Transcript Pituitary Gland (Hypophysis)

Pituitary Gland
Anterior pituitary hormones are
classified into three families:
Somatomammotropin family (GH and PRL).
Glycoprotein hormones (LH, FSH, and TSH).
Opiomelanocortin family (ACTH, β-endorphin,
and related peptides).
Growth Hormone
(GH)
Human GH consists of 191 amino acid residues
(M.W. 22,000) and contains two disulfide bridges.
GH = half-life of about 25 minutes in lean adults.
GH is inactivated mainly by the liver but also by the
kidney.
About 40% of the hormone is bound to "GH-binding
protein" (GHBP).
The GH receptors are single-membrane-bound
proteins. Each of the receptor contains an
extracellular, transmembrane, and intra-cellular
domain.
GH promotes transport and incorporation of amino
acids in skeletal muscle, cardiac muscle, adipose
tissue, and liver and is responsible for the
proportionate growth of visceral organs and lean
body mass during puberty.
GH acts directly on cartilage tissue to promote
the endochondral growth that results in
skeletal growth; however although GH has a
direct effect on chondrocyte stem cells, the
growth-promoting effect of GH is due to its
stimulation of the chondrocytes to produce
insulin-like growth factor I which then acts
locally to stimulate cellular replication in the
distal proliferative zone of the epiphyseal
plate.
GH exerts a "protein-sparing" effect by mobilizing the
body's energy substrates, such as glucose, free fatty
acids, and ketone bodies, in the same tissues in which
it stimulates protein synthesis.
GH inhibits glucose uptake by skeletal muscle by
inhibiting hexokinase activity and by desensitizing
the tissue to the actions of insulin; the effect is to
elevate the blood glucose level.
GH promotes lipolysis in adipocytes, possibly by
increasing the synthesis of hormone-sensitive lipase
(HSL), and ketogenesis in the liver.
GH increases the activity of hepatic
glucose-6-phosphatase, increasing glucose
secretion.
These protein-sparing effects of GH are
diabetogenic and explain how GH
functions as an insulin antagonist.
GH hypersecretion in children causes increased
growth rate and can result in gigantism.
GH excess occurs infrequently in childhood, and
most frequently in middle-aged adulthood,
which leads to acromegaly (acral -- extremities
+ megas -- large), a condition in which the
cartilaginous tissues proliferate, resulting in
distorted overgrowth of the hands, feet,
mandibles, nose, brow, and cheek bones.
The major cause of GH resistance is a
genetic defect in the growth hormone
receptor (GHR) and the resultant
condition is known as Laron-type
dwarfism
Prolactin
Human prolactin (PRL) contains 199 amino acid
residues (M.W. 23,500) and three intramolecular
disulfide bridges.
In healthy adults the anterior pituitary releases
very little PRL under nonstressed conditions,
primarily because PRL release is under
hypothalamic inhibition.
This inhibition is exerted by dopamine or PIH.
Elevated levels of PRL stimulate milk
production in the mammary gland.
After parturition, PRL promotes milk secretion
via a neuroendocrine reflex that involves
sensory receptors in the nipples.
In mammary tissue, prolactin binds to alveolar
cells and stimulates the synthesis of milkspecific proteins (casein, lactalbumin, and
lactoglobulin) by increasing production of their
respective mRNAs.
The Opiomelanocortin Family
ACTH
ACTH
ACTH is a polypeptide of 39 residues.
The first 24 of which are required for corticotropic
activity and do not vary among species.
Because (ACTH) contains the MSH sequence in
residues 6-9 (His-Phe-Arg-Trp), ACTH has intrinsic
melanocyte-stimulating activity.
ACTH can thus cause skin darkening if present in high
concentrations.
ACTH acts mainly on the cells of the zona
fasciculate of the adrenal cortex to
stimulate the synthesis and release of
cortisol.
It also stimulates the secretion of adrenal
androgens from the zona reticularis.
Binding of ACTH to receptors activates
formation of cAMP which mediates cortisol
formation and secretion and protein
synthesis.
