Pathophysiology of Hypothalamic Pituitary Axis Disorders

Question 1

What hormones stimulate and inhibit prolactin secretion in the posterior pituitary?

Answer 1

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)

Question 2

What is GHIH?

Answer 2

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)

Question 3

What are the male and female consequences of pathologically high elevations of prolactin?

Answer 3

Prolactin inhibits GnRH, which is the stimulator for FSH / LH.

Males - impotence / decreased libido and headaches

Females = Galactorrhea and oligomenorrhea

Question 4

Hypoglycemia and fasting tend to stimulate growth hormone. Why then is it there is profound growth failure in malnourished children?

Answer 4

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

Question 5

What is Kallmann Syndrome a type of, and would it be classified as primary or secondary gonadal failure?

Answer 5

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

Question 6

What is the mechanistic etiology of Kallmann syndrome?

Answer 6

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).

Question 7

What symptoms are associated with Kallmann syndrome and what is the treatment?

Answer 7

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

Question 8

What are the two most common types of pituitary adenomas? How does this relate to most common presentation?

Answer 8

1. Prolactinomas
2. Gonadal (non-functional)

Most common presentation is reproductive dysfunction

Prolactin -> GnRH inhibition
Gonadal -> nonfunctional tumor impinges and causes hypopituitarism

Question 9

How do men and women present differently with prolactinoma?

Answer 9

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.

Question 10

What is standard treatment for prolactinoma?

Answer 10

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

Question 11

What are some causes of hyperprolactinemia which are not prolactinoma?

Answer 11

1. Estrogens - i.e. pregnancy or birth control pills -> number one cause of lactotroph hyperplasia
2. Primary hypothyroidism - Increased TRH levels stimulate PRL
3. D2 antagonist antipsychotics, cocaine use / especially abstinence

Question 12

How can pituitary stalk disease be related to prolactin levels?

Answer 12

Compressing lesions (i.e. macroadenoma) of the hypothalamus and pituitary stalk may occur from decreased dopamine levels -> less tonic inhibition of lactotrophs

Question 13

What is macroprolactinemia? How is it prevented?

Answer 13

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.

Question 14

What is seen in the cells of gonadotroph adenoma and what do they secrete?

Answer 14

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.

Question 15

What are the symptoms of acromegaly?

Answer 15

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

Question 16

What are the common causes of death in acromegaly / what important conditions are they at greater risk for?

Answer 16

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

Question 17

What are important, subtle early symptoms of acromegaly?

Answer 17

1. Carpal tunnel syndrome -> due to increase in soft tissue size.
2. Sleep apnea - from enlargement of the tongue, becomes obstructive

Question 18

How is diagnosis of acromegaly made?

Answer 18

1. Increased serum IGF-1 levels -> represents the integration of growth hormone levels
2. 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.

Question 19

Give three medical treatments for the treatment of acromegaly (resection of the pituitary adenoma should be obvious as first-line).

Answer 19

1. Octreotide (GHIH/somatostatin analog)
2. Pegvisomant (GH receptor antagonist)
3. Cabergoline (dopamine agonists have some efficacy in treatment of this condition, mechanism unknown)

Question 20

What is Laron syndrome? What will labs show?

Answer 20

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).

Question 21

Give the mechanism for the following features of Cushing syndrome:

1. Muscle weakness with thin extremities
2. Moon facies, buffalo hump, and truncal obesity
3. Abdominal striae
4. Immune suppression
5. Amenorrhea

Answer 21

1. Muscle weakness with thin extremities - cortisol breaks down muscle to increase gluconeogenesis
2. Moon facies, buffalo hump, and truncal obesity - high glucose levels due to increased gluconeogenesis with trigger high insulin levels -> storage of fat centrally
3. Abdominal striae -> impaired collagen synthesis with thinning of the skin
4. Immune suppression -> inhibition of NF-kB (transcription factor for IL-2, TNFa), inhibition of PLA2, and inhibition of neutrophil margination / migration
5. Amenorrhea - increased ACTH levels stimulate increased androgen:estrogen ratio, inhibit FSH/LH

Question 22

What does Cushing syndrome do to blood pressure / electrolytes and how?

