Preoperative Growth Hormone Research Articles

Morphometric Alterations of the Sphenoid Ostium and other Landmarks in Acromegaly: Anatomical Considerations and Implications in Endoscopic Pituitary Surgery.

The sphenoid ostium (SO) is an important landmark for the endoscopic surgeon. Changes in size and position of the SO and variations in other skull base landmarks in acromegalics have not been adequately evaluated. The authors evaluated the morphometry and location of the SO and other landmarks in acromegaly and compared these findings with those in nonfunctioning pituitary adenomas (NFPAs). In this retrospective case-control study, the dimensions and location of the SO and other skull base landmarks were radiologically evaluated in 18 patients with growth hormone (GH)-secreting adenomas. These findings were analyzed in relation to preoperative GH levels and compared with 18 age- and sex-matched controls with NFPAs. The dimensions of the SO were significantly larger in the GH-adenoma group (P < 0.05). The SO was further from the midline (P = 0.04) and closer to the sphenopalatine foramen (SPF) (P = 0.02) in the GH-adenoma group, and this finding correlated with increasing preoperative GH levels. Acromegalics demonstrated larger intracavernous carotid diameters (P = 0.05) and smaller intercarotid distances than the patients with NFPAs (P = 0.02). The SO is larger and located higher up in the sphenoid face and closer to the SPF in patients with GH adenomas. Increasing GH levels in these patients correlate with the upward and lateral displacement of the SO. These patients demonstrate larger intracavernous carotid diameters and smaller intercarotid distances than patients with NFPAs. These morphological alterations are of particular relevance to the pituitary surgeon.

Long-term outcomes of transsphenoidal surgery for management of growth hormone-secreting adenomas: single-center results.

Transsphenoidal surgery is advocated as the first-line management of growth hormone (GH)-secreting adenomas. Although disease control is defined by strict criteria for biochemical remission, the length of follow-up needed is not well defined in literature. In this report, the authors present their long-term remission rate and identify various predictive factors that might influence the clinical outcome. The authors conducted a single-institute retrospective analysis of all transsphenoidal procedures for GH-secreting adenomas performed from January 2000 to June 2016. The primary outcome was defined as biochemical remission according to the 2010 consensus criteria and measured at the 1-year postoperative mark as well as on the last recorded follow-up appointment.Secondary variables included recurrence rate, patterns of clinical presentation, and outcome of adjuvant therapy (including repeat surgery). Subgroup analysis was performed for patients who had biochemical or radiological "discordance"-patients who achieved biochemical remission but with incongruent insulin-like growth factor 1 (IGF-1)/GH or residual tumor on MRI. Recurrence-free survival analysis was conducted for patients who achieved remission at 1 year after surgery. Eighty-one patients (45 female and 36 male) with confirmed acromegaly treated with transsphenoidal surgery were included. In 62 cases the patients were treated with a pure endoscopic approach and in 19 cases an endoscopically assisted microscopic approach was used.Primary biochemical remission after surgery was achieved in 59 cases (73%) at 1 year after surgery. However, only 41 patients (51%) remained in primary surgical remission (without any adjuvant treatment) at their last follow-up appointment, indicating a recurrence rate of 31% (18 of 59 patients) over the duration of follow-up (mean 100 ± 61 months). Long-term remission rates for pure endoscopic and endoscopically assisted cases were not significantly different (48% vs 52%, p = 0.6). Similarly, no significant difference in long-term remission was detected between primary surgery and repeat surgery (54% vs 33%, p = 0.22).Long-term remission was significantly influenced by extent of resection, cavernous sinus invasion (radiologically as well as surgically reported), and preoperative and early postoperative GH and IGF-1 levels (within 24-48 hours after surgery) as well as by clinical grade, with lower remission rates in patients with dysmorphic features and/or medical comorbidities (grade 2-3) compared to minimally symptomatic or silent cases (grade 1). The long-term surgical remission rate appears to be significantly less than "early" remission rates and is highly dependent on the extent of tumor resection. The authors advocate a long-term follow-up regimen and propose a clinical grading system that may aid in predicting long-term outcome in addition to the previously reported anatomical factors. The role of repeat surgery is highlighted.

