Hypothalamus and Pituitary

Endocrinology part 3
Hypothalamus
o Integrates functions that maintain chemical and
temperature homeostasis
o Controls the release of hormones from the anterior and
posterior pituitary
o Neurosecretory cells of the hypothalamus produce
hormones
o Releasing hormones stimulate the anterior pituitary
(adenohypophysis) to secrete hormones.
o Inhibiting hormones prevent the anterior pituitary
from secreting hormones.
o Hormones of the hypothalamus are called
hypophysiotropic hormones.
o 2 other hormones oxytocin & ADH are not tropic
hormones
Hormone meaning Action
acronym
TRH Thyrotropin-releasing Releases TSH &
hormone prolactin
GnRH Gonadotropin- Releases LH & FSH
releasing hormone
CRH Corticotropin-releasing Releases ACTH
hormone
GHRH Growth hormone- Releases GH
releasing hormone
PRH Prolactin-releasing
hormone
Somatostatin Inhibits GH, TSH
release
Dopamine Inhibits prolactin
release

• Ultra short
Hypothalamus Releasing Hormones: Secretion
o Hypothalamus to pituitary
o Is influenced by emotions • Short
o Can be influenced by the metabolic state of the o Pituitary to adrenal
individual • Long
o is delivered to the anterior pituitary via the o Hypothalamus to adrenal gland
hypothalamic-hypophyseal portal system PITUITARY GLAND
o Usually initiates a three-hormone sequence o To spit mucus
o Hypophysis
o Size just like of grape
o Prtoected by the sphenoid bone
o Detected between 9th and 7th week of gestation
o “Master gland” : without pituitary there is:
* cessation of growth
* profound alterations in intermediary metabolism
* failure of gonadal, thyroidal, adrenal functions

Change of concept about pituitary

o Rather than a “master gland”, it is appropriately
recognized as transponder that translates neural
input into a hormonal product.
o
o
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 o
o Distinguishing features :
 feedback loops,
 pulsatile secretions,
 diurnal rhythms,
 environmental or external modification of
its performance
The Hypophyseal Portal System

Pituitary tumors
o Prolactin-secreting tumors= most common
o Nonfunctioning or null cell tumors
o Tumors secreting GH, gonadotropins, ACTH, TSH

Growth Hormone [GH]; Somatotropin:

o 1/3 of pituitary grade
o Protein
o Released in pulses
o Average interval of 2-3 hours
o Most reproducible is during the onset of
sleep
o Peak level at 2am to 4 am
o When children sleep for an hour the gH also
peaks
o Produced by somatotrophic cells or somatotrophs
o structurally related to prolactin and human placental
3 distinct parts: lactogen
o anterior pituitary- glandular tissue o Major effects are directed to growth of skeletal
[adenohypophysis] muscles and long bones
o Intermediate lobe [pars intermedialis] As a metabolic hormone,
 Poorly developed o GH is considered an amphibolic hormone because it
 Little functional capacity directly influences anabolic and catabolic processes:
 Confused as benign cystic enlargement
❖ Mobilizing fatty acids [lipolysis]
o Posterior pituitary- nervous tissue [ neurohypohysis]
❖ Decreases rate of glucose uptake and metabolism;
Neurohypophysis
promotes gluconeogenesis
o Posterior pituitary
❖ Increase amino acid uptake in cells
o Arising from diencephalon
❖ Antagonistic to insulin
o store and release 2 hormones that have effect on non-
endocrine glands
GH Mediates most of its growth-enhancing effects indirectly
adenohypophysis
via a family of growth-promoting proteins called insulin-like
• The largest portion of the gland
growth hormones (IGFs)
• Synthesizes various hormones in various specific cell
populations
What produce IGFs?
Adenohypophysis hormone
o Liver, skeletal muscle, bone tissue produce IGFs in
Can be classified as
response to GH.
o tropic ( actions are specific for another endocrine glands)
o direct effectors ( act directly on peripheral tissues) o Liver IGFs act as hormones; in other tissues IGFs act as
paracrines
o Biologic amplifier of GH levels
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IGFs stimulate actions required for growth: o Secretion of prolactin is also in 40% of patients
o Uptake of nutrients from blood and their incorporation
into proteins and DNA
o Formation of collagen and deposition of bone matrix

