DHEA supplementation – Specific Health Benefits for Menopausal Women

In a previous article “DHEA – why it is especially important for menopausal women” I explained why DHEA is especially important for women than men, and even more so for peri- and postmenopausal women. In this article, I will cover specific health benefits of DHEA supplementation for menopausal women.

There are indications that women with lower DHEA levels are at higher risk for cardiovascular disease and mortality.[1, 2] In postmenopausal women, lower DHEA(S) levels are linked to higher cardiovascular mortality and all-cause mortality [3] and lower DHEA(S) levels are also associated with a 41% greater risk of stroke, regardless of other risk factors.[4] These observations are supported by experiments showing that treatment with DHEA reduces experimental atherosclerosis [5-7], improves blood vessel (endothelial) function [8-11], and has anti-inflammatory [12-15] and anti-oxidative effects.[8, 12, 16, 17] Notably, some of the anti-atherosclerotic effects of DHEA are mediated by DHEA on its own, and not via its conversion to estrogen.[18]
Because DHEA is the major source of estrogen and testosterone in post-menopausal women, this begs the question if not all post-menopausal women should supplement with DHEA? Several studies show that DHEA supplementation confers significant health benefits beyond mere relief of menopausal symptoms. Notable are its beneficial effects on the bone, vagina, skin and prevention of breast cancer.

 

Breast cancer

Breast cancer is the most-frequently diagnosed cancer and the second-commonest cause of death from cancer in women [19]. Not surprisingly, breast cancer ranks as women’s greatest personal health fear.[20] As women now spend half of their adult lifetime postmenopausal, a safe alternative to traditional (non-bioidentical) hormone replacement therapy (HRT) is required that doesn’t increased risk of breast cancer, as was seen in the Women’s Health Initiative (WHI) [21] and the Million Women Study.[22, 23]
The anti-carcinogenic effect of DHEA in breast cancer can be logically explained by the predominant formation of androgens over estrogens from DHEA in breast tissue, thus providing a higher influence of androgens which are well-known inhibitors of mammary gland proliferation.[24] In fact, DHEA is part of a group of promising chemoprotective agents identified by the US National Cancer Institute (NCI) Division of Cancer Prevention and Control for studies on chemoprevention (i.e. cancer prevention) trials.[25]
Low DHEA levels have been reported to predispose to certain cancers [26], including an increased risk of breast cancer.[27] Low blood levels of DHEA(S) have been found in patients with breast cancer [27, 28] and experimental studies show that DHEA inhibits breast cancer development via several mechanisms.[29-33] The conversion of DHEA to testosterone likely contributes to this breast cancer protection, as it is well documented that testosterone prevents development and progression of many types of breast cancers.[24, 34-42] It should be noted that DHEA administered to postmenopausal women is mainly transformed to androgens rather than estrogens.[43, 44] In this way, DHEA supplementation helps maintain the estrogen-testosterone balance, illustrated in figure 2, which is important for breast cancer prevention.[45]
Figure 2: Illustration of the balance between the stimulatory action of estrogens and the inhibitory effect of androgens on mammary gland and breast cancer proliferation.
From Labrie: DHEA and Cancer Risk or Prevention? In “DHEA in Human Health and Aging”, editor Ronald Ross Watson, 2011
In addition to its conversion into testosterone, DHEA may protect against breast cancer via other mechanisms as well. For example. experimental studies strongly indicate that DHEA inhibit inflammation, carcinogenesis, and atherosclerosis, at least in part, through the inhibition of G6PDH (glucose-6-phosphate dehydrogenase) and free radical formation.[46] G6PDH activity provides energy for cell proliferation (multiplication) [47] and therefore cancer cells activate G6PD to meet their energetic demands as they as multiplying.[48] DHEA also seems to prevent cancer growth by altering gene expression in cancer cells.[49]

Vagina

Vaginal dryness is common consequence of menopause, and affects 50-82% of postmenopausal women.[50, 51] It is commonly associated with sexual dysfunction as it may cause painful intercourse (aka dyspareunia).[52, 53]
Most cases of symptomatic vaginal atrophy require treatment; estrogen therapy is typically considered the therapeutic standard for moderate to severe vaginal atrophy.[54] However, only about 25% of symptomatic women seek medical help [54] for a variety of reasons, most commonly the fear of estrogen-related side effects.[55, 56] There is thus a clear medical need for alternative treatment options for this condition, which negatively impacts women’s wellbeing and sexual function.
Several studies show that intravaginal DHEA (Prasterone) effectively and safely alleviates vaginal atrophy.[57, 58] DHEA supplementation using a 10% DHEA cream in postmenopausal women for 12 months also improves vaginal parameters.[59]
Intravaginal DHEA, via local estrogen and testosterone formation, causes a rapid and efficient reversal of all the symptoms and signs of vaginal atrophy with no or minimal changes in blood levels of estrogen and testosterone, which remain well within the normal postmenopausal range.[57] This is especially beneficial for women with a family history of breast cancer who have a genetic predisposition to develop breast carcinoma, and don’t want to take traditional estrogen HRT.
It is well-recognized that estrogen has a great stimulatory effect on endometrial proliferation and increases risk of endometrial cancer.[23] Therefore, it is especially notable that the estrogenic effect of DHEA on the vagina is not observed in the endometrium, which remains atrophic in all women undergoing DHEA treatment for vaginal atrophy.[57-59] This is the case even when supplementing with DHEA cream or oral DHEA capsules, which raise blood DHEA(S) levels 10-fold.[59-61] DHEA’s stimulatory effect on the vagina in the absence of stimulation of the endometrium is of particular interest because it eliminates the need for progestin/progesterone (which is used to counteract estrogen induced over-stimulation of the endometrium and to prevent endometrial cancer).[23]
How can DHEA stimulate the vagina and treat vaginal atrophy without affecting the endometrium? The absence of effect of DHEA on the endometrium can be explained by the absence in the human endometrium of the enzymes, especially aromatase, needed to convert DHEA into estrogens.[62, 63]
In addition to the beneficial effects of intravaginal DHEA on the symptoms and signs of vaginal atrophy, it improves several domains of sexual dysfunction was observed.[64] One study found that after 12 weeks of treatment, compared to placebo, there were 49% and 23% improvements of the desire domains in the Menopause-Specific Quality of Life (MENQOL) and Abbreviated Sex Function (ASF) questionnaires, respectively. The ASF arousal/sensation domain was improved by 68%, the arousal/lubrication domain by 39%, orgasm by 75%, and dryness during intercourse by 57%.[64]

