HYPERPROLACTINEMIA

HYPERPROLACTINEMIA

Current diagnosis

• Hyperprolactinemia is diagnosed by biochemical tests based on two-site immunoassay, which can be confounded by extreme hyperprolactinemia (hook effect) and biologically inactive macroprolactinemia.

• Hyperprolactinemia can be caused by physiological, pharmacological, or pathological conditions; careful clinical, laboratory, and radiology evaluations are required to identify its underlying cause.

• The most common causes of hyperprolactinemia include medications, prolactinoma, and other pituitary and hypothalamic/pituitary stalk diseases.

• Clinical features of hyperprolactinemia include galactorrhea, menstrual abnormalities (in women), impotence (in men), infertility, and osteoporosis.

• Patients with prolactinoma may also have local compression symptoms including headache, visual disturbance, and hypopituitarism.

• Pituitary magnetic resonance imaging (MRI) is the imaging method of choice for diagnosing prolactinoma and other sellar/parasellar lesions.

Current therapy

• For secondary hyperprolactinemia treatment should be directed at correcting underlying causes.

• Treatment goals for prolactinoma are relief of symptoms and the long-term effects of hyperprolactinemia, and of tumor mass effects.

• The dopamine agonists cabergoline (Dostinex) and bromocriptine (Parlodel) are effective in normalizing the prolactin level and shrinking the tumor in patients with prolactinoma.

• Surgery and radiotherapy of prolactinoma are reserved for patients resistant to or intolerant of medical therapy.

Biochemistry and Physiology of Prolactin

Prolactin is a polypeptide hormone produced by pituitary lactotroph cells. It is also produced locally in a variety of extrapituitary tissues, such as mammary glands, decidua, gonads, brain, liver, fat, pancreas, and the immune system, along with its receptors. Prolactin is highly pleiotropic in terms of its functions. Many of its actions collectively support puerperal lactation. Prolactin displays considerable sequence homology to growth hormone (GH) and placental lactogen. The prolactin and GH receptors both belong to the class I cytokine/hematopoietic receptor superfamily. Prolactin is responsible for maturation of the mammary glands during pregnancy, but plays only a minor role for pubertal mammary development, which requires GH instead. It appears not to be an essential hormone for nonchildbearing individuals. Rare patients deficient for either prolactin or its receptor are largely healthy despite difficulty with fertility and lactation.

Prolactin circulates mainly as a 23-kDa 199-aa polypeptide. Several of its cleavage products exist in blood, which may have functions unrelated to lactation; for example one 16-kDa cleavage product of prolactin displays antiangiogenic and prothrombotic properties, and was implicated in the development of preeclampsia and peripartum cardiomyopathy. Several forms of prolactin aggregate, known as macroprolactins, also exist in circulation in lower levels. They are formed either by covalent bonding of prolactin monomers or by their nucleating around autoimmune IgG. These macroprolactins are not biologically active in vivo and have a prolonged half-life. At times they can build up in the circulation to a level high enough to cause diagnostic difficulties.

Among the major pituitary hormones, prolactin is unique for its predominantly negative mode of regulation by the hypothalamus. It does not have a known hypothalamus-derived releasing hormone.

Instead, lactotrophs are under tonic inhibition by dopamine secreted from hypothalamic neurons. Increase in prolactin output is mostly mediated by withdrawing dopaminergic control in response to environmental cues, such as physical activity, stress, and nipple stimuli (Figure 1). Under experimental and pathological conditions, several factors, including thyrotropin releasing hormone (TRH), vasoactive intestinal peptide (VIP), oxytocin, and vasopressin, have been shown to increase prolactin secretion, but these peptides appear to play only minor and insignificant roles for the physiological regulation of prolactin.

FIGURE 1 Physiology of prolactin and its regulation. At baseline, prolactin production and secretion are under tonic inhibition by dopamine released from hypothalamic neurons. The hypothalamus controls prolactin production by altering output of dopamine after integrating environmental stimuli and changes in hormonal homeostasis. Prolactin increases hypothalamic dopamine output, providing a negative feedback regulatory loop. Estrogen stimulates prolactin synthesis and secretion during pregnancy. Prolactin supports puerperal lactation via its action on the mammary glands, nutrient/calcium metabolism, and brain. Unlike most other anterior pituitary hormones, feedback regulation of prolactin secretion does not occur via factors produced by a peripheral endocrine target  organ.

