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Psychosomatic Medicine 63:62-68 (2001)
© 2001 American Psychosomatic Society

ORIGINAL ARTICLES

Plasma Levels of Neuroactive Steroids Are Increased in Untreated Women With Anorexia Nervosa or Bulimia Nervosa

Palmiero Monteleone, MD, Michele Luisi, MD, PhD, Barbara Colurcio, MD, Elena Casarosa, PhD, Patrizia Monteleone, MD, Raffaele Ioime, MD, Andrea R. Genazzani, MD, PhD and Mario Maj, MD, PhD

From the Institute of Psychiatry (P.M., B.C., R.I., M.M.), University of Naples SUN, Naples; and the Department of Reproductive Medicine and Child Development (M.L., E.C., P.M., A.R.G.), Division of Gynecology and Obstetrics, University of Pisa, Pisa, Italy.

Address reprint requests to: Dr. Palmiero Monteleone, Institute of Psychiatry, University of Naples SUN, Largo Madonna delle Grazie, 80138 Naples, Italy. Email: monteri{at}tin.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: Animal data suggest that neuroactive steroids, such as 3{alpha},5{alpha}-tetrahydroprogesterone (3{alpha},5{alpha}-THP), dehydroepiandrosterone (DHEA), and its sulfated metabolite (DHEA-S), are involved in the modulation of eating behavior, aggressiveness, mood, and anxiety. Anorexia nervosa (AN) and bulimia nervosa (BN) are eating disorders characterized by abnormal eating patterns, depressive and anxious symptoms, enhanced aggressiveness, and endocrine alterations. Previous studies reported decreased blood levels of DHEA and DHEA-S in small samples of anorexic patients, whereas no study has been performed to evaluate the secretion of these neuroactive steroids in BN as well as the production of 3{alpha},5{alpha}-THP in both AN and BN. Therefore, we measured plasma levels of DHEA, DHEA-S, 3{alpha},5{alpha}-THP and other hormones in patients with AN or BN and explored possible relationships between neuroactive steroids and psychopathology.

METHOD: Ninety-two women participated in the study. There were 30 drug-free AN patients, 32 drug-free BN patients, and 30 age-matched, healthy control subjects. Blood samples were collected in the morning for determination of hormone levels. Eating-related psychopathology, depressive symptoms, and aggressiveness were rated by using specific psychopathological scales.

RESULTS: Compared with healthy women, both AN and BN patients exhibited increased plasma levels of 3{alpha},5{alpha}-THP, DHEA, DHEA-S, and cortisol but reduced concentrations of 17ß-estradiol. Plasma testosterone levels were decreased in anorexic women but not in bulimic women. Plasma levels of neuroactive steroids were not correlated with any clinical or demographic variable.

CONCLUSIONS: These findings demonstrate increased morning plasma levels of peripheral neuroactive steroids in anorexic and bulimic patients. The relevance of such hormonal alterations to the pathophysiology of eating disorders remains to be elucidated.

Key Words: anorexia nervosa • bulimia nervosa • cortisol • neuroactive steroids.

