molecular pharmacology pharmacology of the hypothalamus...

Molecular PharmacologyPharmacology of the Hypothalamus

and Pituitary GlandDr. Fuad AL KHIDIR

1

INTRODUCTION

• The hypothalamus and pituitary gland function cooperatively as master regulators of the endocrine system.

• Together, hormones secreted by the hypothalamus and pituitary gland control important homeostatic and metabolic functions, including reproduction, growth, lactation, thyroid and adrenal gland physiology, and water homeostasis.

2

Relationship Between the Hypothalamus and Pituitary Gland

• From a developmental perspective, the pituitary gland consists of two closely associated organs:

The anterior pituitary (adenohypophysis)

The posterior pituitary (neurohypophysis)

• The hypothalamus controls the activity of both lobes.

• The hypothalamus acts as a neuroendocrine transducer by integrating neural signals from the brain and converting those signals into chemical messages (largely peptides) that regulate the secretion of pituitary hormones.

• In turn, the pituitary hormones alter the activities of peripheral endocrine organs.

3

The hypothalamic-pituitary portal system

Neurons in the hypothalamus release regulatory factors that are carried by the hypothalamic-pituitary portal system to the anterior pituitary gland, where they control the release of anterior pituitary hormones.

Posterior pituitary hormones are synthesized in cell bodies of the neurons in the hypothalamus and then transported down axonal pathways to terminals in the posterior pituitary gland. They are then released into the systemic circulation.

Note the separate vascular supplies to the anterior and posterior lobes of the pituitary gland.

4

STIMULATORYHYPOTHALAMICFACTORS

ANTERIORPITUITARY GLANDCELL TYPE

PITUITARYHORMONESRELEASED

MAJOR TARGETORGAN OFHORMONE

HORMONESPRODUCED BYTARGET ORGAN

GHRH, ghrelin Somatotroph GH Liver, cartilage Insulin-like growthfactors

TRH Lactotroph Prolactin Mammary gland

None

TRH Thyrotroph TSH Thyroid gland Thyroxine,triiodothyronine

CRH Corticotroph ACTH Adrenal cortex Cortisol, aldosterone,adrenal androgens

GnRH Gonadotroph LH and FSH Gonads Estrogen, progesterone,testosterone, inhibin

5

Anterior Pituitary Gland Cell Types, Hypothalamic Control Factors, and

Hormonal Targets

1. Hypothalamic-Pituitary-Growth Hormone Axis:

• This axis regulates general processes that promote growth.

• Somatotrophs of the anterior pituitary gland produce and secrete growth hormone (GH) in a pulses.

• Most of the anabolic effects of GH are mediated by insulin-like growth actors, especially insulin-like growth factor 1 (IGF-1), a hormone released into the circulation by hepatocytes in response to stimulation by GH.

6

Factors that regulate GH secretion

• Environmental factors increase GH secretion such as hypoglycemia, sleep, exercise, and adequate nutritional status.

• Endogenous biological inputs that increase GH secretion include hypothalamic GHRH, sex steroids (most notably during puberty), dopamine, and ghrelin (secreted mainly by gastric fundal cells during the fasting state, linking growth with nutritional status and energy balance).

• Environmental factors inhibit GH release, including hyperglycemia, sleep deprivation, and poor nutritional status.

• Endogenous biological factors that inhibit GH secretion are somatostatin, IGF-1, and GH.

7

8

Schematic model of the regulation of GH secretion by central and peripheral neuroendocrine signals.Somatostatin has 14- and 28-amino acid forms that are selectivelyproduced in pancreatic δ-cells, the gastrointestinal tract, and the hypothalamus.

Growth hormone GH

9

GH, also called somatotropin (generic name), is a protein hormone of about 190 amino acid.

Pathophysiology and Pharmacology of Growth Hormone Deficiency

1. Failure to secrete GH or to enhance IGF-1 secretion during puberty results in growth retardation (short stature).

• This may result from:

A. defective hypothalamic release of GHRH (tertiary deficiency)

Treatment:

– GHRH analogue to increase GH such as Tesamorelin

– Alternative exogenous agents currently used to stimulate GH release include glucagon, arginine, clonidine, and insulin –induced hypoglycemia.

10


B. pituitary insufficiency (secondary deficiency)

Treatment:

– Replacement recombinant human GH; (generic name somatropin) administered daily SC or IM injection.

• Some pediatric indications for GH use include idiopathic short stature, chronic kidney disease, Turner’s syndrome, and Prader-Willi syndrome.

• Unapproved use of GH or GH releasing peptides (GHRPs) in competitive sports is common

11

12

HypopituitarismCause: GH or IGF deficiency

Laron DwarfismCause: mutation of GH receptor

Unapproved use of GH by bodybuilders


• Failure of IGF-1 secretion in response to GH (Laron dwarfism or primary deficiency) is one etiology of short stature that is not treated with GH.

Treatment:

• Recombinant IGF-1 (generic name: mecasermin)

• Mecasermin is also approved for use in patients with GH deficiency and antibodies against growth hormone.