Bone

Loss of bone mineral density and osteoporosis is one of the most serious adverse effects of menopause.[65] Therefore, several well-conducted studies (aka RCTs, randomized controlled trials, the golden standard in medical research) evaluated the effects of DHEA replacement on bone mineral density in post-menopausal women.[66-69] The primary outcome in all these studies was bone mineral density, and the supplementation regimen was oral DHEA 50 mg per day versus placebo, for a treatment duration of 1–2 years. In all these studies, blood levels of DHEA(S) in the DHEA supplemented groups increased to young adult levels and was maintained for the duration of the.[66-69] The general conclusion from these studies is that DHEA replacement of 50 mg/day for 1–2 years significantly increases bone mineral density (especially in the lumbar spine), and the DHEA treatment with 50 mg/day is well-tolerated and safe.[66-69]
The 2 year-long study showed that larger increases in bone mineral density can be achieved with longer duration of DHEA supplementation.[69] Women who stayed on DHEA supplementation for a second year had a further 2% increase in lumbar spine bone mineral density and a 2-year increase in bone mineral density of nearly 4%. It is interesting that this increase in bone mineral density is of the same magnitude as that achieved with bisphosphonates.[70]
When comparing DHEA effects in men vs. women, more consistent and greater increases in bone mineral density were found in post-menopausal women. After 2 years of supplementing with 50 mg DHEA per day, in women bone mineral density increases by 4%, while in men on the same DHEA dose and duration, the increase is only 1.6% over their respective pre-treatment baselines.[70] It is possible that DHEA treatment longer than 2 years confers additional bone mineral accrual, and that starting DHEA therapy at a younger age can prevent or attenuate the age-related decline in bone mineral density. The greater benefit in women as opposed to men may be due to the fact that women lose more bone mass after middle-age than men, as illustrated in figure 2, and therefore will respond better to anabolic interventios.
Figure 2: Comparison of aging-related bone mineral loss in men vs. women.
Since estrogen prevents bone loss and thus protects against osteoporosis, this is a common indication for estrogen therapy in post-menopausal women. It is undeniable that estrogen HRT reduces fractures in women, even in those who do not have established osteoporosis or are not at a particularly high risk for fracture.[71]
DHEA supplementation provides a unique benefit in this regard. In contrast to estrogen, which protects against osteoporosis only by inhibiting bone loss, DHEA in addition to inhibiting bone loss also stimulates bone formation.[59] Thus DHEA may help in both prevention and treatment of osteoporosis. This effect may be partly mediated via conversion of DHEA to estrogen and testosterone. While estrogen is known as the “bone preserving” hormone, testosterone is also important for maintenance of strong bones.[72, 73] Notably, there are androgen receptors on bonce cells to which testosterone binds, and addition of testosterone to estrogen therapy enhances estradiol’s effects on postmenopausal bone density [74] by stimulating of bone formation.[75]
Further support for the importance of testosterone in maintenance and formation of bone mass comes from a study showing that the non-aromatizable androgen DHT (dihydrotstosterone), which cannot be converted to estrogen, can protect the female skeleton against the adverse effects of estrogen deficiency.[76] Human bone cells obtained from men and women have similar concentrations of androgen receptors and estrogen receptors, indicating that both testosterone (androgens) and estrogen have an important role in bone mass maintenance.[73]
 [85].
Another mechanism by which DHEA increases bone mineral density is by increasing blood levels of IGF-1 (insulin-like growth factor-1) [69, 77-81], which provides an anabolic stimulus to the bone.[82, 83] Supplementing with 50 mg DHEA/day for 12 months can increase IGF-1 levels up to 20%.[68] As DHEA supplementation does not increase levels of IGF binding protein-3 [68, 69, 81], this translates to a greater bioavailability of IGF-1 in post-menopausal women following DHEA replacement. This is an important effect because free IGF-1, estimated by an increase in the IGF-1/IGFBP-3 ratio, is related with an increase in bone formation marker and decrease in bone resorption.[84] It is unclear whether DHEA exerts direct actions on the growth hormone (GH) / IGF-1 axis or modulates IGF-1 release from the liver. Most likely, increases in both IGF-1, testosterone and estrogen together mediate the beneficial effects of DHEA supplementation on the bone.[82, 85]

