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Shahid Akhtar,1 Birgitte Berg,2 Johan Medina,3 Maya Nicole Gonczi,4 Sophie Hamilton,5 Emily Hildebrand,4 Nicky Kelepouris,6 Jesper Skov Neergaard,7 Claus Sværke,8 Gitte Ter-Borch,2 Niklas Kahr Rasmussen3 1Devices & Digital Health, Novo Nordisk A/S, Søborg, Denmark; 2Clinical Operations, Obesity, Liver Diseases & Devices, Novo Nordisk A/S, Søborg, Denmark; 3Medical & Science, Devices & Digital Health, Novo Nordisk A/S, Søborg, Denmark; 4Human Factors, Research Collective, Tempe, AZ, USA; 5Rare Endocrine Rare Renal Diseases, Novo Nordisk Inc, Plainsboro, NJ, USA; 6Rare Endocrine Disorders, Novo Nordisk Inc, Plainsboro, NJ, USA; 7Safety Surveillance, Cardiovascular Disease, Novo Nordisk A/S, Søborg, Denmark; 8Global Development, Novo Nordisk A/S, Søborg, DenmarkCorrespondence: Shahid Akhtar, Medical & Science, Devices & Digital Health, Novo Nordisk A/S, Vandtårnsvej 108– 110, Søborg, DK-2860, Denmark, Email SAHT@novonordisk.comPurpose: Adherence to growth hormone treatment is known to affect growth outcomes. Both device preference and ease of use have been shown to affect treatment adherence. In this study, we assessed device preference and ease of use with two long-acting growth hormones, somapacitan (Sogroya®, Novo Nordisk A/S) and somatrogon (Ngenla®, Pfizer).Patients and Methods: In a randomized, crossover study conducted between September 20 and November 2, 2023, we recruited 33 adolescents with a growth-related disorder, and 37 caregivers, at six locations in the United States. Each participant was trained in the use of both devices and asked to perform a simulated injection. Device training time, preparation and injection time, and injection completeness were recorded. Participants also completed the Device Handling and Preference Questionnaire (DHPAQ) to indicate their device preference and ease of use opinions. Following conclusion of the “standard” visit, 10 adolescents and 10 caregivers were randomly selected to participate in a sub-study to validate the relevance, comprehensiveness, and comprehension of the DHPAQ.Results: The majority of participants (84.3%; 95% confidence interval [CI]: 74;92) preferred the somapacitan device to the somatrogon device (p

Kevin CJ Yuen,1 Lewis S Blevins,2 David R Clemmons,3 Mads Faurby,4 Andrew R Hoffman,5 Nicky Kelepouris,6 Janice M Kerr,7 Jens Magelund Tarp,4 Maria Fleseriu8 1Barrow Pituitary Center, Barrow Neurological Institute and St. Joseph’s Hospital and Medical Center, University of Arizona College of Medicine and Creighton School of Medicine, Phoenix, AZ, USA; 2Department of Neurosurgery, University of California, San Francisco, CA, USA; 3Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA; 4Global Evidence, Pricing and Access, Novo Nordisk A/S, Søborg, Denmark; 5Department of Medicine, Stanford University, Stanford, CA, USA; 6Department of Medical Affairs BioPharm, CMR, Novo Nordisk Inc., Plainsboro, NJ, USA; 7Department of Endocrinology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; 8Pituitary Center, Departments of Medicine and Neurological Surgery, Oregon Health and Science University, Portland, OR, USACorrespondence: Kevin CJ Yuen, Barrow Pituitary Center, Barrow Neurological Institute and St. Joseph’s Hospital and Medical Center, University of Arizona College of Medicine and Creighton School of Medicine, 475 N. 5th Street, Phoenix, AZ, 85004, USA, Tel +1 602 406-2748, Fax +1 602 406-2770, Email kevin.yuen@commonspirit.orgPurpose: Adult growth hormone deficiency (AGHD) is often underdiagnosed and undertreated, leading to costly comorbidities. Previously, we developed an algorithm to identify individuals in a commercially insured US population with high, moderate, or low likelihood of having AGHD. Here, we estimate and compare direct medical costs by likelihood level.Patients and Methods: Retrospective, observational analysis using the Truven Health MarketScan database to analyze direct medical costs relating to inpatient and outpatient claims, outpatient prescription claims, medication usage, clinical utilization records, and healthcare expenditures. Patients were categorized into groups based on algorithmically determined likelihoods of AGHD. Likelihood groups were further stratified by age and sex. Trajectories of annual costs (USD) by likelihood level were also investigated.Results: The study cohort comprised 135 million US adults (aged ≥ 18 years). Individuals ranked as high-likelihood AGHD had a greater burden of comorbid illness, including cardiovascular disease and diabetes, than those ranked moderate- or low-likelihood. Those in the high-likelihood group had greater mean total direct medical monthly costs ($1844.51 [95% confidence interval (CI): 1841.24;1847.78]) than those in the moderate- ($945.65 [95% CI: 945.26;946.04]) and low-likelihood groups ($459.10 [95% CI: 458.95;459.25]). Outpatient visits accounted for the majority of costs overall, although cost per visit was substantially lower than for inpatient services. Costs tended to increase with age and peaked around the time that individuals were assigned a level of AGHD likelihood. Total direct medical costs in individuals with a high likelihood of AGHD exceeded those for individuals with moderate or low likelihood.Conclusion: Understanding the trajectory of healthcare costs in AGHD may help rationalize allocation of healthcare resources.Plain Language Summary: Growth hormone is an important substance found in the body. Adult growth hormone deficiency (AGHD) is the reduced production of growth hormone unrelated to the normal reduction seen with aging. Untreated AGHD can result in the development of other conditions, known as comorbidities, which can be expensive to manage.Previously, 135 million privately insured people in the US, aged 18– 64 years, were categorized into groups by their likelihood (high, medium, or low) of having AGHD. This study compared the estimated direct medical costs (eg hospital care and medication) across the different likelihood levels. People with a high likelihood of AGHD had more comorbidities than people with a medium/low likelihood, and an average total direct medical monthly cost of $1844.51, nearly twice as much as those with a medium likelihood ($945.65), and four times as much as those with a low likelihood ($459.10). These costs tended to increase with age, with the highest costs associated with people aged 50– 59 years and 60– 64 years. Outpatient costs (for treatments not requiring an overnight hospital stay) accounted for the greatest proportion of total medical costs, ahead of inpatient costs (for treatments requiring an overnight hospital stay) and medication costs.These findings suggest that diagnosing and treating AGHD earlier may help to reduce medical costs over time. Increased testing and treatment will cause an initial increase in the use of healthcare resources, but could improve overall cost effectiveness by reducing the long-term impact of the disease and avoiding unnecessary healthcare use. Keywords: AGHD, cost of comorbidities, cost of disease, likelihood of AGHD, medical costs, Truven Health MarketScan database

