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Flashcards in Endo 3 Deck (155)
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1
Q

where is the pituitary gland located

A

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

2
Q

what is another name for the posterior pituitary

A

neurohypophysis/pars nervosa

3
Q

what is another name for the anterior pituitary

A

adenohypophysis/pars distalis

4
Q

how is the posterior pituitary related to the hypothalamus

A

the posterior pituitary is actually part of the brain–>it is an outgrowth of the hypothalamic tissue

5
Q

how does the posterior pituitary maintain its connection with the hypothalamus

A

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)

6
Q

what is the infundibulum

A

the “connecting stalk” between the hypothalamus and pituitary

7
Q

with what hormone is the supraoptic nucleus associated

A

ADH

8
Q

with what hormone is the paraventricular nucleus associated

A

oxytocin

9
Q

what cell type/layer forms the anterior pituitary

A

ectoderm

10
Q

from where does the anterior pituitary develop

A

originates from a superior outpouching of the oral mucosa (RATHKE’S POUCH) and formed form ectoderm

11
Q

what types of connections exist between the anterior pituitary and the hypothalamus

A

NO direct neuronal connections (unlike in the posterior pituitary)–> only VASCULAR connection

12
Q

how do the hypothalamus and anterior pituitary communicate

A

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

13
Q

describe the blood supply for the pituitary

A

delivered via the hypophyseal branches of the internal carotid arteries and removed by the dural sinuses

14
Q

what are hypothalamic regulatory hormones made of?

A

all hypothalamic regulatory hormones are amino acid based but they vary in size

15
Q

which are the hypothalamic regulatory hormones

A

GnRH
TRH
CRH
GHRH

16
Q

what types of receptors do the hypothalamic regulatory hormones bind to

A

all bind to extracellular G-protein coupled receptors (G-protein coupled receptors cross the membrane 7 times) –> cause downstream signal transduction cascades

17
Q

what are the 3 rhythms (i.e of hormone release) we learned about

A
  1. circadian (diurnal)
  2. ultradian (pulsatile)
  3. infraradian
18
Q

what is the time period associated with the following rhythms?

  1. circadian/diurnal
  2. ultraradian/pulsatile
  3. infraradian
A
  1. 24 hour

2. 24 hour

19
Q

what hormones/processes are associated with the following rhythms?

  1. ultraradian/pulsatile
  2. infraradian
A
  1. GH, LH, FSH secretion

2. menstrual cycle

20
Q

two groups of cells develop from multipotential stem cells that eventually differentiate further into hormone producing cells–> what are they?

A
  1. acidophils

2. basophils

21
Q

name the acidophilic hormone producing cells and which hormones they produce

A
  1. somatotrophs–> growth hormone

2. lactotrophs–> prolactin

22
Q

name the basophilic hormone producing cells and which hormones they produce

A
  1. corticotrophs–> ACTH
  2. thyrotrophs–> TSH
  3. gonadotrophs–> LH, FSH
23
Q

list the stimulating hypothalamic regulatory hormones we need to know and which anterior pituitary hormone they promote secretion of

A
  1. corticotropin releasing hormone (CRH)–> ACTH
  2. gonadotropin-releasing hormone (GnRH)–> LH, FSH
  3. growth hormone-releasing hormone (GHRH)–> growth hormone
  4. prolactin releasing peptides and prolacting releasing hormones (PRPs and PRHs)–> prolactin
  5. thyrotropin releasing hormone–> thyrotropin (TSH); prolactin?
24
Q

list the inhibiting hypothalamic regulatory hormones and the anterior pituitary hormones they inhibit

A
  1. somatostatin (SS)–> inhibits growth hormone, thyrotropin and ACTH release
  2. prolactin inhibiting factors/hormones (dopamine, GABA?)–> inhibit prolactin
25
Q

how do the anterior pituitary hormones exert their effect?

A

all except growth hormone exert action via cAMP

26
Q

how does the structure of TSH, LH and FSH differ? how are they they same?

A

consists of a common alpha-subunit and a unique beta-subunit

27
Q

what does the anterior pituitary do?

