Pituitary Tumor: FREQUENTLY ASKED QUESTIONS

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Pituitary Tumor: FREQUENTLY ASKED QUESTIONS

Pituitary tumors: Answers to Frequently Asked Questions from UVA endocrinologist Dr. Mary Lee Vance.

I. General Questions About a Pituitary Tumor

1. What causes a pituitary tumor to develop?

Pituitary tumors are common. In autopsy studies of patients who did not have known pituitary disease, as many as 26% had a small tumor (adenoma) in the gland. Molecular biology studies have shown that a change in the DNA (genetic mutation) of a pituitary cell can cause unregulated growth of that cell resulting in a pituitary tumor, called an adenoma. There are no known environmental causes. A very uncommon type of pituitary tumor is inherited, this is called Multiple Endocrine Neoplasia, Type I. In this situation, there is usually a family history of endocrine tumors, most commonly a parathyroid tumor causing high blood calcium levels, a pituitary tumor which may or may not produce an excessive amount of a hormone and less commonly, a neuroendocrine tumor of the pancreas. This occurs in fewer than 4% of patients with a pituitary tumor.


2. Is a pituitary tumor a brain tumor?

The pituitary gland is NOT in the brain and pituitary tissue is different from brain tissue. Since the pituitary gland is located at the base of the brain and is connected to the brain by a thin stalk, there is often confusion, particularly by insurance companies, about the classification of a pituitary tumor. A pituitary tumor is NOT a brain tumor.


3. Is a pituitary tumor cancer?

No, in over 99% of patients, this is NOT a cancer; it is benign. Although the tumor is benign, it can cause problems because of its size, causing loss of vision, loss of normal pituitary function (hypopituitarism) and/or headache or because of excessive hormone production by the tumor.


4. What are the symptoms of a pituitary tumor?

This depends on the type of tumor and the size of the tumor. A large tumor may cause loss of vision, particularly peripheral vision, if it compresses the optic chiasm (where the optic [eye] nerves come together, located above the pituitary gland). Headache may also occur; the type of headache varies from patient to patient. Headache may occur with a large or a small tumor. A tumor may interfere with normal pituitary function causing hypothyroidism (low thyroid hormone level), adrenal insufficiency (low cortisol level), hypogonadism (loss of sexual function and fertility in men, loss of menstrual periods or fertility problems in women). Occasionally a pituitary tumor causes diabetes insipidus, which results in frequent urination and excessive thirst. Diabetes insipidus is not high blood sugar levels; it is a problem with the ability of the kidney to retain fluid because of a deficiency of the pituitary hormone, vasopressin (also called antidieuretic hormone) that regulates water balance.

Specific types of tumors cause various symptoms and changes in body function.

Prolactinoma: most commonly causes loss of sexual function and infertility in men. Men may also have enlargement of the breasts, called gynecomastia. In women of reproductive age a prolactin-producing tumor may cause milk in the breasts, a change in menstrual periods or loss of menses or problems becoming pregnant. Women who have gone through menopause do not have a change in menstrual periods to signal the problem; in this situation, headache and loss of vision may be the first indicator of a prolactinoma.

Acromegaly: Enlargement of the hands, feet and face and excessive sweating are the most common features of excessive growth hormone production. Other problems include joint pains (osteoarthritis), sleep apnea (excessive snoring, stopping breathing during sleep), hypertension (high blood pressure), diabetes mellitus (high blood sugar), colon polyps, change in teeth spacing, oily skin and acne.

Cushing's: The term "Cushing's Disease" refers to the overproduction of cortisol by the adrenal glands caused by a pituitary tumor producing too much of the pituitary hormone, ACTH. Dr. Harvey Cushing, a neurosurgeon, first described this condition in the 1920s and the pituitary condition is called Cushing's disease. Excessive cortisol production causes weight gain (particularly in the abdomen and neck), loss of muscle mass (legs, arms) and muscle weakness, depression, difficulty with concentration and memory, sleep disturbance, irritability, thinning of the skin with easy bruising, hypertension, diabetes mellitus, loss of bone mass (osteoporosis) with a risk for bone fractures and weakening of the immune system with a higher risk of developing infections.

TSH Secreting Tumor: This is the least common type of hormone producing pituitary tumor. Excessive TSH stimulates the thyroid gland to produce too much thyroid hormone (hyperthyroidism). Symptoms of hyperthyroidism include weight loss, nervousness, rapid heartbeat, difficulty sleeping, frequent bowel movements and in women, less menstrual flow or loss of menstrual periods.

Non Secretory Tumor: This is a tumor that does not produce an excessive amount of a pituitary hormone that can be measured in the blood. This type of tumor most commonly causes sexual dysfunction in men and loss of regular menses and infertility in premenopausal women. This type of tumor is usually detected after it has become a large, causing loss of vision and/or headache and/or hypogonadism (loss of sexual function in men, loss of menses in premenopausal women), hypothyroidism (low thyroid hormone level) or adrenal insufficiency (low cortisol level).

Craniopharyngioma/Rathke's Cleft Cyst: These tumors are congenital - a problem in the development of the pituitary gland which begins during fetal (in the womb) development, it is present at birth but may not cause a problem until childhood or adulthood until growth causes a problem. This is not a malignant (cancerous) tumor but it often interferes with normal pituitary function causing hypopituitarism (loss of pituitary function) or cause headache or loss of vision. This type of tumor may also cause diabetes insipidus: frequent urination and excessive thirst (not diabetes mellitus [high blood sugar]).

Pituitary Cyst: Any endocrine gland may develop a cyst. This occurs commonly in the ovaries and thyroid gland; a cyst in the pituitary gland is benign (not cancer), but causes a problem because of enlargement causing headache and/or interference with normal pituitary function. Most common symptoms are headache and, if the cyst is large, loss of vision and loss of normal pituitary function. Sometimes a cyst may cause frequent urination and excessive thirst (diabetes insipidus).


5. What is the best treatment for a pituitary tumor?

The best treatment depends on the type of pituitary tumor. Prolactin producing tumors are most successfully treated with medical therapy (pills). In over 90% of patients, medical therapy (pills) reduces tumor size and blood prolactin levels. In approximately 8-10% of patients, medical treatment is not adequately effective and surgery, and possibly radiation therapy, may be necessary.

The best treatment for other types of pituitary tumors is removal of the tumor by an experienced neurosurgeon who performs pituitary surgery frequently. Although most neurosurgeons have some experience with pituitary surgery, only a few have devoted their career to pituitary surgery and have the "best" records of success.


6. If a tumor was successfully removed why are regular visits, blood tests and MRI scans necessary?

Complete removal of a tumor is the desired goal. However, a minority of patients with pituitary tumor will have a recurrence of the tumor. Approximately 16% of patients with a non functioning tumor will have a tumor recurrence within 10 years and 10% require additional treatment (surgery, pituitary radiation). Since it is not possible to predict which patient's tumor will recur, all patients need regular medical follow up. Additionally, a tumor may recur 20 years or more after the original treatment. If the tumor was producing a hormone that caused particular symptoms (Cushing's, Acromegaly, prolactin tumor), the patient is usually the first to recognize this. Measurement of the appropriate hormone level in blood or urine is the most accurate method of determining if the tumor has recurred. Non secretory tumors, craniopharyngiomas and Rathke's cleft cysts do not produce an excessive hormone that can be measured in the blood or urine. The MRI scan is the best method to follow this type of growth for recurrence.


7. Is radiation necessary in all patients? Who should have radiation treatment to the pituitary?

Radiation to the pituitary is not the first line of treatment for most pituitary tumors. It does not produce an immediate effect to lower excessive hormone production or shrink the tumor. Radiation is used when there is tumor remaining after surgery or when surgery is cannot be performed. Pituitary radiation may take several years to be effective. For example, in patients with acromegaly (excessive growth hormone production), growth hormone levels may remain elevated for 10 to 20 years after conventional (fractionated) radiation.


