What is a Prolactinoma?
STIMULATES THE PRODUCTION OF BREAST MILK DURING PREGNANCY
The pituitary is a tiny gland situated at the base of the brain behind the nose and below the optic nerves.The pituitary makes hormones which control the thyroid, ovaries, testes and adrenal glands. Another hormone made by the pituitary is PROLACTIN which stimulates the production of breast milk during pregnancy and breastfeeding.
Prolactin secretion is controlled by a compound called dopamine which is made in the brain. In women, normal prolactin levels are typically less than 25 ng/ml and in men, less than 17 ng/ml. When prolactin levels are elevated in the blood, the condition is referred to as HYPERPROLACTINEMIA.
Hyper- meaning ‘increased’; Prolactin referring to the hormone;-emia meaning ‘in the blood’
Blood prolactin levels are normally elevated during pregnancy and breast feeding and may also be increased with some medications, kidney failure, and chest trauma.
A prolactinoma is an abnormal growth, or tumor, on the pituitary gland . The tumor causes the pituitary to produce too much prolactin leading to hyperprolactinemia. A prolactinoma is almost always benign, meaning it is not a cancer. About 1 in 10,000 people will develop a prolactinoma for which a clear cause is not known. Prolactinomas occur in both sexes, but are more common in women. The tumors are seldom seen in children and are rarely passed from parents to their children. Prolactinomas are usually small and rarely grow, but some (as discussed below) can become very large.
What are the Symptoms of Prolactinoma?
LARGE TUMOR MAY CAUSE PRESSURE ON THE OPTIC NERVES
Prolactinomas come to attention because of the effect of the elevated prolactin on the reproductive system and/or the size of the tumor. A very large tumor may cause pressure on the optic nerves or nearby brain tissue leading to headaches and/or vision problems.
Symptoms in Women
High levels of prolactin made by the tumor interfere with the ability of the ovaries to make estrogen. When estrogen levels are low, women will have absent or irregular menstrual periods, low sex drive, vaginal dryness and difficulty achieving a pregnancy. Because of the effect of elevated prolactin levels on breast tissue, women who are not pregnant or breastfeeding frequently experience a milky breast discharge. This condition is called GALACTORRHEA.
TABLE 1. MOST COMMON PRESENTING SYMPTOMS
Women with prolactinomas will rarely have headaches, visual symptoms or other complaints related to tumor size because most prolactinomas in women are small and often do not progressively increase in size.
Symptoms in Men
Even slight elevations in prolactin levels from very small pituitary tumors can lead to a decrease in sex drive and cause erectile dysfunction. Larger tumors in men are associated with very high levels of prolactin which almost always cause sexual dysfunction. Breast discharge (galactorrhea) can occur in men, but is much less common than in women.
Men with prolactinomas may also seek medical attention because of headaches or vision problems due to large tumors which can cause pressure on the optic nerves. Because of the size of these tumors, prolactin levels are often very high. The high levels of prolactin can limit the ability of the testes to make testosterone and can infrequently cause infertility.
Because of the low estrogen and testosterone levels that may occur with elevated prolactin, some men and women also develop low bone density; however, fractures and osteoporosis are uncommon.
Since prolactin inhibits the ability of the testes to produce testosterone, men with prolactinomas often present to their doctor with decreased sex drive and/or erectile dysfunction.
Absent or Irregular Periods
Low Sex Drive
Difficulty Achieving Pregnancy
Low Sex Drive
What else can cause elevated prolactin levels?
STRESS, PREGNANCY, KIDNEY DISEASE, CHEST TRAUMA, ETC.
There are a few conditions other than prolactinomas that may be associated with hyperprolactinemia. As prolactin is regulated by dopamine, medications that interfere with this substance in the brain can cause elevated prolactin levels.
Drugs prescribed for psychiatric and gastrointestinal disorders may raise prolactin levels to greater than 200 ng/ ml. Other drugs that can cause mild elevations of prolactin levels include estrogens and verapamil, a drug used to treat high blood pressure.
