Abstract
Because dehydroepiandrosterone (DHEA) levels decline dramatically with aging and low DHEA levels correlate with age-related diseases, it has been suggested that old age may represent a condition of DHEA deficiency. Accordingly, there have been some studies of the effects of restoring the DHEA levels of older individuals back to the normal range in the young.
Emerging evidence from these studies shows that prasterone (DHEA replacement) may significantly enhance bone mineral density (BMD). In fact, the improvements of BMD in response to prasterone are accompanied not only by suppression of bone resorption but more importantly, stimulation of bone formation. Thus, prasterone appears to have additional anabolic effects on the skeleton, which represents an advantage over current pharmacologic agents that only inhibit bone loss.
The osteogenic effects in elderly people are consistent with DHEA serving primarily as a precursor to active androgens and estrogens in local tissues such as bone. DHEA replacement may also increase levels of insulin-like growth factor-1, which may contribute to its anabolic effects. Although prasterone may be an effective therapy for improving BMD in both sexes, there appears to be gender differences in responses with more osteogenic effects in older women compared with older men. More studies, particularly randomized, placebo-controlled trials which include fractures as an outcome, are needed to fully define the potential utility of DHEA replacement as an anabolic intervention for age-related osteoporosis. These studies would also be important to gain information on risks associated with long-term DHEA replacement therapy. Further investigations are particularly warranted because prasterone is available over-the-counter in many countries and many older individuals are taking this hormone, without medical supervision, for its purported anti-aging properties.
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References
Hornsby PJ. DHEA: a biologist’s perspective. J Am Geriatr Soc 1997; 45: 1395–401
Sizonenko PC, Paunier L. Hormonal changes in puberty III: correlation of plasma dehydroepiandrosterone, testosterone, FSH, and LH with stages of puberty and bone age in normal boys and girls and in patients with Addison’s disease or hypogonadism or with premature or late adrenarche. J Clin Endocrinol Metab 1975; 41:894–904
Belanger A, Candas B, Dupont A, et al. Changes in serum concentrations of conjugated and unconjugated steroids in 40-to 80-year-old men. J Clin Endocrinol Metab 1994; 79: 1086–90
Orentreich N, Brind JL, Rizer RL, et al. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 1984; 59: 551–5
Orentreich N, Brind JL, Vogelman JH, et al. Long-term longitudinal measurements of plasma dehydroepiandrosterone sulfate in normal men. J Clin Endocrinol Metab 1992; 75: 1002–4
Szathmari M, Szucs J, Feher T, et al. Dehydroepiandrosterone sulphate and bone mineral density. Osteoporos Int 1994; 4: 84–8
Haden ST, Glowacki J, Hurwitz S, et al. Effects of age on serum dehydroepiandrosterone sulfate, IGF-I, and IL-6 levels in women. Calcif Tissue Int 2000; 66: 414–8
Greendale GA, Edelstein S, Barrett-Connor E. Endogenous sex steroids and bone mineral density in older women and men: the Rancho Bernardo Study. J Bone Miner Res 1997; 12: 1833–43
Clarke BL, Ebeling PR, Jones JD, et al. Predictors of bone mineral density in aging healthy men varies by skeletal site. Calcif Tissue Int 2002; 70: 137–45
Garnero P, Sornay-Rendu E, Claustrat B, et al. Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study 3. J Bone Miner Res 2000; 15: 1526–36
Nestler JE, Barlascini CO, Clore JN, et al. Dehydroepiandrosterone reduces serum low density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men. J Clin Endocrinol Metab 1988; 66: 57–61
Mortola JF, Yen SS. The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women. J Clin Endocrinol Metab 1990; 71: 696–704
Usiskin KS, Butterworth S, Clore JN, et al. Lack of effect of dehydroepiandrosterone in obese men. Int J Obes 1990; 14: 457–63
Welle S, Jozefowicz R, Statt M. Failure of dehydroepiandrosterone to influence energy and protein metabolism in humans. J Clin Endocrinol Metab 1990; 71: 1259–64
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: 1360–7
Villareal DT, Holloszy JO, Kohrt WM. Effects of DHEA replacement on bone mineral density and body composition in elderly women and men. Clin Endocrinol (Oxf) 2000; 53: 561–8
Legrain S, Massien C, Lahlou N, et al. Dehydroepiandrosterone replacement administration: pharmacokinetic and pharmacodynamic studies in healthy elderly subjects. J Clin Endocrinol Metab 2000; 85: 3208–17
Arlt W, Haas J, Callies F, et al. Biotransformation of oral dehydroepiandrosterone in elderly men: significant increase in circulating estrogens. J Clin Endocrinol Metab 1999; 84: 2170–6
Labrie F, Diamond P, Cusan L, et al. Effect of 12-month dehydroepiandrosterone replacement therapy on bone, vagina, and endometrium in postmenopausal women. J Clin Endocrinol Metab 1997; 82: 3498–505
