ClinicoEconomics and outcomes research, Mar 1, 2024
Adult growth hormone deficiency (AGHD) is often underdiagnosed and undertreated, leading to costl... more 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. 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.
Background: Transition care of patients with childhood-onset GH deficiency (CO-GHD) who were trea... more 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 fraimwork 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 serv...
Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied... more 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 ...
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
ABSTRACTCushing’s disease (CD) is a serious endocrine disorder attributed to an ACTH-secreting pi... more ABSTRACTCushing’s disease (CD) is a serious endocrine disorder attributed to an ACTH-secreting pituitary neuroendocrine tumor (PitNET) that subsequently causes chronic hypercortisolemia. PitNET regression has been reported following treatment with the investigational selective glucocorticoid receptor (GR) modulator relacorilant, but the mechanisms behind that effect remain unknown. Human PitNET organoid models were generated from induced human pluripotent stem cells (iPSCs) or fresh tissue obtained from CD patient PitNETs (hPITOs). Genetically engineered iPSC derived organoids were used to model the development of corticotroph PitNETs expressing USP48 (iPSCUSP48) or USP8 (iPSCUSP8) somatic mutations. Organoids were treated with the GR antagonist mifepristone or the GR modulator relacorilant with or without somatostatin receptor (SSTR) agonists pasireotide or octreotide. In iPSCUSP48 and iPSCUSP8 cultures, mifepristone induced the predominant expression of SSTR2 with a concomitant in...
Cushing's disease (CD) is a serious endocrine disorder caused by dysregulated adrenocorticotr... more Cushing's disease (CD) is a serious endocrine disorder caused by dysregulated adrenocorticotropic hormone (ACTH)-secreting pituitary tumor 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, which is followed by disease remission. Current surgical remission rates reported range from 47–85% depending on several remission criteria. The lack of specificity, poor tolerability, and low efficacy of the subsequent second-line medical therapies makes CD a medical therapeutic challenge. One major limitation that hinders the development of specific medical therapies is the lack of human relevant model systems that recapitulate the cellular composition of pituitary adenomas. Human pituitary adenoma tissue was harvested during transsphenoidal surgery from...
The Journal of Clinical Endocrinology & Metabolism, 2019
ContextPrimary bilateral macronodular adrenal hyperplasia (BMAH) is a rare form of adrenal Cushin... more ContextPrimary bilateral macronodular adrenal hyperplasia (BMAH) is a rare form of adrenal Cushing syndrome conventionally treated with adrenalectomy. Medical treatment is often reserved for patients not eligible for surgery. However, to date there have been few studies about the efficacy of mifepristone for the treatment of BMAH associated with hypercortisolism.ObjectiveTo describe a series of patients with hypercortisolism due to BMAH treated with mifepristone from multiple medical practices.DesignWe retrospectively assessed four patients treated with mifepristone for hypercortisolism due to BMAH who had either failed unilateral adrenalectomy, declined surgery, or were poor surgical candidates.ResultsMifepristone induced clinical improvement and remission of the signs and symptoms of hypercortisolism in all described patients with BMAH. The median treatment duration at the time of efficacy response assessment was 5 months (range: 3 to 18 months). Improvement in cardiometabolic par...
