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Objective Anorexia nervosa is complicated by high bone resorption, low bone mineral density (BMD), and increased fracture risk. We investigated whether off-label antiresorptive therapy with denosumab increases BMD in women with anorexia nervosa. Design Twelve-month, randomized, double-blind, placebo-controlled study. Methods Thirty ambulatory women with anorexia nervosa and areal BMD (aBMD) T-score Results Baseline mean (±s.d.) age (29 ± 8 (denosumab) vs 29 ± 7 years (placebo)), BMI (19.0 ± 1.7 vs 18.0 ± 2.0 kg/m2), and aBMD (PA spine Z-score −1.6±1.1 vs −1.7±1.4) were similar between groups. PA lumbar spine aBMD increased in the denosumab vs placebo group over 12 months (P = 0.009). The mean (95% CI) increase in PA lumbar spine aBMD was 5.5 (3.8–7.2)% in the denosumab group and 2.2 (−0.3–4.7)% in the placebo group. The change in femoral neck aBMD was similar between groups. Radial trabecular number increased, radial trabecular separation decreased, and tibial cortical porosity decreased in the denosumab vs placebo group (P ≤ 0.006). Serum C-terminal telopeptide of type I collagen and procollagen type I N-terminal propeptide decreased in the denosumab vs placebo group (P < 0.0001). Denosumab was well tolerated. Conclusions Twelve months of antiresorptive therapy with denosumab reduced bone turnover and increased spine aBMD, the skeletal site most severely affected in women with anorexia nervosa.

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

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

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 We aimed to investigate serum GH and IGF-1 levels in relation to intrahepatic lipid content (IHL) and markers of hepatocellular damage and fibrosis in NAFLD. Methods This cross-sectional study included 102 adults (43% women; age 19-67; BMI ≥ 25 kg/m2) without type 2 diabetes. IHL was measured by magnetic resonance spectroscopy; NAFLD was defined by ≥ 5% IHL. Peak-stimulated GH in response to GH releasing hormone and arginine was assessed as was 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 Conclusion Individuals with NAFLD have lower peak-stimulated GH levels but similar IGF-1 levels as compared to controls. Higher peak-stimulated GH levels are associated with lower IHL and less hepatocellular damage. Higher IGF-1 levels are 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.

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.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.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).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.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.

Rates of vitamin D deficiency and nutritional rickets have been rising over the past several decades, particularly in high-risk infants. This pilot study assessed the impact of providing free vitamin D supplements, a culturally-appropriate educational brochure, and a brief counseling session about the importance of both vitamin D supplementation and breastfeeding to the parents of Somali infants at routine office visits from newborn through 6 months of age at three Federally Qualified Health Centers in Colorado. We also assessed the impact this intervention had on rates of breastfeeding.Twenty-five Somali infants aged 24 weeks or less were identified by searching electronic health records and enrolled into a historic control group. The parents were then surveyed by phone regarding breastfeeding and vitamin D supplementation. Subsequently, 37 families with newborn Somali infants were identified and enrolled into the intervention arm of the trial.The intervention group had a higher rate of vitamin D supplementation compared to the historical control group (67 vs. 48 percent, p=0.011) without significantly impacting breastfeeding rates.These results suggest a practical way to increase vitamin D status in this high-risk population. Trial not registered as it was a pilot study, not a phase II to IV prospective clinical trial.

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.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.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.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.

Objectives To assess the impact of virtual education programming for patients with acromegaly. Design We conducted a mixed methods study to evaluate patient attitudes, examine if patient-centered educational forums change these attitudes, and determine the role of virtual education as a means to learn about patients’ unmet needs, self-reported outcomes, and educational priorities. Methods The study included 653 total virtual program registrants. Of these, 78 patients with acromegaly were included in the analysis. The programs consisted of patient-centered livestream education by a multidisciplinary team of pituitary experts and patient presenters. Multiple-choice questions were used to assess attitudes before and after the event, and short answer surveys were used to collect care goals and unmet needs related to treatment. Results Attendance included participants from 37 countries. The number of patients who responded that they had no hope for improvement, had no choice in their treatment, and felt alone living with acromegaly each decreased significantly pre- to post-event (P < 0.05). The number of patients who felt anxious about their acromegaly diagnosis remained unchanged. ‘Quality of life/mental health’ was the most common personal care goals concern followed by ‘medical therapies/tumor control.’ Perceived acromegaly unmet needs were evenly distributed, with five of six categories reported by over 20% of patients. Conclusion Our findings indicate that virtual education may have a significant positive effect on acromegaly patients’ perceptions of their disease. The lessons learned from these virtual programs may be used to inform future virtual education programming for acromegaly and other rare diseases.