8. Are all types of pituitary radiation the same?

No. There are different methods of delivering radiation to the pituitary gland. Conventional (fractionated) radiation refers to delivery of a small amount of radiation every day for 4 to 5 weeks. Stereotactic radiation refers to delivery of a precisely focused beam of radiation to the remaining tumor, usually as one or a few more treatments (Gamma Knife, LINEAC, Cyber knife, proton beam). The decision as to which type of radiation to administer is made only after a careful review of the MRI scan to assess the size and location of the residual tumor. A large tumor that is near the optic chiasm (eye nerves) is not suitable for stereotactic radiation because of the intensity (radiation dose) of the single treatment and risk of damage to vision. Stereotactic radiation is only appropriate for a small tumor that is not near the optic chiasm.


9. What are the side effects of radiation?

Hair loss done not usually occur. The most common side effect is loss of normal pituitary function. This may occur within a year or many years after treatment. One study reported that 50% of patients treated with conventional radiation developed deficiency of one or more pituitary hormones within 2 years of treatment. Studies of Gamma Knife focused radiation suggest that about 1/3rd of patients develop a pituitary hormone deficiency 2 to 3 years after treatment. It is expected that this percentage will increase with longer time after the treatment. Although development of a pituitary hormone deficiency is not desirable, hormone replacement therapy is available. An uncommon side effect is damage to vision. These risks must be weighed against the risk of tumor regrowth.


10. Does a pituitary tumor shorten life expectancy?

Having a pituitary tumor should not shorten life expectancy if it is treated properly and if the patient receives appropriate hormone replacement(s). In large population studies, it appears that patients who had conventional, fractionated, radiation for pituitary disease had an increased mortality (death) risk because of cerebrovascular disease (stroke).

Pituitary hormone deficiency requires hormone(s) replacement. All medications must be taken as directed. Additionally, there is a need for regular medical care and monitoring of hormone treatments. Most patients who have had a pituitary tumor engage in normal work and social activities. If a patient requires steroid (cortisol) replacement, a "Medic Alert" bracelet or necklace should be worn at all times. Another illness such as the flu, pneumonia or an accident requires an increase in the steroid dose. If the patient is brought to the hospital and unable to give the medical history, the physicians will have no way of knowing that additional steroid is necessary. The "Medic Alert" bracelet or necklace notifies physicians of the need for additional steroid (cortisol) administration. With attention to these important details, a patient with a pituitary tumor should have a full and productive life.

Patients with uncontrolled Acromegaly (growth hormone producing tumor) or Cushing's disease (excessive cortisol production) do have an increased risk of dying earlier than expected and for having complications of the high hormone level. Lowering of the hormone level to normal reduces this risk.

Complications associated with pituitary tumors include:

Acromegaly: heart disease, high blood pressure, abnormal lipids (cholesterol), diabetes, sleep apnea, joint disease (osteoarthritis), colon polyps and possibly color cancer, loss of sexual function and infertility. Other problems may include abnormal dental bite (because of growth of lower jaw), oily skin, excessive sweating and cystic acne.

Cushing's disease: weight gain (especially in the abdomen and neck), heart disease, abnormal lipids (cholesterol), diabetes mellitus, high blood pressure, osteoporosis and bone fractures, depression, memory loss, muscle weakness, occasionally kidney stones, loss of sexual function, infertility, loss of menstrual periods, thin skin, easy bruising, red stretch marks, usually on the abdomen.

Prolactinoma: high prolactin is not known to shorten life; however loss of normal testosterone production in men causes a risk of osteoporosis, increases the risk for bone fractures, loss of muscle mass, anemia (low red blood cell count) and fatigue. In women, high prolactin results in loss of regular menstrual cycles, infertility, low estrogen with risk of osteoporosis and bone fractures.

Non-functioning adenoma, Craniopharyngioma, Rathke's Cleft cyst, Pituitary cyst: There is no known risk of premature death as long as appropriate hormone replacement(s) are taken. Complications are related to the adequacy of hormone replacement(s).


II. Diagnosis of Pituitary Tumor

1. How is a pituitary tumor diagnosed?

The diagnosis is made either by an imaging study (MRI, CT scan) that shows a growth in the pituitary gland, because of hormone tests to evaluate pituitary function, including pituitary hormone overproduction or because of loss of vision.

Often an MRI study is obtained because of headaches, because of trauma or loss of vision and an abnormality in the pituitary gland is found. This requires a full Endocrine (hormone) evaluation and eye examination. Endocrine evaluation is to assess pituitary function ( to determine if there is any pituitary hormone deficiency) and pituitary hormone overproduction. In the case of a large tumor that is near or pressing on the optic chiasm (nerves responsible for vision), a thorough eye examination, including visual acuity and visual field examination, is necessary. Necessary blood hormone tests include assessment of adrenal cortisol production (cortisol and ACTH), thyroid function (Free T4 and TSH), growth hormone production (IGF-1 level), gonadal function (Men: testosterone and LH levels; Premenopausal women: menstrual history, LH and estrogen levels), prolactin level and questions about frequent urination. If there is a suspicion of Cushing's a 24 hour urine test for urine free cortisol is needed to determine if excessive cortisol is being produced.


2. Specific Types of Pituitary Tumors

Acromegaly: The best test is a blood IGF-1 level (this is a measure of overall growth hormone production). A single blood growth hormone level may be normal because growth hormone levels vary minute to minute. The best screening test is a blood IGF-1 level. The most reliable test for Acromegaly is measuring blood growth hormone levels after drinking a glucose (sugar) drink. Depending on the clinical features and IGF-1 level, an oral glucose test may not be necessary for diagnosis.

Prolactinoma: A blood prolactin level is necessary to determine if an elevated prolactin level is a prolactinoma in relation to the pituitary MRI findings. Elevated prolactin may occur in several situations: medications that cause a high prolactin (usually a normal MRI of the pituitary), a growth in the pituitary that causes small elevation of prolactin (not a prolactinoma) or a true prolactinoma. The level of prolactin elevation must be related to the MRI findings.

Cushing's Disease: This is the most difficult diagnosis of all pituitary disorders. Why? Weight gain, obesity, depression, diabetes and high blood pressure are very common. Cushing's is not very common. However if there is a question of Cushing's this needs to be evaluated. There are 3 screening tests for Cushing's: 24 hour urine free cortisol level, late night salivary cortisol levels, blood cortisol response to 1 mg of dexamethasone at 11 p.m. (overnight dexamethasone test) with a blood cortisol at 8 a.m. the next day. All of these tests are equally reliable as screening tests (about 95% accurate); a screening test is never 100% accurate. Thus, several tests may be necessary to make the diagnosis of Cushing's syndrome (excess cortisol production; does not identify the source: pituitary, adrenal or ectopic ACTH syndrome).

There are several difficulties regarding the diagnosis of Cushing's, including severe depression (causes increased cortisol production), excessive alcohol use (causes increased cortisol production), medications that change the breakdown of dexamethasone resulting in a high blood cortisol level. If there is a question of Cushing's, it may take repeated testing to either diagnose Cushing's or exclude Cushing's. The most common cause of Cushing's symptoms and body changes is use of a steroid for treatment of other disorders such as asthma, arthritis, joint pain - steroids include pills (prednisone, dexamethasone), occasionally steroid inhalers for asthma, and particularly steroid injections in joints - all of these treatments can cause symptoms of Cushing's. If a steroid has been given, testing will usually show low blood and urine cortisol levels and a low blood ACTH level. This is because steroid treatment turns off the pituitary and adrenal glands temporarily and until the steroid is eliminated from the body (may take many months in the case of steroid injections). Even after the blood levels return to normal, the weight gain, muscle weakness, fatigue may persist for many months (often 6 - 12 months).


