Pituitary Hormones

& Their Control by the

Hypothalamus
Rita Maria Chidiac, M.D.
Physiology Course-2020
Med I
Pituitary Gland = hypophysis - 2 distinct parts & different embryologic
origins

Connects hypothalamus to the pituitary

Neurohypophysis Adenohypophysis
( glial-type cells) (cells of epithelioid
nature )

is almost absent in human

beings
 Pituitary Gland- The Anterior and Posterior lobes
 Anterior pituitary adenohypophysis

Rathke’s pouch ( pharyngeal

epithelium )
Epithelioid cells
 Posterior pituitary neurohypophysis

Outgrowth from hypothalamus

Glial-type cells
Peptide hormones secreted by the anterior pituitary
Adenohypophysis Cell Type
Growth hormone (hGH) Somatotropes
Prolactin (PRL) Lactotropes
Adrenocorticotropin Corticotropes
Hormone (ACTH)
Glycoprotein hormones
Luteinizing hormone (LH) Gonadotropes
Follicle-stimulating hormone (FSH)

Thyroid-stimulating hormone Thyrotropes

Thyrotropin (TSH)
 Peptide Hormones secreted by the Posterior pituitary
Neurohypophysis Cell Type

Antidiuretic hormone Supraoptic nuclei

(vasopressin; ADH)

Oxytocin Paraventricular nuclei

Magnocellular neurons where the posterior pituitary hormones are

syntesized & the hormones are then
transported in the axoplasm of the nerve
fibers from hypothalamus to posterior
pituitary
Metabolic Functions of the Anterior Pituitary Hormones

ACH = adrenal corticosteroid hormones

 Hypothalamic-Pituitary Unit

 The pituitary gland is regulated by 3 interacting

elements
 Hypothalamic releasing hormones (factors) &
Hypothalamic inhibitory hormones
Almost all secretion by the pituitary is controlled by hormonal or nervous signals
from the hypothalamus ( e.g section of pituitary stalk ↓ all pituitary
hormones except for prolactin)

 Feedback effects of circulating hormones

 Paracrine & autocrine secretions of the pituitary
itself
 Hypothalamic hypophyseotropic neurons & the anterior pituitary gland
Neurons in the
hypothalamus secrete
releasing & inhibitory
factors into a rich funnel-
shaped plexus of
capillaries that penetrates
the median eminence.

The median eminence is characterized by an extremely rich

blood supply that arises from the superior hypophyseal
arteries external to the blood- brain barrier.
Hypothalamic- pituitary vasculature
The superior hypophyseal artery sends off many small branches
that form capillary loops which extend into long &
short hypophyseal portal vessels,
form anastomoses & drain into sinusoids
that become the
pituitary portal veins
& enter the vascular
pool of the pituitary.

Systemic blood supply is

maintained by IHA which
supplies predominantly
the posterior pituitary

(IHA)
Posterior pituitary hormones
are derived from direct
neural extensions
 This well-developed plexus results in a tremendous ↑ in the vascular surface area. The
vessels are fenestrated allowing diffusion of the hypothalamic factors to their site of
action in anterior pituitary without significant systemic dilution.

This allows pituitary cells

to be sensitively
regulated by
timed
hypothalamic
hormone secretion.

Retrograde blood flow

toward median eminence
also occurs facilitating
bidirectional functional
hypothalamic-pituitary
interactions.

The hypothalamo-pituitary axis

 Hypothalamic Hormones or Factors
Stimulatory Hormones

 Thyrotropin-releasing hormone (TRH) TSH

 Corticotropin-releasing hormone(CRH) ACTH
 Growth hormone-releasing hormone (GHRH) GH
 Gonadotropin-releasing hormone ( GnRH) FSH
LH

Inhibitory Hormones

 Growth hormone inhibitory (GHIH) XXX GH

somatostatin
 Prolactin inhibitory hormone (PIH) XXX PRL
dopamine
(41 a.as) (3 a.as) (10 a.as)
 Hypothalamus
(44 a.as) (14 a.as)

Pituitary gland

Trophic Hormone

Target Organ

Action
IGF-I = insulin-growth-factor I
 Somatotropic Hormone or Somatotropin (GH)
In contrast to other hormones, GH does not function through a target gland
but exerts its effects directly on all or almost all tissues of the body

Pro Ser Gly Asp Glu

Arg Leu
130
 Single-chain
Thr Arg
Gly Gly
Gln 135 80 Met
Leu
Ile
Ile Ser Leu Leu Leu 125
polypeptide
Phe Arg Ile Thr
Gln
Lys
75 Leu Ser 85 Gln
140 Leu 30 Trp Ile
Gln Glu Gln Glu
Thr Tyr Phe Leu
Leu Glu Gly
Thr 25 Asp
Glu Glu
120
Asn Phe Glu
Tyr Ala Pro
Ala
Ser
Ser
Leu
Tyr 35 Val 90
Glu
70
 191 amino acids
Lys Ile Leu
Lys Gln Gln
145 Pro
Gln Phe Asp
Phe His
Gln Lys Lys
Asp 20 Leu Leu 115
Thr Glu Leu
Thr Arg Arg
Gln
Asn
Glu
His 40 Ser
Leu

65 NH2 Lys 95
 MW = 22 kDa
Glu Asp
Ser Ala Val
150 Arg
Phe
1 Tyr Tyr
His Arg Phe
Pro
Asn Ser
Asn Leu
Thr Ala 110 Val
Ser 15 Met Phe
Asp Asn
Ile Asn
Pro Ala Leu
Asp Asn
Pro 45 Ser Ser
Thr Asp Leu 5 Gln 100
Ala 155 60 Pro Phe Leu Arg Ser
Asn Leu Asp
Leu Ile 10 Pro
Val 105 Ser
Leu Ser Gln
Glu Thr Tyr Ala
Lys Ser Ser Gly
Phe Cys Leu
Asn 160 55 50
Tyr
Gly Met Asp
Leu Asp Lys
Leu Tyr Lys
Cys Arg
Phe 170 Val
165
Glu
Ser 180 175
Arg Thr
Cys Gln Phe
185 Val Val Ile Arg Leu

Glu 190
Gly Ser Cys Gly Phe
COOH
Growth Hormone Effect on Growth : Weight charts of 2
growing littermate rats

In the early stages of development, all organs of the

treated rat increased proportionately in size. After
adulthood, most of the bones stopped lengthening but
many of the soft tissues continued to grow. This is due
to the fact that after epiphyseal closure, further
lengthening of long bones cannot occur even though
most other tissues of the body can continue to grow
throughout life.
 Metabolic Effects of GH
 GH promotes Protein Deposition in tissues by:
+ Enhancement of amino acid transport through the
cell membranes
+ Enhancement of RNA Translation to cause Protein
synthesis by ribosomes
+ Increased Nuclear Transcription of DNA to form RNA
+ Decreased Catabolism of Protein & amino acids
 GH enhances fat utilization for energy:
+ It causes release of fatty acids from adipose tissue
+ It enhances conversion of fatty acids to acetyl-CoA
Large quantities of acetoacetic acid are formed by the liver: Ketogenic effect of GH