Modifiers of growth hormone secretion

STIMULATE SECRETION INHIBIT SECRETION

Sleep Glucose loading

Exercise Beta agonists (epinephrine)

Physiologic stress Alpha blockers (phentolamine)

Amino acids (arginine) Emotional/psychogenic stress

Hypoglycemia Nutritional deficiencies

Sex steroids Insulin deficiency

Alpha-agonists (eg. Thyroxine deficiency

Norepinephrine)

Beta-blockers (propranolol)

o Diffuse overgrowth of ends of long bones/spine can

result to debilitating form of arthritis
GH regulation of secretion o Sleep apnea is common
o Stimulated by GHRH (growth hormone releasing o Teeth gaps are observed
hormone) & “hunger hormone” or ghrelin (produced by o Acromegaly if not treated can result to early death.
the stomach) o It is a progressive disease that affects the whole
o Inhibited by GHIH (growth hormone inhibiting hormone); body.
also called somatostatin [SS] o Tumors are the common cause for the irregular and
o GHIH is also produced in GIT & pancreatic secretions excess GH secretion
GH testing o The procedure of choice for treatment of
o Measurement of IGF-1 [previously called acromegaly is Transsphenoidal adenomectomy
somatomedins] & IGFBP-3 o After surgery, focused radiation is used
o Oral glucose loading o Goal is to reduce GH secretion
 Patient is given oral glucose load  SS analogs
 GH is measured before giving the glucose, 1  Dopaminergic agonists
hour after the glucose and 120 minutes after  GH receptor antagonists
glucose
 Normal is undetectable GH Gigantism
 Acromegaly = GH will rise o Occurs before closure of epiphyseal bones
o Insulin-induced hypoglycemia o No history of tall people in the family
o Combined infusions of GHRH coupled with oral L-DOPA o Person grows abnormally tall often reaching 8-9 ft
 Gold standard with normal body proportions
 Widely used o Elevation of glucose
 3-5ng/mL increase indicates that patient is not o Some cases die due to elevation of blood sugar
GH deficient
GH pathology GH deficiency: Pituitary dwarfism
o acromegaly or gigantism ( excess) o in adults, as a result of structural or functional
Acromegaly occurs after epiphyseal plates close abnormalities of pituitary
o Characterized by overgrowth of bony areas like feet, o In children, this could be due to genetic or tumor
hands, feet, face such as craniopharyngiomas.
o Women most often affected Not all short stature have GH deficiency but on genetic
o Result of pituitary tumor defects:
o Complain of headache and vision problems o More common type is recessive mutation of GHRH
o Enlargement of skull gene
o Usual clothing size will no longer fit o Other causes: loss of GH gene & GH insensitivity
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 Physiologic effect of prolactin is lactation
GH deficiency: Adult symptoms Consequence of excess prolactin is hypogonadism
o Social withdrawal PROLACTIN PATHOLOGY
o Fatigue causes of prolactin increase: Tumors [prolactinomas]
o Loss of motivation o the most common type of functional pituitary tumor
o Osteoporosis o Prolactin is more than 150 ng/mL
o Alterations of body composition o Clinical presentation depends on:
 Age
Popular GH deficient test  If older nonreproductive, it is
o Combination infusions of GHRH and L-arginine overlooked as an exorable
o L-arginine coupled with oral L-DOPA consequence of ageing
o Interpretation: GH level rise above 3-5 ng/mL  Osteoporosis
(normal)  Gender
GH deficiency: treatment  Size of the tumor
o GH replacement [ costly]
o GH is also a performance enhancing drug

