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Objective: Studies in estrogen deficiency states such as primary ovarian insufficiency and Turner syndrome suggest that estrogen status may be an important modulator of mood and emotions. In this study we compared depressive and anxiety symptoms between adolescent and young adult female oligo-amenorrheic athletes (AA) and eumenorrheic females (EM), and explored structural, and functional changes in related brain areas during reward processing, a behavioral construct that is altered in depression and anxiety., Methods: We included (i) 24 AA participating in ≥4 hours/week of aerobic exercise or running ≥20 miles/week for ≥6 months in the preceding year, with lack of menstrual cycles for ≥3 months within at least 6 preceding months of oligo-amenorrhea, OR in premenarchal girls, absence of menses at >15 years), and (ii) 27 EM aged 14-25 years. Participants completed the Beck Depression Inventory-II (BDI-II), State and Trait Anxiety Inventory (STAI), and Mood and Anxiety Symptoms Questionnaire (MASQ). Structural MRI and brain activation during a functional MRI (fMRI) task that probes reward and punishment processing was examined in a subset of 10 AA and 23 EM., Results: Median (IQR) age and BMI of AA and EM groups were 20.6 (19.0-22.6) vs. 20.6 (19.2-23.7) years, p=0.6 and v 20.3 (18.8-21.5) vs. 21.9 (19.6-23.5) kg/m2, p=0.005, respectively. While groups did not differ for BDI-II scores, AA had higher anhedonic depression MASQ scores (p=0.04), and STAI (p=0.03) scores vs. EM. In the fMRI subset, AA had higher caudate volumes vs. EM [F(1, 29)=9.930, p=0.004]. Lower activation observed in the right caudate during reward anticipation in AA compared with EM (p=0.036) suggests blunted reward processing in the striatum in estrogen deficient states., Conclusion: Athletes with amenorrhea had higher depressive and anxiety symptomatology compared to eumenorrheic young women. Exploratory analyses demonstrated increased caudate volumes and decreased caudate activation during reward processing in athletes with amenorrhea suggesting that estrogen may play a role in reward processing., Competing Interests: Over the past 3 years, DP has received consulting fees from Albright Stonebridge Group, Boehringer Ingelheim, Compass Pathways, Engrail Therapeutics, Neumora Therapeutcis former BlackThorn Therapeutics, Neurocrine Bioscences, Neuroscience Software, Otsuka Pharmaceuticals, Sunovion Pharmaceuticals, and Takeda Pharmaceuticals; honoraria from the Psychonomic Society for editorial work and Alkermes, and research funding from NIMH, Dana Foundation, Brain and Behavior Research Foundation, Millennium Pharmaceuticals. In addition, he has received stock options from Compass Pathways, Engrail Therapeutics, Neumora Therapeutics former BlackThorn Therapeutics, and Neuroscience Software. Over the past 3 years, MM has received consulting fees from Sanofi and Abbvie, and served on the scientific advisory board for Abbvie and Ipsen. No funding from these entities was used to support the current work, and all views expressed are solely those of the author. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Baskaran, Kumar, Plessow, Nimmala, Ackerman, Eddy, Pizzagalli and Misra.)

Context: Low energy availability causes disruption of hypothalamic gonadotropin-releasing hormone secretion leading to functional hypothalamic amenorrhea (FHA) and hypoestrogenism, which in turn contributes to decreased bone mineral density (BMD) and increased bone marrow adipose tissue (MAT). Transdermal estradiol administration in physiologic doses increases BMD in adolescents and adults with FHA. However, the impact of estrogen replacement on MAT in relation to changes in BMD has not been studied in adolescents and young adults. We hypothesized that physiologic estrogen replacement would lead to decreases in MAT, associated with increases in BMD., Methods and Materials: We studied 15 adolescent and young adult females with FHA (14-25 years). All participants received a17β- estradiol transdermal patch at a dose of 0.1 mg/day (applied twice weekly) for 12 months. Participants also received cyclic progestin for 10-12 days each month. We quantified MAT (lipid/water ratio) of the fourth lumbar (L4) vertebral body and femoral diaphysis by single proton (1H)-magnetic resonance spectroscopy, and compartmental volumetric BMD of the distal radius and tibia using high-resolution peripheral quantitative computed tomography., Results: Transdermal estradiol therapy over 12 months resulted in a decrease in MAT at the lumbar (L4) vertebra from 0.92 ± 0.55 at baseline to 0.63 ± 0.29 at 12-months (p = 0.008), and an increase in radial and tibial cortical vBMD (p = 0.006, p = 0.0003). Changes in L4 MAT trended to be inversely associated with changes in radial cortical vBMD (rho = -0.47, p = 0.08)., Conclusion: We show that in adolescent and young adult girls with FHA, MAT decreases following transdermal estrogen therapy and these changes are associated with increased cortical vBMD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Mechanical loading improves bone mineral density (BMD) and strength while decreasing fracture risk. Cross-sectional studies show that exercise advantage is lost in oligo-amenorrheic athletes (OA). Longitudinal studies examining the opposing effects of exercise and hypogonadism on bone are lacking in adolescents/young adults., Objective: Evaluate differences in bone accrual over 12 months in OA, eumenorrheic athletes (EA) and non-athletes (NA). We hypothesized that bone accrual would be lower in OA than EA and NA, with differences most pronounced at non-weight bearing trabecular sites., Methods: 27 OA, 29 EA, and 22 NA, 14-25 years old, completed 12-months of the prospective study. Athletes were weight-bearing endurance athletes. Subjects were assessed for areal BMD and bone mineral content (BMC) using DXA at the femoral neck, total hip, lumbar spine and whole body (WB). Failure load (a strength estimate) at the distal radius and tibia was assessed using microfinite element analysis of data obtained via high resolution peripheral quantitative computed tomography (HRpQCT). The primary analysis was a comparison of changes in areal BMD, BMC, and failure load across groups over 12-months at the respective sites., Results: Groups did not differ for baseline age, height or BMI. Percent body fat was lower in both OA and EA compared to NA. OA attained menarche later than EA and NA. Over the follow-up period, OA gained 1.9 ± 2.7 kg of weight compared to 0.5 ± 2.4 kg and 0.8 ± 2.3 kg in EA and NA respectively (p = 0.09); 39% of OA resumed menses. Changes in BMD, BMD Z-scores, and tibial failure load over 12-months did not differ among groups. At follow up, EA had higher femoral neck, hip and WB BMD Z-scores than NA, and higher hip BMD Z-scores than OA (p < 0.05) after adjusting for covariates. At follow-up, radial failure load was lower in OA vs. NA, and tibial failure load lower in OA and NA vs. EA (p ≤ 0.04 for all). Change in weight and fat mass were associated with changes in BMD measures at multiple sites., Conclusion: Despite weight gain and menses recovery in many OA during follow-up, residual deficits persist without catch-up raising concerns for suboptimal peak bone mass acquisition., (Copyright © 2018. Published by Elsevier Inc.)

