LongTerm Management of Prolactinomas

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Long-Term Management of Prolactinomas
APPROACH TO THE PATIENT

• J Clin Endocrinol Metab, August 2007,
  92(8)28612865
• ?????

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• Prolactinomas are a frequent cause of gonadal
  dysfunction and infertility,especially in young
  women.
• The current challenges in management of
  prolactinomas are related to follow-up after
  successful therapy.

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• Issues and questions to be addressed in this
  approach to long-term management of prolactinomas
  include
• 1. The frequency of radiographic monitoring.
  
• 2. Effect of pregnancy and menopause.
• 3. Safety of estrogen in women taking oral
• contraceptives.
• 4. The potential for discontinuation of
  dopamine
• agonist therapy.

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Case 1

• A 32-yr-old woman developed hyperprolactinemia,
  amenorrhea, and galactorrhea after the birth of
  her second child. Her serum prolactin was 95
  ug/liter (normal is 25).
• A pituitary magnetic resonance imaging (MRI) scan
  showed a 6-mm adenoma, and she began treatment
  with cabergoline.

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• For the last 2 yr she has taken 0.5 mg
  cabergoline weekly and has regular menses. Her
  prolactin now is 5 ug/liter, and she does not
  plan future pregnancies. She wants to know when
  to have another MRI and how long she needs to
  take cabergoline.

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Case 2

• While undergoing an evaluation for headaches, a
  50-yr-old man had an MRI that showed a 25-mm
  pituitary mass with suprasellar extension.
• Laboratory testing revealed a serum prolactin of
  1240 ug/liter, a normal free T4, and a total
  testosterone of 150 ng/dl (5.2 nmol/liter)
  (normal is 3001200 ng/dl).
• After 3 months of therapy with cabergoline, his
  prolactin was 15 g/liter and the tumor decreased
  in size to 4 mm.

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• He has now taken 2 mg cabergoline weekly for 36
  months and has no complaints.
• One month ago, his prolactin was 11 ug/liter and
  testosterone 320 ng/dl (11.1 nmol/liter), and an
  MRI showed a 4-mm intrasellar mass.
• He wants to know whether he should have pituitary
  surgery or how long he will need to take the
  dopamine agonist.

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Background

• Prolactinomas are the most common functioning
  pituitary tumor.
• Ninety percent are intrasellar adenomas that
  rarely increase in size.
• The rest are macroadenomas (gt10 mm) that usually
  come to clinical attention because of local mass
  effects.

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• In women most are microadenomas and
  hypersecretion of prolactin leads to amenorrhea,
  galactorrhea and infertility.
• In men frequently present with headache, visual
  loss, or neurological deficit but also have
  hypogonadism and infertility.
• Hyperprolactinemia may lead to bone loss in both
  sex.

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• The goals of therapy are to normalize prolactin,
  restore fertility, reduce tumor size, and
  ameliorate the symptoms of hypogonadism.
• Pituitary surgery does not reliably lead to a
  cure, and a dopamine agonist is the preferred
  treatment for prolactinomas.

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• Bromocriptine normalizes prolactin and decreases
  tumor size in 8090 of patients with
  microadenomas and in 70 with large tumors.
• The selective D2 receptor agonist cabergoline is
  more effective and better tolerated than
  bromocriptine and is also effective in treatment
  of tumors resistant to other dopamine agonists.
• Major shortcoming? cessation of therapy leads to
  recurrence.

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N Engl J Med 20033492035-41.
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Clinical Considerations

• Hormone and radiographic monitoring
• Prolactin normal range (lt25ug/L in woman, lt20
  ug/L in men)

• Close correlation between serum prolactin and
  tumor size.
• It is rare for a prolactinoma to expand
  significantly without a marked increase in
  prolactin.

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• The majority of prolactinomas are microadenomas
  and rarely increase in size over time.
• 139 hyperprolactinemic women with tumors less
  than 10 mm followed longitudinally for over 8 yr,
  only 6.5 showed evidence of tumor expansion.

Gillam MP, Molitch ME, Lombardi G, Colao A 2006
Advances in the treatment of prolactinomas.
Endocr Rev 27485534
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• Macroadenomas account for about 10 of
  prolactinomas and are more frequent in men? delay
  in diagnosis.
• There is no consensus on how frequently to image
  the pituitary after therapy.

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• Microadenomas measure prolactin yearly and do
  not repeat an MRI unless there is a marked
  increase in prolactin (more than 250 ug/liter) or
  clinical signs of tumor expansion such as
  headaches or visual loss.
• Macroadenomas MRI 23 yr after achievement of
  normal prolactin and reduction in tumor size to
  confirm tumor suppression and to ensure that
  prolactin levels are a reliable indicator of
  tumor size.

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The Effect of Pregnancy, Menopause, and Estrogen

• Estrogen stimulates prolactin synthesis and
  induces lactotroph hyperplasia, which leads to
  pituitary enlargement. (during pregnancy).
• Prolactinomas also increase in size during
  pregnancy, but whether the tumor enlargement is
  clinically significant depends on the size of the
  tumor. (Micro. vs Macro.? 3 vs 30).
• No evidence that breastfeeding has an adverse
  effect on tumor growth.

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• When pregnancy is the treatment goal,
  bromocriptine is preferred over cabergoline
  because of its extensive safety record.
• Bromocriptine should be discontinued as soon as
  pregnancy is confirmed.

