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Open Access Research article

Predictors of the resumption of menses in adolescent anorexia nervosa

Astrid Dempfle1, Beate Herpertz-Dahlmann2, Nina Timmesfeld1, Reinhild Schwarte2, Karin M Egberts3, Ernst Pfeiffer4, Christian Fleischhaker5, Christoph Wewetzer6 and Katharina Bühren2*

Author Affiliations

1 Institute of Medical Biometry and Epidemiology, Philipps-University Marburg, Marburg, Germany

2 Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of the RWTH Aachen, Aachen, Germany

3 Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany

4 Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany

5 Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Center Freiburg, Freiburg, Germany

6 Department of Child and Adolescent Psychiatry and Psychotherapy, Kliniken der Stadt Köln, Köln, Germany

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BMC Psychiatry 2013, 13:308  doi:10.1186/1471-244X-13-308


The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-244X/13/308


Received:6 May 2013
Accepted:5 November 2013
Published:15 November 2013

© 2013 Dempfle et al.; licensee BioMed Central Ltd.

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

The resumption of menses is an important indicator of recovery in anorexia nervosa (AN). Patients with early-onset AN are at particularly great risk of suffering from the long-term physical and psychological consequences of persistent gonadal dysfunction. However, the clinical variables that predict the recovery of menstrual function during weight gain in AN remain poorly understood. The aim of this study was to investigate the impact of several clinical parameters on the resumption of menses in first-onset adolescent AN in a large, well-characterized, homogenous sample that was followed-up for 12 months.

Methods

A total of 172 female adolescent patients with first-onset AN according to DSM-IV criteria were recruited for inclusion in a randomized, multi-center, German clinical trial. Menstrual status and clinical variables (i.e., premorbid body mass index (BMI), age at onset, duration of illness, duration of hospital treatment, achievement of target weight at discharge, and BMI) were assessed at the time of admission to or discharge from hospital treatment and at a 12-month follow-up. Based on German reference data, we calculated the percentage of expected body weight (%EBW), BMI percentile, and BMI standard deviation score (BMI-SDS) for all time points to investigate the relationship between different weight measurements and resumption of menses.

Results

Forty-seven percent of the patients spontaneously began menstruating during the follow-up period. %EBW at the 12-month follow-up was strongly correlated with the resumption of menses. The absence of menarche before admission, a higher premorbid BMI, discharge below target weight, and a longer duration of hospital treatment were the most relevant prognostic factors for continued amenorrhea.

Conclusions

The recovery of menstrual function in adolescent patients with AN should be a major treatment goal to prevent severe long-term physical and psychological sequelae. Patients with premenarchal onset of AN are at particular risk for protracted amenorrhea despite weight rehabilitation. Reaching and maintaining a target weight between the 15th and 20th BMI percentile is favorable for the resumption of menses within 12 months. Whether patients with a higher premorbid BMI may benefit from a higher target weight needs to be investigated in further studies.

Keywords:
Resumption of menses; Adolescence anorexia nervosa; Target weight; Menstrual recovery; Outcome; Body mass index; Menarche; Amenorrhea

Background

Anorexia nervosa (AN) is a psychiatric disorder that typically first occurs in adolescence and is the third-most common chronic illness in this age group, after asthma and obesity [1]. AN often has a protracted course and is associated with an array of medical and psychiatric comorbidities [2,3].

Although the DSM-5 has abandoned amenorrhea as a diagnostic criterion for AN, there is general agreement that the resumption of menses is an important indicator of recovery from AN [4-6]. Thus, pediatric and psychiatric guidelines highlight the resumption of menses as an important goal in their recommendations for the treatment of AN [7-9].

Prolonged amenorrhea is a factor that likely contributes to poor physical outcome in AN. Patients with adolescent-onset AN are at particular risk of suffering from long-term physical and neuropsychiatric consequences of continuous gonadal dysfunction. Bone mineral accrual occurs mainly during adolescence [10]. Persistent amenorrhea at this age may lead to reduced peak bone mass and result in an increased risk for bone fractures later in life [11]. Studies have revealed that the normalization of body weight alone does not improve bone density; rather, the optimization of body weight and the normalization of gonadal status are necessary [12-14]. Moreover, in adolescent AN, starvation-induced hormonal deficiencies may lead to impairments in the maturation of certain brain regions that result in deficits in neuropsychological functioning [15-17]. Accordingly, it was shown that abnormal menstrual function in adolescent patients with AN is associated with deficits in verbal learning and memory, visual reproduction, working memory, and mathematical skills [15].

Weight rehabilitation is a prerequisite for reestablishing endocrine function [11,18,19]. During weight gain, fat mass increases resulting in the normalization of gonadal hormones and leptin levels. Leptin is a neuropeptide that is involved in various neuroendocrine and behavioral alterations associated with starvation [11,20]. However, some individuals remain amenorrheic for years despite stable weight recovery [21,22]. Currently, the clinical parameters that predict recovery of hypothalamic-pituitary-ovarian function during weight gain in AN remain poorly understood.

