Pharmacology of the Pharmacology of the Endocrine SystemEndocrine System

TopicsTopics Pituitary and hypothalamic Pituitary and hypothalamic

hormoneshormones Thyroid and antithyroid DrugsThyroid and antithyroid Drugs Adrenal DrugsAdrenal Drugs Pancreatic DrugsPancreatic Drugs Gonadal hormones and inhibitorsGonadal hormones and inhibitors

TheThe Endocrine System Endocrine System

Controls many body functionsControls many body functions

– exerts control by releasing special chemical exerts control by releasing special chemical substances into the blood called substances into the blood called hormoneshormones

– Hormones Hormones affect other endocrine glands or affect other endocrine glands or body systemsbody systems

Endocrine System Endocrine System

Hormone A substance that is releaseA substance that is releasedd in one tissue and in one tissue and

travels through the circulation (usually) to the ttravels through the circulation (usually) to the target tissue. arget tissue.

Hormones reach all parts of the body, but only Hormones reach all parts of the body, but only target cells are equipped to respondtarget cells are equipped to respond

Hormones are secreted in small amounts and Hormones are secreted in small amounts and often in bursts (pulsatile secretion)often in bursts (pulsatile secretion)

Endocrine FunctionsEndocrine Functions

• Maintain Internal Homeostasis

• Support Cell Growth

• Coordinate Development

• Coordinate Reproduction , fertility, sexual function• Facilitate Responses to External Stimuli

4 Classes of Hormones4 Classes of Hormones1.1. Peptide/ Protein Peptide/ Protein ((Range from 3 Range from 3

amino acids to hundreds of amino acids amino acids to hundreds of amino acids in size. )in size. )

2.2. SteroidSteroid3.3. Amine Amine (Thyroid hormones and (Thyroid hormones and

Catecholamines)Catecholamines)4.4. Eicosanoid Eicosanoid (Fatty acid derivatives )(Fatty acid derivatives )

The hormones fall into two general classes based on their solubility in water. The water soluble { amine (epinephrine) and

peptide/protein hormones} are secreted by exocytosis, travel freely in the bloodstream, and bind to cell-surface receptors.

The lipid soluble hormones { thyroid hormone, steroid hormones and Vitamin D3}. diffuse across cell membranes, travel in the bloodstream bound to transport proteins, and diffuse through the membrane of target cells .

NUCLEUS

Signalreceptor

(a) (b)

TARGETCELL

Signal receptorTransportprotein

Water-solublehormone

Fat-solublehormone

Location of receptorsLocation of receptors

- On cell surfaceOn cell surface Peptides and proteinsPeptides and proteins- In cytoplasmIn cytoplasm SteroidsSteroids- In nucleusIn nucleus Thyroid hormonesThyroid hormones

Mechanisms of endocrine diseaseMechanisms of endocrine disease

Endocrine disorders result from: Hormone deficiency, (HRT)(HRT) Hormone excess (Specific antagonists or release (Specific antagonists or release

inhibitors )inhibitors ) Hormone resistance(sensitizers(sensitizers)

Sources of hormones:Sources of hormones:

- Natural Human (GH; LH & FSH; hCG); Animal (Insulin, T3 & T4)- Biosynthetic Insulin (Porcine & Bovine)- Synthetic Most hormones and their antagonists

DNA recombinant technology

Hypothalamic & Pituitary Hormones

Spinal cord

Posteriorpituitary

Cerebellum

Pinealgland

Anteriorpituitary

Hypothalamus

Pituitarygland

Hypothalamus

Thalamus

Cerebrum

Hypothalamus and Pituitary

The output of the hypothalamus-pituitary unit regulates the function of the thyroid, adrenal and reproductive glands and also controls somatic growth, lactation, milk secretion and water metabolism.

Hypothalamic Hs can have effect of stimulating or inhibiting the release of ant. Pit. Hs. Called RELEASING

HORMONES “RH” or INHIBITING HORMONES “IH” respectively, reflecting their influence on ant. Pit. Hs.