Abbreviations: ACTH = adrenocorticotropin hormone; AN = anorexia nervosa; ANOVA = analysis of variance; BDHI = Buss-Durke Hostility Inventory; BITE = Bulimic Investigation Test Edinburgh; BN = bulimia nervosa; CRF = corticotropin-releasing factor; DHEA = dehydroepiandrosterone; DHEA-S = dehydroepiandrosterone-sulfate; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, fourth edition; EDI = Eating Disorder Inventory; GABA = {gamma}-aminobutyric acid; HDRS = Hamilton Depression Rating Scale; HPA = hypothalamic-pituitary-adrenal (axis); OCD = obsessive-compulsive disorder; YBC-EDS = Yale-Brown-Cornell-Eating Disorder Scale; 3{alpha},5{alpha}-THP = 3{alpha},5{alpha}-tetrahydroprogesterone; 5-HT = serotonin.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
It is well known that the central nervous system is a target of steroid hormones. Steroids influence the survival, differentiation, and connectivity of specific neuronal populations in early postnatal life; in adulthood they influence neuronal functions by modulating synaptic transmission (1). Owing to their lipophilic nature, steroids that are produced in various peripheral organs, such as the adrenal glands and the gonads, can easily cross the blood-brain barrier. Furthermore, some steroids are synthesized directly in the brain and are so called neuroactive steroids or "neurosteroids." Indeed, evidence has shown that within the glial cells, pregnenolone can be converted to progesterone, which in turn is sequentially metabolized to 5{alpha}-dihydroprogesterone and 3{alpha},5{alpha}-tetrahydroprogesterone (3{alpha},5{alpha}-THP) or allopregnenolone (2). Allopregnenolone is now recognized to be an important allosteric modulator of both GABA type-A and 5-HT type-3 receptors (3, 4), exhibiting neuroprotective, anxiolytic, anticonvulsant, and antidepressant actions (5). What seems to be missing in the central nervous system is cytochrome P45017{alpha}, which converts pregnenolone to DHEA. However, although synthesis of DHEA and its sulfated metabolite, DHEA-S, has never been demonstrated in the brain, it is intriguing that these steroids remain in the central nervous system after removal of peripheral steroidogenic glands (6). Whatever their source, DHEA and DHEA-S likely have important neurobiological roles, being involved in regulating neuronal survival and differentiation and in modulating cognitive functions, mood, and sense of well-being (5, 7–9). Moreover, it has been shown that DHEA modulates both aggression and feeding behavior, because it inhibits the aggressiveness of castrated male mice against lactating female intruders (10) and decreases food intake and body weight in rats (11). It is commonly believed that DHEA and DHEA-S exert these effects by modulating both 5-HT and GABA transmission in the brain (5).

AN and BN are eating disorders of unknown pathogenesis, characterized by pathological concerns about body weight and body shape and abnormal patterns of feeding behavior and energy expenditure. Moreover, common to individuals with AN and BN are depression, anxiety, and increased aggressiveness (12, 13). Malnutrition-induced hormone alterations occur in both AN and BN patients; in particular, a hyperactivity of the HPA axis due to an overdrive of the CRF/ACTH system has been reported in both disorders (14, 15). Because the secretion of DHEA and DHEA-S by the adrenal gland is believed to be driven by the CRF/ACTH system, it seems plausible that alterations in the production of these adrenal steroids might occur in anorexic and bulimic patients. Furthermore, given the above-mentioned involvement of 3{alpha},5{alpha}-THP, DHEA, and DHEA-S in the modulation of body weight, food intake, aggressive behavior, mood, and anxiety, one may hypothesize that alterations in neurosteroid secretion may play a role in the pathogenesis of some aspects of the psychopathology of AN and BN.

So far only two studies have assessed the production of DHEA and DHEA-S in small samples of patients with AN (16, 17). To the best of our knowledge, these results have not been replicated in larger patient samples, and no information has been provided on the production of DHEA and DHEA-S in patients with BN and of 3{alpha},5{alpha}-THP in both AN and BN. Therefore, to assess whether the secretion of DHEA, DHEA-S, and 3{alpha},5{alpha}-THP is altered in AN and BN and to explore whether such alterations are related to some aspects of the eating disorder psychopathology, we measured plasma levels of these neuroactive steroids, cortisol, testosterone, and 17ß-estradiol in drug-free women with AN or BN and in age-matched, healthy control subjects and assessed possible relationships between these hormones and both eating-related and non–eating-related psychopathology.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Ninety-two women were recruited for the study. Sixty-two were outpatients attending the Eating Disorder Center of our institute, and 30 were healthy control subjects. Thirty patients met DSM-IV criteria for a diagnosis of AN, and 32 met the criteria for BN. Diagnostic assessment was made by a trained interviewer using the Structured Clinical Interview for DSM-IV (18). Of the anorexic women, 20 were exclusively food restrictors and 10 occasionally binged with a frequency no more than twice a week. At the time of the study, two anorexic women had a concomitant diagnosis of OCD, and two, of major depression. Patients with BN were all of the purging subtype, with binge episodes always followed by self-induced vomiting; three of these patients also abused laxatives, and two exercised excessively. Three had a history of AN, two had a concomitant diagnosis of major depression, and one had a concomitant diagnosis of borderline personality disorder. All of the anorexic women and five of the bulimic women were amenorrheic; nine bulimic women were oligomenorrheic; and the remaining patients had normal, regular menses.

