Prolactin is a hormone that primarily affects lactation; however, the clinical effects of hyperprolactinemia extend far beyond the mammary glands and affect distant organs such as the gonads, bones, as well as the brain in cases of tumors. Hyperprolactinemia is the most common endocrine disorder of the hypothalamic-pituitary axis. It is diagnosed when the serum prolactin level is consistently elevated above 25 ng/ml. Prolactin, like other anterior pituitary hormones, is under constant hypothalamic control. However, its predominant control is tonic-inhibitory through the action of prolactin inhibitory factors (PIF). The major PIF is dopamine. Dopamine inhibits prolactin secretion via D-2 receptors on the surface of the anterior pituitary lactotroph cells. Some of the weak prolactin releasing factors (PRF) include thyroid releasing hormone, vasoactive intestinal peptide, angiotensin II, serotonin, and vasopressin. Under normal physiologic conditions, the role of these weak stimulatory agents is not clear, and therefore the predominant control of prolactin secretion remains the inhibitory effect of dopamine.

Biochemistry

prolactin is a glycoprotein hormone secreted primarily by the anterior pituitary lactotrophs. During pregnancy, the decidua secretes prolactin as well, but decidual prolactin does not enter the circulation. It is concentrated in the amniotic fluid with levels exceeding those in the serum (10-100 fold that in the maternal or fetal serum). During pregnancy, the elevation in serum prolactin is solely due to pituitary secretion. Prolactin is secreted in different forms: prolactin (monomer), “big” prolactin (dimer), and “big big” prolactin, a polymer. Prolactin hormone can also vary in the size of the glycoprotein moieties attached to the amino acid basic structure. The three different forms differ in their potency as well: The big big prolactin is less bioactive than the smaller counterparts.

Etiology of Hyperprolactinemia

Prolactinomas

Prolactinomas are pituitary adenomas (a monoclonal tumor) that secrete prolactin. Like other pituitary adenomas, they can be classified into microadenomas or macroadenomas based on their size (less than 10 mm and greater than 10 mm, respectively). It is important to differentiate between the two because microadenomas are unlikely to compress the optic chiasm, while macroadenomas can compress it resulting in visual field damage which can be irreversible. In addition, macroadenomas, through a mass effect, can compromise other pituitary cells (such as gonadotrophs, thyrotrophs, and ACTH releasing cells). The overwhelming majority of prolactinomas are benign tumors, meaning that they do not metastasize to distant organs. Very few cases of malignant prolactinomas are reported in the literature; however, prolactinomas can be locally destructive, especially the macroadenomas. In addition to affecting pituitary function by a local mass effect, they can invade the optic chiasm as well as the adjacent cavernous sinus causing cranial nerve neuropathies (CN III, IV, VI, V2, VI). In women, the slightest elevation in prolactin can cause menstrual disturbances. Men, on the other hand, tend to present with symptoms of local mass effect. Physiologic effects of hyperprolactinemia in men (low libido, impotence, and infertility) are less sensitive to the hyperprolactinemia than symptoms in females (oligomenorrhea or amenorrhea).

When to check a prolactin level?

• Any patient (male or female) with galactorrhea

• Any male patient with erectile dysfunction

• Any female patient with amenorrhea or oligomenorrhea

• Any female patient with symptoms of premenopausal hypogonadism

• Patients with neurological symptoms suggestive of pituitary adenomas (severe headaches, visual field changes)

• Patients with incidental pituitary adenomas discovered while imaging the brain for unrelated reasons

Evaluation

Although prolactin is secreted in a pulsatile fashion, a random blood test usually suffices. If the prolactin is mildly elevated on initial evaluation (<40 ng/ml), it is prudent to repeat it prior to making a diagnosis of hyperprolactinemia. If the mild prolactin elevation is persistent on subsequent testing or if the initial level is greater than 40 ng/ml, then a specific cause should be sought. ATSH level should always be checked to rule out primary hypothyroidism, as this can result in an elevated prolactin level (due to the prolactin stimulating effect of TRH). A renal panel should be checked, as compromised kidney function leads to decreased clearance of prolactin. Brain imaging, using gadolinium enhanced MRI (preferred) or CT scanning is mandatory to rule out hypothalamic-pituitary lesions. Although microadenomas typically produce serum prolactin levels less than 100 ng/ml, while macroadenomas typically show levels greater than 100 ng/ml, a serum level cannot distinguish between the two. For example, a macroadenoma can produce very high serum prolactin levels (greater than 1000 ng/ml), but due to an intrinsic artifact in the immunoassay (termed “the hook” effect), the result is read as a value less than 100 ng/ml. Only when the serum is diluted (1:100 dilution) will the true value of prolactin be measured. In addition, other pituitary tumors (nonfunctioning pituitary macroadenomas and hypothalamic tumors) can cause elevations of prolactin with values less than 100 ng/ml (by compressing the dopaminergic inhibitory fibers from the hypothalamus). Such tumors need to be accurately diagnosed and differentiated from microprolactinomas because their treatment is completely different. Therefore, while the initial blood test is helpful in diagnosing hyperprolactinemia, brain imaging is warranted to accurately identify the cause.

Galactorrhea

Galactorrhea is defined as the presence of a milky nipple discharge at any time in men and in women with no recent history of pregnancy or breast-feeding. Evaluation of galactorrhea in the office includes examining the breast discharge on a slide under a microscope. The finding of fat globules is diagnostic.

Treatment of Hyperprolactinemia

Pregnancy Considerations

For women who desire pregnancy, bromocriptine is the drug of choice to assist in achieving ovulation. It has a well-established safety profile when used during the first few weeks of gestation. Fewer data are available on cabergoline.

For patients with microadenomas, bromocriptine can be stopped after conception. Such patients have a very low incidence of tumor enlargement during pregnancy (<5%) and therefore periodic imaging and visual field testing is not routinely recommended. Nor is it necessary to measure prolactin levels in pregnancy, as there is no correlation between tumor enlargement and serum prolactin levels.

For patients with macroadenomas, the risk of clinically significant tumor enlargement during pregnancy is about 26%. There is no clear answer as to the best therapeutic approach, but three management strategies exist:

1. Stop the bromocriptine (or other dopamine agonist) after conception and closely follow up the patients (with visual field testing and imaging) for signs of tumor enlargement

2. Perform a prepregnancy tumor debulking (however, such patients usually still require bromocriptine to achieve ovulation)

3. Continue bromocriptine for the duration of the pregnancy. The few studies on bromocriptine exposure during late gestation suggest that this is safe for the fetus.

All pregnant patients with macroadenomas should have monthly visual field testing.

Key Points

1. Regardless of the prolactin level, newly diagnosed hyperprolactinemia patients of suspected pituitary origin should have brain imaging performed to rule out a macroadenoma or other stalk compressing lesions.

2. Females tend to present earlier than males due to menstrual disturbances.

3. The primary therapy for prolactinomas is medical. Second line treatment is surgical, and third line is radiotherapy.

4. Patients desiring to conceive should preferably be placed on bromocriptine.

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