Transcript GH Receptor

Anterior Pituitary
Growth Hormone and Prolactin
Matthew L. Fowler, Ph.D., OMS-II
Class of 2015
Cell Biology and Physiology
Block 6
Renal and Reproduction
Learning Objectives
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Anterior Pituitary Structure and Function
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Cell types, vascular supply, development, anatomical function
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Anterior Pituitary Hormones
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Hypothalamic Control
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Roles hypothalamic factors, glucose and IGF-1
Target cells/organs for IGF’s and Longitudinal growth
Actions of GH
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Releasing and inhibitory factors and transport to pituitary
Negative Feedback Mechanisms of Anterior Pituitary Hormone Secretion
Relationship Between GH and IGF’s
Regulation of GH secretion
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Three major families, biosynthetic, structural relationships
Metabolic
Growth-promoting
Prolactin Regulation and Effects
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Abnormal conditions
Hormonal Action
Hormones act through sensors to
effect physiological change.
1.
2.
3.
Hormones circulate in blood bound to a
carrier protein (inactive form)
Hormones bind to a specific receptor on
a target organ yielding a selective
physiological response
Physiological effects or results can
involve:
A.
2nd messenger systems
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B.
Resulting in amplification of the
signal
Nuclear gene transcription
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Resulting in a protein synthesis
response
Hypothalamus and Anterior Pituitary
Functional Anatomy and Origins
Anterior Pituitary (adenohypophysis)
• Rathke’s pouch
– Pharyngeal epithelium cells
Posterior pituitary (neurohypophysis)
• Neural tissue outgrowths from
hypothalamus
Hypothalamus
Functions
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Collects physiological and neural inputs
from all parts of the body
– Pain, olfactory, emotions, water, and
electrolytes
– Senses internal well-being or distress
Pituitary secretions controlled by
hypothalamus
– Hormonal input
– Neural input
Anterior Pituitary
Functions
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Highly vascular
Hypothalamic releasing
hormones/factors (HRFs)
Hypothalamic inhibiting
hormone/factors
– Specialized neurons secrete
– Hypothalamic-hypophysial portal system
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Located in the median eminence
– Act on the glandular cells
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Control secretion of hormone.
Hypothalamic Stimulatory and
Inhibitory Hormones
Hormone
Chemical Composition
Primary Action on Anterior Pituitary
Thyrotropin-Releasing Hormone (TRH)
Tripeptide
Stimulates secretion of TSH by thyrotropes
Gonadotropin-Releasing Hormone (GnRH)
Peptide
Stimulates secretion of FSH and LH by
gonadotropes
Cortiocotropin-Releasing Hormone (CRH)
Peptide
Stimulates secretion of ACTH by corticotropes
Growth Hormone-Releasing Hormone
(GHRH)
Peptide
Stimulates secretion of growth hormone by
somatotropes
Growth Hormone-Inhibitory Hormone
(Somatostatin)
Peptide
Inhibits secretion of growth hormone by
somatotropes
Prolactin-Inhibiting Hormone (PIH)
Dopamine
Inhibits synthesis and secretion of prolactin
by lactotropes
Major Hormones of the
Anterior Pituitary
• Glycoprotein Hormones (LFTs)
– LH, FSH, TSH
– Same a chain (hCG as well)
– Different b-chains (confer specificity)
• Glycosylation increases t½
• Polypeptide Hormones (GAP)
• Corticotropic hormones are derived from
Pro-opiomelanocortin, long peptide chain precursor
– GH, ACTH, PRL
Actions of Anterior Pituitary
Hormones
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Growth Hormone
– Promotes growth of the entire body by affecting protein formation, cell multiplication, and cell
differentiation.
Adrenocorticotropic Hormone
– Controls the secretion of some of the adrenocortical hormones, which affect the metabolism
of glucose, proteins, and fats.
Thyroid-stimulating Hormone
– Controls the rate of secretion of thyroxine and triiodothyronine by the thyroid gland, and
these hormones control the rates of most intracellular chemical reactions in the body.
Prolactin
– Promotes mammary gland development and milk production.
Follicle-stimulating Hormone and Luteinizing Hormone
– Control growth of the ovaries and testes, as well as their hormonal and reproductive
activities.
