Preservation of Neuroendocrine Control of Reproductive Function Despite Severe Undernutrition

Harvard University, Cambridge, Massachusetts, United States
Journal of Clinical Endocrinology & Metabolism (Impact Factor: 6.21). 10/2004; 89(9):4434-8. DOI: 10.1210/jc.2004-0720
Source: PubMed


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.

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    • "These results were confirmed years later in a study aimed at understanding why some women who met criteria for AN amenorrhea maintained their menses despite their low weight. They found that patients with eumenorrhea had higher fat mass percentage and higher leptin levels compared to the amenorrhoeic counterparts with similar weight [12]. Therefore fat mass and consequently leptin secretion seem to be important for the maintenance of menstruation in severely emaciated women. "
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    ABSTRACT: Menstrual dysfunction is a common correlate across women with Eating Disorders. The onset of Eating Disorders commonly occurs during adolescence and it can lead to severe medical complications, such as pubertal delay, deficits in peak bone mass acquisition, altered physical and cognitive development. The pathogenesis of menstrual dysfunction in Eating Disorders is complicated and involves several factors such as hypothalamic-pituitary-ovarian axis impairment, low body fat, hypoleptinemia, increase of androgen levels, abnormal eating behaviors, physical exercise and psychological stressors. This chapter aims to provide a clinical overview of the several pathogenetic mechanisms underlying menstrual dysfunction.
    Full-text · Chapter · Dec 2015
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    • "Body composition and the metabolic milieu at baseline may have played a role in both the time to and quality of recovery of menses. At baseline, both women presented with a BMI and percent body fat within the normal range for exercising women; however, Participant 2 (short-term amenorrhea) presented with a greater percent body fat at baseline than Participant 1. Body fat has been recognized as playing an important permissive role in reproductive function through the effects of leptin, an adipocyte-derived metabolic hormone [33,34]. Leptin binds to receptors in the hypothalamus, stimulating the release of gonadotropin-releasing hormone [35,36] and thereby playing a regulatory role in reproductive function via its influence on gonadotropin pulsatility and reproductive steroid production [37]. "
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    ABSTRACT: Increasing caloric intake is a promising treatment for exercise-associated amenorrhea, but strategies have not been fully explored. The purpose of this case report was to compare and contrast the responses of two exercising women with amenorrhea of varying duration to an intervention of increased energy intake. Two exercising women with amenorrhea of short (3 months) and long (11 months) duration were chosen to demonstrate the impact of increased caloric intake on recovery of menstrual function and bone health. Repeated measures of dietary intake, eating behavior, body weight, body composition, bone mineral density, resting energy expenditure, exercise volume, serum metabolic hormones and markers of bone turnover, and daily urinary metabolites were obtained. Participant 1 was 19 years old and had a body mass index (BMI) of 20.4 kg/m2 at baseline. She increased caloric intake by 276 kcal/day (1,155 kJ/day, 13%), on average, during the intervention, and her body mass increased by 4.2 kg (8%). Participant 2 was 24 years old and had a BMI of 19.7 kg/m2. She increased caloric intake by 1,881 kcal/day (7,870 kJ/day, 27%) and increased body mass by 2.8 kg (5%). Resting energy expenditure, triiodothyronine, and leptin increased; whereas, ghrelin decreased in both women. Resumption of menses occurred 23 and 74 days into the intervention for the women with short-term and long-term amenorrhea, respectively. The onset of ovulation and regular cycles corresponded with changes in body weight. Recovery of menses coincided closely with increases in caloric intake, weight gain, and improvements in the metabolic environment; however, the nature of restoration of menstrual function differed between the women with short-term versus long-term amenorrhea.
    Full-text · Article · Aug 2013 · Journal of the International Society of Sports Nutrition
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    • "In a recent study [1], it was suggested that BMI percentiles between 14 and 39 could be used to estimate treatment goal weight. Others reported that about one third of AN adolescents with ROM did so at weights above population averages [18], and in a comparison of low weight AN patients without and with menses, the latter consumed a more nutritionally ‘balanced’ diet than their amenorrheic counterparts [36,37]. In our own exploratory analyses, about one third of patients without ROM achieved 95% EBW or higher. "
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    ABSTRACT: Background The resumption of menses (ROM) is considered an important clinical marker in weight restoration for patients with anorexia nervosa (AN). The purpose of this study was to examine ROM in relation to expected body weight (EBW) and psychosocial markers in adolescents with AN. Methods We conducted a retrospective chart review at The University of Chicago Eating Disorders Program from September 2001 to September 2011 (N = 225 females with AN). Eighty-four adolescents (Mean age = 15.1, SD = 2.2) with a DSM-IV diagnosis of AN, presenting with secondary amenorrhea were identified. All participants had received a course of outpatient family-based treatment (FBT), i.e., ~20 sessions over 12 months. Weight and menstrual status were tracked at each therapy session throughout treatment. The primary outcome measures were weight (percent of expected for sex, age and height), and ROM. Results Mean percent EBW at baseline was 82.0 (SD = 6.5). ROM was reported by 67.9% of participants (57/84), on average at 94.9 (SD = 9.3) percent EBW, and after having completed an average of 13.5 (SD = 10.7) FBT sessions (~70% of standard FBT). Compared to participants without ROM by treatment completion, those with ROM had significantly higher baseline Eating Disorder Examination Global scores (p = .004) as well as Shape Concern (p < .008) and Restraint (p < .002) subscale scores. No other differences were found. Conclusions Results suggest that ROM occur at weights close to the reference norms for percent EBW, and that high pre-treatment eating disorder psychopathology is associated with ROM. Future research will be important to better understand these differences and their implications for the treatment of adolescents with AN.
    Full-text · Article · Apr 2013 · Journal of Eating Disorders
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