Anterior Pituitary - Maas & Auble

Question 1

How does the hypothalamic-pituitary axis for prolactin release differ from most other pituitary hormones?

Answer 1

Whereas the other anterior pituitary hormones are mostly under direct contol of stimulating hypothalamic hormones (CRH for ACTH, GHRH for GH, etc.), prolactin is primarily under direct inhibitory control by dopamine release from the hypothalamus. Prolactin secretion is increased by a decrease in inhibitory dopamine.

Question 2

What actions does prolactin have on breast tissue?

Answer 2

• Breast differentiation
• Duct prolfieration & branching
• Glandular tissue development
• Milk protein & lactogenic enzyme synthesis

Question 3

Which dopamine receptor is primarily responsible for the inhibition of prolactin in the pituitary? What type of receptor protein is it?

Answer 3

D2, a GPCR

Question 4

What is required for the diagnosis of Hyperprolactinemia?

Answer 4

A single measurement of increased serum prolactin

** >250 ng/ml**

Question 5

Your patient has a prolactin level of 340 ng/ml. Before you consider pathological causes, what **purely **physiological mediators of prolactin levels should you first rule out as the cause?

Answer 5

• Pregnancy
• Lactation
• Exercise
• Sleep
• Stress

Question 6

In general, what types of drugs cause hyperprolactinemia?

Name some drugs in this class.

Answer 6

• Dopamine antagonists (you’re inhibiting the inhibitor!)
  
  • Receptor antagonists
    
    • Metoclopramide (used for GERD, nausea)
    • Risperidone (used for schizophrenia, bipolar)
    • Phenothiazines
    • Butyrophenones
  • Synthesis inhibitors
    
    • Methyldopa (antihypertensive)
• Estrogens

Question 7

If a tumor is indeed at fault, which tumor is most likely when a patient’s prolactin level is:

• Mild (25-100 ng/ml)?
• Moderate (100-250 mg/ml)?
• Severe (>250 mg/ml)?

Answer 7

• Mild: Non-prolactin-secreting pituitary tumor with infundibular stalk compression
• Moderate: Microprolactinoma
• Severe: Prolactinoma

Question 8

What effects would infundibular stalk compression cause on the release of:

• ACTH
• GH
• LH & FSH
• Prolactin

Answer 8

• Decrease (inhibition of CRH transport to the pituitary)
• Decrease (GHRH)
• Decrease (GnRH)
• Increase (inhibition of the inhibitory dopamine)

Question 9

Excluding medications and tumors, what are some other pathological causes of hyperprolactinemia?

Answer 9

• Sarcoidosis
• Irradiation to the brain
• Trauma
  
  • Accidental
  • Pituitary surgery
• Lymphocytic hypophysitis (autoimmune)
• Chronic Renal Failure or Cirrhosis (decreased clearance)

Question 10

How might hyperprolactinemia present in women?

In men?

Answer 10

• Women
  
  • Menstrual irregularities
  • Galactorrhea (50-80% of affected women)
  • Infertility
• Men
  
  • Decreased libido
  • Erectile dysfunction
  • Galacorrhea (less common: 20-30% of affected men)
• Hypogonadism in both sexes

Question 11

Large pituitary tumors such as macroprolactinomas can cause what symptoms secondary to their mass effect?

Answer 11

• Headaches & neurologic deficits
  
  • Cavernous sinus involvement
• Vision changes
  
  • Optic chiasm compression

Question 12

Why do young women typically present with microadenomas (incl. microprolactinoma) whereas older women more often present with macroprolactinomas?

(Hint: men also more often present with macroprolactinomas)

Answer 12

• Young women usually present earlier due to work up of noted menstrual irregularities
• Post-menopausal women (and men) will obviously not notice symptoms like this
  
  • Although, sometimes men will be diagnosed early following a presention of decreased libido and/or ED.

Question 13

What drug class is used to treat hyperprolactinemia?

Name two specific drugs in this class.

Which is preferred, and why?

Answer 13

• Dopamine agonists
  
  • Bromocriptine
  • Cabergoline
    
    • Preferred
    • Higher efficacy (for normalizing prolactin & shrinking tumor size)
    • Higher receptor affinity
    • Fewer side effects (more selective for D2 receptor)
    • Longer half-life (less frequent dosing)

Question 14

What are side effects of dopamine agonists?

Answer 14

• Nausea & Vomiting
• Orthstatic hypotension
• Dizziness
• Nasal congestion

(N.B. Cabergoline is reported to cause cardiac valvulopathy in Parkinson’s patients, but the drug is used at much higher doses in those patients)

Question 15

When is Bromocriptine preffered over Cabergoline in the treatment of hyperprolactinemia, and why?