Objective: Normal-weight oligo-amenorrhoeic athletes (OAA) are at risk for low bone mineral density (BMD). Data are lacking regarding the impact of oestrogen administration on bone outcomes in OAA. Our objective was to determine the effects of transdermal versus oral oestrogen administration on bone in OAA engaged in weight-bearing activity., Methods: 121 patients with OAA aged 14-25 years were randomised to receive: (1) a 17β-estradiol transdermal patch continuously with cyclic oral micronised progesterone (PATCH), (2) a combined ethinyl estradiol and desogestrel pill (PILL) or (3) no oestrogen/progesterone (NONE). All participants received calcium and vitamin D supplementation. Areal BMD was assessed at the lumbar spine, femoral neck, total hip and total body less head using dual-energy X-ray absorptiometry at baseline, 6 and 12 months. Intention-to-treat (ITT) and completers analyses were performed., Results: Randomised groups did not differ for age, body mass index or BMD Z-scores at baseline. For ITT analysis, spine and femoral neck BMD Z-scores significantly increased in the PATCH versus PILL (p=0.011 and p=0.021, respectively) and NONE (p=0.021 and p=0.033, respectively) groups, and hip BMD Z-scores significantly increased in the PATCH versus PILL group (p=0.018). Similar findings were noted in completers analysis., Conclusion: Transdermal estradiol over 12 months improves BMD in young OAA, particularly compared with an ethinyl estradiol-containing contraceptive pill/oral contraceptives., Trial Registration Number: NCT00946192; Pre-results., Competing Interests: Competing interests: MM has served on the Scientific Advisory Board of Novo Nordisk, is a coinvestigator on an investigator-initiated grant from Novo Nordisk and is a consultant for Sanofi Pharmaceuticals., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Female athletes often experience amenorrhoea at various times during training, but this should not be considered normal. Low energy availability is a common cause of menstrual dysfunction, and amenorrhoea can serve as a warning sign of some of the health and performance consequences associated with inadequate energy, including poor bone accrual and low bone mineral density. Adolescence is an important time for bone accrual, growth, and development, making delayed menarche and secondary amenorrhoea particularly concerning in young athletes. The development of disordered eating and eating disorder behaviours also peaks during adolescence. Thus, screening for low energy availability, establishing the various causes of amenorrhoea, and treating amenorrhoea and low energy availability with an interdisciplinary team is most effective., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: We have reported low bone mineral density (BMD), impaired bone structure, and increased fracture risk in participants with anorexia nervosa (AN) and normal-weight oligoamenorrheic athletes (OAs). However, data directly comparing compartment-specific bone parameters in participants with AN, OAs, and controls are lacking., Design: A total of 468 female participants 14 to 21.9 years old were included: 269 with AN, 104 OAs, and 95 normal-weight eumenorrheic controls. Dual-energy x-ray absorptiometry was used to assess areal BMD (aBMD) of the whole body less head (WBLH), spine, and hip. High-resolution peripheral quantitative computed tomography was used to assess volumetric BMD (vBMD), bone geometry, and structure at the non-weight-bearing distal radius and weight-bearing distal tibia., Results: Participants with AN had lower WBLH and hip aBMD z scores than OAs and controls (P < 0.0001). Participants with AN and OAs had lower spine aBMD z scores than controls (P < 0.01). At the radius, total and cortical vBMD, percentage cortical area, and thickness were lower in the AN and OA groups than in controls (P ≤ 0.04); trabecular vBMD was lower in participants with AN than controls. At the tibia, participants with AN had lower measures for most parameters compared with OAs and controls (P < 0.05); OAs had lower cortical vBMD than controls (P = 0.002). Participants with AN and OAs had higher fracture rates than controls. Stress fracture prevalence was highest in OAs (P < 0.0001); nonstress fracture prevalence was highest in participants with AN (P < 0.05)., Conclusion: AN is deleterious to bone at all sites and both bone compartments. A high stress fracture rate in OAs, who have comparable WBLH and hip aBMD measures to controls, indicates that BMD in these women may need to be even higher to avoid fractures.

Cosponsoring Associations: The American Society for Reproductive Medicine, the European Society of Endocrinology, and the Pediatric Endocrine Society. This guideline was funded by the Endocrine Society., Objective: To formulate clinical practice guidelines for the diagnosis and treatment of functional hypothalamic amenorrhea (FHA)., Participants: The participants include an Endocrine Society-appointed task force of eight experts, a methodologist, and a medical writer., Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies., Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society committees and members and cosponsoring organizations reviewed and commented on preliminary drafts of this guideline., Conclusions: FHA is a form of chronic anovulation, not due to identifiable organic causes, but often associated with stress, weight loss, excessive exercise, or a combination thereof. Investigations should include assessment of systemic and endocrinologic etiologies, as FHA is a diagnosis of exclusion. A multidisciplinary treatment approach is necessary, including medical, dietary, and mental health support. Medical complications include, among others, bone loss and infertility, and appropriate therapies are under debate and investigation., (Copyright © 2017 Endocrine Society)

Objective: Both estrogen and exercise may have cognition enhancing benefits; however, young oligomenorrheic/amenorrheic athletes (OA) with estrogen deficiency have not been evaluated for cognitive deficits. Our objective was to determine whether 6 months of estrogen replacement will impact cognitive domains in OA. We hypothesized that estrogen replacement would improve verbal memory and executive control in OA., Methods: We performed cognitive assessments at baseline and after 6 months in 48 OA (14-25 years) randomized to estrogen (EST+) (oral 30 µg ethinyl estradiol [n = 16] or transdermal 100 µg 17-β-estradiol patch [n = 13]) or no estrogen (EST-) (n = 19) in an ongoing clinical trial. Neurocognitive testing included California Verbal Learning Test-Second Edition (CVLT-II) (for verbal memory) and Delis-Kaplan Executive Function System Color-Word Interference Test (D-KEFS-CWIT) (executive control)., Results: On average, subjects (mean ± SEM age: 19.9 ± 3.1 years, body mass index: 20.6 ± 2.3 kg/m²) participated in 10.3 ± 5.9 hours per week of weight-bearing activities of their lower limbs. The EST+ group performed better for CVLT-II verbal memory scores for immediate recall over 6 months of therapy compared to EST- (P < .05) even after controlling for baseline scores and age. Changes in D-KEFS-CWIT scores over 6 months did not differ between the groups. However, the EST+ group had greater improvements in inhibition-switching completion time over 6 months compared with the EST- group after controlling for baseline scores and age (P = .01)., Conclusions: OA show improvements in verbal memory and executive control following 6 months of estrogen replacement. These findings in athletes, who are in their prime of neurocognitive development, underscore the need for future studies exploring cognition in OA., Trial Registration: ClinicalTrials.gov identifier: NCT00946192., (© Copyright 2017 Physicians Postgraduate Press, Inc.)

Clinicians currently use different low-weight cut-offs both to diagnose anorexia nervosa (AN) and to determine AN severity in adolescent girls. The purpose of this study was to evaluate the clinical utility of existing cut-offs and severity criteria by determining which are most strongly associated with risk for low bone mineral density (BMD). Height adjusted BMD Z scores were calculated for 352 females: 262 with AN and 90 healthy controls (controls) (12-20.5 years), using data from the BMD in Childhood Study, for the lumbar spine, whole body less head, and total hip. For most cut-offs used to define low weight (5th or 10th BMI percentile, BMI of 17.5 or 18.5, and 85 or 90% of median BMI), AN had lower BMD Z scores than controls. AN at >85 or >90% expected body weight for height (EBW-Ht) did not differ in BMD Z scores from controls, but differed significantly from AN at ≤85 or ≤90% EBW-Ht. Among AN, any amenorrhea was associated with lower BMD. AN had lower BMD than controls across DSM-5 and The Society for Adolescent Health and Medicine (SAHM) severity categories. The SAHM moderate severity classification was differentiated from the mildly malnourished classification by lower BMD at hip and spine sites. Amenorrhea and %EBW-Ht ≤ 85 or ≤ 90% are markers of severity of bone loss within AN. Among severity categories, BMI Z scores (SAHM) may have the greatest utility in assessing the degree of malnutrition in adolescent girls that corresponds to lower BMD., (© 2017 Wiley Periodicals, Inc.)

