1. Long Term Management of
Prolactinoma
JCEM 92(8): 2861-1865
Janet A. Schlechte
University of Iowa

2. Case 1
• A 32-yr-old woman developed hyperprolactinemia,
amenorrhea, and galactorrhea after the birth of her second
child. Her serum prolactin was 95 μg/liter (normal is 25), a
pituitary magnetic resonance imaging (MRI) scan showed a 6-
mm adenoma, and she began treatment with cabergoline.
• For the last 2 yr she has taken 0.5 mg cabergoline weekly and
has regular menses. Her prolactin now is 5 μg/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.

3. 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
μg/liter, a normal free T4, and a total testosterone of 150 ng/dl (5.2
nmol/liter) (normal is 300–1200ng/dl). After 3 months of therapy
with cabergoline, his prolactin was 15 μg/liter and the tumor
decreased in size to 4mm. He has now taken 2 mg cabergoline
weekly for 36 months and has no complaints. One month ago, his
prolactin was 11 μ g/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.

4. Background
• Prolactinomas are the most common functioning pituitary tumor.
Ninety percent are intrasellar adenomas that rarely increase in size.
The rest are macroadenomas (10 mm) that usually come to clinical
attention because of local mass effects.
• In women, most prolactinomas are microadenomas (10 mm), and
hypersecretion of prolactin leads to amenorrhea, galactorrhea, and
infertility.
• Men with prolactinomas frequently present with headache, visual
loss, or neurological deficit but also have hypogonadism and
infertility.
• Hyperprolactinemia may lead to bone loss in both men and women
due to the inhibitory effect of prolactin on sex steroids.

5. • The goals of therapy are to normalize prolactin, restore
fertility, reduce tumor size, and ameliorate the symptoms of
hypogonadism. In some cases, gonadal function normalizes even
though serum prolactin remains elevated. In this situation, the
clinical response is more important than the absolute level of
prolactin.
• Pituitary surgery does not reliably lead to a cure, and a dopamine
agonist is the preferred treatment for prolactinomas.
• Bromocriptine normalizes prolactinand decreases tumor size in 80–
90% 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.
• Cessation of therapy leads to recurrence of hyperprolactinemia and
tumor reexpansion

6. Clinical consideration
• Normal prolactin levels in women are less than 25μg/liter and less
than 20 μg/liter in men. With macroadenomas, prolactin levels are
generally more than 250 μg/liter and frequently exceed 1000
μg/liter when the tumor is invasive.
• Close correlation between size and serum prolactin.
• The majority of prolactinomas are microadenomas and rarely
increase in size over time.
• In a summary of 139 hyperprolactinemic women with tumors less
than 10 mm followed longitudinally for over 8 yr, only 6.5% showed
evidence of tumor expansion.
• Longitudinal studies have also shown resolution of
hyperprolactinemia, amenorrhea, and galactorrhea without therapy
in women with microadenomas

7. • Macroadenomas account for about 10% of prolactinomas
and are more frequent in men.
• It has been postulated that the higher prevalence of large
tumors in men is due to a delay in diagnosis, but this does
not seem likely in light of the benign natural history of
small tumors.
• Autopsy studies do not show a preponderance of
macroadenomas or a greater number of large tumors in
men.
• The presence of histological markers of aggressiveness
(Ki67 and proliferative cell nuclear antigen) in
macroadenomas suggests greater proliferative activity, but
the markers have limited predictive value.

8. • How frequently to image the pituitary after therapy ?
【measure prolactin yearly and do not repeat an MRI unless there is a
marked increase in prolactin (more than 250 μg/liter) or clinical signs of
tumor expansion such as headaches or visual loss】.
• Because macroadenomas possess a higher growth
potential, more frequent radiographic monitoring is
necessary.
【 repeat an MRI 2–3 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】.

9. Pregnancy
• During pregnancy, estrogen stimulates prolactin synthesis and
induces lactotroph hyperplasia, which leads to pituitary
Enlargement.
• Prolactinomas also increase in size during pregnancy.
• But whether the tumor enlargement is clinically significant
depends on the size of the tumor.( 3% for micro, 30% for
macro ( If R/T or surgery before conception, decrease to <
5% )
• Although breast stimulation stimulates prolactin
release, there is no evidence that breastfeeding has an
adverse effect on tumor growth.

10. • When pregnancy is the treatment goal, bromocriptine is preferred
over cabergoline because of its extensive safety record.
• Administered during the first few weeks of gestation, bromocriptine
is not associated with an increase in the rate of spontaneous
abortions or congenital malformations.
• Women with microadenomas and intrasellar macroadenomas do
not require serial MRI examinations or visual field testing during
pregnancy but should be monitored each trimester for clinical signs
of tumor expansion.
• Pregnant women with large tumors and those with extrasellar
extension who have stopped bromocriptine are at risk for tumor
growth, and formal visual field testing should be done each
trimester.

11. Use of Oral Contraceptives
• Observation: prolactinomas frequently become apparent
after pregnancy or after discontinuation of an oral
contraceptive suggested that estrogen might play a role in the
pathogenesis of prolactinomas ( including animal study ).
• In reality, autopsies of patients treated with estrogen, and
case control studies: no evidence.
• No evidence of tumor growth was seen in premenopausal
women with microadenomas or women with idiopathic
hyperprolactinemia treated with conjugated estrogen or oral
contraceptives for 2–6 yr.
• Microprolactinomas rarely increase in size during pregnancy.
• No trial of estrogen in macroadenoma or invasive disease.

12. • When fertility is not an issue in women with
microprolactinomas, treatment of hypogonadal symptoms
with an oral contraceptive is less expensive and has fewer side
effects than treatment with a dopamine agonist.
• 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.

