Long Term Management of Prolactinoma

JCEM 92(8): 2861-1865Janet A. SchlechteUniversity of Iowa

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.

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.

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.

• 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

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

• 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.

• 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 】 .

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.

• 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.

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.

• 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.

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.

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.

Can Therapy with Dopamine Agonists BeDiscontinued?

• 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 ).

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

• 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.

• 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.

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.

• 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.

Is There a Role for Surgery in Long-TermManagement 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 )

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.

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.

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.