Endocrine and Intracrine Sources of Androgens in Women: Inhibition of Breast Cancer and Other Roles of Androgens and Their Precursor Dehydroepiandrosterone
Fernand Labrie,
Van Luu-The,
Claude Labrie,
Alain Bélanger,
Jacques Simard,
Sheng-Xiang Lin and
Georges Pelletier
Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (Centre Hospitalier de l’Université Laval) and Laval University, Québec City, Québec G1V 4G2, Canada
Correspondence: Address all correspondence and requests for reprints to: Prof. Fernand Labrie, Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (Centre Hospitalier de l’Université Laval), 2705 Laurier Boulevard, Québec City, Québec G1V 4G2, Canada. E-mail: fernand.labrie{at}crchul.ulaval.ca
Serum androgens as well as their precursors and metabolitesdecrease from the age of 30–40 yr in women, thus suggestingthat a more physiological hormone replacement therapy at menopauseshould contain an androgenic compound. It is important to consider,however, that most of the androgens in women, especially aftermenopause, are synthesized in peripheral intracrine tissuesfrom the inactive precursors dehydroepiandrosterone (DHEA) andDHEA sulfate (DHEA-S) of adrenal origin. Much progress in thisnew area of endocrine physiology called intracrinology has followedthe cloning and characterization of most of the enzymes responsiblefor the transformation of DHEA and DHEA-S into androgens andestrogens in peripheral target tissues, where the locally producedsex steroids are exerting their action in the same cells inwhich their synthesis takes place without significant diffusioninto the circulation, thus seriously limiting the interpretationof serum levels of active sex steroids. The sex steroids madein peripheral tissues are then inactivated locally into morewater-soluble compounds that diffuse into the general circulationwhere they can be measured. In a series of animal models, androgensand DHEA have been found to inhibit breast cancer developmentand growth and to stimulate bone formation. In clinical studies,DHEA has been found to increase bone mineral density and tostimulate vaginal maturation without affecting the endometrium,while improving well-being and libido with no significant sideeffects. The advantage of DHEA over other androgenic compoundsis that DHEA, at physiological doses, is converted into androgensand/or estrogens only in the specific intracrine target tissuesthat possess the appropriate physiological enzymatic machinery,thus limiting the action of the sex steroids to those tissuespossessing the tissue-specific profile of expression of thegenes responsible for their formation, while leaving the othertissues unaffected and thus minimizing the potential side effectsobserved with androgens or estrogens administered systemically.
This article has been cited by other articles:
E. Stener-Victorin, G. Holm, F. Labrie, L. Nilsson, P. O. Janson, and C. Ohlsson Are There Any Sensitive and Specific Sex Steroid Markers for Polycystic Ovary Syndrome?
J. Clin. Endocrinol. Metab.,
February 1, 2010;
95(2):
810 - 819.
[Abstract][Full Text][PDF]
G. Secreto, E. Venturelli, E. Meneghini, M. Greco, C. Ferraris, M. Gion, M. Zancan, A. S.C. Fabricio, F. Berrino, A. Cavalleri, et al. Testosterone and Biological Characteristics of Breast Cancers in Postmenopausal Women
Cancer Epidemiol. Biomarkers Prev.,
November 1, 2009;
18(11):
2942 - 2948.
[Abstract][Full Text][PDF]
Z. Shen, T. Saloniemi, A. Ronnblad, P. Jarvensivu, P. Pakarinen, and M. Poutanen Sex Steroid-Dependent and -Independent Action of Hydroxysteroid (17{beta}) Dehydrogenase 2: Evidence from Transgenic Female Mice
Endocrinology,
November 1, 2009;
150(11):
4941 - 4949.
[Abstract][Full Text][PDF]
M.F.R. Sowers, H. Zheng, D. McConnell, B. Nan, C.A. Karvonen-Gutierrez, and J.F. Randolph Jr Testosterone, sex hormone-binding globulin and free androgen index among adult women: chronological and ovarian aging
Hum. Reprod.,
September 1, 2009;
24(9):
2276 - 2285.
