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. 2014 Oct 3;99(10):3536–3542. doi: 10.1210/jc.2014-2261

The Benefits and Harms of Systemic Dehydroepiandrosterone (DHEA) in Postmenopausal Women With Normal Adrenal Function: A Systematic Review and Meta-analysis

Tarig Elraiyah 1, Mohamad Bassam Sonbol 1, Zhen Wang 1, Tagwa Khairalseed 1, Noor Asi 1, Chaitanya Undavalli 1, Mohammad Nabhan 1, Osama Altayar 1, Larry Prokop 1, Victor M Montori 1, Mohammad Hassan Murad 1,✉
PMCID: PMC5393492  PMID: 25279571

Abstract

Context:

Exogenous dehydroepiandrosterone (DHEA) therapy has been proposed to replenish the depletion of endogenous DHEA and its sulfate form, which occurs with advancing age and is thought to be associated with loss of libido and menopausal symptoms.

Objective:

We conducted a systematic review and meta-analysis to summarize the evidence supporting the use of systemic DHEA in postmenopausal women with normal adrenal function.

Methods:

We searched MEDLINE, EMBASE, PsycInfo, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus through January 2014. Pairs of reviewers, working independently, selected studies and extracted data from eligible randomized controlled trials (RCTs). We used the random-effects model to pool across studies and evaluated heterogeneity using the I2 statistic.

Results:

We included 23 RCTs with moderate to high risk of bias enrolling 1188 women. DHEA use was not associated with significant improvement in libido or sexual function (standardized mean difference, 0.35; 95% confidence interval, −0.02 to 0.73; P value = .06; I2 = 62%). There was also no significant effect of DHEA on serious adverse effects, serum lipids, serum glucose, weight, body mass index, or bone mineral density. This evidence warranted low confidence in the results, mostly due to imprecision, risk of bias, and inconsistency across RCTs.

Conclusions:

Evidence warranting low confidence suggests that DHEA administration does not significantly impact sexual symptoms or selected metabolic markers in postmenopausal women with normal adrenal function.

As women advance in age, they experience a decline in T and dehydroepiandrosterone sulfate (DHEAS) (1). The reduction in DHEAS is more prominent than that of T (2). The drop in the levels of these hormones has been linked to postmenopausal symptoms, decline in the sexual function, and reduction in bone mineral density (BMD). A cross-sectional study conducted in 2005 reported decreased sexual responsiveness in women 45 years old or more who were having DHEAS levels below the 10th centile for their age (odds ratio, 3.9; 95% confidence interval [CI], 1.54–9.81; P = .004) (3). A case-control study conducted in 2010 further supported these findings and highlighted this association (4).

Dehydroepiandrosterone (DHEA) is one of the precursors in the biosynthesis process of steroid hormones. Because DHEA exerts its effect through conversion to androgen and/or estrogen, it has been proposed as a replacement therapy that yields clinically beneficial effects mediated by both hormones (5). The proposed androgenic effects are increased libido and improved well-being via conversion to T, whereas its transformation to estrogen is thought to result in improvements in menopausal vasomotor symptoms.

The safety profile of DHEA and its impact on menopausal symptoms, sexual performance, and bone health have been studied in several randomized controlled trials (RCTs). Some of these trials showed a beneficial effect of DHEA on sexual function (6–11), whereas others found no positive effect (12, 13). The same conflicting results have been reported for the effect of DHEA on bone health as assessed by BMD because some studies revealed beneficial effects (6, 12, 14) whereas others did not (15, 16). Menopausal symptoms assessed by the Menopause-Specific Quality of Life Questionnaire (MENQOL) showed no improvement when oral DHEA was compared to placebo (10), whereas the sexual domain score of the same questionnaire showed improvement when vaginal DHEA was studied in women with vaginal atrophy in a different study (17).

In light of these conflicting results, we aimed to conduct this systematic review and meta-analysis to evaluate the effect of DHEA on postmenopausal women. This review was conducted to support The Endocrine Society guideline on androgen use in postmenopausal women.

Materials and Methods

This review was based on a predefined protocol and conformed to the standards set in the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement (18).

