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Background Primary central nervous system lymphomas (PCNSLs) have historically had dismal survival rates until the advent of high-dose methotrexate (HD-MTX) based chemotherapy regimens. With increasing prevalence of autoimmune disease and development of new immunosuppressants, a genetically distinct entity known as iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD) has emerged. Many of these cases arise following methotrexate use, challenging feasibility of standard HD-MTX regimens. The aim of this study was to further characterize this disorder and determine the optimal management strategy. Methods We describe a case of a 76-year-old female with iatrogenic immunodeficiency-associated PCNSL successfully treated with surgical resection followed by an antiviral and rituximab based regimen. We then performed a systematic literature review and identified 58 cases of non-transplant iatrogenic immunodeficiency-associated LPD involving the CNS. We used a linear probability statistical model to determine correlations with outcome. Results Natalizumab was associated with EBV negative tumors (P = .023), and EBV positive tumors were associated with improved outcomes (P = .016). Surgical resection was associated with improved outcomes (P = .032), although limited by potential confounding effect. Antiviral treatment (P = .095), rituximab (P = .111), and stem cell transplant (SCT) (P = .198) showed a trend toward improved outcomes. The remaining treatments including methotrexate showed no improvement. Conclusion We propose that surgical resection, rituximab, and antiviral treatment may be considered as an alternative to standard HD-MTX based regimens when managing iatrogenic immunodeficiency-associated LPD of the CNS. Further study through prospective cohort studies or randomized clinical trials is warranted.

Purpose The long-term effects of long-acting growth hormone (LAGH) analogues on glucose metabolism in adult growth hormone deficiency (AGHD) are not known. We investigated the impact of LAGH somapacitan, administered once-weekly, on glucose metabolism in patients with AGHD. Methods In post hoc-defined analyses, we compared the effects of somapacitan with daily growth hormone (GH) and placebo on fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β) in patients with AGHD across a unique data set from three phase 3 randomized controlled trials (REAL 1, REAL 2 and REAL Japan). Results No new cases of diabetes mellitus were reported with somapacitan. Among GH-naïve patients (n = 120 somapacitan, n = 119 daily GH), higher changes from baseline in FPG, HOMA-IR and fasting insulin levels were observed with daily GH versus somapacitan at 34 weeks, but not at 86 weeks. HbA1c and HOMA-β did not differ between groups at either timepoint. Among treatment-naïve patients, sex, age, fasting insulin, glucose tolerance status and body mass index did not influence changes in glucose metabolism. In previously treated patients (REAL 1 extension: n = 51 somapacitan, n = 52 daily GH; REAL 2: n = 61 and n = 31, respectively; REAL Japan: n = 46 and n = 16, respectively), the difference in changes from baseline were not statistically significant between somapacitan and daily GH for any glucose metabolism parameters. Conclusions Somapacitan, compared with daily GH, did not adversely affect glucose metabolism up to 86 weeks in a large cohort of treatment-naïve or previously treated patients with AGHD. Trial registrations (date of registration): NCT02229851 (2 September 2014), NCT02382939 (3 March 2015), NCT03075644 (7 March 2017).

Endocrine disorders in survivors of childhood, adolescent, and young adult (CAYA) cancers are associated with substantial adverse physical and psychosocial effects. To improve appropriate and timely endocrine screening and referral to a specialist, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) aims to develop evidence and expert consensus-based guidelines for healthcare providers that harmonize recommendations for surveillance of endocrine disorders in CAYA cancer survivors. Existing IGHG surveillance recommendations for premature ovarian insufficiency, gonadotoxicity in males, fertility preservation, and thyroid cancer are summarized. For hypothalamic-pituitary (HP) dysfunction, new surveillance recommendations were formulated by a guideline panel consisting of 42 interdisciplinary international experts. A systematic literature search was performed in MEDLINE (through PubMed) for clinically relevant questions concerning HP dysfunction. Literature was screened for eligibility. Recommendations were formulated by drawing conclusions from quality assessment of all evidence, considering the potential benefits of early detection and appropriate management. Healthcare providers should be aware that CAYA cancer survivors have an increased risk for endocrine disorders, including HP dysfunction. Regular surveillance with clinical history, anthropomorphic measures, physical examination, and laboratory measurements is recommended in at-risk survivors. When endocrine disorders are suspected, healthcare providers should proceed with timely referrals to specialized services. These international evidence-based recommendations for surveillance of endocrine disorders in CAYA cancer survivors inform healthcare providers and highlight the need for long-term endocrine follow-up care in subgroups of survivors and elucidate opportunities for further research.

Context Data on long-term safety of growth hormone (GH) replacement in adults with GH deficiency (GHD) are needed. Objective We aimed to evaluate the safety of GH in the full KIMS (Pfizer International Metabolic Database) cohort. Methods The worldwide, observational KIMS study included adults and adolescents with confirmed GHD. Patients were treated with GH (Genotropin [somatropin]; Pfizer, NY) and followed through routine clinical practice. Adverse events (AEs) and clinical characteristics (eg, lipid profile, glucose) were collected. Results A cohort of 15 809 GH-treated patients were analyzed (mean follow-up of 5.3 years). AEs were reported in 51.2% of patients (treatment-related in 18.8%). Crude AE rate was higher in patients who were older, had GHD due to pituitary/hypothalamic tumors, or adult-onset GHD. AE rate analysis adjusted for age, gender, etiology, and follow-up time showed no correlation with GH dose. A total of 606 deaths (3.8%) were reported (146 by neoplasms, 71 by cardiac/vascular disorders, 48 by cerebrovascular disorders). Overall, de novo cancer incidence was comparable to that in the general population (standard incidence ratio 0.92; 95% CI, 0.83-1.01). De novo cancer risk was significantly lower in patients with idiopathic/congenital GHD (0.64; 0.43-0.91), but similar in those with pituitary/hypothalamic tumors or other etiologies versus the general population. Neither adult-onset nor childhood-onset GHD was associated with increased de novo cancer risks. Neutral effects were observed in lipids/fasting blood glucose levels. Conclusion These final KIMS cohort data support the safety of long-term GH replacement in adults with GHD as prescribed in routine clinical practice.

Growth hormone deficiency (GHD) is a clinical syndrome that can manifest either as isolated or associated with additional pituitary hormone deficiencies. Although diminished height velocity and short stature are useful and important clinical markers to consider testing for GHD in children, the signs and symptoms of GHD are not always so apparent in adults. Quality of life and metabolic health are often impacted in patients with GHD; thus, making an accurate diagnosis is important so that appropriate GH replacement therapy can be offered to these patients. Screening and testing for GHD require sound clinical judgment that follows after obtaining a complete medical history of patients with a hypothalamic-pituitary disorder and thorough physical examination with specific features for each period of life, while targeted biochemical testing and imaging are required to confirm the diagnosis. Random measurements of serum GH levels are not recommended to screen for GHD (except in neonates) as endogenous GH secretion is episodic and pulsatile throughout the lifespan. One or more GH stimulation tests may be required, but existing methods of testing might be inaccurate, difficult to perform, and can be imprecise. Furthermore, there are multiple caveats when interpreting test results including individual patient factors, differences in peak GH cut-offs (by age and test), testing time points, and heterogeneity of GH and IGF-I assays. In this article, we provide a global overview of the accuracy and cut-offs for diagnosis of GHD in children and adults, and discuss the caveats in conducting and interpreting these tests.

