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Purpose The Pituitary Society established the concept and mostly qualitative parameters for defining uniform criteria for pituitary tumor centers of excellence (PTCOEs) based on expert consensus. To validate those previously proposed criteria through collection and evaluation of self-reported activity of several internationally-recognized tertiary pituitary centers, thereby transforming the qualitative 2017 definition into a validated quantitative one, which could serve as the basis for future objective PTCOE accreditation. Methods An ad-hoc prepared database protocol was distributed to 9 Pituitary Centers chosen by the project scientific committee and comprising Centers of worldwide repute, which agreed to provide activity information derived from registries related to the years 2018-2020 and completing the database within 60 days. The database, composed of Excel® spreadsheets with requested specific information on leading and supporting teams provided by each Center, was reviewed by two blinded referees and all 9 of 9 candidate centers satisfied the overall PTCOE definition, according to referees’ evaluations. To obtain objective numerical criteria, median values for each activity/parameter were considered as the ideal PTCOE definition target, whereas the low limit of the range was selected as the acceptable target for each respective parameter. Results Three dedicated pituitary neurosurgeons were considered ideal, whereas one dedicated surgeon was acceptable. Moreover, 100 surgical procedures per year is ideal, while the results indicated that 50 surgeries per year is acceptable. Acute post-surgery complications, including mortality and readmission rates, should ideally be negligible or nonexistent, but acceptable criterion was a rate lower than 10% of patients with complications requiring readmission within 30 days after surgery. Four endocrinologists devoted to pituitary diseases are requested in a PTCOE and the total population of patients followed in a PTCOE should not be less than 850. It appears acceptable that at least one dedicated/expert in pituitary diseases is required in neuroradiology, pathology, and ophthalmology groups, whereas at least two expert radiation oncologists are needed. Conclusion This is, to our knowledge, the first study to survey and evaluate the activity of a relevant number of high-volume centers in the pituitary field. This effort, internally validated by ad-hocreviewers, allowed for transformation of previously formulated theoretical criteria for the definition of a PTCOE to precise numerical definitions based on real-life evidence. The application of a derived objective model can be used by external bodies for accreditation of pituitary centers as PTCOEs.

PURPOSE: To assess long-term quality of life (QoL) in patients with sustained biochemical control of acromegaly, comparing those receiving vs not receiving pharmacotherapy (primary analysis); to assess change in QoL over time (secondary analysis). METHODS: Cross-sectional study, with a secondary longitudinal component, of 58 patients with biochemically controlled acromegaly. All had participated in studies assessing QoL years previously, after having undergone surgery ± radiotherapy. One cohort received medical therapy [MED (n=33)]; the other did not [NO-MED (n=25)]. QoL was assessed by the 36-Item-Short-Form Health Survey (SF-36), Acromegaly Quality of Life Questionnaire (AcroQoL), Gastrointestinal Quality of Life Index (GIQLI), Symptom Questionnaire, and QoL-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA). RESULTS: Mean (±SD) duration of biochemical control was 15.0 ± 6.4 years for MED and 20.4 ± 8.2 years for NO-MED (p=0.007). 58% of subjects scored

Background Systemic glucocorticoid therapy has been used to control headaches associated with lymphocytic hypophysitis (LH), a rare autoimmune inflammation of the pituitary gland and stalk. Steroid-sparing immunosuppressive therapies, like mycophenolate mofetil (MM), have proven to be effective for patients with many systemic inflammatory and rheumatological conditions. However, the safety and efficacy of steroid-sparing immunosuppressive therapies for LH has not been studied. Clinical Case Here we report a case of a 31-year-old male who presented with worsening headache, fatigue, polyuria, insomnia, low libido, and decreased appetite. His laboratory results were consistent with central diabetes insipidus (DI), central hypothyroidism, central adrenal insufficiency, and hypogonadotropic hypogonadism without evidence of growth hormone deficiency. Initial pituitary MRI revealed pituitary enlargement and thickening of the stalk. He was started on desmopressin, levothyroxine, testosterone cypionate, and physiologic glucocorticoid replacement with prednisone 5mg daily. He continued to endorse incapacitating occipital headaches not relieved by ibuprofen, topiramate, gabapentin, amitriptyline, sumatriptan, or rizatriptan, and only temporary relieved by occipital nerve blocks. A pituitary biopsy confirmed the diagnosis of LH. Given his persistent, debilitating headaches, prednisone was increased to supraphysiologic doses. Headaches resolved on prednisone 40mg daily but recurred two months after tapering down to prednisone 5mg daily. Pituitary MRI after 4 months revealed a mild interval increase in enhancement and thickening of the pituitary stalk. Prednisone was increased to 20mg daily, and he was started on MM for progressive inflammation. Prednisone was tapered down to 5mg daily over the course of 3 months as MM dose was increased to 1000mg twice a day. Headaches completely resolved. After 4 months of MM therapy, pituitary MRI showed decrease in size of pituitary stalk thickening and pituitary, consistent with treatment effect. After 6 months of MM therapy, MRI brain showed further decrease in pituitary size and resolution of pituitary stalk thickening. He did not experience any adverse effect on MM. Serial complete blood counts, liver function tests, and basic metabolic panels were normal. Two years after diagnosis and one year on MM therapy, his DI resolved, his adrenal insufficiency was well managed with prednisone 4mg daily, he was euthyroid on levothyroxine 75mcg daily, and his hypogonadism was treated adequately with testosterone cypionate 50mg weekly with improved libido and energy. Conclusion MM was effective in treating intractable headaches caused by biopsy-proven LH. Radiologic signs of improvement in pituitary inflammation coincided with patient's report of headache relief and initiation of MM, without concurrent use of supraphysiologic glucocorticoids. Treatment was well-tolerated with no reported adverse effect. Steroid-sparing immunosuppressive therapy like MM may be considered as a therapy for LH, particularly in patients who depend on prolonged courses of supraphysiologic glucocorticoid treatment to alleviate symptoms. Presentation: No date and time listed

Purpose The phase 3 CHIASMA OPTIMAL trial (NCT03252353) evaluated efficacy and safety of oral octreotide capsules (OOCs) in patients with acromegaly who previously demonstrated biochemical control while receiving injectable somatostatin receptor ligands (SRLs). Methods In this double-blind study, patients (N = 56) stratified by prior SRL dose were randomly assigned 1:1 to OOC or placebo for 36 weeks. The primary end point was maintenance of biochemical control at the end of treatment (mean insulin-like growth factor 1 [IGF-1] ≤ 1.0 × upper limit of normal [ULN]; weeks 34 and 36). Time to loss of IGF-1 response and proportion requiring reversion to injectable SRLs were assessed as broader control measures. Results Mean IGF-1 measurements were 0.80 and 0.97 × ULN for OOC and 0.84 and 1.69 × ULN for placebo, at baseline and end of treatment, respectively. Mean growth hormone (GH) changed from 0.66 to 0.60 ng/mL for OOCs and 0.90 to 2.57 ng/mL for placebo. Normalization of IGF-1 levels (≤ 1.0 × ULN) was maintained in 58.2% for OOCs vs 19.4% for placebo (P = .008); GH levels were maintained ( 1.0 or ≥ 1.3 × ULN definitions) for patients receiving placebo was 16 weeks; for patients receiving OOCs, it was not reached for both definitions during the 36-week trial (P < .0001). Of the patients in the OOC group, 75% completed the trial on oral therapy. The OOC safety profile was consistent with previous SRL experience. Conclusions OOCs may be an effective therapy for patients with acromegaly who previously were treated with injectable SRLs.

Objective The objective of this study is to report results from the open-label extension (OLE) of the OPTIMAL trial of oral octreotide capsules (OOC) in adults with acromegaly, evaluating the long-term durability of therapeutic response. Design The study design is an OLE of a double-blind placebo-controlled (DPC) trial. Methods Patients completing the 36-week DPC period on the study drug (OOC or placebo) or meeting predefined withdrawal criteria were eligible for OLE enrollment at 60 mg/day OOC dose, with the option to titrate to 40 or 80 mg/day. The OLE is ongoing; week 48 results are reported. Results Forty patients were enrolled in the OLE, 20 each having received OOC or placebo, with 14 and 5 patients completing the DPC period as responders, respectively. Ninety percent of patients completing the DPC period on OOC and 70% of those completing on placebo completed 48 weeks of the OLE. Maintenance of response in the OLE (i.e. insulin-like growth factor I (IGF1) ≤ 1.0 × upper limit of normal (ULN)) was achieved by 92.6% of patients who responded to OOC during the DPC period. Mean IGF1 levels were maintained between the end of the DPC period (0.91 × ULN; 95% CI: 0.784, 1.045) and week 48 of the OLE (0.90 × ULN; 95% CI: 0.750, 1.044) for those completing the DPC period on OOC. OOC safety was consistent with previous findings, with no increased adverse events (AEs) associated with the higher dose and improved gastrointestinal tolerability observed over time. Conclusions Patients with acromegaly maintained long-term biochemical response while receiving OOC, with no new AEs observed with prolonged OOC exposure.