Summary: Findings from this 5-year phase 3 study of postmenopausal women with osteoporosis showed that bazedoxifene was associated with an overall favorable safety and tolerability profile, with no evidence of endometrial or breast stimulation. Overall, the results at 5 years were consistent with those seen at 3 years. Introduction: We report safety and tolerability findings from a 5-year randomized, double-blind, phase 3 study of bazedoxifene in postmenopausal women with osteoporosis. Methods: In the core study, healthy postmenopausal women with osteoporosis ( N = 7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. During the 2-year study extension, the raloxifene 60-mg treatment arm was discontinued after the 3-year database was finalized, and subjects receiving bazedoxifene 40 mg were transitioned in a blinded manner to bazedoxifene 20 mg (bazedoxifene 40-/20-mg group) after 4 years. Safety and tolerability data are reported for subjects in the bazedoxifene 20- and 40-/20-mg and placebo groups; efficacy findings are reported elsewhere. Results: A total of 3,146 subjects in the bazedoxifene 20- and 40-mg and placebo groups were enrolled in the extension study (years 4 and 5). Overall, the 5-year incidence of adverse events (AEs), serious AEs, and discontinuations due to AEs were similar among groups. The incidence of hot flushes and leg cramps was higher with bazedoxifene compared with placebo. Venous thromboembolic events, primarily deep vein thrombosis, were more frequently reported in the bazedoxifene groups compared with the placebo group. Reports of cardiac disorders and cerebrovascular events were few and evenly distributed among groups. Bazedoxifene showed a neutral effect on the breast and endometrium. Conclusion: Bazedoxifene was associated with an overall favorable safety and tolerability profile in postmenopausal women with osteoporosis over 5 years of therapy, consistent with findings at 3 years. [ABSTRACT FROM AUTHOR]

Introduction: Children with idiopathic short stature (ISS) are known to have varying responses to growth hormone (GH) treatment (GHT)., Methods: We conducted a post hoc analysis to identify clinical characteristics predictive of good and poor response during year 1 of GHT. Data from the NordiNet® IOS (NCT00960128) and the ANSWER Program (NCT01009905) were used. Patients were grouped according to their response to GHT; good, middle, and poor responders had a change in HSDS of >1.0, 0.4-1.0, and <0.4, respectively. Patients were also grouped according to their responsiveness to GH dose. Logistic regression modelling was performed to identify clinical characteristics predictive of response to GHT., Results: The response analysis set included 207 patients. Patients were 3-11 years old (males) or 3-10 years old (females) at the start of treatment and were prepubertal throughout year 1 of treatment. Age at the start of treatment (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.5; 0.9, p = 0.0169) and distance from target HSDS (OR: 2.05, 95% CI: 1.1; 3.9, p = 0.0259) were found to be significant independent predictors of being in the good- versus poor-response groups. When patients were grouped according to their responsiveness to GH dose, a positive correlation between GH dose and change in HSDS was observed., Conclusion: We identified younger age and further distance from target HSDS as clinical predictors of response to GHT in a heterogenous population of children with ISS. Future studies, designed to identify the genetic determinants of response to GHT, could further facilitate individualisation of GHT., (© 2025 The Author(s). Published by S. Karger AG, Basel.)