A

manufactures and releases hormones

28
Q

list the hormones manufactured and released by the anterior pituitary

A
  1. pro-opiomelanocortin (POMC)
  2. growth hormone
  3. thyroid stimulating hormone
  4. adrenocorticotropic hormone
  5. gonadotropins (LH, FSH)
  6. prolactin
29
Q

list the hormones made by the posterior pituitary

A
  1. oxytocin

2. ADH

30
Q

what does pro-opiomelanocortin (POMC) do?

A

it is a large pro-hormone produced which becomes ACTH, two biological opiates (encephalin, beta-endorphin) and melanocyte stimulating hormone (MSH)

produced by corticotrophs

31
Q

what does growth hormone do? what type of hormone is it? what is its major target?

A

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

32
Q

what regulates GH? what is it inhibited by?

A

regulated by GHRH

inhibited by somatostatin which also inhibits TSH

33
Q

what does TSH do? what kind of hormone is it?

A

thyrotropic

glycoprotein

stimulates normal development and secretory activity of the thyroid gland (release of T3/T4)

34
Q

what regulates TSH? what inhibits it?

A

regulated by: thyrotropin releasing hormone (TRH) which also acts on lactotrophs

inhibited by rising levels of thyroid hormones in the blood

35
Q

what does adrenocorticotropic hormone (ACTH) do? what kind of hormone is it?

A

secreted by corticotrophs

peptide hormone

stimulates the adrenal cortex to release glucocorticoids/corticosteroids (CORTISOL)

helps the body resist stressors (spikes during stress)

36
Q

what is ACTH regulated by? what is it inhibited by?

A

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)

37
Q

what do gonadotropins (LH, FSH) do? what type of hormone are they?

A

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

38
Q

what are LH, FSH regulated by? what are they inhibited by?

A

regulated by: gonadotropic releasing hormone (GnRH)

inhibited by: gonadal hormones and prolactin

39
Q

what does prolactin do? what type of hormone is it?

A

polypeptide hormone

structurally similar to growth hormone

produced by lactotrophs

stimulates milk production of the breast

40
Q

what is prolactin regulated by? what is it inhibited by?

A

inhibited and regulated by: dopamine (prolactin inhibiting hormone/PIH)

stimulated release by: estrogen and reduced dopamine

41
Q

what is a long feedback loop in the context of the HPA axis?

A

target hormone feeds back on the pituitary, hypothalamus and/or the CND to regulate the axis

42
Q

what is a short feedback loop in the context of the HPA axis?

A

anterior pituitary hormone feeds back on the hypothalamus to regulate the axis

43
Q

describe the feedback loops associated with growth hormone

A

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

44
Q

describe the feedback loops associated with prolactin

A

prolactin–> short feedback loop to the hypothalamus

suckling induces inhibition of dopamine which increases prolactin secretions resulting in lactation

45
Q

describe the feedback loops associated with ACTH

A

cortisol from adrenal cortex–> long feedback loop to hypothalamus, short feedback loop to anterior pituitary

ACTH–> short feedback loop to hypothalamus

46
Q

describe the feedback loops associated with TSH

A

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

47
Q

describe the pathway of LH action

A

hypothalamus–> (GnRH)–> anterior pituitary–> gonadotrophs–> (LH)–> interstitial cells–> testosterone production–> promotes secondary sex characteristics

*testosterone feeds back

48
Q

describe the pathway of FSH action

A

hypothalamus–> (GnRH)–> anterior pituitary–> gonadotrophs–> (FSH)–> sertoli cells–> produces inhibin and stimulates spermatogenesis

**inhibin feeds back

49
Q

what is the action of inhibin

A

a family of polypeptide hormones produced by the gonads

specifically inhibits FSH secretion at pituitary

50
Q

symptoms of hypopituitarism

A
  1. lack of energy
  2. weight loss, nausea, vomiting, constipation
  3. amenorrhea and infertility
  4. dry skin, increased pigmentation
  5. cold intolerance
  6. mental status changes (sleepiness, psychosis)

clinical/anatomical:

  1. headaches
  2. diplopia (double vision)
  3. loss of peripheral vision
  4. facial pain/numbness
51
Q

list 8 causes of reduced pituitary function

A
  1. tumors and other mass lesions
  2. traumatic brain injury and subarachnoid hemorrhage
  3. pituitary surgery or radiation
  4. pituitary apoplexy
  5. ischemic necrosis of pituitary (Sheehan syndrome)
  6. hypothalamic lesions
  7. inflammatory disorder and infection
  8. genetic defects (rare)
52
Q

what types of tumors and mass lesions are associated with reduced pituitary function