An underactive thyroid or inadequate thyroid hormone replacement can also raise prolactin levels, as can kidney disease, pregnancy, stress, and chest trauma.
Causes of Hyperprolactinemia
Medications (phenothiazines, metoclopramide, risperidone, selective serotonin reuptake inhibitors, estrogens, verapamil)
Most patients with medication-induced hyperprolactinemia will have prolactin levels between 25 and 100 ng/ml (rarely up to 250 ng/ml). If an elevated prolactin level is due to a medication, the level will usually return to normal 3-4 days after the drug is stopped. It is not possible to determine the cause of an elevated prolactin from the blood level alone. Even if you have a high prolactin level caused by a medication, do not stop any of your medications without first consulting your doctor.
What Testing will be Necessary?
SUSPECTED IN WOMEN WHO HAVE ABSENT OR IRREGULAR MENSTRUAL PERIODS
Hyperprolactinemia is suspected in women who have absent or irregular menstrual periods, abnormal breast discharge, or fertility issues. In men, an elevated prolactin level is suspected in the presence of erectile dysfunction, infertility, headaches, or vision problems.
The first step in the evaluation is to draw a blood sample to determine the prolactin level. The sample can be drawn at any time of day, and a normal level is less than 25 ng/ml in women and less than 17 ng/ml in men. One sample is usually adequate to make the diagnosis. If the prolactin level is just barely elevated, the sample may need to be repeated because even the stress and discomfort of the blood draw itself can affect the results. During the evaluation, your doctor will look for other conditions that could raise prolactin levels and may draw additional blood samples to test other hormone levels.
If your prolactin level is elevated, and all other tests are normal, the next step is to view the pituitary gland by use of a magnetic resonance imaging (MRI) scan with and without contrast dye. The MRI scan will show if there is a tumor on the pituitary, its size, and whether the tumor has affected the optic nerves or other areas around to the pituitary.
The pictures below compare the MRI scans of a microadenoma in a young woman and a macroadenoma in an older man.
31 YEAR OLD WOMAN
A 31-year old woman presented with absent menstrual periods, abnormal breast discharge, and wanted to get pregnant. Her prolactin level was 125 ng/ml.
60 YEAR OLD MAN
A 60-year old man presented with headaches and a low sex drive. His prolactin level was 6,000 ng/ml.
Doctors use different terms to describe the tumor based on its size. Prolactinomas are called MICROADENOMAS if they are smaller than 10 mm (about ½ inch) and MACROADENOMAS if they are 10 mm or larger. Most prolactinomas in women are microadenomas. Prolactinomas in men are more likely to be macroadenomas, although microadenomas are also seen. The large tumors can be associated with extremely high prolactin levels (sometimes greater than 1000 ng/ml). Macroadenomas can push on the optic nerves and men or women with large tumors may need a special eye examination called a formal visual field assessment as part of their initial evaluation. The pictures below compare the MRI scans of a microadenoma in a young woman and a macroadenoma in an older man.
Are there any drawbacks to therapy and how long will I need to take the drug?
STOPPING DRUG LEADS TO RECURRENCE
The major disadvantage of bromocriptine and cabergoline is that stopping either drug leads to recurrence of hyperprolactinemia and tumor regrowth. It is not possible to accurately predict which patients may safely stop the drug.
If you have a microadenoma , your doctor will likely recommend treatment for at least 2 years before considering tapering or stopping the drug.
Since tumor regrowth often occurs, close follow-up and repeat measurements of prolactin will be necessary after stopping medical therapy. Successful long-term discontinuation of the drug may be possible in a few patients, but patients with macroadenomas will likely need medical therapy indefinitely.
Is it Safe to take a Dopamine Agonist for Many Years?
GENERALLY NOT ASSOCIATED WITH SEVERE COMPLICATIONS
Both bromocriptine and cabergoline have been used for years and are generally not associated with severe complications. Recently some patients with Parkinson’s disease who have taken very high doses of cabergoline (3 mg/day) have developed fibrosis, or hardening of the heart valves. Patients with prolactinomas take substantially lower doses of cabergoline (1 to 2 mg/week) and have not been shown to have abnormalities in the heart valves.