Non–small cell lung cancer with pituitary metastasis (NSCLC-PM) is a devastating disease; however, treatment is being revolutionized by a novel therapy targeting highly specific tumor signals, such as the mutation of epidermal growth factor receptors (EGFRs). Long-term management of hormonal defects in this population has become a unique neuroendocrine clinical challenge. We report the case of a 73-year-old female nonsmoker who was diagnosed with stage IV non–small cell lung cancer. The initial staging evaluation revealed a 7 × 11 × 21-mm sellar lesion abutting the optic chiasm and causing clinical hypopituitarism. The patient received three cycles of chemotherapy with carboplatin and pemetrexed, which was discontinued because of major cumulative side effects of myelosuppression and kidney disease. Eight months later, scans demonstrated evidence of disease progression. A repeated lung nodule biopsy revealed an EGFR exon 19 deletion mutation. EGFR-targeted therapy with osimertinib 80 mg daily was initiated. A complete resolution of the pituitary lesion was evident on a follow-up pituitary MRI 5 weeks later and was sustained 1 year after. However, the panhypopituitarism persisted. This is an illustrative case of NSCLC-PM with EGFR exon 19 deletion mutation, wherein osimertinib, a third-generation EGFR‒tyrosine kinase inhibitor, eradicated the sellar metastasis and prevented the need for radiotherapy. However, the neuroendocrine deficits persisted despite anatomic improvement.

Background Patients with low-grade gliomas (LGG) can survive years with their illness. Proton radiotherapy (PRT) can reduce off-target dose and decrease the risk of treatment-related morbidity. We examined long-term morbidity following proton therapy in this updated prospective cohort of patients with LGG. Methods Twenty patients with LGG were enrolled prospectively and received PRT to 54 Gy(RBE) in 30 fractions. Comprehensive baseline and longitudinal assessments of toxicity, neurocognitive and neuroendocrine function, quality of life, and survival outcomes were performed up to 5 years following treatment. Results Six patients died (all of disease) and six had progression of disease. Median follow-up was 6.8 years for the 14 patients alive at time of reporting. Median progression-free survival (PFS) was 4.5 years. Of tumors tested for molecular markers, 71% carried the IDH1-R132H mutation and 29% had 1p/19q co-deletion. There was no overall decline in neurocognitive function; however, a subset of five patients with reported cognitive symptoms after radiation therapy had progressively worse function by neurocognitive testing. Six patients developed neuroendocrine deficiencies, five of which received Dmax ≥20 Gy(RBE) to the hypothalamus–pituitary axis (HPA). Most long-term toxicities developed within 2 years after radiation therapy. Conclusions The majority of patients with LGG who received proton therapy retained stable cognitive and neuroendocrine function. The IDH1-R132H mutation was present in the majority, while 1p/19q loss was present in a minority. A subset of patients developed neuroendocrine deficiencies and was more common in those with higher dose to the HPA.

Purpose Mifepristone is a glucocorticoid and progesterone receptor blocker that can be used for patients with hyperglycemia and Cushing syndrome in whom surgery failed to achieve remission or who were ineligible for surgery. We report a case series of patients with Cushing disease (CD) and central hypothyroidism that presented with increased levothyroxine requirements during mifepristone therapy. Methods Retrospective longitudinal case series of patients with CD and central hypothyroidism treated with mifepristone in a retrospective database at four pituitary centers in the United States. Results Five patients with CD were found, all women, median age 50 (interquartile range 47 to 64.5). They received mifepristone because no adequate response or intolerance to other drugs was observed. Mifepristone initiation was associated with a decrease in free thyroxine levels, mandating a dose increase of a median 1.83 (1.71 to 3.5) times the initial dose of levothyroxine to achieve normal levels. Weight loss was seen in four of five patients, ranging from 3.2 to 42.6 kg in up to 54 months of follow-up. Conclusions Although the mechanism behind the decrease in thyroid hormone level is unknown, intestinal malabsorption, decreased residual thyroid function and increased inactivation of T4 via deiodinases are all potential causes. Whereas therapies for hypercortisolism aim to decrease features of hypercortisolemia such as weight gain and depression, hypothyroidism can hamper these goals. This case series raises awareness on the importance of assessment of thyroid status in patients receiving mifepristone to optimize clinical outcomes.

Context Oxytocin (OT) and vasopressin share anatomical pathways of synthesis and secretion, and patients with central diabetes insipidus (CDI) presumably are at risk for OT deficiency. However, an OT-deficient state in hypopituitary patients has not been established. Objectives We hypothesized that men with CDI compared to patients with similar anterior pituitary deficiencies (APD) but no CDI and healthy controls (HC) of similar age and body mass index, would have lower plasma OT levels, associated with increased psychopathology. Design Cross-sectional. Setting Clinical research center. Participants Sixty-two men (20 CDI, 20 APD, 22 HC), age 18 to 60 years. Interventions Frequent sampling of blood every 5 minutes for OT over 1 hour and validated questionnaires to assess psychopathology. Main outcomes Pooled plasma OT levels; depressive, anxiety, and alexithymia symptoms; and quality of life. Results The mean 1-hour pool of fasting OT levels was lower in CDI compared with APD and HC (P = 0.02 and P = 0.009, respectively), with no differences between APD and HC (P = 0.78). Symptoms of depression, anxiety, and alexithymia were more pronounced in CDI than in HC (P = 0.001, P = 0.004, and P = 0.02, respectively). Although CDI and APD reported worse physical health compared with HC (P = 0.001 and P = 0.005) with no differences between APD and CDI, only CDI reported worse mental health compared with HC (P = 0.009). Conclusions We have demonstrated low plasma OT levels and increased psychopathology in hypopituitary men with CDI, suggestive of a possible OT-deficient state. Larger studies of both sexes are required to confirm these findings and clinically characterize hypopituitary patients with OT deficiency.

Purpose Results are presented from 2 to 3 trials investigating oral octreotide capsules (OOC) as an alternative to injectable somatostatin receptor ligands (iSRLs) in the treatment of acromegaly. Methods CH-ACM-01 was an open-label trial (N = 155) and CHIASMA OPTIMAL was a double-blind placebo-controlled (DPC) trial (N = 56), both investigating OOC as maintenance therapy for patients with acromegaly who were biochemical responders receiving iSRLs. Results Baseline characteristics in both trials reflected those expected of patients with acromegaly responding to treatment and were similar between trials, despite differences in inclusion criteria. OOC demonstrated a consistent degree of biochemical response across trials, with 65% of patients in CH-ACM-01 maintaining response during the core period and 64% of patients in CHIASMA OPTIMAL at the end of the DPC. Mean insulin-like growth factor I (IGF-I) levels remained within inclusion criteria at the end of treatment in both trials. Of 110 patients entering the fixed-dose phase in CH-ACM-01, 80% maintained or improved acromegaly symptoms from baseline to the end of treatment. Over 85% of patients in both trials elected to continue into the extension phases. OOC were found to be well tolerated across both trials, and no dose-related adverse events were observed. Conclusions OOC demonstrated remarkably consistent results for biochemical response, durability of response, and preference to continue with oral treatment across these 2 complementary landmark phase 3 trials, despite differences in the design of each. Trial registration NCT03252353 (August 2017), NCT01412424 (August 2011).

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of parathyroid tumors, pituitary adenomas, and pancreatic neuroendocrine neoplasms (PNENs). MEN1 is caused by germline MEN1 mutations in > 75% of patients, and the remaining 25% of patients may have mutations in unidentified genes or represent phenocopies with mutations in genes such as cell cycle division 73 (CDC73), the calcium sensing receptor (CASR), and cyclin-dependent kinase inhibitor 1B (CDKN1B), which are associated with the hyperparathyroidism-jaw tumor syndrome, familial hypocalciuric hypercalcemia type 1, and MEN4, respectively. Here, we report a heterozygous c.1138C>T (p.Leu380Phe) CDC73 germline variant in a clinically diagnosed MEN1 patient, based on combined occurrence of primary hyperparathyroidism, acromegaly, and a PNEN. Characterization of the PNEN confirmed it was a neuroendocrine neoplasm as it immuno-stained positively for chromogranin and glucagon. The rare variant p.Leu380Phe occurred in a highly conserved residue, and further analysis using RNA-Scope indicated that it was associated with a significant reduction in CDC73 expression in the PNEN. Previously, CDC73 mutations have been reported to be associated with tumors of the parathyroids, kidneys, uterus, and exocrine pancreas. Thus, our report of a patient with PNEN and somatotrophinoma who had a CDC73 variant, provides further evidence that CDC73 variants may result in a MEN1 phenocopy.

OBJECTIVE Acromegaly is associated with impaired quality of life (QoL). We investigated the effects of biochemical control of acromegaly by growth hormone receptor antagonism vs somatostatin analog therapy on QoL. DESIGN Cross-sectional. PATIENTS 116 subjects: n = 55 receiving a somatostatin analog (SSA group); n = 29 receiving pegvisomant (PEG group); n = 32 active acromegaly on no medical therapy (ACTIVE group). MEASUREMENTS Acromegaly QoL Questionnaire (AcroQoL), Rand 36-Item Short Form Survey (SF-36) and Gastrointestinal QoL Index (GIQLI); fasting glucose, insulin and IGF-1 levels (LC/MS, Quest Diagnostics). RESULTS There were no group differences in mean age, BMI or sex [(whole cohort mean ± SD) age 52 ± 14 years, BMI 30 ± 6 kg/m2 , and male sex 38%]. Mean IGF-1 Z-scores were higher in ACTIVE (3.9 ± 1.0) vs SSA and PEG, which did not differ from one another (0.5 ± 0.7 and 0.5 ± 0.7, P

