10/5- Disease of the Hypothalamus and Posterior Pituitary

Question 1

Basics of hypothalamic-pituitary circuit?

Answer 1

Hypothalamus stimulates pituitary, which stimulates endocrine glands to secrete substances to work on distal target organs

• Endocrine glands have negative inhibition back to pituitary and hypothalamus

Question 2

Important!

Answer 2

Know this

Question 3

What does GH stimulate downstream?

Answer 3

IGF-1

Question 4

What hormones are secreted by the anterior pituitary?

Answer 4

• GH
• TSH
• PRL
• LH, FSH
• ACTH

Question 5

What hormones are inhibited by SS?

Answer 5

• GH
• TSH

Question 6

What promotes/inhibits prolactin secretion?

Answer 6

Promotes: TRH

Inhibits: DA

Question 7

What hormones are promoted by TRH?

Answer 7

• TSH
• PRL

Question 8

Where is the hypothalamus in the brain?

Answer 8

Forms the floor of the 3rd ventricle

Question 9

Where is the pituitary?

Answer 9

Housed in the base of the skull in the sphenoid bone “sella turcica”

Question 10

Describe the development/embryological origin of the:

• Hypothalamus
• Posterior pituitary
• Anterior pituitary
• Intermediate lob or “pars intermedia”

Answer 10

Hypothalamus

• derived from the diencephalon (part of the forebrain)
• forms the floor of the third ventricle

Posterior pituitary or ”neurohypophysis”

• arises as an evagination of the ventral hypothalamus and third ventricle

Anterior pituitary or “adenohypophysis” or “pars anterior”

• develops from an evagination of ectoderm from the oropharynx called Rathke’s pouch

Intermediate lobe or “pars intermedia”

• cells eventually integrate into the anterior pituitary in humans

Question 11

Describe the neurohypophysis of the HT and posterior pituitary

Answer 11

• Neurons organized as paraventricular and supraoptic “nuclei” in the hypothalamus
• Axons travel down stalk to the posterior pituitary

Question 12

Describe the vascular connection of the hypothalamic-pituitary axis

Answer 12

Rich vascularization (0.8 ml/g/min)

Internal carotid arteries

• Superior hypophyseal artery
• capillary network in hypothalamus
• forms portal veins draining to the anterior pituitary
• second capillary network in anterior pituitary
• Middle and inferior hypophyseal arteries
• posterior pituitary
• pituitary stalk (infundibulum)

Venous channels:

• Cavernous sinus
• Petrosal sinuses
• Jugular vein

Question 13

What are some input signals received by the hypothalamus?

Answer 13

• Light (circadian rhythms)
• Olfactory
• Neural stimuli
• autonomic
• Molecular stimuli: cytokines, hormones, adipokines and GI peptides, glucose, osmoles

Question 14

How do the input molecules get through the BBB to the hypothalamus?

Answer 14

• Fenestrated capillaries
• Circumventricular organs

Question 15

The hypothalamus integrates the signals and sends outgoing messages (neural and hormonal) to regulate what?

Answer 15

• Appetite
• Circadian rhythms (sleep-wake cycles)
• Energy expenditure
• Temperature (fever)
• Endocrine systems (pituitary)
• Sodium and water balance
• Glucose disposal

Question 16

Describe the basics in the hypothalamic regulation of appetite?

Answer 16

• Leptin (produced by fat cells) stimulates arcuate nucleus, and medial hypothalamus to promote satiety (anorexigenic)
• Ghrelin (produced by stomach) stimulates lateral hypothalamus (feeding center) to promote hunger (orexigenic)

Question 17

If almost everyone has leptin, why is there an obesity epidemic?

Answer 17

The fatter we get, the more resistant our hypothalamus is to the signal to stop eating

Question 18

What is the acronym for coming up with a thorough differential diagnosis?

Answer 18

VINDICATE

V- vascular

I- infection/infiltrative/immune

N- neoplastic

D- drugs

I- idiopathic/iatrogenic

C- congenital

A- autoimmune

T- trauma/surgery

E- endocrine & metabolism/electrolytes

Question 19

What cranial nerves lie in the cavernous sinus that may be impinged upon by large masses in the pituitary (or hypothalamus?)