Childhood growth hormone deficiency (GHD) is a rare disorder associated with significant burden on both patients and caregivers. Although previous reports have detailed aspects of the burden experienced by patients and their caregivers, there is a paucity of first-hand information on the patient and caregiver journeys from their respective voices. To address this need, an advisory board meeting was conducted on September 30, 2022, with 4 pediatric patients with GHD and their caregivers to discuss their experiences prior to GHD diagnosis, during the diagnostic process, and during ongoing treatment with recombinant growth hormone. Feedback from patients and caregivers was reviewed by pediatric endocrinologists, who provided their own perspectives on the patient and caregiver journeys based on the information reported. Despite the small sample size, important insights were obtained: patients and caregivers reported remarkable growth benefits achieved with treatment, which provided strong motivation to remain adherent to daily injection regimens. Patient and caregiver accounts reflected wide variability between families in time from suspicion to diagnosis and in treatment challenges faced, ranging from practical issues such as handling and administration of medication to broader concerns about treatment access and continuity, as well as key knowledge gaps among patients, caregivers, and clinicians. Recommendations are provided to enhance the patient and caregiver journeys, including increasing development and availability of educational materials, providing opportunities for patient advocacy by clinicians and health care providers, and encouraging institutional improvements to ensure that patients continue to receive uninterrupted treatment during their critical period of growth., Competing Interests: Declaration of competing interest BSM is a consultant for Ascendis Pharma, BioMarin, Bristol Myers Squibb, EMD Serono, Endo Pharmaceuticals, Novo Nordisk, Orchard Therapeutics, Pfizer, Provention Bio, and Tolmar and has received research support from Alexion, AbbVie, Aeterna Zentaris, Amgen, Amicus, Lumos Pharma, Lysogene, Novo Nordisk, OPKO Health, Pfizer, Prevail Therapeutics, and Sangamo Therapeutics. NK is an employee of Novo Nordisk Inc. PB has received research funding from and has been an advisor for Novo Nordisk. HT and SDC are caregiver authors who provided accurate feedback according to their knowledge and experience., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Children with growth hormone deficiency (GHD) face multiple challenges that can negatively impact the transition from pediatric to adult endocrinology care. For children with GHD resulting from brain cancer or its treatment, the involvement of oncology care providers and possible disease-related comorbidities add further complexity to this transition., Design: An advisory board of pediatric and adult endocrinologists was convened to help better understand the unique challenges faced by childhood cancer survivors with GHD, and discuss recommendations to optimize continuity of care as these patients proceed to adulthood. Topics included the benefits and risks of growth hormone (GH) therapy in cancer survivors, the importance of initiating GH replacement therapy early in the patient's journey and continuing into adulthood, and the obstacles that can limit an effective transition to adult care for these patients., Results/conclusions: Some identified obstacles included the need to prioritize cancer treatment over treatment for GHD, a lack of patient and oncologist knowledge about the full range of benefits provided by long-term GH administration, concerns about tumor recurrence risk in cancer survivors receiving GH treatment, and suboptimal communication and coordination (e.g., referrals) between care providers, all of which could potentially result in treatment gaps or even complete loss of follow-up during the care transition. Advisors provided recommendations for increasing education for patients and care providers and improving coordination between treatment team members, both of which are intended to help improve continuity of care to maximize the health benefits of GH administration during the critical period when childhood cancer survivors transition into adulthood., Competing Interests: Declaration of competing interest CA served as an advisory board member for Novo Nordisk and Pfizer, an advisor for Tolmar, and a Safety Monitor for OPKO Health. MB served as an occasional advisory board member for Novo Nordisk and Pfizer. DC served as a consultant for Novo Nordisk and Crinetics, Inc. GD served as an advisory board member for Corcept, Novo Nordisk, Pfizer, Recordati, and Strongbridge. MG served on advisory boards for Adrenas, Eton Pharmaceuticals, Neurocrine Biosciences, Novo Nordisk, and Pfizer; is performing clinical trials with Adrenas, Diurnal, Neurocrine Biosciences, Novo Nordisk, and Spruce Biosciences; is a consultant to Crinetics and Spruce Biosciences; is a clinical trial adjudicator for Aeterna Zentaris; has been a member of the data and safety monitoring board for Ascendis; receives royalties from McGraw-Hill and UpToDate; and has been a speaker for Pfizer. NK and RO are employees of Novo Nordisk Inc. BSM is a consultant for Ascendis Pharma, BioMarin, Bristol Myers Squibb, EMD Serono, Endo Pharmaceuticals, Novo Nordisk, Orchard Therapeutics, Pfizer, Provention Bio, and Tolmar and has received research support from Alexion, AbbVie, Aeterna Zentaris, Amgen, Amicus, Lumos Pharma, Lysogene, Novo Nordisk, OPKO Health, Pfizer, Prevail Therapeutics, and Sangamo Therapeutics. HS has received research support from Dexcom, Boehringer-Ingelheim, Novartis, Novo Nordisk, Lilly, Soleno, and Rhythm Pharmaceutical; has participated in advisory boards for Novo Nordisk and Ascendis; and is a current speaker for Novo Nordisk, Ascendis and Rhythm Pharmaceuticals. KCJY has received research grants to Barrow Neurological Institute from Ascendis, Corcept, Crinetics, and Amryt; served as an occasional advisory board member for Novo Nordisk, Ascendis, Sandoz, Corcept, Ipsen, Amryt, Strongbridge, Crinetics, Xeris, and Recordati; and served as an occasional speaker for Recordati, Novo Nordisk, and Corcept., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Hypopituitarism, including growth hormone deficiency (GHD), is a common sequela of traumatic brain injury (TBI). This study explored the coverage of education and training of TBI-induced hypopituitarism in general and GHD in particular, in postgraduate program curricula to identify knowledge gaps and opportunities., Methods: An online survey and qualitative interviews (focus groups) were conducted among endocrinology, neurology, and physiatry postgraduate program directors in the United States (US). The study received an IRB exemption., Results: A total of 419 fellowship and residency programs were invited to participate; 60 program directors completed the survey and 11 of these participated in the focus groups. About half of the respondents considered TBI-induced hypopituitarism important or fairly important to include in the curriculum, and nearly two-thirds considered it an appropriate training component. Neurology program directors considered education regarding hypopituitarism following TBI less important and relevant for their curricula compared with endocrinology and physiatry program directors. About half (53%) of the programs responded that they included TBI-induced pituitary disorders in their curricula. About two-thirds (68%) of endocrinology programs, compared with only one-quarter (25%) of neurology programs, covered TBI-induced pituitary disorders. Respondents identified multiple barriers to expanding hypopituitarism following TBI in the curriculum, including the rarity of condition and lack of time/room in the curriculum. Respondents reported that consensus clinical guidelines and the availability of more data on TBI-induced hypopituitarism, including GHD, would greatly impact the development of educational curricula on this topic., Conclusions: To improve the management of TBI-induced hypopituitarism, education and training should be expanded in US fellowship and residency programs to prepare trainees to effectively screen, diagnose, and treat TBI-induced hypopituitarism, including GHD., (© 2024. The Author(s).)

