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Cushing disease is caused by pituitary tumors that produce excessive amounts of the pituitary hormone ACTH, leading to excessive synthesis of glucocorticoids by the adrenal glands. Many symptoms of Cushing disease result from these high levels of glucocorticoids and they include fat accumulation, high blood pressure and predisposition to diabetes and osteoporosis. Normally when blood glucocorticoids are elevated, they exert a negative feedback effect on the production of pituitary ACTH, thus closing a regulatory loop that keeps both ACTH and glucocorticoid levels in balance. The hallmark of the pituitary corticotroph adenomas that cause Cushing disease is that these tumor cells are no longer sensitive to the feedback action of glucocorticoids. This hormone resistance is likely the first event in the formation of the pituitary tumors. A Montréal research group led by Dr. Jacques Drouin and including collaborators in Canada, France, the Netherlands and United States has just discovered essential components of the molecular mechanism for glucocorticoid feedback control of pituitary ACTH gene expression. Indeed, the Montréal group discovered a large complex made of several proteins that are essential for negative feedback by glucocorticoids; this complex includes proteins that are known for their role in the control of gene expression and remodeling of chromosome (chromatin) structure. One of these essential proteins, BRG1, is also known to be a tumor suppressor. Consistent with the essential functions of these proteins in negative feedback by glucocorticoids, the researchers found that either of these proteins is no longer correctly expressed in about half of pituitary tumors from Cushing disease patients (both adult and pediatric) as well as from dogs with Cushing disease (for unknown reasons, this condition is more frequent in dogs than humans), thus providing a molecular explanation for the hormone resistance that characterizes theses tumors.

This work brings the first molecular insight into the mechanisms of Cushing disease. Beyond explaining hormone resistance, it also identified genes that likely initiate the process of tumor formation. This novel insight will lead to the rationale design of new therapeutic approaches for the more efficient management of patients with Cushing disease.
This work is published in the 15 October issue of Genes and Development (Bilodeau et al, Genes Dev 2006, 20:2871-2886) and it was supported by grants from the National Cancer Institute of Canada and from the Canadian Institutes of Health Research.

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What is Subclinical Cushing's Syndrome?
Cortisol has multiple target organs as illustrated in clinical practice by the spectrum of symptoms associated with chronic cortisol excess as observed in long-standing, overt Cushing's syndrome. The focus of this article is not on overt Cushing's, but rather on "subclinical" Cushing's syndrome (SCS). This could be considered an ambiguity, as why would a physician look for a silent entity that has no detectable impact on a patient's health? Today, SCS refers to autonomous cortisol production that is insufficient to generate the typical, clinically recognizable overt syndrome. However, based on studies published in the medical literature, SCS could be involved in the pathogenesis (development) of non-specific pathologies such as obesity, diabetes, and hypertension.

What populations are most likely to have subclinical Cushing's syndrome?
One might look for SCS in two main patient populations with the expectation that making this diagnosis would lead to a beneficial therapeutic intervention: 1) patients with an incidentally discovered tumor that may inappropriately secrete cortisol (adrenal gland) or ACTH (pituitary gland). Usually these lesions are called incidentalomas. 2) patients that display non-specific pathologies that may be secondary to hypercortisolism such as obesity, diabetes, hypertension, osteoporosis etc..

Subclinical" Cushing's syndrome and adrenal incidentalomas
The first report (Baierwaltes, et al.) of what we may call subclinical cortisol secreting adenomas (SCSA) described 2 patients with no clinical evidence of overt Cushing's that harboured a unilateral adrenal adenoma that showed exclusive uptake during noriodocholesterol scintigraphy (the other adrenal gland was no longer visible, implying decreased function). This suggested that the adrenal tumor produced a slight excess of cortisol that decreased the HPA activity through negative feedback. In vivo demonstration of excessive cortisol production by the tumor responsible for this scintigraphic pattern, came from: 1) catheterization studies that showed a larger cortisol output in the adrenal vein from the tumor side with suppression of the other adrenal gland, and 2) the report of scintigraphic reappearance of the other adrenal gland after ACTH infusion or several months after removal of the tumor.

How frequent are SCSA among adrenal incidentalomas ?
To date the true prevalence is unknown since different criteria have been adopted for the definition of SCSA. For example, in a study that we published in 2001, 41% of incidentalomas matched the historical scintigraphic criteria of unilateral uptake. Using a 60 nmol/L (2.16 ug/dL) threshold for impaired cortisol suppression after low doses of dexamethasone Tsagarakis et al identified 31% as being SCSA. The prevalence decreases to 12% in a German study that used a higher cortisol threshold and a modified Dexamethasone Test. The prevalence falls to around 10% in studies by Italian groups who required at least two abnormal routine tests of the HPA axis with a necessary condition of impaired dex suppression. These studies clearly indicate that no single alteration allows the diagnosis of SCSA.

Are current tests adequate to diagnose SCSA ?
The current biological tests used to diagnose overt Cushing's may be inadapted to patients with subtle hypercortisolism. For example, 24h UFC, has a very low sensitivity in this situation and is elevated in less than 15% of cases. Using a cut off of 140 nmol/L (5ug/dL), 75% of cases suppress with overnight 1 mg dex test. Another frequent problem is the interpretation of HPA axis tests when there are not in agreement with each other. Thus the biological testing for SCS seems to be more complex than that of overt Cushing's. Indeed there is a spectrum of biological activity between tumors that ranges from the non-functioning adenoma to the evident cortisol secreting tumor. Since cortisol output and autonomy is continuously distributed between these two extremes, it is probably pertinent, from a biological point of view, to consider the diagnosis of SCSA as, possible, probable or definitive according to the number and type of biochemical abnormality.

Variable or cyclic hormonogenesis is a classical feature of overt Cushing's that complicates biological diagnosis and could be an even larger problem in diagnosis of mild hypercortisolism. In a recently published Italian prospective follow-up study of adrenal incidentalomas, the authors pointed out that 28 alterations of the HPA axis observed in 23 patients at initial diagnosis were not confirmed during follow up and that only 4 alterations in 3 patients were permanent. We have similar study results that confirm these findings: biological variations of the HPA axis occur not only between patients but also frequently within patients with incidentalomas. 51 consecutive patients from 4 cities in the west of France, with unilateral adenomas characterized by CT and iodocholesterol scintigraphy, were enrolled and followed at yearly intervals for a mean duration of 4 years. In this series, 35% have possible SCSA at baseline and subtle hypercortisolism is confirmed at each follow-up evaluation. 18% of patients classified initially has having non-secreting adenomas display an evolution towards the disease that is confirmed in subsequent evaluations, while up to 20% of patients fluctuate over time between the two conditions (having SCSA or having a non-secreting adenoma). Thus, one take-home lesson could be "take great care in the interpretation of a single set of biological investigations and sample twice before diagnosing biochemical evolution".

Clearly there is no easy way to diagnose SCSA but we need a simple and reliable test useful for screening purposes in order to select individuals for complementary investigations. Ideally this test will have a high negative predictive value when normal. In 2003 the NIH consensus panel on the management of Adrenal Incidentalomas recommended to look for impaired suppression to 1 mg Dex for this purpose. However, there was no real consensus about the definition of adequate cortisol suppression. Some experts recommended the use of the traditional 140 nmol/L (5ug/dL) threshold for post dex cortisol while others proposed further testing of individuals with serum cortisol values between 50 and 140 nmol/L (1.8-5ug/dL) to increase the detection of subclinical hypercortisolism. Several arguments are in favour of using a low threshold. Indeed, many groups have shown that using modern immunoassays, cortisol levels are low following a 1 mg overnight dex suppression test. In our study of a cohort of 70 hospitalized obese subjects, post dex cortisol levels were below the limit of detection of the assay in more than 50% of cases and below 50 nmol/L (1.8ug/dL) in 94% of cases. Also, in a previous study, we found excellent correlation between the 1 mg overnight dex test and presumably more robust 4mg IV test. Thus, assuming that patients are not in acute stressful conditions and do not take drugs known to interfere with dex metabolism, we recommend the use of the 50 nmol/L threshold to screen for SCSA in order to improve the sensitivity of the screening (e.g. to identify all putative cases). Since this threshold might generate up to 15 % of false positives, further testing of patients with a cortisol measurement greater that 50nmol/L is mandatory.