Cortisol balance

Aging and menopause are associated with increased cortisol levels.[86, 87] For more info, see “Menopause HRT basics”. Studies of women experiencing hot flashes in laboratory situations indicate that a cortisol spike follows hot flashes.[88] In line with this, it has been shown that climacteric symptoms are associated with increased 24-hour urinary cortisol level and risk factors for cardiovascular disease, such as insulin resistance and decreased HDL-cholesterol level.[89]
In addition, an increased ratio of cortisol/DHEA(S) (which occurs with aging) is associated with the metabolic syndrome and cancer/all-cause mortality [90, 91], and development of cognitive impairment.[92, 93] As cortisol promotes development and progression of atherosclerosis [89, 94, 95], the elevated cardiovascular risk in post-menopausal women may be due not only to withdrawal from estrogen, but also due to elevation of cortisol. In the same way, menopausal elevation of cortisol may contribute to the increased accumulation of abdominal body fat that occurs in many women after menopause.[96-100]
As DHEA supplementation reduces cortisol levels [61, 101-104] and lowers the cortisol/DHEA ratio, both of which typically increases with age [105, 106], this may be an avenue of additional health benefits for many post-menopausal women. DHEA also inhibits the activity of an enzyme in fat cells called 11beta-HSD1, which increases intracellular cortisol levels [107-109]. Thereby DHEA counteracts cortisol’s fat storing effect [110, 111]. The inhibitory effect of DHEA on 11beta-HSD1 could be a contributing mechanism to the reduction in total body fat mass [112] and abdominal fat that has been seen with DHEA supplementation.[113]

Skin and Wrinkles

Thinning and wrinkling of the skin [114] and loss of skin elasticity and firmness [115] are believed to be caused by decreased collagen synthesis and increased collagen degradation.[116] With increasing age, a decrease in collagen biosynthesis is observed, concomitant with increased collagen degradation.[116] One study found that skin collagen content decreases 2% per postmenopausal year [117], while another study found a decrease in skin collagen by as much as 30% 5 years after menopause.[118] Notably, there are significant correlations between loss of skin collagen content, skin thickness and bone mineral content in postmenopausal women, which indicates that a similar pathology causes bone mass loss and skin aging.[119] In line with this, it is well documented that hormone replacement therapy prevents both osteoporosis [120-122] and skin aging in women after menopause.[123] This also suggest that postmenopausal women with excessive wrinkles and saggy skin may have weak bones and be at increased risk for osteoporosis.

One study found that both skin collagen content and thickness is significantly greater in postmenopausal women treated with estrogen implants, compared with untreated postmenopausal women.[123] In the untreated women, skin collagen content declined in relation to menopausal age but not to chronological age.[123] In line with this, another study found a steep increase in skin extensibility (slackness) during the peri-menopause in untreated women, and that HRT counteracted the menopause related increase in skin extensibility, thereby preventing skin slackness.[124] It was concluded that HRT has a beneficial effect on mechanical properties of skin and thus may slow the progress of biological skin aging.[124]
Testosterone treatment has also been proposed to be an effective way to prevent and reverse skin aging.[125] One study investigated the effect of subcutaneous estradiol plus testosterone implants on the proportion of collagen in the skin of postmenopausal women.[126] Postmenopausal women who had been taking estradiol plus testosterone for 3-14 years had significantly higher collagen content in the skin than in the untreated postmenopausal women.[126] When the untreated postmenopausal women started treatment with the estradiol plus testosterone implants, a significant increase in skin collagen was recorded after 6 months.[126]
Thus, both estrogen and testosterone is important for maintaining youthful skin and preventing skin aging in women.[127, 128] In this regard, DHEA is especially important for menopausal women because the skin contains enzymes that convert DHEA from the blood into estrogen and testosterone, which acts locally inside skin cells.[128-131] Thus, an adequate supply of DHEA to the skin, which can be achieved by keeping blood levels of DHEA(S) in the mid-high reference range by supplementation, will help women prevent skin aging that accelerates after menopause.
Several studies show that DHEA supplementation has beneficial effects on the skin of postmenopausal women. For example, supplementation with DHEA 50 mg/day for 12 months has been shown to significantly increase skin hydration and decrease facial skin pigmentation (yellowness).[132] Another study found that DHEA cream applied daily for 12 months increased skin sebum secretion by 66–79%.[59] Sebum is the oily skin moisturizer produced by skin (sebaceous) glands which lubricate the skin and prevents wrinkling and skin cracking. In addition, DHEA stimulates collagen synthesis and inhibits collagen degradation.[133-135]
It is well recognized that the skin starts to markedly deteriorate after menopause, and that this is mainly caused to a loss of skin collagen content. The skin effects of DHEA supplementation are especially welcomed among women, who are more prone to get wrinkles than men.[136] The reason women are more vulnerable to wrinkles is because they have thinner skin, and because of their thinner skin, as women lose collagen with ageing, they are more likely to develop lines and wrinkles.
DHEA helps counteracting the effects of aging by acting simultaneously on two major skin compartments; namely, the dermis, by stimulating collagen synthesis and deposition, and the epidermis, by modulating keratinocyte proliferation and differentiation.[137] Research suggest that DHEA could exert anti-aging effects in the skin, thanks to DHEA-induced changes in the structural organization of the dermis.[137] Some of the effects observed are reminiscent of wound healing, thus suggesting that DHEA treatment could potentially lead to apparent skin rejuvenation.[137]