Increase in lean body mass

 Diabetogenic Effects of Growth Hormone
Target Effect
Muscle ↓ Glucose uptake

Fat ↓ Glucose uptake

Liver ↑Gluconeogenesis

Muscle, fat, & liver Insulin resistance

Mechanism by which GH causes insulin resistance is unknown: impairment of
insulin action due to increase in fatty acid levels in the blood ??
 GH Stimulates Cartilage & Bone Growth
 ↑GH Growing of long bones in length at
epiphyseal cartilages deposition of
new cartilage
& conversion
into new bone
Bony fusion between shaft & epiphysis with no
further lengthening of bone
 GH stimulates osteoblasts with increase in bone
formation Thicker bones
thoughout life especially membranous bones
 Somatic effects of GH mediated through the effect of
somatomedin C also called insulin-like growth factor-I
(IGF-1)
Somatomedins found to be identical to 2 peptides with a primary structure much like that
of proinsulin with their effects on growth being similar to the effects of insulin.
 Skeletal Maturation & Somatic Growth

 The growth plate is dependent on a variety of

hormonal stimuli including GH, IGF-1, sex
steroids, thyroid hormones, paracrine growth
factors, & cytokines.
 The growth-promoting process also requires
energy, amino acids, vitamins.
 Malnutrition impairs chondrocyte activity & ↓
IGF-1 levels
 GH fails to cause growth if there is inadequate
insulin activity or if carbohydrates are excluded
from the diet Carbohydrates & insulin provide the energy needed for
the metabolism of growth
Insulin’s ability to enhance transport of some amino acids
into cells
Somatotrophs secrete GH in pulses
Short duration of action of GH but prolonged action of IGF-1.
Half-life of GH is < 20 mns; that of IGF-1 is > 20 hours.

This greatly prolongs the growth-promoting

effects of the bursts of GH secretion
 Regulatory Factors in GH secretion

 Growth hormone-releasing hormone (GHRH)

 Somatostatin (SST): SST-14

SST = SRIF ( Somatotropin-releasing inhibiting factor)

SST analogues in GH excess syndromes

 GH – IGF Axis
Factors that stimulate or inhibit secretion of GH
Stimulation Hypothalamus Suppression
Deep sleep GHRH _ SST Obesity
+
α-adrenergic Pituitary β-adrenegic
Fasting, protein deficiency Hyperglycemia
GH
Exercise Glucocorticoids
Sex steroids liver Fat
Aging
Stress lipolysis Hypothyroidism
Hypoglycemia IGF-1 IGF-1
Bone & Muscle
↓ FFA Growth
↑ FFA
↑ blood amino acids GH ( exogenous)
( arginine) IGF-1 inhibition:
Somatostatin
GHRH Malnutrition
Acute, chronic illness
Ghrelin GH receptor deficiency
FFA, free fatty acids
Effect of extreme protein deficiency on the plasma concentration ([ ])of GH in children

Failure of carbohydrate treatment but the

effectiveness of protein treatment in↓ GH [ ].

These results demonstrate that under severe

conditions of protein malnutrition, adequate
calories alone are not sufficient to correct the
excess production of GH protein
deficiency must be corrected before GH [ ] will
return to normal
 In summary, the regulation of GH secretion is
complex.
 Because of the extreme secretion of GH during
starvation & its important long-term effect to promote
protein synthesis & tissue growth, it is proposed that:
+ the major long-term controller of GH secretion is the
long-term state of nutrition of the tissues themselves,
especially their level of protein nutrition.
+ e.g. after a severe bout of exercise when the
muscles’ nutritional status has been taxed ↑ rate of
GH secretion
+ GH, in turn, promotes synthesis of new proteins
while at the same time conserving proteins already
present in the cells
Role of the hypothalamus, GHRH
& SST in
the control of
GH secretion
 Synthesis & release of
4
GHRH & Somatostatin

Most of the control of GH

secretion is mediated through
GHRH rather than SST.
GH & IGF-I negative feedback loops
 Abnormalities of GH
secretion
Panhypopituitarism ↓ secretion of all the
anterior pituitary hormones
 GH Deficiency- Dwarfism
Short Stature

 Short stature with height  2-2.5 standard

deviations below normal
 Delayed bone age
 Growth velocity below the 25th percentile
 A predicted adult height substantially
below the mean parental height
Growth Hormone deficiency
in children- Dwarfism
The pigmies of
Africa & Laron
dwarfs have
congenital defects
in the GH
receptor

Rate of development is greatly ↓. A

child who has reached the age of 10
years has the bodily development of
a child aged 4 to 5 years.
Excess GH in children Gigantism

Excess GH in adults Acromegaly

 A 22-year-old man with
gigantism due to↑ GH is shown
to the left of his identical twin.
↑height &
prognathism

Enlarged
hand

Enlarged
foot
 Clinical Features of Acromegaly
Acromegaly: Acromegaly =acral enlargement or growth marked mainly in the bones of hands & feet as well as the membranous
bones ( cranium, nose, bosses on the forehead, supraorbital ridges, lower jawbone, & portions of the vertebrae because their
growth does not cease at adolescence )

Other Characteristics:
– Enlarged nose, tongue, lips
– Frontal bossing – Vision defect
– Thyroid hypertrophy
– Prognathism
– Cardiomegaly
– Skin tags – Galactorrhea
– Increased perspiration – Hypertension
– Carpal tunnel syndrome – Splenomegaly
– Premature osteoarthritis – Colon polyps
– Enlarged feet and hands Hyperprolactinemia
– Headache
– Fatigue
Posterior pituitary secretes 2 hormones-Antidiuretic
hormone (ADH) & Oxytocin
Pituicytes do not synthesize hormones but act as a
supporting structure for large numbers of terminal
nerve fibers from nerve tracts originating in
the supraoptic & paraventricular nuclei

(pituicytes)
 Hypothalamic control of the Posterior pituitary
ADH & oxytocin are synthesized in
hypothalamic nuclei & are then transported
in combination with ‘carrier’ proteins called
neurophysins down to the nerve endings in
the posterior pituitary.

If the pituitary stalk is cut above the

pituitary gland but the entire
hypothalamus is left intact, the
posterior pituitary hormones continue
to be secreted normally.
H ( hormone) separates from its
associated neurophysin which has
no known function after leaving
nerve terminals

When nerve impulses are transmitted

downward along fibers from hypothalamic
nuclei, H is released from the secretory
granules in nerve endings by exocytosis &
is absorbed into adjacent capillaries.
Vasopressin
Phe
3 4 Gln

2 Tyr Asn
5

H2N Cys
1 s s 6 Cys Pro
7 LArg
8 Gly
9 NH2

Oxytocin
3Ile Gln
4

Tyr
2 5 Asn

H2N Cys
1 s s 6 Cys Pro
7 Leu
8 Gly
9 NH2
Physiological Roles of Oxytocin
 Uterus stimulates frequency & force of
uterine contractions
+ Due to  sensitivity of uterus
+ 30-fold  in oxytocin receptors from early
pregnancy to early labor
 Breast milk let-down by stimulating
contraction of the alveolar myoepithelial cells
+ This is triggered by the suckling reflex which
causes pulsatile release of oxytocin
Case discussions
 A 44-year-old woman presents to her gynecologist with
complaints of not having had a period for the last 8 months.
She reports a negative pregnancy test at home. Upon
further questioning, she reports a daily headache, changes
in vision, & a milky discharge from the breast. She has no
medical problems & is not taking any medications. On
examination, she is noted to have galactorrhea & diminished
perpheral vision bilaterally. The remainder of her examination is
normal. A pregnancy test is repeated & is negative. A thyroid-
stimulating hormone (TSH) level is drawn & is normal. Her
prolactin level is significantly elevated. After a thorough work-up
is completed, she is found to have a pituitary adenoma.