Prolactin also suppresses hypothalamic-pituitary-gonadal axis by inhibiting GnRH release. Abbreviations: DA = dopamine; GnRH = gonadotropin releasing hormone; PRL =  prolactin.

Estrogen is the main driver of prolactin secretion during pregnancy.

Stimulated by persistently elevated estrogen, lactotrophs grow in number and size. By term the pituitary gland can reach 2 to 3 times its normal size, and prolactin levels increase some 20-fold. Along with placental hormones such as estrogen, progesterone, and placental lactogen, prolactin drives the maturation of the mammary glands.

Lactation starts after parturition, when estrogen withdraws from the circulation. Frequent infant suckling maintains physiological hyperprolactinemia, which is important for sustained milk production. In addition, hyperprolactinemia during this critical period provides a natural though unreliable way of contraception. This is achieved by suppression of the hypothalamus-pituitary-gonad axis.

Hyperprolactinemic hypogonadism and parathyroid hormone related peptide (PTHrP) secreted from mammary epithelial cells help mobilize skeletal calcium store in support of milk production.

Through its receptors in liver, intestine, fat, and pancreas, prolactin also adjusts maternal nutrient metabolism for optimal milk output. In the brain, prolactin modifies parental behavior toward closer infant attendance (see Figure 1).

Pathophysiology of Hyperprolactinemia

Physiological hyperprolactinemia as occurs during pregnancy and nursing is essential for child raising through the actions of prolactin in target organs discussed above. Similar changes in these organs under the influence of persistent pathological hyperprolactinemia in the absence of pregnancy and lactation, however, are inappropriate and could lead to a variety of undesired long-term consequences.

Mammary Glands

One common symptom of persistent hyperprolactinemia is galactorrhea, that is, milk production not associated with childbirth or breast feeding. As puerperal lactation normally ends within 6 months after delivery or weaning, any milk production beyond this point is also considered galactorrhea. Since maturation of mammary glands is completed during pregnancy, galactorrhea typically happens in women between 20 to 35 years of age with previous childbirths. It also occurs in nulligravid women, postmenopausal women, and men, although less frequently.

Prolactin is a known mitogen for mammary epithelial cells, and concern has been raised regarding its potential role in the pathogenesis of breast cancer. In a large prospective study by the Women’s Health Initiative (WHI) there was evidence of a significant increase in breast cancer incidence in postmenopausal women with high normal prolactin levels, which is within the highest quartile of the normal range compared with those in the lowest quartile. On the other hand, increased breast cancer risk has not been observed in patients with overt hyperprolactinemia. In fact, early parity and lactation history are strong protective factors against breast cancer.

Further research is required to resolve these seemingly discrepant observations.

Female Reproductive System

Persistent hyperprolactinemia significantly diminishes the pulsatile release of gonadotropin releasing hormone (GnRH). As GnRH neurons do not themselves express prolactin receptors, prolactin exerts its effects on their afferent neurons instead by suppression of secretion of kisspeptin, a potent secretagogue for GnRH. Prolactin receptors are also found in the gonads, and prolactin has been reported to inhibit folliculogenesis and estrogen production in the ovary directly. However, this likely has only a limited contribution to infertility and hypogonadism associated with hyperprolactinemia, for the hypothalamus-pituitary-gonad axis can be reactivated by administration of GnRH or kisspeptin, with return of ovulation and fertility in subjects with hyperprolactinemia.

Male Reproductive System

As in women, hyperprolactinemia causes secondary hypogonadism and infertility in men by suppression of GnRH pulses and a decrease in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. Patients often have low or low normal testosterone levels, and abnormal sperm counts and morphology in semen analysis. Patients usually seek medical attention for diminished libido and impotence. The central nervous system (CNS) actions of prolactin are likely partly responsible for these symptoms, as restoration of testosterone level alone is often inadequate for symptom relief, which occurs only when prolactin levels also return to normal.

Adrenal Glands

Prolactin stimulates the synthesis of androgen in the zona reticularis of the adrenal cortex. Mild elevations in serum levels of adrenal androgens, for example dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S), are seen in approximately 50% of women with hyperprolactinemia. Symptoms of clinical hyperandrogenism such as hirsutism and acne are rare in these patients. When present they are almost always associated with a concurrent increase in testosterone level. Elevation of adrenal androgens in hyperprolactinemia may contribute to the suppression of GnRH release in the hypothalamus and secondary hypogonadism.