Answer 22

1. At high levels, cortisol cross-reacts with mineralocorticoid receptors -> increase Na+ resorption and thus K+ wasting, Increases blood pressure.
2. K+ wasting -> hypokalemia, and alkalosis as body tries to resorb K+ in the distal tubule via H+/K+ antiporter
3. Cortisol increases alpha1 receptor sensitivity of peripheral vessels (stress hormone) -> hypertension

Question 23

What does Cushing syndrome do to bones and how?

Answer 23

Osteoporosis -> inhibition of osteoblast activity directly, as well as increased Ca+2 wasting in GI tract and kidney

Question 24

What screening test is commonly used for Cushing’s syndrome? How does it work?

Answer 24

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

Question 25

What are other screening tests other than the dexamethasone suppression test which can be used for Cushing’s syndrome?

Answer 25

1. 24 hour urine cortisol - will be elevated
2. Midnight salivary cortisol level -> cortisol should be lowest at this time. If increased there is likely an issue (cortisol is lowest at 8am and highest at midnight).

If 2 screening tests are normal, Cushing’s syndrome is unlikely.

Question 26

Give two drugs which are used in the treatment of Cushing’s syndrome.

Answer 26

1. Ketoconazole - inhibits 17,20 desmolase, the first step of steroid synthesis. Think of the tin man opening the witch’s area with the key where she is using her book to make make male/female hormones and moon facies
2. Mifepristone - potent antiprogesterone + potent glucocorticoid receptor antagonist -> remember the medpharm coursepack, it’s real homie.

Question 27

What are some causes of hypopituitarism?

Answer 27

1. Congenital
2. CNS irradiation
3. Mass effect
4. Empty sella syndrome
5. Ischemia (pituitary apoplexy)

Question 28

What is the most common cause of congenital hypopituitarism? What hormones will be low?

Answer 28

Mutation in Pit-1, which causes failure of differentiation of somatotroph stem cells, and subsequent failure to deevelop lactotrophs, somatotrophs, and thyrotrophs (see Kupsky lecture)
-> PRL, GH, and TSH will be low, with relative preservation of ACTH and LH/FSH

Question 29

What hormones are most likely to be affected by CNS irradiation?

Answer 29

More peripherally located cell types in the gland -> GH / PRL, rather than centrall located ACTH / TSH

Question 30

What is pituitary apoplexy and what patients are most susceptible?

Answer 30

Sudden hemorrhage of the pituitary gland. Usually occurs in patients with the presence of an existing pituitary adenoma requiring extra oxygenation -> hemorrhagic infarction.

Question 31

What are the symptoms of pituitary apoplexy?

Answer 31

1. Sudden onset severe headache
2. Visual disturbance -> bitemporal hemianopia
3. Diplopia due to CN3 palsy
4. Features of hypopituitarism -> i.e. emergent cortisol insufficiency leading to hypotension

It is a medical emergency.

Question 32

What is Sheehan syndrome and what causes it?

Answer 32

Ischemic infarct of pituitary following postpartum bleeding -> hypotension leads to infarction of pituitary gland which was increased in size during pregnancy (to secrete more prolactin)

Question 33

What are the presenting symptoms of Sheehan syndrome?

Answer 33

Failure to lactate -> loss of prolactin secretion
Absent menstruation / loss of pubic hair -> failure of LH / FSH secretion
Cold intolerance -> loss of TSH

Question 34

What are the possible causing of central DI?

Answer 34

Pituitary tumor (mass affect disrupting posterior pituitary), autoimmune, trauma, surgery, ischemic encephalopathy, idiopathic

Question 35

What is lymphocytic hypophysitis? Who usually gets it and what might is be confused with?

Answer 35

Primary inflammatory disease with massive infiltration of pituitary via lymphocytes and plasma cells
-> usually occurs in late or post pregnancy, may be easily confused with prolactinoma, but not as much of a prolactin elevation is seen

Question 36

What endocrine manifestation does hemochromatosis cause and why?

Answer 36

Hypogonadism. This is another form of secondary gonadal failure as iron deposits in LH cells, preventing LH release.

Question 37

If a patient has involvement of the pituitary in sarcoidosis, what is the most common presentation?

Answer 37

Thickening of pituitary stalk -> mass effect -> hypothalamic diabetes insipidus! You will see something similar when you review Kupsky’s lecture