Why should subtle hypercortisolism be diagnosed?
Is there evidence that these biochemical abnormalities significantly affect patient's health? What has been most studied to date are the metabolic consequences of subtle hypercortisolism. Numerous studies have shown that cortisol increases hepatic gluconeogenesis, opposes the action of insulin resulting in insulin resistance, promotes hypertension and abdominal fat distribution. Altogether these actions result in the full spectrum of metabolic X syndrome in overt Cushing's and its resultant increase in cardiovascular mortality and morbidity. A number of studies have shown a remarkably high prevalence of obesity, hypertension and impaired glucose metabolism among patients with adrenal incidentalomas. Similar findings were observed in studies dealing more specifically with SCSA. Interestingly, the prevalence of diabetes and hypertension was greater in patients with SCSA than in patients with putatively non-secreting incidentalomas. A study published by Terzolo et al compared non-obese patients with SCSA to patients with non-secreting tumors with equivalent BMI (body mass index). SCSA was associated with increased glycemia 2h after a Glucose Tolerance Test, increased triglyceride levels and a reduced index of insulin sensitivity. Although there was probably important variability among patients, this study suggests that subtle hypercortisolism is specifically associated with an adverse metabolic profile. Such findings were confirmed in another study that also documented the impact of biochemical abnormalities on the vascular system. Compared to controls matched for age and BMI, SCSA patients had accelerated atherosclerosis and frequent impaired cardiac function.

The ultimate justification in looking for subclinical Cushing's will be the demonstration that removal of the tumor reverses end-organ complications. While we are far from that point, a few preliminary studies, involving a limited number of patients, suggest that adrenalectomy reduces the cardiovascular risk. It is also interesting to note that parameters such as insulin sensitivity and blood pressure were also improved after surgery in some patients diagnosed as having non-secreting tumors. Such findings illustrate the lack of close correlation at the individual level between biochemical tests of subtle hypercortisolism and end-organ complications.

Subclinical Cushing's syndrome and pituitary incidentalomas
Very little data is available for the frequency of autonomous ACTH hypersecretion among pituitary incidentalomas. In tests performed at autopsy, the prevalence of ACTH immunostaining among pituitary adenomas is at most 8%. As presented later in this article, Cushing's disease is found in approximately 1.5% of patients with metabolic syndrome X. Thus, to date it is probably wise to screen for subclinical Cushing's in this situation when patients present with features of metabolic syndrome.

Conclusions
In conclusion of the first part of this article, what we clearly need from now on is: 1) to identify variables that correlate with end-organ complications and that may be usable at the individual level. Due to the huge variability in the tissular impact of hypercortisolism, this might be a holy grail! 2) to demonstrate using control studies the short and long-term benefit of surgery in SCSA, however the design of such studies is complicated. 3) To set strategies of monitoring for patients who are not operated on. In light of present knowledge, it is probably wise not only to focus on tumor size and endocrine biology but also to keep an eye on metabolic parameters and the cardiovascular system of patients.

Looking for subclinical Cushing's in other patient populations
To date, the most studied patient population evaluated for SCS, is the diabetic population. Several studies have reported that a significant portion of type 2 diabetics, actually have SCS. Several years ago, we conducted a prospective study in 200 overweight type-2 diabetic patients consecutively referred to our unit for poor metabolic control. None of the patients had overt CS after careful clinical examination. A first screening step was performed with the 1-mg overnight dex test using a low threshold for cortisol suppression to maximize the sensitivity of the procedure. Fifty-two patients had impaired cortisol suppression. Among these, 47 had further evaluation of the HPA axis. Thirty patients (i.e. 15% of the whole series) had normal investigations and were considered as false positives of the 1-mg DST. On the contrary, 17 displayed at least one additional abnormal test. Finally 14 of these underwent a third step of imaging investigations that allowed identification of pituitary dependent Cushing's disease in three patients, a unilateral adrenal tumor showing prevalent or unilateral uptake at iodocholesterol scintigraphy in 8 patients, while no tumor was found in 3 patients. Overall and considering only patients with obvious tumors, we found a 5.5% prevalence of subclinical Cushings.

Given the presumed rarity of Cushing's, we were surprised by these findings and wondered if this was an epidemic limited to the Bordeaux area of France. However, a recent Italian publication (Chiodini, et al.) replicated and improved our study and the higher than anticipated prevalence is not limited to France. The Italian authors studied not only diabetics patients (P) but also control subjects (C) matched for age and BMI (thus most of the controls were obese but did not have type 2 diabetes). Using the same screening strategy as our study, 17% of P had on two occasions impaired 1 mg dex suppression. During the second step of detailed biological investigations, 35 P (12%) and 4 C (2%) had additional markers of impaired HPA axis function and underwent imaging studies. Finally, an adrenal mass was found in 21 P and 3 C, a pituitary microadenoma in 4 P and 1 C, a pulmonary mass in 2 P. Again, no tumor was found in 3 patients. Overall, an impressive prevalence of SCS was found in this study; 9% of P and 2% of C. Since a minority of patients underwent surgery, definitive diagnosis of cortisol or ACTH secretion by tumors is lacking so that the true prevalence of SCC remains to be more precisely determined. However, these studies clearly suggest that type 2 diabetics probably represent a high-risk patient population for SCS. Also, given that the BMI matched controls showed an increased prevalence of 2% compared to the generally accepted incidence of overt Cushing's, perhaps appropriate testing of the obese population should be considered.

The last important point I want to mention is the serious lack of controlled interventional studies to prove the causality of SCS on impaired glucose metabolism e.g. the reversal of metabolic abnormalities after cure of SCS.

Conclusions
In conclusion, we definitely need studies in putative high-risk patients for SCS such as women with PCOS and young patients with osteoporosis. An Italian study presented at the recent Endo 2006 meeting presented data that indicated an elevated prevalence of subclinical Cushing's in a study among osteoporotic patients. Finally interventional studies are urgently needed to confirm the suspected causal links between diabetes and the adrenal tumors found in diabetic patients. Such studies may provide a rationale for a systematic screening of SCS in selected groups of patients.

Editor's Note: Dr. Antoine Tabarin is head of the Endocrinology Department at University Hospital, Bordeaux, France and teaches endocrinology at Bordeaux 2 University. Dr Tabarin is also adjunct associate professor in the department of Neuropharmacology at Scripps Research Institute (La Jolla, CA). Dr. Tabarin has treated Cushing's patients for over 20 years and has published extensively in the area. Dr. Tabarin can be reached at antoine.tabarin@chu-bordeaux.fr

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Since its description in 1992, laparoscopic adrenalectomy has rapidly become the procedure of choice for unilateral adrenalectomy when the adrenal mass is less than 8 cm in size and there are no frank signs of malignancy (eg. invasion of contiguous structures). The postoperative recovery time and long-term morbidity associated with laparoscopic adrenalectomy are significantly reduced when compared to open adrenalectomy.

Among 2550 laparoscopic adrenalectomy procedures reported in the literature, the most frequent adrenal disorder operated laparoscopically was aldosterone-producing adenoma (36.2%) followed by cortisol-producing cortical adenoma (19.1%), apparent nonfunctioning cortical adenoma (18.2%), and pheochromocytoma (18.0%). However, patients with adrenocorticotropin (ACTH) dependent Cushing's syndrome who have experienced failed attempts to remove the ACTH-secreting tumor (pituitary or ectopic) are also ideal candidates for one-stage bilateral laparoscopic adrenalectomy. The types of Cushing's syndrome that can be treated with laparoscopic unilateral or bilateral adrenalectomy are summarized in Table 1.