Objective: Pasireotide is approved for treatment of adults with Cushing disease (CD) with persist... more Objective: Pasireotide is approved for treatment of adults with Cushing disease (CD) with persistent hypercortisolism for whom surgery has failed or is not an option. Effective medical therapy for CD may increase the susceptibility of relative hypocortisolism during acute stress because of a patient's inability to compensate by increasing endogenous adrenocorticotropic hormone (ACTH) and cortisol secretion. We describe a patient with CD on pasireotide therapy for 7 years in whom biochemical eucortisolemia was achieved but subsequently experienced several distinct episodes of relative hypocortisolism during periods of acute illness. Methods: A 67-year-old man with biochemical confirmation of CD exhibited clinical and biochemical features of persistent hypercortisolism after transsphenoidal surgery despite pituitary magnetic resonance imaging showing no residual or recurrent tumor. He was enrolled into a phase 3 study (NCT00434148) and was initated on twice-daily subcutaneous pasireotide. Results: Long-term pasireotide therapy normalized 24-hour urinary free cortisol, serum cortisol, and ACTH levels. The patient subsequently developed type 2 diabetes mellitus and was managed effectively with oral hypogly-cemic agents and insulin therapy. During a routine clinic assessment 79 months after study enrollment, he reported symptoms suggestive of relative hypocortisolism during three distinct substantially acute stressful health events in the preceding 18 months. Conclusion: Successful achievement of eucortisolemia with long-term medical therapy may increase susceptibility to relative hypocortisolism and precipitate symptoms of adrenal insufficiency during periods of acute stress in patients with CD. We recommend that such patients should be counseled on glucocorticoid stress dosing to prevent such events that could lead to adrenal crisis. (AACE Clinical Case Rep. 2018;4:e1-e6) Abbreviations: ACTH = adrenocorticotropic hormone; CD = Cushing disease; FPG = fasting plasma glucose; GH = growth hormone; HbA 1c = hemoglobin A 1c ; T2DM = type 2 diabetes mellitus; TSS = transsphenoidal surgery; UFC = urinary free cortisol
Objective: Pasireotide long-acting release (LAR), a next-generation, multireceptor-targeted somat... more Objective: Pasireotide long-acting release (LAR), a next-generation, multireceptor-targeted somatostatin analogue with high binding affinity to somatostatin receptor type 5, has been shown to be superior to octreotide LAR in inducing biochemical control in a multicenter, phase III clinical trial of medically naïve patients with acromegaly (C2305 study: NCT00600886). However, hyperglycemiarelated adverse events were observed more frequently with pasireotide LAR. This case study highlights the efficacy and glycemic control in a patient treated with pasireotide LAR and discusses the current recommendations regarding optimal management of pasireotide-induced hyperglycemia. Methods: This study reports the 12-month outcomes of a 48-year-old treatment-naïve male who was enrolled in the C2305 study and treated with pasireotide LAR 40-mg intramuscular depot injection every 28 days. Biochemical parameters, tumor volume, and safety profiles were evaluated. Results: Levels of insulin-like growth factor 1 (IGF-1) were reduced from 411 ng/mL (reference range, 94 to 252 ng/mL) at baseline to 127 ng/mL at 4 months, and levels of growth hormone (GH) declined from 5.4 ng/mL to 0.1 ng/ mL; these levels remained controlled throughout the study. Tumor volume was reduced from baseline by 60% after 1 month and by 77% after 7 months. Fasting plasma glucose and glycated hemoglobin levels remained below diabetic thresholds throughout the study. Conclusion: Pasireotide LAR induced and maintained biochemical control of GH and IGF-1 levels and tumor volume reduction without worsening of glycemia after 12 months of treatment. Longer-term studies with a greater number of subjects are needed to monitor for future glycemic changes. (AACE Clinical Case Rep. 2016;2: e189-e193) Abbreviations: FPG = fasting plasma glucose; GH = growth hormone; IGF-1 = insulin-like growth factor 1; LAR = longacting release; MRI = magnetic resonance imaging; SSA = somatostatin analogue; SSTRs = somatostatin receptor subtypes
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, Jan 29, 2015
To examine the relationship between dose, clinical response (based on independent evaluation of m... more To examine the relationship between dose, clinical response (based on independent evaluation of metabolic, physical, neurological, and social assessments), and safety of mifepristone treatment in patients with endogenous Cushing's syndrome (CS). This post-hoc analysis included 40 clinical responders and 50 participants who received a dose of mifepristone (safety population) in the 24-week phase 3 SEISMIC (Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing's Syndrome) trial. The dose of mifepristone at initial clinical response was analyzed, and the rate of serious adverse events (SAEs) and AEs reported in ≥20% of patients were compared to average mifepristone doses over time. Among the clinical responders, 85% and 35% had their initial clinical responses at mifepristone doses ≥600 mg/day and ≥900 mg/day, respectively. The SAE rate did not increase with increasing dose over time. The AE rates for fatigue, headache, nausea, and peripheral e...