III. Medical Treatment of Pituitary Tumors

Any medical therapy for a pituitary tumor should reduce hormone overproduction by the tumor, and, ideally, decrease the size of the pituitary tumor so that if there is a visual abnormality, this is improved. Reduction in tumor size should also improve or relieve headache associated with the tumor. Since not all pituitary tumors produce an excessive amount of a hormone or hormones, the only measure of successful medical therapy for a non hormone-producing tumor is the effect on tumor size and clinical symptoms (visual problems, headache).

A. Prolactin producing tumor (Prolactinoma):

1. What are the benefits and limitations of medical treatment?

Medical therapy is usually more effective than surgery for this type of tumor, particularly for large tumors (macroadenoma, > 10 mm). In patients with large tumors, surgery results in normal prolactin levels in fewer than 20% of patients. Surgery is effective in removing the bulk of the tumor, but the prolactin level remains elevated; surgery does not produce a "cure". In this situation, if the patient has had surgery and still has an elevated prolactin, medical treatment is necessary. In patients who have a small tumor (< 10 mm), the chances of a "cure" with surgery are greater, on the order of 80% to 90%. However, even with successful surgery, there is a risk of recurrence of the tumor at a later date (months, years); approximately 13 to 20% of patients have a recurrence of elevated prolactin within 5 years of surgery.


2. How do the medications work?

Prolactin is normally inhibited (suppressed) by the hypothalamic (brain) hormone, dopamine. This hormone, dopamine, normally travels down the pituitary stalk (connects the brain to the pituitary gland) to inhibit prolactin production. Drugs known as dopamine agonists act like dopamine to inhibit prolactin production. Dopamine agonists available in the U.S. include cabergoline and bromocriptine. Pergolide (Permax) was recently removed from the market because of heart problems in patients with Parkinson's disease - see below for more details. A very effective drug, Norprolac (quinagolide), is only available in Europe and Canada. Cabergoline is a long acting drug and can be taken once or twice a week. Bromocriptine is usually given 3 times a day, always taken with food.

These drugs act on the tumor in the same way - by inhibiting or reducing the amount of prolactin made by the tumor and causing the tumor to shrink. Over 90% of patients treated with one of these medications have a decrease in prolactin and a decrease in tumor size. Some patients are not able to take these medications because of side effects (nausea, vomiting, nasal stuffiness, and constipation). Cabergoline causes fewer side effects than bromocriptine. However, the risk of cabergoline on heart valves in patients with a prolactinoma remains to be determined (see below). Some studies indicate that cabergoline may be more effective than bromocriptine in reducing prolactin and tumor size in some patients.

A minority of patients do not have a good response to these drugs. Why? These drugs act on dopamine "receptors" which are on the surface of the tumor. A receptor can be visualized as a keyhole, the drug is the key - in order for the drug ("key") to be effective, the tumor must have an adequate number of receptors ("keyholes") and the drug must be able to bind (attach) to the receptor (keyhole). In patients who do not have a good response to medication, there are not enough receptors (keyholes) on the tumor surface or the binding to the receptors (keyholes) is not adequate. In this situation, alternative treatments such as surgery and/or radiation therapy may be necessary.

Is there a way to measure a tumor's "receptors"?

No blood tests can determine this. Research studies have been performed and have demonstrated this principle by measuring the number of receptors on tumors removed by surgery. The only way to judge the effect of medical treatment is a trial of a dopamine agonist drug (bromocriptine or cabergoline)


3. Why don't these medications always reduce prolactin to normal?

Although these medications are effective in lowering prolactin and reducing tumor size, the prolactin level may not decrease to normal (< 20). Why?

With a large tumor and very high prolactin level (several hundred, in the thousands), the medication may lower prolactin by 90%; if the level before treatment level is 10,000, a 90% reduction lowers prolactin to 1,000, certainly not normal (normal is usually < 20), but a substantial reduction. The tumor size is decreased but the tumor does not disappear. The medications do not destroy the tumor. An elevated prolactin may be acceptable if there are no other ill effects of the tumor such as headache or loss of vision. The most frequent hormonal problem resulting from an elevated prolactin is hypogonadism (loss of hormone production by the ovaries or testes). Hypogonadism in a pre-menopausal woman results in loss of menstrual periods and difficulty becoming pregnant. Hypogonadism in men causes a low blood testosterone level, loss of sexual interest, impotence (difficulty obtaining an erection) and infertility. Hypogonadism is treatable with hormone replacement, testosterone in men, estrogen and progesterone in women. Restoration of fertility may require additional treatments with injections of the pituitary hormones, LH and FSH.


4. Do these medications "cure" the tumor? Can I stop the medication later?

Usually not. These medications control the tumor and ideally shrink the tumor; they do not destroy the tumor. The medications are only effective as long as they are taken. If the medication is stopped, the prolactin will usually increase and the tumor will also increase in size. This is similar to a person who has high blood pressure. There is no "cure" for high blood pressure - the blood pressure is controlled only as long as the medication is taken. This is the same situation for a patient with a prolactin-producing tumor - the medication must be taken regularly as prescribed, to control the problem.

In the situation of a very small tumor (< 10 mm), the medication is often stopped after 5 years of treatment to see if the prolactin remains normal in approximately 1/3rd of patients. The possible reason for this is that the small tumor has somehow self-destructed (this occurs in a few patients). If the prolactin is normal after stopping the medication, the level should be monitored every few months to make sure it remains normal. Studies have shown that in approximately 16% of patients who had a large tumor (> 10 mm, macroadenoma) continued to have a normal prolactin when the medication was stopped after 5 years of treatment. If the medication is stopped, regular medical follow up and measurement of the blood prolactin level is necessary to determine if restarting medical treatment is necessary.


5. Is one medication more effective than another?

Usually not; the different drugs act the same way. However, a few studies have shown that cabergoline may be more effective than bromocriptine. The responses to different drugs are usually similar in reducing prolactin and tumor size. Most commonly, the benefits of one drug over another are related to:
(a) side effects,
(b) cost,
(c) ease of taking the medication.

Some patients have side effects with one drug and little or no side effects with another drug. The only way to determine this is a trial of a different medication. The most important thing about avoiding side effects is to always take the medication with food. This will minimize side effects such as nausea, vomiting or feeling light-headed.


6. What if I wish to become pregnant?

The only FDA approved medication for pregnancy, bromocriptine, has been given to several thousand women who wished to become pregnant. A worldwide surveillance has shown there that there is no increased risk (above the normal risk in the general population) of birth defects (there is always some risk of birth defects, approximately 15%, even for a woman taking no medications). Cabergoline is not FDA approved for pregnancy; information on several hundred women who became pregnant while taking cabergoline showed no increase in risk (above the normal risk) of birth defects for the baby, Until there is more experience with cabergoline in women who become pregnant, it is prudent for women try to become pregnant to take bromocriptine.


7. How many times a day are these medications taken?

The convenience of taking the medication is important for many patients who are busy with work and other activities. Bromocriptine is usually given three times a day with food, to minimize the risk of side effects such as nausea, lightheadedness, low blood pressure. Some patients can be treated twice a day. Norprolac (not available in the U.S.) is taken once at night. Cabergoline is a long acting drug that is given once or twice a week.


8. Are there any potential risks to taking cabergoline or bromocriptine?

In January 2007, there were 2 published reports of increased risk of developing thickening of heart valves in patients with Parkinson's disease treated with cabergoline or pergolide (pergolide is no longer available). Patients with Parkinson's disease treated with bromocriptine did not have an increased risk of developing thickening of the heart valves. It is important to point out that patients with Parkinson's disease are treated with much higher doses of cabergoline (about a 22 times higher dose per week) than patients with a prolactinoma. There is no current information on risk for heart valve problems in patients with a prolactinoma treated with cabergoline (or previously treated with pergolide) who take much smaller doses. Since most patients with a prolactinoma require long-term treatment, there is a concern that long-term treatment with cabergoline may cause problems with heart valve thickening. For this reason, I recommend an echocardiogram study to assess heart function, valve size and valve function. An echocardiogram is an ultrasound study that involves passing a probe over the chest (heart) and taking pictures of heart muscle and heart valves (no needles; painless).