The ability to predict the magnitude of weight gain required for regular ovulatory cycles and a better understanding of the factors underlying the time lag between weight recovery and menstrual resumption would aid clinicians in determining their patients’ target weights. BMI at admission [23], BMI at discharge [24], and BMI before the onset of AN (“premorbid BMI”) [25,26] have been found to be important factors associated with the recovery of menstrual function and thus may aid in predicting the probability of resumption of menses in patients with AN.

However, there is no agreement on the definition of target weight. The American Psychiatric Association states that “a healthy goal weight for female patients is the weight at which normal menstruation and ovulation are restored” and that a healthy weight is “approximately the same weight at which full physical and psychological vigor were present” [7]. These definitions are based on the finding of two studies [27,28] that normal menstrual cycles are more likely to occur if the difference between the target weight and the body weight at which menstruation ceased is small.

Further studies have shown that in adult women with AN, a BMI higher than 18 kg/m2 is a relevant factor associated with the normalization of reproductive function [24-26,29].

In adolescents, the determination of target weight is even more complex, as both height and weight are expected to increase during this developmental period [30] and absolute BMI changes with age [31]. Golden et al. [30] recommended the use of BMI percentile ranges of the 14-39th percentile to assign a treatment goal weight. Other researchers calculated the percent of expected body weight (%EBW) on the basis of BMI percentiles according to the recommendation of Le Grange et al. [32] and found that 2/3 of the patients resume menses at 95% of their expected body weight (%EBW) [33]. Swenne et al. [28] suggested the use of BMI standard deviation scores (BMI-SDS) to determine weight requirements for the resumption of menses in adolescents. Neither the American Psychiatric Association or American pediatric guidelines [9] nor the NICE guidelines provide a clear recommendation for the determination of target weight. The American Psychiatric Association notes that “the closer a patient is to his or her healthy body weight before discharge, the less the risk he or she has of relapsing and being readmitted” and recommends the use of population reference data (e.g., growth charts of the Centers for Disease Control and Prevention) to set individually appropriate and realistic goals for weight in adolescent patients [7,34]. In the German guidelines [8], the target weight in adolescents is defined as the 25th, but at least the 10th, BMI percentile, based on German reference data [35]. Thus, in our treatment program, we determined a discharge weight that was close to the target weight as defined above according to the German guidelines, and patients had to maintain this weight during outpatient treatment.

The aim of this study was to investigate the impact of several clinical parameters on the resumption of menses in a large, well-characterized, homogenous sample of first-onset adolescent AN patients who were followed up for 12 months.

Methods

Patients

The patients in this study were recruited within a randomized, multi-center clinical trial comparing inpatient and day-patient treatment for adolescent AN (the results of that investigation will be published elsewhere; [36]). The study was performed at four university hospitals (RWTH Aachen, University of Würzburg, Charité Universitätsmedizin Berlin, University of Freiburg and Medical Faculty of Mannheim of Heidelberg University) and one major general hospital (Köln) in various regions of Germany between February 2007 and April 2010, and the follow-up period lasted until April 2011. The inclusion criteria were as follows: female gender, age between 11 and 18 years, a diagnosis of AN based on DSM-IV criteria, and first admission for AN. The weight threshold for inclusion in the study was a BMI below the 10th percentile (based on a large German reference set [35]). This threshold is considered to be consistent with the international convention for the definition of AN [31,37] and corresponds to the German guidelines for eating disorders [8]. Patients were excluded from the study if they had an organic brain disease, a psychotic disorder, bipolar disorder, substance dependence or abuse, serious self-injurious behavior, or an IQ below 85. All patients who were admitted for inpatient treatment were screened for the study. The trial aimed to include a series of consecutively presenting adolescent patients with AN that was as complete as possible.

The study was approved by the local research ethics committees of the four participating universities (RWTH Aachen, University of Wuerzburg, Charité Universitaetsmedizin Berlin, University of Freiburg, Medical Faculty of Mannheim of Heidelberg University) and the ethics committee of the regional Medical Association (Nordrhein; Koeln-Holweide). After a complete description of the study was provided to the subjects, written informed consent was obtained from all participants and their parents or legal guardians.

All patients fulfilling the study criteria were initially admitted to a three-week inpatient care program. Subsequently, the patients were randomized into two treatment settings (continued inpatient or day-patient treatment). An identical multimodal multidisciplinary treatment program was used in both treatment arms that included weight restoration, individual and group nutritional counseling, cognitive-behavioral individual and group therapy, individual family sessions, and a group psychoeducation program for parents (for further details, see [38]). According to the German guidelines for eating disorders [8] and consistent with other clinical practices [30], patients were regularly discharged when they had maintained their predetermined target weight corresponding to the 15-20th age-adjusted BMI percentile for two weeks. Discharge against medical advice was defined as premature drop-out from treatment without achievement of the predetermined target weight. After discharge, patients were provided access to the same outpatient treatment program, including cognitive-behavioral individual and group sessions, joint family sessions, and nutritional therapy (for further details, see [38]). A hospital readmission was initiated if the patients fell below a pre-determined weight (usually corresponding to the 10th BMI percentile). The 12-month follow-up (12 months after admission) was defined as the primary outcome assessment time point.

