Prolactinoma

1
Prolactinoma

• Chou Chien-Wen M.D.
• Chi-Mei Medical CenterRef Endocrinology and
  metabolism clinics of North America 2001 Sep

2
Case Report

• Name ???
• Chart No 20144575
• Sex Female
• CC Headache
• Lab prolactin 56 pg/ml, E2 lt 10 pg/ml, FSH 8.3
  mIU/ml, LH 2.8 mIU/ml, T4 5.54, TSH 2.57 uIU/ml,
  Cortisol 8 AM 7.49 ug/dl
• CT scan of brainSphenoid sinus mass (2 cm) r/o
  pituitary tumor with intra-sinus extension

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A "giant" prolactinoma
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Neuroendocrine Regulation of Prolactin Secretion

• PIF
• Dopamine
• Gonadotropin-associated peptide (GAP)
• Gamma aminobutyric acid (GABA)
• PRF
• TRH
• VIP
• Peptide histidine methionine (PHM)

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Etiology of Hyperprolactinemia

• Pituitary disease
• Hypothalamic disease
• Medications
• TCA
• Neurogenic
• Other
• Idiopathic

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Pituitary disease

• Prolactinomas
• Acromegaly
• Empty sella syndrome
• Lymphocytic hypophysitis
• Cushings disease

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Hypothalamic disease

• Craniopharyngiomas
• Meningiomas
• Dysgerminomas
• Non-secretory pituitary adenomas
• Other tumors
• Sarcoidosis
• Eosinophilic graniuloma
• Neuraxis irradiation
• Vascular
• Pituitary stalk section

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Medications

• Phenothiazines
• Haloperidol
• Monoamine oxidase inhibitorss

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Tricyclic antidepressants

• Reserpine
• Methldopa
• Metoclopramide
• Amoxepin
• Cocaine
• Verapamil
• Fluoxetine
• Protease inhibitors

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Neurogenic

• Chest wall lesions
• Spinal cord lesions
• Breast stimulation

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Other

• Pregnancy
• Hypothyroidism
• Chronic renal failure
• Cirrhosis
• Pseudocyesis
• Adrenal insufficiency

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Idiopathic hyperprolactinemia

• One third, prolactin levels return to normal
• 10-15 of patients, rise in prolactin levels to
  more than 50 over baseline
• Over 2-6 yr follow up, evidence of microadenomas
  developed in 10 of patients

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Pathogenesis and Natural History of Prolactinomas

• Clonal proliferation of a single mutated cell
• Pituitary tumor transforming gene (PTTG),
  localized to chromosome 5q33
• Correlate with tumor invasiveness in
  hormone-secreting adenomas
• Prolactinomas occur in 20 of patients with MEN
  type 1
• More aggressive than sporadic prolactinomas
• Risk of progression from microadenoma to
  macroadenoma is only 7
• One third return to normal levels

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Diagnosis of Prolactinomas

• Prolactin is secreted episodically
• Nonsecreting tumor causing modest prolactin
  elevations (usually lt 150 ng/ml)
• Prolactin-secreting macroadenoma (prolactin
  levels usually gt 250 ng/ml)
• MRI with gadolinium enhancement

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Treatment of Prolactinomas

• Observation
• Surgery
• Radiotherapy
• Medical Therapy

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Observation

• Effects of tumor size or effects of
  hyperprolactinemia
• 93 microprolaactinomas do not enlarge over 4-6
  yr period of observation
• If prolactin levels rise significantly, repeat
  scanning
• 7 will grow to be a macroadenoma
• Other indications for therapy decreased libido,
  sexual dysfunction, menstrual dysfunction,
  galactorrhea, infertility, hirsutism, premature
  osteoporosis
• Without therapy, prolactin levels may return to
  normal in about one third of patients

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Surgery

• Transpheoidal surgery mainly, craniotomy rarely
• 973 of 1321 microadenomas (73.7) and 41111115 of
  1279 macroadenomas (32.4) curatively resected,
  prolactin levels were normalized by 1 to 12 weeks
  following surgery
• Recurreeence of hyperprolactinemia often occurs
  within first yr
• Recurrence rates for microadenomas (114 of 544 or
  21) and macroadenomas (50 of 253 or 19.8)
• Long-term surgical cure rate is about 50-60 for
  microadenomas and 25 for macroadenomas

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Radiotherapy

• Radiotherapy is generally not considered a
  primary mode
• 63 patients treated with irradiation following
  noncurative surgery, 10 years, approximately 30
  of patients had normal prolactin levels

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Medical Therapy

• Bromocriptine
• Pergolide
• Quinagolide
• Cabergoline

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Bromocriptine

• An ergot derivative that binds to and stimulates
  dopamine (D2) receptors on normal and
  adenomatous lactotroph cells
• Serum levels peak after 3 hour, nadir is observed
  at 7 hour
• Continued biologic effect ewven with undetectable
  serum levels
• Considerable interindividual variability,
  implying differences in sensitivity to the drug
• Not only decreases prolactin synthesis but also
  prolactin mRNA and DNA synthesis, cell
  multiplication and tumor growth
• When bromocriptine stop, rapid regrowth of tumor
  cell but not always occur if longer periods of
  treatment

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Bromocriptine

• Treatment to reduce Hyperprolactinemia
• Treatment to reduce Prolactinoma Size
• Long-term Considerations
• Side Effects of Bromocriptine Treatment
• Bromocriptine Resistance
• Other Bromocriptine Routes and Preparations

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Treatment to reduce Hyperprolactinemia

