where is the pituitary gland located
located at the base of the brain
housed in a bony cavity called the SELLA TURCICA within the hypophyseal fossa (a deep depression of the sphenoid bone)
the pituitary gland is covered by dura matter
what is another name for the posterior pituitary
neurohypophysis/pars nervosa
what is another name for the anterior pituitary
adenohypophysis/pars distalis
how is the posterior pituitary related to the hypothalamus
the posterior pituitary is actually part of the brain–>it is an outgrowth of the hypothalamic tissue
how does the posterior pituitary maintain its connection with the hypothalamus
via the hypothalamic-hypophyseal tract which runs through the INFUNDIBULUM
arises from neurons in the supraoptic (ADH) and paraventricular (oxytocin) nuclei of the hypothalamus (i.e neurone originating from the supraoptic nucleus and the paraventricular nucleus in the hypothalamus run through the hypothalamus-hypophyseal tract via the infundibulum to act within the posterior pituitary)
what is the infundibulum
the “connecting stalk” between the hypothalamus and pituitary
with what hormone is the supraoptic nucleus associated
ADH
with what hormone is the paraventricular nucleus associated
oxytocin
what cell type/layer forms the anterior pituitary
ectoderm
from where does the anterior pituitary develop
originates from a superior outpouching of the oral mucosa (RATHKE’S POUCH) and formed form ectoderm
what types of connections exist between the anterior pituitary and the hypothalamus
NO direct neuronal connections (unlike in the posterior pituitary)–> only VASCULAR connection
how do the hypothalamus and anterior pituitary communicate
via vascular connection
primary capillary plexus (MEDIAN EMINENCE) in the infundibulum communicates inferiorly via small hypophyseal portal veins with a secondary capillary plexus in the anterior lobe (this is the hypophyseal portal system)
hypothalamic hormones travel through the portal veins of the anterior pituitary where they increase or decrease anterior pituitary hormone secretion
fenestrated capillaries are present in both the primary and secondary plexi–> these allow for the travel of bulky, large protein hormones
describe the blood supply for the pituitary
delivered via the hypophyseal branches of the internal carotid arteries and removed by the dural sinuses
what are hypothalamic regulatory hormones made of?
all hypothalamic regulatory hormones are amino acid based but they vary in size
which are the hypothalamic regulatory hormones
GnRH
TRH
CRH
GHRH
what types of receptors do the hypothalamic regulatory hormones bind to
all bind to extracellular G-protein coupled receptors (G-protein coupled receptors cross the membrane 7 times) –> cause downstream signal transduction cascades
what are the 3 rhythms (i.e of hormone release) we learned about
- circadian (diurnal)
- ultradian (pulsatile)
- infraradian
what is the time period associated with the following rhythms?
- circadian/diurnal
- ultraradian/pulsatile
- infraradian
- 24 hour
2. 24 hour
what hormones/processes are associated with the following rhythms?
- ultraradian/pulsatile
- infraradian
- GH, LH, FSH secretion
2. menstrual cycle
two groups of cells develop from multipotential stem cells that eventually differentiate further into hormone producing cells–> what are they?
- acidophils
2. basophils
name the acidophilic hormone producing cells and which hormones they produce
- somatotrophs–> growth hormone
2. lactotrophs–> prolactin
name the basophilic hormone producing cells and which hormones they produce
- corticotrophs–> ACTH
- thyrotrophs–> TSH
- gonadotrophs–> LH, FSH
list the stimulating hypothalamic regulatory hormones we need to know and which anterior pituitary hormone they promote secretion of
- corticotropin releasing hormone (CRH)–> ACTH
- gonadotropin-releasing hormone (GnRH)–> LH, FSH
- growth hormone-releasing hormone (GHRH)–> growth hormone
- prolactin releasing peptides and prolacting releasing hormones (PRPs and PRHs)–> prolactin
- thyrotropin releasing hormone–> thyrotropin (TSH); prolactin?
