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OBJECTIVE Stereotactic radiosurgery (SRS) provides a safe and effective therapeutic modality for patients with pituitary adenomas. The mechanism of delayed endocrine deficits based on targeted radiation to the hypothalamic-pituitary axis remains unclear. Radiation to normal neuroendocrine structures likely plays a role in delayed hypopituitarism after SRS. In this multicenter study by the International Radiosurgery Research Foundation (IRRF), the authors aimed to evaluate radiation tolerance of structures surrounding pituitary adenomas and identify predictors of delayed hypopituitarism after SRS for these tumors. METHODS This is a retrospective review of patients with pituitary adenomas who underwent single-fraction SRS from 1997 to 2019 at 16 institutions within the IRRF. Dosimetric point measurements of 14 predefined neuroanatomical structures along the hypothalamus, pituitary stalk, and normal pituitary gland were made. Statistical analyses were performed to determine the impact of doses to critical structures on clinical, radiographic, and endocrine outcomes. RESULTS The study cohort comprised 521 pituitary adenomas treated with SRS. Tumor control was achieved in 93.9% of patients over a median follow-up period of 60.1 months, and 22.5% of patients developed new loss of pituitary function with a median treatment volume of 3.2 cm3. Median maximal radiosurgical doses to the hypothalamus, pituitary stalk, and normal pituitary gland were 1.4, 7.2, and 11.3 Gy, respectively. Nonfunctioning adenoma status, younger age, higher margin dose, and higher doses to the pituitary stalk and normal pituitary gland were independent predictors of new or worsening hypopituitarism. Neither the dose to the hypothalamus nor the ratio between doses to the pituitary stalk and gland were significant predictors. The threshold of the median dose to the pituitary stalk for new endocrinopathy was 10.7 Gy in a single fraction (OR 1.77, 95% CI 1.17–2.68, p = 0.006). CONCLUSIONS SRS for the treatment of pituitary adenomas affords a high tumor control rate with an acceptable risk of new or worsening endocrinopathy. This evaluation of point dosimetry to adjacent neuroanatomical structures revealed that doses to the pituitary stalk, with a threshold of 10.7 Gy, and doses to the normal gland significantly increased the risk of post-SRS hypopituitarism. In patients with preserved pre-SRS neuroendocrine function, limiting the dose to the pituitary stalk and gland while still delivering an optimal dose to the tumor appears prudent.

Nelson’s syndrome is a rare but challenging sequelae of Cushing’s disease (CD) after bilateral adrenalectomy (BLA). We sought to determine if stereotactic radiosurgery (SRS) of residual pituitary adenoma performed before BLA can decrease the risk of Nelson’s syndrome. Consecutive patients with CD who underwent BLA after non-curative resection of ACTH secreting pituitary adenoma and had at least one follow-up visit after BLA were studied. Nelson’s syndrome was diagnosed based on the combination of rising ACTH levels, increasing volume of the pituitary adenoma and/or hyperpigmentation. Fifty patients underwent BLA for refractory CD, and 43 patients (7 men and 36 women) had at least one follow-up visit after BAL. Median endocrine, imaging, and clinical follow-up were 66 months, 69 months, and 80 months, respectively. Nine patients (22%) were diagnosed with the Nelson’s syndrome at median time after BLA at 24 months (range: 0.6–119.4 months). SRS before BLA was associated with reduced risk of the Nelson’s syndrome (HR = 0.126; 95%CI [0.022–0.714], p=0.019), while elevated ACTH level within 6 months after BLA was associated with increased risk for the Nelson’s syndrome (HR = 9.053; 95%CI [2.076–39.472], p=0.003). SRS before BLA can reduce the risk for the Nelson’s syndrome in refractory CD patients requiring BLA and should be considered before proceeding to BLA. Elevated ACTH concentration within 6 months after BLA is associated with greater risk of the Nelsons’ syndrome. When no prior SRS is administered, those with a high ACTH level shortly after BLA may benefit from early SRS.

OBJECTIVEThe role of primary stereotactic radiosurgery (SRS) in patients with medically refractory acromegaly who are not operative candidates or who refuse resection is poorly understood. The aim of this multicenter, matched cohort study was to compare the outcomes of primary versus postoperative SRS for acromegaly.METHODSThe authors reviewed an International Radiosurgery Research Foundation database of 398 patients with acromegaly who underwent SRS and categorized them into primary or postoperative cohorts. Patients in the primary SRS cohort were matched, in a 1:2 ratio, to those in the postoperative SRS cohort, and the outcomes of the 2 matched cohorts were compared.RESULTSThe study cohort comprised 78 patients (median follow-up 66.4 months), including 26 and 52 in the matched primary and postoperative SRS cohorts, respectively. In the primary SRS cohort, the actuarial endocrine remission rates at 2 and 5 years were 20% and 42%, respectively. The Cox proportional hazards model showed that a lower pre-SRS insulin-like growth factor–1 level was predictive of initial endocrine remission (p = 0.03), whereas a lower SRS margin dose was predictive of biochemical recurrence after initial remission (p = 0.01). There were no differences in the rates of radiological tumor control (p = 0.34), initial endocrine remission (p = 0.23), biochemical recurrence after initial remission (p = 0.33), recurrence-free survival (p = 0.32), or hypopituitarism (p = 0.67) between the 2 matched cohorts.CONCLUSIONSPrimary SRS has a reasonable benefit-to-risk profile for patients with acromegaly in whom resection is not possible, and it has similar outcomes to endocrinologically comparable patients who undergo postoperative SRS. SRS with medical therapy in the latent period can be used as an alternative to surgery in selected patients who cannot or do not wish to undergo resection.

In Cushing disease, early post-operative serum cortisol fluctuations have not been adequately characterized, and their association with initial remission and recurrence is unclear.A retrospective cohort study of patients with Cushing disease was conducted at two institutions. A "riser" was defined a priori as a paradoxical increase in serum cortisol with an immediate incremental increase in serum cortisol over three consecutive cortisol draws separated by roughly 6-h (definition 1). Post hoc analyses used a definition of two consecutive increases (definition 2). Risers were compared to non-risers for initial remission and time-to-recurrence.A total of 505 patients with Cushing disease were screened, and 469 had adequate data for group assignment. Analysis of post-operative cortisol showed a subgroup of "risers" with a frequency of 3.6% for definition 1 and 42.6% for definition 2. In these patients, cortisol levels were significantly higher until approximately 36 h post-operatively, and cortisol had a significantly longer mean serum half-life. In the post hoc analysis, definition 2 risers had a lower remission rate compared to non-risers (162/196, 82.7%, versus 243/264, 92.0%) with an odds ratio of 0.41 (0.23-0.73; p = 0.003). For both definitions, recurrence was similar between groups.We found that almost half of Cushing disease patients experienced a temporary increase in serum cortisol level during the early post-operative period. Serum cortisol half-life was longer, and the remission rates were lower, however, recurrence rates were similar to non-risers.

IntroductionDelayed hypopituitarism is the most common complication after stereotactic radiosurgery (SRS) for pituitary adenomas. The aim of this study was to investigate the relationship between the distance from the hypothalamic-pituitary axis to the treatment target and anterior pituitary function preservation after SRS. MethodsBetween 2007 and 2020, consecutive adult patients who underwent single-session SRS for pituitary adenomas with ³6 months of follow-up were included. Distance measurements between hypothalamic-pituitary axis structures and the SRS target volume were quantified on MRI. The primary outcome was anterior pituitary function preservation. Outcomes were compared using multivariable regression and area under the receiver operator characteristic curve (AUROC) analyses. ResultsThe study cohort comprised 224 patients, who were categorized by preservation (n=168) and no preservation (n=56) of anterior pituitary function after SRS. Independent predictors of anterior pituitary function preservation were a greater distance between the center of the pituitary gland and center of the SRS target (OR=1.101 [1.000–1.213], p=0.050), and a shorter clinical follow-up duration (OR=0.985 [0.977–0.993], pConclusionsGreater distance between the normal pituitary gland and the SRS target is associated with anterior pituitary function preservation and increasing this distance should be a goal of adenoma resection. Larger prospective, multi-center studies are necessary to corroborate this finding and establish the effects of distance on hypopituitarism after SRS for pituitary adenomas.

