Testosterone in women-the clinical significance

The Lancet Diabetes and Endocrinology

Volumn 3, Issue 12, 2015, Pages 980-992

  Davis, Susan R ^a   Wahlin Jacobsen, Sarah ^b  

^a MONASH UNIVERSITY   (Australia)

^b Psychiatric Center Copenhagen   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

CONJUGATED ESTROGEN; PLACEBO; TESTOSTERONE; TESTOSTERONE PROPIONATE; TESTOSTERONE UNDECANOATE; ANDROGEN; ESTRADIOL; ESTROGEN;

ANDROGEN THERAPY; ANKLE BRACHIAL INDEX; BONE DENSITY; BREAST CANCER; CARDIOVASCULAR DISEASE; CAROTID ARTERY; CORONARY ARTERY DISEASE; ENDOMETRIUM CANCER; HUMAN; HYPOACTIVE SEXUAL DESIRE DISORDER; OVARY CANCER; POSTMENOPAUSE; PREMENOPAUSE; PRIORITY JOURNAL; REVIEW; SEXUAL AROUSAL; SEXUAL AROUSAL DISORDER; SEXUAL BEHAVIOR; SEXUAL DYSFUNCTION; SEXUAL FUNCTION; SHORT TERM MEMORY; SPATIAL LEARNING; VAGINA ATROPHY; VERBAL MEMORY; ADOLESCENT; ADULT; AGED; BREAST TUMOR; CLINICAL TRIAL (TOPIC); COGNITION; DRUG EFFECTS; ENDOMETRIUM TUMOR; FEMALE; MENOPAUSE; MIDDLE AGED; OVARY TUMOR; PATHOPHYSIOLOGY; PHYSIOLOGY; SKELETAL MUSCLE; VAGINA; VERY ELDERLY; WOMEN'S HEALTH; YOUNG ADULT;

ADOLESCENT; ADULT; AGED; AGED, 80 AND OVER; ANDROGENS; BREAST NEOPLASMS; CARDIOVASCULAR DISEASES; CLINICAL TRIALS AS TOPIC; COGNITION; ENDOMETRIAL NEOPLASMS; ESTRADIOL; ESTROGENS; FEMALE; HUMANS; MENOPAUSE; MIDDLE AGED; MUSCLE, SKELETAL; OVARIAN NEOPLASMS; SEXUAL BEHAVIOR; TESTOSTERONE; VAGINA; WOMEN'S HEALTH; YOUNG ADULT;

EID: 84948090530     PISSN: 22138587     EISSN: 22138595     Source Type: Journal    
DOI: 10.1016/S2213-8587(15)00284-3     Document Type: Review

References (103)

