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FOCUS ON PITUITARY TUMORS Medical treatment of prolactinomas Annamaria Colao and Silvia Savastano Abstract | Prolactinomas, the most prevalent type of neuroendocrine disease, account for approximately 40% of all pituitary adenomas. The most important clinical problems associated with prolactinomas are hypogonadism, infertility and hyposexuality. In patients with macroprolactinomas, mass effects, including visual field defects, headaches and neurological disturbances, can also occur. The objectives of therapy are normalization of prolactin levels, to restore eugonadism, and reduction of tumor mass, both of which can be achieved in the majority of patients by treatment with dopamine agonists. Given their association with minimal morbidity, these drugs currently represent the mainstay of treatment for prolactinomas. Novel data indicate that these agents can be successfully withdrawn in a subset of patients after normalization of prolactin levels and tumor disappearance, which suggests the possibility that medical therapy may not be required throughout life. Nevertheless, multimodal therapy that involves surgery, radiotherapy or both may be necessary in some cases, such as patients who are resistant to the effects of dopamine agonists or for those with atypical prolactinomas. This Review reports on efficacy and safety of pharmacotherapy in patients with prolactinomas. Colao, A. & Savastano, S. Nat. Rev. Endocrinol. 7, 267–278 (2011); published online 22 March 2011; doi:10.1038/nrendo.2011.37 Introduction Prolactin-secreting adenomas are the most pre­dominant Marked growth of untreated microprolactinomas type of all pituitary tumors. The estimated prevalence (<10 mm in diameter) is uncommon. Treatment of is 100 prolactinomas per million adults,1 although asymptomatic patients with prolactinomas is, therefore, Ciccarelli et al.2 reported an even higher prevalence of not always necessary.6,7 Importantly, patients with macro- 775 per million adults in Belgium. The incidence of pro­ prolactinomas (>10 mm in diameter) and hypo­pituitarism lactino­mas varies with age and sex; these tumors occur should receive standard hormone replacement therapy, with the highest frequency in women aged 20–50 years, the same as any other patient with hormone deficien- at which point the ratio between the sexes is estimated cies. Two exceptions to this statement exist. Initiation to be 10:1. In adults aged >60 years, prolactinomas occur of growth hormone (GH) and gonadal steroid replace- with a similar frequency in both sexes.3,4 During child- ment should be delayed until after normoprolactinemia hood, pituitary tumors are rare; however, pro­lactinomas and/or tumor shrinkage are achieved,8 given that both constitute about 50% of all pituitary adenomas in GH and gonadal steroid deficiencies can be restored by this subpopulation.5 normalization of prolactin levels compared with other The most important clinical symptoms of prolactin deficiencies of the pituitary axis. excess are gonadal and sexual dysfunction as a result This Review summarizes the data on medical treat- of tumor expansion in patients with macroadenomas.6 ment of patients with prolactinomas. In particular, we Medical therapy of prolactinomas relies on the use of will focus on previous findings of an association between dopa­mine receptor agonists, such as bromocriptine, cardiac valve disease and treatment with dopamine ago- cabergoline and quinagolide. Given the evidence-based nists in patients with hyperprolactinemia and on the pos- efficacy of these agents, other dopamine agonists, for sibility that permanent control of prolactin levels can be example, lisuride and terguride, as well as the serotonin achieved after withdrawal from these drugs. antagonist metergoline, are rarely used. The dopamine agonist pergolide has been removed from the market Treatment profile of dopamine agonists because of detrimental effects on cardiac valves. In Dopamine agonists can be divided into two classes: the Department of patients with prolactinomas, the main aims of treatment ergot derivatives, which include bromocriptine, per- Molecular and Clinical are the control of hormone excess and shrinkage of the golide and cabergoline, and the non-ergot derivatives, Endocrinology and Oncology, University tumor mass, together with prevention of their clini- for example, quinagolide. Treatment with dopamine ago- Federico II of Naples, cal consequences. At the same time, residual pituitary nists causes a clinically relevant decrease in the size of Italy, Via Sergio Pansini 5, I‑80131 function must be preserved or improved, and tumor prolactinomas through a number of mechanisms. First, Naples, Italy (A. Colao, re­currence or disease progression should be prevented.1 by reducing cell volume indirectly through