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

Purpose This study evaluates the temporal evolution of the spatial relationship between the pituitary adenoma transsphenoidal surgical cavity and the adjacent optic chiasm and discusses implications on timing and choice of radiotherapy modality. Methods This retrospective observational review analyzed factors that might influence the postoperative relationship between the surgical cavity and the optic chiasm, including tumor type, craniocaudal tumor and resection cavity dimensions, the preoperative distance between tumor and the optic chiasm, the presence of cavernous sinus invasion, and the choice of intraoperative packing material. Changes observed on magnetic resonance imaging in the preoperative, immediate (within 72 h), and delayed (≥3 months) postoperative periods were compared. Results Sixty-five patient histories were analyzed. Preoperatively, the pituitary adenoma was apposed to the optic chiasm in 43 patients (66%). Postoperatively, 34 patients (52%) in the immediate postoperative period and 54 patients (83%) in the delayed postoperative period had a distance ≥2 mm between the resection cavity and the optic chiasm. This distance provides a greater margin of safety with adjuvant radiosurgery. Preoperative tumor size showed a strong association with postoperative descent of the optic chiasm. Conclusions Preoperative tumor size and degree of mass effect on the optic chiasm predict postoperative changes. In this study, the distance between the resection cavity and the optic chiasm was greater at ≥3 months postoperatively than in the immediate postoperative period, regardless of preoperative mass effect, indicating radiotherapy planning should be deferred to ≥3 months postoperatively when not precluded by aggressive histological characteristics that necessitate more immediate treatment. Precis To investigate the temporal relationship between the postoperative sellar surgical cavity and the adjacent optic apparatus after transsphenoidal resection of pituitary adenomas and the implications for radiotherapy.

Sodium and water perturbations, manifesting as hyponatraemia and hypernatraemia, are common in patients who had an acute stroke, and are associated with worse outcomes and increased mortality. Other non-stroke-related causes of sodium and water perturbations in these patients include underlying comorbidities and concomitant medications. Additionally, hospitalised patients who had an acute stroke may receive excessive intravenous hypotonic solutions, have poor fluid intake due to impaired neurocognition and consciousness, may develop sepsis or are administered drugs (eg, mannitol); factors that can further alter serum sodium levels. Sodium and water perturbations can also be exacerbated by the development of endocrine consequences after an acute stroke, including secondary adrenal insufficiency, syndrome of inappropriate antidiuretic hormone secretion and diabetes insipidus. Recently, COVID-19 infection has been reported to increase the risk of development of sodium and water perturbations that may further worsen the outcomes of patients who had an acute stroke. Because there are currently no accepted consensus guidelines on the management of sodium and water perturbations in patients who had an acute stroke, we conducted a systematic review of the literature published in English and in peer-reviewed journals between January 2000 and December 2020, according to PRISMA guidelines, to assess on the current knowledge and clinical practices of this condition. In this review, we discuss the signs and symptoms of hyponatraemia and hypernatraemia, the pathogenesis of hyponatraemia and hypernatraemia, their clinical relevance, and we provide our recommendations for effective treatment strategies for the neurologist in the management of sodium and water perturbations in commonly encountered aetiologies of patients who had an acute stroke.

Limited information is available on the utilization and healthcare costs among patients with acromegaly. The purpose of this study was to assess the impact of acromegaly on healthcare utilization and costs by locations of care (LoC).Patients with acromegaly and controls were identified from an analysis of drug and medical claims filed from January 2010 to April 2019 from a US employer database. Each patient with acromegaly was matched with 20 random controls (without acromegaly) selected from the database. Claims were tracked for 12 months postdiagnosis (or matched date for controls). Outcomes by LoC, including costs, services, and likelihood of use, were compared using two-stage regression models or logistic regression models, controlling for demographic and job-related variables, and Charlson comorbidity index scores.Claims from 60 patients with acromegaly and 1,200 controls were analyzed. Compared with the control group, patients with acromegaly had significantly higher likelihoods of receiving care in a physician's office [odds ratio1,000], inpatient [OR = 8.010], outpatient [OR = 12.656], laboratory [OR = 3.681], and 'other' locations [OR = 4.033] (allCompared with matched controls, patients with acromegaly were more likely to utilize healthcare services in nearly all LoCs and accrue higher expenditures at each LoC, with the exception of ED services.

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.

Context Approximately 10% to 20% of prolactinomas are resistant to dopamine agonist therapy. The ErbB signaling pathway may drive aggressive prolactinoma behavior. Objective We evaluated lapatinib, an ErbB1-epidermal growth factor receptor (EGFR)/ErbB2 or human EGFR2 (HER2) tyrosine kinase inhibitor (TKI), in aggressive prolactinomas. Design A prospective, phase 2a multicenter trial was conducted. Setting This study took place at a tertiary referral pituitary center. Patients Study participants included adults with aggressive prolactinomas showing continued tumor growth despite maximally tolerated dopamine agonist therapy. Intervention Intervention included oral lapatinib 1250 mg/day for 6 months. Main Outcome Measures The primary end point was 40% reduction in any tumor dimension assessed by magnetic resonance imaging at study end; tumor response was assessed by Response Evaluation Criteria in Solid Tumors criteria. Secondary end points included prolactin (PRL) reduction, correlation of response with EGFR/HER2 expression, and safety. Results Owing to rigorous inclusion criteria, of 24 planned participants, only 7 consented and 4 were treated. None achieved the primary end point but 3 showed stable disease, including 2 with a 6% increase and 1 with a 16.8% decrease in tumor diameter. PRL response was not always concordant with tumor response, as 2 showed 28% and 59% increases in PRL. The fourth participant had a PRL-secreting carcinoma and withdrew after 3 months of lapatinib because of imaging and PRL progression. EGFR/HER2 expression did not correlate with treatment response. Lapatinib was well tolerated overall, with reversible grade 1 transaminitis in 2 patients, grade 2 rash in 2 patients, and grade 1 asymptomatic bradycardia in 2 patients. Conclusions An oral TKI such as lapatinib may be an effective option for a difficult-to-treat patient with an aggressive prolactinoma.

Over the past few decades, there has been an unprecedented rise in off-label use and misuse of testosterone, growth hormone, thyroid hormone, and adrenal supplements. Testosterone therapy is often promoted to men for the treatment of low energy, lower libido, erectile dysfunction, and other symptoms. Growth hormone is used in attempts to improve athletic performance in athletes and to attenuate aging in older adults. Thyroid hormone and/or thyroid supplements or boosters are taken to treat fatigue, obesity, depression, cognitive impairment, impaired physical performance, and infertility. Adrenal supplements are used to treat common nonspecific symptoms due to "adrenal fatigue," an entity that has not been recognized as a legitimate medical diagnosis. Several factors have contributed to the surge in off-label use and misuse of these hormones and supplements: direct-to-consumer advertising, websites claiming to provide legitimate medical information, and for-profit facilities promoting therapies for men's health and anti-aging. The off-label use and misuse of hormones and supplements in individuals without an established endocrine diagnosis carries known and unknown risks. For example, the risks of growth hormone abuse in athletes and older adults are unknown due to a paucity of studies and because those who abuse this hormone often take supraphysiologic doses in sporadic intervals. In addition to the health risks, off-label use of these hormones and supplements generates billions of dollars of unnecessary costs to patients and to the overall health-care system. It is important that patients honestly disclose to their providers off-label hormone use, as it may affect their health and treatment plan. General medical practitioners and adult endocrinologists should be able to begin a discussion with their patients regarding the unfavorable balance between the risks and benefits associated with off-label use of testosterone, growth hormone, thyroid hormone, and adrenal supplements. Abbreviations: DHEA = dehydroepiandrosterone; FDA = U.S. Food and Drug Administration; GH = growth hormone; IGF-1 = insulin-like growth factor 1; LT3 = L-triiodothyronine; LT4 = levothyroxine; T3 = total triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone.

