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Original Article |
Divisions of Adolescent/Young Adult Medicine (C.M.G., E.G., S.J.E., K.A.B.) and Endocrinology (C.M.G.), Clinical Research Program (H.A.F.), Children’s Hospital, Boston, Massachusetts 02115; Division of Adolescent Medicine, Children’s Hospital of Cincinnati (E.G.), Cincinnati, Ohio 45229-3039; Maine Center for Osteoporosis, St. Joseph Hospital (C.J.R.), Bangor, Maine 04402; Department of Orthopedics, Yale-New Haven Hospital (C.M.G.), New Haven, Connecticut 06510; and Division of Endocrine/Hypertension, Brigham and Women’s Hospital (M.S.L.), Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Catherine M. Gordon, M.D., M.Sc., Children’s Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115. E-mail: catherine.gordon{at}tch.harvard.edu.
Abstract
Young women with anorexia nervosa (AN) have subnormal levels of dehydroepiandrosterone (DHEA) and estrogen that may be mechanistically linked to the bone loss seen in this disease. The purpose of this study was to compare the effects of a 1-yr course of oral DHEA treatment vs. conventional hormonal replacement therapy (HRT) in young women with AN.
Sixty-one young women were randomly assigned to receive oral DHEA (50 mg/d) or HRT (20 µg ethinyl estradiol/0.1 mg levonorgestrel). Anthropometric, nutrition, and exercise data were acquired every 3 months, and bone mineral density (BMD) and body composition were measured by dual energy x-ray absorptiometry (DXA) every 6 months over 1 yr. Serum samples were obtained for measurements of hormones, proresorptive cytokines, and bone formation markers, and urine was collected for determinations of bone resorption markers at each visit.
In initial analyses, total hip BMD increased significantly and similarly (+1.7%) in both groups. Hip BMD increases were positively correlated with increases in IGF-I (r = 0.44; P = 0.030) and the bone formation marker, bone-specific alkaline phosphatase increased significantly only in the DHEA treatment group (P = 0.003). However, both groups gained significant amounts of weight over the year of therapy, and after controlling for weight gain, no treatment effect was detectable. There was no significant change in lumbar BMD in either group. Both bone formation markers, bone-specific alkaline phosphatase and osteocalcin, increased transiently at 6–9 months in those subjects receiving DHEA compared with the estrogen-treated group (P < 0.05). Both DHEA and HRT significantly reduced levels of the bone resorption markers, urinary N-telopeptides (P < 0.05). There was a positive correlation between changes in IGF-I and changes in weight, body fat determined by DXA, and estradiol for both groups. In addition, patients receiving DHEA exhibited improvement on three validated psychological instruments (Eating Attitudes Test, Anorexia Nervosa Subtest, and Spielberger Anxiety Inventory).
Both DHEA and HRT had similar effects on hip and spinal BMD. Over the year of treatment, maintenance of both hip and spinal BMD was seen, but there was no significant increase after accounting for weight gain. Compared with HRT, DHEA appeared to have anabolic effects, evidenced by the positive correlation between increases in hip DXA measurements and IGF-I and significant increases in bone formation markers. Both therapies significantly decreased bone resorption. Replicating results from studies of the elderly, DHEA resulted in improvements in specific psychological parameters in these young women.
EARLY BONE LOSS and fractures are a frequent complication of anorexia nervosa (AN), occurring in over half of patients (1, 2, 3, 4, 5, 6, 7). Despite the presence of profound estrogen deficiency in young women with AN, hormonal replacement therapy (HRT) has yielded conflicting and disappointing results. A previous double-blinded, randomized, controlled trial found that HRT did not prevent bone loss or restore normal bone mass in patients aged 16–43 yr with a variable duration of AN (8). In contrast, Seeman et al. (9) found higher spinal bone mineral density (BMD) in young women who used oral contraceptives than in nonusers in a retrospective cross-sectional sample. Despite the lack of consistent evidence demonstrating its ability to prevent or reverse bone loss in this clinical setting, HRT is commonly prescribed to these patients (10). Accumulating data suggest that in addition to estrogen deficiency, other mechanisms are responsible for the osteoporosis of AN.