Cushing’s disease (CD) is rare disorder that should be adequately managed to optimize long-term prognosis. Treatment of CD is multidisciplinary and often includes surgical resection, adjuvant stereotactic radiosurgery (SRS), and medical treatment. Here we review surgical and radiosurgical treatment strategies for ACTH producing pituitary adenomas. A comprehensive literature review was carried out to review remission and recurrence rates, and complications of surgical and SRS treatments of ACTH producing pituitary adenomas. Surgical resection plays a central role in the management of ACTH secreting pituitary adenomas and usually allows rapid endocrine remission that ranges from 69 to 90%. The most common complications after resection include some degree of new hypopituitarism, diabetes insipidus and CSF leak. Devastating complications, such as injury of vascular and neural structures, are very rare. Surgeon experience and adequate pre-operative imaging are important for safe and successful surgery. Endocrine recurrence rates after resection range from 9 to 30%. SRS is often employed for incompletely resected adenomas. Endocrine remission after SRS ranges from 35 to 72%. The most common complication of SRS is new anterior pituitary gland deficiency. Recurrence rates after GKRS range from 18 to 24%. Transsphenoidal resection of ACTH producing pituitary adenoma is a safe and highly effective procedure for CD in experienced hands. Radiosurgery is more frequently used as treatment of residual and recurrent adenoma and persistent CD. Long-term endocrine and imaging follow-up is important as delayed recurrences and hypopituitarism are not infrequent.

OBJECTIVERecurrent or residual adenomas are frequently treated with Gamma Knife radiosurgery (GKRS). The most common complication after GKRS for pituitary adenomas is hypopituitarism. In the current study, the authors detail the timing and types of hypopituitarism in a multicenter, international cohort of pituitary adenoma patients treated with GKRS.METHODSSeventeen institutions pooled clinical data obtained from pituitary adenoma patients who were treated with GKRS from 1988 to 2016. Patients who had undergone prior radiotherapy were excluded. A total of 1023 patients met the study inclusion criteria. The treated lesions included 410 nonfunctioning pituitary adenomas (NFPAs), 262 cases of Cushing’s disease (CD), and 251 cases of acromegaly. The median follow-up was 51 months (range 6–246 months). Statistical analysis was performed using a Cox proportional hazards model to evaluate factors associated with the development of new-onset hypopituitarism.RESULTSAt last follow-up, 248 patients had developed new pituitary hormone deficiency (86 with NFPA, 66 with CD, and 96 with acromegaly). Among these patients, 150 (60.5%) had single and 98 (39.5%) had multiple hormone deficiencies. New hormonal changes included 82 cortisol (21.6%), 135 thyrotropin (35.6%), 92 gonadotropin (24.3%), 59 growth hormone (15.6%), and 11 vasopressin (2.9%) deficiencies. The actuarial 1-year, 3-year, 5-year, 7-year, and 10-year rates of hypopituitarism were 7.8%, 16.2%, 22.4%, 27.5%, and 31.3%, respectively. The median time to hypopituitarism onset was 39 months.In univariate analyses, an increased rate of new-onset hypopituitarism was significantly associated with a lower isodose line (p = 0.006, HR = 8.695), whole sellar targeting (p = 0.033, HR = 1.452), and treatment of a functional pituitary adenoma as compared with an NFPA (p = 0.008, HR = 1.510). In multivariate analyses, only a lower isodose line was found to be an independent predictor of new-onset hypopituitarism (p = 0.001, HR = 1.38).CONCLUSIONSHypopituitarism remains the most common unintended effect of GKRS for a pituitary adenoma. Treating the target volume at an isodose line of 50% or greater and avoiding whole-sellar radiosurgery, unless necessary, will likely mitigate the risk of post-GKRS hypopituitarism. Follow-up of these patients is required to detect and treat latent endocrinopathies.

The objective of this study is to evaluate the role of Crooke’s changes (CC) in normal the peri-tumoral anterior pituitary gland, in patients with Cushing’s disease (CD) with a histopathological confirmed corticotroph adenoma, and determine if there is any difference in the recurrence and remission rates in CD patients after treatment with Gamma Knife Radiosurgery (GKRS). All patients treated with GKRS for CD from 2005 to 2016 at our institution were identified. Patients had a confirmed adrenocorticotropic (ACTH)-secreting adenoma, i.e. corticotroph adenoma, and normal pituitary gland included in the surgical specimen, and specimens were stained with hematoxylin and eosin and also immunostaining for cytokeratin and ACTH. Statistical analyses were performed in a total of 61 patients who met the inclusion criteria. Additionally, we analyzed 20 patients in each group, with and without CC, after they were matched in a propensity score fashion. Endocrine remission defined as, a normal 24 h urine free cortisol while off suppressive medication, occurred in 48 patients (78.7%), with 76.9% in those with CC and 81.8% in those without CC. There was no statistical significant difference between the two groups in regarding remission (p = 0.312) or recurrence (p = 0.659) in either the unmatched or matched cohorts. The presence or absence of CC in normal pituitary gland does not appear to confer a lower rate of remission or a higher rate of recurrence after GKRS. Patients with pituitary corticotroph adenomas that present with CC features may be well served by Stereotactic radiosurgery (SRS).

OBJECTIVE Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common problem during the postoperative course after pituitary surgery. Although treatment of this condition is well characterized, prevention strategies are less studied and reported. The authors sought to characterize outcomes and predictive factors of SIADH after implementation of routine postoperative fluid restriction for patients undergoing endoscopic transsphenoidal surgery for pituitary adenoma. METHODS In March 2018, routine postoperative fluid restriction to 1000 ml/day for 7 days was instituted for all patients who underwent surgery for pituitary adenoma. These patients were compared with patients who underwent surgery for pituitary adenoma between March 2016 and March 2018, prior to implementation of routine fluid restriction. Patients with preoperative history of diabetes insipidus (DI) or concern for postsurgical DI were excluded. Patients were followed by neuroendocrinologists and neurosurgeons, and sodium levels were checked between 7 and 10 days postoperatively. SIADH was defined by a serum sodium level less than 136 mmol/L, with or without symptoms within 10 days after surgery. Thirty-day readmission was recorded and reviewed to determine underlying reasons. RESULTS In total, 82 patients in the fluid-unrestricted cohort and 135 patients in the fluid-restricted cohort were analyzed. The patients in the fluid-restricted cohort had a significantly lower rate of postoperative SIADH than patients in the fluid-unrestricted cohort (5% vs 15%, adjusted OR [95% CI] 0.1 [0.0–0.6], p = 0.01). Higher BMI was associated with lower rate of postoperative SIADH (adjusted OR [95%] 0.9 [0.9–1.0], p = 0.03), whereas female sex was associated with higher rate of SIADH (adjusted OR [95% CI] 3.1 [1.1–9.8], p = 0.03). There was no difference in the 30-day readmission rates between patients in the fluid-unrestricted and fluid-restricted cohorts (4% vs 7%, adjusted OR [95% CI] 0.5 [0–5.1], p = 0.56). Thirty-day readmission was more likely for patients with history of hypertension (adjusted OR [95% CI] 5.7 [1.3–26.3], p = 0.02) and less likely for White patients (adjusted OR [95% CI] 0.3 [0.1–0.9], p = 0.04). CONCLUSIONS Routine fluid restriction reduced the rate of SIADH in patients who underwent surgery for pituitary adenoma but was not associated with reduction in 30-day readmission rate.

