Transcript 19 - Pegasus @ UCF

Optic
chasm
infudibulum
Median
eminence
Arterial blood
supply
Posterior
pituitary
Hypothalamo-pituitary
portal vessels
Anterior
pituitary
Endocrine
cells
To venous
circulation
Short portal
vessels
To venous
circulation
Arterial blood
supply
Axon to
primary
capillaries
Primary
capillaries
Superior
hypophyseal
artery
Portal
venules
Anterior
pituitary
Median
eminence
Pituitary
stalk
Posterior
pituitary
Secondary
capillaries
Transduction Pathways of
Releasing Hormones
Pathway
Hormone
Location of action
CRH
Corticotrope of anterior
pituitary (ACTH)
TRH
Thyrotrope of anterior
pituitary (TSH)
GnRH
Gonadotrope of anterior
pituitary (LH & FSH)
AVP
Corticotrope of anterior
pituitary; assists CRH in
releasing ACTH
PKAa
PIb
+
+c
+
Transduction Pathways of Releasing
Hormones (cont.)
Pathway
PKAa PIb
Hormone
Location of action
GHRH
Somatomammotrope
of anterior pituitary (GH)
+
Somatostatin
Somatomammotrope
of anterior pituitary
(inhibits GH release)
+d
PRL
Release inhibitor
aPKA,
protein kinase A
bPI, phosphatidylinositol pathway
cThe increase of cytoplasmic calcium concentration
may be important in the actions of PI stimulation
dInhibitory pathway of PKA
(?)
Effects of hypophysectomy
1. Cessation of growth & the retention of juvenile
features.
2. Atrophy of adrenal cortes (zona fasciculata).
3. Atrophy of thyroid.
4. Decreased gonadal function in the adult.
5. Alterations in the metabolism of lipids, proteins,
and carbohydrates.
6. Blanching of pigment cells in the skin of the
lower vertebrates (fishes, amphibians, & reptiles
Growth Hormone (GH)
Somatotropin
I. Chemistry
Straight chain polypeptide of 191 AA (Two S-S
bonds)
Mole Weight: 22,000 deltons
Produced by somatotroph (acidophil) cells
Plasma Concentration 3-10 ng/ml
Circulating half-life: 20-30 minutes
Broken down by the liver
II. Biologic Actions
A. Supports Osteogenesis
(Epiphyseal-diaphyseal plate)
Stimulates release of peptide somatomedin
from the liver
1. Oversecretion (acidophilic adenoma)
(a) Giantism
(b) Acromegaly
2. Undersecretion
(a) Pituitary dwarf
(b) Simmond’s disease (hypophyseal cachexia)
Amino Acid Sequence of HGH
Epiphyseal-Diaphyseal Plate
Facial changes in a patient with acromegaly.
Panel at left shows appearance of normal young
woman. Middle & right show effects of acromegaly
with coarsening of facial features.
Hand of someone with acromegaly (left)
placed next to normal hand (right).
Somatotropin (cont.)
B. Promotes protein synthesis (anabolic effect)
Retards AA catabolism:  transport into
cell.
AA retention causes positive nitrogen phosphate balance.  Na+ + K+ excretion
C. Diabetogenic effect (Houssay animal)
Blocks hexokinase
Somatotropin (cont.)
Affects carbohydrate metabolism by:
1.  hyperglycemia
2. Inhibiting insulin action
3.  muscle glycogen
4. Production of permanent diabetes mellitus
(destroys B cells)
Somatotropin (cont.)
D. Peripheral mobilization of fats
(Pharmacologic doses)
[serum fatty acids]
E. Increase intestinal absorption of calcium
F. Increase renal tubular reabsorption of
phosphorus
Somatotropin (cont.)
III. Regulation of release
A. Stimulation (via Somatotropin Releasing
Hormone) SRH
Deficiency of energy substrate:
1. Hypoglycemia
2. Exercise
3. Fasting
4.  Plasma protein
5. Sleep
Somatotropin (cont.)
B. Inhibition (via somatostatin) IH
1.  Serum glucose
2.  Cortisol
3. REM sleep
Somatotropin (cont.)