β-Endorphin
β-Endorphin is a 31-amino-acid polypeptide
released together with ACTH.
When introduced into the third ventricle of the
brain, it produces dramatic behavioral changes,
but when injected systemically, it does not.
Thus, the function of circulating β-endorphin
remains unclear.
β-Endorphin is an agonist of the opioid
receptors, with evidence suggesting it serves as
the endogenous ligand of the μ-opioid receptor,
the same receptor to which the chemicals
extracted from opium, such as morphine, have
their analgesic and addictive effects (indeed,
the μ-opioid receptor was named based on its
most renowned ligand, morphine).
Melanocyte-stimulating hormone
(MSH)
The melanocyte-stimulating
hormones (collectively referred to
as MSH or intermedins) are a class
of peptide hormones that are produced by
cells in the intermediate lobe of
the pituitary gland.
They stimulate the production and release
of melanin (melanogenesis)
by melanocytes in skin and hair.
MSH signals to the brain have effects on
appetite and sexual arousal.
Melanocyte-stimulating hormone belongs to a
group called the melanocortins. This group
includes ACTH, alpha-melanocyte-stimulating
hormone (α-MSH), beta-melanocytestimulating hormone (β-MSH) and gammamelanocyte-stimulating hormone (γ-MSH);
these peptides are all cleavage products of a
large precursor peptide called proopiomelanocortin (POMC).
α-MSH is the most important melanocortin for
pigmentation.
Glycoprotein Hormones
1.Thyroid-stimulating hormone
(TSH, thyrotropin)
2. Luteinizing hormone (LH) and follicle stimulating
hormone (FSH)
1. Thyroid-stimulating hormone
(TSH, thyrotropin)
TSH stimulates secretion of the thyroid
hormones T4 and T3.
TSH stimulates synthesis of thyroid hormone,
synthesis of thyroglobulin, synthesis of RNA
and protein, uptake and utilization of glucose,
and synthesis of phospholipids.
TSH action is mediated by intracellular cAMP
Release of TSH is stimulated by TRH and
inhibited by circulating T4.
T4 is converted to T3 by 5'-deiodinase.
In the normal adult, the pituitary contains
about 0.3 mg TSH, and the basal level of the
hormone in blood is about 1 ng/mL.
2. Luteinizing hormone (LH)
and follicle stimulating hormone
(FSH)
LH and FSH are synthesized within the
same gonadotrophs but are products of
different genes.
They differ in carbohydrate composition
(and thus in clearance rates); although
their β subunits have the same number of
amino acid residues, they differ in amino
acid sequences.
Adrenal Glands
The adrenal glands, a pair of wellvascularized glands positioned bilaterally
above the cranial poles of the kidney,
consist of two embryologically,
histologically, and functionally distinct
regions.
The outer region of each (adrenal cortex)
accounts for about 80% of the weight of
the gland and produces steroid hormones.
The inner core of each gland (adrenal
medulla) that has assumed an endocrine
function, and synthesizes and secretes
catecholamines and enkephalins.
Aldosterone
The major regulators of aldosterone secretion
are the renin-angiotensin system and
extracellular potassium ions (K+).
The renin-angiotensin system is sensitive to
changes in intravascular volume and arterial
pressure.
While potassium ions is an aldosteroneregulated substance that feeds back to reduce
aldosterone synthesis (simple negative
feedback).
Glucocorticoids
Cortisol (and other glucocorticoids)
promotes the conservation of glucose
as an energy source in several ways:
1. Cortisol induces and maintains the activity of
all of the specifically gluconeogenic enzymes
in the liver by increasing hepatic formation of
glucose. Cortisol promotes its conversion to
hepatic glycogen.
2. Cortisol inhibits glucose utilization in
peripheral tissues, such as skeletal
muscle, adipose tissue, bone matrix,
lymphoid tissue, and skin, by inhibiting
glycolysis and promoting the use of fatty
acids. This action is modulated by insulin
and thyroid hormones but is potentiated
by GH.
