how much vit b-6??????????

This should explain everything

Patient information: Lactotroph adenomas (prolactinomas)

Peter J Snyder, MD
University of Pennsylvania School of Medicine

UpToDate performs a continuous review of over 330 journals and other resources. Updates are added as important new information is published. The literature review for version 12.2 is current through April 2004; this topic was last changed on May 10, 2004. The next version of UpToDate (12.3) will be released in October 2004.

These materials are for your general information and are not a substitute for medical advice. You should contact your physician or other healthcare provider with any questions about your health, treatment, or care. Do not contact UpToDate or the physician authors of these materials.

Lactotroph adenomas (prolactinomas) are benign 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.

They account for 30 to 40 percent of all diagnosed pituitary tumors. They are more commonly diagnosed in women below age 50 than in older women or in men.

Lactotroph adenomas can usually be treated successfully by the use of medication alone. Medication usually not only lowers the serum prolactin concentration substantially, often to normal, but also usually reduces tumor size. A minority of these tumors, however, do not respond to medication and must be treated by surgery or radiation.

CAUSE OF LACTOTROPH ADENOMAS — The normal pituitary gland, a small gland in the middle of the head just below the brain, contains lactotroph cells that produce prolactin, the hormone that stimulates lactation. Lactotroph adenomas arise when one of these normal cells develops a mutation that allows the cell to divide repeatedly, resulting in a large number of cells producing an excessive amount of prolactin. About 10 percent of these adenomas 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 (about 1/2 an inch) in diameter and are called microadenomas. A minority grow larger, occasionally to several centimeters, and are called macroadenomas.

SYMPTOMS OF LACTOTROPH ADENOMAS — The symptoms of lactotroph adenomas fall into two categories: symptoms that result from the elevated blood prolactin concentration and those that result from compression of surrounding tissue.

Symptoms caused by elevated blood prolactin — Elevated blood prolactin causes symptoms by interfering 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, most of the consequences are those of diminished secretion of estradiol, the principal estrogen, or female sex hormone. These include irregular or absent menstrual periods, infertility, menopausal symptoms, such as 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 in a man, the production of testosterone (the principal male sex hormone) and sperm production decrease. The consequences of decreased testosterone production are decreased energy, sex drive, muscle mass and strength, and blood count. Deficiency of testosterone for several years can also lead to bone calcium (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 the nerves to the eyes can impair vision, especially peripheral vision. Pressure on the normal 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 LACTOTROPH ADENOMAS — The diagnosis of lactotroph adenoma is based on finding an elevated blood concentration of prolactin, evidence of a mass in the pituitary gland by magnetic resonance imaging (MRI), and lack of evidence of other causes of an elevated blood prolactin concentration.

Measurement of blood prolactin concentration — The blood prolactin concentration can be measured readily in a single blood sample. The result in a person who has a lactotroph adenoma can range from slightly elevated to a thousand times the upper limit of normal. In general, the degree of prolactin elevation is greater the larger the adenoma.

Magnetic resonance imaging (MRI) — MRI is the best test for identifying tumors of the pituitary gland, although it cannot determine the tumor type. Furthermore, some small adenomas (microadenomas) cannot be detected by MRI, and not all apparent microadenomas secrete prolactin or other hormones.

Evaluating other causes — Other causes of a high blood prolactin concentration include certain medications, especially those used to treat psychoses and estrogens taken orally, and underactivity of the thyroid.

TREATMENT OF LACTOTROPH ADENOMAS — The goals of treatment are to lower the blood prolactin concentration to normal and to decrease the size of large adenomas, especially if they are causing compression of surrounding structures. It is important that the physician and patient discuss the possible benefits and risks of treatment before treatment is begun.

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

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 medications cause intolerable symptoms, the adenoma must be treated in another way.

Medications — A dopamine agonist is the first treatment for a lactotroph adenoma of any size.

Dopamine agonists — Three dopamine agonists are currently available: cabergoline, bromocriptine, and pergolide.