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 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 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.

Background 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. Methods 77 adults ages 18-65 years, BMI ≥25 kg/m2, and BMD T- or Z-score ≤ -1.0 were randomized in a double-blind protocol to daily subcutaneous GH or placebo for 18 months, targeting IGF-1 in the upper quartile of the age-appropriate normal range. There was a post-treatment observation period from 18-24 months. DXA and high-resolution peripheral quantitative CT were performed at baseline, 18 months and 24 months. Volumetric quantitative CT was performed at baseline and 18 months. Results are reported as mean ±SD or mean (95% confidence interval). Results There were no pretreatment differences between the GH (n=39) and placebo groups (n=38), including mean age (48±12y), BMI (33.1±5.7kg/m2) and BMD at any site. Forty-nine subjects (47% female) completed 18 months. P1NP, osteocalcin and CTX increased (p Conclusions We demonstrated that GH administration for 18 months to individuals with overweight/obesity and low BMD decreased some measures of BMD, bone microarchitecture, and bone strength compared with placebo. None of these differences remained significant after 6 months off therapy. A longer duration of treatment, or a longer duration of observation post-treatment, may be necessary to see the expected biphasic decline and then increase in BMD reflecting an expanding remodeling space followed by mineralization that has previously been seen with GH administration in other populations, including individuals with and without GH deficiency. Although future investigation of the effects of GH on bone is required to assess the true long-term impact on skeletal integrity as well as fracture reduction, our study suggests that GH administration for 18 months to adults with overweight/obesity does not improve BMD, bone microarchitecture, or bone strength. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:12 p.m. - 1:17 p.m.

Low bone mineral density (BMD) and increased fracture risk are common complications of anorexia nervosa. We assessed whether 12 months of alendronate subsequent to 12 months of denosumab would 1) maintain the increases in BMD observed with denosumab and 2) result in higher BMD than alendronate for 12 months alone in 30 ambulatory women with anorexia nervosa and areal BMD (aBMD) Z- or T-score At baseline, mean age [29±8 y (mean±SD)], BMI (18.6±1.9 kg/m2), and aBMD (PA lumbar spine Z-score -1.6±1.1) were similar between groups. From 12 to 24 months in the denosumab-to-alendronate group, favorable changes in spine aBMD, radial vBMD, and radial and tibial microarchitecture from 12 months of denosumab were maintained after 12 months of alendronate. However, there was a rebound increase in markers of bone turnover (p In conclusion, this pilot study suggests that 12 months of alendronate maintains BMD gains achieved with 12 months of denosumab administration in some, but not all, women with anorexia nervosa. A more robust response to denosumab may be a risk factor for partial reversal of denosumab-related BMD gains despite alendronate. Therefore, a more effective antiresorptive agent may be necessary to maintain gains in BMD achieved with denosumab therapy in some women with anorexia nervosa. Moreover, sequential therapy of denosumab followed by alendronate over 24 months results in greater improvements in tibial vBMD and microarchitecture than 12 months of alendronate, although increases in aBMD were similar between groups. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 12:30 p.m. - 12:35 p.m.

