CLIMACTERIC 2015;18:1–2
Invited Editorial
DHEA replacement for postmenopausal women: placebo or panacea? J. A. Eden Associate Professor of Reproductive Endocrinology, University of New South Wales; Director, Women’s Health and Research Institute of Australia; Head, Barbara Gross Research Unit, Royal Hospital for Women, Sydney, Australia
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
Key words: DEHYDROEPIANDROSTERONE, DHEA, TRIAL, MENOPAUSE, SEXUAL FUNCTION
ABSTRACT In adults, dehydroepiandrosterone (DHEA) is the most abundant steroid found in serum and its levels fall with age. It can be converted into androgens and estrogens by peripheral tissues. Thus it may be considered to be a pro-hormone. Many websites are promoting oral DHEA as an anti-aging tonic and in some countries it is sold as a supplement. Recent clinical trials of oral DHEA and reviews of those trials have failed to show any health benefits for postmenopausal women. However, there may be a role for vaginal DHEA.
Dehydroepiandrosterone (DHEA) is an adrenal hormone which has been promoted as an ‘anti-aging hormone’ by many websites on the Internet for decades. In some countries, it can be purchased as an over-the-counter supplement with claims that it improves energy, muscle strength, mood disorders such as depression, diabetes, the symptoms of Alzheimer’s disease and even heart disease (e.g. https://www.womentowomen.com/adrenal-health-2/dhea-and-adrenal-imbalance/ 2/). So what are the scientifically proven benefits for postmenopausal women? First, it is well proven that blood levels of DHEA, DHEA sulfate (DHEAS) and androgens, such as testosterone, fall with age. Over the last two decades, there have been some clinical trials performed replacing these sex hormones and hoping to improve symptoms such as general well-being, energy, and sexual desire. DHEAS is the most abundant steroid in serum; however, no receptor for DHEA has yet been found. It can be interconverted into estrogenic and androgenic metabolites in those tissues that have the appropriate enzyme systems. A search was performed with the Sirius search engine at the University of New South Wales using the keywords, ‘DHEA’ and ‘trial’, between the years 1990 and 2015. Using the keyword, ‘DHEA’ alone, 2108 papers were found but, when ‘trial’ was added, the number of papers found fell to 34. Two meta-analyses were found reviewing trials where DHEA was given orally to healthy postmenopausal women.
The most recent systematic review was by Elraiyah and colleagues1. They identified 23 randomized, controlled trials (RCTs) which enrolled a total of 1188 women. They found that oral DHEA replacement did not improve sexual desire (or any other measure of sexuality), nor did it have an effect on metabolic markers such as lipids, fasting glucose, weight or bone mineral density. They noted that some women developed androgenic side-effects (acne, unwanted hair) on active treatment. They concluded that, ‘The evidence is too imprecise, inconsistent, and open to bias,‘ and called for larger, properly constructed trials. The second review was performed by Davis and colleagues2. She points out that much of the evidence supporting benefits of DHEA supplementation in humans is based on rodent studies, ‘whose adrenals do not produce DHEA’. Also, many studies were cross-sectional in type, attempting to correlate serum levels of DHEA(S) with patient symptoms. She found eight published RCTs of oral DHEA treatment for low sexual desire in healthy postmenopausal women. The early studies were flawed by small sample size and short duration of treatment. Two examples of oral DHEA RCTs are now described. First, a RCT study of oral DHEA 50 mg daily versus placebo was performed by Kritz-Silverstein and colleagues3 who studied 110 men and 115 postmenopausal women. Six cognitive function tests (including validated sexual function scores) were measured at baseline and at 3, 6 and 12 months. There
Correspondence: Associate Professor J. Eden, Women’s Health and Research Institute of Australia, Level 12, 97–99 Bathurst St, Sydney, Australia 2000; E-mail: [email protected]
INVITED EDITORIAL © 2015 International Menopause Society DOI: 10.3109/13697137.2015.1017706
Received 05-02-2015 Accepted 06-02-2015
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
DHEA replacement for postmenopausal women was no significant difference between DHEA and placebo for mood, cognition or sexual function in the men or women. Second, Panjari and colleagues4 randomized 93 postmenopausal women, not on estrogen therapy, onto DHEA 50 mg or placebo for 52 weeks. Validated sexual function, general wellbeing and menopause scoring systems were used. No benefits of DHEA therapy were found; however, more women in the active treatment group had androgenic side-effects such as acne or hirsutism. In contrast to these data showing a lack of effect of oral DHEA, there may be a role for giving low doses of DHEA vaginally4,5. The vagina has all the enzyme systems necessary to convert DHEA into estrogens and androgens. Labrie and colleagues have shown that daily vaginal DHEA 6.5 mg estrogenizes the vagina and clinically improves menopauseinduced vaginal atrophy. Furthermore, using mass spectrometry, they showed that vaginal DHEA did not change serum estrogenic or androgenic metabolites. In other words, vaginal low-dose DHEA improves vaginal atrophy without any systemic effects. Davis points out that, for the average woman, twice-weekly vaginal estrogen is probably more convenient3. However, vaginal DHEA may prove to be a useful therapy for women who have been treated for breast cancer, where a truly local estrogenic effect in the vagina is desirable. Further studies
Eden are needed to examine the impact of breast cancer endocrine therapies such as tamoxifen and aromatase inhibitors on the efficacy of vaginal DHEA. In summary, the important recent meta-analysis by Elraiyah1 confirms the work of others such as Davis2 that oral DHEA replacement given to postmenopausal women appears to have no benefit. No effect of DHEA supplementation was found for cognition, ‘anti-aging’ or sexual function. Side-effects from the DHEA treatment included acne and unwanted hair. Despite this evidence, many women around the world are taking DHEA, often compounded and via a number of delivery systems (oral, troche, creams) for dubious reasons. Back in 1996, Skolnick, commenting in JAMA6, said that the ‘Scientific verdict (was) still out on DHEA.‘ It would seem that, nearly two decades later, the jury is in, at least for healthy postmenopausal women – DHEA supplements don’t work. However, there may be a role for the use of vaginal DHEA for some of our patients. Conflict of interest The author reports no confl ict of interest. The author alone is responsible for the content and writing of this paper. Source of funding
Nil.
