Hypothalamus And Pituitary

The tract of Endocrine system are CNS, hypothalamus, pituitary, end organ.

The anterior and posterior pituitary develop from 2 different tissues. Anterior pituitary develops from the ectoderm of the roof of the mouth. Whereas the Posterior pituitary develops form the neural tissue of the third ventricle.

A tumor in the pituitary can cause diplopia by putting pressure on the optic nerves.

The volume of pituitary decreases with age, and increases by up to 50% during pregnancy due to the production of prolactin.

Vascular connections

Posterior pituitary- direct arterial supply from inferior hypophyseal artery

The median emmience and upper stalk- superior hypophyseal artery

Anterior pituitary- supplied by capillary plexus that is derived from portal veins

that carry blood from the superior hypophyseal artery. (through this connection hypothalamus releases hormones into portal veins to effect pituitary) prone to hypoxia when blood pressure drops

Sheehan’s- drop in blood pressure causes necrosis of pituitary.

Hypothalamus

-is responsible for various basic functions : hunger, thrist, blood pressure, temperature regulation, water balance, metabolic rate.

Communication

-the brain sends signals to the hypothalamus, which then regulates the anterior and posterior pituitary via neurotransmitters, mainly dopamine, or hormones.

Characteristics of hypothalamic releasing hormones p.878 Levy 4^th ed.

1. secretion in pulses

2. Action on specific plasma membrane receptors.

3. Transduction of signals through calcium, membrane phosopholipid products,

and cyclic AMP (cAMP) as second messengers.

4. Stimulation of release of stored target anterior pituitary hormones via

exocytosis.

5. Stimulation of synthesis of target anterior pituitary hormones at the

transcriptional level.

6. Modification of the biological activity of target anterior pituitary hormones by

post-translational effects such as glycosylation.

7. Stimulation of hyperplasia and hypertrophy of target cells.

8. Modulation of effects by up-or down-regulation of their own receptors.

-peptide hormones that react on posterior piruitary

-argnine vasopressin (Shapiro) or ADH (Levy)

-oxytocin

-hormones that act on anterior pituitary

• -Thyrotropin Releasing Hormone (TRH)-acts on anterior pituitary to release thyroid hormone, a tripeptide
• -Gonadotropin Releasing Hormone (GnRH)-releases gonadotropin hormone that acts on the ovaries and testis.
• -Somatostatin-inhibitory hormone of Growth hormone
• -Growth Hormone Releasing Hormone (GHRH)- stimulates the release of Growth Hormone.
• -Prolactin Inhibitory Hormone (PIF)- structure is dopamine, prolactionrhea, the flowing of milk at wrong times, can be stopped by the administration of this hormone.
• - Prolactin Releasing Hormone (PRF)-stimulates the release of prolactin
• -Corticotropin Releasing Hormone (CRH)-stimulates the release of ACTH (adrenal cortex hormone).

Pituitary Cells (major)

Corticotroph- releases ACTH, acts on adrenal gland

Thyrotroph-releases TSH, acts on thyroid

Gonadotroph-releases LH and FSH, acts on gonads(ovaries and testes)

Somatotroph-releases GH, acts on all tissues

Mammotroph-releases prolactin, acts on mammary glands and gonads

Anterior Pituitary Hormones Groups

Corticotropnin-lipotropin- all come from a common precursor, hypothalamus PONC

ACTH

Beta-lipoprotein

Beta-endophin

Glycoprotein-alpha and beta subunits, alpha common to all hormones, beta differentiates them

LH

FSH

TSH

Somatomamotrop-evolved from common hormone

GH

PRL

Anterior Lobe

TSH-Thyroid Stimulating Hormone-stimulates thyroid secretion and growth

ACTH-Adrenal Cortex Hormone-stimulates zona fasculata and reticularis

G.H., somatotroph-accelerate body growth and IGF-1 (insulin like growth factor) stimulates growth cartilage

FSH-females ovary follicle growth, males spermatogenesis

LH- stimulates female ovulation and estrogen secretion, males testerone secretion.

PRL-stimulates secretion of milk and maternal hormones

Beta lipotropin- don’t know

Alpha- MSH-causes pigmentation, and shuts off appetite

Genes for alpha and beta parts of hormone are separate, excess of alpha or beta chains may indicate tumor. Hypothyroidism because of mutation in beta genes.