While anorexia nervosa is associated with impaired skeletal integrity, less is known about the skeletal effects of atypical anorexia nervosa, in which psychological criteria for anorexia nervosa are met, but affected individuals are not low weight. Mean bone mineral density (BMD) is higher in atypical anorexia nervosa than in low-weight anorexia nervosa but lower than in healthy controls. However, it is unknown whether bone microarchitecture and strength are affected. We hypothesized that bone microarchitecture and estimated strength would be impaired in women with atypical anorexia nervosa. This was a cross-sectional study of women ages 21-46 years (n=55): n=28 with atypical anorexia nervosa (body mass index (BMI) >18.5 kg/m2), n=27 healthy, normal weight, eumenorrheic controls. Exclusion criteria included use of oral contraceptives. Areal BMD (aBMD) was assessed by DXA. Volumetric BMD (vBMD), microarchitecture, and failure load (a bone strength estimate) at the distal tibia and radius were assessed by high-resolution peripheral quantitative CT. Median(IQR) BMI was lower [19.4(18.6,20.2) vs 22.2(21.5,23.0), p Median lateral spine, total hip, femoral neck, and total radius aBMD Z-scores were lower in atypical anorexia nervosa than healthy controls [lateral spine: -1.1(-2.0,-0.1) vs -0.4(-0.7,0.4), total hip: -0.8(-1.3,0.2) vs 0.2(-0.4,0.7), femoral neck: -0.9(-1.4,0.1) vs -0.1(-0.9,0.6), radius: -0.2(-0.9,0.3) vs 0.1(-0.4,0.6); p≤0.04 for all]. At the tibia, median total, cortical, and trabecular vBMD; cortical thickness; trabecular bone volume fraction; and failure load were lower in atypical anorexia nervosa than healthy controls (p Conclusions We demonstrate that, despite normal weight, women with atypical anorexia nervosa have impaired vBMD, microarchitecture, and estimated strength compared to healthy controls, with differences more pronounced at the weight-bearing tibia vs non-weight-bearing radius. Individuals with amenorrhea had additional impairments in the non-weight-bearing radius, suggesting an effect of systemic estrogen deficiency. Our data suggest that current normal weight is not protective against impaired bone structure and strength in atypical anorexia nervosa. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:30 p.m. - 1:35 p.m.

Background Overweight/obesity are associated with relative growth hormone (GH) deficiency, and GH deficiency has been implicated in the development of nonalcoholic fatty liver disease (NAFLD). NAFLD and its progressive form, nonalcoholic steatohepatitis (NASH), are associated with significant morbidity and mortality, and no approved therapies currently exist. We hypothesized that GH administration would reduce hepatic steatosis, inflammation and fibrosis in individuals with overweight/obesity and NAFLD. Methods A randomized, double-blind, placebo-controlled trial of GH administration in adults with overweight/obesity and NAFLD was conducted (NCT02217345). Fifty-three adults ages 18-70 years with BMI ≥25 kg/m2 and NAFLD were randomly assigned to receive daily subcutaneous GH or placebo for 6 months. Target IGF-1 was upper quartile of normal. Primary endpoints included intrahepatic lipid content (IHL) by proton magnetic resonance spectroscopy (1H-MRS) and radiographic inflammation and fibrosis by LiverMultiScan corrected T1 score (cT1). Secondary endpoints included alanine transaminase (ALT), visceral adipose tissue (VAT) by dual-energy x-ray absorptiometry (DEXA), hsCRP and HOMA-IR. Data are reported as mean ± SD. Results Forty-one subjects completed the 6-month study. Mean age (45±12 years), BMI (33±5 kg/m2), sex distribution (50% female) and baseline IHL (21.4±14.5%) did not differ between the GH and placebo groups. Over the 6-month study period, there was no difference in change in weight between the groups (GH -0.7±3.8% and placebo -0.6±4.0%, p=0.7). Change in absolute percent IHL was significantly greater in the GH vs placebo group (-5.1±10.5% vs 3.8±6.9%, p=0.003), resulting in a net treatment effect of an 8.9% reduction in IHL (95% CI 3.3-14.6%). Improvements in serum ALT (-10±13 IU/L vs -2±12 IU/L, p=0.009) and cT1 score (-11±63 ms vs 27±57 ms, p=0.037) were greater in the GH vs placebo group. There were also significant reductions in DEXA VAT area (-10±9 cm2 vs 0±20 cm2, p=0.050) and hsCRP (-0.8±0.9 mg/dL vs -0.3±1.7 mg/dL, p=0.017) in the GH vs placebo group. In multivariable models controlling for age, sex, change in weight and change in HOMA-IR, significant effects of GH vs placebo were observed on IHL (p=0.012) and ALT (p=0.015) with a trend towards improvement in cT1 score (p=0.088). In a secondary analysis excluding all subjects with >3% weight loss, which has been shown to independently impact NAFLD outcomes, there were significant improvements in IHL (p=0.001), ALT (p=0.040) and cT1 score (p=0.050) in the GH vs placebo group. No subjects were discontinued due to hyperglycemia (fasting glucose ≥126 mg/dL or HbA1c ≥6.5%). Mild edema was the only treatment-emergent side effect that had a significantly greater incidence in the GH vs placebo group (19% vs 0%, p=0.048). Conclusion GH administration reduces hepatic steatosis and markers of hepatic inflammation and fibrosis in adults with overweight/obesity and NAFLD. The GH/IGF-1 axis may offer targetable therapeutic options for NAFLD/NASH. Presentation: Tuesday, June 14, 2022 10:00 a.m. - 10:15 a.m.