13. Beneficial Effects of Pregnancy and Menopause
• Despite the tumor expansion and pituitary growth that occurs
during gestation, observational studies have shown that
pregnancy has a favorable effect on the natural history of
preexisting prolactinomas.
• Prolactin levels are lower after delivery than before conception
and complete remission of hyperprolactinemia has been
reported in 17–37% of women after pregnancy.
• Changes in tumor vasculature resulting in pituitary necrosis,
microinfarction, or hemorrhage have been suggested as
potential mechanisms to explain how pregnancy might lead to
normalization of prolactin.

14. Menopause
• In a retrospective analysis, Karunakaran etal showed that 45%
of hyperprolactinemic patients who passed through
menopause normalized serum prolactin compared with 7% of
controls.

15. Can Therapy with Dopamine Agonists Be
Discontinued?
• The major shortcoming of all dopamine agonists is that
interruption of therapy leads to recurrence of hyperprolactinemia
and tumor regrowth.
• Long-term therapy leads to perivascular fibrosis and cytocidal
effects on pituitary tissue: bromocriptine might lead to
permanent normoprolactinemia.
• The first studies to assess the effect of dopamine agonist
withdrawal showed rapid recurrence of hyperprolactinemia in
over 95% of patients treated for 24 months (bad ). But lower than
pretreatment level ( good ).

16. 13 studies involving 853 patients who were withdrawn from
dopamine agonist therapy between 1983 and 2006
The percentage of subjects achieving a period of normoprolactinemia ranged from 7–69%
(mean 29%). Tumor regrowth was noted in only two individuals

17. • In a comprehensive prospective study, Colao treated patients with
micro- and macroadenomas with cabergoline (1 mg/wk) for 48 and
42 months, respectively. Before drug withdrawal, the cabergoline
was tapered to 0.5 mg/wk, and the drug was withdrawn if 1)
prolactin levels were normal, 2) an MRI showed no tumor or tumor
reduction of at least 50%, 3) the tumor was more than 5 mm from
the optic chiasm, and 4) there was no cavernous sinus invasion.
• From 2–5 yr after cabergoline withdrawal, prolactin was normal in
69% of patients with microadenomas and 64% with
macroadenomas, and no tumor regrowth was observed.
• Although the rate of recurrence was higher among patients who
had evidence of a tumor on MRI at the time of drug withdrawal,
59% with remnant microadenomas and 23%with remnant
macroadenomas had normal prolactin after cabergoline was
withdrawn.

18. • Biswas et al. retrospectively analyzed 89 subjects with
microadenomas treated with cabergoline (0.5–3.0 mg wkly) or
bromocriptine (2.5–10 mg daily) for a mean durationof 3.1 yr.
• Of those who developed recurrent hyperprolactinemia, the
mean time to recurrence was 9.6 months. There was no
difference in remission rates between subjects treated with
cabergoline and bromocriptine.
• Pretreatment prolactin was the only factor significantly
associated with relapse.

19. Who to withdraw drugs
• Patients with microadenomas and those with macroadenomas and
negative MRI scans after treatment are good candidates for drug
withdrawal.
• Because tumor enlargement is uncommon in small tumors, it is not
necessary to obtain a pre-withdrawal MRI in a patient with
microadenoma, and the drug can be stopped without a taper.
• In patients with macroadenomas and negativeMRI scans, the drug
should be slowly tapered before withdrawal.
• During 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.
• Prolactin rising preceding tumor regrowth.

20. • Although a patient with a macroadenoma may not achieve
normoprolactinemia, tumor suppression and normal prolactin
may be attainable at lower doses over time.
• It is not clear whether a dopamine agonist exerts a direct
antitumor effect or whether the normoprolactinemia that
occurs after withdrawal is a manifestation of the natural
history of the disorder.
• Tumor disappearance does occur in patients with
microadenomas without therapy, but it is more difficult to
attribute remission of a macroadenoma to spontaneous
tumor disappearance.

21. Is There a Role for Surgery in Long-Term
Management of Prolactinomas?
• Dopamine agonists are the preferred therapy for prolactinomas
because of the risk of recurrent hyperprolactinemia that
accompanies transsphenoidal surgery.
• Success rates after surgical treatment of microadenomas range
from 73–90% and 30–50% for macroadenomas.
• Although infrequently used, 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.
• Landolt and Osterwalder noted that patients treated with
bromocriptine before surgery were significantly less likely to
normalize prolactin due to perivascular and tumor fibrosis.
(吃過藥的預後比較差?有些study結果剛好相反)

22. Safety of Dopamine Agonists
• Used in doses of 2.5–10 mg daily (bromocriptine) and 0.25–
2mgweekly (cabergoline), long-term adverse effects have not been
reported in patients with prolactinomas.
• In contrast, pleural thickening, parenchymal lung disease, and
serosal fibrosis: reported in patients with Parkinson’s disease s/p
chronic therapy with bromocriptine, cabergoline, and pergolide.
• A recent report of cardiac valve regurgitation in patients with
Parkinson’s disease tx with pergolide and cabergoline.
• The risk of valvular regurgitation appears to be greatest in patients
who receive at least 3mg cabergoline daily, and this dose is 10–20
times higher than that used for usual treatment of macroadenomas.

23. Returning to the Patients: case 1
Because she had a microadenoma and fertility was not an
issue when the diagnosis was made, she could have been
treated with an oral contraceptive instead of a dopamine
agonist. The cabergoline can be discontinued without a taper.
Her prolactin and clinical symptoms should be monitored
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. While taking estrogen, her prolactin level
should be monitored yearly. Another MRI is not necessary
unless she develops clinical signs of tumor expansion or a
marked (250 g/liter) increase in serum prolactin.

24. Case 2
This man is also a candidate for dopamine agonist withdrawal.
The cabergoline should be tapered slowly, and his 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.