Causes of hyperprolactinemia

INTRODUCTION — Prolactin is secreted solely by the lactotroph cells of the pituitary gland. As a result, hyperprolactinemia results almost exclusively from diseases that cause hypersecretion of prolactin by lactotroph cells. Some of these causes are physiologic and others pathologic.

This topic will review the major causes of hyperprolactinemia. The clinical manifestations, diagnosis, and treatment are discussed separately. (See "Clinical manifestations and evaluation of hyperprolactinemia" and "Management of hyperprolactinemia".)

PHYSIOLOGIC CAUSES — Serum prolactin concentrations normally increase substantially during pregnancy and to a lesser degree in response to nipple stimulation during breastfeeding, physical exertion, and stress. The upper normal value for serum prolactin in most laboratories is approximately 20 ng/mL (20 mcg/L SI units).

Meals may stimulate prolactin secretion slightly. Thus, if the prolactin concentration is only slightly high (up to 40 ng/mL [40 mcg/L] in males and postmenopausal females and up to 50 ng/mL [50 mcg/L] in premenopausal females), it should be repeated on a fasting sample before the patient is considered to have hyperprolactinemia.

Pregnancy — Serum prolactin increases throughout pregnancy, reaching a peak at delivery (figure 1) [1]. The magnitude of the increase, however, is quite variable; in one study, the mean value at term was 207 ng/mL, but the range was from 35 to 600 ng/mL (35 to 600 mcg/L SI units) [1]. The probable cause of the hyperprolactinemia is the increasing serum estradiol concentrations during pregnancy. By six weeks after delivery, estradiol secretion has decreased, and the basal serum prolactin concentration is usually normal, even when the mother is breastfeeding.

Nipple stimulation and breast examinations — Nipple stimulation during breastfeeding increases serum prolactin concentrations, presumably via a neural pathway. The magnitude of the increase is directly proportional to the degree of preexisting lactotroph hyperplasia due to estrogen. In the first weeks postpartum, as an example, the serum prolactin concentration increases up to 300 ng/mL above baseline in response to suckling (figure 2); in contrast, several months after delivery, the increase in prolactin in response to suckling in the breastfeeding woman is usually less than 10 ng/mL (10 mcg/L SI units) above baseline (figure 2) [1].

In nonlactating females and males, nipple stimulation, breast imaging (mammography, ultrasound) [2], or breast examination does not increase prolactin secretion [3,4]. Therefore, prolactin may be measured after a breast examination.

Stress — Stress of any kind, physical or psychological, can cause an increase in the serum prolactin concentration. As with all stimuli of prolactin secretion, women have greater increases than men, presumably due to the effect of their higher serum estradiol concentrations on the lactotroph cells. The magnitude of the increase in prolactin in response to stress is small, so the values rarely exceed 40 ng/mL (40 mcg/L SI units).

PATHOLOGIC CAUSES — Hyperprolactinemia due to hypothalamic-pituitary disorders includes:

●Lactotroph adenomas (prolactinomas), which are benign tumors of the lactotroph cell. Serum prolactin concentrations in patients who have lactotroph adenomas can range from minimally elevated to 50,000 ng/mL (50,000 mcg/L SI units); in comparison, in hyperprolactinemia due to other causes, the concentrations rarely exceed 200 ng/mL (200 mcg/L SI units) (figure 3) [5]. (See 'Lactotroph adenomas' below.)

●Conditions associated with decreased dopaminergic inhibition of prolactin secretion. (See 'Decreased dopaminergic inhibition of prolactin secretion' below.)

●Disease in or near the hypothalamus or pituitary that interferes with the secretion of dopamine or its delivery to the pituitary gland. (See 'Other hypothalamic or pituitary disorders' below.)

Lactotroph adenomas — Lactotroph adenomas, like other pituitary adenomas, arise from monoclonal expansion of a single cell that has presumably undergone somatic mutation [6,7]. The pituitary tumor transforming gene is overexpressed in most lactotroph adenomas [8,9]. It also appears to play a role in tumor invasiveness since expression is increased in tumors that invade the sphenoid bone.

Most adenomas that secrete prolactin and cause hyperprolactinemia are comprised solely of lactotroph cells; however, approximately 10 percent are comprised of both lactotroph and either somatotroph or somatomammotroph cells and, therefore, secrete growth hormone as well as prolactin [10].

