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 corrected. Reduction in tumor size should 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 tumor type, particularly for large tumors (macroadenoma, > 10 mm). In patients with large tumors, surgery results in normal prolactin levels in < 20% of patients. Surgery is effective in removing the bulk of the tumor, but prolactin levels remain 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) in the blood vessels 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 (Dostinex), bromocriptine (Parlodel) and pergolide (Permax). A very effective drug, Norprolac, is only available in Europe and Canada. Dostinex is a long acting drug and can be taken once or twice a week; bromocriptine and pergolide are usually given 1 to 3 times a day.

All of these drugs act on the tumor in the same way - by inhibiting or reducing the amount of prolactin made by the tumor and thus 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 (Dostinex) causes fewer side effects than bromocriptine or pergolide, but Dostinex is more expensive than the other drugs. Some studies indicate that cabergoline (Dostinex) may be more effective than bromocriptine or pergolide 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 done which 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, pergolide, 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?

In the situation of 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 it does not disappear. This 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 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; 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 person takes the medication. 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 a year or more to see if the prolactin stays normal. In a minority of patients (around25%), this is successful and the prolactin remains normal. 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. A recent study showed that approximately 15% 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.

Recent studies suggest that after 5 years of medical treatment some patients may have a normal prolactin level after stopping medical treatment. If the medication is stopped, it is necessary to measure the blood prolactin level regularly (at least every 6 months) to determine if the tumor has become overactive and requires medical treatment again.

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 (Dostinex) may be more effective than the other drugs. 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 to 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 or vomiting.

The issue of cost is particularly important for patients who do not have an insurance plan to cover the costs or if there is a high co-pay for medications. There is one potential limitation of taking the less expensive medication (pergolide) in women who wish to become pregnant. Pergolide is only approved in the U.S. for another indication (Parkinson's disease), it is not FDA approved for treatment of a prolactin producing pituitary tumor. There is not enough information about babies born to women taking pergolide to assure us that it is safe for the developing baby. Therefore, we do not prescribe this particular drug to women who wish to become pregnant or who are at risk for becoming pregnant. The FDA approved medication, bromocriptine, ha 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, even for a woman taking no medications). Cabergoline (Dostinex) is also not approved for pregnancy; information on several hundred women who became pregnant while taking cabergoline reveals no increase (above the normal risk) of birth defects for the baby, Until there is more experience with Dostinex in women who become pregnant, it is prudent to take bromocriptine (Parlodel) for women wishing to become pregnant until more is known and if Dostinex becomes FDA approved for pregnancy.

The convenience of taking the medication is important for many patients who are busy with work and other activities. Bromocriptine is often given three times a day; some patients can be treated twice a day. Pergolide is usually given either twice a day or once 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.

6. What is the cost of these medications? The following are the costs at the U Va outpatient pharmacy and may not be the same as a local retail pharmacy. Please note: these are quoted charges that do not reflect insurance coverage or cost to the patient.
Bromocriptine, 2.5 mg three times a day: $ 114/month; $ 1,372/year
Pergolide, 0.05 mg twice a day: $ 10/month; $ 123/year
Pergolide, 0.1 mg twice a day: $ 20/month; $ 246/year
Cabergoline, 0.5 mg once/week: 107/month; 1,289/year
Cabergoline, 0.5 mg twice a week: $ 209/month; $ 2,509/year

7. 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 32 years).

8. 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, pergolide, 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, pergolide, cabergoline) is assessed. A woman may become pregnant taking one of these medications even without having a menstrual period.

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 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 near the pituitary gland). 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?

While the tumor makes growth hormone, 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 make a person grow, 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 get smaller. Because of this, the usual first treatment is surgical removal of as much of the tumor as is 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 colon cancer, and premature heart disease and premature death), it is important to reduce growth hormone and/or 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: bromocriptine (Parlodel), cabergoline (Dostinex), pergolide (Permax)
Somatostatin analogs: Sandostatin LAR, lanreotide (not available in the U.S.).
Growth hormone receptor antagonist, pegvisomant (Somavert).