Answer 15

• In pts undergoing fertility induction that also have hyperprolactinemia
• As initial treatment for macroprolactinomas that have caused compromise of vision, neurologic status, or pituitary function
• For safety reasons
  
  • Bromocriptine has a longer track record for these uses
  • Bromocriptine has a shorter half-life (easier to adjust & compensate for overdoses, I assume)

Question 16

Which hormone(s) positively regulate(s) GH release from the pituitary?

Which hormone(s) negatively regulate(s) GH release from the pituitary?

Answer 16

Positive: GH

Negative: IGF-1 & Somatostatin

Question 17

How does acromegaly present clinically?

Answer 17

[memorizing is probably low-yield, go for broad strokes]

A veritable constellation of symptoms:

• Headache
• Coarse facial features
  
  • Lips, nose, & tongue enlargement
  • Skull growth, esp. supraorbital ridges
  • Lower jaw growth
• Cardiomyopathy, CVD, & HTN
• Thickened skin
• Myopathy
• Increased sweating
• Hand & feet enlargement
  
  • Arthropathy
  • Carpal tunnel syndrome
• Impaired glucose tolerance –> T2DM
• Hepatomegaly
• Colon cancer

Question 18

1. What is typically measured to diagnose acromegaly?
2. What confounds can interfere with this measurement?

Answer 18

1. Serum IGF-1
   
   • Diagnostic in 99% of pts
   • Better than measuring GH
     
     • Longer t1/2
     • Less pulsatile
2. Confounds:
   
   • Malnutrition
   • Acute illness
   • Celiac disease
   • Poorly controlled DM
   • Liver disease
   • Estrogen ingestion

Question 19

You suspect your pt has acromegaly but he also has recently come down with the flu. The illness may interfere with IGF-1 levels. How else could you diagnose acromegaly then and there?

Answer 19

• Oral glucose tolerance test
  
  • Give 100g glucose load & measure GH levels two hours later
  • Glucose normally supresses GH levels to <1 ng/ml within 2hrs
    
    • [This seems to fit with GH being greatest shortly after sleep onset - you’re not eating!]
  • In acromegaly, GH levels may paradoxically increase, remain unchanged, or decrease but not to <1 ng/ml.

Question 20

What non-pharmaceutical options are there for treating acromegaly? Are they effective?

Answer 20

• Transsphenoidal pituitary surgery
  
  • Curative in 65-95% micro-, 40-60% macro-
• Radiation therapy

Question 21

What three drug classes are used to treat acromegaly? Name examples of each.

Answer 21

• Somatostatin Receptor Ligands (SRLs)
  
  • Octreotide
  • Lanreotide
• GH Receptor Antagonist
  
  • Pegvisomat
    
    • Blocks peripheral actions of GH (e.g. liver GH receptor)
• Dopamine agonists - occasionally
  
  • Cabergoline
    
    • 30% of GH-secreting pituitary adenomas are plurihormal and also secrete prolactin

Question 22

What type of receptor is the peripheral GH receptor?

Answer 22

JAK/STAT

Question 23

There are many possible causes of panhypopituitarism / hypopituitarism.

Name as many as you can.

[I would suggest being familiar, not memorizing this point by point.]

Answer 23

1. Mass legions
   
   • pituitary tumors, craniopharyngiomas, cysts, other tumors & cancers
2. Treatment of the skull / brain adjacent to the pituitary
   
   • surgery, radiation, radiosurgery
3. Infiltrative diseases
   
   • lymphocytic hypophysitis, hemochromatosis, sarcoidosis
4. Traumatic
   
   • head injury or perinatal trauma
5. Vascular
   
   • Sheehan’s syndrome (post-partum), pituitary tumor apoplexy
6. Medications
   
   • opiates, glucocorticoids, thyroxine, sex steroids
7. Infections
   
   • Many
8. Genetic
   
   • Combined or isolated defects
9. Developmental
   
   • Ectopic pituitary, pituitary hypoplasia, midline cerebral/cranial malformations

Question 24

Describe the clinical (lab) findings of panhypopituitarism.

Answer 24

• ACTH deficiency or secondary adrenal insufficiency
• TSH deficiency or seconary hypothyroidism
• GH deficiency (in adult)
• Prolactin deficiency
• Gonadotropin deficiency or secondary hypogonadism

(Note that prolactin is also deficient, highlighting the decreased synthetic capability of the pituitary, as opposed to a blockade of transport from the hypothalamus (e.g. tumor), in which prolactin would increase due to loss of negative dopamine feedback.)

Question 25

When trying to make a diagnosis of panhypopituitarism, what is the **key finding** regarding levels of pituitary hormones?

Answer 25

Pituitary hormone levels are **low _or innapropriately not elevated_** given the decreases in T4, cortisol, testosterone/estradiol, and IGF-1.

Question 26

In panhypopituitarism, what **drug** is given to treat the deficiency in: 1. Thyroid hormone? 2. Cortisone? 3. Female sex hormones? 4. Male sex hormones? 5. Growth hormone?