Skeletal System

Premenopausal women with hyperprolactinemia have lower bone density and approximately a 4.5 times higher risk for osteoporotic fractures. Hypogonadism associated with hyperprolactinemia is the main cause of bone loss, whereas restoration of sex hormones with either hormonal replacement or correction of hyperprolactinemia improves bone density. Bone density is preserved in women with hyperprolactinemia who continue to have regular menses.

Nonetheless, not all studies showed a clear correlation between the degree of bone loss and duration of amenorrhea or levels of sex hormones suggesting involvement of additional processes. For example, the levels of parathyroid hormone–related protein (PTHrP) were found to be significantly higher in patients with hyperprolactinemia, and correlated well with bone density measurements. Correction of hyperprolactinemia by dopamine agonists was shown to normalize PTHrP levels.

Etiology of Hyperprolactinemia

Any conditions that affect production or clearance of prolactin can lead to hyperprolactinemia (Table 1). Physiological hyperprolactinemia is transient and adaptive, whereas persistent hyperprolactinemia from pharmacological and pathological causes are often symptomatic with undesired long-term consequences. Pituitary adenomas over-producing prolactin (prolactinomas) are the most important cause of pathological hyperprolactinemia. In addition to the elevated prolactin levels, prolactinomas also produce pathological local mass effects. Secondary hyperprolactinemia is most commonly related to disruption of dopaminergic control of lactotrophs, secondary to the use of dopamine antagonists or hypothalamic and pituitary stalk lesions.

Table 1

Causes of Hyperprolactinemia

PHYSIOLOGICAL

Pregnancy

Lactation and breast stimulation

Neonatal period

Physical activity

Stress

Sexual intercourse

PHARMACOLOGICAL

Dopamine antagonists – antipsychotics and antiemetics Tricyclic antidepressants

Selective serotonin reuptake inhibitors (SSRI)

Antihistamines (H2)

Calcium channel blocker

Proteaseinhibitors

Dopamine synthesis inhibitors

PATHOLOGICAL PITUITARY DISEASES

Prolactinoma

Plurihormonal adenomas

Lymphocytic hypophysitis

Empty sella syndrome

Macroadenoma with or without suprasellar extension

Idiopathic hyperprolactinemia

Hypothalamic/pituitary stalk diseases

Tumors: meningioma, craniopharyngioma, germinoma, metastasis, etc.

Granulomas

Infiltrative diseases

Irradiation

Trauma

NEUROGENIC: chest wall lesions, spinal cord lesions, herpes zoster, and epileptic seizure

PARANEOPLASTIC SYNDROME

SYSTEMIC DISEASES

End-stage renal disease

Cirrhosis

Adrenal insufficiency

Pseudocyesis

Adapted from Bronstein, 2016; Melmed et al.,  2011.

Epidemiology and Natural History of Prolactinoma

Prolactinoma is the most common type of pituitary adenoma, contributing to approximately 40% of pituitary tumor cases.

Prolactinomas are categorized according to size into microprolactinomas (under 1 cm) and macroprolactinomas (larger than 1 cm). Clinically these two conditions behave very differently and can be considered as separate entities. In general, macroprolactinomas tend to grow progressively and are often locally invasive; they are also generally more resistant to treatment and have a higher risk of recurrence. On the other hand, microprolactinomas rarely progress in size (~ 7% of cases) and have a good chance (~ 15% of cases) of going into remission on their own.

The prevalence of prolactinoma has been estimated to be 500 cases per million and incidence about 27 cases per million per year based on survey of asymptomatic populations. In autopsy series, however, lactotroph neoplasms staining positive for prolactin are much more common, being found in approximately 5% of the subjects. They are predominantly microadenomas. Only a small fraction of these small lactotroph neoplasms develop overt hyperprolactinemia by escaping tonic dopaminergic suppression from the hypothalamus, presumably via down-regulation of dopamine D2 receptor-mediated signaling pathway and/or bypassing the portal system for blood supply.

Microprolactinomas predominantly affect women of childbearing age, with a female-to-male ratio of approximately 20:1. Macroprolactinoma on the other hand shows no sex predilection. Neoplastic transformation of lactotroph involves accumulation of genetic and epigenetic events. The best understood candidate genes involved include the pituitary tumor transforming gene (PTTG) and the heparin-binding secretory transforming gene (HST). PTTG expression is positively regulated by estrogen.

Most prolactinomas occur sporadically. The vast majority of prolactinomas are benign, although they can be locally invasive. Malignant prolactinomas, as defined by the presence of extrapituitary metastases, are extremely rare. Familial cases, such as those associated with multiple endocrine neoplasia I (MEN-I) and familial isolated pituitary adenoma (FIPA), typically occur at a younger age and are more often macroprolactinomas that are locally invasive.

