Patient information: High prolactin levels and prolactinomas

HIGH PROLACTIN OVERVIEW

Lactotroph adenomas (prolactinomas) are benign (non-cancerous) tumors of the pituitary gland that produce prolactin and thereby cause higher than normal blood prolactin concentrations. They can cause symptoms, either when the high blood prolactin concentration interferes with the function of the ovaries or testicles or, less commonly, when the adenoma grows large enough to compress nearby structures in the head, such as the nerves to the eyes.

Prolactinomas occur in both men and women but are more commonly diagnosed in women who are less than 50 years than in older women or men.

Lactotroph adenomas can usually be treated successfully with medication alone. Medication lowers the prolactin level in the blood substantially, often to normal, and also usually reduces tumor size. However, a minority of these tumors do not respond to medication and must be treated with surgery or, less commonly, radiation therapy.

CAUSES OF HIGH PROLACTIN

The pituitary is a small gland in the middle of the head just below the brain (figure 1). The pituitary contains lactotroph cells that produce prolactin, the hormone that stimulates lactation (formation of breast milk). Lactotroph adenomas develop when one of these normal cells develops a mutation that allows the cell to divide repeatedly, resulting in a large number of cells that produce an excessive amount of prolactin. About 10 percent produce growth hormone as well as prolactin.

Most lactotroph adenomas occur sporadically, but rarely they occur in families as part of a condition called the multiple endocrine neoplasia type 1 (MEN 1) syndrome.

Most lactotroph adenomas remain small, less than 1 centimeter (0.4 inches) in diameter and are called microadenomas. A minority grow larger, occasionally to several centimeters, and are called macroadenomas.

SYMPTOMS

The symptoms of lactotroph adenomas fall into two categories: symptoms that result from elevated blood prolactin levels and those that result from compression of surrounding tissues.

Symptoms caused by elevated blood prolactin — Elevated blood prolactin interferes with the function of the ovaries in women and the testicles in men. Therefore, it causes symptoms in premenopausal women and in men, but not in postmenopausal women, whose ovaries have stopped functioning.

Women — When a high blood prolactin concentration interferes with the function of the ovaries in a premenopausal woman, secretion of estradiol, the main type of estrogen, decreases. Symptoms include irregular or absent menstrual periods, infertility, menopausal symptoms (hot flashes and vaginal dryness), and, after several years, osteoporosis. High prolactin levels can also cause milk discharge from the breasts.

Men — When a high blood prolactin concentration interferes with the function of the testes, the production of testosterone (the main male sex hormone) and sperm decreases. Low testosterone causes decreased energy, sex drive, muscle mass and strength, and blood count. If levels remain low for several years, bone strength may become decreased (osteoporosis). High blood prolactin also causes difficulty in getting an erection, as well as breast tenderness and enlargement.

Symptoms caused by compression of surrounding tissue — Large adenomas can cause symptoms by pressing on nearby structures in the head. Pressure on nerves to the eyes can impair vision, especially peripheral (side) vision. Pressure on the pituitary gland can decrease production of the hormones that stimulate the thyroid gland and adrenal glands, leading to underactivity of the thyroid and adrenal glands. Pressure can also cause headaches.

DIAGNOSIS OF PROLACTINOMA

A lactotroph adenoma is diagnosed based upon an elevated blood level of prolactin and evidence of a mass in the pituitary gland (as seen on an MRI scan). Other causes of an elevated prolactin level must be evaluated as well.

Measurement of prolactin — The prolactin level can be measured in a single blood sample. The result can range from slightly elevated to a thousand times the upper limit of normal. In general, larger adenomas cause higher prolactin levels.

Magnetic resonance imaging (MRI) — MRI is the best test for identifying masses near the pituitary gland, although MRI cannot determine if the mass is a pituitary adenoma or another abnormality. Furthermore, some small adenomas (microadenomas) cannot be detected by MRI, and not all adenomas secrete prolactin or other hormones.

Evaluating other causes — Other causes of a high blood prolactin level include certain medications, especially those used to treat psychiatric conditions and estrogens taken by mouth, and underactivity of the thyroid (hypothyroidism).

PROLACTINOMA TREATMENT OPTIONS

The goals of treatment are to lower the level of prolactin in the blood to normal and to decrease the size of a large adenoma, especially if it is compressing surrounding structures. It is important that the physician and patient discuss the possible benefits and risks of treatment.

Not all lactotroph adenomas require treatment. If it is large or causing symptoms, it should probably be treated, but if it is small and is not causing symptoms, it does not need to be treated.

When treatment is necessary, most lactotroph adenomas respond well to therapy with medications called dopamine agonists. If an adenoma does not respond to any of these medications or if the medication causes intolerable symptoms, the adenoma must be treated with surgery or radiation therapy.

