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Effects of Oral Androstenedione Administration on Serum Testosterone and Estradiol Levels in Postmenopausal Women

Endocrine Unit (B.Z.L., K.M.L., J.S.F.), Department of Medicine, and Biostatistics Center (H.L.), Massachusetts General Hospital, Boston, Massachusetts 02114; Departments of Medicine and Obstetrics and Gynecology (C.L.), University of Massachusetts Medical School, Worcester, Massachusetts 01655; and Departments of Medicine and Molecular and Medical Pharmacology (D.H.C.), Olympic Analytical Laboratory, University of California at Los Angeles, Los Angeles, California 90025

Address all correspondence and requests for reprints to: Benjamin Z. Leder, Endocrine Unit, Massachusetts General Hospital, Bulfinch 327, Fruit Street, Boston, Massachusetts 02114. E-mail: bzleder{at}partners.org.

Abstract

Androstenedione is a steroid hormone and an intermediate in the synthetic pathway of both testosterone and estradiol in men and women. It is available without prescription and taken with the expectation that it may have beneficial effects on strength, general well-being, libido, and quality of life. Although studies have shown that oral androstenedione increases serum testosterone and estradiol levels in men, the hormonal effects of androstenedione in postmenopausal women are unknown. We randomly assigned 30 healthy postmenopausal women to receive 0, 50, or 100 mg androstenedione as a single oral dose. After androstenedione administration, we made hourly measurements of serum androstenedione, estrone, estradiol, and testosterone concentrations during 12 h of frequent blood sampling. The mean change (±SD) in serum androstenedione area under the curve (AUC) was greater in both the 50-mg (79 ± 39%) and 100-mg dose groups (242 ± 184%) than in the control group (-29 ± 28%) (P < 0.0001 for controls vs. 50-mg group and controls vs. 100-mg group). The mean change in serum androstenedione AUC was also greater in the 100-mg than 50-mg dose group (P = 0.0026). The mean change in serum estrone AUC was greater in both the 50-mg (108 ± 72%) and 100-mg dose groups (116 ± 119%) than in the control group (-5 ± 19%), although the control vs. 100-mg group comparison did not quite meet statistical significance (P < 0.0001 for controls vs. 50-mg group, P = 0.0631 controls vs. 100-mg group). The mean change in serum estradiol AUC remained stable after supplementation in all groups without any between-group differences observed (-11 ± 17%, 2.8 ± 34%, -11 ± 27%, for the control, 50-mg, and 100-mg groups, respectively). The mean change in serum testosterone AUC was greater in both the 50-mg (185 ± 146%) and 100-mg dose groups (457 ± 601%) than in the control group (-27 ± 13%) (P < 0.0001 for controls vs. 50-mg group and for controls vs. 100-mg group). The mean change in testosterone AUC was also greater in the 100-mg dose group than 50-mg dose group (P = 0.0257). There was considerable individual variability in the changes of serum androstenedione, estrone, and testosterone levels in the treated groups with peak serum testosterone levels exceeding the upper limit of normal in 4 of 10 women in the 50-mg dose group and 6 of 10 in the 100-mg dose group. We concluded that the acute administration of both 50-mg and 100-mg of androstenedione increases serum testosterone and estrone levels, but not estradiol levels, in postmenopausal women. If these hormonal effects are sustained during long-term administration, regular use of this supplement by postmenopausal women could thus cause both beneficial and adverse effects.

ANDROSTENEDIONE IS A steroid hormone and the immediate precursor to testosterone and estrone in the endogenous synthetic pathways of androgens and estrogens (1, 2, 3). In the United States, androstenedione is categorized as a dietary supplement by the Dietary Supplement Health and Education Act of 1994 and is available without prescription. Some manufacturers of androstenedione supplements claim that it is an anabolic, performance-enhancing substance and may have beneficial effects on general well-being, libido, and quality of life. These claims have not been substantiated in the peer-reviewed literature.