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• Microadenomas and intrasellar macroadenomas do
  not require serial MRI examinations or visual
  field testing during pregnancy ? monitored each
  trimester for clinical signs of tumor expansion.
• Large tumors and those with extrasellar
  extension formal visual field testing should be
  done each trimester.
• It is not necessary to measure serum prolactin
  throughout pregnancy because levels do not
  uniformly increase during gestation and do not
  correlate with tumor enlargement.

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Use of Oral Contraceptives

• The finding that estrogen given to animals
  induced lactotroph hyperplasia and tumor
  formation led to concerns that estrogen
  administered to women with hyperprolactinemia
  would accelerate tumor growth.
• Autopsies of patients treated with
  pharmacological doses of estrogen do not show an
  increased number of prolactinomas.

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• There are no long-term prospective trials
  demonstrating the safety of physiological doses
  of estrogen in women with prolactinomas.
• No evidence of tumor growth premenopause women
  with microadenoma, idiopathic hyperprolactinemia,
  microadenoma in pregency.

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• No trials examined the effect of estrogen on
  macroadenomas, and women with very large tumors
  and/or tumors with suprasellar extension should
  not be treated with estrogen.
• Oral contraceptives may lead to a mild increase
  in serum prolactin, and prolactin levels should
  be monitored yearly.
• It is not necessary to repeat an MRI in a woman
  taking estrogen unless the prolactin rises
  unexpectedly and exceeds 250 ug/liter.

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Beneficial Effects of Pregnancy and Menopause

• Prolactin levels are lower after delivery than
  before conception and complete remission of
  hyperprolactinemia has been reported in 1737 of
  women after pregnancy.
• Changes in tumor vasculature resulting in
  pituitary necrosis,microinfarction,or hemorrhage.

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• Menopause appears to have a beneficial effect on
  the natural history of hyperprolactinemia.
• A prospective analysis will be necessary to
  confirm potential beneficial effects of pregnancy
  and menopause on remission of hyperprolactinemia.

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Can Therapy with Dopamine Agonists BeDiscontinued

• Shortcoming (1)interruption of therapy leads to
  recurrence, (2) expensive, side effects are not
  infrequent, and compliance can be problematic.
• Table 1 summarizes the results of 13 studies
  involving 853 patients who were withdrawn from
  dopamine agonist therapy between 1983 and 2006.

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Table 1
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• Patients with microadenomas and those with
  macroadenomas and negative MRI scans after
  treatment are good candidates for drug
  withdrawal.
• Microadenomasnot necessary to obtain a
  prewithdrawal MRI in a patient with microadenoma,
  and the drug can be stopped without a taper.

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• Macroadenomas and negative MRI scans, the drug
  should be slowly tapered before withdrawal.
• The first year after drug withdrawal, prolactin
  levels and clinical symptoms should be assessed
  at 3-month intervals because recurrence rates are
  highest in the 12 months after withdrawal.
• Repeating an MRI is not necessary unless
  hyperprolactinemia recurs.
• The possibility that lifelong therapy for
  prolactinomas may be unnecessary is intriguing.

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Is There a Role for Surgery in Long-TermManagemen
t of Prolactinomas?

• Transsphenoidal surgery ?risk of recurrent
  hyperprolactinemia.
• Success ratesmicroadenomas?7390,
  macroadenomas?3050
• Transsphenoidal surgery is an option in
  individuals who cannot tolerate a dopamine
  agonist or in whom the drug is ineffective, but
  dopamine agonists remain the first line of
  therapy.

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• Whether therapy with a dopamine agonist exerts a
  negative effect on surgical outcome remains
  controversial.

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Safety of Dopamine Agonists

• Nausea, vomiting, dry mouth, dyspepsia, or
  dizziness.
• Bromocriptine (2.510 mg daily), Cabergolin
  (0.252 mg weekly)?long term adverse effects not
  reported.
• Pleural thickening, parenchymal lung disease, and
  serosal fibrosis ?Parkinsons disease chronic
  therapy.
• Cardiac valve regurgitation in Parkinsons
  disease. (at least 3 mg cabergoline daily).? very
  high daily doses? Echocardiogram.
• Treatment with any dopamine agonist should use
  the lowest dose and shortest duration possible.

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Returning to the Patients(CASE 1)

• Microadenoma and fertility was not an issue?oral
  contraceptive instead of a dopamine agonist.
• Cabergoline can be discontinued without a
  taper.?prolactin and clinical symptoms every 3
  months during the first year.
• If she is amenorrheic after withdrawal of the
  cabergoline, an oral contraceptive can be used to
  prevent bone loss and treat symptoms of
  hypogonadism.

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CASE 1

• Taking estrogen ? prolactin level should be
  monitored yearly.
• MRI is not necessary unless she develops clinical
  signs of tumor expansion or a marked (250
  ug/liter) increase in serum prolactin.

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CASE 2

• Cabergoline should be tapered slowly.
• Prolactin levels and clinical symptoms should be
  monitored every 3 months in the first year after
  drug withdrawal.
• If normoprolactinemia is not maintained,
  cabergoline should be reinstituted at the lowest
  dose capable of maintaining normoprolactinemia.
• He is not a candidate for transsphenoidal surgery
  because the procedure is not likely to provide a
  cure.

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Conclusions

• Dopamine agonists are the mainstay for therapy of
  prolactinomas.
• Prospective analyses are necessary to define the
  optimal duration of therapy and predictors of
  remission.
• To elucidate whether the apparent remission
  represents an anti-tumor effect of the dopamine
  agonist or the natural history of prolactinomas.

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