list the inhibiting hypothalamic regulatory hormones and the anterior pituitary hormones they inhibit
- somatostatin (SS)–> inhibits growth hormone, thyrotropin and ACTH release
- prolactin inhibiting factors/hormones (dopamine, GABA?)–> inhibit prolactin
how do the anterior pituitary hormones exert their effect?
all except growth hormone exert action via cAMP
how does the structure of TSH, LH and FSH differ? how are they they same?
consists of a common alpha-subunit and a unique beta-subunit
what does the anterior pituitary do?
manufactures and releases hormones
list the hormones manufactured and released by the anterior pituitary
- pro-opiomelanocortin (POMC)
- growth hormone
- thyroid stimulating hormone
- adrenocorticotropic hormone
- gonadotropins (LH, FSH)
- prolactin
list the hormones made by the posterior pituitary
- oxytocin
2. ADH
what does pro-opiomelanocortin (POMC) do?
it is a large pro-hormone produced which becomes ACTH, two biological opiates (encephalin, beta-endorphin) and melanocyte stimulating hormone (MSH)
produced by corticotrophs
what does growth hormone do? what type of hormone is it? what is its major target?
produced by somatotrophs
polypeptide hormone
major target is bone and skeletal muscle
stimulates bone growth/protein synthesis
lipid/carb metabolism (use of fats for energy)
most growth effects are mediated indirectly by IGF-1 (insulin like growth factors) produced by the liver, bone, muscle and other tissues
what regulates GH? what is it inhibited by?
regulated by GHRH
inhibited by somatostatin which also inhibits TSH
what does TSH do? what kind of hormone is it?
thyrotropic
glycoprotein
stimulates normal development and secretory activity of the thyroid gland (release of T3/T4)
what regulates TSH? what inhibits it?
regulated by: thyrotropin releasing hormone (TRH) which also acts on lactotrophs
inhibited by rising levels of thyroid hormones in the blood
what does adrenocorticotropic hormone (ACTH) do? what kind of hormone is it?
secreted by corticotrophs
peptide hormone
stimulates the adrenal cortex to release glucocorticoids/corticosteroids (CORTISOL)
helps the body resist stressors (spikes during stress)
what is ACTH regulated by? what is it inhibited by?
regulated by: corticotrophin-releasing hormone (CRH) which has a daily rhythm
inhibited by: rising levels of glucocorticoids in the blood (also has short feedback mechanism with ACTH itself)
what do gonadotropins (LH, FSH) do? what type of hormone are they?
glycoprotein hormones
regulate function of the gonads (ovary and testes)
FSH stimulates the production of sperm or egg; follicle maturation
LH stimulates production of gonadal hormones (estrogen, testosterone); ovulation
what are LH, FSH regulated by? what are they inhibited by?
regulated by: gonadotropic releasing hormone (GnRH)
inhibited by: gonadal hormones and prolactin
what does prolactin do? what type of hormone is it?
polypeptide hormone
structurally similar to growth hormone
produced by lactotrophs
stimulates milk production of the breast
what is prolactin regulated by? what is it inhibited by?
inhibited and regulated by: dopamine (prolactin inhibiting hormone/PIH)
stimulated release by: estrogen and reduced dopamine
what is a long feedback loop in the context of the HPA axis?
target hormone feeds back on the pituitary, hypothalamus and/or the CND to regulate the axis
what is a short feedback loop in the context of the HPA axis?