Clinical Manifestations

Clinical manifestations of prolactinomas fall under two categories: systemic effects of hyperprolactinemia, and local compression symptoms.

Symptoms of Hyperprolactinemia

Persistent hyperprolactinemia inappropriately recapitulates symptoms associated with normal pregnancy and nursing. In extreme cases, hyperprolactinemia has been associated with delusions of pregnancy in susceptible individuals, for example some women on psychotropic medications.

Menstrual abnormalities and infertility are the most common symptoms associated with hyperprolactinemia in women of childbearing age. These symptoms may be masked by use of oral contraceptive pills, which often delays diagnosis. The mildest cases include women presenting with infertility caused by shortened luteal phase despite preserved regular menses. As the degree of hypogonadism worsens, patients experience menstrual irregularities ranging from anovulatory cycles, to oligomenorrhea and amenorrhea. Patients with amenorrhea may also experience psychological stresses and other menopausal symptoms like vaginal dryness and dyspareunia. Of note, high prolactin levels may sometimes mask vasomotor symptoms of menopausal and perimenopausal women with prolactinoma, who may develop hot flashes once they are successfully treated with dopamine agonists.

Galactorrhea occurs in up to 80% of cases of hyperprolactinemia. This will need to be differentiated from nipple discharges of other causes, especially those from breast neoplasms. Further evaluation with breast imaging and cytology is indicated when the discharge is unilateral, bloody, or associated with a breast mass. Galactorrhea is by definition milklike in appearance, and when in doubt, Sudan Black B staining showing fat globules is confirmatory. Although considered a classic sign and symptom for hyperprolactinemia, galactorrhea per se is a poor predictor for hyperprolactinemia in the absence of additional symptoms, for it can be seen in about 10% of healthy women of childbearing age. If amenorrhea is present at the same time, the patient should be assumed to harbor a prolactinoma unless proven otherwise. The degree of galactorrhea is quite variable, from barely expressible to bothersome bra stain and copious free flow, and does not necessarily reflect the severity of hyperprolactinemia. In fact, the majority of patients with galactorrhea and normal menses have normal prolactin levels. On the other hand, in some patients with extremely high levels of prolactin, galactorrhea could be masked by severe hypogonadism.

Men with hyperprolactinemia mainly present with impotence and diminished libido, which is not always corrected with testosterone replacement. As noted in the section on pathophysiology, these symptoms are not all caused by hypogonadism, but may involve the central effects of prolactin. Other symptoms and signs of hypogonadism, such as loss of body hair and muscle bulk, are less common. Infertility could also occur with decrease in sperm count and morphology, although hyperprolactinemia is only present in approximately 5% of male patients seeking treatment for infertility.

For both male and female patients, persistent hypogonadism from hyperprolactinemia leads to osteoporosis and increased risk of fracture. This could be effectively treated with either sex hormone replacement or dopamine agonists.

Mass Effects of Prolactinomas

Headache is the most common neurological symptom caused by pituitary tumors. It can occur even with microadenomas presumably caused by dural stretch. More severe headache results from larger tumors especially those with extrasellar invasion and occasionally from apoplexy.

Visual disturbance typically only happens with macroadenomas with suprasellar extension impinging on the optic chiasm leading to loss of visual acuity and visual field defects. The typical pattern of visual field defect is bitemporal hemianopsia, which usually starts from the upper field and progresses downward as the tumor impinges upward from below. Ophthalmoparesis typically happens in the setting of apoplexy and only rarely results from parasellar invasion of the cavernous sinus and impingement of cranial nerves III, IV, or VI.

By compressing the rest of the pituitary gland, including the stalk, prolactinoma can cause deficiencies of other anterior pituitary hormones including GH, thyroid-stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH), in addition to hypogonadism from the hyperprolactinemia. The degree of the risk is proportional to tumor size.

CSF rhinorrhea occurs when a macroprolactinoma invades inferiorly into the sphenoid sinus. Other rare compressive symptoms from giant prolactinomas include epilepsy (temporal lobe involvement), exophthalmos, and hydrocephalus. Life- and vision- threatening emergencies could arise from apoplexy and CNS infection.

Laboratory Evaluation

Prolactin assay and pitfalls

Hyperprolactinemia is diagnosed by individual measurements of serum prolactin levels. Patients should be well rested as physical activity stimulates prolactin secretion, but fasting is not needed.