Cabergoline — Cabergoline is taken once or twice a week, is much less likely to cause nausea than other dopamine agonists, and may be effective for treating lactotroph adenomas that are resistant to bromocriptine. For all these reasons, cabergoline is often the best first choice, except for a woman who is trying to become pregnant (Please see the section below on pregnancy). When cabergoline treatment is stopped, high prolactin levels may recur, but in one study, no tumor regrowth was seen.

Bromocriptine — Bromocriptine has been used for 20 years to treat prolactinomas. It should be 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).

Pergolide — Pergolide has been approved by the FDA for the treatment of Parkinson's disease but not for elevated blood prolactin. Its advantage over bromocriptine is that it can be given once a day, and its advantage over cabergoline is that it costs about one-sixth as much. However, the FDA has reported a total of 15 cases of apparent Pergolide-related valvular heart disease. Although the absolute risk of this complication appears to be extremely low, pergolide's labeling is being updated to reflect this potential complication.

Effectiveness of dopamine agonists — Dopamine agonists are very effective for decreasing both the hormone production and the size of most lactotroph adenomas. Bromocriptine, for example, lowers prolactin levels in about 80 percent of all people with lactotroph adenomas and in about 70 percent of those with macroadenomas. Prolactin levels usually fall within the first two to three weeks of treatment, but detectable decreases in tumor size take longer, usually six weeks to six months. Over time, dopamine agonists decrease tumor size in about 90 percent. When vision is affected, it usually begins to improve within days of starting treatment.

If the prolactin concentration decreases to normal or close to normal, the consequences of the elevated prolactin are reversed. In premenopausal women, ovarian function returns, with an increase in estrogen secretion, remission of menopausal symptoms, return of menses, and restoration of fertility. In men, testicular function returns, with an increase in energy, sex drive, muscle mass, blood count, and bone calcium. The ability to get an erection returns and, eventually, breast enlargement regresses.

Side effects of drug therapy — The major side effects of dopamine agonists are nausea, lightheadedness on 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 it needs to be increased, using smaller doses more frequently, and taking the drug with food or at bedtime. In women, intravaginal administration can prevent nausea.

Drug therapy and menopause — Women who have microadenomas usually do not have to continue taking dopamine agonists after menopause, because their ovaries do not secrete estrogen then even if the prolactin is normal. The prolactin should be measured a few months after discontinuation of treatment, to make sure it is not substantially higher than before treatment, then once a year for a few years, and less often thereafter. Women who have macroadenomas should continue taking dopamine agonists after menopause.

Adjusting drug therapy — If one dopamine agonist is ineffective after a month of treatment, the dose may be increased or another dopamine agonist may be used. If none of these agonists is effective or the side effects are intolerable, alternate treatments are available.

Estrogen and progestin — Estrogen, in combination with progestin, is a treatment option for women who have lactotroph microadenomas, especially those who have intolerable side effects to dopamine agonists or 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 can be administered transdermally or in the form of an oral contraceptive. The prolactin concentration should be monitored periodically because of the small chance that the adenoma might grow. Estrogen and progestin treatment should not be used alone in women with lactotroph macroadenomas, because they are more likely to grow in the absence of a specific treatment to prevent their growth.

Fertility drugs — Many women with hyperprolactinemia are able to conceive during dopamine agonist therapy, due to restoration of ovulation. If dopamine agonists do not lower prolactin sufficiently to restore ovulation, however, other medications, such as clomiphene citrate and gonadotropins, can be used to induce ovulation.

Surgery — Surgery is an option for people with lactotroph adenomas in whom dopamine agonists are ineffective or who cannot tolerate these medications. 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.

Surgery can often reduce the blood prolactin concentration, and sometimes to normal, which 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 great 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, to prevent regrowth of residual tissue that could not be removed during surgery for a macroadenoma.

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.

