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Hypothalamic hormones Pituitary hormones Parathyroid hormone. Assoc. Prof. Iv. Lambev E-mail: itlambev@mail.bg www.medpharm-sofia.eu. Hormones (from Greek hormaein – to set in motion) are chemical substances of intense biological activity.

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slide1

Hypothalamic hormones

  • Pituitary hormones
  • Parathyroid hormone

Assoc. Prof. Iv. Lambev

E-mail: itlambev@mail.bg

www.medpharm-sofia.eu

slide2

Hormones (from Greek hormaein– to set in motion)

are chemical substances of intense biological activity.

They are secreted by specific endocrine glands and

are transported in the bloodstream to act on their

distant target organs. Hormones regulate body

functions and maintain homeostasis in the face of

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 therapeutic

importance too.

slide3

Classification of hormones

  • 1. Hypothalamic hormones
  • Thyrotrophin releasing hormone (TRH) – peptide
    • Corticotrophin releasing hormone (CRH) – peptide
    • Gonadotrophin releasing hormone
      • (GnRH – Gonadorelin): LH-RH/FSH-RH – peptide
    • Growth hormone releasing hormone: (GHRH) – peptide
    • Prolactin releasing hormone (PRH): Unknown
    • Prolactin release inhibitory hormone (PRIH):
      • Dopamine (DA)
    • Growth hormone release inhibitory hormone:
      • (GHRIH): Somatostatin – peptide
slide4

2. Pituitary hormones

  • a) Anterior Pituitaryhormones
    • Growth hormone (GH)
    • Prolactin
    • Adrenocorticotropic hormone (ACTH, Corticotrophin)
    • Thyroid stimulating hormones (TSH, Thyrotrophin)
    • Gonadotrophins
      • - Follicle stimulating hormone (FSH)
      • - Luteinizing hormone (LH)
  • b) Posterior Pituitary hormones
    • Oxytocin
    • Antidiuretic hormone (ADH, Vasopressin)
slide5

2. Thyroid hormones

    • Thyroxine (T4), Triiodothyronine (T3)
    • Calcitonin
  • 3. Parathyroid hormone: Parathormone (PTH)
  • 4. Hormones of endocrine pancreas: Insulin, Amylin, Glucagon
  • 5. Adrenal hormones
  • a) Hormones of Adrenal cortex (Steroids)
  • - Glucocorticoids (GCS): Hydrocortisone, Cortisone
    • - Mineralocorticoids: Aldosterone
    • - Sex steroids: Dehydroepiandrosterone (Testost.)
  • b) Hormone of Adrenal medulla:Adrenaline
  • 6. Hormone of Gonads
    • a) Androgens: Testosterone
    • b) Estrogens: Estradiol
    • c) Progestins: Progesterone
slide6

8. Placental hormones

    • Estrogens, Progesterone,
    • Chorionic gonadotrophin
  • 9. Hormne of Adipocytes:
  • Leptin– acts on receptors in the
  • hypothalamus of the brain where
  • it inhibits appetite.
  • 10.Ghrelin is a peptide hormone
  • thatis produced mainly by
  • the fundus of the stomach and
  • epsilon cells ofthe pancreas.
  • Itstimulates hunger.Ghrelin levels increase
  • before meals and decrease after meals.
slide7

Mechanisms of hormone action

1. Action on the cell membrane receptors

a) Through alteration of intracellular cAMP concentration

  • 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
slide8

b) Through the IP3 and DAG generation

  • Oxytocin and Vasopressin (via V1-rec.)
  • Release of intracelullar Ca2+
  • and protein kinase C activation
slide9

c) Direct transmembrane activation

    • of tyrosine kinase
  • GH, Insulin, Prolactin
  • Phosphorylation cascade
  • Regulation of various enzymes
slide11

2. Action on the intracellular

(steroid or thyroid) receptors

  • a) At cytoplasmic receptors:
  • Steroid hormones, Calcitriol
slide12

b) Directly at nuclear receptors:

  • Thyroid hormones (T3, T4)

T3 or T4 penetrates the nucleus

Combines with their receptors

Alters DNA-RNA mediated

protein synthesis

slide13

Hypothalamic and

Pituitary Hormones

Hypothalamic hormones

regulate anterior pituitary

trophic hormones that, in

turn, determine target

gland secretion.