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.

ContextPremenopausal 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.ObjectiveTo investigate trabecular plate and rod structure in premenopausal women.DesignCross-sectional study.SettingClinical research center.ParticipantsA 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).MeasuresTrabecular microarchitecture by ITS.ResultsMean 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).ConclusionsIn 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.

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/m2 , 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

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.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.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 score10), 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.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.ClinicalTrials.gov identifier: NCT02900092.

Introduction: Anorexia nervosa (AN) and atypical AN (defined as weight loss and all the psychological features of AN but BMI>18.5 kg/m2) are serious disorders characterized by undernutrition and complicated by endocrine dysregulation. Predictors of recovery, including serum biomarkers, are lacking. Prior studies have suggested that higher urinary free cortisol (UFC) may predict weight gain in women with AN, but 24-hour urine collections are not feasible in a real-world setting. Like cortisol, the adrenal androgen dehydroepiandrosterone (DHEA) and its sulfated form DHEAS, which has a longer half-life, are stimulated by ACTH. We hypothesized that DHEAS levels would correlate with UFC and be a predictor of weight gain 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 randomized trial. AN and atypical AN were diagnosed by SCID. Baseline DHEAS and 24-hour UFC were measured by LC-MS/MS (Endocrine Sciences, Calabasas Hills, CA). Weight and body composition were assessed at baseline and 6 months later by DXA and cross-sectional abdominal CT at L4. Results: At baseline, mean weight was 51.3 ± 4.9 kg. Of the 18 subjects who gained weight (range 0.1–10.3 kg), 28% were eumenorrheic, 39% amenorrheic, and 33% on oral contraceptives at baseline; baseline reproductive status was similar for subjects who did not subsequently gain weight. In the group as a whole, mean baseline DHEAS level was 173 ± 70 µg/dL (0.7 ± 0.3 times the mean normal range for age) and mean baseline UFC for subjects who completed testing (n=15) was 20 ± 18 µg/24h (normal range 0–50 µg/24h). Higher DHEAS levels at baseline predicted weight gain over 6 months (r=0.61, p Conclusion: In women with AN, higher DHEAS levels are a predictor of weight gain and increases in fat mass, skeletal muscle mass, and abdominal fat. Serum DHEAS correlates with UFC, a predictor of weight gain in prior studies. DHEAS may be a more practical biomarker of recovery, as 24-hour urine collections are challenging. Further studies are needed to determine whether higher DHEAS levels are a marker of global adrenal stress response and a reflection of higher cortisol levels, which may stimulate weight gain, or an independent predictor of weight gain in AN and atypical AN, perhaps through neuromodulation.

In preclinical models, inhibition of the myokine myostatin prevents or improves insulin resistance (IR). However, studies investigating the association between serum myostatin levels and IR in humans are discrepant, perhaps in part because myostatin immunoassays lack specificity and sensitivity. New sensitive and specific myostatin LC-MS/MS assays make it possible to determine if higher serum myostatin levels are independently associated with greater IR in adults with overweight/obesity. If true, therapeutic manipulation of myostatin pathways may be a potential therapeutic target to prevent or treat type 2 diabetes (T2DM) in this high-risk population, in which current strategies, e.g. weight loss, are difficult to implement and maintain. We studied 75 adults (53% women), 20–65 yo, BMI ≥25 kg/m2 and generally healthy without T2DM. Serum myostatin levels (1° independent variable) were measured by LC-MS/MS (Brigham Research Assay Core, Boston, MA), with no cross-reactivity with growth differentiation factor 11 (GDF11), activins or transforming growth factor beta (TGF-β), sensitivity of 0.5 ng/mL and intra- and inter-assay coefficient of variation of 10 and 12%. Insulin sensitivity (IS) (1° dependent variable) was estimated by QUICKI, appendicular lean mass (ALM) by DXA, visceral adipose tissue (VAT) by CT and intrahepatic (IHL) and intramyocellular lipids (IMCL) by MR spectroscopy. Models were run sex- combined and stratified given sex differences in muscle mass. Mean age was 47.9±12.2 years and BMI was 33.2±5.7 kg/m2 (mean±SD). Compared to men, women had lower mean ALM (20.9±3.3 vs 29.2±3.3 kg, p In conclusion, lower serum myostatin levels were associated with greater IS in adults with overweight/obesity, independent of muscle and adipose depots known to be associated with T2DM risk. Future studies should investigate potential sex differences in the association between myostatin and IS. Therapeutic manipulation of myostatin pathways may be a potential therapeutic target to prevent or treat T2DM.

