Endocrine and Intracrine Sources of Androgens in Women: Inhibition of Breast Cancer and Other Roles of Androgens and Their Precursor Dehydroepiandrosterone

In the paper

“We then observed that changes in serum DHEA within the physiological range of young adult men and women led only to small or nonsignificant changes in serum testosterone, DHT, or E 2 , whereas, on the other hand, the concentration of the conjugated metabolites of DHT were markedly increased (27).”

What the sources say

• Not checked yetcites [27] Labrie, 1997, Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: intracrinology., J Clin Endocrinol Metab source

In the paper

“After daily administration of a single dose of DHEA percutaneously, serum DHEA, DHEA-S, and DHEA fatty acid esters increased approximately 175%, 130%, and 250% above control, respectively (Fig. 11),”

What the sources say

• Not checked yetcites Fig. 11

In the paper

“The present data show that elevations in serum DHEA within the physiological range found in young adult women led to only small or even no significant changes in serum testosterone, DHT, or E 2 , whereas, by contrast, the concentrations of the conjugated metabolites of DHT are markedly elevated,”

In the paper

“4-Dione also led to significant growth inhibition in ZR-75-1 cells, although the active concentrations (IC 50 , 15 nm) are in the upper range of the plasma concentrations (1-10 nm) found in women (215-218).”

What the sources say

• Not checked yetcites [215] Rochefort, 1983, The estrogenic and antiestrogenic activities of androgens in female target tissues., Pharmacol Ther source
• Not checked yetcites [216] Abraham, 1974, Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle., J Clin Endocrinol Metab source
• Not checked yetcites [217] Vermeulen, 1979, Factors affecting sex hormone levels in postmenopausal women., J Steroid Biochem source
• Not checked yetcites [218] Mistry, 1986, Endogenous C19-steroids and estradiol levels in human primary breast tumor tissues and their correlation with androgen and estrogen receptors., J Steroid Biochem source

In the paper

“the pure steroidal antiestrogen EM-139 (228), on the other hand, not only completely reversed the effect of E 2 but further inhibited cell number by 30% below control values (P Ͻ 0.01; Fig. 18B).”

What the sources say

• Not checked yetcites [228] Lévesque, 1991, Synthesis and biological activity of new halo-steroidal antiestrogens., J Med Chem source

In the paper

“DHT not only completely blocked the stimulatory effect of E 2 on cell proliferation but also reduced cell growth in the absence of estrogens.”

What the sources say

• Not checked yetcites [208] Poulin, 1988, Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line., Breast Cancer Res Treat source

In the paper

“In ZR-75-1 cells, concentrations of DHT in the incubation medium similar to the plasma levels found in normal women (215-217) and breast cancer patients (Ref.218; 0.3-0.7 nm) are potent inhibitors of the mitogenic effect of E 2 and even inhibit growth in the absence of estrogens (208).”

What the sources say

• Not checked yetcites [208] Poulin, 1988, Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line., Breast Cancer Res Treat source
• Not checked yetcites [215] Rochefort, 1983, The estrogenic and antiestrogenic activities of androgens in female target tissues., Pharmacol Ther source
• Not checked yetcites [216] Abraham, 1974, Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle., J Clin Endocrinol Metab source
• Not checked yetcites [217] Vermeulen, 1979, Factors affecting sex hormone levels in postmenopausal women., J Steroid Biochem source
• Not checked yetcites [218] Mistry, 1986, Endogenous C19-steroids and estradiol levels in human primary breast tumor tissues and their correlation with androgen and estrogen receptors., J Steroid Biochem source

In the paper

“it was found that the growth-inhibitory effect of DHT is clearly additive to that induced by maximally effective concentra- tions of the antiestrogen LY156758, thus indicating an action mediated by a mechanism different from interaction with the estrogen receptor (ER; 229).”

What the sources say

• Not checked yetcites [229] de Launoit, 1991, Characteristics of the biphasic action of androgens and of the potent antiproliferative effects of the new pure antiestrogen EM-139 on cell cycle kinetic parameters in LNCaP human prostatic cancer cells., Cancer Res

In the paper

“Treatment with DHT, on the other hand, not only completely reversed the stimulatory effect of E 2 on tumor growth but also decreased total tumor area to 48 Ϯ 10% of its original size.”