Advantages of the Laparoscopic Approach
Conventional open adrenalectomy via the anterior or posterior approach requires a large incision to gain access to a relatively small gland. Moreover, the incision used for posterior adrenalectomy, with its associated 12th rib resection and subcostal (T12) nerve retraction, has been associated with various incisional and musculoskeletal problems that may persist long after the operation. These incisional problems, including flank pain, bothersome numbness and loss of muscle tone, are especially pronounced and severe in patients with Cushing's syndrome because of poor wound healing, laxity of the abdominal wall, obesity, and musculoskeletal complaints associated with the condition.

Laparoscopic adrenalectomy involves making 1 cm incisions through which the laparoscope and tiny operating instruments are inserted. Several different surgical approaches are used, but the most common is called the lateral transabdominal approach where the small incisions are made on the affected side just below the ribs. Since 1995, numerous studies have evaluated the efficacy of laparoscopic adrenalectomy. Benefits over an open procedure include less analgesia requirement, less blood loss, lower complication rate, shorter hospital stay, more rapid return to normal activity, increased patient satisfaction and less late morbidity. Since laparoscopic adrenalectomy is technically more demanding to perform than conventional posterior adrenalectomy and complication rates generally decrease with a surgeon's experience, laparoscopic adrenalectomies should be performed by endocrine surgeons experienced in the procedure.

At the Mayo Clinic, most patients begin a clear liquid diet the evening of surgery and a regular diet the next day. Patients are encouraged to walk the evening of surgery. Most patients undergoing unilateral adrenalectomy may be dismissed from the hospital on postoperative day 1 or 2. Bilateral adrenalectomy patients and patients who have severe Cushing's syndrome may require more than a 2-day hospitalization.

Rationale and Clinical Scenarios
Unilateral adrenalectomy: As previously mentioned, laparoscopic adrenalectomy is the procedure of choice for removal of a unilateral cortisol-producing adenoma. However, when a malignancy is suspected from imaging studies, the surgical procedure of choice is the open abdominal incision. Also, very large tumors, greater than 10-12 cm in diameter, may be difficult to remove laparoscopically. The risk of adrenocortical cancer increases proportionately to size.
Bilateral Partial Adrenalectomy: In recent years, a surgical procedure called partial adrenalectomy or adrenal sparing surgery has been used in the rare patient that has cortisol-secreting adenomas on both adrenal glands. Partial bilateral adrenalectomy can usually preserve adrenal function in these patients. Partial bilateral adrenalectomy has been done at the Mayo Clinic for the last 10 years.

Bilateral Adrenalectomy: Bilateral laparoscopic adrenalectomy is an excellent treatment option for ACTH-dependent Cushing's syndrome after failed pituitary surgery for Cushing's disease or when the ACTH source cannot be resected or localized as in ectopic ACTH syndrome. To obtain a biological cure in these patients, it is essential that all of the adrenal tissue be removed. Because of the magnification when using a laparoscope, there is actually better visibility of the surgical field, thus decreasing the risk for retained adrenal gland remnants and possible surrounding adrenal rest tissue. Compared to the open approach, bilateral laparoscopic adrenal surgery is associated with much less tissue injury in patients who are immunocompromised and/or are predisposed to delayed wound healing.

Although transsphenoidal surgery for resection of an ACTH-secreting pituitary tumor is the standard of therapy for Cushing's disease, this surgery is not always successful. Such tumors may invade contiguous structures such as the cavernous sinuses, thus precluding complete resection. Other ACTH-secreting pituitary tumors may be so small that they escape detection and resection at the time of surgery. For these reasons, transsphenoidal surgery is associated with a 20-40% failure rate, even for experienced surgeons. Reoperation carries an increased risk of inducing panhypopituitarism in conjunction with the treatment difficulties and complications associated with the hypercortisolism. Therefore, bilateral adrenalectomy has an important therapeutic role in a significant subset of patients with Cushing's disease in whom transsphenoidal surgery has failed and would therefore be placed at high risk of panhypopituitarism with additional cranial surgery.

Sellar radiation therapy is not an optimal therapy for Cushing's disease because its onset of action is slow and its failure rate is unacceptably high. Some degree of pituitary insufficiency is a relatively common side effect, and the mean onset of action is 18 months. Therefore, primary treatment with irradiation is not optimal in patients with clinically significant hypercortisolism and its numerous co-morbidities. Since bilateral laparoscopic adrenalectomy results in immediate cure of hypercortisolism, the role of pituitary irradiation in Cushing's disease in these patients is limited to the treatment of the small subset of patients with large pituitary tumors (Nelson's syndrome). In patients with enlarging pituitary tumors, sellar radiation therapy or gamma knife radiosurgery are used to prevent a locally invasive pituitary tumor from further encroaching on surrounding structures.

Patients with the syndrome of ectopic ACTH secretion often have an unresectable or occult source of ACTH secretion. The metabolic manifestations of cortisol excess may appear suddenly and progress rapidly. In these situations, adrenalectomy offers long-term relief from the symptoms associated with cortisol excess. In our experience, most patients with clinically evident ectopic ACTH syndrome have more indolent tumors, such as bronchial or thymic carcinoid tumors, islet cell tumors, or medullary carcinoma of the thyroid. Carcinoid tumors that secrete ACTH may not be apparent even with careful radiological investigation and may take up to 20 years to localize. When the source of ACTH is unresectable or occult, bilateral laparoscopic adrenalectomy is a life-saving treatment option because of the minimal morbidity associated with the procedure, especially when compared with conventional adrenalectomy. Laparoscopic adrenalectomy is also superior to medical therapy in regard to tolerance, efficacy, and safety. The procedure can successfully treat the symptoms of cortisol excess in patients with malignancy and thus offer improved quality of life and effective palliation of symptoms even in patients with disseminated, untreatable malignancy.

Risks of Laparoscopic Adrenalectomy
When performing laparoscopic adrenalectomy, the surgeon sacrifices some tactile sensation, when compared to open surgery, and the small, flat, friable adrenal gland is manipulated with instruments in a two-dimensional plane. The overall complication rate associated with laparoscopic adrenalectomy from a summary of 2550 procedures was 9.5%. Some complications of laparoscopic adrenalectomy include conversion to open adrenalectomy, bleeding, gland fragmentation, wound hematomas, organ injury, incisional hernia, and incisional pain. Nerve root pain has been reported with the posterior laparoscopic adrenalectomy approach. There is risk of violating the tumor capsule and organ damage during manipulation with the laparoscopic instruments. The mean mortality rate for 2550 procedures was 0.2% and the need to convert to an open procedure was 3.6%.

Summary
Laparoscopic adrenalectomy is safe, effective, curative, and shortens hospitalization and convalescence. Laparoscopic adrenalectomy is the procedure of choice for the surgical management of Cushing's syndrome patients that have cortisol-producing adenomas (unilateral or bilateral), ACTH-dependent Cushing's syndrome and failed surgery for the removal of the source of ACTH, bilateral primary pigmented nodular adrenal disease, and ACTH-independent bilateral adrenal macronodular hyperplasia. The keys to successful laparoscopic adrenalectomy are appropriate patient selection, knowledge of anatomy, delicate tissue handling, meticulous hemostasis, and experience with advanced laproscopic surgery.

Editor's Note: Dr. Young is an Endocrinologist from the Division of Endocrinology, Diabetes, Metabolism, Nutrition and Internal Medicine at the Mayo Clinic, Rochester MN. Dr. Young has been involved in the treatment of Cushing's patients for many years. Dr. Thompson is a surgeon from the Division of Gastroenterologic and General Surgery at the Mayo Clinic, Rochester, MN. Dr. Thompson has performed over 200 laparoscopic adrenalectomies.

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Introduction
A patient who has been treated for a pituitary tumor is always at risk for recurrence of the tumor; this risk is usually small, but real. There is no way to predict in whom or when a pituitary tumor will recur. This statement is not made to frighten a patient, but to emphasize the need for continued regular medical care and follow up so that a recurrence can be detected early and treated promptly. The reported risk of recurrence of a pituitary adenoma varies according to the type of tumor and the length of follow up. In general, most tumors recur within 5 to 6 years of initial pituitary surgery, but recurrence has been reported 25 years after initial treatment, again emphasizing the need for long term follow up. The recurrence rate in patients with Cushing's disease varies between 12% and 15%.