• Adverse effects, including hypoglycemia and rare intracranial hypertension.

• IGF-1 can also be used by bodybuilders to increase muscle mass.

13

14

Human: IGF-1

Pathophysiology and Pharmacology of Growth Hormone Excess

• GH excess usually results from a somatotroph adenoma

• It has two different disease presentations:

– Before closure of the epiphyses: Gigantism; increased IGF-1 levels promote excessive longitudinal bone growth.

– After closure of the epiphyses: Acromegaly; increased IGF-1, can still promote growth of organs and cartilaginous tissue.

• Consequences of a pituitary mass lesion (adenoma) may also cause headache, loss of other pituitary hormone functions (cessation of menstruation), and visual field loss.

15

Pathophysiology and Pharmacology of Growth Hormone Excess

16

GigantismAcromegaly

Management of somatotroph adenoma

Management options for somatotroph adenoma:

• Surgical resection

• Radiation therapy

• Medical options:

1. Somatostatin receptor agonists (also known as somatostatin receptorligands (SRLs) or somatostatin analogues), Octreotide and lanreotide are synthetic, long acting peptides. Pasireotide (first approved for the treatment of Cushing’s disease) has also shown clinical efficacy in the treatment of acromegaly and is now approved for this indication.

Adverse effects:

nausea, diarrhea, gallstones, and glucose dysregulation.

• The efficacy of SRLs lies in their ability to normalize GH and IGF-1 levels in approximately 60–80% of acromegalic patients and to decrease pituitary adenoma size in 40–50% of affected patients.

17

Management of somatotroph adenoma

2. dopamine analogues (bromocriptine, cabergoline): less effective, used as second-line of treatment

3. GH receptor antagonists:

– Pegvisomant: reduces IGF-1, but also increases GH levels by decreasing IGF-1-mediated feedback inhibition of GH secretion.

– Pegvisomant is currently used as a second- or third-line medical agent after SRL therapy has been attempted

18

2. Hypothalamic-Pituitary-Thyroid Axis

Introduction

• The thyroid is an endocrine gland located in the neck.

• Follicular thyroid cells produce and secrete thyroid hormones:

▪ 3,5,3,5 -Tetraiodothyronine (thyroxine (T4))

▪ 3,5,3 -Triiodothyronine (T3)

• Parafollicular C cells of the thyroid gland secrete calcitonin, a regulator of bone mineral homeostasis.

19

Synthesis and Secretion of Thyroid Hormones

• In a normal individual, circulating thyroid hormone consists of:

– 90% T4

– 9% T3: produced by peripheral or extra-thyroidal 5 deiodination of T4

– 1% rT3: is 3,3 ,5 –triiodothyronine, biologically inactive.

• Most of the hormone is bound to plasma proteins (both specific binding proteins and albumin).

20

The thyroid hormones are built on

a backbone of two tyrosine

molecules that are iodinated and

connected by an ether linkage

21

Mechanisms of feedback regulation of thyroid hormone.TSH: Thyrotropin releasing hormone, TSH: thyroid stimulating hormone

Functional effects of thyroid hormones

22


• Iodine is a trace element that is a crucial component ofthyroid hormone structure.

• Thyroid follicular cells, selectively concentrate iodide (I ) via a Na+/I-

symporter located on the basolateral membrane of the cell.

• Iodide is transported across the apical membrane of the cell via a Cl-/I- exchanger into the colloid space

23


• Iodide is then oxidized by thyroid peroxides.

• Reactive iodide intermediate couples to specific tyrosine residues on thyroglobulin (called organification)

• Organification results in thyroglobulin (TG) molecules containing monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues.

24


• Thyroid peroxidase also catalyzes coupling between these residues:

• An MIT joined to DIT generates T3, while the joining of two DITscreates T4.

• The majority of plasma T3 is produced by metabolism of T4 in the circulation

25

Pathophysiology

Two common thyroid diseases are believed to be autoimmune in origin:

1. Hashimoto’s disease results in hypothyroidism:

• Antibodies specific for many thyroid gland proteins, including thyroglobulin and thyroid peroxidase, can be found in the plasma of patients.

• The clinical course of Hashimoto’s thyroiditis involves a gradual inflammatory destruction of the thyroid gland with resultant hypothyroidism.

• Other causes of hypothyroidism and hyperthyroidism include developmental anomalies, subacute (de Quervain’s) thyroiditis, and thyroid adenomas and carcinomas.

26

Treatment of Hypothyroidism

• The exogenous thyroid hormone is structurally identical to endogenous thyroid hormone (generally T4) and is produced by chemical synthesis.

• The extended half-life of T4 allows a patient to take just one thyroid hormone replacement pill per day.

• The efficacy of thyroid hormone replacement is monitored by assays of plasma TSH and thyroid hormone levels.

Drug–drug interactions

• Resins such as cholestyramine may decrease absorption of T4.

• Infection with Helicobacter pylori or usage of proton pump inhibitor also reduce T4 absorption.