IV. Potential Clinical Use for Hypothalmic
Hormones
A. Somatotropin Releasing Hormone
Treats GH deficiency effects-short stature
B. Somatostatin (14 AA peptide)
Treatment of acromegaly
Growth Curve
100
80
% of total
growth
60
40
20
0
4
8
12
Age (years)
16
20
Somatomedin Level (U/mL)
1.2
1.1
•
1.0
•
•
•
•
0.9
•
0.8
0.7
•
0.6
0.5
•
0.4
(8) (6) (6) (4) (5) (5)
0
2
4
6
8
10
Age (years)
(2)
12
14
Adult
P
Growth H. + thyroxine
P
Wt.
Growth H.
P
throxine
control
Age
Prolactin
Chemistry
Unbranched polypeptide of 198 AA (human). It has 3
disulfide bridges and a mole wt. of ~ 25,000. Secreted by
acidphil cells (lactotrophs) of the adenohypophysis. The
“prolactins” have a myriad of effects among vertebrates
and hence a myriad of different names (lactogenic hormone;
mammotrophin; galactin; luteotrophin; etc.) The “N&C”
terminals are similar to those in growth hormone.
Half-life of 15-25 minutes
Serum level 8 ng/mL female : 5 ng/mL male
Prolactin (cont.)
Biologic Actions
A. Non-Humans
1. Luteotropic effect (rats)- maintenance of the
functional activity of the corpus luteum & release
of progesterone (controlled by LH in humans.)
2.Maternal behavior (rabbits)- injections of
prolactin into non-pregnant rabbits results in
nest building.
Ovine (sheep) prolactin. The black bars indicate disulfide bridges.
Prolactin (cont.)
B. Human Functions
1. Mammotrophic effect- stimulates the
mammary epithelium to secrete milk (i.e.
produce milk.)
2. Affects function of adrenals, gonads, steroid
synthesis, and lipolysis.
Prolactin (cont.)
Regulation of Release
A. Secretion (PRH- Prolactin Releasing
Hormone)
1. Pregnancy- reaches peak during parturition
2. Stimulation of nipples (nursing baby)
3. Surgical or psychologic stress
4. Coitus
Prolactin (cont.)
B. Inhibition (PIH- Dopamine)
1. Dopmine is a product of L-Dopa (used to treat
Parkinson’s disease- neurological disordertremors)
2. Estrogen & progesterone- high levels during
pregnancy inhibit action of prolactin. After birth,
milk production increases.
Causes of Increased Concentration
of Production in Serum
Physiological
Pathological
Pharmacological
Pregnancy
Stress
(e.g., surgery)
Pituitary tumors
Pituitary stalk sections
Various drugs (e.g.,
chlorpromazine)
Sleep
Hypothalmic disorders,
Oral contraceptives
Sucking
Exercise
e.g., sarcoid infiltration
Chiari-Frommel syndrome
Estrogens
Thyrotropin-releasing
hormone
Sexual
intercourse
Renal failure
Insulin-induced
Hypothyroidism
hypoglycemia
Arginine
Nelson’s syndrome
Parathormone
Adrenal insufficiency
Ectopic production by tumors
Corticotropin
Adrenocorticotrophic Hormone (ACTH)
Chemistry
Straight chain polypeptide of 39 AA & a mole weight of 4,500.
It is secreted by corticotroph cells (basophil). ACTH has a 13
AA sequence from its N-terminal which is identical with MSH.
It therefore has a natural tendency to melanosize cells like
B-lipotrophin (AA 41-58)
Biologic Actions
1. ACTH controls the release of glucocorticoids (cortisol and
corticosterone) from the zona fasciculata of the adrenal cortex.
2. Release of adrenal androgens
Zona Glomerulosa
Zona
Fasciculata
Medulla
Zona Reticularis
Regulation of Release
Almost any type of physical or mental stress
causes the release of CRH from the hypothalamus. This causes the release of ACTH
which glucocorticods.
Regulation of Release (cont.)
BIOASSAYS
1. Depletion of ascorbic acid (vitamin C).
a) formation of collagen
b) [iron] in body fluids
c) Scurvy (20-30 week deficiency)
Failure of wounds to heal ( collagen)
Cessation of bone growth
Fragile walls of blood vessels
(cont.)
