Hyperprolactinaemia

Question 1

Clinical presentation pre vs post menopausal

Answer 1

Typical sx occur in premenopausal women and men, but not in postmenopausal women.

Question 2

Clinical presentation pre-menopausal women

Answer 2

Causes hypogonadism:
- infertility (48%)
- headache (39%)
- oligomenorrhoea or amenorrhoea (29%)
- galactorrhea less often (24%)

Question 3

Hyperprolactinaemia accounts for what proportion of cases of amenorrhoea (excluding pregnancy)

Answer 3

10-20%

Question 4

How does hyperprolactinaemia cause amenorrhoea

Answer 4

Inhibition of LH and FSH via inhibition of GnRH

Question 5

Degree of hyperprolactinaemia correlates with sx how?

Answer 5

• Prolactin >100ng/mL = overt hypogonadism -> subnormal oestradiol -> amenorrhoea, hot flashes, vaginal dryness
• Moderate, e.g. 50-100ng/mL = amenorrhoea or oligomenorrhoea
• Mild, e.g. 20-50ng/mL, may only cause insufficient progesterone secretion => short luteal phase (may cause infertility even when there is no abnormality of the menstrual cycle = about 20% of those evaluated for infertility)

Question 6

Hyperprolactinaemia and bone density

Answer 6

women with amenorrhoea secondary to hyperprolactinaemia have lower bone mineral density. Increases after restoration of menses but may not return to normal.

Question 7

Hyperprolactinaemia in post-menopausal women

Answer 7

• are already hypogonadal => sx are absent
• hyperprolactinaemia only recognized when lactotroph adenoma becomes large enough to cause headaches or impair vision, or may be found incidentally on imaging

Question 8

Hyperprolactinaemia in men

Answer 8

Also causes hypogonadotropic hypogonadism
- decreased libido, impotence, infertility (4% of men presenting for fertility work up), gynaecomastia, rarely galactorrhea.
- longer term: decreased muscle mass, body hair and osteoporosis

Question 9

Eval of hyperprolactinaemia - aims

Answer 9

• Most patients have a lactotroph adenoma => eval is aimed at exclusion of pharmacologic or extrapituitary causes, and neuroradiologic eval of the hypothalamic-pituitary region

Question 10

Hyperprolactinaemia - hx

Answer 10

• Pregnancy? (physiologic hyperprolactinaemia)
• Medications (oestrogens, neuroleptic drugs such as resperidone, metoclopramide, antidepressants, cimetidine, methyldopa, verapamil)
• Headache, visual sx, sx of hypothyroidism, hx of renal disease

Question 11

Hyperprolactinaemia - exam

Answer 11

Neurological exam with focus on vision field (bitemporal field loss = chiasmal syndrome)
Look for chest wall injury and signs of hypothyroidism or hypogonadism

Question 12

Hyperprolactinaemia - Ix

Answer 12

• prolactin
• eval for hypopituitarism
• primary hypothyroidism
• renal insufficiency (reduced clearance of prolactin)
• MRI of pituitary to look for a mass, unless taking a medication known to cause hyperprolactinaemia or marked renal impairment

Question 13

Hyperprolactinaemia indications for rx

Answer 13

• Existing or impending neurologic sx due to large size of lactotroph adenoma
• Hypogonadism or other sx such as galactorrhoea
• Infertility (even if mild hyperprolactinaemia and normal cycles may have subtle luteal phase dysfunction)

Question 14

1st line rx

Answer 14

Dopamine agonists
- cabergoline 1st line due to efficacy and favourable side-effect profile (less nauseating than Bromocriptine)
- for hyperprolactinaemia of any cause
- including prolactinomas of all sizes because the drug reduces serum prolactin concentrations and decreases the size of most lactotroph adenomas

Question 15

Causes of hyperprolactinaemia:

Answer 15

1. Reduced dopamine inhibition of prolactin release:
   - drugs such as risperidone, metoclopramide, verapamil
   - hypothalamic tumour
   - head trauma, cranial irradiation, surgery
2. Increased prolactin production:
   - hypothyroidism
   - lactotroph adenoma (mico/macro)
   - stress
   - depression
   - PCOS
3. Reduced prolactin clearance:
   - CKD

Question 16

Microadenoma Rx in women wishing to conceive:

Answer 16

• Cabergoline (better tolerated than bromocriptine)
• Evaluate for side effects and measure prolactin at 1 month
• If normalized, continue dose. Gonadal function will likely return over a few months.
• If prolactin slightly high but menstruation normalized, continue current dose
• If neither of the above, but no side effects, increase dose gradually

Question 17

Intolerance to dopamine agonists

Answer 17

• Can trial alternative (i.e. switch between bromocriptine and cabergoline)
• nausea can be avoided by vaginal administration

Question 18

If all dopamine agonists unsuccessful

Answer 18

• transsphenoidal surgery or ovulation induction with clomiphene can be considered for women wishing to become pregnant
• for women not wishing to become pregnant, oestradiol and progesterone replacement can be considered.

Question 19

Follow up after rx of microadenoma

Answer 19

• Once normal serum prolactin achieved, should be treated for at least 1 year
• After one year, if prolactin is normal, dose can be decreased
• If prolactin has been normal for two or more years and no adenoma is seen on MRI, discontinuation of the drug can be considered
• Serum prolactin measurements should be obtained at least every 12 months
• Dopamine agonists should be stopped in women who become pregnant

Question 20

Microadenoma - Rx

Answer 20

Cabergoline
- If vision was abnormal before therapy, should be reassessed within one month
- MRI should be repeated in 6-12 months to determine if size has decreased
- 6 monthly prolactin measurement if stable

Question 21

Macroadenoma - stopping therapy

Answer 21

• if prolactin concentration has been normal for at least 1 year and then adenoma has decreased markedly in size, dose can be decreased gradually
• Discontinuation can be considered if size 1-1.5cm (at initial presentation) and prolactin normal for more than 2 years and whose adenomas can no longer be seen on MRI for > 2 years.
• If initial adenoma >2cm, discontinuation should probably not be considered as the hyperprolactinaemia will probably recur and the adenoma may increase in size

Question 22

Inadequate response/drug intolerance

Answer 22

• Trial alternative dopamine agonist
• Transsphenoidal surgery
  —> f a significant amount of adenoma tissue remains after surgery, radiation therapy should be administered

Question 23

Role of transsphenoidal surgery

Answer 23

• when dopamine agonist rx unsuccessful in lowering the serum prolactin or size of the adenoma, and sx or signs persist after several months of rx at high doses
• or, a woman that has a giant lactotroph adenoma (e.g. >3cm) and wishes to become pregnant even if the adenoma responds to a dopamine agonist.
  —> rationale is that if the patient becomes pregnant and discontinues the agonist, the adenoma may increase to a clinically important size before delivery

Question 24

Limitations of transsphenoidal surgery

Answer 24

• not all adenoma tissue is excised in many patients, esp those with macroadenomas
• the adenoma and hyperprolactinaemia may recur within several years after surgery

Question 25

complications of radiation (if required as adjunct to surgery for giant lactotroph adenoma)

Answer 25

nausea
lassitude
loss of taste and smell
loss of scalp hair
possible damage to the optic nerve and neurologic dysfunction
50% chance of loss of anterior pituitary hormone secretion during subsequent 10 years

