Publications by authors named "Hershel Raff"

116 Publications

Circulating inflammatory biomarkers in adolescents: evidence of interactions between chronic pain and obesity.

Pain Rep 2021 1;6(1):e916. Epub 2021 Apr 1.

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA.

Introduction: The negative effects of chronic pain and obesity are compounded in those with both conditions. Despite this, little research has focused on the pathophysiology in pediatric samples.

Objective: To examine the effects of comorbid chronic pain and obesity on the concentration of circulating inflammatory biomarkers.

Methods: We used a multiple-cohort observational design, with 4 groups defined by the presence or absence of obesity and chronic pain: healthy controls, chronic pain alone, obesity alone, as well as chronic pain and obesity. Biomarkers measured were leptin, adiponectin, leptin/adiponectin ratio (primary outcome), tumor necrosis factor-alpha, interleukin 6, and C-reactive protein (CRP).

Results: Data on 125 adolescents (13-17 years) were analyzed. In females, there was an interaction between chronic pain and obesity such that leptin and CRP were higher in the chronic pain and obesity group than in chronic pain or obesity alone. Within the chronic pain and obesity group, biomarkers were correlated with worsened pain attributes, and females reported worse pain than males. The highest levels of interleukin 6 and CRP were found in youth with elevated weight and functional disability. We conclude that in adolescents, chronic pain and obesity interact to cause dysregulation of the inflammatory system, and this effect is more pronounced in females.

Conclusion: The augmented levels of inflammatory biomarkers are associated with pain and functional disability, and may be an early marker of future pain and disability.
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http://dx.doi.org/10.1097/PR9.0000000000000916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104468PMC
April 2021

New Cutoffs for the Biochemical Diagnosis of Adrenal Insufficiency after ACTH Stimulation using Specific Cortisol Assays.

J Endocr Soc 2021 Apr 18;5(4):bvab022. Epub 2021 Feb 18.

Endocrinology Center and Clinics, Froedtert & the Medical College of Wisconsin, Milwaukee, WI 53051, USA.

Context: The normal cortisol response 30 or 60 minutes after cosyntropin (ACTH) is considered to be ≥18 μg/dL (500 nmol/L). This threshold is based on older serum cortisol assays. Specific monoclonal antibody immunoassays or LC-MS/MS may have lower thresholds for a normal response.

Objective: To calculate serum cortisol cutoff values for adrenocorticotropic hormone (ACTH) stimulation testing with newer specific cortisol assays.

Methods: Retrospective analysis of ACTH stimulation tests performed in ambulatory and hospitalized patients suspected of adrenal insufficiency (AI). Serum samples were assayed for cortisol in parallel using Elecsys I and Elecsys II immunoassays, and when volume was available, by Access immunoassay and LC-MS/MS.

Results: A total of 110 patients were evaluated. Using 18 μg/dL as the cortisol cutoff after ACTH stimulation, 14.5%, 29%, 22.4%, and 32% of patients had a biochemical diagnosis of AI using the Elecsys I, Elecsys II, Access, and LC-MS/MS assays, respectively. Deming regressions of serum cortisol were used to calculate new cortisol cutoffs based on the Elecsys I cutoff of 18 μg/dL. For 30-minute values, new cutoffs were 14.6 μg/dL for Elecsys II, 14.8 μg/dL for Access, and 14.5 μg/dL for LC-MS/MS. Baseline cortisol <2 μg/dL was predictive of subnormal stimulated cortisol values.

Conclusion: To reduce false positive ACTH stimulation testing, we recommend a new serum cortisol cutoff of 14 to 15 μg/dL depending on the assay used (instead of the historical value of 18 μg/dL with older polyclonal antibody assays). Clinicians should be aware of the new cutoffs for the assays available to them when evaluating patients for AI.
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http://dx.doi.org/10.1210/jendso/bvab022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975762PMC
April 2021

Insulin and glucose responses to hypoxia in male and female neonatal rats: Effects of the androgen receptor antagonist flutamide.

Physiol Rep 2021 01;9(1):e14663

Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Advocate Aurora Research Institute, Milwaukee, WI, USA.

Hypoxia is common with preterm birth and may lead to long-term effects on adult pancreatic endocrine function and insulin sensitivity. This phenomenon may be sexually dimorphic due to the hypoxia-induced augmentation of the neonatal androgen surge in male newborns. We evaluated this phenomenon by pretreating neonatal rats on postnatal days (PD) 1, 6, 13, or 20 with flutamide (a nonsteroidal androgen receptor antagonist) at a standard or a high dose (10 or 50 mg/kg) compared to vehicle control. One day later, neonatal rats were exposed to either acute normoxic or hypoxic separation (fasting) for 90 min, and blood was sampled for the measurement of insulin and glucose and the calculation of HOMA-IR as an index of insulin resistance. During normoxic and hypoxic separation (fasting), flutamide increased insulin secretion in PD2, PD7, and PD14 pups, high dose flutamide attenuated insulin secretion, and high dose flutamide attenuated the increase in HOMA-IR due to hypoxia. Our studies suggest a unique role of the androgen receptor in the control of neonatal pancreatic function, possibly by blocking a direct effect of neonatal testosterone or in response to indirect regulatory effects of androgens on insulin sensitivity.
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http://dx.doi.org/10.14814/phy2.14663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780235PMC
January 2021

Prospective Evaluation of Late-Night Salivary Cortisol and Cortisone by EIA and LC-MS/MS in Suspected Cushing Syndrome.