There is a

peripheral hormones

feedback which regulates

hypothalamic and

pituitary hormones.

slide14

Feedback

regulation

of

endocrine

axes

slide15

Neurons that regulate the

anterior lobe cluster in the

mediobasal hypothalamus,

including the paraventricular

(PVN) and the arcuate

(ARC) nuclei secrete

hypothalamic releasing

hormones, which reach the

anterior pituitaryvia the

hypothalamic-adenohypo-

physeal portal system and

stimulate distinct populations

of pituitary cells. These cells,

in turn, secrete the trophic

hormones, which regulate

endocrine organs and other

tissues.

Goodman & Gilman's The Pharmacologic

Basis of Therapeutics - 11th Ed. (2006)

slide16

Corticotrophin releasing hormone (CRH) –

corticoliberin, is a hypothalamic polypeptide for

diagnostic use. It increases ACTH secretion in

Cushing's diseas.

Natural corticotrophin(ACTH) is a 39-amino-acid

polypeptide secreted by the anterior pituitary gland,

obtained from animal pituitaries. The physiological

activity resides in the first 24-amino acids (which

are common to many species) and most of the immu-

nological 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.

slide17

Synthetic corticotrophin tetracosactide has the advantage

that contains shorter amino acid chain (devoid of amino acids

25–39) and so are less likely to cause serious allergy.

In addition, they are not contaminated by animal

proteins which are potent allergens. It consists of the biologically

active first 24 amino acids of natural corticotrophin (from man or

animals) and so it has similar properties, e.g. t1/2 10 min.

slide18

Corticotrophin stimulates the synthesis of corticosteroids (of

which the most important is hydrocortisone) and to a lesser

extent of androgens, by the cells of the adrenal cortex. It has

only a minor effect on aldosterone production. The release of

natural corticotrophin by the pituitary gland is controlled by the

hypothalamus via corticotrophin

releasing hormone (corticoliberin),

production of which is influenced

by stress as well as by the level

of circulating hydrocortisone.

slide19

High plasma concentration of any steroid with glucocorticoid effect prevents release of corticotrophin releasing hormone as well as of ACTH, the lack of which in turn results in adrenocortical hypofunction.

This is the reason why catastrophe may follow the sudden withdrawal of steroid therapy in the chronically treated patient who has an atrophied cortex.

The effects of corticotrophin are those of the steroids (hydrocortisone, androgens) liberated by its action on the adrenal cortex. Prolonged heavy dosage causes Cushing's syndrome.

Tetracosactide (Synacthen®) is used as a test of the capacity

of the adrenal cortex to produce cortisol (hydrocortisone).

slide20

Thyrotrophin releasing hormone (TRH) –

protirelin, is a thripeptide formed in the hypo-

thalamus and controlled by free plasma T4

and T3 concentration. It has been synthesized

and can be used in diagnosis to test the

capacity of the pituitary to release thyroid

stimulating hormone, e.g. to determine

whether hypothyroidism is due to primary

thyroid gland failure or is secondary to pituitary

disease or to a hypothalamic lesion. TRH is

also a potent prolactin-releasing factor.

slide21

Thyroid stimulating hormone (TSH)thyrotrophin,

a glycoprotein of the anterior pituitary,

controls the synthesis and release of thyroid

hormone from the gland, and also the uptake of

iodide. There is a negative feedback of thyroid

hormones on both the hypothalamic secretion of

TRH and pituitary secretion of TSH.

Sermorelin is an analogue of the hypothalamic

growth hormone releasing hormone (somatorelin).

It is used in a diagnostic test for growth hormone

secretion from the pituitary.

slide22

Two hypothalamic factors,

growth hormone-releasing

hormone (GHRH) and

somatostatin (SST),

act on the somatotropes in

the anterior pituitary to

regulate GH secretion. SST

also inhibits GHRH release.

Ghrelin is apotent

stimulator

of GH release.

Goodman & Gilman's The Pharmacologic

Basis of Therapeutics - 11th Ed. (2006)

slide23

Growth hormone (GH), one of the peptide hormones

produced by the anterior pituitary, is required during

childhood and adolescence for attainment of normal

adult size and has important effects throughout post-

natal life on lipid and carbohydrate metabolism, and

on body mass. Its effects are primarily mediated via

insulin-like growth factor 1 (IGF-1) and IGF-2.

Individuals with congenital or acquired deficiency in

GH during childhood or adolescence fail to reach

their predicted adult height and have disproportionately

increased body fat and decreased muscle mass.

Adults with GH deficiency also have disproportionately

small body mass.

slide24

GHis a 191-amino-acid peptide. Two types of

recombinant human growth hormone (rhGH)

are approved for clinical use: Somatrophin (identical

with the native form of human GH) and Somatrem

(with an extra methionine residue at the amino

terminal end).