Before entering the study, patients with concomitant depression, OCD, or borderline personality disorder and six bulimic women being treated with fluvoxamine or clomipramine underwent a 6-week washout period. This period was the longest compatible with the patients’ clinical status as judged by the physician treating the patients. The remaining ones, at the time of the study, had already been drug-free for more than 3 months (16 anorexic and 15 bulimic patients) or had never taken any medication (10 anorexic and 8 bulimic patients).

Control women were mentally healthy, as assessed by a clinical interview, and had no family history of mental disorders, as assessed by the Family History Research Diagnostic Criteria (19). They were regularly menstruating and had normal diets.

Both patients and healthy volunteers had normal findings on physical examination, normal values on routine blood and urine tests, and normal findings on an electrocardiogram. Female control subjects and patients who were menstruating normally were tested during the follicular phase of their menstrual cycle (days 5–10 after the last menses). The follicular phase was chosen to avoid having to monitor ovulation in our outpatients. No subjects were taking oral contraceptives or had a history of alcohol or drug abuse.

Procedure
Subjects gave written informed consent before study participation. Both patients and control subjects underwent a psychopathological assessment. The following instruments were used: 1) EDI (20) and BITE (21), to evaluate eating-related psychopathology; 2) HDRS (22), to measure concomitant depressive symptoms; 3) YBC-EDS (23), to assess obsessive concerns with body image, weight, and caloric intake and compulsive behaviors such as exercising and weighing oneself; and 4) BDHI (24), a self-report questionnaire providing information on hostility and aggression.

After an overnight fast, each subject underwent blood sample collection in the morning, between 8:00 and 9:00 hours. A "butterfly" needle was inserted into a forearm vein, and the catheter was kept patent by a saline infusion, which was slowly infused so that the same amount of fluid would be injected into each individual. Subjects rested supine for 30 minutes, and then blood was withdrawn and collected in tubes with lithium heparin as an anticoagulant. Plasma was separated by centrifugation and stored at -20°C.

Biochemical Analyses
Plasma 17ß-estradiol levels were determined by an immunometric method (MAIA clone) using commercially available kits (Biochem Immunosystem, Milan, Italy). The lower detection limit was 5 pg/ml; intra- and interassay coefficients of variation were 4.3% and 3.2%, respectively. Plasma cortisol concentrations were determined by a double-antibody radioimmunoassay method using a commercially available kit (Biochem Immunosystem). The lower detection limit was 27 nmol/liter. Intra- and interassay coefficients of variation were less than 5% and 8%, respectively. Plasma testosterone concentrations were determined by radioimmunoassay according to the method of d’Istria et al. (25). The lower detection limit was 3 pg/ml. Intra- and interassay coefficients of variation were less than 4% and 10%, respectively.

The 3{alpha},5{alpha}-THP assay was performed after ether extraction and chromatographic partition on C18 Sep-Pak cartridges by using a previously described method (26). Polyclonal antiserum, raised in sheep injected with 3{alpha},5{alpha}-THP carboxymethylether coupled to bovine serum albumin, was provided by Dr. R. H. Purdy (San Diego, CA). The sensitivity of the assay, expressed as a minimal amount of 3{alpha},5{alpha}-THP distinguishable from the zero sample with a 95% probability, was 20 pg per tube, and the intra- and interassay coefficients of variation were 7.2% and 9.1%, respectively. Plasma DHEA samples were extracted with ether, purified through C18 Sep-Pak cartridges, and then assayed by a radioimmunoassay method using a commercially available kit (Radim S.p.A., Pomezia, Italy). The sensitivity of assay was 15 pg/ml, and the intra- and interassay coefficients of variation were 3.1% and 6.9%, respectively. DHEA-S levels were also measured by using a commercially available radioimmunoassay kit (Radim S.p.A.). The sensitivity of assay was 0.02 mg/liter, and the intra- and interassay coefficients of variation were 4.9% and 7.2%, respectively.