 How does hyperprolactinemia cause amenorrhea?

 Why would a physician need to check thyroid studies in patients
with hyperprolactinemia?
 Where are the posterior pituitary hormones synthesized?
 A 45-year-old woman is noted to have fatigue & cold intolerance & is
diagnosed with hypothyroidism. Her physician suspects a pituitary etiology.
Which of the following laboratory findings is most consistent with this
condition?
A. Low TSH, low free thyroxine
B. Elevated TSH, low thyroxine
C. Elevated TSH, elevated thyroxine
D. Low TRH
 A 35-year-old woman experiences anterior pituitary hemorrhagic necrosis (
Sheehan syndrome) after a postpartum hemorrhage. She feels light-headed,
dizzy, & weak. Which of the following hormones most likely is responsible for
her symptoms?
A. ACTH
B. GnRH
C. Prolactin
E. GH
 A 25-year-old woman is undergoing ovulation induction for infertility. She is
given an injection of GnRH on Monday. Serum estradiol is low, & ovarian
ultrasound reveals small follicles. What is the most likely explanation?
A. Ovarian failure
B. Pituitary failure
C. Need for pulsatile hormone
D. More time needed to see an effect
 A 13-year-old boy is brought to the pediatrician
by his mother because of concerns about his
growth. The patient is considerably taller than all his
classmates, has coarse facial features, and has a
prominent jaw. Both parents are short in stature, and
his growth is very abnormal for other family
members. On examination, the patient is noted to be
extremely tall for his age with frontal bossing,
increased hand and foot size, and coarse facial
features with a prominent jaw and an enlarged
tongue. His skin is noted to be oily with numerous
skin tags. After further workup is performed, the
patient is diagnosed with gigantism.
A. With what other pituitary hormones is growth
hormone homologous?
B. How does somatostatin inhibit growth hormone?
 The actions of growth hormone are mediated in part by which
of the following?
A. Insulin
B. Somatomedins
C. Thyroid hormone
D. Estrogen
 A 45-year-old woman has a cerebrovascular accident that
causes necrosis of the posterior pituitary. Which of the
following effects is most likely to be seen?
A. Inability to lactate
B. Hypothyroidism
C. Hypoglycemia
D. Hypernatremia
 Growth hormone acts on which of the following cells to cause
long bone growth?
A. Chondrocytes
B. Osteocytes
C. Intracellular matrix
D. Lymphocytes
Slide 1:
The anterior pituitary is often referred to as the master gland because together with the
hypothalamus it orchestrates the complex regulatory functions of many other endocrine
glands.

Slide 2:
The pituitary gland, also called the hypophysis, is a small gland about 1 cm in diameter and
0.5-1 g in weight. It lies in the sella turcica which is a bony cavity at the base of the brain,
and is connected to the hypothalamus by the pituitary or hypophyseal stalk. Physiologically
it is divisible into 2 distinct parts which have different embryologic origins: the anterior
pituitary (adenohypophysis) is made up of cells of epithelioid nature and the posterior
pituitary (neurohypophysis) is made up of glial type cells. You see here the pars intermedia
and this is almost absent in human beings.

Slide 3:
Embryologically the 2 portions of the pituitary originate from different sources: the anterior
pituitary originates from Rathke’s pouch which is an embryonic invagination of the
pharyngeal epithelium which explains the epithelioid nature of its cells. Whereas the
posterior pituitary originates from a neural tissue outgrowth from the hypothalamus which
explains the presence of large numbers of glial type cells in this gland.

Slide 4:
-6 important peptide hormones are secreted by anterior pituitary and 2 peptide hormones
are secreted by posterior pituitary. The hormones of the anterior pit that are shown in this
slide play major roles in the control of metabolic functions throughout the body. The
anterior pit gland contains several different cell types that synthesize and secrete
hormones, usually there is one cell type for each major hormone formed in the anterior pit.
-With special stains attached to high affinity antibodies that bind with the distinctive
hormones, at least 5 cell types can be differentiated. We have the somatotropes responsible
for growth hormone secretion, lactotropes responsible for prolactin, corticotropes
responsible for adenocorticotropinhormone (ACTH) secretion, the gonadotropes secrete the
glycoprotein hormones LH and FSH, and the thyrotropes secrete TSH. There are 3
glycoprotein hormones, 2 gonadotropic hormones and 1 TSH hormone, these have the
same alpha subunit but are distinguished by their beta subunit. About 30-40% of anterior pit
cells are somatotropes, and about 20% are corticotropes, each of the other cell types
accounts for only 3-5% of the total nevertheless they secrete powerful hormones for
controlling thyroid function, sexual function, and milk secretion by the breasts.
-The somatotropes stain strongly with acid dyes and are therefore called acidophiles, thus
pituitary tumors that secrete large quantities of GH are called acidophilic tumors.

Slide 5:
There are 2 peptides: ADH and oxytocin. The ADH is synthesized in the supraoptic nuclei
whereas oxytocin is synthesized in the paraventricular nuclei and these are the
magnocellular neurons where the posterior pit hormones are synthesized and then
transported in the axoplasm of nerve fibers from the hypothalamus to the posterior pit. The
synthesis of the peptide hormones does not occur in the posterior pit it occurs in the
hypothalamus, so the posterior pit gland constitutes only a storage site for these peptide
hormones and we are going to see at the end of the chapter the pathophysiologic
significance of this.

Slide 6:
-Growth hormone promotes the growth of the entire body by affecting protein formation,
cell multiplication and differentiation, stimulates the secretion of IGF-1, stimulates lipolysis
and inhibits the actions of insulin on carbohydrate and lipid metabolism.
-Adrenocorticotropic hormone/corticotropin controls the secretion of some of the
adrenocortical hormones which affect the metabolism of glucose, proteins and fats. ACTH
also maintains the size of the zona fasciculata and zona reticularis cell layers.
-Thyroid stimulating hormone or thyrotropin controls the rate of secretion of T3 and T4 by
the thyroid gland and these hormones control the rates of most intracellular chemical
reactions in the body and it’s also a growth factor for the follicular cells so it maintains the
size of the follicular cells.
-Prolactin promotes the mammary gland development and milk production.
-We have two separate gonadotropic hormones FSH and LH controlling the growth of the
ovaries and testes as well as their hormonal and their reproductive activities.