Eligibility criteria

Eligible studies were RCTs that enrolled women with surgical or natural menopause and normal adrenal function who were assigned to receive systemic DHEA or placebo and evaluated the outcomes of interest. Trials were included regardless of their size or duration of patient follow-up.

Outcomes of interest were: quality of life and general well-being, sexual function, psychological symptoms related to menopause, lipid profile, glucose tolerance, body measurements, and bone health.

Literature search

An expert reference librarian (L.P.) designed and conducted the electronic search strategy with input from study investigators with expertise in conducting systematic reviews (M.H.M. and T.E.). The search involved multiple databases including Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, PsycInfo, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus, from their inception through January 2014. Controlled vocabulary supplemented with keywords was used to search for DHEA therapy for postmenopausal women, limited to RCTs. We also searched the bibliographies of the included studies to identify any candidate studies that might be missed by the electronic search. Content experts from The Endocrine Society were also queried for potential references. The full search strategy is provided in the Supplemental Data.

Study selection

All relevant abstracts were downloaded into an Endnote library and uploaded to an online reference management system (DistillerSR; Evidence Partners Inc). Reviewers working independently and in duplicate screened the abstracts for eligibility. Disagreements from this level were automatically upgraded to the next level of screening. Full text of eligible abstracts were retrieved and screened in duplicate. Disagreements at this level were resolved by consensus. We calculated the inter-reviewer agreement beyond chance (kappa) during the full-text screening level (19).

Data extraction

Data were extracted in duplicates using a standardized, piloted, web-based form. For each study, we abstracted the following descriptive data: detailed description of baseline characteristics of the participants (ie, age, ethnicity, and patient's description at baseline) and study characteristics (ie, location and setting, follow-up duration, and interventions). A third reviewer compared the reviewers' entered data and resolved inconsistencies by referring to the full text of the article.

Author contact

We contacted the authors of the original studies when data required for analysis were missing or when more clarification was needed. Author contact was done by e-mail. If we did not receive any response, we sent another e-mail 2 weeks later.

Methodological quality and risk of bias assessment

Two reviewers independently assessed the quality of each RCT using the Cochrane Risk of Bias assessment tool (20). We determined the following: how the randomization sequence was generated; how allocation was concealed; whether there were important imbalances at baseline; which groups were blinded (patients, caregivers, data collectors, outcome assessors, data analysts); whether there were any baseline imbalances; whether the analysis was by intention to treat; and how the patients adhered to the assigned medication. The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methods (21).

Statistical analysis

Meta-analysis was done using random effect meta-analysis described by DerSimonian and Laird (22) to account for the heterogeneity between studies as well as within-study variability. Effect sizes were pooled using weighted difference in means (WMD) when outcomes were measured using the same scale and using the standardized mean difference (SMD) when outcomes were measured using multiple scales. Between-study inconsistency was measured by I2 statistics, which estimate the proportion of variation in results across studies that is not due to chance (19). We planned to assess publication bias using the Egger regression asymmetry test and visual inspection using funnel plots whenever we had an adequate number of studies and low heterogeneity (23). Due to multiple testing, we implemented the false discovery rate-controlled procedures proposed by Benjamini and Hochberg (24) and set the P value for significance at .015 instead of the usual .05. All analyses were conducted using STATA, version 12.1 (StataCorp LP).

Subgroup analysis

We conducted subgroup analyses, which were determined a priori, to explain between-study heterogeneity. These subgroups were based on the length of follow-up (<12 mo vs ≥12 mo) and study design (parallel vs crossover). For each subgroup analysis, we conducted a test for interaction (P < .015 was considered to be statistically significant).

Results

Search results and study description

The search identified 479 potentially relevant citations, from which 23 trials were found relevant and were eventually included in our analysis. Figure 1 describes the selection process in more detail. The trials enrolled a total of 1188 postmenopausal women who were assigned to either DHEA or placebo. The average age of participants was 53 years, and they were followed up for various periods of time, ranging from 1.5 to 24 months. Table 1 describes the characteristic of the trials and the interventions.

Figure 1. Selection process.

