodman & Gilman's The Pharmacologic

Basis of Therapeutics - 11th Ed. (2006)

Goodman & Gilman's The PharmacologicBasis of Therapeutics - 11th Ed. (2006)

Vasopressin is a nonapeptide (t1/2 20 min) withtwo separate G-protein coupled target receptorsresponsible for its two roles. The V1 receptor onvascular smooth muscle is coupled to calciumentry. This receptor is not usually stimulated byphysiological concentrations of the hormone. The V2 receptor is coupled to adenylyl cyclase, andregulates opening of the water channel, aquaporin,in cells of the renal collecting duct.Secretion of the antidiuretic hormone is stimulatedby any increase in the osmotic pressure of the bloodsupplying the hypothalamus and by a variety ofdrugs, notably nicotine. Secretion is inhibited by a fallin blood osmotic pressure and by alcohol.

In large nonphysiological doses (pharmaco-therapy) vasopressin causes contraction of all smoothmuscle, raising the blood pressure and causingintestinal colic. The smooth-muscle stimulant effectprovides an example of tachyphylaxis (frequentlyrepeated doses give progressively less effect). It isnot only inefficient when used to raise the bloodpressure, but is also dangerous, since it causesconstriction of the coronary arteries and suddendeath has occurred following its use.For replacement therapy of pituitary diabetesinsipidus the longer acting analogue desmopressinis used.

Desmopressin (des-amino-D-arginine vasopressin)(DDAVP) has two major advantages: the vasocon-strictor effect has been reduced to near insignificanceand the duration of action with nasal instillation,spray or s.c. injection, is 8–20 h (t1/2 75 min) so that,using it once to twice daily, patients are not incon-venienced by frequent recurrence of polyuria duringtheir waking hours and can also expect to spend thenight continuously in bed. The adult dose forintranasal administration is 10–20 micrograms daily.The dose for children is about half that for adults.The bioavailability of intranasal DDAVP is 10%. It isalso the only peptide for which an oral formulationis available, with a bioavailability of only 1%.

The main complication of DDAVP is hypona-traemia which can be prevented by allowing thepatient to develop some polyuria for a short periodduring each week. The requirement for DDAVPmay decrease during intercurrent illness.

Oxytocin is a peptide hormone of the posteriorpituitary gland. It stimulates the contractions of thepregnant uterus, which becomes much more sensitiveto it at term. Patients with posterior pituitarydisease (diabetes insipidus) can, however, go intolabour normally.

Oxytocin is structurally close to vasopressionand it is no surprise that it also has antidiureticactivity. Serious water intoxication canoccur with prolonged i.v. infusions, especiallywhere accompanied by large volumes of fluid. Theassociation of oxytocin with neonatal jaundiceappears to be due to increased erythrocyte fragility causing haemolysis.Oxytocin has been supplanted by the ergotalkaloid, ergometrine, as prime treatment of postpartum haemorrhage.

Oxytocin is reflexly released from the pituitaryfollowing suckling (also by manual stimulation ofthe nipple) and causes almost immediate contractionof the myoepithelium of the breast; it can be used toenhance milk ejection (nasal spray).Oxytocin is used i.v. in the induction of labour. It produces, almost immediately, rhythmic contractionswith relaxation between, i.e. it mimics normal uterineactivity. The decision to use oxytocin requires specialskill. It has a t1/2 of 6 min and is given by i.v. infusionusing a pump; it must be closely supervised; the doseis adjusted by results; overdose can cause uterinetetany and even rupture.

Parathyroid hormone (PTH)

PTH acts chiefly on kidney increasingrenal tubular resorption and bone resorption ofcalcium; it increases calcium absorption from thegut, indirectly, by stimulating the renal synthesis of1α-25-dihydroxycholecalciferol (calcifediol). It increases the rate of bone remodelling (mineral andcollagen) and osteocyte activity with, at high doses,an overall balance in favour of resorption (osteoclastactivity) with a rise in plasma calcium concentration(and fall in phosphate); but, at low doses, thebalance favours bone formation (osteoblast activity).

The main factors involved in maintainingthe concentration of calcium in the plasma

Rang et al. Pharmacology –5st Ed. (2003)

Rang et al. Pharmacology –5st Ed. (2003)