MGH Neuroendocrine Center Bulletin Vol 9, Issue 1, Fall/Winter 2003 - Neuroendocrine Clinical Center & Pituitary Tumor Center at MGH/Harvard

Bulletin Volume 9, Issue 1, Fall/Winter 2003

Articles in this issue:

Figure 1. MRI scans of a man with a macroprolactinoma before (top) and after (bottom) dopamine agonist therapy. Considerable tumor shrinkage is seen, with the tumor no longer adjacent to the optic chiasm. (Arrow indicates optic chiasm).

Diagnosis and Treatment of
Prolactinomas in Men

by Anne Klibanski, M.D.

Introduction

Prolactin-secreting pituitary adenomas are the most common secretory pituitary tumor. They can be either microprolactinomas (<1 cm) or macroprolactinomas (>1 cm). Prolactin-secreting pituitary adenomas are more common in women, and the vast majority of such tumors are microadenomas. Diagnosis of prolactinomas in men is much less common and the majority of men have macroadenomas at the time of diagnosis. In women, hyperprolactinemia is commonly associated with reproductive sequelae and women often present with amenorrhea, oligomenorrhea, infertility or galactorrhea. The presentation of menstrual disturbance in women typically leads to endocrine evaluation, including obtaining a serum prolactin level. In contrast, diagnosis of prolactin-secreting tumors in men is often delayed and in retrospect, many patients report a number of years of symptoms before the diagnosis is finally made.

Men with prolactinomas often present with decreased libido or erectile dysfunction and may see an internist, urologist, psychiatrist, or family therapist prior to having the correct endocrine diagnosis established. In addition, many patients with macroprolactinomas present with symptoms of mass effect due to the large size of the tumor, including headache, visual loss or other neurologic symptoms. Because the presentation of prolactinomas in men differs from women and because there are fewer published data regarding treatment, this review will focus on the diagnosis and management of prolactinomas in men.

Clinical Case

A 32-year-old man was seen at an emergency room for evaluation of severe headaches for six weeks. Previously reported to be in good health, he had noted fatigue for approximately six months, attributed to stress, as well as a decrease in libido. He denied any visual problems. An MRI scan was performed, and showed a large pituitary tumor with marked extension outside of the sella both superiorly and inferiorly (see Figure 1 top). A serum prolactin level was drawn and was markedly elevated at 3,100 ng/ml (normal < 15 ng/ml). Basal thyroid tests were normal. A testosterone level was decreased at 113 ng/dl (normal > 290 ng/dl). A growth hormone releasing hormone/arginine test was notable for undetectable growth hormone levels. A fasting serum cortisol was normal at 20 mcg/dl. Physical examination was remarkable for normal predicted height, mild gynecomastia, and deficient virilization with testicular atrophy.

The patient was started on a dopamine agonist, with normalization of his prolactin level within three months, and an increase in testosterone levels to the normal range. A repeat MRI scan showed a decrease in the size of the tumor and an MRI scan done approximately one year later showed a marked decrease in tumor size with reduction of the mass so that it was no longer impinging on the optic chiasm (Figure 2 bottom). Formal visual field tests were normal.

This patient demonstrates that men with macroprolactinomas may not present until the tumor has reached extensive size and is causing neurologic or other problems. The low testosterone level was associated with signs of hypogonadism. However, it was only the onset of severe headaches which prompted the patient to seek medical attention. In addition, the clinical improvement with dopamine agonist treatment is characteristic of the excellent response to primary medical therapy in the vast majority of such patients. The increase of testosterone into the normal range following normalization of prolactin demonstrates that the hypogonadism in this case was due to the effects of prolactin elevation rather than actual destruction of the gonadotropin-producing cells of the pituitary by the tumor.

Diagnosis

CLINICAL FEATURES

Table 1 includes the common symptoms of an elevated prolactin level in men. Presenting symptoms of a prolactinoma in men are typically dependent on the size of the lesion. In a retrospective review of 46 men with prolactinomas treated with medical therapy alone at MGH, 12 patients had microadenomas and 34 patients had macroadenomas. Patients who present with larger lesions may come to the attention of a physician because of significant headaches or visual loss. Seventy-four percent of patients with macroprolactinomas had a history of headaches. The prevalence of sexual dysfunction and testosterone deficiency was similar in both the macroprolactinoma and microprolactinoma group. The mean prolactin level at presentation in the microprolactinoma group was 99 ng/ml (normal <15 ng/ml) compared to macroadenomas where the median prolactin level was 1415 ng/ml. High prolactin may decrease pulsatile GnRH secretion by the hypothalamus, leading to a decrease in pituitary gonadotropin secretion and subsequent testicular dysfunction. This hypogonadotropic hypogonadism will result in low testosterone levels. Testosterone deficiency in men is associated with a number of complaints related to sexual dysfunction. Overall, in the cohort assessed at MGH, 93 percent of patients with macroadenomas had evidence of testosterone deficiency compared to 74 percent of patients with microadenomas.

Table 1. Clinical and biochemical characteristics at presentation in men with microprolactinomas and macroprolactinomas.� Reprinted from the Journal of Clinical Endocrinology and Metabolism with permission from the Endocrine Society (1).

