Publications by authors named "Karen K Miller"

188 Publications

Physiologic Transdermal Estradiol Replacement Mimics Effects of Endogenous Estrogen on Bone Outcomes in Hypoestrogenic Women with Anorexia Nervosa.

Nutrients 2022 Jun 21;14(13). Epub 2022 Jun 21.

Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.

Background: While physiologic estrogen replacement results in increases in areal bone mineral density (aBMD) in hypoestrogenic adolescent girls and young adult women with AN, data are lacking regarding its impact on measures of volumetric BMD (vBMD), bone geometry, and structure.

Methods: 23 young women with anorexia nervosa (AN) and 27 normal-weight healthy controls (HC) between 14-25 years old were followed for 12 months. AN participants received transdermal 17β-estradiol (continuously) with 10 days of cyclic oral progesterone (100 mg daily) every month for the study duration (AN-E+). DXA was used to measure aBMD and body composition, high resolution peripheral quantitative CT (HRpQCT) to assess vBMD, bone geometry and structure at the distal radius and tibia, and microfinite element analysis to estimate strength.

Results: Groups did not differ for age. Median baseline BMI z-scores were -1.13 (-1.58, -0.38) in AN-E+ vs. 0.08 (-0.40, 0.84) in HC ( < 0.0001). For most HRpQCT parameters and strength estimates, young women with AN receiving physiologic estrogen replacement demonstrated similar changes over 12 months as did normoestrogenic HC. Additionally, radial cortical tissue mineral density, cortical vBMD, and failure load increased ( = 0.01; = 0.02; = 0.004 respectively) over 12 months in AN-E+ compared to HC.

Conclusions: With physiologic estrogen replacement, bone accrual improved in AN to approximate changes observed in normoestrogenic controls followed without any intervention, with additional benefits observed for cortical tissue mineral density, cortical vBMD, and failure load at the radius in AN vs. controls. Thus, this strategy for estrogen replacement effectively mimics the effects of endogenous estrogen on bone structure and estimated strength.
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http://dx.doi.org/10.3390/nu14132557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268216PMC
June 2022

The GH/IGF-1 axis is associated with intrahepatic lipid content and hepatocellular damage in overweight/obesity.

J Clin Endocrinol Metab 2022 Jul 2. Epub 2022 Jul 2.

Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Context: Obesity is a state of relative growth hormone (GH) deficiency, and GH has been identified as a candidate disease-modifying target in nonalcoholic fatty liver disease (NAFLD) because of its lipolytic and anti-inflammatory properties. However, the GH/IGF-1 axis has not been well characterized in NAFLD.

Objective: Investigate GH and IGF-1 in relation to intrahepatic lipid content (IHL) and markers of hepatocellular damage and fibrosis in NAFLD.

Design: Cross-sectional.

Participants: 102 adults (43% women), 19-67yo, BMI ≥25 kg/m 2, without type 2 diabetes.

Measures: IHL by magnetic resonance spectroscopy; NAFLD was defined by ≥5% IHL. Peak-stimulated GH in response to GH releasing hormone and arginine. Serum IGF-1 (LC/MS).

Results: There was no difference in mean age, BMI or sex distribution in NAFLD vs controls. Mean (±SD) IHL was higher in NAFLD vs controls (21.8±13.3% vs 2.9±1.1%, p<0.0001). Mean peak-stimulated GH was lower in NAFLD vs controls (9.0±6.3 vs 15.4±11.2 ng/mL, p=0.003), including after controlling for age, sex, visceral adipose tissue and fasting glucose. In a stepwise model, peak-stimulated GH predicted 14.6% of the variability in IHL (p=0.004). Higher peak-stimulated GH was also associated with lower ALT. Higher IGF-1 was associated with lower risk of liver fibrosis by Fibrosis-4 scores.

Conclusions: Individuals with NAFLD have lower peak-stimulated GH but similar IGF-1 levels versus controls. Higher peak-stimulated GH is associated with lower IHL and less hepatocellular damage. Higher IGF-1 is associated with more favorable fibrosis risk scores. These data implicate GH and IGF-1 as potential disease modifiers in the development and progression of NAFLD.
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http://dx.doi.org/10.1210/clinem/dgac405DOI Listing
July 2022

Dehydroepiandrosterone sulfate levels predict weight gain in women with anorexia nervosa.

Int J Eat Disord 2022 Aug 2;55(8):1100-1107. Epub 2022 Jul 2.

Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

Objective: Anorexia nervosa (AN) is a serious condition characterized by undernutrition, complicated by endocrine dysregulation, and with few predictors of recovery. Urinary free cortisol (UFC) is a predictor of weight gain, but 24-h urine samples are challenging to collect. We hypothesized that serum dehydroepiandrosterone sulfate (DHEAS), which like cortisol is regulated by adrenocorticotropic hormone (ACTH), would predict weight gain and increases in fat mass in women with AN.

Methods: We prospectively studied 34 women with AN and atypical AN, mean age 27.4 ± 7.7 years (mean ± SD), who received placebo in a 6-month randomized trial. Baseline DHEAS and 24-h UFC were measured by liquid chromatography with tandem mass spectrometry. Body composition was assessed at baseline and 6 months by DXA and cross-sectional abdominal CT at L4.

Results: Mean baseline DHEAS level was 173 ± 70 μg/dl (0.7 ± 0.3 times the mean normal range for age) and mean baseline UFC (n = 15) was 20 ± 18 μg/24 h (normal: 0-50 μg/24 h). Higher DHEAS levels predicted weight gain over 6 months (r = 0.61, p < .001). DHEAS levels also predicted increases in fat mass (r = 0.40, p = .03), appendicular lean mass (r = 0.38, p = .04), and abdominal adipose tissue (r = 0.60, p < .001). All associations remained significant after controlling for age, baseline BMI, OCP use, duration of AN, and SSRI/SNRI use. DHEAS levels correlated with UFC (r = 0.61, p = .02).

Discussion: In women with AN, higher serum DHEAS predicts weight gain and increases in fat and muscle mass. Additional studies are needed to confirm these findings and further elucidate the association between DHEAS and weight gain.

Public Significance: Anorexia nervosa is a severe psychiatric condition, and predictors of weight recovery are needed to improve prognostication and guide therapeutic decision making. While urinary cortisol is a predictor of weight gain, 24-h urine collections are challenging to obtain. Like cortisol, dehydroepiandrosterone sulfate (DHEAS) is a hormone produced by the adrenal glands. As a readily available blood test, DHEAS holds promise as more practical biomarker of weight gain in anorexia nervosa.
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http://dx.doi.org/10.1002/eat.23767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9357210PMC
August 2022

Association between muscle mass and diabetes prevalence independent of body fat distribution in adults under 50 years old.

Nutr Diabetes 2022 05 28;12(1):29. Epub 2022 May 28.

Neuroendocrine Unit, Massachusetts General Hospital, Boston, MA, USA.

Background/objectives: Although relatively less muscle mass has been associated with greater diabetes prevalence, whether there is an association between muscle mass and diabetes prevalence independent of body fat distribution is unknown. The objective was to determine whether less skeletal muscle mass is associated with greater diabetes prevalence in young men and women independent of body fat distribution.

Subjects/methods: One thousand seven hundred and sixty-four adults, aged 20-49 years old, from the United States National Health and Nutrition Examination Survey (2005-2006). Body composition, including appendicular lean mass (ALM), was measured by dual-energy x-ray absorptiometry. Diabetes was defined as fasting blood glucose ≥7 mmol/l, 2-h blood glucose ≥11.1 mmol/l on 75 g OGTT, HbA1c ≥ 48 mmol/mol (6.5%), use of diabetes medications, or self-reported diagnosis of diabetes.

Results: The odds of diabetes were 1.31 times higher in men [OR 1.31 (1.18-1.45), p = 0.0001], and 1.24 times higher in women [OR 1.24 (1.05-1.46), p = 0.01], per percent decrease in ALM/weight after controlling for age, race, height, smoking, and education. After additionally controlling for android/gynoid fat, the odds of diabetes were 1.20 times higher per percent decrease in ALM/weight in men [OR 1.20 (1.04-1.37), p = 0.01]; an inverse association was also observed in women, albeit was not statistically significant [OR 1.08 (0.90-1.30), p = 0.42].

