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DHEA and Quality of Life in Women with Adrenal Insufficiency
Abstract & Commentary
By Dónal P. O'Mathúna, PhD. Dr. O'Mathùna is Senior Lecturer in Ethics, Decision- Making & Evidence, School of Nursing, Dublin City University, Ireland; he reports no financial relationship to this field of study.
Synopsis: In women with primary or secondary adrenal insufficiency, a meta-analysis found a small beneficial effect of DHEA supplementation on health-related quality of life and depression, but no significant effect on anxiety or sexual function. The authors concluded that there was insufficient evidence to support the routine use of DHEA in women with adrenal insufficiency.
Source: Alkatib AA, et al. A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufficiency. J Clin Endocrinol Metab 2009;94:3676-3681.
Adrenal insufficiency occurs when the adrenal glands fail to produce adequate levels of several hormones, especially cortisol and, sometimes, aldosterone. The condition can have a range of severities, with the most severe manifestation being Addison's disease. Common symptoms include fatigue, muscle weakness, loss of appetite, weight loss, and mood changes. Nausea, vomiting, and diarrhea can occur, as can low blood pressure, leading to dizziness or fainting. Because of these symptoms, adrenal insufficiency is associated with a decreased quality of life.
Conventional treatment of adrenal insufficiency involves supplementing with the glucocorticoid hormones that the adrenal glands are not producing, or substituting other hormones for them (usually synthetic). However, even when people are receiving adequate glucocorticoid replacement therapy, their quality of life may not improve. Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are also produced by the adrenal glands and their levels are low, if not absent, in adrenal insufficiency. DHEA levels are believed to be tied to indicators of quality of life. For this reason, DHEA replacement therapy has become common for women with adrenal insufficiency. However, the practice remains controversial because randomized, controlled trials of its efficacy have produced inconsistent results. The authors of this study therefore conducted a systematic review of all the available literature on this topic in women.
The authors searched a wide range of electronic databases for abstracts of randomized trials of primary or secondary adrenal insufficiency in which women were treated with at least 20 mg DHEA daily for at least 2 weeks. Eligible studies had to measure the effect of treatment on at least one psychosocial aspect of health-related quality of life (HRQOL), including physical and mental health, social functioning, and sexuality. Reports in any language or any publication type were included.
The literature search identified 341 articles, of which 10 met all inclusion criteria. Two reviewers worked independently on each stage of the review, screening the abstracts, assessing the quality of included studies, and extracting relevant data. Original authors were contacted to provide additional data or clarify aspects of the publications. Five researchers provided additional data for inclusion in the meta-analysis. The reviewers used a random-effects model for meta-analysis. The most commonly used instrument for assessing HRQOL was the 36-Item Short Form Health Survey (SF-36), used in six of the 10 included trials. A global HRQOL score was calculated for each trial and yielded an effect size of 0.21 (95% confidence interval [CI], 0.08-0.33). [An effect size of approximately 0.2 represents a small effect; 0.5, a moderate effect; and 0.8, a large effect.1 When the CI range includes 0, the value is not statistically significant.] Seven of the trials reported objective measures of depression, giving a pooled effect size of 0.23 (95% CI, 0.04-0.42). Five of the trials reported anxiety measurements, giving a pooled effect size of 0.12 (95% CI, -0.04 to 0.27). Four trials measured sexual function, with a pooled effect size of 0.33 (95% CI, -0.06 to 0.72) for libido and 0.27 (95% CI, -0.11 to 0.64) for satisfaction with sex.
Side effects were reported in six of the trials reviewed. The most common side effects were androgen-related, including greasy skin, hirsutism, acne, itchy scalp, and increased odorous sweat. The side effects were well-tolerated and, in some cases, welcome (for example, in women with dry skin and hair). No serious adverse effects were reported.
Overall, the authors concluded that the available evidence suggests a small and "perhaps clinically trivial effect" of DHEA on HRQOL and depression for women with adrenal insufficiency treated for 3-12 months. Statistically significant effects on anxiety or sexual function were not found. As a result, the reviewers concluded that while some women may experience small improvements, the evidence does not warrant the routine use of DHEA in women with adrenal insufficiency.
Adrenal insufficiency affects about 1 in 10,000 people, and its incidence appears to be on the increase.2 At the same time, because of its range of symptoms, it can be difficult to distinguish from other conditions like chronic fatigue syndrome and depression. Patients with adrenal insufficiency have low to undetectable DHEA levels, frequently leading to DHEA supplementation in an attempt to improve HRQOL. Such supplementation has become popular for people with other conditions also, suggesting that this review may have wider implications. This report claims to be the first systematic review of the effect of DHEA on HRQOL for women with adrenal insufficiency. The only other systematic review of DHEA related to quality of life found no evidence to support its effectiveness on cognitive function in middle-aged or elderly people.3
This systematic review and meta-analysis was clearly and thoroughly reported, in keeping with the general QUORUM guidelines for such reports.4 The reviewers examined the quality of all included studies, with most scoring relatively low for their risk of bias. However, two studies lost more than 20% of their participants, and in half of the studies it was not possible to determine if participant blinding had been successful. This is important because of the frequency of androgenic side effects in those receiving DHEA compared to those receiving placebo.
The review combined studies involving participants with both primary and secondary adrenal insufficiency. Primary adrenal insufficiency occurs when the reduced hormone production arises from impairments in the adrenal glands. In the majority of cases, the underlying cause of this impairment is unknown. Secondary adrenal insufficiency arises when the hormones regulating the adrenal gland are produced in insufficient quantities. This is caused by problems in the pituitary gland or hypothalamus, both located at the base of the skull. The differences between patients with different conditions might impact study results. However, the reviewers conducted subgroup analyses where the two types of conditions were examined separately. No differences were found compared to the overall review results.
The studies included six trials with a crossover design and four parallel group trials. In the latter, participants were randomly assigned to one intervention or another and the two groups were treated in parallel. In a crossover trial, all participants receive both interventions, but the order in which each person receives the intervention is randomly assigned.5 Here, each patient acts as his or her own control, reducing within-patient variation. Hence, fewer participants can be enrolled without losing precision. However, crossover trials can be limited by carryover effects, thus leading to the use of washout periods between interventions. Different approaches to including data from crossover and parallel group trials in meta-analyses have been developed.5 The reviewers followed a standard approach, although disagreement continues regarding how best to handle such data in meta-analyses.
This article provides a succinct and clear report of a well-conducted systematic review and meta-analysis. The results of individual studies of DHEA for adrenal insufficiency have shown much variation, with the review showing that overall there is little evidence of its effectiveness for improving general well-being. Although some benefits were found for quality of life and depression, these were small and of questionable clinical significance. Improvements in anxiety or sexual function were not found. Some women may have beneficial effects from DHEA, possibly even from its side effects. However, its routine use in adrenal insufficiency is not supported by the available evidence.
1. Guyatt G, et al. Users' Guide to the Medical Literature: A Manual for Evidence-based Clinical Practice. 2nd ed. New York: McGraw Hill; 2008.
2. Arlt W, Allolio B. Adrenal insufficiency. Lancet 2003;361:1881-1893.
3. Grimley Evans J, et al. Dehydroepiandrosterone (DHEA) supplementation for cognitive function in healthy elderly people. Cochrane Database Syst Rev 2006(4):CD006221.
4. Moher D, et al. Improving the quality of reports of meta-analyses of randomised controlled trials: The QUOROM statement. Lancet 1999;354:1896-1900.
5. Elbourne DR, et al. Meta-analyses involving cross- over trials: Methodological issues. Int J Epidemiol 2002;31:140-149.