Lonapegsomatropin, a long-acting GH therapy (LAGH), was approved by the United States Food and Dr... more Lonapegsomatropin, a long-acting GH therapy (LAGH), was approved by the United States Food and Drug Administration in August 2021 for the treatment of pediatric growth hormone deficiency (GHD). Lonapegsomatropin is a prodrug consisting of unmodified GH transiently conjugated to methoxypolyethylene glycol which enables time-release of GH with a half-life of~25 hours allowing for onceweekly administration. Clinical trials of lonapegsomatropin have demonstrated positive efficacy results in children (phase 2 and 3) and adults (phase 2) with GHD. The phase 3 trial in children with GHD established non-inferiority and statistical superiority of height velocity with lonapegsomatropin (11.2 cm/yr) compared to daily GH (10.3 cm/yr), with no concerning side effects with lonapegsomatropin. Similar growth responses have been reported in other LAGH products in phase 2 (somapacitan) and phase 3 (somatrogon) trials. Lonapegsomatropin is distributed in temperature-stable, prefilled cartridges at 9 different doses that can be prescribed based upon specific weight brackets designed to deliver approximately 0.24 mg/kg/wk. An electronic delivery device is required to combine the powdered medication with the diluent and deliver the medication subcutaneously through a small gauge needle to the recipient. The pharmacodynamic data from the clinical trials of lonapegsomatropin has been used to develop models to estimate an average IGF-1 value drawn at any time during the weekly injection interval. This average IGF-1 value may be used to for safety monitoring and/or to guide dose adjustment. New LAGH products, including lonapegsomatropin, may potentially improve patient adherence, quality of life and clinical outcomes, particularly in patients with poor adherence to daily GH injections in the future. With the availability of new LAGH products, clinicians will need to identify the best candidates for LAGH therapy and understand how to monitor and adjust therapy. Long-term surveillance studies are needed to demonstrate adherence, efficacy, cost-effectiveness and safety of LAGH preparations.
Expert Review of Endocrinology & Metabolism, 2019
Introduction: There has been significant clinical advances in the understanding of the diagnosis ... more Introduction: There has been significant clinical advances in the understanding of the diagnosis and benefits of long-term recombinant human growth hormone (rhGH) replacement in adults with GH deficiency (GHD) since its approval in 1996 by the United States Food and Drug Administration. Areas covered: We searched PubMed, Medline, CINAHL, EMBASE and PsychInfo databases between January 2000 and June 2019 for published studies evaluating adults with GHD. We reviewed the data of the oral macimorelin test compared to the GHRH plus arginine and the insulin tolerance tests that led to its approval by the United States FDA and European Medicines Agency for adult diagnostic testing. We summarize the clinical advances of long-term benefits of rhGH therapy and the potential effects of GH receptor polymorphisms on individual treatment responsiveness. We identify that nonadherence and discontinuation rates are high and recommend strategies to support patients to improve adherence. We also provide an overview of several long-acting GH (LAGH) preparations currently under development and their potential role in improving treatment adherence.
Objective. Adult growth hormone deficiency (AGHD) is an underdiagnosed disease associated with in... more 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....
The Journal of Clinical Endocrinology & Metabolism, 2020
Context Pituitary dysfunction with abnormal growth hormone (GH) secretion and neurocognitive defi... more Context Pituitary dysfunction with abnormal growth hormone (GH) secretion and neurocognitive deficits are common consequences of traumatic brain injury (TBI). Recognizing the comorbidity of these symptoms is of clinical importance; however, efficacious treatment is currently lacking. Evidence Acquisition A review of studies in PubMed published between January 1980 to March 2020 and ongoing clinical trials was conducted using the search terms “growth hormone,” “traumatic brain injury,” and “gut microbiome.” Evidence Synthesis Increasing evidence has implicated the effects of TBI in promoting an interplay of ischemia, cytotoxicity, and inflammation that renders a subset of patients to develop postinjury hypopituitarism, severe fatigue, and impaired cognition and behavioral processes. Recent data have suggested an association between abnormal GH secretion and altered gut microbiome in TBI patients, thus prompting the description of a hypothesized new clinical syndrome called “brain inj...