Cortisol promotes the liberation of fatty acids
from adipose tissue by inducing and
maintaining the synthesis of hormone-sensitive
lipase (HSL), an effect supported by GH.
Adrenal Androgen
(Dehydroepiandrosterone (DHEA))
The zona reticularis is the innermost
layer of the cortex, about equal in size to
the zona glomerulosa in the adult.
Although there is evidence that the zona
fasciculata produces DHEA, no sulfate
ester is formed at that site; and although
the zona reticularis contains cortisolproducing cells from the zona fasciculata,
the major steroid product of this zone is
DHEAS.
Adrenal Medulla
Cells of the adrenal medulla are often referred to
as "chromaffin cells" because they contain
"chromaffin granules," electron-dense membranebound secretory vesicles with an affinity for
chromic ions (hence the name "chromaffin").
Chromaffin granules contain catecholamines
(~20%), various proteins (~35%), ATP (15%), lipids
(~20%), calcium ions, ascorbic acid, and other
substances; they are the adrenal medullary
counterparts of secretory vesicles in ganglion cells.
Phenylethanolamine-N-methyltransferase (PNMT)
Two enzymes responsible for inactivation of
catecholamines are present in most tissues but are
particularly abundant in the liver.
Catechol-O-methyltransferase (COMT) is a cytosolic,
Mg2+-dependent enzyme that catalyzes
methoxylation of catecholamines at the hydroxyl
group at position 3.
COMT utilizes S-adenosylmethionine as the methyl
donor and usually initiates inactivation.
Monoamine oxidase (MAO), a mitochondrial
enzyme that oxidizes the amino side chain of
catecholamines, acts generally (but not
invariably) on methoxylated catecholamines.
About 70% of the total output of urinary
catecholamines is 3-methoxy-4hydroxymandelic acid (also called
vanillylmandelic acid, VMA).
Thyroid gland
The synthesis and release of thyroid
hormone involves a number of steps
1. Uptake of iodide (ATP-dependent Na+, K+ATPase).
2. Activation and Organification of lodide
(catalyzed by thyroperoxidase).
3. Coupling Reaction and Storage as Colloid
(Iodide peroxidase or a "coupling enzyme"
catalyzes the "coupling reaction).
4. Processing of TG and Release of Thyroid
Hormone.
Biological Actions of Thyroid
Hormones
Type
bound to thyroxine-binding globulin (TBG)
bound to transthyretin or "thyroxinebinding prealbumin" (TTR or TBPA)
albumin
unbound T4 (fT4)
unbound T3 (fT3)
Percent
70%
10-15%
15-20%
0.03%
0.3%
Cardiovascular System
Thyroid hormone enhances cardiac
contractility and exerts a positive
chronotropic effect on the heart,
increasing heart rate by a mechanism
that may involve more than a
potentiation of the β-adrenergic
effect.
Intermediary Metabolism
Thyroid hormone increases both lipolysis and
lipogenesis, although lipogenesis is stimulated
before lipolysis, due to early induction of malic
enzyme (malate dehydrogenase), glucose-6phosphate dehydrogenase, and fatty acid synthase.
Thyroid hormone lowers serum cholesterol levels.
In liver, kidney, skeletal muscle, cardiac muscle, and
adipose tissue, thyroid hormone stimulates Na+,K+ATPase gene expression and promotes
thermogenesis.
Growth and Maturation
Thyroid hormone stimulates production of IGF-I
directly (liver) and indirectly (via increased
growth hormone, GH).
Reproductive System
Thyroid hormone increases total plasma androgen
levels by increasing the production of testosteronebinding globulin (TeBG) by the liver.
Reproductive Hormones
Testosterone
Testosterone in plasma exists in two
fractions: TeBG bound (44%) and nonTeBG-bound (56%).
Biological Effects of Androgens
The biological effects of androgenic
hormones can be of two types:
Reproductive (androgenic), i.e., promoting
the primary and secondary sexual
characteristics of a male.
Non-reproductive, which includes anabolic
effects.