J Endocr Soc 2020 Oct 24;4(10):bvaa107. Epub 2020 Jul 24.

Division of Endocrinology and Molecular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.

Context: Late-night salivary cortisol (LNSC) measured by enzyme immunoassay (EIA-F) is a first-line screening test for Cushing syndrome (CS) with a reported sensitivity and specificity of >90%. However, liquid chromatography-tandem mass spectrometry, validated to measure salivary cortisol (LCMS-F) and cortisone (LCMS-E), has been proposed to be superior diagnostically.

Objective Setting And Main Outcome Measures: Prospectively evaluate the diagnostic performance of EIA-F, LCMS-F, and LCMS-E in 1453 consecutive late-night saliva samples from 705 patients with suspected CS.

Design: Patients grouped by the presence or absence of at least one elevated salivary steroid result and then subdivided by diagnosis.

Results: We identified 283 patients with at least one elevated salivary result; 45 had an established diagnosis of neoplastic hypercortisolism (CS) for which EIA-F had a very high sensitivity (97.5%). LCMS-F and LCMS-E had lower sensitivity but higher specificity than EIA-F. EIA-F had poor sensitivity (31.3%) for adrenocorticotropic hormone (ACTH)-independent CS (5 patients with at least 1 and 11 without any elevated salivary result). In patients with Cushing disease (CD), most nonelevated LCMS-F results were in patients with persistent/recurrent CD; their EIA-F levels were lower than in patients with newly diagnosed CD.

Conclusions: Since the majority of patients with ≥1 elevated late-night salivary cortisol or cortisone result did not have CS, a single elevated level has poor specificity and positive predictive value. LNSC measured by EIA is a sensitive test for ACTH-dependent Cushing syndrome but not for ACTH-independent CS. We suggest that neither LCMS-F nor LCMS-E improves the sensitivity of late-night EIA-F for CS.
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http://dx.doi.org/10.1210/jendso/bvaa107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480956PMC
October 2020

Serum soluble urokinase plasminogen activator receptor in adolescents: interaction of chronic pain and obesity.

Pain Rep 2020 Jul-Aug;5(4):e836. Epub 2020 Jul 22.

Department of Anesthesiology, Medical College of Wisconsin and the Jane B. Pettit Pain and Headache Center, Children's Wisconsin, Milwaukee, WI, USA.

Introduction: Obesity in adolescents is increasing in frequency and is associated with short-term and long-term negative consequences that include the exacerbation of co-occurring chronic pain.

Objective: To determine whether the interaction between chronic pain and obesity would be reflected in changes in serum soluble urokinase plasminogen activator receptor (suPAR) concentrations, a novel marker of systemic inflammation associated with obesity, insulin resistance, and cardiovascular disease.

Methods: We measured serum suPAR levels in 146 adolescent males and females with no pain or obesity (healthy controls; n = 40), chronic pain with healthy weight (n = 37), obesity alone (n = 41), and the combination of chronic pain and obesity (n = 28).

Results: Serum suPAR (median [interquartile range]) was not increased by chronic pain alone (2.2 [1.8-2.4] ng/mL) or obesity alone (2.2 [2.0-2.4] ng/mL) but was increased significantly with the combination of chronic pain and obesity (2.4 [2.1-2.7] ng/mL; < 0.019). This finding confirms the proposition that pain and obesity are inflammatory states that display a classic augmenting interaction.

Conclusion: We propose that measurement of serum suPAR can be added to the armamentarium of serum biomarkers useful in the evaluation of mechanisms of inflammation in adolescent obesity and chronic pain.
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http://dx.doi.org/10.1097/PR9.0000000000000836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382552PMC
July 2020

Corticosterone, Adrenal, and the Pituitary-Gonadal Axis in Neonatal Rats: Effect of Maternal Separation and Hypoxia.

Endocrinology 2020 07;161(7)

Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Aurora Research Institute, Milwaukee, Wisconsin.

Hypoxia, a common stressor in prematurity, leads to sexually dimorphic, short- and long-term effects on the adult hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes. We hypothesized that these effects are due to stress-induced increases in testosterone during early postnatal life. We evaluated this phenomenon by systematically assessing the short-term effects of normoxic or hypoxic separation on male and female pups at birth, postnatal hours (H) 2, 4, and 8, and postnatal days (PD) 2 to 7. Our findings were (a) hypoxic separation led to a large increase in plasma corticosterone from 4H-PD4, (b) neither normoxic nor hypoxic separation affected critical adrenal steroidogenic pathway genes; however, a significant decrease in baseline Cyp11a1, Mc2r, Mrap, and Star adrenal expression during the first week of neonatal life confirmed the start of the adrenal stress hyporesponsive period, (c) a luteinizing hormone/follicle-stimulating hormone-independent increase in plasma testosterone occurred in normoxic and hypoxic separated male pups at birth, (d) testicular Cyp11a1, Lhcgr, and Star expression was high at birth and decreased thereafter suggesting a hyporesponsive period in the testes, and (e) elevated estrogen in the early neonatal period occurred independently of gonadotropin stimulation. We conclude that a large corticosterone response to hypoxia during the first 5 days of life occurs as an adaptation to neonatal stress, that the testosterone surge during the first hours after birth occurs independently of gonadotropins but is associated with upregulation of the steroidogenic pathway genes in the testes, and that high postnatal estrogen production also occurs independently of gonadotropins.
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http://dx.doi.org/10.1210/endocr/bqaa085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310600PMC
July 2020

Team triathlon effects on physiological, psychological, and immunological measures in women breast cancer survivors.