Summary

DHEA supplementation is a natural way to restore  physiological levels of estrogen and testosterone in women, and it confers multiple health benefits, beyond relief of menopausal symptoms. Notable are the beneficial effects of DHEA supplementation on the bone, vagina, skin and prevention of breast cancer:
* DHEA, by being preferentially converted to testosterone over estrogen, helps counterbalance the stimulatory effects of estrogen on breast tissue, and thereby reduce breast cancer risk.
* DHEA stimulates the vagina and treats vaginal atrophy without affecting the endometrium. The absence of effect of DHEA on the endometrium can be explained by the absence in the human endometrium of the enzymes, especially aromatase, needed to convert DHEA into estrogens.
* DHEA prevents loss of bone mineral density (via conversion to estrogen) and may possibly even restore previous losses (via conversion to testosterone). It also provides an anabolic stimulus to the bone by elevating IGF-1 levels.
* Women are more prone to develop wrinkles than men, especially after menopause. This is mainly due to loss of skin collagen content. Therefore, stimulation of collagen synthesis and inhibition of collagen degradation by DHEA supplementation provides an anti-aging effect on the skin. Some studies even indicate that DHEA may lead to apparent skin rejuvenation.
References:

1.            Labrie, F., DHEA, important source of sex steroids in men and even more in women. Prog Brain Res, 2010. 182: p. 97-148.

2.            Savineau, J.P., R. Marthan, and E. Dumas de la Roque, Role of DHEA in cardiovascular diseases.Biochem Pharmacol, 2013. 85(6): p. 718-26.

3.            Shufelt, C., et al., DHEA-S levels and cardiovascular disease mortality in postmenopausal women: results from the National Institutes of Health–National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women’s Ischemia Syndrome Evaluation (WISE). J Clin Endocrinol Metab, 2010. 95(11): p. 4985-92.

4.            Jimenez, M.C., et al., Low dehydroepiandrosterone sulfate is associated with increased risk of ischemic stroke among women. Stroke, 2013. 44(7): p. 1784-9.

5.            Gordon, G.B., D.E. Bush, and H.F. Weisman, Reduction of atherosclerosis by administration of dehydroepiandrosterone. A study in the hypercholesterolemic New Zealand white rabbit with aortic intimal injury. J Clin Invest, 1988. 82(2): p. 712-20.

6.            Arad, Y., et al., Dehydroepiandrosterone feeding prevents aortic fatty streak formation and cholesterol accumulation in cholesterol-fed rabbit. Arteriosclerosis, 1989. 9(2): p. 159-66.

7.            Eich, D.M., et al., Inhibition of accelerated coronary atherosclerosis with dehydroepiandrosterone in the heterotopic rabbit model of cardiac transplantation. Circulation, 1993. 87(1): p. 261-9.

8.            Yorek, M.A., et al., Effect of treatment of diabetic rats with dehydroepiandrosterone on vascular and neural function. Am J Physiol Endocrinol Metab, 2002. 283(5): p. E1067-75.

9.            Liu, D. and J.S. Dillon, Dehydroepiandrosterone activates endothelial cell nitric-oxide synthase by a specific plasma membrane receptor coupled to Galpha(i2,3). J Biol Chem, 2002. 277(24): p. 21379-88.

10.          Liu, D. and J.S. Dillon, Dehydroepiandrosterone stimulates nitric oxide release in vascular endothelial cells: evidence for a cell surface receptor. Steroids, 2004. 69(4): p. 279-89.

11.          Simoncini, T., et al., Dehydroepiandrosterone modulates endothelial nitric oxide synthesis via direct genomic and nongenomic mechanisms. Endocrinology, 2003. 144(8): p. 3449-55.

12.          Altman, R., et al., Inhibition of vascular inflammation by dehydroepiandrosterone sulfate in human aortic endothelial cells: roles of PPARalpha and NF-kappaB. Vascul Pharmacol, 2008. 48(2-3): p. 76-84.

13.          Dillon, J.S., Dehydroepiandrosterone, dehydroepiandrosterone sulfate and related steroids: their role in inflammatory, allergic and immunological disorders. Curr Drug Targets Inflamm Allergy, 2005. 4(3): p. 377-85.

14.          Chen, C.C. and C.R. Parker, Jr., Adrenal androgens and the immune system. Semin Reprod Med, 2004. 22(4): p. 369-77.

15.          Gutierrez, G., et al., Dehydroepiandrosterone inhibits the TNF-alpha-induced inflammatory response in human umbilical vein endothelial cells. Atherosclerosis, 2007. 190(1): p. 90-9.

16.          Khalil, A., et al., Dehydroepiandrosterone protects low density lipoproteins against peroxidation by free radicals produced by gamma-radiolysis of ethanol-water mixtures. Atherosclerosis, 1998. 136(1): p. 99-107.

17.          Khalil, A., et al., Age-related decrease of dehydroepiandrosterone concentrations in low density lipoproteins and its role in the susceptibility of low density lipoproteins to lipid peroxidation. J Lipid Res, 2000. 41(10): p. 1552-61.

18.          Cheng, H.H., X.J. Hu, and Q.R. Ruan, Dehydroepiandrosterone anti-atherogenesis effect is not via its conversion to estrogen. Acta Pharmacol Sin, 2009. 30(1): p. 42-53.

19.          Jemal, A., et al., Cancer statistics, 2007. CA Cancer J Clin, 2007. 57(1): p. 43-66.

20.          Walsh-Childers, K., H. Edwards, and S. Grobmyer, Covering women’s greatest health fear: breast cancer information in consumer magazines. Health Commun, 2011. 26(3): p. 209-20.