OBJECTIVECurrent practice guidelines recommend delayed (≥ 3 months after operation) postoperative MRI after transsphenoidal surgery for pituitary adenomas, although this practice defers obtaining important information, such as the presence of a residual adenoma, that might influence patient management during the perioperative period. In this study, the authors compared detection of residual adenomas by means of early postoperative (EPO) MRI (< 48 hours postsurgery) with both surgeon intraoperative assessment and late postoperative (LPO) MRI at 3 months.METHODSAdult patients who underwent microscopic transsphenoidal surgery for pituitary adenomas with MRI preoperatively, < 48 hours after the operation, 3 months postoperatively, and yearly for 4 years were included. The presence or absence of residual tumor was assessed intraoperatively by a single surgeon and postoperatively by 2 neuroradiologists blinded to the intraoperative assessment and other postoperative imaging studies. The presence of residual tumor was confirmed by reresection, tumor growth on imaging, or hormonal evidence. Interreader reliability was calculated at each imaging time point. Specificity, sensitivity, positive predictive value, and negative predictive value for EPO and LPO imaging and intraoperative assessment were determined.RESULTSIn total, 102 consecutive patients who underwent microscopic transsphenoidal resection of a pituitary adenoma were included. Eighteen patients (18%) had confirmed residual tumors (12 confirmed by tumor growth, 5 by surgery, and 1 by biochemical evidence of persistent disease). Interreader reliability for detecting residual tumor on EPO MRI was almost perfect (κ = 0.88) and significantly higher than that for LPO MRI (κ = 0.69, p = 0.03). EPO MRI was highly specific for residual tumor (98%), a finding similar to that for intraoperative assessment (99%, p = 0.60) and significantly higher than that for LPO MRI (81%, p < 0.001). Notably, EPO MRI was significantly more sensitive for residual tumor (100%) than both intraoperative assessment (78%, p = 0.04) and LPO MRI (78%, p = 0.04). EPO MRI had a 100% negative predictive value and was used to find 4 residual tumors that were not identified intraoperatively. Residual tumors found on EPO MRI allowed for reresection during the same hospitalization for 3 patients.CONCLUSIONSEPO MRI after transsphenoidal pituitary surgery can be reliably interpreted and has greater sensitivity for detecting residual tumor than intraoperative assessment and LPO MRI. This result challenges current guidelines stating that delayed postoperative imaging is preferable to early imaging. Pituitary surgeons should consider performing EPO MRI either in addition to or instead of delayed imaging.

Adult growth hormone deficiency (GHD) is a syndrome characterized by adverse phenotypic, metabolic, and quality-of-life features. Over the past 2 decades, there is accumulating evidence demonstrating improvement of most of these parameters when GH is optimally replaced. Appropriate selection of patients at risk of GHD is crucial when considering and performing testing to establish the diagnosis. While generally safe, GH replacement requires careful dose initiation and monitoring to assure effectiveness and tolerance in treated patients. Several consensus clinical practice guidelines recommend evaluation of adults presenting with hypothalamic-pituitary disorders for GHD. However, the clinical practice of managing such patients varies among countries largely due to lack of recognition of the condition, lack of GH availability, and lack of reimbursement of the drug, as demonstrated from a large online survey prepared by the European Society of Endocrinology involving 2148 patients from Europe and Australia. These data reinforce the notion of the large variability of disease recognition, clinical practice and education of adult GHD amongst healthcare professionals, and the lack of availability and reimbursement of the drug contributing to the under-utilization of GH replacement therapy in several countries. This commentary article highlights the fact that despite the publication of several guideline recommendations and positive long-term safety and efficacy data of GH replacement, there is still a need for increased education to enhance the awareness in the general population and improve the knowledge of healthcare professionals and administrators of adult GHD as a disease state to allow for early identification and treatment optimization.

(1) Background: Cushing’s disease (CD) is a serious endocrine disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary neuroendocrine tumor (PitNET) that stimulates the adrenal glands to overproduce cortisol. Chronic exposure to excess cortisol has detrimental effects on health, including increased stroke rates, diabetes, obesity, cognitive impairment, anxiety, depression, and death. The first-line treatment for CD is pituitary surgery. Current surgical remission rates reported in only 56% of patients depending on several criteria. The lack of specificity, poor tolerability, and low efficacy of the subsequent second-line medical therapies make CD a medical therapeutic challenge. One major limitation that hinders the development of specific medical therapies is the lack of relevant human model systems that recapitulate the cellular composition of PitNET microenvironment. (2) Methods: human pituitary tumor tissue was harvested during transsphenoidal surgery from CD patients to generate organoids (hPITOs). (3) Results: hPITOs generated from corticotroph, lactotroph, gonadotroph, and somatotroph tumors exhibited morphological diversity among the organoid lines between individual patients and amongst subtypes. The similarity in cell lineages between the organoid line and the patient’s tumor was validated by comparing the neuropathology report to the expression pattern of PitNET specific markers, using spectral flow cytometry and exome sequencing. A high-throughput drug screen demonstrated patient-specific drug responses of hPITOs amongst each tumor subtype. Generation of induced pluripotent stem cells (iPSCs) from a CD patient carrying germline mutation CDH23 exhibited dysregulated cell lineage commitment. (4) Conclusions: The human pituitary neuroendocrine tumor organoids represent a novel approach in how we model complex pathologies in CD patients, which will enable effective personalized medicine for these patients.

Objective. Adult growth hormone deficiency (AGHD) is an underdiagnosed disease associated with increased morbidity and mortality. Identifying people who may benefit from growth hormone (GH) therapy can be challenging, as many AGHD symptoms resemble those of aging. We developed an algorithm to potentially help providers stratify people by their likelihood of having AGHD. Design. The algorithm was developed with, and applied to, data in the anonymized Truven Health MarketScan® claims database. Patients. A total of 135 million adults in the US aged ≥18 years with ≥6 months of data in the Truven database. Measurements. Proportion of people with high, moderate, or low likelihood of having AGHD, and differences in demographic and clinical characteristics among these groups. Results. Overall, 0.5%, 6.0%, and 93.6% of people were categorized into groups with high, moderate, or low likelihood of having AGHD, respectively. The proportions of females were 59.3%, 71.6%, and 50.4%, respectively. People in the high- and moderate-likelihood groups tended to be older than those in the low-likelihood group, with 58.3%, 49.0%, and 37.6% aged >50 years, respectively. Only 2.2% of people in the high-likelihood group received GH therapy as adults. The high-likelihood group had a higher incidence of comorbidities than the low-likelihood group, notably malignant neoplastic disease (standardized difference −0.42), malignant breast tumor (−0.27), hyperlipidemia (−0.26), hypertensive disorder (−0.25), osteoarthritis (−0.23), and heart disease (−0.22). Conclusions. This algorithm may represent a cost-effective approach to improve AGHD detection rates by identifying appropriate patients for further diagnostic testing and potential GH replacement treatment.

Individuals surviving cancer and brain tumors may experience growth hormone (GH) deficiency as a result of tumor growth, surgical resection and/or radiotherapy involving the hypothalamic-pituitary region. Given the pro-mitogenic and anti-apoptotic properties of GH and insulin-like growth factor-I, the safety of GH replacement in this population has raised hypothetical safety concerns that have been debated for decades. Data from multicenter studies with extended follow-up have generally not found significant associations between GH replacement and cancer recurrence or mortality from cancer among childhood cancer survivors. Potential associations with secondary neoplasms, especially solid tumors, have been reported, although this risk appears to decline with longer follow-up. Data from survivors of pediatric or adult cancers who are treated with GH during adulthood are scarce, and the risk versus benefit profile of GH replacement of this population remains unclear. Studies pertaining to the safety of GH replacement in individuals treated for nonmalignant brain tumors, including craniopharyngioma and non-functioning pituitary adenoma, have generally been reassuring with regards to the risk of tumor recurrence. The present review offers a summary of the most current medical literature regarding GH treatment of patients who have survived cancer and brain tumors, with the emphasis on areas where active research is required and where consensus on clinical practice is lacking.