Subnormal levels of dehydroepiandrosterone (DHEA) may contribute to the bone loss of AN. Some reports have noted decreased levels of serum DHEA or its sulfate ester, DHEA sulfate (DHEAS), in these young women (11, 12, 13, 14). DHEA replacement therapy has previously been shown to decrease bone resorption markers over 3 months in young women with AN (13) and over 1 yr in postmenopausal women (15). Our group recently reported that serum DHEAS levels were inversely correlated with urinary N-telopeptides (NTx) levels in young women with AN, supporting its antiresorptive properties (14). In our short-term study, we also showed increases in bone formation markers after short-term oral DHEA (13). Several studies have found serum IGF-I levels to be low in these patients (16, 17, 18, 19). This finding is significant, as IGFs may mediate the anabolic actions of DHEA on the skeleton (20). Supporting its anabolic properties, previous clinical studies have shown that oral DHEA produced a rise in serum IGF-I in aging men and women (21, 22, 23). One report of short-term administration in adolescents (13) and data from adult cohorts (15, 21, 22, 23) suggest that DHEA may have beneficial effects in countering bone loss. We, therefore, undertook a randomized clinical trial of DHEA vs. HRT in 61 young women with AN. We tested the hypotheses that 1) DHEA administration is more efficacious in preventing bone loss than sex HRT; and 2) the response to hormonal therapy can be predicted by specific clinical and hormonal variables and markers of bone turnover.
Subjects and Methods
Subjects
Sixty-one young women with AN by DSM-IV criteria, aged 14–28 yr (mean age ± SD, 17.8 ± 2.9 yr), participated in the study. An additional 33 patients were approached, but chose not to participate. These individuals did not differ with regard to age or duration of disease from the cohort studied. All subjects were Tanner pubertal stage 5 and post-menarchal. The subjects were recruited from the Eating Disorders Program at Children’s Hospital Boston and a local suburban adolescent medicine practice. All patients were hemodynamically stable, free of other acute or chronic diseases, and were taking no medications known to affect BMD. No subjects regularly consumed alcohol or used cigarettes. Enrolled patients continued to undergo weekly medical assessments by their adolescent health physicians, participated in weekly psychotherapy, and underwent monthly nutritional assessments. All patients gave written informed consent according to the guidelines of the Committee on Clinical Investigation at Children’s Hospital Boston.
Study design and treatment
A list of treatment assignments in randomly permuted blocks of 2 and 4 was prepared by the Children’s Hospital Clinical Research Program and provided to the pharmacy. After recruitment, verification of eligibility, and baseline measurements, each subject’s name was provided to the pharmacy and entered in sequence onto the assignment list.
Thirty-one subjects were assigned to receive micronized DHEA, 50 mg/d orally, and the remaining 30 received Alesse (20 µg ethinyl estradiol and 0.1 mg levonorgestrel). Considering the presumed bone loss that would occur in these patients if no therapy were administered and weight loss was sustained (8), a placebo control was not carried out. Both drugs were dispensed by the pharmacy in a gelatin capsule. Neither study staff nor patients were aware of which drug was assigned to any subject. Pill counts were obtained at each visit.
Data collection
At baseline and 3, 6, 9 and 12 months, subjects had venous blood drawn and a second morning urine collected in the outpatient division of the General Clinical Research Center, Children’s Hospital Boston. Samples were obtained between 0700–1000 h after an overnight fast. At baseline and 12 months, subjects completed validated nutritional (24) and exercise questionnaires, including a detailed assessment of calcium and vitamin D intake (from both diet and supplements) and weekly participation in specific sports activities, as has been used previously (25). The activity questionnaire, developed specifically for youth, asked participants to recall the typical amount of time spent in 17 separate sports and other activities. From responses, a participant’s physical activity was computed in hours per week. At baseline and 6 and 12 months, participants also completed validated psychological instruments, including the Beck Depression Inventory, Spielberger State/Trait Inventory (an anxiety assessment), the Anorexia Nervosa Subtest, and the Eating Attitudes Test (a tool for evaluation body image and anorexic behavior) (26, 27, 28, 29).