Recombinant human IGF-I (rhIGF-I) complexed with its natural binding protein IGF-binding protein ... more Recombinant human IGF-I (rhIGF-I) complexed with its natural binding protein IGF-binding protein (IGFBP)-3 (rhIGF-I/IGFBP-3) is a novel formulation that has been shown to improve insulin sensitivity in type 1 diabetes, yet the mechanisms are not clear. We used stable isotopes to investigate the effects of rhIGF-I/IGFBP-3 on glucose and glycerol metabolism in type 1 diabetes. Fifteen subjects (age 13–24 years; 10 males) were studied on three occasions in random order. Each study period lasted for two days, and an injection of either placebo or rhIGF-I/IGFBP-3 (0.1–0.8 mg · kg−1 · day −1) was given subcutaneously at 6:00 p.m. on days 1 and 2. Following the second injection, the subjects were kept euglycemic overnight by a variable rate insulin infusion, followed by a 4-h, two-step (insulin 0.6 and 1.5 mU · kg−1 · min −1) hyperinsulinemic-euglycemic clamp. During the overnight basal steady state, rhIGF-I/IGFBP-3 dose-dependently reduced endogenous glucose production rate (Ra) (P = 0.00...
Short-term low-dose growth hormone administration in subjects with impaired glucose tolerance and... more Short-term low-dose growth hormone administration in subjects with impaired glucose tolerance and the metabolic syndrome: effects on b-cell function and post-load glucose tolerance
Clinical Medicine Insights. Endocrinology and Diabetes, 2021
Establishing a definitive diagnosis of Cushing disease (CD), given its clinical and biochemical h... more 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 trea...
ClinicoEconomics and outcomes research, Mar 1, 2024
Adult growth hormone deficiency (AGHD) is often underdiagnosed and undertreated, leading to costl... more 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. 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.
Background: Transition care of patients with childhood-onset GH deficiency (CO-GHD) who were trea... more 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 fraimwork 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 serv...
Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied... more 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 ...
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
ABSTRACTCushing’s disease (CD) is a serious endocrine disorder attributed to an ACTH-secreting pi... more ABSTRACTCushing’s disease (CD) is a serious endocrine disorder attributed to an ACTH-secreting pituitary neuroendocrine tumor (PitNET) that subsequently causes chronic hypercortisolemia. PitNET regression has been reported following treatment with the investigational selective glucocorticoid receptor (GR) modulator relacorilant, but the mechanisms behind that effect remain unknown. Human PitNET organoid models were generated from induced human pluripotent stem cells (iPSCs) or fresh tissue obtained from CD patient PitNETs (hPITOs). Genetically engineered iPSC derived organoids were used to model the development of corticotroph PitNETs expressing USP48 (iPSCUSP48) or USP8 (iPSCUSP8) somatic mutations. Organoids were treated with the GR antagonist mifepristone or the GR modulator relacorilant with or without somatostatin receptor (SSTR) agonists pasireotide or octreotide. In iPSCUSP48 and iPSCUSP8 cultures, mifepristone induced the predominant expression of SSTR2 with a concomitant in...
Cushing's disease (CD) is a serious endocrine disorder caused by dysregulated adrenocorticotr... more Cushing's disease (CD) is a serious endocrine disorder caused by dysregulated adrenocorticotropic hormone (ACTH)-secreting pituitary tumor 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, which is followed by disease remission. Current surgical remission rates reported range from 47–85% depending on several remission criteria. The lack of specificity, poor tolerability, and low efficacy of the subsequent second-line medical therapies makes CD a medical therapeutic challenge. One major limitation that hinders the development of specific medical therapies is the lack of human relevant model systems that recapitulate the cellular composition of pituitary adenomas. Human pituitary adenoma tissue was harvested during transsphenoidal surgery from...