Figure 1.

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Table 1.

Description of Included Trials

First Author, Year (Ref.) Location, Setting Sample, n Population Age, y Ethnicity Duration, mo Interventions
Barnhart, 1999 (27) United States, academic hospital 66 Perimenopausal women with altered mood and well-being 45–55 82% CC, 15% AA, 2% AS 6 DHEA (oral, 50 mg) vs placebo
Baulieua, 2000 (6) France, NR 140 Healthy postmenopausal women 60–79 NR 12 DHEA (oral, 50 mg) vs placebo
Bloch, 2013 (28) Israel, academic hospital 25 Health postmenopausal women with HSDD 54 NR 1.5 DHEA (oral, 100 mg) vs placebo
Carranza-Lira, 2002 (29) Mexico, academic hospital 20 Healthy postmenopausal women 54 NR 1 DHEA (oral, 35 mg) vs placebo
Casson, 1995 (30) United States, academic hospital 11 Healthy postmenopausal women 56 NR 1 DHEA (oral, 50 mg) vs placebo
Dayal, 2005 (31) United States, academic hospital 50 Healthy postmenopausal women 57 NR 3 DHEA (oral, 50 mg) vs placebo
Finckh, 2005 (32) Switzerland, academic hospital 52 Postmenopausal women with fibromyalgia 59 NR 3 DHEA (oral, 50 mg) vs placebo
Gómez-Santos, 2012 (33) Spain, academic hospital 61 Healthy postmenopausal women 51.5 NR 3 DHEA (oral, 100 mg) vs placebo
Igwebuike, 2008 (34) United States, academic hospital 31 Sedentary, postmenopausal women 64 100% CC 3 DHEA (oral, 50 mg) vs placebo
Jankowski, 2006 (35) United States, academic hospital 70 Healthy postmenopausal women 68 NR 12 DHEA (oral, 50 mg) vs placebo
Kenny, 2010 (36) United States, major medical institution 99 Postmenopausal women with low DHEAS levels, low bone mass, and frailty 76.6 91% CC, 6% AA, 1% HI, 2% other 6 DHEA (oral, 50 mg) vs placebo
Kritz-Silverstein, 2008 (7) United States, clinical research facility 115 Healthy postmenopausal women 68 NR 12 DHEA (oral, 50 mg) vs placebo
Lasco, 2001 (37) Italy, academic hospital 20 Healthy adrenal-androgen-deficient postmenopausal women 57 NR 12 DHEA (oral, 25 mg) vs placebo
Morales, 1994 (8) United States, academic hospital 17 Healthy perimenopausal women 54.5 NR 6 DHEA (oral, 50 mg) vs placebo
Morales, 1998 (16) United States, academic hospital 10 Healthy nonobese, advanced age, postmenopausal women 54.5 NR 6 DHEA (oral, 100 mg) vs placebo
Mortola, 1990 (9) United States, academic hospital 6 Healthy postmenopausal women 46–61 NR 1 DHEA (oral, 1600 mg) vs placebo
Nair, 2006 (14) United States, academic hospital 57 Elderly postmenopausal women with low DHEA levels 69 NR 24 DHEA (oral, 50 mg) vs placebo
Panjari, 2009 (10, 38) Australia, academic hospital 93 Healthy postmenopausal women with low libido 54 NR 12 DHEA (oral, 50 mg) vs placebo
Srinivasan, 2010 (39) United States, academic hospital 57 Healthy postmenopausal women with low levels of DHEAS 69 NR 24 DHEA (oral, 50 mg) vs placebo
von Mühlen, 2008 (40) United States, academic hospital 115 Healthy postmenopausal women 68.5 NR 12 DHEA (oral, 50 mg) vs placebo
Weiss, 2009 (41) United States, academic hospital 58 Healthy postmenopausal women 70 96% CC, 4% AA 12 DHEA (oral, 50 mg) vs placebo
Wolf, 1997 (11) Germany, academic hospital 15 Healthy postmenopausal women 69.1 NR 1.5 DHEA (oral, 50 mg) vs placebo
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Abbreviations: NR, not reported; HSDD, hypoactive sexual desire disorder; CC, Caucasian; AA, African American; AS, Asian; HI, Hispanic. Age is expressed as mean or range.