SUBJECTS	STUDIES	CONTACT 617-726-3870�
Newly diagnosed Acromegaly patients	� Evaluating preoperative medical treatments	Dr. Laurence Katznelson
Steroid-treated patients with inflammatory bowel disease	� Determination of growth hormone administration on glucocorticoid myopathy	Dr. Laurence Katznelson
HIV positive women with weight loss or fat redistribution	� Evaluating testosterone therapy � Evaluation of bone loss	Dr. Steven Grinspoon
HIV positive men and women with fat redistribution	� Novel treatments to redistribute fat � Determination of growth hormone levels and efficacy of GH secretogogues � Novel dietary strategies	Dr. Steven Grinspoon Dr. Colleen Hadigan �
Women with anorexia nervosa	� New hormonal therapies	Dr. Anne Klibanski
Women with hypopituitarism, ages 18-50	� Testosterone replacement therapy study	Dr. Karen K. Miller
Adolescent girls with anorexia nervosa	� Evaluating bone density and the effects of estrogen replacement	Dr. Anne Klibanski Dr. Madhu Misra
Patients with hypopituitarism (panhypopituitary or partial hypopituitarism)	� GH deficiency/replacement studies	Dr. Beverly M.K. Biller Dr. Karen K. Miller
Female survivors of childhood cancer (ages 16-25)	� Evaluating bone density and effects of estrogen dose or bone density	Dr. Jean Mulder
Patients with acromegaly requiring medical therapy	� Evaluating two different medical therapies	Karen Szczesiul, R.N.

In addition, gynecomastia, breast tenderness, galactorrhea or infertility may occur. Macroadenomas may cause secondary thyroid, adrenal, or growth hormone deficiency. In adolescent boys, prolactinomas may be associated with a delay in puberty, headaches or visual loss and growth arrest, if anterior pituitary function is further compromised by a large tumor, leading to growth hormone deficiency.

Studies have suggested that the growth characteristics of prolactinomas in men may make these tumors more aggressive and therefore more likely to present as larger tumors. Delgrange et al. found that markers of cellular proliferation including Ki-67 and PCNA (proliferating cell nuclear antigen) are higher in prolactinomas from men versus women. Therefore, there may be other gender-related factors which can affect tumor growth rates. Similar gender specific findings have been reported in children with prolactinomas. Colao et al. reported 26 patients with prolactinomas ages 7 to 17 years old. She found that 8 of 9 (89 percent of boys) versus of 7 of 17 (14 percent of girls) had macroprolactinomas at the time of diagnosis. In addition, all seven pre-pubertal males with macroprolactinomas presented with headaches and/or visual symptoms.

Therapeutic Considerations

The overall management goals for men with prolactinomas are comparable to those in women. The goals of therapy are to: 1) alleviate any signs and symptoms of mass effect such as headache, visual loss, or other neurologic sequelae, 2) normalize anterior pituitary function, and/or peripheral hormone levels, 3) provide permanent control of both tumor mass and symptoms. Given the remarkable success of dopamine agonist therapy in treating prolactin-secreting pituitary tumors, medical therapy has become the mainstay of treatment for both micro- and macroprolactinomas. In general, surgery (typically transsphenoidal) is restricted to: 1) patients with pituitary apoplexy, because hemorrhage within the tumor may lead to the rapid development of neurologic sequelae requiring neurosurgical intervention, 2) patients who have persistent chiasmal compression with visual loss despite dopamine agonist therapy, 3) patients unresponsive to, or unable to tolerate dopamine agonist therapy, 4) patients who exhibit continued tumor growth despite medical therapy and, 5) patients who develop a cerebrospinal fluid leak during dopamine agonist treatment. These groups represent only a very small percent of patients with prolactinomas.

In the MGH series, we identified 46 men with prolactinomas who were treated solely with medical management. All patients received medical therapy with a dopamine agonist. The specific medications used included bromocriptine, cabergoline, pergolide, quinagolide, or a combination of therapies. In this series, 83 percent of men with microprolactinomas achieved normalization of prolactin levels compared with 79 percent of men with macroprolactinomas. Seventeen percent of patients with microadenomas showed no evidence of residual tumor and in macroprolactinomas, there was a reduction in tumor size to less than 1 cm in 15 percent of patients and no evidence of residual tumor in 19 percent of patients. No patient had evidence of an increase in tumor size during therapy. Therefore, primary medical therapy in men with micro- and macroprolactinomas is highly efficacious and recommended in the vast majority of patients. In patients with larger tumors, evaluation of anterior pituitary function typically indicates the need for hormone replacement therapy. In our series, no patient with a microadenoma required thyroid or glucocorticoid hormone replacement, whereas a subset of macroadenoma patients did require such therapy.

