Management of recurrent and refractory Cushing disease

Cushing disease is most frequently caused by pituitary adenomas that secrete adrenocorticotrophic hormone. Transsphenoidal surgery is the treatment of choice in patients with these tumors because of reported remission rates of 69-93%. More challenging for neurosurgeons and endocrinologists, however, is management of the remaining patients whose Cushing disease is refractory to initial transsphenoidal surgery or recurs after initial remission. Here, we review the treatment options and latest surgical, medical, and radiosurgical advances for patients who have persistent or recurrent Cushing disease after transsphenoidal surgery.     

Treatment of pituitary-dependent Cushing's syndrome: long-term results of unilateral adrenalectomy followed by external pituitary irradiation compared to transsphenoidal pituitary surgery

BACKGROUND: The preferred treatment of Cushing's disease (CD) nowadays is transsphenoidal pituitary surgery (TPS). Prior to TPS, patients at the Leiden University Medical Centre were treated by unilateral adrenalectomy followed by external pituitary irradiation (UAPI). We report on long-term results of both UAPI and TPS and compare remission, relapse rates, and complications. PATIENTS AND METHODS: A retrospective study was carried out on 130 patients with CD. Patients with pituitary macroadenoma were excluded. Eighty-six and 44 patients underwent UAPI and TPS, respectively. Of these patients, 85 and 41 were evaluable for long-term results. RESULTS: Remission following UAPI and TPS was identical at 64% (54/85 and 27/41). Cumulative relapse was also comparable - 17% (9/54) and 22% (6/27), respectively, - for UAPI and TPS, although the mean follow-up periods were different - 21.4 years and 8.5 years, respectively. Cumulative disease-free survival curves after UAPI and TPS are identical until 5 years of follow-up, but diverge thereafter indicating more sustained remissions following UAPI (P = 0.17, Wilcoxon statistic). Pituitary dysfunction following UAPI (36%) and pituitary surgery (55%) likewise did not differ significantly. However, pituitary dysfunction was an immediate event after TPS, whereas it developed after a mean interval of 17.8 years following UAPI.Low-dose dexamethasone testing during follow-up had no value in predicting therapeutic outcome. CONCLUSIONS: The results of unilateral adrenalectomy followed by external pituitary irradiation do not justify that this therapy is totally abandoned in favour of transsphenoidal pituitary surgery. Unilateral adrenalectomy followed by external pituitary irradiation is a valid therapeutic modality for the treatment of Cushing's disease, and could be considered as alternative to bilateral adrenalectomy and under some circumstances to transsphenoidal pituitary surgery.     

MEGAVOLTAGE PITUITARY IRRADIATION IN THE MANAGEMENT OF CUSHING''S DISEASE AND NELSON''S SYNDROME: LONG-TERM FOLLOW-UP

We report the long-term follow-up of the clinical and biochemical effects of megavoltage pituitary irradiation (radiotherapy; RT), administered as primary or secondary therapy, for pituitary Cushing's disease and Nelson's syndrome in 52 patients. Irradiation was administered, from a 4-15 MeV linear accelerator, via a three-field technique (two lateral, one frontal), to a total dose of 4500 cGy (rad) in 25 fractions over 35 days. Twenty-one patients received RT as primary ablative therapy for Cushing's disease and were under follow-up 5.8 to 15.5 years later (median 9.5 years). All were initially treated with metyrapone to induce normal mean plasma cortisol levels, and all achieved clinical remission on this therapy. At latest follow-up, 12 (57%) are off all therapy, in clinical remission, with a normal mean cortisol through the day; however, only two show completely normal plasma cortisol responses to dynamic testing; four remain on medical therapy with metyrapone or op'DDD and all have required a steady dose reduction accompanied by falling plasma ACTH levels; five have required alternative therapy with bilateral adrenalectomy and/or transsphenoidal hypophysectomy. Fifteen patients received RT for Nelson's syndrome, developing after bilateral adrenalectomy, and have been followed up for 1.5 to 17.3 years (median 9.6 years). Fourteen patients showed progressive depigmentation, shrinkage of the pituitary adenoma and fall in plasma ACTH levels to 1-72% (median 16%) of the pre-RT basal value. In the remaining patient an initial fall in plasma ACTH was followed by tumour enlargement at 6 years, leading to death at 11 years after RT. Of the remaining patients, results are assessed in nine who received RT after unsuccessful transsphenoidal surgery, three after transfrontal surgery for aggressive macroadenomas, and four prophylactically after bilateral adrenalectomy. Radiotherapy remains a valuable second-line therapy for Cushing's disease and its complications.     

