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From the Clinical Research Centers |
Departments of Obstetrics and Gynecology (K.T.B., E.F.) and Medicine (J.A.G., D.J.R., S.K.), and Center for Clinical Epidemiology and Biostatistics (K.T.B., J.A.G., M.S.), University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104; and Division of Endocrinology and Metabolism Medical College of Virginia (J.E.N.), Virginia Commonwealth University, Richmond, Virginia 23298
Address correspondence and requests for reprints to: Kurt T. Barnhart, M.D., M.S.C.E., University of Pennsylvania Medical Center, Department of Obstetrics and Gynecology, 106 Dulles, 3400 Spruce Street, Philadelphia, Pennsylvania 19104.
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Abstract |
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Changes in the serum endocrine profile of women in the DHEA group were significantly greater than the placebo group, including a 242% [95% confidence interval (CI) +60.1, +423.9] increase in DHEAS, a 94.8% (95% CI +34.2, +155.4) increase in testosterone, and a 13.2% (95% CI -27.88, +0.5) decline in cortisol compared to baseline. Women receiving DHEA had a 10.1% (95% CI -15.0, -5.1) decline in high-density lipoprotein and an 18.1% (95% CI -32.2, -3.9) decline in Lp(a) from baseline, but these declines did not significantly differ from women who received placebo. Women receiving DHEA did not have any improvements significantly greater than placebo in the severity of perimenopausal symptoms, mood, dysphoria, libido, cognition, memory, or well-being.
DHEA supplementation significantly effects the endocrine profile, may affect the lipid profile, but does not improve perimenopausal symptoms or well-being compared to placebo.
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Introduction |
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DHEA and its sulfate DHEAS are the most abundant hormones in the human body (8). DHEA is a precursor in the biosynthesis of other sex steroids and is a weak androgen. DHEA levels peak in the 3rd decade of life and progressively decline thereafter (8). Perimenopausal women, ages 45–50 yr, have approximately 50% of peak levels of DHEA (8). Additionally, and the age-related decline in adrenal androgens may be affected by the decline in ovarian function.
The rationale for DHEA supplementation includes that DHEA is recognized as a neurosteroid (9, 10), and its replacement was associated with improved learning potential and memory in aging mice (11, 12, 13). In the human, serum DHEA concentration has been associated with the ability to perform activities of daily living (14), the expression of feelings of well-being (15), and improvements in performance on tests for long-term memory (16). Low concentrations of DHEA have been associated with functional limitation, greater reports of depressed symptomotology, poor subjective perceptions of health and life satisfaction, and poor cognition (17, 18). Persons taking DHEA in open label trials have reported increases in vigor and libido, improvements in concentration and cognition, overall improvement in sense of well-being (2, 3), and improvement in depressive symptoms and verbal memory (19). The only placebo-controlled human study of DHEA replacement assessing well-being noted 82% of the treated women (n = 17) reporting an improvement in well-being compared with less than 10% of those who received placebo (1).
Supplementation of DHEA to older women increases DHEAS and testosterone concentrations to those found in young adults (1, 2, 3, 4, 5, 20). However, the effect of DHEA supplementation on the full endocrine profile of women is unknown. The impact of DHEA supplementation on serum lipid concentrations in women also has not been definitively established. Administration of androgens to women could have a negative impact on cardiovascular risk by detrimentally altering the lipid profile (21, 22). We report here the results of the first randomized double-blind placebo- controlled study examining the effects of oral DHEA supplementation on components of HRQOL, plasma lipid, and serum endocrine concentrations in symptomatic perimenopausal women.