Reproductive (Androgenic) Effects
1. Testes
At puberty, locally produced testosterone promotes
spermatogenesis in the seminiferous tubules, although
it is not known with certainty whether or not the
Sertoli cells contain 5α-reductase.
2. Internal and External Genitalia
In the fetus, testosterone causes differentiation of the
Wolffian ducts into the male-type reproductive tract, and
thereby rescues the tissue from pre-programmed destruction.
The seminal vesicles, which differentiate from the Wolffian
duct as a result of testosterone action, produce 5α-reductase2 from week 13-14 and become DHT-responsive after that;
thus, development and function (but not appearance), may be
regulated by DHT from the second trimester through
adulthood.
At puberty, however, the derivative of the genital tubercle
(clitoris and penis) becomes responsive to testosterone, which
enhances the male-type morphology by promoting growth of
the existing structure.
3. Skin
The hair follicles and sebaceous glands in the androgen
sensitive areas of the skin and sebaceous glands
throughout the body contain 5α-reductase type 1 and
respond to DHT.
At puberty, DHT stimulates the appearance and growth
of terminal hair in certain androgen-sensitive regions of
the body (face, chest, upper pubic triangle, nostrils,
external ear).
DHT stimulates the growth and secretory function
(sebum production) of all sebaceous glands, and thus
predisposes the skin to acne formation.
Male pattern baldness
4. Voice Pitch
Testosterone promotes enlargement of the larynx and
thickening of the vocal folds (vocal cords), causing a
lowering of the voice pitch.
Non-reproductive Effects
1. Skeletal Muscle
Testosterone promotes skeletal muscle growth by
stimulating both hypertrophy and mitosis of myofibrils
and increases the fast-twitch isoform of myosin heavy
chain.
The extent to which skeletal muscle mass can be
increased is limited by the concentration of androgen
receptors in the muscle that can be activated.
.
2. Bone
Androgens promote skeletal growth and maturation by a
direct effect on bone tissue and by an indirect effect on
growth hormone (GH) release.
At puberty, the increasing levels of androgens stimulate
the release of GH and result in accelerated endochondral
growth of the epiphyses of long bones, which causes a
doubling of height gain that is maximal at about mid- to
late puberty.
3. Blood Volume
Testosterone acts on the proximal tubule of the
nephron to promote the reabsorption of K+, Na+,
and Cl-, which, along with stimulated
erythropoiesis, contributes to the androgenassociated increase in blood volume.
4. Erythropoiesis
Androgens stimulate the production of erythropoietin
by the kidney and, in part, cause an increase in
hematocrit by this mechanism.
This may explain why males have a higher hematocrit
than females.
5. Adipose Tissue
Androgens promote truncal-abdominal fat deposition and
favor development of upper body obesity.
6. Liver
Androgens cause a reduction in the plasma levels
of testosterone-estradiol-binding globulin (TeBG),
which results in an increased percentage of
testosterone that is accessible for tissue uptake.
Estrogen
Estrogens are a group of compounds
named for their importance in the estrous
cycle of humans and other animals.
Their name comes from the Greek words
estrus = sexual desire and gen = to
generate.
The three major naturally occurring
estrogens in women are estrone (E1),
estradiol (E2), and estriol (E3).
Estrone is produced during menopause,
estradiol is the predominant form in
nonpregnant females, and estriol is the
primary estrogen of pregnancy.
Structural function
Promote formation of female secondary sex
characteristics
Accelerate metabolism
Reduce muscle mass
Increase fat stores
Stimulate endometrial growth
Increase uterine growth
Increase vaginal lubrication
Thicken the vaginal wall
Maintenance of vessel and skin
Reduce bone resorption, increase bone formation.
Protein synthesis
Increase hepatic production of binding proteins.
Coagulation
Increase circulating level of factors 2, 7, 9, 10, plasminogen.
Decrease antithrombin III.
Increase platelet adhesiveness.