Long-term results of stereotactic radiosurgery to the pituitary gland in Cushing's disease

Gamma radiation from 60Co delivered with stereotactic technique was given to the pituitary gland in 35 patients, aged 18-65 years, with Cushing's disease. The doses were 70-100 Gy in each single irradiation. The size of the sella turcica was normal in the majority of the patients. The observation time was 3-9 years in 29 patients. Out of them, 14 (48%) obtained clinical remission and normal urinary cortisol after one irradiation. Eight achieved remission after two to four irradiations. In total, 22 out of 29 patients (76%) obtained remission. In 12 of them remission was obtained in 1 year and in another 10 within 3 years. No recurrences were observed. Improvement was seen in 2 patients after one and three irradiations. Bilateral adrenalectomy was performed in 5 patients owing to unsatisfactory effect of irradiation. Pituitary insufficiency with gonadotropin, thyrotropin or corticotropin failure was demonstrated in 12 of 22 patients in remission. This occurred 4 months to 7 years after the first irradiation. Another 6 patients were followed less than 3 years after the first irradiation. Two obtained remission after the first treatment, whereas the other 4 improved. Stereotactic pituitary irradiation is suggested as a non-invasive therapeutic alternative in Cushing's disease for example in patients with considerable surgical risk or as a supplement to pituitary microsurgery.     

Hypophysen- und Nebennierenoperationen

Laparoscopic adrenalectomy and transsphenoidal pituitary surgery are currently established as the surgical procedures of choice with a low complication rate. Beyond potential surgical complications, one has to consider endocrine sequelae such as adrenal insufficiency and hypopituitarism. Without adequate endocrine treatment patients are prone to develop potentially lethal complications such as Addisonian crises or pituitary coma. Therefore, all patients should be seen by an endocrinologist before and after surgery. Patients with bilateral adrenalectomy require lifelong substitution of glucocorticoids and mineralocorticoids. Cushing's syndrome patients with unilateral adrenalectomy need temporary substitution. After pituitary surgery, all patients require functional assessment of their pituitary function, and, if necessary, adequate replacement therapy.     

Transsphenoidal microsurgery for Cushing disease. A report of 216 cases

We report cumulative results of the transsphenoidal microsurgical treatment of Cushing disease in 221 patients: 173 patients had selective adenomectomy, 25 had total hypophysectomy, 6 had partial hypophysectomy, and 12 had exploration only. Five patients were excluded from analysis because intraoperative technical difficulties precluded exposure of the pituitary gland. The selection of candidates for transsphenoidal exploration was based on endocrinologic criteria. Magnetic resonance imaging was the preferred radiologic test. Selective venous sampling of adrenocorticotropic hormone further refined the diagnosis when endocrinologic and radiologic procedures were not definitive. Remission of disease was achieved in 164 of 216 (76%) patients analyzed (95% CI, 69 to 81). Among patients with histologic confirmation of adenomas, the percentage having remission was significantly higher (P less than 0.001) in patients with microadenomas than in patients with macroadenomas and in patients with intrasellar adenomas than in patients with extrasellar extension of their adenoma or perforation of the sellar floor by adenoma (P less than 0.001). Five patients had an ectopic source of adrenocorticotropic hormone secretion. Two patients had diffuse pituitary hyperplasia. Complications occurred in 9.3% of the patients, including two deaths that were apparently unrelated to surgery (CI, 5.4 to 13). The results indicate that transsphenoidal surgery is the preferred treatment for most patients with Cushing disease.     