[Abstract][Full Text][PDF]
M. J. Romero-Aleshire, M. K. Diamond-Stanic, A. H. Hasty, P. B. Hoyer, and H. L. Brooks Loss of ovarian function in the VCD mouse-model of menopause leads to insulin resistance and a rapid progression into the metabolic syndrome
Am J Physiol Regulatory Integrative Comp Physiol,
September 1, 2009;
297(3):
R587 - R592.
[Abstract][Full Text][PDF]
M. KULENDRAN, M. SALHAB, and K. MOKBEL Oestrogen-Synthesising Enzymes and Breast Cancer
Anticancer Res,
April 1, 2009;
29(4):
1095 - 1109.
[Abstract][Full Text][PDF]
A. M. Gonzalez-Angulo, K. Stemke-Hale, S. L. Palla, M. Carey, R. Agarwal, F. Meric-Berstam, T. A. Traina, C. Hudis, G. N. Hortobagyi, W. L. Gerald, et al. Androgen Receptor Levels and Association with PIK3CA Mutations and Prognosis in Breast Cancer
Clin. Cancer Res.,
April 1, 2009;
15(7):
2472 - 2478.
[Abstract][Full Text][PDF]
C. L Shufelt and G. D Braunstein Testosterone and the breast
Menopause Int,
September 1, 2008;
14(3):
117 - 122.
[Abstract][Full Text][PDF]
N. E Allen, T. J Key, L. Dossus, S. Rinaldi, A. Cust, A. Lukanova, P. H Peeters, N C. Onland-Moret, P. H Lahmann, F. Berrino, et al. Endogenous sex hormones and endometrial cancer risk in women in the European Prospective Investigation into Cancer and Nutrition (EPIC)
Endocr. Relat. Cancer,
June 1, 2008;
15(2):
485 - 497.
[Abstract][Full Text][PDF]
M. Plourde, C. Manhes, G. Leblanc, F. Durocher, M. Dumont, O. Sinilnikova, I. BRCAs, and J. Simard Mutation analysis and characterization of HSD17B2 sequence variants in breast cancer cases from French Canadian families with high risk of breast and ovarian cancer
J. Mol. Endocrinol.,
April 1, 2008;
40(4):
161 - 172.
[Abstract][Full Text][PDF]
C. Swanson, D. Mellstrom, M. Lorentzon, L. Vandenput, J. Jakobsson, A. Rane, M. Karlsson, O. Ljunggren, U. Smith, A.-L. Eriksson, et al. The Uridine Diphosphate Glucuronosyltransferase 2B15 D85Y and 2B17 Deletion Polymorphisms Predict the Glucuronidation Pattern of Androgens and Fat Mass in Men
J. Clin. Endocrinol. Metab.,
December 1, 2007;
92(12):
4878 - 4882.
[Abstract][Full Text][PDF]
S. Chouinard, O. Barbier, and A. Belanger UDP-glucuronosyltransferase 2B15 (UGT2B15) and UGT2B17 Enzymes Are Major Determinants of the Androgen Response in Prostate Cancer LNCaP Cells
J. Biol. Chem.,
November 16, 2007;
282(46):
33466 - 33474.
[Abstract][Full Text][PDF]
M. S. Cooper and P. M. Stewart Adrenal Insufficiency in Critical Illness
J Intensive Care Med,
November 1, 2007;
22(6):
348 - 362.
[Abstract][PDF]
L. Vandenput, D. Mellstrom, M. Lorentzon, C. Swanson, M. K. Karlsson, J. Brandberg, L. Lonn, E. Orwoll, U. Smith, F. Labrie, et al. Androgens and Glucuronidated Androgen Metabolites Are Associated with Metabolic Risk Factors in Men
J. Clin. Endocrinol. Metab.,
November 1, 2007;
92(11):
4130 - 4137.
[Abstract][Full Text][PDF]
G. D. Braunstein Gynecomastia
N. Engl. J. Med.,
September 20, 2007;
357(12):
1229 - 1237.
[Full Text][PDF]
S. Zhongyi, P. Rantakari, T. Lamminen, J. Toppari, and M. Poutanen Transgenic Male Mice Expressing Human Hydroxysteroid Dehydrogenase 2 Indicate a Role for the Enzyme Independent of Its Action on Sex Steroids
Endocrinology,
August 1, 2007;
148(8):
3827 - 3836.