A
  1. pituitary adenoma
  2. benign tumors
  3. primary and metastatic malignancies
  4. cysts
53
Q

what is one of the most common causes of reduced pituitary function

A

traumatic brain injury and subarachnoid hemorrhage

54
Q

what is pituitary apoplexy

A

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

55
Q

what is ischemic necrosis of the pituitary (Sheehans syndrome)

A

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)

56
Q

what inflammatory disorders/infections can be associated with reduced pituitary function

A

sarcoidosis or TB meningitis

57
Q

when analyzing the growth hormone axis:

  1. what hormones do we measure?
  2. what stimulation test do we do?
  3. when suppression test do we do?
A
  1. IFG-1
  2. stimulation test: insulin induced hypoglycemia, glucagon + arginine
  3. glucose suppression test
58
Q

when do you do suppression testing of hypothalamus/pituitary hormones/axes?

A

when there is a deficiency of the end organ product

59
Q

when do you do stimulation testing of hypothalamus/pituitary hormones/axes?

A

when there is an excess of the end organ product

60
Q

when analyzing the gonadotropic axis:

  1. what hormones do we measure?
  2. what stimulation test do we do?
  3. when suppression test do we do?
A
  1. LH, FSH, testosterone, estradiol
  2. administration of GnRH
  3. excess LH/FSH is rare so dont have test/dont need to know
61
Q

when analyzing the thyroid axis axis:

  1. what hormones do we measure?
  2. what stimulation test do we do?
  3. when suppression test do we do?
A
  1. TSH, free T4
  2. administration of TRH
62
Q

when analyzing the adrenocortical axis:

  1. what hormones do we measure?
  2. what stimulation test do we do?
  3. when suppression test do we do?
A
  1. ACTH, cortisol, urine cortisol
  2. insulin induced hypoglycemia, ACTH stress test
  3. dexamethasone infusion
63
Q

when analyzing the prolactin axis:

  1. what hormones do we measure?
  2. what stimulation test do we do?
  3. when suppression test do we do?
A
  1. prolactin
  2. administration of TSH
64
Q

list the dynamic tests for HPA function

A
  1. triple bolus
  2. GnRH stimulation test
  3. clomiphene stimulation test
  4. insulin induced hypoglycemia
  5. dexamethasone infusion
65
Q

what is the triple bolus test? how is it done and what does it measure?

A

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
66
Q

what is the GnRH stimulation test? how is it done and what does it measure?

A

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

67
Q

what is the clomiphene stimulation test? how is it done and what does it measure?

A

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

68
Q

what is the insulin induced hypoglycaemia test? how is it done and what does it measure?

A

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

69
Q

what is the dexamethasone infusion test? how is it done and what does it measure?

A

should inhibit ACTH and cortisol secretion

if ACTH levels and cortisol levels remain high, you can infer an ACTH producing tumor within the pituitary

70
Q

what structures are above the pituitary

A

optic chiasm

optic nerves

71
Q

what structures are to each side of the pituitary

A

cavernous sinus

cranial nerves that control eye movement and facial sensations

72
Q

what are the two types of cells found in the anterior pituitary

A
  1. chromophobic
  2. 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
73
Q

list 4 neoplasms of the pituitary gland

A
  1. adenoma (i.e leading to acromegaly, cushings)
  2. prolactinoma
  3. glycoprotein adenomas
  4. null cell adenoma
74
Q

what is acromegaly

A

serious systemic condition caused by an adenoma that leads to GH overproduction

effects are IGF-1 mediated

75
Q

what are the symptoms/consequences of acromegaly

A
  1. if untreated, causes bony and soft tissue changes
  2. altered facial appearance
  3. enlargement of feet and hands
  4. sleep apnea
  5. carpal tunnel syndrome
  6. accelerated CV disease
  7. HTN
  8. diabetes mellitus
  9. possible increased risk of colon cancer

