Preservation of neuroendocrine control of reproductive function despite severe undernutrition

Harvard University, Cambridge, Massachusetts, United States
Journal of Clinical Endocrinology &amp Metabolism (Impact Factor: 6.31). 10/2004; 89(9):4434-8. DOI: 10.1210/jc.2004-0720
Source: PubMed

ABSTRACT Anorexia nervosa (AN) is characterized by low weight and self-imposed caloric restriction and leads to severe bone loss. Although amenorrhea due to acquired GnRH deficiency is nearly universal in AN, a subset of patients maintains menses despite low weight. The mechanisms underlying continued GnRH secretion despite low weight in these patients and the impact of gonadal hormone secretion on bone mineral density (BMD) in such eumenorrheic, low-weight patients remain unknown. We hypothesized that 1) eumenorrheic women with AN would have higher body fat and levels of nutritionally dependent hormones, including leptin and IGF-I, than amenorrheic women with AN and comparable body mass index; and 2) BMD would be higher in these women. We also investigated whether the severity of eating disorder symptomatology differed between the groups. We studied 116 women: 1) 42 low-weight women who fulfilled all Diagnostic and Statistical Manual of Mental Disorders (fourth edition) diagnostic criteria for AN, except for amenorrhea; and 2) 74 women with AN and amenorrhea for at least 3 months. The two groups were similar in body mass index (17.1 +/- 0.2 vs. 16.8 +/- 0.2 kg/m(2)), percent ideal body weight (78.2 +/- 0.8% vs. 76.7 +/- 0.8%), duration of eating disorder (70 +/- 13 vs. 59 +/- 9 months), age of menarche (13.2 +/- 0.3 vs. 13.5 +/- 0.2 yr), and exercise (4.5 +/- 1.0 vs. 4.2 +/- 0.5 h/wk). As expected, eumenorrheic patients had a higher mean estradiol level (186.6 +/- 19.0 vs. 59.4 +/- 2.5 nmol/liter; P < 0.0001) than amenorrheic subjects. Mean percent body fat, total body fat mass, and truncal fat were higher in eumenorrheic than amenorrheic patients [20.9 +/- 0.9% vs. 16.7 +/- 0.6% (P = 0.0001); 9.8 +/- 0.5 vs. 7.8 +/- 0.3 kg (P = 0.0009); 3.4 +/- 0.2 vs. 2.7 +/- 0.1 kg (P = 0.006)]. The mean leptin level was higher in the eumenorrheic compared with the amenorrheic group (3.7 +/- 0.3 vs. 2.8 +/- 0.2 ng/ml; P = 0.04). Serum IGF-I levels were also higher in the eumenorrheic than in the amenorrheic group (41.8 +/- 3.7 vs. 30.8 +/- 2.3 nmol/liter; P = 0.02). There were only minor differences in severity of eating disorder symptomatology, as measured by the Eating Disorders Inventory, and where differences were observed, eumenorrheic subjects manifested more severe symptomatology than amenorrheic subjects. Mean BMD at the posterior-anterior and lateral spine were low in both groups, but were higher in patients with eumenorrhea than in those with amenorrhea [posterior-anterior spine T-score, -0.9 +/- 0.1 vs. -1.9 +/- 0.1 (P < 0.0001); lateral spine T-score, -1.2 +/- 0.1 vs. -2.3 +/- 0.2 (P < 0.0001)]. In contrast, preservation of menstrual function was not protective at the total hip (total hip T-score, -0.9 +/- 0.1 vs. -1.1 +/- 0.1; P = 0.27), trochanter, or femoral neck. In summary, patients with eumenorrhea had more body fat and higher serum leptin levels than their amenorrheic counterparts of similar weight. Moreover, reduced bone density was observed in both groups, but was less severe at the spine, but not the hip, in women with undernutrition and preserved menstrual function than in amenorrheic women of similar weight. Therefore, fat mass may be important for preservation of normal menstrual function in severely undernourished women, and this may be in part mediated through leptin secretion. In addition, nutritional intake and normal hormonal function may be independent contributors to maintenance of trabecular bone mass in low-weight women.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bone loss in amenorrheic athletes has been attributed to energy deficiency-related suppression of bone formation, but not increased resorption despite hypoestrogenism. To assess the independent and combined effects of energy deficiency and estrogen deficiency on bone turnover markers in exercising women. PINP, osteocalcin, U-CTX-I, TT3, leptin, and ghrelin were measured repeatedly, and bone mineral density (BMD) was measured once in 44 exercising women. Resting energy expenditure (REE) was used to determine energy status (deficient or replete) and was corroborated with measures of metabolic hormones. Daily levels of urinary estrone and pregnanediol glucuronides (E1G, PdG), were assessed to determine menstrual and estrogen status. Volunteers were then retrospectively categorized into 4 groups: 1) Energy Replete+Estrogen Replete (EnR+E2R), (n=22), 2) Energy Replete+Estrogen Deficient (EnR+E2D), (n=7), 3) Energy Deficient+Estrogen Replete (EnD+E2R), (n=7), and 4) Energy Deficient+Estrogen Deficient (EnD+E2D), (n=8). The groups were similar (p>0.05) with respect to age (24.05+/-1.75 yrs), weight (57.7+/-2.2 kg), and BMI (21.05+/-0.7 kg/m2). By design, REE/FFM (p=0.028) and REE:pREE (p<0.001) were lower in the EnD vs. EnR group, and the E2D group had a lower REE:pREE (p=0.005) compared to the E2R group. The EnD+E2D group had suppressed PINP (p=0.034), and elevated U-CTX-I (p=0.052) and ghrelin (p=0.028) levels compared to the other groups. These same women also had convincing evidence of energy conservation, including