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.

Stereotactic radiosurgery (SRS) is frequently used for Cushing's disease (CD) after failed pituitary surgery. Management of patients with persistent CD after failed SRS is complex, as the alternative therapeutic options harbor significant risks. The outcomes of repeat pituitary radiosurgery, however, have not been described. We sought to determine the outcomes of repeat SRS in patients with CD. We pooled data from five institutions participating in the International Gamma Knife Research Foundation for patients with recurrent or persistent CD ≥ 12 months after initial SRS. Patients were included in the study if they had ≥ 6 months endocrine follow-up after repeat SRS. Twenty patients were included in the study. Repeat single-session SRS was performed 1.3-9.7 years after initial SRS. Median endocrine follow-up was 6.6 years (1.4-19.1 years). Median margin dose was 20 Gy (range 10.8-35 Gy). Endocrine remission after second SRS was noted in 12 patients (60%), with a median time to remission of 6 months (range 2-64 months). Biochemical recurrence occurred in two patients (17%) after initial remission. Overall, the cumulative rates of durable endocrine remission at 5 and 10 years were 47 and 53%, respectively. Two patients (10%) experienced adverse radiation effects, including transient visual loss and permanent diplopia. Repeat SRS achieves lasting biochemical remission in approximately half of patients with CD refractory to both prior microsurgery and SRS. Because of the morbidity of refractory or recurrent CD, repeat SRS should be considered for carefully selected patients with hypercortisolism confirmed one or more years after initial SRS.

Background Nelson's syndrome may be a devastating complication for patients with Cushing's disease who underwent a bilateral adrenalectomy. Previous studies have demonstrated that stereotactic radiosurgery (SRS) can be used to treat patients with Nelson's syndrome. Objective To report a retrospective study of patients with Nelson's syndrome treated with Gamma Knife radiosurgery to evaluate the effect of SRS on endocrine remission and tumor control. Methods Twenty-seven patients with Nelson's syndrome treated with Gamma Knife radiosurgery after bilateral adrenalectomy were included in this study. After radiosurgery, patients were followed with serial adrenocorticotropic hormone (ACTH) levels and MRI sequences to assess for endocrine remission and tumor control. Cox proportional hazards regression analysis was used to evaluate the relationship between the time to remission and potential prognostic factors. Results In 21 patients with elevated ACTH prior to SRS and endocrine follow-up data, 14 (67%) had decreased or stable ACTH levels, and 7 achieved a normal ACTH level at a median of 115 mo (range 7-272) post-SRS. Tumor volume was stable or reduced after SRS in 92.5% of patients (25/27) with radiological follow-up. Time to remission was not significantly associated with the ACTH prior to SRS (P = .252) or with the margin dose (P = .3). However, a shorter duration between the patient's immediate prior transsphenoidal resection and SRS was significantly associated with a shorter time to remission (P = .045). Conclusion This retrospective analysis suggests that SRS is an effective means of achieving endocrine remission and tumor control in patients with Nelson's syndrome.

BACKGROUND In the immediate postoperative period following resection of growth hormone (GH)-secreting pituitary tumors, serum concentrations of GH have limited ability to predict remission of acromegaly. Since many actions of GH actions are mediated by insulin-like growth factor-1 (IGF-I), we aimed to determine the rates of fall of IGF-I during 72 h after surgical resection of pituitary tumors. METHODS We studied patients who were undergoing pituitary surgery for acromegaly. IGF-I was measured by LC-MS and GH by immunoassay. Remission was defined by the combination of serum GH RESULTS During the first 72 h after surgery, the mean (SD) rate of decline of IGF-I was 185 (61) ng/mL per 24 h in those who achieved remission (n = 23), with a mean (SD) apparent half-life of 55 (19) h. IGF-I had decreased to CONCLUSIONS Rapid decline of serum IGF-I during the immediate postoperative period warrants further study as an analytically independent adjunct to GH measurement for early prediction of biochemical remission of acromegaly.

OBJECTIVEStereotactic radiosurgery (SRS) is used for the management of residual or recurrent Cushing’s disease (CD). Increasing experience and technological advancements of Gamma Knife radiosurgery (GKRS) systems can impact the outcomes of CD patients. The authors evaluated the association of their center’s growing experience and the era in which GKRS was performed with treatment success and adverse events in patients with CD.METHODSThe authors studied consecutive patients with CD treated with GKRS at the University of Virginia since installation of the first Gamma Knife system in March 1989 through August 2019. They compared endocrine remission and complication rates between patients treated before 2000 (early cohort) and those who were treated in 2000 and later (contemporary cohort).RESULTSOne hundred thirty-four patients with CD underwent GKRS during the study period: 55 patients (41%) comprised the early cohort, and 79 patients (59%) comprised the contemporary cohort. The contemporary cohort, compared with the early cohort, had a significantly greater treatment volume, radiation prescription dose, maximal dose to the optic chiasm, and number of isocenters, and they more often had cavernous sinus involvement. Endocrine remission rates were higher in the contemporary cohort when compared with the early cohort (82% vs 66%, respectively; p = 0.01). In a Cox regression analysis adjusted for demographic, clinical, and SRS characteristics, the contemporary GKRS cohort had a higher probability of endocrine remission than the early cohort (HR 1.987, 95% CI 1.234–3.199; p = 0.005). The tumor control rate, incidence of cranial nerve neuropathy, and new anterior pituitary deficiency were similar between the two groups.CONCLUSIONSTechnological advancements over the years and growing center experience were important factors for improved endocrine remission rates in patients with CD. Technological aspects and results of contemporary Gamma Knife systems should be considered when counseling patients, planning treatment, and reporting treatment results. Studies exploring the learning curve for GKRS are warranted.

Pituitary adenomas comprise about 3% of all intracranial tumors in pediatric patients. This study examines the role of stereotactic radiosurgery in the management of pediatric acromegaly or patients with Cushing disease (CD).From an international consortium, we retrospectively collected treatment and outcome data on pediatric adrenocorticotrophic hormone and growth hormone-secreting pituitary adenomas treated with Gamma Knife radiosurgery (GKRS). There were a total of 36 patients including 24 with CD and 12 with acromegaly. The data were analyzed to assess outcomes including tumor control, endocrine remission, and adverse effects. Statistical analysis was performed to determine correlation between clinical/treatment parameters and outcomes.At the last follow-up after GKRS, endocrine remission rates for CD and acromegaly were 80% and 42%, respectively. Tumor control was achieved in 87.5% of patients with CD and in 42% of patients with acromegaly. New pituitary hormone deficiency occurred in 7 of the 36 patients at a median time of 18 months after GKRS (range, 12-81 months). The predictive factors for endocrine remission were age15 years (P = 0.015) and margin dose (P = 0.042). The median endocrine follow-up was 63.7 months (range, 7-246 months).GKRS affords reasonable rates of endocrine remission and tumor control in most pediatric patients with functioning adenomas. The most common post-GKRS complication was hypopituitarism, although this occurred in only a few patients. Given the larger at-risk period for pediatric patients, further study is required to evaluate for delayed recurrences and hypopituitarism.

