Mary Lee Vance

Treatment of Adrenocorticotropin-Dependent Cushing’s Syndrome: A Consensus Statement

OBJECTIVEnOur objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushings syndrome, because there is no recent consensus on the management of this rare disorder.nnnPARTICIPANTSnThirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushings syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushings disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushings disease, and 5) management of ectopic ACTH syndrome, Nelsons syndrome, and special patient populations.nnnEVIDENCEnParticipants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking.nnnCONSENSUS PROCESSnParticipants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority.nnnCONCLUSIONSnACTH-dependent Cushings syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushings syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushings disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushings syndrome, early diagnosis and prompt therapy are warranted.

Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist

BACKGROUNDnPegvisomant is a new growth hormone receptor antagonist that improves symptoms and normalises insulin-like growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to 12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days.nnnMETHODSnTreatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and are excluded from the efficacy analysis.nnnFINDINGSnMean serum IGF-1 concentrations fell by at least 50%: 467 mg/L (SE 24), 526 mg/L (29), and 523 mg/L (40) in patients treated for 6, 12 and 18 months, respectively (p<0.001), whereas growth hormone increased by 12.5 mg/L (2.1), 12.5 mg/L (3.0), and 14.2 mg/L (5.7) (p<0.001). Of the patients treated for 12 months or more, 87 of 90 (97%) achieved a normal serum IGF-1 concentration. In patients withdrawn from pegvisomant (n=45), serum growth hormone concentrations were 8.0 mg/L (2.5) at baseline, rose to 15.2 mg/L (2.4) on drug, and fell back within 30 days of withdrawal to 8.3 mg/L (2.7). Antibodies to growth hormone were detected in 27 (16.9%) of patients, but no tachyphylaxis was seen. Serum insulin and glucose concentrations were significantly decreased (p<0.05). Two patients experienced progressive growth of their pituitary tumours, and two other patients had increased alanine and asparate aminotransferase concentrations requiring withdrawal from treatment. Mean pituitary tumour volume in 131 patients followed for a mean of 11.46 months (0.70) decreased by 0.033 cm(3) (0.057; p=0.353).nnnINTERPRETATIONnPegvisomant is an effective medical treatment for acromegaly.

Endoscopic Transsphenoidal Surgery for Acromegaly: Remission Using Modern Criteria, Complications, and Predictors of Outcome

CONTEXTnDespite the growing application of endoscopic transsphenoidal surgery (ETSS), outcomes for GH adenomas are not clearly defined.nnnOBJECTIVEnWe reviewed our experience with ETSS with specific interest in remission rates using the 2010 consensus criteria, predictors of remission, and associated complications.nnnDESIGN AND SETTINGnThis was a retrospective single institution study. PATIENTS, INTERVENTIONS, AND OUTCOME MEASURES: Sixty acromegalic patients who underwent ETSS were identified. Remission was defined as a normal IGF-I and either a suppressed GH less than 0.4 ng/ml during an oral glucose tolerance test or a random GH less than 1.0 ng/ml.nnnRESULTSnRemission was achieved in all 14 microadenomas and 28 of 46 macroadenomas (61%). Tumor size, age, gender, and history of prior surgery were not predictive on multivariant analysis. In hospital postoperative morning GH levels less than 2.5 ng/ml provided the best prediction of remission (P < 0.001). Preoperative variables predictive of remission included Knosp score (P = 0.017), IGF-I (P = 0.030), and GH (P = 0.042) levels. New endocrinopathy consisted of diabetes insipidus in 5%, adrenal insufficiency in 5.4%, and new hypogonadism in 29% of men and 17% of women. However, 41% of hypogonadal men had normal postoperative testosterone levels and 83% of amenorrheic women regained menses. The most common complaints after surgery were sinonasal (36 of 60, 60%) resolving in all but two.nnnCONCLUSIONSnETSS for GH adenomas is associated with high rates of remission and a low incidence of new endocrinopathy. Despite the panoramic views offered by the endoscope, invasive tumors continue to have lower rates of remission.

American Association of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in growth hormone-deficient adults and transition patients - 2009 update.

The American Association of Clinical Endocrinologists Medical Guidelines for Growth Hormone use in Growth Hormone Deficient Adults and Transition Patients – 2009 Update are systematically developed statements to assist health care providers in medical decision making for specific clinical conditions. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with their best clinical judgment. The presented recommendations may not be appropriate in all situations. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual circumstances.