Rapid decrease in adrenal responsiveness to ACTH stimulation after successful pituitary surgery in patients with Cushing's disease

Objective The aim of this study was to investigate the effects of transsphenoidal surgery (TS) on the adrenal sensitivity to ACTH (adrenocorticotropin) stimulation in patients with Cushing’s disease (CD). Methods We measured the cortisol response to 1 μg synthetic ACTH (1–24) 6 days after pituitary surgery in 45 patients with CD. Mean follow‐up period was 56·5 months (SE 4·7). Results In 24 of 28 patients in sustained remission after pituitary surgery, peak cortisol concentrations below 774 nm (28·0 μg/dl) were recorded after stimulation with 1 μg synthetic ACTH (86%). Two patients with recurrent disease after initial remission (late relapse) also showed ACTH‐stimulated peak cortisol levels below 774 nm . Fourteen of 15 patients with persistent CD after surgery (early failure) showed absolute peak cortisol levels >774 nm in response to ACTH stimulation. Conclusion Patients in remission after pituitary surgery for CD showed a rapid decrease of adrenal responsiveness to exogenous ACTH stimulation. This phenomenon may be explained by ACTH‐receptor down‐regulation in the adrenal cortex after complete removal of the pituitary corticotroph adenoma. In our study, the postoperative low‐dose ACTH stimulation test had a sensitivity of 93% and a specificity of 87% in predicting immediate remission of CD after pituitary surgery.     

Postoperative plasma cortisol levels predict long-term outcome in patients with Cushing's disease and determine which patients should be treated with pituitary irradiation after surgery

Transsphenoidal surgery is the treatment of choice for ACTH-producing pituitary adenoma (Cushing's disease) and pituitary irradiation is widely considered the most appropriate treatment for patients with Cushing's disease for whom transsphenoidal surgery has been unsuccessful. We studied 49 consecutive patients who underwent transsphenoidal surgery for the treatment of Cushing's disease at Tokyo Women's Medical University from 1977-1997 with a mean follow-up duration of 87.6 months (range, 24-253 months). We examined the relationship between postoperative endocrinological data, assessed between 3 and 8 weeks after surgery, and long-term outcome and efficacy of pituitary irradiation after surgery. Long-term remission was defined as the regression of the symptom and signs of Cushing's syndrome, and restoration of normal levels of plasma ACTH, cortisol and urinary free cortisol, together with adequate suppression of morning plasma cortisol levels following the administration of low dose (1 mg) of dexamethasone. Thirty patients had no additional treatment after pituitary surgery. Only 1 of 25 patients (4%) whose postoperative plasma cortisol level was less than 2 microg/dl developed recurrent disease whereas 3 out of 5 patients with postoperative plasma cortisol levels higher than 2 microg/dl relapsed. Postoperative external pituitary radiation was used to treat the remaining 19 patients. Four patients who received radiation therapy had a low or undetectable postoperative plasma cortisol level (<2 microg/dl, 56 nmol/L) and all of these patients developed hypopituitarism whereas 5 patients with subnormal plasma cortisol levels (2.0-10.0 microg/dl) remained in remission. Among 10 patients with persistent disease after surgery, 6 entered remission 6-47 months after irradiation but one of them subsequently relapsed after 108 months. These results suggest that 1) additional therapy should be avoided in patients with a postoperative plasma cortisol less than 2 microg/dl because relapse is very rare and radiotherapy will frequently induce hypopituitarism, 2) patients with a subnormal cortisol level following surgery should be treated with pituitary irradiation, because the relapse rate is reportedly high and radiotherapy is effective in preventing relapse, 3) radiotherapy in patients with persistent disease after surgery is effective only in 50% (5/10) of the patients.     