Background: Nonalcoholic fatty liver disease (NAFLD), fatty infiltration of the liver in the absence of alcohol use, is a prevalent and serious complication of obesity. Obesity is a state of relative growth hormone (GH) deficiency, and GH has been identified as a candidate disease-modifying target in NAFLD because of its lipolytic and anti-inflammatory properties. However, it is not known whether individuals with NAFLD phenotyped by proton magnetic resonance spectroscopy (1H-MRS), the gold standard imaging modality for assessment of intrahepatic lipid (IHL) content, have lower peak stimulated GH levels as compared to those of similar age, sex and BMI without NAFLD. Methods: We studied 99 generally healthy adults without diabetes or significant alcohol use, ages 19-67 y and BMI >25 kg/m2. All subjects underwent 1H-MRS for assessment of IHL content. Using a cutoff of >5.5%, 65 subjects had NAFLD and 34 did not (controls). GHRH-arginine stimulation testing was performed. GH was measured by immunoassay and IGF-1 by LC/MS/MS (Quest Diagnostics, CA, USA). Visceral and subcutaneous adipose tissue (VAT/SAT) were assessed by cross-sectional CT at L4. Results are reported as mean ±SD. Results: There was no difference between NAFLD vs controls in mean age (48±12 vs 45±14 y, p=0.30), BMI (33±4 vs 33±7 kg/m2, p=0.96), sex (43% vs 44% female, p=0.90) or premenopausal status (50% vs 60%, p=0.50). Mean IHL was 21.8±13.3% (range 5.5-57.8%) and 2.9±1.1% (range 1.0-4.9%) in the NAFLD and control groups, respectively (p Conclusion: Subjects with NAFLD have lower peak stimulated GH but similar IGF-1 levels compared to non-NAFLD controls of similar age, BMI and sex. Additionally, lower peak stimulated GH was predictive of higher IHL, independent of age, BMI, sex and VAT. This suggests that the relative GH deficiency of obesity may be an independent contributor to the development of NAFLD and that the GH axis and downstream signaling pathways may be a therapeutic target for this disease where few currently exist.

Resistance to selective serotonin reuptake inhibitor and serotonin norepinephrine reuptake inhibitor treatment occurs in about 50% to 70% of patients with major depressive disorder (MDD), a condition associated with significant morbidity that affects women at higher rates than men. Few well-tolerated, effective augmentation therapies are available for such patients, and new therapeutic strategies for resistant depression are needed. The neuroactive steroid metabolite of progesterone, allopregnanolone, is a positive allosteric modulator of GABAA receptors and a putative treatment for mood disorders. We performed a pilot study to determine whether an oral allopregnanolone analog (ganaxolone) may be effective adjunctive therapy for resistant depression in postmenopausal women. Ten postmenopausal women (age 62.8±6.3 years, range 53–69) with resistant depression [current DSM-IV major depressive episode per the Structured Clinical Interview for DSM-IV, Montgomery-Asberg Depression Rating Scale (MADRS) ≥16 despite treatment with an adequately dosed antidepressant for ≥6 weeks] were studied. Open-label ganaxolone (225 mg BID, increased to 450 mg BID if tolerated) was administered for 8 weeks, followed by a 2-week taper. Mean total MADRS depression score (primary endpoint) decreased by 8 weeks [24.4±1.6 (SEM) to 12.8±2.9, p=0.015] and persisted over the two-week taper (p=0.019); 44% of subjects experienced response (score decrease ≥50%) and remission (final score