At each study visit, subjects’ weights (in kilograms) and heights (in centimeters) were determined in a hospital gown after voiding. All weights were obtained on the same scale. Height was obtained using the same stadiometer (Perspective Enterprises, Kalamazoo, MI). Body mass index was calculated using the patient’s weight in kilograms/height in meters2. The percentage of average body weight was determined using standard percentile tables from the National Center for Health Statistics. An interval history was taken at each visit, including a menstrual history, and a physical examination was performed.
Each participant had a BMD measurement of the total body, lumbar spine, total hip, femoral neck and trochanter, and body composition by dual energy x-ray absorptiometry (DXA) with a Hologic 2000 machine (Hologic, Inc., Waltham, MA) at baseline and 6 and 12 months. With this instrument, our precision error (percent coefficient of variation ± SEM) for BMD for premenopausal females was 0.53 ± 0.08% at the spine and 0.77 ± 0.14% at the femoral neck (30).
At each visit, subjects had venous blood samples obtained for osteocalcin and DHEAS measurements by double antibody RIA and for bone-specific alkaline phosphatase (BSAP) levels by immunoradiometric assay (Esoterix Endocrinology, Calabasas Hills, CA), and urinary levels of cross-linked NTx were determined using ELISA on a second morning void (Esoterix Endocrinology, Calabasas Hills, CA). At baseline, levels of FSH, LH, T4, TSH, and PRL were measured using the Immuno-1 System (Bayer Corp., Tarrytown, NY), serum calcium and phosphorus were determined by Ektachem methodology (cholesterol oxidase; Vitros, Johnson \|[amp ]\| Johnson, New Brunswick, NJ), and PTH was determined by chemoluminescent immunoassay (Nichols Institute Diagnostics, San Juan Capistrano, CA). At baseline and 6 and 12 months, serum levels of IL-6, TNF-
, and IL-1ß were determined by a high sensitivity ELISA (R&D Systems, Minneapolis, MN), total estradiol and testosterone were measured by RIA (Esoterix Endocrinology), free testosterone was determined by equilibrium dialysis (Endocrine Sciences, Inc., Calabasas Hills, CA), and IGF-I was measured by extraction RIA (Nichols Institute Diagnostics). At baseline and 3 and 12 months, liver function, total cholesterol, and high density lipoprotein (HDL) levels were measured by Ektachem methodology (cholesterol oxidase; Vitros, Johnson \|[amp ]\| Johnson). At baseline and 12 months, serum glucose was determined by glucose hexokinase methodology (Roche Molecular Biochemicals, Indianapolis, IN), and insulin was determined by a microparticle enzyme immunoassay (Abbot Laboratories, Abbott Park, IL).
Statistical analysis
A power analysis indicated that 29 patients/group were required to detect an expected mean difference of +3.0% with a variability of 3% (ß = 0.20; = 0.05; version 1.0, nQuery Advisor, Statistical Solutions, Cork, Ireland). We randomly assigned 30 patients to each arm.
We used paired t tests for simple comparisons of 12-month changes between the two treatment groups and Pearson correlation coefficient to describe associations between changes in the different variables. Repeated measures ANOVA was used to determine the change in primary end points over time. The ANOVA included a main effect for time (1, 2, or 4 df depending on the frequency of measurement), a main effect for treatment (1 df), and a time x treatment interaction. The main effect of time was used to test whether the end point changed between baseline and 12 months in the sample as a whole. The time x treatment interaction tested whether the mean change differed between those taking DHEA and those taking estrogen. To control for mediating variables, we added potential confounders as continuous covariates in the ANOVA. Similarly, to adjust nutrient intakes for total caloric intake, we added total calories as a covariate. In cases of incomplete data, all available measurements were included in the analysis on the assumption (justified below) that dropouts and missing values were unrelated to treatment assignment or any unaccounted for bias.
Adjusted mean values at each time point and changes between baseline and 12 months were estimated for each group using contrasts derived from the ANOVA. Means and contrasts are reported as an estimate ± SE. We used P < 0.05 as a critical level for statistical significance and refer to tests with 0.05 < P < 0.10 as marginally significant.