• Drugs that increase the activity of certain hepatic P450 enzymes, including rifampin and phenytoin , increase the hepatic clearance o T4.

28

Pathophysiology

29

2. Graves’ disease causes hyperthyroidism

• In this syndrome, an IgG autoantibody specific for the TSH receptor is produced.

• This autoantibody is known as thyroid-stimulating immunoglobulin (TSIg) .

• The antibody acts as an agonist, activating the TSH receptor and thereby stimulating thyroid follicular cells to synthesize and release thyroid hormone.

• Laboratory studies show high plasma thyroid hormone levels, low or undetectable TSH levels, and high TSIg levels.

30

Treatment of hyperthyroidism

Drugs used in hyperthyroidism

131IInorganic

Iodide

Thionamides

Propylthiouracil

Beta-Blockers

(propranolol)

31

Treatment of Hyperthyroidism

Inhibitors of organification and Hormone Release:

• Iodides:

Two distinct types of iodide are used in clinical practice:

• The first agent, 131 I -, is a radioactive iodine isotope that

strongly emits β-particles toxic to cell.

• This agent serves as an alternative to surgery in the treatment of hyperthyroidism.

• The goal is to administer enough 131 I -, to result in an euthyroid state, without precipitating hypothyroidism.

• There is a concern that patients may eventually develop hypothyroidism, however, the development of hypothyroidism is easier to manage clinically than hyperthyroidism.

32


• The second agent is stable inorganic iodide:

• High levels of iodide inhibit thyroid hormone synthesis and release, a phenomenon known as the Wolff-Chaikoff effect .

• This phenomenon has important uses.

• For example, before thyroid gland surgery, high iodide dosing reduces the size and vascularity of the thyroid gland, resulting in technically easier excision.

• Iodide can also have important preventative effects (in the nuclear accident at Chernobyl, large doses of iodide were given to children for a number of days to suppress thyroid gland unction temporarily and thereby to avoid uptake of environmental radioactive iodine

34

The Wolff-Chaikoff Effect. Panel A: a proposed mechanism of the acute Wolff-Chaikoff effect. During the first day of iodine exposure, the sodium-iodide symporter transports the excess iodine into the thyroid, resulting in transientinhibition of thyroid peroxidase (TPO) and a decrease in thyroid hormone synthesis.Panel B: the mechanism that turns off the acute Wolff-Chaikoffeffect. A dramatic decrease in sodium-iodide symporter expression results in decreased iodine transport and the subsequent resumption of thyroid hormone synthesis

35


• Thionamides: propylthiouracil, methimazole, carbimazole(converted to methimazole).

• Thionamides compete with thyroglobulin for oxidized iodide in a process catalyzed by the enzyme thyroid peroxidase .

• Thionamide treatment causes a selective decrease in the organification and coupling of thyroid hormone precursors and thereby inhibits thyroid hormone production.

36


• Thionamides affect the synthesis, but not the secretion, of thyroid hormone, therefore, effects of these drugs are not manifested until several weeks after the initiation of treatment.

• Thionamide treatment often results in goiter formation;inhibition of thyroid hormone production by thionamides results in up-regulation of TSH release by the anterior pituitary gland.

• Propylthiouracil has a short half-life that necessitates dosing three times a day, while methimazole can be administered once daily.

37


Side-effects:• Both propylthiouracil and methimazole are well tolerated.• The most frequent adverse effects:

– Pruritic rash; it may recover spontaneously. – Arthralgias are a common reason for stopping treatment. – Interference with the vitamin K-dependent synthesis of

prothrombin, leading to an increased bleeding tendency.– Three rare but serious complications are agranulocytosis

(usually within the first 90 days of treatment),hepatotoxicity, and vasculitis.

• Because of this risk, all patients taking thionamides should have a baseline measurement of white blood cell count and should be advised to discontinue the drug immediately ifthey develop fever or a sore throat.

38


39

Vasculitic lesion on the ear skin


• Methimazole is generally the preferred agent in clinical practice.

• Two exceptions are thyroid storm and pregnancy.

• In pregnancy, propylthiouracil is the preferred agent safer than methimazole

• A high percentage of patients taking these agents over the course of 6 months to a year may be able to maintain an euthyroid state a after discontinuation of these medications.

40


• β-Adrenergic Blockers

• These are useful for the symptoms of hyperthyroidism.

• Many of the effects of high plasma thyroid hormone levels resemble nonspecific β-adrenergic stimulation (e.g., sweating, tremor, tachycardia), although circulating catecholamine levels are not elevated.

• It is hypothesized that thyroid hormones may increase the responsiveness of tissues such as the heart to β-adrenergic stimulation.

• It has also been demonstrated that β-blockers can reduce peripheral conversion of T4 to T3 (this effect is not thought to be clinically relevant.

• Because of its rapid onset of action and short elimination half-life (9 minutes), esmolol is a preferred parenteral β-adrenergic antagonist for the treatment of thyroid storm.

41

molecular pharmacology pharmacology of the hypothalamus...

Documents