Should I stop cabergoline and change to bromocriptine?

This is a personal decision. However, until more is known about the risk of taking cabergoline for many years, it is reasonable to consider taking bromocriptine instead of cabergoline. The "downside" of taking bromocriptine is that it usually must be taken three times a day with food instead of the more convenient regimen for cabergoline - once or twice a week.


9. What is the cost of these medications? Please note: the cost of cabergoline and bromocriptine shown below are as of March, 2009. A patient should review his/her insurance policy regarding the amount of coverage, the co-pay and the use of a mail order pharmacy which may be cheaper than a local pharmacy.

Bromocriptine, 2.5 mg three times/day:
CVS: $205/month; $2,460/year
Kroger: $221/month; $2,647/year
UVa: $11/month; $129/year

Cabergoline, 0.5 mg twice/week:
CVS: $268/month; $3,216/year
Kroger: $327/month; $3,920/year
UVa: $135/month; $1,624/year


10. If my prolactin level returns to normal, will I be able to get pregnant?

Yes - if the only reason for infertility is the high prolactin level. There are many causes of infertility, but if high prolactin is the only reason, lowering prolactin to normal results in the same chances for pregnancy as the general age-matched population (fertility declines with increasing age, especially after age 32).


11. I don't want to become pregnant now; can I take a birth control pill?

Usually yes - if the prolactin is reduced with medication (bromocriptine or cabergoline), then a birth control pill can be added. It is very important to use "mechanical contraception" (condom and foam; diaphragm; IUD) until the response to medication (bromocriptine, cabergoline) is assessed. A woman may become pregnant taking one of these medications even without having a menstrual period. If there is any wish for or risk for pregnancy, it is important to take folic acid every day (Pre Natal vitamins contain adequate folic acid) since folic acid reduces the risk of the birth defect, spina bifida (abnormal development of the baby's spinal cord resulting in lack of ability to move legs, walk).


12. Will I have to take bromocriptine or cabergoline for the rest of my life?

Possibly, not. As mentioned above, recent studies have shown that in patients who had a microadenoma (< 10 mm) who were treated with medication for 5 years and after the medication was stopped, approximately 1/3rd continued to have a normal prolactin and no tumor growth. In patients who had a large tumor (macroadenoma, > 10 mm) treated for 5 years, the prolactin remained normal in 16% of patients after stopping medication. It is reasonable to stop medication after 5 years of treatment and follow the prolactin level - if prolactin increases above normal or if there is tumor growth on the MRI, medication (bromocriptine or cabergoline) should be re-started.

  

B. Growth hormone producing tumor (Acromegaly)

1. Why should I have treatment after I've had surgery to remove the tumor and I feel better?

An unfortunate fact is that when most patients are diagnosed with acromegaly (usually a delay of 7 to 8 years after the beginning of symptoms), the pituitary tumor is large and may invade areas that the surgeon cannot go into (the arteries on each side of the pituitary gland) or where the tumor has invaded surrounding structures (bone below the gland or coverings around the pituitary gland [called dura mater]). The reported surgical remission rates (normal growth hormone, normal IGF-1) range from 57% to about 75%, depending on the size of the tumor and expertise of the surgeon. Surgery is usually effective in removing the bulk of the tumor and reliving headaches and improving visual problems, but it may not be possible to remove the entire tumor. Additional treatments are necessary to lower growth hormone and IGF-1 levels to normal in order to reduce the risk of the complications of continued excessive growth hormone production.


2. My tumor makes growth hormone, what is the IGF-1 test and why is it important?

The tumor produces growth hormone but its action and effect is dependent on production of another hormone, IGF-1 (insulin-like growth factor-1); IGF-1 is produced, primarily in the liver, in response to the amount of growth hormone made by the pituitary gland. Growth hormone does not cause growth, the liver must respond to growth hormone to produce an adequate amount of IGF-1; IGF-1 is the effector of growth hormone action. The blood IGF-1 level is also a very 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-1 level is the most reliable indicator of overall growth hormone production and is a reliable measure of activity in a patient with acromegaly. A normal blood IGF-1 level indicates remission or, in patients taking medication, control of acromegaly.

What is Somatomedin C?

Somatomedin C and IGF-1 are the same hormone, different names. Growth hormone acts on the body by causing the liver and other tissues to produce a hormone known as "insulin-like growth factor-1" (IGF-1) - it is the IGF-1 (Somatomedin C) that causes the ill effects of too much growth hormone. Growth hormone is released from the pituitary gland in "bursts" or "spurts" - the levels vary considerable from minute to minute, so one measurement does not reflect overall growth hormone production. IGF-1 is more constant in the blood and is a much better and more accurate indicator of overall growth hormone production. The IGF-1 blood test is used to assess the effectiveness of all treatments (surgery, radiation, medical treatment). If a patient is treated with the growth hormone antagonist, see below for description) pegvisomant (Somavert), the only reliable test of effectiveness is the IGF-1 (Somatomedin C) level. Measurement of growth hormone in a patient receiving pegvisomant (Somavert) will result in extremely high growth hormone levels because pegvisomant is a modified growth hormone molecule and is measured as growth hormone in the blood test.


3. What is the role of medical treatment for a growth hormone producing tumor?

Medical treatment is usually given if there is persistent overproduction of growth hormone after surgery. Although medications can lower growth hormone and IGF-1 levels, they do not always cause the tumor to shrink. Because of this, the usual first treatment is surgical removal of as much of the tumor as possible. In the situation of a large tumor, particularly if it has grown into an area that is not accessible to the surgeon, the majority of the tumor may be removed, but a small portion remains - and continues to produce too much growth hormone. Because of the long-term complications of excessive growth hormone (joint problems, diabetes, high blood pressure, facial changes, sweating, risk of colon polyps and possible increased risk of colon cancer, and premature heart disease and premature death), it is important to reduce IGF-1 to normal. Radiation therapy to the remaining tumor is given if surgery is not completely successful. Since it may take months or years before the radiation therapy is effective, medical treatment is used to control excessive growth hormone production while waiting for the radiation to become effective. Medications do not cure the problem - they control the situation. The medication is effective only as long as it is taken as prescribed.


4. What medications are available for treatment of Acromegaly?

Currently used drugs include:
Dopamine agonist drugs: bromocriptine, cabergoline
Somatostatin analogs: Sandostatin LAR, Somatuline (Lanreotide Autogel)
Growth hormone receptor antagonist, pegvisomant (Somavert).


5. How effective are medications?

The dopamine agonist drugs, bromocriptine and cabergoline, may improve symptoms (less sweating, less swelling of hands and feet) but are not very effective in lowering growth hormone and IGF-1 levels to normal (< 10% of patients achieve a normal IGF-1 level). Cabergoline may be more effective than bromocriptine. Since these medications are taken as pills, it is reasonable to try this for 2-3 months; if the IGF-1 remains high, another drug (Sandostatin, Lanreotide, Somavert) should be given.

Sandostatin LAR and Somatuline act on the pituitary gland to reduce (inhibit) growth hormone production, and, as a result, IGF-1 production. Sandostatin LAR is given as an injection in the buttock every 28 days; this is usually administered in a doctor's office. Somatulinel is given as either a self-injection or by someone else at home, once a month.