In the paper

“The androgenic effect was observed at subnanomolar concentrations of the nonaromatizable androgen DHT, regardless of the presence of estrogens, and was competitively reversed by the antiandrogen hydroxyflutamide.”

In the paper

“Moreover, the antiproliferative activity of androgens in estrogen-deprived ZR-75-1 cells is more pronounced and is additive to that exerted by antiestrogens (208,241).”

What the sources say

• Not checked yetcites [208] Poulin, 1988, Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line., Breast Cancer Res Treat source
• Not checked yetcites [241] Poulin, 1989, Antiestrogenic properties of keoxifene trans-4-hydroxytamoxifen, and ICI 164384, a new steroidal antiestrogen, in ZR-75-1 human breast cancer cells., Breast Cancer Res Treat source

In the paper

“The inhibition constant (K i ) value for the reversal of DHT action by hydroxyflutamide was estimated at 39 nm (233), in agreement with the affinity of the antagonist for the AR (227).”

What the sources say

• Not checked yetcites [233] Cheng, 1973, Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (I50) on an enzymatic reaction., Biochem Pharmacol source
• Not checked yetcites [227] Simard, 1986, Characteristics of interaction of the antiandrogen flutamide with the androgen receptor in various target tissues., Mol Cell Endocrinol source

In the paper

“the size of the ZR-75-1 tumors increased by 9.4-fold over a 291-d period (9.5 months) in ovariectomized nude mice supplemented with E 1 ; in contrast, in control ovariectomized mice that received the vehicle alone, tumor size decreased to 36.9% of the initial value during the course of the study (265).”

What the sources say

• Not checked yetcites [265] Couillard, 1998, Effect of dehydroepiandrosterone and the antiestrogen EM-800 on the growth of human ZR-75-1 breast cancer xenografts., J Natl Cancer Inst source

In the paper

“An increase of 135% over control (P Ͻ 0.05) in plasma osteocalcin was concomitantly observed, thus suggesting increased bone formation in agreement with our preclinical data (296).”

What the sources say

• Not checked yetcites [296] Martel

In the paper

“Anthropometric measurements showed no change in body weight but a 9.8% decrease in sc skin fold thickness at 12 months (P Ͻ 0.05; Ref. 297).”

What the sources say

• Not checked yetcites [297] Diamond, 1996, Metabolic effects of 12-month percutaneous DHEA replacement therapy in postmenopausal women., J Endocrinol

In the paper

“DHEA administration stimulated vaginal epithelium maturation in 8 of 10 women who had a maturation value of zero at the onset of therapy, whereas a stimulatory effect was also seen in the three women who had an intermediate vaginal maturation before therapy.”

In the paper

“The index of sebum secretion was 79% increased after 12 months of DHEA therapy, with a return to pretreatment values 3 months after cessation of treatment.”

In the paper

“the estrogenic stimulatory effect observed in the vagina was not found in the endometrium, which remained completely atrophic in all women after 12 months of DHEA treatment (280).”

What the sources say

• Not checked yetcites [280] Labrie, 1997, Effect of 12-month DHEA replacement therapy on bone, vaginum, and endometrium in postmenopausal women., J Clin Endocrinol Metab source

In the paper

“These changes in body fat and muscular surface areas were associated with a 12% decrease (P Ͻ 0.05) of fasting plasma glucose and a 17% decrease (P Ͻ 0.05) in fasting plasma insulin levels.”

In the paper

“In a series of animal models, androgens and DHEA have been found to inhibit breast cancer development and growth and to stimulate bone formation.”

In the paper

“serum DHEA and DHEA-S decrease by 50% between the ages of 21 and 40 yr but also that a similar decrease is observed for serum testosterone (26).”

What the sources say

• Not checked yetcites [26] Zumoff, 1995, Twenty-four-hour mean plasma testosterone concentration declines with age in normal premenopausal women., J Clin Endocrinol Metab

In the paper

“Such local biosynthesis and action of androgens in target tissues eliminates the exposure of other tissues to androgens and thus minimizes the risks of undesirable masculinizing or other androgen-related side effects.”

In the paper

“Our best estimate of the intracrine formation of estrogens in peripheral tissues in women is in the order of 75% before menopause and close to 100% after menopause (25).”

What the sources say

• Not checked yetcites [25] Labrie, 1991, Intracrinology., Mol Cell Endocrinol source

In the paper

“at 70 yr of age, serum DHEA-S levels are decreased to approximately 20% of their peak values, whereas they can decrease by 95% by the age of 85-90 yr (22).”