Menstrual status

Menstrual status was assessed at admission, discharge, and 12 months after admission. Brief assessments of menstrual status were also performed at regular outpatient visits. For amenorrheic patients, we assessed whether the patients were premenarchal (no menarche at age <16 years), had primary amenorrhea (no menarche by the age of ≥16 years [39]), or had secondary amenorrhea.

We compared two different patient groups: those who resumed menstruation spontaneously within the first 12 months after admission to the hospital treatment program and those who did not. The “menstruating group” consisted of patients who were menstruating at any time prior to follow-up and were not taking oral contraceptives (OCs) or who reported spontaneous resumption of menses before the use of OCs. In the “amenorrheic group”, we included patients who were still amenorrheic at the 12-month follow-up. Patients were excluded if menstrual status information was missing at the 12-month follow-up or before the initiation of OCs.

Clinical variables

Clinical variables were assessed at admission, discharge, and 12 months after admission. At each time point, the evaluations consisted of measurements of weight (measured with the patients in their underwear) and height, from which BMIs were calculated. Age- and sex-adjusted BMI standard deviation scores (BMI-SDS), BMI percentiles, and percentages of expected body weight (%EBW, where the expected body weight (EBW) is the median age-adjusted BMI (50th BMI-percentile), and, thus, the %EBW is the observed BMI/EBW × 100 [32]) were calculated based on a large German population-based normative data set [35]. This reference population for children and adolescents was compiled from measurements from 17 studies conducted in different regions in Germany between 1985 and 1999 (17147 males, 17274 females, 0 to 18 years of age). At admission, age, age at AN onset (defined as the earliest of the following times: (1) the approximate time at which weight loss first occurred; (2) at which, despite age-appropriate growth spurts, no further weight gain took place; or (3) at which secondary amenorrhea first occurred), duration of illness (the time between the onset of AN and admission), and premorbid BMI (BMI before illness onset) were assessed. At discharge, the duration of hospital treatment and discharge modality (regular discharge at target weight or discharge against medical advice based on persisting AN symptoms and failure to meet the target weight) were recorded for each patient.

Statistical analysis

Patients who were excluded from the analysis of menstrual status and those who were included were compared with respect to all clinical variables available until discharge (see above) using ANOVA. To compare the menstruating and amenorrheic groups, we performed logistic regression analyses. The independent clinical variables available until discharge were used as predictors (quantitative variables: age at admission, age at AN onset, age at menarche, premorbid BMI and BMI, BMI-SDS, BMI percentile and %EBW (at admission and discharge), duration of hospital treatment; binary variables: premenarchal or postmenarchal state at admission, regular discharge or discharge against medical advice). To analyze the relationship between menstrual status and cuurent weight, we also used %EBW at the 12-month follow-up as an independent variable. Descriptive data (evaluated by univariate analyses) are provided separately for the two groups as the means and standard deviations (or numbers and percent), together with the p-values from univariate logistic regression. Multivariate model selection using a stepwise procedure based on the Akaike information criterion (AIC) was performed. The primary statistical analyses were performed using %EBW as an appropriate measure for body weight in adolescents; in addition, we also report absolute BMI (enabling a better comparison with studies in adult AN patients), BMI percentiles, and BMI-SDS.

To evaluate the predictive accuracy of the logistic models, we used the area under the receiver operating characteristic curve (AUC of the ROC; sensitivity vs. specificity). The AUC is the probability that the risk score of a randomly picked non-menstruating patient is less than the risk score of a menstruating patient and measures the discrimination ability of the variables included in the logistic model. We compared the AUCs of different ROC curves (from models with and without %EBW at follow-up) using DeLong’s test [40].

Treatment setting (inpatient or day-patient) was not considered in the present analysis of menstruation because the durations of treatment and therapy outcomes with respect to BMI at discharge and at the 12-month follow-up were similar in the two treatment arms (95% confidence interval for difference in BMI at 12-month follow-up: -0.11 to 1.02; [36]).

Results

Data at baseline and at the 12-month follow-up

A total of 172 patients were included in the clinical trial. At admission, all patients were amenorrheic. Most of the patients reported secondary amenorrhea, while 36 patients (20.9%) were premenarchal (31 patients) or had primary amenorrhea (5 patients).

At the 12-month follow-up, information about menstruation was missing in 13 patients, and 7 patients were taking OCs and had missing information regarding menstrual status prior to OC use. Thus, a total of 20 patients could not be included in our analyses. However, the excluded patients were similar to the included patients with respect to all investigated variables assessed until discharge (all p-values >0.15).