Rosiglitazone for prevention or adjuvant treatment of Nelson's syndrome after bilateral adrenalectomy

OBJECTIVE: To investigate the effect of Rosiglitazone in three patients treated with bilateral adrenalectomy followed by hyperpigmentation and hypersecretion of ACTH. PATIENTS AND METHODS: One patient had increasing ACTH after previous transsphenoidal surgery for Nelson's syndrome, and two patients without pituitary adenomas had recurrence of Cushing's disease after primary and repeated transsphenoidal surgery with need for bilateral adrenalectomy. The patients developed hyperpigmentation and increasing ACTH at nadir 2-4 h after morning hydrocortisone dose. ACTH during Rosiglitazone therapy (4 mg/day for 4 weeks and then 8 mg/day) was measured at regular intervals 24 h after the latest dose of hydrocortisone. RESULTS: In two patients there was a decrease in ACTH by 40% after 5 months. The first of these patients showed an escape with increasing ACTH to the initial value after 11 months. In the third patient no effect was observed. Tumour development or progression on magnetic resonance imaging was not observed. CONCLUSION: Rosiglitazone might represent an adjuvant therapy in patients with ACTH hypersecretion. Larger long-term studies are needed.     

Cushing’s disease: radiation therapy

The usual first treatment for Cushing’s disease is surgical removal of the pituitary adenoma. In patients in whom surgery is unsuccessful or who decline an operation, radiation to the pituitary offers the possibility of remission. No form of radiation delivery results in immediate control of cortisol production. Thus, until radiation treatment becomes effective, medical therapy to lower cortisol production is indicated. The time to remission with radiation therapy cannot be predicted, medical therapy should be discontinued every 6 months to assess response to radiation treatment; a normal 24 h urine free cortisol being the optimal outcome. There are no prospective studies comparing the results among the different types of radiation delivery. The type of radiation delivery depends on several factors, including the availability of different treatment modalities and the size of the target area (focused high dose radiation with the Gamma knife is not suitable for a large lesion close to the optic nerves or optic chiasm). All types of radiation delivery cause loss of normal pituitary function and patients should be monitored regularly (every 6 months) for development of new hypopituitarism and appropriate hormone replacement(s). Complications of radiation therapy may include adverse effects on vision, normal brain tissue, and with older methods of fractionated radiation delivery, vasculopathy with an increased risk of cerebrovascular disease. Current use of more targeted methods of delivery will hopefully reduce this risk. If pituitary surgery is unsuccessful and the patient undergoes bilateral adrenalectomy, without pituitary radiation, there is a substantial risk, approximately 50% of patients, of development of Nelson’s syndrome (growth of pituitary adenoma, increase in serum ACTH, hyperpigmentation). There is a role for pituitary radiation in the treatment of patients with Cushing’s disease, most commonly as adjunctive therapy after unsuccessful pituitary surgery. Regular medical monitoring is necessary to determine the effectiveness of radiation therapy and development of new pituitary hormone deficiency.     

Current management of Cushing's disease

Cushing's disease (CD) is caused by a pituitary tumour that secretes adrenocorticotropin (ACTH) autonomously, leading to excess cortisol secretion from the adrenal glands. The condition is associated with increased morbidity and mortality that can be mitigated by treatments that result in sustained endocrine remission. Transsphenoidal pituitary surgery (TSS) remains the mainstay of treatment for CD but requires considerable neurosurgical expertise and experience in order to optimize patient outcomes. Up to 90% of patients with microadenomas (tumour below 1 cm in largest diameter) and 65% of patients with macroadenomas (tumour at or above 1 cm in greatest diameter) achieve endocrine remission after TSS by an experienced surgeon. Patients who are not in remission postoperatively or those who relapse may benefit from undergoing a second pituitary operation. Alternatively, radiation therapy to the sella with interim medical therapy, or bilateral adrenalectomy, can be effective as definitive treatments of CD. Medical therapy is currently adjunctive in most patients with CD and is generally prescribed to patients who are about to receive radiation therapy and will be awaiting its salutary effects to occur. Available treatment options include steroidogenesis inhibitors, centrally acting agents and glucocorticoid receptor antagonists. Several novel agents are in clinical trials and may eventually constitute additional treatment options for this serious condition.     

Nelson's syndrome and spontaneous pituitary tumor infarction.

Large, adrenocorticotrophic hormone-secreting pituitary tumors (Nelson's syndrome) developed in four of 12 patients treated with a bilateral adrenalectomy for Cushing's disease. Two of the patients with Nelson's syndrome suffered spontaneous pituitary tumor infarctions. One patient improved under close observation and subsequent radiation therapy, although she ultimately died from her locally invasive tumor. The condition of the other patient-which had stabilized-appeared to be worsened by surgical intervention. The high incidence of these tumors after bilateral adrenalectomy, their large and agressive nature, and their apparent propensity to undergo spontaneous infarction supports the position that initial therapy for Cushing's disease should be directed to the pituitary gland.     