Lactotroph adenomas are relatively common; they account for approximately 30 to 40 percent of all clinically recognized pituitary adenomas. The diagnosis is made more frequently in women than in men, especially between the ages of 20 and 40 years [11], presumably because of the sensitivity of menses to disruption by hyperprolactinemia. However, the adenomas that occur in men are usually larger, in part due to the lack of symptoms or delay in seeking medical attention for symptoms such as erectile dysfunction [12]. In addition, the adenomas in men may have an inherently greater rate of growth [12].

Most lactotroph adenomas are sporadic, but they can rarely occur as part of the multiple endocrine neoplasia type 1 (MEN1) syndrome [13]. Almost all lactotroph tumors are benign, but a rare tumor can be malignant and metastasize [14]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)

Prolactin secretion by lactotroph adenomas is generally characterized by both efficiency and proportionality:

●As a result of their efficiency, even microadenomas (<1 cm in diameter) typically secrete sufficient prolactin to cause hyperprolactinemia.

●As a result of their proportionality, serum prolactin concentrations tend to vary with adenoma size. Adenomas <1 cm in diameter are typically associated with serum prolactin values below 200 ng/mL (200 mcg/L SI units), those approximately 1.0 to 2.0 cm in diameter with values between 200 and 1000 ng/mL (1000 mcg/L SI units), and those greater than 2.0 cm in diameter with values above 1000 ng/mL (1000 mcg/L SI units) (figure 3).

Some lactotroph macroadenomas are associated with only modest elevations of prolactin because of:

●Adenomas that are not well differentiated. These also respond less well to dopamine agonists than the more typical adenomas. (See "Management of hyperprolactinemia".)

●Adenomas that are largely cystic, so only a small portion of the mass is cellular and producing prolactin.

●An artifact in the immunoradiometric assay for prolactin called the "hook effect." This can be obviated by dilution of the sera, which will allow a true assessment of the prolactin concentration [15-17]. This artifact is uncommon.

Decreased dopaminergic inhibition of prolactin secretion — Several conditions interfere with normal dopamine inhibition of prolactin secretion. These include damage to the dopaminergic neurons of the hypothalamus, pituitary stalk section, or drugs that block dopamine receptors on lactotroph cells (table 1).

Other hypothalamic or pituitary disorders — Any disease in or near the hypothalamus or pituitary that interferes with the secretion of dopamine or its delivery to the pituitary can cause hyperprolactinemia [5] (see "Causes, presentation, and evaluation of sellar masses"). These include:

●Tumors of the hypothalamus, both benign (eg, craniopharyngiomas) and malignant (eg, metastatic breast carcinoma). These and infiltrative diseases, below, are not as common causes of elevated prolactin as pituitary adenomas, lactotroph, and others.

●Infiltrative diseases of the hypothalamus (eg, sarcoidosis).

●Section of the hypothalamic-pituitary stalk (eg, due to head trauma or surgery).

●Adenomas of the pituitary other than lactotroph adenomas.

DRUG INDUCED — A number of drugs may cause hyperprolactinemia (table 1) [18,19]. Although drugs can cause hyperprolactinemia, they do not cause lactotroph adenomas. In medication-induced hyperprolactinemia, serum prolactin concentrations are typically in the 25 to 100 ng/mL (25 to 100 mcg/L) range. One exception is the antipsychotic drug, risperidone, which may be associated with serum prolactin concentrations as high as 200 ng/mL (200 mcg/L) [19-21].

Antipsychotics — Antipsychotics are the most common cause of pharmacologically induced hyperprolactinemia. Some of the antipsychotic drugs are known dopamine D₂ receptor antagonists and raise serum prolactin by that mechanism. These include risperidone, phenothiazines, and haloperidol (table 1) [22,23]. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects".)

Serum prolactin concentrations increase within hours after acute administration of these drugs and return to normal within two to four days after cessation of chronic therapy [23]. The magnitude of the elevation varies with the drug. As an example, haloperidol raises the serum prolactin concentration by an average of 17 ng/mL (17 mcg/L SI units), whereas risperidone may raise it by 45 to 80 ng/mL (45 to 80 mcg/L SI units) [22].