Dopamine agonist therapy should be titrated to clinical efficacy determined by the prolactin level, tumor size and tolerability. Cabergoline is usually the first choice because of its increased efficacy and better tolerability compared with other dopamine agonists. However, in the MGH series, we found that the responses to dopamine agonists were comparable. In the majority of patients with microadenomas, a typical dose of cabergoline is 0.5 to 1.0 mg/week. In patients with macroadenomas, doses may be much higher and patients may be titrated up to 3 to 5 mg/week. Although prolactin normalization is typically one goal, some patients can be treated with a dopamine agonist so that tumor mass is controlled. Prolactin levels may not become completely normal despite maximal doses of a dopamine agonist particularly in patients with large tumors. In such cases when the serum prolactin falls and reaches a plateau, continued increases of the dopamine agonist has not proven effective. The final therapeutic target is dependent on clinical response as well as patient tolerance to the medication.

Follow-up MRIs in patients with microprolactinomas are typically done first at 6 months and then yearly though there are no clinical studies which have evaluated scanning intervals. If stable, subsequent scans can be scheduled less frequently unless symptoms or a significant rise in prolactin prompt an earlier scan. In patients with macroprolactinomas who have visual loss, visual fields and/or scans should initially be followed every three to four weeks, depending on the severity of visual loss, following the initiation of medical therapy. If the chiasm is decompressed, but visual loss continues, optic nerve damage may have occurred prior to treatment. However, if chiasmal compression continues with visual loss despite maximal medical therapy, surgical intervention by a skilled pituitary neurosurgeon should be seriously considered. Although many tumors do show a decrease in tumor size, this may take many weeks, months, or even longer. If the tumor is not causing any neurologic symptoms, stabilization of tumor mass is typically a reasonable goal even though the scan may not normalize.

Reproductive Issues

Figure 2. Serum PRL levels at baseline and after dopamine agonist administration in men with microprolactinomas and macroprolactinomas. PRL levels are displayed as loge values. The shaded area represents the normal range for serum PRL levels (<15 ng/mL). Reprinted from the Journal of Clinical Endocrinology and Metabolism with permission from the Endocrine Society (1).

Reproductive dysfunction and androgen deficiency are important parts of the evaluation and therapeutic consideration in men with prolactinomas. Restoration of normal testosterone levels and testicular function is dependent upon normalization of prolactin as well as the integrity of the pituitary gonadotrophs. Hypogonadism in men with prolactinomas may be directly attributable to the effects of an elevated prolactin in suppressing pulsatile GnRH and gonadotropin secretion. In such a "functional hypogonadal" state, normalization of prolactin will lead to restoration of the hypothalamic-pituitary-testicular axis. Testosterone normalization and normal reproductive function can then be expected. However, if the mass is large and has caused compression of the gonadotrophs, prolactin normalization may not result in normal testosterone levels. Waiting several months after the prolactin has been controlled is advised before making a final determination as to whether a normal prolactin will result in normal gonadal function. If it does not, then testosterone replacement, assuming that there are no contraindications to testosterone therapy, is indicated. Options include gel, patch and intramuscular injection. When fertility is desired, exogenous gonadotropin therapy can directly stimulate both androgen production as well as spermatogenesis by the testes. In some men, continued sexual dysfunction has been reported in the presence of an elevated prolactin despite normal testosterone concentrations. In this situation, attempts should be made to normalize prolactin if at all possible, although limitations in terms of dopamine receptor number and function as well as medication tolerability must be considered.

Summary and Conclusions

The majority of men with prolactinomas are diagnosed with macroprolactinomas. This may be attributable to a delay in diagnosis as symptoms may not prompt medical evaluation until they are quite severe. This may be due to a lack of a clear clinical marker of prolactin excess in men, in contrast to the disruption of menses seen in women and may also suggest differences in underlying tumor characteristics in men. The initial treatment goals are to alleviate mass effect, normalize or treat underlying anterior pituitary deficiencies and provide chronic treatment of the mass effect and associated hormone abnormalities. The vast majority of patients with prolactinomas can be medically treated, including both macroprolactinomas as well as microprolactinomas. Dopamine agonist therapy is effective in controlling prolactin hypersecretion as well as reducing and/or stabilizing tumor mass. Transsphenoidal surgery is reserved for patients with acute neurologic events such as apoplexy or patients who are unresponsive to medical therapy. The overall outcome of men with prolactinomas treated with appropriate medical therapy for tumor control as well as hormone sequelae is excellent in the vast majority of cases. Physicians should promptly assess patients with symptoms suggestive of hyperprolactinemia and/or a pituitary tumor with appropriate hormone and radiologic studies.

References

1. Pinzone JJ, Katznelson L, Danila DC, et al. Primary medical therapy of micro- and macroprolactinomas in men. J Clin Endocrinol Metab. 2000; 85:3053-7.
2. De Rosa M, Colao A, Di Sarno A, et al. Cabergoline treatment rapidly improves gonadal function in hyperprolactinemic males: a comparison with bromocriptine. Euro J Endocrinol. 1998; 138:286-93.
3. Delgrange E, Trouillas J, Maiter D, et al. Sex-related differences in the growth of prolactinomas: a clinical and proliferation marker study. J Clin Endocrinol Metab. 1997; 82:2102-7.
Colao A, Loche S, Cappa M, et al. Prolactinomas in children and adolescents. Clinical presentation and long-term follow-up. J Clin Endocrinol Metab. 1998; 83:2777-80.