Support Care Cancer 2020 Dec 20;28(12):6095-6104. Epub 2020 Apr 20.

Program in Exercise Science, Department of Physical Therapy, Marquette University, PO Box 1881, Milwaukee, WI, 53201-1881, USA.

Purpose: Exercise after breast cancer diagnosis and treatment improves cancer-related outcomes, although the mechanisms involved are not clear. This study evaluated the impact of exercise on body composition, strength, endurance, quality of life (QOL), fatigue, and endocrine and inflammatory biomarkers in breast cancer survivors participating in a highly monitored, clinically supervised, moderate-intensity exercise program. The association of hormonal and inflammatory biomarkers with the observed physiological changes was assessed.

Methods: Female breast cancer survivors (BCS; n = 46) who engaged in a goal-oriented 14-week triathlon exercise training program were compared to an untrained control group of female BCS (n = 16). Psychosocial metrics, QOL, cancer-related fatigue, and exercise self-efficacy were evaluated via pre- and post-exercise intervention questionnaires. Serum estradiol and inflammatory biomarkers (C-reactive protein (CRP), sTNFR1a, estradiol, leptin, and adiponectin) were measured prior to the exercise training program start and after the completion of the goal triathlon.

Results: After exercise training, the exercise group had lower BMI and arm circumferences. Greater positive change was noted in the trained group for QOL, fatigue, and self-efficacy questionnaires. Functional endurance improved in the trained but not the control group. Knee and elbow strength were not different between the groups, except that knee flexion at 180 degrees∙sec was higher in trained. The only significantly different biomarker was adiponectin, which decreased in the trained group.

Conclusions: Group triathlon exercise training may be beneficial to BCS by significantly improving their psychosocial measures, functional endurance, and BMI.
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http://dx.doi.org/10.1007/s00520-020-05457-2DOI Listing
December 2020

The effects of flutamide on the neonatal rat hypothalamic-pituitary-adrenal and gonadal axes in response to hypoxia.

Physiol Rep 2019 12;7(24):e14318

Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Aurora Research Institute, Milwaukee, Wisconsin.

Hypoxia is common with preterm birth and may lead to long-term effects on the adult hypothalamic-pituitary-adrenal (HPA) axis that are sexually dimorphic due to neonatal androgens. Although the adult rat adrenal does not express appreciable CYP17 activity, the neonatal rat adrenal may synthesize androgens that could be a critical local factor in the development of adrenal function. We evaluated these phenomena by pretreating the neonatal rats on postnatal days (PD) 1, 6, 13, 20 with flutamide (a nonsteroidal androgen receptor antagonist) at a standard or a high dose (10 mg/kg or 50 mg/kg) compared to vehicle control. One day later, neonatal rats were exposed to acute hypoxia and blood was sampled. We found that (a) in PD2 pups, flutamide augmented corticosterone responses in a sexually dimorphic pattern and without an increase in ACTH, (b) PD7 and PD14 pups had the smallest corticosterone response to hypoxia (c) PD21 pups had an adult-like corticosterone response to hypoxia that was sexually dimorphic, (d) flutamide attenuated ACTH responses in PD7 hypoxic pups, and (e) high-dose flutamide suppressed the HPA axis, FSH, and estradiol. Flutamide demonstrated mixed antagonist and agonist effects that changed during the first three weeks of neonatal life. We conclude that the use of flutamide in neonatal rats to evaluate androgen-induced programming of subsequent adult behavior is not optimal. However, our studies suggest neonatal androgens play a role in regulation of adrenal function that is sexually dimorphic and changes during early development.
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http://dx.doi.org/10.14814/phy2.14318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930936PMC
December 2019

Bedtime Salivary Cortisol and Cortisone by LC-MS/MS in Healthy Adult Subjects: Evaluation of Sampling Time.

J Endocr Soc 2019 Aug 26;3(8):1631-1640. Epub 2019 Jun 26.

Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Aurora Research Institute, Milwaukee, Wisconsin.

The measurement of late-night salivary cortisol is a mainstay in the diagnosis of Cushing syndrome. Furthermore, the measurement of salivary cortisol is useful in assessing the cortisol awakening response. Because the salivary glands express 11--hydroxysteroid dehydrogenase, the measurement of salivary cortisone may improve the performance of salivary corticosteroid measurements. We measured salivary cortisol by enzyme immunoassay (EIA) and salivary cortisol and cortisone by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in only 50 µL of saliva sampled from 54 healthy subjects (aged 20 to 64 years). We allowed patients to sample at their normal bedtime (2025 to 2400 hours) to answer a common question as to whether sampling at the normal bedtime is equivalent to the standard required sampling at 2300 to 2400 hours. We found that the salivary cortisol and cortisone results by LC-MS/MS correlated well with salivary cortisol measured with the US Food and Drug Administration-cleared EIA. Furthermore, the upper limit of normal of salivary cortisol by EIA for bedtime samples was lower than the previously published upper limit of normal with sampling required at 2300 to 2400 hours. There were no significant effects of age or sex on any of the salivary steroid measurements. We conclude that (i) salivary cortisol and cortisone can be reliably measured by LC-MS/MS in small volumes of saliva and (ii) that patients can be evaluated using saliva sampled at their normal bedtime, rather than being required to stay awake until 2300 to 2400 hours.
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http://dx.doi.org/10.1210/js.2019-00186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682408PMC
August 2019

A commentary on Diagnosing Cushing's disease in the context of renal failure.