Effect of growth hormone and somatomedin-C axis on fracture healing

Aim: Many studies have examined the effects of different calciotropic hormones on fracture healing, whereas few studies focus on growth factors. Local detection of somatomedin C (IGF-1) in fracture callus, application of growth hormone (GH) and IGF-1 as non-union treatment, and low GH and IGF-1 levels in osteoporotic fractures indicate that these hormones are effective in fracture healing. However, most of these studies are based on post fracture GH and IGF-1 levels. GH and IGF-1 are also involved in acute phase response and can change due to trauma. The aim of this study is to investigate the change in GH and IGF-1 levels in patients treated with osteotomy, in which an iatrogenic fracture is created, and to evaluate the effect of these hormones on fracture healing by comparing the results before and after the fractures. Methods: Patients who were diagnosed with developmental dysplasia of the hip and underwent surgery between 2014-2015 were prospectively followed for this cohort study. Forty-one patients were included, and two groups were formed. Patients who underwent open reduction and soft tissue release without osteotomy (n=20) were included in the first group. Patients who underwent pelvic osteotomy (n=21), in which iatrogenic fractures were created, were included in the second group. Blood samples were obtained from all patients pre-operatively and on the 1st and 28th postoperative days. Friedman and Mann-Whitney U tests were used for statistical analysis. Results: Mean age of the first group, comprising 19 females (95%) and 1 male (5%), was 11.25 months (Range: 6-25 months). Mean age of the second group, including 17 females (85.7%) and 4 males (14.3%), was 74.4 months (Range: 24-120 months). While there was no significant difference between pre- and postoperative GH values in the first group (P=0.05), postoperative GH levels were significantly higher than preoperative GH levels in the second group (P&lt;0.001). Postoperative IGF-1 levels were significantly lower than preoperative IGF-1 levels in both groups (P&lt;0.001). When the difference of preoperative and postoperative 1st day GH and IGF-1 values were compared between two groups, GH changes were found significantly higher in the second group (P&lt;0.001) whereas serum IGF-1 changes were significantly lower in the second group (P=0.043). Conclusion: IGF-1 is inadequate in the investigation of fracture healing due to its short half-life and local production. On the other hand, GH plays an active role in fracture healing and increases significantly in comparison to pre-fracture values. Considering the GH increase during fracture healing, it may be beneficial to support patients with pathological fracture healing with growth hormone.

Associations of Ki-67 Labeling Index with Clinical and Paraclinical Features of Growth Hormone-Secreting Pituitary Adenomas: A Single Center Report from Iran.

BackgroundAcromegaly is a rare disorder resulting from benign growth hormone (GH)-secreting pituitary adenomas in 90% of the cases. In recent years, many researchers have studied the Ki-67 index level of pituitary tumors and its relationship with demographics, biochemical parameters, clinical behavior, and recurrence rate.ObjectivesThis study aimed to evaluate the correlation of Ki-67 index level with clinicoradiological and endocrinological parameters in confirmed GH-secreting pituitary adenomas, as well as with the surgical response and medical treatment after surgery.MethodsWe collected the medical and pathologic records of 49 patients with GH-secreting pituitary adenoma who underwent surgeries from 2008 to 2017 in Shariati hospital affiliated to Tehran University of Medical Sciences.ResultsAccording to MRI reports, 94% of the tumors were macroadenomas. The MRI findings also revealed the median maximal adenoma diameter of 18.5 mm. About 40% of the patients achieved remission three months after the surgery. Younger patients had a significantly higher Ki-67 index level (P = 0.036). We did not observe any significant difference in the Ki-67 index level regarding gender, tumor type, maximal tumor diameter, tumor invasiveness, tumor secretory type, and remission. Interestingly, the Ki-67 index level was negatively correlated with the insulin-like growth factor-1 (IGF-1) level at the last follow-up (P = 0.02). In logistic regression analysis, patients with higher preoperative GH serum levels had a better outcome.ConclusionsOur results indicated a negative correlation between age and Ki-67 index level. However, there was no association between the Ki-67 index level and some tumor behaviors, as well as short- and long-term remission.

Clinical Characteristics and Postoperative Recovery of Hypopituitarism in Patients with Nonfunctional Pituitary Adenoma

To investigate the clinical characteristics of hypopituitarism and its reversibility after surgery for nonfunctional pituitary adenoma (NFPA); analyze the correlation between tumor size and hypopituitarism incidence; and predict hypopituitarism by tumor volume and maximum diameter. We retrospectively reviewed 164 patients with NFPA who underwent surgical treatment at Peking Union Medical College Hospital from January 2016 to December 2016. Demographic, imaging, and endocrine data were collected during preoperative, postoperative, and long-term follow-up (21.1 ± 3.3 months) periods. Differences in hormone levels were analyzed by paired and independent samples t-tests. The cut-off values of tumor size and volume to predict hypopituitarism were calculated by receiver operating characteristic curves. In total, 80.4% (132/164) of patients had anterior pituitary hypofunction and 48.4% patients had hypogonadism; the recovery rate of luteinizing hormone was 80.9%, and follicular-stimulating hormone was 60%. In total, 36.5% of patients had hypothyroidism; the recovery rate of thyroxine was 85%, free thyroxine was 87.8%, and thyroid-stimulating hormone was 100.0%. Finally, 27.4% of patients had insulin-like growth factor 1 (IGF-1)/growth hormone (GH) hypofunction, and the recovery rate of IGF-1 was 77.8%. The preoperative free thyroxine, thyroxine, GH, IGF-1, follicular-stimulating hormone, and luteinizing hormone levels were significantly lower in the giant adenoma group (n= 43) than in the large adenoma group (n= 121). The hypopituitarism predictive cut-off value of tumorvolume was 3105.1 mm3 and that of tumor diameter was 23.5 mm. NFPA has a significant influence on gonadal hormone, IGF-1/GH, and thyroid hormone. NFPA can cause single- or multiple-hormone reduction in each pituitary target gland. Tumor size is positively correlated with the incidence and degree of hypopituitarism. NFPA-induced hypopituitarism is significantly recovered after surgical treatment.