Data Analysis
The BMDP statistical software package (27) was used for data analysis. Because there were significant deviations from normality in the data, nonparametric statistical analyses were used. Where the Kruskal-Wallis ANOVA showed significant differences among the groups, the Mann-Whitney U test was used to assess differences between patients and control subjects. The Spearman rank order correlation test was used to examine the relationships between 3{alpha},5{alpha}-THP, DHEA, and DHEA-S values and between demographic, clinical, and hormonal data. Significance levels were modified to adjust for correlation across multiple variables.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Demographic and Clinical Data
The Kruskal-Wallis ANOVA showed significant intergroup differences in body weight (p < .0001) and body mass index (p < .0001) but not in age or height. With respect to healthy women, anorexic patients had significantly lower body weight and body mass index, whereas no significant difference in these parameters was observed between bulimic and healthy women and between anorexic women of the restricting subtype and those of the binge-purging subtype ( Table 1).


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  		Table 1. Demographic and Clinical Characteristics of the Study Samplea
 
In the bulimic group, mean binge/vomiting frequency was 1.8 ± 1.3 episodes per day.

The Kruskal-Wallis ANOVA showed significant intergroup differences in EDI (p < .0001), BITE (p < .0001), HDRS (p < .0001), YBC-EDS (p < .0001), and BDHI (p < .0005) total scores. Compared with healthy women, anorexic and bulimic patients had significantly higher scores on standardized assessments of eating-related psychopathology, depression, and aggressiveness (Table 1).

No significant differences were observed in any psychometric measure between anorexic women of the restricting type and those of the binge-purging type.

Hormonal Data
The Kruskal-Wallis ANOVA showed significant intergroup differences in plasma levels of 3{alpha},5{alpha}-THP (p < .0001), DHEA (p < .0005), DHEA-S (p < .001), 17ß-estradiol (p < .0001), testosterone (p < .0001), and cortisol (p < .0001). Compared with healthy women, both anorexic and bulimic patients exhibited significantly higher concentrations of plasma 3{alpha},5{alpha}-THP, DHEA, DHEA-S, and cortisol but significantly lower plasma levels of 17ß-estradiol ( Figure 1 and Table 2). Eumenorrheic bulimic women had plasma levels of 17ß-estradiol higher than those of bulimic women with menstrual irregularities (58.2 ± 45.5 pg/ml vs. 21.3 ± 14.7 pg/ml, respectively; Z = 2.42; p < .008) and not significantly different from those of healthy control subjects. Plasma testosterone concentrations were significantly decreased in anorexic patients but not in bulimic patients (Table 2). The ratios of plasma DHEA to cortisol and of plasma DHEA-S to cortisol did not significantly differ among the groups (Table 2). The significance of these differences did not change after patients with concomitant major depression or OCD were excluded.



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  		Fig. 1. Plasma levels of DHEA, DHEA-S, and 3{alpha},5{alpha}-THP in healthy women and in women with AN or BN. Data are mean ± SD. *p < .01; **p < .0001 vs. healthy women (Mann-Whitney U test).

 

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  		Table 2. Plasma Hormone Concentrations of Healthy Control Subjects and Patients With Eating Disordera
 
No significant differences were observed in any hormonal measure between anorexic women of the restricting type and those of the binge-purging type.

We tested menstruating women between days 5 and 10 after the last menses, a time when potentially wide variations in plasma levels of 17ß-estradiol may occur. To exclude differences in estrogen levels that may have affected neurosteroid results, we performed an analysis of covariance with 17ß-estradiol as the covariate. This analysis showed that plasma levels of 17ß-estradiol did not account for differences in blood concentrations of DHEA (F(1,88) = 0.41, NS), DHEA-S (F(1,88) = 0.27, NS), and 3{alpha},5{alpha}-THP (F(1,88) = 0.84, NS).