What the sources say

• Not checked yetcites [22] Migeon, 1957, Dehydroepiandrosterone and androsterone levels in human plasma. Effect of age and sex: day-to-day and diurnal variations., J Clin Endocrinol Metab source

In the paper

“These steroids are then metabolized in the same cells into inactive glucuronidated and sulfated metabolites, which finally diffuse in the extracellular compartment and can be measured in the circulation.”

In the paper

“it has been found that Western women having a low excretion of adrenal androgenic metabolites respond more poorly to endocrine therapy and have a shorter survival time (188 -190).”

What the sources say

• Not checked yetcites [188] Bulbrook, 1973, Effect of steroidal contraceptives on levels of plasma androgen sulphates and cortisol., Lancet source
• Not checked yetcites [189] Juret, 1968, New biological evidence on the hormone dependence of breast cancer (preliminary note)., Rev Fr Etud Clin Biol
• Not checked yetcites [190] Masnyk, 1978, Prediction of response to adrenalectomy in the treatment of advanced breast cancer., J Natl Cancer Inst source

In the paper

“In fact, the postmenopausal ovary is well known to secrete testosterone, and most authors agree that it also secretes some 4-dione (147, 148).”

What the sources say

• Not checked yetcites [147] Judd, 1974, Endocrine function of the postmenopausal ovary: concentration of androgens and estrogens in ovarian and peripheral vein blood., J Clin Endocrinol Metab source
• Not checked yetcites [148] Longcope, 1980, Steroid secretion by the postmenopausal ovary., Am J Obstet Gynecol source

In the paper

“Peripheral serum testosterone decreases by 50% after ovariectomy in postmenopausal women, thus indicating that the approximately equal contribution of the ovaries and adrenals to serum testosterone remains after menopause.”

What the sources say

• Not checked yetcites [158] Judd, 1974, Effect of oophorectomy on circulating testosterone and androstenedione levels in patients with endometrial cancer., Am J Obstet Gynecol source
• Not checked yetcites [159] Maroulis, 1976, Ovarian and adrenal contributions to peripheral steroid levels in postmenopausal women., Obstet Gynecol

In the paper

“the evidence obtained leaves little doubt that the antiproliferative effect of androgens does not result from competition for binding to the ER, but rather is caused by an AR-mediated mechanism that is additive to blockade of the ER by an antiestrogen.”

In the paper

“As previously described, MPA is a compound having a complex series of activities, namely progestational, glucocorticoid, and androgenic (231).”

What the sources say

• Not checked yetcites [231] Poulin, 1990, Multiple actions of synthetic “progestins” on the growth of ZR-75-1 human breast cancer cells: an in vitro model for the simultaneous assay of androgen, progestin, estrogen and glucocorticoid agonistic and antagonistic activities of compounds., Breast Cancer Res Treat source

In the paper

“Such data on ER expression provide an explanation for at least part of the antiestrogenic effects of androgens on breast cancer cell growth and provide an explanation for the observations showing that the specific inhibitory effects of androgen therapy are additive to the standard treatment limited to blockade of estrogens by antiestrogens (229).”

What the sources say

• Not checked yetcites [229] de Launoit, 1991, Characteristics of the biphasic action of androgens and of the potent antiproliferative effects of the new pure antiestrogen EM-139 on cell cycle kinetic parameters in LNCaP human prostatic cancer cells., Cancer Res

In the paper

“This inhibitory effect of androgens on intracellular ER concentrations may be expected to leave the relative effectiveness of the competitive blockade of estrogen action by antiestrogens unaffected, while decreasing the efficiency of any residual estrogenic stimulation of cell growth.”

In the paper

“the human adrenals secrete large amounts of the precursor steroids DHEA and DHEA-S, both of which are converted into androgens in target intracrine tissues (25,35,78,92,249,254,255).”