Dynamic tests such as TRH stimulation do not appear to add to diagnostic value and are not recommended. The level of prolactin may provide valuable diagnostic clues. Secondary hyperprolactinemia rarely exceeds 150 ng/ml. On the other hand, a prolactin level of greater than100 ng/ml is highly suggestive, and severe hyperprolactinemia of greater than 500 ng/ml is virtually diagnostic for prolactinoma. In rare occasions, secondary hyperprolactinemia can produce prolactin levels in the prolactinoma range. For example, risperidone (Risperdal)-induced hyperprolactinemia could be as high as 250 to 500 ng/ml, and patients with end-stage renal disease who are on antipsychotics or antiemetics can have prolactin levels greater than 1000 ng/ml. The size of the prolactinoma shows a rough correlation with the serum prolactin level. Patients with microprolactinomas usually have prolactin levels in the range of 50 to 300 ng/ml, whereas those with macroprolactinomas have levels of 200 to 5000 ng/ml.

Most clinical laboratories measure prolactin using a two-site immunoassay. A capture antibody first affixes prolactin in the sample onto a solid matrix. Subsequently a second signal antibody is attached to the now immobilized prolactin. The signal antibody is engineered to carry either a radioisotope or a chemiluminescent enzyme to provide a readout. The assay is accurate within its designed linear range, which is typically under 10,000 ng/ml. Beyond this level both capture and signal antibodies could be saturated preventing the signal antibody to attach. As a result, signal outputs will be falsely diminished. This phenomenon, known as the hook effect, produces a falsely low reading that could lead to the misdiagnosis of a macroprolactinoma as a nonfunctioning pituitary tumor. This artifact can be circumvented by repeating the assay with a hundred-fold diluted sample. Many laboratories also opt for an additional washout step to eliminate excess prolactin before adding the signal antibody, preempting the artifact.

Macroprolactinemia is another potential diagnostic pitfall masquerading as true hyperprolactinemia. Macroprolactins are biologically inactive prolactin aggregates that could accumulate in blood to a high level. Macroprolactinemia does not cause any morbidities, but could contribute to analytical difficulties as the antibodies used in prolactin assays crossreact with macroprolactins. Most laboratories rely on polyethylene glycol (PEG) precipitation to determine the proportion of macroprolactins and the true concentration of monomeric prolactin. Up to 25% of monomeric prolactin can be also precipitated by PEG potentially masking true hyperprolactinemia. Therefore patients with macroprolactinemia may still need to be further evaluated if clinical suspicion is high for true hyperprolactinemia.

Other supporting laboratory tests

After confirming hyperprolactinemia, a simple chemistry panel may reveal or suggest the underlying cause such as chronic kidney disease and cirrhosis. A pregnancy test (beta human chorionic gonadotropin [βhCG] level) is essential for women of childbearing age, and hypothyroidism needs to be ruled out with a TSH assay. Both pregnancy and hypothyroidism may have presenting symptoms of sellar mass and hyperprolactinemia and therefore be mistaken for prolactinoma.

For established prolactinoma cases it is important to also assess other pituitary axes. Up to 20% of GH-secreting tumors cosecrete prolactin, and IGF-1 level is an essential screening test for these cases. If hypogonadism is suspected, levels of LH, FSH, and sex hormones (testosterone or estrogen) should be obtained. Screening for central hypothyroidism and secondary adrenal insufficiency should be done with TSH, free thyroxine (T4), and morning cortisol levels, respectively, for patients with pituitary tumors larger than 6 mm.

Neuroimaging

Pituitary imaging should be considered for all patients with unexplained significant hyperprolactinemia, especially if there are signs or symptoms of local compression. MRI with and without gadolinium contrast with dedicated pituitary protocol is the test of choice. Compared with other modalities MRI provides superior soft tissue contrast revealing the tumor’s inner structure and its relationship to surrounding tissues, including cavernous sinus, pituitary stalk, and optic chiasm. Computed tomography (CT) scan still has a role for patients with metal implants or other contraindications for MRI, and is especially useful for revealing bony erosions and tissue calcification; its use is limited by suboptimal soft tissue contrast and exposure to ionizing radiation.

Visual field testing

A formal visual field test with a perimeter is recommended when suprasellar extension of a pituitary adenoma brings it close to the optic chiasm. Improvement or worsening in visual field often precedes imaging evidence of tumor shrinkage or expansion during treatment. Therefore visual field testing is an excellent monitoring tool for patients under treatment for macroadenoma and visual impairment.