The Pituitary GlandThe Pituitary Gland The Pituitary Gland is divided into 2 areas, with separate types of

hormone production. The anterior pituitary makes and releases H under

regulation of the hypothalamus Growth Hormone (GH) Thyroid-stimulating Hormone (TSH) Adrenocorticotropin (ACTH) Follicle-stimulating Hormone (FSH) ), Leutinizing Hormone (LH), Prolactin

– The posterior pituitary stores and secretes H that are made in the hypothalamus: oxytocin and antidiuretic hormone (ADH)

HypothalumusHypothalumus Ant. pituitaryAnt. pituitary Post. PituitaryPost. Pituitary

Growth hormone-Growth hormone-releasing releasing hormone(GHRH) hormone(GHRH) ++ Growth Hormone (GH), Growth Hormone (GH), Antidiuretic Antidiuretic

Hormone Hormone Growth hormone-Growth hormone-releasing inhibiting releasing inhibiting hormone (GHRIH)_hormone (GHRIH)_ SomatostatinSomatostatinThyrotropin-releasing Thyrotropin-releasing hormone (TRH)+hormone (TRH)+

Thyroid Stimulating Thyroid Stimulating Hormone (TSH), Hormone (TSH), OxytocinOxytocin

Corticotropin-releasing Corticotropin-releasing hormone (CRH)+hormone (CRH)+

Adrenocorticotropic Adrenocorticotropic Hormone (ACTH), Hormone (ACTH),

Gonadotropin-releasing Gonadotropin-releasing hormone (GnRH)+ hormone (GnRH)+

Follicle-stimulatingFollicle-stimulatingHormone (FSH), Hormone (FSH), Luteinizing Luteinizing Hormone(LH).Hormone(LH).

Dopamine _Dopamine _ Prolactin,Prolactin,

Hypothalamic hormones:Hypothalamic hormones:1- Growth Hormone- Releasing Hormone(GHRH):1- Growth Hormone- Releasing Hormone(GHRH): Together with somatostatin controls release of the GH Together with somatostatin controls release of the GH

from the ant. pit. from the ant. pit. It is released from hypothalamus in a pulsatile

fashion, with 5-9 major pulses detected per day.

• GHRH release is enhanced by α2-adrenergic agonists (e.g. clonidine) and opioids.

• GHRH release is increased by vigorous exercise.

Diagnostic Uses of GHRH (Sermorelin)Diagnostic Uses of GHRH (Sermorelin)To test pituitary function in patients with GH To test pituitary function in patients with GH

deficiency.deficiency. GH deficiency could reflect either a hypothalamic or a pit. defect.GH deficiency could reflect either a hypothalamic or a pit. defect. If the primary defect is hypothalamic, as is most If the primary defect is hypothalamic, as is most

common, GHRH will elicit an increase in GH release. common, GHRH will elicit an increase in GH release. If the defect is at the level of the pituitary, there will be If the defect is at the level of the pituitary, there will be

no increase in GH following GHRH administration.no increase in GH following GHRH administration. Therapeutic Uses of GHRH to enhance GH secretionTherapeutic Uses of GHRH to enhance GH secretion Pulsatile subcutaneous delivery of GHRH,

mimicking the normal endogenous patterns (e.g. ~ every 3 hours) has been used to stimulate GH release in patients with GH deficiency that is not of pituitary origin.

IV, SC, intranasalIV, SC, intranasal

Inhibits GH release and TSH from the ant. pituitary . Inhibits release of most GI hormones, reduces gastric acids and pancreatic

secretion. (glucagon , insulin & gastrin),

Therapeutic Uses Somatostatin Therapeutic Uses Somatostatin Somatostatin is of no clinical value because of it's short half-life (<3 min)Octreotide ,a synthetic somatostatin analogue with a longer duration of action Lanreotide is much longer acting, and is administered only twice a month. used to treat: Acromegaly, Gastrinoma ,Glucagonoma & Other Endocrine

Tumors , and esophageal varices bleeding. (Inhibits Mesenteric vasodilatation induced by glucagon)

A/E: GI disturb. postprandial hyperglycemia.Gall stones often form as a result of decreased biliary flow and gall bladder

contraction.

2- 2- Somatostatin (Growth hormone-Somatostatin (Growth hormone-releasing inhibiting hormone (GHRIH):releasing inhibiting hormone (GHRIH):

3- Thyrotropin-Releasing 3- Thyrotropin-Releasing Hormone(TRH):Hormone(TRH):

Stimulates release of thyrotropin (TSH) from the ant pit. Is used in diagnostic testing of thyroid dysfunction Protirelin: IV

4- Corticotropin Releasing Hormone(CRH) 4- Corticotropin Releasing Hormone(CRH)

It It stimulates secretion of both ACTH & beta –endorphin (a closely related peptide ) from the ant. pituitary .

CRH can be used in the diagnoses of abnormalities of ACTH secretion .

