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The Clinical Use of Dehydroepiandrosterone in postmenopausal women

Bethany L. Bramwell, BS Pharm, RPhWalgreensWest Plains Missouri

AbstractA basic understanding of the distinct metabolism, mechanism of action, and clinical use of dehydroepiandrosterone and its metabolites is critical to balancing the hormone milieu in postmenopausal women. To date, studies of dehydroepiandrosterone therapy in women with adrenal insufficiency suggest that they are the most likely group to gain health benefits from dehydroepiandrosterone replacement therapy. Our understanding of the potential long-term health benefits of replacing dehydroepiandrosterone along with other deficient hormones is still only in its infancy. With the evidence currently available, however, one can reasonably suggest that dehydroepiandrosterone offers the promise of a safe and efficient replacement therapy for specific symptoms common to postmenopausal women. This article reviews the metabolism, physiology, and clinical use of dehydroepiandrosterone in postmenopausal women. The clinical effectiveness of dehydroepiandrosterone for vulvovaginal atrophy, sexual dysfunction, osteoporosis, adrenal and immunological function, cardiovascular disease, and, in combination, hormone replacement therapy is reviewed. In addition, the use of the dehydroepiandrosterone metabolite 7-keto-dehydroepiandrosterone for weight loss is discussed.

The medical and nonmedical use of pro-hormones is not new; for decades bodybuild-ers and athletes have understood the benefits and risks associated with the supplementa-tion of steroid hormone precursors. There is increasing popular and scientific interest in supplementation with the prohormones dehy-droepiandrosterone (DHEA), 7-Keto-DHEA,

and 7-alpha-hydroxy-DHEA for a myriad of uses ranging from Al-zheimer’s, to weight loss, to HIV/AIDS. A solid understanding of the distinct metabolism, mechanism of action, and clinical use of each of these prohormones is vital to the practitioner tasked in balancing the

466 www.ijpc.comInternational Journal of Pharmaceutical CompoundingVol. 14 No. 6 | November/December 2010

hormone milieu in postmenopausal women, as well as managing vari-ous androgen deficiency-related disease states. Despite the identification of DHEA and its sulfate metabolite DHEAS more than 80 years ago, there is still considerable speculation as to the extent of their physiological role and controversy as to their therapeutic significance. While first isolated in 1934 by German Dr. Adolf Butenandt,1 work on DHEA in the 1960s by French Dr. Etienne-Emile Baulieu2 brought significant attention to DHEA as an endog-enous adrenal and neurohormone. In 1996, DHEA was skyrocketed to “the superstar of superhormones” by the popularity of Dr. William Regelson’s book titled The Superhormone Promise.

Physiology DHEA, also known as prasterone, and its sulfated metabolite DHEAS are the most abundant circulating steroid hormones in women.3 DHEA is an endogenous prohormone produced in the ad-renal glands, the liver, in minute amounts in the neurons and glial cells in the brain, and, in men, is secreted by the testes.4 Humans, along with other primates, are unique in their adrenal production of copious amounts of DHEA,5 and no nuclear or membrane receptors specific for DHEA or DHEAS have been identified to date.6 Instead, they act as a reservoir of precursors for the intracellular production of both androgens and estrogens in nonreproductive tissues. It is estimated that before menopause 75% and after meno-pause 100% of total estrogens in women are synthesized in peripheral intracrine tissues from inactive adrenal precursors.7 Most of DHEA’s actions are via its activity at the androgen receptor (AR) or estrogen recep-tor (ER) after its conversion to androgen or estrogen. However, direct effects of DHEA at the AR and ER have been identified. DHEA also increases bioavailable insulin-like growth factor 1 and directly effects neurotransmitter receptors.8 DHEA levels generally peak around age 20 and begin a rapid descent after age 25.4 By the time a woman reaches menopause, her DHEA secretion has decreased by an average of 60%. Unlike the majority of men, with a lifetime of testicular activity, DHEA becomes the exclusive source for sex steroids in women after menopause.9 And, because there is no feedback mechanism controlling DHEA secretion, women who are deficient will remain so without clinical intervention.10 Metabolism of DHEA differs according to gender as well as varies in individual cells and tissues, which increases the difficulty in under-standing the steroid hormone cascade. In addition, distinct species-specific metabolic routes and cellular interconversions of DHEA and its metabolites prevent traditional extrapolation of animal models to human physiology. DHEA is an intermediate in the production of testosterones and estrogens. In the liver, DHEA is converted to 7-alpha-hydroxy-DHEA which is then oxidized to 7-oxo-DHEA (also known as 7-keto-DHEA) in both liver and kidney.11 All androgen-and estrogen-sensitive peripheral tissues have the necessary enzymes to convert DHEA, allowing local synthesis and control of the intracel-lular levels of sex hormones according to local needs.5 Humans hy-