anterior pituitary hormone feeds back on the hypothalamus to regulate the axis
describe the feedback loops associated with growth hormone
GH causes the liver to produce IGF-1
IGF-1–> long feedback loop to the hypothalamus, short feedback loop to anterior pituitary
GH–> short feedback loop to the hypothalamus, ultra-short feedback loop to the anterior pituitary
describe the feedback loops associated with prolactin
prolactin–> short feedback loop to the hypothalamus
suckling induces inhibition of dopamine which increases prolactin secretions resulting in lactation
describe the feedback loops associated with ACTH
cortisol from adrenal cortex–> long feedback loop to hypothalamus, short feedback loop to anterior pituitary
ACTH–> short feedback loop to hypothalamus
describe the feedback loops associated with TSH
T3/T4 produced from thyroid–> long feedback loop to hypothalamus, short feedback loop to anterior pituitary
no connecting loop of TSH to hypothalamus, only T3/T4
describe the pathway of LH action
hypothalamus–> (GnRH)–> anterior pituitary–> gonadotrophs–> (LH)–> interstitial cells–> testosterone production–> promotes secondary sex characteristics
*testosterone feeds back
describe the pathway of FSH action
hypothalamus–> (GnRH)–> anterior pituitary–> gonadotrophs–> (FSH)–> sertoli cells–> produces inhibin and stimulates spermatogenesis
**inhibin feeds back
what is the action of inhibin
a family of polypeptide hormones produced by the gonads
specifically inhibits FSH secretion at pituitary
symptoms of hypopituitarism
- lack of energy
- weight loss, nausea, vomiting, constipation
- amenorrhea and infertility
- dry skin, increased pigmentation
- cold intolerance
- mental status changes (sleepiness, psychosis)
clinical/anatomical:
- headaches
- diplopia (double vision)
- loss of peripheral vision
- facial pain/numbness
list 8 causes of reduced pituitary function
- tumors and other mass lesions
- traumatic brain injury and subarachnoid hemorrhage
- pituitary surgery or radiation
- pituitary apoplexy
- ischemic necrosis of pituitary (Sheehan syndrome)
- hypothalamic lesions
- inflammatory disorder and infection
- genetic defects (rare)
what types of tumors and mass lesions are associated with reduced pituitary function
- pituitary adenoma
- benign tumors
- primary and metastatic malignancies
- cysts
what is one of the most common causes of reduced pituitary function
traumatic brain injury and subarachnoid hemorrhage
what is pituitary apoplexy
caused by sudden hemorrhage into the pituitary gland–> often occurring into a pituitary adenoma
causes sudden onset excruciating headache and diplopia
may cause CV collapse
what is ischemic necrosis of the pituitary (Sheehans syndrome)
pregnancy induced hyperplasia of the pituitary and mass drop in BP leading to ischemia (i.e pituitary overgrows its blood supply in response to pregnancy and bleed in delivery can lead to drop in BP)
what inflammatory disorders/infections can be associated with reduced pituitary function
sarcoidosis or TB meningitis
when analyzing the growth hormone axis:
- what hormones do we measure?
- what stimulation test do we do?
- when suppression test do we do?
- IFG-1
- stimulation test: insulin induced hypoglycemia, glucagon + arginine
- glucose suppression test
when do you do suppression testing of hypothalamus/pituitary hormones/axes?
when there is a deficiency of the end organ product
when do you do stimulation testing of hypothalamus/pituitary hormones/axes?
when there is an excess of the end organ product
when analyzing the gonadotropic axis:
- what hormones do we measure?
- what stimulation test do we do?
- when suppression test do we do?
- LH, FSH, testosterone, estradiol
- administration of GnRH
- excess LH/FSH is rare so dont have test/dont need to know
when analyzing the thyroid axis axis:
- what hormones do we measure?
- what stimulation test do we do?
- when suppression test do we do?
- TSH, free T4
- administration of TRH
- –
when analyzing the adrenocortical axis:
- what hormones do we measure?
- what stimulation test do we do?
- when suppression test do we do?
- ACTH, cortisol, urine cortisol
- insulin induced hypoglycemia, ACTH stress test
- dexamethasone infusion
when analyzing the prolactin axis:
- what hormones do we measure?
- what stimulation test do we do?
- when suppression test do we do?
- prolactin
- administration of TSH
- –
list the dynamic tests for HPA function
- triple bolus
- GnRH stimulation test
- clomiphene stimulation test
- insulin induced hypoglycemia
- dexamethasone infusion
what is the triple bolus test? how is it done and what does it measure?
admin: insulin, TRH, GnRH
- insulin causes decreased glucose resulting in ACTH and GH release
- TRH stimulated TSH and prolactin release
- GnRH stimulates LH and FSH release
what is the GnRH stimulation test? how is it done and what does it measure?
monitor increase in LH (x3-6) and FSH (x20-50) in response to GnRH administration
**men with hypothalamic or pituitary disease have reduced or normal response that is often inadequate for distinguishing between pituitary and hypothalamic disorder
what is the clomiphene stimulation test? how is it done and what does it measure?