inhibition of S. Savastano). hormone secretion in an early phase; second, via inhibi- Correspondence to: Competing interests tion of gene transcription and prolactin synthesis at a A. Colao The authors declare no competing interests. later stage; and finally, by inducing perivascular fibrosis [email protected] NATURE REVIEWS | ENDOCRINOLOGY VOLUME 7 | MAY 2011 | 267 © 2011 Macmillan Publishers Limited. All rights reserved REVIEWS Key points for intravaginal administration. Despite initial promising data,21,22 none of these formulations has been introduced ■■ Medical treatment of prolactinomas with cabergoline, quinagolide or bromocriptine is very efficacious; cabergoline has demonstrated superiority into the market. in efficacy to other drugs in many studies ■■ Cardiac valve disease induced by cabergoline treatment in patients with Cabergoline hyperprolactinemia is still a matter of debate In contrast with bromocriptine, which has a partial ■■ In the absence of unequivocal proof excluding a negative effect of affinity for the D1 receptor, cabergoline is a selective cabergoline in patients with hyperprolactinemia, all patients who receive D2 eceptor agonist with widely known beneficial effects long-term cabergoline treatment should undergo regular echocardiographic in resolving hyperprolactinemia.23 Chronic cabergoline follow-up treatment at a twice-weekly dose of 1 mg significantly ■■ Long-term discontinuation of cabergoline or bromocriptine in patients with reduces serum prolactin levels in up to 95% of women hyperprolactinemia of any cause has shown a variable rate of tumor recurrence; with hyperprolactinemia.24 In a large study that included predictors of recurrence before cabergoline withdrawal are tumor diameter and data from 455 patients,25 cabergoline treatment achieved prolactin levels normalization of prolactin levels in 86% of 425 patients, ■■ Resistance to dopamine agonists is a rare phenomenon that characterizes that is, in 92% of 244 patients with idiopathic hyper­ a group of tumors that generally manifest with a more aggressive behavior prolactinemia or microprolactinomas and in 77% of than usual 181 patients with macroprolactinomas. Only 13% of the patients included in this study reported clinically rele­ and cell necrosis.9 A more extensive discussion of this vant adverse effects, and only 4% of all patients discon- topic can be found elsewhere.6,10 tinued treatment as a result of these adverse events.25 In a comparative retrospective study by Di Sarno et al.,26 the Bromocriptine efficacy of cabergoline was demonstrated to be greater Bromocriptine, the oldest drug for medical treatment than that obtained using bromocriptine. of prolactinomas, was introduced into clinical practice At treatment start, the median dose of caber­goline 25 years ago.6,9–11 This ergot alkaloid is derived by semi- is usually 0.5 mg per week in patients with idiopathic 26 synthesis and has D2 receptor agonist and D1 receptor hyperprolactinemia or microprolactinomas. For indivi­ antagonist properties. Although the most widely used duals with macroprolactinomas, treatment with caber­ drug in patients with hyperprolactinemia is cabergoline, goline should be initiated at very low doses (0.25 mg bromocriptine is still frequently prescribed as the best weekly) to avoid a too rapid effect on tumor shrink- alternative to cabergoline.12 Compared with cabergoline, age,27,28 as this emergency condition can cause intra- bromocriptine has a shorter half-life and is administered tumoral hemorrage that requires immediate surgical two or three times daily. Once daily administration may intervention. The dosage is then increased according to be recommended in some patients who are highly sensi- the individual patient’s condition in order to control pro- tive to the drug. The therapeutic dose generally ranges lactin excess. After 12–24 months of caber­goline therapy, between 2.5 mg and 15.0 mg per day, with most patients a reduction in tumor mass (by ≥20% compared with receiving 7.5 mg or less.13–19 In patients with treatment baseline values) is observed in >80% of cases, whereas resistance, bromocriptine doses can be increased to total tumor disappearance occurs in 26–36% of patients. 20–30 mg per day.17 Cabergoline treatment of patients previously treated In 80–90% of patients with microprolactinomas and with bromo­criptine or quinagolide has been reported in 70% of individuals with macroprolactinomas, bromo­ to cause a further shrinkage of the tumor in the major- criptine treatment controls hyperprolactinemia and thus ity of indivi­duals, even in those considered resistant to restores gonadal function and reduces tumor size.10,11 dopamine agonists.29 As expected, the rate of control of Tumor mass effects, such as headaches and visual

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