Conclusions: Less muscle mass was associated with greater diabetes prevalence independent of body fat distribution in young men. The association was not statistically significant in women after controlling for android and gynoid adiposity. Low muscle mass could be a causal factor in the development of type 2 diabetes or a correlated marker of higher metabolic risk.
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http://dx.doi.org/10.1038/s41387-022-00204-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9148314PMC
May 2022

Sprouting Angiogenesis in Human Pituitary Adenomas.

Front Oncol 2022 5;12:875219. Epub 2022 May 5.

Nephrology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.

Introduction: Angiogenesis in pituitary tumors is not fully understood, and a better understanding could help inform new pharmacologic therapies, particularly for aggressive pituitary tumors.

Materials And Methods: 219 human pituitary tumors and 12 normal pituitary glands were studied. Angiogenic genes were quantified by an angiogenesis qPCR array and a TaqMan probe-based absolute qPCR. Angiogenesis inhibition in pituitary tumors was evaluated with the endothelial tube formation assay and in RbΔ19 mice.

Results: 71 angiogenic genes, 40 of which are known to be involved in sprouting angiogenesis, were differentially expressed in pituitary tumors. Expression of endothelial markers CD31, CD34, and ENG was significantly higher in pituitary tumors, by 5.6, 22.3, and 8.2-fold, respectively, compared to in normal pituitary tissue. There was no significant difference in levels of the lymphatic endothelial marker LYVE1 in pituitary tumors compared with normal pituitary gland tissue. Pituitary tumors also expressed significantly higher levels of angiogenesis growth factors, including VEGFA (4.2-fold), VEGFB (2.2), VEGFC (19.3), PGF (13.4), ANGPT2 (9.2), PDGFA (2.7), PDGFB (10.5) and TGFB1 (3.8) compared to normal pituitary tissue. Expression of VEGFC and PGF was highly correlated with the expression of endothelial markers in tumor samples, including CD31, CD34, and ENG (endoglin, a co-receptor for TGFβ). Furthermore, VEGFR inhibitors inhibited angiogenesis induced by human pituitary tumors and prolonged survival of RbΔ19 mice.

Conclusion: Human pituitary tumors are characterized by more active angiogenesis than normal pituitary gland tissue in a manner consistent with sprouting angiogenesis. Angiogenesis in pituitary tumors is regulated mainly by PGF and VEGFC, not VEGFA and VEGFB. Angiogenesis inhibitors, such as the VEGFR2 inhibitor cabozantinib, may merit further investigation as therapies for aggressive human pituitary tumors.
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http://dx.doi.org/10.3389/fonc.2022.875219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9117625PMC
May 2022

Association of Traumatic Brain Injury With the Risk of Developing Chronic Cardiovascular, Endocrine, Neurological, and Psychiatric Disorders.

JAMA Netw Open 2022 04 1;5(4):e229478. Epub 2022 Apr 1.

Harvard Medical School, Boston, Massachusetts.

Importance: Increased risk of neurological and psychiatric conditions after traumatic brain injury (TBI) is well-defined. However, cardiovascular and endocrine comorbidity risk after TBI in individuals without these comorbidities and associations with post-TBI mortality have received little attention.

Objective: To assess the incidence of cardiovascular, endocrine, neurological, and psychiatric comorbidities in patients with mild TBI (mTBI) or moderate to severe TBI (msTBI) and analyze associations between post-TBI comorbidities and mortality.

Design, Setting, And Participants: This prospective longitudinal cohort study used hospital-based patient registry data from a tertiary academic medical center to select patients without any prior clinical comorbidities who experienced TBI from 2000 to 2015. Using the same data registry, individuals without head injuries, the unexposed group, and without target comorbidities were selected and age-, sex-, and race-frequency-matched to TBI subgroups. Patients were followed-up for up to 10 years. Data were analyzed in 2021.

Exposures: Mild or moderate to severe head trauma.

Main Outcomes And Measures: Cardiovascular, endocrine, neurologic, and psychiatric conditions were defined based on International Classification of Diseases, Ninth Revision (ICD-9) or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). Associations between TBI and comorbidities, as well as associations between the comorbidities and mortality, were analyzed.

Results: A total of 4351 patients with mTBI (median [IQR] age, 45 [29-57] years), 4351 patients with msTBI (median [IQR] age, 47 [30-58] years), and 4351 unexposed individuals (median [IQR] age, 46 [30-58] years) were included in analyses. In each group, 45% of participants were women. mTBI and msTBI were significantly associated with higher risks of cardiovascular, endocrine, neurologic, and psychiatric disorders compared with unexposed individuals. In particular, hypertension risk was increased in both mTBI (HR, 2.5; 95% CI, 2.1-2.9) and msTBI (HR, 2.4; 95% CI, 2.0-2.9) groups. Diabetes risk was increased in both mTBI (HR, 1.9; 95% CI, 1.4-2.7) and msTBI (HR, 1.9; 95% CI, 1.4-2.6) groups, and risk of ischemic stroke or transient ischemic attack was also increased in mTBI (HR, 2.2; 95% CI, 1.4-3.3) and msTBI (HR, 3.6; 95% CI, 2.4-5.3) groups. All comorbidities in the TBI subgroups emerged within a median (IQR) of 3.49 (1.76-5.96) years after injury. Risks for post-TBI comorbidities were also higher in patients aged 18 to 40 years compared with age-matched unexposed individuals: hypertension risk was increased in the mTBI (HR, 5.9; 95% CI, 3.9-9.1) and msTBI (HR, 3.9; 95% CI, 2.5-6.1) groups, while hyperlipidemia (HR, 2.3; 95% CI, 1.5-3.4) and diabetes (HR, 4.6; 95% CI, 2.1-9.9) were increased in the mTBI group. Individuals with msTBI, compared with unexposed patients, had higher risk of mortality (432 deaths [9.9%] vs 250 deaths [5.7%]; P < .001); postinjury hypertension (HR, 1.3; 95% CI, 1.1-1.7), coronary artery disease (HR, 2.2; 95% CI, 1.6-3.0), and adrenal insufficiency (HR, 6.2; 95% CI, 2.8-13.0) were also associated with higher mortality.

Conclusions And Relevance: These findings suggest that TBI of any severity was associated with a higher risk of chronic cardiovascular, endocrine, and neurological comorbidities in patients without baseline diagnoses. Medical comorbidities were observed in relatively young patients with TBI. Comorbidities occurring after TBI were associated with higher mortality. These findings suggest the need for a targeted screening program for multisystem diseases after TBI, particularly chronic cardiometabolic diseases.
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http://dx.doi.org/10.1001/jamanetworkopen.2022.9478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9051987PMC
April 2022

Quality of life after long-term biochemical control of acromegaly.

Pituitary 2022 Jun 27;25(3):531-539. Epub 2022 Apr 27.

Neuroendocrine Unit, Massachusetts General Hospital, 55 Fruit Street, Bulfinch 457, Boston, MA, 02114, USA.

Purpose: To assess long-term quality of life (QoL) in patients with sustained biochemical control of acromegaly, comparing those receiving vs not receiving pharmacotherapy (primary analysis); to assess change in QoL over time (secondary analysis).

Methods: Cross-sectional study, with a secondary longitudinal component, of 58 patients with biochemically controlled acromegaly. All had participated in studies assessing QoL years previously, after having undergone surgery ± radiotherapy. One cohort received medical therapy [MED (n = 33)]; the other did not [NO-MED (n = 25)]. QoL was assessed by the 36-Item-Short-Form Health Survey (SF-36), Acromegaly Quality of Life Questionnaire (AcroQoL), Gastrointestinal Quality of Life Index (GIQLI), Symptom Questionnaire, and QoL-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA).

Results: Mean (± SD) duration of biochemical control was 15.0 ± 6.4 years for MED and 20.4 ± 8.2 years for NO-MED (p = 0.007). 58% of subjects scored < 25% of normal on ≥ 1 SF-36 domain and 32% scored < 25% of normal on ≥ 4 of 8 domains. Comparing MED vs NO-MED and controlling for duration of biochemical control, there were no significant differences in QoL by SF-36, AcroQOL, GIQLI, Symptom Questionnaire, or QoL-AGHDA. Growth hormone deficiency (GHD) but not radiotherapy predicted poorer QoL. In MED, QoL improved over time in three AcroQoL domains and two GIQLI domains. In NO-MED, QoL worsened in two SF-36 domains and two Symptom Questionnaire domains; QoL-AGHDA scores also worsened in subjects with GHD.