What about Surgery?
DOPAMINE AGONISTS ARE VERY EFFECTIVE
In general, surgery is not recommended as primary therapy for prolactinomas because the dopamine agonists are very effective and because surgery is not always curative.
For patients with microadenomas , pituitary surgery may be necessary if cabergoline or bromocriptine don’t work or if the medications cause serious side effects. Patients with macroadenomas may need surgery if there is progressive growth of the tumor despite medical therapy. The surgical outcome is highly dependent on the skill of the surgeon and surgery should only be performed by a neurosurgeon with extensive experience in transsphenoidal pituitary surgery. Radiation therapy is rarely used in the treatment of prolactinomas.
Transsphenoidal literally means ‘through the sphenoid sinus’. It is a surgical procedure to remove pituitary tumors performed by inserting the surgical instruments into the nose and through the sphenoid bone, a small butterfly-shaped bone at the base of the skull.
What about Treatment during Pregnancy?
NORMAL FOR PROLACTIN LEVELS TO RISE AS PREGNANCY PROGRESSES
If the tumor is threatening your vision and you are trying to get pregnant, some doctors recommend treatment with bromocriptine. Cabergoline is also safe and over 90% of women can achieve a pregnancy with use of either drug.
However, bromocriptine or cabergoline should be stopped as soon as you become pregnant. Only rare individuals with very large tumors will need to continue bromocriptine during pregnancy. Some endocrinologists recommend surgery prior to pregnancy when tumors are very large, as the normal pituitary and/or the tumor may grow, especially during late pregnancy.
Keep in mind that cabergoline will rapidly normalize prolactin levels and you could become pregnant even before your periods resume. You will need to use contraception if you do not desire a pregnancy immediately.
It is not necessary to routinely measure prolactin levels during pregnancy as it is normal for prolactin levels to rise as pregnancy progresses.
In women with microadenomas, it is not necessary to have an MRI scan or visual field examination during pregnancy as the risk of tumor enlargement is very small (less than 2%). In women with macroadenomas, it is advisable to monitor formal visual fields during each trimester.
Over 90% of women with prolactinomas can achieve a pregnancy while receiving treatment with dopamine agonists.
Is Treatment Always Necessary?
ESTROGEN & TESTOSTERONE THERAPY IS SAFE
Small prolactinomas rarely increase in size so it is not necessary to treat with cabergoline or bromocriptine to prevent tumor growth. It is important, however, to maintain normal estrogen and testosterone levels to avoid low levels of key sex steroids, and to prevent bone loss.
When pregnancy is not an issue, your doctor may recommend treatment with estrogen or testosterone instead of bromocriptine or cabergoline. Estrogen therapy in women and testosterone therapy in men is safe and well tolerated and will help prevent premature bone loss.
Prolactin levels should also be monitored during therapy with estrogen or testosterone. An increase in the size of a prolactinoma is usually preceded by a substantial increase in prolactin level so it is not necessary to do regular MRI scans unless your prolactin level increases markedly or you develop headaches or prominent visual changes.
How are Prolactinomas Treated?
PRESCRIPTION MEDICATION FOR DRUGS CALLED DOPAMINE AGONISTS
The treatment of choice for all patients with prolactinomas is a prescription medication for drugs called dopamine agonists. These drugs work like dopamine to control prolactin secretion.
The two drugs approved for the treatment of hyperprolactinemia in the United States are Parlodel® ( bromocriptine ) and Dostinex® ( cabergoline ). In addition to the drugs approved in the US, a third drug, Norprolac® ( quinagolide ), is approved in Europe, Australia, and Canada. All of the approved drugs are available in generic form and are effective at lowering prolactin levels and reducing tumor size in over 90% of patients. Prolactin levels typically normalize within days and tumor shrinkage is usually apparent within 3-6 months after therapy is started.
