2 Hypothalamus And Pituitary Unit Flashcards
The function of the hypothalamus-pituitary unit is to …
Coordinate the physiologic response of organs that together maintain homeostasis
Hormones released from the Anterior Pituitary are responsible for…
Metabolism Growth and development Reproduction Lactation Response to stress
(ACTH, GH, TSH, Prolactin, LH, FSH)
Hormones released from the Posterior Pituitary are responsible for …
Water balance Parturition and Lactation Regulation of BP Cardiac Function Diuresis
(Oxytocin and Arginine Vasopressin/ADH)
____________ neurons project their axons down the infundibular process and terminate in the posterior pituitary, where they release their hormones into a capillary bed
Magnocellular neurons
___________ neurons are the neurovascular link between the hypothalamus and the anterior lobe of the pituitary
Parvicellular neurons
They are neurosecretory and project axons to the median eminence, where they secrete releasing hormones
Parvicellular neurons release what?
Releasing hormones
RHs flow down the pituitary stalk in the hypothalamo-hypophyseal portal vessels to the anterior pituitary. RHs and inhibiting hormones regulate the secretion of tropic hormones from cell types of the anterior pituitary.
What hormones are released from Magnocellular neurons
Oxytocin, ADH, NP (neurophysin)
Originate from Paraventricular nuclei (PVN) and supraoptic nuclei (SON)
What hormones are released from Parvicellular neurons?
CRH, TRH, GnRH, GHRH, Somatostatin, DA
These in turn lead to the release of ACTH, TSH, LH/FSH, GH, PRL from anterior pituitary
What is the pituitary hormone and target cell of GHRH?
GH (increased synthesis from somatotrophs, 45%) —> Growth via IGF production in liver and energy metabolism
What is the pituitary hormone and target cell of TRH?
TSH (increased synthesis from thyrotrophs, 3-5%) —> Growth of thyroid gland and synthesis of T3/T4
Prolactin (increased synthesis from mammotrophs, 10-15%) —> breath development and milk production in mammary glands
What is the pituitary hormone and target cell of Somatostatin?
GH and TSH (decreased synthesis)
What is the pituitary hormone and target cell of GnRH?
LH (increased synthesis) —> Ovulation and synthesis of estrogen in women, secretion of testosterone from Leydig cells in men
FSH (increased synthesis in gonadotrophs, 15%) —> development of follicle in women, initiation of spermatogenesis in men
What is the pituitary hormone and target cell of CRH?
ACTH (increased synthesis from corticotrophs, 15%) —> growth of the adrenal gland and synthesis of corticosteroids
What is the pituitary hormone and target cell of PRF?
Prolactin (increased synthesis from lactotrophs) —> breast development and milk production
What is the pituitary hormone and target cell of Dopamine)
Inhibits prolactin synthesis (aka PIH)
Where are hormones of the posterior pituitary produced?
Synthesized in the hypothalamic neuronal cell bodies of magnocellular neurons, in the supraoptic and paraventricular nuclei
Both OT and ADH are synthesized in the peptide fashion as preprohormones
How big are ADH and Oxytocin?
Both are nonapeptides (consist of 9 amino acids)
What are some cool traits of the posterior pituitary hormones (ADH and OT)?
Released into fenestrated pituitary capillaries upon stimulation via action potentials
Co-secreted with NEUROPHYSINS
Both have a short plasma half-life of ~8 minutes
Cysteine residues form a disulfide bride that confers its activity. When disulfide bridges are knocked off in the liver, the hormone becomes inactive.
Carrier proteins that prevent the diffusion of hormones out of the axons in the posterior pituitary
Neurophysins, NP-I and NP-II
NP-I goes with Oxytocin (think you drink your mama’s milk first in life) and NP-II goes with ADH
A defect or lack of neurophysins (specifically NP-II) which leads to the release of ADH at inappropriate levels
Central Diabetes Insipidus
What is the physiologic effects of oxytocin in lactating breasts?
Stimulates milk ejection (myoepithelial cell contraction)
The suckling of the nipple also stimulates OT release —> afferent sensory signals that elicit an increase in OT in circulation (POSITIVE FEEDBACK)
What is the physiologic effect of oxytocin in the pregnant uterus?
Produces rhythmic smooth muscle contraction to induce labor.
Release of OT is stimulated with distention of the cervix as well as the contraction of the uterus during parturition (POSITIVE FEEDBACK)
In addition to controlling lactation and uterine contractions, oxytocin is also…
A cardiovascular and cardio metabolic hormone.
Both OT synthesis and receptors (OTR) occur in the heart.
A specific OT-natriuretic peptide-NO axis resides in the heart.
OT causes ANP/BNP release from cardiomyopathy and ANP, in turn, stimulates the release of NO from the vascular endothelium (a cardio-protective system!).
Where are OT, ANP and BNP found in the heart?
OT is found in atria and ventricles, but is 3-4x more abundant in atria
ANP is found in atria and ventricle but is more abundant in atria
BNP is found mainly in the ventricles
What does OT respond to in terms of cardiac function?