Daily recombinant human GH (rhGH) is currently approved for use in children and adults with GH deficiency (GHD) in many countries with relatively few side-effects. Nevertheless, daily injections can be painful and distressing for some patients, often resulting in non-adherence and reduction of treatment outcomes. This has prompted the development of numerous long-acting GH (LAGH) analogues that allow for decreased injection frequency, ranging from weekly, bi-weekly to monthly. These LAGH analogues are attractive as they may theoretically offer increased patient acceptance, tolerability, and therapeutic flexibility. Conversely, there may also be pitfalls to these LAGH analogues, including an unphysiological GH profile and differing molecular structures that pose potential clinical issues in terms of dose initiation, therapeutic monitoring, incidence and duration of side-effects, and long-term safety. Furthermore, fluctuations of peak and trough serum GH and IGF-I levels and variations in therapeutic efficacy may depend on the technology used to prolong GH action. Previous studies of some LAGH analogues have demonstrated non-inferiority compared to daily rhGH in terms of increased growth velocity and improved body composition in children and adults with GHD, respectively, with no significant unanticipated adverse events. Currently, two LAGH analogues are marketed in Asia, one recently approved in the United States, another previously approved but not marketed in Europe, and several others proceeding through various stages of clinical development. Nevertheless, several practical questions still remain, including possible differences in dose initiation between naive and switch-over patients, methodology of dose adjustment/s, timing of measuring serum IGF-I levels, safety, durability of efficacy and cost-effectiveness. Long-term surveillance of safety and efficacy of LAGH analogues are needed to answer these important questions.

ContextLong-acting GH (LAGH) preparations are currently being developed in an attempt to improve adherence. The profile of GH action following administration of LAGH raises practical questions about clinical monitoring and long-term safety and efficacy of these new therapeutic agents.MethodsRecent literature and meeting proceedings regarding LAGH preparations are reviewed.ResultsMultiple LAGH preparations are currently at various stages of development, allowing for decreased GH injection frequency from daily to weekly, biweekly, or monthly. Following administration of LAGH, the serum peak and trough GH and IGF-I levels vary depending upon the mechanism used to prolong GH action. Randomized, controlled clinical trials of some LAGH preparations have reported non-inferiority compared with daily recombinant human GH (rhGH) for improved growth velocity and body composition in children and adults with GH deficiency (GHD), respectively. No significant LAGH-related adverse events have been reported during short-term therapy.ConclusionMultiple LAGH preparations are proceeding through clinical development with some showing promising evidence of short-term clinical efficacy and safety in children and adults with GHD. The relationship of transient elevations of GH and IGF-I following administration of LAGH to efficacy and safety remain to be elucidated. For LAGH to replace daily rhGH in the treatment of individuals with GHD, a number of practical questions need to be addressed including methods of dose adjustment, timing of monitoring of IGF-I, safety, efficacy, and cost-effectiveness. Long-term surveillance of efficacy and safety of LAGH preparations will be needed to answer these clinically relevant questions.

Sodium perturbations are a common complication after pituitary surgery, with hyponatremia being the most frequent. Postoperative assessments should be tailored to the early and late periods, and monitoring sodium perturbations is recommended. Cerebral salt wasting is rare after pituitary surgery, and diagnosis and management can be challenging. Providing patient counseling and close postoperative follow-up is important to effectively manage diabetes insipidus and reduce hospital readmissions due to sodium perturbations.

Purpose Clinical trials have demonstrated the favorable efficacy/safety profile of pasireotide in patients with Cushing’s disease (CD). We report interim long-term results of an ongoing real-world evidence study of subcutaneous pasireotide in patients with CD. Methods Adults with CD receiving pasireotide, initiated before (prior-use) or at study entry (new-use), were monitored for ≤ 3 years during a multicenter observational study (http://clinicaltrials.gov identifier NCT02310269). Primary objective was to assess long-term safety of pasireotide alone or with other CD therapies. Results At the time of this interim analysis, 127 patients had received pasireotide (new-use, n = 31; prior-use, n = 96). Eight patients had completed the 3-year observation period, 53 were ongoing, and 66 had discontinued. Among 31 new-use and 92 prior-use patients with ≥ 1 safety assessment, respectively: 24 (77%) and 37 (40%) had drug-related adverse events (AEs); 7 (23%) and 10 (11%) had serious drug-related AEs. Most common drug-related AEs were nausea (14%), hyperglycemia (11%) and diarrhea (11%); these were more frequently reported in new users and mostly of mild-to-moderate severity. 14 (45%) new-use and 15 (16%) prior-use patients experienced hyperglycemia-related AEs. Mean urinary free cortisol (mUFC) was within normal range at baseline and months 1, 12 and 24, respectively, in: 1/16 (6%), 9/18 (50%), 1/3 (33%) and 0/0 new users; 28/43 (65%), 15/27 (56%), 27/33 (82%) and 12/19 (63%) prior users. Conclusions Pasireotide is well tolerated and provides sustained reductions in mUFC during real-world treatment of CD. The lower rate of hyperglycemia-related AEs in prior users suggests that hyperglycemia tends not to deteriorate if effectively managed soon after onset. Clinical Trial Registration Number: NCT02310269.

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.

Objective Cushing disease (CD) is characterized by chronic hypercortisolism caused by an adrenocorticotropic hormone-secreting pituitary adenoma. Surgery remains the first-line treatment option; however, medical therapy is essential if surgery is contraindicated or fails to achieve remission or when recurrence occurs after surgical remission. Osilodrostat (Isturisa), a novel steroidogenic inhibitor, is now approved for the treatment of CD in the United States and Cushing syndrome in Europe. Herein, we review pharmacology and data on the efficacy, safety, and clinical use of osilodrostat and provide guidance on its use in treating patients with CD. Methods We reviewed the literature and published clinical trial data of osilodrostat use in patients with Cushing syndrome. Detailed information related to the clinical assessment of osilodrostat use, potential drug-to-drug interactions, drug initiation, dose titration, and the monitoring of drug tolerability were discussed. Results Clinical trial data demonstrated that osilodrostat, by virtue of inhibiting 11-β hydroxylase, potently and rapidly decreased the 24-hour urinary free cortisol levels and sustained these reductions, with improved glycemia, blood pressure, body weight, and quality of life as well as lessened depression. Osilodrostat may interact with certain drugs, resulting in QT prolongation, which requires careful assessment of concomitant medications and periodic monitoring using electrocardiogram, respectively. The common adverse effects include adrenal insufficiency, hypokalemia, edema, and hyperandrogenic symptoms, which can be minimized using a slower up-titration dosing regimen. Conclusion Osilodrostat is an effective, new treatment option for CD, with positive effects on cardiovascular and quality of life parameters as well as tolerable adverse effects. This article provides a review of the pharmacology of osilodrostat and offers practical recommendations on the use of osilodrostat to treat CD.