[Abstract][Full Text][PDF]
S. N. Birrell, L. M. Butler, J. M. Harris, G. Buchanan, and W. D. Tilley Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer
FASEB J,
August 1, 2007;
21(10):
2285 - 2293.
[Abstract][Full Text][PDF]
M. Schumacher, R. Guennoun, A. Ghoumari, C. Massaad, F. Robert, M. El-Etr, Y. Akwa, K. Rajkowski, and E.-E. Baulieu Novel Perspectives for Progesterone in Hormone Replacement Therapy, with Special Reference to the Nervous System
Endocr. Rev.,
June 1, 2007;
28(4):
387 - 439.
[Abstract][Full Text][PDF]
M. Panjari and S. R. Davis DHEA therapy for women: effect on sexual function and wellbeing
Hum. Reprod. Update,
May 1, 2007;
13(3):
239 - 248.
[Abstract][Full Text][PDF]
S. Rinaldi, L. Dossus, A. Lukanova, P. H.M. Peeters, N. E. Allen, T. Key, S. Bingham, K.-T. Khaw, D. Trichopoulos, A. Trichopoulou, et al. Endogenous Androgens and Risk of Epithelial Ovarian Cancer: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC)
Cancer Epidemiol. Biomarkers Prev.,
January 1, 2007;
16(1):
23 - 29.
[Abstract][Full Text][PDF]
S. S. Tworoger, A. H. Eliassen, S. A. Missmer, H. Baer, J. Rich-Edwards, K. B. Michels, R. L. Barbieri, M. Dowsett, and S. E. Hankinson Birthweight and Body Size throughout Life in Relation to Sex Hormones and Prolactin Concentrations in Premenopausal Women
Cancer Epidemiol. Biomarkers Prev.,
December 1, 2006;
15(12):
2494 - 2501.
[Abstract][Full Text][PDF]
A. L. Eriksson, M. Lorentzon, D. Mellstrom, L. Vandenput, C. Swanson, N. Andersson, G. L. Hammond, J. Jakobsson, A. Rane, E. S. Orwoll, et al. SHBG Gene Promoter Polymorphisms in Men Are Associated with Serum Sex Hormone-Binding Globulin, Androgen and Androgen Metabolite Levels, and Hip Bone Mineral Density
J. Clin. Endocrinol. Metab.,
December 1, 2006;
91(12):
5029 - 5037.
[Abstract][Full Text][PDF]
M. Grube, K. Kock, S. Karner, S. Reuther, C. A. Ritter, G. Jedlitschky, and H. K. Kroemer Modification of OATP2B1-Mediated Transport by Steroid Hormones
Mol. Pharmacol.,
November 1, 2006;
70(5):
1735 - 1741.
[Abstract][Full Text][PDF]
G. Perez-Palacios, R. Santillan, R. Garcia-Becerra, E. Borja-Cacho, F. Larrea, P. Damian-Matsumura, L. Gonzalez, and A. E Lemus Enhanced formation of non-phenolic androgen metabolites with intrinsic oestrogen-like gene transactivation potency in human breast cancer cells: a distinctive metabolic pattern.
J. Endocrinol.,
September 1, 2006;
190(3):
805 - 818.
[Abstract][Full Text][PDF]
M. E. Sherman, J. V. Lacey, S. S. Buys, D. J. Reding, C. D. Berg, C. Williams, and P. Hartge Ovarian Volume: Determinants and Associations with Cancer among Postmenopausal Women.
Cancer Epidemiol. Biomarkers Prev.,
August 1, 2006;
15(8):
1550 - 1554.
[Abstract][Full Text][PDF]
M. H. Slagter, L. J.G. Gooren, A. Scorilas, C. D. Petraki, and E. P. Diamandis Effects of Long-term Androgen Administration on Breast Tissue of Female-to-Male Transsexuals
J. Histochem. Cytochem.,
August 1, 2006;
54(8):
905 - 910.
[Abstract][Full Text][PDF]
L. F. Macedo, Z. Guo, S. L. Tilghman, G. J. Sabnis, Y. Qiu, and A. Brodie Role of androgens on mcf-7 breast cancer cell growth and on the inhibitory effect of letrozole.
Cancer Res.,
August 1, 2006;
66(15):
7775 - 7782.