Context: Despite having normal growth hormone (GH) secretion, individuals with Turner syndrome (TS) have short stature. Treatment with recombinant human GH is recommended for TS girls with short stature., Objective: This work aimed to evaluate the effectiveness and safety of Norditropin (somatropin, Novo Nordisk) with up to 10 years of follow-up in children with TS., Methods: Secondary analysis was conducted of Norditropin data from 2 non-interventional studies: NordiNet® IOS (NCT00960128) and the ANSWER program (NCT01009905)., Results: A total of 2377 girls with TS were included in the safety analysis set (SAS), with 1513 in the treatment-naive effectiveness analysis set (EAS). At the start of treatment, 1273 (84%) participants were prepubertal (EAS); mean (SD) age was 8.8 (3.9) years. Mean (SD) dose received at the start of GH treatment was 0.045 (0.011) mg/kg/day (EAS). Mean (SD) baseline insulin-like growth factor-1 (IGF-I) SD score (SDS) was -0.86 (1.52), and mean (SD) duration of GH treatment (SAS) was 3.8 (2.8) years.Height SDS (HSDS) increased throughout follow-up, with near-adult HSDS reached by 264 (17%) participants (mean [SD] -1.99 [0.94]; change from baseline +0.90 [0.85]). During the study, 695 (46%) participants (EAS) entered puberty at a mean (SD) age of 12.7 (1.9) years (whether puberty was spontaneous or induced was unknown). Within the SAS, mean IGF-I SDS (SD) at year 10 was 0.91 (1.69); change from baseline +1.48 (1.70). Serious adverse reactions were reported in 10 participants (epiphysiolysis [n = 3])., Conclusion: GH-treated participants with TS responded well, without new safety concerns. Our real-world data are in agreement with previous studies., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Effectiveness and safety data on GH replacement therapy (GHRT) in older adults with adult GH deficiency (AGHD) are limited., Objective: To compare GHRT safety and clinical outcomes in older (≥60 years and, for some outcomes, ≥75 years) and middle-aged (35-<60 years) patients with AGHD., Design/setting: Ten-year follow-up, real-world data from 2 large noninterventional studies-NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program-were analyzed., Patients: GH-naïve and non-naïve patients with AGHD., Intervention: Norditropin® (somatropin)., Main Outcome Measures: Outcomes included GH exposure, IGF-I standard deviation scores (SDS), body mass index (BMI), glycated hemoglobin (HbA 1c ), serious and nonserious adverse reactions (SARs and NSARs, respectively), and serious adverse events (SAEs). Adverse reactions were events with possible/probable causal relationship to GHRT., Results: The effectiveness analysis set comprised 545 middle-aged and 214 older patients (19 aged ≥75 years) from NordiNet® IOS. The full analysis set comprised 1696 middle-aged and 652 older patients (59 aged ≥75 years) from both studies. Mean GH doses were higher in middle-aged vs older patients. For both age groups and sexes, mean IGF-I SDS increased following GHRT, while BMI and HbA 1c changes were similar and small.Incidence rate ratios (IRRs) did not differ statistically between older and middle-aged patients for NSARs [IRR (mean, 95% confidence interval) 1.05 (.60; 1.83)] or SARs [.40 (.12; 1.32)]. SAEs were more frequent in older than middle-aged patients [IRR 1.84 (1.29; 2.62)]., Conclusion: Clinical outcomes of GHRT in AGHD were similar in middle-aged and older patients, with no significantly increased risk of GHRT-related adverse reactions in older patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Early initiation of growth hormone (GH) therapy is recommended for short children born small for gestational age (SGA); however, real-world data indicate that treatment is often delayed., Objective: We aimed to assess the impact of patient age at GH therapy initiation on long-term growth outcomes and safety in short children born SGA., Methods: Analysis of pooled data from NordiNet® International Outcome Study (NCT00960128; 469 European clinics) and the ANSWER Program (NCT01009905; 207 US clinics), two large, complementary observational studies. Patients received GH as prescribed by their treating physician. Enrolled patients born SGA were categorized into three groups based on their age at GH treatment initiation: 2 to <4 years, 4 to <6 years, and ≥6 years. Patient characteristics at birth and GH initiation, auxology, and safety data were evaluated., Results: The effectiveness analysis (treatment-naïve and prepubertal patients at GH initiation) included 3318 patients: 10.7% aged 2 to <4 years at therapy initiation, 31.6% aged 4 to <6 years, and 57.7% aged ≥6 years. Following 8 years of therapy, the mean improvement in height standard deviation score from baseline was significantly greater in the 2 to <4 years group vs the 4 to <6 years (+2.5 vs +2.2; P = 0.0054) and ≥6 years groups (+2.5 vs +1.7; P < 0.0001). No unexpected safety events were reported., Conclusion: Early initiation of GH therapy in short children born SGA may be an important contributor to height optimization. The data are reassuring regarding the long-term safety of GH therapy in this population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Growth hormone (GH) therapy can increase linear growth in patients with growth hormone deficiency (GHD), Turner syndrome (TS), Noonan syndrome (NS), and Prader-Willi syndrome (PWS), although outcomes vary by disease state., Objective: To assess growth and identify factors associated with growth response with long-term GH therapy., Methods: Data from pediatric patients with GHD, TS, NS, and PWS obtained at GH treatment initiation (baseline) and annually for 5 years in the ANSWER Program and NordiNet® IOS were analyzed retrospectively. Height standard deviation score (HSDS) was assessed over time, and multivariate analyses determined variables with significant positive effects on growth outcomes in each patient cohort., Results: Data from patients with GHD (n = 12 683), TS (n = 1307), NS (n = 203), and PWS (n = 102) were analyzed. HSDS increased over time during GH treatment in all cohorts. Factors with significant positive effects on Δ HSDS were younger age at GH initiation and lower HSDS at baseline (all cohorts) and higher GH dose (GHD and TS only); sex had no effect in any cohort. The modeling analysis showed that Δ HSDS was greatest in year 1 and attenuated over consecutive years through year 5. Estimated least-squares mean Δ HSDS values at year 5 by cohort were 1.702 (females) and 1.586 (males) in GHD, 1.033 in TS, 1.153 in NS, and 1.392 in PWS., Conclusion: Long-term GH therapy results in large increases in HSDS in patients with GHD, TS, NS, and PWS. Greater gains in HSDS can be obtained with higher GH doses and earlier initiation of treatment., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Adult growth hormone deficiency (AGHD) is associated with an increased risk of cardiovascular (CV) disease. Long-term growth hormone (GH) treatment could improve CV outcomes. The objective of this study was to evaluate CV disease risk in patients with AGHD who received GH replacement therapy for up to 10 years as part of NordiNet® IOS (NCT00960128) and the ANSWER Program (NCT01009905). The studies were observational, non-interventional and multicentre, monitoring long-term effectiveness and safety of GH treatment. NordiNet® IOS involved 23 countries (469 sites) across Europe and the Middle East. The ANSWER Program was conducted in the USA (207 sites). This analysis included patients aged 18-75 years who were GH naïve at study entry, who had ≤10 years of GH treatment data and who could be assessed for CV risk for at least 1 follow-up year. The main outcome measure was risk of CV disease by age 75 years, as calculated with the Multinational Cardiovascular Risk Consortium model (Brunner score) using non-high-density lipoprotein cholesterol adjusted for age, sex and CV risk factors. The results of this analysis showed that CV risk decreased gradually over the 10-year period for GH-treated patients. The risk was lower for patients treated for 2 and 7 years vs age- and sex-matched control groups (not yet started treatment) (14.51% vs 16.15%; P = 0.0105 and 13.53% vs 16.81%; P = 0.0001, respectively). This suggests that GH treatment in people with AGHD may reduce the risk of CV disease by age 75 years compared with matched controls.

