Diagnostic Investigations

Causes of Hyperprolactinemia

The causes of hyperprolactinemia can be divided simply into physiologic, pharmacologic, and pathologic (Table 2). The normal PRL range for nonpregnant women is <500 mU/L (20 [g/L) and for men <300 mU/L (12 [g/L). Pregnancy is the most common cause of hyperprolactinemic amenorrhea, and serum PRL concentrations may rise as high as 8000 mU/L (320 [g/L) during the third trimester. Normal lactation is also associated with quite marked elevation of serum PRL. As predicted from the physiologic dopaminergic inhibition of PRL secretion, treatment with dopamine receptor antagonist drugs commonly induces hyperprolactinemia. Serum PRL levels may rise as high as 5000 mU/L (200 [ig/L). This is a particular problem with the major tranquilizers (e.g., chlorpromazine) and anti-emetics (e.g., metoclopramide). A source of potential confusion may arise if a patient does not reveal that he or she is taking an over-the-counter preparation, such as a combined medication for the treatment of migraine, which contains both an analgesic and an anti-emetic. Similarly, some nonprescribed herbal or alternative remedies contain constituents that cause PRL elevation. Thus, a comprehensive drug history is essential. With regard to pathologic causes of hyperprolactinemia, it is important to exclude primary hypothyroidism. Modest hyperprolactinemia is present in 40% ofpatients, although only 10% have levels > 600 mU/L (24 ^g/L). Nevertheless, some young women with hypothyroidism may present with menstrual disturbance and galactorrhea, together with few typical hypothyroid symptoms. Once venipuncture stress, pregnancy, interfering drugs, and primary hypothyroidism are excluded, significant hyperprolactinemia is usually associated with a pituitary adenoma (Table 2).

Interpretation of Prolactin Immunoassay Results

Macroprolactin

PRL in human serum exists in multiple molecular forms, with three dominant species identified by gel filtration chromatography: monomeric PRL (23 kDa), big PRL (50-60 kDa), and big-big PRL (macroprolactin, 150-170 kDa). Macroprolactin is a complex of PRL, with an IgG antibody that is detected by most, but not all, PRL immunoassays. The clinical significance and biologic activity of macroprolactin remain contentious. Recent studies have indicated that this PRL species is present in significant amounts in up to 20% of hyperprolactinemic sera. However, many patients with macroprolactinemia do not exhibit typical hyperprolactinemic symptoms, and preliminary data suggest that this prolactin variant is virtually never associated with macroprolactinoma. The presence of macroprolactin can be confirmed by a simple polyethylene glycol precipitation method (8). Presently, there is little justification for detailed pituitary investigation after the finding of macroprolactinemia in an essentially asymptomatic individual.

Prolactin Hook Effect

If serum PRL concentrations are extremely high (as in some men with giant prolactinomas), the amount of PRL antigen may cause antibody saturation in PRL immunoradiometric assays (IRMAs), leading to artifactually low PRL results. This is known as the high-dose hook effect and has been occasionally recognized in other immunoassays (e.g., P-human chorionic gonadotropin [hCG]). This artifact may lead to misdiagnosis and inappropriate surgery for some patients with macroprolactinoma. If an IRMA is employed, serum PRL should always be assayed in dilution in any patient with a large pituitary lesion that might be a prolactinoma (9).

Dynamic Prolactin Function Tests

Several dynamic tests have been proposed for the evaluation of hyperprolactinemia. However, a recent survey showed that only 15% of UK

clinical endocrinologists routinely use dynamic PRL function tests, with most using thyrotropin-releasing hormone (TRH) rather than a dopamine antagonist. In our experience, the intravenous (iv) administration of a dopamine antagonist (such as 10 mg metoclopramide) is a simple well-tolerated procedure that provides clinically useful information, particularly for patients with modest serum PRL elevations. Dopamine antagonist administration to normal individuals results in a marked rise in serum PRL concentration (to at least three times basal) together with little or no change in serum thyroid-stimulating hormone (TSH) (<2 mU/L rise). In contrast, patients with pituitary microlesions and macrolesions have blunted PRL responses. Patients with microprolac-tinomas may, in addition, show exaggerated TSH responses owing to enhanced dopaminergic tone on the anterior pituitary thyrotrophs (via short-loop hypo-thalamic feedback).