MEDICATIONS TO TREAT PROLACTINOMAS

A dopamine agonist is the best first treatment for a lactotroph adenoma of any size. Two dopamine agonists are currently available for this purpose: cabergoline and bromocriptine.

Bromocriptine — Bromocriptine has been used for 25 years to treat prolactinomas. It is taken twice a day. While it is usually very effective in lowering blood prolactin levels, it can cause side effects, including dizziness, nausea, and nasal stuffiness. Many of the side effects can be avoided by taking the medication with meals or at bedtime and by starting with a very low dose (1/4 to 1/2 tablet).

Cabergoline — Cabergoline is taken once or twice a week, and is much less likely to cause nausea compared to other dopamine agonists. It may be effective for treating lactotroph adenomas that are resistant to bromocriptine. For all these reasons, cabergoline is the best first choice, except in women who are trying to become pregnant (see 'Becoming pregnant' below.

Effectiveness of dopamine agonists — Dopamine agonists are very effective for decreasing prolactin levels and the size of most lactotroph adenomas. Cabergoline, which appears to be the most effective dopamine agonist, lowers prolactin levels in about 90 percent of people who have lactotroph adenomas, often to a level that is normal. It also decreases the size of micro- and macroadenomas to normal. Prolactin levels usually fall within the first two to three weeks of treatment, but detectable decreases in adenoma size require more time, usually several weeks to months. When vision is affected, it usually begins to improve within days of starting treatment.

If the prolactin level decreases to normal or near normal levels, the effects of the elevated prolactin are reversed. In premenopausal women, ovarian function returns, estrogen levels increase, menstrual periods return, and fertility returns. In men, testicular function returns, causing an increase in energy, sex drive, muscle mass, blood count, and bone calcium. The ability to have an erection returns and, eventually, breast enlargement regresses.

Side effects of drug therapy — The major side effects of dopamine agonists are nausea, lightheadedness after standing, and mental fogginess. These side effects are most likely to occur when treatment first begins and when the dose is increased. They can be minimized by starting with a small dose, increasing the dose slowly if needed, using small doses more frequently, and taking the drug with food or at bedtime. In women, intravaginal administration can decrease or prevent nausea.

Cabergoline has been associated with valvular heart disease in people with Parkinson disease. This appears to be dose-dependent, and the doses of dopamine agonists used for Parkinson disease (often >3 mg/day or 20 mg/week) are typically much higher than those used for hyperprolactinemia (0.5 to 2 mg/week). To date, there have been no reports of valvular heart disease in people being treated for hyperprolactinemia. However, experts recommend using the lowest dose of cabergoline necessary to lower prolactin to normal.

How long is medication needed? — If the prolactin level remains normal and no adenoma is seen on MRI for two or more years, a trial period without medication can be considered. Monitoring of the prolactin level, and less frequently, the size of the pituitary, would continue during this time. If the prolactin levels begin to rise or the adenoma grows in size, a dopamine agonist may be recommended.

If the dopamine agonist is not effective in lowering the prolactin level or if the person cannot tolerate the medication side effects, surgery to remove the adenoma may be considered (see 'Surgery for prolactinoma' below.

Issues in women

Drug therapy and menopause — Women who have microadenomas usually do not have to continue taking dopamine agonists after menopause. The prolactin is usually measured a few months after treatment is stopped to be sure that it is not substantially higher than before treatment. This is usually done once per year for a few years, and less often thereafter. Women who have macroadenomas should continue taking dopamine agonists after menopause.

Estrogen and progestin — Estrogen, in combination with progestin, is a treatment option for women who have lactotroph microadenomas, especially women who have intolerable side effects with dopamine agonists and those who do not want to become pregnant.

The rationale for estrogen treatment is that the only known harmful effects of an elevated blood prolactin in a woman is decreased ovarian function, including diminished secretion of estrogen. Estrogen doses and regimen are discussed in a separate topic review. (See "Patient information: Postmenopausal hormone therapy".)

The prolactin concentration should be monitored periodically because of the small chance that the adenoma could grow. Estrogen and progestin treatment are not recommended as the only treatment in women with a lactotroph macroadenoma.

Becoming pregnant — A woman who has a lactotroph adenoma and wishes to become pregnant can usually do so with little risk to herself or her developing child. However, the woman should discuss her desire to become pregnant with an endocrinology specialist before attempting to become pregnant. Issues to address include which treatment is best before attempting to become pregnant, when to discontinue dopamine agonist treatment, the chance that the adenoma will grow during pregnancy, what would be done if it does grow, and whether or not breastfeeding is advisable. These considerations are influenced greatly by whether the adenoma was less than 1 centimeter (microadenoma) or greater than 1 centimeter (macroadenoma) prior to treatment.