Since a single report 4 decades ago that the oral administration of 100 mg androstenedione increased serum testosterone levels in two women (4), research on androstenedione use has focused on the effects of the supplement in men. Although single androstenedione doses of up to 300 mg are necessary to increase serum testosterone levels modestly in men, doses as small as 100 mg increase serum estradiol concentrations, often into the supraphysiological range (5, 6, 7, 8, 9, 10, 11, 12, 13).

Menopause is associated with the cessation of menses and very low levels of circulating estrogens. Most, but not all, studies indicate that serum testosterone and androstenedione concentrations also decrease slightly after the menopause (14, 15, 16, 17, 18, 19). Serum androgen levels are even lower in women who have undergone oophorectomy, (20, 21, 22) and postmenopausal women receiving estrogen (23). Hormone replacement therapy (HRT) with estrogens (+ progesterone) is often used to treat menopausal symptoms and prevent bone loss. More recently some investigators have proposed that combining estrogen with androgen administration provides advantages over traditional HRT (24, 25, 26). Because androstenedione is converted to both testosterone and estradiol in men, androstenedione administration may be a means of providing physiologic testosterone and estrogen replacement in postmenopausal women.

To assess the hormonal and pharmacokinetic effects of androstenedione in postmenopausal women and to determine whether androstenedione could potentially provide physiologic estrogen and androgen replacement in this population, we randomized 30 postmenopausal women to receive 0 mg (controls), 50 mg, or 100 mg androstenedione as a single oral dose. After androstenedione administration, we then measured serum sex hormone concentrations hourly for 12 h.

Subjects and Methods

Study subjects

We studied 30 healthy volunteers between the ages of 47 and 64 yr. All subjects were postmenopausal and had not had a menstrual period for at least 1 yr. Baseline estradiol levels were required to be less than 25 pg/ml with FSH levels in the postmenopausal range (18–153 U/liter). All subjects had normal liver function and renal function. Women with a history of cardiopulmonary disease, malignancy, major psychiatric disease, or substance abuse were excluded. Women were also excluded if they reported using medications known to affect steroid hormone or steroid hormone-binding protein levels within 6 months before study enrollment. All subjects were recruited through approved postings at Massachusetts General Hospital and affiliated institutions and advertisements in local newspapers. The study was approved by the Human Research Committee at Partners Healthcare Systems, and all study participants gave written informed consent.

Protocol

After screening, subjects were randomly allocated by computer-generated assignment to one of the three treatment groups: no androstenedione (controls, n = 10), 50 mg androstenedione (Nutratech, Fairfield, NJ) in a single oral dose (n = 10), or 100 mg androstenedione in a single oral dose (n = 10). Androstenedione supplements were administered to all noncontrol subjects at approximately 0800 h. All subjects were fasting for a minimum of 8 h before androstenedione administration and then remained fasting for an additional 2 h after androstenedione administration. Serum androstenedione, testosterone, estradiol, and estrone concentrations were measured immediately before supplement administration (time 0) and then hourly for 12 h.

Analysis of androstenedione

The androstenedione was obtained in bulk powder form from the manufacturer. Fifty-milligram doses were weighed and placed in capsules by a research pharmacist at Massachusetts General Hospital. Four portions of the bulk powder were analyzed for trace contaminants by HPLC and LC-tandem mass spectrometry (LC-MS-MS). All portions contained androstenedione as determined by HPLC and LC-MS-MS (PE-Sciex API 300; Applied Diagnostics, Foster City, CA). The mass spectrum of the androstenedione peak was identical to that of the reference standard of 4-androstene-3,17-dione (lot 18-C0226, Sigma, St. Louis, MO). Other peaks were present in the chromatograms; however, all were less than 1% of the androstenedione peak. Of these peaks, none were 19-norandrostenedione, dehydroepiandrosterone (DHEA), or 19-norandrosterone. Miniscule amounts of testosterone were identified (mean = 0.67%, range 0.60–0.70%). Given the known poor oral bioavailability of testosterone, this amount of testosterone (no more than 670 µg for the group that received the 100-mg dose of androstenedione) would not have contributed appreciable amounts to the serum testosterone levels in our subjects. For example, when 20 mg isotopic-labeled testosterone (more than 25 times the amount given to subjects in our highest dose group) was given to normal men, peak levels of labeled testosterone were only100–220 ng/dl (27). Thus, the calculated expected contribution to serum testosterone levels in our subjects attributable to testosterone contamination is no more than 10 ng/dl.