5. Which medication is more effective?

The dopamine agonist drugs, bromocriptine (Parlodel). Pergolide (Permax) and cabergoline (Dostinex), improve symptoms but are not very effective in lowering growth hormone and IGF-1 levels to normal (< 10%). Cabergoline (Dostinex) may be more effective than the other drugs. Since this medication is 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 lanreotide act on the pituitary gland to reduce (inhibit) growth hormone, and subsequently, 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.

Sandostatin LAR (octreotide) and lanreotide reduce growth hormone and IGF-1 levels in approximately 90% of patients. However lowering of these hormone levels 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 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, others use a small pump (worn on the belt or in a shirt pocket) which delivers the medication continuously (the needle under the skin is changed every 2 or 3 days). The long acting preparation, Sandostatin LAR is more convenient to take (once every 28 days) but requires a visit to the doctor’s office. Lanreotide (not currently available in the U.S.) is usually administered every 14-30 days depending on the response.

Some patients have a better response to the combination of bromocriptine or cabergoline and octreotide (Sandostatin), especially if the tumor makes too much 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 Somavert 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 (usually self-administered) once a day.

6. What are the side effects of these medications?

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

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

Cabergoline (Dostinex): occasional nausea, vomiting, dizziness; fewer side effects than bromocriptine or pergolide.

Sandostatin LAR, 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 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, the patient is given a single injection of the shorting acting Sandostatin to make sure there are not side effects and then the patient is given an injection of long acting Sandostatin – Sandostatin LAR.

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. 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 remaining tumor growth, but regular MRI scans are necessary to make sure there is no growth.

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

Occasionally, but not usually. 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). If the patient cannot undergo surgery, medical treatment, preferably with Sandostatin, is used. Again, this is not a cure; medical treatment with a somatostatin drug controls the problem,optimally in approximately 45 to 60% of patients.

8. Does medical treatment shrink the tumor?

Octreotide, Sandostatin LAR and lanreotide: Approximately one-third of patients have a reduction in tumor size. The amount of tumor shrinkage is usually modest, approximately 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): 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-1 production and does not cause reduction in tumor size.

9. What is the cost of medical treatments? These are charges from the U Va outpatient pharmacy; charges at a local pharmacy may be different. Please note: these are quoted charges that do not reflect insurance coverage or cost to the patient.

U Va Outpatient pharmacy charges:
Bromocriptine, 5 mg 3 times a day: $ 228/month; $ 2,743/year
Bromocriptine, 5 mg 4 times a day: $ 306/month; $ 3,648/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.

10 mg/month: $ 15,710/year
20 mg/month: $ 16,260/year
30 mg/month: $ 24,420/year

Pegvisomant (Somavert) self-injection 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.

10 mg/day: $ 34,218 per year
20 mg/day: $ 51,330 per year
30 mg/day: $ 68,437 per year

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

Yes.

Sandostatin LAR: Novartis has an assistance program for patients who qualify. The Novartis patient assistance telephone number is: 1-877-LAR-INFO. If the patient has Medicare – this cost is covered by Medicare since the injection of Sandostatin LAR must be administered at a doctor's office.

Pegvisomant (Somavert): The Pfizer Bridge program works with PSI, and independent company, to provide assistance for patients who qualify. The 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 have radiation treatment and take medication?

Some patients are not cured with surgery. The reasons for this are most commonly related to 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 nerves controlling eye movements) and the membrane surrounding the gland (dura mater). In this situation, the surgeon 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, relieving pressure on the optic nerve.

C. ACTH producing tumor (Cushing's Disease)

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

Yes and no. There is a medication that can reduce cortisol production by the adrenal glands, but this 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 do not treat the source of the problem - the pituitary gland. Ketoconazole (Nizoral) 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.

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 it is not yet known if this is an effective treatment. This is a potentially exciting area of research, but it is currently a research project.