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droxylate DHEA at several positions, as well as interconvert 7-alpha-hydroxy-DHEA, 7-beta-hydroxy-DHEA, and 7-oxo-DHEA. The 7-oxo derivatives are more active than the parent DHEA, and they do not appear to convert to either androgens or estrogens.12 DHEA supplementation changes the circulating androgen/estrogen ratio in a gender-specific fashion. Interestingly, women tend to convert more DHEA to testosterone, whereas men convert more to estradiol. DHEA protects the body from the effects of physical stress and inflammation, decreases pain, and improves immune system function.13 DHEA administration increases all of the steroid hormones, except cortisol, which decreases.14 DHEA also increases libido and sexual re-sponsiveness; improves motivation, sense of well-being, and rapid-eye movement (REM) phase sleep; and enhances memory.15-17

Because DHEA promotes the formation of other hormones, it can help alleviate menopausal symptoms and/or decrease the amount of other hormones required in replacement therapies. DHEA also protects against autoimmune diseases like lupus erythematosus and rheumatoid arthritis.4 DHEA levels are often low in patients with cardiovascular disease (CVD), fibromyalgia, HIV/AIDS, and certain cancers. However, stud-ies conflict on whether or not supplementation improves disease pro-gression and quality of life in these patients. In evaluating the evidence for the clinical use of DHEA, more than mere association between high or low levels of DHEA and a disease risk should be considered; we should also require data that demonstrates the outcomes associated with direct intervention.

Effects of DHEA on Hormonal Milieu In women, DHEA levels are directly related to well-being, cogni-tive function, and functional status.8 Regarding the clinical use of DHEA in women whose saliva level indicates low DHEAS, Dr. Kenna Stephenson writes in her book Awakening Athena: “DHEA enhances libido, helps build bone mass, lowers the levels of cholesterol and tri-glycerides, improves the sense of well-being and increases alertness.18” DHEA supplementation increses the levels of all sex hormones, while decreasing cortisol levels. Consequently, the appropriate dose of DHEA to add to estrogen and progesterone replacement therapy in androgen deficient postmenopausal women is debated by practi-tioners. In postmenopausal women (1 to 6 years since menopause) the addition of 10 mg/day oral DHEA added to 50 mcg transdermal estradiol and 100 mg/day oral micronized progesterone results in a significantly higher increase in testosterone and estradiol and a significantly lower decrease in cortisol level than without DHEA.19 Evidence suggests that 10 mg/day of oral DHEA may be the proper dose to replace androgen deficiencies. However, the number of years since menopause, the adrenal function of the individual, and the extent of androgen deficiency need to be considered when replacing DHEA along with estrogens and progesterone.

Cardiovascular Disease Research to date has not demonstrated consistent effects of DHEA on cardiovascular risk. In postmenopausal women, DHEAS is associ-ated with a less atherogenic lipid profile and low DHEAS levels are

By the time a woman reaches menopause, her DHEA secretion

has decreased by an average of 60%.

Unlike the majority of men, with a lifetime of testicular activity, DHEA becomes the

exclusive source for sex steroids in

women after meno-pause. And, because there is no feedback mechanism control-ling DHEA secretion,

women who are deficient will remain

so without clinical intervention.