Conclusion: A history of acromegaly and development of GHD, but not pharmacologic or radiotherapy, are detrimental to QoL, which remains poor over the long-term despite biochemical control.
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http://dx.doi.org/10.1007/s11102-022-01224-0DOI Listing
June 2022

Impact of GH administration on skeletal endpoints in adults with overweight/obesity.

Eur J Endocrinol 2022 Apr 21;186(6):619-629. Epub 2022 Apr 21.

Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

Objective: Overweight/obesity is associated with relative growth hormone (GH) deficiency and increased fracture risk. We hypothesized that GH administration would improve bone endpoints in individuals with overweight/obesity.

Design: An 18-month, randomized, double-blind, placebo-controlled study of GH, followed by 6-month observation.

Methods: In this study, 77 adults (53% men), aged 18-65 years, BMI ≥ 25 kg/m2, and BMD T- or Z-score ≤ -1.0 were randomized to daily subcutaneous GH or placebo, targeting IGF1 in the upper quartile of the age-appropriate normal range. Forty-nine completed 18 months. DXA, volumetric quantitative CT, and high-resolution peripheral quantitative CT were performed.

Results: Pre-treatment mean age (48 ± 12 years), BMI (33.1 ± 5.7 kg/m2), and BMD were similar between groups. P1NP, osteocalcin, and CTX increased (P < 0.005) and visceral adipose tissue decreased (P = 0.04) at 18 months in the GH vs placebo group. Hip and radius aBMD, spine and tibial vBMD, tibial cortical thickness, and radial and tibial failure load decreased in the GH vs placebo group (P < 0.05). Between 18 and 24 months (post-treatment observation period), radius aBMD and tibia cortical thickness increased in the GH vs placebo group. At 24 months, there were no differences between the GH and placebo groups in bone density, structure, or strength compared to baseline.

Conclusions: GH administration for 18 months increased bone turnover in adults with overweight/obesity. It also decreased some measures of BMD, bone microarchitecture, and bone strength, which all returned to pre-treatment levels 6 months post-therapy. Whether GH administration increases BMD with longer treatment duration, or after mineralization of an expanded remodeling space post-treatment, requires further investigation.
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http://dx.doi.org/10.1530/EJE-21-1061DOI Listing
April 2022

The Upregulation of Molecules Related to Tumor Immune Escape in Human Pituitary Adenomas.

Front Endocrinol (Lausanne) 2021 21;12:726448. Epub 2021 Oct 21.

Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.

Human pituitary adenomas are one of the most common intracranial neoplasms. Although most of these tumors are benign and can be treated medically or by transsphenoidal surgery, a subset of these tumors are fast-growing, aggressive, recur, and remain a therapeutic dilemma. Because antibodies against immune checkpoint receptors PD-1 and CLTA-4 are now routinely used for cancer treatment, we quantified the expression of mRNA coding for PD-1, CLTA-4, and their ligands, PD-L1, PD-L2, CD80, and CD86 in human pituitary adenomas and normal pituitary glands, with the ultimate goal of exploiting immune checkpoint therapy in aggressive pituitary adenomas. Aggressive pituitary adenomas demonstrated an increased expression of PD-L2, CD80, and CD86 in compared to that of normal human pituitary glands. Furthermore, aggressive pituitary tumors demonstrated significantly higher levels of CD80 and CD86 compared to non-aggressive tumors. Our results establish a rationale for studying a potential role for immune checkpoint inhibition therapy in the treatment of pituitary adenomas.
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http://dx.doi.org/10.3389/fendo.2021.726448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566912PMC
February 2022

The effect of short-term high-caloric feeding and fasting on bone microarchitecture.

Bone 2022 01 25;154:116214. Epub 2021 Sep 25.

Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States of America.

Background: States of chronic overnutrition and undernutrition are both associated with impaired bone health and increased fracture risk but there are no data on bone microarchitecture following short-term controlled nutritional challenges.

Objective: The purpose of our study was to evaluate the impact of short-term high-caloric feeding and fasting on bone microarchitecture. We hypothesized that both high-caloric feeding and fasting would have negative effects on microarchitecture.

Materials And Methods: We recruited 23 adult healthy subjects (13 males, 10 females, mean age 33.2 ± 1.4 years, mean BMI 26.0 ± 1.5 kg/m). Subjects underwent an in-patient 10-day high-caloric visit (caloric intake with goal to achieve 7% weight gain), after which they went home to resume a normal diet for 13-18 days (stabilization period), and were then readmitted for a 10-day in-patient fasting stay (no caloric intake). All subjects underwent HRpQCT (XtremeCT, Scanco Medical AG, Brüttisellen, Switzerland) of the distal tibia and distal radius after each visit to assess volumetric bone mineral density (vBMD), trabecular and cortical microarchitecture, and strength estimates. The Wilcoxon signed rank test was used to perform within group comparisons.

Results: During the high-caloric period, there was a mean increase in weight by 6.3 + 1.7% (p < 0.0001). There were no significant changes in bone parameters in the distal tibia or distal radius (p > 0.05). During the stabilization period there was a significant reduction in weight by -2.7 + 1.9% (p < 0.0001) but no change in bone parameters (p > 0.05). During the fasting period there was a further reduction in weight by -8.8 + 1.2% (p < 0.0001). In the distal tibia, there was a significant increase in total and cortical vBMD, trabecular and cortical parameters as well as strength estimates (p < 0.05). In the distal radius there was an increase in total and trabecular vBMD (p < 0.05), while there were no changes in other microarchitecture parameters or strengths estimates.

Conclusion: Short-term fasting after high-caloric feeding improves vBMD, bone microarchitecture and strength estimates of the distal tibia, while short-term high-caloric feeding does not change vBMD or microarchitecture. These results suggest that short-term fasting after high-caloric feeding in healthy individuals improves bone health and that these changes can be detected using HRpQCT in-vivo.
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http://dx.doi.org/10.1016/j.bone.2021.116214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8671292PMC
January 2022

Distinct Hepatic Gene-Expression Patterns of NAFLD in Patients With Obesity.

Hepatol Commun 2022 01 11;6(1):77-89. Epub 2021 Aug 11.

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Approaches to manage nonalcoholic fatty liver disease (NAFLD) are limited by an incomplete understanding of disease pathogenesis. The aim of this study was to identify hepatic gene-expression patterns associated with different patterns of liver injury in a high-risk cohort of adults with obesity. Using the NanoString Technologies (Seattle, WA) nCounter assay, we quantified expression of 795 genes, hypothesized to be involved in hepatic fibrosis, inflammation, and steatosis, in liver tissue from 318 adults with obesity. Liver specimens were categorized into four distinct NAFLD phenotypes: normal liver histology (NLH), steatosis only (steatosis), nonalcoholic steatohepatitis without fibrosis (NASH F0), and NASH with fibrosis stage 1-4 (NASH F1-F4). One hundred twenty-five genes were significantly increasing or decreasing as NAFLD pathology progressed. Compared with NLH, NASH F0 was characterized by increased inflammatory gene expression, such as gamma-interferon-inducible lysosomal thiol reductase (IFI30) and chemokine (C-X-C motif) ligand 9 (CXCL9), while complement and coagulation related genes, such as C9 and complement component 4 binding protein beta (C4BPB), were reduced. In the presence of NASH F1-F4, extracellular matrix degrading proteinases and profibrotic/scar deposition genes, such as collagens and transforming growth factor beta 1 (TGFB1), were simultaneously increased, suggesting a dynamic state of tissue remodeling. Conclusion: In adults with obesity, distinct states of NAFLD are associated with intrahepatic perturbations in genes related to inflammation, complement and coagulation pathways, and tissue remodeling. These data provide insights into the dynamic pathogenesis of NAFLD in high-risk individuals.
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http://dx.doi.org/10.1002/hep4.1789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8710788PMC
January 2022

The biochemical diagnosis of adrenal insufficiency with modern cortisol assays: Reappraisal in the setting of opioid exposure and hospitalization.

