Hook Effect

The hook effect may occur when serum specimens being assayed contain very high PRL levels, as can be the case in patients with large PRL-secreting pituitary macroadenomas. In these patients, PRL is present in vast stoichiometric excess to the two assay antibodies in the test solution, thus preventing the formation of the heterotrimeric complex (capture antibody—PRL—reporter antibody). The hook effect can cause substantial under-reporting of PRL levels. This artifact is clinically significant, since patients with adenomas that are thought to be PRL-secreting will be generally offered a trial of medical therapy. In contrast, failure to diagnose a prolactinoma based on a normal or low prolactin level in a patient with a large pituitary adenoma may likely lead to a recommendation for surgery rather than medical therapy. In one study, the hook effect was reported in 5.6% of 69 patients with macroadenomas. The frequency of hook effect using current assay techniques is uncertain. To detect this possible artifact, PRL measurements should be obtained both in undiluted and diluted (1 : 100) serum specimens in patients with large macroadenomas.

Macroprolactin

Monomeric PRL normally accounts for approximately 90% of circulating PRL, the rest consisting of PRL multimers of varying molecular mass, sometimes associated with immunoglobulin. Multimeric PRL species are collectively termed macroprolactin (as previously noted). Macroprolactin can be resolved and separated from monomeric PRL by gel filtration. In routine practice, polyethylene glycol (PEG) precipitation has been used to separate macroprolactin from PRL monomers (only the latter is left in the supernatant after centrifugation). Of note, hyperprolactinemia can be solely attributed to the presence of macroprolactin, only if the monomeric PRL level present in the serum is within the reference range.

Macroprolactin appears to have decreased bioactivity in some, but not all, bioassays. Women with macroprolactinemia who were treated with DA agonists were reported to experience resolution of galactorrhea (if originally present) but had no consistent improvement in menstrual cyclicity. Macroprolactinemia should be considered in patients with hyperprolactinemia who lack typical symptoms attributable to PRL excess. However, the presence of macroprolactinemia does not obviate the need for pituitary imaging, since some patients with pituitary adenomas may exhibit macroprolactinemia. Therefore the clinical utility of assessing macroprolactin in symptomatic patients is limited.

Heterophilic Antibodies

Heterophilic antibodies, including human antimouse or other antianimal immunoglobulins and the rheumatoid factor autoantibody, may cause assay interference by bridging the capture and reporter antibodies in the absence of analyte (i.e., PRL), thus giving rise to artifactually high PRL levels. Heterophilic antibodies may also confound many other assays, in addition to PRL immunoassays. Using blocking animal sera or heterophilic antibody blocking tubes can help prevent this type of interference.

Exogenous Biotin

Several immunoassay platforms use biotinylated capture antibodies that collect the analyte being assayed onto streptavidin-coated microbeads. Measurement of hormone levels in patients taking biotin supplements in large doses is subject to possible interference, if the immunoassay platform in use employs the biotin-streptavidin reaction. In these cases, ingested biotin may prevent the formation of the streptavidin-biotin complex in the assay solution, leading to under-reporting of the analyte being measured by sandwich immunoassays (including PRL) or overreporting of hormones measured using competition assays.

Changes in Prolactin Levels With Age

Immediately following delivery, PRL levels in neonates are elevated about 10 times above baseline, presumably as a consequence of high levels of placental estrogen, and decrease toward baseline over several months. Subsequently, PRL levels rise somewhat during adolescence. In women, PRL levels decrease by approximately 50% within about 2 years after menopause. In older men, PRL levels also decline by about 50% in comparison with young adults.

Prolactin Levels During Physiologic Stress

Acutely, exercise leads to an increase in serum PRL levels, which is not sustained long term in long distance runners. Other forms of physiologic stress, such as acute illness or injury, also lead to a two- to threefold increase in PRL levels, lasting about 1 hour, which is not sustained in patients with prolonged illness. Women have a more robust prolactin response than men.

Prolactin Levels During the Menstrual Cycle

Prolactin levels are lower in the follicular phase and rise during the luteal phase in some women. In addition, PRL and LH secretion are synchronous in the luteal phase.

Prolactin Levels During Pregnancy and the Postpartum State

During pregnancy, PRL levels increase continuously and may reach 10-fold or higher levels over those in non-pregnant women. This is a consequence of estrogen secretion by the placenta, which leads to lactotroph hyperplasia and stimulates PRL secretion, preparing the breast for lactation postpartum.

After delivery, basal PRL levels remain elevated in women who are nursing. In addition, PRL secretory peaks occur rapidly at the time of each suckling event. Within several months, there is a gradual decline in basal PRL levels towards normal as well as a decrease in the amplitude of secretory spikes in response to suckling. These events occur as a consequence of a gradual decrease in intensity of breast-feeding, while formula is being introduced into the infant’s diet. Menses resume as postpartum hyperprolactinemia abates.