Pituicytoma in a patient with Cushing’s disease: case report and review of the literature

Pituicytoma is an exceptionally rare low-grade glioma (WHO grade I) of the neurohypophysis and infundibulum. We are reporting the case of a 48-year-old man who presented with severe Cushing′s syndrome. Endocrinological evaluation unequivocally confirmed pituitary-dependent Cushing’s syndrome (=Cushing’s disease). Cranial MR-imaging displayed a conspicuous area in the dorsal and basal pituitary gland and a minimal bulging of the pituitary gland paramedian of the pituitary stalk on the right side. Transsphenoidal inspection revealed a small tumor in the basal and dorsal pituitary gland. Surprisingly, the definite postoperative histopathological diagnosis of the removed tumor was pituicytoma and not pituitary adenoma. Hence, the microadenoma responsible for Cushing’s disease was not yet removed and persistent hypercortisolism necessitated transsphenoidal re-operation. During re-operation, hemihypophysectomy was performed on the right side. The non-tumorous specimen of the adeno-hypophysis showed signs of Crooke’s hyalinization consistent with Cushing’s disease. Undetectable postoperative ACTH- and cortisol levels provided clear evidence that the underlying ACTH-source was successfully removed during re-operation. Coincidence of pituicytoma and pituitary-dependent Cushing’s disease has not previously been reported.

     

Significant GH deficiency after long-term cure by surgery in adult patients with Cushing's disease

OBJECTIVE: Impaired GH secretion usually accompanies Cushing's syndrome and a variable proportion of patients reportedly fail to recover normal GH secretion after successful treatment. This wide variability is most probably due to differences in the treatment (i.e. surgery and/or radiotherapy), timing of patient re-evaluation after surgery and dynamic tests employed to challenge GH secretion, and hinders a precise assessment of risk of GH deficiency after cure. The aim of the present study is to evaluate GH secretory status after long-term cure of Cushing's disease achieved by surgery alone. DESIGN AND METHODS: We studied 34 patients (27 females and 7 males, age range 21-68 years) formerly affected by Cushing's disease. Patients were studied 2-20 years (median 3.3 years) following remission of hypercortisolism; all patients underwent transsphenoidal surgery with the removal of an ACTH-secreting adenoma; repeat pituitary surgery for relapse was performed in two patients while bilateral adrenalectomy was necessary in two patients. In all subjects, the GH response to GHRH+arginine stimulation was evaluated. At the time of testing, 13 patients were still on steroid replacement therapy. RESULTS: In long-term surgical remission, 22 patients (65.0%) presented subnormal GH secretion; partial GH deficiency (GH peak <16.5 microg/l) was found in 11 patients and severe GH deficiency (GH peak <9 microg/l) in another 11. Male gender and length of hypercortisolism were risk factors for postsurgical GH deficiency. CONCLUSIONS: This study demonstrates the presence of GH deficiency in a high percentage of patients with Cushing's disease after long-term remission of hypercortisolism obtained by surgery alone. Male gender and length of hypercortisolism are the most significant predictors of postsurgical GH deficiency. This finding is significant as it highlights that even the most favourable therapeutical course, i.e. remission achieved by surgery alone, is accompanied by impaired GH secretion. Assessment of GH secretion is therefore recommended for all patients cured from Cushing's disease, even if not submitted to radiotherapy. Studies on the clinical impact of GH deficiency and the use of GH replacement therapy seem warranted in patients cured from Cushing's disease.     