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Methods |
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The study was conducted at the University of Pennsylvania Medical Center (UPMC) from July 1996 through July 1997. Study participants were perimenopausal women, ages 45–55 yr, with symptoms of fatigue, lack of energy, anxiety, tension, irritability, depression, insomnia, forgetfulness, concentration difficulties, decreased libido, or global reports of a decreased sense of well-being. Perimenopausal status was defined as a previous history of normal regular menstrual cycles with a current status of at least 2 months of amenorrhea within the past year, but no more than 12 months of amenorrhea (8, 23). Perimenopausal symptoms were self-rated on a Daily Symptom Rating (DSR) calendar (24, 25) for 3 weeks before study entry. We defined the presence of symptoms as an average score of moderate or severe (3 or 4 on a scale of 0–4) for two or more of the target symptoms in the pre-enrollment symptom rating. Women were excluded if they had any contraindication to hormonal replacement therapy; had exposure to an injectable or implantable sex steroid within 6 months (including estrogen replacement or DHEA supplementation) or a systemic steroid within 90 days of treatment; used antidepressants and/or antianxiolitics; had a current diagnosis of major psychiatric disorder, diabetes mellitus, hypercholesterolemia, or cardiovascular disease; or had abnormal renal or liver function. The Institutional Review Board of the UPMC approved the protocol, and all women gave written, informed consent for their participation. Subjects were recruited using advertisements in local media and were not compensated for participation in the study.
Treatment protocol
After screening for eligibility criteria and obtaining informed consent, subjects were randomized, double-blind, to receive a daily capsule of 50 mg DHEA, or identical placebo capsule, for 3 months. At the baseline visit, before group assignment, standard validated cognitive performance tests, interviewer-conducted mood assessments, and subject self-report questionnaires were completed (see Study Instruments and Laboratory Assays). Subjects were instructed to take the study medication at 2000 h each evening. Blood was obtained between 0800 and 1000 h after an overnight fast for endocrine and lipid evaluations. Subjects returned at 1, 2, and 3 months for collection of a blood sample and the completion of interviews, performance tests, and questionnaires. Subjects rated symptoms daily on the DSR calendar for the duration of the study.
Study instruments and laboratory assays
Serum endocrine assays. Serum was separated from blood at the time of collection by centrifugation and frozen at -70 C. Levels of testosterone, DHEA, DHEAS, estrone, sex hormone binding globulin (SHBG), and cortisol were measured using standard assay kits at the Core Laboratory of the General Clinical Research Center at UPMC in two batches. Specifically, DHEA was determined by RIA (DPC, Los Angeles, CA). DHEA was extracted from serum with dichloromethane. The recovery of DHEA was greater than 85%. The sensitivity of assay was 0.1 ng/mL. The cross-reactively for DHEAS was 0.07%. The intra-assay coefficient of variation was 6.9%. DHEAS was measured by RIA (ICN Pharmaceutical, Inc., Costa Mesa, CA). The sensitivity of the assay was 1.5 µg/dL. The cross-reactivity to DHEA was 0.08%. The intra-assay coefficient of variation was 4.6%. The total testosterone was determined by RIA (DPC). The range of assay was between 4 and 1600 ng/dL. The sensitivity of the assay was 0.5 ng/dL. The intra-assay coefficient of variation was 6.8%. Estrone levels were determined by RIA (ICN Pharmaceutical Inc.). The range of assay was 7.5–2000 pg/mL. The sensitivity of the assay was 1.5 pg/mL. The intra-assay coefficient of variation was 7.8%. The circulating concentration of SHBG was determined by immunoradiometric assay (Diagnostic System Laboratories, Inc., Webster, TX). The lowest concentration of SHBG that can be detected is 0.5 nM/L. The intra-assay coefficient of variation was 4.3%. Cortisol was measured by RIA (DPC). The sensitivity of assay was 0.5 µg/dL. The intra-assay coefficient of variation was 5.3%. During the time period of the study, the inter-assay coefficients of variation for the described assays when performed in multiple runs by the Core Laboratory of the General Clinical Research Center were all less than 10%.