Eur J Endocrinol 2019 Oct;181(4):C9-C11

Endocrinology Center and Clinics, Medical College of Wisconsin, Menomonee Falls, Wisconsin, USA.

The diagnosis of endogenous hypercortisolism (Cushing's syndrome) is extremely challenging. Chronic kidney disease (CKD) increases the activity of the hypothalamic-pituitary-adrenal axis making the diagnosis of Cushing's syndrome even more challenging. This is particularly so since urine free cortisol (UFC) testing is not useful in CKD. The case report by Stroud et al. in this issue of the European Journal of Endocrinology highlights this problem by finding normal UFC in a patient with pituitary ACTH-dependent Cushing's syndrome. Elevated late-night salivary cortisol (LNSC) testing was diagnostic and pituitary adenomectomy was curative. LNSC measurement is the diagnostic test of choice in patients with suspected Cushing's syndrome, particularly in the presence of CKD..
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http://dx.doi.org/10.1530/EJE-19-0560DOI Listing
October 2019

A Long-Acting Neutralizing Monoclonal ACTH Antibody Blocks Corticosterone and Adrenal Gene Responses in Neonatal Rats.

Endocrinology 2019 07;160(7):1719-1730

Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Aurora Research Institute, Milwaukee, Wisconsin.

The control of steroidogenesis in the neonatal adrenal gland is of great clinical interest. We have previously demonstrated that the postnatal day (PD) 2 rat exhibits a large plasma corticosterone response to hypoxia in the absence of an increase in plasma ACTH measured by RIA, whereas the corticosterone response to exogenous ACTH is intact. By PD8, the corticosterone response to hypoxia is clearly ACTH-dependent. We hypothesized that this apparently ACTH-independent response to hypoxia in the newborn rat is due to an increase in a bioactive, nonimmunoassayable form of ACTH. To evaluate this phenomenon, we pretreated neonatal rats with a novel, specific, neutralizing anti-ACTH antibody (ALD1611) (20 mg/kg or 1 mg/kg IP) on the morning of PD1, PD7, and PD14. Twenty-four hours later, we measured hypoxia- or ACTH-stimulated plasma ACTH and corticosterone. For long-term effects, ALD1611 was given on PD1 and pups were studied on PD8 and PD15. Pretreatment with ALD1611 significantly decreased baseline corticosterone and completely blocked the corticosterone response to hypoxia and exogenous ACTH stimulation at all ages. The effect of 1 mg/kg ALD1611 on PD1 had dissipated by PD15. The decrease in corticosterone in ALD1611-treated pups was associated with decreases in baseline and hypoxia- and ACTH-stimulated adrenal Ldlr, Mrap, and Star mRNA expression at all ages. The adrenal response to hypoxia in the newborn rat is ACTH-dependent, suggesting the release of nonimmunoassayable, biologically active forms of ACTH. ALD1611 is useful as a tool to attenuate stress-induced, ACTH-dependent adrenal steroidogenesis in vivo.
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http://dx.doi.org/10.1210/en.2019-00117DOI Listing
July 2019

Assay-Specific Spurious ACTH Results Lead to Misdiagnosis, Unnecessary Testing, and Surgical Misadventure-A Case Series.

J Endocr Soc 2019 Apr 20;3(4):763-772. Epub 2019 Feb 20.

Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.

The proper clinical evaluation of pituitary and adrenal disorders depends on the accurate measurement of plasma ACTH. The modern two-site sandwich ACTH immunoassay is a great improvement compared with older methods but still has the potential for interferences such as heterophile antibodies and pro-opiomelanocortin (POMC) and ACTH fragments. We report the cases of five patients in whom the diagnosis or differential diagnosis of Cushing syndrome was confounded by erroneously elevated results from the Siemens ACTH Immulite assay [ACTH(Immulite)] that were resolved using the Roche Cobas or Tosoh AIA [ACTH(Cobas) and ACTH(AIA), respectively]. In one case, falsely elevated ACTH(Immulite) results owing to interfering antibodies resulted in several invasive differential diagnostic procedures (including inferior petrosal sinus sampling), MRI, and unnecessary pituitary surgery. ACTH(Cobas) measurements were normal, and further studies excluded the diagnosis of Cushing syndrome. In three cases, either Cushing disease or occult ectopic ACTH were suspected owing to elevated ACTH(Immulite) results. However, adrenal (ACTH-independent) Cushing syndrome was established using ACTH(AIA) or ACTH(Cobas) and proved surgically. In one case, ectopic ACTH was suspected owing to elevated ACTH(Immulite) results; however, the ACTH(Cobas) findings led to the diagnosis of alcohol-induced hypercortisolism that resolved with abstinence. We have concluded that ACTH(Immulite) results can be falsely increased and alternate ACTH assays should be used in the diagnosis or differential diagnosis of clinical disorders of the hypothalamic-pituitary-adrenal axis.
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http://dx.doi.org/10.1210/js.2019-00027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446888PMC
April 2019

Glucocorticoid Receptor Mutations and Hypersensitivity to Endogenous and Exogenous Glucocorticoids.

J Clin Endocrinol Metab 2018 10;103(10):3630-3639

National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.