Among newer antipsychotics, the highest prevalence of hyperprolactinemia has been observed with amisulpride (89 percent), an atypical antipsychotic available in some countries but not the United States; it has not been observed with clozapine (table 1) [24]. The anticonvulsant topiramate has also been used as an antipsychotic, and since it has an inhibitory effect on prolactin secretion, the suggestion has been made that it could be used in psychiatric conditions when hyperprolactinemia should be avoided [25].

SSRIs — Selective serotonin reuptake inhibitors (SSRIs) cause little, if any, increase in the serum prolactin concentration (table 1). In one study [26], 20 mg of paroxetine a day caused no increase in the serum prolactin concentration after one week but did cause a slight increase, although still to only high-normal to slightly high values, after three weeks.

In another study in patients receiving fluoxetine chronically [27], the mean basal serum prolactin concentration was no different from that in untreated patients with similar diseases. Thus, SSRIs do not appear to cause clinically significant hyperprolactinemia.

Other — A number of other drugs have been associated with hyperprolactinemia, including (table 1):

●Metoclopramide [28] and domperidone [29] are gastric motility drugs. Like some of the antipsychotics, dopamine D₂ receptor antagonists raise serum prolactin by that mechanism.

●The antihypertensive drug methyldopa, which is not commonly used now, increases prolactin secretion by a similar mechanism to the gastric motility drugs. Methyldopa inhibits dopamine synthesis [30].

●Verapamil may raise serum prolactin concentrations [31], but other calcium channel blockers do not [32]. The mechanism of this verapamil-induced increase is not known.

In one report, hyperprolactinemia occurred in 8.5 percent of 449 men taking verapamil, as compared with only 3 percent of control men [33]. The elevated serum prolactin concentration persisted during continued drug administration in 14 of 15 men and returned to normal in all nine after the drug was stopped.

OTHER CAUSES

Germline loss-of-function mutation — A germline, loss-of-function mutation in the prolactin receptor gene (PRLR) resulting in prolactin insensitivity has been identified as a cause of familial hyperprolactinemia [34]. The family included three sisters: two with oligomenorrhea, one with primary infertility, and all with serum prolactin concentrations in the 100 to 180 ng/mL range (4.35 to 7.83 nmol/L) and normal pituitary magnetic resonance imaging (MRI). The sisters' father and one of the sisters' sons also carried the mutation; in contrast with the affected female family members, their serum prolactin concentrations were only minimally elevated (20 to 21 ng/mL [0.87 to 0.91 nmol/L]), and they had no other clinical manifestations.

The heterozygous mutation in PRLR results in an amino acid change from histidine to arginine at codon 188, resulting in a loss of downstream signaling by Janus kinase 2 (JAK2) and signal transducer and activator of transcription factor 5 (STAT5). The oligomenorrhea and infertility suggest that the hyperprolactinemia is having a biologic effect, which in turn suggests that there are functioning prolactin receptors in some tissues.

Idiopathic hyperprolactinemia — In a substantial number of patients whose serum prolactin concentration is between 20 and 100 ng/mL (20 and 100 mcg/L SI units), no cause can be found. Although many of these patients may have microadenomas not visible on imaging studies, in most of them, the serum prolactin concentrations change little during follow-up for several years [35-37]. In one report, as an example, only 1 of 59 patients who were followed for an average of 6.5 years developed a detectable pituitary adenoma, and approximately 20 percent had a normal serum prolactin concentration when it was last measured [37].

Estrogen — Estrogen increases prolactin secretion proportionate to the degree of estrogenization. The mechanism by which estrogen stimulates prolactin secretion appears to involve binding of estrogen to the estrogen receptor, which then binds to an estrogen response element on the prolactin gene in the lactotroph cell of the pituitary [38,39].

Amounts of estrogen that are physiologic for a woman increase the basal serum prolactin concentration minimally but explain the greater prolactin response of women compared with men to almost all physiologic stimuli [40].

Greater amounts of estrogen, such as occur in pregnancy, increase basal serum prolactin concentrations, as described above. (See 'Pregnancy' above.)

The amount of estrogen in hormonal contraceptives generally does not cause hyperprolactinemia. (See "Management of hyperprolactinemia", section on 'Treatment of women with estradiol'.)