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associated with increased CVD risk and all-cause mortal-ity.20,21 Although declines in androgens are associated with cardiovascular risk, it remains to be seen whether replacement therapy will improve the risk factors. Preliminary studies report possible benefits of DHEA supplementation in patients with atherosclerotic plaques. There is conflicting evidence regarding the use of DHEA in patients with heart failure or diminished ejection fraction.22 Oral DHEA supplementation (50 mg/day) seems to reduce triglycerides, low-density lipoprotein (LDL), and total cholesterol, but also decreases high-density lipo-protein (HDL).23 Most studies conclude that oral DHEA supplementation results in an unfavorable lipoprotein profile. Lowering of the large HDL particles and the resulting potential adverse clinical implications are cited as concerns for the impact of DHEA supplementation on cardiovascular risk factors. Long-term, lower-dose studies are warranted.

Aging Skin Oral DHEA supplementation increases epidermal thickness, sebum production (a desirable effect for most postmenopausal women), skin

hydration, and decreases facial skin pigmentation in elderly wom-en.24 Topical DHEA exerts an anti-aging effect in the skin through

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468 www.ijpc.comInternational Journal of Pharmaceutical CompoundingVol. 14 No. 6 | November/December 2010

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FoRMuLAS uSeD in the tReAtMent oF VARiouS heALth iSSueS oF PoStMenoPAuSAL WoMen

Rx 7-KETO-DHEA 5-Mg SLOW-RELEASE CAPSULES

For #100 capsules

Rx DHEA 13-Mg VAgINAL SUPPOSITORIES

For 30 suppository molds

7-keto-DHEA 0.5 gMicrocrystalline cellulose 13.8 gMethocel E4M Premium 10 gSize #1 capsules 100 Each

METHOD OF PREPARATION1. Calculate the required quantity of each ingredient for the total

amount to be prepared.2. Weigh and/or measure each ingredient accurately.3. Blend the DHEA powder with the microcrystalline cellulose

geometrically, followed by the Methocel E4M Premium, and mix well.

4. Encapsulate into 100 size #1 capsules.5. Package and label.

STABILITYA beyond-use date of up to 6 months can be used for this preparation.

DHEA = dehydroepiandrosterone

DHEA 0.39 gWitepsol H-15 54.9 g2-mL suppository molds 30 Each

METHOD OF PREPARATION1. Calculate the required quantity of each ingredient for the total

amount to be prepared.2. Weigh and/or measure each ingredient accurately.3. Melt the Witepsol H-15 base, using low heat, until fluid.4. Incorporate the DHEA and mix until uniform.5. Pour into molds, cool, and trim if necessary.6. Package and label.

STABILITYA beyond-use date of up to 6 months can be used for this preparation.

DHEA = dehydroepiandrosterone

Rx DHEA 10-Mg SLOW-RELEASE CAPSULES

For 100 capsules

DHEA 1 gMicrocrystalline cellulose 13.5 gMethocel E4M Premium 10 gSize #1 capsules 100 Each

METHOD OF PREPARATION1. Calculate the required quantity of each ingredient for the total

amount to be prepared.2. Weigh and/or measure each ingredient accurately.3. Blend the DHEA powder with the microcrystalline cellulose

geometrically, followed by the Methocel E4M Premium, and mix well.

4. Encapsulate into 100 size #1 capsules.5. Package and label.

STABILITYA beyond-use date of up to 6 months can be used for this preparation.

DHEA = dehydroepiandrosterone

Rx DHEA 10-Mg/ML VAgINAL CREAM

For 30 mL

DHEA 0.3 gEthoxydiglycol 0.3 mLBHRT cream base of choice qs 30 mL

METHOD OF PREPARATION1. Calculate the required quantity of each ingredient for the total

amount to be prepared.2. Weigh and/or measure each ingredient accurately.3. Mix the DHEA with the ethoxydiglycol to form a smooth paste.4. Incorporate the BHRT cream geometrically into the mixture and

mix until uniform.5. Package and label.

STABILITYA beyond-use date of up to 30 days can be used for this preparation.