• Microadenomas — Microadenomas rarely increase in size during the course of pregnancy. The best treatment to restore fertility in women with a microadenoma is a dopamine agonist. Bromocriptine does not appear to increase the risk of miscarriage or birth defects when it is taken to restore fertility and discontinued early in pregnancy,

Less information is available about the safety of cabergoline, although the available information does not indicate that it increases the risk of birth defects. Bromocriptine, therefore, appears to be the safest dopamine agonist to use to restore fertility, although a woman who has severe side effects from bromocriptine could reasonably choose cabergoline. Dopamine agonist treatment should be discontinued as soon as pregnancy is diagnosed. There is insufficient information about the safety of these medications during later stages of pregnancy.

If dopamine agonists do not lower prolactin sufficiently to restore ovulation, other medications, such as clomiphene citrate or gonadotropins, may be recommended to induce ovulation. Once pregnancy is diagnosed, the dopamine agonist should be discontinued. (See "Patient information: Infertility treatment with clomiphene (Clomid® or Serophene®)".)

During the course of the pregnancy it is possible for the adenoma to increase in size. To monitor for an increase in size, the woman should let her healthcare provider know if she develops new or worsening headaches or worsening vision.

• Macroadenomas — Macroadenomas may increase in size during the course of pregnancy. Signs that the adenoma is growing include new or worsening headaches or changes in vision.

If vision worsens, the woman should see an ophthalmologist. An MRI may be recommended to determine if there has been an increase in adenoma size. If so, bromocriptine is usually recommended to decrease the size. There is little information about the effect of bromocriptine on the fetus during the second and third trimesters; the available information suggests that bromocriptine does not harm the fetus. If necessary, surgery to remove the adenoma can be performed during the second trimester.

If the adenoma was greater than 2 cm in diameter or was affecting vision prior to treatment, surgery is usually recommended before the woman tries to become pregnant. Surgery is recommended because growth of the adenoma during pregnancy can potentially interfere with vision or cause headaches. Following surgery, a dopamine agonist may be recommended to restore fertility. (See 'Surgery for prolactinoma' below.)

Breastfeeding — If a woman wishes to breastfeed, she should not resume dopamine agonist treatment until breastfeeding is completed. If there was a significant increase in the size of the adenoma during pregnancy, most experts recommend that the woman not breastfeed so that she may restart dopamine agonist treatment.

SURGERY FOR PROLACTINOMA

Surgery is an option when dopamine agonists are ineffective or not tolerated. Surgery may also be the best choice for a woman with very large macroadenoma who wants to become pregnant, because dopamine agonists must be discontinued during pregnancy, and during this time the adenoma may grow.

During surgery, a small incision is made in the nose (figure 2). The incision is extended through the sphenoid sinus, allowing the surgeon to visualize and remove the adenoma. An endoscope (a thin, lighted tube with a camera) may be used to ensure that the adenoma has been removed completely.

Surgery can often reduce the blood prolactin concentration, sometimes to normal. This is more likely for a microadenoma than a macroadenoma. Even if the prolactin is lowered to within the normal range shortly after surgery, the level may become elevated in the next several years. Potential side effects of surgery include worsening of vision, hemorrhage, and meningitis, which are all uncommon, and hormonal deficiencies. The risk of complications is less when the procedure is performed by a surgeon who has had significant experience operating on the pituitary gland.

Radiation therapy — Radiation therapy can shrink lactotroph adenomas and lower blood prolactin levels, but these effects usually take several years. Therefore, radiation is used only as secondary treatment of macroadenomas, to prevent regrowth of substantial residual tissue that could not be removed during surgery.

The possible side effects of radiation treatment include transient nausea, fatigue, loss of taste and smell, and loss of hair at specific sites on the scalp. About half of those who receive pituitary radiation therapy develop pituitary hormone deficiencies within 10 years.

WHERE TO GET MORE INFORMATION

Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two people are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.uptodate.com/patients). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

Some of the most pertinent include:

Patient Level Information:
Patient information: Postmenopausal hormone therapy
Patient information: Infertility treatment with clomiphene (Clomid® or Serophene®)

Professional Level Information:
Causes of hyperprolactinemia
Causes, presentation, and evaluation of sellar masses
Clinical manifestations and diagnosis of hyperprolactinemia
Management of lactotroph adenoma (prolactinoma) during pregnancy
Pituitary incidentaloma
Treatment of hyperprolactinemia due to lactotroph adenoma and other causes

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable.

• National Library of Medicine

      (www.nlm.nih.gov/medlineplus/healthtopics.html)

• National Institute of Diabetes and Digestive and Kidney Disorders

      (www.niddk.nih.gov/)

• The Hormone Foundation

      (www.hormone.org/public/pituitary.cfm, available in English and Spanish)

• Pituitary Network Association

      (www.pituitary.org)

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