Sandostatin LAR (octreotide) and Somatuline reduce growth hormone and IGF-1 levels in approximately 90% of patients. Lowering of IGF-1 to normal occurs in approximately 45% to 60% of patients. The reason for this is the same as the response that occurs with medical treatment of prolactin producing tumors - the number of "receptors" on the tumor on which the medication can act. Short-acting octreotide must be given at least every 8 hours by a subcutaneous (under the skin) injection. A very small needle (insulin syringe and needle) is used and the discomfort is usually not a problem for most patients. Some patients have a better response giving the injection every 6 hours. The long acting preparation, Sandostatin LAR is more convenient to take (once every 28 days) but requires a visit to the doctor's office for the injection. Somatuline is usually self-administered or administered by someone else once a month at home.

Some patients have a better response to the combination of bromocriptine or cabergoline and octreotide (Sandostatin, Somatuline), especially if the tumor makes too much of two hormones: growth hormone and prolactin. 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 directly on the pituitary tumor - it blocks the action of growth hormone at the liver to reduce production of IGF-1. Up to 97% of patients treated with pegvisomant have a reduction in IGF-1 to normal. Since the medication doesn't act on the tumor, there is a risk of continued growth of the tumor and means that regular MRI scans are necessary to find out if there is growth of the pituitary tumor. This medication is given as an injection under the skin (self-administered) once a day.


6. What are the side effects of these medications?

Bromocriptine: nausea, vomiting, dizziness, nasal stuffiness, constipation. Side effects are minimized by always taking the medication with food.

Cabergoline: occasional nausea, vomiting, dizziness; fewer side effects than bromocriptine.

Sandostatin LAR, Somatuline: 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 18% of people develop gallstones or gall bladder sludge. The gallstones may not cause a problem, but there is always a risk of developing problems.

When beginning treatment with Sandostatin LAR, the recommendation is to first take the short acting preparation (octreotide) as an injection 3 times a day for a week in case side effects are too bothersome. If there are bothersome side effects, the long acting preparation, Sandostatin LAR, may not be suitable. In some centers (and at U Va), the patient is given a single injection of the short-acting Sandostatin to make sure there are not side effects and then the patient is given an injection of long acting Sandostatin LAR later in the day.

Pegvisomant (Somavert): Development of abnormal liver tests occurred in 2 of approximately 150 patients treated with this drug. The tests returned to normal when the medication was stopped. The reason for this side effect is not known. 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 (I suggest every 6 months). Enlargement of 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 reduce the risk of tumor growth, but regular MRI scans are still necessary to make sure there is no growth.


7. Can medical treatment be used instead of surgery for Acromegaly?

Occasionally. Most patients have a macroadenoma (tumor > 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) or if the tumor is pressing on the optic chiasm causing loss of vision. If the patient cannot undergo surgery, medical treatment, preferably with a somatostatin drug (Sandostatin LAR, Somatuline) is used because these medications act directly on the tumor and may prevent tumor growth. Again, this is not a cure; medical treatment with a somatostatin drug controls the problem, with optimal control (normal blood IGF-1 level) in approximately 40 to 60% of patients.


8. Does medical treatment shrink the tumor?

Octreotide, Sandostatin LAR and Somatuline: Approximately one-third of patients have a reduction in tumor size. The amount of tumor shrinkage is usually modest, approximately 20% to 30% shrinkage. In patients with a large tumor, surgery is recommended as the first treatment to remove as much as possible with medical treatment afterward if there is continued excessive growth hormone production.

Pegvisomant (Somavert): Does not cause tumor shrinkage. This medication does not act directly on the tumor - it acts to block the action of growth hormone on the liver and reduces IGF-1 production and does not cause reduction in tumor size.


9. What is the cost of medical treatments? Please note: the costs of the drugs are as of March, 2009. A patient should review his/her insurance policy regarding the amount of coverage, the co-pay and the use of a mail order pharmacy which may be cheaper than a local pharmacy.

Bromocriptine, 2.5 mg three times/day:
CVS: $205/month; $2,460/year
Kroger: $221/month; $2,647/year
UVa: $11/month; $129/year

Cabergoline, 0.5 mg twice/week:
CVS: $268/month; $3,216/year
Kroger: $327/month; $3,920/year
UVa: $135/month; $1,624/year

Sandostatin LAR: This medication is administered in a physician's office as a once/month injection; there may be a charge for the injection. Medicare patients: this is covered by Medicare since it is administered in the physician's office. The manufacturer, Novartis, also has a home administration program in which a nurse comes to the home to administer the injection (this does not apply to Medicare patients).

Source: Novartis Pharmaceuticals:
10 mg/month: $ 1,555/month; $ 18,660/year
20 mg/month: $ 2,067/month; $ 24,804/year
30 mg/month: $ 3,069/month; $ 36,828/year

Somatuline: May be administered as a deep subcutaneous (below the skin) by a partner or by the patient, once a month.

Source: Tercica/Ipsen Pharmaceuticals:
60 mg/month: $ 2,178/month; $ 26,136/year
90 mg/month: $ 2,874/month; $ 34,488/year
120 mg/month: $ 4,362/month; $ 52,344/year

Pegvisomant (Somavert) self-injection, under the skin, once a day: Please note: this medication is dispensed through the Pfizer Bridge Program, the prices quoted are the actual wholesale cost provided by Pfizer. This cost may be covered by the patient's pharmacy benefit or under major medical coverage, depending on the type of insurance policy.

Source: Pfizer :
10 mg/day: $ 2,363/month; $ 28,350/year
15 mg/day: $ 3,544/month; $ 42,527/year
20 mg/day: $ 4,725/month; $ 56,700/year


10. Since octreotide, Sandostatin LAR, Somatuline and pegvisomant (Somavert) are so expensive, is there any financial help available?

Yes, possibly.
Sandostatin LAR: Novartis has an assistance program for patients who qualify. The Novartis patient assistance telephone number is: 1-877-LAR-HELP (1-877-527-4357). If the patient has Medicare - this cost is covered by Medicare since the Sandostatin LAR injection must be administered at a doctor's office.

Somatuline: Assistance Program: Patient Services, Inc., telephone number: 1-800-366-7741 or 1-804-744-3813.

Pegvisomant (Somavert): The Pfizer Bridge program works with PSI, and independent company, to provide assistance for patients who qualify for financial reasons. The Pfizer Bridge program telephone number is 1-800-645-1280, The PSI telephone number is 1-800-366-7741.


11. I have had surgery, why do I still have a problem and have to undergo radiation treatment and take medication?

Some patients are not cured with surgery. The reason for this is most commonly because of the size of the tumor: the larger the tumor, the less likely it can be removed completely. Additionally, the tumor may have spread to nearby structures such as bone, the cavernous sinus (location of carotid artery and the nerves controlling eye movements) and the membrane surrounding the gland (dura mater). In this situation, the neurosurgeon removes all that can be safely removed, but if the tumor has invaded surrounding structures such as bone or the cavernous sinus or the membrane covering the pituitary, excessive growth hormone production may persist. Surgery is usually the first step to remove as much of the tumor as possible, since the medical treatments do not always shrink the tumor and, if present, relieve the pressure on the optic nerve or improve vision problems.

  

C. ACTH producing tumor (Cushing's Disease):

1. Are there any medical treatments for ACTH producing tumors?

Yes and no. There are medications that can reduce cortisol production by the adrenal glands, but medication does not have any effect on the pituitary overproduction of the hormone ACTH (the pituitary hormone that stimulates the adrenal glands to make too much cortisol). Thus, medication is used to control adrenal gland cortisol overproduction, but does not treat the source of the problem - the pituitary gland. Ketoconazole is a medication that reduces adrenal gland cortisol production. This medication is most often used in patients who have persistent Cushing's after surgery and/or radiation, while waiting for the radiation to become effective. If a drug to lower cortisol is prescribed, careful monitoring is necessary to determine if the dose is effective (measure 24 hour urine cortisol level), to make sure it does not reduce cortisol to below normal (measure morning blood cortisol level) and to make sure there is no ill effect on the liver. Another medication that reduces cortisol production by the adrenal glands is mitotane (Lysodren). Mitotane is used to treat patients with cancer of the adrenal glands, but is also effective in reducing cortisol production in patients with pituitary Cushing's.