Endoscopic Endonasal Approach to the Growth Hormone–Secreting Pituitary Adenomas: Endocrinologic Outcome in 68 Patients

The endoscopic endonasal approach has recently become an acceptable option for resection of all pituitary adenomas. We assessed biochemical outcome of endoscopic endonasal surgery in growth hormone (GH)-secreting adenomas, including remission rate, predictors of remission, and associated complications. Sixty-eight consecutive patients with acromegaly who underwent endoscopic endonasal surgery were analyzed prospectively. Tumors were classified according to size, Knosp grade, and Hardy-Wilson classification. Biochemical remission was defined as normal serum insulin-like growth factor 1 level and either a suppressed GH serum level less than 0.4 μg/L during an oral glucose tolerance test or a random GH level less than 1.0 μg/L at least 3 months after surgery. Total biochemical remission rate was 64.7%. Gross total resection was achieved in 61 of the 68 patients (89.7%). Remission was achieved in 12 of 16 microadenomas (75%) and 32 of 52 macroadenomas (61.5%). Based on univariate logistic regression analysis, preoperative variables predictive of remission were age (P=0.004), Knosp grade (P= 0.023), and preoperative GH levels (P= 0.042). Three patients (4.4%) experienced postoperative panhypopituitarism, and permanent diabetes insipidus was seen in 4 patients (5.9%). Two patients (2.9%) developed cerebrospinal fluid leaks, which were treated by lumbar puncture in one case and early surgical repair in the other case. Endoscopic endonasal adenoma resection leads to a high rate of endocrinologic remission in GH-secreting adenomas with a low complication rate. Patients with older age, higher preoperative GH levels, and higher Knosp grades are less likely to achieve remission.

Somatotrophic Adenoma in Children Younger than 14 Years: Clinical Features and Treatment of 22 Cases at a Large Pituitary Center.

To investigate the clinical features of somatotrophic adenoma in children younger than 14 years and to evaluate the short-term and long-term outcomes of transsphenoidal surgery. This single-center retrospective study included 22 patients with somatotrophic adenoma who were admitted to our institution between January 1997 and January 2017. The patients' demographics, hormone levels, imaging characteristics, surgical outcomes, and follow-up data were summarized. The average age of patients at diagnosis was 10.3 years, and the average disease duration was 42.5 months. Growth acceleration was observed in 90.9% of patients. Mixed somatolactotrophic adenoma was identified in 36.4% of patients. In total, 77.3% of tumors on imaging were macroadenomas or giant adenoma, and 50% were invasive. Twenty-one patients underwent tumor resection, and the remission rate after a single transsphenoidal surgery was 45%. Preoperative growth hormone levels (P= 0.017), growth hormone nadir (P= 0.003), and tumor size (P= 0.026) were the most likely influencing factors associated with the surgical remission rate. Postoperative cerebral spinal fluid leakage (15%) was the main complication of transsphenoidal surgery. During a median follow-up period of 42.5 months, 72.7% of the patients obtained remission after monotherapy or combined treatment, and no recurrence was observed. Somatotrophic adenomas in children younger than 14 years tend to be macroadenomas with a shorter disease duration than that observed in adults. Transsphenoidal surgery is safe and effective and could represent a preferred treatment option. The combination of surgery, medication, and radiation is recommended to achieve optimal long-term outcomes.

Endoscopic therapy and curative effect in pituitary adenoma patients complicated by acromegalic cardiomyopathy.

The study aimed to retrospectively analyze the clinical characteristics of patients with pituitary adenomas complicated by acromegalic cardiomyopathy and to evaluate the effect of endoscopic surgery. Eighty-six pituitary adenoma patients complicated by acromegalic cardiomyopathy who were treated with endoscopic surgery in the First Affiliated Hospital of Soochow University from January 2010 to December 2016 were enrolled. We noted patient clinical characteristics and explored the relationships with surgical treatment. Before and after surgery, all patients underwent an examination of pituitary endocrinology, brain magnetic resonance (MR), and echocardiography. The serum levels of growth hormone (GH), left ventricular end-diastolic diameter (LVIDd), interventricular septal thickness (IVST), left ventricular posterior wall thickness (LVPWT), left ventricular ejection fraction (EF), and mitral valve (E/A ratio) were examined with non-invasive methods, and the results were compared. Of the 86 patients, there were 23 with microadenomas, 27 with large adenomas, and 36 with giant adenomas. There were 28 patients with invasive adenomas and 58 with non-invasive adenomas. The pre-operative mean GH level was 71.23 ± 3.29μg/L, which was positively correlated with tumor volume (r = 0.751, P < 0.01). Via trans-sphenoidal endoscopic pituitary adenoma resection, 51 patients underwent total tumor resections, 25 underwent subtotal resections, 8 underwent major part resections, and 2 underwent partial resections. After surgery, the GH mean level was 3.81 ± 1.03μg/L, which was significantly different (t = 3.72, P < 0.01) from the pre-operative level. Cardiac function indices, including LVIDd, IVST, LVPWT, E/A, and EF, were significantly improved. The long-term curative rate was 39.17% and the remission rate was 77.29%. For pituitary adenoma patients complicated by acromegalic cardiomyopathy, endoscopic surgery resulted in a good curative effect and the growth hormone levels were maintained, which can significantly improve cardiac structure and function.