Objective/design: Approximately 2.9 million children and adults in the US experience traumatic brain injuries (TBIs) annually, most of which are considered mild. TBI can induce varying consequences on pituitary function, with growth hormone deficiency (GHD) among the more commonly reported conditions. Panels of pediatric and adult endocrinologists, neurologists, physical medicine and rehabilitation specialists, and neuropsychologists convened in February and October 2020 to discuss ongoing challenges and provide strategies for detection and optimal management of patients with mild TBI and GHD., Results: Difficulties include a low rate of seeking medical attention in the population, suboptimal screening tools, cost and complexity of GHD testing, and a lack of consensus regarding when to test or retest for GHD. Additionally, referrals to endocrinologists from other specialists are uncommon. Recommendations from the panels for managing such patients included multidisciplinary guidelines on the diagnosis and management of post-TBI GHD and additional education on long-term metabolic and probable cognitive benefits of GH replacement therapy., Conclusion: As patients of all ages with mild TBI may develop GHD and/or other pituitary deficiencies, a multidisciplinary approach to provide education to endocrinologists, neurologists, neurosurgeons, traumatologists, and other providers and guidelines for the early identification and management of persistent mild TBI-related GHD are urgently needed., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: KCJY has received research grants to Barrow Neurological Institute from Ascendis and has served on advisory boards for Ascendis, Pfizer, Sandoz, and Novo Nordisk. ACB, NK, TS, and JMT are employees of Novo Nordisk. LSB declares no conflicts of interest. DRC served as a consultant for Pfizer and Novo Nordisk. ARH has served on advisory boards for Novo Nordisk. ARH conducted this research as part of a personal outside consulting arrangement with Novo Nordisk. The research and research results are not, in any way, associated with Stanford University. JMK has no potential conflicts of interest to report. MF has received research support as principal investigator to OHSU from Ascendis and has been a scientific consultant to Ascendis, Novo Nordisk, and Pfizer., (Copyright © 2022 Kevin C. J. Yuen et al.)

Adult growth hormone deficiency (AGHD) is a rare and serious condition associated with significant morbidity, including reduced quality of life, and is underdiagnosed and often missed in patients. Although the onset of AGHD can occur in either childhood or adulthood, adult-onset AGHD is more difficult to identify as it lacks the auxologic signs caused by GHD during childhood, includes symptoms that tend to be nonspecific, and lacks reliable, simple biomarker testing options. A panel of 9 patients with AGHD (3 with childhood onset; 6 with adult onset) was assembled to share their first-hand experiences, to help reveal important areas of need, increase health literacy, and to raise awareness about GHD among patients, caregivers, and healthcare practitioners. Interviews with patients yielded valuable insights from the patient perspective to supplement prior knowledge about AGHD symptomatology, biomarker testing, and treatment outcomes. Some patients described a burdensome and ineffective screening process that sometimes included many visits to different specialists, repeated rounds of biomarker testing, and, in some cases, excessive delays in AGHD diagnosis. All patients expressed frustration with insurance companies that often resist and/or delay treatment authorization and reimbursement and frequently require additional testing to verify the diagnosis, often leading to treatment gaps. These findings emphasize the necessity of more efficient identification and screening of patients with possible AGHD, better recognition by clinicians and insurance providers of the importance of sustained GH replacement therapy during adulthood, and better patient support for accessing and maintaining uninterrupted GH replacement therapy for patients with documented AGHD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Mutations in PTPN11 are associated with Noonan syndrome (NS). Although the effectiveness of growth hormone therapy (GHT) in treating short stature due to NS has been previously demonstrated, the effect of PTPN11 mutation status on the long-term outcomes of GHT remains to be elucidated., Methods: This analysis included pooled data from the observational American Norditropin Studies: Web-Enabled Research Program (NCT01009905) and the randomized, double-blinded GHLIQUID-4020 clinical trial (NCT01927861). Pediatric patients with clinically diagnosed NS and confirmed PTPN11mutation status were eligible for inclusion. The effectiveness analysis included patients who were GHT-naïve and pre-pubertal at GHT start. Growth outcomes and safety were assessed over 4 years of GHT (Norditropin®, Novo Nordisk A/S)., Results: A total of 69 patients were included in the effectiveness analysis (71% PTPN11 positive). The proportion of females was 32.7 and 30.0% in PTPN11-positive and negative patients, respectively, and mean age at GHT start was 6.4 years in both groups. Using general population reference data, after 4 years of GHT, the mean (s.d.) height SD score (HSDS) was -1.9 (1.1) and -1.7 (0.8) for PTPN11-positive and PTPN11-negative patients, respectively, with no statistical difference observed between groups. The mean (s.d.) change in HSDS at 4 years was +1.3 (0.8) in PTPN11-positive patients and +1.5 (0.7) in PTPN11-negative patients (no significant differences between groups). Safety findings were consistent with previous analyses., Conclusions: GHT resulted in improved growth outcomes over 4 years in GHT-naïve, pre-pubertal NS patients, irrespective of PTPN11 mutation status.