1. Simpson ER, Davis SR Minireview: aromatase and the regulation of estrogen biosynthesis-some new perspectives. Endocrinology 2001, 142:4589-4594.
2. Wahlin-Jacobsen S, Pedersen AT, Kristensen E, et al. Is there a correlation between androgens and sexual desire in women?. J Sex Med 2015, 2:358-373.
3. Randolph JF, Zheng H, Avis NE, Greendale GA, Harlow SD Masturbation frequency and sexual function domains are associated with serum reproductive hormone levels across the menopausal transition. J Clin Endocrinol Metab 2015, 100:258-266.
4. Wierman ME, Arlt W, Basson R, et al. Androgen therapy in women: a reappraisal: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2014, 99:3489-3510.
5. Davis SR, Panjari M, Stanczyk FZ Clinical review: DHEA replacement for postmenopausal women. J Clin Endocrinol Metab 2011, 96:1642-1653.
6. Rothman MS, Carlson NE, Xu M, et al. Reexamination of testosterone, dihydrotestosterone, estradiol and estrone levels across the menstrual cycle and in postmenopausal women measured by liquid chromatography-tandem mass spectrometry. Steroids 2011, 76:177-182.
7. Bungum L, Franssohn F, Bungum M, Humaidan P, Giwercman A The circadian variation in Anti-Müllerian hormone in patients with polycystic ovary syndrome differs significantly from normally ovulating women. PLoS One 2013, 8:e68223.
8. Davison SL, Bell R, Donath S, Montalto JG, Davis SR Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab 2005, 90:3847-3853.
9. Burger HG, Dudley EC, Cui J, Dennerstein L, Hopper JL A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. J Clin Endocrinol Metab 2000, 85:2832-2838.
10. Herold DA, Fitzgerald RL Immunoassays for testosterone in women: better than a guess?. Clin Chem 2003, 49:1250-1251.
11. Harwood DT, Handelsman DJ Development and validation of a sensitive liquid chromatography-tandem mass spectrometry assay to simultaneously measure androgens and estrogens in serum without derivatization. Clin Chim Acta 2009, 409:78-84.
12. Legro RS, Schlaff WD, Diamond MP, et al. Total testosterone assays in women with polycystic ovary syndrome: precision and correlation with hirsutism. J Clin Endocrinol Metab 2010, 95:5305-5313. the Reproductive Medicine Network.
13. Davis SR, Davison SL, Donath S, Bell RJ Circulating androgen levels and self-reported sexual function in women. JAMA 2005, 294:91-96.
14. Basson R, Brotto LA, Petkau AJ, Labrie F Role of androgens in women's sexual dysfunction. Menopause 2010, 17:962-971.
15. Rosen R, Brown C, Heiman J, et al. The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther 2000, 26:191-208.
16. Diagnostic and statistical manual of mental disorders 1994, American Psychiatric Association, American Psychiatric Press, Washington, DC.
17. Elraiyah T, Sonbol MB, Wang Z, et al. Clinical review: The benefits and harms of systemic testosterone therapy in postmenopausal women with normal adrenal function: a systematic review and meta-analysis. J Clin Endocrinol Metab 2014, 99:3543-3550.
18. Davis SR, Moreau M, Kroll R, et al. Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med 2008, 359:2005-2017. the APHRODITE Study Team.
19. Somboonporn W, Davis S, Seif MW, Bell R Testosterone for peri- and postmenopausal women. Cochrane Database Syst Rev 2005, 4. CD004509.
20. Baldassarre M, Perrone AM, Giannone FA, et al. Androgen receptor expression in the human vagina under different physiological and treatment conditions. Int J Impot Res 2013, 25:7-11.
21. Berman JR, Almeida FG, Jolin J, Raz S, Chaudhuri G, Gonzalez-Cadavid NF Correlation of androgen receptors, aromatase, and 5-alpha reductase in the human vagina with menopausal status. Fertil Steril 2003, 79:925-931.
22. Salinger SL Proliferative effect of testosterone propionate on human vaginal epithelium. Acta Endocrinol (Copenh) 1950, 4:265-284.