Outcomes and management of patients with Cushing's disease without pathological confirmation of tumor resection after transsphenoidal surgery

CONTEXT: Despite the success of transsphenoidal surgery (TSS) for the treatment of Cushing's disease, in a number of cases, an ACTH-staining pituitary adenoma is not identified histologically. The clinical significance of lack of histological confirmation remains unclear. SETTING: This was a retrospective review of patients treated at the University of Virginia Medical Center. PATIENTS: Of 490 TSS procedures for Cushing's disease between 1993 and 2004, we identified 111 cases without histological adenoma confirmation. MAIN OUTCOME MEASURE: Remission and recurrence of Cushing's disease were measured. RESULTS: Overall, 50% of these patients achieved remission, a figure lower than for our entire series (79%) and for patients with histological confirmation of an ACTH-staining adenoma (88%) (P < 0.001). Patients with a history of two prior TSS achieved remission less often than patients with a history of fewer TSS (P = 0.026). No other factors influenced remission rates. Although the overall recurrence rate (21%, seven of 33 evaluated) was not different from previously published long-term studies, in three of seven cases of recurrence, early recurrences were noted between 2 and 4 months after remission. In patients who did not achieve remission, the most common and effective treatment options were repeat TSS, gamma-knife radiosurgery, and bilateral adrenalectomy. CONCLUSION: The lower remission rate in patients without histological evidence of an adenoma is most likely a result of a decreased rate of adenoma extirpation. The incidence of early recurrence may be a unique feature of this patient population; patients without histological confirmation of tumor resection therefore require close and consistent monitoring postoperatively.     

Surgery for acromegaly: Evolution of the techniques and outcomes

This paper presents an overview of the evolution of pituitary surgery for acromegaly. It begins with the first case, attempted in 1893, through the initial transsphenoidal successes in 1907–1910, to the development of effective craniotomy approaches, and ultimately to the resurrection of the transsphenoidal approach in the 1970s and thereafter. Today, the minimally endoscopic transnasal endoscopic approach is fast becoming the norm. Indications for surgery include active acromegaly, visual loss and other forms of mass effect, pituitary tumor apoplexy, and failure of other therapies (medical, radiation). Contraindications include advanced age, debility or other medical conditions increasing the risk of general anaesthesia or surgery. Surgery for acromegaly has the advantage of immediate lowering of the growth hormone excess, with endocrine remission rates of 70% for microadenomas and 50% for macroadenomas. When surgery fails to obtain remission, a program of therapy is designed for the patient to include adjunctive medical therapy (dopamine agonists, somatostatin analogs, and growth hormone receptor antagonists), radiation therapy or radiosurgery (Gamma knife, Cyberknife, etc.).     

Surgical management of GH-secreting pituitary adenomas: an outcome study using modern remission criteria.

The results of transsphenoidal surgery as initial therapy for GH-secreting pituitary adenomas in 57 acromegalic patients were analyzed retrospectively. Patients with prior surgery or radiation therapy were excluded from the study. Three different criteria were used to define remission: glucose-suppressed (nadir) GH less than 1.0 microg/liter, a normal sex- and age-adjusted IGF-I level, and postoperative random GH levels of 2.5 microg/liter or less. Additionally, we analyzed the neuropathological data, including immunohistochemistry and ultrastructural categorization, and the surgical complications. The short-term remission rate (6-wk postoperative follow-up visit), as determined by a random GH measurement of 2.5 microg/liter or less, was 48.8%; the remission rate, as determined by nadir GH, was 51.4%. For 57 patients followed for 12 months or more after surgery (mean, 37.7 months), surgical remission was achieved in 70.2%, 66.7%, and 61.1%, respectively, for patients assessed by normal IGF-I, random GH, and nadir GH. One patient (1.1%) developed recurrence of active acromegaly 81 months after initially successful surgical therapy. Extrasellar growth of the tumor (P = 0.04) and dural invasion by the adenoma (P = 0.008) were significant univariate predictors of a poor outcome. Tumor size was significantly greater in patients with persistent or recurrent acromegaly (P = 0.02). Patients with tumors of the ultrastructural categories of mixed GH/PRL cell and mammosomatotroph adenomas had the lowest remission rates (50% and 42.9%, respectively). There were no perioperative deaths, and there was no serious morbidity. The permanent complication rate was 3.3% (1 permanent DI and 2 nasal septal perforations). Surgical management of acromegaly currently provides prompt, effective, and satisfactory initial treatment for the majority of patients. Using stringent criteria for remission, primary transsphenoidal surgery for GH-secreting pituitary adenomas is effective and often definitive therapy for acromegaly. These results provide a benchmark for the contemporary results of surgical management as assessed by modern outcome criteria.     