Nipple stimulation, either acute or chronic (by nipple rings), may cause hyperprolactinemia in some healthy women who are not nursing.

Prolactin Inhibitory Factors

Several lines of evidence indicate that hypothalamic DA is the most important PRL inhibitory factor under physiologic conditions. DA is present in hypothalamic portal vessels at levels that are sufficient to suppress PRL secretion. Stimuli that elicit PRL secretion also lead to a decrease in DA levels in the hypophyseal portal circulation. Mice with targeted disruption of D2 receptors, whose absence prevents DA action in pituitary lactotrophs, develop hyperprolactinemia, lactotroph hyperplasia, and multiple prolactinomas. Infusion of DA in low doses leads to suppression of PRL secretion in humans. Estradiol partially reverses the effects of DA infusion on PRL secretion. Pharmacologic agents that inhibit DA receptors lead to hyperprolactinemia in humans.

DA is synthesized in neurons whose perikarya are located in the dorsal arcuate nucleus and the ventromedial nucleus of the hypothalamus. This neuronal pathway is termed the tuberoinfundibular DA pathway . Axon terminals originating from these neurons terminate in the median eminence, where DA is released, enters the hypophyseal portal system, and traverses the pituitary stalk to reach pituitary lactotrophs in the pars distalis, where DA activates D2 receptors to suppress PRL secretion. Mice with disrupted PRL genes do not synthesize any PRL and have substantially decreased DA in the tuberoinfundibular DA pathway, consistent with the existence of a positive effect of secreted PRL on hypothalamic DA release, generating a short loop feedback mechanism of secreted PRL that negatively regulates its own secretion.

Whether other physiologically relevant PRL inhibitory factors exist is a matter of controversy. Some data suggest that gonadotropin releasing hormone (GnRH)–associated protein (GAP) as well as gamma-aminobutyric acid (GABA) can suppress PRL in experimental paradigms, but their relevance in humans is unclear.

Prolactin Releasing Factors

Several factors have been proposed as being stimulatory of PRL secretion (as detailed later). However, their physiologic relevance is uncertain in many cases. Overall, their role appears relatively minor in comparison with the inhibitory role of DA on PRL secretion.

Prolactin Receptor

PRL exerts its actions by activating its cognate receptor, which is a member of the class 1 (hematopoietic) cytokine receptor superfamily. In humans, the PRLR gene is located on chromosome 5 and contains 10 exons, which yield several diverse receptor isoforms as a result of alternative splicing of the primary transcript. These are broadly grouped into long, intermediate, and short isoforms, most of which possess the same extracellular and transmembrane domains but differ in the length of the intracellular domain. There is also a soluble isoform, which lacks transmembrane and intracellular domains. The long PRL receptor isoform is predominant in humans and is widely expressed in many cell types. The extracellular domain contains two disulfide bridges that are critical for PRL binding. The intracellular domain contains two conserved regions (Boxes 1 and 2), one of which (Box 1) is recognized by tyrosine kinases.

The long isoform receptor is already dimerized before ligand binding occurs and can only initiate signaling upon PRL binding to the extracellular domain of the receptor homodimer. Signaling primarily involves activation of the Janus kinase 2 (JAK2)—signal transducer and activator of transcription 5 (STAT5) pathway. In addition, the mitogen-activated protein kinase (MAPK) pathway is activated, and the phosphatidylinositol 3 kinase (PI3K) pathway is also recruited. Activation of these pathways results in altered transcription of target genes in the nucleus that mediate PRL actions.

Prolactin Effects on the Breast

PRL has a critical role in breast development during pregnancy and milk synthesis postpartum, as well as in pathologic states of PRL excess. Of note, PRL stimulates alveolar tissue growth indirectly by stimulating, in synergy with progesterone, the synthesis of the receptor activator of NF-kappa B ligand (RANKL) and insulin-like growth factor 2 (IGF2), both of which act in a paracrine manner to induce alveolar tissue growth. In addition to PRL, several other hormones, including placental lactogen, GH, insulin, cortisol, thyroxine, estrogen, and progesterone, have important roles in the development of breast tissue during pregnancy in preparation for lactation. Of note, high levels of estrogen prevent milk production during pregnancy. In contrast, some degree of estrogen priming of the breast is needed for lactation, and this likely explains the infrequent occurrence of galactorrhea in postmenopausal women and men with hyperprolactinemia. After the placenta is delivered, the rapid decline in estrogen relieves its inhibitory effect on milk production. Postpartum suppression of PRL secretion by bromocriptine leads to a rapid decline in milk production.