Objective: Nonresponse to selective serotonin reuptake inhibitor and serotonin norepinephrine reuptake inhibitor treatment is common in patients with major depressive disorder (MDD), particularly in women, occurring in about 70% of patients despite adequate dosing. Well-tolerated augmentation strategies are needed, particularly ones that do not cause or exacerbate symptoms such as fatigue and sexual dysfunction. Low-dose testosterone has been shown to improve depression symptom severity, fatigue and sexual function in small studies of women not formally diagnosed with MDD. We sought to determine whether adjunctive low-dose transdermal testosterone improves depression symptom severity, fatigue, and sexual function in women with treatment-resistant MDD. A functional MRI (fMRI) substudy examined effects of testosterone on activity in the anterior cingulate cortex (ACC), a brain region important in mood regulation. Methods: Randomized, double-blind, placebo-controlled, 8-week trial of adjunctive testosterone cream (AndroFeme® 1, Lawley Pharmaceuticals, Australia) in 101 women, ages 21–70, with treatment-resistant MDD. Testosterone was titrated to achieve blood levels near the upper normal reference limit. Primary outcome measure was depression severity by Montgomery-Asberg Depression Rating Scale (MADRS). Secondary endpoints included fatigue, sexual function, and safety measures. fMRI substudy (n=20) primary outcome was change in ACC activity. Results: Mean age was 47±14 (SD) years and mean baseline MADRS score was 26.6±5.9. Eighty-seven (86%) participants completed 8 weeks of treatment. MADRS depression scores decreased in both arms [testosterone: 26.8±6.3 to 15.3±9.6; placebo: 26.3±5.4 to 14.4±9.3 (baseline to 8 weeks, respectively)], with no difference between groups (p=0.91). Fatigue and sexual function improved without differences between groups. There were no group differences in side effects. fMRI results demonstrated a relationship between ACC activation and androgen levels pretreatment but no difference in ACC activation with treatment. Conclusions: This rigorously designed, double-blinded clinical trial did not find significant group differences between adjunctive low dose transdermal testosterone and placebo for antidepressant augmentation in women with treatment-resistant MDD and had a high placebo response rate. Low-dose testosterone was well tolerated but failed to differentially impact overall depressive symptom severity, fatigue, or sexual dysfunction. Testosterone did not result in greater activity in a brain region (ACC) implicated in MDD etiopathology compared to placebo. Thus, the addition of low-dose testosterone to ineffective antidepressant treatment should not be recommended for women with MDD. Further studies using strategies designed to reduce placebo effects may be warranted.

Anorexia nervosa is complicated by low bone mineral density (BMD) and increased fracture risk associated with low bone formation and high bone resorption. The spine, particularly its trabecular component as measured by lateral spine dual-energy x-ray absorptiometry (DXA), is most severely affected. Low BMD and bone formation are associated with relative insulin-like growth hormone-1 (IGF-1) deficiency. Our objective was to determine whether bone anabolic therapy with off-label recombinant human (rh)IGF-1 followed by antiresorptive therapy with risedronate would increase BMD more than risedronate alone 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) (Z- or T-score

Acromegaly results in impaired quality of life (QoL), which improves but does not normalize after biochemical control of growth hormone (GH) excess. There are few data regarding long-term QoL in patients with sustained biochemical control of acromegaly. We hypothesized that QoL would continue to improve over time but remain poor. We studied 2 cohorts with biochemically controlled (normal IGF-1 level) acromegaly. MED (n=42) underwent surgery but required somatostatin analog (n=30) or GH receptor antagonist monotherapy (n=12); n=16 had undergone radiation. SURG (n=24) were in remission after surgery ± radiation (n=10). GH stimulation testing was performed in all SURG; n=11 had GH deficiency (GHD). QoL was assessed at 2 timepoints by the 36-Item-Short-Form Health Survey (SF-36) (MED, SURG), Acromegaly Quality of Life Questionnaire (AcroQoL) (MED), Gastrointestinal Quality of Life Index (GIQLI) (MED), Symptom Questionnaire (SQ) (SURG), and QoL-Assessment of GHD in Adults (AGHDA) (SURG). Time between timepoints 1 and 2 was 5.4 ± 1.0 vs 13.6 ± 1.2 years (MED vs SURG, p