Background: The glucocorticoid receptor (GR) consists of two alternatively spliced isoforms: GRα, which activates gene transcription, and GRβ, a dominant-negative receptor. Theoretically, inactivating variants of GRβ could result in glucocorticoid hypersensitivity.

Design: A 46-year-old woman presented for evaluation of adrenal insufficiency prompted by low plasma cortisol levels and multiple unexplained symptoms but without clinical evidence of glucocorticoid insufficiency. To explain these findings, extensive clinical, genetic, and molecular studies were performed.

Methods: Standard clinical methods assessed the patient's hypothalamic-pituitary-adrenal axis. Validated molecular techniques were used for receptor sequencing, stable transfections, stimulation of candidate genes, cDNA arrays, Ingenuity Pathway Analysis, volcano analysis, and isolation and analysis of the patient's mononuclear cells.

Results: Clinical studies excluded primary or secondary adrenal insufficiency, established consistently low basal cortisol levels, and demonstrated hypersensitivity to ultra-low-dose dexamethasone. Receptor sequencing identified two variants of GR9β (A3669G and G3134T) as well as the known Bcl1 polymorphism. Reductionist studies using stable osteosarcoma cell lines transfected with the GRβ variants demonstrated glucocorticoid hypersensitivity of transcribed genes on cDNA array analysis. The patient's monocytes responded to hydrocortisone with exaggerated stimulation of the candidate genes GILZ and FKBP5.

Conclusion: Two variants of the dominant-negative GRβ, in conjunction with a common Bcl1 intron variant, resulted in hypersensitivity to endogenous and exogenous glucocorticoids and, as a reflection of severity, low circulating cortisol levels without clinical evidence of glucocorticoid insufficiency. This prismatic case exemplifies the unique effects of variants of a dominant-negative receptor.
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http://dx.doi.org/10.1210/jc.2018-00352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179182PMC
October 2018

Programming of the Adult HPA Axis After Neonatal Separation and Environmental Stress in Male and Female Rats.

Endocrinology 2018 07;159(7):2777-2789

Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Aurora Research Institute, Milwaukee, Wisconsin.

Maternal separation, hypoxia, and hypothermia are common stressors in the premature neonate. Using our rat model of human prematurity, we evaluated sexual dimorphisms in the long-term effects of these neonatal stressors on behavior of the hypothalamic-pituitary-adrenal (HPA) axis in adult rats. Neonatal rats were exposed daily on postnatal days 2 to 6 to maternal separation with normoxia, with hypoxia allowing spontaneous hypothermia, with hypothermia per se, and with hypoxia while maintaining isothermia with external heat. The major findings were that (a) prior maternal-neonatal separation during the first week of postnatal life attenuated the plasma ACTH and corticosterone response to restraint stress in adult male but not female rats, (b) prior neonatal hypothermia augmented the plasma ACTH and corticosterone response to restraint stress in adult male rats, but not female rats, and (c) changes in hypothalamic, pituitary, and adrenal mRNA expression did not account for most of these HPA axis effects. Most of the programming effects on adult HPA axis was attributed to prior maternal-neonatal separation alone (with normoxia) because the addition of hypoxia with spontaneous hypothermia, hypothermia per se, and hypoxia while preventing hypothermia during maternal-neonatal separation had minimal effects on the HPA axis. These results may inform strategies to prevent sexually dimorphic sequelae of neonatal stress including those due to medical interventions.
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http://dx.doi.org/10.1210/en.2018-00370DOI Listing
July 2018

Effect of a melanocortin type 2 receptor (MC2R) antagonist on the corticosterone response to hypoxia and ACTH stimulation in the neonatal rat.

Am J Physiol Regul Integr Comp Physiol 2018 07 2;315(1):R128-R133. Epub 2018 May 2.

Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Aurora Research Institute , Milwaukee, Wisconsin.

The adrenal stress response in the neonatal rat shifts from ACTH-independent to ACTH-dependent between postnatal days 2 (PD2) and 8 (PD8). This may be due to an increase in an endogenous, bioactive, nonimmunoreactive ligand to the melanocortin type 2 receptor (MC2R). GPS1574 is a newly described MC2R antagonist that we have shown to be effective in vitro. Further experimentation with GPS1574 would allow better insight into this seemingly ACTH-independent steroidogenic response in neonates. We evaluated the acute corticosterone response to hypoxia or ACTH injection following pretreatment with GPS1574 (32 mg/kg) or vehicle for GPS1574 in PD2, PD8, and PD15 rat pups. Pretreatment with GPS1574 decreased baseline corticosterone in PD2 pups but increased baseline corticosterone in PD8 and PD15 pups. GPS1574 did not attenuate the corticosterone response to hypoxia in PD2 pups and augmented the corticosterone response in PD8 and PD15 pups. GPS1574 augmented the corticosterone response to ACTH in PD2 and PD15 pups but had no significant impact on the response in PD8 pups. Baseline adrenal Mrap and Star mRNA increased from PD2 to PD15, whereas Mrap2 mRNA expression was low and did not change with age. The data suggest that GPS1574 is not a pure MC2R antagonist, but rather acts as a biasing agonist/antagonist. Its ability to attenuate or augment the adrenal response may depend on the ambient plasma ACTH concentration and/or developmental changes in early transduction steroidogenic pathway genes.
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http://dx.doi.org/10.1152/ajpregu.00009.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087887PMC
July 2018

Differentiation of pathologic/neoplastic hypercortisolism (Cushing syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as Pseudo-Cushing syndrome): response to Letter to the Editor.

