Search

ObjectiveStudies 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.MethodsWe 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.ResultsMedian (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.ConclusionAthletes 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.

ObjectiveAnorexia nervosa (AN) is commonly associated with depression, anxiety, and deficits in socioemotional functioning. Basal levels of oxytocin, a neurohormone with antidepressant, anxiolytic, and prosocial properties, are low in women with AN. However, the relationship between oxytocin and psychopathology of AN/atypical AN has not been examined in individuals with primarily food restriction (AN/AtypAN-R) or those with restriction plus binge/purge behaviors (AN/AtypAN-BP) alone, which is important to further elucidate the neurobiology of different AN presentations. We investigated whether oxytocin levels are related to eating, affective, and socioemotional psychopathology in women with AN/AtypAN-R and separately AN/AtypAN-BP.MethodsIn a cross-sectional study of 53 women with low-weight AN or atypical AN based on DSM-5 (AN/AtypAN-R: n=21, AN/AtypAN-BP: n=32), we obtained fasting serum oxytocin levels and self-report measures of psychopathology, including the Eating Disorder Examination–Questionnaire (EDE-Q), Beck Depression Inventory-IA (BDI), State-Trait Anxiety Inventory (STAI), and Toronto Alexithymia Scale (TAS-20).ResultsIn individuals with AN/AtypAN-R, oxytocin levels were negatively associated with eating psychopathology (EDE-Q Global Score: r=-0.49, p=0.024), depressive and anxiety symptoms (BDI Total Score: r=-0.55, p=0.009; STAI Trait Score: r=-0.63, p=0.002), and socioemotional symptoms (TAS-20 Difficulty Identifying Feelings Score: r=-0.49, p=0.023). In contrast, in those with AN/AtypAN-BP oxytocin levels were negatively associated with depressive symptoms only (BDI Total Score: r=-0.52, p=0.049).ConclusionsThese findings support the notion that AN/AtypAN-R and AN/AtypAN-BP might have divergent underlying neurobiology. Understanding these differences is crucial to develop targeted treatments for a population with high levels of chronicity, for which no specific pharmacological treatments are currently available.Clinical trial registrationhttps://clinicaltrials.gov, identifier: NCT01121211.

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.

Purpose: Combined hormonal contraceptive therapy has been associated with negative bone mineral density outcomes that may be route-dependent [i.e., combined oral contraception (COC) vs. contraceptive vaginal ring (CVR)] and involve the hepatic growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. The objective of the pilot study was to assess the impact of route of contraceptive administration on IGF-I and procollagen type I N-terminal propeptide (PINP) responses to an IGF-I Generation Test. We hypothesized that the peak rise in IGF-I and PINP concentration and area under the curve (AUC) would be attenuated following COC, but not CVR, use.Methods: Healthy, premenopausal women not taking hormonal contraception were recruited. Women were enrolled in the control group (n = 8) or randomly assigned to COC (n = 8) or CVR (n = 8) for two contraceptive cycles. IGF-I Generation Tests were used as a probe to stimulate IGF-I release and were completed during the pre-intervention and intervention phases. Serum IGF-I and PINP were measured during both IGF-I Generation Tests. The study was registered at ClinicalTrials.gov (NCT02367833).Results: Compared to the pre-intervention phase, peak IGF-I concentration in response to the IGF-I Generation Test in the intervention phase was suppressed in the COC group (p < 0.001), but not the CVR or Control groups (p > 0.090). Additionally, compared to the pre-intervention phase, PINP AUC during the intervention phase was suppressed in both COC and CVR groups (p < 0.001), while no difference was observed in the control group (p = 0.980).Conclusion: These data suggest that changes in recombinant human GH-stimulated hepatic IGF-I synthesis in response to combined hormonal contraception (CHC) use are dependent on route of CHC administration, while the influence on PINP is route-independent. Future research is needed to expand these results with larger randomized control trials in all age ranges of women who utilize hormonal contraception.Clinical Trial Registration:www.ClinicalTrials.gov registration NCT02367833.

Objective: We sought to compare the short and long-term outcomes of MBS in adolescents vs. adults who have undergone a Roux-en-Y gastric bypass (RYGB) or Sleeve gastrectomy (SG).Design: Retrospective cohort study.Setting: Single tertiary care academic referral center.Participants: One hundred fifty adolescent (≤ 21-years) and adult (>21-years) subjects with severe obesity between 15 and 70 years of age who underwent RYGB or SG.Outcomes: Metabolic parameters, weight and height measures were obtained pre-and post-surgery (at 3 and 6 months, and then annually for 4 years).Results: Median pre-surgical body mass index (BMI) was higher in adolescents (n = 76) vs. adults (n = 74): 50 (45–57) vs. 44 (40–51) kg/m2 (p < 0.0001). However, obesity related complications were greater in adults vs. adolescents: 66 vs. 21% had hypertension, 68 vs. 28% had dyslipidemia, and 42 vs. 21% had type 2 diabetes mellitus (all p < 0.010). % BMI reduction and % weight loss (WL) were greater in adolescents vs. adults at all time points (p < 0.050). %WL was higher in adolescents who underwent SG at each time point (p < 0.050), and trended higher among adolescents who underwent RYGB (p = 0.060), compared to adults with the respective procedure. Follow-up data showed greater resolution of type 2 diabetes and hypertension in adolescents than adults (87.5 vs. 54.8%; p = 0.04, and 68.7 vs. 35.4%; p = 0.040).Conclusion: Adolescents compared to adults had greater reductions in BMI and weight, even at 4 years, and greater resolution of type 2 diabetes and hypertension. Earlier intervention in the treatment of severe obesity with MBS may lead to better outcomes.

The Wnt-β-catenin pathway receptor, low-density lipoprotein receptor-related protein 5 (LRP5), is a known regulator of bone mineral density. It has been hypothesized that specific human polymorphisms in LRP5 impact bone density, in part, by altering the anabolic response of bone to mechanical loading. Although experiments in animal models support this hypothesis, there is limited evidence that LRP5 polymorphisms can alter the anabolic response of bone to mechanical loading in humans. Herein, we report a young male who harbors a rare LRP5 missense mutation (A745V) and who provides potential proof of principle for this mechanotransduction hypothesis for low bone density. The subject had no history of fractures until age 18, a year into a career in competitive distance running. As he continued to run over the following 2 years, his mileage threshold to fracture steadily and rapidly decreased until he was diagnosed with severe osteoporosis (lumbar spine BMD Z-score of −3.2). By contextualizing this case within the existing LRP5 and mechanical stress literature, we speculate that this represents the first documented case of an individual in whom a genetic mutation altered the anabolic response of bone to mechanical stress in a manner sufficient to contribute to osteoporosis.