The drugs are used in children with growth hormone

deficiency, while the bone epiphyses are still open,

to prevent dwarfism (underdevelopment of the body)

and provide normal growth. Treatment improves

exercise performance and increases lean body

mass. It may improve overall quality of life.

slide26

Possibilities of abuse have also arisen, e.g. creation

of “super” sports people. Less dubious, but not yet

a licensed indication of GH, is the potential for

accelerated wound healing reported in children

with large cutaneous burns. GH is a popular compo-

nent of anti-aging programmes. Serum levels of GH

normally decline with aging. GH is one of the drugs

banned 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 other

somatostatin analogues and to a lesser degree

by bromocriptine.

slide27

Somatostatin (growth hormone release inhibiting hormone)

  • occurs in other parts of the brain as well as in the hypothalamus,
  • and also in pancreas, stomach, and intestine.It inhibits
  • secretion of GH, thyrotrophin, insulin, glucagon, gastrin, CCK
  • (cholecystokinine), secretin, motilin, VIP (vasoactive intestinal
  • peptide), GIP (gastric inhibitory peptide), 5-HT, etc.
  • Radiolabelled somatostatin is used to localise metastases from
  • neuroendocrine tumours which often bear somatostatin receptors.
  • Octreotide is a synthetic analogue of somatostatin having
  • a longer action (t1/2 1.5 h).
  • Lanreotideis much longer acting, and is administered only
  • twice a month. Main indications: acromegaly/gigantism,
  • carcinoid (serotonin secreting)tumours,
  • and other rare tumours of the GIT.
slide28

A 22-year-old man with gigantism due to excess growth hormone

is 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.

slide29

Pituitary adenoma

  • Lacotrophic – secrete
  • prolactin (galactorrhea,
  • infertility, impotence)
  • Somatotrophic – secrete GH
  • (acromegaly)
  • Corticotrophic – secrete
  • ACTH (Cushing’s disease)
  • Gonadotrophic – secrete
  • LH & FSH (no symptoms)
  • Thyrotrophic – secrete TSH
  • (occasionaly hyperthyroidism)
  • Transsphenoidal resection
  • of pituitary tumour mass
  • via the endonasal approach
slide30

Gonadorelin (gonadotrophin releasing hormone –

GnRH) releases luteinising hormone (LH) and

follicle-stimulating hormone (FSH). It has

use in the assessment of pituitary function. Intermittent

pulsatile administration evokes secretion of

gonadotrophins (LH and FSH) and is used to treat

infertility. But continuous use evokes tachyphylaxis

due to down-regulation of its receptors, i.e.

gonadotrophin release and therefore gonadal

secretions are reduced.

Longer-acting analogues – agonists of GnRH

(buserelin, goserelin, nafarelin, deslorelin, and leuprorelin)

are used to suppress androgen secretion

in prostatic carcinoma.

slide31

Other uses may include endometriosis,

precocious puberty, and contraception. All these

drugs need to be administered by a parenteral

route, by i.m. injection or intranasally.

Follicle stimulating hormone (FSH) stimulates the

development 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 and

is obtained from the urine of pregnant women.

slide32

The predominant action of hCG is that of LH.

It induces progesterone production by the corpus

luteum and, in the male – gonadal testosterone

production. It is used in hypopituitary anovular and

other infertility in both sexes. It is also used

for cryptorchidism in prepubertal boys (6 years of

age; if it fails to induce testicular descent, there is

time for surgery before puberty to provide maximal

possibility of a full functional testis). It may also

precipitate puberty in men where this is delayed.

slide33

Prolactin is secreted by the lactotroph cells of the

anterior pituitary gland. Its control is by tonic

hypothalamic inhibition through prolactin inhibitory

factor (PIF), probably dopamine, opposed by a

prolactin releasing factor (PRF) in both women and

men and, despite its name, it influences numerous

biological functions. Prolactin secretion is

controlled 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. Medical

treatment is with bromocriptine, cabergoline, or

quinagolide at bedtime.

slide34

In hypopituitarism there is a partial or complete

deficiency of hormones secreted by the anterior

lobe of the pituitary. The posterior lobe hormones

may also be deficient in a few cases, e.g.

when a tumour has destroyed the pituitary.

Patients suffering from hypopituitarism

may present in coma, in which case

treatment is for a severe acute

adrenal insufficiency. Maintenance

therapy is required, using

hydrocortisone, thyroxine,

oestradiol, and progesterone

(in women) and testosterone (in

men), or GH analogues (somatrophin

or somatrem).

slide35

Hypothalamic neurons

in the supraoptic (SON)

and paraventricular (PVN)

nuclei synthesize arginine

vasopressin (AVP) or

oxytocin (OXY).