Endoscopic Transsphenoidal Approach for Acromegaly with Remission Rates in 401 Patients: 2010 Consensus Criteria.

Transsphenoidal surgery is the first-choice treatment for acromegaly. Postoperative remission is an important predictor of outcome. Various factors have been described as markers of remission: preoperative mean growth hormone (GH) and insulin-like growth factor-1 levels, cavernous sinus invasion, tumor size, extrapseudocapsular resection, and experience of the surgeon. A total of 401 patients underwent 432 endoscopic transsphenoidal surgeries between August 1997 and June 2016 at the Pituitary Research Centre of Kocaeli University. The remission rates were evaluated according to the 2010 consensus criteria using preoperative and postoperative data including overall remission, cavernous sinus invasiveness, extrapseudocapsular resection, resection rate, and preoperative and postoperative GH levels. Total resection was performed in 311 (77.56%) of 401 patients according to early (24-hour) postoperative magnetic resonance imaging. Overall, remission was achieved in 273 (68.1%) of 401 patients. Remission was achieved in 186 (63.3%) of 294 patients with macroadenomas, 87 (81.3%) of 107 patients with microadenomas, and 35 (40.7%) of 86 patients with cavernous sinus invasion. Remission was seen in 21 (75%) of 28 patients who underwent pseudocapsular resection. According to preoperative GH levels, remission was achieved in 205 (72.4%) of 273 patients with GH levels below 20 ng/mL but decreased to 11 (37.9%) of 29 patients with GH levels over 60 ng/mL. There was, conversely, a very strongly significant correlation with cavernous sinus invasion (P < 0.001; r:-0.953) and also a very strongly significant correlation with extrapseudocapsular resection (P < 0.001; r: 0.810). However, remission was very weakly but reversely significantly correlated with adenoma size and volume. The most significant factors for remission are cavernous sinus invasion and extrapseudocapsular resection. Higher remission rates can be achieved with the removal of small remnants by meticulous sweeping and by total resection. Preoperative and postoperative GH levels are predictive of remission.

Reoperation for growth hormone-secreting pituitary adenomas: report on an endonasal endoscopic series with a systematic review and meta-analysis of the literature.

OBJECTIVE Surgery is generally the first-line therapy for acromegaly. For patients with residual or recurrent tumors, several treatment options exist, including repeat surgery, medical therapy, and radiation. Reoperation for recurrent acromegaly has been associated with poor results, with hormonal control usually achieved in fewer than 50% of cases. Extended endonasal endoscopic approaches (EEAs) may potentially improve the results of reoperation for acromegaly by providing increased visibility and maneuverability in parasellar areas. METHODS A database of all patients treated in the authors' center between July 2004 and February 2016 was reviewed. Cases involving patients with acromegaly secondary to growth hormone (GH)-secreting adenomas who underwent EEA were selected for chart review and divided into 2 groups: first-time surgery and reoperation. Disease control was defined by 2010 guidelines. Clinical and radiological characteristics and outcome data were extracted. A systematic review was done through a MEDLINE database search (2000-2016) to identify studies on the surgical treatment of acromegaly. Using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, the included studies were reviewed for surgical approach, tumor size, cavernous sinus invasion, disease control, and complications. Cases were divided into reoperation or first-time surgery for comparative analysis. RESULTS A total of 44 patients from the authors' institution were included in this study. Of these patients, 2 underwent both first-time surgery and reoperation during the study period and were therefore included in both groups. Thus data from 46 surgical cases were analyzed (35 first-time operations and 11 reoperations). The mean length of follow-up was 70 months (range 6-150 months). The mean size of the reoperated tumors was 14.8 ± 10.0 mm (5 micro- and 6 macroadenomas). The patients' mean age at the time of surgery was younger in the reoperation group than in the first-time surgery group (34.3 ± 12.8 years vs 49.1 ± 15.7 years, p = 0.007) and the mean preoperative GH level was also lower (7.7 ± 13.1 μg/L vs 25.6 ± 36.8 μg/L, p = 0.04). There was no statistically significant difference in disease control rates between the reoperation (7 [63.6%] of 11) and first-time surgery (25 [71.4%] of 33) groups (p = 0.71). Univariate analysis showed that older age, smaller tumor size, lower preoperative GH level, lower preoperative IGF-I level, and absence of cavernous sinus invasion were associated with higher chances of disease control in the first-time surgery group, whereas only absence of cavernous sinus invasion was associated with disease control in the reoperation group (p = 0.01). There was 1 case (9%) of transient diabetes insipidus and hypogonadism and 1 (9%) postoperative nasal infection after reoperation. The systematic review retrieved 29 papers with 161 reoperation and 2189 first-time surgery cases. Overall disease control for reoperation was 46.8% (95% CI 20%-74%) versus 56.4% (95% CI 49%-63%) for first-time operation. Reoperation and first-time surgery had similar control rates for microadenomas (73.6% [95% CI 32%-98%] vs 77.6% [95% CI 68%-85%]); however, reoperation was associated with substantially lower control rates for macroadenomas (27.5% [95% CI 5%-57%] vs 54.3% [95% CI 45%-62%]) and tumors invading the cavernous sinus (14.7% [95% CI 4%-29%] vs 38.5% [95% CI 27%-50%]). CONCLUSIONS Reoperative EEA for acromegaly had results similar to those for first-time surgery and rates of control for macroadenomas that were better than historical rates. Cavernous sinus invasion continues to be a negative prognostic indicator for disease control; however, results with EEA show improvement compared with results reported in the prior literature.