Slide 7:
-The hypothalamus receives signals from many sources in the nervous system, thus when a
person is exposed to pain a portion of the pain signal is transmitted into the hypothalamus,
even the [] of nutrients, electrolytes, water and various hormones in the blood excite or
inhibit various portions of the hypothalamus, thus the hypothalamus is a collecting center
for info concerning the internal well-being of the body and much of this info is used to
control the secretions of the many globally important pituitary hormones.
-Hypothalamic releasing hormones and hypothalamic inhibitory hormones are conducted to
the anterior pit through minute blood vessels called hypothalamic hypophyseal portal
vessels, and in the anterior pit these releasing and inhibitory hormones act on glandular
cells to control their secretion. Whenever we talk about hypothalamic releasing factors
these are stimulatory to pit hormone secretions, on the other hand hypothalamic inhibitory
hormones inhibit pit hormone secretion.
-The pit gland is under tonic stimulation by the hypothalamic factors except for prolactin
secretion from the anterior pit which is under tonic inhibition. If there is removal of the pit
gland and this pit gland is transplanted to some other part of the body so it is removed from
its normal position beneath the hypothalamus, or when there is pit stalk section the rates of
the anterior pit hormone secretion will decrease to very low levels EXCEPT for prolactin. A
hallmark of hypopituitarism is a decrease in anterior pit hormone secretion with an increase
in prolactin. In contrast, secretion from the posterior pit is controlled by nerve signals that
originate in the hypothalamus and terminate in posterior pit.
-Another level of regulatory control of pit secretion is the feedback control by circulating
hormones, a third type is paracrine and autocrine secretions of the pit itself.

Slide 8:
The neurons in the hypothalamus that secrete the releasing and inhibitory factors, these
neurohormones are transported by the axons to be released from the axon terminals into
the rich funnel shaped plexus of capillaries at the median eminence. And then these
hormones are transported to anterior pit cells to be released from the pit capillary sinuses.
The median eminence is characterized by an extremely rich blood supply and this arises
from the superior hypophyseal arteries and this is external to the blood brain barrier.

Slide 9:
-The superior hypophyseal artery sends off many small branches that form capillary loops
which extend into long and short hypophyseal portal vessels, form anastomoses and drain
into the sinusoids that become the pit portal veins and enter the vascular pool of the
pituitary.
-This hypothalamic hypophyseal portal circulation with the release of hypothalamic factors
from the fenestrated sinusoids at the anterior pit cells allows for the tight control of the
hypothalamus over pit gland secretion.
-Systemic blood supply is maintained by the inferior hypophyseal artery which supplies
predominantly the posterior pituitary and then the posterior pit hormones which are
derived from direct neural extensions are released into circulating blood to exert their
effects in the body.

Slide 10
Shown here talking about the same thing with the well-developed plexus of capillaries that
result in increase of vascular surface area and the vessel being fenestrated allowing the
diffusion of hypothalamic factor to their site of action in the anterior pituitary without
systemic significant dilution. This will allow the pituitary cell to be sensitively regulated by
timed hypothalamic hormone secretion. So talking about the same thing in the previous 2
slides.
In addition to what we said, that this slide shows the large bodied neuro, magnocellular
neuron up and u can see that they are responsible for the secretion of AVP vasopressin and
oxytocin. In contrast u see the small bodied neuron and these are responsible for releasing
the hypothalamic factor and inhibitory factor. There is not only anterograde blood flow but
also retrograde blood flow towards the median eminence and this is important to facilitate
the bidirectional functional hypothalamic pituitary interaction and one that accounts for
feedback regulation or control.

Slide 11
This slide shows the different hypothalamic hormones or factors, the stimulatory hormones
or factors are the TRH > stimulates the synthesis and release of TSH.
The CRH stimulates the synthesis and secretion of ACTH or corticotropin or
adrenocorticotropin.
GHRH is stimulatory for GH
And the GnRH is stimulatory for gonadotropin secretion, FSH and LH.
The inhibitory hormones are the GHIH and called somatostatin that inhibits GH secretion
and PIH inhibits prolactin secretion which is dopamine.
We already mentioned that for most of the anterior pituitary hormones, it is the releasing
hormones, the stimulatory hormones that are imp, only for PRL, the hypothalamic inhibitory
hormone exerts more control.

Slide 12
In this slide and the next one u see the different hypothalamic pituitary target organ axis
with the trophic hormones in each axis producing its effects on the body. The target organ
or gland is the last site in the axis that is being targeted knowing the GH does not work
through 1 target organ as seen in the intro chapter.
1st axis: hypothalamic pituitary adrenal axis.
Starting with CRH that is the hypothalamic peptide, that is 41 a.a that stimulates
corticotrophs cells to produce ACTH.
ACTH will act on adrenal cortex to increase cortisol production which then feedbacks at
level of hypothalamus to turn off CRH secretion and at the level of corticotroph cell to turn
off ACTH secretion.
Ultimately, after the cortisol produced the effect on body regarding homeostasis.
The 2nd axis is the thyroid axis.
Starting with 3 a.a peptide TRH secreted by the hypothalamus and increases the TSH
production from the thyrotroph cells in the pituitary. The TSH will increase thyroxin and
triiodothyronine production from thyroid gland. These will produce effect on body
regarding thermogenesis and protein synthesis and when there is excess level, feedback at
level of the TRH to turn it off and at level of pituitary to turn off TSH secretion.
Somatostatin is a hormone from hypothalamus that inhibits TSH secretion.
The gonadal axis starts with GnRH (10a.a) increase gonadotropic secretion of FSH and LH
and acts on sex organs to increase sex steroids; estradiol progesterone, testosterone and
inhibin and these affect ovulation and spermatogenesis, these steroids feedback at level of
hypothalamus to turn off GnRH secretion and at level of pituitary to turn off gonadotropin
secretion.

Slide 13
GH axis. Its on a dual control with a stimulatory effect from GHRH which is a 44a.a the
hypothalamic hormone and inhibitory control by somatostatin which is 14a.a. the GH acts
on the liver to produce IGF-1 or insulin growth factor 1 which feedback on hypothalamus to
turn off GHRH and on the level of the somatotroph cell on pituitary to turn off GH secretion.
There is also feedback control from GH itself on the somatotroph cell . some kind of
autocrine control and GH will stimulate somatostatin release from hypothalamus (another
kind of inhibition for GH secretion).
So IGF-1 will exert its action on the cartilage chondrocytes.
The last axis prolactin, the Prolactin produced from pituitary lactotrophs is under inhibition
of dopamine.
PRL is important for mammary gland development and lactation post-delivery.
The PRL itself is stimulated by many factors, the VIP, TRH and GnRH and also estrogen will
stimulate PRL release and also suckling during pregnancy; but the main controller of PRL
secretion from pituitary is dopamine which is inhibitory.