Galactorrhea is defined as the secretion of milky fluid from one or both breasts in women who have either never been pregnant or have stopped nursing for over 12 months. Galactorrhea may rarely occur in men. Galactorrhea has been reported in 1% to 45% of women, depending on examination techniques and the patient population under study, and can be an important clue to the presence of PRL excess. Evaluation of PRL levels and thyroid function is advisable in women with galactorrhea. However, only 28% of women with galactorrhea and regular menses have hyperprolactinemia.

Prolactin Effects on Gonadotropin Secretion

In experimental animals, PRL appears to have an essential role in the regulation of the reproductive axis. Thus, mice with targeted disruption of either the PRL gene or the PRL receptor gene have abnormal estrous cycles and are infertile. Whether physiologic PRL levels have an important role with regards to the regulation of the reproductive axis in humans is less clear. Healthy women who are administered bromocriptine to decrease PRL levels to approximately 5 ng/mL have no change in gonadotropin pulsatility, but exhibit higher estradiol levels in the late follicular phase and lower progesterone levels during the luteal phase of the menstrual cycle.

Hyperprolactinemia leads to a marked decrease in gonadotropin secretion, including decreased LH pulse frequency and amplitude, as demonstrated by frequent serum sampling ( Fig. 3.2 ). In menopausal women, hyperprolactinemia blunts gonadotropin levels, which are restored by bromocriptine therapy that lowers PRL levels.

Impaired luteinizing hormone (LH) pulsatile release was present in a hyperprolactinemic patient (top panel) , which was restored after tumor resection (lower panel) .

Secretory pulses are shown by arrows . Dashed lines represent baselines, which were calculated by the Pulsar software.

(Modified from Stevenaert Beckers A, Vandalem JL, Hennen G: Early normalization of luteinizing hormone pulsatility in women with microprolactinomas. J Clin Endocrinol Metab 62:1044–1047, 1986, with permission.)

PRL appears to exert direct effects on hypothalamic neurons to suppress GnRH secretion. In vitro, PRL leads to a decrease in GnRH secretion by hypothalamic neuronal cell lines. Hyperprolactinemic mice develop central hypogonadism, characterized by low gonadotropin and sex steroid levels. These animals have decreased kisspeptin 1 expression in the arcuate and anteroventral periventricular nucleus. These data are corroborated by studies in rats, which are also consistent with the hypothesis that PRL in excess blunts kisspeptin 1 expression in the hypothalamus. In hyperprolactinemic mice, administration of kisspeptin 1 restores the function of their reproductive axis, consistent with the hypothesis that kisspeptin 1-expressing neurons in the hypothalamus have a major role in the pathogenesis of hyperprolactinemia-induced hypogonadism.

In experimental animals, hyperprolactinemia blunts gonadotropin secretion after GnRH administration, suggesting that PRL may also directly influence gonadotroph function. However, the findings of similar studies in humans have been less consistent with observations made in animals. Hyperprolactinemic women also exhibit lack of a positive effect of estradiol on gonadotropin secretion.

Prolactin Effects on the Ovary

In experimental animals, PRL has a role in maintaining the function of corpus luteum after ovulation. At physiologic levels, PRL stimulates the expression of 3 beta hydroxy­steroid dehydrogenase (type 2) and has an important role stimulating progesterone synthesis in human granulosa cells. However, studies in humans have not been conclusive with regard to the physiologic role of PRL on ovarian function. In healthy women, bromocriptine administration that suppresses PRL levels attenuates progesterone secretion and leads to shorter luteal phases in some, but not all, studies.

At high levels, PRL inhibits aromatase expression in rat granulosa cells and decreases estradiol and progesterone synthesis in human ovaries. In aggregate, available data suggest that PRL excess suppresses the reproductive axis in women at several levels, leading to oligo-amenorrhea. It should be noted that patients presenting with both amenorrhea and galactorrhea are likely to have hyperprolactinemia (75% of 471 patients in aggregated case series). Typically these patients present with secondary, rather than primary, amenorrhea. Low libido and sexual dysfunction is also common in this group. On the other hand, young patients with hyperprolactinemia developing before the onset of puberty may present with primary amenorrhea. These younger patients appear to be less likely to have galactorrhea and may even present with delayed puberty as a result of estrogen deficiency induced by PRL excess.

Hyperprolactinemia appears to be common among women presenting with infertility, representing about one-third of 367 women with infertility in aggregated case series. In a more recent study of women with infertility, the prevalence of hyperprolactinemia was 46%. Although most of these patients also have amenorrhea and galactorrhea, some patients manifest neither symptom but nevertheless have shorter luteal phases. Treatment of hyperprolactinemia in these patients increases progesterone synthesis during the luteal phase and improves fertility. Preovulatory, transient hyperprolactinemia in eumenorrheic women has also been associated with infertility.

Hyperprolactinemia is variably present in women with the polycystic ovary syndrome (PCOS) and is presumed to be a consequence of sustained elevations in estradiol levels that stimulate PRL secretion, though this hypothesis is not universally accepted. In these patients, bromocriptine therapy that suppresses PRL levels may lead to a decrease in testosterone and LH levels and regular menstrual cycles.