Eur J Endocrinol 2018 03;178(3):L3

Departments of MedicineSurgery, and Physiology, Medical College of Wisconsin and Endocrine Research Laboratory, Aurora St Luke's Medical Center, Aurora Research Institute, Milwaukee, Wisconsin, USA.

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http://dx.doi.org/10.1530/EJE-17-1034DOI Listing
March 2018

Insulin sensitivity, leptin, adiponectin, resistin, and testosterone in adult male and female rats after maternal-neonatal separation and environmental stress.

Am J Physiol Regul Integr Comp Physiol 2018 01 6;314(1):R12-R21. Epub 2017 Sep 6.

Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Aurora Research Institute , Milwaukee, Wisconsin.

Care of premature infants often requires parental and caregiver separation, particularly during hypoxic and hypothermic episodes. We have established a neonatal rat model of human prematurity involving maternal-neonatal separation and hypoxia with spontaneous hypothermia prevented by external heat. Adults previously exposed to these neonatal stressors show a sex difference in the insulin and glucose response to arginine stimulation suggesting a state of insulin resistance. The current study used this cohort of adult rats to evaluate insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)], plasma adipokines (reflecting insulin resistance states), and testosterone. The major findings were that daily maternal-neonatal separation led to an increase in body weight and HOMA-IR in adult male and female rats and increased plasma leptin in adult male rats only; neither prior neonatal hypoxia (without or with body temperature control) nor neonatal hypothermia altered subsequent adult HOMA-IR or plasma adiponectin. Adult male-female differences in plasma leptin were lost with prior exposure to neonatal hypoxia or hypothermia; male-female differences in resistin were lost in the adults that were exposed to hypoxia and spontaneous hypothermia as neonates. Exposure of neonates to daily hypoxia without spontaneous hypothermia led to a decrease in plasma testosterone in adult male rats. We conclude that neonatal stressors result in subsequent adult sex-dependent increases in insulin resistance and adipokines and that our rat model of prematurity with hypoxia without hypothermia alters adult testosterone dynamics.
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http://dx.doi.org/10.1152/ajpregu.00271.2017DOI Listing
January 2018

Increase in the circulating endocannabinoid 2-arachidonoylglycerol is associated with gabapentin use in septic ICU patients.

Endocrine 2017 10 5;58(1):203-204. Epub 2017 Sep 5.

Neuroscience Research Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.

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http://dx.doi.org/10.1007/s12020-017-1399-xDOI Listing
October 2017

DIAGNOSIS OF ENDOCRINE DISEASE: Differentiation of pathologic/neoplastic hypercortisolism (Cushing's syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing's syndrome).

Eur J Endocrinol 2017 May 8;176(5):R205-R216. Epub 2017 Feb 8.

Departments of MedicineSurgery, and Physiology, Medical College of Wisconsin and Endocrine Research Laboratory, Aurora St Luke's Medical Center, Aurora Research Institute, Milwaukee, Wisconsin, USA.

Endogenous hypercortisolism (Cushing's syndrome) usually implies the presence of a pathologic condition caused by either an ACTH-secreting neoplasm or autonomous cortisol secretion from a benign or malignant adrenal neoplasm. However, sustained or intermittent hypercortisolism may also accompany many medical disorders that stimulate physiologic/non-neoplastic activation of the HPA axis (formerly known as pseudo-Cushing's syndrome); these two entities may share indistinguishable clinical and biochemical features. A thorough history and physical examination is often the best (and sometimes only) way to exclude pathologic/neoplastic hypercortisolism. The presence of alcoholism, renal failure, poorly controlled diabetes and severe neuropsychiatric disorders should always raise suspicion that the presence of hypercortisolism may be related to physiologic/non-neoplastic Cushing's syndrome. As late-night salivary cortisol and low-dose dexamethasone suppression have good sensitivity and negative predictive value, normal studies exclude Cushing's syndrome of any form. However, these tests have imperfect specificity and additional testing over time with clinical follow-up is often needed. When there is persistent diagnostic uncertainty, secondary tests such as the DDAVP stimulation test and the dexamethasone-CRH test may provide evidence for the presence or absence of an ACTH-secreting tumor. This review will define and characterize the numerous causes of physiologic/non-neoplastic hypercortisolism and provide a rational clinical and biochemical approach to distinguish it from pathologic/neoplastic hypercortisolism (true Cushing's syndrome).
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http://dx.doi.org/10.1530/EJE-16-0946DOI Listing
May 2017

Is the hypothalamic-pituitary-adrenal axis disrupted in type 2 diabetes mellitus?

Endocrine 2016 Nov 30;54(2):273-275. Epub 2016 Sep 30.

Endocrinology Center, Froedtert/Medical College of Wisconsin, North Hills Health Center, Menomonee Falls, WI, 53051, USA.

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http://dx.doi.org/10.1007/s12020-016-1108-1DOI Listing
November 2016

Sex differences in adult rat insulin and glucose responses to arginine: programming effects of neonatal separation, hypoxia, and hypothermia.