Multimodality treatment: In the ideal situation, a pituitary tumor can be removed completely by an expert pituitary neurosurgeon and the patient is free of the problem forever. Unfortunately, this is not always the case. While pituitary adenomas are benign (not cancer), they may, and do, cause ongoing problems for some patients that require several treatments. Since many pituitary tumors are large and invade structures that are not accessible to the neurosurgeon, called invasive tumors, it is apparent before the first operation that a patient may require additional treatment after surgery. Even when the entire tumor is removed, if the tumor recurs, there is a role for more than one treatment to address the problem (a recurrent tumor may be more "aggressive" than the original tumor). So, what is "multimodality treatment"? This involves a stepwise use of combined therapies to control the problem and to hopefully produce a resolution of the problem (no excessive hormone production by the tumor, no tumor growth). To achieve these goals, some patients require surgery, medical treatment and pituitary radiation. This is usually the case in patients who have a large and invasive tumor, but may also apply to the patient who has a recurrence of the original tumor.

Why do pituitary tumors recur?
Even with successful surgery (remission of hormone over production and/or no visible tumor on the post operative MRI scan), the most likely reason that a tumor recurs is that a few tumor cells that cannot be seen, even with the operating microscope, remain. Over time, these cells grow and divide and produce a new tumor. It is important to emphasize that even when all visible tumor is removed, there may be a few remaining cells in the area of the original tumor or in an area that cannot be removed surgically (tumor cells invading the bone [sellar bone] below the pituitary, invading the membrane [dura] around the pituitary, and/or invading the cavernous sinus [area on each side of the pituitary that contains the artery that provides blood to the front part of the brain and nerves that control eye movements]).
Patients who have had surgery and/or radiation for a pituitary tumor often have loss of pituitary hormone production requiring hormone replacements, including growth hormone. The possible role of growth hormone replacement and the frequency of tumor recurrence has been questioned. This has been monitored for over 16 years. Surveillance studies of patients receiving growth hormone replacement have shown that the risk of tumor recurrence in patients treated with growth hormone is no greater than the risk of tumor recurrence in patients who were not treated with growth hormone.

How is tumor recurrence detected?
In a patient with a hormone producing tumor, the patient usually experiences some or all of the symptoms that were present at the original diagnosis. A patient with a history of Cushing's disease often reports mood changes, depression, difficulty sleeping, weight gain, fatigue, facial hair growth, loss of hair from the head, thinning of the skin, bruising, new diabetes or worsening of diabetes control and/or increased blood pressure. In the early stages of recurrence of Cushing's, the physical changes may be minimal, but the patient is aware of feeling "different". In my 25 years of practice, I have learned, from patients, that the patient is usually correct about these symptoms, even if the initial hormone tests are normal. With time, the blood, salivary and urine tests become abnormally elevated. Treatment cannot be initiated until abnormal test results are obtained.

Does post-operative pituitary radiation prevent tumor recurrence?
Yes and no. Post-operative pituitary radiation reduces the risk of tumor recurrence, but does not guarantee that a tumor will not recur. Several studies have shown that post-operative pituitary radiation lowers the risk of re-growth of a pituitary tumor; however, any form of pituitary radiation may cause loss of normal pituitary hormone production, requiring hormone replacement(s).

What are the treatment options for a recurrent tumor?
Treatment of a recurrent tumor depends on the location and/or size of the tumor and, ultimately, the patient's preference after carefully considering all options. In general, the treatments include another pituitary operation, pituitary radiation and/or medications to control hormone over production or bilateral adrenalectomy. If the recurrent tumor causes loss of vision, the most effective treatment is an immediate second operation; there is no other treatment that offers the possibility of improvement of vision.

Surgery: If there is a visible tumor on the MRI scan that is not extending into the cavernous sinus (beyond the large artery that provides blood to the front part of the brain and not within the reach of the neurosurgeon), a second operation offers the possibility of immediate improvement, particularly if there is hormone overproduction (Cushing's, acromegaly, prolactinoma). In patients with Cushing's disease the reported success rate with the first operation ranges from 80% to 90%; the reported success rate with a second surgery is approximately 50%. Sometimes with a recurrent tumor, a more extensive removal of the gland is performed in an attempt to provide the best possible outcome. The success of pituitary surgery is directly related to the experience and expertise of the neurosurgeon.

Pituitary Radiation: All forms of pituitary radiation require time (often months to years) to be effective; there is no immediate effect. This is an important consideration in patients who have a hormone-producing tumor (Cushing's disease, acromegaly, prolactinoma) because, until the radiation becomes effective, the patient has the ongoing effects of excessive hormone production. There is no way to predict when or if the radiation treatment will lower hormone overproduction to normal. Additionally, an expected effect of pituitary radiation is loss of normal pituitary hormone production (radiation affects both the tumor and the normal pituitary gland) requiring hormone replacement(s). The risk of loss of pituitary function increases over time after radiation treatment which means that regular hormone tests are necessary to detect the need for hormone replacement(s). Although loss of normal pituitary function is not desirable, all of the important hormones can be replaced. A benefit of pituitary radiation is control of tumor growth; pituitary radiation reduces, but does not guarantee, the risk of tumor growth. If a patient decides to have pituitary radiation, medical treatment to lower excessive hormone production is also given to control the problem while waiting for a beneficial effect of the radiation; the medication is discontinued every 6 months and hormone tests are measured to see if the radiation has become effective.

Medical Treatment: There are no consistently proven medications that reduce pituitary tumor production of ACTH (the pituitary hormone that causes the adrenal glands to produce excessive cortisol). However, there are medications that act on the adrenal glands to reduce cortisol production (ketoconazole, metyrapone). However, these medications do not address the pituitary problem and without pituitary radiation, there is the risk of continued growth of the pituitary tumor. Medical treatment may cause side effects: any medication may lower cortisol to below normal causing adrenal insufficiency (too little cortisol production) - emphasizing the need for very close monitoring of blood and urine cortisol levels and adjustment of the medication dose to avoid adrenal insufficiency. Ketoconazole may cause abnormalities in liver tests, which means that liver tests should be measured before treatment and regularly when the patient is taking this medication. If liver tests become abnormal, ketoconazole is stopped immediately. Metyrapone may cause fatigue, nausea and vomiting, usually depending on the dose. If this occurs, the dose may have to be reduced.

Bilateral adrenalectomy: Successful removal of both adrenal glands results in immediate loss of cortisol production requiring life-long replacement of cortisol (hydrocortisone or prednisone) and another adrenal hormone to maintain normal sodium and potassium balance (medication: Florinef). Bilateral adrenalectomy is usually the "last resort" treatment for patients who cannot tolerate medical treatment to control excessive cortisol production while awaiting a beneficial effect of pituitary radiation. Removal of the adrenal glands without addressing the source of the problem (the pituitary gland) causes the risk of further growth of the pituitary tumor. This is called "Nelson's syndrome" named after the physician who first described this condition. Nelson's syndrome developed in patients who did not have pituitary radiation. Approximately one-third of patients with Cushing's disease who have the adrenal glands removed (and no pituitary radiation) develop Nelson's syndrome. Pituitary radiation reduces the risk of developing Nelson's syndrome. Features of Nelson's syndrome include an increase in the blood ACTH level (hormone produced by the pituitary tumor), darkening of the skin and pituitary tumor growth. The high ACTH levels are not harmful medically, but the accompanying darkening of the skin may be disturbing to the patient. The main concern is continued growth of the pituitary tumor; if this occurs, the patient may require another pituitary surgery or radiation.