Prolactin Effects on the Testis

Whether PRL at physiologic levels is relevant to the regulation of the reproductive axis in males has been a matter of debate. Male mice with targeted deletion of the PRL gene have normal testosterone levels, despite decreased gonadotropin levels, and are fully fertile. On the other hand, approximately 50% of male mice with targeted disruption of the PRL receptor gene have decreased fertility despite apparently normal spermatogenesis. In healthy men, bromocriptine administration for 8 weeks leads to a decrease in testosterone levels, both at baseline as well as after human chorionic gonadotropin (hCG) administration. In human sperm, PRL increases fructose utilization, glycolysis, and glucose oxidation.

Available data suggest that PRL in excess suppresses the reproductive axis in men at several levels. In addition to decreased gonadotropin pulsatility, both baseline and hCG-stimulated testosterone levels are often reduced in hyperprolactinemic men. These patients frequently present with sexual dysfunction (low libido and/or erectile dysfunction) as a consequence of central hypogonadism. Up to 25% of men presenting with erectile dysfunction are hyperprolactinemic. Gynecomastia and/or galactorrhea may develop in hyperprolactinemic men, but are much less frequent than sexual dysfunction in this population. Infertility may also occur in hyperprolactinemic men. Up to 5% of men presenting with infertility have been reported to be hyperprolactinemic. Cabergoline therapy that suppresses PRL excess often leads to improvement in sexual function and recovery of the reproductive axis provided that pituitary gonadotrophs remain intact. Whether PRL normalization is essential for recovery of erectile function is uncertain.

Prolactin Effects on the Adrenal Cortex

Hyperandrogenism of adrenal origin, based on the presence of elevated dehydroepiandrosterone sulfate (DHEA-S) levels, has been reported in some, but not all, studies of women with hyperprolactinemia. Elevation in testosterone levels may also occur in some patients as a consequence of conversion from androgenic precursors. Hirsutism may occur in women with elevated PRL levels, but it is not clear if it correlates well with DHEA-S levels. Bromocriptine therapy that suppresses PRL excess may lead to improvement in DHEA-S levels in women with hyperprolactinemia.

Prolactin and the Skeleton

Several lines of evidence suggest that abnormalities in PRL levels or action are often associated with abnormal bone metabolism. Mice with targeted deletion of the PRL receptor gene have low bone mineral density (BMD) and decreased bone formation. These animals also have low sex steroid levels, which may account for the low BMD, rather than the absence of PRL action.

In humans, PRL excess is associated with deleterious effects on bone. Women and men with hyperprolactinemia and hypogonadism have decreased BMD and increased risk of morphometric vertebral fractures. DA agonist therapy that suppresses PRL excess leads to improvement in BMD. Of note, hyperprolactinemic women who have regular menstrual cycles also have normal BMD. These data are most consistent with the hypothesis that PRL-induced sex steroid deficiency, but not PRL excess per se, underlies the development of low BMD in hyperprolactinemic patients.

Prolactin Deficiency

PRL deficiency may occur in patients with pituitary macroadenomas or other large sellar masses, wherein it is frequently associated with multiple additional pituitary hormone deficiencies. In these patients, the presence of PRL deficiency generally indicates advanced pituitary failure as a consequence of destruction of pituitary tissue by tumoral hemorrhage or pituitary surgery. PRL deficiency may also occur in women with Sheehan syndrome (postpartum pituitary infarction in the setting of hemorrhagic shock as a consequence of obstetric complications). These patients classically present with failure of lactation and postpartum amenorrhea. Sheehan syndrome is currently uncommon in the United States and other Western countries because of advances in obstetric care. Isolated, idiopathic PRL deficiency has been reported in three patients, who were unable to lactate, but suffered no other evident manifestations. In clinical studies, recombinant human PRL has been administered with success in some patients with PRL deficiency but is not currently FDA-approved as replacement therapy.

Hyperprolactinemia—Causes

Hyperprolactinemia is relatively common in the general population (0.4%) and can be caused by diverse etiologies ( Box 3.1 ).

Hyperprolactinemia—Diagnosis

Patients with hyperprolactinemia require careful evaluation, including history and physical examination. Confirmation of PRL levels by repeat testing after overnight fasting is advisable, particularly in patients with mild hyperprolactinemia. Women of reproductive age should have a pregnancy test. Evaluation of kidney, liver, and thyroid function is also advisable. If no obvious cause is found to explain the presence of hyperprolactinemia, such as pregnancy or primary hypothyroidism, patients should undergo pituitary imaging by magnetic resonance imaging (MRI) using a pituitary protocol (or computed tomography [CT] if MRI is contraindicated, such as in patients with most pacemakers).