Context: Areal bone mineral density (BMD) is lower, particularly at the spine, in low-weight women with anorexia nervosa (AN). However, little is known about vertebral integral volumetric BMD (Int.vBMD) or vertebral strength across the AN weight spectrum, including "atypical" AN [body mass index (BMI) ≥18.5 kg/m2]., Objective: To investigate Int.vBMD and vertebral strength, and their determinants, across the AN weight spectrum., Design: Cross-sectional observational study., Setting: Clinical research center., Participants: 153 women (age 18 to 45): 64 with low-weight AN (BMI <18.5 kg/m2; 58% amenorrheic), 44 with atypical AN (18.5≤BMI<23 kg/m2; 30% amenorrheic), 45 eumenorrheic controls (19.2≤BMI<25 kg/m2)., Measures: Int.vBMD and cross-sectional area (CSA) by quantitative computed tomography of L4; estimated vertebral strength (derived from Int.vBMD and CSA)., Results: Int.vBMD and estimated vertebral strength were lowest in low-weight AN, intermediate in atypical AN, and highest in controls. CSA did not differ between groups; thus, vertebral strength (calculated using Int.vBMD and CSA) was driven by Int.vBMD. In AN, Int.vBMD and vertebral strength were associated positively with current BMI and nadir lifetime BMI (independent of current BMI). Int.vBMD and vertebral strength were lower in AN with current amenorrhea and longer lifetime amenorrhea duration. Among amenorrheic AN, Int.vBMD and vertebral strength were associated positively with testosterone., Conclusions: Int.vBMD and estimated vertebral strength (driven by Int.vBMD) are impaired across the AN weight spectrum and are associated with low BMI and endocrine dysfunction, both current and previous. Women with atypical AN experience diminished vertebral strength, partially due to prior low-weight and/or amenorrhea. Lack of current low-weight or amenorrhea in atypical AN does not preclude compromise of vertebral strength., (Copyright © 2017 by the Endocrine Society)

Context: Young amenorrheic athletes (AA) have lower bone mineral density (BMD) and an increased prevalence of fracture compared with eumenorrheic athletes (EA) and non-athletes. Trabecular morphology is a determinant of skeletal strength and may contribute to fracture risk., Objectives: To determine the variation in trabecular morphology among AA, EA, and non-athletes and to determine the association of trabecular morphology with fracture among AA., Design and Setting: A cross-sectional study performed at an academic clinical research center., Participants: 161 girls and young women aged 14-26 years (97 AA, 32 EA, and 32 non-athletes)., Main Outcome Measure: We measured volumetric BMD (vBMD) and skeletal microarchitecture using high-resolution peripheral quantitative computed tomography. We evaluated trabecular morphology (plate-like vs. rod-like), orientation, and connectivity by individual trabecula segmentation., Results: At the non-weight-bearing distal radius, the groups did not differ for trabecular vBMD. However, plate-like trabecular bone volume fraction (pBV/TV) was lower in AA vs. EA (p=0.03), as were plate number (p=0.03) and connectivity (p=0.03). At the weight-bearing distal tibia, trabecular vBMD was higher in athletes vs. non-athletes (p=0.05 for AA and p=0.009 for EA vs. non-athletes, respectively). pBV/TV was higher in athletes vs. non-athletes (p=0.04 AA and p=0.005 EA vs. non-athletes), as were axially-aligned trabeculae, plate number, and connectivity. Among AA, those with a history of recurrent stress fracture had lower pBV/TV, axially-aligned trabeculae, plate number, plate thickness, and connectivity at the distal radius., Conclusions: Trabecular morphology and alignment differ among AA, EA, and non-athletes. These differences may be associated with increased fracture risk., (Copyright © 2015. Published by Elsevier Inc.)

Context: Various fat depots have differential effects on bone. Visceral adipose tissue (VAT) is deleterious to bone, whereas subcutaneous adipose tissue (SAT) has positive effects. Also, marrow adipose tissue (MAT), a relatively newly recognized fat depot is inversely associated with bone mineral density (BMD). Bone mass in athletes depends on many factors including gonadal steroids and muscle mass. Exercise increases muscle mass and BMD, whereas, estrogen deficiency decreases BMD. Thus, the beneficial effects of weight-bearing exercise on areal and volumetric BMD (aBMD and vBMD) in regularly menstruating (eumenorrheic) athletes (EA) are attenuated in oligo-amenorrheic athletes (OA). Of note, data regarding VAT, SAT, MAT and regional muscle mass in OA compared with EA and non-athletes (C), and their impact on bone are lacking., Methods: We used (i) MRI to assess VAT and SAT at the L4 vertebra level, and cross-sectional muscle area (CSA) of the mid-thigh, (ii) 1H-MRS to assess MAT at L4, the proximal femoral metaphysis and mid-diaphysis, (iii) DXA to assess spine and hip aBMD, and (iv) HRpQCT to assess vBMD at the distal radius (non-weight-bearing bone) and tibia (weight-bearing bone) in 41 young women (20 OA, 10 EA and 11 C 18-25 years). All athletes engaged in weight-bearing sports for ≥ 4 h/week or ran ≥ 20 miles/week., Main Outcome Measures: VAT, SAT and MAT at L4; CSA of the mid-thigh; MAT at the proximal femoral metaphysis and mid-diaphysis; aBMD, vBMD and bone microarchitecture., Results: Groups had comparable age, menarchal age, BMI, VAT, VAT/SAT and spine BMD Z-scores. EA had higher femoral neck BMD Z-scores than OA and C. Fat mass was lowest in OA. SAT was lowest in OA (p = 0.048); L4 MAT was higher in OA than EA (p = 0.03). We found inverse associations of (i) VAT/SAT with spine BMD Z-scores (r = -0.42, p = 0.01), (ii) L4 MAT with spine and hip BMD Z-scores (r = -0.44, p = 0.01; r = -0.36, p = 0.02), and vBMD of the radius and tibia (r = -0.49, p = 0.002; r = -0.41, p = 0.01), and (iii) diaphyseal and metaphyseal MAT with vBMD of the radius (r ≤ -0.42, p ≤ 0.01) and tibia (r ≤ -0.34, p ≤ 0.04). In a multivariate model including VAT/SAT, L4 MAT and thigh CSA, spine and hip BMD Z-scores were predicted inversely by L4 MAT and positively by thigh CSA, and total and cortical radius and total tibial vBMD were predicted inversely by L4 MAT. VAT/SAT did not predict radius or tibia total vBMD in this model, but inversely predicted spine BMD Z-scores. When L4 MAT was replaced with diaphyseal or metaphyseal MAT in the model, diaphyseal and metaphyseal MAT did not predict aBMD Z-scores, but diaphyseal MAT inversely predicted total vBMD of the radius and tibia. These results did not change after adding percent body fat to the model., Conclusions: VAT/SAT is an inverse predictor of lumbar spine aBMD Z-scores, while L4 MAT is an independent inverse predictor of aBMD Z-scores at the spine and hip and vBMD measures at the distal tibia and radius in athletes and non-athletes. Diaphyseal MAT independently predicts vBMD measures of the distal tibia and radius., (Copyright © 2015. Published by Elsevier Inc.)

Introduction: This study was aimed to compare fracture prevalence in oligoamenorrheic athletes (AA), eumenorrheic athletes (EA), and nonathletes (NA) and determine relationships with bone density, structure, and strength estimates., Methods: One hundred seventy-five females (100 AA, 35 EA, and 40 NA) 14-25 yr old were studied. Lifetime fracture history was obtained through participant interviews. Areal bone mineral density (BMD) was assessed by DXA at the spine, hip, and whole body (WB). Bone structure was assessed by HRpQCT at the radius and tibia, and strength by finite element analysis., Results: AA, EA, and NA did not differ in age, sexual maturity, or height. AA had lower BMI, and older menarchal age than EA and NA (P ≤ 0.001). Bone mineral density Z-scores were lower in AA versus EA at the total hip, femoral neck, spine, and whole body (P ≤ 0.001). Lifetime fracture risk was higher in AA than EA and NA (47%, 25.7%, 12.5%; P ≤ 0.001), largely driven by stress fractures in AA versus EA and NA (32% vs 5.9% vs 0%). In AA, those who fractured had lower lumbar and WB BMD Z-scores, volumetric BMD (vBMD) of outer trabecular region in radius and tibia, and trabecular thickness of the radius (P ≤ 0.05). In AA, those who had two or more stress fractures had lower lumbar and WB BMD Z-scores, total cross-sectional area, trabecular vBMD, stiffness, and failure load at radius; and lower stiffness and failure load at tibia versus those with fewer than two stress fractures (P ≤ 0.05)., Conclusion: Weight-bearing athletic activity increases BMD but may increase stress fracture risk in those with menstrual dysfunction. Bone microarchitecture and strength differences are more pronounced in AA with multiple stress fractures. This is the first study to examine fractures in relation to bone structure in adolescent female athletes.