There are some experiments in mice that suggest that the diabetes medication, rosiglitazone, may reduce the size of implanted ACTH producing tumors and reduce cortisol production. This treatment is now under investigation in patients with Cushing's disease, but early results have not yet shown that this is an effective treatment in most patients. This is a potentially exciting area of research, but it is currently a research project.

SOM 230: SOM 230 is an experimental drug; it is a somatostatin analog that may have some benefit in the treatment of Cushing's disease. This drug is only available at centers that are participating in clinical trials.


2. What are the side effects of ketoconazole?

Ketoconazole: the most common side effect is nausea and abnormalities in liver function. Before this medication is taken, a blood test should be measured to make sure there are no liver abnormalities. It is a good idea to have regular liver tests when taking ketoconazole. If fatigue or jaundice occurs, liver tests must be measured and if the liver tests are abnormal, the medication stopped immediately. If liver tests become abnormal, they usually return to normal after the ketoconazole is stopped. Other side effects include vomiting, abdominal pain and itching.


3. What are the side effects of mitotane (Lysodren)?

Mitotane (Lysodren): decreased appetite, nausea, vomiting - up to 80% of patients (usually receiving high doses); depression, sleepiness, dizziness - this occurs in up to 40% of patients (usually receiving high doses).


4. I had pituitary surgery for Cushing's, why do I have to take steroid (cortisol) replacement (hydrocortisone (Cortef), prednisone or dexamethasone)?

This is the best outcome after pituitary surgery. It means that the tumor has been removed successfully and that the remaining normal ACTH producing cells in the pituitary gland are still suppressed (relatively "asleep"). It may take several months for the normal ACTH producing cells to regain function to stimulate the adrenal glands to produce a normal amount of cortisol (hormone necessary for life). In the mean time, steroid replacement is necessary to protect against adrenal insufficiency. At a later date, the need for continued steroid replacement is determined by blood tests off of the steroid medication.

If a person has to take steroid replacement (hydrocortisone, prednisone, dexamethasone) he/she should wear a Medic Alert bracelet or necklace, which identifies the need for steroid treatment.


5. I have been cured of my Cushing's - why don't I feel normal, 6 months after my surgery?

This is a common question and a very common problem. Cushing's affects every system of the body; it causes problems gradually, particularly its effect on muscles and body fat. With Cushing's, muscles become thin and weak. It takes a long time for the body to "repair" itself, usually 9 to 12 months. It is quite common for patients to still feel weak and have achy muscles and joint pains several months after successful surgery. Patients may also notice dry skin and itching - this is part of recovery. Frequent use of skin moisturizers is recommended. More positively, the problems with depression, concentration and memory seem to improve fairly soon after successful treatment according to questionnaires completed by our patients who had successful pituitary surgery. Usually most patients have improvement in mood and depression within 3 to 6 months after successful treatment. However, they are still frustrated that they are not "back to normal". Unfortunately, the excess weight does not "magically" disappear - it takes time and a weight reduction diet to return to normal body weight. The important word here is: patience. With dieting, it is possible to loose the weight gained with Cushing's. Patients who have high blood pressure and/or diabetes: with successful treatment, some patients no longer require medication for high blood pressure and/or diabetes. In other patients, the amount of medication to treat these conditions may be reduced.


D. Non functioning pituitary tumor:

1. Is there any medical treatment for this type of tumor?

Generally, no. There are no specific medical treatments for this type of tumor. The best treatment is pituitary surgery to remove the tumor. Bromocriptine has been used in a few patients who could not have surgery. A small minority of patients have had some improvement in vision because of slight reduction in tumor size and relief of pressure on the optic chiasm (eye nerves above the pituitary gland). However, this medicine does not cause dramatic tumor shrinkage - the best treatment is to remove as much of the tumor as possible with surgery.

If surgery has to be delayed for a short time, dexamethasone may be given to reduce swelling and hopefully relieve the pressure on the optic chiasm (this is not effective in everyone). However, dexamethasone is not an effective treatment long term treatment for this tumor, it is used as a temporary measure to try to reduce pressure on the optic (eye) nerve in a patient who has lost vision and who cannot have surgery immediately. The most important and most effective treatment is to remove the tumor surgically.


2. Should I try medication such as bromocriptine before surgery?

Not if there loss of vision. Unless there is a reason surgery cannot be performed, a trial of bromocriptine is reasonable, but the probability of shrinkage of the tumor is extremely low; the best treatment is prompt removal of as much of the tumor as possible.


3. Will I need additional treatment after surgery?

Additional treatment such as pituitary radiation may be necessary to treat remaining tumor and to prevent re-growth. However, since these tumors are slow growing, radiation treatment is not routinely recommended as long as there is no tumor growth over time. It is important to have an MRI scan at least once a year to detect any tumor regrowth. Since there is no blood test to indicate excessive hormone production, the MRI scan is the only way to determine if there is regrowth of the tumor.

  

E. Craniopharyngioma:

1. Is a craniopharyngioma a pituitary tumor?

Technically, no. A craniopharyngioma arises from abnormal development of the pituitary gland during fetal (in the womb) development. It may be located within the pituitary gland or above the pituitary gland. This is a tumor that one is born with and may enlarge at any time, even in people over 60 years of age. It is not a cancer. A craniopharyngioma may be discovered in childhood or at any age in adulthood. This type of tumor does not produce hormones but frequently interferes with normal pituitary gland function and may cause diabetes insipidus (a disorder of water balance with frequent urination and excessive thirst; this is not sugar diabetes).


2. Is there medical treatment for a craniopharyngioma?

No, there are no medicines to treat this type of tumor. Most patients require hormone replacement(s) because of damage to the normal pituitary gland by the tumor. Surgery is the first choice because radiation treatment does not cause an immediate decrease in tumor size. A craniopharyngioma may be large and invade brain tissue and because of this, removal of as much as possible is necessary. Some patients also require radiation treatment if there is remaining tumor after surgery; radiation treatment is used to prevent growth of any remaining tumor.


IV. Replacement Therapy for Hypopituitarism

1. What is hypopituitarism?

Hypopituitarism means that one or more of the pituitary hormones is not being produced normally and hormone replacement is necessary.


2. Why does hypopituitarism happen?

A pituitary tumor, craniopharyngioma or Rathke's cleft cyst may cause the loss of normal pituitary function; usually because of pressure (compression) by the tumor on the normal pituitary gland. Other causes of loss of normal pituitary function, destruction of the normal gland, include bleeding into a tumor which destroys the normal gland (called pituitary apoplexy), surgery and radiation therapy. Regardless of the cause, hormone replacement(s) is required.


3. Is hypopituitarism loss of all normal pituitary function?

No. Some patients have only 1 hormone deficiency, others have 2 or 3, and others have complete loss of pituitary function.


4. What are the pituitary hormones and what do they do?


Pituitary Hormone


Target Organ


Regulates


ACTH


Adrenal glands


Adrenal cortisol production


TSH


Thyroid gland


Thyroid hormone production


LH, FSH


Ovaries, testes


Reproduction, sexual function


GH (growth hormone)


Whole body, bones


Growth, body composition


Prolactin


Breast


Milk production for nursing


ADH (vasopressin)


Kidney


Water, salt balance


ACTH deficiency: this hormone stimulates the adrenal glands to produce cortisol. Cortisol is necessary for life. Lack of adequate cortisol causes fatigue, weight loss, nausea, vomiting, low blood pressure and may result in shock and death unless this is treated.