There is a good correlation between PRL levels and tumor size in patients with PRL-secreting pituitary adenomas. As a corollary, patients with PRL-secreting macroadenomas generally have PRL levels over 200 ng/mL. In contrast, PRL levels tend to be lower (below 150 ng/mL) in patients with nonfunctioning sellar masses causing stalk effect. As a word of caution, PRL levels should be rechecked in dilution in patients with very large sellar masses who have modest PRL elevations in order to detect a possible hook effect immunoassay artifact which may occur in patients with exuberant PRL secretion (as noted previously). Patients with a microadenoma and modest PRL elevation may have either a functioning tumor (microprolactinoma) or a clinically nonfunctioning adenoma causing stalk effect. Regular pituitary imaging can be helpful in making this distinction, since a prolactinoma will generally shrink in size in response to DA agonist therapy, whereas a nonfunctioning adenoma will not get smaller, and may even enlarge, despite the institution of DA agonist therapy that normalizes PRL levels.

Epidemiology and Natural History

PRL-secreting tumors represent the most common type of functioning pituitary adenoma. The incidence of these tumors was previously reported as being 10 cases per million per year, and their prevalence as approaching 100 patients per million in the general population. However, more recent studies from several European countries, including Belgium, the United Kingdom, Finland, Iceland, and Switzerland, have suggested that the incidence and prevalence of these tumors is substantially higher (about five times) than previously reported.

By definition, tumors below 10 mm in greatest diameter are termed microadenomas, whereas those that reach or exceed 10 mm are termed macroadenomas. This classification is clinically relevant, as larger tumors are more likely to cause mass effect or invade neighboring structures and have a greater growth potential. Most prolactinomas are microadenomas. However, a larger proportion of macroadenomas occurs in men than women.

A plethora of autopsy studies have identified the presence of clinically unsuspected pituitary adenomas in about 11% of subjects autopsied, with almost all (over 99%) of these tumors being microadenomas. These data are corroborated by the findings of imaging studies, which have identified the presence of incidental pituitary hypodensities consistent with microadenomas in 10% to 20% of study subjects. In autopsy studies, approximately 40% of adenomas examined by immunohistochemistry showed PRL immunostaining.

Several studies have reported on the natural history of untreated microprolactinomas. Out of a total of 139 women followed for up to 8 years, tumor growth was detected in nine patients (6.5%). These studies predated the use of MRI for pituitary imaging, but nevertheless do suggest that the growth potential of microprolactinomas is fairly low.

Macroadenomas are proportionately more common in children or adolescents than in adults, and are also more common in men than in women. Larger tumors tend to have a higher proliferation (Ki67) index. In some cases, tumor growth has been associated with estrogen administration. However, predictors and mechanisms of tumor growth remain poorly understood. It may be noted that most prolactinomas are benign, with frankly malignant tumors, which are, by definition, associated with intracranial or extracranial metastases, being exceedingly rare.

Pathogenesis

PRL-secreting pituitary adenomas are monoclonal tumors. Factors involved in the pathogenesis of these neoplasms are unknown in most cases. Of note, mutations in the gene encoding the D2 dopamine receptor or the gene encoding the G _i2 alpha subunit, which couples the D2 receptor to adenyl cyclase, have been found in up to 15% of prolactinomas that are resistant to DA agonist therapy. Somatic mutations in several putative oncogenes or tumor suppressor genes, including ras, myc, Pit-1, PROP-1, c-fos, MENIN, and others, have not been found in these tumors.

PRL-secreting pituitary adenomas develop in about 20% of patients with the multiple endocrine neoplasia 1 (MEN1) syndrome, caused by germline inactivating mutations of the MENIN gene, which is a tumor suppressor gene. Prolactinomas in these patients have been previously reported to behave more aggressively and be more resistant to medical therapy in comparison with sporadic tumors. On the other hand, more recent data in patients with the MEN1 syndrome suggest that prolactinomas generally respond well to medical therapy in this population. The coexistence of a prolactinoma (or other pituitary adenoma) and hypercalcemia secondary to primary hyperparathyroidism defines an index case for MEN1 and has been reported in approximately 14% of patients without known familial disease who were screened for hypercalcemia. About one-third of these patients were also found to have gastrin-secreting enteropancreatic neuroendocrine tumors, which constitute another cardinal manifestation of MEN1. As a corollary, it is advisable to measure serum calcium levels in all patients with presumed prolactinomas.

The syndrome of familial isolated pituitary adenoma (FIPA) has been the subject of substantial investigation in the recent past. In some of these patients, germline, inactivating mutations in the gene encoding the aryl hydrocarbon receptor interacting protein (AIP) have been identified and impart predisposition to pituitary tumor formation. This is transmitted as an autosomal dominant trait with incomplete penetrance and is associated with increased risk of developing GH-secreting tumors, prolactinomas, or co-secreting tumors. Pituitary adenomas present at a younger age in patients with AIP gene mutations and appear to be more aggressive and resistant to medical therapy.