Approved medical treatments: Parlodel® (bromocriptine) and Dostinex® (cabergoline) in United States, Europe, Canada, and Australia; Norprolac® (quinagolide) in Europe, Canada, and Australia.
While both bromocriptine and cabergoline are effective, cabergoline works better to lower prolactin levels and reduce tumor size with fewer side effects. Another major advantage of cabergoline is the fact that it can be taken once or twice weekly. Bromocriptine is less expensive, but must be taken 2-3 times daily and has more side effects including nausea, low blood pressure, and dizziness. These symptoms may be lessened by starting with a lower dose and by taking the drug at bedtime or with a snack.
Frequently Asked Questions
Can Acromegaly Shorten My Life?Patients with uncontrolled Acromegaly have an increased risk of dying earlier than expected. Lowering of the excessive hormone level to normal reduces this risk. Complications associated with acromegaly that can affect your life span include: heart failure, high blood pressure, abnormal cholesterol, diabetes, snoring and other sleep-related breathing problems, and joint disease.
Why Should I Have Treatment After I’ve Had Surgery to Remove the Tumor and I Feel Better?Unfortunately, by the time most patients are diagnosed with acromegaly (usually a delay of many years after beginning of symptoms), the pituitary tumor is large and may invade areas that the surgeon cannot easily access or the tumor has invaded surrounding structures. The surgical remission rates depend on the size of the tumor and expertise of the surgeon. Surgery is usually effective in removing the bulk of the tumor, relieving headaches, and improving visual problems, but it may not be possible to remove the entire tumor. Additional treatments are often necessary to lower serum GH and IGF-I levels to normal, in order to reduce the risk of the complications of continued excessive growth hormone production.
My Tumor Makes Growth Hormone, What is the IGF-I Test and Why is it Important?"While the tumor makes growth hormone, its action and effect is dependent on production of IGF-I (insulin-like growth factor-one); Blood IGF-I is produced, primarily in the liver, in response to the amount of GH made by the pituitary gland. The blood IGF-I level is a reliable indicator of overall growth hormone production. Since blood growth hormone levels fluctuate every few minutes over 24 hours, a single growth hormone level is only a “snapshot” in time and does not reflect overall growth hormone production. The blood IGF-I level is the most reliable indicator of overall growth hormone production. A normal blood IGF-I level usually indicates remission or, in patients taking medication, control of acromegaly.
What is Somatomedin-C?Somatomedin-C is an older name for the same hormone, IGF-I.
What is the Role of Medical Treatment for a Growth Hormone Producing Tumor?Medical treatment is usually given if patients are not cured by surgery. In some cases, medical therapy may be used as the first line of therapy or for few months before surgery. This depends on the size and location of the tumor. Although medications can lower growth hormone and/or IGF-I levels, they do not always shrink the tumor. Because of the long-term complications of excessive growth hormone (joint problems, diabetes, high blood pressure, facial changes, risk of colon polyps, and premature heart disease and premature death), it is important to reduce growth hormone and/or IGF-I to normal. Radiation therapy to the remaining tumor is another option. Since it may take several years before the radiation therapy is effective, medical treatment is used to control excessive growth hormone production while waiting for the effects of radiation. Medications do not cure the problem - they control it. The medication is effective only as long as it is taken as prescribed.
What Medications are Available for Treatment of Acromegaly?Currently used drugs include: Dopamine Agonist: Cabergoline (Dostinex) Somatostatin Aanalogs: Octreotide (Sandostatin), octreotide LAR (Sandostatin LAR), lanreotide autogel (Somatuline depot). Growth Hormone Receptor Antagonist: Pegvisomant (Somavert).