Summary and Conclusions
Recurrence of a pituitary tumor is obviously distressing to the patient and the physician. If a patient has a recurrence of the tumor, prompt treatment is necessary to reduce the adverse effects of excessive hormone production, to remove or control the tumor, to replace deficient hormones and to restore the patient to a productive life. This is possible and quite probable, but may require several types of treatments.

Editor's Note: Dr. Mary Lee Vance is a Professor of Medicine and Neurosurgery at the University of Virginia Health Sciences Center in Charlottesville, Virginia. Dr. Vance has been involved in the treatment of pituitary tumors and Cushing's Disease for many years.

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New Research on Drug Therapy for Cushing's Disease
by Anthony P. Heaney MD, PhD

Cushing's disease is caused by an ACTH-secreting pituitary tumor, 90% of which are < 1 cm diameter. Despite their small size, these microadenomas cause elevated, non-suppressible ACTH levels, leading to adrenal-derived cortisol hypersecretion and a myriad of disabling and sometimes life-threatening symptoms including abnormal fat deposition, skin thinning, psychological disturbances, hypertension, diabetes, osteoporosis and muscle weakness.
Unless treated, Cushing's disease is associated with high morbidity and ultimately mortality. In experienced specialized centers, the majority of ACTH-secreting microadenomas can be successfully resected by transsphenoidal pituitary surgery, but surgical "cure" rates for larger ACTH-secreting pituitary tumors are achieved less often. Post-surgical persistence of ACTH hypersecretion may require pituitary-directed radiation, effects of which may not be manifest for many years, and like extensive surgical pituitary tumor resection, ultimately leads to partial- or total hypopituitarism in a large number of cases. Although hypercortisolism may be completely resolved by adrenalectomy, this procedure does not suppress, and may act as a stimulus to pituitary tumor growth, and is associated with other co-morbidity.

While some GH (growth hormone) and PRL (prolactin) secreting pituitary tumors require surgery, often times these tumors can be treated by drug therapy alone. The drug therapy used, dopamine agonists and somatostatin analogs, effectively suppress PRL and GH hypersecretion respectively and control tumor growth. No similarly effective drug therapies for ACTH-secreting pituitary tumors currently exist, and surgical excision is currently the only effective treatment.
The therapeutic goal in the treatment of patients with Cushing's disease is normalization of plasma ACTH, and serum cortisol values, tumor shrinkage, and preservation of anterior pituitary function. Current drug-based therapy for Cushing's Disease includes neuromodulator drugs that act at the hypothalamic-pituitary level, such as serotonin antagonists (cyproheptadine, ketanserin, retanserin) dopamine agonists (bromocriptine, cabergoline), GABA agonists (sodium valproate), and somatostatin receptor ligands (octreotide). These drug-based treatments for Cushing's disease, have all been reported to work occasionally, however, they do not impact on pituitary tumor growth, and have rarely shown real clinical efficacy when used as sole treatment. Ketoconazole and other drugs that act on the adrenal glands to decrease steroid synthesis, can lower cortisol levels, but do not decrease tumor size and are rarely effective for long-term control of hypercortisolism. Thus, current drug therapy is largely reserved for pre-operative treatment of severe hypercortisolism, for patients awaiting pituitary radiation-induced cortisol suppression, in cases where the tumor cannot be located, or whenever a definitive treatment is delayed, perhaps due to intercurrent illness.

Current Laboratory Research
To identify potential drug targets, initial studies are often performed on tumor cells grown in dishes in the laboratory. Human pituitary tumor cells are difficult to grow in dishes, thus mouse cells, which grow more readily, are often used. Our laboratory has been experimenting with both ACTH secreting human and mouse cells grown in dishes. We have recently found that drugs that bind to the peroxisome-proliferator activating receptor-gamma (PPAR- g) dramatically influence ACTH secretion and cell growth, thus these drugs may lead to novel therapeutic approaches in Cushing's disease.

Normal cells tightly control cell growth and ACTH secretion by what genes are tuned on or off and how much of a gene product is present (expressed). Some gene products are often over-expressed in tumor cells when compared to normal cells. PPAR-g is a member of the nuclear receptor superfamily, like the better-known estrogen receptor, and regulates expression of other genes. Compounds that bind to PPAR-g and mediate its actions (called ligands) include the thiazolidinedione compounds (TZD's) that are commonly employed in the treatment of type II diabetes. The PPAR-g is expressed at high levels in several cancers including breast, prostate and colon cancer, and treatment of cancer cells with PPAR-g ligands, such as TZD's, inhibits prostate and colon tumor cell growth.

We recently demonstrated that PPAR-g expression is only found in the ACTH-secreting cells in the normal human pituitary, and is abundantly expressed in ACTH secreting tumors surgically removed from patients with Cushing's disease. When human and mouse ACTH secreting tumors grown in dishes were treated with PPAR-g drugs such as the TZD rosiglitazone , growth of the tumor cells was reduced. In addition, the TZD-treatment killed the ACTH secreting tumor cells and inhibited ACTH secretion. We also examined the effects of the TZD-drug treatment on ACTH secreting pituitary tumors after they were inoculated subcutaneously in mice. Animals that were treated with high doses of rosiglitazone intermixed in their food developed smaller tumors and ACTH and corticosterone levels were dramatically lower compared to the mice that just received regular food.

Potential Clinical Utility in Humans
These findings suggest a potential role for these TZD drugs in the management of human pituitary ACTH secreting tumors, as in addition to exerting inhibitory effects on pituitary tumor growth, they also inhibit tumor ACTH synthesis and secretion. Rosiglitazone, a potent thiazolidinedione oral antidiabetic agent, has been extensively and safely used to treat diabetes in humans. Thus far, we have treated three patients with failed pituitary surgery for Cushing's Disease with standard doses of rosiglitazone. A favorable response was observed in two out of the three patients. While these clinical findings are very preliminary, combined with the abundant and selective PPAR-g expression in ACTH secreting pituitary tumors, they support evaluation of the potential use of TZD's in treating patients with Cushing's disease in controlled clinical trials. A clinical trial protocol is currently under development at Cedars Sinai.

Editor's Note: Anthony P. Heaney MD, PhD is Medical Director of the Carcinoid and Neuroendocrine Tumor Center and Director of the Endocrine Fellowship Program at Cedars-Sinai. Dr. Heaney is also Associate Professor of Endocrinology at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). Dr. Heaney's primary areas of research interest involve the genesis of pituitary tumors and innovative treatments for Cushing's syndrome.

Spring '96
Patient Experiences: A Study by Pamela Miller Gotch, RN, MSN

Editor's Note: Pamela Miller Gotch, RN, MSN, is a nurse in the Endocrinology and Diabetes Department at St. Luke's Medical Center in Milwaukee, WI. She works directly with Dr. Findling, who is world renowned for his expertise in Cushing's and is on the CSRF Medical Advisory Board. Cushing's patients from all over the country visit St. Luke's to take advantage of their expertise in petrosal sinus sampling which can be used to locate a tumor. In 1993, Pamela conducted a survey to determine the impact of Cushing's on patients lives. Sixty two questionnaires were mailed and forty one were returned. This work was presented at the Endocrine Nurses Society meeting in 1993, and later published as part of the Endocrine Clinics of North America issue on Cushing's in 1994. Over the past 12 years at St. Luke's, Pamela has personally worked with many Cushing's patients and their families. She was kind enough to grant us an interview.

Question: What led you to study Cushing's and what did you hope to learn as a result of this study?
Answer: Dr. Findling is a known expert in the area and he was asked to give a presentation at the Endocrine Nurses Society, of which I am a member. Traditionally, the endocrinologist has a nurse partner, as I think endocrinologists recognize that they are part of a team. Dr. Findling asked me to be his co-speaker, and initially, they wanted me to talk about diagnostic testing. Quite honestly, I didn't think that would be terribly interesting, and I thought that there was a bigger story to tell. The story I felt needed to be told, was the suffering of the people with Cushing's syndrome. So, I asked patients anonymously through a 2 page questionnaire, did it impact your life, how did it impact your life, and is there anything that we could do differently that would help you more?