• Normal prolactin levels were achieved only in
  70-80
• Substantial reductions in prolactin levels to
  still slightly elevated levels often enough to
  restore ovulation and menses 80-90

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Treatment to reduce Prolactinoma Size (1)

• 8 series of totaling 112 patients
• 45 patients (40.2), gt 50 reduction in tumor
  size
• 32(28.6), 25-50 reduction in tumor size
• 14 (12.5), a less than 25 reduction
• 21 (18.7) no evidence of any reduction
• High resolution CT scans to determine whether
  bromocriptine could also reduce the size of
  microadenomas
• 15 patients, six tumors disappeared completely, 5
  decrease approximately 50 in volume and 4
  remained unchanged with treatment lasting 3 to 12
  months

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Treatment to reduce Prolactinoma Size (2)

• The time course of tumor size reduction is
  variable
• Some patients experience an extremely rapid
  decrease in tumor size with significant changes
  in visual fields within 24-72 hours and
  significant changes noted on scan within 2 weeks
• Others, little change may be noted at 6 weeks but
  scanning at 6 or 12 months may show significant
  changes
• Continued tumor size decreases progressively
  after 1 yr for up to several yrs
• Frequently accompanied by a restoration of other
  pituitary hormonal axes

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Treatment to reduce Prolactinoma Size (3)

• Extent of tumor size reduction did not correlate
  with basal prolactin levels, nadir prolactin
  levels achieved, the percent fall in prolactin or
  whether prolactin levels reached normal
• Some patients had excellent reduction in
  prolactin levels into normal range but only
  modest changes in tumor size, whereas other had
  persistent hyperprolactinemia (although gt 88
  suppression from basal values) with almost
  complete disappearance of tumor
• A reduction in prolactin levels always preceded
  any detectable change in tumor size

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Long-term Considerations

• Perivascular fibrosis developed in tumors,
  adversely affect subsequent surgery
• Specific for macroadenomas and does not affect
  microadenomas
• Prolonged bromocriptine treatment up to 10
  years seems to be well-tolerated
• Bromocriptine withdraw after 1 yr resulted in
  tumor reexpansion in 3 of 4 patients
• More prolonged therapy lasting 3-4 yrs,
  bromocriptine withdrawl results in a resumption
  of hyperprolactinemia in 80-90 of patients and
  in tumor reenlargement in 10-20

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Side Effects of Bromocriptine Treatment

• Most common side effects nausea and vomiting
  3-5
• Usually transient but may recur with each dose
  increase
• Orthostatic hypotension
• Digital vasospasm, nasal congestion and
  depression
• Minimized by starting with 1.25 mg/d with snack
  at bedtime
• Gradually increased to 2.5 mg bid with meals over
  7-10 days
• Higher than 7.5 mg/d usually does not necessary
• Psychotic reaction 8 of 600 patients, resolve
  within 72 h of discontinuing the medication

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Bromocriptine Resistance

• 5-10 do not respond to bromocriptine or only
  minimal responses
• Decreased numbers of dopamine receptors
• Also defects in posttranscriptional splicing

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Intragvaginal bromocriptine administration

• Bromocriptine levels rise more slowly but
  eventually to higher levels
• Drug effect lasts for up to 24 hours
• Gastrointestinal side effects are much less

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Pergolide

• Pergolide (Permax) approved by FDA for treatment
  of Parkinsons disease
• Controlled hyperprolactinemia with single daily
  doses of 50 to 150 ug
• Comparability with bromocriptine with respect to
  tolerance and efficacy
• 39 patients, 29 (75) gt 50 reduction, 4 (10)
  25-50 reduction, 2 (5) lt 25 reduction, 4 (10)
  no change in tumor size

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Quinagolide

• CV 205-502
• Nonergot dopamine agonist with similar tolerance
  and efficacy to bromocriptine and pergolide that
  can be given once daily
• 50 of patients resistant to bromocriptine
  respond to quinagolide

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Cabergoline

• Long half-life, given orally once or twice weekly
• Slow elimination from pituitary tissue,
  high-affinity binding to pituitary dopamine
  receptors, extensive enterohepatic recycling
• After oral administration. Plateau of effect
  between 48-120 hours
• 320 macroadenoma, 91 (28.4), gt 50 reduction, 91
  (28.4), 25-50 reduction, 47 (14.8) lt25
  reduction, 91 (28.4) no change in tumor size

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Pregnancy and Dopamine Agonist Therapy

• Effects of Dopamine Agonists on the Developing
  Fetus
• Effect of Pregnancy on Prolactinoma Size

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Effects of Dopamine Agonists on the Developing
Fetus

• Mechanical contraception should be used until the
  first two to three cycles have occurred
• Dopamine agonist can be stopped after being given
  for only 3-4 weeks of gestation
• Not been found to cause any increase in
  spontaneous abortion, ectopic pregnancies,
  trophoblastic disease, multiple pregnancies or
  congenital malformations
• Long-term follow-up of 64 children between ages
  of 6 months and 9 years shown no ill effects
• Over 100 women, no abnormalities were noted with
  the use of bromocriptine throughout gestation,
  except in one infant with an undescended testicle
  and one with talipes deformity

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Effect of Pregnancy on Prolactinoma Size

• In women with microadenomas, the risk for
  significant symptomatic enlargement was 1.3 (376
  patients)
• In women with macroadenomas, the risk was higher
  23.3 (86 patients)
• Bromocriptine has been used successfully during
  pregnancy to reduce symptomatic tumor enlargement
  rapidly