23. Raghunandan C, Agrawal S, Dubey P, Choudhury M, Jain A A comparative study of the effects of local estrogen with or without local testosterone on vulvovaginal and sexual dysfunction in postmenopausal women. J Sex Med 2010, 7:1284-1290.
24. Fernandes T, Costa-Paiva LH, Pinto-Neto AM Efficacy of vaginally applied estrogen, testosterone, or polyacrylic acid on sexual function in postmenopausal women: a randomized controlled trial. J Sex Med 2014, 11:1262-1270.
25. Witherby S, Johnson J, Demers L, et al. Topical testosterone for breast cancer patients with vaginal atrophy related to aromatase inhibitors: a phase I/II study. Oncologist 2011, 16:424-431.
26. Spoletini I, Vitale C, Pelliccia F, Fossati C, Rosano GM Androgens and cardiovascular disease in postmenopausal women: a systematic review. Climacteric 2014, 17:625-634.
27. Jones RD, Hugh Jones T, Channer KS The influence of testosterone upon vascular reactivity. Eur J Endocrinol 2004, 151:29-37.
28. Worboys S, Kotsopoulos D, Teede H, McGrath BP, Davis SR Evidence that parenteral testosterone therapy may improve endothelium-dependent and -independent vasodilation in postmenopausal women already receiving estrogen. J Clin Endocrinol Metab 2001, 86:158-161.
29. Montalcini T, Gorgone G, Gazzaruso C, Sesti G, Perticone F, Pujia A Endogenous testosterone and endothelial function in postmenopausal women. Coron Artery Dis 2007, 18:9-13.
30. Navarro-Dorado J, Orensanz LM, Recio P, et al. Mechanisms involved in testosterone-induced vasodilatation in pig prostatic small arteries. Life Sci 2008, 83:569-573.
31. Maggio M, Cattabiani C, Lauretani F, et al. The relationship between sex hormones, sex hormone binding globulin and peripheral artery disease in older persons. Atherosclerosis 2012, 225:469-474.
32. Bernini GP, Sgro' M, Moretti A, et al. Endogenous androgens and carotid intimal-medial thickness in women. J Clin Endocrinol Metab 1999, 84:2008-2012.
33. Golden SH, Maguire A, Ding J, et al. Endogenous postmenopausal hormones and carotid atherosclerosis: a case-control study of the atherosclerosis risk in communities cohort. Am J Epidemiol 2002, 155:437-445.
34. Ouyang P, Vaidya D, Dobs A, et al. Sex hormone levels and subclinical atherosclerosis in postmenopausal women: the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 2009, 204:255-261.
35. Calderon-Margalit R, Schwartz SM, Wellons MF, et al. Prospective association of serum androgens and sex hormone-binding globulin with subclinical cardiovascular disease in young adult women: the "Coronary Artery Risk Development in Young Adults" women's study. J Clin Endocrinol Metab 2010, 95:4424-4431.
36. Debing E, Peeters E, Duquet W, Poppe K, Velkeniers B, Van den Brande P Endogenous sex hormone levels in postmenopausal women undergoing carotid artery endarterectomy. Eur J Endocrinol 2007, 156:687-693.
37. Naessen T, Sjogren U, Bergquist J, Larsson M, Lind L, Kushnir MM Endogenous steroids measured by high-specificity liquid chromatography-tandem mass spectrometry and prevalent cardiovascular disease in 70-year-old men and women. J Clin Endocrinol Metab 2010, 95:1889-1897.
38. Sievers C, Klotsche J, Pieper L, et al. Low testosterone levels predict all-cause mortality and cardiovascular events in women: a prospective cohort study in German primary care patients. Eur J Endocrinol 2010, 163:699-708.
39. Laughlin GA, Goodell V, Barrett-Connor E Extremes of endogenous testosterone are associated with increased risk of incident coronary events in older women. J Clin Endocrinol Metab 2010, 95:740-747.
40. Scarabin-Carré V, Canonico M, Brailly-Tabard S, et al. High level of plasma estradiol as a new predictor of ischemic arterial disease in older postmenopausal women: the three-city cohort study. J Am Heart Assoc 2012, 1:e001388.
41. Benn M, Voss SS, Holmegard HN, Jensen GB, Tybjærg-Hansen A, Nordestgaard BG Extreme concentrations of endogenous sex hormones, ischemic heart disease, and death in women. Arterioscler Thromb Vasc Biol 2015, 35:471-477.