Question: What kind of a response did you get?
Answer: We had a very high response rate of 63% which included a mix of pituitary and adrenal based patients. We were overwhelmed with peoples stories. Many did not confine themselves to the 2 page questionnaire. One woman wrote a play about how she felt about Cushing's, many wrote on the back of the page and included extra letters, all pouring their hearts out about how potentially devastating this health problem can be. When this work was presented, I think that everyone listening in that lecture hall could not have been unmoved or unchanged. Just listening to peoples stories, as I read many quotes. Dr. David Aron was in the audience, and he invited me to turn this study into a manuscript for publication in the Endocrine Clinics of North America issue on Cushing's, of which he was co-editor. I feel honored to have been able to help people tell their stories.

Question: What is the overall impact on patient's lives?
Answer: Well, I have to use the word devastating. Over 70% of the people indicated that Cushing's greatly affected their lives. The physical symptoms are of course devastating; the weakness, fatigue, mental problems and the change in body image. All these are devastating. But as with any major health problem, of a long standing nature, out of devastation can come tremendous strength. It's not always 100% negative. People told me that their belief in themselves is stronger now than when their journey started, they are more assertive, and they understand other's sufferings much better. Many people have tremendous growth out of this experience, but it is a long process. People have to be prepared for a long journey.

Question: Could you comment on some of the mental difficulties that patients encountered.
Answer: My study said that 85% experienced some type of mental difficulty. This is consistent with other studies. Many things were very, very frightening for people. Several said, " I feared I was loosing my mind." The male patients tended to use the word violent, while women described crying. "I can't stop crying" they said. People's memories were impaired. Simple things that they had done all their lives became very difficult. They were fumbling and bumbling through life. Emotional instability was a concern as people didn't have control over their emotions. Cases of severe depression were heart breaking. I will always remember one particular case where the patient had tried to commit suicide and then underwent shock therapy. That was, of course, before obtaining the diagnosis of Cushing's. In that case there was anger involved, and rightfully so. To have gone through that with no need.

Question: How did patients describe the effects on family life, friends, work and school?
Answer: Many people felt left out of family life. I think that this was mostly unintentional, but when you can't participate in family activities such as picnics, and ball games, your family tends to assume that you won't go even if asked. They carry on without you and you become a distant spectator. The men were particularly bothered by the fact that they could not play with their children, as were the grandparents. Mothers were very concerned about their children. One woman actually said, " I was a bad mother", which I'm sure she wasn't, but that is an emotional burden that she will carry for the rest of her life. Several stated that Cushing's led to the demise of their marriage, others felt it brought it close to that. Cushing's doesn't effect just the person, it effects the family. Families count on you for a role that you are just unable to fill. They find someone or someway to replace those roles and you are left behind.

There were a couple of students, and one teen who talked about how difficult school was. She would fall asleep in class and couldn't keep up with studies. More importantly, was the devastation on her self esteem. She said " I lost my self esteem, I was fat and people made fun of me." She was very hurt by these comments. Jobs were definitely effected, partially or mostly due to cognitive functions. There is memory is impairment, confusion, and of course emotional instability. Those that said that Cushing's had very little effect on their life were home makers who wondered what would have happened if they had been working outside the home. Cushing's effects all arenas of life.

Question: As Cushing's patients, we are concerned about recovery. What can you tell us about recovery and how long it takes?
Answer: In this study, 18 out of 41, or 44% said that they were recovered. The recovery period was anywhere from less than 6 months to 30 months. Some patients who did not yet consider themselves recovered still fell within the 30 months window. I think it is important to recognize that recovery is in the eye of the beholder. I also think it is important to realize that physicians don't look at recovery like patients look at recovery. Physicians look at the biological recovery, where as patients look at their life. I think the medical sociologist, Engel, phrased it the best when he said "The patient's criteria (for recovery) has to do with how one feels, how one functions, and how one relates."

Some people who viewed recovery only from a physical standpoint, meaning they were off glucocorticoid replacement, and living life as previously, said they were recovered. I think these people, because of their definitions, were truly recovered in their minds eye. The experience was truly, truly behind them. Many patients said "I'm recovered, but". The "but" included things such as "I am not as strong as before, I fear a recurrence, I have osteoporosis and will always have to be careful, and I can't loose weight.." I think recovery is a yes, but, situation. For some, you never recover from an experience like this, because you will always look at things differently after it. One person said "I will never look at chronically ill patients the same way again", others said "I am reborn", meaning that they will never look at life the same. For some people, it was a horrible negative experience, but for others, there was hope. I think that the message of hope is an important one.

Question: Were most patients able to return to work?
Answer: Only 5 out of the 41 responses were not yet back to work. Of the five, some were still experiencing fatigue and weakness and did not feel they could keep up with the required pace. A few were dealing with other health problems, and one was still experiencing mental health problems. Another felt that her appearance and the prospect of medical costs scared off potential employers. One patient did suggest using the time off to polish job skills by taking a class.

Question: Do you have any suggestions for patients who are trying to cope with Cushing's?
Answer: The best thing I can do is use the words from the patients. They said, "Hang in there, because you will get better. Have faith, be positive, don't give up, but it's a long journey." Other suggestions included, ask as many questions of your health care providers as you possibly can, make sure you fully understand everything before they carry out a procedure on you, accept any and all support from family and friends. Sometimes we have a tendency to tough it out, but realize that it is OK to lean on your family and friends. Some said, "If I hadn't talked to someone else about Cushing's, I would have literally gone crazy." One patient said, "It is difficult to have patience through a long recovery, but there is a pot of gold at the end of the rainbow." "Be prepared for ups and downs." " Surround yourself with lot's of loving supporters, keep a positive attitude." " You must let your family know everything about Cushing's." "Cushing's is a living nightmare, you need to talk about it." "It's a long road ahead, but there is light at the end of the tunnel." I think patients in general wanted to help others to maintain hope. I think your newsletter, and possibly the internet, can make it easier for people to talk to each other. Many physicians don't have enough patients to form a support group, but ask your doctor to speak to another patient who is willing to be what I call a peer counselor, that is a past patient who is willing to share their thoughts, feelings and fears. I do think that if you ask, most endocrinologists will make an effort to reach out and find someone for them to speak with.

Question: How can family and friends be most helpful?.
Answer: There are ways that family and friends can be helpful. Going to doctors appointments can be very important. Many studies have shown that a Cushing's patient's thinking is impaired. Explanations of Cushing's and the diagnostics are complex. It is always good to have another pair of ears. I also think that they can help them physically. One woman spoke about how her wonderful family helped her by laying out her clothes. She was a teacher, and she did not miss any school. Her family picked up a number of things so that she could concentrate on one thing, keeping her job. I think that helping people go to the grocery store would be a good idea. Many mentioned they dreaded the task of shopping, as it was difficult to do physically. Take them there, when it isn't busy. This may be inconvenient to the helper, but can be so helpful. Look for little tiny ways that you can help them save their physical energy, like putting groceries away or picking something up. Little things can help so much.

Question: Do you have anything else that you would like to add?
Answer: There is a deficiency in the literature regarding Cushing's that is easily available to patients. Things like your newsletter can raise questions in a patient's mind, which can then be discussed with their physician. Cushing's can be a diagnostic dilemma, and physicians and patients need to be as certain as is absolutely possible about the cause of Cushing's prior to undertaking treatment. I believe that patients can help make their physician a better physician by asking questions.

I would also like to say that we all play a role in healing ourselves. When you have been through an experience like Cushing's, you need to help yourself heal physically. Sometimes physicians will recommend physical therapy, or rehab programs. I think patients should really think about that, and be compliant in doing their exercises at home. Such a program can really help in physical recovery. I think people have to heal mentally. I think this involves talking about their experience with others who are good listeners. Unfortunately, not all friends are going to be those people. It might be a nurse in the doctor's office, a counsellor, or a minister. We are sometimes hurt by those we care for the most, but some people can't be the therapeutic listener that we think they should be. Find someone else. People also need to heal spiritually. Many people commented about prayer, finding a deepening within themselves, finding a strength, and in general finding positive things in devastation.