Objective: The study aims to assess the cardiovascular safety of growth hormone (GH) treatment in patients with Noonan syndrome (NS) in clinical practice., Design: The study design involves two observational, multicentre studies (NordiNet® IOS and the ANSWER Program) evaluating the long-term effectiveness and safety of GH in >38,000 paediatric patients, of which 421 had NS., Methods: Serious adverse events, serious adverse reactions (SARs) and non-serious adverse reactions (NSARs) were reported by the treating physicians. Cardiovascular comorbidities at baseline and throughout the studies were also recorded., Results: The safety analysis set comprised 412 children with NS (29.1% females), with a mean (s.d.) baseline age of 9.29 (3.88) years, treated with an average GH dose of 0.047 (0.014) mg/kg/day during childhood. Cardiovascular comorbidities at baseline were reported in 48 (11.7%), most commonly pulmonary valve stenosis (PVS) and atrial septal defects. Overall, 22 (5.3%) patients experienced 34 safety events. The most common were the NSARs: headache (eight events in seven patients) and arthralgia (five events in three patients). Two SARs occurred in one patient (brain neoplasm and metastases to spine). No cardiovascular safety events were recorded in patients with NS. Five cardiovascular comorbidities in five patients were reported after initiation of GH treatment: three cases of unspecified cardiovascular disease, one ruptured abdominal aortic aneurysm and one PVS., Conclusions: GH treatment had a favourable safety profile in patients with NS, including those with cardiovascular comorbidities. Prospective studies are warranted to systematically assess the safety of GH treatment in patients with NS and cardiovascular disease.

Purpose: Data on the safety of growth hormone (GH) replacement therapy during pregnancy are limited. We report a combined analysis of data from pregnant women treated with GH while enrolled in two non-interventional, multicenter studies: NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program., Methods: Pregnancy data were pooled from NordiNet® IOS and the ANSWER Program. Data were collected during routine clinic visits by participating physicians using a web-based system. Patients exposed to GH replacement therapy during pregnancy were included in the analysis., Results: The study population included 40 female patients with typical causes of adult GH deficiency (GHD). Overall, there were 54 pregnancies. Of these, 47 were exposed to GH between conception and delivery. In 48.9% of pregnancies exposed to GH, the dose was > 0.6 mg/day. GH was continued past conception and then stopped during the first, second, and third trimester, in 27.7%, 17.0%, and 2.1% of pregnancies, respectively. In 29.8%, GH was continued throughout pregnancy, with an unchanged dose in most cases. Of the 47 GH-exposed pregnancies, 37 (78.7%) progressed to normal delivery. There were three adverse events reported in two pregnancies., Conclusion: These real-world data suggest that there were no new safety signals related to GH exposure in women with GHD during pregnancy. These results are consistent with findings from previous studies reporting data in pregnancies exposed to GH at conception or throughout pregnancy. This observational study in additional pregnancies provides further evidence that GH exposure does not adversely affect pregnancy outcome., Clinical Trial Registration: ClinicalTrials.gov NCT00960128 (date of registration: August 13, 2009) and NCT01009905 (date of registration: November 5, 2009)., (© 2021. The Author(s).)