LACTOTROPH ADENOMAS AND PREGNANCY — 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, but she and her physician must consider factors in addition to those when she is not pregnant. The reason for the additional considerations is that dopamine agonists often restore fertility, but they do not eliminate the adenoma and are not known to be safe to take throughout the pregnancy. The special considerations a woman who is contemplating pregnancy should discuss with her physician before attempting to become pregnant include which treatment is best to treat the adenoma 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, and whether or not nursing 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, so the best treatment to restore fertility in a woman who has a microadenoma is a dopamine agonist. Of these, the most information is available about bromocriptine, which , when taken to restore fertility and discontinued early in pregnancy, does not appear to increase the risk of miscarriage or birth defects. Less information is available about cabergoline, but the information available so far does not indicate that it increases birth defects. No observations are available about pergolide and birth defects. Bromocriptine, therefore, appears to be the safest dopamine agonist to use to restore fertility, but a woman who gets severe side effects from bromocriptine could reasonably choose cabergoline.

Dopamine agonist treatment should be discontinued as soon as pregnancy has been diagnosed, because insufficient information is available about the use of these medications throughout the entire course of pregnancy.

During the course of the pregnancy the possibility of a clinically significant increase in the size of the adenoma should be evaluated, even though such an increase is unlikely, by looking for the development, or increase in frequency, of headaches and worsening of vision.

If a woman wishes to breast feed, she should not resume dopamine agonist treatment until she is no longer breast feeding.

Macroadenomas — Macroadenomas may increase in size during the course of pregnancy. If the size of the adenoma prior to treatment was less than 2 centimeters (about 1 inch) in diameter and was not causing symptoms, such as impairment of vision, a dopamine agonist could still be considered as the best means of restoring fertility. If the adenoma was greater than 2 cm in diameter or was causing impairment of vision prior to treatment, surgery should be considered to decrease adenoma size before attempting to restore fertility by use of a dopamine agonist. Once pregnancy has been diagnosed, the dopamine agonist should be discontinued.

Women who have macroadenomas that do not respond to dopamine agonists should not attempt to become pregnant unless and until the size can be decreased sufficiently by surgery so that the risk of a clinically significant increase during pregnancy seems small.

During the course of pregnancy, the possibility of a clinically significant increase in size should be evaluated frequently, at least every two months, by looking for worsening of headaches or vision. If vision appears to worsen, vision should be assessed by an opthalmologist. If headaches or vision worsen significantly, an MRI should be performed to determine if there has been an increase in adenoma size. If so, bromocriptine should be administered to decrease the size. There is little information about the effect of bromocriptine use during the second and third trimesters on the fetus, but that information does not suggest that bromocriptine harms the fetus then. If necessary to restore vision, surgery could be performed during the second trimester.

Breast feeding requires a longer period when dopamine agonist treatment should not be taken, so breast feeding should be considered only if there was no evidence of a clinically significant increase in adenoma size during pregnancy.

WHERE TO GET MORE INFORMATION — Your doctor is the best resource for finding out important information related to your particular case. Not all patients with a lactotroph adenoma are alike, and it is important that your situation is evaluated by someone who knows you as a whole person.

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

Some of the most pertinent include:

Professional Level Information:
Causes of hyperprolactinemia
Clinical manifestations and diagnosis of hyperprolactinemia
Management of lactotroph adenoma (prolactinoma) during pregnancy
Pituitary incidentaloma
Causes; presentation; and evaluation of sellar masses

A number of other sites on the internet have information about health and medical issues. 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 their information is updated is variable.

National Library of Medicine
(http://www.nlm.nih.gov/medlineplus/)

National Institute of Diabetes and Digestive and Kidney Disorders (the division of the National Institutes of Health concerned with hormonal and endocrine disorders)
(http://www.niddk.nih.gov/)

The Hormone Foundation
(http://www.hormone.org/)

Pituitary Network Association
(http://www.pituitary.com/)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES
1. Schlechte, J, Dolan, K, Sherman, B, et al. The natural history of untreated hyperprolactinemia: A prospective analysis. J Clin Endocrinol Metab 1989; 68:412.
2. Biller, BM, Molitch, ME, Vance, ML, et al. Treatment of prolactin-secreting macroadenomas with the once-weekly dopamine agonist cabergoline. J Clin Endocrinol Metab 1996; 81:2338.
3. Biller, BM, Baum, HB, Rosenthal, DI, et al. Progressive trabecular osteopenia in women with hyperprolactinemic amenorrhea. J Clin Endocrinol Metab 1992; 75:692.