Frequently Asked Questions About Transsphenoidal Surgery For Cushing's Disease (ACTH Secreting Pituitary Tumors) - A Patient Guide

by Brooke Swearingen, M.D. and Beverly M.K. Biller, M.D.

1. What is Cushing's syndrome?

Cushing's syndrome refers to the physical and emotional difficulties caused by an elevated cortisol level. Features of excess cortisol include weight gain, especially centrally, fatigue, easy bruisability, excess hair growth (termed hirsutism), susceptibility to infection, depression, menstrual irregularities in women, decreased libido and erectile dysfunction in men, high blood pressure, diabetes, and weak and brittle bones (osteoporosis). Many of these are non-specific, meaning that people who have them usually do not have Cushing's syndrome. Most patients who do have Cushing's syndrome have some, but not all, of these features. There is a characteristic appearance in many patients who have excess cortisol which includes a round, reddened face, excess fat pad in the back of the neck ("buffalo hump"), excess fat in the collarbone area, central weight gain, primarily in the abdomen, with relative thinning of the arms and legs, and abdominal stretch marks. In the majority of cases, it can be cured, with improvement in all of these features.

2. What are the causes of Cushing's syndrome?

The normal production of cortisol involves three parts of the body. An area in the brain, called the hypothalamus, produces a hormone called corticotropin releasing hormone (CRH). This hormone travels via blood vessels to the pituitary gland, located just below the brain, and triggers release of adrenocorticotropic hormone
(ACTH). The ACTH travels through the bloodstream and when it reaches the adrenal glands, which lie above each kidney, cortisol is released. Cushing's syndrome can be caused in several ways. The most common cause is actually a side effect of the medical use of glucocorticoids (steroids) to treat many conditions. However, Cushing's syndrome can result from a tumor somewhere in the body which is overproducing either cortisol, or the hormone which triggers release of cortisol, ACTH. The most common tumor-related cause is a growth on the pituitary called a corticotroph adenoma. Cushing's disease refers specifically to the form of Cushing's syndrome which is due to a pituitary tumor. These are nearly always benign, and are typically small (<1 cm). The pituitary tumor makes too much ACTH, which causes the adrenal glands to overproduce cortisol. Other more rare causes of Cushing's syndrome can include excess production of cortisol by an adrenal tumor, or overproduction of ACTH by a tumor elsewhere in the body (termed ectopic Cushing's).

3. How is the diagnosis of Cushing's disease made?

The diagnosis is made through a comprehensive evaluation by an endocrinologist. This includes taking a detailed medical history, performing a physical examination, and obtaining laboratory and radiologic tests. These might include measurement of cortisol levels in the blood, urine, and/or saliva, blood ACTH levels, dexamethasone suppression testing and/or CRH stimulation testing. Imaging studies of the pituitary, such as head MRIs, will sometimes, but not always, show a pituitary tumor. Some tumors are so small (< 1mm) that they do not show up on scans. To confirm a pituitary source for the excess ACTH, a procedure known as an inferior petrosal sinus catheterization is sometimes performed. This is a procedure which should be performed at centers specializing in this technique. The petrosal sampling involves measuring ACTH levels in blood draining from the pituitary gland. Small catheters are threaded up through the large veins in the leg until they reach small veins near the pituitary. If the endocrine tests indicate a pituitary source for the excess ACTH, transsphenoidal surgery is recommended even if the MRI does not show a tumor.

4. How is Cushing's disease treated?

The best treatment is almost always transsphenoidal surgery performed by a surgeon with extensive experience in pituitary tumor removal.

5. How is this surgery performed?

Most pituitary tumors can be removed transsphenoidally. The approach is through the sphenoid sinus, one of the facial air spaces behind the nose. Rarely, a craniotomy might be required, where the skull is opened to reach the tumor. There are three basic approaches to the sella, which is the bony cavity in the skull base where the pituitary gland is located. Many neurosurgeons now use a direct transnasal approach, cutting through the back wall of the nose to enter the sphenoid sinus. It is also possible to make an incision (cut) along the front of the nasal septum, and make a tunnel back to the sphenoid sinus. Finally, sometimes an incision is made under the lip, then passing through the upper gum, and entering the nasal cavity and then the sphenoid sinus.

6. How does the surgeon see the tumor?

The opening through which transsphenoidal surgery is performed is very small, about ½ an inch. Therefore, it is not possible to look directly at the surgical area or tumor. However, with modern technology there are tools for visualizing the area of the tumor through the small hole. This is done by using a high-powered operating microscope, or a fiberoptic endoscope. The operating microscope allows binocular vision (seeing with both eyes at once, allowing depth perception) with extremely high quality optics. This is very important for tiny tumors, like those responsible for Cushing's disease. The endoscope provides a wider field of view, but usually with monocular images (only one image which is flat, without depth) as seen on a television screen. At the Massachusetts General Hospital, a direct transnasal approach is used, whether we use the microscope or the endoscope, or both. With the direct transnasal approach, the need for postoperative nasal packing (bandaging in the nose) is minimized, regardless of whether the microscope or endoscope is used.