Endoscopic vs Microsurgical Transsphenoidal Surgery for Acromegaly: Outcomes in a Concurrent Series of Patients Using Modern Criteria For Remission

CONTEXTnIt is unclear whether endoscopic transsphenoidal surgery (ETSS) or microsurgical transsphenoidal surgery (MTS) is a superior surgical approach for pituitary adenomas.nnnOBJECTIVEnThe objective of the study was to compare the outcome of surgery with ETSS and MTS by experienced pituitary surgeons using criteria of remission using current consensus criteria for acromegaly.nnnDESIGN AND SETTINGnThis was a retrospective review of prospectively recorded outcomes. The study was conducted at a tertiary referral center. Patients, Interventions, and Outcome Measures: Remission was defined as a normal IGF-I level and either suppressed GH less than 0.4 ng/mL during an oral glucose tolerance test or random GH less than 1.0 ng/mL. The Youden indices were calculated to determine the optimal cutoffs for using immediate postoperative GH levels to predict the results of later testing for remission.nnnRESULTSnPreoperative demographics and tumor characteristics were not significantly different between patients undergoing ETSS (72 patients) or MTS (41 patients). Overall, postoperative remission was achieved in 20 of 23 microadenomas (87%) and 59 of 90 macroadenomas (66%). Remission rates and perioperative complications were not significantly different between ETSS and MTS groups, except for self-reported sinusitis and alterations in taste or smell, which were significantly higher in patients treated with ETSS. Preoperative variables predicting remission in multivariate analysis included GH less than 45 ng/mL [odds ratio (OR) 6.4, P = .010)] and Knosp score of 0-2 (OR 6.8, P < .001). Postoperative in-hospital GH less than 1.15 ng/mL provided the best predictor of remission (OR 7.7, P < .001; sensitivity of 73%, specificity of 85%) defined by follow-up testing.nnnCONCLUSIONSnOutcomes of transsphenoidal surgery for acromegaly by experienced pituitary surgeons do not differ between endoscopic and microscopic techniques. Regardless of the mode of resection, patients with high preoperative GH levels and Knosp scores are less likely to achieve remission. An immediate postoperative GH level of less than 1.15 ng/mL provides the best immediate predictor of remission, but long-term outcomes are indicated.

Quality of life in patients with a pituitary adenoma.

A validated quality of life (QOL) measure, the SF-36 questionnaire, was used to assess patients perception of the impact of a pituitary adenoma, prior to treatment, on his or her physical and mental functioning. Of 270 new patients evaluated for pituitary disease at the University of Virginia Pituitary Clinic, 168 met the criteria for inclusion (pituitary hormone hypersecretion and/or pituitary adenoma) into this prospective study. Results of the SF-26 questionnaire in 36 patients with acromegaly, 42 patients with Cushings disease, 39 patients with a prolactinoma and 51 patients with a non functioning macroadenoma prior to treatment were compared with those of the normal population; a comparison of results among patients with different types of pituitary adenomas was also performed. Patients with a pituitary adenoma had a significantly decreased QOL compared with the normal population in both physical and mental measures (p < 0.05). There were different degrees of perceived impairment depending on the type of pituitary adenoma. Patients with acromegaly had impairment in measures of physical function while patient with Cushings disease had impairment in all but one measures compared with the normal population and with patients with other types of pituitary adenomas. Patients with a prolactinoma had impairment in mental measures and patients with a non-functioning adenoma had impairment in both physical and mental measures compared with the normal population. Patients with a pituitary adenoma have an impaired quality of life that should be routinely assessed in conjunction with endocrine and anatomic studies before and after treatment.

OUTCOMES AFTER REPEAT TRANSSPHENOIDAL SURGERY FOR RECURRENT CUSHING'S DISEASE

OBJECTIVETo systematically analyze patient outcomes after repeat transsphenoidal (TS) surgery for recurrent Cushings disease. METHODSWe retrospectively reviewed records of all patients with recurrent Cushings disease who underwent repeat TS surgery for resection of a pituitary corticotroph adenoma at the University of Virginia Medical Center from 1992 to 2006. Remission at follow-up was defined as a normal postoperative 24-hour urine free cortisol, or continued need for glucocorticoid replacement after repeat TS surgery. Recurrence of the disease was defined as an elevated 24-hour urine free cortisol with clinical symptoms consistent with Cushings disease while not receiving glucocorticoid replacement. Multivariate logistic regression was performed to evaluate the effect of potential predictors on remission. Recurrence rates, subsequent treatments, and the final endocrine status of the patients are presented. RESULTSWe identified 36 patients who underwent repeat TS surgery for recurrent Cushings disease. The mean age of the patients was 40.3 years (range, 17.1–63.0 yr), and 26 were women. The median time to recurrence after initial successful TS surgery was 36 months (range, 4 mo–16 yr). Remission after repeat TS surgery was observed in 22 (61%) of the 36 patients. During the same time period, of the 338 patients who underwent first-time TS surgery for Cushings disease, remission was achieved in 289 (85.5%). The odds of failure (to achieve remission) for patients with repeat TS surgery for recurrent Cushings disease were 3.7 times that of patients undergoing first-time TS surgery (odds ratio, 3.7; 95% confidence interval, 1.8–7.8). Two of the 22 patients with successful repeat TS surgery had a second recurrence at 6 and 11 months, respectively. Complete biochemical and clinical remission after stereotactic radiosurgery, adrenalectomy, and ongoing ketoconazole therapy was achieved in 30 (83.3%) of the 36 patients, and active disease continued in 6 patients (16.7%). CONCLUSIONAlthough the success of repeat TS surgery for recurrence of Cushings disease is less than that of initial surgery, a second procedure offers a reasonable possibility of immediate remission. If the operation is not successful, other treatments, including pituitary radiation, medical therapy, and even bilateral adrenalectomy, are required.