Clin Endocrinol (Oxf) 2022 01 8;96(1):21-29. Epub 2021 Sep 8.

Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

Objective: We aimed to (1) examine the diagnosis of opioid-induced adrenal insufficiency, and (2) investigate the diagnostic value of a morning cortisol <83 nmol/L (3 µg/dl) for the diagnosis of adrenal insufficiency, using newer more specific cortisol assays and cut-offs.

Design: Retrospective study (5/2015-10/2020).

Participants: Cohort 1 (N = 75): adults who underwent cosyntropin stimulation testing and opioid exposure for >30 days. Cohort 2 (N = 854): adults, with or without opioid exposure, who had a morning cortisol level measured the same day as stimulation testing.

Measurements: Peak cortisol during cosyntropin stimulation testing. Sensitivity and specificity of morning serum cortisol for adrenal insufficiency.

Results: The prevalence of adrenal insufficiency in patients with chronic opioid exposure who underwent cosyntropin stimulation testing was 4.0% using a cortisol cutoff of <405 nmol/L (14.7 µg/dl) versus 19% using the traditional cutoff of <500 nmol/L (18.1 µg/dl). For hospitalized patients with and without opioid-exposure, 14 of 22 (64%) patients with morning cortisol levels of <83 nmol/L (3 µg/dl) passed cosyntropin stimulation testing. A morning cortisol level of <348 nmol/L (12.6 µg/dl) had 100% sensitivity (95% confidence interval: 84.5%-100%) for the diagnosis of adrenal insufficiency.

Conclusion: Applying a cutoff of <405 nmol/L (14.7 µg/dl), opioid-induced adrenal insufficiency is rare. Nearly 1 out of 6 patients would be reclassified as having adrenal insufficiency applying the guideline-recommended cutoff of <500 nmol/L (18.1 µg/dl). Serum morning cortisol <83 nmol/L (3 µg/dl) is not a valid diagnostic test for adrenal insufficiency in hospitalized patients, whether or not receiving opioids.
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http://dx.doi.org/10.1111/cen.14587DOI Listing
January 2022

Sequential Therapy With Recombinant Human IGF-1 Followed by Risedronate Increases Spine Bone Mineral Density in Women With Anorexia Nervosa: A Randomized, Placebo-Controlled Trial.

J Bone Miner Res 2021 11 2;36(11):2116-2126. Epub 2021 Sep 2.

Neuroendocrine Unit, Massachusetts General Hospital, Boston, MA, USA.

Anorexia nervosa is complicated by low bone mineral density (BMD) and increased fracture risk associated with low bone formation and high bone resorption. The lumbar spine is most severely affected. Low bone formation is associated with relative insulin-like growth factor 1 (IGF-1) deficiency. Our objective was to determine whether bone anabolic therapy with recombinant human (rh) IGF-1 used off-label followed by antiresorptive therapy with risedronate would increase BMD more than risedronate or placebo in women with anorexia nervosa. We conducted a 12-month, randomized, placebo-controlled study of 90 ambulatory women with anorexia nervosa and low areal BMD (aBMD). Participants were randomized to three groups: 6 months of rhIGF-1 followed by 6 months of risedronate ("rhIGF-1/Risedronate") (n = 33), 12 months of risedronate ("Risedronate") (n = 33), or double placebo ("Placebo") (n = 16). Outcome measures were lumbar spine (1° endpoint: postero-anterior [PA] spine), hip, and radius aBMD by dual-energy X-ray absorptiometry (DXA), and vertebral, tibial, and radial volumetric BMD (vBMD) and estimated strength by high-resolution peripheral quantitative computed tomography (HR-pCT) (for extremity measurements) and multi-detector computed tomography (for vertebral measurements). At baseline, mean age, body mass index (BMI), aBMD, and vBMD were similar among groups. At 12 months, mean PA lumbar spine aBMD was higher in the rhIGF-1/Risedronate (p = 0.03) group and trended toward being higher in the Risedronate group than Placebo. Mean lateral lumbar spine aBMD was higher, in the rhIGF-1/Risedronate than the Risedronate or Placebo groups (p < 0.05). Vertebral vBMD was higher, and estimated strength trended toward being higher, in the rhIGF-1/Risedronate than Placebo group (p < 0.05). Neither hip or radial aBMD or vBMD, nor radial or tibial estimated strength, differed among groups. rhIGF-1 was well tolerated. Therefore, sequential therapy with rhIGF-1 followed by risedronate increased lateral lumbar spine aBMD more than risedronate or placebo. Strategies that are anabolic and antiresorptive to bone may be effective at increasing BMD in women with anorexia nervosa. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595577PMC
November 2021

Bone marrow adipose tissue composition following high-caloric feeding and fasting.

Bone 2021 11 27;152:116093. Epub 2021 Jun 27.

Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States of America.

Background: Bone marrow adipose tissue (BMAT) plays a role in systemic energy metabolism and responds to nutritional changes. Chronic starvation as well as visceral adiposity are associated with BMAT accumulation. Two types of BMAT have been described which differ in anatomic location (proximal-regulated-rBMAT vs distal-constitutive-cBMAT) and composition (higher unsaturated lipids of cBMAT compared to rBMAT).

Objective: To determine the response of BMAT composition to short-term high-caloric feeding and fasting. We hypothesized that high-feeding and caloric restriction would be associated with differences in BMAT composition according to the skeletal site.

Materials And Methods: We examined 23 healthy subjects (13 m, 10 f, mean age 33 ± 7 years, BMI 26 ± 1.5 kg/m) who were admitted for a 10-day high-caloric stay (caloric intake with goal to achieve 7% weight gain) followed by discharge home for 13-18 days to resume normal diet (stabilization period), followed by a 10-day fasting stay (no caloric intake). Subjects underwent single voxel proton MR spectroscopy (1H-MRS) at 3T of the lumbar spine (L4) (rBMAT), the femoral diaphysis and distal tibial metaphysis (cBMAT) to determine BMAT composition (unsaturation index, UI and saturation index, SI). Within group comparisons were performed by the Wilcoxon signed rank test.

Results: After the high-calorie visit, SI of L4 increased compared to baseline (0.62 ± 0.27 to 0.70 ± 0.28, p = 0.02), and there was a trend of an increase in femoral SI and UI (p ≥ 0.07), while there was no significant change in tibial BMAT (p ≥ 0.13). During the stabilization period, SI of L4 decreased (0.70 ± 0.28 to 0.57 ± 0.21, p < 0.0001) and SI of the femoral diaphysis decreased (5.37 ± 2.27 to 5.09 ± 2.43, p = 0.03), while there was no significant change in UI or tibial BMAT (p ≥ 0.14). During the fasting period, SI of L4 increased (0.57 ± 0.21 to 0.63 ± 0.30, p = 0.03), while there was no change in UI (p = 0.7). SI and UI of femoral diaphysis decreased (5.09 ± 2.43 to 4.68 ± 2.15, p = 0.03, and 0.62 ± 0.42 to 0.47 ± 0.37, p = 0.02, respectively) and UI of the tibial metaphysis decreased (1.48 ± 0.49 to 1.24 ± 0.57, p = 0.04).

Conclusion: 1H-MRS is able to quantify BMAT composition during short-term nutritional challenges, showing a significant increase in SI of rBMAT during high caloric feeding and a differential response to fasting with an increase in SI of rBMAT and a decrease in SI and UI of femoral cBMAT and decrease in UI of tibial cBMAT.
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http://dx.doi.org/10.1016/j.bone.2021.116093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323345PMC
November 2021

Effect of Transdermal Estradiol and Insulin-like Growth Factor-1 on Bone Endpoints of Young Women With Anorexia Nervosa.

J Clin Endocrinol Metab 2021 06;106(7):2021-2035

Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Context: Anorexia nervosa (AN) is prevalent in adolescent girls and is associated with bone impairment driven by hormonal alterations in nutritional deficiency.

Objective: To assess the impact of estrogen replacement with and without recombinant human insulin-like growth factor-1 (rhIGF-1) administration on bone outcomes.