5- Gonadotropin-Releasing Hormone:5- Gonadotropin-Releasing Hormone:(GnRH):(GnRH):

Stimulate the gonadotroph cell to produce and release Stimulate the gonadotroph cell to produce and release LH LH and and FSHFSH,,

Gonadorelin, Buserelin, NafarelinGonadorelin, Buserelin, Nafarelin GnRH agonists, SC infusion in GnRH agonists, SC infusion in pulsespulses mimic mimic physiological physiological

GnRH, stimulates ovulation.GnRH, stimulates ovulation. In contrast, In contrast, steadysteady dosing inhibits gonadotropin release by dosing inhibits gonadotropin release by

causing down –regulation (desensitization) of GnRH receptors causing down –regulation (desensitization) of GnRH receptors in pituitary cells that normally release gonadotropins .in pituitary cells that normally release gonadotropins .

GnRH is used in the diagnosis & treatment (by pulsatile GnRH is used in the diagnosis & treatment (by pulsatile administration) of administration) of hypogonadalhypogonadal states in females & males . states in females & males .

Continuous GnRH agonists are used in sex H-dependent Continuous GnRH agonists are used in sex H-dependent conditions: prostate & breast cancers, uterine fibroids, conditions: prostate & breast cancers, uterine fibroids, endometriosis or precocious puberty .endometriosis or precocious puberty .

6- Prolactin-Inhibiting Hormone 6- Prolactin-Inhibiting Hormone (PIH,dopamine):(PIH,dopamine): Dopamine is the physiologic inhibitor of prolactin Dopamine is the physiologic inhibitor of prolactin

release release

Because of its peripheral effects & the need for Because of its peripheral effects & the need for parenteral administration, dopamine is not useful in parenteral administration, dopamine is not useful in the control of hyperprolactinemia, but the control of hyperprolactinemia, but bromocrptine bromocrptine & other orally active ergot –derivatives (eg& other orally active ergot –derivatives (eg. . CabergolineCabergoline, , pergolinepergoline) are effective in reducing ) are effective in reducing prolactin secretion from the normal glands as well as prolactin secretion from the normal glands as well as from prolactinomas .from prolactinomas .

Also used in treatment of acromegalyAlso used in treatment of acromegaly

A/E: orthostatic hypotension, Psychiatric manifestationsA/E: orthostatic hypotension, Psychiatric manifestations

Pituitary HormonesPituitary Hormones

Anterior pituitary Hormones

Growth HormoneGrowth Hormone• Derived from the somatotroph cells • Its secretion is controlled by GHRH and

somatostatin;• GH secretion is high in newborn, deceasing at 4 yr

to an intermediate level, which is then maintained until puberty, when there is further decline.

• Insulin-like growth factor 1 (IGF-1) released from the liver inhibits GH secretion by stimulating somatostatin secretion from the hypothalamus,

Growth Hormone ActivityGrowth Hormone Activity1. Increases plasma free fatty acids (source of energy for

muscle tissue)

2. Increases hepatic glucose output

3. Decreases insulin sensitivity in muscle

4. Is protein anabolic hormone

Growth Hormone DeficiencyGrowth Hormone DeficiencyCan have a genetic basis or can be acquired as a result

of damage to the pituitary or hypothalamus by a tumor, infection, surgery, or radiation therapy.

In childhood: short stature and adiposity, hypoglycemia.Adults : generalized obesity, reduced muscle mass.

GROWTH HORMONE EXCESSGROWTH HORMONE EXCESS Mainly benign pituitary tumor In adults causes acromegaly, If this occurred before the long bone epiphyses

close, it leads to the rare condition, gigantism. Treatment of excess GH disorders:- Synthetic Somatostatin (Octreotide)- DA agonists (Bromocriptine)- Surgical removal / Radiotherapy of the tumor- GH Antagonists (Pegvisomant)

An excess of GH An excess of GH can cause can cause gigantism, while a gigantism, while a lack of GH can lack of GH can cause dwarfismcause dwarfism

Clinical uses of GHClinical uses of GHSomatotropinSomatotropin

GH deficiency in children & adults. GH deficiency in children & adults. Children with short stature that is due to Children with short stature that is due to

factors other than GH deficiency:factors other than GH deficiency: Idiopathic short stature, Turner syndrome, Chronic Idiopathic short stature, Turner syndrome, Chronic

renal failurerenal failureA/EA/E: : Hypothyroidism, Pancreatitis, Gynecomastia, Hypothyroidism, Pancreatitis, Gynecomastia,

Possibilities of abuse have also arisen, e.g. creation of “super” sports people.