Anterior Pituitary Hormones
Summary Table
Cell Type
Hormone
Chemical
Composition
Physiological Action
Somatotropes
Growth Hormone (GH)
Polypeptide
Stimulates body growth; stimulates secretion of IGF-1;
stimulates lipolysis; inhibits actions of insulin on carbohydrate
and lipid metabolism; acts as a PRL receptor agonist
Corticotropes
Adrenocorticotropic
Hormone (ACTH)
Polypeptide
Stimulates production of glucocorticoids and androgens by the
adrenal cortex; maintains size of zona fasciculata and zona
reticularis of cortex
Thyrotropes
Thyroid Stimulating
Hormone (TSH)
Glycoprotein
Stimulates production of thyroid hormones by thyroid follicular cells;
maintains size of follicular cells
Gonadotropes
Follicle-stimulating
Hormone (FSH)
Glycoprotein
Luteinizing Hormone (LH)
Glycoprotein
Stimulates development of ovarian follicles; regulates
spermatogenesis in the testis
Causes ovulation and formation of the corpus luteum in the ovary;
stimulates production of estrogen and progesterone by the ovary;
stimulates testosterone production by the testis
Prolactin (PRL)
Polypeptide
Lactotropes
(Mammotropes)
Stimulates milk secretion and production
Tissue Targets
Important Note
• All of the hormones of the
anterior pituitary have
specific target tissues
Exception
• GH has numerous
target tissues
GH Circulation
• Multiple forms circulate
• Degraded in liver and kidney
• 40-50% circulates bound to GH Binding Protein which
is the GH Receptor (GHR)
• GHR is a member of the cytokine/GH/PRL/erythropoietin
receptor subfamily
– Increases GH t½
– Actions mediated through JAK/STAT pathways
Regulation of GH Secretion
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Pathways from the
hypothalamus:
1.
Stimulatory
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2.
Inhibitory
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GHRH
GHIH (Somatostatin)
Also inhibits TSH
Tertiary pathway:
3.
Ghrelin
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From stomach and
hypothalamic neurons
Increases appetite
Possible growth/nutrient supply
coordination?
GH Receptor
Once GH is secreted it circulates freely in the plasma
-about 40% is bound to HG-binding protein
formed from cleavage of extracellular domain of GH receptor
high affinity binding increases the half-life of GH (25 min)
GH binds to s specific receptor in tissues
> 620 AA protein with a single membrane spanning segment
> excessively glycosylated
> tyrosine kinase associated protein (no intrinsic activity)/related to cytokine
receptors
> can form a dimer when GH binds and bridges to another receptor
> increases the activity of JAK2 family
binding triggers a series of protein phosphyrlations that modulate
GH and JAK2 activity
JAK (Janus kinase) is the associated tyrosine kinase activity for GH (and cytokines)
STAT (signal transducer and activator of transcription)
>auto-phosphorylated (remember the insulin receptor)
>dimerizes
> accumulates in the nucleus where it stimulates gene transcription
GH-Regulation by Feedback Loops
Short loop feedback
Long loop feedback
Daily Variations in GH Secretion
• Secreted in pulsatile pattern
– Similar to ACTH
• Highest in morning
• Lowest in day/afternoon
• Secretion increases during:
– First 2 hours of deep (slow-wave)
sleep
– Strenuous exercise (stressor)
GH Patterns and Measurement
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Anabolic
Secretion increases
through puberty
– Decreased urea production
during synthesis
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Due to AA utilization
Declines with age
– May account for muscle
wasting
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Measured via IGF-1
– [GH] variable
– IGF-1 has longer t½
Biological Activities of GH
• Know the actions
on this summary
diagram
• Lipolysis
– Adipose tissue
– Due to GH-induced
enzymatic activity of
hormone sensitive
lipase (HSL)
Synergism with other hormones
GH is one of the Stress Hormones
increased by emotional and physical distress
increases lipolysis and protein synthesis
inhibits insulin action to reduce blood glucose
GH is secreted in response acute hypoglycemia
Obesity inhibits GH secretion
Other hormones that interplay with GH
T3-enhances IGF-1 and GH release and bone maturation
estrogens
GH is a diabetogenic hormone
GH opposes insulin action to decrease glucose levels in blood
in skeletal muscle and adipose tissue (not liver)
produces insulin insensitivity
When GH is secreted in excess, GH can cause diabetes. Insulin levels
rise in response to excess GH and damage to pancreatic β cells may
occur.
The absence of excess GH results in secretion declines.
Normal levels of GH help maintain normal pancreatic function and
normal insulin levels.
Diabetogenic effects of GH
Target Tissue
Effect
Muscle
Decreased glucose uptake
Adipose
Increased lipolysis
Liver
Increased gluconeogenesis
Muscle, Fat and liver
Insulin resistance
These are short –term actions—minutes to hours
GH increases skeletal growth
Distinct from short term effect –growth is a long term effect
• GH increases visceral growth
• GH promotes long-bone length
• GH promotes cartilage and periosteal growth
• Most of these effects are mediated by Insulin like Growth Factors
(IGFs) that are made in the liver in response to GH
• IGFs are multi-functional hormones
regulate cellular differentiation, proliferation and
metabolism
Diseases/Syndromes-- GH Deficiency
Predictably, over or under expression of GH can results in syndrome
With results on organ growth, linear growth and carbohydrate and
lipid metabolism.
