Pathophysiology of Hypothalamic Pituitary Axis Disorders Flashcards
What hormones stimulate and inhibit prolactin secretion in the posterior pituitary?
Prolactin is continuously secreted on a basal level unless it is inhibited. There is no dedicated releasing hormone, but are things which loosely stimulate it.
Stimulate: Estrogen, thyroid releasing hormone (TRH)
Inhibit: Dopamine (PHIH)
What is GHIH?
Growth hormone inhibiting hormone, also called somatostatin
Somatostatin has since been renamed because it actually inhibits everything in the anterior pituitary. It is now called Somatotropin Release-Inhibiting Factors (SRIF)
What are the male and female consequences of pathologically high elevations of prolactin?
Prolactin inhibits GnRH, which is the stimulator for FSH / LH.
Males - impotence / decreased libido and headaches
Females = Galactorrhea and oligomenorrhea
Hypoglycemia and fasting tend to stimulate growth hormone. Why then is it there is profound growth failure in malnourished children?
Although GH levels are higher, there is a decrease in IGF-1 production from the liver because the liver cannot adequately respond to GH.
- > lower IGF-1 leads to growth failure in children.
- > IGF-1 is also important for decreasing circulating GH levels by negative feedback
What is Kallmann Syndrome a type of, and would it be classified as primary or secondary gonadal failure?
Type of hypogonadotropic (leads to low TSH/LH) hypogonadism
- > secondary gonadal failure (gonads fail because of something external to them)
- primary gonadal failure would be if there was failure to develop at the level of the target organ
What is the mechanistic etiology of Kallmann syndrome?
Due to various possible sporadic mutations, with 15% caused by a mutation in KAL1 -> failure to produce neural cell adhesion protein (anosmin)
As a result, GnRH neurons cannot migrate from their original spot in the olfactory placode through the cribriform plate into the hypothalamus (arcuate nucleus).
What symptoms are associated with Kallmann syndrome and what is the treatment?
Hypogonadotropic hypogonadism - Associated with failure to initiate / complete puberty, lack of secondary sexual characteristics, and infertility
Anosmia - Since Kallmann syndrome is associated with failed development of the olfactory placode
Treatment: Pulsatile GnRH or FSF / LH, or estrogen / testosterone
What are the two most common types of pituitary adenomas? How does this relate to most common presentation?
- Prolactinomas
- Gonadal (non-functional)
Most common presentation is reproductive dysfunction
Prolactin -> GnRH inhibition
Gonadal -> nonfunctional tumor impinges and causes hypopituitarism
How do men and women present differently with prolactinoma?
Women - present early when it is still a microadenoma (<1cm) with galactorrhea (not pathognomonic), amenorrhea, or oligomenorrhea (if you have irregular periods, should always check). Often presents with decreased bone density due to decreased estrogen.
Men - Present with macroadenoma (>1 cm), present very late because they do not seek medical attention for gonadal dysfunction. Typically present with visual field defects / headaches.
What is standard treatment for prolactinoma?
Dopamine agonists - cabergoline (first line due to more convenient dosing) and bromocriptine
-> will actually decrease the tumor size, can be stopped after 2 years for microadenoma, probably needed indefinitely for macroadenoma
Transsphenoidal surgery if tumor is dopamine resistant
What are some causes of hyperprolactinemia which are not prolactinoma?
- Estrogens - i.e. pregnancy or birth control pills -> number one cause of lactotroph hyperplasia
- Primary hypothyroidism - Increased TRH levels stimulate PRL
- D2 antagonist antipsychotics, cocaine use / especially abstinence
How can pituitary stalk disease be related to prolactin levels?
Compressing lesions (i.e. macroadenoma) of the hypothalamus and pituitary stalk may occur from decreased dopamine levels -> less tonic inhibition of lactotrophs
What is macroprolactinemia? How is it prevented?
Patients have a slight prolactin elevation without MRI evidence of microadenoma.
Due to polymer of prolactin -> associated IgG antibody forms aggregates which are actually biologically inactive.
Prevent by pre-treatment with polyethylene glycol to break up the aggregates and measure true prolactin levels.
What is seen in the cells of gonadotroph adenoma and what do they secrete?
Cells stain positively for LH / FSH, but they lack the ability to secrete active hormones -> non-functional adenomas.
They actually secrete alpha-subunits, parts of FSH / LH.
Rarely, FSH / LH may be actually elevated, but are NOT biologically active.
What are the symptoms of acromegaly?
Think acral (distal extremities) + megaly (large)
Prognathism - enlarged chin Acral growth - large hands / feet Visceromegaly - increased organ size Hypermetabolism -> diabetes, HTN Hyperhidrosis - increased sweating Arthritic complaints -> joint swelling
What are the common causes of death in acromegaly / what important conditions are they at greater risk for?
Congestive heart failure -> most common cause of death
Patients also have increased relative risk of colon and breast cancer
-> IGF-1 has a permissive effect in tumorigenesis
What are important, subtle early symptoms of acromegaly?
- Carpal tunnel syndrome -> due to increase in soft tissue size.
- Sleep apnea - from enlargement of the tongue, becomes obstructive
How is diagnosis of acromegaly made?
- Increased serum IGF-1 levels -> represents the integration of growth hormone levels
- Glucose suppression test -> if IGF-1 is inconclusive, glucose can be given. A positive test is failure to suppress GH levels by administration of glucose.
Give three medical treatments for the treatment of acromegaly (resection of the pituitary adenoma should be obvious as first-line).
- Octreotide (GHIH/somatostatin analog)
- Pegvisomant (GH receptor antagonist)
- Cabergoline (dopamine agonists have some efficacy in treatment of this condition, mechanism unknown)
What is Laron syndrome? What will labs show?
A specific type of dwarfism which is caused by a lack of responsiveness to growth hormone (defective growth hormone receptors).
Labs show decreased IGF-1 (liver can’t respond) but increased GH hormones (lack of IGF-1 negative feedback).
Give the mechanism for the following features of Cushing syndrome:
- Muscle weakness with thin extremities
- Moon facies, buffalo hump, and truncal obesity
- Abdominal striae
- Immune suppression
- Amenorrhea
- Muscle weakness with thin extremities - cortisol breaks down muscle to increase gluconeogenesis
- Moon facies, buffalo hump, and truncal obesity - high glucose levels due to increased gluconeogenesis with trigger high insulin levels -> storage of fat centrally
- Abdominal striae -> impaired collagen synthesis with thinning of the skin
- Immune suppression -> inhibition of NF-kB (transcription factor for IL-2, TNFa), inhibition of PLA2, and inhibition of neutrophil margination / migration
- Amenorrhea - increased ACTH levels stimulate increased androgen:estrogen ratio, inhibit FSH/LH
What does Cushing syndrome do to blood pressure / electrolytes and how?
- At high levels, cortisol cross-reacts with mineralocorticoid receptors -> increase Na+ resorption and thus K+ wasting, Increases blood pressure.
- K+ wasting -> hypokalemia, and alkalosis as body tries to resorb K+ in the distal tubule via H+/K+ antiporter
- Cortisol increases alpha1 receptor sensitivity of peripheral vessels (stress hormone) -> hypertension
What does Cushing syndrome do to bones and how?
Osteoporosis -> inhibition of osteoblast activity directly, as well as increased Ca+2 wasting in GI tract and kidney
What screening test is commonly used for Cushing’s syndrome? How does it work?
Overnight dexamethasone suppression test
-> 1 mg of dexamethasone is taken at 10pm. Plasma cortisol is drawn next morning at 8am. If cortisol is suppressed to <5 micrograms/dL, Cushing’s syndrome is very unlikely