Approximately 10% of prolactinomas are resistant to DA agonist therapy. Decreased expression of D2 DA receptors, including the long DA receptor isoform, decreased D2 receptor density, and DA binding sites on pituitary lactotrophs have been reported in these tumors and may underlie resistance to DA agonists. In addition, decreased expression of transforming growth factor beta 1 (TGF beta1) and several components of its signaling cascade (Smad2 and Smad3) have been reported in tumors resistant to DA agonist therapy. Animal data suggest that TGF beta1 inhibits lactotroph proliferation and PRL secretion, raising the possibility that restoration of TGF beta1 activity might be efficacious as a therapy in patients with prolactinomas that are resistant to DA agonists.

Pathology

PRL-secreting pituitary adenomas are almost always benign. In rare cases, distant metastases within the cranium or in remote locations, such as liver or bone, may develop and are essential to define the presence of malignancy in these patients. Some prolactinomas may co-secrete other hormones, most often GH, but in some cases TSH, ACTH, or FSH. Acidophil stem cell adenomas often have oncocytic features and co-secrete PRL and GH. Symptoms attributable to hyperprolactinemia most often predominate over those related to GH excess in these patients.

Clinical Manifestations

In addition to symptoms and signs directly attributable to PRL excess, patients with PRL-secreting macroadenomas may manifest symptoms related to mass effect or anterior hypopituitarism. Headache may occur as a result of pressure exerted on the dura and can be particularly severe and acute in the setting of pituitary apoplexy, generally occurring as a consequence of hemorrhage within an adenoma. Tumors extending superiorly into the suprasellar cistern may impinge upon the optic apparatus, causing a variety of visual field deficits. Bitemporal hemianopsia is typically noted in patients whose tumors compress the optic chiasm. Central scotomas may develop in patients with compression of one of the prechiasmatic optic nerves and homonymous hemianopsia may occur as a consequence of impingement onto one of the optic tracts. Rarely, large tumors may extend into the third ventricle, causing obstructive hydrocephalus.

Tumors extending laterally often involve the cavernous sinus and may encase the intracavernous segment of the internal carotid artery, but are very unlikely to cause arterial narrowing. Clinical manifestations attributable to compression of the cranial nerves (III, IV, V1, V2, or VI) coursing through the cavernous sinuses, namely ophthalmoplegia, facial pain or numbness, are very uncommon in patients with pituitary adenomas, including prolactinomas. Nevertheless, such symptoms may occur in patients with pituitary apoplexy or occasionally in patients with large, aggressive adenomas. Rarely, large tumors may impinge upon the ipsilateral temporal lobe, causing complex partial seizures.

Tumors extending inferiorly often erode into the sphenoid base and may involve the sphenoid sinus or even the posterior nasopharynx. These patients may rarely develop cerebrospinal fluid rhinorrhea in response to DA agonist therapy. In these cases, medical therapy causes dramatic tumor shrinkage, which unmasks gaps present in the bone and dura, leading to cerebrospinal fluid leakage. These patients typically require neurosurgical intervention in order to close these defects and prevent the attendant risk of meningitis.

Patients with macroadenomas may also develop anterior hypopituitarism and all require thorough evaluation of anterior pituitary function. Of note, diabetes insipidus is extremely unlikely to develop in patients with pituitary adenomas in the absence of surgical intervention. As a corollary, patients who present with central diabetes insipidus and a sellar mass should be suspected of harboring a nonadenomatous lesion (such as a craniopharyngioma or metastasis or an infiltrative lesion), rather than a pituitary adenoma.

Hyperprolactinemia is generally proportionate to tumor size in patients with prolactinomas. Women frequently present with galactorrhea, secondary amenorrhea, or infertility. In a total of 21 case series (1621 women), galactorrhea was present in 85% of women and oligomenorrhea in 93% of women. Men often present with low libido, erectile dysfunction, infertility, gynecomastia, or uncommonly, galactorrhea. In a total of 16 case series (444 men), erectile dysfunction was present in 78% and galactorrhea was present in 11%. As already mentioned, men are more likely than women to harbor macroadenomas. Whether this gender difference is only related to biologic factors, such as sex steroids, which may influence tumor behavior, is debatable; delayed recognition of pituitary adenomas in men who may ignore their symptoms and attribute them to aging is another possibility.

Children and adolescents may present with primary amenorrhea and delayed puberty. As already noted, younger patients are more likely to have macroadenomas, which are resistant to DA agonist therapy. Adolescents with hyperprolactinemia are at increased risk of developing low BMD, which is likely a consequence of hypogonadism occurring during a critical time of peak bone mass acquisition.