OBJECTIVEThe relationship between growth hormone (GH) and insulin-like growth factor–1 (IGF-1) in patients with acromegaly as serial levels drop over time after treatment has not been examined previously. Knowledge of this relationship is important to correlate pretreatment levels that best predict response to treatment. To examine the correlation between GH and IGF-1 and IGF-1 z-scores over a wide range of GH levels, the authors examined serial GH and IGF-1 levels at intervals before and after surgery and radiosurgery for acromegaly.METHODSThis retrospective analysis correlates 414 pairs of GH and IGF-1 values in 93 patients with acromegaly.RESULTSAbsolute IGF-1 levels increase linearly with GH levels only up to a GH of 4 ng/ml, and with IGF-1 z-scores only to a GH level of 1 ng/ml. Between GH levels of 1 and 10 ng/ml, increases in IGF-1 z-scores relative to changes in GH diminish and then plateau at GH concentrations of about 10 ng/ml. From patient to patient there is a wide range of threshold GH levels beyond which IGF-1 increases are no longer linear, GH levels at which the IGF-1 response plateaus, IGF-1 levels at similar GH values after the IGF-1 response plateaus, and of IGF-1 levels at similar GH levels.CONCLUSIONSIn acromegaly, although IGF-1 levels represent a combination of the integrated effects of GH secretion and GH action, the tumor produces GH, not IGF-1. Nonlinearity between GH and IGF-1 occurs at GH levels far below those previously recognized. To monitor tumor activity and tumor viability requires measurement of GH levels.

Background Targeted stereotactic radiosurgery (SRS) with sparing of the residual pituitary is the traditional radiosurgical method for pituitary adenomas. Whole-sella SRS is an alternative choice for radiologically indeterminate or large adenomas, the safety and efficacy of which has yet to be determined. Objective To determine if whole-sella SRS in acromegaly would have comparable radiographic and biochemical control to targeted SRS. We performed a multicenter, retrospective matched cohort study to compare outcomes between groups. Methods We conducted a retrospective review of acromegalic patients who underwent SRS from 1990 to 2016 at 10 centers participating in the International Radiosurgery Research Foundation. Whole-sella and targeted SRS patients were then matched in a 1:1 ratio. Results A total of 128 patients were eligible for inclusion. Whole-sella patients had a higher pre-SRS random serum growth hormone, larger treatment volume, and higher maximum point dose to the optic apparatus. The rates of initial/durable endocrine remission, new loss of pituitary function, and new cranial neuropathy were similar between groups. Mortality and new visual deficit were higher in the whole-sella cohort, though not statistically significant. Conclusion There was no difference in biochemical remission or recurrence between treatment groups. Although not statistically significant, the higher rates of tumor regression and lower rates of mortality and new visual deficit may suggest consideration of targeted SRS over whole-sella SRS in acromegaly treatment. Further research is needed to determine the association between visual deficits and mortality with whole-sella SRS.

OBJECTIVEGamma Knife radiosurgery (GKRS) provides a safe and effective management option for patients with all types of pituitary adenomas. The long-term adverse effects of targeted radiation to the hypothalamic-pituitary axis in relationship to radiation dose remain unclear. In this retrospective review, the authors investigated the role of differential radiation doses in predicting long-term clinical outcomes and pituitary function after GKRS for pituitary adenomas.METHODSA cohort of 236 patients with pituitary tumors (41.5% nonfunctioning, 58.5% functioning adenomas) was treated with GKRS between 1998 and 2015. Point dosimetric measurements, with no minimum volume, to 14 consistent points along the hypothalamus bilaterally, pituitary stalk, and normal pituitary were made. Statistical analyses were performed to determine the impact of doses to critical structures on clinical, radiological, and endocrine outcomes.RESULTSWith a median follow-up duration of 42.9 months, 18.6% of patients developed new loss of pituitary function. The median time to endocrinopathy was 21 months (range 2–157 months). The median dose was 2.1 Gy to the hypothalamus, 9.1 Gy to the pituitary stalk, and 15.3 Gy to the normal pituitary. Increasing age (p = 0.015, HR 0.98) and ratio of maximum dose to the pituitary stalk over the normal pituitary gland (p = 0.013, HR 0.22) were independent predictors of new or worsening hypopituitarism in the multivariate analysis. Sex, margin dose, treatment volume, nonfunctioning adenoma status, or ratio between doses to the pituitary stalk and hypothalamus were not significant predictors.CONCLUSIONSGKRS offers a low rate of delayed pituitary insufficiency for pituitary adenomas. Doses to the hypothalamus are low and generally do not portend endocrine deficits. Patients who are treated with a high dose to the pituitary stalk relative to the normal gland are at higher risk of post-GKRS endocrinopathy. Point dosimetry to specific neuroanatomical structures revealed that a ratio of stalk-to-gland radiation dose of 0.8 or more significantly increased the risk of endocrinopathy following GKRS. Improvement in the gradient index toward the stalk and normal gland may help preserve endocrine function.

Achievement of biochemical remission with preservation of normal pituitary function is the goal of treatment for Cushing's disease. For patients with persistent or recurrent Cushing's disease after transsphenoidal resection, radiation therapy may be a safe and effective treatment. Stereotactic radiosurgery is favored over conventional fractionated external beam radiation. Hormonal recurrence rates range from 0% to 36% at 8 years after treatment. Tumor control rates are high. New pituitary hormone deficiency is the most common adverse effect after stereotactic radiosurgery and external beam radiation. The effects of radiation planning optimization and use of adjuvant medication on endocrine remission rates warrant investigation.

Background Stereotactic radiosurgery (SRS) is a treatment option for persistent or recurrent acromegaly secondary to a growth hormone secreting pituitary adenoma, but its efficacy is inadequately defined. Objective To assess, in a multicenter, retrospective cohort study, the outcomes of SRS for acromegaly and determine predictors. Methods We pooled and analyzed data from 10 participating institutions of the International Gamma Knife Research Foundation for patients with acromegaly who underwent SRS with endocrine follow-up of ≥6 mo. Results The study cohort comprised 371 patients with a mean endocrine follow-up of 79 mo. IGF-1 lowering medications were held in 56% of patients who were on pre-SRS medical therapy. The mean SRS treatment volume and margin dose were 3.0 cm3 and 24.2 Gy, respectively. The actuarial rates of initial and durable endocrine remission at 10 yr were 69% and 59%, respectively. The mean time to durable remission after SRS was 38 mo. Biochemical relapse after initial remission occurred in 9%, with a mean time to recurrence of 17 mo. Cessation of IGF-1 lowering medication prior to SRS was the only independent predictor of durable remission (P = .01). Adverse radiation effects included the development of ≥1 new endocrinopathy in 26% and ≥1 cranial neuropathy in 4%. Conclusion SRS is a definitive treatment option for patients with persistent or recurrent acromegaly after surgical resection. There appears to be a statistical association between the cessation of IGF-1 lowering medications prior to SRS and durable remission.

Background Stereotactic radiosurgery (SRS) is used to manage patients with Cushing disease (CD) who have failed surgical/medical management. Because many patients with recurrent/persistent CD lack an identifiable adenoma on neuroimaging, whole-sellar SRS has been increasingly used. Thus, we sought to define the outcomes of patients undergoing whole-sellar SRS. Methods An international, multicenter, retrospective cohort design was used to define clinical/endocrine outcomes for patients undergoing whole-sellar SRS for CD. Propensity-score matching was used to compare patients undergoing whole-sellar SRS and patients who underwent discreet adenoma-targeted SRS. Results A total of 68 patients underwent whole-sellar SRS, with a mean endocrine follow-up of 5.3 years. The mean treatment volume was 2.6 cm3, and the mean margin dose was 22.4 Gy. The 5-year actuarial remission rate was 75.9%, and the median time to remission was 12-months. Treatment volumes >1.6 cm3 were associated with shorter times to remission (P Conclusions Whole-sellar GKRS is effective in controlling CD when an adenoma is not clearly defined on imaging or when an invasive adenoma is suspected at the time of initial surgery. Patients who undergo whole-sellar SRS have outcomes and rates of new pituitary hormone deficiency similar to those of patients who undergo discrete adenoma-targeted GKRS.