Therefore, the final sample used in the analysis included 152 patients. Seventy-two of these patients (47%) had spontaneously resumed menses during the follow-up period. However, 80 patients (53%) were still amenorrheic. Among these patients, 25 were premenarchal and 5 had primary amenorrhea. The clinical data at admission, discharge, and the 12-month follow-up are provided in Table 1.

Table 1. Clinical data at admission, discharge and 12 months after admission for patients with and without spontaneous resumption of menses within the first 12 months after admission

There was a strong association between patients’ %EBW at the 12-month follow-up and the resumption of menses (p = 0.0003, univariate logistic regression). The %EBW at follow-up was the variable that best discriminated between groups, as shown by an AUC of 0.69. Considering the absolute BMI data, this result means that a reduction in BMI of 1 kg/m2 approximately doubled the odds of persistent amenorrhea (OR = 1.94).

Prognostic variables for the resumption of menstruation

Among the variables that were available until discharge and could thus be used as prognostic factors, the most important variable for the resumption of menstruation was “no menarche at admission” (p = 0.00003, univariate logistic regression; AUC of 0.67). Patients who had never menstruated before had a 14-fold increase in the odds of remaining amenorrheic compared with the patients with secondary amenorrhea (OR = 13.8). A multiple logistic regression (adjusted for age; p = 0.17) revealed that no menarche (p = 0.0003), premorbid %EBW (p = 0.04), duration of hospital treatment (p = 0.03), and regular discharge at the target weight (p = 0.01) were the relevant prognostic factors prior to discharge. The joint predictive value of these clinical variables was high (AUC of 0.76). Although %EBW at the 12-month follow-up was strongly correlated with the resumption of menses, it did not add much to the discrimination power of the multivariate logistic regression (AUC of 0.83, p = 0.2 for the difference between AUCs, DeLong test, Figure 1). In the multiple logistic regression model, only no menarche at admission (p = 0.0005), premorbid %EBW (p = 0.007), and %EBW at follow-up (p = 0.0009) were significant, and the discharge variables (i.e., duration of treatment (p = 0.08) and regular discharge (p = 0.16)) were no longer significant. The parameter estimate for premorbid %EBW was inversely correlated with the resumption of menses compared with %EBW at the 12-month follow-up, i.e., a high premorbid %EBW lowered the odds of resumption of menses. Using absolute BMI or BMI-SDS instead of %EBW (for all time points) yielded almost identical results.

thumbnailFigure 1. ROC of two different logistic regression models (red: model including premorbid %EBW, no menarche at admission, duration of hospital treatment and regular discharge with target weight; black: model including premorbid %EBW, no menarche at admission, duration of hospital treatment, regular discharge with target weight and %EBW at 12-month follow-up).

Discussion

In the present study, we investigated the resumption of menses 12 months after the initiation of hospital treatment in a large sample of female patients with first-onset AN. In 47% of the adolescent patients, menses spontaneously returned within the first 12 months after admission. This finding corresponds to the findings of previous studies [18,29,30,33]. As expected, deviation from “normal age-appropriate” BMI (%EBW) at the 12-month follow-up had the largest impact on menstrual status. Patients who resumed menses had an average BMI of almost 19 kg/m2 (or BMI-SDS: -0.8), whereas those who had not resumed menstruation had, on average, a significantly lower BMI of 17.5 kg/m2 (BMI-SDS: -1.4). This result is in accordance with previous studies in adolescent and adult AN patients. Swenne et al. [28] found that adolescent patients had a BMI of 19.2 kg/m2 (or BMI-SDS: -0.59) when they started menstruating again. In several studies in adult AN patients, the mean current BMI in those who had resumed menses was found to be between 18.5 and 19.1 kg/m2 and was significantly higher than the BMIs of patients with persistent amenorrhea [24-26,29]. In the study of Golden et al. [30], patients had a mean BMI percentile of 27 at resumption of menses. Although the BMI at the exact time point of resumption of menses was not evaluated in our study, we found that those patients who were menstruating at the 12-month follow-up had a similar mean BMI percentile of 24. A recent study examined resumption of menses in relation to %EBW and found that two-thirds of the adolescent patients resumed menses at weights of approximately 95% EBW [33]. Golden et al. [27] also reported that 86% of the patients who achieved approximately 90% of their standard body weight resumed menses within 6 months. In our study, patients resumed menstruation at a very similar %EBW. The mean %EBW of the patients who spontaneously resumed menses was 91 at the 12-month follow-up, while those who were still amenorrheic had weights of approximately 86% EBW. However, in the present study and other studies, the current (age-adjusted) BMIs of amenorrheic and menstruating girls exhibited considerable overlap [22,25,28,30,41,42], which suggests an impact of additional factors on the resumption of menses.

Thus, an important aim of this study was the identification of further anthropometric and clinical factors that may predict the normalization of menstrual status and are easily acquired at the time of initial hospital treatment.