Introduction The coronavirus disease 2019 (COVID‐19) is currently a major pandemic challenge, and cancer patients are at a heightened risk of severity and mortality from this infection. In recent years, immune checkpoint inhibitor (ICI) use to treat multiple cancers has increased in oncology, but equally has raised the question of whether ICI therapy and its side‐effects is harmful or beneficial during this pandemic. Methods A combination of published literature in PubMed between January 2010 and December 2020, recommended guidelines in non‐cancer patients, and clinical experience was utilized to outline recommendations on glucocorticoid timing and dosing regimens in ICI‐treated patients presenting with AI during this COVID‐19 pandemic. Results The potential immune interaction between ICIs and COVID‐19 require major consideration because these agents act at the intersection between effective cancer immunotherapy and increasing patient susceptibility, severity and complications from the SARS‐CoV‐2 sepsis. Furthermore, ICI use can induce autoimmune adrenal insufficiency (AI) that further increases infection susceptibility. Thus, ICI‐treated cancer patients with AI may be at greater risk of COVID‐19 infection. Glucocorticoids are the cornerstone for replacement therapy, and for treatment and mitigation of adrenal crisis and relief of mass effects in ICI‐related hypophysitis. High‐dose glucocorticoids have also been used with cytotoxic chemotherapy as part of cancer treatment, and iatrogenic AI may arise after glucocorticoid discontinuation that increases the risk of adrenal crisis. Furthermore, in patients who develop the “long COVID‐19” syndrome, when to discontinue glucocorticoid therapy becomes crucial to avoid unnecessary prolongation of therapy and the development of iatrogenic hypercortisolemia. Conclusion During the COVID‐19 pandemic, much of cancer care have been impacted and an important clinical question is how to optimally manage ICI‐related AI during these unprecedented times. Herein, we suggest practical recommendations on the timing and dosing regimens of glucocorticoids in different clinical scenarios of ICI‐treated cancer patients presenting with AI during this COVID‐19 pandemic., Cancer patients treated with immune checkpoint inhibitors (ICIs) who develop adrenal insufficiency may be at a greater risk of severity and mortality from the COVID‐19 infection. The effects of ICIs and the appropriate use of glucocorticoids is crucial in optimally managing these patients and preventing unnecessary hypercortisolemia and worsening of symptoms of some patients, including those with long COVID‐19. We suggest practical recommendations on the timing and dosing regimens of glucocorticoids in different clinical scenarios of ICI‐treated cancer patients with AI during this COVID‐19 pandemic.

Purpose The test with the highest diagnostic accuracy for diabetes insipidus is copeptin measurement after hypertonic saline infusion. However, the procedure is cumbersome and unpleasant due to rapid sodium increase. An oral stimulation test would be highly desirable. Macimorelin, an oral ghrelin agonist, is a newly approved diagnostic test for growth hormone (GH) deficiency, but its effects on copeptin/vasopressin are unknown and the effects on other pituitary hormones only scarcely investigated. Methods In this prospective, interventional, proof-of-concept study Copeptin and anterior pituitary hormones were measured in 28 healthy volunteers on two test days at baseline, 30, 45, 60, 90 and 120 min after a single dose of macimorelin (first visit: 0.5 mg/kg, second visit: 0.75 mg/kg). Results Baseline copeptin levels were 5.26 pmol/L [1.57, 6.81] and did not change after macimorelin intake (0.5 mg/kg: maximal median change 0.40 [− 0.49, 0.65] pmol/L, p = 0.442; 0.75 mg/kg: − 0.13 [− 0.45, 0.17] pmol/L, p = 0.442. Median GH levels increased from 3.67 mU/L with a maximal median change of 94.66 [IQR 56.5; 110.96] mU/L, p Conclusion We confirm an increase of GH upon macimorelin in healthy volunteers. However, macimorelin did not stimulate copeptin and therefore does not provide an oral test alternative for the diagnosis of diabetes insipidus. Additionally, a stimulatory effect was seen for prolactin and fT4, but not for ACTH and gonadotropic hormones. Registration The trial was registered on ClinicalTrials.gov (NCT03844217) on February 18, 2019.

OBJECTIVE A comprehensive quality improvement (QI) program aimed at all aspects of patient care after pituitary surgery was initiated at a single center. This initiative was guided by standard quality principles to improve patient outcomes and optimize healthcare value. The programmatic goal was to discharge most elective patients within 1 day after surgery, improve patient safety, and limit unplanned readmissions. The program is described, and its effect on patient outcomes and hospital financial performance over a 5-year period are investigated. METHODS Details of the patient care pathway are presented. Foundational elements of the QI program include evidence-based care pathways (e.g., for hyponatremia and pain), an in-house research program designed to fortify care pathways, patient education, expectation setting, multidisciplinary team care, standard order sets, high-touch postdischarge care, outcomes auditing, and a patient navigator, among other elements. Length of stay (LOS), outcome variability, 30-day unplanned readmissions, and hospital financial performance were identified as surrogate endpoints for healthcare value for the surgical epoch. To assess the effect of these protocols, all patients undergoing elective transsphenoidal surgery for pituitary tumors and Rathke’s cleft cysts between January 2015 and December 2019 were reviewed. RESULTS A total of 609 adult patients who underwent elective surgery by experienced pituitary surgeons were identified. Patient demographics, comorbidities, and payer mix did not change significantly over the study period (p ≥ 0.10). The mean LOS was significantly shorter in 2019 versus 2015 (1.6 ± 1.0 vs 2.9 ± 2.2 midnights, p < 0.001). The percentage of patients discharged after 1 midnight was significantly higher in 2019 versus 2015 (75.4% vs 15.6%, p < 0.001). The 30-day unplanned hospital readmission rate decreased to 2.8% in 2019 from 8.3% in 2015. Per-patient hospital profit increased 71.3% ($10,613 ± $19,321 in 2015; $18,180 ± $21,930 in 2019), and the contribution margin increased 42.3% ($18,925 ± $19,236 in 2015; $26,939 ± $22,057 in 2019), while costs increased by only 3.4% ($18,829 ± $6611 in 2015; $19,469 ± $4291 in 2019). CONCLUSIONS After implementation of a comprehensive pituitary surgery QI program, patient outcomes significantly improved, outcome variability decreased, and hospital financial performance was enhanced. Future studies designed to evaluate disease remission, patient satisfaction, and how the surgeon learning curve may synergize with other quality efforts may provide additional context.

Establishing a definitive diagnosis of Cushing disease (CD), given its clinical and biochemical heterogeneity, initiating effective treatment to control the effects of hypercortisolism, and managing recurrence are challenging disease aspects to address. Mifepristone is a competitive glucocorticoid receptor antagonist that is approved in the US by the Food and Drug Administration to control hyperglycemia secondary to endogenous hypercortisolism (Cushing syndrome) in patients who have glucose intolerance or type 2 diabetes mellitus and have failed surgery or are not candidates for surgery. Herein, we describe 6 patients with CD who received mifepristone as adjunct/bridge therapy in the following clinical settings: to assess clinical benefits of treatment for suspected recurrent disease, to control hypercortisolism preoperatively for severe disease, to control hypercortisolism during the COVID-19 pandemic, and to provide adjunctive treatment to radiation therapy. The patients were treated at multiple medical practice settings. Mifepristone treatment in each of the described cases was associated with clinical improvements, including improvements in overall glycemia, hypertension, and weight loss. In addition, in one case where biochemical and radiological evidence of disease recurrence was uncertain, clinical improvement with mifepristone pointed toward likely disease recurrence. Adverse events associated with mifepristone reported in the 6 cases were consistent with those previously reported in the pivotal trial and included cortisol withdrawal symptoms, antiprogesterone effects (vaginal bleeding), hypothyroidism (treated with levothyroxine), and hypokalemia (treated with spironolactone). These cases show how mifepristone can potentially be utilized as a therapeutic trial in equivocal cases of CD recurrence; as a presurgical treatment strategy, particularly during the COVID-19 pandemic; and as bridge therapy, while awaiting the effects of radiation.

