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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

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We aimed to (1) examine the diagnosis of opioid-induced adrenal insufficiency, and (2) investigate the diagnostic value of a morning cortisol83 nmol/L (3 µg/dl) for the diagnosis of adrenal insufficiency, using newer more specific cortisol assays and cut-offs.Retrospective study (5/2015-10/2020).Cohort 1 (N = 75): adults who underwent cosyntropin stimulation testing and opioid exposure for30 days. Cohort 2 (N = 854): adults, with or without opioid exposure, who had a morning cortisol level measured the same day as stimulation testing.Peak cortisol during cosyntropin stimulation testing. Sensitivity and specificity of morning serum cortisol for adrenal insufficiency.The prevalence of adrenal insufficiency in patients with chronic opioid exposure who underwent cosyntropin stimulation testing was 4.0% using a cortisol cutoff of405 nmol/L (14.7 µg/dl) versus 19% using the traditional cutoff of500 nmol/L (18.1 µg/dl). For hospitalized patients with and without opioid-exposure, 14 of 22 (64%) patients with morning cortisol levels of83 nmol/L (3 µg/dl) passed cosyntropin stimulation testing. A morning cortisol level of348 nmol/L (12.6 µg/dl) had 100% sensitivity (95% confidence interval: 84.5%-100%) for the diagnosis of adrenal insufficiency.Applying a cutoff of405 nmol/L (14.7 µg/dl), opioid-induced adrenal insufficiency is rare. Nearly 1 out of 6 patients would be reclassified as having adrenal insufficiency applying the guideline-recommended cutoff of500 nmol/L (18.1 µg/dl). Serum morning cortisol83 nmol/L (3 µg/dl) is not a valid diagnostic test for adrenal insufficiency in hospitalized patients, whether or not receiving opioids.

To examine the clinical presentation and longitudinal outcome of Pituitary Apoplexy (PA) after gonadotropin-releasing hormone agonist (GnRHa) in a series of patients and compare to prior reports. A retrospective chart review was performed on seven patients receiving GnRHa who developed PA. Prior reported cases were analyzed. Six men (median age 72 years) with prostate cancer and one woman (aged 22 years) undergoing oocyte donation presented with PA between 1990 and 2020. Most presented with within 24 h of the first dose, but two developed PA 1 to 5 months after GnRHa initiation. The main clinical manifestations were headache (100%), nausea and vomiting (86%). While no patients had a previously known pituitary tumor, all had imaging demonstrating sellar mass and/or hemorrhage at presentation. Among those surgically treated (5/7), 80% (4/5) of patients had pathologic specimens that stained positive for gonadotropins; the remaining patient’s pathologic specimen was necrotic. At the time of PA, the most common pituitary dysfunction was hypocortisolism. Central adrenal insufficiency and central hypothyroidism were reversible in a subset. Pituitary imaging remained stable. This is the first report of a case series with PA after GnRHa administration with longitudinal follow-up. Although infrequent, PA can be life-threatening and should be suspected among patients receiving GnRHa, with or without a known pituitary adenoma, who develop acute headache, nausea and/or vomiting. Since hypopituitarism was reversible in a subset, ongoing pituitary function testing may be indicated.

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.

Objectives To assess the impact of virtual education programming for patients with acromegaly. Design We conducted a mixed methods study to evaluate patient attitudes, examine if patient-centered educational forums change these attitudes, and determine the role of virtual education as a means to learn about patients’ unmet needs, self-reported outcomes, and educational priorities. Methods The study included 653 total virtual program registrants. Of these, 78 patients with acromegaly were included in the analysis. The programs consisted of patient-centered livestream education by a multidisciplinary team of pituitary experts and patient presenters. Multiple-choice questions were used to assess attitudes before and after the event, and short answer surveys were used to collect care goals and unmet needs related to treatment. Results Attendance included participants from 37 countries. The number of patients who responded that they had no hope for improvement, had no choice in their treatment, and felt alone living with acromegaly each decreased significantly pre- to post-event (P < 0.05). The number of patients who felt anxious about their acromegaly diagnosis remained unchanged. ‘Quality of life/mental health’ was the most common personal care goals concern followed by ‘medical therapies/tumor control.’ Perceived acromegaly unmet needs were evenly distributed, with five of six categories reported by over 20% of patients. Conclusion Our findings indicate that virtual education may have a significant positive effect on acromegaly patients’ perceptions of their disease. The lessons learned from these virtual programs may be used to inform future virtual education programming for acromegaly and other rare diseases.