Endoscopic Transsphenoidal Approach for Surgical Treatment of Growth Hormone Secreting Pituitary Adenoma: Endocrinological Outcome in 49 Patients Based on 2010 Consensus Criteria for Remission - Preliminary Result

Background: Nowadays, the endoscopic transsphenoidal approach is the initial option for resection of all pituitary adenomas. The current study reported the experience with endoscopic transsphenoidal surgery remission rates using the 2010 consensus criteria, predictors of remission, and the associated complications. Methods: A prospectively collected database of 49 patients with acromegaly who underwent endoscopic endonasal transsphenoidal surgery was analyzed. Tumors were classified according to size, as well as the Knosp and the Hardy-Wilson classifications. Endocrinological remission was defined as normal insulin-like growth factor (IGF)-I level and either a suppressed growth hormone (GH) level < 0.4 ng/mL during an oral glucose tolerance test, or a random GH level < 1.0 ng/mL at least 3 months after the surgery. The extent of resection was evaluated on postoperative contrast-enhanced magnetic resonance imaging (MRI). Results: Biochemical remission was achieved in 7 of 9 (77.8%) microadenoma and 28 of 40 (70%) macroadenoma. The total remission rate was 71.4% and gross total resection was achieved in 45 of 49 (91.8%) patients. Tumor size, age, gender, history of prior surgery, suprasellar extension, and sphenoid sinus invasion were not associated with remission rate. Preoperative variables predictive of remission included the Knosp score (P = 0.041) and GH levels (P = 0.047). Two patients (4.1%) experienced postoperative pan hypopituitarism, and permanent DI was observed in 3 (6.1%) patients. One patient (2%) had cerebrospinal fluid (CSF) leaks treated with serial lumbar punctures. The median follow-up period was 25.45 months; ranged from 3 to 49. Conclusions: Endoscopic transsphenoidal adenoma resection leads to a high rate of endocrinological remission in patients with low acromegaly complication. Patients with high preoperative GH levels and the Knosp scores are less likely to achieve remission.

Preliminary analysis of the clinical features and surgical efficacy in patients with growth hormone-secreting pituitary adenoma

Objective To study the relationship between the clinical features of growth hormone (GH)-secreting pituitary adenomas and surgical treatment. Methods A total of 167 patients with GH adenoma underwent surgical treatment at the Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University from January 2011 to October 2013 were enrolled. The clinical features of the patients were observed. Its relationship with surgical efficacy was investigated. Immunohistochemical staining was used to observe the hormone expression of adenoma. Results In the 170 patients, the ratio of male and female was 1 ∶1.12 (79/88). The patients of 30 to 50 years accounted for 63.7% (n=106). Twenty-two patients (13.2%) had microadenoma, 117 (70.1%) had macroadenoma, and 28 (16.8%) had giant adenoma. Sixty-three patients (37.7%) had invasive adenoma and 104 (62.3%) had non-invasive adenoma. The resection extent of non-invasive adenomas was higher than that of the invasive ones, and there was significant difference (P=0.01). The median preoperative plasma GH level was 27 ng/ml; there were 43 patients (25.8%) the preoperative prolactin >normal value (20 ng/ml). The preoperative GH level was positively correlated with tumor volume (r=0.285, P<0.01). The preoperative and postoperative GH levels were positively correlated with tumor volume (r=0.541, P<0.01). Immunohistochemistry showed that the plurihormonal positive expression of adenoma accounted for 51.8% (79/164). Single GH hormone positive expression accounted for 48.2% (79/164). There was no significant difference in the invasion and the preoperative GH level between the two groups. The patients were followed up for 0.6 to 4.3 years, 150 of 158 patients with acromegaly were relieved; after procedure, 21.4% of patients with diabetes were cured (9/42) and 21.4% (9/42) were relieved; 16.3% (7/43) of hypertension were cured and 14.0% (6/43) were relieved. Conclusions Ghomas are common in young and middle-aged adults. Most of them are macroadenoma when the diagnosis is clear. The preoperative GH level is associated with the tumor volume. Surgical treatment is effective for part of the patients complicating with hypertension and diabetes. The extent of surgical resection of invasive ghomas is not as ideal as non-invasive ones. Key words: Growth hormone-secreting pituitary adenoma; Disease attributes; Tumor volume; Surgery

Transsphenoidal surgery for acromegaly: predicting remission with early postoperative growth hormone assays.