21.          Rossouw, J.E., et al., Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA, 2002. 288(3): p. 321-33.

22.          Beral, V., Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet, 2003. 362(9382): p. 419-27.

23.          Beral, V., et al., Endometrial cancer and hormone-replacement therapy in the Million Women Study.Lancet, 2005. 365(9470): p. 1543-51.

24.          Labrie, F., et al., Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone. Endocr Rev, 2003. 24(2): p. 152-82.

25.          Kelloff, G.J., et al., New agents for cancer chemoprevention. J Cell Biochem Suppl, 1996. 26: p. 1-28.

26.          Regelson, W. and M. Kalimi, Dehydroepiandrosterone (DHEA)–the multifunctional steroid. II. Effects on the CNS, cell proliferation, metabolic and vascular, clinical and other effects. Mechanism of action? Ann N Y Acad Sci, 1994. 719: p. 564-75.

27.          Zumoff, B., et al., Abnormal 24-hr mean plasma concentrations of dehydroisoandrosterone and dehydroisoandrosterone sulfate in women with primary operable breast cancer. Cancer Res, 1981. 41(9 Pt 1): p. 3360-3.

28.          Thomas, B.S., et al., Plasma dehydroepiandrosterone concentration in normal women and in patients with benign and malignant breast disease. Eur J Cancer, 1976. 12(5): p. 405-9.

29.          Li, S., et al., Prevention by dehydroepiandrosterone of the development of mammary carcinoma induced by 7,12-dimethylbenz(a)anthracene (DMBA) in the rat. Breast Cancer Res Treat, 1994. 29(2): p. 203-17.

30.          Gordon, G.B., L.M. Shantz, and P. Talalay, Modulation of growth, differentiation and carcinogenesis by dehydroepiandrosterone. Adv Enzyme Regul, 1987. 26: p. 355-82.

31.          Schwartz, A.G., L. Pashko, and J.M. Whitcomb, Inhibition of tumor development by dehydroepiandrosterone and related steroids. Toxicol Pathol, 1986. 14(3): p. 357-62.

32.          Shilkaitis, A., et al., Dehydroepiandrosterone inhibits the progression phase of mammary carcinogenesis by inducing cellular senescence via a p16-dependent but p53-independent mechanism.Breast Cancer Res, 2005. 7(6): p. R1132-40.

33.          Hakkak, R., et al., Dehydroepiandrosterone intake protects against 7,12-dimethylbenz(a)anthracene-induced mammary tumor development in the obese Zucker rat model. Oncol Rep, 2010. 24(2): p. 357-62.

34.          Dimitrakakis, C. and C. Bondy, Androgens and the breast. Breast Cancer Res, 2009. 11(5): p. 212.

35.          Dimitrakakis, C., et al., A physiologic role for testosterone in limiting estrogenic stimulation of the breast. Menopause, 2003. 10(4): p. 292-8.

36.          Hofling, M., et al., Testosterone inhibits estrogen/progestogen-induced breast cell proliferation in postmenopausal women. Menopause, 2007. 14(2): p. 183-90.

37.          Zhou, J., et al., Testosterone inhibits estrogen-induced mammary epithelial proliferation and suppresses estrogen receptor expression. FASEB J, 2000. 14(12): p. 1725-30.

38.          Glaser, R.L. and C. Dimitrakakis, Reduced breast cancer incidence in women treated with subcutaneous testosterone, or testosterone with anastrozole: a prospective, observational study. Maturitas, 2013. 76(4): p. 342-9.

39.          Davis, S.R., et al., The effect of transdermal testosterone on mammographic density in postmenopausal women not receiving systemic estrogen therapy. J Clin Endocrinol Metab, 2009. 94(12): p. 4907-13.

40.          Davis, S.R., et al., The incidence of invasive breast cancer among women prescribed testosterone for low libido. J Sex Med, 2009. 6(7): p. 1850-6.

41.          Schwartz, A.G., Inhibition of spontaneous breast cancer formation in female C3H(Avy/a) mice by long-term treatment with dehydroepiandrosterone. Cancer Res, 1979. 39(3): p. 1129-32.

42.          Glaser, R.L. and C. Dimitrakakis, Rapid response of breast cancer to neoadjuvant intramammary testosterone-anastrozole therapy: neoadjuvant hormone therapy in breast cancer. Menopause, 2014. 21(6): p. 673-8.

43.          Labrie, F., et al., Metabolism of DHEA in postmenopausal women following percutaneous administration. J Steroid Biochem Mol Biol, 2007. 103(2): p. 178-88.

44.          Stanczyk, F.Z., et al., Pharmacokinetics of dehydroepiandrosterone and its metabolites after long-term oral dehydroepiandrosterone treatment in postmenopausal women. Menopause, 2009. 16(2): p. 272-8.

45.          Labrie, F., DHEA and Cancer Risk or Prevention?, in DHEA in Human Health and Aging, R.R. Watson, Editor. 2011, CRC Press. p. 159-179.

46.          Schwartz, A.G. and L.L. Pashko, Dehydroepiandrosterone, glucose-6-phosphate dehydrogenase, and longevity. Ageing Res Rev, 2004. 3(2): p. 171-87.

47.          Tian, W.N., et al., Importance of glucose-6-phosphate dehydrogenase activity for cell growth. J Biol Chem, 1998. 273(17): p. 10609-17.

48.          Jiang, P., W. Du, and M. Wu, Regulation of the pentose phosphate pathway in cancer. Protein Cell, 2014.

49.          Ho, H.Y., et al., Dehydroepiandrosterone induces growth arrest of hepatoma cells via alteration of mitochondrial gene expression and function. Int J Oncol, 2008. 33(5): p. 969-77.