Plasma lipid and apoprotein assays. Assays were performed at the Lipid Research Laboratory of UPMC, a Centers for Disease Control-certified lipid laboratory standardized for lipid quantitation. The laboratory participates in the ALERT quality control program for lipid and apolipoprotein quantitation. All assays were run using commercially available reagents on a Cobas Fara II autoanalyzer (Roche Diagnostics, New Brunswick, NJ). All assays used EDTA-anticoagulated plasma and were performed on the day the specimen was obtained. The cholesterol and triglyceride assays were enzymatic assays using reagents from Sigma Chemical Co. (St. Louis, MO). The sensitivity of the assay was 2 mg/dL and 10 mg/dL, respectively. The interassay coefficients of variation were 3% for cholesterol and 6% for triglyceride. The high-density lipoprotein (HDL) cholesterol assay was a heparin manganese precipitation method using reagents from Sigma Chemical Co. The sensitivity of the assay was 2 mg/dL, and the interassay coefficient of variation was 5%. The low-density lipoprotein (LDL) was calculated using the Friedewald formula following standard protocols. The apoA-1, apoB, and Lp(a) assays were immunoturbidometric assays using reagents from Diasoren, Inc. (Stillwater, MN). The sensitivity of the assays were 15 mg/dL, 20 mg/dL, and 4.9 mg/dL, and the interassay coefficients of variation were 7%, 7%, and 9%, respectively. The values for apoA-1, apoB, and Lp(a) are monitored by participation in the ALERT program.
Perimenopausal symptoms and HRQOL. Perimenopausal symptoms were evaluated by both validated subject and clinician-administered assessments. Subjects completed a 15-item DSR scale rated on a scale of 0 (none) to 4 (severe) throughout the study (24, 25). A total symptom score was calculated by summing all scores over a 3-week period preceding each study visit. Aspects of HRQOL were assessed at each visit. Mood was assessed using the Profile of Mood Scale (26). Dysphoria was assessed using both the Hamilton Depression Rating Scale (Ham-D) (27) and the Center of Epidemiologic Studies Depression Scale (28). Libido was assessed using one of the questions contained in the Ham-D. Quality of life was assessed with the SmithKline Beecham Quality of Life Self-Report Questionnaire (29). Memory was assessed using the Buschke Immediate Recall and Delayed Recall tests (30). Cognition was assessed with the Symbol Copying and the Digit Symbol Substitution Tests (31, 32, 33). A trained interviewer administered all performance tests and interviews.
Sample size and power
The trial was designed to detect a clinically significant change in the severity of perimenopausal symptoms and well being. No previous data exist to estimate the magnitude and SD of the treatment effect in this population. Sample size estimates were based on the ability to detect a difference in change from baseline between women taking active medication and placebo. Sample size was calculated to detect at least a 0.75 SD of the change in each outcome variable. Using a two-sided, type I error of 0.05, and a type II error of 0.20, a detectable difference of 0.75 SD would require 29 subjects per group.
Statistical analysis
The primary analysis was a comparison of the mean change score (score at baseline—score at the end of the trial) for each variable, stratified by treatment group, using analysis of covariance to adjust for baseline values. Because dropout was small (9%) and balanced, the primary analysis was conducted for those who completed the trial. Initially, a term for interaction between therapy and baseline level for each variable was included and tested for significance at the 0.10 level. The influence of initial level did not differ by treatment group, and the interaction term was not included in final models. Results are reported as mean change score (±SD). A positive change score for measures of symptoms and HRQOL reflects improvement. A positive change score for measures of lipid and endocrine variables reflects an increase in the concentration of that variable. We also report average percentage change from baseline with 95% confidence intervals (CI).
Baseline comparisons of characteristics for subjects by study group
were conducted using t tests and the 
test. The
distribution of Lp(a) concentrations was skewed, and the analysis was
performed after log transformation of this variable. A paired
t test was used to assess for changes over time within each
group. Statistical significance was considered at P =
0.05 using two-sided tests.
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Results |
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A total of 66 women were randomized, and 60 women completed the trial (30 in each arm). An equal number of women taking active medication and placebo elected to withdraw from the study. Three women discontinued the study because of adverse events: one developed a rash, one complained of abdominal pain and fatigue (both randomized to placebo), and one reported parasthesia and numbness of an upper extremity (randomized to DHEA). Three additional women withdrew consent during the study period.
An intent to treat analysis of all 66 women was conducted using the last available data carried to the end of the study. The results from this analysis did not differ from the primary analysis.