Design: Double-blind, randomized, placebo-controlled 12-month longitudinal study.

Participants: Seventy-five adolescent and young adult women with AN age 14 to 22 years. Thirty-three participants completed the study.

Intervention: Transdermal 17-beta estradiol 0.1 mg/day with (i) 30 mcg/kg/dose of rhIGF-1 administered subcutaneously twice daily (AN-IGF-1+) or (ii) placebo (AN-IGF-1-). The dose of rhIGF-1 was adjusted to maintain levels in the upper half of the normal pubertal range.

Main Outcome Measures: Bone turnover markers and bone density, geometry, microarchitecture, and strength estimates.

Results: Over 12 months, lumbar areal bone mineral density increased in AN-IGF-1- compared to AN-IGF-1+ (P = 0.004). AN-IGF-1+ demonstrated no improvement in areal BMD in the setting of variable compliance to estrogen treatment. Groups did not differ for 12-month changes in bone geometry, microarchitecture, volumetric bone mineral density (vBMD), or strength (and results did not change after controlling for weight changes over 12 months). Both groups had increases in radial cortical area and vBMD, and tibia cortical vBMD over 12 months. Levels of a bone resorption marker decreased in AN-IGF-1- (P = 0.042), while parathyroid hormone increased in AN-IGF-1+ (P = 0.019). AN-IGF-1- experienced irregular menses more frequently than did AN-IGF-1+, but incidence of all other adverse events did not differ between groups.

Conclusions: We found no additive benefit of rhIGF-1 administration for 12 months over transdermal estrogen replacement alone in this cohort of young women with AN.
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http://dx.doi.org/10.1210/clinem/dgab145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427708PMC
June 2021

Concussion and Risk of Chronic Medical and Behavioral Health Comorbidities.

J Neurotrauma 2021 06 6;38(13):1834-1841. Epub 2021 Apr 6.

Harvard Medical School, Boston, Massachusetts, USA.

While chronic neurological effects from concussion have been studied widely, little is known about possible links between concussion and long-term medical and behavioral comorbidities. We performed a retrospective cohort study of 9205 adult patients with concussion, matched to non-concussion controls from a hospital-based electronic medical registry. Patients with comorbidities before the index visit were excluded. Behavioral and medical comorbidities were defined by codes. Groups were followed for up to 10 years to identify comorbidity incidence after a concussion. Cox proportional hazards models were used to calculate associations between concussion and comorbidities after multi-variable adjustment. Patients with concussion were 57% male (median age: 31; interquartile range [IQR] = 23-48 years) at enrollment with a median follow-up time of 6.1 years (IQR = 4.2-9.1) and well-matched to healthy controls. Most (83%) concussions were evaluated in outpatient settings (5% inpatient). During follow-up, we found significantly higher risks of cardiovascular risks developing including hypertension (hazard ratio [HR] = 1.7, 95% confidence interval [CI]: 1.5-1.9), obesity (HR = 1.7, 95% CI: 1.3-2.0), and diabetes mellitus (HR = 1.8, 95% CI: 1.4-2.3) in the concussion group compared with controls. Similarly, psychiatric and neurological disorders such as depression (HR = 3.0, 95% CI: 2.6-3.5), psychosis (HR = 6.0, 95% CI: 4.2-8.6), stroke (HR = 2.1 95% CI: 1.5-2.9), and epilepsy (HR = 4.4, 95% CI: 3.2-5.9) were higher in the concussion group. Most comorbidities developed less than five years post-concussion. The risks for post-concussion comorbidities were also higher in patients under 40 years old compared with controls. Patients with concussion demonstrated an increased risk of development of medical and behavioral health comorbidities. Prospective studies are warranted to better describe the burden of long-term comorbidities in patients with concussion.
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http://dx.doi.org/10.1089/neu.2020.7484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219193PMC
June 2021

Effects of growth hormone receptor antagonism and somatostatin analog administration on quality of life in acromegaly.

Clin Endocrinol (Oxf) 2021 01 11;94(1):58-65. Epub 2020 Sep 11.

Neuroendocrine Unit, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.

Objective: Acromegaly is associated with impaired quality of life (QoL). We investigated the effects of biochemical control of acromegaly by growth hormone receptor antagonism vs somatostatin analog therapy on QoL.

Design: Cross-sectional.

Patients: 116 subjects: n = 55 receiving a somatostatin analog (SSA group); n = 29 receiving pegvisomant (PEG group); n = 32 active acromegaly on no medical therapy (ACTIVE group).

Measurements: Acromegaly QoL Questionnaire (AcroQoL), Rand 36-Item Short Form Survey (SF-36) and Gastrointestinal QoL Index (GIQLI); fasting glucose, insulin and IGF-1 levels (LC/MS, Quest Diagnostics).

Results: There were no group differences in mean age, BMI or sex [(whole cohort mean ± SD) age 52 ± 14 years, BMI 30 ± 6 kg/m , and male sex 38%]. Mean IGF-1 Z-scores were higher in ACTIVE (3.9 ± 1.0) vs SSA and PEG, which did not differ from one another (0.5 ± 0.7 and 0.5 ± 0.7, P < .0001 vs ACTIVE). Eighty-three per cent of PEG previously received somatostatin analogs, which had been discontinued due to lack of efficacy (52%) or side effects (41%). There were no differences in the four QoL primary end-points (AcroQoL Global Score, SF-36 Physical Component Summary Score, SF-36 Mental Health Summary Score and GIQLI Global Score) between SSA and PEG. Higher HbA1c, BMI and IGF-1 Z-scores were associated with poorer QoL in several domains.

Conclusion: Our data support a comparable QoL in patients receiving pegvisomant vs somatostatin analogs, despite the fact that the vast majority receiving pegvisomant did not respond to or were not able to tolerate somatostatin analogs.
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http://dx.doi.org/10.1111/cen.14309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9217182PMC
January 2021

Low-Dose Testosterone Augmentation for Antidepressant-Resistant Major Depressive Disorder in Women: An 8-Week Randomized Placebo-Controlled Study.

Am J Psychiatry 2020 10 14;177(10):965-973. Epub 2020 Jul 14.

Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston (Dichtel, Kimball, Miller); Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston (Nyer, Mischoulon, Deckersbach, Dougherty, Yeung, Cassano, Hahn, Farabaugh, Pedrelli, Trinh, Dording, Cusin, Papakostas, Chang, Fisher, Shapero, Chen, Fava); Department of Psychiatry, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston (Brady); Biostatistics Center, Massachusetts General Hospital, Boston (Schoenfeld); Butler Hospital and Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Medicine, Brown University, Providence, R.I. (Carpenter, Tyrka, Price); Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston (Rao); Mayo Clinic Endocrine Laboratory, Rochester, Minn. (Singh).

Objective: Low-dose testosterone has been shown to improve depression symptom severity, fatigue, and sexual function in small studies in women not formally diagnosed with major depressive disorder. The authors sought to determine whether adjunctive low-dose transdermal testosterone improves depression symptom severity, fatigue, and sexual function in women with antidepressant-resistant major depression. A functional MRI (fMRI) substudy examined effects on activity in the anterior cingulate cortex (ACC), a brain region important in mood regulation.

Methods: The authors conducted an 8-week randomized double-blind placebo-controlled trial of adjunctive testosterone cream in 101 women, ages 21-70, with antidepressant-resistant major depression. The primary outcome measure was depression symptom severity as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary endpoints included fatigue, sexual function, and safety measures. The primary outcome of the fMRI substudy (N=20) was change in ACC activity.

Results: The participants' mean age was 47 years (SD=14) and their mean baseline MADRS score was 26.6 (SD=5.9). Eighty-seven (86%) participants completed 8 weeks of treatment. MADRS scores decreased in both study arms from baseline to week 8 (testosterone arm: from 26.8 [SD=6.3] to 15.3 [SD=9.6]; placebo arm: from 26.3 [SD=5.4] to 14.4 [SD=9.3]), with no significant difference between groups. Improvement in fatigue and sexual function did not differ between groups, nor did side effects. fMRI results showed a relationship between ACC activation and androgen levels before treatment but no difference in ACC activation with testosterone compared with placebo.