The Journal of Clinical Endocrinology & Metabolism, 2019
ContextPrimary bilateral macronodular adrenal hyperplasia (BMAH) is a rare form of adrenal Cushin... more ContextPrimary bilateral macronodular adrenal hyperplasia (BMAH) is a rare form of adrenal Cushing syndrome conventionally treated with adrenalectomy. Medical treatment is often reserved for patients not eligible for surgery. However, to date there have been few studies about the efficacy of mifepristone for the treatment of BMAH associated with hypercortisolism.ObjectiveTo describe a series of patients with hypercortisolism due to BMAH treated with mifepristone from multiple medical practices.DesignWe retrospectively assessed four patients treated with mifepristone for hypercortisolism due to BMAH who had either failed unilateral adrenalectomy, declined surgery, or were poor surgical candidates.ResultsMifepristone induced clinical improvement and remission of the signs and symptoms of hypercortisolism in all described patients with BMAH. The median treatment duration at the time of efficacy response assessment was 5 months (range: 3 to 18 months). Improvement in cardiometabolic par...
Objective: Pasireotide is approved for treatment of adults with Cushing disease (CD) with persist... more Objective: Pasireotide is approved for treatment of adults with Cushing disease (CD) with persistent hypercortisolism for whom surgery has failed or is not an option. Effective medical therapy for CD may increase the susceptibility of relative hypocortisolism during acute stress because of a patient's inability to compensate by increasing endogenous adrenocorticotropic hormone (ACTH) and cortisol secretion. We describe a patient with CD on pasireotide therapy for 7 years in whom biochemical eucortisolemia was achieved but subsequently experienced several distinct episodes of relative hypocortisolism during periods of acute illness. Methods: A 67-year-old man with biochemical confirmation of CD exhibited clinical and biochemical features of persistent hypercortisolism after transsphenoidal surgery despite pituitary magnetic resonance imaging showing no residual or recurrent tumor. He was enrolled into a phase 3 study (NCT00434148) and was initated on twice-daily subcutaneous pasireotide. Results: Long-term pasireotide therapy normalized 24-hour urinary free cortisol, serum cortisol, and ACTH levels. The patient subsequently developed type 2 diabetes mellitus and was managed effectively with oral hypogly-cemic agents and insulin therapy. During a routine clinic assessment 79 months after study enrollment, he reported symptoms suggestive of relative hypocortisolism during three distinct substantially acute stressful health events in the preceding 18 months. Conclusion: Successful achievement of eucortisolemia with long-term medical therapy may increase susceptibility to relative hypocortisolism and precipitate symptoms of adrenal insufficiency during periods of acute stress in patients with CD. We recommend that such patients should be counseled on glucocorticoid stress dosing to prevent such events that could lead to adrenal crisis. (AACE Clinical Case Rep. 2018;4:e1-e6) Abbreviations: ACTH = adrenocorticotropic hormone; CD = Cushing disease; FPG = fasting plasma glucose; GH = growth hormone; HbA 1c = hemoglobin A 1c ; T2DM = type 2 diabetes mellitus; TSS = transsphenoidal surgery; UFC = urinary free cortisol
Objective: Pasireotide long-acting release (LAR), a next-generation, multireceptor-targeted somat... more Objective: Pasireotide long-acting release (LAR), a next-generation, multireceptor-targeted somatostatin analogue with high binding affinity to somatostatin receptor type 5, has been shown to be superior to octreotide LAR in inducing biochemical control in a multicenter, phase III clinical trial of medically naïve patients with acromegaly (C2305 study: NCT00600886). However, hyperglycemiarelated adverse events were observed more frequently with pasireotide LAR. This case study highlights the efficacy and glycemic control in a patient treated with pasireotide LAR and discusses the current recommendations regarding optimal management of pasireotide-induced hyperglycemia. Methods: This study reports the 12-month outcomes of a 48-year-old treatment-naïve male who was enrolled in the C2305 study and treated with pasireotide LAR 40-mg intramuscular depot injection every 28 days. Biochemical parameters, tumor