In children with growth failure: Can be treated with GH injections
short stature
mild obesity
delayed puberty
Causes can be found at every step of the
hypothalamic-pituitary-target organ axis.
GH Deficiency
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Laron Dwarfism
Psychosocial Dwarfism
Combined Pituitary Hormone Deficiency
Panhypopituitary dwarfism
African pigmy
Laron Dwarfism
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Reported in 1966—severe resistance to GH
Autosomal recessive
Mutations in GH receptor
LOW levels of IGF-1 and IGFBP
Dwarfs have a striking resistance to cancer and diabetes (village in
Ecuador 2011)
• Seen in Israel and people with Sephardic roots
• Treatment by synthetic IGF-1
Psychosocial Dwarfism
Kaspar Hauser Syndrome
• Failure to thrive / short stature and intellect
• Abusive and neglectful environment
-Kaspar Hauser was abandoned at the Nuremburg
gate in 1828 after 17 years of neglect and isolation in
a dungeon
• Very short stature, immature sexual deveopment
• Very low GH
Combined Pituitary Hormone
deficiency
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Decreased pituitary hormone secretion
Delayed or absent puberty, hypothryoidism, Infertility
Mostly sporadic , incidence 1/8000 worldwide
If familial, can be autosomal dominant
or recessive
• Most common mutation found
• PROP1 (prophet of pit) gene---affects
transcription factors that direct pituitary
cellular development
Combined Pituitary Hormone Deficiency
CPHD
Panhypopituitary Dwarfism
GH Deficiency—from birth, brain injury
Proportionate stature
treated by injections of GH
African Pygmy
Height in West Central African tribes---maybe a “hot spot” on chromosome 3
Short height may also have selected for stronger immunity and other advantageous
factors ---Science Now (online 2012)
Excessive GH-Gigantism
• Increased linear bone growth due
to intense hormonal stimulation before the
the long bone epiphyses close.
• Frequently, pituitary adenoma is the
cause
• Treated with somatostatin analogues
inhibit GH secretion.
World’s tallest man at 8’11” with his father.
Excessive GH-Acromegaly
Before
After
Excessive bone growth after epiphyseal closure at
puberty.
Because of its pathogenesis and slow progression,
the disease is hard to diagnose in the early stages and
is frequently missed for many years, until changes in
Goal for the treatment of acromegaly is to reduce
external features, especially of the face, become noticeable.
the production of growth hormone and to alleviate
pressure on surrounding tissues.
The common treatment for managing acromegaly
is transsphenoidal surgery to remove the pituitary
adenoma.
extract the tumor through a small incision in the back
wall of the nasal cavity.
Therapeutic Interventions in GH
conditions
IGFs
IGFs
IGFs
Complimentary regulation of GH and insulin
coordinates nutrient availability
Insulin Like Growth Factors
“Somatomedins”
IGFs resemble insulin in structure and function
Two family members:
IGF-1  major form in adults
IGF-2  major form in the fetus
They cross-react with insulin receptor
Produced in many tissues and have autocrine, paracrine and
Endocrine roles
Both act through Type 1 IGF receptors (insulin/EGF family) have an
Insulin Like Growth Factors
“Somatomedins”
• Liver may be main source of circulating IGFs but they are known to
be made in other tissues
• IGFs circulate in blood complexed with IGF Binding Proteins
• IGFBP increase half-life of IGFs ---binding proteins degraded by
protease that releases active IGFs locally
-possible role in prostate cancer
• Serum IGF levels correlate with growth in children
• GH stimulates IGF in liver (IGF measure of GH in serum)
• PTH and estradiol stimulate osteoblastic IGF-1 production
• IGFs are mitogenic and stimulate all metabolism of chondrocyte.
Prolactin
• Lactotrope cells in anterior pituitary produce prolactin
(PRL) hormone
• 199 aa single chain protein structurally related to GH
and hPL
• PRL receptor also acts through JAK/STAT
signaling pathways
• Major functions in breast development and
lactation will be covered in Reproduction
Prolactin
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In context of other pituitary hormones it should be appreciated
that PRL is not part of a pituitary feedback loop.
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PRL acts directly on non-endocrine cells (breast) to induce physiological changes
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PRL is regulated by inhibition of secretion (mediated via dopamine neurons) (Drugs that
block dopamine increase PRL)
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There may also be a Prolactin Releasing Factor (PRF)
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TRH and hormones of the glucagon family (glucagon, secretin, VIP, Gastric Inhibitory
Peptide (GIP) can release PRL.
Pathophysiology of PRL
• Overproduction PRL galatorrhea
(excessive milk secretion) and/or infertility
• Causes—
-Disruption of hypothalamic axis
– Destruction of the hypothalamus
– Prolactinomas
Increased PRL secretion results from removal of inhibition normally
regulating PRL—that is a “loss of tonic inhibition by dopamine”
Treatment is by a dopamine agonist=bromocriptine