BHRT = bioidentical hormone replacement therapyDHEA = dehydroepiandrosterone

469www.ijpc.com International Journal of Pharmaceutical CompoundingVol. 14 No. 6 | November/December 2010

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stimulation of collagen biosynthesis, improved structural organization of the dermis, and modulation of keratinocyte metabolism. DHEA topical cream in concentrations ranging from 0.1% to 2% applied to the face, arms, backs of hands, and upper chest results in significant increases in dermal AR expression.25 Also, the expression of procol-lagen 1 and 2 mRNAs increases, as well as proteins affecting procol-lagen synthesis, especially at the 1% and 2% concentrations. DHEA cream also results in dose-dependent expression of collagen and genes required for the maturation and deposition of collagen in the skin. Topical DHEA also reduces the expression of genes associated with cornification of keratinocytes.26 Overall, topical DHEA improves skin brightness, decreases the papery appearance of aging skin, and coun-teracts epidermal atrophy.

Osteoporosis DHEA treatment in women results in increased bone formation and higher bone mineral density (BMD) along with elevated levels of osteocalcin, an indicator of bone formation and a descrease in bone re-sorption.7 Oral DHEA (50 mg to 100 mg/day) seems to improve BMD in body and lumbar spine in older women.27 Application of topical DHEA 10% cream in 60- to 70-year-old women significantly increases BMD in the hip after 12 months of treatment.16

Depression Although its precise role is unclear, DHEA seems to be involved in the pathophysiology of depression. In addition to a correlation between DHEA levels and mood, clinical research indicates oral DHEA supple-mentation may improve symptoms of depression and dysthymia.4 After six weeks of DHEA monotherapy, dysthymic patients note improve-

ments in lack of energy and motivation, emotional "numbness," sadness, inability to cope, and worry.28

Levels of DHEAS may be important in predicting remission rates after pharmacological treatment for depression. In patients treated for major depressive episode with either venlafaxine or mirtazepine, those who remit after treatment have lower DHEAS levels, whereas patients without remission of depression do not show significant declines in DHEAS.29 Research suggests that treatment outcomes for major depres-sion depend upon DHEAS concentrations rather than direct antidepres-sant drug effects, and the change in DHEAS levels can serve as a marker of treatment response.

Vulvovaginal Atrophy DHEA can be a highly efficient treatment for reversing the signs and symptoms of vaginal atrophy, presumably through local androgen and estrogen formation. Daily intravaginal application of DHEA in concentrations ranging from 0.25% to 1% can decrease the percentage of parabasal cells, increase superficial cells, and decrease vaginal pH.30 After one week of DHEA treatment, the maturation value of the vaginal epithelial cells increases significantly.31 Improvements are also seen in vaginal secretions, epithelial surface thickness, and epithelial integrity. Minimal changes in serum DHEA levels are seen with doses up 23.4 mg daily over one week. Intravaginal doses of DHEA up to 13 mg/day result in minimal or no changes in serum sex hormone levels after 12 weeks of treatment.32 No effects on the endometrium have been observed.

Libido and Sexual Dysfunction Metabolism of DHEA into both androgens and estrogens locally in the cells of the vaginal lining improves sexual function in postmeno-pausal women with vaginal atrophy. DHEA 1% applied intravaginally daily results in increased sexual desire, arousal, sensation, orgasm, and improves dryness during intercourse.33 A single 300-mg dose of DHEA has also been shown to improve response to sexual stimuli in postmeno-pausal women.4

Adrenal Response and Immune System Function DHEA induces a change in adrenal enzymatic activity and can mod-ify circulating levels of androgens and progestins in both early and late menopausal women, presumably by modulating the age-related changes in adrenal gland function. DHEA supplementation results in significant increases in all steroids except for cortisol, which decreases significantly, after three to six months of therapy.14 Several factors are involved in the age-related decline in immune system function, but the hypothalamus-pituitary-adrenal axis plays an important role. The imbalance between cortisol and DHEA, with their opposing actions on immune function, emphasizes the importance of DHEA supplementation in aging women. The cortisol/DHEA ratio is a major determinant of age-related immunological changes.34 Ad-ministration of DHEA can improve cellular immune function during systemic inflammation, and DHEA and DHEAS have regulatory effects in immune homeostasis and are regulated by the nervous system, and it is seems that they may be an integral element of neuroimmunomodula-tion. It is unclear whether the low DHEAS levels seen in autoimmune

Rx DHEA 2% FACIAL NIgHT CREAM

For 30 g

DHEA 0.6 gGlycerin 0.6 mLCosmetic night cream of choice qs 30 g

METHOD OF PREPARATION1. Calculate the required quantity of each ingredient for the total

amount to be prepared.2. Weigh and/or measure each ingredient accurately.3. Mix the DHEA powder with the glycerin to form a smooth

paste.4. Incorporate the mixture geometrically into the cream base and

mix until uniform.5. Package and label.

