MANAGEMENT OF HYPERPROLACTINEMIA

Expectant Treatment

Women with radiologic evidence of a microadenoma or functional hyperprolactinemia who do not wish to conceive may be followed without treatment by measuring prolactin levels once yearly. Many of these women have deficient estrogen, and low estrogen levels in combination with hyperprolactinemia have been shown to be associated with the early onset of osteoporosis. If the woman has low estrogen levels, exogenous estrogen should be administered. Either replacement estrogen-progestin therapy, as is used for postmenopausal women, or oral contraceptives can be utilized. Corenblum and Donovan reported that a group of women with both functional hyperprolactinemia and prolactin-secreting pituitary microadenomas who were treated with either cyclic estrogen and progestin or oral contraceptives for several years did not have an increase in the size of the adenomas or a marked increase in prolactin levels. Mean prolactin levels actually declined with both treatment regimens. Testa reported that 2 years of OC use in a group of women with hyperprolactinemia with microadenoma did not alter the size of the adenoma. Since side effects and cost are less and compliance is better with exogenous estrogen than with bromocriptine, it is not necessary to use the latter agent unless ovulation and pregnancy are desired. Individuals with hyperprolactinemia with or without microadenomas who have adequate estrogen levels as shown by the presence of oligomenorrhea or amenorrhea with estradiol levels above 40 pg/ml who do not wish to conceive should be treated with periodic progestin withdrawal (medroxyprogesterone acetate 10 mg per day for 10 days each month) or combination oral contraceptives to prevent endometrial hyperplasia.

Medical Therapy

The initial treatment for macroadenomas, as well as for women with hyperprolactinemia who are anovulatory and wish to conceive, should be a dopamine receptor agonist. Bromocriptine, methysergide, metergoline, and cabergoline have been used with success, but only bromocriptine (2-Br-alpha-ergocryptine mesylate) and cabergoline are approved for use in the United States (Figure 39-8) . The greatest amount of clinical experience has been with use of bromocriptine. This semisynthetic ergot alkaloid was developed in 1967 to inhibit prolactin secretion. It directly stimulates dopamine receptors, and as a dopamine receptor agonist it inhibits prolactin secretion both in vitro and in vivo. After ingestion, bromocriptine is rapidly absorbed, with peak blood levels reached 1 to 3 hours later. Serum prolactin levels remain depressed for about 14 hours after ingestion of a single dose, after which time the drug is not detectable in the circulation. For this reason
 the drug is usually given at least twice daily, with initial therapy being started at one half of the 2.5-mg tablet to minimize side effects. The most frequent side effects are orthostatic hypotension (with an incidence of 15%), which can produce fainting and dizziness as well as nausea and vomiting. To minimize these symptoms the initial dose should be taken in bed and with food at nighttime. Less frequent adverse symptoms include headache, nasal congestion, fatigue, constipation, and diarrhea. Most of these reactions are mild, occur early in the course of treatment, and are transient. To reduce the adverse symptoms, the dose should be gradually increased every 1 to 2 weeks until prolactin levels fall to normal. The usual therapeutic dose is 2.5 mg twice or three times a day, but larger doses are sometimes used when a macroadenoma is present.

Adverse effects, such as nausea, vomiting, and nasal congestion, occur in about half the women taking oral bromocriptine and may cause them to discontinue treatment. Vermesh
et al. reported that the drug was very well absorbed vaginally without the presence of side effects. Furthermore, when a single tablet was placed deep in the posterior vaginal fornix, therapeutic blood levels persisted for more than 24 hours, during which time prolactin levels remained suppressed . Ginsburg et al. subsequently reported that this method of bromocriptine administration was well accepted, effective, and well tolerated in a group of 31 hyperprolactinemic women, 17 of whom could not tolerate oral bromocriptine. Minor side effects occurred in only three women. The tablet is placed digitally deep in the vagina nightly at bedtime. A single 2.5-mg dose reduced prolactin concentrations in 90% of patients treated and brought the levels to normal in one third of women. Higher doses do not appear to be more effective. Ginsburg et al. recommended that the drug be administered vaginally instead of orally for all women as a smaller dose of drug can be used, once-daily administration is more convenient, and side effects are fewer.

Bromocriptine is approved for treatment of adverse symptoms associated with hyperprolactinemia, such as galactorrhea, as well as anovulatory infertility with and without the presence of a prolactin-secreting adenoma. In hyperprolactinemic women without adenomas, prolactin levels return to normal in more than 90%, fertility is restored in 80%, and galactorrhea is eradicated in 60% with bromocriptine therapy. In women with hyperprolactinemia and a microadenoma, similar rates of success have been reported. Therefore bromocriptine is the treatment of choice for women with prolactin-secreting microadenomas who wish to ovulate or are bothered by galactorrhea.
Despite administration of up to 20 mg of bromocriptine per day orally, about 10% of individuals with microadenomas fail to have prolactin levels return to normal, probably because of individual differences in the sensitivity of lactotrophs to bromocriptine. Nevertheless, despite the persistently elevated prolactin levels, many of these women ovulate and conceive.