Context: Growth hormone (GH) treatment has a generally good safety profile; however, concerns about increased mortality risk in adulthood have been raised., Objective: This work aims to assess the long-term safety of GH treatment in clinical practice., Methods: Data were collected from 676 clinics participating in 2 multicenter longitudinal observational studies: the NordiNet International Outcome Study (2006-2016, Europe) and ANSWER Program (2002-2016, USA). Pediatric patients treated with GH were classified into 3 risk groups based on diagnosis. Intervention consisted of daily GH treatment, and main outcome measures included incidence rates (events/1000 patient-years) of adverse drug reactions (ADRs), serious adverse events (SAEs), and serious ADRs, and their relationship to GH dose., Results: The combined studies comprised 37 702 patients (68.4% in low-risk, 27.5% in intermediate-risk, and 4.1% in high-risk groups) and 130 476 patient-years of exposure. The low-risk group included children born small for gestational age (SGA; 20.7%) and non-SGA children (eg, with GH deficiency; 79.3%). Average GH dose up to the first adverse event (AE) decreased with increasing risk category. Patients without AEs received higher average GH doses than patients with more than one AE across all groups. A significant inverse relationship with GH dose was shown for ADR and SAE incidence rates in the low-risk group (P = .003 and P = .001, respectively) and the non-SGA subgroup (both P = .002), and for SAEs in the intermediate- and high-risk groups (P = .002 and P = .05, respectively)., Conclusions: We observed no indication of increased mortality risk nor AE incidence related to GH dose in any risk group. A short visual summary of our work is available (1)., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Macimorelin is an orally active growth hormone secretagogue indicated for the diagnosis of adult growth hormone deficiency. The primary objective of this study was to evaluate the effect of macimorelin on the baseline and placebo-corrected mean QT interval using Fridericia's formula (ΔΔQTcF). Secondary objectives were to determine QTcF for moxifloxacin; evaluate the effects of macimorelin on other cardiac intervals (PR, QRS, RR), heart rate, and electrocardiogram morphology parameters; characterize pharmacokinetics; and assess safety of macimorelin. The phase 1 thorough QT/QTc study, designed according to the International Council for Harmonisation E14 guideline, was a randomized, placebo-controlled, double-blind, 3-way complete crossover study comparing the effect of macimorelin 2.0 mg/kg with placebo and moxifloxacin 400 mg (positive control). Data were collected over a 3-month span from male (n=36) and female participants (n=24) aged 18 to 55 years with body mass index between 18.5 and 30.0 kg/m 2 . Fifty-six participants received all 3 treatments. The ΔΔQTcF for macimorelin showed a prolongation with a maximum mean value of 9.61 milliseconds (2-sided 90% confidence interval, 7.81 milliseconds and 11.41 milliseconds) at 4 hours after dosing. The 2-sided 90% confidence interval of this value also exceeded the 10 millisecond threshold at 3 hours after dosing. Assay sensitivity was confirmed with moxifloxacin. Other electrocardiogram parameters evaluated were not influenced by macimorelin. Macimorelin did not raise other safety concerns and was well tolerated. In summary, a single supratherapeutic dose of macimorelin prolonged cardiac repolarization according to the regulatory guideline., (© 2020 GlaxoSmithKline. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

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., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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 <37 kg/m2 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%).

Background: Growth hormone (GH) deficiency is common in patients with Prader-Willi syndrome (PWS) and leads to short adult stature. The current study assessed clinical outcomes based on real-world observational data in pediatric patients with PWS who were treated with GH., Methods: Data from patients previously naïve to treatment with GH who began therapy with somatropin were collected from 2006 to 2016 in the observational American Norditropin® Studies: Web-Enabled Research (ANSWER) Program® and NordiNet® International Outcome Study. Variables affecting change from baseline in height standard deviation scores (HSDS; n = 129) and body mass index standard deviation scores (BMI SDS; n = 98) were determined., Results: Patients included in both HSDS and BMI SDS analyses were treated with a mean GH dose of 0.03 mg/kg/d (SD, 0.01 mg/kg/d). Results from the HSDS analysis revealed that baseline age and years on treatment had a significant impact on the change in HSDS. In the BMI SDS analysis, longer GH treatment time led to a greater change in BMI SDS from baseline, and patients with a higher BMI at the start of treatment had a greater decrease in BMI over time., Conclusions: GH is effective in the management of children with PWS. Earlier treatment resulted in a greater gain in height, and a longer treatment period resulted in better outcomes for both height and BMI., Trial Registration: This study was registered with ClinicalTrials.gov ( NCT01009905 ) on November 9, 2009.

Objective: Macimorelin is an orally active ghrelin receptor agonist indicated for the diagnosis of adult growth hormone (GH) deficiency in the United States. This phase 1 study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of macimorelin (including a supratherapeutic dose to be used in a thorough QT trial) in healthy adults., Design: Participants were randomized to receive macimorelin 0.5, 1.0, or 2.0 mg/kg or placebo in 1 of 3 sequential ascending-dose cohorts. Blood samples for pharmacokinetic and pharmacodynamic assays were collected pre-dose and at specified time points over a 24-h period. Pharmacokinetic parameters assessed included area under the concentration-time curve (AUC), maximum concentration (C max ) of macimorelin in plasma, time to C max (t max ), and terminal elimination half-life (t 1/2 ). Pharmacodynamic assessments evaluated levels of GH, adrenocorticotropic hormone, thyroid-stimulating hormone, cortisol, and prolactin. Safety was assessed based on treatment-emergent adverse events (TEAEs), vital signs, 12‑lead electrocardiograms, and laboratory parameters., Results: A total of 28 healthy adults were enrolled and completed the study. Macimorelin AUC and C max showed less than dose-proportional increases following administration of 0.5 and 1.0 mg/kg. Mean t 1/2 was 3.51 h for macimorelin 0.5 and 1.0 mg/kg and 8.29 h for macimorelin 2.0 mg/kg; median t max occurred at 0.5 to 0.75 h. GH levels increased after dosing, with a t max of 0.75 h to 1.0 h. Mean GH C max was similar with the macimorelin 0.5- and 1.0-mg/kg doses (31.9 and 37.8 ng/mL, respectively) and was ~50% lower with macimorelin 2.0 mg/kg (18.4 ng/mL). Transient increases were observed in adrenocorticotropic hormone, cortisol, and prolactin, which were not dose related. A total of 19 TEAEs were reported in 35.7% (10/28) of participants; all TEAEs were mild or moderate and resolved. A total of 12 drug-related TEAEs were reported in 8 participants. Headache was the most common drug-related TEAE. All doses of macimorelin prolonged mean QTcF by 10 to 11 ms. There were no clinically meaningful changes in vital signs or laboratory parameters., Conclusions: Single-dose administration of macimorelin 0.5 to 2.0 mg/kg was well tolerated. Macimorelin exposure was less than dose-proportional over the dose range studied. Administration of macimorelin stimulated GH production, with the greatest increases observed in the macimorelin 0.5- and 1.0-mg/kg groups., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RS and NA are employees of Aeterna Zentaris GmbH, and NK and VO are employees of Novo Nordisk, Inc., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To examine all-cause mortality rates in patients with acromegaly on pegvisomant and identify pertinent risk factors, including insulin-like growth factor I (IGF-I)., Design: Retrospective cohort analysis of data from ACROSTUDY (global surveillance study of patients with acromegaly treated with pegvisomant)., Methods: Kaplan-Meier analyses and Cox regression techniques were used to examine survival rates. Standardized mortality ratios (SMR) with reference to general population (WHO GBD 2016) were estimated. Multiplicative multiple Poisson regression models were used to characterize the association between SMR, IGF-I, and other risk factors associated with mortality risk., Results: The study consisted of 2077 subjects who were followed for a median interval of 4.1 years, contributing to 8957 patient-years. Higher on-treatment IGF-I (P = 0.0035), older attained age (P < 0.0001), and longer duration of acromegaly (>10 years) before starting pegvisomant (P = 0.05) were associated with higher mortality rates. In reference to general population rates, higher SMR (1.10, 1.42, and 2.62, at attained age 55 years) were observed with higher serum IGF-I category (SMR trend: 1.44 (44%)/per fold level of IGF-I/ULN (95% CI: 1.10, 1.87), P = 0.0075). SMR increased per year of younger attained age (1.04 (1.02-1.04), P < 0.0001) and were higher for longer disease duration (>10 years) before starting pegvisomant (1.57 (1.02, 2.43), P = 0.042). Serum IGF-I levels within the normal range during pegvisomant therapy were associated with all-cause mortality rates that were indistinguishable from the general population., Conclusions: Higher on-treatment IGF-I, older attained age, and longer duration of acromegaly before starting pegvisomant are associated with higher all-cause mortality rates. Younger patients with uncontrolled acromegaly have higher excess all-cause mortality rates in comparison with older patients.