7. How is the tumor removed?

The tumor is usually soft and can be removed with small surgical instruments called curettes. In order to remove a large tumor through a small hole, the tumor itself has to be cut into small pieces. As the surgeon cores out the center of tumor, the peripheral margin of the tumor has to fall into an area that can be reached by the surgeon. In Cushing's disease, the tumor is usually small, often too small to be seen on an MRI scan. The surgeon has to dissect through the gland, taking multiple biopsies, to look for the tumor. If found, the tumor is removed with a small margin of normal tissue, to try to remove all of the abnormal area, but to preserve as much normal pituitary gland function as possible. It is important that the neuropathologist examining the specimens intra-operatively be experienced in the diagnosis of pituitary tumors, in order to aid the surgeon during the procedure. The pathologist examines biopsies during the operation, and can confirm whether adenoma has been found. If the tumor has grown beyond the pituitary, into the cavernous sinus or dura, it cannot be completely removed; and additional treatment (radiation, adrenalectomy or medication) will be required to achieve normal cortisol levels.

8. How should I choose a surgeon for my pituitary operation?

It has been shown that the success of surgery is dependent on the amount of experience the surgeon has at performing pituitary operations. Surgeons with the most experience generally have the highest rates of cure, meaning complete tumor removal. In addition, the rate of complications is lowest among experienced pituitary surgeons. Surgeons at major pituitary centers, such as the Massachusetts General Hospital Neuroendocrine Clinical Center, operate on patients with pituitary tumors every week.

9. What are the risks of the surgery?

The most common risk is damage to the normal pituitary gland. For macroadenomas (>1cm) this happens between 5-10% of the time when the operation is performed by an expert pituitary surgeon. In Cushing's disease, where extensive dissection of the pituitary gland may be required to find a tiny tumor, hormone insufficiency may be caused in about 20% of cases. This means that new hormone replacement might be required after the surgery, possibly including thyroid hormone, cortisol, growth hormone, estrogen or testosterone. Damage to the posterior, or back portion, of the pituitary gland may produce a condition know as diabetes insipidus, which will lead to frequent urination and excessive thirst, since the kidneys will no longer adequately concentrate the urine. This can be controlled with a nasal spray or pill form of a medication called DDAVP. Permanent diabetes insipidus, meaning a need to take this medication long-term, occurs only 1-2% of the time after pituitary surgery.

10. Are there other more serious complications?

Yes, but they are very rare. There is a very small chance of damaging the carotid arteries which are located on either side of the pituitary. This is a potentially devastating complication which could lead to stroke or death. It occurs very infrequently, when the operation is performed by an expert pituitary surgeon, with an incidence of less than 1/1000 cases. There could also be post-operative bleeding into any residual tumor or into the sella, which could lead to worsening pressure on the optic nerves or chiasm and possible visual loss. This is also a very rare complication, but might require re-operation to remove the blood clot. A spinal fluid leak sometimes occurs because pituitary tumors are separated from the spinal fluid which bathes the brain by a very thin membrane. In order to prevent a spinal fluid leak, the tumor bed is packed with a small piece of abdominal fat taken from a tiny incision made in the abdominal skin. Despite this, spinal fluid leaks occur with an incidence of about 1%. If this happens, there is a risk of infection, called meningitis. If a spinal fluid leak occurs it may require a second operation to patch the leak and treatment with antibiotics. The risk of all complications is higher with less experienced surgeons.

11. How long does the operation take?

The procedure itself usually takes about three hours. Patients go to the recovery room for two to three hours after the surgery and are then admitted to the hospital floor. There is no need to stay in an Intensive Care Unit. Most patients are discharged from the hospital in just one or two days.

12. How will I feel after the surgery?

You will have a sinus headache and nasal congestion. This will gradually improve over a few weeks. You can take decongestants which will help these symptoms. It is common for patients undergoing transsphenoidal surgery to feel fatigued for two to three weeks after the surgery and this gradually improves. Patients with Cushing's disease often have a prolonged recovery from surgery as they are recovering from the effects of their disease, beyond just recovering from the surgery itself. If you are cured of your Cushing's disease, your postoperative cortisol levels will be quite low, and you will have the opposite problem from Cushing's syndrome, termed hypoadrenalism. This means that the body is not producing enough cortisol. This may cause symptoms such as fatigue, poor appetite, weight loss, headache, nausea, low energy, and weakness. Sometimes the skin peels, such as after a sunburn. You will actually require cortisol replacement, in the form of pills taken once or twice daily, until your own pituitary gland recovers. The endocrinologist managing your hormone replacement must walk a fine line between giving you too much cortisol replacement, which would prolong the effects of excess cortisol, versus giving you too little cortisol, which would make you feel unwell. Typically, the cortisol medication is started at a higher dose than the body would normally make, to minimize "steroid withdrawal" symptoms. Gradually, based on evaluations of the patient to assess recovery, the dose is reduced to replacement levels. Testing is performed to determine whether the pituitary-adrenal system is recovering. In the majority of patients, the system recovers 6 to 18 months after the surgical removal of the pituitary tumor. The cortisol replacement pills can then be stopped.