Management

Medical Therapy

DA agonist therapy represents the cornerstone of management of most patients with prolactinomas who require therapy. Bromocriptine and cabergoline are both ergot alkaloid derivatives, and are currently approved by the Food and Drug Administration (FDA) for use in patients with hyperprolactinemia and prolactinomas. Pergolide is no longer available in the United States. Quinagolide, a non-ergot compound, was never introduced in the United States, but is available for use in several other countries.

Bromocriptine was the first drug in this class used to treat prolactinomas and hyperprolactinemia. Bromocriptine normalizes PRL levels in approximately 75% of patients and leads to resumption of menses in the majority of treated women. In addition to inhibiting PRL secretion, bromocriptine inhibits DNA synthesis and cell proliferation, leading to a decrease in tumor size.

About 76% of patients treated with bromocriptine experience a decrease in tumor size over a treatment period of up to 10 years. An example of a tumor response to bromocriptine therapy is shown in Fig. 3.3 . Tumor size reduction is variable in patients treated with bromocriptine. In approximately 40% of 112 patients reported in a total of 10 studies, there was a greater than 50% decrease in tumor size after the institution of bromocriptine therapy. Some tumors can completely disappear on follow-up MRI examinations. In patients with macroadenomas impinging on the chiasm, an improvement in visual field deficits occurs in more than 80% of treated patients and may be noticeable within 1 to 3 days after the institution of bromocriptine therapy. Visible decreases in tumor size occur with a variable time course and can be observed within a period of several weeks to several months on therapy. Pituitary function may also improve in patients whose tumors shrink on bromocriptine therapy. The extent of tumor shrinkage and the magnitude of reduction in PRL levels are not well correlated in all patients. Some of the patients whose tumors do not respond adequately to bromocriptine therapy may be effectively treated with cabergoline (as will be detailed later).

Sagittal ( left , top , and bottom panels) and coronal ( right , top , and bottom panels) magnetic resonance images of a patient with hyperprolactinemia and a pituitary macroadenoma, obtained before (top) and after (bottom) the institution of bromocriptine therapy.

There is substantial decrease in tumor size on medical therapy. Arrows point to the tumor.

(From Molitch ME: Medical treatment of prolactinomas. Endocrinol Metab Clin N Am 28:143–169, 1999, with permission.)

Bromocriptine therapy is usually initiated at a dose of 0.625 mg to 1.25 mg daily, taken in a single nightly dose to optimize tolerance, and is advanced every 3 to 7 days to a dose of 2.5 mg daily. Dose titration may occur in 4-week intervals toward achieving normal PRL levels, provided that the medication remains well-tolerated. The medication is generally given in two or even three divided daily doses, when the total daily dose exceeds 2.5 mg daily to improve effectiveness and tolerance; total daily doses exceeding 10 mg are rarely needed.

Adverse effects associated with bromocriptine therapy most commonly include nausea and orthostatic dizziness. These can be minimized with gradual dose titration and intravaginal administration in some cases. In some patients, these adverse effects may improve over time. Less common adverse effects include headache, nasal congestion, constipation, digital vasospasm, vivid dreams, or nightmares. Pituitary tumor fibrosis may occur in some patients and hinder subsequent attempts at transsphenoidal resection. Rarely, systemic fibrotic manifestations have been reported, including mediastinal and retroperitoneal fibrosis. The association between DA agonist use and cardiac valvulopathy will be discussed later. Other rare, but serious, adverse effects include the development of psychosis or impulsivity, both of which resolve after medication discontinuation. Patients with history of psychosis are, in general, not good candidates for DA agonist therapy. However, psychotic reactions can occur even in patients without such history. Medical therapy of prolactinomas in patients prescribed neuroleptics, which act as DA antagonists, should be carefully reviewed with the treating psychiatrist in order to avoid precipitating an increase in psychiatric symptoms.

Among patients whose tumors decrease in size in response to bromocriptine therapy, the medication dose can often be downtitrated, as the therapeutic benefits can generally be maintained on a lower dose. Eventually, some patients can be considered to be weaned off the medication after a treatment period of 2 to 3 years. Good candidates for DA agonist withdrawal are those who have maintained normoprolactinemia and have no visible tumor on follow-up MRI examinations. Of note, recurrence of hyperprolactinemia may occur after bromocriptine withdrawal. About 20% to 50% of patients with microadenomas and 16% of patients with macroadenomas maintain normal PRL levels after medication withdrawal. As a corollary, patients who are withdrawn from therapy should be warned of the risk of recurrence and monitored with serial PRL levels and MRI examinations to detect possible recurrence, which should prompt the reinstitution of therapy.

Cabergoline is another ergot alkaloid derivative with a very long half-life after oral administration, which generally allows for infrequent dosing (once or twice a week). Cabergoline has high affinity for D2 receptors in the pituitary and is very slowly eliminated as a consequence of its slow release from pituitary binding sites and extensive enterohepatic cycling.