Methodological quality

The overall risk of bias of the included trials was moderate to high (Figure 2). Although 65% of the trials implemented adequate randomization methods, 90% blinded study investigators and participants, and 60% measured the patients' adherence to treatment, less than 20% clearly described an allocation concealment technique. Analysis followed the intention-to-treat principle in less than one-third of the trials. More details about the methodological quality are described in Supplemental Table 1.

Figure 2. Risk of bias.

Figure 2.

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Meta-analysis

Table 2 provides the pooled estimates and 95% CI values for the relevant outcomes, as well as heterogeneity and statistical significance.

Table 2.

Meta-analysis Results

Outcome No. of Studies Difference in Meansb Lower Limit of 95% CI Upper Limit of 95% CI P Valuec I2, %
Sexual and psychological outcomes
    QoL/general well-beinga 7 −0.19 −0.38 0.00 .054 0
    Depressed mooda 3 −0.30 −0.67 0.06 .107 55
    Anxiety/distressa 3 −0.11 −0.40 0.18 .470 0
    Libido/sexual functiona 5 0.35 −0.02 0.73 .064 62
Lipid profile and blood glucose
    Total cholesterol, mg/dL 8 −6.76 −15.27 1.76 .120 26
    HDL, mg/dL 11 −2.36 −4.81 0.08 .058 11
    LDL, mg/dL 11 −2.11 −7.35 3.13 .430 0
    Triglyceride, mg/dL 10 −7.96 −18.35 2.42 .133 29
    Blood glucose, mg/dL 5 0.01 −0.93 0.95 .978 0
Bone health
    Total body BMD, g/cm2 1 0.00 −0.11 0.12 .973 NA
    Total spine BMD, g/cm2 4 0.01 0.002 0.027 .020 0
    Total hip BMD, g/cm2 7 0.00 −0.00 0.01 .159 13
Body composition
    Weight, kg 6 0.41 −0.41 1.23 .328 0
    BMI, kg/m2 5 −0.07 −0.71 0.57 .826 0
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Abbreviations: QoL, quality of life; LDL, low-density lipoprotein; HDL, high-density lipoprotein; NA, Not applicable (I2 is not meaningful if number of studies is less than three).

a

Results are presented as a SMD.

b

Difference in means is calculated as DHEA group minus placebo group.

c

Significance level is set at P = .015 due to multiple testing.

Sexual and psychological outcomes

DHEA was associated with no statistically significant improvement in libido and sexual function (SMD, 0.35; 95% CI, −0.02 to 0.73; I2 = 62%; n = 5 RCTs). No significant improvement was found in any of the other sexual-related outcomes that were tested, including quality of life and general well-being (SMD, −0.19; 95% CI, −0.38 to 0.00; I2 = 0%; n = 7); depressed mood (SMD, −0.30; 95% CI, −0.67 to 0.06; I2 = 55%; n = 3); and anxiety and distress (SMD, −0.11; 95% CI, −0.40 to 0.18; I2 = 0%; n = 3). Quality of evidence overall (confidence in estimates) was low, rated down due to the risk of bias, imprecision of the estimates, and significant inconsistency for the outcomes of depressed mood and libido.

Lipid profile and blood glucose

There was no significant difference between DHEA and placebo in any of the lipid profile and glucose outcomes. The quality of evidence for all these outcomes is low due to the risk of bias and imprecision.

Bone health

We could not find RCTs assessing the effect of DHEA on fracture risk. Four studies evaluated its effect on spine BMD, seven on hip, and only one on total body BMD. The pooled estimates from these studies did not show any beneficial effect of DHEA on BMD. No significant differences between the intervention and the placebo group were detected for spine BMD (WMD, 0.01 g/cm2; 95% CI, 0.00 to 0.03; I2 = 0%; n = 4), total hip BMD (WMD, 0.00 g/cm2; 95% CI, −0.00 to 0.01; I2 = 13%; n = 7), or whole-body BMD (WMD, 0.00 g/cm2; 95% CI, −0.11 to 0.12; n = 1). The quality of evidence for all these outcomes is low due to the risk of bias and imprecision.