STABILITYA beyond-use date of up to 30 days can be used for this preparation.

DHEA = dehydroepiandrosterone

470 www.ijpc.comInternational Journal of Pharmaceutical CompoundingVol. 14 No. 6 | November/December 2010

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conditions, chronic fatigue syndrome, fibromyalgia, CVD, and certain cancers is a causative or resulting factor. Of potential clinical importance, the DHEA metabolite 7-keto-DHEA has also been shown to modulate immune system function via stimulation of interleukin-2 production by lymphocytes.4

Obesity In postmenopausal women, endogenous androgens play an important role in the maintenance of beneficial patterns of metabolic and morpho-metric parameters.35 The metabolic effects of DHEA seem to contribute to its antiobesity action, and the majority of studies evaluating the effect of DHEA on weight loss support its use for this purpose. DHEA blocks glucose-6-phosphate-dehydrogenase (G6PD), an enzyme essential for adipose tissue production, and decreases fatty acid synthetase activ-ity,36 resulting in a decrease in fat mass and an increase in lean mass.27 Higher doses of DHEA (50 mg/day for six months) may reduce the risk factors for metabolic syndrome in overweight elderly patients. DHEA supplementation decreases insulin resistance and levels of sex hormone binding globulin (SHBG) significantly in obese late postmenopausal women. Replacement therapy with 50 mg of oral DHEA over 12 weeks can significantly increase insulin sensitivity in hypoadrenal women, sug-gesting DHEA could play a role in preventing type 2 diabetes. Citing increases in metabolism and thermogenesis, the DHEA metabolite, 7-keto-DHEA, has been promoted for weight loss. Popular claims made regarding 7-keto-DHEA include increases in lean body mass and muscle mass, stimulated thyroid activity, improvements in im-mune system function, boosting memory, and slowing the aging process. Proponents of 7-keto-DHEA claim the benefits of its parent DHEA, without the adverse effects. Neither oral nor topical 7-keto-DHEA has been shown to convert to testosterone or estradiol, nor does it have a clinically significant effect on serum steroid hormone levels, nor does it activate AR.4 In obese patients, 7-keto-DHEA stimulates production of thermogenic enzymes in the liver resulting in increased basal metabolic rate and increased triiodothyronine (T3) levels, and it promotes ther-mogenesis at about 2.5 times the rate of its parent DHEA, presumably through the stimulation of hepatic thermogenic enzymes. Significant increases in T3 have been seen with the use of 7-keto-DHEA in obese patients when used over 4 weeks.37

Early evidence indicates that 7-keto-DHEA may decrease body weight and body fat percentage in obese females, possibly by increasing resting metabolic rate (RMR) above basal levels.4 A decline in RMR, while frustrating for the patient, is normal, with restricted-calorie dieting. In preliminary studies, 7-keto-DHEA has been shown to reverse the normal decline in RMR seen in patients on a calorie-restricted dieting.37 RMR comparison in patients receiving 7-keto-DHEA supplementation and placebo shows that during placebo treatment, RMR decreases by 3.9%, while RMR increases by 1.4% in the 7-keto group. Compared to exercise and diet alone, 100 mg of 7-keto-DHEA administered twice daily combined with moderate exercise and a reduced-calorie diet significantly reduces body weight and body fat composition. While no changes in serum testosterone, estradiol, TSH, or T4 are seen, significant increases in T3 are noted in patients supplemented with 7-keto-DHEA.