2. What are the side effects of ketoconazole (Nizoral)?

Ketoconazole (Nizoral): 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. If the patient develops fatigue or jaundice, liver tests should be measured again and 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. I had 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 completely and that the rest of the gland is still suppressed (relatively "asleep"). It may take several months for the normal ACTH producing cells to regain function. In the mean time, steroid replacement is necessary to protect against adrenal insufficiency (steroid is necessary for normal life). At a later date, the need for continued steroid replacement is determined by blood tests.

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.

4. 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 several months after successful surgery or successful radiation treatment. More positively, the problems with depression, concentration and memory seem to improve fairly soon after successful treatment according to questionnaires completed by our patients after successful pituitary surgery. Usually most patients have improvement in mood and depression 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.

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 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). The most important and most effective treatment is to remove the tumor surgically.

2. Should I try medication before surgery?

Not if there loss of vision. Unless there is a reason surgery cannot be performed, the best treatment is removal of as much of the tumor as possible. Additional treatment such as pituitary radiation may be necessary to treat any remaining tumor and to prevent re-growth. It is important to have an MRI scan once a year to detect any tumor re-growth. Since there is no blood test to indicate excessive hormone production, the MRI scan is the only way to determine if there is re-growth 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. 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.
 

III. 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 may cause the loss of normal pituitary function; usually this occurs because of pressure (compression) by the tumor of the normal gland. Other causes of loss of normal pituitary function, destruction of the normal gland, include bleeding into a tumor and normal gland (called pituitary apoplexy), surgery and radiation therapy. Regardless of the cause, hormone replacement 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 pituitary hormone deficiencies.

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
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 is one of the 2 pituitary controlled hormones that are 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 loss of fertility in men.

Growth hormone deficiency: this is the most common pituitary hormone deficiency and occurs in 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 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.

ADH (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 cause 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 necessary.

Pills:

Adrenal Insufficiency: hydrocortisone (or prednisone or dexamethasone)

Thyroid hormone for an underactive thyroid

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.

Injections: testosterone (male hormone), growth hormone

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 placed under the lip, used 2 or three 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 an optimal 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 he illness - this mimics the body's normal response to illness. Patients who require steroid replacement should also wear a bracelet or necklace, 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).

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. It is not known if this risk applies to younger women who have lost function of the ovaries because of a pituitary tumor. Estrogen proyects the bones to reduce the risk of developing osteoporosis (thinning of the bones) which is best taken with calcium and vitamin D for maximum effect. However, there are other very effective medications to treat osteoporosis. 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 situation, regular mammograms, pelvic exams and pap smears are necessary. Currently, estrogen replacement is given to control menopausal symptoms for the short term (usually 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. 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 (erectile dysfunction). Every man receiving testosterone replacement should have a regular 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 prostate cancer, testosterone treatment may promote growth of the cancer, which emphasizes the need for regular prostate examinations and a PSA test.

10. Is fertility possible in a patient with loss of pituitary function? Yes, but it takes more effort.

Women: If the pituitary hormones (LH and FSH) that regulate the ovaries are not functioning properly, it is extremely 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, most insurance companies do not pay for fertility treatments), pregnancy is possible in a woman who had pituitary hormone deficiency.

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 the desired results.

11. 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. Bone density may also be lower in adults who are growth hormone deficient. In addition to physical features of GH deficiency in adults, some patients experience symptoms of fatigue, loss of energy and social isolation. Growth hormone replacement is relatively new; it has been used in Europe for approximately 15 years and in the U.S. since 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) and 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 patient’s 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 the result of a stimulation test before agreeing to provide 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 for a patient (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 is expensive, usually around $10,000/year or more, depending on the optimal 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 this age group are a craniopharyngioma or a Rathke’s cleft cyst (these are developmental disorders that begin during fetal [in the womb] life but may not become evident until later). The hallmarks 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.

Another cause of growth failure or delayed puberty is in children who were treated for leukemia with brain (and spinal) radiation to prevent leukemia recurrence. Brain radiation may cause pituitary gland failure that cause 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, pergolide) 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 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.

Future fertility: Another issue that must be addressed is the possibility of being a father or mother in adulthood. 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 production (men) and estrogen and progesterone (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 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 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 since future fertility cannot be guaranteed after treatment.

Summary

The 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.