Howlett: Anterior And Posterior Pituitary

Front 1

Origin of posterior and anterior pituitary

Back 1

Posterior pituitary (Neurohypophysis) is of neural origin. Hormones are synthesized in hypothalamic magnocellular neurons and released into the capillary plexus of the inferior hypophyseal artery.

Anterior Pituitary (Adenohypophysis) is of ectodermal (oropharynx) origin. Hormones are synthesized in pituitary cells.

Front 2

Hypothalamus: inputs

Back 2

The hypothalamus integrates light, sleep-wake cycles, sensory inputs (thalamus), emotion, fear, smell (limbic system), and higher cognitive function (neocortex) to coordinate endocrine function with the regulation of behaviors and autonomic nervous system function.

Front 3

Hypothalamus: neurotransmitters, releasing factors

Back 3

Neurotransmitters: norepinephrine, dopamine, acetylcholine, serotonin, GABA, opioid peptides

Anterior:
Hypothalamic releasing factors are released from small bodied neuronsneurons into the capillary plexus of the median eminence, which escapes the blood-brain barrier.

Posterior:
Large neurons in the paraventricular and supraoptic nuclei of the hypothalamus actually synthesize the hormones AVP and oxytocin (OT). These hormones travel down the axons of the hypothalamic neurons to the posterior pituitary where the nerve terminals release the hormones, like neurotransmitters, into a rich plexus of vessels.

Front 4

Anterior pituitary gland: hormone exit

Back 4

Anterior Pituitary hormones exit via efferent veins to the general circulation, short portal veins to the hypothalamus, or tanycytes in the 3rd ventricle ependyma. This is the source of the short feed-back loops.

Front 5

Anterior pituitary gland: cell types and hormones

Back 5

15-20% Corticotrophs
-ACTH, b-LPH

3- 5% Thyrotrophs
-TSH

10-15% Gonadotrophs
-LH, FSH

40-50% Somatotrophs
-GH

10-25% Mammotrophs (Lactotrophs)
-Prolactin

Front 6

TSH, LH, FSH structure and functions

Back 6

Heterodimeric glycosylated proteins: α subunit is in common; b subunit is antigenically and functionally unique

TSH
-Maintains thyroid & stimulates release of thyroid hormones

LH
-Steroidogenesis: Targets Leydig cells of testes. Triggers ovulation of ovarian follicle and maintains corpus luteum estrogen and progesterone production
-Chorionic Gonadotropin is homologous to LH (but only made in placenta)

FSH
-Targets Sertoli cells in testes. Stimulates follicle growth in ovary.

Front 7

TSH, LH, FSH: release

Back 7

Regulators of TSH release
-Thyrotropin-Releasing Hormone TRH stimulates TSH release
-Somatostatin (SS, GHRIH, or GIH) inhibits GH & TSH release

Stimulators of LH & FSH release
-Gonadotropin-Releasing Hormone (GnRH,LHRH, LRF)

Front 8

ACTH, g-MSH, b-Endorphin: structure and function

Back 8

All from pro-opiomelanocortin
-Cleaved in anterior pituitary

ACTH: Stimulates glucocorticoid synthesis and release

g-MSH: Melanocyte Stimulating Hormone Stimulates melanocytes via melanotropin1 (MCR1) receptors to increase melanin synthesis. Both MSH and ACTH can bind melanocortin receptors and increase skin pigmentation in humans.

b-Endorphin: Opioid peptide selective for the m-opioid receptor.