Cabergoline is more effective than bromocriptine in normalizing PRL levels and restoring gonadal function and is generally better tolerated. In one partially double-blind randomized clinical trial of 459 women, most of whom had microprolactinomas, cabergoline therapy led to PRL normalization in 83% and restoration of regular menses in 72% of patients. In the same study, bromocriptine therapy led to PRL normalization in 59% and restoration of regular menses in 52% of patients. Similarly, cabergoline therapy leads to restoration of gonadal function in the large majority of hyperprolactinemic men.

Cabergoline is also effective in reducing tumor size in most patients with prolactinomas. In one study of hyperprolactinemic patients with macroadenomas who were treated with cabergoline therapy, 96% out of 26 patients who were treatment-naive experienced a decrease in tumor diameter exceeding 50% over baseline. In the same study, 64% out of 33 patients who were resistant to bromocriptine experienced a decrease in tumor diameter exceeding 50% over baseline after the institution of cabergoline therapy. Overall, available data indicate that many patients who do not respond to bromocriptine therapy can be treated effectively with cabergoline.

Cabergoline therapy is usually initiated at a dose of 0.25 to 0.5 mg per week, taken at bedtime with a small snack, and is generally titrated every 4 to 6 weeks, aiming to restore normoprolactinemia. More rapid dose titration can be appropriate in patients with large tumors causing mass effect. Most patients can be effectively treated with a total dose of 3.5 mg per week or less. About 10% of patients can be resistant to cabergoline (as well as bromocriptine), even in high doses, and may often require additional therapies, including pituitary surgery, radiation therapy, and/or temozolomide chemotherapy (as will be subsequently discussed).

Cabergoline use has been associated with the same adverse effects noted among patients who are treated with bromocriptine, albeit less frequently. In a clinical trial of 459 hyperprolactinemic women, cabergoline therapy was discontinued in 3% of women because of adverse effects, whereas bromocriptine was discontinued in 12% of women because of adverse effects. Many patients who cannot tolerate bromocriptine can be treated safely with cabergoline, administered either orally or intravaginally. Indeed, published guidelines recommend using cabergoline over bromocriptine in most cases, based on greater efficacy and better tolerance of cabergoline therapy, except in the setting of preconception or pregnancy.

Cardiac valvulopathy has been reported in some patients with Parkinson disease who were treated with very high doses of cabergoline (or pergolide, but not bromocriptine). In these patients, fibrotic lesions in the endocardium occur as a consequence of serotonin (5HT2B) receptor activation by cabergoline and can lead to clinically significant valvular regurgitation. A higher cumulative dose exposure is associated with a higher risk of valvulopathy. In contrast, patients treated with usual cabergoline doses (up to 2.0 mg/week) appear to be at low risk of valvulopathy. It appears sensible to inform patients as to available data and consider performing periodic echocardiographic monitoring on a case by case basis (particularly in patients who require larger than usual cabergoline doses).

Among patients whose tumors decrease in size in response to cabergoline therapy, the medication dose can often be downtitrated, as the therapeutic benefits can generally be maintained on a lower dose. Cabergoline withdrawal can be eventually considered in patients who have responded well to medical therapy for at least 2 to 3 years, remain normoprolactinemic, and have no visible residual tumor on MRI. In a study of hyperprolactinemic patients who had achieved normoprolactinemia on cabergoline therapy, recurrence rates (5-year Kaplan-Meier estimates) for hyperprolactinemia after drug withdrawal were higher among patients with visible residual tumor on MRI and were also higher among patients with macroadenomas than those with microadenomas. Among 105 patients with microadenomas, hyperprolactinemia recurred in 42% of patients with visible residual tumor on MRI and 26% of patients without visible residual tumor at the time of medication withdrawal. Among 70 patients with macroadenomas, hyperprolactinemia recurred in 78% of patients with visible residual tumor on MRI and 33% of patients without visible residual tumor. All patients who are eventually withdrawn from cabergoline therapy should be made aware of the risk of recurrence, and be followed with serial PRL levels and pituitary MRI examinations.

Pergolide is another DA agonist, which was previously used off-label in the United States to treat hyperprolactinemia. Pergolide appears to be comparable to bromocriptine with regard to efficacy and tolerability in patients with hyperprolactinemia. In high doses, pergolide was also used to treat Parkinson disease and was FDA-approved for that indication. The medication was withdrawn from the United States in 2007 because it was associated with cardiac valvulopathy, when administered in high doses in patients with Parkinson disease.

Quinagolide is a non-ergot DA agonist that has been used to treat hyperprolactinemia in some countries. Approximately 50% of hyperprolactinemic patients who are resistant to bromocriptine can be treated effectively with quinagolide. In addition, some patients tolerate quinagolide better than bromocriptine. It is not approved by the FDA and is not currently available in the United States.