High Prolactin: Why It Happens and When to Treat

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By Adriana Ioachimescu, MD, PhD, FACE
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Prolactin is a hormone secreted by the pituitary gland that induces breast milk production after childbirth. The pituitary gland is located in the brain. Prolactin secretion is controlled by a brain compound called dopamine. Normal blood levels of prolactin are usually below 25 ng/mL in women and 17 ng/mL in men. It is normal for prolactin to increase above these levels during pregnancy and breastfeeding.

Hyperprolactinemia – a Common Endocrine Problem

High prolactin (or hyperprolactinemia) is a relatively common endocrine problem, affecting roughly 90 women and 30 men out of 100,000. Women in the 25-35 age group have the highest risk to develop hyperprolactinemia.

Hyperprolactinemia can be a sign of a pituitary tumor called prolactinoma. Patients with sizeable tumors that compress the surrounding tissues may experience headaches, changes in vision and low pituitary hormones (hypopituitarism). Hypopituitarism may result in low cortisol and thyroid hormone production, which require replacement hormone therapy.

High prolactin can interfere with the function of ovaries in women and testicles in men. This is called hypogonadism and may cause infertility, low energy, hot flashes, sexual dysfunction and mood changes, as well as bone loss and risk of fractures. Other manifestations of low estrogen in women of childbearing age include irregular or cessation of periods, acne, excess facial hair or vaginal dryness. Men with low testosterone may notice erectile dysfunction, decreased muscle mass and decreased facial hair.

Hyperprolactinemia has effects on the breast tissue, causing milky discharge from breasts (galactorrhea) in women and enlarged breasts (gynecomastia) in men.

"When the cause of hyperprolactinemia is not clear, physicians can do additional blood tests to check for interference with laboratory assays (like macroprolactin)."

Causes of hyperprolactinemia

  • Prolactin-secreting tumors represent the most common type of the pituitary adenomas, which are usually benign (non-cancerous). The process of adenoma formation is not completely understood and entails proliferation of the prolactin-secreting cells. Fewer than 5% of patients have a family history of pituitary adenoma or other endocrine tumors. While most patients are women with adenomas smaller than 1 cm (0.4 inches), larger tumors can occur, especially in men.
  • Other tumors in the pituitary region can cause hyperprolactinemia (non-secretory pituitary adenoma, growth-hormone secreting adenoma, craniopharyngioma and Rathke’s cleft cysts). These tumors do not secrete prolactin, but cause elevation of prolactin because of compression of the pituitary stalk that connects the hypothalamus to the pituitary gland. Interference with prolactin control results in excessive release of prolactin from the normal pituitary tissue (stalk effect). The distinction is important because treatments are different in prolactinomas than in other types of tumors.
  • Several medications can increase prolactin levels by interference with dopamine in the brain. Several medications prescribed for psychiatric conditions (phenothiazines, butyrophenones risperidone, etc.) and metoclopramide (prescribed for gastrointestinal conditions) can significantly increase prolactin levels. High prolactin can also be caused by opiate painkillers, oral estrogen and blood pressure medications (for example, verapamil).
  • Underactive thyroid (hypothyroidism) and renal insufficiency can cause hyperprolactinemia.
  • The term idiopathic hyperprolactinemia is used when a cause for elevated prolactin cannot be identified. The prolactin level is usually mildly elevated and will probably return to normal on its own, usually after a few months.

How to differentiate between prolactinoma and other causes of high prolactin

  • Highest prolactin levels are seen in patients with prolactin-producing pituitary adenomas, especially those with large tumors. In general, the prolactin level is elevated 5 to 10 times above normal in patients with small prolactinomas and greater than 10 times for larger prolactinomas.
  • In case of stalk effect from other types of tumors, prolactin level is usually in the same range as for small prolactinomas, which can be confusing. A pituitary MRI (magnetic resonance imaging) study is usually helpful because it indicates tumor size and location. MRI cannot determine the type of pituitary tumor, but its results are useful in correlation with physical exam and blood test results for establishing the diagnosis.
  • When hyperprolact-inemia is caused by medications, their discontinuation for approximately three days typically normalizes prolactin levels. Physicians can advise whether this approach is safe and order a repeated prolactin level. Patients should not stop these medications on their own. MRI evaluation of the pituitary gland is necessary in cases where medications cannot be temporarily discontinued.
  • Hypothyroidism or kidney disease are detected by blood tests.
  • When the cause of hyperprolactinemia is not clear, physicians can do additional blood tests to check for interference with laboratory assays (like macroprolactin).

How is hyperprolactinemia treated?

Hyperprolactinemia is usually treated with medications called dopamine agonists. In the United States, bromo-criptine and cabergoline oral tablets are approved for this indication. They reduce prolactin levels and the size of prolactin-secreting tumors in most patients.

Patients with prolactinomas may require surgery if they do not respond or tolerate the dopamine agonists or if they develop sudden vision changes. Patients with hyperprolactinemia due to stalk effect may also require surgical treatment.

When hyperprolactinemia is related to a medication, substitution with another drug is usually attempted. Treatment with bromocriptine or cabergoline in patients with hyperprolactinemia caused by antipsychotics is usually not recommended because of potential exacerbation of the underlying psychiatric disease. Replacing estrogen in women and testosterone in men is helpful for symptoms of hypogonadism and in improving bone strength when the medication causing hyperprolactinemia cannot be stopped.

Hyperprolactinemia from underactive thyroid is usually reversible after thyroid hormone administration.

Idiopathic (arising spontaneously or for which the cause is unknown) hyperprolactinemia may be treated with dopamine agonists if patients have significant symptoms.

For prolactinomas, tumor size is an important factor to consider. If the tumor is small, patients can be observed without any treatment. For breast symptoms or infertility, dopamine agonists are usually prescribed. Women with amenorrhea (an abnormal absence of menstruation) but without bothersome breast symptoms or desire for pregnancy can be treated with either dopamine agonists or estrogen replacement. For larger prolactinomas, treatment is important to decrease the tumor size.

"Fertility is another important consideration in treatment with dopamine agonists. Even small tumors can cause infertility, and treatment may be required to restore normal ovarian function in women and normal testicular function in men. "

Fertility and Pregnancy

Fertility is another important consideration in treatment with dopamine agonists. Even small tumors can cause infertility, and treatment may be required to restore normal ovarian function in women and normal testicular function in men. Women with sizeable prolactinomas also require treatment to shrink the tumor before becoming pregnant. Once pregnancy is achieved, patients are usually advised to stop the dopamine agonists. These, however, can be restarted if headaches or vision changes occur. Surgery in the second trimester of pregnancy is rarely needed in women with enlarging prolactinomas. Pregnant women with tumors larger than 1 cm require ophthalmological evaluations at baseline and during pregnancy. Dopamine agonists are held during breastfeeding, unless there is evidence of significant tumor enlargement during pregnancy.

How long to treat?

Duration of treatment with dopamine agonists is difficult to predict. If prolactin levels are normal on a small dose of dopamine agonist and MRI does not show a tumor after two years of treatment, stopping the medication can be attempted. In this case, hyperprolactinemia could return and dopamine agonists may need to be restarted.

Menopause is an important milestone for women with small prolactinomas because maintaining ovarian function is no longer necessary. Dopamine agonists can be stopped while patient is monitored. However, women with large prolactinomas usually have to continue the dopamine agonists because of the risk of tumor regrowth.