In both anorexic and bulimic patients, no significant correlation emerged between plasma concentrations of neuroactive steroids and those of the remaining hormones or subjects’ age, body weight, body mass index, duration of illness, and HDRS and BDHI total scores.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Two main results emerge from this study: 1) We found increased plasma concentrations of 3{alpha},5{alpha}-THP, DHEA, DHEA-S, and cortisol but decreased plasma levels of 17ß-estradiol in anorexic and bulimic women; and 2) in both anorexic and bulimic patients, plasma levels of neuroactive steroids did not correlate with depressive symptoms, aggressiveness, or clinical measures of nutritional status, such as body weight and body mass index.

Zumoff et al. (16) previously found decreased mean daily values of plasma DHEA and DHEA-S in 14 anorexic patients with a concomitant increase in plasma cortisol concentrations, whereas Winterer et al. (17) reported reduced baseline and ACTH-stimulated blood concentrations of DHEA and DHEA-S in six underweight anorexic women with normal blood cortisol values. It is possible that the use of mean daily values of adrenal androgens in the first study and the different hormonal milieu of anorexic women in the second study may have been responsible for the discrepancy with our findings. Moreover, differences in the sample sizes and in the patients’ nutritional status, expressed by the percentage of desired body weight (Zumoff et al.’s study), the percentage of ideal body weight (Winterer et al.’s study), or the body mass index (present study), may have contributed to the inconsistency of results.

To the best of our knowledge, this is the first study exploring the production of DHEA and its sulfated metabolite in patients with BN.

It is known that the major source of blood DHEA and DHEA-S is the adrenal gland, and it is assumed that the secretion of DHEA, DHEA-S, and glucocorticoids by this gland is regulated by the CRF/ACTH axis. There is considerable evidence that this axis is hyperactive in both AN and BN (14, 15). Therefore, although changes in the catabolism of adrenal steroids cannot be excluded, it seems likely that the enhanced production of both adrenal androgens and cortisol in our bulimic and anorexic patients is related to the hyperactivity of the CRF/ACTH axis.

The concomitant hyperproduction of adrenal androgens and glucocorticoids leads to a preservation of the DHEA and DHEA-S to cortisol ratios in both AN and BN patients. Therefore, our findings support the idea that in eating disorders, which can be considered chronic stress conditions with potentially serious somatic consequences, there is no dissociation of the secretion of cortisol and DHEA, as it occurs in adrenarche, puberty, normal aging, severe medical illnesses, and acute stress (28–30). As a consequence, our data do not confirm the hypothesis of Zumoff et al. (16) that in acutely ill postpubertal anorexic women there is a regression to a prepubertal status of functioning that affects not only the reproductive axis but also the HPA system.

The pathophysiological significance of the hyperproduction of DHEA and DHEA-S in both anorexic and bulimic women is not simple to explain. It is well known that hypothalamic 5-HT is involved in the modulation of feeding behavior (31), and impaired 5-HT transmission has been documented in both AN and BN (12, 13). Animal data have suggested that DHEA and DHEA-S modulate feeding behavior by increasing the amount or activity of 5-HT in the hypothalamus (11). Therefore, it is possible that the enhanced production of these neurosteroids in patients with eating disorders may represent an attempt to counteract a neurotransmitter dysfunction potentially involved in the genesis or maintenance of the aberrant eating behavior.