What the sources say

• Not checked yetcites [25] Labrie, 1991, Intracrinology., Mol Cell Endocrinol source
• Not checked yetcites [35] Labrie
• Not checked yetcites [78] Labrie, 1988, Androgenic activity of dehydroepiandrosterone and androstenedione in the rat ventral prostate., Endocrinology source
• Not checked yetcites [92] Labrie, 1997, The key role of 17β-HSDs in sex steroid biology., Steroids source
• Not checked yetcites [249] Labrie, 1989, Stimulation of androgen-dependent gene expression by the adrenal precursors dehydroepiandrosterone and androstenedione in the rat ventral prostate., Endocrinology source
• Not checked yetcites [254] Labrie, 1996, High bioavailability of DHEA administered percutaneously in the rat., J Endocrinol
• Not checked yetcites [255] Labrie, 1995, DHEA and peripheral androgen and estrogen formation: intracrinology., Ann NY Acad Sci source

In the paper

“the first androgen successfully used in the treatment of advanced breast cancer was testosterone propionate (250).”

What the sources say

• Not checked yetcites [250] Nathanson, 1947, Endocrine aspects of human cancer., Recent Prog Res

In the paper

“Labrie and colleagues (78, 249) first demonstrated that DHEA possesses relatively potent androgenic activity and stimulates androgen-dependent gene expression in the rat ventral prostate.”

What the sources say

• Not checked yetcites [78] Labrie, 1988, Androgenic activity of dehydroepiandrosterone and androstenedione in the rat ventral prostate., Endocrinology source
• Not checked yetcites [249] Labrie, 1989, Stimulation of androgen-dependent gene expression by the adrenal precursors dehydroepiandrosterone and androstenedione in the rat ventral prostate., Endocrinology source

In the paper

“DHEA can be converted in vivo and in vitro into the weak estrogen 5-diol, which interacts with the ER and can exert weak estrogen-like effects independent from aromatase (253,(267)(268)(269).”

What the sources say

• Not checked yetcites 253,(267)(268)(269)

In the paper

“human ZR-75-1 breast cancer cells do not express 3␤-HSD and are thus unable to synthesize androgens, thus explaining the stimulatory effect of DHEA on the growth of these cells under in vitro conditions (253)”

What the sources say

• Not checked yetcites [253] Poulin, 1986, Stimulation of cell proliferation and estrogenic response by adrenal C19-Δ5 -steroids in the ZR-75-1 human breast cancer cell line., Cancer

In the paper

“an absence of estrogens does not exist in women where comparable levels of E 2 are found in breast cancer tissue in pre-and postmenopausal women (272).”

What the sources say

• Not checked yetcites [272] Poortman, 1983, Subcellular distribution of androgens and oestrogens in target tissue., J Steroid Biochem source

In the paper

“recent data suggest that progestins exert a negative impact on breast cancer (2-5), with recent reports indicating an increased risk of the disease in women (6,7).”

What the sources say

• Not checked yetcites [2] Horwitz, 1992, The molecular biology of RU486. Is there a role for antiprogestins in the treatment of breast cancer?, Endocr Rev
• Not checked yetcites [3] Musgrove, 1991, Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor α, epidermal growth factor receptor, c-fos, and c-myc genes., Mol Cell Biol source
• Not checked yetcites [4] Clarke, 1990, Progestin regulation of cellular proliferation., Endocr Rev source
• Not checked yetcites [5] Colditz, 1995, The use of estrogens and progestins and the risk of breast cancer in postmenopausal women., N Engl J Med source
• Not checked yetcites [6] Ross, 2000, Effect of hormone replacement therapy on breast cancer risk: estrogen vs. estrogen plus progestin., J Natl Cancer Inst source
• Not checked yetcites [7] Magnusson, 1999, Breast-cancer risk following long-term oestrogen- and oestrogen-progestin-replacement therapy., Int J Cancer source

In the paper

“DHEA is well known to be converted into androgens, and treatment with DHEA is known to induce androgen-sensitive gene expression in the rat ventral prostate (78, 249).”

What the sources say

• Not checked yetcites [78] Labrie, 1988, Androgenic activity of dehydroepiandrosterone and androstenedione in the rat ventral prostate., Endocrinology source
• Not checked yetcites [249] Labrie, 1989, Stimulation of androgen-dependent gene expression by the adrenal precursors dehydroepiandrosterone and androstenedione in the rat ventral prostate., Endocrinology source

In the paper

“by itself, DHEA does not possess any significant androgenic or estrogenic activity, its activity being dependent upon its transformation into androgens and/or estrogens in peripheral target intracrine tissues (25).”