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.

Patients undergoing cranial irradiation are at high risk for development of subsequent pituitary deficiencies. Patients with meningiomas can expect to live many years after treatment and are therefore particularly vulnerable to long-term sequalae of radiation therapy (RT). The purpose of this study was to determine the rates and timing of onset of pituitary dysfunction across each hypothalamic-pituitary axis in patients with meningiomas in the sellar region.Data from 74 patients with meningiomas in the sellar or perisellar region who underwent RT between 2001 and 2017 at a single academic center were analyzed. Dose-volume histograms were generated to determine the dose of radiation to the pituitary gland. Pituitary function tests were evaluated before and after completion of RT.There was a 20% risk for new hypopituitarism across any hypothalamic-pituitary axis after RT at a median follow-up of 43 months. Identified rates of dysfunction across each axis were 24% for thyroid and adrenal, 19% for growth hormone, and 10% for gonadal. Median time to develop deficiencies ranged from 11 months for growth hormone deficiency to 32 months for adrenal insufficiency. Deficiencies were likely to be correlated, with increased risk for thyroid dysfunction in patients with adrenal, gonadal, or prolactin deficiencies (P .05). On univariate analysis, mean dose to the pituitary gland and male sex were associated with increased risk for post-RT thyroid deficiency (P = .01 and P = .004, respectively). There was no difference in rates of hypothyroidism after protons compared with photons (P = .14).Cranial irradiation for sellar meningiomas carries a risk for subsequent hypopituitarism that appears to be dose dependent and may occur years after completion of RT. Growth hormone deficiency and gonadal dysfunction were likely underestimated here secondary to a lack of routine testing. Given the favorable tumor prognosis in this patient population, early and long-term endocrine follow-up is warranted.

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).

To examine the clinical presentation and longitudinal outcome of Pituitary Apoplexy (PA) after gonadotropin-releasing hormone agonist (GnRHa) in a series of patients and compare to prior reports.A retrospective chart review was performed on seven patients receiving GnRHa who developed PA. Prior reported cases were analyzed.Six men (median age 72 years) with prostate cancer and one woman (aged 22 years) undergoing oocyte donation presented with PA between 1990 and 2020. Most presented with within 24 h of the first dose, but two developed PA 1 to 5 months after GnRHa initiation. The main clinical manifestations were headache (100%), nausea and vomiting (86%). While no patients had a previously known pituitary tumor, all had imaging demonstrating sellar mass and/or hemorrhage at presentation. Among those surgically treated (5/7), 80% (4/5) of patients had pathologic specimens that stained positive for gonadotropins; the remaining patient's pathologic specimen was necrotic. At the time of PA, the most common pituitary dysfunction was hypocortisolism. Central adrenal insufficiency and central hypothyroidism were reversible in a subset. Pituitary imaging remained stable.This is the first report of a case series with PA after GnRHa administration with longitudinal follow-up. Although infrequent, PA can be life-threatening and should be suspected among patients receiving GnRHa, with or without a known pituitary adenoma, who develop acute headache, nausea and/or vomiting. Since hypopituitarism was reversible in a subset, ongoing pituitary function testing may be indicated.