Answer 19

CNs 3, 4, V1, V2

Question 20

Dysregulation of hypothalamic function can cause what diseases in relation to its normal functions:

• Appetite
• Energy expenditure
• Circadian rhythms
• Temperature
• Endocrine systems
• Sodium/water balance
• Limbic system

Answer 20

• Appetite: hypothalamic obesity/anorexia
• Energy expenditure
• Circadian rhythms: disturbed sleep-wake signals
• Temperature: fever/hypothermia
• Endocrine systems: panhypopituitarism
• Sodium/water balance: diabetes isnpidus
• Limbic system: emotional liability, apathy, memory loss

Question 21

Dysfunctional levels of anterior pituitary hormones include what?

Answer 21

• Decreases in: GH, TSH, LH/FSH, ACTH
• Increases in prolactin

Question 22

What are the posterior pituitary hormones?

Answer 22

• Anti-diuretic hormone (ADH or vasopressin)
• Oxytocin

Question 23

What is Kallmann’s syndrome?

Answer 23

Isolated hypogonadotropic hypogonadism with anosmia (decreased sense of smell)

• X-linked KAL gene mutation (adhesion molecule) causes abnormal migration of GnRH and olfactory neurons during development
• Hypoplasia of the olfactory lobes
• No GnRH pulsatile secretion; no gonadotropins (LH/FSH)

Question 24

What is hypothalamic amenorrhea?

Answer 24

Disordered GnRH pulsatility

• Decreased LH surge during menstrual cycle
• Lack of follicle development and anovulation
• Decreased estrogen production (loss of bone mass)
• ?Leptin

Question 25

What is anorexia nervosa?

Answer 25

“A disordered hypothalamus without an identifiable analotomical hypothalamic defect” - Weight loss * Loss of fat decreases leptin levels and there is dysregulation of neuropeptides involved in appetite - Endocrine dysfunction * Hypothalamic Amenorrhea due to low gonadotropins (LH and FSH) * Low TSH, T3, and T4 * Normal to high GH but low IGF-1

Question 26

What is stored in the posterior pituitary? - Where are these substances made?

Answer 26

- The posterior pituitary stores and secretes oxytocin and arginine vasopressin (AVP) or anti-diuretic hormone (ADH) - Both hormones are synthesized in cell bodies located in the **paraventricular** neucleus (PVN) and the **supraoptic** nucleus (SON) as precursors pro-pressophysin and pro-oxyphysin

Question 27

Describe the production of posterior pituitary hormones and their modification as they travel

Answer 27

- Precursor molecules are cleaved - They travel with their respective neurophysins in granules down long axons through the infundibular stalk to the posterior pituitary - When neurons fire, the granules fuse with the axonal plasmalemma and ADH and oxytocin are released separately from the neurophysins

Question 28

How is the posterior pituitary visualized on CT? (CT or x-ray?)

Answer 28

Posterior pituitary shines brighter (without contrast) because of high numbers of granules

Question 29

What functions is oxytocin involved in?

Answer 29

"Labor, love, and lactation" **Parturation** - Initiation and completion of labor - Fergusson reflex (cervical dilation) - Contraction of uterine myometrium: delivery, and clamping down on vessels to prevent blood loss **Lactation** - Mechanoreceptors/touch receptors enhance milk flow by widening ducts and promoting emptying of milk from the alveoli

Question 30

What functions is Vasopressin (ADH) involved in (based on receptor subtypes)?

Answer 30

**V1-** vasoconstriction - Vascular sm - Liver - Platelets - CNS **V2**- increased production and action of aquaporin2 water channels in principal cells of renal tubule - Basolateral membrane of distal nephron **V3-** enhanced ACTH release

Question 31

What is the mechanism of AVP (ADH) action?

Answer 31

- G-protein coupled V2 receptors in the collecting duct of the nephron - Acts via cyclic AMP to increase permeability of the tubular cell to water - Increase in water-conduction channels (aquaporins) - Glomerular filtrate becomes highly concentrated (water resorbed; anti-diuresis) - Lack of ADH -\> impermeability and marked diuresis

Question 32

How is vasopressin release regulated? What stimulates it?