Objectives: Disordered eating may negatively impact bone in athletes. However, it is not known whether this effect is independent of the associated amenorrhea and relative hypercortisolemia. We aimed to compare attitudes, feelings, and cognitions associated with disordered eating using the Three-Factor Eating Questionnaire (TFEQ) and Eating Disorder Inventory-2 (EDI-2) in normal-weight oligomenorrheic athletes (OA), eumenorrheic athletes (EA), and nonathletes, and determine the associations with bone independent of confounders., Method: 109 OA, 39 EA, and 36 nonathletes (14-25 years) completed the TFEQ and EDI-2. Dual-energy X-ray absorptiometry was used to assess spine bone mineral density (BMD), and high-resolution pQCT to assess radius microarchitecture. We measured integrated cortisol (q 20', 11 PM-7 AM), bone formation (procollagen Type 1 N-terminal propeptide, P1NP), and resorption (C-telopeptide, CTX) markers in a subset., Results: OA had lower spine BMD Z-scores than EA. Cognitive eating restraint (CER), drive for thinness (DT), ineffectiveness, and interoceptive awareness (IA) were higher in OA than EA (p < 0.05); CER was higher in OA versus nonathletes (p = 0.03). Pulsatile cortisol was positively associated with DT, ineffectiveness, and IA (p < 0.03). CER was inversely associated with BMD Z-scores and P1NP, and ineffectiveness with radius cross-sectional area even after controlling for age, BMI, amenorrhea duration, and cortisol (p < 0.03)., Discussion: Higher CER in athletes independently predicts lower BMD., (© 2015 Wiley Periodicals, Inc.)

Irisin and FGF21 are novel hormones implicated in the "browning" of white fat, thermogenesis, and energy homeostasis. However, there are no data regarding these hormones in amenorrheic athletes (AA) (a chronic energy deficit state) compared with eumenorrheic athletes (EA) and non-athletes. We hypothesized that irisin and FGF21 would be low in AA, an adaptive response to low energy stores. Furthermore, because (i) brown fat has positive effects on bone, and (ii) irisin and FGF21 may directly impact bone, we hypothesized that bone density, structure and strength would be positively associated with these hormones in athletes and non-athletes. To test our hypotheses, we studied 85 females, 14-21 years [38 AA, 24 EA and 23 non-athletes (NA)]. Fasting serum irisin and FGF21 were measured. Body composition and bone density were assessed using dual energy X-ray absorptiometry, bone microarchitecture using high resolution peripheral quantitative CT, strength estimates using finite element analysis, resting energy expenditure (REE) using indirect calorimetry and time spent exercising/week by history. Subjects did not differ for pubertal stage. Fat mass was lowest in AA. AA had lower irisin and FGF21 than EA and NA, even after controlling for fat and lean mass. Across subjects, irisin was positively associated with REE and bone density Z-scores, volumetric bone mineral density (total and trabecular), stiffness and failure load. FGF21 was negatively associated with hours/week of exercise and cortical porosity, and positively with fat mass and cortical volumetric bone density. Associations of irisin (but not FGF21) with bone parameters persisted after controlling for potential confounders. In conclusion, irisin and FGF21 are low in AA, and irisin (but not FGF21) is independently associated with bone density and strength in athletes.

Context: Oxytocin has been implicated in the modulation of energy metabolism in animals. Oxytocin knockout mice develop obesity without a change in food intake, suggesting that a lack of oxytocin may reduce metabolic rate. Furthermore, administration of oxytocin centrally reduces food intake in rats, an effect reversed by an oxytocin antagonist, implying that oxytocin may regulate appetite and energy intake. We have previously demonstrated that young female athletes (in a higher energy expenditure state than nonathletes) have low nocturnal oxytocin compared with nonathletes. Whether oxytocin is associated with measures of energy homeostasis in athletes is unknown., Objective: We hypothesized that oxytocin, a signal for energy availability, would be associated with other measures of energy homeostasis in young female athletes., Design and Setting: We performed a cross-sectional study of 45 females, aged 14-21 years [15 amenorrheic athletes (AA), 15 eumenorrheic athletes, and 15 nonathletes] of comparable body mass index., Methods: Dual x-ray absorptiometry was performed to assess body composition. Indirect calorimetry was used to measure resting energy expenditure (REE). Fasting levels of oxytocin, energy homeostasis hormones irisin and fibroblast growth factor-21, and appetite-regulating hormone peptide YY were obtained., Results: In AA, oxytocin secretion was positively correlated with surrogate measures of energy availability, including weight (r = 0.65, P = .009) and body mass index (r = 0.61, P = .016). Furthermore, oxytocin was associated with REE (r = 0.80, P = .0003), independent of lean mass, and with irisin (r = 0.74, P = .002) and fibroblast growth factor-21 (r = 0.58, P = .024). In eumenorrheic athletes, oxytocin was associated with REE (r = 0.59, P = .021), independent of lean mass. In nonathletes, oxytocin secretion was not significantly associated with measures of energy homeostasis., Conclusions: In AA, oxytocin secretion is associated with measures of energy availability and expenditure, suggesting that oxytocin may be involved in regulation of energy balance in energy deficient states. Further studies determining the role of oxytocin in appetite and energy homeostasis in athletes are warranted.

Aims: Low-weight hypogonadal conditions such as anorexia nervosa are associated with marked changes in body composition, hemodynamic and hematological parameters, and liver enzymes. The impact of athletic activity in normal-weight adolescents with/without amenorrhea on these parameters has not been assessed. Our aim was to examine these parameters in normal-weight athletes and nonathletes and determine any associations with body composition, oligo-amenorrhea, and exercise intensity., Methods: We assessed vital signs, complete blood counts, liver enzymes, and regional body composition in 43 oligo-amenorrheic athletes (OAA), 24 eumenorrheic athletes (EA), and 23 nonathletes aged 14-21 years., Results: The BMI was lower in OAA than in EA. Systolic and pulse pressure and temperature were lowest in OAA. Blood counts did not differ among groups. Aspartate aminotransferase (AST) was higher in both groups of athletes, while alanine aminotransferase (ALT) was higher in OAA than in EA and nonathletes. Total and regional fat were lower in OAA than in other groups, and these factors were associated positively with heart rate and inversely with liver enzymes., Conclusions: Athletic activity is associated with higher AST levels, whereas menstrual dysfunction is associated with lower total and regional fat and higher ALT levels. Higher liver enzymes are associated with reductions in total and regional fat.