Responds to volume overload to regulate BP
CV effects
• Vasodilation
• Increased NO production
• Negative chronotropic effect (slows heart beat)
• Negative inotropic effect (lessens contraction)
Renal effects • Natriuresis • Kaliuresis • Diuresis •Decreased plasma volume
Endocrine effects
• Decreased cortisol, aldosterone, renin
OT regulates cardiac function by …
Modulating the parasympathetic system and inotropicity
Local OT—> Bradycardia, Negative inotropy, Increased glucose uptake
PItuitary OT —> ANP —> NO Synthesis —> dilation of coronary resistance vessels
In prediabetes, clinical studies show that OT …
Increases peripheral glucose uptake by a GLUT4 mechanism but NOT via the insulin receptor pathway —> therapeutic effect of OT?
ADH/AVP is released following…
An increase in plasma osmolarity
Osmoreceptors (found in anterior hypothalamus and outside the BBB) have directo contact with the systemic circulation
With dehydration, loss of intracellular water and an increase in plasma Na+ and Cl- is detected by osmoregulators and signal ADH/AVP magnocellular neurons to stimulate release
How sensitive are the osmoreceptors that control ADH/AVP release?
Release occurs before stimulation of thirst.
Sensitivity of the system is very high - 1% change in osmolarity above the threshold (~280-284 mOsm/L) produces an increase in ADH/AVP release
What is the target for ADH/AVP and what does it do?
Targets the kidney by acting on a V2 receptor
Water is reabsorbed from distal tubule and collecting duct via aquaporins 1-4
Results in an increase in plasma volume and decrease in osmolarity, and low urine output
ADH/AVP is released following a decrease in blood volume, but…
It’s not as sensitive to blood volume change as it is to changes in plasma osmolarity. (A decrease in blood volume of 8-10% elicits an increase in ADH release)
A decrease in BP decreases the stretch of the baroreceptors and decreases their rate of firing —> release of ADH/AVP from magnocellular neurons and stimulating thirst center
A decrease in BP is also perceived by the macula dense, resulting in the release of renin —> ang II sensitized the osmoreceptors leading to enhanced ADH/AVP release
Secretory rates of GH are about ________ in teens and _______ in adults
~700 guys/day for teens, 400 ug/day for adults
Levels are higher in children and teens, reflecting growth
Levels decline with aging, reflecting loss of lean body mass, fitness, protein synthesis, metabolic rate
During puberty, when GH levels increase, _______ levels increase in parallel
IGF-1 (Insulin-like growth factor)
Secretion of GH follows a ________ pattern
Diurnal (daily and nocturnal)
Levels remain low during day but increase with sleep (sharp rise at onset, during slow wave sleep, then steady drop throughout sleep time).
70% of total daily secretion occurs during sleep, released in pulsatile bursts
GH secretion is greater in _________ women
Premenopausal (before ovulation: effect of estradiol)
Testosterone also amplifies the secretion of GH in males
The pattern and frequency of pulse release is the same for males and females
The principle regulators of GH release are…
GH-releasing hormone (GHRH) and somatostatin
GHRH acts on somatotrophs to induce transcription, synthesis, and release of GH and proliferation of somatotrophs
GHRH binds to G protein-coupled receptor —> activating adenylate cyclase and PKA —> phosphorylation of CREB —> activation and increased transcription of the PIT-1 gene —> PIT-1 activates transcription of GH gene
Somatostatin produces inhibitory effect through binding to a Gi protein-coupled somatostatin receptor —> decreased adenylate cyclase —> inhibition of CREB and PIT-1
Proteins/factors that are the ultimate intracellular targets of GHRH to allow for production of GH
CREB (cAMP response element binding protein)
PIT-1 (pituitary-specific transcription factor)
Factors that stimulate GH release
HYPOglycemia***** Decreased FFAs ARGININE***** Fasting/starvation/exercise Stress SLEEP**** Thyroid hormone Adrogens Ghrelin
Factors that inhibit GH release
HYPERglycemia Increased FFAs Obesity Aging GH IGF-1
________ is used clinically to evaluate GH status
Arginine
Given intravenously, it suppresses somatostatin release allowing GH to be secreted unopposed.
Insulin challenges are also used (to induce hypoglycemia, another release stimulating factor)
DIRECT physiologic effects of GH
Direct effects on cellular responses by binding to a GH receptor at target tissues
INDIRECT physiologic effects of GH
Indirect effects by stimulating the production of hepatic IGF-1, a mediator of GH’s effect on tissues
Direct actions of GH related to muscle
GH is a protein anabolic hormone
Increases amino acid uptake and incorporates it into protein
Enhances cell proliferation and represses protein degradation
Produces positive nitrogen balance - muscle wasting, normal to aging, is in part caused by lower GH secretion
Direct actions of GH related to adipose tissue
GH activates hormone-sensitive lipase and mobilizes lipids for energy use by tissues during fasting
Direct actions of GH related to carbohydrate metabolism
GH alters carb metabolism by a secondary increase in FFAs —> decreasing glucose uptake by muscle and adipocytes
GH stimulates hepatic gluconeogenesis (b/c it wants to produce glucose)
Net effect is an increase in glucose and subsequent rise in plasma insulin. GH may induce a diabetogenic effect - meaning GH antagonizes the action of insulin, and may lead to diabetes with over-secretion of GH
Why do patients with acromegaly and gigantism often co-present with diabetes?