Objective: The phase 3 CHIASMA OPTIMAL study assessed efficacy and safety of oral octreotide capsules (OOC) in patients with acromegaly controlled on injectable somatostatin receptor ligands (SRLs). Sensitivity analyses were conducted for efficacy endpoints using two methods of imputation (i.e., the process of replacing clinical data with substitution values) to address missing data points due to some subjects reverting back to their prior injectable SRL treatment. Methods: Patients were ≥18 years of age and had evidence of active acromegaly with an average IGF-I ≤ 1.0 x ULN (utilizing the IDS iSYS assay calibrated to WHO recombinant reference standard 02/254). At baseline, patients were randomized to receive OOC or placebo for 36 weeks. The primary endpoint was proportion of patients maintaining biochemical response, defined as IGF-I ≤1.0 x ULN (2-value average at weeks 34 and 36) (Samson et al. ENDO 2020). Per study protocol, patient study discontinuations were considered non-responders regardless of clinical response at the time of discontinuation (non-response imputation). Additional exploratory analyses were performed utilizing the last observation carried forward (LOCF) analysis, as well as a completers analysis of response among the subgroup that completed the entire 36 weeks on study drug. The response rates reported for the primary end point are slightly adjusted for stratification differences as prespecified in the statistical analysis plan. Results: Twenty-eight patients received OOC and 12 failed to maintain biochemical response based on the primary endpoint. Seven of these 12 patients discontinued treatment early - 5 due to treatment failure and 2 due to AEs. The remaining 5 patients completed the 36-week protocol on study drug. Of these 5 patients, 4 had IGF-I values between >1.0 and ≤1.3 x ULN and 1 completed the study with an IGF-I of 1.7 x ULN with no clinical symptoms. 58.2% of patients in the OOC group met the primary endpoint of maintenance of biochemical response at the end of study using the non-response imputation. Using LOCF imputation, 64.3% (18/28) of patients met this endpoint. Of those completing the study (N=21), 76.2% maintained response. Conclusion: CHIASMA OPTIMAL primary endpoint was assessed using the non-response imputation for patients who discontinued treatment early, with a 58.2% response rate. However, when assessing the response rate based on LOCF imputation, or in study completers, similar to other phase 3 studies for acromegaly, the rate was imputed at 64.3% and 76.2%, respectively.

Context Clinical multiple endocrine neoplasia type 1 (MEN-1) is diagnosed by the presence of at least 2 MEN-1–associated tumors. Many patients with acromegaly and clinical MEN-1 yield negative testing for MEN1 mutations. While cases of acromegaly and primary hyperparathyroidism (PHP) with negative genetic testing have been reported, its prevalence among patients with acromegaly is undetermined, and the clinical presentation has not been well characterized. Objectives The main goals of this study are: (1) To determine the prevalence of clinical MEN-1 with PHP in patients with acromegaly and characterize their clinical features; and (2) to evaluate the genetic basis for the coexistence of acromegaly and PHP. Design Retrospective record review and genetic analysis. Setting Clinical Research Centers. Participants 414 patients with acromegaly. Interventions Clinical evaluation and DNA sequencing for MEN1, CDKN1A, CDKN1B, CDKN2B, CDKN2C, and AIP genes. Main outcome measurements Clinical and genetic analysis. Results Among patients with acromegaly, clinical MEN-1, as defined by the presence of at least one other MEN-1-associated tumor, was present in 6.6%. PHP occurred in 6.1%; more than half had parathyroid hyperplasia. DNA sequencing was unrevealing for genetic mutations, except for 1 case of a CDC73 mutation. Acromegaly was diagnosed at an older age with a higher prevalence of malignancies (specifically breast and thyroid) in patients with coexisting PHP than those with isolated acromegaly. Conclusions A distinct phenotype is described in patients with clinical MEN-1 and negative genetic testing for mutations previously associated with this syndrome. Further studies are needed to identify other genes that may explain the association between PHP and acromegaly.

Data on the impact of withdrawal from long-acting somatostatin receptor ligand (SRL) injections on disease activity in patients with acromegaly are limited. The phase 3 Octreotide capsules versus Placebo Treatment In MultinationAL centers (OPTIMAL) study assessed the efficacy and safety of oral octreotide capsules in adult patients with acromegaly responding to injectable SRL therapy. The placebo-controlled arm of this study allowed for assessment of acromegaly biochemical and disease activity in patients after withdrawal from SRL treatment. A multinational, randomized, placebo-controlled study was conducted in 56 adult patients with active acromegaly. Patients were ≥ 18 years of age, had evidence of active disease (defined as IGF-I ≥1.3 x ULN after last pituitary surgery), and an average IGF-I ≤ 1.0 x ULN in response to a stable dose of SRL injection. Patients were randomized, 1 month following their last injection, to octreotide capsule or placebo for 36 weeks, with an option to enroll in an open-label extension. The primary aim was to determine the proportion of patients maintaining biochemical response, defined as IGF-I ≤1.0 x ULN (average of week 34 and 36). The trial met the primary endpoint, with 58% (16/28) of patients receiving octreotide capsules maintaining IGF-I response vs 19% (5/28) receiving placebo (P=0.008). The median time to loss of response (2 criteria evaluated: IGF-I >1.0 and ≥ 1.3 x ULN for 2 consecutive visits) was 16 weeks in the placebo group, while it was not reached in the octreotide capsule group. Of the 5 patients in the placebo group who maintained their biochemical response at 36 weeks, only 2 (7% of placebo group) did not meet loss of response criteria. When IGF-I values for any 2 consecutive visits were analyzed for patients receiving placebo, 93% (26/28) lost response based on IGF-I > 1 x ULN and 79% (22/28) lost response based on IGF-I ≥ 1.3 x ULN. Irrespective of biochemical control of acromegaly, 26/28 patients receiving placebo experienced active disease-related symptoms reported as AEs of special interest (AESIs). Most common AESIs (≥ 5%) included arthralgia/arthritis (60.7%), soft tissue swelling (35.7%), headache (32.1%), hyperhidrosis (25%), carpal tunnel (14.3%), musculoskeletal pain (14.3%), weight increased (7.1%) and tongue disorders (7.1%). The 5 patients receiving placebo with controlled IGF-I at 36 weeks received active medical treatment in the open label extension by decision of their study PIs, as they were deemed to have either lost their response during the study or had continuing active acromegaly symptoms. 93% of patients receiving placebo lost response following withdrawal of injectable SRLs, with a median duration of 16 weeks. All 5 patients receiving placebo who met the primary endpoint criteria at the end of the study were assessed clinically to have active disease and were continued on oral SRL treatment in the open label extension.

Background: Injectable somatostatin receptor ligands (SRLs) are currently the most widely used medical therapy for acromegaly worldwide. Oral octreotide capsules (OOC) have been formulated as a potential therapy for this disorder and the safety and efficacy were evaluated in the CHIASMA OPTIMAL pivotal study (Samson et al. ENDO 2020). As reported, mean IGF-I levels of the OOC treatment group were maintained within normal range at the end of treatment in all patients. However, some patients may not respond to OOC treatment (25% of OOC group and 68% of placebo groups required rescue, P=0.003). This analysis describes the degree and rapidity with which patients achieve biochemical control (IGF-I ≤1.0 x ULN) when reverted to their prior injectable SRL treatment. Methods: Patients with confirmed acromegaly and receiving a stable dose of injectable SRL (≥3 months) were randomized to OOC (40mg/day; N=28) or placebo (N=28) for 36 weeks. Patients were dose titrated to 60 or 80mg of OOC (or placebo) through week 24 at investigator discretion based on increased IGF-I levels and/or worsening acromegaly signs/symptoms. Patients could be rescued via reversion to prior injectable SRL therapy if they met the predefined withdrawal criteria (i.e., IGF-I ≥1.3 x upper limit of normal [ULN] for 2 consecutive visits on the highest dose, and exacerbation of clinical signs/symptoms) or discontinued treatment early for any other reason. In the study, 7 patients in the OOC group and 19 in the placebo group required rescue. The change in IGF-I from Baseline was compared to the end of the Double-blind Placebo Controlled period. Results: In patients rescued up to week 32 and in whom there were at least 4 weeks of follow up, baseline IGF-I levels (mean of Screening Visit 2 and Baseline) were 0.80 and 0.87 x ULN in the OOC and placebo groups, respectively. In patients receiving rescue therapy, the end of study IGF-I levels (mean of week 34 and 36) were 0.80 and 0.89 x ULN in the OOC and placebo groups, respectively, virtually unchanged. The median time to return to normal baseline IGF-I values following loss of response was 4.0 weeks after discontinuing OOC and 4.0 weeks after discontinuing placebo treatment. Therefore, most patients who required rescue following a short trial of therapy with OOC returned to their baseline values following a single SRL injection. Conclusion: Most treatment failures in the CHIASMA OPTIMAL trial (on either OOC or placebo) rescued with injectable SRL re-established their baseline response levels after a single injectable SRL administration (at pre-study dose). Based on this data, patients may potentially be treated with OOC and for those not responding, either not biochemically controlled or who have adverse effects, they may be able to return to injectable SRLs with immediate IGF-I control after one SRL injection.