Context: Stress fractures are common in endurance athletes. Whereas studies have described distal tibia bone structure in athletes, there are few data regarding hip geometric parameters. Hip structural analysis (HSA) using dual-energy x-ray absorptiometry is a validated technique to assess hip bone structure., Objectives: The purpose of this study was to compare hip geometry in young oligoamenorrheic athletes (AAs), eumenorrheic athletes (EAs), and nonathletes using HSA. We hypothesized that AAs would have impaired bone structure compared with that of EAs., Design: This was a cross-sectional study., Setting: The setting was a clinical research center., Subjects: We enrolled 55 AAs, 24 EAs, and 23 nonathletes of normal weight who were 14 to 22 years old. Athletes ran ≥20 miles/wk or were engaged in weight-bearing sports for ≥4 hours/wk., Main Outcome Measures: Dual-energy x-ray absorptiometry was used for HSA and hip areal bone mineral density (aBMD)., Results: Hip aBMD Z-scores were lower in AAs and in nonathletes than in EAs (P = .002). A larger proportion of AAs than EAs and nonathletes had hip Z-scores <-1 (30.9, 4.2, 17.4%, P = .01). At the narrow neck, trochanteric region, and femoral shaft, subperiosteal width, cross-sectional moment of inertia, and section modulus were higher in EAs than in nonathletes; values in AAs did not differ from those of nonathletes. Cross-sectional area was lower in AAs and in nonathletes than in EAs. Groups did not differ for cortical thickness or buckling ratio. Group differences were lost after adjustment for lean mass but not aBMD., Conclusions: In an eugonadal state, athletic activity confers benefits for hip structure independent of aBMD. This advantage is lost in AAs, who do not differ from nonathletes for most parameters and fare worse than EAs for cross-sectional area.

Objective: Preclinical data indicate that oxytocin, a hormone produced in the hypothalamus and secreted into the peripheral circulation, is anabolic to bone. Oxytocin knockout mice have severe osteoporosis, and administration of oxytocin improves bone microarchitecture in these mice. Data suggest that exercise may modify oxytocin secretion, but this has not been studied in athletes in relation to bone. We therefore investigated oxytocin secretion and its association with bone microarchitecture and strength in young female athletes., Design: Cross-sectional study of 45 females, 14-21 years (15 amenorrheic athletes (AA), 15 eumenorrheic athletes (EA), and 15 nonathletes (NA)), of comparable bone age and BMI., Methods: We used high-resolution peripheral quantitative CT to assess bone microarchitecture and finite element analysis to estimate bone strength at the weight-bearing distal tibia and non-weight-bearing ultradistal radius. Serum samples were obtained every 60  min, 2300-0700  h, and pooled for an integrated measure of nocturnal oxytocin secretion. Midnight and 0700  h samples were used to assess diurnal variation of oxytocin., Results: Nocturnal oxytocin levels were lower in AA and EA than in NA. After controlling for estradiol, the difference in nocturnal oxytocin between AA and NA remained significant. Midnight and 0700  h oxytocin levels did not differ between groups. At the tibia and radius, AA had impaired microarchitecture compared with NA. In AA, nocturnal oxytocin correlated strongly with trabecular and cortical microarchitecture, particularly at the non-weight-bearing radius. In regression models that include known predictors of microarchitecture in AA, oxytocin accounted for a substantial portion of the variability in microarchitectural and strength parameters., Conclusions: Nocturnal oxytocin secretion is low in AA compared with NA and associated with site-dependent microarchitectural parameters. Oxytocin may contribute to hypoestrogenemic bone loss in AA.

Context: Lower bone density in young amenorrheic athletes (AA) compared to eumenorrheic athletes (EA) and non-athletes may increase fracture risk during a critical time of bone accrual. Finite element analysis (FEA) is a unique tool to estimate bone strength in vivo, and the contribution of cortical microstructure to bone strength in young athletes is not well understood., Objective: We hypothesized that FEA-estimated stiffness and failure load are impaired in AA at the distal radius and tibia compared to EA and non-athletes despite weight-bearing exercise., Design and Setting: Cross-sectional study; Clinical Research Center, Subjects: 34 female endurance athletes involved in weight-bearing sports (17 AA, 17 EA) and 16 non-athletes (14-21 years) of comparable age, maturity and BMI OUTCOME MEASURES: We used HR-pQCT images to assess cortical microarchitecture and FEA to estimate bone stiffness and failure load., Results: Cortical perimeter, porosity and trabecular area at the weight-bearing tibia were greater in both groups of athletes than non-athletes, whereas the ratio (%) of cortical to total area was lowest in AA. Despite greater cortical porosity in EA, estimated tibial stiffness and failure load was higher than in non-athletes. However, this advantage was lost in AA. At the non-weight-bearing radius, failure load and stiffness were lower in AA than non-athletes. After controlling for lean mass and menarchal age, athletic status accounted for 5-9% of the variability in stiffness and failure load, menarchal age for 8-23%, and lean mass for 12-37%., Conclusion: AA have lower FEA-estimated bone strength at the distal radius than non-athletes, and lose the advantage of weight-bearing exercise seen in EA at the distal tibia., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Amenorrhea is common in young athletes and is associated with low fat mass. However, hormonal factors that link decreased fat mass with altered gonadotropin pulsatility and amenorrhea are unclear. Low levels of leptin (an adipokine) and increased ghrelin (an orexigenic hormone that increases as fat mass decreases) impact gonadotropin pulsatility. Studies have not examined luteinizing hormone (LH) secretory dynamics in relation to leptin or ghrelin secretory dynamics in adolescent and young adult athletes. We hypothesized that 1) young amenorrheic athletes (AA) would have lower LH and leptin and higher ghrelin secretion than eumenorrheic athletes (EA) and nonathletes and 2) higher ghrelin and lower leptin would be associated with lower LH secretion. This was a cross-sectional study. We examined ghrelin and leptin secretory patterns (over 8 h, from 11 PM to 7 AM) in relation to LH secretory patterns in AA, EA, and nonathletes aged 14-21 yr. Ghrelin and leptin were assessed every 20 min and LH every 10 min. Groups did not differ for age, bone age, or BMI. However, fat mass was lower in AA than in EA and nonathletes. AA had lower LH and higher ghrelin pulsatile secretion and AUC than nonathletes and lower leptin pulsatile secretion and AUC than EA and nonathletes. Percent body fat was associated positively with LH and leptin secretion and inversely with ghrelin. In a regression model, ghrelin and leptin secretory parameters were associated independently with LH secretory parameters. We conclude that higher ghrelin and lower leptin secretion in AA related to lower fat mass may contribute to altered LH pulsatility and amenorrhea.

Context: Bone mineral density (BMD) is lower in young amenorrheic athletes (AA) compared to eumenorrheic athletes (EA) and nonathletic controls and may contribute to fracture risk during a critical time of bone accrual. Abnormal bone microarchitecture is an independent determinant of fracture risk and has not been assessed in young athletes and nonathletes., Objective: We hypothesized that bone microarchitecture is impaired in AA compared to EA and nonathletes despite weight-bearing exercise., Design and Setting: We conducted this cross-sectional study at the Clinical Research Center of Massachusetts General Hospital., Subjects and Outcome Measures: We assessed BMD and bone microarchitecture in 50 subjects [16 AA, 18 EA, and 16 nonathletes (15-21 yr old)] using dual-energy x-ray absorptiometry and high-resolution peripheral quantitative computed tomography., Results: Groups did not differ for chronological age, bone age, body mass index, or vitamin D levels. Lumbar BMD Z-scores were lower in AA vs. EA and nonathletes; hip and femoral neck BMD Z-scores were highest in EA. At the weight-bearing tibia, athletes had greater total area, trabecular area, and cortical perimeter than nonathletes, whereas cortical area and thickness trended lower in AA. Trabecular number was lower and trabecular separation higher in AA vs. EA and nonathletes. At the non-weight-bearing radius, trabecular density was lower in AA vs. EA and nonathletes. Later menarchal age was an important determinant of impaired microarchitecture. After controlling for covariates, subject grouping accounted for 18-24% of the variability in tibial trabecular number and separation., Conclusion: In addition to low BMD, AA have impaired bone microarchitecture compared with EA and nonathletes. These are the first data to show abnormal bone microarchitecture in AA.