Serum measurements

Serum testosterone (Diagnostic Products, Los Angeles, CA), estrone, and androstenedione (Diagnostic Systems Laboratories, Inc., Webster, TX) concentrations were measured by RIA. The intra- and interassay coefficients of variation for testosterone, estrone, and androstenedione were 5.1%, 5.0%, and 3.8% and 10.1%, 10.0%, and 8.7%, respectively. The cross-reactivity of androstenedione in the testosterone assay was 0.5%. Because estradiol levels were very low in our subjects at baseline, an ultrasensitive semiautomated estradiol immunoassay was used. This assay was modified from the Diagnostics Automated Chemiluminescent System E2–6 17ß-estradiol assay (Bayer Corp. , Tarrytown, NY) and has intra- and interassay coefficients of variation of 8–12% and 3–12%, respectively. The analytic sensitivity of this assay is 1 pg/ml, and there is no significant cross-reactivity with other steroid hormones. All samples for an individual subject were analyzed in the same assay.

Statistical analysis

The primary end point was net change in area under the curve (AUC) during the periods of frequent blood sampling for each gonadal steroid. Net change in AUC was defined as the total AUC minus the baseline AUC (calculated by assuming no change in hormone levels after the time 0 measurement). The mean net change in AUC for each hormone was then compared (after log transformation) using an analysis of covariance, adjusting for the baseline level of the hormone. Between-group differences in mean baseline-to-peak change for each hormone (defined as the highest levels achieved during frequent blood sampling minus the baseline level) were also compared by analysis of covariance, adjusting for the baseline level of the hormone. Baseline clinical characteristics were compared using the Kruskal-Wallis test. P values (two-sided) less than 0.05 are considered statistically significant. All data are expressed as mean ± SD unless otherwise indicated.

Results

Table 1 shows the baseline clinical characteristics and serum hormone levels of the study groups. Although there appeared to be some differences among groups (particularly higher weight and body mass index in the control group), none was statistically significant.

View larger version (31K): [in this window] [in a new window]   Figure 1. Mean ± SEM serum steroid hormone levels during the 12-h blood sampling. •, Controls; , 50-mg group; , 100-mg group.

View larger version (20K): [in this window] [in a new window]   Figure 2. Mean ± SEM percentage change in AUC for each steroid hormone. *, P < 0.0001, compared with controls; #, P = 0.0631, compared with controls; &, P < 0.05, compared with 50-mg group;

Mean baseline and peak serum hormone levels are shown in Table 2. There was considerable individual variability in the peak serum androstenedione, estrone, and testosterone levels in the treated groups. Peak serum testosterone levels exceeded the upper limit of normal in 4 of 10 women in the 50-mg dose group and 6 of 10 in the 100-mg dose group. Peak serum androstenedione levels exceeded the upper limit of normal (200 ng/dl) in all women in the 100-mg dose group and 8 of 10 in the 50-mg dose group.

This study shows that a single dose of oral androstenedione increases serum testosterone, androstenedione, and estrone levels in postmenopausal women but has no effect on serum estradiol levels. These results contrast with those reported in numerous studies done in men showing that androstenedione administration increases serum estradiol levels but does not affect serum testosterone levels at equivalent doses (5, 6, 7, 8, 9, 10, 11, 12, 13). For example, in our previous study done in young men, 100 mg androstenedione increased estradiol AUC significantly by nearly 50% but did not increase testosterone AUC (11). There are several possible explanations for the differences in the hormonal effects of androstenedione between men and women. First, because baseline serum testosterone levels in men are higher than in women, the changes in serum testosterone seen in this study (although dramatic on a percentage basis) may have been missed in young men. Moreover, patterns of steroid metabolism differ in men and women. For example, rates of peripheral aromatization of androgens to estrogens are approximately 50% lower in women, compared with men (2), a difference that might explain the failure of androstenedione administration to increase serum estradiol in women. Furthermore, it is possible that androstenedione metabolism is dominated by aromatization in the setting of high testosterone levels (i.e. in men), whereas oxidation of androstenedione (conversion to testosterone) is the preferred pathway of androstenedione metabolism in the setting of low testosterone levels (i.e. in women). This latter hypothesis could be tested by exploring the hormonal effects of androstenedione administration in hypogonadal men.