OBJECTIVE Acromegaly is associated with increased morbidity and mortality. Limited data are available on these patients' utilization and costs of health care. This study assessed the impact of acromegaly on employees' health benefit (direct and indirect) costs and absenteeism. METHODS A retrospective analysis was conducted of drug and medical claims and employer data (from January 2010 to April 2019) of patients with an acromegaly diagnosis and matched controls from a U.S. employee database. Patient claims were tracked for 12 months postdiagnosis (or matched) date. Outcomes were analyzed using separate 2-part regression models, controlling for clinical, demographic, and job-related variables. RESULTS Forty-seven patients with acromegaly and 940 controls were identified. Cohorts were similar in most demographic and job-related variables. Patients with acromegaly had a significantly higher Charlson comorbidity index score and higher incidence of claims for several comorbidities. Acromegaly drugs represented 16.3% of the acromegaly cohort's total costs. Total health benefit costs were $54 821 higher (P < .05) for patients compared with controls, with direct costs representing 79.8% of the difference. Total indirect costs were higher for patients with acromegaly, with short-term and long-term disability comprising most of the difference between the acromegaly and control groups. Patients with acromegaly had significantly more short-term disability days than controls, but total sick days were similar for the 2 groups. CONCLUSION The presence of acromegaly was associated with increased direct and indirect employee health benefit costs and increased work absenteeism.

Context Traumatic brain injury (TBI) is considered the “signature” injury of veterans returning from wartime conflicts in Iraq and Afghanistan. While moderate/severe TBI is associated with pituitary dysfunction, this association has not been well established in the military setting and in mild TBI (mTBI). Screening for pituitary dysfunction resulting from TBI in veteran populations is inconsistent across Veterans Affairs (VA) institutions, and such dysfunction often goes unrecognized and untreated. Objective This work aims to report the experience of a pituitary clinic in screening for and diagnosis of pituitary dysfunction. Methods A retrospective analysis was conducted in a US tertiary care center of veterans referred to the VA Puget Sound Healthcare System pituitary clinic with a history of TBI at least 12 months prior. Main outcome measures included demographics, medical history, symptom burden, baseline hormonal evaluation, brain imaging, and provocative testing for adrenal insufficiency (AI) and adult-onset growth hormone deficiency (AGHD). Results Fatigue, cognitive/memory problems, insomnia, and posttraumatic stress disorder were reported in at least two-thirds of the 58 patients evaluated. Twenty-two (37.9%) were diagnosed with at least one pituitary hormone deficiency, including 13 (22.4%) AI, 12 (20.7%) AGHD, 2 (3.4%) secondary hypogonadism, and 5 (8.6%) hyperprolactinemia diagnoses; there were no cases of thyrotropin deficiency. Conclusion A high prevalence of chronic AI and AGHD was observed among veterans with TBI. Prospective, larger studies are needed to confirm these results and determine the effects of hormone replacement on long-term outcomes in this setting.

Acromegaly is a rare disorder of chronic growth hormone (GH) hypersecretion, frequently caused by a pituitary adenoma, resulting in excessive generation of insulin-like growth factor-I (IGF-I), the mediator of most of the GH effects. Clinical manifestations of acromegaly may be subtle or severe, and characterized by somatic overgrowth, multiple comorbidities, physical disfigurement, and increased mortality. Gigantism develops when GH hypersecretion occurs in young patients before epiphyseal bone closure occurs. There is an equal gender predisposition in acromegaly and the average age at diagnosis ranges between 40 and 50 years, while a minority of cases (up to 5%) are diagnosed before the age of 20. Due to its insidious clinical onset, slow progression, and variable clinical spectrum, diagnosis is often delayed. Furthermore, there are some patients with physical features that resemble acromegaly but with normal GH/IGF-I axis (termed “pseudoacromegaly”); in these patients, the correct diagnosis can be challenging due to the rarity and significant overlap of physical features. Otherwise, diagnosing acromegaly in most cases is usually straightforward based on the identification of clinical symptoms and signs, biochemical confirmation by measuring serum IGF-I levels and assessing nadir serum GH levels during an oral glucose tolerance test, and by performing pituitary magnetic resonance imaging. In recent years, clinicopathological studies of pituitary tumors have demonstrated that each tumor type has a distinct pathophysiology resulting in varying clinical manifestations that may require different therapeutic approaches. Because of the association of excess comorbidities and mortality with acromegaly, it is thus important to detect and optimally treat patients early to reduce the risks of long-term morbidity and premature death.

Daily recombinant human GH (rhGH) is currently approved for use in children and adults with GH deficiency (GHD) in many countries with relatively few side-effects. Nevertheless, daily injections can be painful and distressing for some patients, often resulting in non-adherence and reduction of treatment outcomes. This has prompted the development of numerous long-acting GH (LAGH) analogs that allow for decreased injection frequency, ranging from weekly, bi-weekly to monthly. These LAGH analogs are attractive as they may theoretically offer increased patient acceptance, tolerability, and therapeutic flexibility. Conversely, there may also be pitfalls to these LAGH analogs, including an unphysiological GH profile and differing molecular structures that pose potential clinical issues in terms of dose initiation, therapeutic monitoring, incidence and duration of side-effects, and long-term safety. Furthermore, fluctuations of peak and trough serum GH and IGF-I levels and variations in therapeutic efficacy may depend on the technology used to prolong GH action. Previous studies of some LAGH analogs have demonstrated non-inferiority compared to daily rhGH in terms of increased growth velocity and improved body composition in children and adults with GHD, respectively, with no significant unanticipated adverse events. Currently, two LAGH analogs are marketed in Asia, one recently approved in the United States, another previously approved but not marketed in Europe, and several others proceeding through various stages of clinical development. Nevertheless, several practical questions still remain, including possible differences in dose initiation between naïve and switch-over patients, methodology of dose adjustment/s, timing of measuring serum IGF-I levels, safety, durability of efficacy and cost-effectiveness. Long-term surveillance of safety and efficacy of LAGH analogs are needed to answer these important questions.

Objective The macimorelin test is approved for the diagnosis of adult growth hormone deficiency (AGHD) based on its efficacy vs the insulin tolerance test (ITT). Macimorelin has a significant advantage over ITT in avoiding hypoglycemia. Analyses were conducted to determine whether macimorelin performance is affected by age, BMI, or sex, and evaluate its performance vs ITT over a range of GH cutpoints. Design Post hoc analyses of data from a previous randomized phase 3 study included participants aged 18–66 years with BMI 2 and high (Group A), intermediate (Group B), or low (Group C) likelihood for AGHD based on pituitary history, and matched controls (Group D). Methods Probability of AGHD was estimated using unadjusted, age-adjusted, BMI-adjusted, and sex-adjusted logistic models. Area under the curve (AUC) of the estimated receiver operating characteristic (ROC) curve (range, 0–1; 1 = perfect) was compared for adjusted vs unadjusted models. Separate analyses evaluated agreement, sensitivity, and specificity for macimorelin and ITT using cutpoints of 2.8, 4.0, 5.1, and 6.5 ng/mL. Results For participants in Group A (n = 41) and Group D (n = 29), unadjusted, age-adjusted, BMI-adjusted, and sex-adjusted models had ROC AUCs (95% CIs) of 0.9924 (0.9807–1), 0.9924 (0.9807–1), 0.9916 (0.9786–1), and 0.9950 (0.9861–1), respectively. Conclusions Macimorelin performance was not meaningfully affected by age, BMI, or sex, indicating robustness for AGHD diagnosis. Of the 4 GH cutpoints evaluated, the cutpoint of 5.1 ng/mL provided maximal specificity (96%) and high sensitivity (92%) and was in good overall agreement with the ITT at the same cutpoint (87%).

