In June 2005, an ad hoc Expert Committee formed by the Pituitary Society convened during the 9th International Pituitary Congress in San Diego, California. Members of this committee consisted of invited international experts in the field, and included endocrinologists and neurosurgeons with recognized expertise in the management of prolactinomas. Discussions were held that included all interested participants to the Congress and resulted in formulation of these guidelines, which represent the current recommendations on the diagnosis and management of prolactinomas based upon comprehensive analysis and synthesis of all available data.

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Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas

Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass. Medical therapy with dopamine agonists is highly effective in the majority of cases and represents the mainstay of therapy. Recent data indicating successful withdrawal of these agents in a subset of patients challenge the previously held concept that medical therapy is a lifelong requirement. Complicated situations, such as those encountered in resistance to dopamine agonists, pregnancy, and giant or malignant prolactinomas, may require multimodal therapy involving surgery, radiotherapy, or both. Progress in elucidating the mechanisms underlying the pathogenesis of prolactinomas may enable future development of novel molecular therapies for treatment-resistant cases. This review provides a critical analysis of the efficacy and safety of the various modes of therapy available for the treatment of patients with prolactinomas with an emphasis on challenging situations, a discussion of the data regarding withdrawal of medical therapy, and a foreshadowing of novel approaches to therapy that may become available in the future.

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Advances in the treatment of prolactinomas.

Substances that alter the measurable concentration of the analyte or alter antibody binding can potentially result in immunoassay interference. Interfering, endogenous substances that are natural, polyreactive antibodies or autoantibodies (heterophiles), or human anti-animal antibodies together with other unsuspected binding proteins that are unique to the individual, can interfere with the reaction between analyte and reagent antibodies in immunoassay. Lipaemia, cross-reactivity, and exogenous interferences due to pre-analytical variation, matrix and equipment reaction also affect immunoassay. Interfering substances may lead to falsely elevated or falsely low analyte concentration in one or more assay systems depending on the site of the interference in the reaction and possibly result in discordant results for other analytes. The prevalence of interference is generally low in assays containing blocking agents that neutralise or inhibit the interference but is often higher in new, untested immunoassays. A wide range of analytes measured by immunoassay including hormones, tumour markers, drugs, cardiac troponin and microbial serology may be affected. Interference in immunoassay may lead to the misinterpretation of a patient's results by the laboratory and the wrong course of treatment being given by the physician. Laboratories should put processes in place to detect, test and report suspected interferences. It is equally important that physicians communicate any clinical suspicion of discordance between the clinical and the laboratory data to the laboratory. The detection of interference may require the use of an alternate assay or additional measurements, before and after treatment with additional blocking reagent, or following dilution of the sample in non-immune serum. It is imperative that laboratories inform physicians of the follow-up procedure and report on the presence of any interference. The establishment of on-going laboratory-physician contact is essential to the continuing awareness of wrong patient results due to interference.

Interferences in Immunoassay

Prolactinomas in women commonly present as small intrasellar tumors, but are usually much larger in men. This discrepancy has generally been attributed to differences in the delay before diagnosis. However, studies comparing clinical and pathological correlates of growth of these tumors in both sexes are lacking. We conducted a retrospective study comparing 45 men and 51 women bearing prolactinoma to determine whether the predominance of large tumors in men was due to a delay in diagnosis or, rather, to a fundamental sex-related difference in tumor growth. Basal PRL levels (mean +/- SEM, 2789 +/- 573 ng/mL) and mean tumor diameter (26 +/- 2 mm) were significantly higher in men than in women (292 +/- 74 ng/mL and 10 +/- 1 mm, respectively; P < 0.001), but were not correlated to the age at diagnosis or the duration of symptoms. Giant tumors (n = 8) occurred in males only. The frequencies of bromocriptine-resistant tumors (30 vs.5%; P < 0.01) and invasive macroadenomas (52 vs.27%; P < 0.001) were significantly greater in men than those in women. Lastly, macroprolactinomas in males exhibited higher indexes of proliferating cells by Ki-67 immunoreactivity (2.6 +/- 1.1% of positive nuclei) than did similar tumors in female patients (0.4 +/- 0.2%; P = 0.08). We conclude that the predominance of large prolactinomas in men is due to a high frequency of rapidly growing tumors, which are often invasive and frequently bromocriptine resistant.

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Sex-related difference in the growth of prolactinomas : a clinical and proliferation marker study.

Clinical practice. Prolactinoma.

OBJECTIVE Large amounts of antigen may produce falsely low values in immunoradiometric assays due to the so-called high dose, hook effect. The study was designed to identify the clinical and biochemical features of patients with pituitary macroadenomas in whom a high dose PRL hook effect was documented. DESIGN The clinical and biochemical features of four patients with the high dose PRL hook effect were compared with those of 54 patients with pituitary non-functioning adenomas and 11 with macroprolactinomas who underwent transsphenoidal microsurgery between 1989 and 1994. MEASUREMENTS The presence of the high dose PRL hook effect was confirmed by an increase in the initial PRL concentration when the immunoradiometric assay was processed after dilutions of the serum. This phenomenon was observed in 5.8% (4/69) of patients with pituitary macroadenomas. Undiluted median (range) PRL levels were 9140 (1530-83850), 1530 (162-3210) and 2110 mU/l (1470-45,000) in patients with macroprolactinoma, non-functioning macroadenoma and the hook effect, respectively. In patients with the hook effect, the median PRL levels increased to 384,720 (317,520-950,000) mU/l when the assay was performed after serum dilution. The proportion of males was 9.9% (1/11) in the macroprolactinoma group, 46.3% (25/54) in the non-functioning macroadenoma group and 100% (4/4) in patients with the hook effect. Patients with prolactinoma and non-functioning adenoma had mean tumour sizes of 20 +/- 9 and 27 +/- 11 mm (SD), respectively, while in the hook effect group it was 51 +/- 10 mm. CONCLUSION This study suggests that the high dose PRL hook effect is observed particularly in patients with very large tumours. The immunoradiometric PRL assay must be performed with serum dilution in order to overcome the high dose PRL hook effect in all new patients with pituitary macroadenomas who may have a prolactinoma.

François Blain

Papers

High prolactin levels may be missed by immunoradiometric assay in patients with macroprolactinomas.