Slide14
All the major anterior pituitary hormones except for GH exert their principal effects by
stimulating target glands including thyroid glands, adrenal cortex ovaries testicles and
mammary glands so the function of each of the hormones is so concerned with the
functions of their respective target glands except for GH discussed in other chapters.
GH in contrast does not function through a target gland but function directly on all or
almost all tissue of body that are capable of growing. It promotes increase in sizes and
increase in mitosis and development of greater number of cells and different types of cells
such as bone growth cells and early muscle cells.
The somatotropic hormones or somatotropin growth hormone is a single chain polypeptide
with 191 a.a and mw 22 KDa.

Slide15
The experiment illustrates the GH effect on growth.
U can see the typical weight charts of 2 littermate rats one of which received daily injections
of GH hormone and the other did not receive.
The y-axis the body weight and the x-axis the age of the rate.
the blue curve is a control rat which did not receive GH.
U have gradual increase in body weight and this will reach a plateau after 200 days of life in
comparison, the red curves illustrates the effect of GH injection on body weight. There is
marked enhancement of growth in the injected hormone starting in the early days of life
and even after the 2 rats reach adulthood.
In the early stages of development, all organs of the treated rats increased proportionately
in size.
After adulthood was reached, most of the bones stopped lengthening but many soft tissues
continue to grow and this results from the fact that once the epiphysis of the long bone
united with the shaft, further lengthening of the bones cannot occur. Even though most
other tissues of the body can continue to grow throughout life.

Slide 16
In addition to its growth promoting effect, the GH has important metabolic effect on the
body. Most importantly its effect on enhancing protein deposition in the tissues. Although
the exact mechanism by which GH increases protein deposition are unknown, a series of
different effects all of which could lead to enhanced protein deposition.
1st, GH enhances the a.a transport through the cell membrane to the interior of the cell this
increase the a.a concentrations in the cell. This control of a.a transport is similar to the
effect of insulin In controlling glucose transport in the membrane.
Now even when the a.a concentration are not increasing in the cell, GH still increases RNA
translation causing protein to be synthesized in greater amounts by ribosomes in the
cytoplasm and over more prolonged periods, 24 to 48 hours, GH also stimulates the
transcription of DNA in nucleus causing the formation of increased quantities of RNA.
In addition to the increase of protein synthesis, there is a decrease in the breakdown of cell
protein.
So in summary, GH enhances almost all aspects of a.a uptake and protein synthesis by cells
while in the same time reducing the breakdown of protein.
On another hand, its effect on fat metabolism are catabolic. GH has a special effect on
releasing the fatty acids from the adipose tissue by activating the hormone sensitive triacyl
glycerol lipase in the adipocytes with hydrolysis of already stored triglycerides and the
release of free fatty acids and therefore increasing the concentration of fatty acids in the
body fluids.
In addition, GH enhances the conversion of fatty acids to acetyl-CoA used for energy by
most cells of the body and then its conversion to acetoacetic acid in the liver which is one of
the ketone bodies leading to a state of ketosis when GH levels are high. This is why GH has
been termed the ketogenic hormone. Therefore, under the influence of GH, fat is used for
energy in preference to the use of carbohydrates.
The net effect of GH by enhancing protein deposition on one hand and increasing lipolysis
on another hand is increase in lean body mass. This is why GH is termed anabolic hormone
and used illegally by athletes to increase body mass but that doesn’t mean to increase
physical performance and can cause unhealthy pathologic state similar to acromegaly where
we have increase GH secretion from a tumor.

Slide 17
Shows the effect of GH on carbohydrate metabolism. It has multiple effects that influences
carbohydrate metabolism including decreased glucose uptake in tissues such as skeletal m
and fat, increase glucose production by liver i.e gluconeogenesis and increased insulin
secretion. Each of these effects results from GH insulin resistance which attenuates insulin’s
action to stimulate the uptake and utilization of glucose in skeletal m and adipose tissue and
to inhibit gluconeogenesis. this leads to increase the blood glucose concentration and a
compensatory increase in insulin secretion. For these reasons, GH effects are called
diabetogenic and excess secretion of GH can cause metabolic disturbances similar to those
found in type 2 diabetes who are also resistant to the metabolic effects of insulin., now the
mechanism by which GH causes insulin resistance is unknown could be impairment of
insulin action due to increase in fatty acid levels in the blood.

Slide18
Although GH stimulates increase deposition of protein and increase growth in almost all
tissues of body, it’s obvious effect is to increase bone growth the skeletal frame. The 2
mechanisms of bone growth are:
1st in response to GH stimulation, the long bones grow in length at epiphyseal cartilages
where the epiphysis at the end of the bone are separated from the shaft. This growth first
causes deposition of new cartilages followed by its conversion into new bones thus
elongating the shaft and pushing the epiphysis further and further apart. At the same time
the epiphyseal cartilage itself is progressively used up so by late adolescent, no additional
epiphyseal cartilage remains to provide for further long bone growth, at this time bony
fusion occurs between shaft and epiphyses with no further lengthening of bone can occur
and this is when adolescent reaches final adult height.
2nd under GH effect there is stimulation of osteoblastic bone formation. The osteoblast in
the bone periosteum and in some bone cavities deposit new bone on the surfaces of older
bone. Simultaneously the osteoclasts in the bone remove old bone. When the rate of
deposition is greater than that of resorption the thickness of the bone increases and the
bone can continue to be thicker throughout life under the influence of GH and this is true
for membranous bones i.e skull and jaw bones. The jaw bones can be stimulated to grow
even after adolescence causing forward protrusions of the chin and lower teeth and also
bones of skull can grow in thickness and give rise to bony protrusion over the eyes.
In addition, hands and feet bones can continue to grow after adolescent with increase in
ring and shoe size.
How does GH produce its effects on growth? It has been realized that when GH is supplied
directly to cartilage chondrocytes cultured outside the body, proliferation or enlargement of
chondrocyte fails to occur.
Yet GH inject into intact animal causes proliferation and growth of the same cell.
GH causes the liver and to a much less extent other tissues to form several small proteins
called somatomedins that have potent effect of increasing all aspects of bone growth.
Somatomedins were found to be identical to 2 peptides with a primary structure much like
that of proinsulin with their effects on growth being similar to insulin effect o growth.
Therefore, the somatomedins are called IGF. Insulin like growth factors.
At least 4 are isolated and the most imp is somatomedin c also called insulin like growth
facto 1 or igf1. Its concentration in the plasma closely follows the rate of GH secretion so
most of the GH effects or growth effects of GH result from somatomedin c rather than from
direct effect of GH on the bones and other peripheral tissues.

Slide19
For normal skeletal maturation and optimal growth and development, several factors need
to be satisfied. The Growth plate is dependent on .., reading the 1st sentence.
For example, permanent hypogonadism that is permanent deficiency of testosterone in
males or estrogen in females results in delayed skeletal maturation, a prolonged period of
growth and tall stature with long legs and arms and this due to unfused epiphyses because
of low levels of sex steroids. Also thyroid hormones are important for optimal growth.
If a child has congenital hypothyroidism and is inadequately treated with thyroid hormones
replacement, the child will end up with short stature.
Reading the 2nd sentence, if there is malnutrition there is impairment of chondrocyte
activity with decrease of IGF1 levels.
Also there is necessity of insulin and carbohydrates for growth promoting actions of GH.
GH fails to cause growth in animals that lack in pancreas. It also fails to cause growth if
carbohydrates are excluded from the diet. This shows that adequate insulin activity and
adequate availability of carbohydrate are necessary for GH to be effective., part of this
requirement for carbohydrates and insulin is to provide the energy needed for the
metabolism of growth, but there are other effects as well especially important is the
insulin’s ability to enhance transport of some a.a into cells in the same way that it stimulates
glucose transport. And we know that also GH increases transport of a.a through the cell
membranes but maybe another set of a.a than those stimulated by insulin.
So in this way, both GH and insulin work synergistically to increase protein deposition and to
promote growth.