The neuroactive steroid 3α-5α-tetrahydroprogesterone (allopregnanolone), a metabolite of progesterone, is a positive allosteric modulator of GABA(A) receptors, and low levels have been implicated in the etiology of mood disorders. However, it is not known whether metabolism of progesterone to allopregnanolone varies across the menstrual cycle or is low after menopause. We hypothesized that the allopregnanolone/progesterone ratio would decrease from the follicular to luteal phase. We also hypothesized that postmenopausal women would have lower levels of progesterone and allopregnanolone but similar allopregnanolone/progesterone ratios as premenopausal women in the follicular phase. Serum fasting allopregnanolone and progesterone levels were measured by gas chromatography-mass spectrometry in ten premenopausal women at the follicular, mid-cycle, and luteal phases of the menstrual cycle and in twenty-four postmenopausal women. Although allopregnanolone and progesterone levels increased from the follicular to luteal phase, the allopregnanolone/progesterone ratio decreased 8-fold [0.33 ± 0.08 (follicular) vs 0.16 ± 0.09 (mid-cycle) vs 0.04 ± 0.007 (luteal), p=0.0003]. Mean allopregnanolone and progesterone levels were lower in postmenopausal than premenopausal women at all menstrual cycle phases (p

Background: Neuroactive steroids such as 3α-5α-tetrahydroprogesterone (allopregnanolone) and 5α-androstane-3α,17β-diol (3α-androstanediol) are modulators of traditional neurotransmitter receptors and have been implicated in the etiopathology of psychiatric disorders, including depression, but levels have not been assessed in women with treatment-resistant major depressive disorder (MDD). We hypothesized that allopregnanolone, 3α-androstanediol, and the ratio of these steroid levels to their precursors (progesterone and testosterone, respectively) would be lower in postmenopausal women with treatment-resistant MDD than non-depressed controls. Methods: Fasting serum neuroactive steroid levels measured by gas chromatography/mass spectrometry were compared in women with treatment-resistant MDD (MDD, n=12) [Montgomery-Asberg Depression Rating Scale (MADRS) >12 despite an adequately dosed antidepressant] and in healthy controls without depression (HC, n=28). All subjects were postmenopausal nonsmokers; none were receiving systemic estrogen. Results: Mean age and BMI did not differ between groups. In MDD, mean number of antidepressants per subject was 1.5±0.5 (SD), with 58% receiving selective serotonin reuptake inhibitors and 50% bupropion. Mean MADRS was 24.4±5.8 (moderate depression severity). In MDD vs HC, the mean allopregnanolone/progesterone ratio was lower (0.20±0.19 vs 0.47±0.46, p=0.03) and progesterone levels were higher (153±177 vs 57±50 pg/mL, p=0.04). There was no difference in mean allopregnanolone levels between groups. Compared with HC, MDD subjects had lower serum free testosterone (0.21±0.16 vs 0.38±0.18 ng/dL, p=0.006) and a trend toward lower total testosterone (13.3±5.9 vs 18.6±9.9 ng/dL, p=0.06). There was no difference in 3α-androstanediol levels or 3α-androstanediol/total testosterone ratio between groups. There was a trend toward a positive association between progesterone levels and depression severity (r=0.34, p=0.06) and an inverse association between the allopregnanolone/progesterone ratio and depression severity (r=-0.36, p=0.07). Lower free testosterone levels were associated with greater depression severity (r=-0.45, p=0.03). Conclusion: In postmenopausal women with treatment-resistant MDD, the allopregnanolone/progesterone ratio was lower and progesterone levels higher than in non-depressed controls. Allopregnanolone levels did not differ between groups. This may be due to reduced metabolism of progesterone to allopregnanolone and could have treatment implications. Additionally, testosterone levels were lower in depressed women, but there was no difference in 3α-androstanediol levels or the 3α-androstanediol/total testosterone ratio between depressed and non-depressed women, suggesting that testosterone may play a greater role in depression symptomatology than its metabolite.

No study has investigated tibial or radial bone structure or estimated strength by high-resolution peripheral quantitative CT (HRpQCT) in women across the weight spectrum. We studied 139 women, 17-46yo: 1) anorexia nervosa (AN n=74), 2) lean controls (HC n=33) and 3) overweight/obese (OB n=32). All HC and OB were eumenorrheic. Areal BMD (aBMD) and appendicular lean mass (ALM) were measured by DXA; cortical and trabecular volumetric BMD (vBMD), cortical thickness, cortical porosity, failure load (finite element analysis) and trabecular plate parameters (individual trabecular segmentation) at the tibia and radius by HRpQCT. Mean age was similar among groups. Mean BMI was 17.7 ± 2.1 vs 22.6 ± 1.4 vs 35.2 ± 3.2 kg/m2 (p