13. How long will I be out of work?

Most patients recover from the surgery in two to three weeks. Some people return to work sooner than that. As noted above, however, patients with Cushing's disease can have a prolonged period of recovery, so some patients are out of work longer.

14. How will we know if the entire tumor has been removed?

The endocrinologist will test your hormone levels after the surgery, including serum and urine cortisol levels. If you are cured, these levels should be very low and you will need to take a pill to replace cortisol until your own system recovers as noted above. Usually it is possible to determine if you are cured within one to two weeks of the surgery.

15. What is the chance of being cured?

The overall cure rate for Cushing's disease is between 80-90% when the operation is performed by an experienced pituitary surgeon.

16. What if I am not cured?

If residual tumor remains in an accessible location, your surgeon may recommend a second operation. Second operations carry a higher risk of damage to the normal pituitary gland and you have a higher likelihood of requiring long-term hormone replacement. If no further tumor can be removed, you may be referred for radiation therapy. This treatment is planned by a radiation oncologist. Single fraction radiosurgery (a single dose, given on one day) is effective in curing Cushing's disease in many cases and comes in several forms, including proton beam, gamma knife and LINAC. It may take one or more years before the radiation is effective. In the meantime, drugs to suppress cortisol secretion by the adrenal glands are used to control the effects of excess cortisol, while waiting for the radiation to become effective. In some cases, removal of both adrenal glands, termed bilateral adrenalectomy, may be advised. This does not treat the tumor directly, so your doctor will need to watch carefully for growth of the tumor with periodic head scans and ACTH levels.

17. Who will take care of me in the hospital and afterward?

At a major pituitary center, such as the Neuroendocrine Clinical Center at Massachusetts General Hospital, you will be managed by a team of physicians. This includes your neurosurgeon, a staff neuroendocrinologist and the residents, fellows and nurses who work with them. The team will follow you until you are returned to the care of your local endocrinologist and primary care physician. Endocrine follow-up is very important, to determine whether replacement of any of the hormones controlled by the pituitary (cortisol, thyroxine, estrogen/testosterone, growth hormone or vasopressin) is needed, as well as to adjust cortisol replacement until it is no longer needed.

18.What is the chance of the Cushing's disease coming back?

The chance of recurrence is small: only 5-10%. You should see an endocrinologist on a regular basis and more frequently if you have any concerns that the Cushing's disease might be returning.

19. What will improve if I am cured?

Virtually all of the physical and emotional problems associated with Cushing's disease resolve in the 1-2 years after cure in most patients.

Bone Loss in Women of Reproductive Age - - Part II.

by Karen K. Miller, M.D.

Table 1. Causes of Bone Loss in Women of Reproductive Age: Medication Use

I. Immunosuppressants
A. Chronic glucocorticoid therapy
B. Cyclosporine A

II. Anti-convulsants
A. Phenytoin
B. Carbamazepine

III. Heparin

IV. Medications that induce hypogonadism
A. GnRH agonists
B. Depot medroxyprogesterone acetate

Although bone loss is most prevalent in post-menopausal women, a subset of young women are also at high risk. Women with estrogen deficiency and chronic systemic illness and those taking medications that result in bone loss are most vulnerable (Tables 1 and 2). Part I of this article reviewed causes of bone loss associated with estrogen deficiency in women of reproductive age (Neuroendocrine Center Bulletin, Fall/Winter 2002, Volume 8, Issue 1). This article, Part II, will focus on bone loss secondary to medication use and systemic disease. Health implications of bone loss in young women include increased fracture risk in the short-term and later in life.

Medication Use

Chronic glucocorticoid therapy is associated with severe and rapid bone loss. The incidence of atraumatic fractures in patients who receive supraphysiologic glucocorticoid therapy is 30 to 50 percent 1,2. Even chronic use of inhaled steroids for asthma may result in bone loss, particularly at high doses 3. Although alternate day steroid regimens may preserve adrenal function, they do not appear to protect against bone loss 4. The addition of cyclosporine A to glucocorticoid regimens increases the risk of bone loss in transplant patients. In one report, the combination resulted in a 44 percent fracture rate in less than three years 5. Other medications resulting in bone loss include anti-convulsants, which exert deleterious effects on both vitamin D metabolism and bone turnover 6,7. Heparin has been shown to reduce bone density even in pregnant women, in whom high serum estrogen levels might be expected to protect against bone loss 8. Supraphysiologic doses of levothyroxine (i.e. those used for the treatment of thyroid tumors and resulting in suppression of TSH) reduce bone density in post-menopausal women not taking estrogen. However, eumenorrhea appears to protect against bone loss from this
cause 9.