What the sources say

• Not checked yetcites [25] Labrie, 1991, Intracrinology., Mol Cell Endocrinol source

In the paper

“DHEA, secondary to its predominant transformation into androgens in mammary gland tissue, exerts an inhibitory effect on mammary carcinoma development and growth, an effect that counteracts and can even completely neutralize the stimulatory effect of estrogens.”

In the paper

“it is likely that endogenous androgens and DHEA play an important physiological role in the control of normal breast tissue growth and function and that this antagonism between androgens and estrogens is also operative in breast cancer.”

In the paper

“A group of researchers have reported that DHEA is inhibitory on breast cancer growth in the presence of estrogens, whereas it can be stimulatory on experimental models in which estrogens are absent (197,270).”

What the sources say

• Not checked yetcites [197] Secreto, 1991, Serum and urinary androgens and risk of breast cancer in postmenopausal women., Cancer Res
• Not checked yetcites [270] Boccuzzi, 1992, Opposite effects of dehydroepiandrosterone on the growth of 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinomas., Anticancer Res

In the paper

“all these benefits, including improved libido, have been obtained without significant side effect (73, 74).”

What the sources say

• Not checked yetcites [73] Baulieu, 2000, Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a sociobiomedical issue., Proc Natl Acad Sci USA source
• Not checked yetcites [74] Stomati, 2000, Six-months oral dehydroepiandrosterone supplementation in early and late postmenopause., Gynecol Endocrinol source

In the paper

“The 70 -95% reduction in the formation of DHEA and DHEA-S by the adrenals during aging results in a dramatic reduction in the formation of androgens and estrogens in peripheral target tissues, which could well be involved in the pathogenesis of age-related diseases such as insulin resistance (307, 308) and obesity (309 -311).”

What the sources say

• Not checked yetcites [307] Schriock, 1988, Divergent correlations of circulating dehydroepiandrosterone sulfate and testosterone with insulin levels and insulin receptor binding., J Clin Endocrinol Metab source
• Not checked yetcites [308] Coleman, 1982, Therapeutic effects of dehydroepiandrosterone (DHEA) in diabetic mice., Diabetes source
• Not checked yetcites [309] Nestler, 1988, Dehydroepiandrosterone reduces serum low density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men., J Clin Endocrinol Metab source
• Not checked yetcites [310] MacEwen, 1991, Obesity in the dog: role of the adrenal steroid dehydroepiandrosterone (DHEA)., J Nutr source
• Not checked yetcites [311] Tchernof, 1995, Reduced testosterone and adrenal C19 steroid levels in obese men., Metabolism source

In the paper

“DHEA has been shown to have immunomodulatory effects in vitro (313) and in vivo in fungal and viral diseases (314), including HIV (315), and a stimulatory effect of DHEA on the immune system has been described in postmenopausal women (316).”

What the sources say

• Not checked yetcites [313] Suzuki, 1991, Dehydroepiandrosterone enhances IL2 production and cytotoxic effector function of human T cells., Clin Immunol Immunopathol source
• Not checked yetcites [314] Rasmussen, 1992, Effectiveness of dehydroepiandrosterone in reduction of cryptosporidial activity in immunosuppressed rats., Antimicrob Agents Chemother source
• Not checked yetcites [315] Henderson, 1992, Dehydroepiandrosterone (DHEA) and synthetic DHEA analogs are modest inhibitors of HIV-1 IIIB replication., AIDS Res Hum Retroviruses source

In the paper

“DHEA replacement in Addison's disease is associated with an improvement in psychological well-being, mood, and fatigue (70).”

What the sources say

• Not checked yetcites [70] Hunt, 2000, Improvement in mood and fatigue after dehydroepiandrosterone replacement in Addison’s disease in a randomized, double blind trial., J Clin Endocrinol Metab

In the paper

“Testosterone administration to elderly men increases the fractional synthetic rate of muscle protein as well as muscle strength (320).”

What the sources say

• Not checked yetcites [320] Urban, 1995, Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis., Am J Physiol

In the paper

“women, at menopause, are not only deprived from estrogens because of a rapid loss of ovarian activity but also have been deprived from androgens for a longer period because of a progressive decrease of serum DHEA levels starting quite a few years before menopause.”