requires surgery

76
Q

what is cushiness disease

A

excess ACTH–> cortisol from a pituitary adenoma/tumor

77
Q

what are the symptoms of cushings

A
  1. thinning of the skin and proximal muscle wasting
  2. increased abdominal fat
  3. cushingoid face (moon face and plethoric cheeks)
  4. buffalo hump
  5. increased appetite
  6. HTN
  7. osteoporosis
78
Q

what is the most common type of pituitary adenoma

A

prolactinoma

79
Q

what are the results of prolactinomas

A

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

80
Q

how common are glycoprotein adenomas

A

rare

81
Q

what are the results of glycoprotein adenomas

A

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
82
Q

what are null cell adenomas

A

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

83
Q

what is the usual order of loss of pituitary function? (due to where cells are located in the pituitary)

A

Go Look For The Adenoma Please

GH
LH
FSH
TSH
ACTH
Prolactin (almost never lose prolactin)
84
Q

because of its location, enlargement of the pituitary (i.e due to a tumor) can have a great many effects–> what are they?

A
  1. can cause greater amounts of the corresponding pituitary hormones to be produced
  2. exert mass effects on hypothalamus
  3. compress optic chiasm (visual impairment)
  4. compress normal pituitary tissue (loss of gonadotropins)
  5. compress pituitary stalk–>loss of transport
85
Q

what is a mass effect

A

a mass effect is the effect of a growing mass that results in secondary pathological effects by pushing on or displacing surrounding tissue

86
Q

how do you treat acromegaly

A

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

87
Q

how do you treat prolactinomas

A

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

88
Q

what region of the hypothalamus controls the circadian clock

A

superchiasmatic nucleus

89
Q

where do the releasing hormones enter circulation?

A

at the pituitary stalk

90
Q

from what embryological structure is the anterior pituitary derived

A

from Rathke’s pouch, an invagination of oral ectoderm

91
Q

from which embryological structure is the posterior pituitary derived

A

from neuroectoderm, specifically cells in the floor of the third ventrical

92
Q

where are granular cell tumors found

A

in the posterior pituitary

rarely symptomatic

may have mass effect, headaches, visual symptoms, diabetes insipidus

93
Q

where would you find a craniopharyngioma

A

in the sella turcica

94
Q

what is the function of the posterior pituitary

A

release neurohormones from the hypothalamus

95
Q

what is the physiological role of oxytocin

A

strong stimulant of uterine contractions–> released during childbirth

also a trigger for “milk letdown”

96
Q

what is the physiological role of ADH

A

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

97
Q

what would you call a condition in which you had a deficiency in ADH

A

central diabetes insipidus

98
Q

what is central diabetes insipidus

A

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

99
Q

what is the condition called when you have ADH hypersecretion

A

syndrome of inappropriate ADH secretion (SIADH)

100
Q

what is SIADH

A

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

101
Q

what are the actions of growth hormone

A
  1. growth
    - growth of the skeleton, muscle and connective tissue
    - increases growth of cells in the viscera (i.e liver, intestines, kidney)
  2. 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

102
Q

what are growth hormone’s metabolic actions in the following tissues:

  1. liver
  2. muscle
  3. adipose tissue
A
  • liver–> increases blood glucose production (gluconeogenesis)
  • muscle–> decreases glucose uptake
  • adipose tissue–> increased lipolysis
103
Q

what is the pattern of GH secretion?

A

ultradian rhythm–> PULSATILE

circadian rhythm–> peaks during DEEP sleep, which is why sleep/wake cycles are important for growth promotion

104
Q

how is GH release regulated

A
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

105
Q

how does sleep affect GH release

A

serotonergic and cholinergic fibres stimulate GHRH neurons in the arcuate nucleus (hypothalamus) leading to GHRH/GH release

106
Q

how does hypoglycaemia affect GH release

A

in the setting of hypoglycemia, norepinephrine stimulates GHRH and inhibit somatostatin (periventricular nucleus) leading to GH release

107
Q

what is the function of GH binding proteins

A

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

108
Q

what type of receptor is the GH receptor

A

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)

109
Q

what stimulates ADH release

A

hypoosmolality

cold

drugs (alcohol, glucocorticoids)

110
Q

what is the Jak-STAT system

A

JAK –> janus kinase (family of tyrosine kinases)