Background: In clinical practice, most patients responding to injectable somatostatin receptor ligands exhibit IGF-I variability around the upper limit of normal (ULN) during long-term follow up. These fluctuations are thought to result from various factors such as assay variability, nutrition, comorbid conditions, concomitant medications and other unknown factors. The magnitude of this variability, and the factors affecting it, is not well understood in patients with acromegaly treated with injectable SRLs. Methods: IGF-I levels of patients responding to and stably treated with injectable SRLs were measured over time in the CHIASMA OPTIMAL phase III study. Two time periods were assessed - Period 1, three assessments during screening phase before randomization to octreotide capsules (N=56), and Period 2 - multiple assessments up to week 36, in patients rescued with SRL injections for at least 12 weeks (N=21). The time from the last injection to each of the 3 assessments in period 1 [Screening visits 1 and 2 (SV1 & SV2), and Baseline (BL)], was on average 6.8 ± 10.7 (SD), 15.8 ± 2.7, and 29.0 ± 1.8 days respectively. Correlation with various demographics and Baseline characteristics, including age, gender, weight, BMI and residual tumor size to IGF-I variability was assessed. Percent change for each individual patient from Minimal to Maximal IGF-I values within each period was computed and the overall population mean was calculated (lowest value was used as the denominator and all other values were expression as a positive % above this value). Results: The overall mean within-patient percent change of IGF-I levels during Period 1 was 20.48 ± 15.56 (range: 0.6-81). Mean IGF-I levels for SV1, SV2 and BL were 0.78 ± 0.18, 0.79 ± 0.18, and 0.85 ± 0.22 x ULN respectively. The overall increase in mean IGF-I levels from SV1 to BL (longest time interval) was statistically significant (p=0.0002; paired T-test). Analysis of IGF-I levels in patients during Period 2, revealed that the overall mean within-patient percent change of IGF-I levels was 15.27 ± 12.20 (range: 0-41.5). The mean duration of follow up during this period, after patients were already treated for ≥12 weeks with injectable SRL, was 1.72 (± 1.29) months. The variability observed in Period 2 was similar to that observed in the entire sample evaluated in Period 1. No significant differences were found in the mean IGF-I percent change between any demographic or baseline characteristic subgroup examined. Conclusion: IGF-I levels fluctuate in patients with acromegaly who are responsive to injectable SRLs. These fluctuations are wide and can be up to 81% higher than the lowest (most controlled) value, with an average increase of approximately 20%. Significant IGF-I increases were observed at the end of the long acting SRL injection interval. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Background: Injectable somatostatin receptor ligands (SRLs) are the most widely used therapy to control acromegaly. Oral octreotide capsules have been formulated as a potential therapy for this disorder and the efficacy and safety was evaluated in the CHIASMA OPTIMAL prospective phase 3 study in patients with acromegaly who were controlled on injectable SRL treatment of varying doses (Samson et al. ENDO 2020). Methods: Patients with confirmed acromegaly, who had been receiving a stable dose of injectable SRL (≥3 months) up until study entry, were randomized to receive octreotide capsules (40 mg/day) or placebo for 36 weeks. Patients were dose titrated to 60 or 80 mg of oral octreotide or equivalent placebo through week 24 at the investigator’s discretion based on increase of IGF-I levels or worsening of acromegaly signs and symptoms. The primary efficacy endpoint was the proportion of patients who maintained their biochemical response at the end of 36 weeks, defined as average IGF-I ≤1 x ULN between Weeks 34 and 36. An analysis evaluated maintenance of response based on prior dose of injectable SRL. Prior doses of injectable SRL were categorized based on the following classifications: octreotide 10 mg every 4 weeks or lanreotide 60 mg every 4 weeks or 120 mg every 8 weeks were stratified as low; octreotide 20 mg every 4 weeks or lanreotide 90 mg every 4 weeks or 120 mg every 6 weeks were stratified as medium; octreotide 30 mg or 40 mg or lanreotide 120 mg every 4 weeks were stratified as high. Randomization was stratified based on low dose vs med/high dose and efficacy results compared for these strata. The response rates reported for the primary end point are slightly adjusted for stratification differences as prespecified in the statistical analysis plan. Results: Six patients (21.4%) in the octreotide capsule group had received prior treatment with low doses of injectable SRLs while 22 (78.6%) had received prior treatment with medium-high doses of injectable SRLs. Maintenance of response was observed in 16 patients receiving oral octreotide. This included 66.7% of patients (n=4) previously receiving low doses of injected SRLs and 54.5% of patients (n=12) on medium-high injected doses. The treatment effect was consistent irrespective of prior dose of injectable SRL (odds ratio: 5.4 in low dose and 5.9 in medium-high dose). Conclusion: The CHIASMA OPTIMAL study recruited a population receiving predominantly medium-high doses of injectable SRLs and demonstrated maintenance of response in 58% of patients. Oral octreotide treatment effect was consistent irrespective of prior dose of injectable SRL.

Distinguishing non-specific signs and symptoms of acromegaly from treatment emergent adverse events (TEAEs) in patients treated with somatostatin receptor ligands has proven difficult given limited data from placebo-controlled studies. The phase 3 Octreotide capsules versus Placebo Treatment In MultinationAL centers (OPTIMAL) study provides a novel data set to evaluate the incidence of adverse events from patients randomized to octreotide capsules or placebo. A multinational, randomized, placebo-controlled study was conducted in 56 adult patients with active acromegaly. Eligible patients were ≥18 years of age, had active disease (IGF-I ≥1.3 x ULN after last pituitary surgery), and an average IGF-I ≤1.0 x ULN in response to a stable dose of somatostatin receptor ligand injection. Patients were randomized to octreotide capsule or placebo (28 per group) for 36 weeks, followed by an optional open-label extension for up to 1 year. Safety and tolerability were evaluated based on incidence of AEs, including incidence of new or worsening adverse events of special interest (AESIs). In this study, the safety profile of octreotide capsules was consistent with the known safety profile of injectable octreotide (Melmed et al 2015). No new or unexpected safety signals were detected. Nearly all patients (55/56) experienced a TEAE (28 patients [100.0%] in the octreotide capsule group and 27 patients [96.4%] in the placebo group). Thirty-three patients (58.9%) experienced a TEAE considered to be related to study drug by the blinded PI (64.3% of the octreotide capsule group [18 patients, 40 events] and 53.8% of the placebo group [15 patients, 41 events]). TEAEs with an incidence ≥5% that were more common in the octreotide capsule group vs placebo group included GI disorders, increased blood glucose, sinusitis, osteoarthritis, and cholelithiasis. TEAEs with an incidence ≥5% that were more common in the placebo group vs octreotide capsule group included arthralgia, headache, fatigue, hyperhidrosis, and peripheral swelling. GI disorders were the most common TEAE, reported in 64% of all patients (36/56) and at similar rates between octreotide capsule (68%) and placebo groups (61%). AESIs (defined as new or worsening signs of acromegaly) were observed in 15 patients (53.6%, 34 events total) in the octreotide capsule group and more frequently in 26 patients (92.9%, 82 events total) in the placebo group. In this study, the safety profile of octreotide capsules was consistent with the known safety profile of injectable octreotide. Most patients receiving octreotide capsules or placebo demonstrated TEAEs, although the profile of most common TEAEs varied between groups. TEAEs observed in the placebo group may be indicative of underlying disease activity. Further analysis may elucidate the difference between treatment related AEs and signs/symptoms of active disease in acromegaly.

PURPOSE: In view of mounting attention related to possible brain retention of gadolinium-based contrast agents (GBCAs) in patients with normal renal function, our purpose was to detail results from a survey of pituitary experts to assess: 1) the timing interval and frequency of pituitary magnetic resonance imaging (MRI) following surgical and/or medical and/or radiation therapy of pituitary tumors, 2) awareness of the types of GBCAs used and their possible safety issues. METHODS: The Pituitary Society Education Committee composed a survey with 12 multiple choice questions, 8 of which specifically addressed the time interval and frequency of MRI in the longitudinal management of pituitary tumors. The survey was distributed at two meetings; the International Pituitary Neurosurgeons Society conference in San Diego, CA, on February 18th, 2018, and the Pituitary Society Membership and Career Development Forum, Chicago, IL on March 18th, 2018. RESULTS: There is consensus among pituitary endocrinologists and neurosurgeons that long-term repeated imaging is recommended in most pituitary tumors, although the precise strategy of timing varied depending on the specialist group and the specific clinical context of the adenoma. The data also suggest that International Pituitary Neurosurgeons Society neurosurgeons, as well as Pituitary Society neuroendocrinologists, are sometimes unaware of which contrast agents are used by their institution, and many are also unaware that evidence of long-term brain retention has been reported with the use of GBCAs in patients with normal function. CONCLUSIONS: International pituitary endocrinologists and pituitary neurosurgeons experts suggest ongoing MRIs for the management of pituitary tumors; strategies vary based on clinical context, but also on individual experience and practice.

Background: Based on the CHIASMA OPTIMAL study, oral octreotide capsules (OOC) were recently approved in the US as a long-term maintenance therapy for patients with acromegaly previously responding to injectable octreotide or lanreotide, somatostatin receptor ligands (SRLs). Results on longer-term efficacy and safety of OOC from the first 48 weeks of the open-label extension (OLE) of this study are presented here. Methods: Eligible patients had the option to enroll in the OLE of CHIASMA OPTIMAL following the double-blind placebo-controlled (DPC) period; 90% of patients who received OOC in the DPC period enrolled. All patients entering the OLE were initiated on a 60 mg/day dose of OOC and titrated up or down based on insulin-like growth factor I (IGF-I) level and/or acromegaly signs or symptoms. End points in the OLE were exploratory and included the proportion of patients who completed week 48 of the OLE, the proportion who completed as responders (defined as average IGF-I ≤1.0 × upper limit of normal [ULN] at weeks 46/48), and changes in IGF-I from baseline of DPC and OLE until week 48 of the OLE; multiple imputation (MI) was used for missing data. Results: Forty patients entered the OLE (n=20 each; OOC and placebo). Median exposure to OOC in the OLE was > 1 year for those who had been on placebo in the DPC and ≤ 21 months for those who had been on OOC. Dosing of OOC at the end of their participation in the OLE was 40 mg, n=3; 60 mg, n=10; and 80 mg, n=27. In those who received OOC during the DPC, 90% (n=18) completed 48 weeks of the OLE. Of responders at the end of the DPC period (n=14), 92.6% maintained response at OLE week 48. In patients from the OOC group who completed the DPC on study drug, average IGF-I using MI was 0.91 and 0.90 × ULN at OLE baseline and week 48, respectively. The mean change in IGF-I from the baseline of the DPC to OLE week 48 was 0.06 × ULN in patients who completed the DPC on OOC (n=19). In those who received placebo during the DPC, 70% (n=14) completed 48 weeks of the OLE. Of responders at the end of the DPC (n=5), 100% maintained response at OLE week 48. In patients from the placebo group who completed the DPC and did not revert to prior injectable therapy (n=9), the average IGF-I values were 1.09 and 0.87 × ULN at OLE baseline and week 48 respectively, using MI. The mean change in IGF-I from the baseline of the DPC to OLE week 48 was 0.08 × ULN in patients who completed the DPC on placebo (n=9). The most common treatment-emergent adverse events (TEAEs) were gastrointestinal; most were mild or moderate. The incidence of TEAEs was similar between patients who were on OOC or placebo during the DPC. The safety profile during the OLE did not show new concerns with increased duration of drug exposure. Conclusion: Long term maintenance of biochemical response to OOC is durable as assessed following ≤ 21 months of treatment. The OOC safety profile in the extension study is consistent with that of injectable SRLs but without injection-related AEs.