Most of their axons project

directly to the posterior

pituitary, from which AVP

and OXY are secreted into

the systemic circulation to

regulate their target tissues.

Goodman & Gilman's The Pharmacologic

Basis of Therapeutics – 11th Ed. (2006)

slide36

Vasopressin is a nonapeptide (t1/2 20 min) with

two separate G-protein coupled target receptors

responsible for its two roles. The V1 receptor on

vascular smooth muscle is coupled to calcium

entry. This receptor is not usually stimulated by

physiological concentrations of the hormone.

The V2 receptoris coupled to adenylyl cyclase, and

regulates opening of the water channel, aquaporin,

in cells of the renal collecting duct.

Secretion of the antidiuretic hormone is stimulated

by any increase in the osmotic pressure of the blood

supplying the hypothalamus and by a variety of

drugs, notably nicotine. Secretion is inhibited by a fall

in blood osmotic pressure and by alcohol.

slide37

In large nonphysiological doses (pharmacotherapy)

vasopressin causes contraction of all smooth

muscle, raising the blood pressure and causing

intestinal colic. The smooth-muscle stimulant effect

provides an example of tachyphylaxis (frequently

repeated doses give progressively less effect). It is

not only inefficient when used to raise the blood

pressure, but is also dangerous, since it causes

constriction of the coronary arteries and sudden

death has occurred following its use.

For replacement therapy of pituitary diabetes

insipidus the longer acting analogue desmopressin

is used.

slide38

Desmopressin (des-amino-D-arginine vasopressin)

(DDAVP) has two major advantages: the vasocon-

strictor effect has been reduced to near insignificance

and 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 during

their waking hours and can also expect to spend the

night continuously in bed. The adult dose for

intranasal administration is 10–20 micrograms daily.

The dose for children is about half that for adults.

The bioavailability of intranasal DDAVP is 10%. It is

also the only peptide for which an oral formulation

is available, with a bioavailability of only 1%.

slide39

The main complication of DDAVP is hyponatraemia

which can be prevented by allowing the patient

to develop some polyuria for a short period

during each week. The requirement for DDAVP

may decrease during intercurrent illness.

Terlipressinis an analogue of vasopressin

used in NA-resistant septic shock and

esophageal varices.

Oxytocin is a peptide hormone of the posterior

pituitary gland. It stimulates the contractions of the

pregnant uterus, which becomes much more sensitive

to it at term. Patients with posterior pituitary disease

(diabetes insipidus) can, however, go into labour normally.

slide40

Oxytocin is structurally close to vasopressin

and it is no surprise that it also has antidiuretic

activity. Serious water intoxication can

occur with prolonged i.v. infusions, especially

where accompanied by large volumes of fluid.

The association of oxytocin with neonatal

jaundice appears to be due to increased

erythrocyte fragility causing haemolysis.

Oxytocin has been supplanted by the

Methylergometrine (Methergin®), as the prime

treatment of postpartum haemorrhage.

Neonatal jaundice

slide41

Oxytocin is reflexly released from the pituitary

following suckling (also by manual stimulation of

the nipple) and causes almost immediate contraction

of the myoepithelium of the breast; it can be used to

enhance milk ejection (nasal spray).

Oxytocin is usedi.v. in the induction of labour. It

produces, almost immediately, rhythmic contractions

with relaxation between, i.e. it mimics normal uterine

activity. The decision to use oxytocin requires special

skill. It has a t1/2 of 6 min and is given by i.v. infusion

using a pump; it must be closely supervised; the dose

is adjusted by the results; overdose can cause uterine

tetany and even rupture.

slide42

Atosiban is a modified form of oxytocin that inhibits

the action of this hormone on the uterus, leading to

a cessation of contractions.It is used i.v.as a

tocolytic to halt premature labor.

Barusibanis three to four timesmorepotent

antagonist than atosiban with higheraffinity and

selectivity for the oxytocin receptor.

slide43

Parathyroid hormone (PTH)

PTHacts chiefly on the kidney increasing

renal tubular reabsorption and bone resorption of

calcium; it increases calcium absorption from the

gut, indirectly, by stimulating the renal synthesis of

25-hydroxycholecalciferol (calcifediol).

It increases the rate of bone remodelling (mineral and

collagen) and osteocyte activity with, at high doses,

an overall balance in favour of resorption (osteoclast

activity) with a rise in plasma calcium concentration

(and fall in phosphate); but, at low doses, the

balance favours bone formation (osteoblast activity).

slide44

The main

factors

involved in

maintaining

the

concentration

of calcium in

the plasma

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