Physiol Rep 2016 Sep;4(18)

Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Aurora Research Institute, Milwaukee, Wisconsin Departments of Medicine, Surgery, and Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin

Acute neonatal hypoxia, a common stressor, causes a spontaneous decrease in body temperature which may be protective. There is consensus that hypothermia should be prevented during acute hypoxia in the human neonate; however, this may be an additional stress with negative consequences. We hypothesize that maintaining body temperature during hypoxia in the first week of postnatal life alters the subsequent insulin, glucose, and glucagon secretion in adult rats. Rat pups were separated from their dam daily from postnatal days (PD) 2-6 for the following 90 min experimental treatments: (1) normoxic separation (control), (2) hypoxia (8% O) allowing spontaneous hypothermia, (3) normoxic hypothermia with external cold, and (4) exposure to 8% O while maintaining body temperature using external heat. An additional normoxic non-separated control group was performed to determine if separation per se changed the adult phenotype. Plasma insulin, glucose, and glucagon responses to arginine stimulation were evaluated from PD105 to PD133. Maternal separation (compared to non-separated neonates) had more pronounced effects on the adult response to arginine compared to the hypoxic, hypothermic, and hypoxic-isothermic neonatal treatments. Adult males exposed to neonatal maternal separation had augmented insulin and glucose responses to arginine compared to unseparated controls. Additionally, neonatal treatment had a significant effect on body weight gain; adults exposed to neonatal maternal separation were significantly heavier. Female adults had significantly smaller insulin and glucose responses to arginine regardless of neonatal treatment. Neonatal maternal separation during the first week of life significantly altered adult beta-cell function in a sexually dimorphic manner.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037920PMC
http://dx.doi.org/10.14814/phy2.12972DOI Listing
September 2016

Do the Effects of the Triorganotin Tributyltin on the Hypothalamic-Pituitary-Adrenal Axis In Vivo Contribute to Its Environmental Toxicity?

Authors:
Hershel Raff

Endocrinology 2016 08;157(8):2996-8

Departments of Medicine, Surgery, and Physiology, Medical College of Wisconsin, and Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Aurora Research Institute, Milwaukee, Wisconsin 53215.

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http://dx.doi.org/10.1210/en.2016-1400DOI Listing
August 2016

CORT, Cort, B, Corticosterone, and now Cortistatin: Enough Already!

Authors:
Hershel Raff

Endocrinology 2016 09 28;157(9):3307-8. Epub 2016 Jul 28.

Departments of Medicine, Surgery, and Physiology, Medical College of Wisconsin, and Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Aurora Research Institute, Milwaukee, Wisconsin 53215.

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http://dx.doi.org/10.1210/en.2016-1500DOI Listing
September 2016

Dissociation of ACTH and cortisol in septic and non-septic ICU patients.

Endocrine 2017 Jan 18;55(1):307-310. Epub 2016 Jul 18.

Aurora Critical Care Service, Aurora St. Luke's Medical Center, Milwaukee, WI, 53215, USA.

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http://dx.doi.org/10.1007/s12020-016-1034-2DOI Listing
January 2017

Effect of Novel Melanocortin Type 2 Receptor Antagonists on the Corticosterone Response to ACTH in the Neonatal Rat Adrenal Gland In Vivo and In Vitro.

Front Endocrinol (Lausanne) 2016 21;7:23. Epub 2016 Mar 21.

Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA; Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Aurora Research Institute, Milwaukee, WI, USA.

Stress-induced increases in neonatal corticosterone demonstrate a unique shift from ACTH independence to ACTH dependence between postnatal day 2 (PD2) and day 8 (PD8) in newborn rats. This shift could be due to the binding of a bioactive, non--immunoreactive plasma ligand to the adrenocortical melanocortin 2 receptor (MC2R) (ACTH receptor). A potent MC2R antagonist would be useful to evaluate this phenomenon in the neonate. Therefore, we investigated the acute corticosterone response to ACTH(1-39) injection in rat pups pretreated with newly developed MC2R antagonists (GPS1573 and GPS1574), which have not been tested in vivo. The doses used in vivo were based on their in vitro potency, with GP1573 being more potent than GPS1574. GPS1573 (PD2 and PD8), GPS1574 (PD2 only), or vehicle were injected intraperitoneally (ip) 10 min before baseline sampling. Then, 0.001 mg/kg of ACTH(1-39) was injected ip, and subsequent blood samples obtained for the measurement of plasma corticosterone. Pretreatment of PD2 pups with GPS1573 demonstrated augmentation, rather than inhibition, of the corticosterone response to ACTH. In PD8 pups, pretreatment with 0.1 mg/kg GPS1573, but not 4 mg/kg, augmented the corticosterone response to ACTH. Pretreatment with GPS1574 attenuated the plasma corticosterone response to ACTH at 30 min in PD2 pups. The activity of these two compounds in vivo do not match their potency in vitro, with GPS1573 leading to a small augmentation of the corticosterone response to ACTH in vivo while GPS1574 resulted in inhibition.
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http://dx.doi.org/10.3389/fendo.2016.00023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800183PMC
April 2016

Measurement of Salivary Cortisone to Assess the Adequacy of Hydrocortisone Replacement.

Authors:
Hershel Raff

J Clin Endocrinol Metab 2016 04 18;101(4):1350-2. Epub 2016 Mar 18.

Departments of Medicine, Surgery, and Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; and Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Aurora Research Institute, Milwaukee, Wisconsin 53215.