The absence of menarche at hospital admission strongly predicted persistent amenorrhea at the 12-month follow-up. Patients who did not have their menarche before the onset of AN were unlikely to start menstruating within the first 12 months after admission. This important finding has not been reported previously. However, many other studies included only patients with secondary amenorrhea (e.g., [22,25,29,41], while in our study, one-fifth of the patients were still premenarchal at admission. The finding that the absence of menarche before the onset of AN predicted a worse outcome corresponds to the results of other studies that a very low age at onset, e.g., childhood AN, is associated with a worse long-term outcome compared with that in patients with adolescent onset of AN [2,43,44].

The duration of hospital treatment also had predictive value. Patients who required longer hospital stays to reach their target weights (16.8 weeks vs. 14.7 weeks) were more likely to have persistent amenorrhea at the 12-month follow-up. However, the factors underlying this finding remain unclear. Longer hospital treatment durations may imply more severe courses of illness that cause difficulties in gaining weight or considerable differences between the weight at admission and the target weight. In our study, the different variables at discharge, such as %EBW, regular discharge at target weight, and duration of treatment, were strongly related, and their individual effects could not be precisely distinguished. Willer et al. [45] also reported that increased lengths of hospital stays predicted rehospitalization, which may be an indicator of worse outcomes. However, longer hospital treatment durations also shortened the time between discharge (discharge normally occurred when the target weight was maintained for two weeks) and the 12-month follow-up. It has previously been shown that the length of time after weight rehabilitation is an important determinant of the recovery of the menstrual cycle [22] and that some adolescent girls with AN only resume menses several years after weight restoration [21,27]. Thus, for complete recovery of menstrual function, longer periods of weight stabilization without energy deficits may be necessary [23].

The achievement of target weight (defined as the 15-20th age-adjusted BMI percentile) before discharge from hospital treatment was a significant positive predictor of the resumption of menses at the 12-month follow-up. After adjusting for other relevant clinical variables, patients with high premorbid BMIs were found to be less likely to resume menses by the follow-up, most likely because there was still a significant difference between target weight (as defined above) and the weight at which menstruation was suspended. Accordingly, the findings of other studies indicated that premorbid weight [25,26] and the weight at which menstruation ceased may help to predict the weight required for the return of menstruation [27,28]. Thus, the determination of an adequate target weight is essential, as sufficient weight rehabilitation and stabilization are necessary for the resumption of menses. Especially in young patients with AN, weight restoration and recovery of hypothalamic-pituitary-gonadal function are of particular importance, as they are the most important preconditions for bone recovery [13,46]. In addition, sex hormones were shown to be of great importance for brain maturation during adolescence [17,47]. Growth charts based on large population-based data sets can aid in the estimation of appropriate ranges of expected weights based on current age and height. In adolescents with secondary amenorrhea, the weight at which menstruation ceased and premorbid weight should also be considered. Based on our findings and those of others, a target weight between the 15th and 20th BMI percentile seems to be an adequate treatment goal.

Strengths and limitations

Some limitations of the present study should be considered. First, the time of follow-up was limited to 12 months. Second, the study only included young, non-chronic patients with a relatively short duration of illness and moderate to severe AN. Thus, our results may not be applicable to patients with more chronic courses of AN. Third, biological parameters, such as hormone levels (e.g., gonadotropins, estrogens, and leptin), or data on body composition that may also influence the resumption of menses have not been investigated.

The study also has several methodological advantages. We investigated a large sample of adolescent AN patients who participated in a standardized treatment program and had a low rate of loss to follow-up. The patients in our sample represented a typical population of adolescents with AN seeking inpatient treatment [48-51]. In addition, we were able to assess a rather young sample consisting of a large number of premenarchal patients, which allowed us to demonstrate that early AN onset may result in protracted hormonal deficits. Finally, follow-up data were assessed personally by well-trained and experienced therapists.

Conclusions

The recovery of menstrual function in adolescent patients with AN should be a major treatment goal to prevent severe long-term somatic and psychiatric sequelae. Patients with premenarchal onset of AN and those with a high premorbid BMI are obviously at particular risk for protracted amenorrhea despite weight rehabilitation. While these two risk factors cannot be influenced by treatment, others can be addressed by adequate treatment strategies. In particular, discharging patients only after they have reached their individual target weight and supporting them to maintain this weight can influence outcome positively. The calculation of an individual target weight should be based on population-based reference data. A target weight corresponding to a range between the 15th and 20th BMI percentile seems to be favorable in terms of the resumption of menses. Whether patients with a higher premorbid BMI may benefit from a higher target weight should be investigated in further studies.

Competing interest

Dr. Fleischhaker received grants by Bristol-Myers-Squibb, Novartis, and Otsuka; Dr. Bühren, Dr. Dempfle, Dr. Egberts, Dr. Herpertz-Dahlmann, Dr. Pfeiffer, Ms Schwarte, Dr. Timmesfeld and Dr. Wewetzer declare that they have no competing interests for this paper.

Authors’ contributions

All authors contributed extensively to the work presented in this paper. BH-D was in charge of conception and design of the study and supervised the project. RS, KB, CF, KE, EP and CW carried out treatment of the patients and data acquisition. AD and NT performed the analysis and supported the interpretation of the data. KB and AD wrote the article. BH-D did the revision of the manuscript. All authors read and approved the final manuscript.