Slide20
It shows the pulsatile secretion of GH.
On the y-axis GH concentration in ng/ml and on x-axis the timing over 24hrs.
As u can see the GH secretion occurs in secrete but irregular pulses. Between the pulses,
circulating GH decreases to undetectable levels with the current assays?? The amplitude of
the secretory pulses is maximum with strenuous exercise and at night shortly after the
onset of deep sleep. Because of this episodic release random measurements of GH are of
little value, the diagnosis of GH deficiency and GH excess and in order to diagnose GH
deficiency, provocation tests are required.
GH attaches only weekly to the plasma proteins in the blood and is therefore released from
the blood into the tissues rapidly having a half-life in the blood of less than 20 mns vs
somatomedin c or igf1 which attaches strongly to a carrier protein in the blood that like igf1
is produced in response to GH. As a result, igf1 is released only slowly from the blood to the
tissues with a ½ life of about 24 hours and this greatly prolongs the growth promoting effect
of the burst of GH secretion.
Slide 21
Regulatory factors in GH secretion. 2 main factors: GHRH which is stimulatory for GH
secretion and somatostatin which is 14a.a which is inhibitory. This inhibitory effect on GH
release ahs set the basis for the treatment of GH excess syndromes with somatostatin
analogues. Now for many years it was believed that GH was secreted primarily at period of
growth and disappears from the blood in periods of adolescence. This has proved to be
untrue, after adolescence, secretion slowly decreases with aging finally falling to about 25%
of the adolescent level and very old age. And we know that GH secretion is pulsatile,
increasing and decreasing. The precise mechanism that controls the secretion of GH is not
fully understood but there are other factors than GHRH and somatostatin that are related to
a person’s state of nutrition and stress that also known to inhibit or stimulate the secretion
of GH.

Slide 22
This slide is busy and shows the GH-IGF axis.
U have the factors that stimulate GH secretion on the left and those that inhibit GH
secretion on the right.
In the middle, u have the hypothalamic factors starting with the GHRH stimulating GH
secretion from the pituitary gland. Then the GH will act on the liver to increase IGF1
production form the liver. Growth promoting effects of GH working through IGF1 in
promoting bone and muscle growth and other somatic effects. On the other hand, u can
find IGF 1 inhibition is found in malnutrition, in malnutrition u have low IGF1 levels and in
acute/chronic illness this can decrease IGF1 and GH receptor deficiency of course.
U can see that GH mediates its metabolic effects on fat and carbohydrates and protein
metabolism directly. Now the stimulatory effect deep sleep is a physiological stimulator of
GH secretion. Fasting and protein deficiency so when u have starvation or fasting, protein
deficiency is a potent stimulator for GH secretion. Exercise seen in the previous slide also
stimulates GH secretion and this is the basis that u can use for GH deficiency testing i.e
when a child is suspected to have GH deficiency, u tell him to go up and down the stairs and
then u test GH levels. In a child with GH deficiency, the GH level is not going to increase, but
in normal children u will have increase in GH secretion. Because exercise is a stimulator for
GH secretion.
Sex steroids we have seen examples of that.
Stress itself increases GH.
Acute decrease in glucose levels also increases GH and this is also another provocative test
used for GH deficiency testing and diagnosis so u give insulin to the child and this insulin will
lower acutely the glucose concentration in the blood and once the glucose level is below
45mg/dl there is a potent stimulation of GH secretion. So children with GH deficiency will
not increase their GH secretion after the hypoglycemia testing or the insulin tolerance test.
Decrease in free fatty acids increases GH secretion.
Increase in blood amino acids like arginine will increase GH secretion.
GHRH is also stimulatory and ghrelin is a peptide secreted by stomach upon meal ingestion
also stimulates GH secretion.
On the right there are suppressive factors. Obesity itself suppresses GH.
Beta adrenergic stimulation inhibits GH secretion. So on the left alpha adrenergic
stimulation and on the right beta adrenergic factors or stimulation will inhibit GH secretion.
Hyperglycemia in state whereby there is insulin deficiency and inadequate insulin dosing in
type 1 diabetic patients this also suppresses GH secretion. Type 1 diabetic children who are
mistreated or inadequately treated with insulin end up having short stature. Excess
glucocorticoids either from exogenous sources like asthmatic children, or from endogenous
secretion from tumors, excess cortisol also suppresses GH and can affect growth. Of course
aging is a physiological normal situation whereby there is decrease in GH secretion.
Hypothyroidism we mentioned it.
IGF 1 if inhibitory to GH secretion this by feedback regulation.
Increased in FFA , exogenous GH intake and somatostatin.

Slide 23
This slide shows the effect of extreme protein deficiency on the plasma concentration of GH
in children. y–axis is plasma growth hormone in ng/ml and on the x-axis the nutrition status
of the children.
In the 1st column u have very high levels of GH to start with tat 40ng/ml found in children
with extreme protein deficiency during protein malnutrition condition called kwashiorkor.
Then the children are given carbohydrate meal for 3 days. The GH levels stay up elevated at
40ng/ml in the 3rd and 4th column u can see the levels after treatment with protein
supplements for 3 and 25 days with a concomitant increase in the hormone. And these
results demonstrate that under severe conditions of severe malnutrition, adequate calories
alone are not sufficient to correct the excess production of GH. Protein deficiency must be
corrected before GH concentration will return to normal. We have seen that hypoglycemia
increase GH secretion and this is under acute condition. So under acute condition, the
hypoglycemia is a far more potent stimulator of GH stimulation than is an acute decrease in
protein intake. Conversely, in chronic condition, GH secretion seems to correlate more with
the degree of cellular protein depletion than with the degree of glucose in sufficiency.

Slide26
In this slide we see the synthesis and release of GHRH and somatostatin. First the
neurosecretory cells in arcuate nucleus secrete GHRH 44 a.a that reaches the somatotrophs
cells via the hypophyseal portal blood supply. Then GHRH interacts with its G-protein
coupled receptor in the somatotroph cell that is adenyl cyclase activation, cAMP generation
with PKA activation to lead in an increase in intracellular Ca concentration in the
somatotroph cell with increase in GH synthesis and release.
On the other hand, u see cell in periventricular region releasing somatostatin, a hormone
that inhibits GH secretion. The somatostatin interacts with a G-protein coupled protein
receptor however interacting with a G inhibitory subunit. Alpha subunit and there is a
decrease in cAMP generation and decrease in GH release.