Acromegaly results in impaired quality of life (QoL), which improves but does not normalize after biochemical control of growth hormone (GH) excess. There are few data regarding long-term QoL in patients with sustained biochemical control of acromegaly. We hypothesized that QoL would continue to improve over time but remain poor. We studied 2 cohorts with biochemically controlled (normal IGF-1 level) acromegaly. MED (n=42) underwent surgery but required somatostatin analog (n=30) or GH receptor antagonist monotherapy (n=12); n=16 had undergone radiation. SURG (n=24) were in remission after surgery ± radiation (n=10). GH stimulation testing was performed in all SURG; n=11 had GH deficiency (GHD). QoL was assessed at 2 timepoints by the 36-Item-Short-Form Health Survey (SF-36) (MED, SURG), Acromegaly Quality of Life Questionnaire (AcroQoL) (MED), Gastrointestinal Quality of Life Index (GIQLI) (MED), Symptom Questionnaire (SQ) (SURG), and QoL-Assessment of GHD in Adults (AGHDA) (SURG). Time between timepoints 1 and 2 was 5.4 ± 1.0 vs 13.6 ± 1.2 years (MED vs SURG, p

Introduction: The positive predictive value of a low morning serum cortisol to diagnose adrenal insufficiency (AI) is reported to be >90%, which is the basis for guidelines recommending morning cortisol as the first-line test for central AI. A level

Results are presented from 2 to 3 trials investigating oral octreotide capsules (OOC) as an alternative to injectable somatostatin receptor ligands (iSRLs) in the treatment of acromegaly.CH-ACM-01 was an open-label trial (N = 155) and CHIASMA OPTIMAL was a double-blind placebo-controlled (DPC) trial (N = 56), both investigating OOC as maintenance therapy for patients with acromegaly who were biochemical responders receiving iSRLs.Baseline characteristics in both trials reflected those expected of patients with acromegaly responding to treatment and were similar between trials, despite differences in inclusion criteria. OOC demonstrated a consistent degree of biochemical response across trials, with 65% of patients in CH-ACM-01 maintaining response during the core period and 64% of patients in CHIASMA OPTIMAL at the end of the DPC. Mean insulin-like growth factor I (IGF-I) levels remained within inclusion criteria at the end of treatment in both trials. Of 110 patients entering the fixed-dose phase in CH-ACM-01, 80% maintained or improved acromegaly symptoms from baseline to the end of treatment. Over 85% of patients in both trials elected to continue into the extension phases. OOC were found to be well tolerated across both trials, and no dose-related adverse events were observed.OOC demonstrated remarkably consistent results for biochemical response, durability of response, and preference to continue with oral treatment across these 2 complementary landmark phase 3 trials, despite differences in the design of each. Trial registration NCT03252353 (August 2017), NCT01412424 (August 2011).

Objective: To report the first case of 2 synchronous pituitary adenomas, 1 corticotroph and 1 somatotroph, with distinct molecular lineages confirmed by differential hormone and S-100 protein expression. Methods: A case report followed by a literature review are presented. Results: A 68-year-old woman presented for evaluation of resistant hypertension. Biochemical testing demonstrated adrenocorticotropic hormone (ACTH)-dependent hypercortisolemia and growth hormone (GH) excess. Pituitary magnetic resonance imaging (MRI) revealed a 2 cm left sellar lesion consistent with a pituitary macroadenoma. The patient therefore underwent transsphenoidal surgery for a presumed cosecreting ACTH and GH macroadenoma. Tumor immunohistochemical staining (IHC) was positive for ACTH, but negative for GH. Postoperative biochemical testing confirmed remission from Cushing disease, but the insulin-like growth factor 1 (IGF-1) level remained elevated. Postoperative MRI demonstrated a small right sellar lesion that, in retrospect, had been present on the preoperative MRI. Resection of the right lesion confirmed a GH-secreting adenoma with negative ACTH staining. After the second surgery, the IGF-1 level normalized and blood pressure improved. Further pathologic examination of both surgical specimens demonstrated differential expression of S-100 protein, a folliculostellate cell marker. Reverse transcription polymerase chain reaction of messenger ribonucleic acid from the left sellar lesion was positive for ACTH and negative for GH, confirming the IHC results. Germline mutations in genes known to be associated with pituitary adenoma syndromes (MEN1, CDC73, CDKN1A, CDKN1B, CDKN2B, CDKN2C, and AIP) were not detected. Conclusion: Although the pathogenesis of synchronous pituitary adenomas has not been fully elucidated, this case report suggests that they can have distinct molecular lineages.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of parathyroid tumors, and neuroendocrine tumors (NETs) of the pituitary and pancreas. MEN1 is caused by germline mutations of the tumor suppressor gene MEN1, which are found in >75% of MEN1 patients. The remaining patients may have mutations involving: as yet unidentified genes; or other genes with known involvement in endocrine tumors, e.g. cyclin dependent kinase inhibitor 1B (CDKN1B) which is associated with MEN4. Here, we report a patient who had primary hyperparathyroidism, acromegaly, and a pancreatic NET that showed immuno-staining for glucagon and chromogranin A, which are consistent with MEN1. However, mutational analysis did not identify a MEN1 mutation, and analysis of other genes was undertaken, after informed consent was obtained from the patient. These genes include: CDKN1B; CDKN1A; CDKN2B; CDKN2C;cell cycle division 73 (CDC73), causative for hyperparathyroidism-jaw tumour (HPT-JT) syndrome, an autosomal dominant disorder characterised by occurrence of parathyroid tumors, ossifying fibromas of the jaw, renal tumours and uterine tumors; calcium sensing receptor (CASR), causative for familial hypocalciuric hypercalcemia type 1 (FHH1); and aryl-hydrocarbon receptor-interacting protein (AIP), causative for familial pituitary tumors. This revealed a heterozygous c.1138C>T (p.Leu380Phe) missense mutation of CDC73. This is likely a disease-causing mutation as: 1) the p.Leu380Phe substitution is not present in >120,000 alleles of The Exome Aggregation Consortium (ExAc) database; 2) involves an evolutionary conserved Leu380 residue; and 3) is situated within the parafibromin domain predicted to interact with the polymerase associated factor 1 (PAF1) and RNA polymerase II, (POLR2A) complex. In addition, RNA-Scope analysis, to detect specific CDC73 mRNA transcripts in paraffin embedded sections, of the patient’s pancreatic NET revealed that CDC73 mRNA expression was significantly decreased by >13% (p

Objective Little has been published describing hypophysitis after nivolumab or pembrolizumab treatment. We aimed to (i) assess the risk of hypophysitis following nivolumab or pembrolizumab treatment, (ii) characterize the clinical presentation and outcomes in these patients and (iii) compare these patients to hypophysitis following ipilimumab and ipilimumab plus nivolumab (combo). We hypothesized that headaches, pituitary enlargement on MRI and multiple anterior pituitary hormone deficiencies would occur less often in the nivolumab/pembrolizumab group versus ipilimumab or combo hypophysitis patients. Design and methods We conducted a multi-center retrospective review utilizing the Research Patient Database registry to evaluate individuals diagnosed with hypophysitis following treatment with nivolumab/pembrolizumab (n = 22), ipilimumab (n = 64) and combo (n = 20). Encounter notes, radiologic imaging and laboratory results for these patients were comprehensively reviewed. Results Hypophysitis was rare following treatment with nivolumab/pembrolizumab (0.5%, 17/3522) compared to ipilimumab (13.6%, 34/250), P P P P = 0.001 versus combo for headache and P Conclusions This study represents the first comprehensive cohort analysis of nivolumab or pembrolizumab-associated hypophysitis in a large patient group. Hypophysitis occurs rarely with these medications, and these patients have a distinct phenotype compared to hypophysitis after treatment with ipilimumab or ipilimumab plus nivolumab.