This is the first study assessing the secretion of 3{alpha},5{alpha}-THP in people with eating disorders. We found increased blood levels of this neuroactive steroid in both anorexic and bulimic women. 3{alpha},5{alpha}-THP has been shown to possess anxiolytic properties in different animal models (32). Intracerebroventricular administration of 3{alpha},5{alpha}-THP reduces the anxiety evoked by CRF (33), decreases the release of CRF stimulated by pharmacological challenges in hypothalamic explants (34), and attenuates the response of the HPA axis to stress (34). Therefore, elevated plasma levels of 3{alpha},5{alpha}-THP in patients with eating disorders may represent an endogenous counterregulatory mechanism to counteract the hyperactivity of the HPA axis experienced during the acute phases of the illnesses. It is noteworthy that DHEA has significant antiglucocorticoid properties, because it is able to antagonize glucocorticoid action in several animal models (35, 36). Hence, it is possible that the elevation of 3{alpha},5{alpha}-THP, DHEA, and DHEA-S in anorexic and bulimic women may represent an adaptive phenomenon that occurs to antagonize the potentially deleterious effects (either behavioral and metabolic) of HPA hyperactivity. Such an effect may explain, among other things, why anorexic and bulimic patients, despite having significantly increased levels of plasma cortisol, do not present the typical signs of Cushing’s syndrome. Moreover, given the involvement of neuroactive steroids in the modulation of anxiety, it is possible that the increased production of 3{alpha},5{alpha}-THP, DHEA, and DHEA-S in anorexic and bulimic patients is somehow linked to the anxiety dimension of the eating disorders. Because we did not rate anxiety levels in our patients, this hypothesis remains to be proved in future studies.

Finally, because alterations of DHEA and/or DHEA-S have been found in depressed patients (37, 38) and in aggressive individuals with conduct disorders (39), it would be reasonable to presume that the present findings are related to concomitant depressive symptoms and aggressiveness occurring in our patients. However, we did not find any correlation between 3{alpha},5{alpha}-HTP, DHEA, or DHEA-S plasma levels and depressive symptoms or aggressiveness in either anorexic or bulimic patients. Although the lack of a statistical correlation does not exclude a possible link between two variables, the present findings support the idea that depressive symptoms and aggressiveness are not connected to neurosteroid changes in patients with eating disorders.

Minor results of our study were the findings of decreased blood levels of 17ß-estradiol in both the AN and BN patient groups and of decreased concentrations of plasma testosterone in anorexic patients but not bulimic patients. The decreased plasma values of estrogens are in line with the dysfunction of the hypothalamic-pituitary-gonadal axis occurring in all anorexic women and in some of our bulimic patients. This is consistent with the present finding that plasma levels of 17ß-estradiol were decreased only in bulimic women with menstrual irregularities. Differences in plasma levels of 17ß-estradiol did not account for differences in plasma concentrations of neuroactive steroids between patients and control subjects. The decreased baseline testosterone concentrations in our anorexic women are in line with some, but not all, literature data (40, 41). In agreement with our results, Raphael et al. (42) found normal blood levels of testosterone in 12 bulimic subjects. Although we did not measure plasma levels of luteinizing hormone in our patients, the lowered testosterone levels in anorexic as compared with bulimic patients were probably related to the suppression of luteinizing hormone secretion given the apparent greater insult to the hypothalamic-pituitary-ovarian axis in the former. None of these baseline hormone measures were significantly correlated with either clinical variables or plasma concentrations of the neurosteroids.

A major limitation of our study is that our findings refer to a single morning measurement of blood hormone levels, despite the well-recognized circadian rhythmicity and pulsatility in the secretion of these substances. Therefore, we cannot exclude the possibility that phase shifts in the circadian rhythms may have affected our results. Moreover, it is possible that an enhanced perceived stress in the experimental situation could have affected these findings, especially those of cortisol. However, both our patients and control subjects underwent a 30-minute resting period before blood was drawn. This is a commonly accepted procedure to minimize the effect of acute stress due to the experimental situation on the HPA axis. Future studies exploring the circadian rhythmicity of 3{alpha},5{alpha}-HTP, DHEA, and DHEA-S production in patients with eating disorders may help to clarify both issues.

In conclusion, we found increased plasma concentrations of the neuroactive steroids 3{alpha},5{alpha}-HTP, DHEA and DHEA-S in untreated patients with AN or BN. The mechanisms underlying these changes and their role in the pathophysiology of eating disorders remain to be elucidated.

Received for publication February 1, 2000.


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 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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