TT3 levels that were 29% lower (p=0.057) and ghrelin levels that were 44% higher (p=0.028) than that observed in the other groups. Energy deficiency was associated with suppressed osteocalcin, and TT3 (p<0.05), whereas estrogen deficiency was associated with decreased E1G (p<0.02), and lower L2-L4 BMD (p=0.033). Leptin was significant in predicting markers of bone formation, but not markers of bone resorption. When the energy status of exercising women was adequate (replete), there were no apparent perturbations of bone formation or resorption, regardless of estrogen status. Estrogen deficiency in exercising women, in the presence of an energy deficiency, was associated with bone loss and involved suppressed bone formation and increased bone resorption. These findings underscore the importance of avoiding energy deficiency, which is associated with hypoestrogenism, to avoid bone health problems.
    Bone 07/2008; 43(1):140-8. DOI:10.1016/j.bone.2008.03.013 · 4.46 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objectives of review. The goal of this review is to highlight selected advances during 2003–2004 in research on the psychobiology of the eating disorders. Summary of recent findings. Studies in bulimia nervosa (BN) have demonstrated associations between alterations in serotonin function and comorbid psychiatric disorders, while studies in both BN and anorexia nervosa (AN) have provided additional evidence for persistent, possibly trait-related alterations in serotonin regulation. Studies of leptin function have shown an association between circulating levels of the protein and symptom patterns during the course of recovery from AN. Studies of ghrelin function have provided new evidence for altered postprandial release of the peptide in BN and binge-eating disorder, and elevated baseline levels of the peptide in AN. Future directions. Additional research will be needed to assess both categorical and dimensional clinical correlates of alterations in these neuro-biological systems. Studies in individuals who have recovered from the eating disorders will be valuable in identifying stable psychobiological characteristics. Future results may lead to new pharmacological treatment approaches.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although physical exercise is generally beneficial for health, female athletes run an elevated risk of developing chronic energy deficiency, with ensuing severe consequences such as reproductive dysfunction, bone demineralization, more frequent injuries, impaired performance, and adverse cardiovascular effects. However, at present little is known about these issues with respect to sportswomen competing at the Olympic level, or about the long-term cardiovascular consequences of intense training for women. Our aims were to characterize patterns of weight control in female and male Olympic athletes, as well as to assess the menstrual status, body composition, biomarkers of energy availability and circulating levels of sex hormones in Olympic sportswomen. In addition, cardiovascular function and the associated serum lipid levels and body composition of postmenopausal former elite athletes were compared to these same parameters in control subjects. Among the 223 Swedish athletes who competed in the 2002 and 2004 Olympic Games, those participating in sports that emphasize leanness demonstrated less desirable strategies for weight and more frequent illness than competitors in other disciplines, particularly in the case of the male athletes. Among 90 of these sportswomen, and especially among the endurance athletes, menstrual dysfunction (MD) was frequent. The most common cause of MD was polycystic ovary syndrome (PCOS), rather than hypothalamic inhibition. Furthermore, no signs of chronic energy deficiency, as evaluated on the basis of body fat content and biomarkers of energy availability, were observed. Bone mineral density (BMD) was generally high and none of these athletes exhibited osteopenia or osteoporosis. Furthermore, among 20 postmenopausal former elite athletes we observed enhanced endothelial function in those not utilizing hormone replacement therapy, whereas the use of such therapy was associated with endothelial function similar to that of sedentary control subjects. Serum levels of cholesterol and low-density lipoprotein, body fat content and the frequency of ST-depressions in exercising electrocardiograms were lower in the former athletes; whereas the exercise capacity, dimensions of the left and right cardiac ventricles, and left atrial and stroke volumes were all significantly greater than in control subjects. We conclude that the weight control practices employed by Olympic athletes participating in disciplines that emphasize leanness appear to be suboptimal, although female athletes may have adopted healthier nutritional practices than the men. Furthermore, our findings challenge the contemporary concept that reproductive dysfunction in sportswomen is typically a consequence of chronic energy deficiency. Here, the single most frequent underlying cause of menstrual disturbances in Olympic athletes was the hyperandrogenic disorder PCOS. Long-term strenuous exercise is associated with minor changes in cardiac structure, but overall beneficial effects on exercise capacity, vascular function and cardiovascular risk factors.