Background: Anorexia nervosa is a serious psychiatric illness with significant mortality and no approved medical therapies. Comorbid affective disorders are highly prevalent, and we have shown that relative androgen deficiency in anorexia nervosa is associated with depression and anxiety symptom severity. As women with anorexia nervosa are relatively testosterone deficient, we hypothesized that physiologic testosterone therapy would improve weight, depressive and anxiety symptoms, and eating disorder symptoms and behavior. Methods: 90 women 18-45 yo with anorexia nervosa and free testosterone levels below the median for healthy young women were randomized to testosterone 300 mcg daily or placebo patch (Procter & Gamble) for 6 months. % free testosterone was measured by equilibrium dialysis and total testosterone by HTLC (Mayo Labs). Psychiatric disorders were diagnosed using the Structured Clinical Interview for DSM-IV. Depression and anxiety symptom severity were assessed [Hamilton Depression Rating Scale (HAM-D); Hamilton Anxiety Rating Scale (HAM-A)]. Eating disorder psychopathology/behaviors were assessed [Eating Disorder Examination (EDE) and Eating Disorder Inventory-2 (EDI-2)]. Primary outcome was BMI. Secondary outcomes were HAM-D, HAM-A, EDE, and EDI-2 scores. Results: Baseline characteristics, including mean testosterone levels, did not differ between the active and placebo groups. Mean age was 27±7(SD) years, BMI 18.3±1.6 kg/m2, and free testosterone 0.4±0.2 ng/dL (normal: 0.3-1.9 ng/dL). 64% of subjects met criteria for major depressive disorder and 68% for generalized anxiety disorder. Mean HAM-D score was 15±4 (moderate depression severity) and mean HAM-A score was 15±5 (mild anxiety severity). Groups did not differ in % of subjects who started/discontinued (44%) or changed psychiatric medication dose (30%) during the study. Mean increase in serum free testosterone was 0.9±0.9 ng/dL in the testosterone group. Mean BMI increased by 0.02±1.01 kg/m2 in the active, and 0.5±1.1 kg/m2 in the placebo, group (p=0.03) over 6 months. At 4 weeks, there was a trend toward a greater decrease in mean depression (-1.6±2.8 vs -0.7±3.0, p=0.09 by HAM-D), but not anxiety, severity score in the testosterone vs. placebo group. At 6 months, mean HAM-D and HAM-A scores decreased similarly in both groups [HAM-D -2.9±4.9 (testosterone) vs -3±5 (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 EDE or EDI-2 scores between groups. Testosterone was well-tolerated with no difference between groups in androgenic side effects. Conclusion: Contrary to what was hypothesized, low-dose testosterone therapy for 6 months in women with anorexia nervosa resulted in less weight gain, and did not lead to sustained improvements in depression, anxiety, or disordered eating symptoms, relative to placebo.

Asplenic patients are at increased risk for sepsis and fulminant infection. Sepsis in these patients is typically secondary to encapsulated bacteria, with Streptococcus pneumoniae being the most frequent pathogen. Rare complications of severe sepsis include purpura fulminans and bilateral adrenal hemorrhage (Waterhouse-Friderichsen syndrome). We present the case of a 36-year-old woman, healthy except for splenectomy years prior for idiopathic thrombocytopenic purpura treatment, who presented with fever. Upon presentation to our hospital, three hours after symptoms onset, she had purpura fulminans and shock. Despite timely antimicrobials and maximal resuscitative efforts, her disease progressed and she expired 12 hours after symptoms onset. Autopsy revealed bilateral adrenal hemorrhage; acute adrenal crisis likely contributed to her refractory shock. Prior to her presentation, she had not received guideline-based post-splenectomy care. Sepsis in asplenic patients can be fulminant and rapidly fatal. Streptococcus pneumoniae remains the most frequent cause, despite decreasing rates in recent years related to widespread pneumococcal vaccination. Guideline-based vaccinations and “pill-in-pocket” therapy can be life-saving for asplenic patients. Purpura fulminans represents an extreme manifestation of disseminated intravascular coagulation, is more common in asplenic patients, and portends a poor prognosis. Waterhouse-Friderichsen syndrome can be seen concurrently with purpura fulminans and further portends a poor prognosis; pre-mortem diagnosis requires a high index of suspicion.