Statistical analyses were performed with SPSS software (SPSS, Inc., Chicago, IL) and the SAS MIXED procedure (SAS Institute, Inc., Cary, NC).
Results
Sample retention and compliance
Ten patients discontinued the study for reasons unrelated to the study medication or study protocol. Six were receiving HRT, and four were receiving DHEA. At baseline, these subjects did not differ from the remaining cohort with regard to duration of AN; duration of amenorrhea; baseline hip, lumbar, or total body BMD; weight; body mass index; or responses on psychological instruments (Beck Depression Index, Eating Attitudes Test, Anorexia Nervosa Subtest, or Spielberger State/Trait Assessment).
Pill counts were obtained at each visit. At each return visit, the counts ranged from 0–8 pills, with a mean ± SD across visits of 2.5 ± 2.2 pills.
Weight, body fat, and menstrual history
Both treatment groups gained significant amounts of weight over the course of the study (HRT group: adjusted mean, 5.9 ± 4.9 kg; range, –1.8 to +18.2; DHEA group: adjusted mean, 6.8 ± 8.6 kg; range -6.8 to +38.5; P < 0.001). The weight changes were directly correlated with increases in serum IGF-I and estradiol (Table 2
). One patient lost weight in the HRT group, and five patients lost weight in the DHEA group. There were no between-group differences in weight gain (P > 0.60 for interaction). For both groups, the bone formation marker BSAP was positively correlated with increases in weight (DHEA group: r = 0.47; P = 0.027; HRT group: r = 0.50; P = 0.056). There was also a corresponding significant increase in both lean body and fat mass by DXA for each group (Table 1). For lean body mass, the mean increase was +1.3 kg (P = 0.002) for the HRT group and +1.9 kg (P < 0.001) for the DHEA group. For fat mass, the mean increase was +3.5 kg (P = 0.002) for the HRT group and +4.3 kg (P = 0.004) for the DHEA group.
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Bone density data
Lumbar BMD did not change significantly over the course of the study for either group. The mean change was a small, but statistically insignificant, increase in each group: 0.0095 ± 0.0092 g/cm2 (adjusted mean ± SE) with HRT and 0.0045 ± 0.0087 g/cm2 with DHEA (Fig. 1A). There was no significant correlation between fat mass or lean body mass by DXA and lumbar BMD for either group.
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). Both changes in hip BMD represented a 12-month increase of 1.7%, and both were significant (P < 0.03); however, the mean change did not differ between DHEA and estrogen-treated participants (P > 0.90 for time x treatment interaction). The increase in hip BMD was positively correlated with increases in weight over the year for the HRT (r = 0.49; P = 0.018) and DHEA groups (r = 0.64; P < 0.001). Controlling the ANOVA for weight attenuated the increase in hip BMD; after adjustment for weight, neither treatment group showed a statistically significant change (P > 0.40). For the DHEA group alone, there was a positive correlation between the increase in hip DXA and the increase in IGF-I (r = 0.44; P = 0.030). The increase in bone density was not correlated with changes in exercise, calcium, vitamin D, or overall caloric intake for either group. There was no significant correlation between lean body mass determined by DXA and hip BMD for either group, but a positive correlation was noted between fat mass and hip BMD (HRT group: r = 0.53; P = 0.009; DHEA group: r = 0.55, P = 0.003).
We conducted post hoc power calculations for BMD change using the attained sample size and SEs from the observed data. We had 86% power to detect the hypothesized 3% increase in lumbar BMD in the DHEA group had it occurred; the actual change was only 0.5%, detectable with 8% power. For hip BMD, the observed change in the DHEA group was 2% (unadjusted for weight), statistically significant, but not distinguishable from the increase in the HRT group. After controlling for weight, we had 82% power to detect the hypothesized 3% treatment effect (differential change between DHEA and HRT) had it occurred.
Biochemical data
At baseline, thyroid function tests and serum levels of calcium, phosphorus, PTH, and PRL were with normal limits. Mean serum LH and FSH levels were at the lowest end of the normal range.