[Abstract][Full Text][PDF]
W. Arlt, F. Hammer, P. Sanning, S. K. Butcher, J. M. Lord, B. Allolio, D. Annane, and P. M. Stewart Dissociation of Serum Dehydroepiandrosterone and Dehydroepiandrosterone Sulfate in Septic Shock
J. Clin. Endocrinol. Metab.,
July 1, 2006;
91(7):
2548 - 2554.
[Abstract][Full Text][PDF]
F Labrie Future perspectives of selective estrogen receptor modulators used alone and in combination with DHEA.
Endocr. Relat. Cancer,
June 1, 2006;
13(2):
335 - 355.
[Abstract][Full Text][PDF]
S. S. Tworoger, S. A. Missmer, A. H. Eliassen, D. Spiegelman, E. Folkerd, M. Dowsett, R. L. Barbieri, and S. E. Hankinson The Association of Plasma DHEA and DHEA Sulfate with Breast Cancer Risk in Predominantly Premenopausal Women.
Cancer Epidemiol. Biomarkers Prev.,
May 1, 2006;
15(5):
967 - 971.
[Abstract][Full Text][PDF]
G. Juhasz-Vedres, E. Rozsa, G. Rakos, M. B. Dobszay, Z. Kis, J. Wolfling, J. Toldi, A. Parducz, and T. Farkas Dehydroepiandrosterone Sulfate Is Neuroprotective when Administered Either before or after Injury in a Focal Cortical Cold Lesion Model
Endocrinology,
February 1, 2006;
147(2):
683 - 686.
[Abstract][Full Text][PDF]
J. C. Havelock, W. E. Rainey, K. D. Bradshaw, and B. R. Carr The post-menopausal ovary displays a unique pattern of steroidogenic enzyme expression
Hum. Reprod.,
January 1, 2006;
21(1):
309 - 317.
[Abstract][Full Text][PDF]
T. Suzuki, Y. Miki, Y. Nakamura, T. Moriya, K. Ito, N. Ohuchi, and H. Sasano Sex steroid-producing enzymes in human breast cancer
Endocr. Relat. Cancer,
December 1, 2005;
12(4):
701 - 720.
[Abstract][Full Text][PDF]
R Kaaks, S Rinaldi, T J Key, F Berrino, P H M Peeters, C Biessy, L Dossus, A Lukanova, S Bingham, K-T Khaw, et al. Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition
Endocr. Relat. Cancer,
December 1, 2005;
12(4):
1071 - 1082.
[Abstract][Full Text][PDF]
D. J. Bettoun, A. Scafonas, S. J. Rutledge, P. Hodor, O. Chen, C. Gambone, R. Vogel, S. McElwee-Witmer, C. Bai, L. Freedman, et al. Interaction between the Androgen Receptor and RNase L Mediates a Cross-talk between the Interferon and Androgen Signaling Pathways
J. Biol. Chem.,
November 25, 2005;
280(47):
38898 - 38901.
[Abstract][Full Text][PDF]
F Labrie, V Luu-The, A Belanger, S-X Lin, J Simard, G Pelletier, and C Labrie Is dehydroepiandrosterone a hormone?
J. Endocrinol.,
November 1, 2005;
187(2):
169 - 196.
[Abstract][Full Text][PDF]
A. G. Schwartz, G. M. Prysak, V. Murphy, F. Lonardo, H. Pass, J. Schwartz, and S. Brooks Nuclear Estrogen Receptor {beta} in Lung Cancer: Expression and Survival Differences by Sex
Clin. Cancer Res.,
October 15, 2005;
11(20):
7280 - 7287.
[Abstract][Full Text][PDF]
G. Buchanan, S. N. Birrell, A. A. Peters, T. Bianco-Miotto, K. Ramsay, E. J. Cops, M. Yang, J. M. Harris, H. A. Simila, N. L. Moore, et al. Decreased Androgen Receptor Levels and Receptor Function in Breast Cancer Contribute to the Failure of Response to Medroxyprogesterone Acetate
Cancer Res.,
September 15, 2005;
65(18):
8487 - 8496.
[Abstract][Full Text][PDF]
S. Bhasin Female Androgen Deficiency Syndrome--An Unproven Hypothesis
J. Clin. Endocrinol. Metab.,
August 1, 2005;
90(8):
4970 - 4972.