Early detection of residual disease may benefit management strategies in patients undergoing transsphenoidal surgery for acromegaly. This requires establishing objective thresholds for early postoperative growth hormone (GH) assays, and incorporating these parameters into a scale for outcome prediction. We analyzed a database containing the records of 86 patients who had undergone gross total transsphenoidal resection of GH-secreting pituitary adenomas. Early postoperative biochemical testing included a morning fasting basal GH assay on the first postoperative day (POD1) and a second GH assay following suppression with 100 g of oral glucose on the seventh postoperative day (POD7). Remission was defined as a normal IGF-1 with either a GH nadir <0.4 ng/ml following suppression with oral glucose or a basal fasting GH <1 ng/ml on follow-up dated >3 months after surgery. Receiver operator characteristic (ROC) curves identified optimal thresholds for all biochemical parameters. Logistic regression analysis assessed the statistical significance of factors associated with cure. A point system was developed, employing regression coefficients obtained from the multivariate statistical model to quantify the impact of each predictor on cure. Remission was achieved in 34.6 % of patients and was associated with smaller, non-invasive tumors with lower preoperative, POD1 and POD7 GH levels. Optimal thresholds obtained from the ROC analysis suggested that lower POD1 and POD7 GH values provided good sensitivity and specificity for cure, despite modest predictive values. The model with the best ability to predict outcome included size, POD1 GH and POD7 GH levels, with a score of ≥95 demonstrating high specificity for prediction of remission. Early postoperative GH assays are highly sensitivity and specific. The scoring system that we propose provided excellent predictive value and requires further validation in larger cohorts and in different populations. The model may help guide the intensity of follow-up and enable early identification of residual disease.

Factors Associated with Biochemical Remission after Microscopic Transsphenoidal Surgery for Acromegaly

Objectives To analyze surgical outcomes and predictive factors of disease remission in acromegaly patients who underwent microscopic transsphenoidal surgery (TSS) for a growth hormone (GH)-secreting adenoma. Design A 6-year retrospective review of 86 consecutive acromegaly surgeries. Setting Procedures performed at a single institution by a single surgeon. Participants Seventy acromegaly patients. Main Outcome Measures Demographic information, preoperative laboratory values, tumor imaging data, and morphological and immunohistochemical data were collected. Predictive values using the latest and most stringent biochemical remission criteria were determined using univariate and multivariate statistical analyses. Results Remission rate for 59 (18 males) acromegaly patients meeting the study inclusion criteria was 52.5%. Remission rates for micro- and macroadenomas were 81.8% and 45.8%, respectively. Patients of older age, with a smaller tumor, lower Knosp grade, lower preoperative GH, and insulinlike growth factor 1 levels were more likely to achieve remission. Remission rate decreased significantly with repeat surgeries. Those patients with adenomas that stained positive for somatostatin receptor subtype 2A were less likely to experience tumor recurrence and more likely to respond to medical treatment with persistent or elevated GH hypersecretion. Conclusions Microscopic TSS continues to be a viable means for treating acromegaly patients. Patients should be followed long term.

A rare association between Rathke’s cyst and hypophysitis in a patient with delayed sex development and growth failure

We report an 18-year-old Japanese male with a lack of secondary sex characterization and growth failure caused by a rare association between Rathke's cyst and hypophysitis. He was referred to us because of delayed secondary sex characterization. Endocrinological examination showed panhypopituitarism, and the replacement of hydrocortisone, levothyroxine, and desmopressin acetate (DDAVP) was initiated. Brain magnetic resonance imaging (MRI) showed a suprasellar region and a swollen pituitary stalk. The mass was partially resected using the transsphenoidal approach. The pathological diagnosis was hypophysitis and Rathke's cyst. Follow-up MRI performed 1 year after surgery showed that the size of sellar region had not changed. After surgery, in addition to pre-operative hormonal replacement, growth hormone and testosterone were initiated. Two years later, the size of sellar region remains unchanged. In conclusion, while an association between Rathke's cyst and hypophysitis is rare, we suggest that this condition should be included in differential diagnosis of the sellar region, even in adolescents.