100mg of clomiphene citrate is given x5-7 days to test the HPA
interrupts the negative feedback loop and stimulates release of gonadotrophic hormones from pituitary
expect x2 of LH and x20-50 of FSH if the patient is normal and has intact HPA
what is the insulin induced hypoglycaemia test? how is it done and what does it measure?
insulin administration will cause hypoglycemia in a patient which should result in rise in GH
if patient has problems with memmosomatropes or somatotrophs, GH will not rise after administration
what is the dexamethasone infusion test? how is it done and what does it measure?
should inhibit ACTH and cortisol secretion
if ACTH levels and cortisol levels remain high, you can infer an ACTH producing tumor within the pituitary
what structures are above the pituitary
optic chiasm
optic nerves
what structures are to each side of the pituitary
cavernous sinus
cranial nerves that control eye movement and facial sensations
what are the two types of cells found in the anterior pituitary
- chromophobic
- chromophilic–> acidophilic and basophilic
- acidophilic cells are smaller cells that secrete GH and Prolactin
- basophilic cells are larger cells with granular cytoplasm that secrete ACTH, FSH, LH and TSH
list 4 neoplasms of the pituitary gland
- adenoma (i.e leading to acromegaly, cushings)
- prolactinoma
- glycoprotein adenomas
- null cell adenoma
what is acromegaly
serious systemic condition caused by an adenoma that leads to GH overproduction
effects are IGF-1 mediated
what are the symptoms/consequences of acromegaly
- if untreated, causes bony and soft tissue changes
- altered facial appearance
- enlargement of feet and hands
- sleep apnea
- carpal tunnel syndrome
- accelerated CV disease
- HTN
- diabetes mellitus
- possible increased risk of colon cancer
requires surgery
what is cushiness disease
excess ACTH–> cortisol from a pituitary adenoma/tumor
what are the symptoms of cushings
- thinning of the skin and proximal muscle wasting
- increased abdominal fat
- cushingoid face (moon face and plethoric cheeks)
- buffalo hump
- increased appetite
- HTN
- osteoporosis
what is the most common type of pituitary adenoma
prolactinoma
what are the results of prolactinomas
excessive prolactin
stimulates inappropriate milk production from breasts
in women, most are micro adenomas and there is only a small elevation in prolactin
in men, most are macro adenomas, and you get large elevations in prolactin leading to loss of libido and vision
how common are glycoprotein adenomas
rare
what are the results of glycoprotein adenomas
excessive FSH, LH, TSH
in a TSH secreting adenoma:
- hyperthyroidism due to excessive thyroid hormone
- many patients have thyroid tx of some sort
- very aggressive and invasive–need surgery and radiation
what are null cell adenomas
macroadenomas
make up half of non-functioning tumors
make up 20% of pituitary adenomas
present with mass effect and hypopituitarism
immuno-negative for pituitary hormones or scant glycoprotein staining–> related to glycoprotein adenomas
indolent behavior–40% rate of invasion
what is the usual order of loss of pituitary function? (due to where cells are located in the pituitary)
Go Look For The Adenoma Please
GH LH FSH TSH ACTH Prolactin (almost never lose prolactin)
because of its location, enlargement of the pituitary (i.e due to a tumor) can have a great many effects–> what are they?