If pregnancy occurs after ovulation is induced with bromocriptine, therapy is usually discontinued, although there is no evidence that the drug is teratogenic or adversely affects pregnancy outcome. If pregnancy is not desired but bromocriptine is used to treat galactorrhea, therapy is usually continued for at least 12 months, after which it should be discontinued for a few weeks. Most women with microadenomas have recurrence of hyperprolactinemia, amenorrhea, and galactorrhea, although about 10% to 20% have permanent remission after discontinuing bromocriptine treatment. Moriondo et al. reported that after 1 year of bromocriptine treatment, 11% of women with microadenomas had persistent normalization of prolactin, with return of regular menses after the drug was discontinued. This incidence of permanent remission reached 22% after 2 years of treatment. A higher rate of permanent remission occurred in women treated with 10 mg per day than with lower dosages, but higher doses of drug increase the incidence of adverse reactions and cause discontinuation of treatment. These investigators found that after bromocriptine was discontinued, there was a 40% reduction in mean prolactin levels in all women treated, and about 60% had a greater than 30% reduction from pretreatment prolactin levels after the drug was discontinued. Rasmussen et al. reported the results of discontinuation of long-term (median of 2 years) bromocriptine therapy in 75 hyperprolactinemic women. In about half the women it was necessary to reinstate treatment because prolactin levels rose. However, in the other half further treatment was unnecessary because mean prolactin levels decreased more than 60% and either returned to normal or were only slightly elevated. More than half of these 33 women resumed regular menses without further treatment. These data indicate that the remissions were drug related and not spontaneous. Using CT scans before and during bromocriptine therapy, Bonneville et al. found that about 75% of individuals with microadenomas had reduction in tumor size during bromocriptine treatment, and in 40% the tumor had disappeared. To determine are usually promptly relieved. Following subsequent surgical removal of these bromocriptine-treated tumors, histologic examination revealed a reduction of tumor cell size, with shrinkage of the cytoplasm being greater than the nucleus. In addition, there are modifications of cell structure and morphology as compared with tumors removed without prior medical treatment. The organelles responsible for prolactin synthesis shrink, indicating that bromocriptine impairs prolactin synthesis as well as release. The reduction in size of macroadenomas usually occurs rapidly, within a few weeks after starting treatment, but following withdrawal of drug the tumor size may increase just as rapidly; thus the drug should be withdrawn cautiously. In contrast to the frequent occurrence of pituitary insufficiency, including diabetes insipidus, after surgical or radiologic treatment of large tumors, bromocriptine treatment is not accompanied by any type of pituitary insufficiency.
Because permanent remission rarely occurs following withdrawal of bromocriptine treatment from individuals with large tumors, long-term treatment is usually necessary. The drug has been administered in some individuals for up to 12 years without problems, and once biochemical, radiologic, and clinical responses to treatment are established, they are generally maintained over a long-term period. Bromocriptine has also been successfully used to treat individuals with failure of, or recurrence after, operation or irradiation therapy.

Molitch et al. reported the results of a 1-year prospective multicenter study of the use of bromocriptine as primary therapy for prolactin-secreting macroadenomas in 27 individuals. Bromocriptine dosage ranged from 5 to 12.5 mg daily, with 7.5 mg being the most frequent dose. Prolactin levels fell in all individuals, and to 11% or less of pretreatment values in all but one. Of this group, two thirds had prolactin levels decrease to normal during treatment. Tumor shrinkage was observed in all individuals, being reduced by more than 50% in half the patients and by about 50% in an additional 20% of the study group. Visual field impairment disappeared in 9 of the 10 individuals with abnormalities. In two thirds of the individuals reduction in tumor size occurred by 6 weeks, but in one third it was not evident until 6 months, indicating there were both rapid and slow responses of tumor to drug treatment. Therefore at least a 6-month trial of medical therapy is warranted for individuals with a macroadenoma.

Because of these excellent results, the poor initial results of operation, and the high recurrence rates, these investigators concluded that bromocriptine should be used as the initial management of individuals with prolactin-secreting macroadenomas. After maximal shrinkage of tumor, medical therapy can be continued or operative treatment used. The cost of continuing bromocriptine treatment is considerable; it is inconvenient to take medication several times a day, and some individuals have unpleasant side effects with the higher dosages that may be necessary. Therefore some individuals prefer operative treatment. If they elect to have an operation, the drug should be continued until the time of operation to prevent tumor expansion. The rates of success after operation are no different among individuals who received or did not receive bromocriptine before the operation.