PROLACTIN-a protein
o Structure similar to GH and human placenta
lactogen
o Produced by prolactin cells or lactotrophs
o Females: Stimulates and maintains milk production
following childbirth
o Males: involved in testicular function
o Considered as stress hormone
o Classified as direct effector hormone
o Unique among anterior pituitary hormones
o Regulation is tonic inhibition
o Neural excitability in th ebrain
Prolactin regulation
Stimulated by Idiopathic galactorrhea
o TRH o Seen in women who have been pregnant several times
o Estrogen [ decrease level allows prolactin to induce and has no pathologic implication
lactation]
o stressors [exercise, seizures] Hyperprolactinemia tests
o Stimulation of breast o TSH and Free T4 or total thyroxine and T3 resin uptake
o PIF once believed to be an inhibitor  To eliminate primary hypothyroidism
 Dopamine is now the PIF  T4 and T3 can be factors that elevate prolactin
 The only neuroendocrine signal that inhibits o If tumor is suspected, tests of other pituitary function
prolactin (basal cortisol, LH, FSH, & gender specific gonadal
MEDICATIONS CAUSING HYPERPROLACTINEMIA steroid ( either estradiol or testosterone)
o Phenothiazines
o Butyrophenones Management of prolactinemia
o Metoclopramide o Dopamine agonists are most common treatment to
o Reserpine shrink tumor. Ex are: Bromocriptine mesylate or
o Tricyclic antidepressants cabergoline
o Alpha methyldopa o Side effect of Bromocriptine mesylate: orthostatic
hypotension, dizziness and nausea
o Antipsychotics
o Cabergoline has fewer adverse effects

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o Neurosurgery is not a primary mode of prolactinemia o Released by corticotropin release hormone (CRH) &
management. ADH
o External beam radiotherapy is reserved for high surgical o Regulated by hypothalamic-pituitary
risk patients with locally aggressive macroadenomas who o Affected by both internal & external factors:
are unable to tolerate dopamine agonists  fever,
 hypoglycemia,
Thyroid Stimulating Hormone [TSH]- glycoprotein  stressors
o Also called thyrotropin Gonadotropins-glycoproteins
o stimulates normal secretion of thyroid hormone & o Produced by Gonadotrophs
growth of thyroid gland o they are: Luteinizing hormone (LH) and Follicle-
stimulating Hormone (FSH)
Regulation of TSH o Gonadotropins regulate functions of gonads
o Released from thyrotropic cells or Thyrotropes
after TRF stimulation FSH function
o regulation by hypothalamus –pituitary o Females:
o Inhibited by GHIH or somatostatin [SS]  stimulates growth & development of ovarian
follicles,
 promotes secretion of estrogen by ovaries.
o Males:
 required for sperm production
LH function
In females:
o Works with FSH to cause egg-containing follicles to
mature
o Triggers ovulation and promotes synthesis of ovarian
hormones
In males:
o LH stimulates the interstitial cells of the testes to
produce testosterone
Gonadotropin regulation
o Gonadotropins are virtually absent in pre-pubertal age

Adrenocorticotropic hormone [ACTH]-peptide

o Also called corticotropin
o Secreted by corticotropic cells or Corticotropes
o It is split from a prohormone: pro-opiomelanocortin
(POMC)
o stimulates growth & secretion of adrenal cortex
Regulation of ACTH
o Follows a circadian rhythm
 Time of day