- can cause greater amounts of the corresponding pituitary hormones to be produced
- exert mass effects on hypothalamus
- compress optic chiasm (visual impairment)
- compress normal pituitary tissue (loss of gonadotropins)
- compress pituitary stalk–>loss of transport
what is a mass effect
a mass effect is the effect of a growing mass that results in secondary pathological effects by pushing on or displacing surrounding tissue
how do you treat acromegaly
1st line:transsphenoidal pituitary surgery and adenoma removal (cures 85% of those with a timor less than 1cm)
cure may be difficult in patients with large of invasive tumors –> may need radiation and/or medical intervention to control GH levels
the higher the pre-op GH level the lower the chance of a cure
2nd line: somatostatin analogue (OCREOTIDE) –> decreases GH release and shrinks tumor
3rd line: GH receptor antagonist (Pegvisomat) –> doesn’t block GH secretion just its effects; decreases IGF-1 release; doe snot shrink tumor
how do you treat prolactinomas
1st line: dopamine agonist therapy (80% successful) i.e bromocriptidine, cabergoline
most see a reduction in prolactinoma size and improvement of symptoms
2nd line: surgery
3rd line: radiation
what region of the hypothalamus controls the circadian clock
superchiasmatic nucleus
where do the releasing hormones enter circulation?
at the pituitary stalk
from what embryological structure is the anterior pituitary derived
from Rathke’s pouch, an invagination of oral ectoderm
from which embryological structure is the posterior pituitary derived
from neuroectoderm, specifically cells in the floor of the third ventrical
where are granular cell tumors found
in the posterior pituitary
rarely symptomatic
may have mass effect, headaches, visual symptoms, diabetes insipidus
where would you find a craniopharyngioma
in the sella turcica
what is the function of the posterior pituitary
release neurohormones from the hypothalamus
what is the physiological role of oxytocin
strong stimulant of uterine contractions–> released during childbirth
also a trigger for “milk letdown”
what is the physiological role of ADH
inhibits/prevents urine formation–> prevents wide swings in water balance by helping avoid dehydration and water overload
act on distal tubules and collecting ducts of the kidney to reabsorb water and concentrate urine
hypothalamic neurons called osmoreceptors continually monitor the solute concentration of blood
what would you call a condition in which you had a deficiency in ADH
central diabetes insipidus
what is central diabetes insipidus
due to low ADH
syndrome marked by output of huge amounts of urine and intense thirst
can be caused by a blow to the head or anything which damages the hypothalamus or posterior pituitary
condition isnot serious when thirst centre is operating and a person drinks enough water to avoid dehydration
what is the condition called when you have ADH hypersecretion
syndrome of inappropriate ADH secretion (SIADH)
what is SIADH
syndrome of inappropriate ADH secretion (SIADH)
can be due to general anaesthesia, neoplasm or administration of certain drugs
results in HYPONATREMIA
marked by retention of fluid, headache, and disorientation due to brain edema, weight gain and decreased solute concentrations in the blood
requires careful monitoring of blood sodium levels and fluid restriction
what are the actions of growth hormone
- growth
- growth of the skeleton, muscle and connective tissue
- increases growth of cells in the viscera (i.e liver, intestines, kidney) - metabolic actions
- counter regulatory hormone that opposes insulin action
- liver–> increases blood glucose production (gluconeogenesis)
- muscle–> decreases glucose uptake
- adipose tissue–> increased lipolysis
- promotes protein synthesis
**released in a prolonged fast to counteract action of insulin
what are growth hormone’s metabolic actions in the following tissues:
- liver
- muscle
- adipose tissue
- liver–> increases blood glucose production (gluconeogenesis)
- muscle–> decreases glucose uptake
- adipose tissue–> increased lipolysis
what is the pattern of GH secretion?