42. Haring R, Hannemann A, John U, et al. Age-specific reference ranges for serum testosterone and androstenedione concentrations in women measured by liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab 2012, 97:408-415.
43. Ding EL, Song Y, Manson JE, et al. Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N Engl J Med 2009, 361:1152-1163.
44. Peter A, Kantartzis K, Machann J, et al. Relationships of circulating sex hormone-binding globulin with metabolic traits in humans. Diabetes 2010, 59:3167-3173.
45. Davis SR, Robinson PJ, Moufarege A, Bell RJ The contribution of SHBG to the variation in HOMA-IR is not dependent on endogenous oestrogen or androgen levels in postmenopausal women. Clin Endocrinol (Oxf) 2012, 77:541-547.
46. Worsley R, Robinson PJ, Bell RJ, Moufarege A, Davis SR Endogenous estrogen and androgen levels are not independent predictors of lipid levels in postmenopausal women. Menopause 2013, 20:640-645.
47. Janssen I, Powell LH, Kazlauskaite R, Dugan SA Testosterone and visceral fat in midlife women: the Study of Women's Health Across the Nation (SWAN) fat patterning study. Obesity (Silver Spring) 2010, 18:604-610.
48. Pugeat M, Nader N, Hogeveen K, Raverot G, Déchaud H, Grenot C Sex hormone-binding globulin gene expression in the liver: drugs and the metabolic syndrome. Mol Cell Endocrinol 2010, 316:53-59.
49. Selva DM, Hogeveen KN, Innis SM, Hammond GL Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene. J Clin Invest 2007, 117:3979-3987.
50. Golden SH, Ding J, Szklo M, Schmidt MI, Duncan BB, Dobs A Glucose and insulin components of the metabolic syndrome are associated with hyperandrogenism in postmenopausal women: the atherosclerosis risk in communities study. Am J Epidemiol 2004, 160:540-548.
51. Sutton-Tyrrell K, Wildman RP, Matthews KA, et al. Sex-hormone-binding globulin and the free androgen index are related to cardiovascular risk factors in multiethnic premenopausal and perimenopausal women enrolled in the Study of Women Across the Nation (SWAN). Circulation 2005, 111:1242-1249. the SWAN Investigators.
52. Davis SR, Papalia MA, Norman RJ, et al. Safety and efficacy of a testosterone metered-dose transdermal spray for treating decreased sexual satisfaction in premenopausal women: a randomized trial. Ann Intern Med 2008, 148:569-577.
53. Iellamo F, Volterrani M, Caminiti G, et al. Testosterone therapy in women with chronic heart failure: a pilot double-blind, randomized, placebo-controlled study. J Am Coll Cardiol 2010, 56:1310-1316.
54. Rosario ER, Chang L, Head EH, Stanczyk FZ, Pike CJ Brain levels of sex steroid hormones in men and women during normal aging and in Alzheimer's disease. Neurobiol Aging 2011, 32:604-613.
55. Brown CM, Mulcahey TA, Filipek NC, Wise PM Production of proinflammatory cytokines and chemokines during neuroinflammation: novel roles for estrogen receptors alpha and beta. Endocrinology 2010, 151:4916-4925.
56. Bixo M, Bäckström T, Winblad B, Andersson A Estradiol and testosterone in specific regions of the human female brain in different endocrine states. J Steroid Biochem Mol Biol 1995, 55:297-303.
57. Pike CJ, Carroll JC, Rosario ER, Barron AM Protective actions of sex steroid hormones in Alzheimer's disease. Front Neuroendocrinol 2009, 30:239-258.
58. Aleman A, Bronk E, Kessels RP, Koppeschaar HP, van Honk J A single administration of testosterone improves visuospatial ability in young women. Psychoneuroendocrinology 2004, 29:612-617.
59. Postma A, Meyer G, Tuiten A, van Honk J, Kessels RP, Thijssen J Effects of testosterone administration on selective aspects of object-location memory in healthy young women. Psychoneuroendocrinology 2000, 25:563-575.
60. Drake EB, Henderson VW, Stanczyk FZ, et al. Associations between circulating sex steroid hormones and cognition in normal elderly women. Neurology 2000, 54:599-603.