Acknowledgement

This study was supported by the German Federal Ministry of Education and Research (BMBF No. 01GV0602, 01GV0623). This trial is registered with the International Standard Randomised Controlled Trial Number Register (ISRCTN67783402) and Deutsches Register Klinischer Studien (DRKS00000101).

We would like to thank our patients and their parents for participating in this study.

References

  1. Gonzalez A, Kohn MR, Clarke SD: Eating disorders in adolescents.

    Aust Fam Phys 2007, 36:614-619. OpenURL

  2. Wentz E, Gillberg IC, Anckarsater H, Gillberg C, Rastam M: Adolescent-onset anorexia nervosa: 18-year outcome.

    Br J Psychiatr: J Mental Sci 2009, 194:168-174. Publisher Full Text OpenURL

  3. Schulze UM, Schuler S, Schlamp D, Schneider P, Mehler-Wex C: Bone mineral density in partially recovered early onset anorexic patients - a follow-up investigation.

    Child Adolesc Psychiatr Mental Health 2010, 4:20. BioMed Central Full Text OpenURL

  4. Nogal P, Pniewska-Siark B, Lewinski A: Analysis of treatment efficacy in girls with anorexia nervosa (III).

    Neuro Endocrinol Lett 2009, 30:32-38. OpenURL

  5. Levine RL: Endocrine aspects of eating disorders in adolescents.

    Adolesc Med 2002, 13:129-143.

    vii

    PubMed Abstract OpenURL

  6. Couturier J, Lock J: What is recovery in adolescent anorexia nervosa?

    Int J Eat Disord 2006, 39:550-555. PubMed Abstract | Publisher Full Text OpenURL

  7. American Psychiatric Association:

    Practice Guideline for the treatment of patients with eating disorders. 3rd edition. 2006. OpenURL

  8. Herpertz S, Herpertz-Dahlmann B, Fichter M, Tuschen-Caffier B, Zeeck A: S3-Leitlinie Diagnostik und Behandlung der Essstörungen. New York: Sprinher-Verlag Berlin Heidelberg; 2011. OpenURL

  9. Rosen DS: American Academy of Pediatrics Committee on Adolescence: Identification and management of eating disorders in children and adolescents.

    Pediatrics 2010, 126:1240-1253. PubMed Abstract | Publisher Full Text OpenURL

  10. Misra M, Katzman D, Miller KK, Mendes N, Snelgrove D, Russell M, Goldstein MA, Ebrahimi S, Clauss L, Weigel T, et al.: Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa.

    J Bone Min Res: Offic J Am Soc Bone Min Res 2011, 26:2430-2438. Publisher Full Text OpenURL

  11. Miller KK: Endocrine dysregulation in anorexia nervosa update.

    J Clin Endocrinol Metabol 2011, 96:2939-2949. Publisher Full Text OpenURL

  12. Dominguez J, Goodman L, Sen Gupta S, Mayer L, Etu SF, Walsh BT, Wang J, Pierson R, Warren MP: Treatment of anorexia nervosa is associated with increases in bone mineral density, and recovery is a biphasic process involving both nutrition and return of menses.

    Am J Clin Nutr 2007, 86:92-99. PubMed Abstract | Publisher Full Text OpenURL

  13. Miller KK, Lee EE, Lawson EA, Misra M, Minihan J, Grinspoon SK, Gleysteen S, Mickley D, Herzog D, Klibanski A: Determinants of skeletal loss and recovery in anorexia nervosa.

    J Clin Endocrinol Metabol 2006, 91:2931-2937. Publisher Full Text OpenURL

  14. Misra M, Prabhakaran R, Miller KK, Goldstein MA, Mickley D, Clauss L, Lockhart P, Cord J, Herzog DB, Katzman DK, Klibanski A: Weight gain and restoration of menses as predictors of bone mineral density change in adolescent girls with anorexia nervosa-1.

    J Clin Endocrinol Metabol 2008, 93:1231-1237. Publisher Full Text OpenURL

  15. Chui HT, Christensen BK, Zipursky RB, Richards BA, Hanratty MK, Kabani NJ, Mikulis DJ, Katzman DK: Cognitive function and brain structure in females with a history of adolescent-onset anorexia nervosa.

    Pediatrics 2008, 122:e426-e437. PubMed Abstract | Publisher Full Text OpenURL

  16. Kaye WH, Fudge JL, Paulus M: New insights into symptoms and neurocircuit function of anorexia nervosa.

    Nat Rev Neurosci 2009, 10:573-584. PubMed Abstract | Publisher Full Text OpenURL

  17. Mainz V, Schulte-Ruther M, Fink GR, Herpertz-Dahlmann B, Konrad K: Structural brain abnormalities in adolescent anorexia nervosa before and after weight recovery and associated hormonal changes.