50.          Mac Bride, M.B., D.J. Rhodes, and L.T. Shuster, Vulvovaginal atrophy. Mayo Clin Proc, 2010. 85(1): p. 87-94.

51.          Santoro, N. and J. Komi, Prevalence and impact of vaginal symptoms among postmenopausal women. J Sex Med, 2009. 6(8): p. 2133-42.

52.          Levine, K.B., R.E. Williams, and K.E. Hartmann, Vulvovaginal atrophy is strongly associated with female sexual dysfunction among sexually active postmenopausal women. Menopause, 2008. 15(4 Pt 1): p. 661-6.

53.          Tan, O., K. Bradshaw, and B.R. Carr, Management of vulvovaginal atrophy-related sexual dysfunction in postmenopausal women: an up-to-date review. Menopause, 2012. 19(1): p. 109-17.

54.          North American Menopause, S., The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position statement of The North American Menopause Society.Menopause, 2007. 14(3 Pt 1): p. 355-69; quiz 370-1.

55.          Barbaglia, G., et al., Trends in hormone therapy use before and after publication of the Women’s Health Initiative trial: 10 years of follow-up. Menopause, 2009. 16(5): p. 1061-4.

56.          Chism, L.A., Overcoming resistance and barriers to the use of local estrogen therapy for the treatment of vaginal atrophy. Int J Womens Health, 2012. 4: p. 551-7.

57.          Labrie, F., et al., Intravaginal dehydroepiandrosterone (Prasterone), a physiological and highly efficient treatment of vaginal atrophy. Menopause, 2009. 16(5): p. 907-22.

58.          Labrie, F., et al., Effect of intravaginal DHEA on serum DHEA and eleven of its metabolites in postmenopausal women. J Steroid Biochem Mol Biol, 2008. 111(3-5): p. 178-94.

59.          Labrie, F., et al., Effect of 12-month dehydroepiandrosterone replacement therapy on bone, vagina, and endometrium in postmenopausal women. J Clin Endocrinol Metab, 1997. 82(10): p. 3498-505.

60.          Panjari, M., et al., The safety of 52 weeks of oral DHEA therapy for postmenopausal women.Maturitas, 2009. 63(3): p. 240-5.

61.          Stomati, M., et al., Six-month oral dehydroepiandrosterone supplementation in early and late postmenopause. Gynecol Endocrinol, 2000. 14(5): p. 342-63.

62.          Bulun, S.E., et al., Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev, 2005. 57(3): p. 359-83.

63.          Baxendale, P.M., M.J. Reed, and V.H. James, Inability of human endometrium or myometrium to aromatize androstenedione. J Steroid Biochem, 1981. 14(3): p. 305-6.

64.          Labrie, F., et al., Effect of intravaginal dehydroepiandrosterone (Prasterone) on libido and sexual dysfunction in postmenopausal women. Menopause, 2009. 16(5): p. 923-31.

65.          Khosla, S., Pathogenesis of Osteoporosis. Transl Endocrinol Metab, 2010. 1(1): p. 55-86.

66.          Jankowski, C.M., et al., Effects of dehydroepiandrosterone replacement therapy on bone mineral density in older adults: a randomized, controlled trial. J Clin Endocrinol Metab, 2006. 91(8): p. 2986-93.

67.          Nair, K.S., et al., DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med, 2006. 355(16): p. 1647-59.

68.          von Muhlen, D., et al., Effect of dehydroepiandrosterone supplementation on bone mineral density, bone markers, and body composition in older adults: the DAWN trial. Osteoporos Int, 2008. 19(5): p. 699-707.

69.          Weiss, E.P., et al., Dehydroepiandrosterone replacement therapy in older adults: 1- and 2-y effects on bone. Am J Clin Nutr, 2009. 89(5): p. 1459-67.

70.          Harris, S.T., et al., Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA, 1999. 282(14): p. 1344-52.

71.          de Villiers, T.J. and J.C. Stevenson, The WHI: the effect of hormone replacement therapy on fracture prevention. Climacteric, 2012. 15(3): p. 263-6.

72.          Clarke, B.L. and S. Khosla, Androgens and bone. Steroids, 2009. 74(3): p. 296-305.

73.          Manolagas, S.C., C.A. O’Brien, and M. Almeida, The role of estrogen and androgen receptors in bone health and disease. Nat Rev Endocrinol, 2013. 9(12): p. 699-712.

74.          Davis, S.R., et al., Testosterone enhances estradiol’s effects on postmenopausal bone density and sexuality. Maturitas, 1995. 21(3): p. 227-36.

75.          Raisz, L.G., et al., Comparison of the effects of estrogen alone and estrogen plus androgen on biochemical markers of bone formation and resorption in postmenopausal women. J Clin Endocrinol Metab, 1996. 81(1): p. 37-43.

76.          Coxam, V., et al., Effects of dihydrotestosterone alone and combined with estrogen on bone mineral density, bone growth, and formation rates in ovariectomized rats. Bone, 1996. 19(2): p. 107-14.

77.          Genazzani, A.D., et al., Oral dehydroepiandrosterone supplementation modulates spontaneous and growth hormone-releasing hormone-induced growth hormone and insulin-like growth factor-1 secretion in early and late postmenopausal women. Fertil Steril, 2001. 76(2): p. 241-8.

78.          Morales, A.J., et al., The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women. Clin Endocrinol (Oxf), 1998. 49(4): p. 421-32.