61. Wolf OT, Kirschbaum C Endogenous estradiol and testosterone levels are associated with cognitive performance in older women and men. Horm Behav 2002, 41:259-266.
62. Flöter A, Carlström K, von Schoultz B, Nathorst-Böös J Administration of testosterone undecanoate in postmenopausal women: effects on androgens, estradiol, and gonadotrophins. Menopause 2000, 7:251-256.
63. Kocoska-Maras L, Zethraeus N, Rådestad AF, et al. A randomized trial of the effect of testosterone and estrogen on verbal fluency, verbal memory, and spatial ability in healthy postmenopausal women. Fertil Steril 2011, 95:152-157.
64. Möller MC, Bartfai AB, Rådestad AF Effects of testosterone and estrogen replacement on memory function. Menopause 2010, 17:983-989.
65. Davis SR, Davison SL, Gavrilescu M, et al. Effects of testosterone on visuospatial function and verbal fluency in postmenopausal women: results from a functional magnetic resonance imaging pilot study. Menopause 2014, 21:410-414.
66. Davison SL, Bell RJ, Robinson PJ, et al. Continuous-combined oral estradiol/drospirenone has no detrimental effect on cognitive performance and improves estrogen deficiency symptoms in early postmenopausal women: a randomized placebo-controlled trial. Menopause 2013, 20:1020-1026.
67. Davison SL, Bell RJ, Gavrilescu M, et al. Testosterone improves verbal learning and memory in postmenopausal women: Results from a pilot study. Maturitas 2011, 70:307-311.
68. Davis SR, Jane F, Robinson PJ, et al. Transdermal testosterone improves verbal learning and memory in postmenopausal women not on oestrogen therapy. Clin Endocrinol (Oxf) 2014, 81:621-628.
69. Cherrier MM, Matsumoto AM, Amory JK, et al. The role of aromatization in testosterone supplementation: effects on cognition in older men. Neurology 2005, 64:290-296.
70. Shah S, Bell RJ, Savage G, et al. Testosterone aromatization and cognition in women: a randomized, placebo-controlled trial. Menopause 2006, 13:600-608.
71. Clarke BL, Khosla S Androgens and bone. Steroids 2009, 74:296-305.
72. Slemenda C, Longcope C, Peacock M, Hui S, Johnston CC Sex steroids, bone mass, and bone loss. A prospective study of pre-, peri-, and postmenopausal women. J Clin Invest 1996, 97:14-21.
73. Rariy CM, Ratcliffe SJ, Weinstein R, et al. Higher serum free testosterone concentration in older women is associated with greater bone mineral density, lean body mass, and total fat mass: the cardiovascular health study. J Clin Endocrinol Metab 2011, 96:989-996.
74. Lee JS, LaCroix AZ, Wu L, et al. Associations of serum sex hormone-binding globulin and sex hormone concentrations with hip fracture risk in postmenopausal women. J Clin Endocrinol Metab 2008, 93:1796-1803.
75. Davis SR, McCloud P, Strauss BJG, Burger H Testosterone enhances estradiol's effects on postmenopausal bone density and sexuality. Maturitas 1995, 21:227-236.
76. Barrett-Connor E, Young R, Notelovitz M, et al. 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 1999, 44:1012-1020.
77. Watts NB, Notelovitz M, Timmons MC, Addison WA, Wiita B, Downey LJ Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause. Obstet Gynecol 1995, 85:529-537.
78. Miller KK, Biller BM, Beauregard C, et al. Effects of testosterone replacement in androgen-deficient women with hypopituitarism: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 2006, 91:1683-1690.
79. Popat VB, Calis KA, Kalantaridou SN, et al. Bone mineral density in young women with primary ovarian insufficiency: results of a three-year randomized controlled trial of physiological transdermal estradiol and testosterone replacement. J Clin Endocrinol Metab 2014, 99:3418-3426.
80. Dobs AS, Nguyen T, Pace C, Roberts CP Differential effects of oral estrogen versus oral estrogen-androgen replacement therapy on body composition in postmenopausal women. J Clin Endocrinol Metab 2002, 87:1509-1516.