At baseline, serum levels of estradiol were significantly below the mean level for adolescents in the early follicular phase (P < 0.001). Estradiol levels increased significantly only in those subjects receiving DHEA (Table 1). Total testosterone levels were normal at baseline and increased significantly only in the group receiving DHEA, as did free testosterone levels (Table 1). Levels of SHBG decreased significantly only in the DHEA group (-42%; P < 0.001).
Mean baseline levels of DHEAS (178 vs. 233 µg/dl; P = 0.022) were significantly below the mean for age. Levels of DHEAS increased only in those subjects receiving DHEA (81%; P = 0.004). The mean serum IGF-I level was subnormal at baseline in both groups and increased significantly in both treatment groups [estrogen group, +29% (P = 0.006); DHEA group, +33% (P = 0.005)]. Increases in IGF-I were significantly correlated with increases in weight, fat mass determined by DXA, and serum estradiol for both groups (Table 2).
There was no significant change in osteocalcin in either group comparing baseline levels to those at 12 months. However, a strong time x treatment interaction effect was identified for osteocalcin, with significant increases in osteocalcin seen in the DHEA group at 6–9 months compared with those subjects receiving estrogen (P < 0.001; Fig. 2). BSAP, a second bone formation marker, showed a significant increase in the DHEA group alone (+27%; P = 0.003). There was a significant decrease in NTx in both groups: 26% decrease in the E2 group (P = 0.001) and 16% decrease in the DHEA group (P = 0.019). The 12-month decrease in NTx did not differ between groups, but repeated measures analysis of the full time course showed NTx falling more rapidly in the HRT group at 3, 6, and 9 months, with a marginally significant time x treatment interaction (P = 0.08).
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were undetectable; levels of IL-6 were detectable, but low. There were no significant changes noted when comparing baseline and 12 months in either group. Lipid panels and liver function tests were normal throughout the study. Fasting serum glucose and insulin levels and 2-h glucose tolerance tests were also normal. No signs of hirsutism or acne were noted. On clinical histories, no headaches or bloating were noted by patients in either group.
Nutrition and activity data
Daily caloric intake decreased by 174 kcal (10%) in the HRT group and 233 kcal (15%) in the DHEA group. Neither decrease was statistically significant by itself, but the main effect for time by ANOVA (combining the two treatment groups) was significant (P = 0.02). Accordingly, we adjusted all nutrient analyses for total energy intake.
For the HRT group there was a significant decrease in energy-adjusted vitamin D consumption over the course of the study (23%; P < 0.05). For the DHEA group the decrease was greater (30%; P = 0.08), but not significantly so (P > 0.60 for interaction). There was also no significant change in energy-adjusted calcium or caffeine intake for either group, and levels of vitamins C, B6, and K; zinc; and magnesium did not significantly change over the course of the study and were not different between groups. Weekly exercise decreased 20% over the course of the study in the DHEA group (P < 0.05), but did not change in the HRT group (P > 0.60).
Psychological data
Comparing baseline to 12 months, there were no significant differences in scores on any of the psychological instruments administered to the HRT group (Fig. 3). For the DHEA group, there were significant decreases, implying improved clinical status, for the following parameters: Anorexia Nervosa Subtest, decreased body image concerns (24% decrease; P = 0.010); Eating Attitudes Test, improvement in attitude toward eating (26% decrease; P = 0.007); and Spielberger State/Trait Inventory, decreased anxiety (12% decrease; P = 0.011; Fig. 3).
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In this randomized controlled trial of DHEA vs. HRT in young women with AN we found no significant differences between the effects of these therapies on BMD. In initial analyses, both therapies appeared to increase total hip BMD and resulted in a maintenance of lumbar BMD. However, both groups exhibited an unexpected and significant mean weight increase, and treatment effects were abolished after adjusting for weight gain. Both treatments resulted in significant decreases in bone resorption markers. Unlike HRT, DHEA exhibited anabolic properties, including enhanced levels of bone formation markers only in this treatment group and a positive correlation between increases in hip BMD and increases in IGF-I. Subjects receiving DHEA also exhibited favorable changes in specific psychological variables, as have been reported in studies of aging men and women who received DHEA treatment.