Answer 26

1. Levothyroxine (T4) 2. Hydrocortisone 3. Estrogen and progesterone (if uterus present.) 4. Testosterone 5. recombinant Growth Hormone

Question 27

When treating the thyroid deficiency of a pt with panhypopituitarism, what should you adjust the dosage of levothyroxine based on?

Answer 27

Dose according to **free T4**, *not* TSH

Question 28

What extra drug treatments are required for **fertility** in a man or woman with panhypopituitarism?

Answer 28

* Female: **Gonadotropins** & other fertility drugs * Male: **hCG** injections 3x/week

Question 29

What drug is used to treat mineralocorticoid deficiency in panhypopituitarism?

Answer 29

**Trick question** *[sorry again]* - no treatment required! Mineralocortocoids are part of the RAAS system, which is **not** compromised in hypopituitarism (**secondary** adrenal insufficiency). Mineralocorticoid replacement **would** be required in a **primary**** **adrenal insufficiency (or other defect in RAAS).

Question 30

Regarding rGH replacement therapy for **hypopituitarism** or isolated **GH** **deficiency**: 1. How often is it given? 2. What time of day? 3. What route? 4. What two factors is the dosing based upon? 5. What should be monitered to determine any dose changes?

Answer 30

Daily subQ injection 1. **Once daily** 2. **Evening**, to mimic the normal diurnal pattern of GH release 3. SubQ 4. Dosing based on: * mg/kg/week * etiology of disease 5. IGF-1 levels

Question 31

Name four possible clinical signs of growth hormone deficiency in **neonates**.

Answer 31

1. Jaundice 2. Hypoglycemia 3. Microphallus 4. Traumatic delivery (*contributing factor*)

Question 32

Name 7 possible clinical signs of GH deficiency in children (i.e., older than an infant).

Answer 32

1. Propensity for **hypoglycemia** 2. Increased fat 3. High-pitched voice 4. Microphallus 5. Absent or delayed puberty in the adolescent 6. Weight less affect than height 7. Physical skull defects / midline craniofacial abnormalaties * Occasionally present * Cleft lip, cleft palate, single central incisor

Question 33

What type of test is used to diagnose GH deficiency in children? Can you name specific examples?

Answer 33

* **Stimulation** **tests** * Exercise * Levodopa * Clonidine * Arginine HCl * Glucagon * GHRH * Insulin (rarely used any more - more dangerous, esp. in infants)

Question 34

Who will require higher dosing of rGH: a child with a true growth hormone deficiency or a child with idiopathic short stature (ISS)?

Answer 34

ISS requires higher dose. **GH deficiency**: body ready & able to respond to GH once it has some! **ISS**: Some defect **downstream** of GH causes "resistance" to the hormone's effects.

Question 35

Name two genetic disorders that can result in short stature **despite adequate GH production**.

Answer 35

1. Turner's Syndrome (most often caused by monosomy X) 2. Noonan's Syndrome (several signalling genes implicated; some yet unknown)

Question 36

What specific structures **within the cavernous sinus **can be compromised by enlargement of the pituitary?

Answer 36

* Internal carotid artery * CNs III, IV, V (V1 & V2), and VI

Question 37

What should **initial** treatment be for a **macroprolactinoma** that has *already* caused compromise of vision, neurologic function, and pituitary function?

Answer 37

**Dopamine agonists** are **still** the favored initial treatment, **not** surgery. They are effective in reducing prolactin and shrinking the tumor in \>80% of pts.

Question 38

Is it important to treat patients with a microprolactinoma even if they are **asymptomatic**?

Answer 38

No. Unless symtoms present (whether from prolactin effects or a tumor mass effect), treatment is usually not needed.

Question 39

What is the major serum binding protein of IGF-1?

Answer 39

IGFBP-3

Question 40

What are general metabolic effects of GH?

Answer 40

* Antagonizes insulin * Increases lipolysis & FFA production * Increases protein synthesis

Question 41

Name two symtoms of **primary** adrenal insufficiency that will **not** be present in **secondary** adrenal insufficiency. Why?

Answer 41

* Hyperkalemia * Deficient **mineralocortocoid** activity results in decreased potassium excretion. Mineralocortocoid activity is preserved in secondary insufficiency. * Hyperpigmentation * Excessive **ACTH** stimulates **melanocytes**. ACTH is increased in primary insufficiency (loss of negative feedback) but is decreased in secondary insufficiency.

Question 42

What symptoms of primary hypothyroidism are not present in secondar hypothyroidism?

Answer 42

**None**. Unlike adrenal insufficiency, priamry and secondary hypothyroidism are indistinguishable on the basis of clinical features alone. Labs are needed.

Question 43

What are side effects of GH treatment in children?

Answer 43

S/E are fortunately **rare**, but can include: * SCFE * scoliosis * pseudotumor cerebri * snoring / OSA from tonsil grwoth * Cancer risk? * Debated. In practice, children with other dispositions for cancer are not recommended for GH therapy.