Conclusions: Adjunctive transdermal testosterone, although well tolerated, was not more effective than placebo in improving symptoms of depression, fatigue, or sexual dysfunction. Imaging in a subset of participants demonstrated that testosterone did not result in greater activation of the ACC.
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http://dx.doi.org/10.1176/appi.ajp.2020.19080844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748292PMC
October 2020

Effects of Open-Label, Adjunctive Ganaxolone on Persistent Depression Despite Adequate Antidepressant Treatment in Postmenopausal Women: A Pilot Study.

J Clin Psychiatry 2020 06 9;81(4). Epub 2020 Jun 9.

Neuroendocrine Unit, BUL 457B, Massachusetts General Hospital, Boston, MA 02114.

Objective: The neuroactive steroid metabolite of progesterone, allopregnanolone, is a positive allosteric modulator of γ-aminobutyric acid-A (GABAA) receptors and a putative treatment for mood disorders. This pilot study was performed to determine whether an oral allopregnanolone analog (ganaxolone) may be effective adjunctive therapy for persistent depression despite adequate antidepressant treatment in postmenopausal women.

Method: Ten postmenopausal women (mean ± SD age: 62.8 ± 6.3 years; range, 53-69 years) with persistent depression despite adequate antidepressant treatment (current DSM-IV-TR major depressive episode per the Structured Clinical Interview for DSM-IV-TR, Montgomery-Asberg Depression Rating Scale [MADRS] score ≥ 16, and treated with an adequately dosed antidepressant for ≥ 6 weeks) were studied from December 2016 to April 2018. Open-label ganaxolone (225 mg twice daily, increased to 450 mg twice daily if tolerated) was administered for 8 weeks, followed by a 2-week taper.

Results: Mean ± SEM total MADRS score (primary endpoint) decreased by 8 weeks (24.4 ± 1.6 to 12.8 ± 2.9, P = .015), and the decrease persisted over the 2-week taper (P = .019); of the 9 subjects who completed the full 8-week treatment period, 44% (4/9) experienced response (MADRS score decrease ≥ 50%) and remission (final MADRS score < 10), which persisted in 100% and 50% of subjects at 10 weeks, respectively. Secondary endpoints showed significant improvement, including Inventory of Depressive Symptomatology-Self-Report score (P = .003), MADRS reduced sleep subscale score (P < .001), total Symptoms of Depression Questionnaire (SDQ) score (P = .012), and scores on SDQ subscales for disruptions in sleep quality (P = .003) and changes in appetite and weight (P = .009) over 8 weeks. No significant effects were observed on quality of life or sexual function. All subjects experienced sleepiness and fatigue; 60% experienced dizziness.

Conclusions: In this open-label, uncontrolled pilot study, adjunctive ganaxolone appears to exert antidepressant effects but produces sedation with twice-daily dosing. Ganaxolone may also improve sleep, which may be useful in patients with depression and insomnia.

Trial Registration: ClinicalTrials.gov identifier: NCT02900092.
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http://dx.doi.org/10.4088/JCP.19m12887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738196PMC
June 2020

Association between muscle mass and insulin sensitivity independent of detrimental adipose depots in young adults with overweight/obesity.

Int J Obes (Lond) 2020 09 13;44(9):1851-1858. Epub 2020 May 13.

Harvard Medical School, Boston, MA, USA.

Background/objective: Less muscle mass has been associated with greater insulin resistance, but whether the association is independent of deleterious adipose depots in young adults with overweight/obesity who are at high risk for type 2 diabetes (T2DM) but are otherwise metabolically healthy is not known. The objective of this study was to determine whether muscle mass is independently associated with insulin sensitivity (IS) in young adults with overweight/obesity.

Subjects/methods: Cross-sectional Clinical Research Center study of 132 adults, 21-45yo, BMI ≥ 25 kg/m and metabolically healthy without T2DM. Primary independent variable: percent ideal appendicular lean mass (ALM) calculated as measured ALM divided by predicted ALM for age, weight, and height, calculated using validated NHANES data-based equation. Primary dependent variable: IS by Matsuda index.

Results: Mean age was 34.3 ± 6.8 years, and mean BMI 35.8 ± 5.8 kg/m (mean ± SD). Individuals in the highest % ideal ALM tertile had mean IS 45% higher than the lowest tertile [6.94 ± 0.85 vs 4.80 ± 0.56 (mean ± SEM), p = 0.008] (sex interaction p = 0.003). Men in the highest % ideal ALM tertile had mean IS twice the lowest tertile (5.47 ± 0.68 vs 2.68 ± 0.34, p = 0.001), which remained significant controlling for visceral/subcutaneous and intermuscular adipose tissue, and intramyocellular and intrahepatic lipids (p = 0.03). The association was not significant in women.

Conclusions: Muscle mass is associated with IS independent of detrimental adipose depots in young men with overweight/obesity, at risk for T2DM but currently metabolically healthy. Muscle mass relative to sex, age, weight, and height-specific norms may be used to ascertain individual T2DM risk associated with low muscle mass.
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http://dx.doi.org/10.1038/s41366-020-0590-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483278PMC
September 2020

Clinical MEN-1 Among a Large Cohort of Patients With Acromegaly.

J Clin Endocrinol Metab 2020 06;105(6)

Academic Endocrine Unit, OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK.

Context: Clinical multiple endocrine neoplasia type 1 (MEN-1) is diagnosed by the presence of at least 2 MEN-1-associated tumors. Many patients with acromegaly and clinical MEN-1 yield negative testing for MEN1 mutations. While cases of acromegaly and primary hyperparathyroidism (PHP) with negative genetic testing have been reported, its prevalence among patients with acromegaly is undetermined, and the clinical presentation has not been well characterized.

Objectives: The main goals of this study are: (1) To determine the prevalence of clinical MEN-1 with PHP in patients with acromegaly and characterize their clinical features; and (2) to evaluate the genetic basis for the coexistence of acromegaly and PHP.

Design: Retrospective record review and genetic analysis.

Setting: Clinical Research Centers.

Participants: 414 patients with acromegaly.

Interventions: Clinical evaluation and DNA sequencing for MEN1, CDKN1A, CDKN1B, CDKN2B, CDKN2C, and AIP genes.

Main Outcome Measurements: Clinical and genetic analysis.

Results: Among patients with acromegaly, clinical MEN-1, as defined by the presence of at least one other MEN-1-associated tumor, was present in 6.6%. PHP occurred in 6.1%; more than half had parathyroid hyperplasia. DNA sequencing was unrevealing for genetic mutations, except for 1 case of a CDC73 mutation. Acromegaly was diagnosed at an older age with a higher prevalence of malignancies (specifically breast and thyroid) in patients with coexisting PHP than those with isolated acromegaly.

Conclusions: A distinct phenotype is described in patients with clinical MEN-1 and negative genetic testing for mutations previously associated with this syndrome. Further studies are needed to identify other genes that may explain the association between PHP and acromegaly.
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http://dx.doi.org/10.1210/clinem/dgaa142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180000PMC
June 2020

Uncertain Association Between Concussion and Hypogonadism-Reply.

JAMA Neurol 2020 06;77(6):774-775

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jamaneurol.2020.0476DOI Listing
June 2020

Lower Oxytocin Levels Are Associated with Lower Bone Mineral Density and Less Favorable Hip Geometry in Hypopituitary Men.

Neuroendocrinology 2021 20;111(1-2):87-98. Epub 2020 Feb 20.

Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA,

Introduction: Hypopituitary patients are at risk for bone loss. Hypothalamic-posterior pituitary hormones oxytocin and vasopressin are anabolic and catabolic, respectively, to the skeleton. Patients with hypopituitarism may be at risk for oxytocin deficiency. Whether oxytocin and/or vasopressin contribute to impaired bone homeostasis in hypopituitarism is unknown.

Objectives: To determine the relationship between plasma oxytocin and vasopressin levels and bone characteristics (bone mineral density [BMD] and hip structural analysis [HSA]) in patients who have anterior pituitary deficiencies only (APD group) or with central diabetes insipidus (CDI group).

Methods: This is a cross-sectional study. Subjects included 37 men (17 CDI and 20 APD), aged 20-60 years. Main outcome measures were fasting plasma oxytocin and vasopressin levels, and BMD and HSA using dual X-ray absorptiometry.