Objective: Lean mass is associated with bone mineral density (BMD) in athletes, attributable to the anabolic pull of muscle on bone. Fat mass is also important, and subcutaneous fat positively and visceral fat negatively correlates with BMD in obese adolescents. The contribution of regional body composition to low BMD in amenorrheic athletes (AA) has not been elucidated. We hypothesized that in adolescent athletes (runners), BMD is associated positively with total fat (surrogate for subcutaneous fat) and lean mass, and inversely with percent trunk fat and trunk-to-extremity fat ratio (surrogates for visceral fat)., Design: Cross-sectional study., Subjects and Methods: We examined BMD and body composition using dual energy X-ray absorptiometry (DXA) in 21 AA and 19 eumenorrheic athletes (EA) (12-18 years) (runners). We report total hip and height-adjusted BMD [lumbar bone mineral apparent density (LBMAD) and whole body bone mineral content/height (WBBMC/Ht)]., Results: AA had lower BMD than EA. Lean mass was less strongly associated with hip BMD in AA than EA; fat mass was positively associated with LBMAD in EA. Percent trunk fat and trunk-to-extremity fat ratio were inversely associated with lumbar and WB measures in AA. In a regression model, lean and fat mass were positively, and percent trunk fat and trunk-to-extremity fat ratio negatively associated with LBMAD and WBBMC/Ht for all athletes, even after controlling for serum estradiol., Conclusions: DXA surrogates for visceral fat are inversely associated with bone density in athletes.

Adolescent female athletes are at increased risk for low bone mineral density (BMD) secondary to exercise-induced hypogonadism. Of particular concern is that the adolescent years are also a critical time for bone accrual, and deficits incurred during this period could lead to suboptimal peak bone mass acquisition and subsequent fracture risk in later life. Although weight-bearing exercise is typically associated with an increase in BMD, amenorrheic athletes have lower BMD than eumenorrheic athletes and nonathletic controls as a consequence of low energy availability and subsequent hypogonadism. It is important to recognize that critical interactions exist between net energy availability and the hypothalamo-pituitary-gonadal (H-P-G) axis that are key to the development of a hypogonadal state when energy intake cannot keep pace with expenditure. While the link between energy availability and gonadtotropin pulsatility patterns is well established, the actual metabolic signals that link the two are less clear. Decreased energy availability in athletes is associated with decreases in fat mass, and alterations in adipokines (such as leptin and adiponectin) and fat-regulated hormones (such as ghrelin and peptide YY). These hormones impact the H-P-G axis in animal models, and it is possible that in athletes alterations in fat-related hormones signal the state of energy availability to the hypothalamus and contribute to suppression of gonadotropin pulsatility, hypothalamic amenorrhea and consequent decreased BMD. A better understanding of pathways linking low energy availability with functional hypothalamic amenorrhea and low BMD is critical for the development of future therapeutic strategies addressing these issues in amenorrheic athletes., (Copyright © 2010 S. Karger AG, Basel.)

Context: Anorexia nervosa (AN) and functional hypothalamic amenorrhea (HA) are associated with low bone density, anxiety, and depression. Women with AN and HA have elevated cortisol levels. Significant hypercortisolemia, as in Cushing's disease, causes bone loss. It is unknown whether anxiety and depression and/or cortisol dysregulation contribute to low bone density in AN or HA., Objective: Our objective was to investigate whether hypercortisolemia is associated with bone loss and mood disturbance in women with HA and AN., Design and Setting: We conducted a cross-sectional study in a clinical research center., Participants: We studied 52 women [21 healthy controls (HC), 13 normal-weight women with functional HA, and 18 amenorrheic women with AN]., Outcome Measures: Serum samples were measured every 20 min for 12 h overnight and pooled for average cortisol levels. Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry (DXA) at anteroposterior and lateral spine and hip. Hamilton Rating Scales for Anxiety (HAM-A) and Depression (HAM-D) were administered., Results: BMD was lower in AN and HA than HC at all sites and lower in AN than HA at the spine. On the HAM-D and HAM-A, AN scored higher than HA, and HA scored higher than HC. Cortisol levels were highest in AN, intermediate in HA, and lowest in HC. HAM-A and HAM-D scores were associated with decreased BMD. Cortisol levels were positively associated with HAM-A and HAM-D scores and negatively associated with BMD., Conclusions: Hypercortisolemia is a potential mediator of bone loss and mood disturbance in these disorders.

Background: Bone mineral density (BMD) is lower in amenorrheic athletes (AA) compared with eumenorrheic athletes (EA). Decreased energy availability and altered levels of appetite regulating hormones (ghrelin and leptin) in AA contribute to hypogonadism, an important cause of low BMD. The role of other nutritionally regulated hormones such as peptide YY (PYY) and adiponectin in mediating gonadal status and bone metabolism remains to be determined., Objectives: Our objective was to determine whether PYY and adiponectin are higher in AA compared with EA and contribute to hypogonadism and impaired bone metabolism in AA., Methods: We determined PYY and adiponectin in 16 AA, 15 EA and 16 non-athletic controls 12-18 years old, and other nutritionally dependent hormones including ghrelin, leptin and IGF-1. We also measured testosterone, estradiol, PINP and NTX (markers of bone formation and resorption) and BMD., Results: PYY was higher in AA than EA (111+/-52 vs. 61+/-29 pg/ml, p<0.05), whereas adiponectin did not differ between groups. Although activity scores did not differ, BMI was lower in AA than EA and a larger proportion (62.5% vs. 6.7%) reported disordered eating, indicating lower energy availability. PYY and adiponectin were independent predictors of testosterone in a regression model (p=0.01 and 0.04), but did not predict estradiol. PYY, but not adiponectin, was an independent and negative predictor of PINP (p=0.002) and lumbar bone mineral apparent density Z-scores (p=0.045) in this model., Conclusion: High PYY levels (but not adiponectin) differentiate AA from EA, and may be an important factor contributing to low bone density in athletes.

Objectives: Neuroendocrine factors may predict which athletes develop amenorrhea and which athletes remain eugonadal. Specifically, ghrelin and leptin have been implicated in regulation of GnRH secretion, with ghrelin having inhibitory and leptin, facilitatory effects. We hypothesized that adolescent athletes with amenorrhea (AA) would have higher ghrelin and lower leptin levels than eumenorrheic athletes (EA) and would predict levels of gonadal steroids., Design: Cross-sectional., Subjects and Measurements: We enrolled 58 girls, 21 AA, 19 EA and 18 nonathletic controls 12-18 years old. Fasting blood was drawn for active ghrelin, leptin, E(2) and testosterone. Athletes were > 85% of ideal body weight for age based on body mass index (BMI)., Results: AA girls had lower BMI than EA and controls (P = 0.003). Log ghrelin was higher in AA than in EA and controls (P < 0.0001), and remained higher after controlling for BMI Z-scores. Leptin was lower in AA than in the other groups (P < 0.0001), however, the differences did not persist after controlling for BMI Z-scores. Testosterone was lower in AA than in EA and controls (P = 0.002) and log E(2) trended lower in AA (P = 0.07). We observed inverse associations of log active ghrelin with testosterone (P = 0.01), and positive associations of leptin with testosterone and log E(2) (P = 0.02 and 0.009)., Conclusion: Higher ghrelin levels, even after controlling for BMI, and lower leptin in AA compared with EA and controls, and their inverse and positive associations, respectively, with gonadal steroids suggest endocrine perturbations that may explain why hypogonadism occurs in some but not all athletes.