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Melanocyte-
stimulating H.
Adrenocorticotropic
MELANOCYTE STIMULATING HORMONE [ MSH]-peptide
o Precursor is proopiomelanocortin(POMC)
o also known as melanotropins or intermedins
o MSH stimulate the production and release
of melanin (a process referred to as melanogenesis)
by melanocytes in skin and hair
o MSH actions in the brain have effects
on appetite and sexual arousal
o May play a role in fat metabolism.
High MSH seen in:
o pregnancy
o Cushing's disease due to excess ACTH (MSH and ACTH
share the same precursor)
o acanthosis nigricans in the axilla
Hyperpigmentation occurs in
o Hands
o Nipple
o buccal mucosa
o new scars become hyperpigmented, whereas older
ones do not darken.
o Different levels of MSH are not the major cause of
racial variation in skin colour. However, in many red-
headed people, and other people who do not tan well,
there are variations in their hormone receptors,
causing them not respond to MSH in the blood.
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Endorphins=peptide
o any of a group of hormones secreted within the brain
and nervous system
o They activate the body's opiate receptors, causing an
analgesic effect.
o Inhibit pain perception.
o Effects mimicked by heroin and other opiate drugs.
ANTERIOR PITUITARY HORMONE CONTROL
Pulsatility
o All anterior pituitary hormones are secreted in a pulsatile
fashion.
o The pulse frequency of secretion is regulated by neural
modulation and is specific for each hypothalamic-
pituitary-end-organ unit.
Pulsatility: Three Levels of Integration
o Hypothalamic stimulation–from CNS
o Pituitary stimulation–from hypothalamic trophic Hs
o Endocrine gland stimulation–from pituitary trophic
Hs
Cyclicity
o The nervous system regulates the cyclic nature of
hormone through external signals
Zeitgeber (time giver)
o It is the process of entraining or synchronizing external
cues into the function of internal biologic clocks.
o Hormones are secreted in different amounts depending o Tumors compress or replace normal tissue or
of the time of the day [circadian or diurnal pattern] interrupting the flow of hypothalamic hormones by
destroying the pituitary stalk
HypoPituitarism causing tumors
o Parasellar tumors [meningiomas and gliomas]
o Metastatic tumors [ breast & lung]
o Hypothalamic tumors [craniopharyngiomas or
dysgerminomas]
Pituitary tumors
o Postpartum ischemic necrosis of the pituitary
following a complicated delivery (Sheehan’s
syndrome) typically presents as profound,
unresponsive shock or as failure to lactate in the
puerperium.
 6 weeks after childbirth
 Reproductive organs will return to non-
gestational state and function
Panhypopituitarism causing tumors
Most common are:
o Large, nonsecretory pituitary tumors
(Chromophobe adenomas or null cell carcinomas)
o Macroprolactinomas
Rarer type:
HYPOPITUITARISM
o Hemorrhage or pituitary tumor apoplexy
o Failure of pituitary or hypothalamus
Treatment
 Primary if pituitary defect
• Replacement therapy
 Receptors are insensitive to ACTH o Thyroxine
 Secondary if hypothalamus defect o Glucocorticoids
 Quality or quantity of CRF o Gender specific sex steroids
o PANHYPOHYPOPITUITARISM means all pituitary POSTERIOR PITUITARY
hormones are low or zero resulting to complete loss of o May be classified as nonendocrine
o Only storage and releasing organs
pituitary function
o Paraventricular and supraoptic
o MONOTROPIC HORMONE DEFICIENCY means a loss of
o Release ADH and oxytocin
only one pituitary hormone o Extension of the forebrain
Causes of hypopituitarism o Comprised of the endings of axons from cell bodies in
o Pituitary tumors the hypothalamus (supraoptic and paraventricular)
o Parapituitary/hypothalamic tumors o Axons pass from the hypothalamus to the posterior
o Trauma pituitary via the hypothalamohypophysial tract
o Posterior pituitary hormones are synthesized in the cell
o Radiation therapy/surgery
bodies of neurons in the supraoptic and paraventricular
o Infarction
nuclei and is closely linked to the production of
o Infection
neurophysin
o Infiltrative disease
o Immunologic
o Familial
o Idiopathic
Pituitary tumors
o Direct effects of tumors or the sequelae of treatment of
tumors are the most common causes of pituitary failure

