Posterior Pituitary and Hypothalamic Hormones

Question 1

Anterior pituitary receives […] from neuroendocrine cells in the […].

Answer 1

Anterior pituitary receives vascular supply from neuroendocrine cells in the median eminence.

Question 2

Posterior pituitary receives […] from the […] and paraventricular nucleus […].

Answer 2

Posterior pituitary receives neuronal communication from the supraoptic nucleus (SON) and paraventricular nucleus (PVN).

Question 3

Posterior Pituitary (pars nervosa, neurohypophysis) secretes…

Answer 3

• vasopressin (ADH)
• oxytocin

Question 4

Vasopressin (ADH)

Answer 4

• Vasopressin originally received its name because of its ability to increase blood pressure via vasoconstriction when administered in pharmacologic amounts.
• However, it is more appropriately called antidiuretic hormone (ADH) because its most important physiologic action is to promote reabsorption of water from the distal renal tubules.

Question 5

Oxytocin

Answer 5

•Oxytocin accelerates birth by stimulation of uterine smooth muscle contraction, and promotes milk ejection from the mammary gland.

Question 6

VP (ADH) and Oxytocin

Answer 6

• Each hormone is a nine amino acid peptide containing a 1-6 disulfide bridge and a C-terminal glycine amide.
• These hormones are highly homologous, differing only in two amino acids.

Question 7

Where are the major sites of synthesis for VP and oxytocin?

Answer 7

• Cell bodies of the magnocellular neurons within the hypothalamus (supraoptic nucleus, SON; paraventricular nucleus, PVN) are the major sites of synthesis of ADH (VP) and oxytocin.
• The nerve terminals of the cells in which these hormones are stored and secreted are located in the posterior pituitary.
• Hence these hormones must be transported by axoplasmic flow to nerve endings in the posterior pituitary where, upon appropriate stimulation, the hormones are released into the circulation.
• Each is transported through axons in noncovalent association with specific carrier proteins called neurophysins.
• Most of the secreted hormone is released into the blood to participate in a true endocrine type of communication.
• A small portion of these hormones is released into the extrahypothalamic areas of the central nervous system, where it is thought they produce neuromodulatory effects.

Question 8

Neurophysins

Answer 8

•Neurophysins I and II are synthesized with oxytocin and ADH/VP, respectively, each as a part of a single pro-protein coded for by a single gene.

Question 9

Synthesis of ADH (Oxytocin)

Answer 9

• The VP/ADH gene is expressed in both the supraoptic and paraventricular nuclei (oxytocin also).
• The gene codes for a composite precursor protein, prepro-vasopressin, that is processed by proteolytic cleavage to yield the vasopressin hormone and its neurophysin II carrier.
• The N-terminal portion of the precursor protein contains a signal peptide targeting it for secretion, just as we discussed for insulin and glucagon, other peptide hormones.
• The signal peptide is cleaved by the signal peptidase in the cisternal space of the rough endoplasmic reticulum to yield pro-vasopressin.
• The central portion of this molecule consists of neurophysin II.
• Neurophysin II is an intrinsic part of the hormone precursor and accompanies the vasopressin, after processing in the Golgi apparatus, for packaging in neurosecretory granules.
• Basic amino acids (lysine/arginine) are present at the sites of proteolytic processing, and enzymatic cleavage is carried out by specific, trypsin-like enzymes.
• Note that a glycoprotein of unknown function is included on the proprotein of vasopressin in the C-terminal region.

Question 10

Answer 10

Question 11

Secretion of ADH

Answer 11

• ADH secretion by exocytosis (stimulus-secretion coupling) occurs by firing the neuron that originates in the supraoptic nucleus of the hypothalamus (or paraventricular nucleus).
• An osmoreceptor, in the nuclei, can sense a 2-3% increase (particles/volume) in osmolality in the fluid that perfuses it.
• When osmolality increases, ADH is secreted to promote water retention at the kidney, and thereby lower osmolality to normal.
• As a consequence of increased osmolality or decreased blood volume, acetylcholine is released from the preganglionic fiber.
• This signal triggers the supraoptic (or paraventricular) nucleus of the hypothalamus to synthesize and process ADH.
• The ADH, carried on neurophysin II in neurosecretory granules, travels down the long axon of the vasopressinergic neuron.
• The axonal action potential causes depolarization and uptake of calcium that triggers the fusion of the granules with the surface followed by exocytosis of the vasopressin-neurophysin complex through fenestrations in the blood vessels.
• The vasopressin-neurophysin complex dissociates in the circulation.