ultradian rhythm–> PULSATILE
circadian rhythm–> peaks during DEEP sleep, which is why sleep/wake cycles are important for growth promotion
how is GH release regulated
dual regulation: both GHRH (+) and somatostatin (-) influence GH release
most evidence suggests that SS may not modulate pulse frequency, but instead the magnitude of basal and pulsatile GH secretion
surges are most prominent during pubertal growth
amplitude and frequency of surges is regulated by the hypothalamus
how does sleep affect GH release
serotonergic and cholinergic fibres stimulate GHRH neurons in the arcuate nucleus (hypothalamus) leading to GHRH/GH release
how does hypoglycaemia affect GH release
in the setting of hypoglycemia, norepinephrine stimulates GHRH and inhibit somatostatin (periventricular nucleus) leading to GH release
what is the function of GH binding proteins
40% of circulating GH is bound to high affinity glycoprotein–> this glycoprotein is a soluble version of its own receptor
function is to reduce rate of GH degradation (extending its half life) and act as a reservoir for GH
what type of receptor is the GH receptor
extracellular receptor (tyrosine kinase) which is a member of the JAK family
activation of the receptor initiates a cascade of phosphorylation reactions (activation of JAK kinase)
what stimulates ADH release
hypoosmolality
cold
drugs (alcohol, glucocorticoids)
what is the Jak-STAT system
JAK –> janus kinase (family of tyrosine kinases)
STAT–> signal transducers and activators of transcription
this system is involved in GH signalling
describe the steps involved in GH signalling via the Jak-Stat system
- in the absence of GH binding, the receptor is believed to be present as a dimer with JAK molecules constitutively bound
- GH binds to one molecule of the dimer, inducing the second receptor to bind to a different portion of GH
- JAK molecules now dimerize, and there is cross phosphorylation of the JAK molecules (become “P-JAK”)
- receptor tyrosines are phosphorylated by P-JAK
- regions in the receptor phosphorylated by P=JAK are recognized by SH2-domains in intracellular signalling molecules, most importantly STAT molecules, which are phosphorylated by P-JAK
- P-STAT dimerization, nuclear translocation of P-STAT and regulation of gene expression
what is IGF-1
hormone similar in structure to insulin
plays an important role in childhood growth and continues to have anabolic effects in adults
where is IGF-1 primarily produced
in the liver as an endocrine hormone (also produced in muscle etc… but acts as paracrine there)
what stimulates IGF-1 production
growth hormone
produced throughout life but highest during puberty
what is the function of IGF-1
stimulates systemic body growth and has growth promoting effects on almost every cell in the body (especially muscle, cartilage, bone, liver, kidney)
how do you classify causes of hypogonadism
either primary (involving the testes) or secondary (involving the hypothalamus or pituitary)
what cause of hypogonadism would you consider in the context of high LH/FSH
consider primary (testicular failure)–> lots of hormone, nothing happening
what cause of hypogonadism would you consider in the context of low LH/FSH
consider secondary cause (investigate pituitary or hypothalamus)
list 2 congenital causes of low pituitary production of LH/FSH
- idiopathic
2. familial hypogonaditrophic hypogonadism –> kallmann’s syndrome
what is familial hypogonaditrophic hypogonadism (kallmann’s syndrome)?
congenital cause of low LH/FSH
mutations in GnRH receptor, LH or FSH mutation etc…
in 50% of those affected it is autosomal dominant
list 5 acquired causes of low pituitary production of LH/FSH
- severe illness, stress, malnutrition
- drugs–> dopamine antagonists or serotonin agonists (increased prolactin secretion)
- hyperprolactinemia (elevated prolactin inhibits hypothalamic GnRH secretion)
- stellar mass lesion
- hemochromatosis (both pituitary and testes can be affected by iron deposition)
what is a stellar mass lesion
possible acquired cause of low LH/FSH
neoplastic and non-neoplastic lesions in the hypothalamus or pituitary that can affect gonadotrophic function directly or indirectly
adenomas that extend into the suprestellar region can impair GnRH secretion and mildly increase prolactin secretion
distinguished from prolactinomas because prolactin would be way higher
presence of diabetes insipidus suggests the possibility of a craniopharyngioma, infiltrative disorder or other hypothalamic lesion
how can hemochromatosis affect pituitary production of LH/FSH
both the pituitary and the testes can be affected by excessive iron deposition
the pituitary defect is the predominant lesion in most patients with hemochromatosis and hypogonadism