Thyroid-stimulating Hormone Thyroid-stimulating Hormone (TSH)(TSH)

Also called thyrotrophinAlso called thyrotrophin Stimulates secretion of thyroid

hormone & growth of thyroid gland.Diagnostic Uses of TSHDiagnostic Uses of TSH In patients who have been treated In patients who have been treated

surgically for thyroid carcinoma, to surgically for thyroid carcinoma, to test for recurrencetest for recurrence

Adrenocorticotropin (ACTH)Adrenocorticotropin (ACTH)

Stimulates cortisol secretion by the adrenal cortex & promotes growth of adrenal cortex

Diagnostic useDiagnostic use: as a test of the capacity of the adrenal cortex to produce cortisol;

Follicle Follicle ––stimulating hormone stimulating hormone (FSH)(FSH)

• Females: stimulates growth & development of ovarian follicles, promotes secretion of estrogen by ovaries.

• Males: required for sperm production 3 preparations are available for clinical use: Urofollitropin ,purified from of the urine of post menopausal

women, 2 recombinant forms, follitropin alpha & follitropin beta. These products are used in combination with other drugs to

treat infertility in women & men.

Leutinizing hormone (LH)Leutinizing hormone (LH)• Females: responsible for ovulation, formation of corpus luteum

in the ovary, and regulation of ovarian secretion of female sex hormones.

• Males: stimulates cell in the testes to secrete testosterone • Lutropin alfa, approved for use in combination with

follitropin alfa for stimulation of follicular development in infertile women with profound LH deficiency. .

ProlactinProlactin Secreted by lactotroph cells of the ant. Pit., which increase

in number during pregnancy. Its secretion is stimulated by estrogen

• Females: stimulates breast development and milk production.

• Males: involved in testicular function No preparation of prolactin is available for use in prolactin-

deficient patients. For patients with symptomatic hyperprolactinemia,

inhibition of prolactin secretion can be achieved with dopamine agonists, which act in the pituitary to inhibit prolactin release.

Posterior pituitary Hormones

OxytocinOxytocin• It is synthesized in the hypothalamus & It is synthesized in the hypothalamus &

transported to the post. Pit.transported to the post. Pit.• It is an effective stimulant of It is an effective stimulant of uterine uterine

contractions contractions & is used intravenously to induce & is used intravenously to induce or reinforce or reinforce laborlabor . .

• Induces the Induces the release of milkrelease of milk• Suckling sends a message to the hypothalamus Suckling sends a message to the hypothalamus

via the nervous system to release oxytocin, via the nervous system to release oxytocin, which further stimulates the milk glandswhich further stimulates the milk glands

Clinical uses of oxyticinClinical uses of oxyticinIV, IMIV, IM Induction of laborInduction of labor Control of postpartum bleedingControl of postpartum bleeding

A/EA/E : :fetal distress, placental abruption, or fetal distress, placental abruption, or

uterine ruptureuterine ruptureexcessive fluid retention excessive fluid retention

Vasopressin (antidiuretic hormone Vasopressin (antidiuretic hormone ADH)ADH)

• It is synthesized in the hypothalamus & transported to It is synthesized in the hypothalamus & transported to the post. Pit.the post. Pit.

The function of The function of ADHADH is to is to increase water conservation increase water conservation by by the kidney. the kidney.

If there is a If there is a highhigh level of ADH secretion, the kidneys level of ADH secretion, the kidneys reabsorbreabsorb water. water.

If there is a If there is a lowlow level of ADH secretion, the kidneys level of ADH secretion, the kidneys releaserelease water in water in dilute urinedilute urine..

ADH release increases if blood pressure falls or blood ADH release increases if blood pressure falls or blood becomes too salty.becomes too salty.

ADH causes peripheral blood vessel constriction to help ADH causes peripheral blood vessel constriction to help elevate blood pressure .elevate blood pressure .

Clinical usesClinical uses Diabetes insipidus, Diabetes insipidus, Nocturnal enuresis (by decreasing Nocturnal enuresis (by decreasing

nocturnal urine production)nocturnal urine production)A/E: hyponatremia and seizures A/E: hyponatremia and seizures

Synthetic ADH drugsSynthetic ADH drugs– Vasopressin: IV, IMVasopressin: IV, IM– Desmopressin: IV, IM. PO, intranasalDesmopressin: IV, IM. PO, intranasal