[Full Text][PDF]
S. R. Davis, S. L. Davison, S. Donath, and R. J. Bell Circulating Androgen Levels and Self-reported Sexual Function in Women
JAMA,
July 6, 2005;
294(1):
91 - 96.
[Abstract][Full Text][PDF]
J. Simard, M.-L. Ricketts, S. Gingras, P. Soucy, F. A. Feltus, and M. H. Melner Molecular Biology of the 3{beta}-Hydroxysteroid Dehydrogenase/{Delta}5-{Delta}4 Isomerase Gene Family
Endocr. Rev.,
June 1, 2005;
26(4):
525 - 582.
[Abstract][Full Text][PDF]
F. Hammer, S. Subtil, P. Lux, C. Maser-Gluth, P. M. Stewart, B. Allolio, and W. Arlt No Evidence for Hepatic Conversion of Dehydroepiandrosterone (DHEA) Sulfate to DHEA: In Vivo and in Vitro Studies
J. Clin. Endocrinol. Metab.,
June 1, 2005;
90(6):
3600 - 3605.
[Abstract][Full Text][PDF]
R. Kaaks, F. Berrino, T. Key, S. Rinaldi, L. Dossus, C. Biessy, G. Secreto, P. Amiano, S. Bingham, H. Boeing, et al. Serum Sex Steroids in Premenopausal Women and Breast Cancer Risk Within the European Prospective Investigation into Cancer and Nutrition (EPIC)
J Natl Cancer Inst,
May 18, 2005;
97(10):
755 - 765.
[Abstract][Full Text][PDF]
E. R. Simpson, M. Misso, K. N. Hewitt, R. A. Hill, W. C. Boon, M. E. Jones, A. Kovacic, J. Zhou, and C. D. Clyne Estrogen--the Good, the Bad, and the Unexpected
Endocr. Rev.,
May 1, 2005;
26(3):
322 - 330.
[Full Text][PDF]
F. Labrie, A. Belanger, V. Luu-The, C. Labrie, J. Simard, L. Cusan, J. Gomez, and B. Candas Gonadotropin-Releasing Hormone Agonists in the Treatment of Prostate Cancer
Endocr. Rev.,
May 1, 2005;
26(3):
361 - 379.
[Abstract][Full Text][PDF]
K. Townsend, C. M. Banwell, M. Guy, K. W. Colston, J. L. Mansi, P. M. Stewart, M. J. Campbell, and M. Hewison Autocrine Metabolism of Vitamin D in Normal and Malignant Breast Tissue
Clin. Cancer Res.,
May 1, 2005;
11(9):
3579 - 3586.
[Abstract][Full Text][PDF]
D. Desaulniers, G. M. Cooke, K. Leingartner, K. Soumano, J. Cole, J. Yang, M. Wade, and A. Yagminas Effects of Postnatal Exposure to a Mixture of Polychlorinated Biphenyls, p,p'-dichlorodiphenyltrichloroethane, and p-p'-dichlorodiphenyldichloroethene in Prepubertal and Adult Female Sprague-Dawley Rats
International Journal of Toxicology,
March 1, 2005;
24(2):
111 - 127.
[Abstract][Full Text][PDF]
F. Labrie, V. Luu-The, E. Calvo, C. Martel, J. Cloutier, S. Gauthier, P. Belleau, J. Morissette, M.-H. Levesque, and C. Labrie Tetrahydrogestrinone induces a genomic signature typical of a potent anabolic steroid
J. Endocrinol.,
February 1, 2005;
184(2):
427 - 433.
[Abstract][Full Text][PDF]
A. Lukanova and R. Kaaks Endogenous Hormones and Ovarian Cancer: Epidemiology and Current Hypotheses
Cancer Epidemiol. Biomarkers Prev.,
January 1, 2005;
14(1):
98 - 107.
[Abstract][Full Text][PDF]
J. J. Christiansen, C. H. Gravholt, S. Fisker, N. Moller, M. Andersen, B. Svenstrup, P. Bennett, P. Ivarsen, J. S. Christiansen, and J. O. L. Jorgensen Very short term dehydroepiandrosterone treatment in female adrenal failure: impact on carbohydrate, lipid and protein metabolism
Eur. J. Endocrinol.,
January 1, 2005;
152(1):
77 - 85.