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 o Hormones are stored in vesicles in the posterior
pituitary until release into the circulation
Oxytocin- a peptide
• Is synthesized as the precursor hormone: prepro-
oxyphysin
• Oxy: rapid; tocia: childbirth
• Is a cyclic nonapeptide, with disulfide bridge
connecting amino acid residues 1 & 6.
• Secretion is increased during labor resulting to
contraction of uterine smooth muscles
• Acts primarily on the mammary gland (“letdown
reflex”)and uterus
• increases contraction of smooth muscle of the vas
deferens thus may also act to facilitate sperm
transport (non-pregnancy state)
• oxytocin has been shown to have effects on
pituitary, renal, cardiac and immune function.
Pitocin
o Synthetic oxytocin which is used in obstetrics to
induce labor
o Oxytocin are linked to biosocial behaviors
 Mother infant bonding
 Child nurturing
AVP-arginine vasopressin- a peptide
o Is also known as antiduretic hormone (ADH-old name)
o Also a cyclic nonapeptide with an identical disulfide
bridge
o Differs from oxytocin by only 2 amino acids
o causes vasoconstriction, primarily of visceral blood
vessels, raising blood pressure. This response targets
ADH receptors found on vascular smooth muscle
Regulation of AVP Secretion
* Response to changes in blood pressure:
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- Blood pressure receptors in heart, aortic arch, and carotid
artery
- Increased blood pressure results in decreased AVP release
- decreased water reabsorption
- decreased blood volume, blood pressure
- Decreased blood pressure results in increased AVP
release
- increased water reabsorption
- increased blood volume, pressure
Vasopressin major action is to regulate renal free water
excretion
AVP and Water Balance
Action: increases permeability of the distal convoluted tubule
and collecting ducts to water
Result:
- increased water reabsorption from urine
- decreased urine volume
- decreased osmolality of interstitial fluids
- increased blood pressure
Regulation of AVP Secretion
Response to osmolality of interstitial fluid:
- Osmoreceptors in the brain detect changes in osmolality of
the interstitial fluid or blood.
- Increased osmolality results in increased [solutes] AVP
release
- increased water reabsorption
- decreased osmolality of fluids
- Decreased osmolality results in decreased ADH
release = NEGATIVE FEEDBACK!
- decreased water reabsorption
- increased osmolality of fluids
Regulation of AVP Secretion
AVP release is also inhibited by alcohol, caffeine (diuretics) –
dehydrating effect “dry mouth” or intense thirst morning
after → INCREASED urine output.
- decreased water reabsorption
- increased urinary volume
- potential for dehydration
Some drugs can also antagonize ADH release: diuretics used
to treat high bp, edema, or CHF.
Feedback mechanisms in the control of blood osmotic
pressure—the control of ADH.

Treatment of vasopressin excess

o Conivaptan and tolvaptan
( vasopressin V2 receptor antagonists)
POSTERIOR PITUITARY PATHOLOGY
DIABETES INSIPIDUS (DI)= Insufficient AVP
• impaired water reabsorption form the DCT and CT
• diabetes = overflow
• insipidus = tasteless
o increase urine volume 10 times [polyuria]
o intense thirst [ polydipsia]
o Hypothalamic DI
 Autoimmunity to vasopressin secreting
neurons
 Trauma
 Disease affecting pituitary stalk
 Various CNS and pituitary tumors
 30% of patients with DI
o Idiopathic DI
Tests
o Water deprivation
o Monitoring of fluid osmolality

ADH hypersecretion
o Can occur in children with meningitis or in adults
who have neurosurgery, hypothalamic injury, or
cancer [particularly lung cancer]
o Can also occur after general anesthesia
SIADH
o Syndrome of inappropriate ADH secretion
o Marked by retention of fluid, headache,
disorientation due to brain edema, weight gain &
decreased solute concentration in the blood
o Manage through: fluid restriction; monitoring of Na
levels