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

Pegvisomant (PEG) is an effective therapy for acromegaly. Its safety in women seeking fertility and during pregnancy has been scarcely reported. A retrospective chart review was performed in three patients with acromegaly who received PEG while attempting to conceive. Published studies regarding this topic were analyzed. Four pregnancies in three women with acromegaly are reported. In the first patient, PEG was withdrawn three days before embryo transfer in her first pregnancy and 2 weeks prior to transfer in the second pregnancy. Each transfer resulted in a healthy full-term newborn. In the second and third patients, PEG was withdrawn at diagnosis of pregnancy. No fetal complications occurred during gestations which resulted in three full-term newborns (one single and one twin pregnancy). No abnormalities in development were found in the five live births described. Few cases of pregnancies in women exposed to PEG have been reported and therefore safety cannot be clearly established. In this series, all four pregnancies had good outcomes with discontinuation of the drug before or at first knowledge of conception. A review of the literature reveals no evident drug-related abnormalities in the offspring, even in the few women with continued use of PEG throughout pregnancy. Preconception therapy with PEG resulted in successful fertility outcomes. Although few cases have been reported, these four pregnancies with PEG use prior to or at the time of conception were not associated with significant maternal or fetal complications. More studies are needed to establish the safety of PEG preconception.

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.

OBJECTIVE To characterize a cohort of patients with cyclic Cushing's disease (CD) in comparison with noncyclic CD using late night salivary cortisol (LNSC) and examine the diagnostic sensitivity of LNSC in comparison with that of 24-hour urine-free cortisol (UFC) in this population. DESIGN Retrospective study of patients with CD seen in our institution between 2008 and 2017. PATIENTS A total of 205 patients, including 17 (8%) with cyclic CD (based on a minimum of 3 peaks and 2 troughs in cortisol levels). In a secondary analysis, 38 patients (19%) with cyclic CD were identified (based on a criterion of at least 2 peaks and 1 trough). MEASUREMENTS Data on presentation, laboratory tests and outcomes were extracted. The diagnostic sensitivity of LNSC vs UFC in establishing cyclic CD was calculated. Kaplan-Meier analyses of recurrence after transsphenoidal pituitary surgery (TSS) were performed. RESULTS The interval between presentation and TSS was significantly longer in patients with cyclic CD (P

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).

The aim of this study was to evaluate the proportion of patients with acromegaly who remained on long-term lanreotide depot after completion of an open-label multicenter phase III clinical trial (SALSA: A Multi Center Open Label Study to Assess the Ability of Subjects With Acromegaly or Their Partners to Administer Somatuline Autogel), compare baseline and long-term follow-up symptoms scores, and correlate scores with individual longitudinal clinical outcomes.Records of all subjects previously enrolled at the Massachusetts General Hospital site of SALSA were reviewed. Those who remained on lanreotide were interviewed and asked to complete a questionnaire that they had filled out in SALSA in 2007 regarding their current symptomatology and injection side effects, as well as to complete the Acromegaly Quality of Life Questionnaire. Furthermore, clinical, biochemical, and radiographic data related to acromegaly and its comorbidities were tracked throughout follow-up.Six out of 7 patients chose to remain on lanreotide, and 5 of them continued lanreotide depot through last follow-up, for up to 8 years or in 1 case until death. In all cases, lanreotide remained well tolerated, and insulin-like growth factor-1 levels and pituitary imaging remained well controlled on stable doses. While comorbidities persisted or developed, the self-reported symptom score after up to 8 years of therapy showed a significant decrease in frequency or resolution in symptoms that were reported at baseline.This study shows a significant decrease in frequency or resolution in self-reported symptoms in well-controlled patients receiving long-term lanreotide therapy.AcroQoL = Acromegaly Quality of Life Questionnaire GH = growth hormone GI = gastrointestinal IGF-1 = insulin-like growth factor-1 SALSA = A Multi Center Open Label Study to Assess the Ability of Subjects With Acromegaly or Their Partners to Administer Somatuline Autogel.

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