Question 26

Patient counselling before pregnancy

Answer 26

• Discuss options for lowering serum prolactin to normal to restore ovulation
• Counsel re potential risks of treatment during pregnancy to her and the fetus
  –> Maternal risk of adenoma growth: depends on size of the adenoma before pregnancy.
  —> high levels of oestradiol in pregnancy increase the size of the pituitary by double by the 3rd trimester (in normal pregnancy). Similarly, higher levels of oestradiol in pregnancy may increase the size of the lactotroph adenoma -> may lead to neurological sx and most importantly visual impairment
  —> for microadenomas (<10mm diameter) the risk of growth is very low
  —> significantly higher for macroadenomas (> 20%)
• Fetal risk of dopamine agonist exposure
  —> typically discontinued once pregnancy is confirmed, however by this time pregnancy has usually progressed at least 2 weeks => fetus is exposed.
  —> Available evidence suggests that the fetus is not at risk of harm from this exposure (no increase risk of miscarriage or malformations)

Question 27

Counselling before pregnancy in the case of macroadenoma

Answer 27

• higher risk of clinically important enlargement during pregnancy
• once adenoma size has decreased dramatically and is well within the confines of the sella and ovulation has been restored, pregnancy can be attempted

Question 28

when should transsphenoidal surgery be used before an attempted pregnancy?

Answer 28

• If the adenoma elevates the optic chiasm and does not shrink substantially in response to a dopamine agonist –> recommend surgery to reduce size and reduce risk of symptomatic expansion occurring in pregnancy
• if the macroadenoma is unresponsive to a dopamine agonist, even if not elevating the optic chiasm, because the agonist is unlikely to be effective if the adenoma enlarges during pregnancy
• If the macroadenoma is elevating the optic chiasm and causing marked visual impairment
• If the macroadenoma is responsive to dopamine agonist, but in a prior pregnancy became so large that it caused marked visual impairment

Question 29

Carbergoline dose

Answer 29

• Now used as first line as more likely to be tolerated and more effective
• Starting dose = 0.25mg twice/week
• Nocte to reduce the small chance of nausea and orthostatic hypotension
• Increase if the serum prolactin concentration does not normalize after 1-2 months

Question 30

During pregnancy

Answer 30

• Sx:
  —> see at routine intervals (3 /12 for microadenomas, may need more frequent for larger macroadenomas) and ask about HA and change in vision + assess visual fields
• Serum prolactin:
  —> normal for levels to increase to as high as 400ng/mL => often not useful to measure this
• Pituitary MRI:
  —> not required routinely, but if a patient develops severe headaches or visual field abnormalities, pituitary MRI without contrast should be performed to assess adenoma size

Question 31

Rx of enlarging adenoma in pregnancy

Answer 31

If enlarged to a degree to account for HA and/or visual field defect, pt should be treated with a dopamine agonist throughout the remainder of the pregnancy.
—> see at least once/month to reevaluate sx and visual fields
—> if unsuccessful after several weeks and vision is compromised, consider transsphenoidal surgery in the second trimester.
—> In the 3rd trimester, surgery should be deferred until after delivery, if possible

Question 32

Pituitary apoplexy

Answer 32

= Sudden haemorrhage into the pituitary
- Rare event
- Potential serious neuro and endocrine consequences
- Can occur in pts with micro or macroadenomas, during any trimester
- Most dramatic presentation = sudden onset excruciating headache, diplopia due to pressure on the oculomotor nerves, and hypopituitarism
- All pituitary hormonal deficiencies can occur, but the sudden onset of ACTH and therefore cortisol deficiency is the most serious as it can cause life-threatening hypotension
—> Rx high dose hydrocortisone

Question 33

Breastfeeding and dopamine agonists

Answer 33

• Breastfeeding increases serum prolactin concentrations but does not appear to increase the risk of adenoma growth
• Dopamine agonist therapy, which lowers serum prolactin and inhibits lactation, should be witheld until breastfeeding is complete.
• Breastfeeding is contraindicated in women who have visual field impairment because they should be rx with dopamine agonist

Question 34

Normalization of prolactin after pregnancy

Answer 34

• Serum prolactin should be measured 3/12 after delivery in women who do not breastfeed or 3/12 after cessation of breastfeeding
• Recurrence after pregnancy is more likely with macroadenomoas, but both may regress.

Question 35

What % of microadenomas will regress after pregnancy and breastfeeding

Answer 35

> 40%