81. Key TJ, Verkasalo PK, Banks E Epidemiology of breast cancer. Lancet Oncol 2001, 2:133-140.
82. Davis SR Cardiovascular and cancer safety of testosterone in women. Curr Opin Endocrinol Diabetes Obes 2011, 18:198-203.
83. Peters AA, Buchanan G, Ricciardelli C, et al. Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer. Cancer Res 2009, 69:6131-6140.
84. Somboonporn W, Davis S Testosterone effects on the breast: implications for testosterone therapy for women. Endocr Rev 2004, 25:374-388.
85. Key TJ, Appleby PN, Reeves GK, et al. Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies. Lancet Oncol 2013, 14:1009-1019. the Endogenous Hormones and Breast Cancer Collaborative Group.
86. Key TJ, Appleby PN, Reeves GK, et al. Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: reanalysis of 18 prospective studies. Steroids 2015, 99:49-55. for the Endogenous Hormones and Breast Cancer Collaborative Group.
87. Bulun SE, Simpson ER Aromatase expression in women's cancers. Adv Exp Med Biol 2008, 630:112-132.
88. Misso ML, Jang C, Adams J, et al. Adipose aromatase gene expression is greater in older women and is unaffected by postmenopausal estrogen therapy. Menopause 2005, 12:210-215.
89. Simpson E, Rubin G, Clyne C, et al. The role of local estrogen biosynthesis in males and females. Trends Endocrinol Metab 2000, 11:184-188.
90. Agency EM. Withdrawal assessment report for Intrinsa. London, UK: 2010.
91. Tamimi RM, Hankinson SE, Chen WY, Rosner B, Colditz GA Combined estrogen and testosterone use and risk of breast cancer in postmenopausal women. Arch Intern Med 2006, 166:1483-1489.
92. Jick SS, Hagberg KW, Kaye JA, Jick H Postmenopausal estrogen-containing hormone therapy and the risk of breast cancer. Obstet Gynecol 2009, 113:74-80.
93. Ness RB, Albano JD, McTiernan A, Cauley JA Influence of estrogen plus testosterone supplementation on breast cancer. Arch Intern Med 2009, 169:41-46.
94. Dimitrakakis C, Jones RA, Liu A, Bondy CA Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy. Menopause 2004, 11:531-535.
95. Davis SR, Wolfe R, Farrugia H, Ferdinand A, Bell RJ The incidence of invasive breast cancer among women prescribed testosterone for low libido. J Sex Med 2009, 6:1850-1856.
96. Glaser RL, Dimitrakakis C Reduced breast cancer incidence in women treated with subcutaneous testosterone, or testosterone with anastrozole: a prospective, observational study. Maturitas 2013, 76:342-349.
97. White WB, Grady D, Giudice LC, Berry SM, Zborowski J, Snabes MC A cardiovascular safety study of LibiGel (testosterone gel) in postmenopausal women with elevated cardiovascular risk and hypoactive sexual desire disorder. Am Heart J 2012, 163:27-32.
98. Snabes MC, Berry SD, Berry DA, Zborowski JD, White WB Low cardiovascular event rate in post-menopausal women with increased cardiac risk: initial findings from the ongoing blinded Libigel (testosterone gel) cardiovascular safety study. Endocr Rev 2010, 31(suppl):S1299.
99. Ose J, Fortner RT, Rinaldi S, et al. Endogenous androgens and risk of epithelial invasive ovarian cancer by tumor characteristics in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 2015, 136:399-410.
100. Allen NE, Key TJ, Dossus L, et al. Endogenous sex hormones and endometrial cancer risk in women in the European Prospective Investigation into Cancer and Nutrition (EPIC). Endocr Relat Cancer 2008, 15:485-497.
101. Perrone AM, Cerpolini S, Maria Salfi NC, et al. Effect of long-term testosterone administration on the endometrium of female-to-male (FtM) transsexuals. J Sex Med 2009, 6:3193-3200.
102. Spark RF Intrinsa fails to impress FDA advisory panel. Int J Impot Res 2005, 17:283-284.
103. Chen W, Zouboulis CC, Orfanos CE The 5 alpha-reductase system and its inhibitors. Recent development and its perspective in treating androgen-dependent skin disorders. Dermatology 1996, 193:177-184.