Results: Mean BMD and HSA variables did not differ between the CDI and APD groups. Mean BMD Z-scores at most sites were lower in those participants who had fasting oxytocin levels below, rather than above, the median. There were positive associations between fasting oxytocin levels and (1) BMD Z-scores at the spine, femoral neck, total hip, and subtotal body and (2) favorable hip geometry and strength variables at the intertrochanteric region in CDI, but not APD, participants. No associations between vasopressin levels and bone variables were observed in the CDI or ADP groups.

Conclusions: This study provides evidence for a relationship between oxytocin levels and BMD and estimated hip geometry and strength in hypopituitarism with CDI. Future studies will be important to determine whether oxytocin could be used therapeutically to optimize bone health in patients with hypopituitarism.
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http://dx.doi.org/10.1159/000506638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372692PMC
October 2021

TWO SYNCHRONOUS PITUITARY ADENOMAS CAUSING CUSHING DISEASE AND ACROMEGALY.

AACE Clin Case Rep 2019 Sep-Oct;5(5):e276-e281. Epub 2019 Jun 7.

Objective: To report the first case of 2 synchronous pituitary adenomas, 1 corticotroph and 1 somatotroph, with distinct molecular lineages confirmed by differential hormone and S-100 protein expression.

Methods: A case report followed by a literature review are presented.

Results: A 68-year-old woman presented for evaluation of resistant hypertension. Biochemical testing demonstrated adrenocorticotropic hormone (ACTH)-dependent hypercortisolemia and growth hormone (GH) excess. Pituitary magnetic resonance imaging (MRI) revealed a 2 cm left sellar lesion consistent with a pituitary macroadenoma. The patient therefore underwent transsphenoidal surgery for a presumed cosecreting ACTH and GH macroadenoma. Tumor immunohistochemical staining (IHC) was positive for ACTH, but negative for GH. Postoperative biochemical testing confirmed remission from Cushing disease, but the insulin-like growth factor 1 (IGF-1) level remained elevated. Postoperative MRI demonstrated a small right sellar lesion that, in retrospect, had been present on the preoperative MRI. Resection of the right lesion confirmed a GH-secreting adenoma with negative ACTH staining. After the second surgery, the IGF-1 level normalized and blood pressure improved. Further pathologic examination of both surgical specimens demonstrated differential expression of S-100 protein, a folliculostellate cell marker. Reverse transcription polymerase chain reaction of messenger ribonucleic acid from the left sellar lesion was positive for ACTH and negative for GH, confirming the IHC results. Germline mutations in genes known to be associated with pituitary adenoma syndromes (, , , , , , and ) were not detected.

Conclusion: Although the pathogenesis of synchronous pituitary adenomas has not been fully elucidated, this case report suggests that they can have distinct molecular lineages.
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http://dx.doi.org/10.4158/ACCR-2019-0057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876961PMC
June 2019

Biochemical Control in Acromegaly With Multimodality Therapies: Outcomes From a Pituitary Center and Changes Over Time.

J Clin Endocrinol Metab 2020 03;105(3)

Neuroendocrine Unit, Massachusetts General Hospital. Department of Medicine, Harvard Medical School, Boston, MA.

Purpose: To determine the prevalence of insulin-like growth factor-1 (IGF-1) normalization with long-term multimodality therapy in a pituitary center and to assess changes over time.

Methods: Patients with acromegaly (N = 409), with ≥1 year of data after surgery and at least 2 subsequent clinic visits were included in long-term analysis (N = 266). Biochemical data, clinical characteristics, and therapeutic interventions were reviewed retrospectively.

Results: At diagnosis, mean [standard deviation] age was 43.4 [14.3] years, body mass index was 28.5 (24.9-32.1) kg/m2 (median, interquartile range), serum IGF-1 index (IGF-1 level/upper limit of normal) was 2.3 [1.7-3.1], and 80.5% had macroadenomas. Patients with transsphenoidal surgery after 2006 were older [46.6 ± 14.3 vs 40.0 ± 13.4 years; P < 0.001]. Age and tumor size correlated inversely. Overall (N = 266), 93.2% achieved a normal IGF-1 level during 9.9 [5.0-15.0] years with multimodality therapy. The interval to first normal IGF-1 level following failed surgical remission was shorter after 2006: 14.0 (95% confidence interval, 10.0-20.0) versus 27.5 (22.0-36.0) months (P = 0.002). Radiation therapy and second surgery were rarer after 2006: 28 (22%) versus 62 (47.0%); P < 0.001 and 12 (9.4%) versus 28 (21.2%); P = 0.010, respectively. Age at diagnosis increased over time periods, possibly reflecting increased detection of acromegaly in older patients with milder disease. Male gender, older age, smaller tumor and lower IGF-1 index at diagnosis predicted long-term sustained IGF-1 control after surgery without adjuvant therapies.

Conclusion: The vast majority of patients with acromegaly can be biochemically controlled with multimodality therapy in the current era. Radiotherapy and repeat pituitary surgery became less frequently utilized over time. Long-term postoperative IGF-1 control without use of adjuvant therapies has improved.
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http://dx.doi.org/10.1210/clinem/dgz187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8660161PMC
March 2020

Association of Concussion Symptoms With Testosterone Levels and Erectile Dysfunction in Former Professional US-Style Football Players.

JAMA Neurol 2019 12;76(12):1428-1438

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.

Importance: Small studies suggest that head trauma in men may be associated with low testosterone levels and sexual dysfunction through mechanisms that likely include hypopituitarism secondary to ischemic injury and pituitary axonal tract damage. Athletes in contact sports may be at risk for pituitary insufficiencies or erectile dysfunction (ED) because of the high number of head traumas experienced during their careers. Whether multiple symptomatic concussive events are associated with later indicators of low testosterone levels and ED is unknown.

Objective: To explore the associations between concussion symptom history and participant-reported indicators of low testosterone levels and ED.

Design, Setting, And Participants: This cross-sectional study of former professional US-style football players was conducted in Boston, Massachusetts, from January 2015 to March 2017. Surveys on past football exposures, demographic factors, and current health conditions were sent via electronic and postal mail to participants within and outside of the United States. Analyses were conducted in Boston, Massachusetts; the data analysis began in March 2018 and additional analyses were performed through June 2019. Of the 13 720 male former players eligible to enroll who were contacted, 3506 (25.6%) responded.

Exposures: Concussion symptom score was calculated by summing the frequency with which participants reported 10 symptoms, such as loss of consciousness, disorientation, nausea, memory problems, and dizziness, at the time of football-related head injury.

Main Outcomes And Measures: Self-reported recommendations or prescriptions for low testosterone or ED medication served as indicators for testosterone insufficiency and ED.

Results: In 3409 former players (mean [SD] age, 52.5 [14.1] years), the prevalence of indicators of low testosterone levels and ED was 18.3% and 22.7%, respectively. The odds of reporting low testosterone levels or ED indicators were elevated for previously established risk factors (eg, diabetes, sleep apnea, and mood disorders). Models adjusted for demographic characteristics, football exposures, and current health factors showed a significant monotonically increasing association of concussion symptom score with the odds of reporting the low testosterone indicator (highest vs lowest quartile, odds ratio, 2.39; 95% CI, 1.79-3.19; P < .001). The ED indicator showed a similar association (highest quartile vs lowest, odds ratio, 1.72; 95% CI, 1.30-2.27; P < .001).

Conclusions And Relevance: Concussion symptoms at the time of injury among former football players were associated with current participant-reported low testosterone levels and ED indicators. These findings suggest that men with a history of head injury may benefit from discussions with their health care clinicians regarding testosterone deficiency and sexual dysfunction.
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http://dx.doi.org/10.1001/jamaneurol.2019.2664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714010PMC
December 2019

Community-Delivered Heated Hatha Yoga as a Treatment for Depressive Symptoms: An Uncontrolled Pilot Study.

J Altern Complement Med 2019 Aug 10;25(8):814-823. Epub 2019 Jul 10.

1Depression Clinical and Research Program (DCRP), Department of Psychiatry, Massachusetts General Hospital, Boston, MA.