Cabergoline is a long-acting dopamine receptor agonist. This agent has a direct inhibitory effect on pituitary lactotrophs to decrease prolactin secretion. It is given orally in doses of 0.25 to 1.0 mg twice a week. Peak plasma levels occur in 2 to 3 hours and this drug has a half-life of 65 hours. Its slow elimination and long half-life produces a prolonged prolactin-lowering effect. The initial dose is 0.25 mg twice weekly and the dosage may be increased at intervals of 4 weeks to achieve a satisfactory response. In a randomized trial with bromocryptine, cabergoline lowered prolactin levels to normal in 83% of women, induced ovulation in 72%, and eliminated galactorrhea in 90%. The effectiveness of cabergoline was greater than bromocryptine. Adverse effects, particularly nausea, headaches, and dizziness, occurred with both agents but were less frequent, less severe, and of shorter duration with cabergoline. Therefore cabergoline is better tolerated than bromocryptine and has higher continuation rates. In contrast to the numerous clinical studies performed with bromocryptine there are very few reports of the effects of carbergoline when it is used to treat hyperprolactinemia in women. It is recommended that after serum prolactin levels have remained normal for 6 months carbogoline be discontinued to determine if the prolactin levels stay low without therapy.

Operative Approaches

Transsphenoidal microsurgical resection of prolactinoma has been widely used for therapy, and numerous reports of large series of individuals treated by this technique have been published. In a review of these studies Randall et al. concluded that transsphenoidal operations have minimal risk with a mortality of less than 0.5%, all deaths being reported to occur after treatment of macroadenomas. The risk of temporary postoperative diabetes insipidus is 10% to 40%, but the risk of permanent diabetes insipidus and iatrogenic hypopituitarism is less than 2%. The initial cure rate, with normalization of prolactin levels and return of ovulation, is relatively high for microadenomas (65% to 85%) and less so with macroadenomas (20% to 40%). Vision can return to normal in 85% of patients with loss of acuity and visual field defects.

The initial cure rate is related to the pretreatment prolactin levels. Those tumors with levels less than 100 ng/ml have an excellent prognosis (85%), and those with levels greater than 200 ng/ml have a poor prognosis (35%). Operative treatment of tumors in individuals older than 26 with amenorrhea for more than 6 months carries a poorer prognosis than tumors in younger women with a shorter duration of amenorrhea. Nevertheless, long-term follow-up of patients after operation indicates that late recurrence of hyperprolactinemia is common. Serri et al. followed 28 women with microadenomas and 16 with macroadenomas for 6 years after operation. Although prolactin levels normalized and menses resumed in 24 (85%) of those with microadenomas and 5 (31%) of those with macroadenomas who had a good initial postoperative response, hyperprolactinemia recurred in half of those with microadenoma and 4 of the 5 with macroadenomas after a mean period of 4 and 2.5 years, respectively (Figure 39-14) . There was no significant difference in recurrence rates for those who conceived and those who did not. Rodman et al. reported a lower postoperative recurrence rate (about 20% for both microadenomas and macroadenomas) following initial cure rates of 85% and 37%, respectively. The risk of recurrence in both series appeared to be related to the immediate postoperative prolactin levels, being greater in persons with a prolactin level greater than 10 ng/ml.

The relatively high rates of late recurrence indicate that these individuals have an underlying hypothalamic defect in dopamine regulation that continues after operative removal of the adenoma.
Because of the good results with medical therapy, surgery is recommended only for women with macroadenoma who fail to respond to medical therapy or have poor compliance with this regimen. It is best to reduce the size of macroadenomas maximally with bromocriptine before surgical removal of these extrasellar tumors.

Radiation Therapy

External radiation with cobalt, proton beam, or heavy particle therapy and brachytherapy with yttrium-90 rods implanted in the pituitary have all been used to treat macroadenomas but are not the primary mode of treatment. Results of such therapy have been inconsistent, and there is a delay of several months between treatment and resumption of ovulation. Furthermore, damage to normal pituitary tissue occurs, frequently leading to abnormal anterior pituitary function as well as diabetes insipidus. Damage to the optic nerves may also occur. Thus radiation therapy should be used only as adjunctive management following incomplete operative removal of large tumors.