I also need to commend Dr. Aron for including this work in a medical publication, and also, to thank Dr. Findling for his support and compassion.

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Editor's Note: Dr. Weiss is Professor & Chairman of the Department of Neurosurgery at the University of Southern California. He has been Chairman of the American Board of Neurosurgery, The Residency Review Committee for Neurosurgery, and the Editorial Board of The Journal of Neurosurgery. He has also served as VicePpresident of the American Academy of Neurosurgery and the Congress of Neurological Surgeons, Secretary of the American Association of Neurological Surgeons and is presently Associate Editor of The Journal of Neurosurgey.

Question: Some Cushing's patients have found that their insurance companies will not refer them to an "expert" pituitary surgeon. Why is an expert pituitary surgeon necessary?
Answer: While there are no literature references that state exact percentages, the cure rate for pituitary tumors is directly related to the experience of the surgeon. Neurosurgery is a broad field that includes surgery on the brain, the pituitary gland, and the spine. In general, greater than 70% of the procedures done by neurosurgeons are on the spine, with an occasional brain or pituitary procedure. The greater cure rate obtained by an experienced pituitary surgeon stems from technical repetition of the procedure, which yields a greater appreciation for subtle changes in the physical appearance of tumor tissue, as well as superior mobilization of the gland to discover all of a tumor. In general, a neurosurgeon that performs 1 pituitary surgery every other week, or between 20-25 such surgeries a year, should be proficient in the procedure. The pituitary surgeon need not be a "Cushing's tumor expert", as ACTH secreting pituitary tumors account for only about 15% of all pituitary tumors. From a surgical perspective, the techniques employed and the skills required are the same for all transsphenoidal pituitary surgeries. There are situations, such as Nelson's, where consultation with a very experienced pituitary surgeon who has done thousands of pituitary surgeries may be warranted.

Question: How long has the trans-sphenoidal surgical approach been the preferred surgical method and what does it entail?
Answer: The modern era of trans-sphenoidal surgery dates to the early 1960's (the procedure was actually first described in 1904). The advent of this procedure made a dramatic difference in the treatment of pituitary tumors.

In general, the procedure involves an incision in the upper gum, which allows access to the pituitary gland with specialized instruments. The surgeon then views the area to determine the location of the tumor. In cases of small tumors, the tumor is removed, leaving the pituitary gland primarily intact. Only when the tumor has spread thoughout the entire gland, is the removal of the entire pituitary necessary. This rarely happens with ACTH secreting tumors, as they are usually small enough that the tumor can be removed without removing the pituitary. In general, most transsphenoidal procedures take about 2 1/2 hours.

After surgery, patients are most usually kept in intensive care for at least one night so that blood pressure, heart rate, and replacement medications can be continuously monitored. The patient then spends approximately another 3 days in a surgical care unit before going home. Following surgery, patients will have packing in their nasal cavity for a day or so; it is not uncommon for patients to experience increased thirst and to have some headache (usually resolved by Tylenol) while the packs are in place. Most patients are walking and eating mostly normal foods within a few days.

Question: What is the determining factor in whether all of a pituitary tumor can be removed?
Answer: Tumors vary in their size and invasiveness. The most common reason that a tumor cannot be completely removed, is that it has invaded adjacent structures such as the cavernous sinus, or the dura or bone of the sella that surrounds the pituitary. Often times, such invasion cannot be adequately visualized on an MRI, and the full extent of invasion is not known until observed during surgery.

Tumors are catagorized according to their size and invasiveness. The rating scale I use is the Hardy scale, which ranks tumors from Stage I to Stage IV, Stage I being the smallest and least invasive. In Stage I tumors, those less than 1 cm in size with no invasion, our statistics reveal that 91% of these tumors can be successfully removed completely. In contrast, stage 4 tumors, that are larger than 1 cm in size and show diffuse invasion, can be completely removed less than 10% of the cases.

Cushing's tumors tend to be smaller (Stage I or II) perhaps because patients become symptomatic before these tumors have an opportunity to become extremely large. Because of the tiny size of tumors frequently seen in Cushing's disease, the tumors are not always visible on an MRI, and very few effect the optic nerve. Early diagnosis, while the tumor is still small, is important to maximize the opportunities for a full recovery.

Question: What is the treatment of choice for Nelson's syndrome?
Answer: Nelson's tumors are difficult tumors to manage. If the tumor is localized to the pituitary, another transphenoidal resection may be in order. Dr. Ed Oldfield, of NIH, has published results from multiple transsphenoidal surgeries and these results indicate, that if the tumor can be visualized, it is worth trying the procedure again. If the tumor is not localized to the pituitary gland, but rather has invaded adjacent structures, removal of the entire pituitary will not result in a cure. Nelson's is a case where the patient should see a very experienced neurosurgeon in a facility that has access to the latest radiation technology. The newer stereotaxic radiation therapies are often carried out by neurosurgeons, as the procedure is very focused to a particular area, and can be viewed as a surgery. The most common kinds of stereotaxic radiation include Gamma Knife, Proton Beam, and Linac. There are differences between these that make one technique perferable over another, depending on the specific tumor.

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What should be included in a "baseline" eye examination?

• Visual acuity ("center vision")
• Visual field ("peripheral or side vision")
• Pupil exam ("the black part of the eye")
• Slit Lamp exam (exam of the structures of the "front part of the eye")
• Motility exam ("how the eye moves")
• Dilated fundus exam ("looking at the back of the eye including the optic nerve")

What symptoms will the patient have?

• Unexplained usually painless decreased visual acuity or visual field-common
• Double vision (diplopia)-less common
• Droopy eyelid (ptosis)-less common

Why every patient with a pituitary adenoma should have an eye exam?

• Visual loss may be the presenting and only sign of pituitary tumor
• Visual improvement may indicate treatment response of pituitary tumor
• Progressive visual loss may indicate recurrence of tumor
• Baseline ophthalmologic exam

What is the eye doctor looking for?

• Decreased visual acuity or visual field
• Abnormalities in the response of the pupil
• Abnormal eye movements
• Optic atrophy (visible damage to the optic nerve)

How does a pituitary adenoma decrease vision?

• Pituitary tumors (and other types of brain tumors) can cause visual loss by pressure (compression) of the visual pathway
• Depending on where the tumor is located the vision loss may be in one or both eyes and may affect central ision or side vision

How does a pituitary tumor cause double vision?

• Compression of the nerves that control eye movement (ocular motor nerves or cranial nerves III, IV, and VI)
• Loss of vision can cause loss of the ability to keep the eyes aligned (fusion)

How does pressure on the anterior visual pathway cause visual loss?

• Pressure on the optic nerve causes loss of vision in the ipsilateral ("same side") eye
• Pressure on the optic chiasm causes a bitemporal hemianopsia ("loss of temporal side vision in each eye")
• Pressure on the optic tract causes a homonymous hemianopsia
  • Homo: same
  • Hemi: half
  • Opsia: loss of vision

What factors make it more or less likely that the patient with visual loss due to a pituitary tumor will recover vision?

• Age (younger patients do better)
• Vasculopathic risk factors: patients without hypertension, diabetes or other medical problems do better
• Duration of visual loss (the longer the symptoms have been present, the less likely the vision will return
• Presence of optic atrophy (optic atrophy implies some component of irreversible visual loss)

What is the anatomy of the visual pathway?

• Visual information passes through the cornea (the clear part of the eye), the lens, to the retina (like film in a camera) and to the optic nerve, optic chiasm (a crossing point), then to the optic radiations and the occipital cortex
• Pituitary adenomas affect the anterior (or front part of the brain) visual pathway

Is the visual loss reversible after treatment?

• If the pressure on the visual pathway can be relieved most patients experience improvement in vision after treatment

How often should I see the eye doctor?

• Preoperative baseline
• Postoperative baseline
• Postoperative 3 months
• Postoperative 9-12 months
• Yearly if stable

When should I call my eye doctor?