To compare and describe the time to endocrine remission and new hypopituitarism among patients with growth hormone (GH) and adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas after radiosurgery, controlling for several known prognostic factors.An institutional review board-approved, institutional retrospective analysis of patients with GH- and ACTH-secreting pituitary adenomas was performed, with matching for patient sex, age at radiosurgery, interval between the last resection and radiosurgery, use of previous radiation therapy, whole sella treatment, suprasellar extension, cavernous sinus invasion, and margin dose. Endocrine remission was defined as a normal serum insulin-like growth factor-1 (GH secreting) or a normal 24-hour urine-free cortisol (ACTH secreting) level without suppressive medications. Endocrine remission and the incidence of new hypopituitarism after single-fraction radiosurgery were recorded and compared between the 2 groups.The data from 242 patients were evaluated, 121 with GH-secreting tumors and 121 with ACTH-secreting tumors. Of the 242 patients, 75% had cavernous sinus invasion and 10% had suprasellar extension at radiosurgery. The median radiosurgical marginal dose was 25 Gy to the 50% isodose line between each group. After multivariable adjustment, the factors associated with an increased time to endocrine remission included patient age (hazard ratio [HR] 1.016; P = .023), cavernous sinus invasion (HR 1.793; P = .004), and the presence of acromegaly (HR 2.912; P .001). The incidence of new hypopituitarism developing after stereotactic radiosurgery was 29% and did not appreciably differ by adenoma subtype (P = .180).After radiosurgery, patients with ACTH-secreting tumors achieved endocrine remission sooner than did those with GH-secreting tumors. These results provide insight into the relative tumor biology and disease course after radiosurgery that will serve to further improve clinical outcomes and patient treatment in the future.

SummaryIntroduction For patient with a recurrent or residual acromegaly or Cushing's disease (CD) after resection, gamma knife radiosurgery (GKRS) is often used. Hypopituitarism is the most common adverse effect after GKRS treatment. The paucity of studies with long-term follow-up has hampered understanding of the latent risks of hypopituitarism in patients with acromegaly or CD. We report the long-term risks of hypopituitarism for patients treated with GKRS for acromegaly or CD. Methods From a prospectively created, IRB-approved database, we identified all patients with acromegaly or CD treated with GKRS at the University of Virginia from 1989 to 2008. Only patients with a minimum endocrine follow-up of 60 months were included. The median follow-up is 159·5 months (60·1–278). Thorough radiological and endocrine assessments were performed immediately before GKRS and at regular follow-up intervals. New onset of hypopituitarism was defined as pituitary hormone deficits after GKRS requiring corresponding hormone replacement. Results Sixty patients with either acromegaly or CD were included. Median tumour volume at time of GKRS was 1·3 cm3 (0·3–13·4), and median margin dose was 25 Gy (6–30). GKRS-induced new pituitary deficiency occurred in 58·3% (n = 35) of patients. Growth hormone deficiency was most common (28·3%, n = 17). The actuarial overall rates of hypopituitarism at 3, 5 and 10 years were 10%, 21·7% and 53·3%, respectively. The median time to hypopituitarism was 61 months after GKRS (range, 12–160). Cavernous sinus invasion of the tumour was found to correlate with the occurrence of a new or progressive hypopituitarism after GKRS (P = 0·018). Conclusions Delayed hypopituitarism increases as a function of time after radiosurgery. Hormone axes appear to vary in terms of radiosensitivity. Patients with adenoma in the cavernous sinus are more prone to develop loss of pituitary function after GKRS.

Context: Although Crooke's changes in the pituitary corticotrophs were initially described in 1935, the prevalence in which the changes occur in patients with Cushing's syndrome (CS) has not been established. Objective: This study aimed to determine the prevalence and assess clinical features associated with the presence or absence of Crooke's changes in a large set of patients with CS. Design: Information from a prospective computer database and retrospective chart review was analyzed. Setting: The setting was an academic medical center. Patients: Consecutive patients (N = 213) who received surgery with a preoperative diagnosis of Cushing's disease are included. Intervention: The patients received pituitary surgery and specimens obtained underwent pathological analysis. Main Outcome Measure: The presence or absence of Crooke's changes was determined by histopathological analysis of the normal pituitary tissue included with the specimen obtained at surgery. Cortisol production was measured by 24-hour urine cortisol production. Results: Crooke's changes occurred in 144 of 177 patients (81%) with a histologically demonstrated ACTH-staining tumor and in 74% of 213 patients diagnosed with CS who had pituitary surgery. The presence of Crooke's changes correlated with the finding of an ACTH-staining tumor removed at surgery and with the degree of hypercortisolism. Among patients with histologically established ACTH-staining tumors the prevalence of Crooke's changes was particularly high in patients with a 24-h urinary free cortisol (UFC) of at least 4-fold the upper limit of normal, in which 91% of patients had Crooke's changes, compared with 74% of patients whose maximum UFC was less than 4-fold the upper limit of normal (P = .008). Conclusions: Crooke's changes occur in 75–80% of patients with CS, and depend on the degree of hypercortisolism and individual variability. Almost all patients with UFC at least 4-fold the upper limit of normal have them, whereas with less severe hypercortisolism the expression of Crooke's changes varies from person to person.

Prolactinomas are the most common functioning pituitary adenomas. Dopamine agonists (DA) are generally very effective in treating prolactinomas by inducing tumor volume regression and endocrine remission. A minority of patients do not respond to DA or are intolerant because of side-effects. Microsurgical resection when possible is the next treatment option, but cavernous sinus, dural, or bone involvement may not allow for complete resection. We reviewed the outcome of patients with medically and surgically refractory prolactinomas treated with Gamma Knife radiosurgery (GKRS) during a 22 years follow-up period. We reviewed the patient database at the University of Virginia Gamma Knife center during a 25-year period (1989–2014), identifying 38 patients having neurosurgical, radiological and endocrine follow-up. Median age at GKRS treatment was 43 years. Median follow-up was 42.3 months (range 6–207.9). 55.3 % (n = 21) were taking a dopamine agonist at time of GKRS. 63.2 % (n = 24) had cavernous sinus tumor invasion. Endocrine remission (normal serum prolactin off of a dopamine agonist) was achieved in 50 % (n = 19). GKRS induced hypopituitarism occurred in 30.3 % (n = 10). Cavernous sinus involvement was shown to be a significant negative prognosticator of endocrine remission. Taking a dopamine agonist drug at the time of GKRS showed a tendency to decrease the probability for endocrine remission. GKRS for refractory prolactinomas can lead to endocrine remission in many patients. Hypopituitarism is the most common side effect of GKRS.

Context Cushing disease (CD) due to adrenocorticotropic hormone-secreting pituitary tumors can be a management challenge. Objective To better understand the outcomes of stereotactic radiosurgery (SRS) for CD and define its role in management. Design International, multicenter, retrospective cohort analysis. Setting Ten medical centers participating in the International Gamma Knife Research Foundation. Patients Patients with CD with >6 months endocrine follow-up. Intervention SRS using Gamma Knife radiosurgery. Main Outcome Measures The primary outcome was control of hypercortisolism (defined as normalization of free urinary cortisol). Radiologic response and adverse radiation effects (AREs) were recorded. Results In total, 278 patients met inclusion criteria, with a mean follow-up of 5.6 years (0.5 to 20.5 years). Twenty-two patients received SRS as a primary treatment of CD. Mean margin dose was 23.7 Gy. Cumulative initial control of hypercortisolism was 80% at 10 years. Mean time to cortisol normalization was 14.5 months. Recurrences occurred in 18% with initial cortisol normalization. Overall, the rate of durable control of hypercortisolism was 64% at 10 years and 68% among patients who received SRS as a primary treatment. AREs included hypopituitarism (25%) and cranial neuropathy (3%). Visual deficits were related to treatment of tumor within the suprasellar cistern (P = 0.01), whereas both visual (P < 0.0001) and nonvisual cranial neuropathy (P = 0.02) were related to prior pituitary irradiation. Conclusions SRS for CD is well tolerated and frequently results in control of hypercortisolism. However, recurrences can occur. SRS should be considered for patients with persistent hypercortisolism after pituitary surgery and as a primary treatment in those unfit for surgery. Long-term endocrine follow-up is essential after SRS.