The hormonal effects of oral DHEA, the immediate precursor to androstenedione in the intrinsic gonadal-steroid synthetic pathway, have been studied extensively in postmenopausal women. Most of these studies report that oral DHEA administration increases serum testosterone levels in postmenopausal women (28, 29, 30, 31, 32). Studies have also shown that oral DHEA administration increases serum estradiol levels in postmenopausal women and women with panhypopituitarism (28, 32, 33). It is unclear why oral DHEA may be a better substrate for metabolism to estradiol than is androstenedione, but it may be because oral DHEA is converted to DHEA-sulfate (DHEAS) after administration. DHEAS is bound strongly to albumin and has a very low metabolic clearance rate (about 12 liters/d, compared with the metabolic clearance rate of androstenedione of 1800–2000 liters/d) (34). Thus, a single dose of DHEA provides sustained increases in DHEAS levels (30), and circulating DHEAS is available for both desulfation and aromatization in peripheral tissues (35).

Because our study measured the response to only a single dose of androstenedione, the clinical implications remain somewhat speculative. It is unknown, for example, whether the changes in gonadal steroids observed in this study would remain constant over time or whether changes in conversion rates would occur during chronic administration. The pattern of the changes, however, suggests several possible physiologic consequences. Serum estradiol levels did not increase after androstenedione administration, and estrone increased marginally, whereas testosterone levels increased dramatically. Given that the estrogenic potency of estrone is considerably less than that of estradiol (36, 37), it thus seems likely that androstenedione, if given over prolonged periods, will have more androgenic than estrogenic effects in postmenopausal women. Furthermore, if the hormonal effects of androstenedione remain constant during chronic administration, it would appear that it is an unsuitable substitute for conventional HRT in postmenopausal women. Conversely, oral androstenedione supplementation could potentially be used to provide androgenic supplementation in women who desire combined estrogen-androgen replacement therapy. Over the past several years, the role of androgen therapy in postmenopausal women has become an area of increasing clinical interest. Compared with traditional HRT, combined testosterone and estrogen therapy improves vasomotor symptoms, sexual function, and psychological well-being in postmenopausal women (both surgically and nonsurgically induced) (38, 39, 40, 41, 42, 43). Additionally, compared with traditional HRT, combined testosterone and estrogen therapy increases bone mineral density and muscle strength and has beneficial effects on body composition (42, 43, 44, 45). Thus, if the short-term hormonal effects of oral androstenedione are sustained during long-term administration, androstenedione use may provide similar beneficial effects. Furthermore, as an inexpensive, orally active agent without the documented hepatotoxicity associated with oral administration of 17-alkylated derivatives of testosterone (46, 47, 48), oral androstenedione may be a useful addition to the current treatment options available at the menopause.

Over-the-counter androstenedione supplements were originally marketed as performance-enhancing substances and legal alternatives to traditional anabolic/androgenic steroids. The original users of the supplement were male body builders, but its popularity has widened since its introduction in the late 1990s. In a recent survey done in five health clubs in Boston, Massachusetts, for example, 3% of women responders reported using androstenedione or other adrenal hormone dietary supplements at least once, a percentage suggesting that as many as 200,000 women in the United States have used these substances (49). Despite this widespread use, however, it is not known if androstenedione is anabolic or performance enhancing in men or women. Given the significant increases in testosterone observed in postmenopausal women in this study, however, and the ability of even small testosterone doses to affect muscle mass and strength in women (43), it is certainly possible that female users of oral androstenedione could experience anabolic effects. Finally, although harmful effects of androstenedione have not yet been documented, androstenedione use could have deleterious effects, particularly in high doses. For example, because androstenedione increases serum testosterone levels in women, hirsutism and virilization are potential long-term problems. In children, androstenedione use could lead to precocious puberty.