79.          Morales, A.J., et al., Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab, 1994. 78(6): p. 1360-7.

80.          Villareal, D.T., J.O. Holloszy, and W.M. Kohrt, Effects of DHEA replacement on bone mineral density and body composition in elderly women and men. Clin Endocrinol (Oxf), 2000. 53(5): p. 561-8.

81.          Jankowski, C.M., et al., Increases in bone mineral density in response to oral dehydroepiandrosterone replacement in older adults appear to be mediated by serum estrogens. J Clin Endocrinol Metab, 2008. 93(12): p. 4767-73.

82.          Locatelli, V. and V.E. Bianchi, Effect of GH/IGF-1 on Bone Metabolism and Osteoporsosis. Int J Endocrinol, 2014. 2014: p. 235060.

83.          Giustina, A., G. Mazziotti, and E. Canalis, Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev, 2008. 29(5): p. 535-59.

84.          Niemann, I., et al., The association between insulin-like growth factor I and bone turnover markers in the general adult population. Bone, 2013. 56(1): p. 184-90.

85.          Callewaert, F., et al., Skeletal sexual dimorphism: relative contribution of sex steroids, GH-IGF1, and mechanical loading. J Endocrinol, 2010. 207(2): p. 127-34.

86.          Woods, N.F., et al., Increased urinary cortisol levels during the menopausal transition. Menopause, 2006. 13(2): p. 212-21.

87.          Woods, N.F., E.S. Mitchell, and K. Smith-Dijulio, Cortisol levels during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women’s Health Study. Menopause, 2009. 16(4): p. 708-18.

88.          Meldrum, D.R., et al., Pituitary hormones during the menopausal hot flash. Obstet Gynecol, 1984. 64(6): p. 752-6.

89.          Cagnacci, A., et al., Increased cortisol level: a possible link between climacteric symptoms and cardiovascular risk factors. Menopause, 2011. 18(3): p. 273-8.

90.          Phillips, A.C., et al., Cortisol, DHEA sulphate, their ratio, and all-cause and cause-specific mortality in the Vietnam Experience Study. Eur J Endocrinol, 2010. 163(2): p. 285-92.

91.          Phillips, A.C., et al., Cortisol, DHEAS, their ratio and the metabolic syndrome: evidence from the Vietnam Experience Study. Eur J Endocrinol, 2010. 162(5): p. 919-23.

92.          Kalmijn, S., et al., A prospective study on cortisol, dehydroepiandrosterone sulfate, and cognitive function in the elderly. J Clin Endocrinol Metab, 1998. 83(10): p. 3487-92.

93.          Lupien, S.J., et al., Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat Neurosci, 1998. 1(1): p. 69-73.

94.          Hadoke, P.W., J. Iqbal, and B.R. Walker, Therapeutic manipulation of glucocorticoid metabolism in cardiovascular disease. Br J Pharmacol, 2009. 156(5): p. 689-712.

95.          Whitworth, J.A., et al., Cardiovascular consequences of cortisol excess. Vasc Health Risk Manag, 2005. 1(4): p. 291-9.

96.          Duclos, M., et al., Increased cortisol bioavailability, abdominal obesity, and the metabolic syndrome in obese women. Obes Res, 2005. 13(7): p. 1157-66.

97.          Wallerius, S., et al., Rise in morning saliva cortisol is associated with abdominal obesity in men: a preliminary report. J Endocrinol Invest, 2003. 26(7): p. 616-9.

98.          Poehlman, E.T., Menopause, energy expenditure, and body composition. Acta Obstet Gynecol Scand, 2002. 81(7): p. 603-11.

99.          Toth, M.J., et al., Menopause-related changes in body fat distribution. Ann N Y Acad Sci, 2000. 904: p. 502-6.

100.        Shi, H. and D.J. Clegg, Sex differences in the regulation of body weight. Physiol Behav, 2009. 97(2): p. 199-204.

101.        Genazzani, A.R., et al., Long-term low-dose oral administration of dehydroepiandrosterone modulates adrenal response to adrenocorticotropic hormone in early and late postmenopausal women.Gynecol Endocrinol, 2006. 22(11): p. 627-35.

102.        Kroboth, P.D., et al., Influence of DHEA administration on 24-hour cortisol concentrations. J Clin Psychopharmacol, 2003. 23(1): p. 96-9.

103.        Alhaj, H.A., A.E. Massey, and R.H. McAllister-Williams, Effects of DHEA administration on episodic memory, cortisol and mood in healthy young men: a double-blind, placebo-controlled study.Psychopharmacology (Berl), 2006. 188(4): p. 541-51.

104.        McQuade, R. and A.H. Young, Future therapeutic targets in mood disorders: the glucocorticoid receptor. Br J Psychiatry, 2000. 177: p. 390-5.

105.        Otte, C., et al., A meta-analysis of cortisol response to challenge in human aging: importance of gender. Psychoneuroendocrinology, 2005. 30(1): p. 80-91.

106.        Stein-Behrens, B.A. and R.M. Sapolsky, Stress, glucocorticoids, and aging. Aging (Milano), 1992. 4(3): p. 197-210.

107.        Apostolova, G., et al., Dehydroepiandrosterone inhibits the amplification of glucocorticoid action in adipose tissue. Am J Physiol Endocrinol Metab, 2005. 288(5): p. E957-64.