In the current study we found that hip BMD, unadjusted for weight, increased, and spinal BMD was unchanged. Both groups exhibited significant weight gain, and the increase in BMD appeared to be attributable to both weight gain and corresponding IGF-I increases, the latter of which is a factor highly influenced by nutrition. Differentiating the effect of treatment on BMD from the effect of weight gain was difficult because of the surprising and striking weight gain exhibited in both groups. As DXA has difficulty in discriminating fat from bone (31), we tested whether body fat was a potential confounder in our initial analyses. There was a significant correlation seen between fat mass determined by DXA and hip BMD, not a surprising finding given the significant increases in fat mass seen in each group. We also controlled for activity and intake of calcium and vitamin D, but no correlation was found between these variables and hip BMD, thus ruling out these variables as potential confounders. Theoretically, increases in hip BMD could be a biomechanical response, with the bone responding to and strengthened by the greater tissue mass around it. This issue is particularly relevant at the hip, a weight-bearing site and one that should be considered in future intervention trials.
Four earlier studies have shown low serum levels of DHEAS in patients with AN (11, 12, 13, 14). Antiresorptive properties have been previously reported as were exhibited in the DHEA-treated group of the current study. DHEA replacement decreased bone resorption markers short-term in young women with AN (13) and in a longitudinal study of elderly women (15). In another study of postmenopausal women, the agent chromium picolinate raised serum DHEAS levels, but decreased urinary excretion of both hydroxyproline and calcium, suggesting antiresorptive effects of DHEA (32). Recent in vitro data suggest that DHEA may inhibit secretion of the proresorptive cytokine IL-6 by human marrow cells in culture more significantly and consistently than either testosterone or estrogen (33). Comparing responses of bone resorption markers over 1 yr in the current study, DHEA and HRT were equally efficacious as antiresorptive agents.
Levels of serum IGF-I have been shown to be subnormal in AN (16, 17, 18, 19). Replacement of a recombinant form of this factor short-term resulted in increased levels of bone formation markers (34), suggesting that IGF-I has anabolic effects on bone. In the current study a positive correlation was seen between IGF-I and increases in hip BMD over the year of treatment in the DHEA group only. As has been shown previously (14, 19), IGF-I was nutritionally dependent, with significant positive correlations noted between IGF-I and both weight and fat mass determined by DXA. This factor was also positively correlated with serum estradiol levels, a notable finding as estradiol is synthesized within fat tissue (35). A striking finding was the significant increase in IGF-I seen after estrogen therapy. In postmenopausal women, oral estrogen has been reported to decrease serum IGF-I (36, 37). The current data highlight the sensitivity of this peptide to nutrition and body weight, as IGF-I rose despite administration of oral estrogen.
Striking increases in weight were seen in both treatment groups that were surprising and without explanation. Patients with AN are typically highly resistant to weight gain, and the significant weight gain observed was unexpected. Our entry criteria did not include a strict screen as to where a young woman was in her clinical course. Stricter physical and psychological entry criteria may be needed for future intervention trials. The frequent visits to adolescent providers may have served as a positive intervention for these patients. It is also noteworthy that patients continued to undergo frequent medical, psychiatric. and nutritional assessments, the standard treatment for young women with eating disorders, which could have led to clinical improvement. The effect of steroids, both DHEA and estrogen/progestin, on appetite was not measured in the current protocol and should be monitored in future studies. Lastly, these results raise the possibility that treatment with nondrug modalities that focuses on weight gain may have a profound effect on bone markers and bone mass in these patients.
Intake of calories and specific nutrients was monitored over the protocol, as well as the activity of the participants. It is notable that although weight increased in both groups, reported caloric intake decreased. Interestingly, reported intake of calcium and vitamin D also decreased, which is notable as each has potential beneficial effects on BMD. Patient denial, characteristic of this disorder, was evident, as healthy consumption of the RDA for calcium and vitamin D was reinforced at each study visit. Levels of vitamin C, zinc, magnesium, and other nutrients that are potentially beneficial to bone were unchanged over the course of the study. Exercise decreased in both groups and significantly so in the DHEA group. This finding is noteworthy, as the initial increase in hip BMD found did not appear to be attributed to positive effects from exercise, thus ruling out this variable as a confounder.