We conclude that a single oral dose of androstenedione increases serum testosterone but not serum estradiol levels in postmenopausal women. If these short-term effects are sustained, regular use of this supplement in postmenopausal women could potentially have both beneficial and adverse effects. Long-term studies are needed to define the potential clinical applications and side effect profile of this readily available and widely used substance. In the interim, given that androstenedione is clearly converted to potent steroid hormones in both sexes, its continued classification as a dietary supplement remains highly questionable.

Acknowledgments

We are grateful to the nursing staff of the Mallinckrodt General Clinical Research Center for its meticulous performance of the study protocol and to Charlene Franz for her invaluable help in analyzing the serum sex steroids.

Footnotes

This work was supported by NIH Grants K23-RR16310 (to B.Z.L.), K24-DK02759 (to J.S.F.), and RR-1066 (to the Massachusetts General Hospital Clinical Research Center); and a grant from the Sport Consortium (NCAA, NFL, and United States Anti-Doping Agency; to D.H.C.).

Abbreviations: AUC, Area under the curve; DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate; HRT, hormone replacement therapy; LC-MS-MS, LC-tandem mass spectrometry.

Received July 5, 2002.

Accepted August 27, 2002.

References

1. Horton R, Tate JF 1966 Androstenedione production and interconversion rates measured in peripheral blood and studies on the possible site of conversion to testosterone. J Clin Invest 45:301–313
2. Longcope C, Kato T, Horton R 1969 Conversion of blood androgens to estrogens in normal adult men and women. J Clin Invest 48:2191–2201
3. Weinstein RL, Kelch RP, Jenner MR, Kaplan SL, Grumbach MM 1974 Secretion of unconjugated androgens and estrogens by the normal and abnormal human testis before and after human chorionic gonadotropin. J Clin Invest 53:1–6
4. Mahesh VB, Greenblatt RB 1962 The in vivo conversion of dehydroepiandrosterone and androstenedione to testosterone in the human. Acta Endocrinol 41:400–406
5. Broeder CE, Quindry J, Brittingham K, Panton L, Thomson J, Appakondu S, Breuel K, Byrd R, Douglas J, Earnest C, Mitchell C, Olson M, Roy T, Yarlagadda C 2000 The Andro Project: physiological and hormonal influences of androstenedione supplementation in men 35 to 65 years old participating in a high-intensity resistance training program. Arch Intern Med 160:3093–3104[Abstract/Free Full Text]
6. Brown GA, Vukovich MD, Reifenrath TA, Uhl NL, Parsons KA, Sharp RL, King DS 2000 Effects of anabolic precursors on serum testosterone concentrations and adaptations to resistance training in young men. Int J Sport Nutr Exerc Metab 10:340–359[Medline]
7. Brown GA, Vukovich MD, Martini ER, Kohut ML, Franke WD, Jackson DA, King DS 2001 Effects of androstenedione-herbal supplementation on serum sex hormone concentrations in 30- to 59-year-old men. Int J Vitam Nutr Res 71:293–301[CrossRef][Medline]
8. Earnest CP, Olson MA, Broeder CE, Breuel KF, Beckham SG 2000 In vivo 4-androstene-3, 17-dione and 4-androstene-3 beta, 17 beta-diol supplementation in young men. Eur J Appl Physiol 81:229–232[CrossRef][Medline]
9. Ballantyne CS, Phillips SM, MacDonald JR, Tarnopolsky MA, MacDougall JD 2000 The acute effects of androstenedione supplementation in healthy young males. Can J Appl Physiol 25:68–78[Medline]
10. King DS, Sharp RL, Vukovich MD, Brown GA, Reifenrath TA, Uhl NL, Parsons KA 1999 Effect of oral androstenedione on serum testosterone and adaptations to resistance training in young men. JAMA 281:2020–2028[Abstract/Free Full Text]
