Pharmacologic Therapy

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Dopamine is the principal neurotransmitter responsible for the inhibition of prolactin secretion from the anterior pituitary. Thus, dopamine agonists are the main pharmacologic therapy used for management of hyperprolactinemia.40 Treatment with dopamine agonists has proven to be extremely effective in normalizing serum prolactin level, restoring gonadal function, decreasing tumor size, and improving visual fields.40 Patients with macroprolactinomas generally require a higher dose to normalize prolactin levels compared with patients with microprolactinomas.43

Two dopamine agonists are used for the management of hyperprolactinemia, bromocriptine, and cabergoline (Table 46-5).39,45 Because these two dopamine agonists are ergot derivatives, they are contraindicated in combination with potent cytochrome P-450 subfamily IIIA polypeptide 4 (CYP3A4) inhibitors, including protease inhibitors (e.g., ritonavir and indinavir), azole antifungals (e.g., ketoconazole and itraconazole), and some macrolide antibiotics (e.g., erythromycin and clarithromycin). Furthermore, ergot derivatives can cause constriction of peripheral and cranial blood vessels. These medications are also contraindicated in patients with uncontrolled hypertension, severe ischemic heart disease, or peripheral vascular disorders. Caution should be exercised with concomitant use of other ergot derivates and in patients with impaired renal or hepatic function, dementia, concurrent antihypertensive therapy, or a history of psychosis, peptic ulcer disease, or cardiovascular disease.

Bromocriptine

Bromocriptine directly binds to the D2 receptors on the lactotroph cells to exert its effect. Bromocriptine normalizes prolactin level in more than 90% of patients, restores

menstrual cycles, and reduces tumor size in 62% of patients. Adverse effects such as nausea, dizziness, and orthostatic hypotension often limit 5% to 10% of patients from continuing treatment. Thus, start bromocriptine at a low dose (e.g., 0.625-1.25 mg) at bedtime (taken with a snack) to decrease adverse effects.41 Slowly titrate up to the optimal therapeutic dose (2.5-15 mg/day) because most adverse effects subside with continual treatment.43 If the adverse GI effects are not tolerable, bromocriptine can be administered vaginally at a reduced dose (2.5 mg/day).46 Owing to its short half-life of only 6 hours, bromocriptine must be administered in divided doses, which may compromise patient adherence.

Cabergoline

Cabergoline has a higher affinity for D2 receptors than bromocriptine. It is a long-acting dopamine agonist capable of inhibiting pituitary prolactin secretion for at least 7 days after a single oral dose.45 The prolonged duration of action allows for once- or twice-weekly administration. Cabergoline appears to be significantly better tolerated than bromocriptine. Transient elevations of serum alkaline phosphatase, bilirubin, and aminotransferases have been reported in a few patients treated with cabergoline. Cabergoline is more effective in normalizing prolactin levels and restoring menses than bromocriptine.45 It also may be effective in treating hyperprolactinemia in patients who are resistant to or intolerant of bromocriptine and in men and women with micro- and macroprolactinomas.39 Given its favorable safety and efficacy profile and ease of administration, cabergoline has replaced bromocriptine as first-line therapy for the management of hyperprolactinemia.4 Withdrawal of pergolide from the U.S. market due to increased risk for valvular heart disease raised concerns about the safety of cabergoline. In patients with prolactinomas, tricuspid regurgitation was associated

with higher cabergoline cumulative dose of more than 280 mg. However, recent studies suggest the lower doses of cabergoline commonly used in the management of hyperprolactinemia do not appear to increase the risk of clinically significant valvular heart diseases.48,49

Nonpharmacologic Therapy

In a small number of patients who have failed or are intolerant of dopamine agonists, transsphenoidal adenomectomy may be necessary. Surgical treatment is also considered in patients with nonprolactin-secreting tumors or macroprolactinomas that jeopardize the optic chiasm. 0 Nonetheless, surgical intervention does not reliably

lead to long-term cure and may cause permanent complications. Radiation therapy is reserved for failures of both pharmacologic therapy and surgery.40 However, normalization of prolactin levels with radiation therapy may take 10 years to show full benefit, and radiation-induced hypopituitarism may require lifelong hormone replacement.

Management of Hyperprolactinemia in Pregnancy

Most women with hyperprolactinemia require dopamine agonist therapy to achieve regular ovulatory cycles and pregnancy. Since restoration of the ovulatory cycle may occur within 1 week of initiating therapy, it is necessary to caution patients regarding their potential to become pregnant.50

FIGURE 46-4. Management of hyperprolactinemia. (From Ref. 42.)

Overall, there is reassuring worldwide experience that bromocriptine use during pregnancy does not increase fetal malformations, spontaneous miscarriage, ectopic pregnancy, or multiple births.39,41 Furthermore, no teratogenic effects have been reported in women who received cabergoline during the first and second trimesters of pregnancy.41"45 Despite these data, women who become pregnant while on a dopamine agonist should discontinue treatment immediately to minimize fetal exposure. Because cabergoline has a prolonged half-life, women who plan to become pregnant should discontinue the drug at least 1 month before planned conception.

Microadenomas rarely cause complications during pregnancy. However, untreated macroprolactinomas carry about 15% to 35% risk of tumor enlargement and potentially can jeopardize vision.43 Therefore, monitor women with macroprolactinomas closely for the development of headache and visual impairments. Baseline and routine visual field examinations are essential. Evidence of abnormal visual fields may indicate tumor growth and should be followed by an MRI. Should tumors enlarge, bromo-criptine is the preferred choice over cabergoline because of greater experience with this drug during pregnancy.41'50

Table 46-5 Comparison of Dopamine Agonists for Treatment of Hyperprolactemia

Bromocriptine ¡f*.irk>[lLL|J

Cabcrgolinr

Starting dose Tjlrflling

Usually effective dose Msnimal dose Dosing frequency Dowac in hfpjtic innilfldtAcy Dosage in renal failure Adverse effects

Gilt

Û6Î5-1JS ring/day At bedtime 1JS rttrr ¡IWimiflB M 1-WH+ inliiy.il ï.i-lS mg/darf 40 Tigyyay

Miy t* required ¡n«ulL' tufMlitr w iirlioiis.

No Quidelii'ieí arí auiitshle None

Diziiness, heada:!», syncope, narisea, voinilMvgt Gkracnps, oMhosiatc hypotension i

OLÍ mg/ïwek, of 4ÎS mg twlceftneek rïïfj iH'ifnínr,.: A v^H^r ¡rice*Y¿k t-j injViwek 4.'j mg/ureek Once or t^ke weekly

DtA.1 letAjakjns rruytk' racommertíJed fe* u¿t¡íntíi*¡[h wv^ie heiHUí failure CeI hilol-Pugh «c*« of to oí highen None

Similar bur uihoiiarc hypotension lesfewnrmn

S. nwdfíltlr íspeWvt SS. irniíe^íisensr.f. from lïrfs. ffil 45.

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