Objective: To evaluate use of pegvisomant, a growth hormone (GH) receptor antagonist, as monotherapy in ACROSTUDY, a global safety surveillance study set in 14 countries (373 sites)., Methods: A descriptive analysis of safety, magnetic resonance imaging (MRI) reading, and treatment outcomes in 710 subjects who received at least 1 pegvisomant dose as monotherapy during and up to 5 years follow-up in ACROSTUDY., Results: Subjects received a mean of 5.4 years of pegvisomant and were followed in ACROSTUDY for a mean of 3.8 years. A total of 1,255 adverse events (AEs) were reported in 345 subjects (48.6%). Serious AEs (SAEs) were reported in 133 (18.7%) subjects, including 22 deaths, none of which were attributed to pegvisomant use. Of 670 (94%) subjects with at least 1 liver function test (LFT) reported in ACROSTUDY, 8 (1.2%) had reported increases in transaminases >3 times the upper limit of normal (ULN). No liver failure was reported. Based on central MRI reading, 12 of 542 subjects (2.2%) had a confirmed increase or increase/decrease in tumor size. Injection-site reactions were reported in 2.3%. At 5 years of therapy, insulin-like growth factor 1 (IGF-1) level was reported normal in 67.5% (mean dose 17.2 mg/day) and elevated in 29.9% (mean dose 19.8 mg/day). Subjects on 20 mg per day or more rose from 36% at 3 years to 41% at 5 years of therapy., Conclusions: ACROSTUDY data indicate that pegvisomant used as sole medical therapy is safe and effective for patients with acromegaly. The reported low incidence of pituitary tumor size increase and liver enzyme elevations are reassuring and support the positive benefit-risk of pegvisomant therapy.

Purpose/methods: A patient with osteitis deformans (Paget's disease) and hemifacial spasm underwent magnetic resonance tomographic angiography. Bone-modulating bisphosphonates and botulinum injection were administered to treat the hemifacial spasm., Results/conclusions: Computed tomography showed marked temporal bone overgrowth. Magnetic resonance tomographic angiography showed no vascular compression of the facial nerve root. The hemifacial spasm failed to resolve with intravenous pamidronate. Subsequent botulinum injection rendered the patient spasm free for 22 weeks. Further research on the use of bisphosphonates in the treatment of pagetoid hemifacial spasm is required.

We have previously shown that neonatal exposure of rats to pharmacologic doses of diethylstilbestrol via daily injections resulted in a significant decrease in the estrogen-binding capacity of the uterine estrogen receptor (ER). In this study, we examined the effects of physiologic and pharmacologic doses of estradiol (E2) administered to adult ovariectomized rats via Silastic implants. Two days after implantation, uteri were removed, weighted, and homogenized, and ER levels were determined in the supernatant (hydroxylapatite assay) and low-speed pellet (nuclear exchange assay). Implants containing E2 concentrations of 0.005 or 0.05 mg/ml increased cytosolic but not total ER-binding capacity, whereas 0.5 or 5.0 mg of E2/ml implants decreased the binding capacity of cytosol ER to 40% and total ER to 50% of control values. The 0.005-mg/ml dose increased cytosol ER without increasing uterine weight; all higher doses significantly increased uterine weight. Determination of ER protein by an ER radioimmunoassay showed the same extent of reduction of ER concentration as the binding assays, demonstrating that the loss in E2 binding capacity is homologous down-regulation. The down-regulation of ER was maximal at 24 hr and was completely reversible after implant removal, although the time required to recover from down-regulation was dose dependent. Uterine weight also returned to control levels slowly after implant removal. Neither the sedimentation rate of the down-regulated ER nor the Kd of the cytosolic ER changed following long-term implantation; however, the Kd of the nuclear ER decreased significantly. This is the first demonstration of in vivo homologous down-regulation of uterine ER. ER down-regulation may play a role in several biologic processes.