There are no known studies of concurrent exposure to high temperature and yoga for the treatment of depression. This study explored acceptability and feasibility of heated (Bikram) yoga as a treatment for individuals with depressive symptoms. An 8-week, open-label pilot study of heated yoga for depressive symptoms. 28 medically healthy adults (71.4% female, mean age 36 [standard deviation 13.57]) with at least mild depressive symptoms (Hamilton Rating Scale for Depression [HRSD-17] score ≥10) who attended at least one yoga class and subsequent assessment visit. Participants were asked to attend at least twice weekly community held Bikram Yoga classes. Assessments were performed at screening and weeks 1, 3, 5, and 8. Hypotheses were tested using a modified-intent-to-treat approach, including participants who attended at least one yoga class and subsequent assessment visit ( = 28). Almost half of our subjects completed the 8-week intervention, and close to a third attended three quarters or more of the prescribed 16 classes over 8 weeks. Multilevel modeling revealed significant improvements over time in both clinician-rated HRSD-17 ( = 0.003;  = 1.43) and self-reported Beck Depression Inventory (BDI;  < 0.001,  = 1.31) depressive symptoms, as well as the four secondary outcomes: hopelessness ( = 0.024,  = 0.57), anxiety ( < 0.001,  = 0.78), cognitive/physical functioning ( < 0.001,  = 1.34), and quality of life ( = 0.007,  = 1.29). Of 23 participants with data through week 3 or later, 12 (52.2%) were treatment responders (≥50% reduction in HRSD-17 score), and 13 (56.5%) attained remission (HRSD score ≤7). More frequent attendance was significantly associated with improvement in self-rated depression symptoms, hopelessness, and quality of life. The acceptability and feasibility of heated yoga in this particular sample with this protocol warrants further attention. The heated yoga was associated with reduced depressive symptoms, and other improved related mental health symptoms, including anxiety, hopelessness, and quality of life.
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http://dx.doi.org/10.1089/acm.2018.0365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763961PMC
August 2019

Disrupted Oxytocin-Appetite Signaling in Females With Anorexia Nervosa.

J Clin Endocrinol Metab 2019 10;104(10):4931-4940

Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts.

Context: In healthy females, oxytocin levels decrease postmeal, corresponding to increased satiety. The postprandial response of oxytocin in females with anorexia nervosa (AN)/atypical AN is unknown.

Objectives: To determine the pattern of postprandial serum oxytocin levels in females with AN/atypical AN, relationship with appetite, and effect of weight, eating behavior, and endogenous estrogen status.

Design: Cross-sectional.

Setting: Clinical research center.

Participants: 67 women (36 with AN [<85% expected body weight (EBW)]; 31 with atypical AN [≥ 85% EBW)]), age 22.4 ± 0.9 (mean ± SEM) years, categorized by weight, restricting vs binge/purge behavior, and estrogen status.

Interventions: Standardized mixed meal.

Main Outcome Measurements: Blood sampling for oxytocin occurred fasting and 30, 60, and 120 minutes postmeal. Subjective appetite was assessed using visual analog scales.

Results: In females with AN/atypical AN, oxytocin levels decreased from fasting to 60 (P = 0.002) and 120 (P = 0.005) minutes postmeal. The decrease in oxytocin from fasting to 120 minutes was greater in females with atypical AN than AN (P = 0.027) and did not differ by restricting vs binge/purge behavior or estrogen status. Controlling for caloric intake, the decrease in oxytocin was inversely related to the decrease in hunger postmeal in females with atypical AN (P = 0.04).

Conclusions: In females with AN/atypical AN, oxytocin levels decrease postmeal, as established in healthy females. Weight, but not restricting vs binge/purging nor endogenous estrogen status, affects postprandial oxytocin levels. The postprandial change in serum oxytocin levels is related to appetite in females with atypical AN only, suggesting a disconnect between oxytocin secretion and appetite in the undernourished state.
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http://dx.doi.org/10.1210/jc.2019-00926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734487PMC
October 2019

Differences in Trabecular Plate and Rod Structure in Premenopausal Women Across the Weight Spectrum.

J Clin Endocrinol Metab 2019 10;104(10):4501-4510

Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts.

Context: Premenopausal women with anorexia nervosa (AN) and obesity (OB) have elevated fracture risk. More plate-like and axially aligned trabecular bone, assessed by individual trabeculae segmentation (ITS), is associated with higher estimated bone strength. Trabecular plate and rod structure has not been reported across the weight spectrum.

Objective: To investigate trabecular plate and rod structure in premenopausal women.

Design: Cross-sectional study.

Setting: Clinical research center.

Participants: A total of 105 women age 21 to 46 years: (i) women with AN (n = 46), (ii) eumenorrheic lean healthy controls (HCs) (n = 29), and (iii) eumenorrheic women with OB (n = 30).

Measures: Trabecular microarchitecture by ITS.

Results: Mean age (±SD) was similar (28.9 ± 6.3 years) and body mass index differed (16.7 ± 1.8 vs 22.6 ± 1.4 vs 35.1 ± 3.3 kg/m2; P < 0.0001) across groups. Bone was less plate-like and axially aligned in AN (P ≤ 0.01) and did not differ between OB and HC. After controlling for weight, plate and axial bone volume fraction and plate number density were lower in OB vs HC; some were lower in OB than AN (P < 0.05). The relationship between weight and plate variables was quadratic (R = 0.39 to 0.70; P ≤ 0.0006) (i.e., positive associations were attenuated at high weight). Appendicular lean mass and IGF-1 levels were positively associated with plate variables (R = 0.27 to 0.67; P < 0.05). Amenorrhea was associated with lower radial plate variables than eumenorrhea in AN (P < 0.05).

Conclusions: In women with AN, trabecular bone is less plate-like. In women with OB, trabecular plates do not adapt to high weight. This is relevant because trabecular plates are associated with greater estimated bone strength. Higher muscle mass and IGF-1 levels may mitigate some of the adverse effects of low weight or excess adiposity on bone.
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http://dx.doi.org/10.1210/jc.2019-00843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735760PMC
October 2019

A Randomized Placebo-Controlled Trial of Low-Dose Testosterone Therapy in Women With Anorexia Nervosa.

J Clin Endocrinol Metab 2019 10;104(10):4347-4355

Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts.

Context: Anorexia nervosa (AN) is a psychiatric illness with considerable morbidity and no approved medical therapies. We have shown that relative androgen deficiency in AN is associated with greater depression and anxiety symptom severity.

Objective: To determine whether low-dose testosterone therapy is an effective endocrine-targeted therapy for AN.

Design: Double-blind, randomized, placebo-controlled trial.

Setting: Clinical research center.

Participants: Ninety women, 18 to 45 years, with AN and free testosterone levels below the median for healthy women.

Intervention: Transdermal testosterone, 300 μg daily, or placebo patch for 24 weeks.

Main Outcome Measures: Primary end point: body mass index (BMI). Secondary end points: depression symptom severity [Hamilton Depression Rating Scale (HAM-D)], anxiety symptom severity [Hamilton Anxiety Rating Scale (HAM-A)], and eating disorder psychopathology and behaviors.

Results: Mean BMI increased by 0.0 ± 1.0 kg/m2 in the testosterone group and 0.5 ± 1.1 kg/m2 in the placebo group (P = 0.03) over 24 weeks. At 4 weeks, there was a trend toward a greater decrease in HAM-D score (P = 0.09) in the testosterone vs placebo group. At 24 weeks, mean HAM-D and HAM-A scores decreased similarly in both groups [HAM-D: -2.9 ± 4.9 (testosterone) vs -3.0 ± 5.0 (placebo), P = 0.72; HAM-A: -4.5 ± 5.3 (testosterone) vs -4.3 ± 4.4 (placebo), P = 0.25]. There were no significant differences in eating disorder scores between groups. Testosterone therapy was safe and well tolerated with no increase in androgenic side effects compared with placebo.

Conclusion: Low-dose testosterone therapy for 24 weeks was associated with less weight gain-and did not lead to sustained improvements in depression, anxiety, or disordered eating symptoms-compared with placebo in women with AN.
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http://dx.doi.org/10.1210/jc.2019-00828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736210PMC
October 2019
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