Systemic Illness

Table 2. Causes of Bone Loss in Women of Reproductive Age: Systemic Disease

I. Endocrine disorders
A. Cushing's syndrome
B. Hyperparathyroidism
C. Growth hormone deficiency
D. Estrogen deficiency (see Part I of this article)

II. Gastrointestinal diseases
A. Celiac sprue
B. Inflammatory bowel disease
C. Cystic fibrosis
D. Chronic liver disease

As with glucocorticoid administration, endogenous glucocorticoid excess due to Cushing's disease causes severe bone loss. Osteopenia, however, can reverse completely after cure of Cushing's. Hyperparathyroidism is another well-known cause of bone loss 10,11. As with Cushing's disease, surgical cure results in improvement of bone density, with an 8 to 12 percent increase in bone mass observed during the first 2 to 4 years following curative surgery 12. Both childhood and adult-onset growth hormone deficiency are associated with reductions in bone density 13. Gastrointestinal diseases associated with bone loss include chronic liver disease 14, celiac sprue, cystic fibrosis, and inflammatory bowel disease. Although malabsorption, with resultant vitamin D deficiency and secondary hyperparathyroidism 15, is a contributing factor to bone loss in bowel luminal disease, repletion of vitamin D to normal serum levels is not always sufficient to restore skeletal health, because calcium malabsorption may persist. Osteopenia is attributable to glucocorticoid therapy in many patients with inflammatory bowel disease. However, inflammatory bowel disease appears to cause osteoporosis even in the absence of such
therapy 16, with a 40% increase in fracture rate reported in one study 17. However, the high prevalence of glucocorticoid use contributes to the bone loss in many of the patients and confounds many of the studies investigating the effects of inflammatory bowel disease on bone density.

Diagnosis

Although bone density testing is not recommended routinely for pre-menopausal women, it is indicated in such women at risk for bone loss. Annual follow-up scans to determine the trend in bone density over time and the effectiveness of therapy are important, even in women with normal bone densities at baseline. Measurement of AP lumbar spine bone density is usually the most useful site, because the spine is composed primarily of trabecular bone, which is most often affected by metabolic disease. In addition, spinal bone density measurements have the greatest precision. Therefore, changes in bone density over time can be detected earlier at this site. However, radial bone density should be measured in women with hyperparathyroidism, which causes cortical, more than trabecular, bone loss. It should be noted that trabecular bone loss also commonly occurs in women with hyperparathyroidism. Therefore, spine bone density should also be measured in this population.

Therapy

In patients with Cushing's syndrome and hyperparathyroidism, substantial, even full, recovery of bone mass can occur within a few years of successful treatment of the underlying disease.
Similarly, some studies have demonstrated improvements in bone mineral density after treatment of celiac sprue with institution of a gluten-free diet 18. Bisphosphonates have been shown to be effective in glucocorticoid-induced osteoporosis and are FDA-approved for women of reproductive age for this indication only. In many centers, bisphosphonates are given prophylactically to patients who will be undergoing organ transplantation to prevent rapid, early and severe bone loss due to immunosuppressant treatment. Bisphosphonates should be used with caution in women of reproductive age and only in those with severe bone loss. It is not known whether they are safe in pregnancy or during lactation. Intermittent PTH administration has recently been FDA-approved to treat postmenopausal osteoporosis and is not approved for use in young women. It should not be used in such patients until concerns regarding rodent data demonstrating development of osteosarcomas with high dose therapy, are satisfactorily resolved.

Conclusion

Measurement of bone density is indicated in young women at risk for bone loss secondary to medication use or systemic disease. A number of medications cause bone loss in women of reproductive age, including supraphysiologic glucocorticoid therapy, anti-convulsants, heparin and cyclosporine A. Cushing's syndrome, hyperparathyroidism, chronic liver disease, celiac sprue, inflammatory bowel disease and growth hormone deficiency are also associated with bone loss in this population. Osteopenia in women of reproductive age is associated with an increased fracture risk in many of these populations. Moreover, women who experience bone loss during their reproductive years enter menopause with reduced bone density. Therefore, bone density testing in women of reproductive age at risk for bone loss is important, and early intervention, when safe and effective therapies are available, is critical.