• Blurry central or side vision
• Double vision
• Droopy eyelid

One additional note:
Persons with Cushing's should also be checked for cataracts since long term exposure to cortisol increases your chances of cataracts.

Andrew G. Lee, M.D.
Baylor College of Medicine
Division of Neurosurgery
MD Anderson Cancer Center
University of Texas
Neuro-ophthalmology Unit
Department of Ophthalmology
Neurology, and Neurosurgery
Baylor College of Medicine
Division of Neurosurgery
MD Anderson Cancer Center
University of Texas

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Dr. Anne Klibanski is a Professor of Medicine at Harvard Medical School and is Chief of the Neuroendocrine Unit at Massachusetts General Hospital in Boston.

Osteoporosis is a common, multifactorial disorder clearly associated with increased morbidity and mortality. It has only been recognized relatively recently that because of the complex hormone disorders which accompany pituitary disease, patients with this condition are at higher risk for the development of osteoporosis and fractures. Patients with pituitary disease should be evaluated for the possibility of osteoporosis. If identified, underlying hormonal and metabolic factors should be aggressively searched for and corrected as is appropriate for an individual patient. Bone health is a life-long process and the thinking that osteoporosis is only a disease of the elderly is completely untrue. As early as childhood and adolescence peak bone mass is developed, and will be an important factor in bone strength throughout life. Adolescents with pituitary disease and associated hormone abnormalities may be at even greater risk for the development of osteoporosis because not only do the lose established bone, they also fail to achieve peak bone mass in their early life. Therefore, patients with pituitary disease of all ages should discuss osteoporosis with their physicians as a part of their overall health concerns.

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Editor's Note: Dr. Barbara Lukert is a Professor of Medicine, Endocrinology, Metabolism and Genetics and Director of the Hiatt Osteoporosis Center at the University of Kansas Medical Center in Kansas City, Kansas. Dr. Lukert has been involved with the study and treatment of osteoporosis for many years.

Excessive production of cortisol by the body or chronic use of corticosteroids (CS) for treatment of disease causes accelerated bone loss and in about 30% of patients it causes osteoporosis related fractures. The first fractures usually occur in the vertebrae.

Corticosteroid-induced osteoporosis (CIO) results from multiple effects on calcium and bone metabolism. CS inhibit the absorption of calcium from the intestine and increase the loss of calcium in the urine. These events, in turn, cause calcium to be mobilized from bone to maintain a normal blood calcium level. The production of estrogen in women and testosterone in men is inhibited by CS. Deficiency of these gonadal hormones causes increased breakdown of bone. At the same time that bone is being broken down, CS impair the ability of the bone forming cells (osteoblasts) to lay down new bone.

As a result of all of these effects, CS cause the most rapid rate of bone loss observed in patients. Steroid-induced osteoporosis is similar to postmenopausal osteoporosis but the bone loss associated with steroids is much more rapid, and the bone appears to be more fragile than in patients with postmenopausal osteo-porosis.

Osteonecrosis is different than osteoporosis in that it can occur without significant bone loss, and can occur very soon after steroid levels become elevated. Osteonecrosis means death of bone. This problem most frequently occurs in the hip, the shoulder, or the distal thigh bone. It is thought that the bone dies because CS cause a significant increase in the amount of fat in the center of the bone, in the bone marrow. This increase in fat in a closed space which cannot expand causes pressure on the small, thin, blood vessels which nourish the bone. This causes the bone to die due to lack of blood supply. Sometimes the bone will heal if the patient just doesn't bare weight on the bone for several weeks. At other times, joint replacement is required.

All patients requiring treatment with steroids such as prednisone, or patients with excessive production of cortisol due to an ACTH producing pituitary tumor or adrenal tumor should have their bone density measured in the spine and hip using dual energy x-ray. This will tell you how much bone you have lost, will help determine how aggressive treatment should be to prevent bone loss, and will allow future assessment of response to treatment. The amount of calcium that is being lost in the urine should be measured, and if high, efforts made to reduce the loss. If there is any reason to suspect that the patient has vitamin D deficiency, the serum level of 25-hydroxy vitamin D should be measured. Estradiol levels should be measured in women and testosterone levels in men.

Patients with elevated cortisol levels or taking CS should limit the sodium in their diet to no more than 3 grams (3000 milligrams) daily. They should eat a well balanced diet and consume about 1500 mg of calcium a day (if their urine calcium is not elevated). Exercise is important and it would be helpful to walk for 30 minutes daily. If the patient has trouble getting up out of a chair without using their arms or difficulty climbing stairs, they should be instructed in exercises which specifically strengthen the quadriceps and pelvic girdle muscles since these particular muscle groups are weakened by steroids. Women who are postmenopausal or premenopausal women whose estradiol levels are low should be given hormone replacement if they do not have other contraindications. Likewise, men with low testosterone should be give replacement therapy if it is not contraindicated.

Hormone replacement, the bisphos-phonate drugs Fosamax and Didronel, and calcitonin have all been shown to prevent steroid-induced bone loss. The response to these drugs is very similar to that seen in women with postmenopausal osteoporosis.

In most instances a considerable amount of bone is regained when the cortisol levels return to normal or the administration of steroids is stopped. In patients requiring replacement doses of cortisol, it is important to keep the dose as low as possible but adequate to maintain normal levels.

Steroid-induced osteoporosis is a preventable and treatable disease. We need to be more diligent in recognizing it.

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Editor's Note: This article originally appeared in the Fall, 1998 issue of the Cushing's Support and Research Foundation (CSRF) newsletter and was updated in June, 2003. Dr. Hershel Raff, Ph.D. is a Professor of Medicine and Physiology at the Medical College of Wisconsin's Endocrine Research Laboratory at St. Luke's Medical Center in Milwaukee, Wisconsin.

Cushing's syndrome - endogenous hypercortisolism - is characterized by a loss of circadian rhythmicity. In normal patients, cortisol levels peak in the early morning hours and decrease to substantially lower levels at night. Rather than the normal decrease in late evening cortisol, patients with Cushing's syndrome of any cause fail to decrease cortisol secretion in the late evening. Therefore, the measurement of elevated late evening cortisol is helpful in the diagnosis of Cushing's syndrome. Obtaining a late night, unstressed plasma cortisol is virtually impossible in most clinical practices. Salivary cortisol is in equilibrium with the free, biologically active portion of cortisol in the plasma. Therefore, if one obtains a saliva sample in patients at bedtime in their homes under unstressed conditions, one can make the diagnosis of endogenous hypercortisolism.

A simple way to sample saliva is by using a Salivette made by the Sarstedt Company (Newton, NC). This device consists of a cotton tube and plastic tubes. The patient only has to chew the cotton tube for 2-3 minutes and place it inthe plastic tube. The tube is then mailed to our lab for analysis.

We currently recommend obtaining 2 salivary cortisol samples at 11 PM in any patient in whom Cushing's syndrome is suspected. If these are abnormal, the diagnosis can be confirmed using urine free cortisol or the low dose dexamethasone suppression test. Due to the convenience of sample collection, the patient can sample saliva several evenings in a row. In fact, our clinical endocrinologists routinely order 2-3 consecutive late-evening salivary cortisol samples. Our research (Raff H, Raff JL, Findling JW. 1998 Late-Night Salivary Cortisol as a Screening Test for Cushing's Syndrome. J Clin Endocrinol Metab. 83:2681-2686 and Raff H, Findling JW A physiologic approach to diagnosis of the Cushing syndrome. Ann Intern Med. 2003 Jun 17;138(12):980-91. Review) has shown that the combination of late-evening salivary cortisol and urine free cortisol is very accurate in diagnosing Cushing's syndrome in most patients. Doctors can obtain a kit by contacting ACL Client Services at 1-800-877-7016 or Salimetrics at 800-790-2258 . The analytical method used at ACL Labs and at Salimetrics is now FDA cleared for the diagnosis of Cushing's syndrome.