    Psychosom Med 2012, 74:574-582. PubMed Abstract | Publisher Full Text OpenURL

  18. van Elburg AA, Eijkemans MJ, Kas MJ, Themmen AP, de Jong FH, van Engeland H, Fauser BC: Predictors of recovery of ovarian function during weight gain in anorexia nervosa.

    Fertil Steril 2007, 87:902-908. PubMed Abstract | Publisher Full Text OpenURL

  19. Misra M, Prabhakaran R, Miller KK, Tsai P, Lin A, Lee N, Herzog DB, Klibanski A: Role of cortisol in menstrual recovery in adolescent girls with anorexia nervosa.

    Pediatr Res 2006, 59:598-603. PubMed Abstract | Publisher Full Text OpenURL

  20. Muller TD, Focker M, Holtkamp K, Herpertz-Dahlmann B, Hebebrand J: Leptin-mediated neuroendocrine alterations in anorexia nervosa: somatic and behavioral implications.

    Child Adolesc Psychiatr Clin North Am 2009, 18:117-129. Publisher Full Text OpenURL

  21. Herpertz-Dahlmann BM, Wewetzer C, Schulz E, Remschmidt H: Course and outcome in adolescent anorexia nervosa.

    Int J Eat Disord 1996, 19:335-345. PubMed Abstract | Publisher Full Text OpenURL

  22. Jacoangeli F, Masala S, Staar Mezzasalma F, Fiori R, Martinetti A, Ficoneri C, Novi B, Pierangeli S, Marchetti G, Simonetti G, Bollea MR: Amenorrhea after weight recover in anorexia nervosa: role of body composition and endocrine abnormalities.

    Eat Weight Disord: EWD 2006, 11:e20-e26. Publisher Full Text OpenURL

  23. Holtkamp K, Hebebrand J, Mika C, Grzella I, Heer M, Heussen N, Herpertz-Dahlmann B: The effect of therapeutically induced weight gain on plasma leptin levels in patients with anorexia nervosa.

    J Psychiatr Res 2003, 37:165-169. PubMed Abstract | Publisher Full Text OpenURL

  24. Rigaud D, Pennacchio H, Bizeul C, Reveillard V, Verges B: Outcome in AN adult patients: a 13-year follow-up in 484 patients.

    Diabetes Metabol 2011, 37:305-311. Publisher Full Text OpenURL

  25. Dei M, Seravalli V, Bruni V, Balzi D, Pasqua A: Predictors of recovery of ovarian function after weight gain in subjects with amenorrhea related to restrictive eating disorders.

    Gynecol Endocrinol: Offic J Int Soc Gynecol Endocrinol 2008, 24:459-464. Publisher Full Text OpenURL

  26. Favaro A, Santonastaso P: Seasonality and the prediction of weight at resumption of menses in anorexia nervosa.

    Fertil Steril 2009, 91:1395-1397. PubMed Abstract | Publisher Full Text OpenURL

  27. Golden NH, Jacobson MS, Schebendach J, Solanto MV, Hertz SM, Shenker IR: Resumption of menses in anorexia nervosa.

    Arch Pediatr Adolesc Med 1997, 151:16-21. PubMed Abstract | Publisher Full Text OpenURL

  28. Swenne I: Weight requirements for return of menstruations in teenage girls with eating disorders, weight loss and secondary amenorrhoea.

    Acta Paediatr 2004, 93:1449-1455. PubMed Abstract | Publisher Full Text OpenURL

  29. Abbate Daga G, Campisi S, Marzola E, Rocca G, Peris C, Campagnoli C, Peloso A, Vesco S, Rigardetto R, Fassino S: Amenorrhea in eating disorders: poor stability of symptom after a one-year treatment.

    Eat Weight Disord: EWD 2012, 17:e78-e85. OpenURL

  30. Golden NH, Jacobson MS, Sterling WM, Hertz S: Treatment goal weight in adolescents with anorexia nervosa: use of BMI percentiles.

    Int J Eat Disord 2008, 41:301-306. PubMed Abstract | Publisher Full Text OpenURL

  31. Hebebrand J, Wehmeier PM, Remschmidt H: Weight criteria for diagnosis of anorexia nervosa.

    Am J Psychiatr 2000, 157:1024. Publisher Full Text OpenURL

  32. Le Grange D, Doyle PM, Swanson SA, Ludwig K, Glunz C, Kreipe RE: Calculation of expected body weight in adolescents with eating disorders.

    Pediatrics 2012, 129:e438-e446. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  33. Faust JP, Goldschmidt AB, Anderson KE, Glunz C, Brown M, Loeb KL, Katzman DK, Le Grange D: Resumption of menses in anorexia nervosa during a course of family-based treatment.

    J Eat Disord 2013, 1:12.

    Epub

    BioMed Central Full Text OpenURL

  34. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, DSM-V. 5th edition. Washongton, DC: American Psychiatric Association; 2013. OpenURL

  35. Krohmeyer-Hauschild K, Wabisch M, Kunze D, Geller D, Geiss HC, Hesse V, Hippel A, Johnsen D, Korte W, Menner K, et al.: Perzentile für den Body Mass Index für das Kindes- und Jugendalter unter Heranziehung verschiedener deutscher.