BackgroundWhile surgery is the first-line treatment for patients with endogenous hypercortisolism (Cushing syndrome [CS]), mifepristone has been shown to be a beneficial medical treatment option, as demonstrated in the SEISMIC (Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing Syndrome) trial. Mifepristone is a competitive glucocorticoid receptor antagonist and progesterone receptor antagonist that is associated with several treatment effects and adverse events that clinicians need to be aware of when considering its use. The objective of this review was to provide updated clinical management recommendations for patients with CS treated with mifepristone.MethodsA panel of endocrinologists from the US with extensive experience in treating patients with CS, including with mifepristone, convened as part of a clinical advisory board to develop a consensus on the practical, real-world clinical management of patients on mifepristone.ResultsComprehensive considerations and recommendations are provided for managing mifepristone-associated effects, including symptoms of cortisol withdrawal, hypokalemia, and change in thyroid function; effects related to its antiprogesterone activity; and rash. Additional management strategies to address concomitant medications and special clinical situations, such as surgery and use in specific populations, are also provided.ConclusionSafe and effective use of mifepristone requires clinical judgment and close patient monitoring to ensure optimal clinical outcomes. These consensus recommendations provide useful, practical guidance to clinicians using mifepristone.

Highlights • Rapid media coverage of COVID-19 has prompted new hypotheses for research of its impact in patients with GH disorders. • Adherence of GH therapy in children and adults with GH deficiency remains unexpectedly high during the COVID-19 pandemic. • Risk factors of COVID-19 may be associated with decreased GH secretion suggesting a role of GH therapy in COVID-19 patients with GH deficiency. • Increased vigilance should be paid to COVID-19 acromegaly patients, as normalizing GH levels might improve outcomes. • The proposed hypotheses of normalizing GH levels in COVID-19 acromegaly should encourage further studies in these patients.

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

Objective Most patients with childhood-onset growth hormone deficiency (CO-GHD) receive treatment with exogenous growth hormone (GH) to facilitate the attainment of their full potential adult height. Recent evidence suggests that continuing GH administration during the transition period between the end of linear growth and full adult maturity is necessary for proper body composition and bone and muscle health, and may also have beneficial effects on metabolic parameters, bone mineral density, and quality of life. The timing of this transition period coincides with the transfer of care from a pediatric to an adult endocrinologist, creating the potential for a care gap as a consequence of losing the patient to follow-up. Design An advisory board comprising both pediatric and adult endocrinologists was assembled to address current clinical unmet needs and to collaborate on a structured transitional plan for optimal management of patients with CO-GHD. Insights/conclusion The advisors suggest collaborative, multidisciplinary approaches to ensure continuity of care; ongoing testing and monitoring of GHD status into adulthood; and a clearly structured protocol that includes practical guidance for clinicians to establish best practices for transitioning older adolescents with persistent CO-GHD to adult care.

Objective: In December 2019, a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused an outbreak of coronavirus disease 2019 (COVID-19) that resulted in a global pandemic with substantial morbidity and mortality. Currently, there is no specific treatment or approved vaccine against COVID-19. The underlying associated comorbidity and diminished immune function of some pituitary patients (whether caused by the disease and its sequelae or treatment with excess glucocorticoids) increases their risk of contracting and developing complications from COVID-19 infection. Methods: A review of studies in PubMed and Google Scholar published between January 2020 to the time of writing (May 1, 2020) was conducted using the search terms ‘pituitary,’ ‘coronavirus,’ ‘COVID-19’, ‘2019-nCoV’, ‘diabetes mellitus’, ‘obesity’, ‘adrenal,’ and ‘endocrine.’ Results: Older age and pre-existing obesity, hypertension, cardiovascular disease, and diabetes mellitus increase the risk of hospitalization and death in COVID-19 patients. Men tend to be more severely affected than women; fortunately, most men, particularly of younger age, survive the infection. In addition to general comorbidities that may apply to many pituitary patients, they are also susceptible due to the following pituitary disorder–specific features: hypercortisolemia and adrenal suppression with Cushing disease, adrenal insufficiency and diabetes insipidus with hypopituitarism, and sleep-apnea syndrome and chest wall deformity with acromegaly. Conclusion: This review aims to focus on the impact of COVID-19 in patients with pituitary disorders. As most countries are implementing mobility restrictions, we also discuss how this pandemic has affected patient attitudes and impacted our decision-making on management recommendations for these patients. Abbreviations: ACE = angiotensin-converting enzyme; AI = adrenal insufficiency; ARB = angiotensin receptor blocker; ARDS = acute respiratory disease syndrome; COVID-19 = coronavirus disease 2019; CPAP = continuous positive airway pressure; DI = diabetes insipidus; DM = diabetes mellitus; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2

Background: Acromegaly (ACRO) is a rare, chronic disorder of growth hormone hypersecretion associated with increased morbidity that can affect work productivity. Data on ACRO employees’ health costs and work absenteeism are limited. Aims: To assess the impact of ACRO on employees’ health benefit costs and absenteeism. Methods: A US employee database of prescription (Rx) drug, medical claims, and absenteeism (payment and time) from Jan 2010 to Apr 2019 was analyzed. Employees with the diagnosis (Dx) of ACRO were identified based on claims with ICD-9/-10 codes 253.0x/E22.0. A 12 month study period followed each employee’s first ACRO Dx in the database (the index date). ACRO patients in the study had ≥ 2 ACRO Dxs > 30 days apart, or 1 ACRO Dx plus either a pituitary adenoma Dx or a pituitary surgery or radiosurgery claim during the study period. Controls were matched to each ACRO employee on demographic, job-related variables, region, and Charlson comorbidity index (CCI) score. Costs were adjusted using the general Consumer Price Index (CPI), medical CPI, and Rx cost CPI. Outcomes included direct costs (medical and Rx), indirect costs (absence payments by benefit type), and lost time (absences by benefit type). Outcomes were analyzed using two-part regression models (logistic followed by generalized linear) for each outcome, controlling for demographic and job-related variables, region, and CCI scores. Data are shown as likelihood or mean ± standard error. Findings are significant at P < 0.05. Results: Participants were 18–65 yr old with continuous eligibility for medical and Rx benefits for the study period. Forty seven ACRO patients and 940 controls were identified. ACRO employees were similar to the controls in most demographic (age, gender, race) and job-related variables (tenure, full-/part-time status, exempt status, salary), but had a higher CCI (0.60 ± 0.15 vs 0.30 ± 0.03; P = 0.029) and a higher incidence of chronic lung disease (31.9 vs 17.4%; P = 0.012), hyperlipidemia (27.7 vs 16.0%, P = 0.035), arthritis (19.1 vs 3.7%), diabetes (31.9 vs 8.3%), hypertension (40.4 vs 13.6%), and thyroid disease (31.9 vs 8.9%) (P < 0.0001). Patients with ACRO were 64.3% more likely to have undergone an MRI (P < 0.0001).Total indirect costs (including sick leave and disability) were higher for ACRO patients ($10,530 vs $1,157; P < 0.05) with both short-term and long-term disability comprising 96% of the difference. Compared with employees without ACRO, employees with ACRO used more short-term disability (10.9 vs 0.9 days; P = 0.0076) and had more total days absent from work (12.7 vs 3.3 days; P < 0.05). Conclusions: Our findings indicate that ACRO has far-reaching implications on direct and indirect employee health benefit costs and increased work absenteeism. Awareness by employers of ACRO-induced increased absenteeism is important to tailor working conditions and to prevent unrealistic work expectations.