Diagnosis

Prolactin testing is usually prompted by suggestive signs and symptoms of hyperprolactinemia such as menstrual abnormalities, infertility, and galactorrhea. A careful history, including medication use, physical examination, and routine laboratory evaluation (see preceding sections) are invaluable for uncovering secondary causes. Pituitary imaging should be performed when no other underlying causes are found especially if the levels of prolactin are higher than 100 ng/ml. A diagnostic algorithm shown in Figure 2 provides a framework for a structured and cost-effective workup of hyperprolactinemia.

FIGURE 2   Diagnostic algorithm for hyperprolactinemia. If hyperprolactinemia occurs in the absence of relevant clinical symptoms and signs, one should rule out macroprolactinemia by PEG precipitation. When hyperprolactinemia is confirmed, pregnancy should be ruled out with a βhCG test. In the absence of pregnancy, if the PRL level is higher than 100 ng/dl, the pretest probability for a prolactinoma is high enough to justify a pituitary MRI scan, even if potential secondary causes exist. Regardless of prolactin levels secondary causes should be carefully evaluated with medication history, physical examination, and laboratory tests such as thyroid function tests and chemistry panel, and appropriately treated. If hyperprolactinemia remains unexplained or persists despite correction of other contributing factors, a pituitary MRI is in order. Patients with negative sellar findings have idiopathic hyperprolactinemia. Patients with sellar mass may  have either prolactinoma or pseudoprolactinoma. The latter is suggested by a discordant prolactin level less than 150 ng/ml for a large sellar, or a parasellar mass greater than 1 cm, after hook effect has been ruled out. Abbreviations: βhCG = β human chorionic  gonadotropin; MRI = magnetic resonance imaging; PEG = polyethylene glycol; PRL = prolactin.

Differential Diagnosis

An exhaustive list of etiologies has been provided in Table 1. A few entities deserve additional comments.

Drug-induced hyperprolactinemia is common and at times may produce serum prolactin levels matching those in patients with prolactinoma (see prior section on laboratory evaluation). A more typical range of prolactin level is 25 to 100 ng/ml for drug-induced hyperprolactinemia. It is not always possible to correlate in time the initiation of the culprit drug with the onset of symptoms, or rise of prolactin levels. The way to confirm medication-related hyperprolactinemia is to discontinue the putative offending agent(s) for three days before repeating a prolactin assay. Some medications may require a longer period of abstinence, and in such cases the level of prolactin can be retested later if the second value is reduced but still elevated. Before discontinuing psychotropic medications, one should consult with the prescribing psychiatrist to prevent worsening of the patient’s mental symptoms.

Pseudoprolactinoma refers to a nonfunctioning sellar or suprasellar mass associated with hyperprolactinemia caused by stalk disruption. The prolactin level is seldom above 150 ng/ml. However, before making such a diagnosis one must exclude hook effect with a hundred-fold diluted sample. Prolactin levels are typically normalized within several days after initiation of dopamine agonists as lactotrophs are still sensitive to dopamine, but local compressive symptoms do not improve. In contrast, patients with true macroprolactinoma experience more gradual decrease in prolactin levels after they are put on dopamine agonists, but they could expect improvement in compressive symptoms within 12 hours to days, and imaging evidence of tumor shrinkage in weeks.

Polycystic ovary syndrome (PCOS) and hyperprolactinemia are among the most common causes of menstrual irregularities and infertility, and affect women of similar ages. PCOS has also been associated with hyperprolactinemia. However, multiple studies have shown that the prevalence of hyperprolactinemia in women with PCOS is not significantly higher than that of matched populations. Although mild elevations of DHEA-S or DHEA are common in patients with hyperprolactinemia, hirsutism is rare, and when present is always associated with an increase in testosterone level, likely reflecting possible coexisting PCOS. Therefore the presence of hyperprolactinemia in patients with PCOS or hirsutism warrants additional evaluation.

Management of Secondary Hyperprolactinemia

Treatment of secondary hyperprolactinemia should focus on correcting the underlying conditions, for example treating hypothyroidism, and resection of nonfunctioning pituitary tumors. For drug-induced hyperprolactinemia, the responsible medications should be removed or replaced with alternatives. Newer antipsychotics such as aripiprazole (Abilify) may be used in place of older agents such as risperidone because they have better metabolic/hormonal profiles. For irreversible conditions such as end- stage renal disease, hyperprolactinemia can be effectively controlled with dopamine agonists. Ectopic prolactin secretion, which occurs in paraneoplastic syndrome, is a rare exception where dopamine agonists are ineffective, because extrapituitary production of prolactin is driven by alternative promoters, which do not respond to dopamine. Asymptomatic patients with modest hyperprolactinemia may not need treatment, however, and sex hormone replacement may be adequate for correcting hypogonadism if fertility is not desired.