STAT–> signal transducers and activators of transcription

this system is involved in GH signalling

111
Q

describe the steps involved in GH signalling via the Jak-Stat system

A
  1. in the absence of GH binding, the receptor is believed to be present as a dimer with JAK molecules constitutively bound
  2. GH binds to one molecule of the dimer, inducing the second receptor to bind to a different portion of GH
  3. JAK molecules now dimerize, and there is cross phosphorylation of the JAK molecules (become “P-JAK”)
  4. receptor tyrosines are phosphorylated by P-JAK
  5. 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
  6. P-STAT dimerization, nuclear translocation of P-STAT and regulation of gene expression
112
Q

what is IGF-1

A

hormone similar in structure to insulin

plays an important role in childhood growth and continues to have anabolic effects in adults

113
Q

where is IGF-1 primarily produced

A

in the liver as an endocrine hormone (also produced in muscle etc… but acts as paracrine there)

114
Q

what stimulates IGF-1 production

A

growth hormone

produced throughout life but highest during puberty

115
Q

what is the function of IGF-1

A

stimulates systemic body growth and has growth promoting effects on almost every cell in the body (especially muscle, cartilage, bone, liver, kidney)

116
Q

how do you classify causes of hypogonadism

A

either primary (involving the testes) or secondary (involving the hypothalamus or pituitary)

117
Q

what cause of hypogonadism would you consider in the context of high LH/FSH

A

consider primary (testicular failure)–> lots of hormone, nothing happening

118
Q

what cause of hypogonadism would you consider in the context of low LH/FSH

A

consider secondary cause (investigate pituitary or hypothalamus)

119
Q

list 2 congenital causes of low pituitary production of LH/FSH

A
  1. idiopathic

2. familial hypogonaditrophic hypogonadism –> kallmann’s syndrome

120
Q

what is familial hypogonaditrophic hypogonadism (kallmann’s syndrome)?

A

congenital cause of low LH/FSH

mutations in GnRH receptor, LH or FSH mutation etc…

in 50% of those affected it is autosomal dominant

121
Q

list 5 acquired causes of low pituitary production of LH/FSH

A
  1. severe illness, stress, malnutrition
  2. drugs–> dopamine antagonists or serotonin agonists (increased prolactin secretion)
  3. hyperprolactinemia (elevated prolactin inhibits hypothalamic GnRH secretion)
  4. stellar mass lesion
  5. hemochromatosis (both pituitary and testes can be affected by iron deposition)
122
Q

what is a stellar mass lesion

A

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

123
Q

how can hemochromatosis affect pituitary production of LH/FSH

A

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

124
Q

list the consequences of not replacing testosterone

A
  1. low sexual desire
  2. CAD
  3. type II DM
  4. obesity and metabolic syndrome
  5. osteoporosis
125
Q

why does not replacing testosterone lead to low sexual desire

A

testosterone is required for normal sexual function and erectile function

126
Q

why does not replacing testosterone lead to CAD

A

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

127
Q

why does not replacing testosterone lead to type II DM

A

type II diabets doubles the risk of hypogonadism–FSH and LH are usually somewhat low

128
Q

why does not replacing testosterone lead to obesity and metabolic syndrome

A

central obesity plus 2 of (HTN, reduced HDL, raised TG, raised fasting glucose) –> metabolic syndrome

low testosterone is associated with increased insulin resistance

129
Q

why does not replacing testosterone lead to osteoporosis

A

may be associated with increased fracture risk with decreased levels of testosterone

130
Q

apart from those already mentioned, what may be some other consequences of not replacing testosterone in a man

A
  1. fatigue
  2. muscle loss/atrophy
  3. poor sleep
  4. difficulty concentrating
  5. memory loss (difficulty choosing words in language)
  6. shyness
  7. depression
  8. anxiety
  9. gynecomastia
  10. hot flashes
  11. decrease in growth of body hair
  12. irritability
  13. infertility
  14. shrinking of testicles
  15. achy muscles
  16. night sweats
131
Q

list the actions of testosterone

A
  1. masculinization of male fetus
  2. secondary sexual changes and growth in puberty
  3. modulation of sexual response–proven in men
  4. metabolic
    - bone density, red cell production, sperm production, body fat, CV health, insulin sensitivity, prostate growth, cognition and mood, muscle strength and volume
132
Q

how does testosterone affect the following:

  1. bone
  2. muscle
  3. skeleton
  4. blood
  5. prostate
  6. mood
  7. sex drive
  8. sex function
  9. hair
  10. voice
A
  1. growth of long bones associated with pubertal growth spurt; bone loss is observed with low testosterone
  2. growth of muscles associated with pubertal growth spurt; increase in muscle strength
  3. refer to bone
  4. stimulated red cell production
  5. stimulated prostate growth
  6. improves energy, cognition and mood
  7. low testosterone is linked to loss of sexual desire
  8. 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
  9. growth of pubic, axillary, beard, chest, abdominal and back hair–> loss of testosterone linked with fine body hair and smooth skin
  10. growth of larynx with voice deepening
133
Q

why do we care about sex hormone binding globulin (SHBG)?

A

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

134
Q

list states that could cause increased SHBG

A
age
cirrhosis
estrogen
anticonvulsants
hyperthyroidism
HIV infection
135
Q

list states that could cause decreased SHBG

A
obesity/metabolic syndrome
glucocorticoids
androgens
hypothyroidism
type II DM
nephrotic syndrome
136
Q

what are the current screening recommendations for homechromatosis

A

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

137
Q

why do some people think that we should more routinely screen for hemochromatosis

A

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

138
Q

what is the rational behind the limited screening done for hemochromatosis

A

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)

139
Q

hemochromatosis presentation is highly variable. what are some of the symptoms is can present with

A

it can present with any of the following symptoms:

  1. arthritis
  2. abnormal liver function
  3. cirrhosis
  4. liver cancer
  5. glucose intolerance and diabetes
  6. severe fatigue
  7. cardiomyopathy and arrhythmias
  8. heart failure
  9. chronic abdominal pain
  10. hypopituitarism
  11. hypogonadism
  12. grey/bronze skin pigmentation
140
Q

what is the principal manifestation of classic hemochromatosis

A
hepatomegaly
abdominal pain
abnormal skin pigmentation
deranged glucose homeostasis or DM
cardiac dysfunction 
atypical arthritis 

for some patients, the presenting complaint is hypogonadism

141
Q

what is a significant cause of death in those with hemochromatosis

A

hepatocellular carcinoma (risk is 200X the general population)

142
Q

how is hemochromatosis inherited

A

autosomal recessive inheritance

caused by utation in the HFE (C282Y) gene in 85% of cases

143
Q

what are the biochemical findings in iron overload

A

high serum iron

high % saturation of transferrin

low serum transferring (TIBC)

high ferritin

**genetic testing (C282Y) and liver biopsy (rare) can be done

144
Q

describe normal iron absorption

A

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

145
Q

list foods that increase iron absorption by forming soluble iron chelates

A

ascorbic acid
sugars
amino acids

146
Q

list foods that decrease iron absorption (by forming insoluble iron complexes)

A

phosphates (dairy)
oxalates and phytates (veggies)
tannates (tea)

147
Q

what are the two forms in which iron can be stored

A
  1. ferritin

2. hemosiderin

148
Q

how is iron balance controlled

A

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

149
Q

what is hepcidin

A

the central regulator of iron absorption

150
Q

where is hepcidin produced

A

it is a polypeptide hormone produced by the liver in response to iron demands

151
Q

what does hepcidin do

A

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)

152
Q

what is the defect in hemochromatosis that leads to iron overload

A

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

153
Q

describe the ramifications of iron overload at the tissue level

A
  1. the liver is nearly always enlarged and may become cirrhotic (increased risk of HCC)
  2. damage to islet cells can cause diabetes (2/3 of patients)
  3. may show increased skin pigmentation (increase in melanin) and iron deposition in skin
  4. CHF and arrhythmias
  5. testicular atrophy caused by reduced gonadotropins by the pituitary gland
  6. arthritis in 1/2 of patients
154
Q

how can hemochromatosis be acquired?

A

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

155
Q

what does TIBC measure

A

the maximum amount of iron that serum proteins can bind

indirect way of assessing transferrin levels

[serum iron]/TIBC –> transferring saturation