2. Depletion of cholesterol.
3. Incubation methods:
Incubate adrenal slices with ACTH.
Measure cortisones produced.
4. Maintenance of adrenal weight in
animals.
Thyrotropin
I. CHEMISTRY:
TSH, FSH, & LH are glycoproteins
produced by basophil cells and having
chemically dissimilar subunits noncovalently linked together.
Thyrotropin (cont.)
Subunits:
a) Alpha - this subunit is identical in the
identical in the three hormones.
b) Beta - provides hormonal specificity.
Produced by thyrotroph (basophil) cells
Mole wt. 26,000
Circulating half-life is 60 minutes
Broken down by kidney
Thyrotropin (cont.)
II. BIOLOGIC ACTIONS
1. Maintenance of the structural and
functional integreties of the thyroid
gland.
2. Controls iodine uptake (iodide pump)
3. Maintains normal secretory epitheliumlow columnar.
Thyrotropin (cont.)
4. Causes production and release of
thyroxine.
Thyroid Follicles
Normal
colloid
Hyperactive
(hyperthyroidism)
secretory
epithelium
depleted
colloid
Hypoactive
Thyrotropin (cont.)
III. Regulation of release
A. Stimulation (via thyrotropin releasing
hormone)
Negative feedback
1)  thyroxine
2)  body temperature
B. Inhibition
1)  serum thyroxine
2)  body temperature
Thyrotropin (cont.)
IV. Assay Methods
A. Bioassay
1)  height of secretory epithelium
2) Number of colloid droplets in cells
3) Iodine depletion in 1-day old chicks
4) Uptake of radioactive iodine
B. Radioimmunoassay
Folliculotropin
Follicle Stimulating Hormone (FSH)
Chemistry
Same as Thyrotropin (produced by
gonadotroph cells)
Alpha= 92 AA
Beta= 118 AA
Biologic Action
A. Female
1. Stimulates young ovarian follicles to develop
multiple layers of granulosa cells & form antra.
Folliculotropin (cont.)
2. Stimulate production of estrogen by developing
follicle
B. Male
Stimulates the seminiferous tubulesspermatogenesis
Regulation of release
Concentration of circulating estrogensnegative feedback.
Note: Both estrogen production & completed
spermatogenesis require LH.
OOGONIA NUMBERS
(Text P. 630)
•
•
•
•
5 months of gestation = 7 million
Birth = 2 million
Puberty = 300,000 to 400,000
Released during sexual maturity (40
years) = 480
Germinal
epithelium
Corpus
Corpus luteum
albicans
Time
Ovulation
Primary follicle
Corona radiata
Secondary oocyte
Zona pellucida
Growing
primary follicle
Primary oocyte
Secondary follicle
Antrum
Graafian
follicle
Time
Cumulus
oophorous
ESTROGENS
(17 BETA ESTRADIOL)
Biologic Actions
1. Act as “growth hormones” stimulating
mitosis in the mammary glands and the
female reproductive system (uterus and
vagina).
ESTROGENS (cont.)
2. Promote the deposition of fat in the
breast, thighs and buttocks, thereby
decreasing the specific gravity in females.
3. Promote the early closing of the growth
plates.
Spermatic cord
Efferent ductules
epididymis
Rete testis within
mediastinum testis
testis
Seminiferous tubules
Lumen of seminiferous tubule
Interstitial
cells
Germinal
epithelial cells
Basement
membrane
Spermatazoa
Lutotropin
Interstitial Cell Stimulating
Hormone (ICSH)
Chemistry
Same as Thyrotropin
Half-life of one hour
Alpha=96 AA
Beta=120 AA
Lutotropin (cont.)
Biologic Action
A. Female
1. Release of estrogen from developing follicle.
2. Promotes ovulation. Ovulatory surge in
concentration just before ovulation.
3. Affects luteinization of ruptured follicle.
4. Causes release of progesterone from corpus
luteum
Lutotropin (cont.)
Biologic Action
B. Male
1. Affects spermatogenesis- completes process.
2. Stimulates Leydig cells to produce testosterone.
Regulation of Release
Negative feedback with progesterone
Note: This is why HCG is needed during
pregnancy