Background: Gonadotropin-releasing hormone agonists (GnRHa), used in the treatment of prostate cancer (PC) and for reproductive purposes in women, have been implicated as the cause of pituitary apoplexy (PA), a potentially life-threatening condition. The pathophysiology of PA after GnRHa has not been completely elucidated. Proposed mechanisms include a stimulatory effect of GnRHa on pituitary adenoma cell metabolism, causing mismatched blood supply prompting hemorrhage or infarction. Prior documentation of PA associated with GnRHa has been scarce and limited to case reports. Methods: This is a detailed clinical case series of GnRH-induced PA from a single institution, obtained by a Research Patient Data Repository query. Clinical characteristics of the patients including demographics, detailed history, time interval between GnRHa and PA, physical exam, biochemical data, pituitary imaging and pathology were reviewed. Results: Seven cases were identified between 1990-2020; six men (aged 55 – 83 years) receiving treatment for PC and one woman (aged 22 years) receiving GnRHa for oocyte donation. All patients presented with headache; four within 48 hours of, one >1 month after, and one 5 months after, receiving GnRHa. One patient had insufficient data on time between GnRHa and PA. Most patients (86%) presented with nausea and vomiting. Other symptoms included ophthalmoplegia (43%), visual field defects (17%), and altered consciousness (29%). All patients had sellar masses and/or evidence of hemorrhage on MRI. Five patients underwent pituitary surgery while the others were managed medically. Of those who underwent surgical resection, 80% had positive histopathological staining for gonadotropins. Five patients with reliable hypothalamic-pituitary-adrenal (HPA) axis testing had impairment of this axis after PA; 40% recovered adrenal function. Central hypothyroidism occurred in 60% of whom 66% recovered. Hyponatremia occurred in 43%. Conclusions: Patients with gonadotrope-secreting adenomas may develop PA in response to GnRHa, more frequently in elderly men who are receiving GnRHa treatment for PC. This may be due to older age and higher prevalence of GnRHa use in this group. However, as demonstrated here and in prior case reports, women are not exonerated from this complication. Headache and adrenal insufficiency are typically present. HPA axis recovers in a subset. While most patients present

Late-night salivary cortisol (LNSC) is well-validated in the diagnosis of Cushing's disease (CD). The accuracy of LNSC during follow-up of patients undergoing transsphenoidal surgery (TSS) has not been fully characterized.We examined the accuracy of LNSC in establishing remission and identifying recurrence in postoperative patients with CD.This is a retrospective study.Records of patients with CD who underwent TSS by a single neurosurgeon in our tertiary center (2005-2014) were analyzed (N = 224). Patients were selected for further investigation (n = 165) if there was at least one available LNSC test obtained after TSS (either within 3 months or during long-term follow-up). Extracted data included demographic and clinical characteristics, magnetic resonance imaging and laboratory data (morning serum cortisol, 24-hour urine free cortisol [UFC], LNSC) .Remission was defined as nadir morning serum cortisol less than 5 mcg/dl and nadir 24-hour UFC less than 23 mcg. Recurrence was considered definite if confirmed surgically or prompted radiotherapy.Surgical remission occurred in 89% of 89 patients with available LNSC data. LNSC, obtained within 3 months of TSS, established remission with 94% sensitivity and 80% specificity at a cutpoint of 1.9 nmol/l (area under the curve [AUC] = 0.90). At a median follow-up of 53.5 months, LNSC established recurrence (75% sensitivity and 95% specificity) at a cutpoint of 7.4 nmol/l (AUC = 0.87), and 24-hour UFC established recurrence (68% sensitivity and 100% specificity) at a cutpoint of 1.6-fold above normal (AUC = 0.82).LNSC may accurately establish remission after TSS and identify recurrence more accurately than 24-hour UFC during long-term follow-up.

BACKGROUND In this prospective study, the authors evaluated potential treatment toxicity and progression-free survival in patients with low-grade glioma who received treatment with proton radiation therapy. METHODS Twenty patients with World Health Organization grade 2 glioma who were eligible for radiation therapy were enrolled in a prospective, single-arm trial of proton therapy. The patients received proton therapy at a dose of 54 Gy (relative biological effectiveness) in 30 fractions. Comprehensive baseline and regular post-treatment evaluations of neurocognitive function, neuroendocrine function, and quality of life (QOL) were performed. RESULTS All 20 patients (median age, 37.5 years) tolerated treatment without difficulty. The median follow-up after proton therapy was 5.1 years. At baseline, intellectual functioning was within the normal range for the group and remained stable over time. Visuospatial ability, attention/working memory, and executive functioning also were within normal limits; however, baseline neurocognitive impairments were observed in language, memory, and processing speed in 8 patients. There was no overall decline in cognitive functioning over time. New endocrine dysfunction was detected in 6 patients, and all but 1 had received direct irradiation of the hypothalamic-pituitary axis. QOL assessment revealed no changes over time. The progression-free survival rate at 3 years was 85%, but it dropped to 40% at 5 years. CONCLUSIONS Patients with low-grade glioma tolerate proton therapy well, and a subset develops neuroendocrine deficiencies. There is no evidence for overall decline in cognitive function or QOL. Cancer 2015;121:1712–1719. © 2015 American Cancer Society.

Context Both acromegaly and adult growth hormone deficiency (GHD) are associated with increased fracture risk. Sufficient data are lacking regarding cortical bone microarchitecture and bone strength, as assessed by microfinite element analysis (µFEA). Objective To elucidate both cortical and trabecular bone microarchitecture and estimated bone strength in men with active acromegaly or GHD compared to healthy controls. Design and subjects Cross-sectional study at a clinical research center, including 48 men (16 with acromegaly, 16 with GHD and 16 healthy controls). Outcome measures Areal bone mineral density (aBMD), cortical and trabecular bone microarchitecture and estimated bone strength (µFEA) at the radius and tibia. Results aBMD was not different between the 3 groups at any skeletal site. At the radius, patients with acromegaly had greater cortical area (P P = 0.0038), cortical pore volume (P P = 0.0008), but lower trabecular bone density (P = 0.0010) compared to controls. At the tibia, patients with acromegaly had lower trabecular bone density (P = 0.0082), but no differences in cortical bone microstructure. Compressive strength and failure load did not significantly differ between groups. These findings persisted after excluding patients with hypogonadism. Bone microarchitecture was not deficient in patients with GHD. Conclusions Both cortical and trabecular microarchitecture are altered in men with acromegaly. Our data indicate that GH excess is associated with distinct effects in cortical vs trabecular bone compartments. Our observations also affirm the limitations of aBMD testing in the evaluation of patients with acromegaly.

Background Treatment of aggressive pituitary adenomas typically involves a multimodality approach based on histopathological features and may include pharmacotherapy, surgery, and occasionally radiation therapy. In cases of treatment-refractory tumor progression, chemotherapy may be considered; however, no standard chemotherapeutic regimen has been established. Literature review suggests that temozolomide may have a beneficial role in a subset of cases. To understand the efficacy of temozolomide in progressive pituitary tumors, we reviewed the outcomes of cases at our center. Methods We performed a retrospective chart review to report the outcome and unique features of 7 patients with aggressive functioning pituitary adenomas or carcinomas treated with temozolomide. Tumor pathology included somatotroph (n = 1), corticotroph (n = 3), and lactotroph (n = 3) tumors. Results Four of the 7 patients had at least 2 prior resections, and all had prior radiation and surgery before treatment with temozolomide. Notably, all patients showed response to therapy, defined as either stable disease (43%) or partial response (57%). Median progression-free survival was 1.66 years, and median overall survival was 4 years. Conclusion Our data suggest that temozolomide has an important role in the management of aggressive functioning pituitary tumors that are resistant to standard therapies, and that optimization of therapy with temozolomide may involve individualized regimens. Future prospective clinical trials should be considered.

Ipilimumab (Ipi) is approved by the Food and Drug Administration for the treatment of unresectable or metastatic melanoma. Little is known about Ipi-induced hypophysitis (IH), an important treatment complication.The objectives of the study were as follows: 1) to examine the prevalence of IH, 2) to characterize the clinical course and treatment outcomes in IH, 3) to identify the risk factors for the development of IH, and 4) to determine optimal strategies for the management of IH.This was a retrospective review.The study was conducted at a tertiary referral center.One hundred fifty-four adult patients with metastatic melanoma were evaluated at Massachusetts General Hospital and were treated with Ipi between March 2008 and December 2013.The intervention included treatment with Ipi.Pituitary magnetic resonance imaging, pituitary hormone assessment, and patient survival were measured.IH was diagnosed in 17 patients (11%). Male gender (P = .02) and older age (P = .005), but not the cumulative dose of Ipi, were risk factors for IH. All patients with IH had anterior hypopituitarism (none had diabetes insipidus). Hypopituitarism was persistent in most individuals (76%). Diffuse pituitary enlargement was observed exclusively in all cases of IH and, upon retrospective review of magnetic resonance imaging scans, this finding preceded the clinical diagnosis of hypophysitis in eight patients. Pituitary enlargement resolved rapidly (within 40 d in seven of seven patients). Median survival in patients with IH was 19.4 vs 8.8 months (P = .05) in the remainder of the cohort.Male gender and older age are risk factors for IH. Pituitary enlargement is sensitive and specific for IH in the appropriate setting, can precede the clinical diagnosis, and resolves rapidly. Anterior pituitary function recovery is uncommon. The incidence of hypophysitis may positively predict survival in melanoma patients treated with Ipi.

Context: Temozolomide (TMZ) is an alkylating agent primarily used to treat tumors of the central nervous system. We describe 2 patients with apparent TMZ-induced central diabetes insipidus. Using our institution's Research Patient Database Registry, we identified 3 additional potential cases of TMZ-induced diabetes insipidus among a group of 1545 patients treated with TMZ. Case Presentations: A 53-year-old male with an oligoastrocytoma and a 38-year-old male with an oligodendroglioma each developed symptoms of polydipsia and polyuria approximately 2 months after the initiation of TMZ. Laboratory analyses demonstrated hypernatremia and urinary concentrating defects, consistent with the presence of diabetes insipidus, and the patients were successfully treated with desmopressin acetate. Desmopressin acetate was withdrawn after the discontinuation of TMZ, and diabetes insipidus did not recur. Magnetic resonance imaging of the pituitary and hypothalamus was unremarkable apart from the absence of a posterior pituitary bright spot in both of the cases. Anterior pituitary function tests were normal in both cases. Using the Research Patient Database Registry database, we identified the 2 index cases and 3 additional potential cases of diabetes insipidus for an estimated prevalence of 0.3% (5 cases of diabetes insipidus per 1545 patients prescribed TMZ). Conclusions: Central diabetes insipidus is a rare but reversible side effect of treatment with TMZ.