Studies comparing primary medical treatment of acromegaly with surgery are often non-randomized, and not stratified by illness severity. We prospectively compared primary medical therapy with pituitary surgery in patients with acromegaly. All patients had macroadenomas, at least one random human growth hormone (GH) level ≥12.5 ng/mL, elevated IGF-I levels and failure to suppress GH to

The subtypes of somatotroph-cell pituitary adenomas have been correlated with clinical and histopathological variables. Densely granulated somatotroph-cell (DG) adenomas are typically highly responsive to somatostatin analog drugs, whereas sparsely granulated somatotroph-cell (SG) are less responsive. The aim of the study is to determine the effect of stereotactic radiosurgery (SRS) on remission and development of new pituitary deficiency according to the different subtypes of growth hormone (GH) secreting adenomas. A total of 176 patients underwent SRS for acromegaly at the University of Virginia. Diagnosis of acromegaly was based on the combination of clinical features and biochemical assessment including the serum GH level, and age- and gender-matched serum insulin-like growth factor-1 level. All patients underwent endocrine and neuro-imaging evaluations before and after SRS. Histological specimens were available in 73 patients. The histopathological examination showed 34 patients had a DG adenoma, 19 had a SG adenoma, eight had a mixed DG/SG pattern, while other rare mixed subtypes were present in 12 patients. Patients who had a SG adenoma were more likely to be younger and female, and the SG adenomas appeared to be more invasive into the cavernous sinus. With a median follow-up of 67 months (range 6–188 months), 55/73 patients (75.3 %) achieved remission. The median time to remission was 26 months (range 6–102 months). The actuarial remission rates in the DG adenoma group at 2, 4, and 6 years post-radiosurgery were 35.1, 71.4, and 79.3 %, respectively, while those in SG adenoma group were 35.4, 73.1, and 82.1 %, respectively. While patients who had a SG adenoma may be less responsive to medical therapy, they exhibited similar responses to SRS as patients with a DG adenoma. For SG adenomas, which respond less well to medical therapy, earlier SRS may be reasonable for consideration.

The role of stereotactic radiosurgery (SRS) in acromegaly is being assessed.We evaluated the efficacy and safety of SRS for patients with acromegaly. Prognostic factors related to outcomes were also analyzed.This was a retrospective study of patients treated with SRS at the University of Virginia; the data were collected from 1989 to 2012, with a median follow-up of 61.5 months.A total of 136 patients underwent SRS for acromegaly. Diagnosis of acromegaly was based on the combination of clinical features and biochemical assessment, including the serum GH level and age- and gender-matched serum IGF-1 level. All patients underwent a complete endocrine evaluation, neuroimaging study, and ophthalmic examinations before SRS.After withdrawal of GH- or IGF-1-altering medications, patients who had an oral glucose tolerance test GH of1.0 ng/mL or normal IGF-1 were considered in remission. Post-radiosurgical hypopituitarism was defined as a decrease in one or more hormones below normal.With a median follow-up of 61.5 months, 65.4% of the patients achieved remission. The mean time to remission was 27.5 months. The actuarial remission rates at 2, 4, 6, and 8 years after radiosurgery were 31.7, 64.5, 73.4, and 82.6%, respectively. Favorable prognostic factors for remission included a higher margin radiation dose, higher maximum dose, and lower initial IGF-1 level. New pituitary hormone deficiency occurred in 43 patients (31.6%); two patients (1.5%) developed panhypopituitarism. Corresponding risk factors for new pituitary hormone deficiency were a margin dose25 Gy and tumor volume2.5 mL. Other complications included an adverse radiation effect in one patient, visual deterioration in four, and new oculomotor nerve palsy in one.SRS affords a reasonable rate of endocrine remission in patients with acromegaly and generally does so with a low rate of adverse effects.

Object Cushing's disease is a challenging neuroendocrine disorder. Although resection remains the primary treatment option for most patients, the disease persists if there is residual or recurrent tumor. Stereotactic radiosurgery has been used to treat patients with persistent Cushing's disease after a prior resection. The authors report on the long-term risks and benefits of radiosurgery for Cushing's disease. Methods A retrospective review of a prospectively collected database of radiosurgery patients was undertaken at the University of Virginia. All patients with Cushing's disease treated with Gamma Knife surgery (GKS) were identified. Those without at least 12 months of clinical and radiological follow-up were excluded from this analysis. Rates of endocrine remission, tumor control, and adverse events were assessed. Statistical methods were used to identify favorable and unfavorable prognostic factors. Results Ninety-six patients with the required follow-up data were identified. The mean tumor margin dose was 22 Gy. The median follow-up was 48 months (range 12–209.8 months). At the last follow-up, remission of Cushing's disease occurred in 70% of patients. The median time to remission among all patients was 16.6 months (range 1–165.7 months). The median time to remission in those who had temporarily stopped taking ketoconazole at the time of GKS was 12.6 months, whereas it was 21.8 months in those who continued to receive ketoconazole (p < 0.012). Tumor control was achieved in 98% of patients. New loss of pituitary function occurred in 36% of patients. New or worsening cranial neuropathies developed in 5 patients after GKS, with the most common involving cranial nerves II and III. Conclusions Gamma Knife surgery offers a high rate of tumor control and a reasonable rate of endocrine remission in patients with Cushing's disease. The cessation of cortisol-lowering medications around the time of GKS appears to result in a more rapid rate of remission. Delayed hypopituitarism and endocrine recurrence develop in a minority of patients and underscore the need for long-term multidisciplinary follow-up.

Object Nelson's syndrome (NS) is a significant and frequent risk for patients with Cushing's disease (CD) who undergo bilateral adrenalectomy. A recent study has shown tumor progression in 47% of patients at risk for NS. The authors sought to define the rate of NS in patients who were treated with Gamma Knife stereotactic radiosurgery (GK SRS) prior to bilateral adrenalectomy. Methods Consecutive patients with CD who were treated with GK SRS after pituitary surgery but before bilateral adrenalectomy were included. Serial MRI sequences were analyzed to evaluate for pituitary tumor growth. Clinical evaluations were performed to screen for NS. Follow-up for adrenocorticotropic hormone levels and hormone studies of other pituitary axes was performed. Results Twenty consecutive patients were followed with neuroimaging and clinically for a median of 5.4 years (range 0.6–12 years). One patient (5%) developed pituitary tumor growth consistent with NS 9 months after adrenalectomy. By Kaplan-Meier analysis, progression-free survival was 94.7% at 1, 3, and 7 years. No predisposing factors were identified for the tumor progression. Two patients developed new pituitary dysfunction and no patient developed cranial neuropathy or visual deficit after GK SRS. Conclusions These findings suggest that GK SRS not only serves a role as second-line therapy for CD, but that it also provides prophylaxis for NS when used before bilateral adrenalectomy.

THIS REPORT DETAILS a case of an adult cyanotic patient with hitherto unrepaired and unpalliated tetralogy of Fallot (TOF), who during the preoperative workup also was diagnosed with pheochromocytoma. The simultaneous presence of the two conditions presented significant perioperative challenges, most significantly the effect of α-blockade instituted for control of symptoms of pheochromocytoma on the management of TOF, the decision regarding the sequence of operations for the two conditions, and the subsequent perioperative management of a patient with moderately impaired right ventricular function. This is the first case report that describes an adult patient with complete repair of TOF followed by resection of pheochromocytoma. Informed consent was given by the patient.