Body composition

The two parameters we tested to assess the effect of DHEA on body composition were body weight and body mass index (BMI). The administration of DHEA was not associated with any significant change in either parameter compared to placebo. The WMD for body weight was 0.41 kg (95% CI, −0.41 to 1.23; I2 = 0%;, n = 6), whereas the WMD for BMI was −0.07 kg/m2 (95% CI, −0.71 to 0.57; I2 = 0%; n = 5). The quality of evidence for all these outcomes is low due to the risk of bias and imprecision.

Other adverse events

Most of the trials included in our review concluded that DHEA use was not associated with any significant adverse effects. The most frequently reported adverse effects were dermatological or androgenic symptoms. One study reported chest pain and palpitations in five women (four receiving DHEA and one receiving placebo). Data on adverse effects were in general sparse and heterogeneous; thus, inappropriate for meta-analysis. Data on adverse effects are summarized in Supplemental Table 3. In brief, it didn't seem that the use of DHEA was associated with any significant adverse effects.

Subgroup analysis

We tested the effect of DHEA based on the duration of follow-up and study design; no significant subgroup interactions were found for any of the subgroups. Subgroup analyses are presented in Supplemental Table 2.

Publication bias

Due to the small number of studies per each outcome, methods to detect publication bias could not be applied because these methods usually require at least 10 to 20 studies to reliably test for bias (23, 25).

Discussion

Main findings

We conducted this systematic review to assess the benefits and harm of DHEA use in postmenopausal women. We found that DHEA was associated with no significant improvement in libido and sexual function. There was no significant effect on serum lipids, glucose, or BMD (except for a small change in lumber spine BMD). Also, no difference was detected when different subgroups were evaluated.

Limitations and strengths

The strength of this systematic review relates to its systematic nature with predefined protocol-driven methods and outcomes. We carried out multiple techniques to reduce the chance of error and bias, including duplicate independent study selection, data extraction, and assessment of the risk of bias. A comprehensive search of multiple databases and collaboration with content experts from The Endocrine Society further strengthened this evidence synthesis.

The overall confidence in the results warranted by this body of evidence is low due to increased risk of bias, imprecision, and inconsistency for some key outcomes (depressed mood and libido).

Comparison with previous reviews

Our conclusions are similar to those of previous reviews. In 2010, Panjari and Davis (5) systematically reviewed the literature and provided a qualitative summary stating that the recent trials do not support a benefit of oral DHEA therapy for postmenopausal women. A more recent literature review conducted by Davis et al (26) in 2011 concluded that oral DHEA did not show any benefit with regard to impaired sexual function, well-being, and cognitive performance in postmenopausal women. They also reported that it has no favorable effects on lipids and carbohydrate metabolism. Our review updates the evidence to the present time and offers meta-analytic estimates.

Implications

Because the evidence is too imprecise, inconsistent, and open to bias, larger and longer randomized trials able to precisely measure not only intermediate outcomes but also patient-important outcomes that directly inform postmenopausal women's decisions to use or not to use DHEA will be necessary. The associated clinical practice guidelines from The Endocrine Society will provide practical recommendations regarding androgen use in postmenopausal women.

Conclusion

Evidence warranting low confidence in estimates suggests that DHEA cannot significantly improve sexual symptoms or other metabolic parameters in postmenopausal women with normal adrenal function.

Acknowledgments

This review was partially funded by a contract from The Endocrine Society.

Disclosure Summary: T.E., M.B.S., Z.W., T.K., N.A., C.U., M.N., O.A., L.P., V.M.M., and M.H.M. have nothing to declare.

Funding Statement

This review was partially funded by a contract from The Endocrine Society.

Footnotes

Abbreviations:
BMD
bone mineral density
BMI
body mass index
CI
confidence interval
DHEA
dehydroepiandrosterone
DHEAS
DHEA sulfate
RCT
randomized controlled trial
SMD
standardized mean difference
WMD
weighted difference in means.

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