CAUSAS DE HIPERPROLACTINEMIA

PHYSIOLOGIC CAUSES

Serum prolactin concentrations normally increase substantially during pregnancy and to a lesser degree in response to nipple stimulation and stress. The upper normal value for serum prolactin in most laboratories is about 20 ng/mL (20 mcg/L SI units).
PREGNANCY — Serum prolactin increases throughout pregnancy, reaching a peak at delivery. 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). 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 — Nipple stimulation 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 a few hundred ng/mL above baseline in response to suckling; 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. In nonlactating women, nipple stimulation or breast examination usually does not increase prolactin secretion.

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, the values rarely exceeding 40 ng/mL (40 mcg/L SI units).

Pathologic hyperprolactinemia can be caused by the following:
• Lactotroph adenomas (prolactinomas), which are benign tumors of the lactotroph cell.
• Decreased dopaminergic inhibition of prolactin secretion.
• Other conditions, including decreased clearance of prolactin.
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).

LACTOTROPH ADENOMAS — Lactotroph adenomas, like other pituitary adenomas, arise from monoclonal expansion of a single cell that has presumably undergone somatic mutation. The pituitary tumor transforming gene is overexpressed in most lactotroph adenomas. 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, about 10 percent are comprised of both lactotroph and either somatotroph or somatomammotroph cells and therefore secrete growth hormone as well as prolactin.
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, 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. In addition, the tumors in men may have an inherently greater rate of growth.
Most lactotroph adenomas are sporadic, but they can rarely occur as part of the multiple endocrine neoplasia type 1 syndrome. Almost all lactotroph tumors are benign but a rare tumor can be malignant and metastasize.
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).
There are exceptions to both generalizations. As an example, occasional patients have a large lactotroph adenoma but only modest hyperprolactinemia. Such adenomas are generally less well differentiated and respond less well to dopamine agonists than the more typical tumors. Another example is a lactotroph adenoma that is largely cystic, so only a small portion of the mass is cellular and producing prolactin. In yet other patients who have lactotroph macroadenomas but only modest elevation of the reported serum prolactin concentration, the reason for the discrepancy between the large size of the adenoma and modest elevation of the prolactin concentration is due to an artifact in the immunoradiometric assay for prolactin. This artifact, called the "hook effect," can be obviated by dilution of the sera, which will allow a true assessment of the prolactin concentration.
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.
Hypothalamic and pituitary disease — Any disease in or near the hypothalamus or pituitary that interferes with the secretion of dopamine or its delivery to the hypothalamus can cause hyperprolactinemia. These include:
• Tumors of the hypothalamus, both benign (eg, craniopharyngiomas) and malignant (eg, metastatic breast carcinoma)
• 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 USE — A number of drugs may cause hyperprolactinemia. Although drugs can cause hyperprolactinemia, they do not cause prolactinomas. Several drugs are known dopamine D2 receptor antagonists and raise serum prolactin by that mechanism. These include antipsychotic drugs such as risperidone, phenothiazines, haloperidol, and butyrophenones. and the gastric motility drugs metoclopramide and domperidone . 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. 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). Among newer antipsychotics, the highest prevalence of hyperprolactinemia has been observed with amisulpride (89 percent); it has not been observed with clozapine.
The antihypertensive drugs methyldopa and reserpine, neither of which is commonly used now, increase prolactin secretion by a similar mechanism. Methyldopa inhibits dopamine synthesis, while reserpine inhibits dopamine storage.
Verapamil may raise serum prolactin concentrations, but other calcium channel blockers do not. The mechanism of this verapamil-induced increase is not known. Hyperprolactinemia occurred in 8.6 percent of 449 men taking verapamil in one report, as compared with only 3 percent of control men. 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.
Selective serotonin reuptake inhibitors (SSRIs) cause little if any increase in the serum prolactin concentration. In one study, 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, the mean basal serum prolactin concentration was no different from that in untreated patients with similar diseases. These drugs, in short, do not appear to cause clinically significant hyperprolactinemia.

OTHER CAUSES

ESTROGEN — Estrogen increases prolactin secretion proportionate to the degree of estrogenization. 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. Greater amounts of estrogen, such as occur in pregnancy, increase basal serum prolactin concentrations, as described above. The amount of estrogen in hormonal contraceptives generally does not cause hyperprolactinemia.
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.

HYPOTHYROIDISM — Hypothyroidism predisposes to hyperprolactinemia. However, basal serum prolactin concentrations are normal in most hypothyroid patients, and only the serum prolactin response to stimuli, such as TRH (thyrotropin-releasing hormone), is increased. In the few hypothyroid patients who have elevated basal serum prolactin concentrations, the values return to normal when the hypothyroidism is corrected. 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.
The mechanism of hyperprolactinemia in hypothyroidism is not known. Both enhanced hypothalamic synthesis of TRH and increased pituitary responsiveness to TRH have been described. The management of hyperprolactinemia due to hypothyroidism is discussed separately.

CHEST WALL INJURY — Chest wall injuries, such as severe burns, increase prolactin secretion, presumably due to a neural mechanism similar to that of suckling.

CHRONIC RENAL FAILURE — The serum prolactin concentration is high in patients who have chronic renal failure and returns to normal after renal transplantation. The major mechanism is a threefold increase in prolactin secretion and there is a one-third decrease in metabolic clearance rate.

IDIOPATHIC HYPERPROLACTINEMIA — In a substantial number of patients whose serum prolactin concentration is between 20 and 100 ng/mL (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. 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 about 20 percent had a normal serum prolactin concentration when it was last measured.

MACROPROLACTINEMIA — Two causes of hyperprolactinemia due to decreased clearance of prolactin include chronic renal failure (discussed above) and big prolactin. The most common form of prolactin in serum is 23 kD in size and is not glycosylated, but a small amount of a 25 kD glycosylated form can also be detected. In rare cases, glycosylated prolactin, which appears to circulate in aggregates, accounts for most of the prolactin. In this situation the prolactin has been called "big prolactin" and the condition referred to as "macroprolactinemia." The elevated serum prolactin concentration in these patients can be distinguished from hyperprolactinemia of other causes by gel filtration or polyethylene glycol precipitation. In one series of 1106 patients with hyperprolactinemia, approximately 10 percent had macroprolactinemia.
The clinical manifestations of macroprolactinemia were described in a series of 55 women ages 18 to 55. None had a history of amenorrhea, eight had oligomenorrhea before age 40, and one had galactorrhea. 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. Thus, macroprolactinemia appears to be a benign clinical condition.
Equally rare is a raised serum prolactin level due to complexing of normal-sized prolactin with circulating prolactin antibodies. In this situation, the free prolactin concentration is normal and causes no biologic abnormalities.
These entities are not of clinical significance directly, but are of clinical significance in an indirect way because they can be misdiagnosed and treated as ordinary hyperprolactinemia. Misdiagnosis can be avoided by asking the laboratory to pretreat the serum with polyethylene glycol to precipitate the macroprolactin before the immunoassay for prolactin


REFERÊNCIA:
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