What the sources say

• Not checked yetcites [23] Labrie, 1997, Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging., J Clin Endocrinol Metab source
• Not checked yetcites [25] Labrie, 1991, Intracrinology., Mol Cell Endocrinol source
• Not checked yetcites [27] Labrie, 1997, Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: intracrinology., J Clin Endocrinol Metab source
• Not checked yetcites [33] Labrie, 2000, Intracrinology: role of the family of 17β-hydroxysteroid dehydrogenases in human physiology and disease., J Mol Endocrinol source
• Not checked yetcites [84] Labrie, 1992, Structure, function and tissue-specific gene expression of 3β-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase enzymes in classical and peripheral intracrine steroidogenic tissues., J Steroid Biochem Mol Biol source
• Not checked yetcites [86] Labrie, 1995, The human type II 17β-hydroxysteroid dehydrogenase gene encodes two alternatively-spliced messenger RNA species., DNA Cell Biol source
• Not checked yetcites [90] Labrie, 1994, Structure, regulation and role of 3β-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase and aromatase enzymes in formation of sex steroids in classical and peripheral intracrine tissues., Baillière’s Clin Endocrinol Metab source
• Not checked yetcites [92] Labrie, 1997, The key role of 17β-HSDs in sex steroid biology., Steroids source
• Not checked yetcites [261] Labrie, 1992, Structure and tissue-specific expression of 3β-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase genes in human and rat classical and peripheral steroidogenic tissues., J Steroid Biochem Mol Biol source
• Not checked yetcites [280] Labrie, 1997, Effect of 12-month DHEA replacement therapy on bone, vaginum, and endometrium in postmenopausal women., J Clin Endocrinol Metab source

In the paper

“The use of ERT requires the addition of progestins to counteract the endometrial proliferation induced by estrogens, whereas both estrogens and progestins could increase the risk of breast cancer (5,318).”

What the sources say

• Not checked yetcites [5] Colditz, 1995, The use of estrogens and progestins and the risk of breast cancer in postmenopausal women., N Engl J Med source
• Not checked yetcites [318] Bardon, 1985, RU486, a progestin and glucocorticoid antagonist, inhibits the growth of breast cancer cells via the progesterone receptor., J Clin Endocrinol Metab source

In the paper

“The observed stimulatory effect of DHEA on bone mineral density and the increase in serum osteocalcin, a marker of bone formation, are of particular interest for the prevention and treatment of osteoporosis and indicate a unique activity of DHEA on bone physiology, namely a stimulation of bone formation, whereas ERT and HRT can only reduce the rate of bone loss.”

In the paper

“at physiological replacement doses, DHEA does not stimulate the endometrium, thus removing the need to use a progestin to counteract the stimulation of the endometrium by estrogen.”

In the paper

“Although bone formation, inhibition of mammary gland proliferation, stimulation of sebaceous glands, muscle mass increase, and improved libido are attributed to the formation of androgens in the corresponding target tissues, the decreased insulin resistance and vaginal maturation are best explained by the local formation of estrogens.”

In the paper

“The absence of stimulation of the endometrium by DHEA eliminates the need for progestin replacement therapy, thus avoiding the fear of progestininduced breast cancer added to the well known stimulatory effect of estrogens.”

In the paper

“A significant improvement in mood and well-being was observed in patients with major depression (331) and midlife asthenia (332), whereas no effect was detected in perimenopausal women (333).”

What the sources say

• Not checked yetcites [331] Wolkowitz, 1999, Double-blind treatment of major depression with dehydroepiandrosterone., Am J Psychiatry source
• Not checked yetcites [332] Bloch, 1999, Dehydroepiandrosterone treatment of midlife dysthymia., Biol Psychiatry source
• Not checked yetcites [333] Barnhart, 1999, The effect of dehydroepiandrosterone supplementation to symptomatic perimenopausal women on serum endocrine profiles, lipid parameters, and health-related quality of life., J Clin Endocrinol Metab

In the paper

“In summary, at physiological replacement doses, DHEA has been found in clinical studies to induce a series of beneficial effects closely associated with the protection of women's health, whereas no negative effects have been observed.”

In the paper

“scores of activity of daily living were improved by DHEA in patients with myotonic dystrophy (329), whereas no change was observed in healthy elderly men (330).”

What the sources say

• Not checked yetcites [329] Sugino, 1998, A pilot study of dehydroepiandrosterone sulfate in myotonic dystrophy., Neurology source
• Not checked yetcites [330] Flynn, 1999, Dehydroepiandrosterone replacement in aging humans., J Clin Endocrinol Metab