[Abstract][Full Text][PDF]
A. H. Payne and D. B. Hales Overview of Steroidogenic Enzymes in the Pathway from Cholesterol to Active Steroid Hormones
Endocr. Rev.,
December 1, 2004;
25(6):
947 - 970.
[Abstract][Full Text][PDF]
G. Pelletier, V. Luu-The, S. Li, J. Ouellet, and F. Labrie Cellular Localization of mRNA Expression of Enzymes Involved in the Formation and Inactivation of Hormonal Steroids in the Mouse Prostate
J. Histochem. Cytochem.,
October 1, 2004;
52(10):
1351 - 1356.
[Abstract][Full Text][PDF]
S. Nakamura, M. Yoshimura, M. Nakayama, T. Ito, Y. Mizuno, E. Harada, T. Sakamoto, Y. Saito, K. Nakao, H. Yasue, et al. Possible Association of Heart Failure Status With Synthetic Balance Between Aldosterone and Dehydroepiandrosterone in Human Heart
Circulation,
September 28, 2004;
110(13):
1787 - 1793.
[Abstract][Full Text][PDF]
N. J. MacLusky, T. Hajszan, and C. Leranth Effects of Dehydroepiandrosterone and Flutamide on Hippocampal CA1 Spine Synapse Density in Male and Female Rats: Implications for the Role of Androgens in Maintenance of Hippocampal Structure
Endocrinology,
September 1, 2004;
145(9):
4154 - 4161.
[Abstract][Full Text][PDF]
L.M. Rivera-Woll, M. Papalia, S.R. Davis, and H.G. Burger Androgen insufficiency in women: diagnostic and therapeutic implications
Hum. Reprod. Update,
September 1, 2004;
10(5):
421 - 432.
[Abstract][Full Text][PDF]
R. T. Chatterton Jr., A. S. Geiger, S. A. Khan, I. B. Helenowski, B. D. Jovanovic, and P. H. Gann Variation in Estradiol, Estradiol Precursors, and Estrogen-related Products in Nipple Aspirate Fluid from Normal Premenopausal Women
Cancer Epidemiol. Biomarkers Prev.,
June 1, 2004;
13(6):
928 - 935.
[Abstract][Full Text][PDF]
W. Somboonporn and S. R. Davis Testosterone Effects on the Breast: Implications for Testosterone Therapy for Women
Endocr. Rev.,
June 1, 2004;
25(3):
374 - 388.
[Abstract][Full Text][PDF]
C. E. Wood, J. M. Cline, M. S. Anthony, T. C. Register, and J. R. Kaplan Adrenocortical Effects of Oral Estrogens and Soy Isoflavones in Female Monkeys
J. Clin. Endocrinol. Metab.,
May 1, 2004;
89(5):
2319 - 2325.
[Abstract][Full Text][PDF]
M. Leblanc, M.-C. Belanger, P. Julien, A. Tchernof, C. Labrie, A. Belanger, and F. Labrie Plasma Lipoprotein Profile in the Male Cynomolgus Monkey under Normal, Hypogonadal, and Combined Androgen Blockade Conditions
J. Clin. Endocrinol. Metab.,
April 1, 2004;
89(4):
1849 - 1857.
[Abstract][Full Text][PDF]
T. Hajszan, N. J. MacLusky, and C. Leranth Dehydroepiandrosterone Increases Hippocampal Spine Synapse Density in Ovariectomized Female Rats
Endocrinology,
March 1, 2004;
145(3):
1042 - 1045.
[Abstract][Full Text][PDF]
M. Neves-e-Castro Menopause in crisis post-Women's Health Initiative? A view based on personal clinical experience
Hum. Reprod.,
December 1, 2003;
18(12):
2512 - 2518.
[Abstract][Full Text][PDF]
M. Leblanc, C. Labrie, A. Belanger, B. Candas, and F. Labrie Bioavailability and Pharmacokinetics of Dehydroepiandrosterone in the Cynomolgus Monkey
J. Clin. Endocrinol. Metab.,
September 1, 2003;
88(9):
4293 - 4302.
[Abstract][Full Text][PDF]