Conclusion A basic understanding of the distinct metabolism, mechanism of ac-tion, and clinical use of DHEA and its metabolites is critical to balanc-

ing the hormone milieu in postmenopausal women. To date, studies of DHEA therapy in women with adrenal insufficiency suggest that these are the most likely to gain health benefits from DHEA replacement therapy. Our understanding of the potential long-term health benefits of replacing DHEA along with other deficient hormones is still only in its infancy. With the evidence currently available, however, one can reason-ably suggest that DHEA offers the promise of a safe and efficient replace-ment therapy for specific symptoms common to postmenopausal women.

References 1. Kryger A. WellnessMD. DHEA or Dehydroepiandrosterone. [Well-

nessMD Website.] December 11, 2008. Available at: www.well-nessmd.com/dhea.html. Accessed September 18, 2010.

2. Biography: Étienne-Émile Baulieu. [Answers.com Website.] Avail-able at: www.answers.com/topic/tienne-mile-baulieu. Accessed September 18, 2010.

3. Lardy H, Marwah A, Marwah P. C(19)-5-ene steroids in nature. Vitam Horm 2005; 71: 263–299.

4. Natural Medicines Comprehensive Database. DHEA and 7-keto-DHEA. [Natural Medicines Comprehensive Database Website.] Available at: www.naturaldatabase.com. Accessed September 16, 2010.

5. Labrie F, Luu-The V, Bélanger A et al. Is dehydroepiandrosterone a hormone? J Endocrinol 2005; 187(2): 169–196.

6. Arnold JT, Blackman MR. Does DHEA exert direct effects on androgen and estrogen receptors, and does it promote or prevent prostate cancer? Endocrinology 2005; 146(11): 4565–4567.

7. Labrie F, Bélanger A, Luu-The V et al. DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: Its role during aging. Steroids 1998; 63(5–6): 322–328.

8. Berr C, Lafont S, Debuire B et al. Relationships of dehydroepi-androsterone sulfate in the elderly with functional, psychological, and mental status, and short-term mortality: A French community-based study. Proc Natl Acad Sci U.S.A. 1996; 93(23): 13410–13415.

9. Labrie F, Martel C, Balser J. Wide distribution of the serum dehydroepiandrosterone and sex steroid levels in postmenopausal women: Role of the ovary? Menopause 2010; 28: [In print].

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

11. Robinzon B, Michael KK, Ripp SL et al. Glucocorticoids inhibit interconversion of 7-hydroxy and 7-oxo metabolites of dehydroe-piandrosterone: A role for 11beta-hydroxysteroid dehydrogenases? Arch Biochem Biophys 2003; 412(2): 251–258.

12. Lardy H, Partridge B, Kneer N et al. Ergosteroids: Induction of thermogenic enzymes in liver of rats treated with steroids derived from dehydroepiandrosterone. Proc Natl Acad Sci USA 1995; 92(14): 6617–6619.

13. Casson PR, Andersen RN, Herrod HG et al. Oral dehydroepi-androsterone in physiologic doses modulates immune function in postmenopausal women. Am J Obstet Gynecol 1993; 169(6): 1536–1539.

14. Genazzani AR, Pluchino N, Begliuomini S 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): 627–635.

15. Morales AJ, Nolan JJ, Nelson JC et al. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 1994; 78(6): 1360–1367.

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16. Labrie F, Diamond P, Cusan L et al. Effect of 12-month dehydro-epiandrosterone replacement therapy on bone, vagina, and endo-metrium in postmenopausal women. J Clin Endocrinol Metab 1997; 82(10): 3498–3505.

17. Legrain S, Massien C, Lahlou N et al. Dehydroepiandrosterone replacement administration; Pharmacokinetic and pharmacody-namic studies in healthy elderly subjects. J Clin Endocrinol Metab 2000; 85(9): 3208–3217.

18. Stephenson K. Awakening Athena. Tyler, TX: Health, Heart, and Mind Institute; 2004.

19. Pluchino N, Ninni F, Stomati M et al. One-year therapy with 10mg/day DHEA alone or in combination with HRT in post-menopausal women: Effects on hormonal milieu. Maturitas 2008; 59(4): 293–303.