TSH deficiency: this hormone stimulates the thyroid gland to produce thyroid hormone. Low thyroid hormone causes fatigue (loss of energy), weight gain, constipation, feeling cold and memory problems. Thyroid hormone regulates body metabolism and is necessary for life.

LH and FSH deficiency: these hormones control the reproductive system and sexual function. Deficiency of these hormones causes loss of menstrual periods and infertility in women and causes loss of sexual function, a low blood testosterone level and infertility in men.

Growth hormone deficiency: this is the most common pituitary hormone deficiency and may occur in up to approximately 85% of patients who have a pituitary tumor. Loss of growth hormone in children causes lack of normal growth (growth retardation, short stature). In adults, symptoms of decreased energy and vitality are common. Changes in body composition can also occur - more fat is accumulated (especially in the abdomen) and a decrease in muscle mass occurs. There is also a loss of bone density and an increased risk of bone fractures.

Prolactin deficiency: inability to nurse after pregnancy. There are no known ill effects in men.

Anitdiuretic horomone (ADH (also called vasopressin) deficiency: this hormone is produced by the posterior or back part of the pituitary and is responsible for water and sodium (salt) balance. Deficiency of this hormone causes excessive and frequent urination and excessive thirst. If the patient does not drink an adequate amount of water, the blood sodium can increase abnormally and causes dehydration. Many patients can drink enough water to maintain a normal blood sodium level, but this is extremely inconvenient for the patient - having to drink large amounts of water (day and night) and urinating every hour or so to make up for the large urine losses from the kidneys.


5. Can all of these hormones be replaced?

Yes, all except prolactin.


6. What does hormone replacement involve? What do I have to do?

What do you have to do? In order to have a beneficial effect, the medication(s) must be taken as prescribed; if not, there will be no benefit and there may be harmful medical consequences.

Medications: Hormone replacement is administered with pills, injections, skin patches, a skin gel and a nasal spray, depending on the type of hormone.

Pills:

Adrenal Insufficiency: hydrocortisone (or prednisone or dexamethasone)

Thyroid hormone for an underactive thyroid gland

Sex Hormones: Estrogen (female hormone), progesterone (female hormone)
Testosterone pills for men may cause liver damage and should not be used.

Vasopressin (for diabetes insipidus): dDAVP; generic desmopressin.

Injections:

Testosterone (male hormone).

Growth hormone

Fertility drugs: hormones that stimulate the ovaries and testes.

Skin patches: estrogen (female hormone) and testosterone (male hormone)

Skin Gel: testosterone (male hormone) - Androgel, Testim

Nasal spray: dDAVP for diabetes insipidus

Buccal (mouth) pellet: Testosterone (Striant) placed under the lip, used 2 or 3 times/day

The most important thing about any hormone replacement is that the medication(s) must be taken as prescribed and the beneficial effects and any side effects need to be monitored regularly by an Endocrinologist. If the medications are not taken as directed, serious medical problems can occur. The most important principle is that one dose does not fit every patient. Any hormone replacement may require adjustment of the dose based on blood tests, assessment of how the patient feels and any side effects. When beginning any hormone replacement, the need for dose adjustment (increase or decrease) is quite common to achieve the goal of the best dose for each patient. Hormone replacement is like a "tailor made suit" - adjustments in the dose are necessary to achieve the best dose and regimen for the individual patient.

If hormone replacement requires steroid (cortisol) replacement (hydrocortisone, prednisone, dexamethasone) - this medication must be increased if another illness occurs, such as flu, kidney infection, pneumonia. The hydrocortisone (or prednisone or dexamethasone) dose should be doubled for the duration of the illness - this mimics the body's normal response to illness. Patients who require steroid replacement should also wear a bracelet or necklace ("Medic Alert"), which identifies the need for steroid treatment (the doctors in an emergency room need to know this in the case of an accident or illness so that adequate steroid treatment can be given immediately).


7. How long do I have to take hormone replacement?

If the pituitary gland does not recover normal function, hormone replacement is usually life long. Depending on the tumor type, the treatment and the effects of treatment, some patients have return of normal pituitary function and replacement hormone(s) can be stopped. This should only be done with the appropriate blood testing to make sure the pituitary gland has resumed normal function. Do not stop the medication on your own without supervision from your Endocrinologist.


8. Why should a woman take estrogen (female hormone) treatment?

Estrogen relieves symptoms of menopause (hot flashes). However, recent results of the Women's Health Initiative study showed a small but increased risk of developing breast cancer and heart disease in postmenopausal women who took estrogen and progesterone replacement for 10 years or more.

Replacement of estrogen and progesterone in premenopausal women is not known to increase the risk of developing breast cancer or other problems. If a premenopausal woman decides to take estrogen and progesterone replacement, the medications should be stopped at the usual time of menopause (around 50 years old). Estrogen protects the bones to reduce the risk of developing osteoporosis (thinning of the bones) and should be taken with calcium and vitamin D for best effect on bone health. There are also very effective medications to treat osteoporosis in postmenopausal women. Estrogen treatment is not given to a woman who has had breast cancer or who has a strong family history of breast cancer. In every woman, regular mammograms, pelvic exams and pap smears are necessary. Currently, estrogen replacement is given to control menopausal symptoms in women of postmenopausal age (usually around 50 years of age) for the short term (a year or two, usually not more than 5 years).


9. Why should a man take testosterone (male hormone) treatment?

Testosterone is not only necessary for sexual function, it is important to protect the bones against osteoporosis (loss of bone mass and increased risk for bone fractures), to preserve normal muscle mass and strength and normal blood production by the bone marrow (prevent anemia). The effects of long-term testosterone deficiency include a higher risk of bone fracture, loss of muscle mass and muscle strength and low red blood cell count (anemia) as well as loss of interest in sex and loss of sexual function (ED: erectile dysfunction). Every man receiving testosterone replacement should have a prostate exam and a blood PSA test (screening test for prostate cancer) at least once a year. Testosterone does not cause prostate cancer, but if a man has undiagnosed prostate cancer, testosterone treatment may promote growth of the cancer, which emphasizes the need for regular prostate examinations and the blood PSA test.


10. Is fertility possible in a patient with loss of pituitary function?

Yes, but it takes effort and time.

Women: If the pituitary hormones (LH and FSH) that regulate the ovaries are not produced adequately by the pituitary gland, it is unlikely for a woman to become pregnant without additional medical treatment. It is possible to stimulate the ovaries with LH and FSH injections, this may take several months of injections before ovulation occurs and pregnancy is achieved. Although it requires more "work" (and cost, many insurance companies do not pay for fertility treatments), pregnancy is very possible in a woman who has pituitary deficiency of the hormones that control ovarian function.

Men: Men who do not produce testosterone and who have a low sperm count can be treated with pituitary hormones (LH and FSH) to stimulate the testes to produce testosterone and sperm. Sperm production takes a long time - the normal sperm cycle is around 72 days - in order to increase testosterone and sperm production, it may require a year of more of treatment to achieve an adequate sperm count to achieve pregnancy.


11. Should a man have his sperm frozen? If so, when?

If a man is interested in future fertility, it is a good idea to have a semen analysis to determine the sperm count and quality of the sperm (motility [normal movement] and percentage of normal forms). If the semen analysis is normal or near normal, it is a very good idea to freeze ("bank") sperm for future use. Sperm banks are usually available in cities. The timing of a semen analysis and banking sperm is important: ideally, before surgery or pituitary radiation. However, it can be done soon after an operation or pituitary radiation. Once a firm diagnosis of hypogonadism (loss to testicular function) is made and if the sperm count is very low, fertility drugs are probably the best option for achieving fertility.