Question 12

Mechanisma of ACtion via V1 and V2 Receptors

Answer 12

• The most important physiologic target cells of ADH in mammals are those of the distal convoluted tubules and collecting structures of the kidney.
• The crucial determinant of the response of these kidney cells to ADH is their high concentration of specific ADH (type V2 vasopressin) receptors.
• These receptors are linked to adenylyl cyclase so that cAMP mediates the effects of ADH in the renal tubule.
• Once protein kinase A (PKA) is activated by cAMP, PKA is tethered to intracellular vesicles that contain aquaporin-2 water channels.
• PKA then phosphorylates the aquaporin-2 proteins.
• Cytoplasmic vesicles containing multiphosphorylated aquaporin-2 water channels move to, and fuse with the apical membrane, thereby inserting the water channels in membrane to enhance transepithelial water reabsorption.

•High concentrations of ADH also increase blood pressure, via a vasopressor effect.

• Its vasoconstricting properties have led to the use of vasopressin in the management of shock and of severe gastrointestinal or postpartum hemorrhage.
• Unlike the action on kidney, the vascular effect of vasopressin to increase blood pressure following binding to V1 receptors.
• Unlike the V2 receptor, the V1 receptor is coupled to Gq.
• Thus, it activates the phospholipase C triggered pathway that cleaves PIP2 to generate IP3/Ca2+ and DAG as second messengers. T

•he anterior pituitary contains V3 ADH receptors that, when activated, enhance the effect of CRH on the release of ACTH (adrenocorticotropic hormone).

Question 13

ADH Abnormalities

Answer 13

•neurogenic diabetes insipidus (central diabetes insipidus)

-hyposecretion of ADH

•neurgenic diabetes insipidus

-resistance to ADH

•SIADH

Question 14

Neurogenic Diabetes Insipidus (Central Diabetes Insipidus)

Answer 14

• Abnormalities causing decreased secretion (hyposecretion) of ADH lead to neurogenic diabetes insipidus also referred to as central diabetes insipidus.
• The disorder is distinct from the more common diabetes mellitus, which is caused by insulin deficiency.

-Both diseases are characterized by the production of large volumes of urine.

• Symptoms of diabetes insipidus include excessive output of urine of low specific gravity, with increases in plasma osmolality, and compensatory thirst accompanied by drinking large amounts of fluids.
• Patients with diabetes insipidus may lose up to 20 liters of water per day.
• Neurogenic diabetes insipidus can be inherited or acquired.
• Inherited defects have been identified in the AVP-NPII gene leading to either altered vasopressin or neurophysin II.
• A defect in the osmoreceptor also has been reported.
• An acquired block in axonal transit to the posterior pituitary due to idiopathic, primary or secondary tumors, infiltrative diseases (.e.g., Langerhans cell histiocytosis), head injury, stroke or neurosurgery all can cause central diabetes insipidus.

•The symptoms may be controlled by ADH replacement therapy using desmopressin acetate

Question 15

Neurogenic Diabetes Insipidus - resistance to ADH

Answer 15

• Nephrogenic diabetes insipidus is associated with conditions that affect renal resistance to the water-retaining effect of ADH.
• Nephrogenic diabetes insipidus is of two types, hereditary (most common) and acquired. In hereditary nephrogenic diabetes insipidus, the target cells fail to respond to the circulating ADH (end organ insensitivity).
• ADH resistance may be caused by defective type V2 ADH receptors, an X-linked disorder, or by post-receptor defects in the signal transduction cascade, such as mutations in the gene encoding the aquaporin-2 water channel.
• The acquired form of the disease occurs secondarily to chronic renal disease, hypokalemia, hypercalcemia or sickle cell anemia.

-Patients receiving lithium treatment for manic-depressive disorders may develop the acquired disease type because lithium can decrease the number of V2 receptors or can reduce gene expression of aquaporin-2.

• Both defects present with normal or high concentrations of ADH, dehydration, hypernatremia, elevated blood chloride, and high daily urine output.
• Patients must be treated by controlling the physiological symptoms, i.e. keeping the patient well hydrated.

Question 16

SIADH

Answer 16

• Hypersecretion of ADH produces the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) that has a variety of potential causes.
• Continued secretion occurs despite the presence of hypo-osmolality because these pathologies bypass the normal route of control. To properly treat SIADH, understanding the cause of this excessive hormone secretion in each case must be made.
• ADH antagonists are available that include conivaptan (Vaprisol), tolvaptan (Samsca) and demeclocycline (Declomyxin)