References 1. Elraiyah T, Sonbol MB, Wang Z, et al. The benefits and harms of systemic DHEA in postmenopausal women with normal adrenal function: a systematic review and meta-analysis. J Clin Endocrinol Metab 2014;99:3536–42 2. Davis SR, Panjari M, Stanczyk FZ. Clinical review: DHEA replacement for postmenopausal women. J Clin Endocrinol Metab 2011;96:1642–53 3. Kritz-Silverstein D, von Muhlen D, Laughlin GA, Bettencourt R. Effects of dehydroepiandrosterone supplementation on cognitive function and quality of life: the DHEA and Well-Ness (DAWN) trial. J Am Geriatr Soc 2008;56: 1292–8
2
4. Panjari M, Bell RJ, Jane F, et al. A randomized trial of oral DHEA treatment for sexual function, well-being and menopausal symptoms in postmenopausal women with low libido. J Sex Med 2009;6:2579–90 5. Panjari M, Davis SR. Vaginal DHEA to treat menopause related atrophy: a review of the evidence. Maturitas 2011;70:22–5 6. Labrie F, Martel C, Berube R, et al. Intravaginal prasterone (DHEA) provides local action without clinically significant changes in serum concentrations of estrogens or androgens. J Steroid Biochem Mol Biol 2013;138:359–67 7. Skolnick A. Scientific verdict still out on DHEA. JAMA 1996;276:1365–7
Climacteric
Invited Editorial
DHEA replacement for postmenopausal women: placebo or panacea? J. A. Eden Associate Professor of Reproductive Endocrinology, University of New South Wales; Director, Women’s Health and Research Institute of Australia; Head, Barbara Gross Research Unit, Royal Hospital for Women, Sydney, Australia
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
Key words: DEHYDROEPIANDROSTERONE, DHEA, TRIAL, MENOPAUSE, SEXUAL FUNCTION
ABSTRACT In adults, dehydroepiandrosterone (DHEA) is the most abundant steroid found in serum and its levels fall with age. It can be converted into androgens and estrogens by peripheral tissues. Thus it may be considered to be a pro-hormone. Many websites are promoting oral DHEA as an anti-aging tonic and in some countries it is sold as a supplement. Recent clinical trials of oral DHEA and reviews of those trials have failed to show any health benefits for postmenopausal women. However, there may be a role for vaginal DHEA.
Dehydroepiandrosterone (DHEA) is an adrenal hormone which has been promoted as an ‘anti-aging hormone’ by many websites on the Internet for decades. In some countries, it can be purchased as an over-the-counter supplement with claims that it improves energy, muscle strength, mood disorders such as depression, diabetes, the symptoms of Alzheimer’s disease and even heart disease (e.g. https://www.womentowomen.com/adrenal-health-2/dhea-and-adrenal-imbalance/ 2/). So what are the scientifically proven benefits for postmenopausal women? First, it is well proven that blood levels of DHEA, DHEA sulfate (DHEAS) and androgens, such as testosterone, fall with age. Over the last two decades, there have been some clinical trials performed replacing these sex hormones and hoping to improve symptoms such as general well-being, energy, and sexual desire. DHEAS is the most abundant steroid in serum; however, no receptor for DHEA has yet been found. It can be interconverted into estrogenic and androgenic metabolites in those tissues that have the appropriate enzyme systems. A search was performed with the Sirius search engine at the University of New South Wales using the keywords, ‘DHEA’ and ‘trial’, between the years 1990 and 2015. Using the keyword, ‘DHEA’ alone, 2108 papers were found but, when ‘trial’ was added, the number of papers found fell to 34. Two meta-analyses were found reviewing trials where DHEA was given orally to healthy postmenopausal women.