12. Is growth hormone important in adults?

Yes. Growth hormone (GH) does more than stimulate growth in children. In adults, growth hormone affects all aspects of metabolism (body energy) and affects body composition (fat mass, muscle mass, bone density). Adults who are growth hormone deficient may have an increased amount of body fat and decreased amount of muscle mass. Bone density in adults with growth hormone deficiency may be lower than normal adults; there is also an increased risk of bone fracture in growth hormone deficient adults. Additionally, some patients with growth hormone deficiency experience symptoms of fatigue, loss of energy and social isolation. Growth hormone replacement is relatively new; it has been used in Europe for approximately 25 years and was approved in the U.S. in 1996. Studies of GH replacement demonstrate that muscle mass increases, fat mass decreases, and after 18 months, bone mass increases; weight does not change (it is not a weight loss hormone). Growth hormone caused a preferential reduction in fat within the abdomen (visceral fat); this is important because increased visceral fat is associated with a higher risk of developing heart disease. Some patients have improvement in exercise ability and muscle strength. Questionnaires to assess growth hormone's effects on psychological measures showed that growth hormone treated patients had improvement in energy level and an overall sense of well being.

The diagnosis of growth hormone deficiency is usually made with a stimulation test because a single growth hormone level and the IGF-1 level are not adequate for the diagnosis (IGF-1 may actually be normal in a patient with growth hormone deficiency). In patients who have 3 or 4 pituitary hormone deficiencies, growth hormone deficiency is highly likely (over 90% chance of GH deficiency), and if the blood IGF-1 level is below normal, a stimulation test may not be necessary. Since growth hormone treatment is expensive, most insurance companies require a report of a stimulation test before agreeing to financial reimbursement or coverage. Stimulation tests to diagnose growth hormone deficiency in adults include administration of insulin to lower the blood sugar level, arginine and growth hormone releasing hormone. These tests require measurement of several growth hormone levels, before and after administration of the stimulating drug.

Growth hormone is administered by an injection under the skin once a day. The needle used is a very tiny needle (growth hormone deficient children give themselves this injection every day). Growth hormone replacement must be monitored by evaluating the clinical response (how the patient feels), any of side effects (most commonly swelling, edema, muscle aches, tingling in the fingers) and by measuring the blood IGF-1 level to determine if the dose is correct (again, one dose doesn't fit all when it comes to hormone replacement therapy).

Growth hormone replacement is FDA approved for patients who have pituitary disease and who have an abnormal growth hormone stimulation test. Growth hormone replacement in adults is expensive, usually between $7,000 to $10,000/year, depending on the dose. Therefore, most insurance companies require documentation of the need for this medication and the results of the stimulation test before agreeing to reimbursement.


Childhood and Adolescent Pituitary Disorders

Although a pituitary tumor (adenoma) is more common in adults, children and adolescents may also have this problem. The most common types of tumors in the pituitary region in this age group are a craniopharyngioma or a Rathke's cleft cyst (developmental disorders that occur during fetal [in the womb] life but may not become obvious until later). The hallmark of any type of a pituitary problem in children and adolescents is failure to grow, slowing of the growth rate and/or failure of sexual development (puberty). This emphasizes the need to monitor growth regularly. There is a condition known as "constitutional delay of growth and puberty" that may be assumed to be the problem. Constitutional delay of growth and puberty means that during adolescence the patient does not have the expected normal growth spurt or begin puberty until age 15 or 16. Constitutional delay of growth and puberty may be "familial" meaning that there is a family history of late development, usually in a parent. However, this disorder cannot be diagnosed without appropriate hormone studies and an MRI study of the pituitary gland and brain to make sure that there is not a pituitary tumor or craniopharyngioma or Rathke's cleft cyst causing this delay in growth or puberty.

Another cause of growth failure or delayed puberty is in children who were treated for leukemia with brain and spinal cord radiation to prevent leukemia recurrence. Brain radiation may cause pituitary gland failure that causes not only growth failure and failure to go through puberty, it may also cause thyroid failure (hypothyroidism) and adrenal gland failure (adrenal insufficiency). Children who have undergone brain radiation require regular measurement of growth and development and hormone blood tests to detect these problems.

The treatment of a pituitary tumor, a craniopharyngioma or Rathke's cleft cyst is the same as for adults. A prolactin producing tumor is usually first treated with medication (bromocriptine, cabergoline) while all other types of tumors require surgery to remove as much of the tumor as possible. As in adults, additional treatment may be necessary including pituitary radiation and medications to control excessive hormone production and to replace any deficient hormones. Diagnosis and treatment of growth hormone deficiency is very important to restore a normal growth rate and hopefully achieve a normal predicted final height (this is also dependent on genetic and nutritional factors).

There are specific psychological and social issues in children and adolescents who have a pituitary problem. The delay in growth and/or puberty may cause emotional difficulties because of being "different" from his or her friends and schoolmates. The need to take medications, including a daily growth hormone injection, may add to a sense of being "different" or "sick". Children and adolescents may resist the need to take medications, may become depressed and/or withdrawn because of feeling "different" or "sick". This may have an impact on school performance, participating in sports (feeling of having an abnormal body compared with friends and schoolmates; lack of breast development in girls, lack of beard development in boys) and participating in social events (feeling too short to go to a dance). These are very important issues for these children and adolescents and must be addressed by discussing this at home, counseling in many circumstances and with appropriate hormone therapy or therapies to promote normal growth and pubertal development. Children and adolescents who require hormone treatments should be reassured that they can lead a normal life and participate in sports and social activities as long as they take their medications as prescribed.

Childhood/Adolescent Cushing's Disease: The hallmarks of Cushing's disease in children are weight gain and slowing or stopping of growth, resulting in obesity and short stature. It is important to measure height and weight at least once a year and plot the value on a growth chart (hopefully most Pediatricians do this). When a child has a decline in his or her growth rate, with weight gain, this needs to be evaluated. If thyroid hormone levels are normal, the child should be evaluated for Cushing's (24 hour Urine Free Cortisol, best test).

Future fertility:Another issue that must be addressed is the possibility of being a father or mother as an adult. This concern may not be expressed by an adolescent, but it is probably a concern. If the pituitary problem has resulted in loss of pituitary function, particularly the ability to be a father or mother in the future, the issue must be discussed. Future fertility IS possible without a functioning pituitary gland. Fortunately, the pituitary hormone hormones (LH, FSH) can be administered to stimulate the testes and ovaries to produce testosterone and sperm (men) and estrogen and progesterone and production of an egg (ovulation) (women). The bottom line: it will take more "work" to restore potential fertility, but fertility is possible. A child or adolescent with pituitary failure should be told this early on to reduce anxiety and concern about a future "normal life". It is uncommon for a child or adolescent to talk about this issue, but it is very important to address this issue when pituitary failure is diagnosed with the hope of avoiding or reducing anxiety/distress/concern about this issue. Yes, fertility is possible, but it will require treatment and time.

In adolescent boys who have gone through some of the stages of puberty, sperm production may be normal when the diagnosis of a pituitary problem is made. The only way to determine this is to have a semen analysis with measurement of the number of sperm, the sperm motility (movement) and the amount of normal sperm (percentage). If the semen analysis shows a reasonable sperm count, motility and percentage of normal sperm forms, it is wise to have the sperm "banked" (frozen) for potential future fertility. The semen analysis should be done before pituitary surgery or radiation treatment or soon afterward since future fertility cannot be guaranteed after treatment. This procedure is also recommended for adult men who may wish to preserve potential fertility.

Summary

A patient with a pituitary tumor is a challenge for the patient, her/his family and the physicians caring for the patient. Working together, the goal is to achieve the correct diagnosis, appropriate treatment(s) and ultimate outcomes that result in restoring a patient to normal function. This challenge can be met successfully with the coordinated efforts of the patient, the family and the physicians resulting in the best possible outcomes for the patient and his or her family.

Contact

Phone: 434-982-3591 or toll-free 800-650-2650
Fax: 434-924-5894