Baseline comparisons
The baseline characteristics of the women randomly assigned to receive placebo or DHEA were similar. The mean age (placebo 48.3 ± 3 yr vs. DHEA 48.8 ± 2 yr; P = 0.3), weight (placebo 68.7 ± 11.8 kg vs. DHEA 69.5 ± 12.7 kg; P = 0.6), and baseline serum FSH concentration (placebo 27.7 ± 27 mIU/mL vs. DHEA 38.3 ± 26.3 mIU/mL; P = 0.14) were not statistically different between the two groups. There were no significant differences between the groups in racial distribution (82% Caucasian, 15% African American and 2% Asian), education level, or number of missed menstrual cycles. All women had normal serum values of liver transaminases, blood urea nitrogen, creatinine and complete blood count both before enrollment and after completion of the study.
The mean baseline values of serum endocrine parameters, plasma lipid
parameters, severity of perimenopausal symptoms, and the components of
HRQOL are included in Tables 1
, 2, 3, and 4, respectively. At baseline
there was no significant difference between study groups in any
variable, with the exception of serum triglyceride concentration, which
was significantly higher in women randomized to receive placebo.
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. Women taking DHEA had a significant
increase in serum DHEA, DHEAS, and testosterone and a significant
decrease in cortisol concentration compared with those who received
placebo.
The average percentage change from baseline in serum DHEAS,
testosterone, estrone, and cortisol concentrations, for each study
group at 3 months, are presented in Fig. 1. Serum DHEAS concentration increased
242% (95% CI +60.1, +423.9) from baseline in women taking DHEA and
decreased 5% (95% CI -11.1, +1.2) in women taking placebo. Serum
testosterone increased 94.8% (+34.2, +155.4) in DHEA group compared
with 24.1% (95% CI -10.8 - +150.4) in the placebo group. Serum
cortisol decreased 13.2% (95% CI -27.88, -0.5) in the DHEA group
compared with an increase of 7.4% (95% CI -0.7, +22.5) in the
placebo group. Serum DHEA increased 20.5% (95% CI -6.3, +49.1) in
women taking DHEA and decreased 0.3% (95% CI -26.1, +23.1) in women
taking placebo. No significant changes from baseline were noted for
SHBG or estrone in women who received DHEA or placebo. The increases in
serum DHEAS and testosterone were noted after 1 month and persisted
through the duration of the study, whereas a significant decrease in
serum cortisol was noted only after 3 months of study medication.
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There were no statistically significant differences in change scores
between those taking DHEA and placebo on any of the variables in the
lipid profile.
The average percentage change from baseline in total cholesterol, HDL,
LDL, and Lp(a) for each study group at monthly intervals are presented
in Fig. 2. After 3 months, HDL
concentration decreased 10.1% (95% CI -15.0, -5.1) from baseline in
women taking DHEA and decreased 3% (95% CI -2.3, +2.4) in women
taking placebo. Serum Lp(a) concentration decreased 18.1% (95% CI
-32.2, -3.9) in the DHEA group and decreased 7.9% (95% CI -20.2,
+4.4) in the placebo group. No significant change from baseline was
noted in total cholesterol, triglycerides, LDL, Apo A1, or Apo B in
women taking DHEA or placebo. The decrease from baseline in HDL and
Lp(a) were noted after 1 month and persisted for the duration of the
study.
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. The
mean change scores assessing aspects of HRQOL are presented in Table 4. There were no statistically
significant differences in change scores between those taking DHEA as
compared to placebo after 3 months of study medication for any of these
measures. However, all subjects (both those taking active medication
and those taking placebo) had statistically significant decreases in
total perimenopausal symptoms and improvement in the components of
HRQOL after 3 months compared to baseline (P < 0.01
for all comparisons, paired t tests, stratified by treatment
group). |
Discussion |
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The endocrinological impact of DHEA supplementation in this study confirms the increase in a woman’s serum androgen concentration with 50 mg oral DHEA (1, 20). We noted that DHEA supplementation resulted in a 242% increase in serum DHEAS and a 95% increase in testosterone compared to placebo. Importantly, this is the first study to demonstrate a significant decrease in serum cortisol with DHEA supplementation. The 13% decrease in cortisol concentration compared to baseline was noted only after 3 months of supplementation and may reflect negative feedback of exogenous DHEA on the hypothalamic-pituitary-adrenal axis. The mechanism and clinical significance of this decline is unknown but demonstrates the significant impact of DHEA supplementation on the hormonal milieu of a perimenopausal woman. We also noted a slight increase in serum estrone in women receiving DHEA supplementation, consistent with an earlier study (20). However, it is important to emphasize that the increase in estrone concentration was not clinically significant and should not be considered a substitute for estrogen replacement therapy.