It is unclear whether endoscopic transsphenoidal surgery (ETSS) or microsurgical transsphenoidal surgery (MTS) is a superior surgical approach for pituitary adenomas.The 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.This 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.Preoperative 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.Outcomes 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.

BACKGROUND Studies of new-onset Gamma Knife stereotactic radiosurgery (SRS)-induced hypopituitarism in large cohort of pituitary adenoma patients with long-term follow-up are lacking. OBJECTIVE We investigated the outcomes of SRS for pituitary adenoma patients with regard to newly developed hypopituitarism. METHODS This was a retrospective review of patients treated with SRS at the University of Virginia between 1994 and 2006. A total of 262 patients with a pituitary adenoma treated with SRS were reviewed. Thorough endocrine assessment was performed immediately before SRS and in regular follow-ups. Assessment consisted of 24-hour urine free cortisol (patients with Cushing disease), serum adrenocorticotropic hormone, cortisol, follicle-stimulating hormone, luteinizing hormone, insulin-like growth factor-1, growth hormone, testosterone (men), prolactin, thyroid-stimulating hormone, and free T(4). RESULTS Endocrine remission occurred in 144 of 199 patients with a functioning adenoma. Tumor control rate was 89%. Eighty patients experienced at least 1 axis of new-onset SRS-induced hypopituitarism. The new hypopituitarism rate was 30% based on endocrine follow-up ranging from 6 to 150 months; the actuarial rate of new pituitary hormone deficiency was 31.5% at 5 years after SRS. On univariate and multivariate analyses, variables regarding the increased risk of hypopituitarism included suprasellar extension and higher radiation dose to the tumor margin; there were no correlations among tumor volume, prior transsphenoidal adenomectomy, prior radiation therapy, and age at SRS. CONCLUSION SRS provides an effective and safe treatment option for patients with a pituitary adenoma. Higher margin radiation dose to the adenoma and suprasellar extension were 2 independent predictors of SRS-induced hypopituitarism.

Circulating microRNAs (miRNAs) in plasma are being studied for use as biomarkers of specific diseases and as markers of administration of pharmaceutical agents. Administration of recombinant human growth hormone (rhGH) is prohibited by sporting authorities, but it continues to be used by athletes attempting to gain an unfair advantage in athletic competition. Current methods for detection of rhGH use rely on immunoassay technology and are limited by a short time-frame in which detection of rhGH is possible. We hypothesized that administration of rhGH would alter expression of circulating miRNAs and that any changes could be detected. To identify potential miRNA targets, we utilized miRNA microarrays for screening. Confirmatory testing used real-time reverse-transcriptase (RT) quantitative PCR (qPCR) assays of selected miRNAs in 35 plasma samples obtained from (1) individuals with no known pituitary disorders, (2) patients with excess GH production, and (3) patients receiving therapeutic replacement doses of rhGH. We identified and confirmed four miRNAs that were differentially expressed in all individuals using therapeutic replacement doses of rhGH when compared to individuals with naturally high levels of GH and normal controls. This study further develops the hypothesis that circulating miRNAs may be used as biomarkers for detection of doping in sports.

Background Growth hormone (GH) is present in human lymphocytes and the relative concentration of GH mRNA in circulating cells is reportedly increased in patients with acromegaly. No quantitative assay has been described to measure GH in circulating cells. Methods To measure GH mRNA, we used real-time reverse-transcriptase (RT) quantitative PCR (qPCR) with nested primers, a synthetic nucleotide standard and SYBR Green I detection. Blood samples from volunteers with and without pituitary disorders were collected in PAXgene Blood RNA tubes. Essential MIQE guidelines were followed during sample preparation and assay development. Results RT-qPCR assay was specific for GH mRNA and was linear from ≤ 90 to ≥ 90,000 copies of GH mRNA per reaction. Day-to-day imprecision (CV) was 31%–46% at mean concentrations of 3400 and 2630 copies/mL of blood, respectively (n = 10). The variability (CV) of results in samples collected from a single individual over a year and assayed in a single run was 28% (n = 17 samples). The mean concentrations of GH mRNA in blood were statistically indistinguishable in patients with acromegaly, control subjects, and patients receiving replacement doses of recombinant GH. Moreover, GH mRNA concentrations in blood were not correlated with concentrations of insulin-like growth factor-I in plasma. Conclusions The RT-PCR assay quantifies GH mRNA at concentrations present in circulating cells. The present study suggests that the absolute concentration of GH mRNA in circulating cells is not altered in patients with acromegaly.

BACKGROUND Nonfunctioning pituitary adenomas recur after microsurgery. Gamma Knife radiosurgery (GKRS) has been used to treat recurrent adenomas. OBJECTIVE To evaluate the long-term rates of tumor control and development of hypopituitarism in patients with nonfunctioning pituitary adenomas after GKRS. METHODS Forty-eight patients with a nonfunctioning pituitary adenoma treated between 1991 and 2004 at the University of Virginia were studied. All patients had more than 4 years of clinical and imaging follow-up. RESULTS All patients underwent follow-up imaging and endocrine evaluations, with a duration ranging from 50 to 215 months (median, 80.5 months) and 57 to 201 months (median, 95 months), respectively. New hormone deficiency after GKRS occurred in 19 of 48 patients (39%). Corticotropin/cortisol deficiency developed in 8% of patients, thyroid hormone deficiency in 20.8%, gonadotropin deficiency in 4.2%, growth hormone/insulin-like growth factor 1 in 16.7%, and diabetes insipidus in 2%. Panhypopituitarism including diabetes insipidus developed in 1 patient. Overall, control of tumor volume was 83%. Tumor volume decreased in 36 patients (75%), increased in 8 patients (17%), and was unchanged in 4 patients (8%). Tumor volumes greater than 5 mL at the time of GKRS were associated with a significantly greater rate of growth (P = .003) compared with an adenoma with a volume of 5 mL or less. CONCLUSION GKRS resulted in a high and durable rate of tumor control in patients with a nonfunctioning pituitary adenoma. A higher preoperative tumor volume was associated with an increased rate of tumor growth.

Object Gamma Knife surgery (GKS) is a common treatment for recurrent or residual pituitary adenomas. This study evaluates a large cohort of patients with a pituitary adenoma to characterize factors related to endocrine remission, control of tumor growth, and development of pituitary deficiency. Methods A total of 418 patients who underwent GKS with a minimum follow-up of 6 months (median 31 months) and for whom there was complete follow-up were evaluated. Statistical analysis was performed to evaluate for significant factors (p < 0.05) related to treatment outcomes. Results In patients with a secretory pituitary adenoma, the median time to endocrine remission was 48.9 months. The tumor margin radiation dose was inversely correlated with time to endocrine remission. Smaller adenoma volume correlated with improved endocrine remission in those with secretory adenomas. Cessation of pituitary suppressive medications at the time of GKS had a trend toward statistical significance in regard to influencing endocrine remission. In 90.3% of patients there was tumor control. A higher margin radiation dose significantly affected control of adenoma growth. New onset of a pituitary hormone deficiency following GKS was seen in 24.4% of patients. Treatment with pituitary hormone suppressive medication at the time of GKS, a prior craniotomy, and larger adenoma volume at the time of radiosurgery were significantly related to loss of pituitary function. Conclusions Smaller adenoma volume improves the probability of endocrine remission and lowers the risk of new pituitary hormone deficiency with GKS. A higher margin dose offers a greater chance of endocrine remission and control of tumor growth.