Morales AJ, Haubrich RH, Hwang JY, et al. The effect of six months treatment with a 100mg 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: 421–32
Casson PR, Santoro N, Elkind-Hirsch K, et al. Postmenopausal dehydroepiandrosterone administration increases free insulin-like growth factor-I and decreases high-density lipoprotein: a six-month trial. Fertil Steril 1998; 70: 107–10
Baulieu EE, Thomas G, Legrain S, 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: 4279–84
Sun Y, Mao M, Sun L, et al. Treatment of osteoporosis in men using dehydroepiandrosterone sulfate. Chin Med J (Engl) 2002; 115: 402–4
Arlt W, Callies F, Koehler I, et al. Dehydroepiandrosterone supplementation in healthy men with an age-related decline of dehydroepiandrosterone secretion. J Clin Endocrinol Metab 2001; 86: 4686–92
Kahn AJ, Halloran B. Dehydroepiandrosterone supplementation and bone turnover in middle-aged to elderly men. J Clin Endocrinol Metab 2002; 87: 1544–9
Gordon CM, Grace E, Emans SJ, et al. Changes in bone turnover markers and menstrual function after short-term oral DHEA in young women with anorexia nervosa. J Bone Miner Res 1999; 14: 136–45
Callies F, Fassnacht M, van Vlijmen JC, et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency: effects on body composition, serum leptin, bone turnover, and exercise capacity. J Clin Endocrinol Metab 2001; 86: 1968–72
Martel C, Sourla A, Pelletier G, et al. Predominant androgenic component in the stimulatory effect of dehydroepiandrosterone on bone mineral density in the rat. J Endocrinol 1998; 157: 433–42
Hunt PJ, Gurnell EM, Huppert FA, et al. Improvement in mood and fatigue after dehydroepiandrosterone replacement in Addison’s disease in a randomized, double blind trial. J Clin Endocrinol Metab 2000; 85: 4650–6
Arlt W, Callies F, van Vlijmen JC, et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 1999; 341: 1013–20
Yen SS, Morales AJ, Khorram O. Replacement of DHEA in aging men and women: potential remedial effects. Ann N Y Acad Sci 1995; 774: 128–42
Flynn MA, Weaver-Osterholtz D, Sharpe-Timms KL, et al. Dehydroepiandrosterone replacement in aging humans. J Clin Endocrinol Metab 1999; 84: 1527–33
Labrie F, Luu-The V, Labrie C, et al. DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology. Front Neuroendocrinol 2001; 22: 185–212
Nawata H, Tanaka S, Tanaka S, et al. Aromatase in bone cell: association with osteoporosis in postmenopausal women. J Steroid Biochem Mol Biol 1995; 53: 165–74
Ishida Y, Killinger DW, Khalil MW, et al. Expression of steroid-converting enzymes in osteoblasts derived from rat vertebrae. Osteoporos Int 2002; 13: 235–40
Brader JM, Sobek L, Oettel M. Dehydroepiandrosterone stimulates the estrogen response element. J Steroid Biochem Mol Biol 1997; 62: 461–6
Kasperk CH, Wakley GK, Hierl T, et al. Gonadal and adrenal androgens are potent regulators of human bone cell metabolism in vitro. J Bone Miner Res 1997; 12: 464–71
Genazzani AD, Stomati M, Strucchi C, et al. Oral dehydroepiandrosterone supplementation modulates spontaneous and growth hormone-releasing hormoneinduced growth hormone and insulin-like growth factor-1 secretion in early and late postmenopausal women. Fertil Steril 2001; 76: 241–8
Straub RH, Konecna L, Hrach S, et al. Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence. J Clin Endocrinol Metab 1998; 83: 2012–7
Gordon CM, LeBoff MS, Glowacki J. Adrenal and gonadal steroids inhibit IL-6 secretion by human marrow cells. Cytokine 2001; 16: 178–86
Bellido T, Jilka RL, Boyce BF, et al. Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens: the role of the androgen receptor. J Clin Invest 1995; 95: 2886–95
Peters JM, Zhou YC, Ram PA, et al. Peroxisome proliferator-activated receptor alpha required for gene induction by dehydroepiandrosterone-3 beta-sulfate. Mol Pharmacol 1996; 50: 67–74
Poynter ME, Daynes RA. Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappaB signaling, and reduces inflammatory cytokine production in aging. J Biol Chem 1998; 273: 32833–41
Scheven BA, Milne JS. Dehydroepiandrosterone (DHEA) and DHEA-S interact with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) to stimulate human osteoblastic cell differentiation. Life Sci 1998; 62: 59–68
Khosla S, Melton III LJ, Riggs BL. Clinical review 144: estrogen and the male skeleton. J Clin Endocrinol Metab 2002; 87: 1443–50
Acknowledgements
The author’s research is supported by the following awards from the National Institute of Health: K23RR16191-01, RR00036, DK56341, and AG13629. The author wishes to thank Dr Reina Armamento-Villareal for her suggestions and review of this paper.
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Villareal, D.T. Effects of Dehydroepiandrosterone on Bone Mineral Density. Treat Endocrinol 1, 349–357 (2002). https://doi.org/10.2165/00024677-200201060-00001
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DOI: https://doi.org/10.2165/00024677-200201060-00001