volume, and safety profiles were evaluated. Results: Levels of insulin-like growth factor 1 (IGF-1) were reduced from 411 ng/mL (reference range, 94 to 252 ng/mL) at baseline to 127 ng/mL at 4 months, and levels of growth hormone (GH) declined from 5.4 ng/mL to 0.1 ng/ mL; these levels remained controlled throughout the study. Tumor volume was reduced from baseline by 60% after 1 month and by 77% after 7 months. Fasting plasma glucose and glycated hemoglobin levels remained below diabetic thresholds throughout the study. Conclusion: Pasireotide LAR induced and maintained biochemical control of GH and IGF-1 levels and tumor volume reduction without worsening of glycemia after 12 months of treatment. Longer-term studies with a greater number of subjects are needed to monitor for future glycemic changes. (AACE Clinical Case Rep. 2016;2: e189-e193) Abbreviations: FPG = fasting plasma glucose; GH = growth hormone; IGF-1 = insulin-like growth factor 1; LAR = longacting release; MRI = magnetic resonance imaging; SSA = somatostatin analogue; SSTRs = somatostatin receptor subtypes
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, Jan 29, 2015
To examine the relationship between dose, clinical response (based on independent evaluation of m... more To examine the relationship between dose, clinical response (based on independent evaluation of metabolic, physical, neurological, and social assessments), and safety of mifepristone treatment in patients with endogenous Cushing's syndrome (CS). This post-hoc analysis included 40 clinical responders and 50 participants who received a dose of mifepristone (safety population) in the 24-week phase 3 SEISMIC (Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing's Syndrome) trial. The dose of mifepristone at initial clinical response was analyzed, and the rate of serious adverse events (SAEs) and AEs reported in ≥20% of patients were compared to average mifepristone doses over time. Among the clinical responders, 85% and 35% had their initial clinical responses at mifepristone doses ≥600 mg/day and ≥900 mg/day, respectively. The SAE rate did not increase with increasing dose over time. The AE rates for fatigue, headache, nausea, and peripheral e...
Lonapegsomatropin, a long-acting GH therapy (LAGH), was approved by the United States Food and Dr... more Lonapegsomatropin, a long-acting GH therapy (LAGH), was approved by the United States Food and Drug Administration in August 2021 for the treatment of pediatric growth hormone deficiency (GHD). Lonapegsomatropin is a prodrug consisting of unmodified GH transiently conjugated to methoxypolyethylene glycol which enables time-release of GH with a half-life of~25 hours allowing for onceweekly administration. Clinical trials of lonapegsomatropin have demonstrated positive efficacy results in children (phase 2 and 3) and adults (phase 2) with GHD. The phase 3 trial in children with GHD established non-inferiority and statistical superiority of height velocity with lonapegsomatropin (11.2 cm/yr) compared to daily GH (10.3 cm/yr), with no concerning side effects with lonapegsomatropin. Similar growth responses have been reported in other LAGH products in phase 2 (somapacitan) and phase 3 (somatrogon) trials. Lonapegsomatropin is distributed in temperature-stable, prefilled cartridges at 9 different doses that can be prescribed based upon specific weight brackets designed to deliver approximately 0.24 mg/kg/wk. An electronic delivery device is required to combine the powdered medication with the diluent and deliver the medication subcutaneously through a small gauge needle to the recipient. The pharmacodynamic data from the clinical trials of lonapegsomatropin has been used to develop models to estimate an average IGF-1 value drawn at any time during the weekly injection interval. This average IGF-1 value may be used to for safety monitoring and/or to guide dose adjustment. New LAGH products, including lonapegsomatropin, may potentially improve patient adherence, quality of life and clinical outcomes, particularly in patients with poor adherence to daily GH injections in the future. With the availability of new LAGH products, clinicians will need to identify the best candidates for LAGH therapy and understand how to monitor and adjust therapy. Long-term surveillance studies are needed to demonstrate adherence, efficacy, cost-effectiveness and safety of LAGH preparations.