Management of Prolactinoma

The goals for managing prolactinomas are twofold: treating symptomatic hyperprolactinemia, and relief of tumor mass effects. Treatment thus needs to be tailored to the patient’s unique clinical picture and the desired outcome. Mass effects are not a concern for microprolactinomas, whereas for patients with giant prolactinomas (defined as > 4 cm or > 2 cm of suprasellar extension) and extreme hyperprolactinemia, normalization of prolactin levels is less likely, and treatment should focus on reversal or minimization of mass effects. The following are appropriate options in specific settings.

Observation

Active surveillance is appropriate for patients with microprolactinoma who are asymptomatic or not troubled by galactorrhea, especially if fertility is not a concern. As long as regular menses are preserved there do not seem to be any long-term consequences from hyperprolactinemia. Bone mineral density appears to be preserved in these patients. It is noteworthy that a significant fraction of patients may have tumor resolution during surveillance without treatment. Tumor expansion is a rare event and serial measurements of serum prolactin level are effective for monitoring interval tumor growth. Pituitary imaging is indicated when there is significant increase in prolactin level or emergence of local compression symptoms.

Hormonal Replacement

For patients with microprolactinoma bothered only by symptoms related to hypogonadism including menstrual abnormalities, sexual dysfunction, and osteoporosis, but who no longer desire fertility, hormonal replacement is a valid alternative to dopamine agonists, especially when the latter are not tolerated or are contraindicated.

This can be achieved with oral contraceptive pills in premenopausal women, or testosterone in men. This approach compares favorably to dopamine agonists in terms of cost and side effects. Patients may experience slight increases in prolactin level, but tumor progression has not been associated with use of oral contraceptive pills for up to 2 years. It would be prudent to use lower doses of estradiol (≤ 30 µg/day), and closely monitor patients for prolactin level and tumor growth.

Dopamine Agonists

Medical treatment with dopamine agonists has replaced surgery as the first line treatment for prolactinomas. They are noninvasive and effective in reducing prolactin secretion and shrinking the tumor over time. Complications that could occur as a consequence of a macroprolactinoma receding from its previously occupied spaces include apoplexy, optic chiasm herniation, and CSF leak.

Patients with microprolactinoma may discontinue treatment upon menopause because their treatment goal has been fulfilled. Patients with macroprolactinoma, on the other hand, may require life-long treatment to prevent tumor regrowth. A small fraction of patients with macroprolactinoma with smaller tumors may enter long-term remission if complete tumor resolution occurs after prolonged treatment. The Endocrine Society practice guidelines suggest that tapering or discontinuing dopamine agonists may be attempted in patients who have been treated for at least 2 years and experienced complete biochemical and radiographic resolution. The risk for recurrence after drug discontinuation is proportional to the size of adenoma at the time of the diagnosis; therefore it may not be worthwhile to attempt to discontinue dopamine agonists in patients presenting with tumors larger than 2 cm.

Three dopamine agonists are currently used for treating hyperprolactinemia, including bromocriptine, cabergoline, and quinagolide (available only in Europe). Bromocriptine was the first dopamine agonist available, therefore has the best established safety record. It is still the only dopamine agonist approved by the Food and

Drug Administration (FDA) to be used in pregnancy, when indicated. Cabergoline is a more specific agonist of the D2 dopamine receptor, and is superior in many respects to bromocriptine, for example because of dosing convenience, tolerability, and treatment efficacy.

Many patients not controlled with bromocriptine may achieve normal prolactin levels after switching to cabergoline, which has become the drug of choice for cases not involving pregnancy. The safety data for cabergoline are not as extensive as those for bromocriptine. Common side effects for this class of drugs include nausea, orthostatic hypotension, fatigue, mental fogginess, and less frequently, nasal stuffiness, Raynaud phenomenon, constipation, depression, and psychosis. Nausea is more common in patients taking bromocriptine; for these patients the intravaginal route can be tried. Patients receiving higher doses of cabergoline are at risk of developing cardiac valvulopathy. This has so far been a concern for patients with Parkinson’s disease, who may require much higher doses. However, the life-long exposure to high cumulative doses in patients with resistant prolactinoma is considerable, and regular echocardiogram surveillance is recommended for patients taking doses higher than 2 mg/week. Dosing regimens for bromocriptine and cabergoline are listed in Table 2. In general, patients should be started on the lowest doses and titrated upwards monthly based on the serum prolactin level until treatment goals are reached.