Fusiform dilatation of the cavernous carotid artery in acromegalic patients

Surgeons undertaking transsphenoidal surgery in patients with acromegaly confront multiple unique challenges secondary to the anatomic alterations caused by growth hormone-secreting tumors. The senior author has noted a fusiform dilatation of the cavernous carotid artery in many acromegalic patients. The authors aim to quantify this dilatation and correlate it with potential contributing factors. Clinical and radiographic data were retrospectively assessed in acromegalic patients undergoing transsphenoidal surgery from 2000 through 2011. Randomly selected patients with nonsecreting pituitary adenomas were used as the control cohort. Demographic information, comorbidities, and preoperative growth hormone and insulin-like growth factor-1 levels were recorded. Magnetic resonance (MR) imaging variables included tumor size, diameters of the petrous, cavernous, and supraclinoid segments of the carotid artery, and extent and location of cavernous sinus invasion. Independent correlations between acromegaly and each variable were assessed with multivariate regression analysis. Forty randomly selected patients with growth hormone-secreting adenomas who underwent surgery and had MR imaging with thin coronal slices of the pituitary region were enlisted in our study cohort. The mean age was 45.7 years. Forty-two males (52.5 %) were included in the study. Mean carotid artery diameter measurements for acromegalic and control patients, respectively, were 4.2 vs. 3.8 mm (petrous carotid), 5.0 vs. 4.0 mm (cavernous carotid), and 3.3 vs. 2.9 mm (supraclinoid carotid). Multivariate analysis showed only age and cavernous carotid diameter were statistically significant independent variables (p = 0.02, p < 0.001, respectively). Age, tumor size, growth-hormone or insulin-like growth factor-1 levels, and cavernous sinus invasion did not correlate with cavernous carotid artery diameter. In patients with acromegaly, there is a fusiform dilatation of the cavernous carotid artery that must be considered when planning transsphenoidal surgery.

Routine Intensive Care Unit–Level Care After Elective Craniotomy: Time to Rethink

Transsphenoid surgery is the treatment of choice for growth hormone (GH)-producing pituitary adenomas. The measures that may predict postoperative remission need to be elucidated.Transsphenoid surgery was performed in 163 patients by a single neurosurgeon from 1992 until 2010. Thirty-three patients were lost to follow-up, and the results of the remaining 130 are presented here.A total of 81.5% of patients obtained a first postoperative day GH level less than 5 μg/L, whereas 60.5% achieved a value less than 2.5 μg/L. A total of 56.9% had achieved both a GH less than 2.5 μg/L and normal insulin-like growth factor I (IGF-I) on delayed follow-up and could be regarded as in remission. Duration of symptoms before surgery, age, preoperative GH, and IGF-I levels did not significantly influence a patient's remission. Analysis showed that cavernous sinus extension and larger tumor size were associated with decreased remission rate, whereas sellar floor invasion or suprasellar extension did not significantly influence remission.The results of our study show that transsphenoid surgery is an optimal treatment modality for GH-secreting pituitary adenoma. Suprasellar or sellar floor invasion, and preoperative GH or IGF-I do not necessarily predict poor outcomes. Large tumor size and cavernous sinus extension contribute to greater recurrence rates.

Preoperative Prediction of Growth Hormone (GH)/Insulin-Like Growth Factor-1 (IGF-1) Axis Modification and Postoperative Changes in Candidates for Bariatric Surgery

Several factors alter the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in obese patients, but GH/IGF-1 correlation with anthropometric parameters and lipid metabolism is still unclear. We evaluated this relationship and the postoperative axis modifications in candidates for bariatric surgery. Eighty-eight patients (males/females (M/F), 34/54) scheduled for bariatric surgery (biliopancreatic diversion or laparoscopic-adjustable gastric banding) between 2008 and 2010 were included in this observational, open, prospective study. Preoperative serum GH concentrations were found near the lowest limit of normal range in both sexes, with males showing the lowest values (130 vs. 1,405 pg/ml; p < 0.01). Serum concentrations of IGF-1 were within the normal range (M/F, 179/168.5 ng/ml), whereas IGF-binding protein (BP)1 and 3 values were at the lowest limits of normal range in both sexes (M/F 1.8/3.1 μg/ml and M/F 4.1/4.2 μg/ml, respectively). A statistically significant inverse correlation was found between GH, IGF-1, and IGF-BP1-3 values and total cholesterol, LDL-cholesterol, and triglycerides values in both sexes. GH and IGF-BP1-3 values were also inversely related to waist circumference and waist/hip ratio (WHR). GH, IGF-1, and IGF-BP1 and 3 values (35 cases) increased 1 year postoperatively in both sexes, mainly after malabsorptive procedures. Our results support the hypothesis that GH deficiency associated with low levels of binding proteins in obese patients may be an endocrine response to visceral fat and high levels of non-esterified fatty acids, assessable in daily clinical practice by WHR, total and LDL-cholesterol, and triglycerides. In these patients, malabsorptive procedures might be the treatment of choice due to the metabolic adaptations induced.