In the current study decreased anxiety and improved attitudes toward body image and eating were reported on validated questionnaires. Self-reported improvements in physical and psychological well-being have been reported previously in age-advanced men and women after oral DHEA administration (21). That cohort received the same 50-mg dose as that administered to subjects in the current study (21). In patients with Addison’s disease, improvement in mood and fatigue was seen after 12 wk of replacement with 50 mg oral DHEA (38). These combined results suggest that DHEA may have properties as a neurosteroid with abilities to enhance mood and cognition (39, 40, 41).
Both DHEA and HRT were shown to be safe over the year of treatment. No hirsutism, acne, or adverse androgenic or other effects were seen after DHEA therapy, which are theoretical risks of this therapy. At the same time, no headaches or bloating were reported in the young women receiving either HRT or DHEA. Lipid panels, liver function tests, and 2-h oral glucose tolerance tests were also followed, with no significant changes noted after either therapy.
The current results must be interpreted in light of acknowledged limitations. First, data about nutritional intake and exercise were obtained through self-report, with its associated limitations. The data were reported by adolescents with AN, a disease in which patient denial is common. However, these young women typically overreport food intake and underreport exercise, which would tend to bias results toward the null. Nonetheless, a discrepancy was noted between reported intake and weight gain in the current study, calling into question the validity of this methodology for this patient group. An unexpected finding was the lack of a significant increase in serum estradiol levels in the group receiving HRT. As compliance with the study medication appeared to be good, this finding is probably assay-related and deserves further study. It is noteworthy that bone turnover markers were obtained in a cohort of young women. Even though each subject was at least 2 yr postmenarchal at study entry to minimize the accelerated bone turnover associated with growth, there are fewer data on the normal range for adolescents compared with adults. Lastly, it must be acknowledged that the absence of a placebo group leaves questions unanswered about treatment efficacy that are independent of weight changes.
In summary, we report that 1 yr of treatment with oral DHEA or HRT had similar skeletal effects, with maintenance of hip and spinal BMD seen, but no significant increases at either site in our final analyses. The data presented suggest that DHEA has both anabolic and antiresorptive effects on bone. These findings suggest a theoretical advantage of DHEA over standard estrogen/progestin, although no between-group differences were seen after 1 yr of therapy. IGF-I was shown to be nutritionally dependent, replicating what has been reported previously. Lastly, DHEA resulted in improvements in psychological variables, suggesting that it is a well-tolerated agent for young women with AN and may help to reverse some of the emotional disturbances associated with this disease.
Acknowledgments
We thank the dedicated nurses at the General Clinical Research Center for their excellent patient care. We also gratefully acknowledge Irena Clark, B.A., M.H.P.; Pamela Sale, B.A.; Suzanne Muggeo, B.A.; Seema Khandelwal, B.A.; and Julie Burgess, B.S., for technical assistance with this study, and Charles Hakala (Belmar Pharmacy, Lakewood, CO) for supplying the micronized DHEA.
Footnotes
This work was supported in part by the following grants: NIH Grants MO1-RR-2172 and RO1-AG-12271, Project 5-T71-MC-0000-10-S1-R0 from the Maternal and Child Health Bureau, and a grant from the Department of Defense (U.S. Army, Bone Health and Military Readiness).
Abbreviations: AN, Anorexia nervosa; BMD, bone mineral density; BSAP, bone-specific alkaline phosphatase; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; DXA, dual energy x-ray absorptiometry; HRT, hormone replacement therapy; NTx, urinary N-telopeptides.
Received April 5, 2002.
Accepted August 13, 2002.
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 K. K. Dhatariya and K. S. Nair Dehydroepiandrosterone: Is There a Role for Replacement? Mayo Clin. Proc., October 1, 2003; 78(10): 1257 - 1273. [Abstract] [PDF]
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) or HRT (•) assigned at random to 51 young women with AN. Symbols indicate the mean ± SE from repeated measures ANOVA.No significant changes (P < 0.05) were seen at the lumbar spine (A), but significant increases in total hip BMD (B) were noted in each group between baseline and 12 months.
