Basics of hypothalamic-pituitary circuit?
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
What does GH stimulate downstream?
What hormones are secreted by the anterior pituitary?
- LH, FSH
What hormones are inhibited by SS?
What promotes/inhibits prolactin secretion?
What hormones are promoted by TRH?
Where is the hypothalamus in the brain?
Forms the floor of the 3rd ventricle
Where is the pituitary?
Housed in the base of the skull in the sphenoid bone "sella turcica"
Describe the development/embryological origin of the:
- Posterior pituitary
- Anterior pituitary
- Intermediate lob or "pars intermedia"
- 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
Describe the neurohypophysis of the HT and posterior pituitary
- Neurons organized as paraventricular and supraoptic “nuclei” in the hypothalamus
- Axons travel down stalk to the posterior pituitary
Describe the vascular connection of the hypothalamic-pituitary axis
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)
- Cavernous sinus
- Petrosal sinuses
- Jugular vein
What are some input signals received by the hypothalamus?
- Light (circadian rhythms)
- Neural stimuli
- Molecular stimuli: cytokines, hormones, adipokines and GI peptides, glucose, osmoles
How do the input molecules get through the BBB to the hypothalamus?
- Fenestrated capillaries
- Circumventricular organs
The hypothalamus integrates the signals and sends outgoing messages (neural and hormonal) to regulate what?
- Circadian rhythms (sleep-wake cycles)
- Energy expenditure
- Temperature (fever)
- Endocrine systems (pituitary)
- Sodium and water balance
- Glucose disposal
Describe the basics in the hypothalamic regulation of appetite?
- 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)
If almost everyone has leptin, why is there an obesity epidemic?
The fatter we get, the more resistant our hypothalamus is to the signal to stop eating
What is the acronym for coming up with a thorough differential diagnosis?
E- endocrine & metabolism/electrolytes
What cranial nerves lie in the cavernous sinus that may be impinged upon by large masses in the pituitary (or hypothalamus?)
CNs 3, 4, V1, V2
Dysregulation of hypothalamic function can cause what diseases in relation to its normal functions:
- Energy expenditure
- Circadian rhythms
- Endocrine systems
- Sodium/water balance
- Limbic system
- 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
Dysfunctional levels of anterior pituitary hormones include what?
- Decreases in: GH, TSH, LH/FSH, ACTH
- Increases in prolactin
What are the posterior pituitary hormones?
- Anti-diuretic hormone (ADH or vasopressin)
What is Kallmann's syndrome?
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)
What is hypothalamic amenorrhea?
Disordered GnRH pulsatility
- Decreased LH surge during menstrual cycle
- Lack of follicle development and anovulation
- Decreased estrogen production (loss of bone mass)
What is anorexia nervosa?
“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
What is stored in the posterior pituitary?
- Where are these substances made?
- 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
Describe the production of posterior pituitary hormones and their modification as they travel
- 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
How is the posterior pituitary visualized on CT? (CT or x-ray?)
Posterior pituitary shines brighter (without contrast) because of high numbers of granules
What functions is oxytocin involved in?
"Labor, love, and lactation"
- Initiation and completion of labor
- Fergusson reflex (cervical dilation)
- Contraction of uterine myometrium: delivery, and clamping down on vessels to prevent blood loss
- Mechanoreceptors/touch receptors enhance milk flow by widening ducts and promoting emptying of milk from the alveoli
What functions is Vasopressin (ADH) involved in (based on receptor subtypes)?
- Vascular sm
V2- increased production and action of aquaporin2 water channels in principal cells of renal tubule
- Basolateral membrane of distal nephron
V3- enhanced ACTH release
What is the mechanism of AVP (ADH) action?
- 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
How is vasopressin release regulated?
What stimulates it?
- 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
ADH deficiency causes what disorder?
What are the signs/symptoms of diabetes insipidus?
- 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)
How is primary polydypsia distinct from diabetes insipidus?
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)
What are some causes of central DI?
Anything that threatens hypothalamus or posterior pituitary
What is the "triphasic response"?
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
What is the basis of nephrogenic DI/what is the problem?
Renal resistance to ADH
How is Diabetes Insipidus diagnosed?
- For what suspected conditions is it done
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)
What is desmopressin?
Desamino D-8 arginine vasopressin
- Decreased vasopressor activity (D-arg change)
- Increased half life ins erum Oral, nasal, subcutaneous (100 mcg: 10mcg: 1 mcg)
What is the normal response to water deprivation test?
- Maximally concentrated urine, so no additional response to DDAVP
- ADH will come back high at the end of the test
What is the response to water deprivation in central DI?
- Distinguishing central from partial
- 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
- Urine Osm 300-400 (greater than serum Osm)
- DDAVP causes 10-50% increase in serum osm
- Low AVP (ADH) levels
What is the response to water deprivation in nephrogenic DI?
- May concentrate urine somewhat (300 – 500 mOsm/kg)
- DDAVP < 10% increase in urine Osm because resistant - High AVP (ADH)
What is the response to water deprivation in primary polydypsia?
- 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
How to treat Central DI?
- (Chlorthalidone, clofibrate, carbamazepine)
How to treat nephrogenic DI?
Treat underlying cause
- 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
- Prostaglandins inhibit ADH
- Use of NSAIDs may increase the ability of endogenous ADH to work
- Lithium induced dysfunction