Context: This Commentary discusses the study of Debono et al (19) and focuses on the potential use of multiple salivary cortisone measurements to evaluate the adequacy of hydrocortisone replacement therapy. Salivary cortisone, typically measured using liquid chromatography-tandem mass spectrometry, accurately reflects plasma free cortisol because of the expression of 11-β -hydroxysteroid dehydrogenase in the salivary gland. Debono et al showed that multiple, sequential salivary cortisone measurements obtained over a 12-hour period correlated with plasma free cortisol in subjects receiving intravenous or oral hydrocortisone (authentic cortisol).

Conclusions: Hopefully, these studies will lead to a simplified protocol with fewer samples for the measurement of salivary cortisone that can reliably assess the adequacy of hydrocortisone replacement in patients with adrenal insufficiency. This protocol has to be cost-effective and be feasible to obtain timed salivary samples accurately at home. It would be a significant advance to be able to monitor hydrocortisone replacement therapy with as few as one or two salivary cortisone measurements.
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http://dx.doi.org/10.1210/jc.2016-1228DOI Listing
April 2016

Intermittent neonatal hypoxia elicits the upregulation of inflammatory-related genes in adult male rats through long-lasting programming effects.

Physiol Rep 2015 Dec;3(12)

Endocrine Research Laboratory, Aurora St. Luke's Medical Center Aurora Research Institute, Milwaukee, Wisconsin Departments of Medicine, Surgery, and Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin

The long-term effects of neonatal intermittent hypoxia (IH), an accepted model of apnea-induced hypoxia, are unclear. We have previously shown lasting "programming" effects on the HPA axis in adult rats exposed to neonatal IH. We hypothesized that neonatal rat exposure to IH will subsequently result in a heightened inflammatory state in the adult. Rat pups were exposed to normoxia (control) or six cycles of 5% IH or 10% IH over one hour daily from postnatal day 2-6. Plasma samples from blood obtained at 114 days of age were analyzed by assessing the capacity to induce transcription in a healthy peripheral blood mononuclear cell (PBMC) population and read using a high-density microarray. The analysis of plasma from adult rats previously exposed to neonatal 5% IH versus 10% IH resulted in 2579 significantly regulated genes including increased expression of Cxcl1, Cxcl2, Ccl3, Il1a, and Il1b. We conclude that neonatal exposure to intermittent hypoxia elicits a long-lasting programming effect in the adult resulting in an upregulation of inflammatory-related genes.
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http://dx.doi.org/10.14814/phy2.12646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760434PMC
December 2015

Cushing syndrome: update on testing.

Authors:
Hershel Raff

Endocrinol Metab Clin North Am 2015 Mar 4;44(1):43-50. Epub 2014 Nov 4.

Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Aurora Research Institute, 2801 West KK River Parkway, Suite 245, Milwaukee, WI 53215, USA. Electronic address:

Endogenous hypercortisolism (Cushing syndrome) is one of the most enigmatic diseases in clinical medicine. The diagnosis and differential diagnosis of Cushing syndrome depend on proper laboratory evaluation. In this review, an update is provided on selected critical issues in the diagnosis and differential diagnosis of Cushing syndrome: the use of late-night salivary cortisol in initial diagnosis and for postoperative surveillance, and the use of prolactin measurement to improve the performance of inferior petrosal sinus sampling to distinguish Cushing disease from ectopic adrenocorticotropic hormone (ACTH) syndrome during differential diagnosis of ACTH-dependent Cushing syndrome.
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http://dx.doi.org/10.1016/j.ecl.2014.10.005DOI Listing
March 2015

Cushing's syndrome: from physiological principles to diagnosis and clinical care.

J Physiol 2015 Feb 5;593(3):493-506. Epub 2015 Jan 5.

Departments of Medicine, Surgery, and Physiology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA; Endocrine Research Laboratory, Aurora St Luke's Medical Center, Aurora Research Institute, Milwaukee, WI, 53215, USA.

The physiological control of cortisol synthesis in the adrenal cortex involves stimulation of adrenocorticotrophic hormone (ACTH) by hypothalamic corticotrophin-releasing hormone (CRH) and then stimulation of the adrenal by ACTH. The control loop of the hypothalamic-pituitary-adrenal (HPA) axis is closed by negative feedback of cortisol on the hypothalamus and pituitary. Understanding this system is required to master the diagnosis, differential diagnosis and treatment of endogenous hypercortisolism--Cushing's syndrome. Endogenous Cushing's syndrome is caused either by excess ACTH secretion or by autonomous cortisol release from the adrenal cortex. Diagnosis of cortisol excess exploits three physiological principles: failure to achieve the normal nadir in the cortisol diurnal rhythm, loss of sensitivity of ACTH-secreting tumours to cortisol negative feedback, and increased excretion of free cortisol in the urine. Differentiating a pituitary source of excess ACTH (Cushing's disease) from an ectopic source is accomplished by imaging the pituitary and sampling for ACTH in the venous drainage of the pituitary. With surgical removal of ACTH or cortisol-secreting tumours, secondary adrenal insufficiency ensues because of the prior suppression of the HPA axis by glucocorticoid negative feedback. Medical therapy is targeted to the anatomical location of the dysregulated component of the HPA axis. Future research will focus on new diagnostics and treatments of Cushing's syndrome. These are elegant examples of translational research: understanding basic physiology informs the development of new approaches to diagnosis and treatment. Appreciating pathophysiology generates new areas for inquiry of basic physiological and biochemical mechanisms.
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http://dx.doi.org/10.1113/jphysiol.2014.282871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324701PMC
February 2015