Context Combination therapy with somatostatin receptor ligand (SRL) plus pegvisomant for patients with acromegaly is recommended after a maximizing dose on monotherapy. Lower-dose combination regimens are not well studied. Objective To compare cost-effectiveness and efficacy of 3 lower-dose combination regimens in controlled and uncontrolled acromegaly Design and Setting Prospective, randomized, open-label, parallel arm study at a tertiary referral pituitary center. Patients Adults with acromegaly regardless of response to prior SRL and biochemical control status at baseline, stratified by an SRL dose required for insulin-like growth factor (IGF)-I normalization during any 3-month period within 12 months preceding enrollment. Intervention Combination therapy for 24 to 32 weeks on arm A, high-dose SRL (lanreotide 120 mg/octreotide long-acting release [LAR] 30 mg) plus weekly pegvisomant (40-160 mg/week); arm B, low-dose SRL (lanreotide 60 mg/octreotide LAR 10 mg) plus weekly pegvisomant; or arm C, low-dose SRL plus daily pegvisomant (15-60 mg/day) Main Outcome Measure Monthly treatment cost in each arm in participants completing ≥ 24 weeks of therapy. Results Sixty patients were enrolled and 52 were evaluable. Fifty of 52 (96%) demonstrated IGF-I control regardless of prior SRL responsiveness (arm A, 14/15 [93.3%]; arm B, 22/23 [95.7%]; arm C, 14/14 [100%]). Arm B was least costly (mean, $9837 ± 1375 per month), arm C was most expensive (mean, $22543 ± 11158 per month), and arm A had an intermediate cost (mean, $14261 ± 1645 per month). Approximately 30% of patients required pegvisomant dose uptitration. Rates of adverse events were all Conclusions Low-dose SRL plus weekly pegvisomant represents a novel dosing option for achieving cost-effective, optimal biochemical control in patients with uncontrolled acromegaly requiring combination therapy.

Background: Acromegaly (ACRO) is a rare, chronic growth hormone hypersecretory disorder associated with increased morbidity and mortality. Limited information is available on the utilization and costs of healthcare by patients with ACRO. Aims: To assess the impact of ACRO healthcare utilization and costs by locations of care (LoC). Methods: A US database of prescription (Rx) drug and medical claims from Jan 2010 to Apr 2019 was analyzed. Patients with an ACRO diagnosis (Dx) were identified based on claims with ICD-9/-10 codes 253.0x/E22.0. The 12-month study period followed each patient’s first ACRO Dx in the database (the index date). ACRO patients included in the study had ≥ 2 ACRO Dxs > 30 days apart, or 1 ACRO Dx plus either a pituitary adenoma Dx or a pituitary surgery or radiosurgery claim during the study period. Costs were adjusted using the medical and Rx cost Consumer Price Indexes (CPIs). Study subjects were 18–65 yr old and had continuous eligibility during the study period. Eligible ACRO patients were matched with 20 subjects who did not have ACRO. Outcomes by LoC included costs, services, and likelihood of use and were compared using separate two-part regression models (logistic followed by generalized linear) for each outcome, controlling for demographic and job-related variables, region, and Charlson comorbidity index (CCI) scores. The likelihood models only used logistic regression. Data are shown as likelihoods or mean ± standard error. Findings are significant at P < 0.05. Results: A total of 60 patients with ACRO and 1200 controls were compared. Compared with controls, patients with ACRO had a higher likelihood of using the physician’s office (100% vs 91%, P < 0.0001), inpatient (22% vs 3%, P < 0.0005), outpatient (89% vs 38%, P < 0.0001), laboratory (62% vs 31%, P < 0.0001), and “other” locations (e.g., ambulance and claims without a specific location code, 55% vs 23%, P < 0.0001). Services performed at each LoC were higher for patients with ACRO (P < 0.01, all except outpatient hospital). Total costs were higher for the ACRO cohort compared with controls ($25,770 vs $4,059, P < 0.05). Costs by LoC were consistently higher (all reported P < 0.001) for patients with ACRO compared to controls, with differences highest in the following settings: outpatient hospital/clinic ($9,611 ± $1,793 vs $1,355 ± $74), inpatient ($8,646 ± $2,388 vs $739 ± $115), physicians’ office ($4,762 ± $678 vs $1,301 ± $43), other ($2,001 ± $583 vs $367 ± $29), and laboratory ($508 ± $93 vs $66 ± $4). Neither the costs nor likelihoods of treatment in the emergency department were significantly different between cohorts. Conclusions: Compared with commercially insured people without ACRO, patients with ACRO had greater health care utilization, in all care locations, indicating a greater burden and higher costs of ACRO patients on the healthcare system.

Background: Transition care of patients with childhood-onset GH deficiency (CO-GHD) who were treated with GH during childhood remains an ongoing challenge with substantial variation in coordination of care, clinical assessment, and management among pediatric and adult services. Despite the availability of clinical guidelines providing a framework for transition care of adolescents with CO-GHD, many patients discontinue therapy during the transition phase. Methods: A panel of pediatric and adult US endocrinologists with extensive experience in treating transition patients convened in October 2019 as part of an advisory board to address current clinical unmet needs and to share learnings based on a structured transitional plan to strive for optimal management of these patients. Results: It is acknowledged that pediatric endocrinologists play a crucial role in initiating the transition process, which involves close communication and direct collaboration between pediatric and adult services to reduce delays in identifying patients and resuming GH therapy in adulthood; adult endocrinologists need to increase their awareness of the importance of potential benefits and extent of long-term safety of GH therapy in adult patients. There is also a need for consensus guidelines or a white paper that focuses on transition care and endorsed by pediatric and adult organizations. Because not all patients with CO-GHD will have persistent GHD as adults, there is a need to improve the identification and timely retesting of those who will require continuity of GH therapy into adulthood. An increase in accessibility for retesting and guidance on appropriate GH dosing once persistent GHD is confirmed are other important factors. Certain subpopulations of pediatric patients (e.g., cancer survivors; patients with congenital hypopituitarism, optic nerve hypoplasia, treated sellar masses, and traumatic brain injury) should be prioritized in determinations of when and how retesting should be performed. The viewpoints of both pediatric and adult endocrinologists were presented at this meeting, and comprehensive considerations and suggestions were discussed. Conclusion: Transition care of patients with CO-GHD requires a collaborative multidisciplinary approach to ensure continuity of care between pediatric and adult services and to improve bone health and reduce long-term cardiometabolic risks. The major challenge is to effectively ensure that transition patients are retested and offered adult GH therapy without delay. Current guidelines should be more focused on transition patients, addressing key areas of uncertainty as evidenced by variable clinical practices. A clearly structured transition protocol is vital, and these insights provide useful, practical guidance to clinicians to establish best practices when transitioning adolescents with persistent CO-GHD to adult services.

To discuss the rationale of developing long-acting growth hormone (LAGH) preparations, to describe the technologies designed to prolong GH action, and to address key issues regarding efficacy, safety, and monitoring while on treatment.Recombinant human GH is currently approved for daily use and has been shown to restore longitudinal growth, and improve body composition with relatively few side-effects in children and adults with GH deficiency, respectively. However, daily injections can be inconvenient, painful and distressing for some patients, resulting in decreased adherence and efficacy. Over a dozen pharmaceutical companies have designed LAGH preparations that are at various stages of development using a number of different methods to prolong GH action.LAGH will represent an advancement over daily recombinant human GH injections because of fewer injections that may offer increased acceptance, tolerability, and therapeutic flexibility to patients that potentially can improve treatment outcomes. However, given the unphysiological profile of LAGH preparations, long-term surveillance of efficacy and safety are needed. This review summarizes recent developments of LAGH preparations, and highlights the importance of long-term surveillance registries to assess for efficacy and safety that will be essential for understanding the impact of prolonged exposure to these compounds.