Table 2

Use of Dopamine Agonists in Hyperprolactinemia

Surgery

With the availability of the second generation dopamine agonists, surgery is mostly reserved for the following situations: (1) patients intolerant of, or resistant to, dopamine agonists; (2) women with macroprolactinoma who are planning for conception, to forestall tumor expansion during pregnancy; (3) pituitary apoplexy threatening neurological and visual functions if not managed urgently. Transsphenoidal tumor resection is the standard surgical approach. Perioperative mortality and morbidity are low in the hands of experienced pituitary surgeons in high volume centers. Major surgical complications include visual loss, CNS infection, stroke, and oculomotor palsy. Craniotomy is occasionally needed for masses with extrasellar extensions that may be inaccessible by the transsphenoidal route, with higher risk for complications. Postoperatively patients need to be monitored for signs of diabetes insipidus and secondary adrenal insufficiency, which may be transient or permanent.

Radiotherapy

Radiotherapy is inadequate as a primary treatment for prolactinoma as its efficacy is poor and latency long. It is also associated with long- term complications including permanent hypopituitarism, cerebrovascular accidents, and secondary intracranial malignancies. Currently it is reserved mostly for patients with invasive prolactinomas failing medical/surgical treatment. Stereotactic radiosurgery is preferred over conventional fractionated radiotherapy for more convenient dosing, better efficacy, and lower rate of complications. However, radiosurgery should not be attempted for tumors in close proximity to the visual apparatus (less than 5 mm of clearance), as it is associated with an unacceptably high rate of vision loss.

Management of Prolactinoma During Pregnancy

Mild hyperprolactinemia is part of normal pregnancy and there are concerns for the safe use of dopamine agonists in pregnant women. There is convincing evidence that as long as bromocriptine is withdrawn within a week after confirmation of pregnancy, obstetric outcome is not altered. Less robust data to date also suggest that maintenance of bromocriptine treatment till term or early withdrawal of cabergoline is also safe. Until there is incontrovertible evidence for the absolute safety of these dopamine agonists, it is prudent to discontinue these drugs as soon as pregnancy is confirmed. For the same reason, bromocriptine is the preferred agent for fertility induction in women with hyperprolactinemia, although cabergoline would also be acceptable if bromocriptine is not tolerated. The major indication to treat prolactinomas medically during pregnancy is the concern for tumor expansion. Such risk is negligible for microprolactinomas. For patients with macroprolactinoma, however, symptomatic tumor expansion during pregnancy can occur in up to about 30% of cases. This risk can be significantly reduced if the patient has been treated with a dopamine agonist for at least a year with evidence of tumor shrinkage, or has undergone pituitary surgery or radiotherapy prior to pregnancy. Until these conditions are met, women of childbearing age with macroprolactinomas should be advised to take nonhormonal contraceptive measures. For patients who fail to achieve tumor shrinkage with dopamine agonists or cannot tolerate them, prophylactic surgery prior to pregnancy may be considered, after careful discussion with the patient on surgical risks and the possibility of permanent hypopituitarism, which further impairs fertility. The Endocrine Society practice guidelines recommend against measurement of serum prolactin levels during pregnancy. Instead the patient should be followed clinically for any signs or symptoms of tumor expansion. MRI without gadolinium and visual field testing should be done when clinical suspicion arises. If tumor expansion is confirmed, the patient should be reinitiated on bromocriptine. Debulking surgery is reserved for patients failing or not tolerating medical treatment. Lactation usually does not cause tumor progression, and patients are encouraged to breastfeed their infants with close surveillance. They should not take either bromocriptine or cabergoline, however, as both are secreted in the milk.

Management of Treatment-Resistant Prolactinoma

Several other treatment options are available for patients who fail the highest tolerated doses of dopamine agonists, surgery, and radiation. An alkylating agent, temozolomide (Temodar), has been successfully used in the treatment of invasive pituitary adenoma and pituitary carcinoma. Selective estrogen receptor modulators (SERMs), including raloxifene (Evista) and tamoxifen (Nolvadex), have been found to be useful adjuncts that can reduce prolactin level and inhibit tumor growth.

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