The indications, efficacy, and safety of radiation therapy and stereotactic radiosurgery for Cushing's disease are evaluated.We queried PubMed using the terms, 'Cushing's disease', 'radiotherapy', and 'radiosurgery', then evaluated each study for the number of patients, method of radiation delivery, type of radiation therapy or radiosurgical device used, treatment parameters (e.g. maximal dose, tumor margin dose), length of follow-up, tumor-control rate, complications, rate of hormone normalization, newly onset loss of pituitary function, and method used to assess endocrine remission.A total of 39 peer-reviewed studies with 731 patients were included. The reported rates of tumor-volume control following radiotherapy and radiosurgery vary considerably from 66-100%. Additionally, the reported rates of endocrine remission vary substantially from 17-100%. The incidence of serious complications following radiosurgery is quite low. Although post-treatment hypopituitarism and disease recurrence were uncommon, they did occur, and this underscores the necessity for long-term follow-up in these patients.Radiosurgery and, in the modern era, less commonly, radiation therapy, offer both well tolerated and reasonably effective treatment for recurrent or residual Cushing's adenomas.

Lymphocytic hypophysitis is a relatively uncommon autoimmune inflammatory disorder affecting the pituitary gland. It most frequently occurs in women of child-bearing age. The authors report on their experience with a patient who presented with diplopia and marked enlargement of the pituitary gland. She underwent transsphenoidal surgery, and histopathological analysis confirmed the diagnosis of lymphocytic hypophysitis. The disease proved refractory to resection, and any attempt at withdrawal of corticosteroid therapy resulted in a return of the patient's symptoms and enlargement of the sellar contents. The patient underwent Gamma Knife surgery (GKS) to the sella and both cavernous sinuses. After GKS, the patient was able to discontinue steroid therapy without return of her symptoms. Follow-up MR images demonstrated no evidence of recurrence of lymphocytic hypophysitis. For persistent lymphocytic hypophysitis, GKS is a reasonable treatment option.

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.

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 (10 mm), 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 5 mm by preoperative MRI were COUP-TFI immunonegative. Two tumors, measuring 9 and 11 mm, showed consistent (90%) expression of COUP-TFI, and three adenomas (5, 11, and 18 mm) 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.

Refractory Cushing disease (CD) is associated with considerable morbidity and mortality. Bilateral adrenalectomy (BA) offers effective permanent treatment. Both open and laparoscopic approaches have been used, but longterm comparisons are few.We reviewed 40 consecutive BA for refractory CD from 1995 through 2007. Surgical results were evaluated. A Short Form-36 Quality-of-Life (QOL) survey was performed.Eighty-five percent (34 of 40) of patients were women, and median age was 41.9 years (range, 22.2 to 78.3 years). All had persistent CD after transsphenoidal operation (mean, 1.7; range, 1 to 3). Median followup was 5.0 years. Thirty-eight percent (15 of 40) of procedures were performed laparoscopically; 1 was converted to open. There were no operative or 30-day mortalities, and there was 1 90-day mortality. Morbidities occurred in 7 of 40 (18%) patients. Median length of stay was shorter in the laparoscopic group (4 versus 6 days; p0.001). All patients achieved clinical reversal of hypercortisolism, including the 5 (13%) with ectopic adrenal tissue. Elevated serum ACTH (200 ng/mL) was present during followup in 33% (13 of 40). A QOL survey demonstrated 86% of patients felt good to excellent compared with 1 year pre-BA. Chronic fatigue was present most or all of the time in 46%, and patients were below population norms on 7 of 8 Short Form-36 scales. No difference was evident in QOL between laparoscopic and open adrenalectomy.Our experience demonstrates excellent survival and clinical results, despite the inherent risk in patients with CD. There are persistent fatigue and QOL deficits that are not ameliorated by laparoscopic compared with open resection.

Object Outcomes of therapy for Cushing's disease (CD) vary depending on different aspects of presentation and diagnostic studies. The authors designed this study to verify the remission rate and outcomes after transsphenoidal surgery (TSS) for patients with CD who had positive findings on MR imaging. Methods Patients who had presented with CD at the University of Virginia for initial treatment between July 1992 and December 2005 were retrospectively reviewed. The patients included in the study were considered to be optimal surgical candidates, defined as an adult (> 18 years of age) with classic clinical features of CD, laboratory studies confirming a central (pituitary/hypothalamic) adrenocorticotropic hormone–dependent source of disease, and an MR imaging study revealing a microadenoma in the sella turcica. Results A total of 167 patients fulfilled the criteria. Thirty were men (18%) and 137 were women (82%). The mean age was 42.3 years (range 18.2–77 years). All patients underwent TSS. Surgical remission was achieved in 148 patients (88.6%), which was correlated with the surgeon's intraoperative identification of an adenoma (p = 0.03). Histopathological confirmation of an adrenocorticotropic hormone–secreting adenoma strongly correlated with remission (p = 0.0001). Three patients (1.8%) had postoperative cerebrospinal fluid leaks, and 1 patient had meningitis. Transient diabetes insipidus was diagnosed and treated in 10 patients (6%), whereas permanent diabetes insipidus occurred in 8 patients (4.8%). Panhypopituitarism followed the surgery in 14 patients (8.3%), 13 of whom underwent total hypophysectomy (9 initially and 4 with early reoperations), and in 1 of 10 patients who underwent subtotal hypophysectomy. Nineteen patients (12.8%) who were initially in remission developed recurrent CD after an average of 50 months. The mean follow-up for the 167 patients was 39 months (range 6–157 months). Gamma Knife surgery was the most common modality of radiotherapy used to treat 31 patients (18.5%) who did not achieve remission or later presented with recurrent disease. Bilateral adrenalectomies were performed in 10 patients in the series (6%), 2 of whom developed Nelson's syndrome. The overall posttreatment remission rate was 95.8%. Conclusions Even in patients with ideal diagnostic criteria of CD, there remain a significant number of cases in which TSS alone is not adequate to assure long-lasting remission. A multidisciplinary approach is essential to the achievement of satisfactory overall remission rates.

Objective To review the underlying causes of pituitary lesions, a rational approach to their diagnosis, and therapeutic options. Methods The types of pituitary lesions and their clinical manifestations are reviewed, and treatment strategies and long-term follow-up are discussed. Results A pituitary adenoma is quite common and poses a challenge to the clinician to determine the clinical significance, the appropriate diagnosis, the need for treatment, and the appropriate therapy or therapies. The treatment of a pituitary adenoma depends on the type of tumor; a prolactinoma is treated medically with a dopamine agonist drug, and other lesions are usually treated by transsphenoidal surgical removal. Replacement of a deficient hormone or hormones is necessary for optimal functioning. Some patients require more than one treatment, including surgical intervention, replacement of a hormone or hormones, medications to lower hormone hypersecretion to normal (for prolactinoma, acromegaly, or Cushing disease), pituitary radiation therapy (optimally with focused irradiation such as the Gamma Knife or LINEAC), and, in the situation of persistent Cushing disease, bilateral adrenalectomy as a last resort. Lifelong monitoring is necessary for all these patients. Conclusion The goal is to decrease the mass effect of the adenoma, to restore normal pituitary function, and to suppress hormone hypersecretion. Achievement of this goal necessitates the cooperation and interdisciplinary efforts of several medical specialties. (Endocr Pract. 2008;14:757-763)

Objective: Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushing’s syndrome, because there is no recent consensus on the management of this rare disorder. Participants: Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushing’s syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushing’s disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushing’s disease, and 5) management of ectopic ACTH syndrome, Nelson’s syndrome, and special patient populations. Evidence: Participants 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. Consensus Process: Participants 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. Conclusions: ACTH-dependent Cushing’s syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushing’s syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushing’s disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushing’s syndrome, early diagnosis and prompt therapy are warranted.

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.

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 ≤ 2 μg/dl within 72-h surgery) was achieved in 97 (45.1%) patients. Patients who had postoperative serum cortisol of more than 2 μg/dl were 2.5 times more likely to have a recurrence than patients who had serum cortisol less than or equal to 2 μg/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.