Prolactin inhibits GnRH on Pituitary, which causes less LH and FSH, which leads to no period and loss of libido

TSH regulation (Levy p.880 Fig. 49-6)

Regulation of thyroid-stimulating hormone (TSH) secretion. Thyroxine (T₄) and triiodothyronine (T₃) from the thyroid gland exert negative feedback on the pituitary by blocking the action of thyroid-releasing hormone (TRH). Negative feedback of T₄ and T₃ also occurs at the level of the hypothalamus. Somatostatin and dopamine each inhibit TSH secretion tonically. TRH down-regulates its own receptor, and the releasing hormone loses effectiveness. Growth Horomone will reduce TSH secretion, therefore GH is used as a treatment for overproduction of TSH. Hormone secretion is episodic, pulses intricate multiple rythms of hormone secretion.

CRH (cytokine releasing hormone)

Releases ACTH, as does ADH (anti-diurteic hormone). Some cells co-secrete CRH and ADH. ADH functions to retain fluid. CRH receptors are in the brain, spinal cord, immune cells, and GI tract. On immune cells, CRH stimulates the release of cytokines. CRH causes central nervous system arousal, increased blood pressure, and increased sympathetic system activity. CRH decreases synthesis of gonadotropin-releasing horomone (GnRH)(which causes a decrease in reproductive function), feeding behavior, and growth. CRH is a stress hormone, so women who were in concentration camps had high CRH levels, which lead to a decrease in GnRH, which then caused amonorhea (no monthly period).

ACTH and MSH

ACTH has 39 amino acids, only need the first 24 to be biologically active, which is the synthetic form used for clinical purposes (called Synacthin or Cortrisyn)

Alpha-MSH-most important pigmentary hormone, cleaved from ACTH

Beta –MSH- found in mammals, cleaved from gamma lipotropin

Gamma MSH- cleaved from the N-terminal peptide.

Regulation of ACTH

CRH release from the hypothalamus is stimulated by stress, sleep/wake, norepnephrine, acetylcholine, and serotonin. CRH is inhibited by endorphins. ADH release is stimulated by sleep/wake. ADH and CRH stimulate the release of ACTH from pituitary, which then stimulates the adrenal to release Cortisol.. ACTH acts as negative feed back on the hypothalamus to decrease CRH secretion via short feed back loop. Cortisol can either work via short feed back loop and inhibit the pituitary from releasing ACTH, or long feedback loop and inhibit hypothalamus from secreting CRH. CRH can also act via ultra short feedback loop and shut off its own secretion.

Stimulation of ACTH Inhibition of ACTH

CRH Cortisol increase

Cortisol decrease

Adrenalectomy

Metyrapone

Stress

Psychiatric disturbances

Depression

Neurotransmitters

Serotonin

Acetylcholine

Metyropoine drug causes a drop (block) in Cortisol, which causes an increase in ACTH.

Prolonged use of steroids cause lack of response to ACTH, leads to atrophy of adrenal cortex.

Factors of ACTH secretion

Stress vs. Diurnal rhythm vs. feedback

Stress will over-ride the other 2

Diurnal rhythm overrides feedback

Chronic inhibition of CRH, due to hypersecretion of Cortisol or therapeutic administration of Cortisol analogs, will eliminate stress response, and one can die without steroid administration. Can take up to one year for recovery after removal of inhibition.

Posterior Pituitary (magnocellular)

ADH (Anti-diuretic or arginine vasopressin)-primary role is to conserve body water and regulate the Osmolarity of body fluids.

Oxytocin (OCT)- primary role is to eject milk

Both are secreted with a protein carrier (neurophysins).

ADH

Synthesis : 1. SON and PVN ( hypothalamus)

Migration down supra-optico-hypophysial tract

Storage + release: Posterior lobe ( Magnacellular)

Axons of PVN reach Median eminence and secreted into portal circulation stimulating ACTH

Also: Co-synthesis of ADH with CRH

For permanent DI need destruction of nuclei

Metabolized in liver and kidney

1/2t: 15- 20 min

ADH Action

• This is all about control of water balance to maintain normal osmolality and normovolemia

• Primary determinant of rate of free water excretion

• Augment water permeability of luminal membranes of cortical and medullary collecting tubules.