References

1. Adinoff A, Hollister J. Steroid-induced fractured and bone loss in patients with asthma. N Engl J Med 1983; 309:265-8.
2. Lukert B, Raisz L. Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med 1990 Mar; 112:352-64.
3. Hanania N, Chapman K, Sturtridge W, Szalai J, Kesten S. Dose-related decrease in bone density among asthmatic patients treated with inhaled corticosteroids. J Allergy Clin Immunol 1995; 96:571-9.
4. Gluck O, Murphy W, Hahn T, Hahn B. Bone loss in adults receiving alternate day glucocorticoid therapy. A comparison with daily therapy. Arthritis Rheum 1981; 24:892-8.
5. Rich G, Mudge G, Laffel G, LeBoff M. Cyclosporine A and prednisone-associated osteoporosis in heart transplant recipients. J Heart Lung Transplant 1992; 11:950-8.
6. Dent C, Richens A, Rowe D, Stamp T. Osteomalacia with long-term anticonvulsant therapy in epilepsy. 1970 4:69-72.
7. Valimaki M, Tiihonen M, Laitinen K, et al. Bone mineral density measured by dual-energy x-ray absorptiometry and novel markers of bone formation and resorption in patients on anti-epileptic drugs. J Bone Miner Res 1994 9:631-637.
8. Dahlman T. Osteoporotic fractures and the recurrence of thromboembolism during pregnancy and the puerperium in 184 women undergoing thromboprophylaxis with heparin. Am J Obstet Gynecol 168:1265-1270.
9. Faber J, Galloe A. Changes in bone mass during prolonged subclinical hyperthyroidism due to L-thyroxine treatment: a meta-analysis. Eur J Endocrinol 1994 130:350-356.
10. Manning P, Evans M, Reid I. Normal bone mineral density following cure of Cushing's syndrome. Clin Endocrinol 1992; 36:229-34.
11. Hermus A, Smals A, Swinkels L, et al. Bone mineral density and bone turnover before and after surgical cure of Cushing's syndrome. J Clin Endocrin Metab 1995; 80:2859-65.
12. Silverberg S, Gartenberg F, Jacobs T, et al. Increased bone density after parathyroidectomy in primary hyperparathyroidism. J Clin Endocrinol Metab 1995; 80:729-734.
13. Bing-You R, Denis M, Rosen C. Low bone mineral density in adults with previous hypothalamic-pituitary tumors: correlations with serum growth hormone responses to GH-releasing hormone, insulin-like growth factor I, and IGF binding protein 3. Calcif Tissue Int 1993 52:183-187.
14. Ninkovic M, Love SA, Tom B, Alexander GJ, Compston JE. High prevalence of osteoporosis in patients with chronic liver disease prior to liver transplantation. Calcif Tissue Int 2001 69(6):321-326.
15. Selby P, Davies M, Adams J, Mawer E. Bone loss in celiac disease is related to secondary hyperparathyroidism. J Bone Miner Res 1999 14:652.
16. Bjarnason I, Macpherson A, Mackintosh C, Buxton-Thomas M, Forgacs I, Moniz Z. Reduced bone density in patients with inflammatory bowel disease. Gut 1997 40:228.
17. Bernstein C, Blanchard J, Leslie W, Wajda A, Yu B. The incidence of fracture among patients with inflammatory bowel disease. Ann Intern Med 2000 133:795
18. Kemppainen T, Kroger H, Janatuinen E, et al. Bone recovery after a gluten-free diet: a 5-year follow-up study. Bone 1999 25:355.

* Neuroendocrine Clinical Center - New Location *

The Neuroendocrine Clinical Center has recently moved to a new location within Massachusetts General Hospital. The new location is Zero Emerson Place, Suite 112. To schedule an appointment, please call 617-726-7948.

SUPPORTING OUR PROGRAM

Tax deductible contributions can made to the Neuroendocrine Clinical Center to support educational endeavors and clinical research activities. Please contact Ruth Nally at 617-726-3897 for further information.

RESEARCH STUDIES AVAILABLE

Your patients may qualify for research studies in the Neuroendocrine Clinical Center. We are currently accepting the following categories of patients for screening to determine study eligibility. Depending on the study, subjects may receive free testing, medication and/or stipends.

SUBJECTS	STUDIES	CONTACT� 617-726-3870
Newly diagnosed Acromegaly patients	� Evaluating preoperative medical treatments	Dr. Laurence Katznelson
Steroid-treated patients with inflammatory bowel disease	� Determination of growth hormone administration on glucocorticoid myopathy	Dr. Laurence Katznelson
Elderly men with testosterone deficiency	� Evaluating a new form of testosterone replacement	Dr. Laurence Katznelson
HIV positive women with weight loss or fat redistribution	� Evaluating testosterone therapy � Evaluation of bone loss	Dr. Steven Grinspoon
HIV positive men and women with fat redistribution	� Novel treatments to redistribute fat � Determination of growth hormone levels and efficacy of GH secretogogues � Novel dietary strategies	Dr. Steven Grinspoon Dr. Colleen Hadigan �
Women with anorexia nervosa	� New hormonal therapies	Dr. Anne Klibanski
Women with hypopituitarism, ages 18-50	� Testosterone replacement therapy study	Dr. Karen K. Miller
Adolescent girls with anorexia nervosa	� Evaluating bone density and the effects of estrogen replacement	Dr. Anne Klibanski Dr. Madhu Misra
Patients with hypopituitarism (panhypopituitary or partial hypopituitarism)	� GH deficiency/replacement studies	Dr. Beverly M.K. Biller Dr. Karen K. Miller
Female survivors of childhood cancer (ages 16-25)	� Evaluating bone density and effects of estrogen dose or bone density	Dr. Jean Mulder

* PULLOUT FEATURE - PATIENT GUIDE *

The Neuroendocrine Clinical Center includes a patient education feature from time to time in this Bulletin. These consist of a separate pullout section which can be reproduced and handed out to patients who have questions about the topic being addressed. This issue includes "Frequently Asked Questions About Transsphenoidal Surgery For Cushing's Disease (ACTH Secreting Pituitary Tumors: A Patient Guide". Authored by Brooke Swearingen, M.D., the renowned expert pituitary surgeon at Massachusetts General Hospital, and endocrinologist Beverly M.K. Biller, M.D., it answers the 19 most commonly asked questions by patients requiring transsphenoidal surgery for Cushing's disease.

DONATIONS
Tax deductible contributions can made to the Neuroendocrine Clinical Center to support educational endeavors and clinical research activities. Please contact Ruth Nally at 617-726-3897 for further information.

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