Objective: We hypothesized that, despite increased activity, bone density would be low in athletes with amenorrhea, compared with athletes with eumenorrhea and control subjects, because of associated hypogonadism and would be associated with a decrease in bone formation and increases in bone-resorption markers., Methods: In a cross-sectional study, we examined bone-density measures (spine, hip, and whole body) and body composition by using dual-energy radiograph absorptiometry and assessed fasting levels of insulin-like growth factor I and bone-turnover markers (N-terminal propeptied of type 1 procollagen and N-telopeptide) in 21 athletes with amenorrhea, 18 athletes with eumenorrhea, and 18 control subjects. Subjects were 12 to 18 years of age and of comparable chronologic and bone age., Results: Athletes with amenorrhea had lower bone-density z scores at the spine and whole body, compared with athletes with eumenorrhea and control subjects, and lower hip z scores, compared with athletes with eumenorrhea. Lean mass did not differ between groups. However, athletes with amenorrhea had lower BMI z scores than did athletes with eumenorrhea and lower insulin-like growth factor I levels than did control subjects. Levels of both markers of bone turnover were lower in athletes with amenorrhea than in control subjects. BMI z scores, lean mass, insulin-like growth factor I levels, and diagnostic category were important independent predictors of bone mineral density z scores., Conclusions: Although they showed no significant differences in lean mass, compared with athletes with eumenorrhea and control subjects, athletes with amenorrhea had lower bone density at the spine and whole body. Insulin-like growth factor I levels, body-composition parameters, and menstrual status were important predictors of bone density. Follow-up studies are necessary to determine whether amenorrhea in athletes adversely affects the rate of bone mass accrual and therefore peak bone mass.

Objective: Anorexia nervosa is associated with low bone mineral density (BMD) and deficits in bone microarchitecture and strength. Low BMD is common in atypical anorexia nervosa, in which criteria for anorexia nervosa are met except for low weight. We investigated whether women with atypical anorexia nervosa have deficits in bone microarchitecture and estimated strength at the peripheral skeleton. Method: Measures of BMD and microarchitecture were obtained in 28 women with atypical anorexia nervosa and 27 controls, aged 21–46 years. Results: Mean tibial volumetric BMD, cortical thickness, and failure load were lower, and radial trabecular number and separation impaired, in atypical anorexia nervosa versus controls (p <.05). Adjusting for weight, deficits in tibial cortical bone variables persisted (p <.05). Women with atypical anorexia nervosa and amenorrhea had lower volumetric BMD and deficits in microarchitecture and failure load versus those with eumenorrhea and controls. Those with a history of overweight/obesity or fracture had deficits in bone microarchitecture versus controls. Tibial deficits were particularly marked. Less lean mass and longer disease duration were associated with deficits in high‐resolution peripheral quantitative computed tomography (HR‐pQCT) variables in atypical anorexia nervosa. Discussion: Women with atypical anorexia nervosa have lower volumetric BMD and deficits in bone microarchitecture and strength at the peripheral skeleton versus controls, independent of weight, and particularly at the tibia. Women with atypical anorexia nervosa and amenorrhea, less lean mass, longer disease duration, history of overweight/obesity, or fracture history may be at higher risk. This is salient as deficits in HR‐pQCT variables are associated with increased fracture risk. Public Significance: Atypical anorexia nervosa is a psychiatric disorder in which psychological criteria for anorexia nervosa are met despite weight being in the normal range. We demonstrate that despite weight in the normal range, women with atypical anorexia nervosa have impaired bone density, structure, and strength compared to healthy controls. Whether this translates to an increased risk of incident fracture in this population requires further investigation. [ABSTRACT FROM AUTHOR]

Functional hypothalamic amenorrhea is a state of reversible hypogonadism common in adolescents and young women that can be triggered by energy deficit or emotional stress or a combination of these factors. Energy deficit may be a consequence of (i) reduced caloric intake, as seen in patients with eating disorders, such as anorexia nervosa, or (ii) excessive exercise, when caloric intake is insufficient to meet the needs of energy expenditure. In these conditions of energy deficit, suppression of the hypothalamic secretion of gonadotrophin-releasing hormone (with resulting hypoestrogenism) as well as other changes in hypothalamic-pituitary function may occur as an adaptive response to limited energy availability. Many of these adaptive changes, however, are deleterious to reproductive, skeletal, and neuropsychiatric health. Particularly, normoestrogenemia is critical for normal bone accrual during adolescence, and hypoestrogenemia during this time may lead to deficits in peak bone mass acquisition with longstanding effects on skeletal health. The adolescent years are also a time of neurological changes that impact cognitive function, and anxiety and depression present more frequently during this time. Normal estrogen status is essential for optimal cognitive function (particularly verbal memory and executive function) and may impact emotion and mood. Early recognition of women at high risk of developing hypothalamic amenorrhea and its timely management with a multidisciplinary team are crucial to prevent the severe and long-term effects of this condition. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective DSM-5 revised the diagnostic criteria for anorexia nervosa (AN) by eliminating the amenorrhea requirement, liberalizing weight and psychological criteria, and adding the formal diagnosis of 'atypical AN' for individuals with AN psychological symptoms without low weight. We sought to determine whether bone density (BMD) is impaired in women diagnosed with AN using the new, more liberal, DSM-5 criteria. Method Cross-sectional study of 168 women, 18 − 45y: (1) AN by DSM-IV ( DSM-IV AN ) ( n = 37), (2) AN by DSM-5 but not DSM-IV criteria ( DSM-5 AN) ( n = 33), (3) atypical AN ( ATYPICAL AN) ( n = 77), (4) healthy comparison group ( HC) ( n = 21). Measurements included dual energy X-ray absorptiometry, Eating Disorder Examination-Questionnaire, Eating Disorder Inventory-2, Hamilton Depression and Anxiety Rating Scales. Results BMD Z-score <−1.0 was present in 78% of DSM-IV, 82% of DSM-5, and 69% of ATYPICAL. Mean Z-scores were comparably low in DSM-IV and DSM-5, intermediate in ATYPICAL, and highest in HC. Lack of prior low weight or amenorrhea was, but history of overweight/obesity was not, protective against bone loss. Mean lean mass and percent fat mass were significantly lower in all AN groups than HC. DSM-IV, DSM-5, and ATYPICAL had comparable psychopathology. Discussion Despite liberalizing diagnostic criteria, many women diagnosed with AN and atypical AN using DSM-5 criteria have low BMD. Presence or history of low weight and/or amenorrhea remain important indications for DXA. Loss of lean mass, in addition to fat mass, is present in all AN groups, and may contribute to low BMD. The deleterious effect of eating disorders on BMD extends beyond those with current low weight and amenorrhea. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2017; 50:343-351) [ABSTRACT FROM AUTHOR]

Background: The effect of chronic exercise activity on brown adipose tissue (BAT) is not clear, with some studies showing positive and others showing negative associations. Chronic exercise is associated with increased resting energy expenditure (REE) secondary to increased lean mass and a probable increase in BAT. Many athletes are in a state of relative energy deficit suggested by lower fat mass and hypothalamic amenorrhea. States of severe energy deficit such as anorexia nervosa are associated with reduced BAT. There are no data regarding the impact of chronic exercise activity on BAT volume or activity in young women and it is unclear whether relative energy deficiency modifies the effects of exercise on BAT. Purpose: We assessed cold induced BAT volume and activity in young female athletes compared with non-athletes, and further evaluated associations of BAT with measures of REE, body composition and menstrual status. Methods: The protocol was approved by our Institutional Review Board. Written informed consent was obtained from all participants prior to study initiation. This was a cross-sectional study of 24 women (16 athletes and8 non-athletes) between 18–25 years of age. Athletes were either oligo-amenorrheic (n = 8) or eumenorrheic (n = 8).We used PET/CT scans to determine cold induced BAT activity, VMAX Encore 29 metabolic cart to obtain measures of REE, and DXA for body composition. Results: Athletes and non-athletes did not differ for age or BMI. Compared with non-athletes, athletes had lower percent body fat (p = 0.002), higher percent lean mass (p = 0.01) and trended higher in REE (p = 0.09). BAT volume and activity in athletes trended lower than in non-athletes (p = 0.06; p = 0.07, respectively). We found negative associations of BAT activity with duration of amenorrhea (r = -0.46, p = 0.02).BAT volume correlated inversely with lean mass (r = -0.46, p = 0.02), and positively with percent body fat, irisin and thyroid hormones. Conclusions: Our study shows a trend for lower BAT in young female athletes compared with non-athletes, and shows associations of brown fat with menstrual status and body composition. Brown fat may undergo adaptive reductions with increasing energy deficit. [ABSTRACT FROM AUTHOR]