• Attain osmotic equilibrium with hypertonic interstitium of kidney

• (Osmolality in urine can go from <100> 1200 – Maximal effect of ADH depends on maximal concentration in the kidney interstitium. Urine goes from dilute to concentrated.

• countercurrent mechanism

Stimuli of ADH

• Osmotic changes of 1% , Most sensitive factor

• Osmotic Threshold – 280 mmol\kg (normal 275 – 295 mmol\kg)

• Osmoreceptor in hypothalamus

• Peak renal action 5pg/ml, very sensitive

• Volume 8 - 10% change, less sensitive

• Greater response of VP, hypovolemia – levels over 100pg/ml, does want

• Nausea

• Low cardiac output

• Nicotine

• Hypoxia, Pain (post op), stress

Osmotic Stimuli

• Osmoreceptors 3thd ventricle region hypothalamus, (organum vasculosum lamina terminalis) – stimulate SON

• Cholinergic neurons outside blood barrier go to SON and PVN

• Chronic catecholaminergic inhibitory fibers from arterial baroreceptors going to tractus solitarium in medulla.

Osmoreceptors

• Measure osmotic gradient between plasma and osmoreceptor cell.

• Cell: water permeable: Hypernatremia shrinks cell = activation cation channels = depolarization = increased ADH secretion.

• Hyponatremia: dilates cell = polarization = suppression ADH secretion

• Plasma sodium primary osmotic determinant (very important)

• Urea – ineffective osmole

• Glucose enters cell immediately and usually not effective. In insulin deficiency = increase of ADH

• Posm <>

• Maximal urine concentration: 1200 mosmol/kg

Hydroosmotic Action of ADP

AVP receptor in renal collecting duct cells

G protein receptor activation AC – V2 R

AC = CAMP = PKA activation, inactivated by phosphodiesterase

PKA activation activates mRNA of AQ-2 water channels and translocation of AQ-2 to plasma membrane

AQP-2

• AQP-2 is AVP regulated water channel

• Present in cytoplasmic vesicles and have trafficking to membrane under AVP.

• Water loading leads to internalization, aggregation in clathrin pits and back to vesicles in cytoplasm

• PKA phosphorylation of serine 256 in C-terminal of AQP-2 makes the action

• Osmotic water movement in cell = systemic circulation across basolateral membrane

Summation

As Osmolarity increases, vasopressin secretion increases, which in turn increases urine Osmolarity.

Thrist

• Thirst center is in hypothalamus

• Hyperosmolar state stimulates thirst

• Osmotic threshold 2 -5 osmol/kg above ADH

• Oropharyngeal mechanoreceptors involved. Large fluid intake drops thirst sensation.

• Thirst + ADH = decrease osmol and increase intervesicular Volume

Summation

As Osmolarity increases, water intake increases, plasma Osmolarity increases, vasopressin increases, which leads to thrist.

Volume and Pressure

Volume depletion: vomiting, cirrhosis, heart failure secret ADH in spite of low Posm.

(Shapiro skipped the rest but they were in the slides and text)

Parasympathetic afferent in carotid sinus = vasomotor center medulla = PVN.

Mean arterial pressure = cardiac output x systemic vascular resistance

Release of renin and norepinephrine more sensitive than AV

The hormone works by activating a receptor that then activates Phospholipase C, which through a cascade activates protein kinase C.

Summation

As blood volume decreases, vasopressin increases. A larger stimulus is required, thus the release is larger.

Hypovolemia

• Stimulates the generation of brain rennin and Angiotension II

• Brain Angiotension II enhances release of ADH on addition to increasing thrist sensation

Hypervolemia

Causes the release of atrial naturetic peptide (ANP) from cardiac myocyte with brain NP from SON. This inhibits ADH to give diuressis.

Interaction osmotic and volume stimuli

Volume depletion enhances output in presence of hyperosmolar state

Hypovolemia and hypoosmolar state – volume over rides osmolar state = hyponatremia

Chronic hypervolemia shifts osmotic threshold upward = elevation Posm and sodium

concentration

Agents that alter vasopressin release

Stimulate Inhibit

Vincristine Alcohol

Cyclophosphamide ANP

Category: Physiology Notes