Perioperative management of patients undergoing pituitary surgery.

The management of a patient who requires pituitary surgery should be a constant collaboration between the neurosurgeon and the endocrinologist. Because the pituitary gland is an anatomic and functional entity, both medical specialties are necessary to treat these patients for the best possible outcome. The notion that pituitary surgery is always curative is not accurate because of the risk for tumor recurrence. A patient with a pituitary lesion who undergoes surgery is clinically identical to a patient with diabetes mellitus--these patients require lifelong monitoring and management as indicated by the clinical, endocrine and anatomic findings. Because there is always a risk for tumor recurrence, appropriate surgical or radiation treatment and hormone replacement may be required at any time after the initial operation. In the patient who undergoes postoperative pituitary radiation, the risk for developing a new pituitary hormone deficiency ranges from 33% to 50%, and is probably higher over time. Thus, these patients must receive regular evaluations regarding the need for additional treatment and hormone replacements. A regular program of life long assessment of pituitary function and anatomy, appropriate hormone replacement and close collaboration with a pituitary surgeon is the ideal care of these patients. Only with such a program can a patient with a pituitary adenoma achieve the best possible outcome.

From Fixed to Individual Dosing in Growth Hormone-Deficient Adults

Initial research studies of growth hormone (GH) replacement in adults employed what is now considered to be high doses of GH, from 12 to 25 µg/kg per day. While the beneficial effects of GH were demonstrated, there was a considerable incidence of side effects, most commonly edema and arthralgia. These side effects abated with a dose reduction. More recently, the Growth Hormone Research Society recommended initiating GH replacement at a dose of 0.3 mg/day irrespective of total or ideal body weight. The United States Food and Drug Administration approved pharmaceutical company package inserts that recommended beginning with a dose of 6 µg/kg per day with a maximum dose of 25 µg/kg per day and limiting the maximal dose to 12.5 µg/kg per day in adults over the age of 35 years. These should be considered as guidelines.

Immunohistochemistry of COUP-TFI: an adjuvant diagnostic tool for the identification of corticotroph microadenomas

Cushing’s disease is caused by an ACTH-producing pituitary tumor, and accounts for 10–15% of pituitary tumors. The majority of corticotroph tumors are microadenomas (<10xa0mm), and accurate histologic identification of these tumors can be challenging because of their small size and the presence of nests of normal corticotroph cells in the anterior pituitary. Retinoic acid has been shown to inhibit ACTH production and induce apoptosis in corticotroph tumor cells. The expression of the orphan nuclear receptor COUP-TFI antagonizes retinoic acid signaling and has been shown to be expressed in normal corticotroph cells, but absent in corticotroph tumor cell lines. We analyzed 34 corticotroph tumor specimens by immunohistochemistry using a goat polyclonal IgG antibody with epitope mapping to the N-terminus of human COUP-TFI. Segments of normal pituitary in each of the 34 specimens demonstrate COUP-TFI immunoreactivity in normal corticotroph cells. Twenty-nine of 34 ACTH producing tumors were immunonegative for COUP-TFI. All of the tumors measuring less than 5xa0mm by preoperative MRI were COUP-TFI immunonegative. Two tumors, measuring 9 and 11xa0mm, showed consistent (>90%) expression of COUP-TFI, and three adenomas (5, 11, and 18xa0mm) showed heterogenous (20–80%) expression of COUP-TFI. Immunohistochemistry of COUP-TFI may be a useful adjuvant diagnostic tool in distinguishing corticotroph microadenomas from nests of normal corticotroph cells in the anterior pituitary. Furthermore, this study identifies two unique corticotroph tumor populations which differ in their expression of COUP-TFI, the presence of which occurs more frequently in macroadenomas.