Slide27
This slide shows the GH and IGF1 negative feedback loops.
1st the GH stimulates the secretion of IGF1 from peripheral target tissue then IGF1 inhibits
GH release directly by suppressing the somatotroph cells and indirectly by 2 ways.
It inhibits GHRH release from the arcuate nucleus from hypothalamus and stimulates the
secretion of somatostatin from the periventricular nuclei and these are long loops of
feedback inhibition. GH on another hand inhibits its own secretion via short loops of –
feedback on the somatotroph and this is a kid of autocrine control.
 Slide 28
In the next few slides we’ll talk about abnormalities in GH secretion starting with GH
deficiency which could result from isolated GH deficiency or it can be associated with other
pituitary hormones deficiency in the context for example of pituitary tumors compressing
the pituitary stalk and preventing the hypothalamic hormones from increase pituitary
hormone secretion; any way GH deficiency is associated with short stature , or dwarfism.

Slide29
In GH deficiency, there is short stature.. reading.
So in general all the physical parts of the body development in an appropriate proportion to
one another but the rate of development is decreased. so a child who has reached the age
of 10 years may have the bodily development of a child 4-5 years. The same person of age
20 years may have the bodily development of a child ages 7-10 years.

Slide30
This slide shows the growth curve of normally growing children between the 3 rd and 97th
percentile. U also have child who is small but growing parallel to centile. This child has
probably a constitutional delay in growth which is not a pathological condition. But looking
down on the curve, this is a child with GH deficiency and u can see the severe delay in
growth. The child has 10 years of chronological age but the bodily development of a child
aged 4 to 5 years. These children with GH deficiency can be treated with GH injections if a
diagnosis is made promptly they can reach optimal adult height similar to parental height.
Now those children who have associated pituitary deficiencies need to be treated with
other replacement hormones like thyroid hormones, cortisol, sex steroids to be able to have
normal sexual development as well as optimal growth dev. For children who lack GH
receptors, cannot be treated with GH injections, but need treatment with recombinant
synthetic IGF1 these are the cases of children of Africa typically these children and patient s
have very low levels of igf1 and very elevated levels of GH.

Slide 31
We’re going to talk in next few slides about GH excess syndromes.
If excess GH occurs before epiphyseal closure in the adolescent the child will end up being a
giant and this is called gigantism.
If the excess GH from the tumor come after epiphyseal closure i.e in adults, it will produce
acromegaly. The long bones stop to grow after epiphyseal closure but however the bones
can grow thickness and soft tissues can continue to grow.
Anecdotally speaking, severe GH deficiency and pathologic increase in GH secretion are
exemplified by john desump(? Dk shu esmo) who ended up having 100cm of final height and
alton the giant with 2.72m of height.

Slide 32
This is a 22 year old man with gigantism and this is due to excess GH secretion before
epiphyseal closure. He is standing next to his twin brother. U can see the final height much
bigger than that of his brother with enlarged hands and feets.

Slide 33
The clinical features of acromegaly.
Acromegaly stands for.. reading the 1st sentence fo2.
W then aam bte2ra li aal chmel then li aal yamin.
Acromegaly can occur at any level.
Galactorrhea can be due to GH effect cz GH and PRL have homology of a.a sequences. So GH
interacts with PRL receptors in mammary glands and can cause galactorrhea or milk
secretion. however, the PRL cannot interfere with GH receptors.

Slide 34
This is one of my patients who continues to have active acromegaly bcz of incomplete
removal of GH secreting tumor.
U can see the frontal bossing the widening of nasal bridge, the protrusion of the lower jaw
and the facial perspiration.
On the right u can see the sausage like fingers. This is a patient who is a carpenter and
because of the deformities of GH excess on articulations and soft tissue growth he was
unable to pursue his career and was unemployed at the age of 30 years with active
acromegaly now for more than 25 years. ( haram  )

Slide 35
Acromegalic patients develop dental malocclusion, dental carries due to protrusion of the
lower jaw and this is seen here on my patient.

Slide 36
Another patient of mine who was cured from her acromegaly but who died prematurely
from cardiovascular complications of GH excess. (haram  )

Slide 37
We have already mentioned the posterior pituitary hormones and these are the ADH and
the oxytocin. The post pituitary gland is also called neurohypophysis and is composed
mainly of glial like cells called pituicytes. They do not secrete hormones they act as
supporting structures for large numbers of terminal fibers and terminal nerve endings from
the nerve tract that originate in the supraoptic and paraventricular nuclei of the hypoth.
These tracts pass to the neurohypophysis through the pituitary stalk. The nerve endings are
bulbous that contain many secretory granules and these endings lie on the surfaces of
capillaries where they secrete 2 posterior pituitary hormones, the ADH called vasopressin
and oxytocin. These 2 hormones are synthesized within the magnocellular neurons of the
hypothalamus.

Slide 38
These hormones then are transported in combination with carrier proteins called
neurophysins down to the nerve endings in the post pituitary. When the nerve impulses are
transmitted downward along the fibers from the hypothalamic nuclei, the hormone is
released from the secretory granule in the nerve ending by exocytosis and is absorbed into
the adjacent capillaries. The hormone separates from its associative neurophysins which has
no known function after leaving the nerve terminal. If the pituitary stalk is cut above the
pituitary gland but the entire hypothalamus is left intact, the post pituitary hormones
continue to be secreted normally after a transient decrease for a few days.
So in this case, anterior pituitary deficiency will occur with no associated post pituitary
hormone deficiency; and this is due to the fact that these post pituitary hormones are
secreted by the cut ends of the fibers within the hypothalamus and not by the nerve
endings in the post pituitary. It is due to the fact that they are synthesized in the
hypothalamic nuclei. In case there is involvement of the hypothalamic synthesis, so injury to
hypothalamic neurons, then there will be a decrease in the ADH and oxytocin hormones.

Slide 39
These 2 hormones are almost identical, except that in Vasopressin, Phenylalanine and
Arginine replace Isoleucine and Leucine of the Oxytocin molecule.

Slide 40:
This slide is showing the physiologic roles of oxytocin.
It acts on the uterus and stimulates the frequency and the force of uterine contractions, and
this contributed by the increased sensitivity of the uterus due to a 30-fold increase in the
oxytocin receptors from early pregnancy to early labor.
Also it acts on the breast and helps in the milk let-down by stimulating contraction of the
alveolar myoepithelial cells. And this is triggered by the suckling reflex, which causes
pulsatile release of the oxytocin. This is a kind of positive feedback control that we
mentioned previously in the introductory chapter.