The most recent systematic review was by Elraiyah and colleagues1. They identified 23 randomized, controlled trials (RCTs) which enrolled a total of 1188 women. They found that oral DHEA replacement did not improve sexual desire (or any other measure of sexuality), nor did it have an effect on metabolic markers such as lipids, fasting glucose, weight or bone mineral density. They noted that some women developed androgenic side-effects (acne, unwanted hair) on active treatment. They concluded that, ‘The evidence is too imprecise, inconsistent, and open to bias,‘ and called for larger, properly constructed trials. The second review was performed by Davis and colleagues2. She points out that much of the evidence supporting benefits of DHEA supplementation in humans is based on rodent studies, ‘whose adrenals do not produce DHEA’. Also, many studies were cross-sectional in type, attempting to correlate serum levels of DHEA(S) with patient symptoms. She found eight published RCTs of oral DHEA treatment for low sexual desire in healthy postmenopausal women. The early studies were flawed by small sample size and short duration of treatment. Two examples of oral DHEA RCTs are now described. First, a RCT study of oral DHEA 50 mg daily versus placebo was performed by Kritz-Silverstein and colleagues3 who studied 110 men and 115 postmenopausal women. Six cognitive function tests (including validated sexual function scores) were measured at baseline and at 3, 6 and 12 months. There
Correspondence: Associate Professor J. Eden, Women’s Health and Research Institute of Australia, Level 12, 97–99 Bathurst St, Sydney, Australia 2000; E-mail: [email protected]
INVITED EDITORIAL © 2015 International Menopause Society DOI: 10.3109/13697137.2015.1017706
Received 05-02-2015 Accepted 06-02-2015
Climacteric Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
DHEA replacement for postmenopausal women was no significant difference between DHEA and placebo for mood, cognition or sexual function in the men or women. Second, Panjari and colleagues4 randomized 93 postmenopausal women, not on estrogen therapy, onto DHEA 50 mg or placebo for 52 weeks. Validated sexual function, general wellbeing and menopause scoring systems were used. No benefits of DHEA therapy were found; however, more women in the active treatment group had androgenic side-effects such as acne or hirsutism. In contrast to these data showing a lack of effect of oral DHEA, there may be a role for giving low doses of DHEA vaginally4,5. The vagina has all the enzyme systems necessary to convert DHEA into estrogens and androgens. Labrie and colleagues have shown that daily vaginal DHEA 6.5 mg estrogenizes the vagina and clinically improves menopauseinduced vaginal atrophy. Furthermore, using mass spectrometry, they showed that vaginal DHEA did not change serum estrogenic or androgenic metabolites. In other words, vaginal low-dose DHEA improves vaginal atrophy without any systemic effects. Davis points out that, for the average woman, twice-weekly vaginal estrogen is probably more convenient3. However, vaginal DHEA may prove to be a useful therapy for women who have been treated for breast cancer, where a truly local estrogenic effect in the vagina is desirable. Further studies
Eden are needed to examine the impact of breast cancer endocrine therapies such as tamoxifen and aromatase inhibitors on the efficacy of vaginal DHEA. In summary, the important recent meta-analysis by Elraiyah1 confirms the work of others such as Davis2 that oral DHEA replacement given to postmenopausal women appears to have no benefit. No effect of DHEA supplementation was found for cognition, ‘anti-aging’ or sexual function. Side-effects from the DHEA treatment included acne and unwanted hair. Despite this evidence, many women around the world are taking DHEA, often compounded and via a number of delivery systems (oral, troche, creams) for dubious reasons. Back in 1996, Skolnick, commenting in JAMA6, said that the ‘Scientific verdict (was) still out on DHEA.‘ It would seem that, nearly two decades later, the jury is in, at least for healthy postmenopausal women – DHEA supplements don’t work. However, there may be a role for the use of vaginal DHEA for some of our patients. Conflict of interest The author reports no confl ict of interest. The author alone is responsible for the content and writing of this paper. Source of funding
Nil.
References 1. Elraiyah T, Sonbol MB, Wang Z, et al. The benefits and harms of systemic DHEA in postmenopausal women with normal adrenal function: a systematic review and meta-analysis. J Clin Endocrinol Metab 2014;99:3536–42 2. Davis SR, Panjari M, Stanczyk FZ. Clinical review: DHEA replacement for postmenopausal women. J Clin Endocrinol Metab 2011;96:1642–53 3. Kritz-Silverstein D, von Muhlen D, Laughlin GA, Bettencourt R. Effects of dehydroepiandrosterone supplementation on cognitive function and quality of life: the DHEA and Well-Ness (DAWN) trial. J Am Geriatr Soc 2008;56: 1292–8
2
4. Panjari M, Bell RJ, Jane F, et al. A randomized trial of oral DHEA treatment for sexual function, well-being and menopausal symptoms in postmenopausal women with low libido. J Sex Med 2009;6:2579–90 5. Panjari M, Davis SR. Vaginal DHEA to treat menopause related atrophy: a review of the evidence. Maturitas 2011;70:22–5 6. Labrie F, Martel C, Berube R, et al. Intravaginal prasterone (DHEA) provides local action without clinically significant changes in serum concentrations of estrogens or androgens. J Steroid Biochem Mol Biol 2013;138:359–67 7. Skolnick A. Scientific verdict still out on DHEA. JAMA 1996;276:1365–7
Climacteric