Hypothyroidism — Hypothyroidism predisposes to hyperprolactinemia. However, basal serum prolactin concentrations are normal in most hypothyroid patients [41], and only the serum prolactin response to stimuli, such as thyrotropin-releasing hormone (TRH), is increased [42]. In the few hypothyroid patients who have elevated basal serum prolactin concentrations, the values return to normal when the hypothyroidism is corrected [43,44]. It is important to recognize hypothyroidism as a potential cause of an enlarged pituitary gland (due to thyrotroph hyperplasia, lactotroph hyperplasia, or both) and hyperprolactinemia and not to confuse this entity with a lactotroph adenoma. (See "Causes, presentation, and evaluation of sellar masses".)

The mechanism of hyperprolactinemia in hypothyroidism is not known. Both enhanced hypothalamic synthesis of TRH and increased pituitary responsiveness to TRH have been described [42]. The management of hyperprolactinemia due to hypothyroidism is discussed separately. (See "Management of hyperprolactinemia", section on 'Hypothyroidism'.)

Decreased clearance of prolactin — Two causes of hyperprolactinemia due to decreased clearance of prolactin include chronic renal failure and macroprolactinemia.

Macroprolactinemia — Macroprolactinemia is an umbrella term used to describe aggregates of prolactin and antibodies (in particular, antiprolactin autoantibodies) that range in size from approximately 150 to 170 kD. The most common form of native prolactin in serum is 23 kD in size [45].

These complexes are immunologically detectable but not biologically active, so they appear to cause no clinical abnormality. As an example, in a series of 55 women ages 18 to 55 years, none had a history of amenorrhea, eight had oligomenorrhea before age 40 years, and one had galactorrhea [46]. All subjects had pituitary imaging; no macroadenomas and four microadenomas were seen (consistent with the prevalence of incidentalomas in the normal population). Similar results were seen in a second study of 51 patients [47]. Thus, macroprolactinemia appears to be a benign clinical condition [46].

Although these entities are not of clinical significance directly, they are of clinical significance indirectly because they can be misdiagnosed and treated as prolactin hypersecretion [48]. Misdiagnosis can be avoided by asking the laboratory to pretreat the serum with polyethylene glycol to precipitate the macroprolactin before the immunoassay for prolactin. (See "Clinical manifestations and evaluation of hyperprolactinemia", section on 'Macroprolactin'.)

Chronic kidney disease — The serum prolactin concentration is high in patients who have chronic kidney disease and returns to normal after kidney transplantation [49]. The major mechanism is a threefold increase in prolactin secretion, and there is a one-third decrease in metabolic clearance rate [50]. Hyperprolactinemia persists, however, during dialysis [51].

Chest wall injury — Chest wall injuries, such as severe burns, increase prolactin secretion, presumably due to a neural mechanism similar to that of suckling [52].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyperprolactinemia/prolactinoma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Prolactinoma (The Basics)")

●Beyond the Basics topics (see "Patient education: High prolactin levels and prolactinomas (Beyond the Basics)")

SUMMARY

●Physiologic causes – Physiologic causes of hyperprolactinemia include pregnancy, breastfeeding, and stress.

Food has only a small effect on serum prolactin concentrations; therefore, fasting is usually not necessary when having serum prolactin measured. However, if an initial value is mildly elevated (21 to 40 ng/mL), the measurement should be repeated on a fasting specimen.

While breastfeeding increases serum prolactin concentrations, nipple stimulation or breast examination does not increase prolactin levels in nonlactating females or males. Therefore, prolactin may be measured after a breast examination. (See 'Physiologic causes' above.)

●Pathologic causes – Pathologic causes of hyperprolactinemia include lactotroph adenomas (prolactinomas), other hypothalamic and pituitary disorders, and medications, most commonly antipsychotics. (See 'Pathologic causes' above and 'Drug induced' above.)

A germline, loss-of-function mutation in the prolactin receptor gene (PRLR) resulting in prolactin insensitivity has been identified as a cause of familial hyperprolactinemia. (See 'Germline loss-of-function mutation' above.)

●Other causes – Other causes include idiopathic hyperprolactinemia, hypothyroidism, chest wall injury, chronic kidney disease, and macroprolactinemia due to "big prolactin." (See 'Other causes' above.)