20. Noyan V, Yucel A, Sagsoz N. The association of androgenic sex steroids with serum lipid levels in postmenopausal women. Acta Obstet Gynecol Scand 2004; 83(5): 487–490.

21. Shufelt C, Bretsky P, Almeida CM et al. DHEA-S levels and car-diovascular 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; [In print].

22. Medline Plus Website. Available at: www.nlm.nih.gov/medlin-eplus/druginfo/natural/patient-dhea.html. Accessed September 19, 2010.

23. Srinivasan M, Irving BA, Dhatariya K et al. Effect of dehydroepi-androsterone replacement on lipoprotein profile in hypoadrenal women. J Clin Endocrinol Metab 2009; 94(3): 761–764.

24. Nouveau S, Bastien P, Baldo F et al. Effects of topical DHEA on aging skin: A pilot study. 2008; 59(2): 174–181.

25. El-Alfy M, Deloche C, Azzi L et al. Skin responses to topical dehydroepiandrosterone: Implications in anti-ag[e]ing treatment? Br J Dermatol 2010; [In print].

26. Calvo E, Luu-The V, Morissette J et al. Pangenomic changes induced by DHEA in the skin of postmenopausal women. J Steroid Biochem Mol Biol 2008; 112(4–5): 186–193.

27. Villareal DT, Holloszy JO, Kohrt WM. Effects of DHEA replace-ment on bone mineral density and body composition in elderly women and men. Clin Endocrinol (Oxf) 2000; 53(5): 561–568.

28. Bloch M, Schmidt PJ, Danaceau MA. Dehydroepiandrosterone treatment of midlife dysthymia. Biol Psychiatry 1999; 45(12): 1533–1541.

29. Paslakis G, Luppa P, Gilles M et al. Venlafaxine and mirtazapine treatment lowers serum concentrations of dehydroepiandros-terone-sulfate in depressed patients remitting during the course of treatment. J Psychiatr Res 2010; 44(8): 556–560.

30. Labrie F, Archer D, Bouchard C et al. Intravaginal dehydroepian-drosterone (Prasterone), a physiological and highly efficient treat-ment of vaginal atrophy. Menopause 2009; 16(5): 907–922.

31. Labrie F, Cusan L, Gomez JL 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): 178–194.

32. Labrie F, Archer D, Bouchard C et al. Serum steroid levels during 12-week intravaginal dehydroepiandrosterone administration. Menopause 2009; 16(5): 897–906.

33. Labrie F, Archer D, Bouchard C et al. Effect of intravaginal dehy-droepiandrosterone (Prasterone) on libido and sexual dysfunction in postmenopausal women. Menopause 2009; 16(5): 923–931.

34. Buford TW, Willoughby DS. Impact of DHEA(S) and cortisol on immune function in aging: A brief review. Appl Physiol Nutr Metab 2008; 33(3): 429–433.

35. Casson PR, Toth MJ, Johnson JV et al. Correlation of serum androgens with anthropometric and metabolic indices in healthy, nonobese postmenopausal women. J Clin Endocrinol Metab 2010; 95(9): 4276–4282.

36. Shepherd A, Cleary MP. Metabolic alterations after dehydroepi-androsterone treatment in Zucker rats. Am J Physiol 1984; 246(2 Pt 1): E123–E128.

37. Kaiman DS, Colker CM, Swain MA et al. A randomized, double-blind, placebo-controlled study of 3-acetyl-7-oxo-dehydroepi-androsterone in healthy overweight adults. Current Therapeutic Research 2000; 61(7): 435–442.

38. Zenk JL, Frestedt JL, Kuskowski MA. HUM5007, a novel com-bination of thermogenic compounds, and 3-acetyl-7-oxo-dehy-droepiandrosterone: Each increases the resting metabolic rate of overweight adults. J Nutr Biochem 2007; 18(9): 629–634.

Address correspondence to Bethany L. Bramwell, BS Pharm, RPh, Compound-ing Pharmacist, Walgreens District #306, Walgreens, 1010 Worley Drive, West Plains, MO 65775. E-mail: bethany.bramwell@walgreens.com

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