Sawers and coworkers reviewed 84 patients with hyperprolactinemia whose screening had included a domperidone test and high-resolution magnetic resonance imaging (MRI) (10). They found that 18 of 20 patients with normal PRL responses to domperidone had normal MRI scans, and the other 2 had only microadenomas. In contrast, 18 of the remaining 64 patients with abnormal PRL responses had lesions greater than 10 mm in diameter. Of the rest, 63% had microadenomas. Dopamine antagonist testing can therefore identify a subset of hyperprolactinemic patients for whom detailed pituitary imaging is mandatory. Conversely, a normal PRL response to domperidone obviates the need for pituitary imaging and can reduce usage of this limited resource.

Dopamine antagonist testing can also be useful before and after surgery for microprolactinoma. Webster and colleagues described a series of 82 patients with hyperprolactinemia submitted to surgery for suspected prolactinoma (11). No tumor was found in three cases, including the only two patients with normal PRL and TSH responses to domperidone. Overall, 79% of patients had early postoperative normalization of serum PRL, but there were three relapses during long-term follow-up. Two of these had persistently abnormal PRL and TSH responses to domperidone, even when basal PRL levels remained normal.

Thus, although few patients with microprolactinoma are now treated surgically, these data are important because they indicate that dopamine antagonist testing can confirm (or refute) the presence of a microprolactinoma with reasonable certainty. Clinicians may regard this confirmatory biochemical evidence to be helpful in the medical management of such patients when histologic proof of the diagnosis will not be forthcoming.

TRH testing is less discriminatory and generally not helpful in hyper-prolactinemia investigation. However, the test may have limited use in the evaluation of patients with GH- or gonadotrophin-secreting tumors, a proportion of whom will show paradoxical stimulation of hormone release.

Diagnostic Value of the Basal Serum Prolactin Concentration

Most patients with microprolactinomas have basal serum PRL concentrations less than 5000 mU/L (200 ^g/L). In patients with pituitary macrolesions, the basal serum PRL is of considerable diagnostic value. A value greater than 5000 mU/L is virtually diagnostic of a macroprolactinoma and with a level greater than 10,000 mU/L (400 ^g/L), there is no other possible diagnosis. A serum PRL concentration lower than 2000 mU/L (18 ^g/L) in a patient with a pituitary macrolesion usually indicates disconnection hyperprolactinemia rather than tumoral secretion of the hormone. This is due most commonly to a nonfunctioning pituitary macroadenoma, although intrasellar craniopharyn-gioma and numerous other neoplastic and inflammatory pathologies may masquerade as pseudopituitary adenomas (12). An intermediate serum PRL level (2000-5000 mU/L or 80-200 ^g/L) in a patient with a large pituitary lesion produces an area of diagnostic uncertainty that dynamic PRL function tests cannot resolve; approx 50% of such patients will have true prolactinomas and the remainder disconnection hyperprolactinemia (12,13).

Pituitary Imaging and Ophthalmological Assessment

This is similar to the assessment of patients with other pituitary and para-pituitary lesions and is described in Chapters 5 and 6.

General Pituitary Function

Larger pituitary masses may cause hypopituitarism by either direct pituitary compression or disruption of hypothalamic control mechanisms. Patients with microprolactinomas usually have normal GH, adenocorticotropic hormone (ACTH), and TSH function. However, with macroprolactinomas, the degree of hypopituitarism is likely to be proportional to the size of the tumor. With the largest tumors, ACTH and TSH deficits may be present at diagnosis in approx 20% of patients, and GH deficiency is almost invariable. All patients with macroprolactinomas should have full pituitary function testing, using the methods described in Chapter 12.

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