Late recurrences of Cushing's disease after initial successful transsphenoidal surgery

CONTEXT: Few studies have systematically analyzed the long-term recurrence rates of Cushing's disease after initial successful transsphenoidal surgery. SETTING: This was a retrospective review of patients treated at the University of Virginia Medical Center. PATIENTS: A total of 215 subjects with Cushing's disease who underwent initial transsphenoidal surgery for resection of a presumed pituitary microadenoma from 1992-2006 were included. MAIN OUTCOME MEASURES: Remission and recurrence rates of Cushing's disease were examined. Recurrence was defined as an elevated 24-h urine free cortisol with clinical symptoms consistent with Cushing's disease. RESULTS: Of the 215 patients who underwent transsphenoidal surgery for Cushing's disease, surgical remission was achieved in 184 (85.6%). The mean length of follow-up was 45 months. Actuarial recurrence rates of Cushing's disease after initially successful transsphenoidal surgery at 1, 2, 3, and 5 yr were 0.5, 6.7, 10.8, and 25.5%, respectively. Among the 184 patients who achieved remission, 32 (17.4%) patients followed for more than 6 months ultimately had a recurrence of Cushing's disease. The median time to recurrence was 39 months. Immediate postoperative hypocortisolemia (serum cortisol < or = 2 microg/dl within 72-h surgery) was achieved in 97 (45.1%) patients. Patients who had postoperative serum cortisol of more than 2 microg/dl were 2.5 times more likely to have a recurrence than patients who had serum cortisol less than or equal to 2 microg/dl (odds ratio = 2.5; 95% confidence interval 1.12-5.52; P = 0.022). CONCLUSIONS: A quarter of the patients with Cushing's disease who achieve surgical remission after transsphenoidal surgery, recur with long-term follow-up. This finding emphasizes the need for continued biochemical and clinical follow-up to ensure remission after surgery.     

Stereotactic radiosurgery for treatment of Cushing disease: an Australian experience

Stereotactic radiation therapy has emerged as an alternative to conventional radiotherapy for treatment of Cushing disease. The aim of this study was to investigate the efficacy and safety of this treatment. Records of patients with Cushing disease treated with stereotactic radiation were reviewed. Seventeen patients underwent stereotactic radiosurgery. Ten achieved remission after a mean of 23 (95% confidence interval, 15–31) months, and two developed hormone deficiencies.     

PPAR-γ in Cushing's Disease

The majority of pituitary tumors that cause Cushing's disease are small (<1 cm diameter), and most disease morbidity is due to the effects of elevated, non-suppressible, ACTH levels that these tumors secrete. Tumor-derived ACTH leads to adrenal-derived steroid hypersecretion and results in many disabling and sometimes life-threatening symptoms including abnormal fat deposition, skin thinning, psychological disturbances, hypertension, diabetes, osteoporosis and muscle weakness. Cushing's disease is associated with high morbidity and ultimately mortality. In experienced specialized centers, 70% of corticotroph microadenomas can be successfully resected by transsphenoidal pituitary surgery. However, surgical “cure” rates for larger ACTH-secreting pituitary tumors are achieved in only 30% of cases, and recent reports highlight a significant recurrence rate after longer term follow-up even in smaller tumors. Post-surgical persistence of ACTH hypersecretion may require pituitary-directed radiation, but this treatment may take some time to be effective, and like extensive surgical pituitary tumor resection, ultimately leads to partial- or total hypopituitarism in ∼80% 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. Although some currently available drug-based treatments for Cushing's disease effectively control hypercortisolism, their drawback has been that they do not impact on pituitary tumor growth. Recent studies have identified the potential utility of peroxisome-proliferator activating receptor-gamma (PPAR-γ) novel ligands in in vitro, and in vivo Cushing's disease models, and have paved the way for early clinical studies to develop novel therapeutic approaches in Cushing's disease.