The use of dopamine agonists (DAs) has been associated with increased impulsivity and impulse control disorders in several diseases, including Parkinson's disease. Such an effect of DAs on impulsivity has not been clearly characterized in hyperprolactinemic patients, where DAs are the mainstay of therapy. We studied the effects of DAs on impulsivity in hyperprolactinemic patients treated at a tertiary pituitary center, using validated psychometric tests. Cross-sectional study. Impulsivity was evaluated in 30 subjects, 10 hyperprolactinemic patients on DAs compared to two control groups; one comprising untreated hyperprolactinemic patients (n = 10) and a second group consisting of normoprolactinemic controls with pituitary lesions (n = 10). Measures of impulsivity included both self-report questionnaires as well as laboratory-based tasks. Hyperprolactinemic patients on DAs had a higher score (mean ± SD) in one self-report measure of impulsivity, the attention subscale of the Barratt Impulsiveness Scale (16.2 ± 2.7), as compared to the hyperprolactinemic control group (12.3 ± 2.5) and the normoprolactinemic group (14.7 ± 4.4) (p = 0.04). No statistically significant difference was found between groups with regards to the other impulsivity scales. In the DA-treated group, a correlation was observed between increased impulsivity (as assessed in the Experiential Discounting Task) and higher weekly cabergoline dose (r(2) = 0.49, p = 0.04). The use of DAs in hyperprolactinemic patients is associated with an increase in one aspect of impulsivity. This effect should be further characterized in larger, longitudinal studies.

Introduction:Treatment of aggressive pituitary adenomas typically involves a multimodality approach based on histopathological features and may include pharmacotherapy, surgery and radiation therapy. In cases of treatment-refractory tumor progression, chemotherapy may be considered. However, no standard chemotherapeutic regimen has been established. Anecdotal reports suggest that temozolomide may have a beneficial role in a subset of cases.Materials and Methods:In this case series and institutional experience we report the outcome and unique clinical characteristics of seven patients with aggressive pituitary tumors treated with temozolomide given at various dose regimens.Results:Tumor pathology included somatotrope (n=1), corticotrope (n=3), and lactotrope (n=3) tumors. Four of the seven patients had at least two prior resections, and all had prior radiation and surgery before treatment with temozolomide was considered. Notably, all patients showed response to therapy, defined as either stable disease (43%) or partial response (57%), using standard tumor response assessment parameters. Excluding the two patients who remain on therapy to date, total duration of therapeutic benefit ranged between 5–15 months. Three patients showed radiographic and clinical benefit beyond one year.Conclusions:Our data suggest that temozolomide may have an important role in the management of aggressive functioning pituitary tumors that are resistant to standard therapies, and that optimization of therapy with temozolomide may involve individualized regimens. Future prospective clinical trials should be considered.

Surgical resection is often not curative in patients with acromegaly and long-acting somatostatin analogues (lanreotide or octreotide) are often needed. This study assessed the efficacy and safety of self- or partner-administration of lanreotide in patients with acromegaly. This was a six-month, single-arm, open-label study conducted at 13 endocrinology clinics. Fifty-nine patients received deep subcutaneous lanreotide injections every 28 days. Twelve patients started on 120 mg lanreotide and forty-seven started on 90 mg lanreotide. At week 16, the dose was adjusted to 60, 90 or 120 mg based on insulin-like growth factor-1 (IGF-1) levels at week 12. Fifty-nine patients with acromegaly either switched from long-acting octreotide (switch; n = 33) or were somatostatin analogue treatment-naïve or not currently taking long-acting octreotide (“other”; n = 26). The key endpoints included the percentage of patients/partners able to self- or partner-inject lanreotide and those with normal IGF-1 or growth hormone (GH) levels at week 24/early termination. 100% of patients/partners correctly self- (n = 41) or partner-injected (n = 18) lanreotide by week 4. By week 24/early termination, IGF-1 levels were controlled in 93.7% of switch and 46.2% of “other” patients, while GH levels were controlled in 76.9% and 39.1% of patients, respectively. Both IGF-1 and GH were controlled in 73.1% of switch and 30.4% of “other” patients. Most switch patients (81%) reported they preferred lanreotide over long-acting octreotide for future use (P = 0.0001). Self- or partner-administration of lanreotide is generally well tolerated and associated with IGF-1 and GH control in many lanreotide-naïve patients with acromegaly.

Context: Both GH deficiency (GHD) and GH excess are associated with a decreased quality of life. However, it is unknown whether patients with GHD after treatment for acromegaly have a poorer quality of life than those with normal GH levels after cure of acromegaly. Objective: The aim of the study was to determine whether patients with GHD and prior acromegaly have a poorer quality of life than those with GH sufficiency after cure of acromegaly. Design and Setting: We conducted a cross-sectional study in a General Clinical Research Center. Study Participants: Forty-five patients with prior acromegaly participated: 26 with GHD and 19 with GH sufficiency. Intervention: There were no interventions. Main Outcome Measures: We evaluated quality of life, as measured by 1) the Quality of Life Adult Growth Hormone Deficiency Assessment (QoL-AGHDA); 2) the Short-Form Health Survey (SF-36); and 3) the Symptom Questionnaire. Results: Mean scores on all subscales of all questionnaires, except for the anger/hostility and anxiety subscales of the Symptom Questionnaire, showed significantly impaired quality of life in the GH-deficient group compared with the GH-sufficient group. Peak GH levels after GHRH-arginine stimulation levels were inversely associated with QoL-AGHDA scale scores (R = −0.53; P = 0.0005) and the Symptom Questionnaire Depression subscale scores (R = −0.35; P = 0.031) and positively associated with most SF-36 subscale scores. Conclusions: Our data are the first to demonstrate a reduced quality of life in patients who develop GHD after cure of acromegaly compared to those who are GH sufficient. Further studies are warranted to determine whether GH replacement would improve quality of life for patients with GHD after cure from acromegaly.

Context: Data regarding gender-specific efficacy of GH on critical endpoints are lacking. There are no randomized, placebo-controlled studies of physiological GH therapy solely in women. Objective: Our objective was to determine the effects of physiological GH replacement on cardiovascular risk markers and body composition in women with GH deficiency (GHD). Design: This was a 6-month, randomized, placebo-controlled, double-blind study. Setting: The study was conducted at the General Clinical Research Center. Study Participants: 43 women with GHD due to hypopituitarism were included in the study. Intervention: Study participants were randomized to receive GH (goal mid-normal serum IGF-1) or placebo. Main Outcome Measures: Cardiovascular risk markers, including high-sensitivity C-reactive protein, tissue plasminogen activator, and body composition, including visceral adipose tissue by cross-sectional computed tomography, were measured. Results: Mean daily GH dose was 0.67 mg. The mean IGF-1 sd score increased from −2.5 ± 0.3 to −1.4 ± 0.9 (GH) (P < 0.0001 vs. placebo). High-sensitivity C-reactive protein decreased by 38.2 ± 9.6% (GH) vs.18.2 ± 6.0% (placebo) (P = 0.03). Tissue plasminogen activator and total cholesterol decreased, and high-density lipoprotein increased. Homeostasis model assessment-insulin resistance and other markers were unchanged. Body fat decreased [−5.1 ± 2.0 (GH) vs. 1.9 ± 1.0% (placebo); P = 0.002] as did visceral adipose tissue [−9.0 ± 5.9 (GH) vs. 4.3 ± 2.7% (placebo); P = 0.03]. Change in IGF-1 level was inversely associated with percent change in visceral adipose tissue (r = −0.61; P = 0.002), total body fat (r = −0.69; P < 0.0001), and high-sensitivity C-reactive protein (r = −0.51; P = 0.003). Conclusions: Low-dose GH replacement in women with GHD decreased total and visceral adipose tissue and improved cardiovascular markers, with a relatively modest increase in IGF-1 levels and without worsening insulin resistance.

Background: The increased morbidity and mortality of acromegaly makes early diagnosis and therapy critical. However, whether the type of medical professional who first diagnoses acromegaly, the major complaint prompting medical attention, or the management paradigms used in the setting of novel medical therapies have changed over time has not been well explored. Objectives: Our objective was to identify the medical professional who first suspected acromegaly and the complaint prompting the diagnosis, and if these have changed. Additional goals were to assess the interval from symptom onset to diagnosis of acromegaly and to compare treatment trends over consecutive decades. Design: This was a case-record retrospective study. Setting: The study was performed in a neuroendocrine clinical center at a tertiary care center. Subjects: A total of 100 patients (45 men and 55 women) with acromegaly referred from 1985–2005 was included in the study. Results: Acral changes (24%) and headaches (20%) were most prevalen...