diagnosis of hemochromatosis is suggested by association of characteristic skin discoloration, hepatic enlargement or dysfunction, diabetes mellitus, arthritis, cardiac conduction defects and hypogonadism
list the consequences of not replacing testosterone
- low sexual desire
- CAD
- type II DM
- obesity and metabolic syndrome
- osteoporosis
why does not replacing testosterone lead to low sexual desire
testosterone is required for normal sexual function and erectile function
why does not replacing testosterone lead to CAD
vascular tissue has many androgen receptors–> evidence that testosterone is protective against CAD
also there is an inverse relationship between testosterone levels and LDL, TG, fibrinogen levels, BMI and waist-hip ration which all improve CAD risk
why does not replacing testosterone lead to type II DM
type II diabets doubles the risk of hypogonadism–FSH and LH are usually somewhat low
why does not replacing testosterone lead to obesity and metabolic syndrome
central obesity plus 2 of (HTN, reduced HDL, raised TG, raised fasting glucose) –> metabolic syndrome
low testosterone is associated with increased insulin resistance
why does not replacing testosterone lead to osteoporosis
may be associated with increased fracture risk with decreased levels of testosterone
apart from those already mentioned, what may be some other consequences of not replacing testosterone in a man
- fatigue
- muscle loss/atrophy
- poor sleep
- difficulty concentrating
- memory loss (difficulty choosing words in language)
- shyness
- depression
- anxiety
- gynecomastia
- hot flashes
- decrease in growth of body hair
- irritability
- infertility
- shrinking of testicles
- achy muscles
- night sweats
list the actions of testosterone
- masculinization of male fetus
- secondary sexual changes and growth in puberty
- modulation of sexual response–proven in men
- metabolic
- bone density, red cell production, sperm production, body fat, CV health, insulin sensitivity, prostate growth, cognition and mood, muscle strength and volume
how does testosterone affect the following:
- bone
- muscle
- skeleton
- blood
- prostate
- mood
- sex drive
- sex function
- hair
- voice
- growth of long bones associated with pubertal growth spurt; bone loss is observed with low testosterone
- growth of muscles associated with pubertal growth spurt; increase in muscle strength
- refer to bone
- stimulated red cell production
- stimulated prostate growth
- improves energy, cognition and mood
- low testosterone is linked to loss of sexual desire
- low testosterone is linked to loss of nocturnal erections, delayed and minimal ejaculate and erectile dysfunction (variable); visually induced erections are NOT dependent on testosterone
- growth of pubic, axillary, beard, chest, abdominal and back hair–> loss of testosterone linked with fine body hair and smooth skin
- growth of larynx with voice deepening
why do we care about sex hormone binding globulin (SHBG)?
we want to measure total cholesterol–> the current recommended measure for diagnosing low testosterone states in men
BUT we must use calculated free testosterone if theres a disease state that could alter SHBG
list states that could cause increased SHBG
age cirrhosis estrogen anticonvulsants hyperthyroidism HIV infection
list states that could cause decreased SHBG
obesity/metabolic syndrome glucocorticoids androgens hypothyroidism type II DM nephrotic syndrome
what are the current screening recommendations for homechromatosis
population wide screening is NOT recommended
screen people with whom you have a high suspicion
- all cases of unexplained arthritis
- CHF/cardiomyopathy
- adult onset diabetes
- persistent elevated liver function enzymes
- cirrhosis
- secondary hypogonadism
- skin pigmentation
- persistent unexplained elevated ferritin
do for family cascade studies–> all first degree relative with HFE related hemochromatotis
why do some people think that we should more routinely screen for hemochromatosis
because it is a common inherited disorder with associated morbidity and mortality
there are sensitive screening tests and effective tx for the disorder that is safe and readily available in the form of phlebotomy
further, individuals identified in the pre-cirrhotic stage and treated have survival rates equivalent to the general population
therefore, it in fact satisfies many of the requirements of WHO/USPSTF requirements for a disease that is eligible for screening
what is the rational behind the limited screening done for hemochromatosis
the relationship between genotype and clinical phenotype is unclear (i.e not everyone inheriting the two mutant copies of the gene will develop significant disease) and there are concerns about how to best accomplish the screening (i.e at what age, general population or not, what type of screening) and social and ethical issues surrounding screening (i.e undue stress)