Testosterone replacement therapy to women results in significant declines in HDL (24) and, therefore, has potential to influence cardiovascular disease (CVD) risk (22). DHEA is also an androgen precursor and, therefore, could have a similar effect on a woman’s lipid profile (21, 34). The findings of this study regarding serum metabolic predictors of CVD risk are contradictory. We found both a 10% decline in serum HDL and an 18% decline in serum Lp(a) concentrations with DHEA supplementation. Because we noted a mild decline in both HDL and Lp(a) in women who did not receive DHEA, these changes were significant compared with baseline but not statistically different if compared with subjects who received placebo. Although an impact on HDL has not been demonstrated in all studies (4), a decline in HDL has been demonstrated when supplementing DHEA at doses as high as 1600 mg/day (3) and as low as 25 mg/day (5). A decline in serum HDL concentrations could be detrimental to CVD risk (22).
A decline in serum Lp(a) may be beneficial (22). Estrogen replacement therapy is well established to cause a decline in Lp(a) (22). A decline in Lp(a) has also been reported with the use of androgenic anabolic steroids, such as stanozolol and danazol (35). Therefore, the finding that DHEA reduced Lp(a) is plausible and could be clinically relevant. The direction and magnitude of changes in plasma lipid parameters need to be confirmed before DHEA can be recommended for widespread use.
All subjects in this trial significantly improved from baseline in all study variables assessing the severity of perimenopausal symptoms and aspects of HRQOL, regardless if they received DHEA or placebo. However, there were no improvements for women taking DHEA that were significantly greater than the improvements for women taking placebo. Therefore, our findings do not support the conclusion that DHEA significantly lessens the severity of perimenopausal symptoms or any aspect of HRQOL compared to placebo. This study was designed to have adequate statistical power to detect a relatively small difference in change scores between the groups for these outcomes (0.75 SD). Therefore, the finding that all subjects in this trial significantly improved compared to baseline regardless of treatment calls into question the validity of previous findings based on case reports or open-label trials because they lack adequate control. A possible reason that all women noted improvement in perimenopausal symptoms and HRQOL is the attention they received from a health care provider, which validated their symptoms, resulting in perceived improvement. Additionally, subconscious improvement secondary to the known observation of an investigator similar to a Hawthorne effect (36) or regression to the mean may have been contributing factors.
The study was restricted to perimenopausal women. The results cannot be extrapolated to other populations. Peri- menopause is characterized by fluctuations in a woman’s menstrual cycle that are hypothesized to contribute to the large number of affective, cognitive, and physical symptoms during this period (37, 38). It is possible that any improvements in perimenopausal symptoms caused by the reversal of the age-related decline in adrenal androgens with DHEA supplementation are overshadowed by the symptoms associated with the fluctuation in ovarian steroids. Further study will be required to establish whether DHEA supplementation has any beneficial effect in other populations such as a subset of women with specific severe symptoms or menopausal women.
Based on the findings of this study, we conclude that DHEA supplementation should be used only under medical supervision with surveillance of endocrine and lipid parameters. There is no evidence that DHEA should be considered an alternative to estrogen replacement therapy, and its use should not be promoted based on putative beneficial changes in well being and HRQOL. Further study is needed to fully understand the long-term benefits and risks of DHEA supplementation in women.
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Acknowledgments |
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Footnotes |
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Received January 6, 1999.
Revised August 4, 1999.
Accepted August 9, 1999.
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