BACKGROUND: This is a prospective study to evaluate potential treatment toxicity and progression free survival (PFS) of low grade glioma patients treated with proton radiation therapy. METHODS: Twenty WHO grade II glioma patients indicated for radiation therapy (8 new high risk diagnoses; 12 recurrent/progressive disease) were enrolled on a prospective single arm trial of proton therapy receiving 54 Gy(RBE) in 30 fractions. Comprehensive baseline and regular post treatment evaluations of neurocognitive function, neuroendocrine function, and quality of life (QOL) were performed. RESULTS: All 20 patients (median age 37.5 years) tolerated treatment without difficulty. Median follow up after proton therapy was 5.1 years. Baseline level of intellectual functioning on a standardized IQ measure was within the normal range for the group and remained stable over time. Performances in the cognitive domains of visuospatial ability, language function, attention/working memory, and processing speed were also in the normal range at baseline and did not decline over time. New endocrine dysfunction was detected in six patients and all but one had direct irradiation of the hypothalamic-pituitary axis. QOL assessment showed no change over time with the extended follow up. PFS at 3 years was 85% and at 5 years was 40%. CONCLUSIONS: Low grade glioma patients tolerate proton therapy well and a subset develops neuroendocrine deficiencies. There was no evidence for decline in cognitive function or QOL which may be partially attributable to reduced radiation dose to the normal brain by use of proton therapy. PFS was similar to that of photon based therapy.

Adrenal hypoplasia congenita (AHC) is an X-linked disorder that typically presents with adrenal insufficiency during infancy. Hypogonadotropic hypogonadism (HHG) has been identified as a component of this disorder in affected individuals who survive into childhood. Recently, AHC was shown to be caused by mutations in DAX-1, a protein that is structurally similar in its carboxyterminal region to orphan nuclear receptors. We studied two kindreds with clinical features of AHC and HHG. DAX-1 mutations were identified in both families. In the JW kindred, a single base deletion at nucleotide 1219 was accompanied by an additional base substitution that resulted in a frameshift mutation at codon 329 followed by premature termination. In the MH kindred, a GGAT duplication at codon 418 caused a frameshift that also resulted in truncation of DAX-1. Baseline luteinizing hormone (LIT), follicle-stimulating hormone (FSH), and free-alpha-subunit (FAS) levels were determined during 24 h of frequent (q10 min) venous sampling. In patient MH, baseline LH levels were low, but FAS levels were within the normal range. In contrast, in patient JW, the mean LH and FSH were within the normal range during baseline sampling, but LH secretion was erratic rather than showing typical pulses. FAS was apulsatile for much of the day, but a surge was seen over a 3-4-h period. Pulsatile gonadotropin releasing hormone (GnRH) (25 ng/kg) was administered every 2 h for 7 d to assess pituitary responsiveness to exogenous GnRH. MH did not exhibit a gonadotropin response to pulsatile GnRH. JW exhibited a normal response to the first pulse of GnRH, but there was no increase in FAS. In contrast to the priming effect of GnRH in GnRH-deficient patients with Kallmann syndrome, GnRH pulses caused minimal secretory responses of LH and no FAS responses in patient JW. The initial LH response in patient JW implies a deficiency in hypothalamic GnRH. On the other hand, the failure to respond to pulsatile GnRH is consistent with a pituitary defect in gonadotropin production. These two cases exemplify the phenotypic heterogeneity of AHC/HHG, and suggest that DAX-1 mutations impair gonadotropin production by acting at both the hypothalamic and pituitary levels.

BACKGROUND Inferior petrosal sinus sampling (IPSS) is a useful technique for confirming a pituitary source of adrenocorticotropic hormone (ACTH) overproduction in Cushing disease. Uncertainty remains regarding the appropriate course of therapy when an ectopic tumor is predicted by IPSS but none can be found and in circumstances when the procedure cannot be successfully completed owing to technical or anatomic limitations. OBJECTIVE To determine an appropriate course of action after nondiagnostic IPSS. METHODS We reviewed 288 IPSS procedures in 283 patients between 1986 and 2010 at our center. An IPS:peripheral ACTH ratio ≥ 2 at baseline or ≥ 3 after corticotrophin-releasing hormone was considered predictive of a pituitary source of ACTH. A procedure was considered nondiagnostic if the procedure was successfully performed and the results predicted an ectopic source but none could be found despite extensive imaging or if the IPS could not be bilaterally cannulated because of technical difficulties or anatomic variants. RESULTS The sensitivity, specificity, positive predictive value, and negative predictive value of IPSS for detecting a pituitary source in Cushing disease were 94%, 50%, 98%, and 29%, respectively. We identified 3 categories of nondiagnostic IPSS comprising 44 of the total procedures. These patients underwent exploratory transsphenoidal surgery, and in 42 of these patients (95%), a pituitary source was surgically proven, with a remission rate of 83%. CONCLUSION Transsphenoidal surgery should be considered in cases of ACTH-dependent Cushing disease and noncentralized or technically unsuccessful IPSS without evidence of ectopic tumor.

Both growth hormone (GH) excess and GH deficiency are associated with abnormalities in body composition and biomarkers of cardiovascular risk in patients with pituitary disorders. However, the effects of developing GH deficiency after definitive treatment of acromegaly are largely unknown.To determine whether development of GH deficiency after definitive therapy for acromegaly is associated with increased visceral adiposity and biomarkers of cardiovascular risk compared with GH sufficiency after definitive therapy for acromegaly.Cross-sectional.We studied three groups of subjects, all with a history of acromegaly (n = 76): subjects with subsequent GH deficiency (GHD; n = 31), subjects with subsequent GH sufficiency (GHS; n = 25) and subjects with active acromegaly (AA; n = 20). No study subjects were receiving somatostatin analogues, dopamine agonists or hGH.Body composition (by DXA), abdominal adipose tissue depots (by cross-sectional CT), total body water (by bioimpedance analysis) and carotid intima-media thickness (IMT) were measured. Fasting morning serum was collected for high-sensitivity C-reactive protein (hsCRP), lipids and lipoprotein levels. An oral glucose tolerance test was performed, and homoeostasis model of assessment-insulin resistance (HOMA-IR) was calculated.Abdominal visceral adipose tissue, total adipose tissue and total body fat were higher in subjects with GHD than GHS or AA (P 0·05). Subcutaneous abdominal fat was higher, and fibrinogen and IMT were lower in GHD (but not GHS) than AA (P 0·05). Patients with GHD had the highest hsCRP, followed by GHS, and hsCRP was lowest in AA (P 0·05). Fasting glucose, 120-min glucose, fasting insulin, HOMA-IR and per cent total body water were lower in GHD and GHS than AA (P 0·05). Triglycerides were higher in GHS than AA (P 0·05). Lean body mass, mean arterial pressure, total cholesterol, HDL and LDL were comparable among groups.Development of GHD after definitive treatment of acromegaly may adversely affect body composition and inflammatory biomarkers of cardiovascular risk but does not appear to adversely affect glucose homoeostasis, lipids and lipoproteins, or other cardiovascular risk markers.

The effects of GH replacement therapy in patients who develop GH deficiency (GHD) after cure of acromegaly have not been established in a placebo-controlled study.The objective of the study was to determine whether GH replacement improves body composition, cardiovascular risk markers and quality of life in patients with GHD and prior acromegaly.This was a 6-month, randomized, placebo-controlled study.The study was conducted at a clinical translational science center.Participants included 30 subjects with prior acromegaly and current GHD.INTERVENTIONs included GH or placebo.Body composition (dual-energy x-ray absorptiometry and cross-sectional computed tomography at L4), cardiovascular risk markers (high-sensitivity C-reactive protein (hsCRP), total, high-density lipoprotein and low-density lipoprotein cholesterol, fibrinogen, and carotid intimal-medial thickness), and quality of life were measured.The mean GH dose at 6 months was 0.58 +/- 0.26 mg/d. Total fat mass, visceral adipose tissue (-15.3 +/- 18.6 vs. 1.3 +/- 12.5%, P = 0.01), and total abdominal fat decreased, and fat-free mass increased, in the GH vs. placebo group. Mean hsCRP levels decreased, but there was no GH effect on other cardiovascular risk markers. There was no change in glycosylated hemoglobin or homeostasis model assessment insulin resistance index. Quality of life improved with GH. Side effects were minimal.This is the first randomized, placebo-controlled study of the effects of GH replacement therapy on body composition and cardiovascular end points in patients who have developed GH deficiency after treatment for acromegaly, a disease complicated by metabolic and body composition alterations and increased cardiovascular risk. GH replacement decreased visceral adipose tissue, increased fat-free mass, decreased hsCRP, and improved quality of life in patients with GHD after cure of acromegaly, with minimal side effects and without an increase in insulin resistance.

Acromegaly is a rare disease most often caused by the prolonged secretion of excess growth hormone from a pituitary adenoma. The disease is associated with multiple significant comorbidities and increased mortality. The delay to diagnosis is often long. This may be because of low disease awareness among health care professionals, the insidious onset of differentiating features, and because patients are likely to present with complaints typical of other conditions more frequently seen in primary care. Early identification of acromegaly facilitates prompt treatment initiation and may minimize the permanent effects of excess growth hormone. The primary treatment for many patients will be pituitary surgery, although not all patients will be eligible for surgery or achieve a surgical cure. If biochemical control is not achieved following surgery, other treatment options include medical therapy and radiation therapy. Improved biochemical control may only alleviate rather than reverse the associated comorbidities. Thus, lifelong monitoring of patient health is needed, with particular attention to the management of cardiovascular risk factors. It is additionally important to consider the impact of both disease and treatment on patients' quality of life and minimize that impact where possible, but particularly for chronic therapies. For the majority of patients, chronic therapy is likely to include somatostatin analog injections. In some circumstances, it may be possible to extend the dosing interval of the analog once good biochemical control is achieved. Additional convenience may be gained from the possibility of self-/partner administration of treatment or administration of treatment by a health care professional at home. Overall, it is clear that the care of patients with acromegaly requires a highly coordinated approach involving numerous specialties (eg, endocrinology, surgery, cardiology). Further, patients' needs must be at the core of management and every effort must be made to improve health care experiences and minimize treatment burdens.