How Do the Medications Differ?The dopamine agonist drug cabergoline may improve symptoms but is not very effective, resulting in a normal hormone levels in less than 30%. In addition, patients more likely to respond are those in whom IGF-I and GH levels are only slightly elevated. Octreotide-LAR and Lanreotide Autogel lower growth hormone, and therefore, IGF-I levels. They are given as an injection every 28 days or sometimes less frequently. They reduce growth hormone and IGF-I levels in approximately 90% of patients. However lowering these hormone levels to normal occurs in approximately 45% to 60% of patients. Some patients have a better response to the combination of octreotide or lanreotide and cabergoline. In patients who still have mild elevations of IGF-I levels during octreotide or lanreotide treatment, the addition of cabergoline may reduce IGF-I levels to normal. Regardless of which regimen in used, these medications do not cure the disease; they control excessive growth hormone production by the tumor. Therefore, the medication(s) is effective only as long as it is taken regularly. Pegvisomant (Somavert): This medication does not act on the pituitary tumor - it blocks the action of growth hormone at the liver and other sites to reduce production of IGF-I. Approximately 80% of patients treated with Somavert have a reduction in IGF-I to normal. Because the medication doesn’t act on the tumor, the tumor itself is not treated. Although most tumors that secrete growth hormone grow slowly, there is a risk of continued growth of the tumor in Somavert-treated patients. This medication therefore is not typically used without other treatments if the tumor is large or showing signs of growth. Regular MRI scans are necessary to find out if there is growth of the pituitary tumor in patients treated with Somavert. This medication is given as an injection under the skin with a small needle similar to the needle used to give insulin for diabetes and is self-administered once a day. Sometimes pegvisomant is administered less frequently (one or twice a week) or daily in lower doses in association with octreotide, lanreotide or cabergoline when GH and IGF-I are not completely controlled by these medications alone.
What Are the Side Effects of These Medications?Cabergoline: Occasional nausea, vomiting, dizziness (especially with standing up quickly). At much higher dosages (us used in patients with Parkinson’s disease) it may cause damage to the heart valves. Octreotide, Lanreotide: When beginning treatment: loose stools, light-colored stools, occasional diarrhea and abdominal cramping. This side effect usually lessens or disappears within 1 to 2 weeks. The long-term side effect is the risk of developing gallstones - approximately 25% of people develop gallstones or gall bladder sludge seen on ultrasound testing. The gallstones usually do not cause a problem, and in most patients do not cause symptoms. However, there is always a small risk of developing problems. Pegvisomant (Somavert): Development of abnormal liver tests occurs in some patients, more frequently if they have diabetes and/or are co-treated with octreotide or lanreotide. The tests return to normal when the medication is stopped. Therefore, it is recommended that liver tests be measured before beginning treatment and every month for the first 6 months of pegvisomant treatment and at regular intervals afterward. Growth of the remaining tumor has occurred in a few patients; this means that regular MRI studies are necessary to detect this. Previous radiation treatment to the tumor appears to make it less likely that there will be tumor growth, but regular MRI scans are necessary to make sure there is no growth.
Can Medical Treatment Be Used Instead of Surgery for Acromegaly?Occasionally, but not usually. Most patients have a macroadenoma (tumor greater than 1 cm) at the time of diagnosis. In this situation, surgery to remove as much of the tumor as possible is usually the first treatment. This is particularly important if the tumor is close to the eye nerves (optic chiasm). If the patient cannot undergo surgery, or there is no clear benefit of surgery, medical treatment, preferably with is used.
Does Medical Treatment Shrink the Tumor?Approximately one-third of patients have a reduction in tumor size when treated with octreotide or lanreotide. The amount of tumor shrinkage is usually modest, approximately 30%. Pegvisomant (Somavert): No; this medication does not act directly on the growth hormone producing tumor - it acts to block the action of growth hormone on the liver and reduces IGF-I production and does not cause reduction in tumor size.
Can Patients Receive Financial Assistance in Receiving These Medications?Sandostatin LAR: The Novartis patient assistance telephone number is: 1-877-LAR-HELP. Somatuline Depot: The Ipsen patient assistance number is called PACE and the number is 1-866-435-5677. Pegvisomant (Somavert): The Pfizer Bridge program telephone number is 1-800-645-1280.