Lipid
Increase HDL, triacylglycerol
Decrease LDL, fat deposition
Progesterone
Progesterone also known as P4 (pregn-4-ene3,20-dione) is a C-21 steroid hormone involved
in the female menstrual cycle, pregnancy
(supports gestation) and embryogenesis of
humans and other species.
Progesterone is sometimes called the
"hormone of pregnancy", and it has many
roles relating to the development of the fetus:
Progesterone has key effects via non-genomic
signalling on human sperm as they migrate through
the female tract before fertilization occurs, though
the receptor(s) as yet remain unidentified.
Since eggs release progesterone, sperm may use
progesterone as a homing signal to swim toward
eggs.
During implantation and gestation,
progesterone appears to decrease the
maternal immune response to allow
for the acceptance of the pregnancy.
Pancreatic hormones
The pancreas is a glandular organ in the digestive
system and endocrine system of vertebrates.
It is an endocrine gland producing several
important hormones including insulin,
glucagon, somatostatin, and pancreatic
polypeptide which circulate in the blood.
Insulin
Proinsulin is the prohormone precursor
to insulin made in the beta cells of the islets of
Langerhans, specialized regions of the pancreas.
Proinsulin is synthesized in the endoplasmic
reticulum, where it is folded and its disulfide
bonds are oxidized. It is then transported to
the Golgi apparatus where it is packaged into
secretory vesicles, and where it is processed by
a series of proteases to form mature insulin.
Mature insulin has 35 fewer amino acids; 4
are removed altogether, and the remaining
31 form the C-peptide.
The C-peptide is abstracted from the center
of the proinsulin sequence; the two other
ends (the B chain and A chain) remain
connected by disulfide bonds.
Increased glycogen synthesis.
Increased lipid synthesis.
Increased esterification of fatty acids – forces
adipose tissue to make fats (i.e., triglycerides) from
fatty acid esters.
Decreased proteolysis
Decreased lipolysis
Decreased gluconeogenesis
Increased amino acid uptake – forces cells to absorb
circulating amino acids; lack of insulin inhibits
absorption.
Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1),
which starts many protein activation cascades (2). These include translocation of Glut4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis
(4), glycolysis (5) and triacylglycerol (6).
Glucagon
Glucagon, a peptide hormone secreted by
the pancreas, raises blood glucose levels.
The pancreas releases glucagon when blood
sugar (glucose) levels fall too low. Glucagon causes
the liver to convert stored glycogen into glucose,
which is released into the bloodstream.
Glucagon is a 29-amino acid polypeptide.
Glucagon is generated from the cleavage
of proglucagon secreted by pancreatic islet α
cells.
Glucagon generally elevates the amount
of glucose in the blood by
promoting gluconeogenesis and glycogenolysis.
Glucose is stored in the liver in the form of
glycogen, which is a polymer made up of glucose
molecules.
Liver cells (hepatocytes) have glucagon
receptors. When glucagon binds to the glucagon
receptors, the liver cells convert the glycogen
polymer into individual glucose molecules, and
release them into the bloodstream, in a process
known as glycogenolysis.
As these stores become depleted, glucagon then
encourages the liver and kidney to synthesize
additional glucose by gluconeogenesis.
Glucagon turns off glycolysis in the liver, causing
glycolytic intermediates to be shuttled to
gluconeogenesis.
Glucagon also regulates the rate of glucose
production through lipolysis.
Somatostatin
Somatostatin (also known as growth
hormone-inhibiting hormone (GHIH)) is
a peptide hormone that regulates
the endocrine system and
affects neurotransmission and cell
proliferation via interaction with G proteincoupled somatostatin receptors and
inhibition of the release of numerous
secondary hormones.
Somatostatin has two active forms produced by
alternative cleavage of a single preproprotein: one of
14 amino acids, the other of 28 amino acids.
In the anterior pituitary gland, the effects of
somatostatin are:
Inhibit the release of growth hormone (GH) (thus
opposing the effects of Growth Hormone-Releasing
Hormone (GHRH))
Inhibit the release of thyroid-stimulating
hormone (TSH).