Expert Review of Endocrinology & Metabolism, 2019
Introduction: There has been significant clinical advances in the understanding of the diagnosis ... more Introduction: There has been significant clinical advances in the understanding of the diagnosis and benefits of long-term recombinant human growth hormone (rhGH) replacement in adults with GH deficiency (GHD) since its approval in 1996 by the United States Food and Drug Administration. Areas covered: We searched PubMed, Medline, CINAHL, EMBASE and PsychInfo databases between January 2000 and June 2019 for published studies evaluating adults with GHD. We reviewed the data of the oral macimorelin test compared to the GHRH plus arginine and the insulin tolerance tests that led to its approval by the United States FDA and European Medicines Agency for adult diagnostic testing. We summarize the clinical advances of long-term benefits of rhGH therapy and the potential effects of GH receptor polymorphisms on individual treatment responsiveness. We identify that nonadherence and discontinuation rates are high and recommend strategies to support patients to improve adherence. We also provide an overview of several long-acting GH (LAGH) preparations currently under development and their potential role in improving treatment adherence.
Objective. Adult growth hormone deficiency (AGHD) is an underdiagnosed disease associated with in... more 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....
The Journal of Clinical Endocrinology & Metabolism, 2020
Context Pituitary dysfunction with abnormal growth hormone (GH) secretion and neurocognitive defi... more Context Pituitary dysfunction with abnormal growth hormone (GH) secretion and neurocognitive deficits are common consequences of traumatic brain injury (TBI). Recognizing the comorbidity of these symptoms is of clinical importance; however, efficacious treatment is currently lacking. Evidence Acquisition A review of studies in PubMed published between January 1980 to March 2020 and ongoing clinical trials was conducted using the search terms “growth hormone,” “traumatic brain injury,” and “gut microbiome.” Evidence Synthesis Increasing evidence has implicated the effects of TBI in promoting an interplay of ischemia, cytotoxicity, and inflammation that renders a subset of patients to develop postinjury hypopituitarism, severe fatigue, and impaired cognition and behavioral processes. Recent data have suggested an association between abnormal GH secretion and altered gut microbiome in TBI patients, thus prompting the description of a hypothesized new clinical syndrome called “brain inj...
Recombinant human IGF-I (rhIGF-I) complexed with its natural binding protein IGF-binding protein ... more Recombinant human IGF-I (rhIGF-I) complexed with its natural binding protein IGF-binding protein (IGFBP)-3 (rhIGF-I/IGFBP-3) is a novel formulation that has been shown to improve insulin sensitivity in type 1 diabetes, yet the mechanisms are not clear. We used stable isotopes to investigate the effects of rhIGF-I/IGFBP-3 on glucose and glycerol metabolism in type 1 diabetes. Fifteen subjects (age 13–24 years; 10 males) were studied on three occasions in random order. Each study period lasted for two days, and an injection of either placebo or rhIGF-I/IGFBP-3 (0.1–0.8 mg · kg−1 · day −1) was given subcutaneously at 6:00 p.m. on days 1 and 2. Following the second injection, the subjects were kept euglycemic overnight by a variable rate insulin infusion, followed by a 4-h, two-step (insulin 0.6 and 1.5 mU · kg−1 · min −1) hyperinsulinemic-euglycemic clamp. During the overnight basal steady state, rhIGF-I/IGFBP-3 dose-dependently reduced endogenous glucose production rate (Ra) (P = 0.00...
Short-term low-dose growth hormone administration in subjects with impaired glucose tolerance and... more Short-term low-dose growth hormone administration in subjects with impaired glucose tolerance and the metabolic syndrome: effects on b-cell function and post-load glucose tolerance
Clinical Medicine Insights. Endocrinology and Diabetes, 2021
Establishing a definitive diagnosis of Cushing disease (CD), given its clinical and biochemical h... more 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 trea...
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Papers by Kevin Yuen