11. Leder BZ, Longcope C, Catlin DH, Ahrens B, Schoenfeld DA, Finkelstein JS 2000 Oral androstenedione administration and serum testosterone concentrations in young men. JAMA 283:779–782[Abstract/Free Full Text]
12. Rasmussen BB, Volpi E, Gore DC, Wolfe RR 2000 Androstenedione does not stimulate muscle protein anabolism in young healthy men. J Clin Endocrinol Metab 85:55–59[Abstract/Free Full Text]
13. Wallace MB, Lim J, Cutler A, Bucci L 1999 Effects of dehydroepiandrosterone vs androstenedione supplementation in men. Med Sci Sports Exerc 31:1788–1792[Medline]
14. Overlie I, Moen MH, Morkrid L, Skjaeraasen JS, Holte A 1999 The endocrine transition around menopause—a five year prospective study with profiles of gonadotropins, estrogens, androgens and SHBG among healthy women. Acta Obstet Gynecol Scand 78:642–647[CrossRef][Medline]
15. Rannevik G, Jeppsson S, Johnell O, Bjerre B, Laurell-Borulf Y, Svanberg L 1995 A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas 21:103–113[CrossRef][Medline]
16. Longcope C, Jaffee W, Griffing G 1981 Production rates of androgens and oestrogens in post-menopausal women. Maturitas 3:215–223[CrossRef][Medline]
17. Longcope C, Franz C, Morello C, Baker R, Johnston Jr CC 1986 Steroid and gonadotropin levels in women during the peri-menopausal years. Maturitas 8:189–196[CrossRef][Medline]
18. Judd HL 1976 Hormonal dynamics associated with the menopause. Clin Obstet Gynecol 19:775–788[Medline]
19. Labrie F, Belanger A, Cusan L, Gomez JL, Candas B 1997 Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab 82:2396–2402[Abstract/Free Full Text]
20. Judd HL, Lucas WE, Yen SS 1974 Effect of oophorectomy on circulating testosterone and androstenedione levels in patients with endometrial cancer. Am J Obstet Gynecol 118:793–798[Medline]
21. Shifren JL, Schiff I 2000 The aging ovary. J Womens Health Gend Based Med 9:S3–S7
22. Vermeulen A 1976 The hormonal activity of the postmenopausal ovary. J Clin Endocrinol Metab 42:247–253[Abstract]
23. Casson PR, Elkind-Hirsch KE, Buster JE, Hornsby PJ, Carson SA, Snabes MC 1997 Effect of postmenopausal estrogen replacement on circulating androgens. Obstet Gynecol 90:995–998[Abstract]
24. Sherwin BB 1998 Use of combined estrogen-androgen preparations in the postmenopause: evidence from clinical studies. Int J Fertil Womens Med 43:98–103[Medline]
25. Davis SR, Burger HG 1996 Clinical review 82: androgens and the postmenopausal woman. J Clin Endocrinol Metab 81:2759–2763[CrossRef][Medline]
26. Hoeger KM, Guzick DS 1999 The use of androgens in menopause. Clin Obstet Gynecol 42:883–894[CrossRef][Medline]
27. Baba S, Shinohara Y, Kasuya Y 1980 Differentiation between endogenous and exogenous testosterone in human plasma and urine after oral administration of deuterium-labeled testosterone by mass fragmentography. J Clin Endocrinol Metab 50:889–894[Abstract]
28. Genazzani AD, Stomati M, Strucchi C, Puccetti S, Luisi S, Genazzani AR 2001 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 76:241–248[CrossRef][Medline]
29. Morales AJ, Haubrich RH, Hwang JY, Asakura H, Yen SS 1998 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) 49:421–432[CrossRef][Medline]
30. Mortola JF, Yen SSC 1990 The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women. J Clin Endocrinol Metab 71:696–704[Abstract]
31. Morales AJ, Nolan JJ, Nelson JC, Yen SSC 1994 Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 78:1360–1367[Abstract]