    Stichproben Monatsschrift für Kinderheilkunde 2001, 149:807-818. Publisher Full Text OpenURL

  36. Herpertz-Dahlmann B, Schwarte R, Krei M, Egberts KM, Warnke A, Wewetzer C, Pfeiffer E, Fleischhaker C, Scherag A, Holtkamp K, et al.:

    Day Patient Treatment after Short Inpatient Care vs. Inpatient Treatment in Adolescent Anorexia Nervosa: a multicenter, randomized open-label, non-inferiority trial.

    under revision

    OpenURL

  37. Lock J, Le Grange D, Agras WS, Moye A, Bryson SW, Jo B: Randomized clinical trial comparing family-based treatment with adolescent-focused individual therapy for adolescents with anorexia nervosa.

    Arch Gen Psychiatr 2010, 67:1025-1032. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  38. Herpertz-Dahlmann B, Salbach-Andrae H: Overview of treatment modalities in adolescent anorexia nervosa.

    Child Adolesc Psychiatr Clin North Am 2009, 18:131-145. Publisher Full Text OpenURL

  39. Master-Hunter T, Heiman DL: Amenorrhea: evaluation and treatment.

    Ame Fam Phys 2006, 73:1374-1382. OpenURL

  40. DeLong ER, DeLong DM, Clarke-Pearson DL: Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach.

    Biometrics 1988, 44:837-845. PubMed Abstract | Publisher Full Text OpenURL

  41. Arimura C, Nozaki T, Takakura S, Kawai K, Takii M, Sudo N, Kubo C: Predictors of menstrual resumption by patients with anorexia nervosa.

    Eat Weight Disord: EWD 2010, 15:e226-e233. OpenURL

  42. Tinahones FJ, Martinez-Alfaro B, Gonzalo-Marin M, Garcia-Almeida JM, Garrido-Sanchez L, Cardona F: Recovery of menstrual cycle after therapy for anorexia nervosa.

    Eat Weight Disord: EWD 2005, 10:e52-e55. Publisher Full Text OpenURL

  43. Russell GFM: Anorexia nervosa of early onset and ity impact on puberty. In Feeding problems and eating disordersin children and adolescents. Edited by Cooper PJ, Stein A. Chur, Switzerland: Harwood Academic; 1992:85-112. OpenURL

  44. Herpertz-Dahlmann B, Vloet JA, Dempfle A, Egberts KM, Kappel V, Pfeiffer E, Bühren K: Outcome of childhood-onset anoerexia nervosa 7.5 years after inpatient treatment. Oral presentation at the Eating Disorders Research Society 19th Annual Meeting. Maryland, USA: Bethesda; 2013. OpenURL

  45. Willer MG, Thuras P, Crow SJ: Implications of the changing use of hospitalization to treat anorexia nervosa.

    Am J Psychiatr 2005, 162:2374-2376. PubMed Abstract | Publisher Full Text OpenURL

  46. Mehler PS, MacKenzie TD: Treatment of osteopenia and osteoporosis in anorexia nervosa: a systematic review of the literature.

    Int J Eat Disord 2009, 42:195-201. PubMed Abstract | Publisher Full Text OpenURL

  47. Neufang S, Specht K, Hausmann M, Gunturkun O, Herpertz-Dahlmann B, Fink GR, Konrad K: Sex differences and the impact of steroid hormones on the developing human brain.

    Cerebr Cortex 2009, 19:464-473. Publisher Full Text OpenURL

  48. Castro J, Deulofeu R, Gila A, Puig J, Toro J: Persistence of nutritional deficiencies after short-term weight recovery in adolescents with anorexia nervosa.

    Int J Eat Disord 2004, 35:169-178. PubMed Abstract | Publisher Full Text OpenURL

  49. Gowers SG, Clark A, Roberts C, Griffiths A, Edwards V, Bryan C, Smethurst N, Byford S, Barrett B: Clinical effectiveness of treatments for anorexia nervosa in adolescents: randomised controlled trial.

    Br J Psychiatr: J Mental Sci 2007, 191:427-435. Publisher Full Text OpenURL

  50. Salbach-Andrae H, Schneider N, Seifert K, Pfeiffer E, Lenz K, Lehmkuhl U, Korte A: Short-term outcome of anorexia nervosa in adolescents after inpatient treatment: a prospective study.

    Eur Child Adolesc Psychiatr 2009, 18:701-704. Publisher Full Text OpenURL

  51. van Elburg AA, Hillebrand JJ, Huyser C, Snoek M, Kas MJ, Hoek HW, Adan RA: Mandometer treatment not superior to treatment as usual for anorexia nervosa.

    Int J Eat Disord 2012, 45:193-201. PubMed Abstract | Publisher Full Text OpenURL

Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-244X/13/308/prepub