Pregnancy

Many women with hyperprolactinemia with or without adenomas wish to become pregnant. A small percentage conceive spontaneously, while most require treatment to induce ovulation. Barbieri and Ryan compiled a literature review of the pregnancy courses of 275 women with adenomas, the majority of whose conceptions had been induced by bromocriptine. They reported that of 215 women with microprolactinomas, less than 1% had changes in visual fields, radiologic evidence of tumor enlargement, or neurologic signs. About 5% developed headaches during pregnancy. Of 60 women with macroprolactinomas, 20% developed adverse changes in visual fields and polytomographic or neurologic signs during pregnancy, and some of them required bromocriptine or operative treatment during pregnancy or shortly postpartum. For this reason excision of macroprolactinomas before pregnancy is attempted has been recommended. Nevertheless, because pituitary function is usually diminished after operation, induction of ovulation must be performed with complicated and expensive gonadotrophin treatment. Bromocriptine treatment does not interfere with pituitary function and is thus the therapy of choice for women with macroadenomas who wish to conceive. Continuous bromocriptine treatment throughout pregnancy for women with macroadenomas has been recommended by some, because with this therapy visual disturbances are rare. Despite a lowering of prolactin levels, there is no effect on placental hormone production, and pregnancy outcome does not appear to be affected.

Nevertheless, since bromocriptine crosses the placenta and suppresses fetal prolactin levels, its long-term effects on the newborn are unknown. Therefore it is now advised that women with macroadenomas discontinue the drug after conception, as do those with microadenomas, and have therapy reinitiated if and when symptoms of visual disturbance or severe headaches occur. Most women who conceive after bromocriptine treatment have ingested the drug for a few weeks after conception. In a review of 1410 such pregnancies compiled by Turkalj et al. there was a spontaneous abortion rate of 11%, ectopic pregnancy rate of 0.7%, and twin pregnancy rate of 1.8%. The incidence of minor (2.5%) and major (1%) congenital defects was similar to pregnancy outcomes in untreated populations of women. The mean amount of drug ingested and duration of postconception treatment were similar in mothers who had normal children and those with defects. Thus ingestion of bromocriptine during pregnancy does not appear to increase the risk of congenital abnormalities, spontaneous abortion, or multiple gestation. Postnatal surveillance of more than 200 children born in this series has revealed no adverse effects to date.

Ruiz-Velasco and Tolis compiled the obstetric histories of nearly 2000 pregnancies occurring in hyperprolactinemic women that have been reported in the literature. Most of these pregnancies were induced with bromocriptine. There was a term delivery rate of 85%, an abortion rate of 11%, a prematurity rate of 2%, and a multiple pregnancy rate of 1.2%. Although prolactin levels increased during pregnancy, after delivery the levels returned to pretreatment values in about 85%. A postpartum increase over pretreatment levels was uncommon (3%), while prolactin levels returned to normal in 13%. Likewise, among women who had postpartum radiologic sellar examination, 84% showed no change, 9% improved, and 7% worsened. Thus stopping treatment during pregnancy only occasionally results in tumor growth. It is advised that women with macroadenomas have monthly visual field examination and neurologic testing during pregnancy, but this is probably unnecessary for women with microadenomas unless they develop symptoms of headache or visual disturbances.
Following delivery, breast-feeding may be initiated without adverse effects on the tumors. Godo et al. reported that use of bromocriptine before conception and during pregnancy did not affect the incidence of persistent lactation following discontinuation of nursing. The incidence of menstrual abnormalities and degree of galactorrhea were usually similar to the state that existed before starting bromocriptine therapy. Therefore, following completion of nursing, as well as for women who do not breast-feed at all, bromocriptine should be ingested for 2 to 3 weeks and then discontinued. At that time serum prolactin measurement should be performed and treatment reinstituted according to the findings.

Women with Hyperprolactinemia Who Do Not Wish to Conceive

For women who do not wish to conceive and for whom galactorrhea is not a problem, no therapy is necessary unless estrogen levels are low. Thus to prevent osteoporosis in this clinical situation, estrogen-progestin hormone replacement or oral contraceptives should be given regardless of whether an adenoma is present. Long-term evaluation of all women with hyperprolactinemia should be performed. Unless a macroadenoma is present, measurement of prolactin levels once a year is advisable. Repeat imaging studies are unnecessary unless symptoms of headaches or visual disturbances occur or prolactin levels increase substantially. If bromocriptine therapy is used, temporary discontinuation of medication every year is advisable, with prolactin measurement 6 weeks later. If the level is normal, repeat prolactin measurements should be made semiannually. If the level is increased, therapy may be reinitiated. During medical treatment of macroadenomas, MRI or CT and visual field examination should be performed every 6 months to determine the effect of medication on the tumor. At these intervals a decision about whether to continue long-term bromocriptine treatment or remove the tumor surgically can be made.

Comprehensive Gynecology 4th edition (September 6, 2002) by Morton A. MD Stenchever (Editor), William, MD Droegemueller (Editor), MD Herbst Arthur L. (Editor), Daniel R., Jr, MD Mishell (Editor), Arthur L. Herbst