Front 9

GH and prolactin: structure and function

Back 9

Growth Hormone (GH, Somatotropin, STH)
-Protein anabolic, lipolytic hormone, stimulates growth, and triggers somatomedin release
-GH is 92% homologous to Placental Lactogen

Prolactin (PRL)
-Mammary gland development in pregnancy, milk protein production after parturition, lactation in response to nursing

Front 10

ACTH release

Back 10

Stimulators of ACTH release
-Corticotropin-Releasing Hormone CRH
-AntiDiuretic Hormone ADH (aka arg-Vasopressin, AVP)
-Urocortin
-Brain Natriuretic Peptide BNP

Front 11

GH-releasing hormone
Somatostatin
TRH
Dopamine

Back 11

GH-Releasing Hormone GRH, GHRH, GRF
-Stimulates GH, prolactin (& ACTH) release

Somatostatin SS, GHRIH, GIH
-Inhibits GH (& TSH) release

Thyrotropin-Releasing Hormone TRH
-Stimulates prolactin (& TSH) release

Dopamine (aka Prolactin-Inhibitory Factor PIF)
-Inhibits prolactin release

Front 12

Prolactin: stimulation and inhibition

Back 12

Lactotroph population and prolactin gene expression are increased in response to estrogen (pregnancy). Estrogen increases sensitivity to stimulation byTRH and decreases sensitivity to inhibition by dopamine.

Prolactin release is stimulated by suckling as a neuroendocrine reflex mediated by a decrease in dopamine (arcuate nucleus).

Prolactin short feedback loop increases dopamine synthesis in hypothalamus (arcuate nucleus), thereby increasing dopaminergic inhibitory tone.

Front 13

Effects of nursing

Back 13

Inhibit DA release (arcuate), which leads to prolactin release

Stimulate oxytocin release (paraventricular and supraoptic)

Inhibit GnRH (preoptic)

Front 14

Actions of prolactin: mammary gland, milk

Back 14

Mammogenic: Breast differentiation, duct proliferation and branching, glandular tissue development.

Lactogenic: Promotes initiation of milk production by alveolar cells. Promotes milk protein synthesis (β-casein, α-lactalbumin), sugar (lactose) and milk fat production by mammary epithelial cells, lactogenic enzyme synthesis.
-Note that until parturition, milk production is suppressed by progesterone and estrogens.

Galactopoeitic: Maintains milk production after it has been established.

Prolactin modulates parenting behaviors.

Front 15

Non-mammary stimuli for prolactin release

Back 15

Prolactin release is under complex regulation by dopamine, serotonin, β-endorphin, GnRH, GABA, angiotensin II, arg-vasopressin (AVP, ADH) and somatostatin. TRH stimulates prolactin release even in the presence of dopamine inhibitory tone.

Prolactin levels are high during sleep.

Prolactin release is stimulated by stress.

Front 16

Actions of prolactin: reproductive and cytokine

Back 16

Prolactin receptors also found in ovary: inhibits progesterone biosynthesis and luteal cell hypertrophy during pregnancy.

Prolactin modulates reproductive behaviors.

Prolactin serves as a cytokine to regulate lymphocyte responses.

Front 17

Prolactin cellular action

Back 17

Prolactin’s cellular actions are via a tyrosine-kinase-like cytokine receptor, which has equal affinity for somatotropin (Growth Hormone) in breast, ovaries and liver.

Front 18

Pathway of hypothalamus to posterior pituitary

Back 18

Magnocellular neurons (paraventricular nucleus makes oxytocin and suproptic nucleus makes AVP/ADH) project to the pars nervosa of the neurohypophysis

Parvicellular neurons project to median eminence.

Vesicle release occurs in response to action potentials that result in Ca2+-mediated exocytosis.

Front 19

Oxytocin synthesis

Back 19

Transcription of RNA
RNA processing with splicing
-Two components: oxytocin (9AA) and neurophysin 1 (10kD peptide)

Front 20

Oxytocin action

Back 20

“Milk Let-down Factor”
-Contraction of myoepithelial cells of breast resulting in milk let-down
-In response to suckling or tactile stimulation

Uterine myometrial contraction especially during childbirth –
-Facilitates labor: vaginal and cervical stretch stimulates release
-Used therapeutically to “induce” labor and decrease post-partum uterine bleeding
-May assist with sperm motility via uterine contractions.
-Receptors and tissue response increased by estrogens / decreased by progesterone