Answer 32

- Osmoreceptors in anterior hypothalamus stimulate vasopressin release when serum osmolality is high - Low pressure detected by baroreceptors in heart/major vessels can override the osmoreceptors to trigger release of vasopressin when BP is low

Question 33

ADH deficiency causes what disorder?

Answer 33

Diabetes insipidus

Question 34

What are the signs/symptoms of diabetes insipidus?

Answer 34

- Polydipsia - Polyuria (nocturia) - Large volume urine (\> 3 L/d) - Concentrated plasma (Na and Osm but normal if thirst intact) - Inappropriately dilute urine (max concentrating ability is 800-1200) * Complete DI: under 100 mOsm/kg * Partial DI: 100-800 (or 600ish)

Question 35

How is primary polydypsia distinct from diabetes insipidus?

Answer 35

Primary polydipsia (psychogenic) can look similar but plasma sodium or Osmoles are lower because of excess fluid intake (drinking drives urine output rather than urine output drives drinking)

Question 36

What are some causes of central DI?

Answer 36

Anything that threatens hypothalamus or posterior pituitary

Question 37

What is the "triphasic response"?

Answer 37

Classic changes in water balance following pituitary stalk damage - Posterior pituitary "shocked" and not releasing Vasopressin (0-4 days) - Urine output increases greatly - Interphase has release of ADH from damaged neurons (or from recovering) - In recovering, may swing back too far the other direction - If permanent damage to the pituitary, pt will have permanent problems

Question 38

What is the basis of nephrogenic DI/what is the problem?

Answer 38

Renal resistance to ADH

Question 39

How is Diabetes Insipidus diagnosed? - For what suspected conditions is it done - Process

Answer 39

_Goal is to see if pt concentrates urine_ - Central DI (complete or partial) - Nephrogenic DI - Primary polydypsia **Deprive pt of water over hours** - Measure every 1-2 hrs (ADH level, serum Na, serum Osm, urine Osm, urine output) - Monitor BP and weight (stop when orthostatic or 2-3% weigh tloss) **Give DDAVP** (desmopressin) to see if they can respond by concentrating urine (urine Osm rise)

Question 40

What is desmopressin?

Answer 40

Desamino D-8 arginine vasopressin - Decreased vasopressor activity (D-arg change) - Increased half life ins erum Oral, nasal, subcutaneous (100 mcg: 10mcg: 1 mcg)

Question 41

What is the normal response to water deprivation test?

Answer 41

- Maximally concentrated urine, so no additional response to DDAVP - ADH will come back high at the end of the test

Question 42

What is the response to water deprivation in central DI? - Distinguishing central from partial

Answer 42

- Excellent response to DDAVP - ADH will come back low at the end of the test **Complete central Di:** - Urine Osm under 100 mOsm/kg (less than serum Osm) - DDAVP causes \> 50% increase in urine Osm - Undetectable or very low AVP (ADH) levels **Partial Di:** - Urine Osm 300-400 (greater than serum Osm) - DDAVP causes 10-50% increase in serum osm - Low AVP (ADH) levels

Question 43

What is the response to water deprivation in nephrogenic DI?

Answer 43

- May concentrate urine somewhat (300 – 500 mOsm/kg) - DDAVP \< 10% increase in urine Osm because resistant - High AVP (ADH)

Question 44

What is the response to water deprivation in primary polydypsia?

Answer 44

- Concentrate urine (300-800 mOsm/kg) - Increase in AVP levels with water deprivation - Doesn’t respond further to DDAVP because endogenous AVP (ADH) already high

Question 45

How to treat Central DI?

Answer 45

- DDAVP - (Chlorthalidone, clofibrate, carbamazepine)

Question 46

How to treat nephrogenic DI?

Answer 46

**Treat underlying cause** **Thiazide diuretics** - Hydrochlorothiazide 25 mg once to twice per day - Mild volume depletion increases proximal tubule resorption of water and decreases the water delivered to the collecting tubules - Can combine with amiloride to decrease hypokalemia and enhance the effect **NSAIDs** - Prostaglandins inhibit ADH - Use of NSAIDs may increase the ability of endogenous ADH to work - Indomethacin - Lithium induced dysfunction