hemochromatosis presentation is highly variable. what are some of the symptoms is can present with
it can present with any of the following symptoms:
- arthritis
- abnormal liver function
- cirrhosis
- liver cancer
- glucose intolerance and diabetes
- severe fatigue
- cardiomyopathy and arrhythmias
- heart failure
- chronic abdominal pain
- hypopituitarism
- hypogonadism
- grey/bronze skin pigmentation
what is the principal manifestation of classic hemochromatosis
hepatomegaly abdominal pain abnormal skin pigmentation deranged glucose homeostasis or DM cardiac dysfunction atypical arthritis
for some patients, the presenting complaint is hypogonadism
what is a significant cause of death in those with hemochromatosis
hepatocellular carcinoma (risk is 200X the general population)
how is hemochromatosis inherited
autosomal recessive inheritance
caused by utation in the HFE (C282Y) gene in 85% of cases
what are the biochemical findings in iron overload
high serum iron
high % saturation of transferrin
low serum transferring (TIBC)
high ferritin
**genetic testing (C282Y) and liver biopsy (rare) can be done
describe normal iron absorption
5-10% of ingested iron is normally absorbed in the duodenum and upper small intestine
most dietary iron is in ferric (Fe3+) state–> converted into ferrous (Fe2+) state by FERRIC REDUCTASE on the brush border
iron enters cell via divalent metal transporter (DMT1)
once inside enterocyte, iron can either be incorporated into ferritin for storage (most lost via mucosal shedding) or transferred across the basolateral membrane into the plasma by transmembrane protein FERROPORTIN
once in the plasma, Fe2+ is converted back into Fe3+ by the membrane protein HEPHAESTIN and then bound to TRANSFERRIN (2 binding sites for iron)
transferrin delivers iron to cells with a transferrin receptor–> membrane bound dimeric protein, binds two transferring molecules
entire receptor-transferrin complex is endocytosed and formed into a vesicle
at acidic pH of vesicle, iron is released from the vesicle into cytosol and the receptor/transferrin is exocytosed and recycled
once inside the cell, iron can be either incorporated into heme or stored as ferritin
list foods that increase iron absorption by forming soluble iron chelates
ascorbic acid
sugars
amino acids
list foods that decrease iron absorption (by forming insoluble iron complexes)
phosphates (dairy)
oxalates and phytates (veggies)
tannates (tea)
what are the two forms in which iron can be stored
- ferritin
2. hemosiderin
how is iron balance controlled
iron loss is a continuous and unregulated process, so iron balance is controlled through absorption
absorption can increase three fold via stimulation by iron deficiency, pregnancy and erythropoiesis
central regulator is hepcidin
what is hepcidin
the central regulator of iron absorption
where is hepcidin produced
it is a polypeptide hormone produced by the liver in response to iron demands
what does hepcidin do
controls iron balance via absorption
controls flow of iron out of intestinal cells, macrophages, RE and liver cells by binding to ferroportin
hepcidin-herroportin complex is then taken up into the cell and degraded
high levels of hepcidin restrict flow of iron into blood (i.e in response to iron overload)
low levels of hepcidin promote release of iron into circulation (i.e in cases of iron deficiency)
what is the defect in hemochromatosis that leads to iron overload
deficiency of hepcidin is the reason behind increased iron absorption in hemochromatosis (especially in the forms that are due to missense mutations in genes that encode HFE)
reduced hepcidin results in increased iron export from enterocytes and macrophages and therefore there is an up regulation of iron absorption and mobilization leading to iron loading of hepatocytes
describe the ramifications of iron overload at the tissue level
- the liver is nearly always enlarged and may become cirrhotic (increased risk of HCC)
- damage to islet cells can cause diabetes (2/3 of patients)
- may show increased skin pigmentation (increase in melanin) and iron deposition in skin
- CHF and arrhythmias
- testicular atrophy caused by reduced gonadotropins by the pituitary gland
- arthritis in 1/2 of patients
how can hemochromatosis be acquired?
can be acquired as a complication of anemias in which there is ineffective erythropoiesis (beta-thalassemia major)
patients with multiple blood transfusions can become iron overloaded
alcoholics with liver disease can also develop issues with iron stores
use of medicinal iron supplements DOES NOT cause hemochromatosis by itself
what does TIBC measure
the maximum amount of iron that serum proteins can bind
indirect way of assessing transferrin levels
[serum iron]/TIBC –> transferring saturation