B/c the overproduction of GH induces a diabetogenic effect, antagonizes the action of insulin, with a net effect of increasing blood glucose
The diabetes is unrelated to pancreatic function
_____ promotes growth of bones, soft tissue, and visceral growth, the indirect actions of GH.
IGF-1
Sex steroids, insulin, and thyroid hormones regulate IGF-1 production in the liver
IGF are proteins but must be bound to _____ to be transported in the plasma
Binding proteins
IGF-1 is transported bound to IGF-BP (BP1-6 are synthesized in the liver in response to GH)
_______ is the major transporter for IGF-1, binding ~80% of IGF-1
IGF-BP3
After GH increases production of IGF1 and IGFBP3 in the liver, what do they do?
CHONDROCYTES increase amino acid uptake, protein synthesis, RNA/DNA synthesis, collagen, chondroitin sulfate, and cell size/number —> INCREASE LINEAR GROWTH
MUSCLE increase amino acid uptake and protein synthesis —> INCREASE LEAN BODY MASS
TISSUE/ORGANS increase protein synthesis, RNA/DNA synthesis, and cell size/number —> INCREASE ORGAN SIZE AND FUNCTION
GHRH can suppress its own release through…
An ultrashort feedback loop
GH can feedback to suppress GHRH release and exerts an _________ inhibitory effect on somatotrophs
Autocrine
In both fed and fasting situations, the plasma GH levels are …
Increased
However, the effects are opposing - abundance of food favors anabolic/growth states, while scarcity of food favors catabolic state
In the fed state, when protein and energy intake are both ample _________ is favored
Protein synthesis
Protein intake —> increased GH, IGF, and insulin —> protein synthesis and growth but no change in caloric storage
GH facilitates insulin action to promote growth
In the fed state, when carbs alone are ingested, ________ is favored
Storage
CHO intake —> decreased GH (b/c hyperglycemia inhibits release), no change in IGF and increased insulin —> no change in protein synthesis or growth but increased caloric storage
In the fasted state, ____________ is favored
Glucose sparing
Fasting —> increased GH (b/c hypoglycemia promotes release), decreased IGF and decreased insulin —> caloric mobilization, decreased protein synthesis and growth
The GH released in response to hypoglycemia enhance lipolysis, increase hepatic gluconeogenesis, and decrease peripheral glucose uptake
In addition to increased GH due to hypoglycemia, fasting causes what other hormone level changes?
Decreased insulin, increased glucagon, and increased cortisol
Together with the GH, the increased cortisol promotes production of IGF-BP3 —> further limits the availability to IGF-1 to tissues. This is one mechanism by which growth is diverted by GH under fasting conditions
Dwarfism is also classified as a form of _________
Hypopituitarism
The term panhypopituitarism is used to describe a deficiency in more than one anterior pituitary hormone (ie Thyroid, ACTH)
The most frequent cause of hypopituitarism is …
Traumatic injury, such as that linked to surgery, or MVAs.
Blood loss or hypoperfusion of the pituitary gland or stalk, or ischemic damage during postpartum period that can lead to pituitary insufficiency
Sheehan Syndrome
_______ results from GH deficiency before puberty
Dwarfism
Well-proportioned bodies and normal intelligence
If deficiency is limited GH, can have a normal life span
May appear “pudgy” b/c of loss of GH-induced lipolysis
GH resistant individuals with genetic defect in expression of the GH receptor in the liver —> Normal to high serum GH levels but NO IGFs in response to GH
Laron dwarf
Also have failure to produce IGF-BPs
Type of dwarfism with normal serum GH levels, but do not exhibit the normal rise in IGFs with puberty
African Pigmy
Not as severe as Laron dwarfism
Partial defect in GH receptors and do not totally lack the IGF response to GH
________ occurs with GH hypersecretion after the epiphyses closes in adults
Acromegaly
Caused primarily by a tumor of the somatotrophs. IGF-1 levels are elevated.
Favors appositional growth of bone and soft tissue deformities (not linear growth)
Visceral enlargement, enlarged hands and feet, and decreased fat content
Propensity to be diabetic. Very slow in onset
How is Acromegaly treated?
Surgery
Octreotide (somatostatin analogues)
Dopamine analogues
GH receptor antagonists (if PRL is co-secreted)
Why might you see gynecomastia and lactation in patients with acromegaly?
If prolactin and mammosomatotrophs are involved as well
Treat with GH-receptor antagonists
Excess GH secretion before puberty resulting in increased linear growth because of stimulation of epiphyseal plates
Gigantism
Typically a pituitary involvement - tumor growth eventually compresses other components of the anterior pituitary, decreasing secretion of other hormones
Frequently manifests with hyperinsulinemia and glucose intolerance or diabetes
Typical cause of death for patients with gigantism
Cardiac hypertrophy