The Outcome of Surgery in Patients with Growth Hormone Secreting Adenomas: Early Surgical Sntervention is Essential for improving the Surgical Cure Rate

Object: During the last 10 years, 129 consecutive transsphenoidal operations for growth hormone (GH) secreting pituitary adenomas have been carried out. In the present study, 120 of the patients involved in these operations have been reviewed to evaluate the accuracy of diagnosis of adenoma, the cure rate, and to ascertain the favorable surgical effects of early surgical intervention. Methods: A total of 120 GH secreting adenomas, including 95 patients with typical acromegaly and 25 patients with no apparent clinical features of acromegaly, were evaluated. The pituitary tumors were investigated by means of Magnetic Resonance (MR) imaging at 1.5T and 3T, composite 3T-MRI and [11C] Methionine-positron Emission Tomography (MET-PET) imaging and histological and immunohistochemical staining. The modern remission criteria (a glucose suppressed [nadir] GH level of less than 1.0 ng/ml, a random GH level of 2.5 ng/ml or less, and a normal sex and age adjusted insulin-like growth factor-1 [IGF-1] level) were used. To assess remission we examined these criteria at 1, 6 and 12 months after surgery. Results: The diagnostic accuracy of 3T-MRI and composite MET-PET fusion 3T- MRI in localizing adenoma was 87 and 100%, respectively. The mean age of patients with pre-clinical acromegaly and acromegaly was 37.3 and 51.1 years, respectively. The mean preoperative GH levels in these patients were 4.85 and 34.7 ng/ml for preclinical acromegaly and acromegaly, respectively. The mean preoperative IGF-1 levels for pre-clinical acromegaly and acromegaly were 323 and 822 ng/ml, respectively. The mean volume of the adenoma in patients with pre-clinical acromegaly and acromegaly were 1.26 and 3.84 cm3, respectively. There was a significant difference (P <0.0001) between the pre-clinical acromegaly and acromegaly groups in terms of age, GH and IGF-1 levels, and tumor volume. The overall cure rate for growth hormone-secreting adenoma was 73% using modern criteria; the surgical cure rate for acromegaly patients was 65%, while the surgical cure rate for patients without obvious clinical features of acromegaly was 100%. Patients with pre-clinical acromegaly had a tendency to have smaller sized adenomas, a younger age, lower GH and IGF-1 levels, and a better surgical cure rate relative to patients with typical acromegaly. No complications such as carotid artery injury, hypothalamic injury, cerebrospinal fluid fistula or permanent diabetes insipidus occurred. Only one acromegaly patient had hypopituitarism after surgery. Conclusions: Early detection of GH secreting adenoma is important since early surgical intervention can achieve a 100% cure rate without serious complications.

The CXCR4 antagonist AMD3100 suppresses hypoxia-mediated growth hormone production in GH3 rat pituitary adenoma cells

Pituitary adenomas produce the chemokine stromal cell-derived factor (SDF-1α/CXCL12) and its receptor, CXCR4. A recent study indicated that CXCL12 and CXCR4 are concomitantly up-regulated in hypoxia. The objective of this study was to analyze the molecular mechanism of hypoxia-mediated CXCR4 up-regulation and assess the effect of pharmacological inhibition of CXCR4 by the receptor blocker, AMD3100, on pituitary function. CXCR4 expression in pituitary adenoma tissues was determined by a tissue microarray analysis of 62 pituitary adenoma samples. CXCR4 expression was significantly elevated and positively correlated with Knosp grade in pituitary adenomas (P < 0.005), and was higher in macroadenoma and growth hormone (GH)-producing adenomas. Pre-operative serum GH levels were significantly correlated with CXCR4 levels in the microarray (P < 0.0001). The relative expression of genes/gene categories that were modulated by up-regulated CXCL12/CXCR4 signaling was determined by a comparative transcriptome analysis of wild-type and CXCR4-knockdown cells in normoxia and hypoxia using the rat GH-producing and prolactin-producing pituitary adenoma cell line, GH3. Real-time reverse transcriptase-polymerase chain reaction analysis (RT-PCR) showed that CXCR4 mRNA expression in GH3 cells was increased by hypoxia (1% oxygen), and a cDNA microarray analysis revealed that inhibin β-C expression was diminished. siRNA-mediated CXCR4 knockdown blocked the hypoxia-induced decrease in inhibin β-C mRNA expression, as did inhibition of CXCR4 activity with AMD3100. An ELISA study demonstrated that GH secretion by wild-type GH3 cells was moderately enhanced by hypoxia and further potentiated by exposure to recombinant SDF-1α/CXCL12 protein. Conversely, hypoxia-induced GH secretion was reduced in CXCR4-silenced cells and in cells treated with the CXCR4 antagonist, AMD3100, notwithstanding the presence of SDF-1α/CXCL12 protein. These latter observations reflect the failure of hypoxia to suppress expression of inhibin β-C in cells deficient in CXCR4 or in which CXCR4 signaling was blocked. Together, these results indicate that the SDF-1α/CXCL12-CXCR4 signaling pathway interfaces with the classical endocrine pathway to up-regulate GH production via suppression of inhibin β-C. Because it blocks CXCR4 and prevents hypoxia-induced down-regulation of inhibin β-C expression, AMD3100 has promise as a molecular-targeting agent in the treatment of GH-producing adenomas.