32. Stomati M, Monteleone P, Casarosa E, Quirici B, Puccetti S, Bernardi F, Genazzani AD, Rovati L, Luisi M, Genazzani AR 2000 Six-month oral dehydroepiandrosterone supplementation in early and late postmenopause. Gynecol Endocrinol 14:342–363[Medline]
33. Young J, Couzinet B, Nahoul K, Brailly S, Chanson P, Baulieu EE, Schaison G 1997 Panhypopituitarism as a model to study the metabolism of dehydroepiandrosterone (DHEA) in humans. J Clin Endocrinol Metab 82:2578–2585[Abstract/Free Full Text]
34. Longcope C 1998 Androgen metabolism and the menopause. Semin Reprod Endocrinol 16:111–115[Medline]
35. Martel C, Melner MH, Gagne D, Simard J, Labrie F 1994 Widespread tissue distribution of steroid sulfatase, 3ß-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3ß-HSD), 17ß-HSD 5-reductase and aromatase activities in the rhesus monkey. Mol Cell Endocrinol 104:103–111[CrossRef][Medline]
36. Korenman SG 1969 Comparative binding affinity of estrogens and its relation to estrogenic potency. Steroids 13:163–177[CrossRef][Medline]
37. Emmens CW, Cox RI, Martin L 1962 Antiestrogens. Rec Progr Horm Res 18:415–458
38. Simon J, Klaiber E, Wiita B, Bowen A, Yang HM 1999 Differential effects of estrogen-androgen and estrogen-only therapy on vasomotor symptoms, gonadotropin secretion, and endogenous androgen bioavailability in postmenopausal women. Menopause 6:138–146[Medline]
39. Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP, Burki RE, Ginsburg ES, Rosen RC, Leiblum SR, Caramelli KE, Mazer NA 2000 Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 343:682–688[Abstract/Free Full Text]
40. Sherwin BB, Gelfand MM 1987 The role of androgen in the maintenance of sexual functioning in oophorectomized women. Psychosom Med 49:397–409[Abstract/Free Full Text]
41. Sherwin BB, Gelfand MM, Brender W 1985 Androgen enhances sexual motivation in females: a prospective, crossover study of sex steroid administration in the surgical menopause. Psychosom Med 47:339–351[Abstract/Free Full Text]
42. Davis SR, McCloud P, Strauss BJ, Burger H 1995 Testosterone enhances estradiol’s effects on postmenopausal bone density and sexuality. Maturitas 21:227–236[CrossRef][Medline]
43. Dobs AS, Nguyen T, Pace C, Roberts CP 2002 Differential effects of oral estrogen versus oral estrogen-androgen replacement therapy on body composition in postmenopausal women. J Clin Endocrinol Metab 87:1509–1516[Abstract/Free Full Text]
44. Barrett-Connor E, Young R, Notelovitz M, Sullivan J, Wiita B, Yang HM, Nolan J 1999 A two-year, double-blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women. Effects on bone mineral density, symptoms and lipid profiles. J Reprod Med 44:1012–1020[Medline]
45. Watts NB, Notelovitz M, Timmons MC, Addison WA, Wiita B, Downey LJ 1995 Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause. Obstet Gynecol 85:529–537[Abstract]
46. Bagheri SA, Boyer JL 1974 Peliosis hepatis associated with androgenic-anabolic steroid therapy. A severe form of hepatic injury. Ann Intern Med 81:610–618
47. Ishak KG, Zimmerman HJ 1987 Hepatotoxic effects of the anabolic/androgenic steroids. Semin Liver Dis 7:230–236[Medline]
48. Turani H, Levi J, Zevin D, Kessler E 1983 Hepatic lesions in patients on anabolic androgenic therapy. Isr J Med Sci 19:332–337[Medline]
49. Kanayama G, Gruber AJ, Pope Jr HG, Borowiecki JJ, Hudson JI 2001 Over-the-counter drug use in gymnasiums: an underrecognized substance abuse problem? Psychother Psychosom 70:137–140[CrossRef][Medline]

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