Males
-no potent physiological actions
-receptors found in testes, epididymus and prostate

Front 21

Oxytocin: regulation

Back 21

Positive regulation:
-Sensory information regarding infant need (cry)
-Tactile/pressure stimuli travel via spinothalamic tract;
-brainstem connections to hypothalamus regulate oxytocin release

Negative regulation: pain, fear, stress

Oxytocin and Vasopressin (ADH) are differentially regulated

Front 22

Oxytocin: pharmacokinetics

Back 22

Circulates unbound in plasma
T1/2 = 3-5 min
Degraded in liver and kidney, mammary glands and uterus

Front 23

Oxytocin: deficiency, excess

Back 23

Oxytocin deficiency
-prolonged labor
-difficulties with milk let-down

Oxytocin excess
-no known pathogenic problems

Oxytocin is commonly used to facilitate labor

Front 24

Vasopressin: synthesis

Back 24

Hypertonic environment detected by circumventricular organs {organum vasculosum lamina terminalis (OVLT) and subfornical organ (SFO)} mechanosensitive cation channels on osmosensory neurons which project to magnocellular neurons in the PVN (paraventricular) & SON (supraoptic) of the anterior hypothalamus.

Synthesis of preproneurophysin II

Cleavage of proNpII to AVP occors in secretory granule during transit to posterior pituitary.

Front 25

Vasopressin: pharmacokinetics

Back 25

Plasma T1/2 = 15-20 min;
degraded in liver and kidney

Front 26

Vasopressin: mechanism of action

Back 26

AVP increases osmotic permeability of the collecting tubules and ducts to water: AVP enhances water permeability & thus, water reabsorption

Major action is on V2 receptors via cAMP-mediated phosphorylation of aquaporin 2, which translocates to the luminal (apical) membrane, facilitating water movement across the luminal surface of the collecting ducts to reabsorb water from the glomerular filtrate. NOTE: AQP1 and AQP3 are INSENSITIVE to AVP action.

Front 27

Vasopressin: actions

Back 27

At high concentrations (e.g. hypovolemic shock), AVP acts on V1 receptors in vascular smooth muscle to promote vasoconstriction.

Renal collecting ducts
-V2 receptor
-increases H2O reabsorption

Renal glomerulus
-V1 receptor
-decreases GFR
Renal JG cells
-V1 receptor
-suppresses renin release
Arterioles
-V1 receptor
-vasoconstriction
Anterior pituitary
-V1 receptor
-increases ACTH release

Front 28

SIADH Syndrome of Inappropriate (high) secretion of AVP(ADH): causes, result, clinical picture

Back 28

Causes: 1-neoplasms (eg. pulmonary carcinoma) producing AVP (ADH) or ADH-like peptides; 2- head trauma causing AVP release; 3-reduced effective circulating volume of congestive heart failure; 4- iatrogenic (clofibrate, phenothiazines stimulate AVP release; chorpropamide increases renal sensitivity to AVP)

Result: patient is hypervolemic (Increase total body water)
-High urine osmolarity compared to plasma
-Hypo-osmolarity: Low plasma osmolarity <270mOsM
-Hyponatremia: Plasma Na+ low < 130mEq/L

Clinical picture: weight gain; cellular swelling causes weakness, N&V, lethargy, mental confusion….stupor, coma, seizures

Front 29

Diabetes: clinical presentation, causes

Back 29

Diabetes Insipidus: Too little vasopressin
or lack of response to vasopressin

increased urine output (25 L /day)
increased thirst, increased plasma Na+

CAUSES of Diabetes Insipidus:
Neurogenic - insufficient ADH, possibly due to e.g., defective processing of pro-NpII hormone.
Nephrogenic -insufficient renal response to ADH, e.g., AQP2 mutation
Behavioral – e.t\g., compulsive H2O intake, increased plasma vol, decreased plasma osmolality.