Aims: Low-weight hypogonadal conditions such as anorexia nervosa are associated with marked changes in body composition, hemodynamic and hematological parameters, and liver enzymes. The impact of athletic activity in normal-weight adolescents with/without amenorrhea on these parameters has not been assessed. Our aim was to examine these parameters in normal-weight athletes and nonathletes and determine any associations with body composition, oligo-amenorrhea, and exercise intensity. Methods: We assessed vital signs, complete blood counts, liver enzymes, and regional body composition in 43 oligo-amenorrheic athletes (OAA), 24 eumenorrheic athletes (EA), and 23 nonathletes aged 14-21 years. Results: The BMI was lower in OAA than in EA. Systolic and pulse pressure and temperature were lowest in OAA. Blood counts did not differ among groups. Aspartate aminotransferase (AST) was higher in both groups of athletes, while alanine aminotransferase (ALT) was higher in OAA than in EA and nonathletes. Total and regional fat were lower in OAA than in other groups, and these factors were associated positively with heart rate and inversely with liver enzymes. Conclusions: Athletic activity is associated with higher AST levels, whereas menstrual dysfunction is associated with lower total and regional fat and higher ALT levels. Higher liver enzymes are associated with reductions in total and regional fat. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective Amenorrhoea and low bone density are common in excessive exercisers, yet endocrine factors that differentiate adolescent amenorrhoeic exercisers ( AE) from eumenorrhoeic exercisers ( EE) are unclear. We have previously reported that high ghrelin and low leptin predict lower LH secretion in AE. Leptin and ghrelin impact cortisol secretion, and hypercortisolaemia can inhibit LH pulsatility. We hypothesized that higher cortisol secretion in young endurance weight-bearing AE compared with EE and nonexercisers predicts lower LH secretion, lower levels of a bone formation marker and higher levels of a bone resorption marker. Design Cross-sectional. Subjects We studied 21 AE, 18 EE and 20 nonexercisers aged 14-21 years ( BMI 10th-90th%iles). Measurements Subjects underwent frequent sampling (11 p.m. to 7 a.m.) to assess cortisol, ghrelin, leptin and LH secretory dynamics. Fasting levels of a bone formation ( P1 NP) and bone resorption ( CTX) marker were measured. Results BMI did not differ among groups. Cortisol pulse amplitude, mass, half-life and area under the curve ( AUC) were highest in AE ( P = 0·04, 0·007, 0·04 and 0·003) and were associated inversely with fat mass ( r = −0·29, −0·28 and −0·35, P = 0·03, 0·04 and 0·007). We observed inverse associations between cortisol and LH AUC ( r = −0·36, P = 0·008), which persisted after controlling for fat mass, leptin and ghrelin AUC. Cortisol correlated positively with CTX in EE and inversely with P1 NP in nonexercisers. Conclusions Higher cortisol secretion in AE compared with EE and nonexercisers is associated with lower LH secretion. Effects of leptin and ghrelin on LH secretion may be mediated by increased cortisol. [ABSTRACT FROM AUTHOR]

Functional hypothalamic amenorrhea (FHA) is associated with low BMD and decreased rates of bone mass accrual, particularly in conditions of severe undernutrition, such as anorexia nervosa. In addition to immediate fracture risk, the finding of impaired bone metabolism in young women raises concerns about reduced peak bone mass, an important determinant of bone health in later life. Appropriate treatment of FHA is, therefore, crucial for restoration of BMD and for bone mass accrual. Vescovi et al. have performed a systematic review of the literature in order to assess therapeutic strategies that aim to reverse bone loss in women with FHA. In this Practice Point commentary, I discuss the extent to which hormonal and nonhormonal therapies have, or have not, been beneficial in optimizing bone health. In addition, I emphasize the importance of weight gain and recovery of reproductive function in the preservation of bone health in women with FHA. [ABSTRACT FROM AUTHOR]

Highlights • Oligo-amenorrrheic athletes have greater eating disorder pathology than controls. • Estrogen replacement improves drive for thinness and body dissatisfaction scores. • Administration of transdermal estradiol (vs. the pill) reduces uncontrolled eating. Abstract Objective Estrogen replacement prevents worsening body dissatisfaction with weight gain in adolescents with anorexia nervosa. However, the impact of estrogen administration on eating disorder (ED) pathology in normal-weight young women with exercise-induced amenorrhea is unknown. We hypothesized that (1) normal-weight oligo-amenorrheic athletes (OA) would show greater ED pathology than eumenorrheic athletes (EA) and non-athletes (NA), and (2) 12 months of estrogen replacement would improve those symptoms. Trial design Randomized trial. Methods One hundred seventeen OA, 50 EA, and 41 NA completed the Eating Disorder Inventory-2 (EDI-2) for measures of Drive for Thinness (DT) and Body Dissatisfaction (BD) and the Three-Factor Eating Questionnaire-R18 (TFEQ-R18). OA were then randomized to receive 100 mcg transdermal 17β-estradiol with cyclic progesterone (PATCH), an oral contraceptive pill (30 mcg ethinyl estradiol + 0.15 mg desogestrel) (PILL), or no estrogen (E-) for 12 months. Data are reported for the subset that completed questionnaires at 0 and 12 months between 11/2009 and 10/2016. Results OA showed higher EDI-2 DT and TFEQ-R18 Cognitive Restraint scores than EA and NA and higher EDI-2 BD scores than EA. Over 12 months, the E+ group (PATCH+PILL), compared to E-, showed improved trajectories for EDI-2 DT and BD scores. In 3-group comparisons, PATCH outperformed E- for decreases in EDI-2 DT and BD, and the PILL for TFEQ-R18 Uncontrolled Eating. Conclusion In OA, 12 months of estrogen replacement improves ED pathology trajectories, emphasizing the broad importance of normalizing estrogen levels. Clinical Trial Registration ClinicalTrials.gov identifier: NCT00946192. [ABSTRACT FROM AUTHOR]

Background Associations of bone mineral density (BMD) with specific food components, including dietary fiber and isoflavones (that have a negative association with serum estrogen), are unclear and need to be determined, particularly in populations more likely to consume large amounts of these nutrients (such as young athletes). Objective To determine dietary intake of specific food components in athletes with oligoamenorrhea (OA) compared to athletes with eumenorrhea (EA) and nonathletes (NA), and associations of the dietary intake of these nutrients with lumbar spine BMD. Design and subjects This cross-sectional study evaluated 68 OA, 24 EA, and 26 NA individuals aged 14 to 23 years. Measurements included 4-day food records, a dual x-ray absorptiometry scan evaluating lumbar spine BMD and body composition, and hormone levels. Multivariate analysis was used to estimate associations of nutrients with lumbar spine BMD. Results Compared with EA and NA, OA had higher intake of fiber, phytic acid, and vegetable protein (all P values <0.0001). Intake of isoflavones, genistein, and daidzein was higher in OA than NA ( P =0.003 and P= 0.0002, respectively). OA had lower consumption of energy from saturated fatty acids than NA ( P =0.002). After controlling for confounders such as body weight, menstrual status (indicative of estrogen status), calcium intake, and serum vitamin D (known BMD determinants), lumbar spine BMD z scores were inversely associated with dietary fiber (β=–.30; P =0.01), vegetable protein (β= –.28; P =0.02), phytic acid (β=–.27; P =0.02), genistein (β=–.25; P =0.01), and daidzein (β=–.24; P =0.01), and positively associated with percent energy from fatty acids (β=.32; P =0.0006). Conclusions Compared with EA and NA, OA had a higher dietary intake of fiber, vegetable protein, and phytic acid, which were inversely associated with lumbar spine BMD z scores. Further studies are needed to assess dietary recommendations for OA to optimize bone accrual. [ABSTRACT FROM AUTHOR]