Slide 42:
So now we will start with the case discussions.
A 44-year-old woman presents to her gynecologist with complaints of not having had a
period for the last 8 months. She reports a negative pregnancy test at home. So this
important: whenever you have amenorrhea, or cessation of mences for more than 3
months, any patient who is in the reproductive age group needs to have pregnancy test.
Upon further questioning, she reports a daily headache, changes in vision, & a milky
discharge from the breast. So the daily headache and the changes in vision we mentioned
already the mechanical compression from a pituitary tumor; so we mentioned this when we
talked about acromegaly and excess GH excess state from GH secreting tumor. The milky
discharge is galactorrhea from the breast. She has no medical problems & is not taking any
medications. On examination, she is noted to have galactorrhea (so this is the milk ejection
or the milk release from the breast) & diminished perpheral vision bilaterally. The
remainder of her examination is normal. A pregnancy test is repeated & is negative. A
thyroid-stimulating hormone (TSH) level is drawn & is normal. Her prolactin level is
significantly elevated. After a thorough work-up is completed, she is found to have a
pituitary adenoma.
So most probably this patient has prolactin secreting tumor and this excess prolactin is
contributing to her presentation. Now the pregnancy test again is important whenever you
amenorrhea to rule out a pregnancy state. The TSH, why is it done, and we are going to
answer the questions now.
1- How does hyperprolactinemia cause amenorrhea?

So prolactin is important like we said for glandular mammary development, and it is

important for lactation post-delivery. However when you have excess prolactin secretion
from a tumor or from any other pathologic state, this prolactin will inhibit the GnRH
secretion from the hypothalamus and will turn off the gonadal axis. So in this case if you do
the levels of LH and FHS and estradiol, you are going to have them low.
2- Why would a physician need to check thyroid studies in patients with
hyperprolactinemia?

You remember we talked about that the main hypothalamic factor that controls prolactin
secretion is dopamine, which is inhibitory for prolactin secretion. On the other hand, I
mentioned already that there are factors that stimulate prolactin secretion, like GnRH,
estradiol, pregnancy state with high estrogen also stimulates prolactin; I mentioned also
TRH: TRH is another prolactin releasing factor. So whenever there is a decrease in T4 and T3
secretion there will be increase in TRH by feedback control, and this TRH can increase
prolactin secretion without having a tumor secreting prolactin. So on the basis of high TRH
the prolactin will be increased and produce symptoms of amenorrhea. So when you correct
the hypothyroid state, the prolactin level goes back to normal. And this is why whenever
you get hyperprolactinemia you need to check thyroid function test.
3- Where are the posterior pituitary hormones synthesized?

We just reported that the pituitary hormones oxytocin and ADH are synthesized in
hypothalamic neurons, in the paraventricular and supraoptic nuclei of the hypothalamus.

Slide 43:
 A 45-year-old woman is noted to have fatigue & cold intolerance & is diagnosed with
hypothyroidism. Her physician suspects a pituitary etiology. Which of the following
laboratory findings is most consistent with this condition?

So hypothyroidism is associated with low thyroid hormone secretion from the thyroid gland,
most commonly related to a primary thyroid process, either granular destruction by
autoimmune process or by surgical removal of the thyroid gland, and we are going to see
this in the next chapter. So primary hypothyroidism will be associated with low free T4 and
an elevated TSH. For a pituitary etiology, there will be a low TSH and a low free T4, and in
this case the TRH from the hypothalamus will be elevated from feedback control. The
answer C here: elevated TSH and elevated thyroxine is wrong: this will hyperthyroidism due
to a central etiology. So the answer here is A.
 A 35-year-old woman experiences anterior pituitary hemorrhagic necrosis ( Sheehan
syndrome) after a postpartum hemorrhage. She feels light-headed, dizzy, & weak.
Which of the following hormones most likely is responsible for her symptoms?

The answer here is A: ACTH, because there will be low cortisol secretion from the adrenal
glands, and cortisol plays an important role in maintaining the blood pressure, it has a
permissive role for the other vasopressor agents to be effective. GnRH deficiency will
produce gonadal dysfunction and sexual dysfunction and this is not reported in the
presentation. Prolactin deficiency will produce inability to lactate post-delivery. GH
deficiency will produce a different state whereby there is metabolic syndrome with
increased in fat mass and decrease in muscle mass, so it will not produce dizziness or light-
headedness.
 A 25-year-old woman is undergoing ovulation induction for infertility. She is given an
injection of GnRH on Monday. Serum estradiol is low, & ovarian ultrasound reveals
 small follicles. What is the most likely explanation?
A. Ovarian failure

B. Pituitary failure
C. Need for pulsatile hormone
D. More time needed to see an effect
We know that there is pulsatile secretion of GnRH, between 60 to 90 min pulsations for the
GnRH to turn on the gonadal axis. So when GnRH is given as 1 injection, it is not able to
stimulate the ovaries and not used for fertility for that purpose. So pulsatile secretion is the
answer, and the pulsatile treatment should be given every 60-90 min to mimic the normal
pulsatility that is seen in normal menstruating women for normal ovulation induction.

Slide 44:
(Reads slide)
A. With what other pituitary hormones is growth hormone homologous?
So the question to that is prolactin; there is 22% analogy between the amino acid sequence
of prolactin and GH, and I have told you already that growth hormone interacts with
prolactin receptor in the mammary gland, and can account for the galactorrhea that is seen
in excess GH syndrome, but however the prolactin does not interact with the GH receptor
and is not associated with growth effects.
B. How does somatostatin inhibit growth hormone?
Somatostatin is secreted from the hypothalamus; it interacts with the somatotroph cells and
is interacting with α subunit that is inhibitory and there is decrease in adenylyl cyclase
activity, decrease in cAMP, and has decrease in [Ca2+] in the somatotroph cells with
decrease in the GH release. Now the symptoms reported by this 13-year-old boy are
symptoms of gigantism due to GH excess from a tumor, and because it is occurring before
epiphyseal closure, these children end up giants, so they end up with height much more
than the family height or the parental height, and this is due because there is stimulation of
the lengthening of the bones before bony fusion occurs. If GH excess occurs after epiphyseal
fusion, or bony fusion, then there will be acromegaly and the acromegalic features that we
already mentioned in the lecture.

Slide 45:
(Reads 1st question with answers)
Of course it is somatomedins, or specifically somatomedin C or IGF-1 (Insulin-like Growth
Factor 1), that is produced mainly by the liver under the effect of GH. Insulin, thyroid
hormone and estrogen play an important role in promoting optimal growth, but however,
they do not mediate GH effect on growth.
(Reads 2nd question with answers)
Now the posterior pituitary hormones are both ADH and oxytocin. We know that they are
synthesized in the hypothalamic neurons: the supraoptic nuclei and the paraventricular
nuclei, but however we need of course an injury that is in the hypothalamus to produce
such a deficiency, but here they are presenting that there is posterior pituitary hormone
deficiency, in the question. So the inability to lactate is mainly related to prolactin
deficiency; we know that prolactin is an anterior pituitary hormone, so this is not the
answer. Hypothyroidism: from pituitary etiology, also it is from TSH and this from anterior
pituitary. Hypoglycemia could occur from ACTH and GH deficiency, and this bot the case.
Hypernatremia is due to ADH, whereby there is diabetes insipidus with increased in free
water clearance; and if the patient is unable to drink there will be hypernatremia. So the
answer here is D.
(Reads 3rd question)
Typically, it acts on the chondrocytes, and it will stimulate chondrocyte proliferation and
then their conversion into bone. So cartilage chondrocyte is main target, not the osteocytes,
not the intracellular matrix, and not the lymphocytes.