108.        Tagawa, N., et al., Alternative mechanism for anti-obesity effect of dehydroepiandrosterone: possible contribution of 11beta-hydroxysteroid dehydrogenase type 1 inhibition in rodent adipose tissue.Steroids, 2011. 76(14): p. 1546-53.

109.        McNelis, J.C., et al., Dehydroepiandrosterone exerts antiglucocorticoid action on human preadipocyte proliferation, differentiation, and glucose uptake. Am J Physiol Endocrinol Metab, 2013. 305(9): p. E1134-44.

110.        Rask, E., et al., Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab, 2001. 86(3): p. 1418-21.

111.        Rask, E., et al., Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity. J Clin Endocrinol Metab, 2002. 87(7): p. 3330-6.

112.        Libe, R., et al., Effects of dehydroepiandrosterone (DHEA) supplementation on hormonal, metabolic and behavioral status in patients with hypoadrenalism. J Endocrinol Invest, 2004. 27(8): p. 736-41.

113.        Villareal, D.T. and J.O. Holloszy, Effect of DHEA on abdominal fat and insulin action in elderly women and men: a randomized controlled trial. JAMA, 2004. 292(18): p. 2243-8.

114.        Tan, C.Y., et al., Skin thickness measurement by pulsed ultrasound: its reproducibility, validation and variability. Br J Dermatol, 1982. 106(6): p. 657-67.

115.        Henry, F., et al., Age-related changes in facial skin contours and rheology. J Am Geriatr Soc, 1997. 45(2): p. 220-2.

116.        Fisher, G.J., et al., Mechanisms of photoaging and chronological skin aging. Arch Dermatol, 2002. 138(11): p. 1462-70.

117.        Brincat, M., et al., Skin collagen changes in postmenopausal women receiving different regimens of estrogen therapy. Obstet Gynecol, 1987. 70(1): p. 123-7.

118.        Affinito, P., et al., Effects of postmenopausal hypoestrogenism on skin collagen. Maturitas, 1999. 33(3): p. 239-47.

119.        Brincat, M., et al., A study of the decrease of skin collagen content, skin thickness, and bone mass in the postmenopausal woman. Obstet Gynecol, 1987. 70(6): p. 840-5.

120.        Delaney, M.F., Strategies for the prevention and treatment of osteoporosis during early postmenopause. Am J Obstet Gynecol, 2006. 194(2 Suppl): p. S12-23.

121.        McClung, M.R., The menopause and HRT. Prevention and management of osteoporosis. Best Pract Res Clin Endocrinol Metab, 2003. 17(1): p. 53-71.

122.        Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause, 2010. 17(1): p. 25-54; quiz 55-6.

123.        Brincat, M., et al., Long-term effects of the menopause and sex hormones on skin thickness. Br J Obstet Gynaecol, 1985. 92(3): p. 256-9.

124.        Pierard, G.E., et al., Effect of hormone replacement therapy for menopause on the mechanical properties of skin. J Am Geriatr Soc, 1995. 43(6): p. 662-5.

125.        Makrantonaki, E. and C.C. Zouboulis, Androgens and ageing of the skin. Curr Opin Endocrinol Diabetes Obes, 2009. 16(3): p. 240-5.

126.        Savvas, M., et al., Type III collagen content in the skin of postmenopausal women receiving oestradiol and testosterone implants. Br J Obstet Gynaecol, 1993. 100(2): p. 154-6.

127.        Pierard, G.E., et al., Revisiting the cutaneous impact of oral hormone replacement therapy. Biomed Res Int, 2013. 2013: p. 971760.

128.        Zouboulis, C.C., et al., Sexual hormones in human skin. Horm Metab Res, 2007. 39(2): p. 85-95.

129.        Chen, W., et al., Testosterone synthesized in cultured human SZ95 sebocytes derives mainly from dehydroepiandrosterone. Exp Dermatol, 2010. 19(5): p. 470-2.

130.        Fritsch, M., C.E. Orfanos, and C.C. Zouboulis, Sebocytes are the key regulators of androgen homeostasis in human skin. J Invest Dermatol, 2001. 116(5): p. 793-800.

131.        Chen, W., D. Thiboutot, and C.C. Zouboulis, Cutaneous androgen metabolism: basic research and clinical perspectives. J Invest Dermatol, 2002. 119(5): p. 992-1007.

132.        Baulieu, E.E., et al., Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a sociobiomedical issue. Proc Natl Acad Sci U S A, 2000. 97(8): p. 4279-84.

133.        Yoshida, K., et al., Effect of dehydroepiandrosterone sulphate, oestrogens and prostaglandins on collagen metabolism in human cervical tissue in relation to cervical ripening. J Int Med Res, 1993. 21(1): p. 26-35.

134.        Shin, M.H., et al., Modulation of collagen metabolism by the topical application of dehydroepiandrosterone to human skin. J Invest Dermatol, 2005. 124(2): p. 315-23.

135.        Lee, K.S., K.Y. Oh, and B.C. Kim, Effects of dehydroepiandrosterone on collagen and collagenase gene expression by skin fibroblasts in culture. J Dermatol Sci, 2000. 23(2): p. 103-10.

136.        S., F. and H.I. Maibach, Gender Differences in Skin, in Textbook of Aging Skin, M.A. Farage , K.W. Miller, and H.I. Maibach, Editors. 2010, Springer Berlin Heidelberg. p. 999-1017.

137.        Calvo, E., et al., Pangenomic changes induced by DHEA in the skin of postmenopausal women. J Steroid Biochem Mol Biol, 2008. 112(4-5): p. 186-93.