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Medical University of Sofia, Faculty of Medicine
Department of Pharmacology and Toxicology
Hypothalamic hormones
Pituitary hormones
Parathyroid hormone
Assoc. Prof. Ivan Lambev
e-mail: [email protected]
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 their
distant 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 synthesis release inhibitors have significant therapeutic
importance 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. Thyroid
Thyroxine (T4), Triiodthyronine (T3)
Calcitonin
3. Parathyroid: Parathormone (PTH)
4. Pancreas (Islets of Langerhans): Insulin, Glucagon
5. Adrenals
a) Cortex
- Glucocorticoids (GCS): Hydrocortisone, Cortisone
- Mineralcorticoids: Aldosterone
- Sex steroids: Dehydroepiandrosterone (…Testost.)
b) Medulla: Adrenaline, Noradrenaline
6. Gonads
a) Androgens: Testosterone
b) Estrogens: Estradiol
c) Progestins: Progesterone
7. Hypothalamic hormones (factors)
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 factor (PRF): Unknown
Prolactin release inhibitory hormone (PRIH):
Dopamine (DA)
Growth hormone release inhibitory hormone
(GHRIH): Somatostatin – peptide
8. Placental hormones
Prolactin, Progesterone, Chorionic gonadotrophin
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
b) Through the IP3 and DAG generation
Oxytocin, Vasopressin (via V1-rec.)
Release of intracelullar Ca2+
and protein kinase C activation
c) Direct transmembrane activation
of tyrosine kinase
GH, Insulin, Prolactin
Phosphorilation cascade
Regulation of various enzymes
2. Action on the intracellular
(steroid or thyroid) receptors
Effector
Coupling
Time scale
Examples
gene transcription
via DNA
hours
Steroide hormones
thyroid hormones
calcitriol
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 mediated
protein synthesis
Hypothalamic and
Pituitary Hormones
Hypothalamic hormones
regulate anterior pituitary
trophic hormones that, in
turn, determine target
gland secretion.
There is a
peripheral hormones
feed back which regulate
hypothalamic and
pituitary hormones
Feedback
regulation
of
endocrine
axes
Goodman & Gilman's The Pharmacologic
Basis of Therapeutics - 11th Ed. (2006)
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 pituitary via the
hypothalamic-adenohypophyseal portal system and
stimulate distinct populations
of pituitary cells. These cells,
in turn, secrete the trophic
hormones, which regulate
endocrine organs and other
tissues.
Corticotrophin releasing hormone (CRH) –
corticoliberin, is a hypothalamic polypeptide for
diagnostic use. It increases ACTH secretion in
Cushing's disease secondary to pituitary ACTHsecreting adenoma.
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 immunological activity resides in the remaining 15 aminoacids. The pituitary output of corticotrophin responds
rapidly to physiological requirements by the
familiar negative-feedback homeostatic mechanism.
Synthetic corticotrophin tetracosactide has the
advantage that they are shorter amino acid chains
(devoid of amino acids 25–39) and so are less likely
to 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 natural
corticotrophin (from man or animals) and so it has
similar properties, e.g. t1/2 10 min.
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.
High plasma concentration of any steroid with
glucocorticoid effect prevents release of corticotrophin releasing hormone and so of ACTH, lack of
which in turn results in adrenocortical hypofunction.
This is the reason why catastrophe may follow 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 the clinical picture of Cushing's syndrome.
Corticotrophin is used
principally in diagnosis
and rarely in treatment.
It is inactive if taken
orally and has to be
injected like other peptide
hormones.
Rang et al. Pharmacology –
5st Ed. (2003)
Diagnostic use: as a test of the capacity of the
adrenal cortex to produce cortisol; with the short
test, the plasma cortisol (hydrocortisone) concentration is measured before and after an i.m.
injection of tetracosactide (Synacthen®).
Therapeutic use of ACTH is seldom appropriate
because the peptide hormone has to be injected;
selective glucocorticoid action (without mineralocorticoid effect) cannot be obtained, and clinical
results are irregular.
Thyrotrophin releasing hormone (TRH) –
protirelin, is a tripeptide formed in the hypothalamus 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.
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.
Goodman & Gilman's The Pharmacologic
Basis of Therapeutics - 11th Ed. (2006)
Two hypothalamic factors, growth
hormone-releasing hormone
(GHRH) and somatostatin (SST),
act on the somatotropes in the
anterior pituitary to regulate
growth 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 multiple
actions on the hypothalamus. IGF-1 feeds back at the anterior
pituitary to inhibit growth hormone secretion and also to inhibit further
GHRH release by the hypothalamus.
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 postnatal life on lipid and carbohydrate metabolism, and
on body mass. Its effects are primarily mediated via
insulin-like growth factor 1 (IGF-1)
and to a lesser extent both directly and through
insulin-like growth factor 2 (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.
GH is a 191-amino-acid peptide. Its structure closely
resembles that of prolactin. 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 191 amino acids of GH plus 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.
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 component of anti-aging programs. 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, hypertension 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.
Somatostatin (growth hormone release inhibiting
hormone) occurs in other parts of the brain as well
as in the hypothalamus, and also in some peripheral tissues, e.g. pancreas, stomach. It inhibits
secretion of thyrotrophin, insulin, gastrin and 5-HT.
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).
Lanreotide is much longer acting, and is administered 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 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.
Transsphenoidal resection
of pituitary tumour mass via
the endonasal approach.
Gonadorelin (gonadotrophin releasing hormone –
GnRH) releases luteinising hormone (LH) and
follicle-stimulating hormone (FSH). It has
use in 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 of GnRH (buserelin,
goserelin, nafarelin, deslorelin and leuprorelin) are
used to suppress androgen secretion in prostatic
carcinoma.
Rang et al.
Pharmacology –
5st Ed. (2003)
The regulation of gonadotrophin release from the
anterior pituitary by endogenouse GnRH and drugs
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
development of ova and of spermatozoa. It is prepared 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 gonadotrophin – hCG) is secreted by the placenta and
is obtained from the urine of pregnant women.
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.
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. Hyperprolactinaemia may be caused by drugs (with antidopaminergic actions e.g. metoclopramide), hypothyroidism, or prolactin secreting adenomas. Medical
treatment is with bromocriptine, cabergoline, or
quinagolide at bedtime.
Goodman & Gilman's The Pharmacologic
Basis of Therapeutics - 11th Ed. (2006)
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 as 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).
Hypothalamic neurons
in the supraoptic (SON)
and paraventricular (PVN)
nuclei synthesize arginine
vasopressin (AVP) or
oxytocin (OXY).
Goodman & Gilman's The Pharmacologic
Basis of Therapeutics - 11th Ed. (2006)
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.
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 receptor is 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.
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.
Desmopressin (des-amino-D-arginine vasopressin)
(DDAVP) has two major advantages: the vasoconstrictor 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 inconvenienced 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%.
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.
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.
Oxytocin is structurally close to vasopression
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 ergot
alkaloid, ergometrine, as prime treatment of
postpartum haemorrhage.
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 used i.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 results; overdose can cause uterine
tetany and even rupture.
Parathyroid hormone (PTH)
PTH acts chiefly on kidney increasing
renal tubular resorption and bone resorption of
calcium; it increases calcium absorption from the
gut, indirectly, by stimulating the renal synthesis of
1α-25-dihydroxycholecalciferol (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).
Rang et al.
Pharmacology –
5st Ed. (2003)
The main factors involved in maintaining
the concentration of calcium in the plasma