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Safety Issues in Chronic Androgen Therapy in Post-menopausal Women: What we know, what we don’t know . Adrian S. Dobs, M.D., M.H.S. Professor of Medicine The Johns Hopkins University School of Medicine Baltimore, MD. Effects of Testosterone and Its Metabolites in Women.
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Safety Issues in Chronic Androgen Therapy in Post-menopausal Women: What we know, what we don’t know Adrian S. Dobs, M.D., M.H.S. Professor of Medicine The Johns Hopkins University School of Medicine Baltimore, MD
Outline of Safety Concerns of Testosterone Administration to Women • Androgenic effects • Cardiovascular • Lipids • Vascular • Glucose tolerance • Hematopoietic • Endometrial and breast effects • Recommendations
Effect of Testosterone on Acne, Hirsutism and Virilization • Clinical presentation: Acne, hirsutism, clitoromegaly, temporal balding, voice deepening • All commonly associated with high doses of testosterone • Rare in low dose androgen replacement • Mild acne and hirsutism reported in cases of methyl testosterone • Dose and duration dependent and mostly reversible Hickok, Obstet Gynecol 1993;82:919-24, Lobo, Fertil Steril 2004;79:1341-1352
90 80 70 60 50 40 Worse 30 Same 20 Better 10 0 Estrogen + CEE 0.625 Estrogen + CEE 1.25 Androgen Androgen- Hi - Low Hirsutism Scores in Women on Estrogens and Androgens % of Women Barrett-Connor, J Reprod Med 1999
Outline of Safety Concerns of Testosterone Administration to Women • Androgenic effects • Cardiovascular • Lipids • Vascular • Glucose tolerance • Hematopoietic • Endometrial and breast effects • Recommendations
2 1.8 1.6 1.4 Testosterone 1.2 T - adjusted for risks 1 0.8 FAI - p=0.02 0.6 FAI - adjusted for risks 0.4 0.2 0 1st Qtr 2nd Qtr 3rd Qtr 4th Qtr Odds Ratio of Cardiovascular Events by Quartile of Endogenous Hormone Levels n=200 Women’s Health Study Rexrode, Circulation 2003;108:1688-93
Effects of Exogenous Testosterone on Serum Lipids • Clinical: Oral androgens – significant reduction in HDL, neutral to LDL, lowers TG • Physiology: Changes in hepatic lipase • Data from women: • Effect mainly dependent on route of administration and type • Aromatizable androgens are generally neutral
15 10 5 0 -5 Estrogen -10 -15 Estrogen + 2.5 methyl T -20 -25 -30 -35 HDL LDL TG % Change in Lipids in Women Randomized to Estrogen vs. with Estrogen and Methyltestosterone * * Dobs, JCEM, 2002
Placebo Baseline 150 mg 300 mg 250 200 150 100 Lipid Level (mg/dL) 50 0 Total HDL LDL Triglycerides Lipid Parameters Did Not Change with Transdermal T Administration Cholesterol Shifren, et al. JCEM
Effect of Testosterone on Vasculature • Clinical: Endothelial dysfunction is an early marker of disease • Epidemiology: Decrease in Flow-Mediated Vasodilation after menopause • Measurement: Endothelial-independent dilation (glyceryl trinitrate induced) measured at the brachial artery
18 16 14 12 10 0 8 6 wks 6 4 2 0 FMD - Test FMD- Control GTN- Test Effect of T on the Vasculature Reactivity in Women p<0.05 p<0.05 Worbys, JCEM 2001;86;158-61
Plasma Viscosity • Clinical: Increased plasma viscosity is an established risk factor for CV disease and predicts CAD • Physiology: Affected by fibrinogen and triglycerides • Women: Small study of methyl T – viscosity decreased Neumann, Br Heart J 1991;66:425-430. Sweetman Eur Heart J 1996;17:1814-20. Ernst, Fibrinogen BMJ 1991;303:596-7.
Coagulation and Blood • Clinical: Hypercoagulation and polycythemia are CV risk factors • Physiology: Androgens stimulate hematopoiesis • Erythropoiten, Erythroid Colony Units • Men: Erythrocytosis can be observed in men with excess testosterone administration (injectable) • Women: No effect on clotting factors in 22 young women using implants • No reports of polycythemia in women Buckler. Clin Endocrinol 1998;49:173-8. Shahidi, NEJM 1973;289:72-80. Barrett-Connor J Reprod Med 1999;44:1012-20. 20, 25
Glucose Metabolism • Clinical: Hyperglycemia and hyperinsulinism are clear risk factor of CV risk • Women: No evidence of changes in fasting glucose or insulin sensitivity • Caveat: Unclear relationship to Polycystic Ovarian Disease Shifren, NEJM 2000;343:682-826. Lovejoy, JCEM 1996;81:3298-0330
Placebo 120 Baseline 150 mg 300 mg 100 80 60 Mean Concentration (SEM) 40 20 0 Fasting Glucose Insulin (mg/dL) (U/L) Carbohydrate Metabolism Did Not Change with Transdermal T Administration Sifren et al. NEJM 2000;343:682-688
Endogenous Testosterone and Cardiovascular Risk in Women • Polycystic Ovarian Syndrome/Metabolic syndrome – obesity, hyperinsulinism, hyperandrogenism, hyperlipidemia • Mechanism – Hyperinsulinism stimulates testosterone production from the ovary and decreases SHBG from the liver • Question – Is there an effect of testosterone per se on CV risk or via its metabolism to estradiol?
Outline of Safety Concerns of Testosterone Administration to Women • Androgenic effects • Cardiovascular • Lipids • Vascular • Glucose tolerance • Hematopoietic • Endometrial and breast effects • Recommendations
6 5 4 Estradiol (p=0.0001) 3 Testosterone (p=0.02, adjusted p=0.06) 2 1 0 1st Qtr 2nd Qtr 3rd Qtr 4th Qtr Odds Ratios for Endometrial Cancer by Quartiles of Steroid Hormone in Post-Menopausal Women Lukanova, Int J Cancer 2004;108:425-432
Endometrial Hyperplasia and Cancer • Reports of hyperplasia and cancer with high doses of T (transsexuals) • No cancers reported with low doses • Endometrial hyperplasia in 1/107 given methyl T as well as 1/111 of estrogen only • 6% incidence of cystic endometrial hyperplasia • Stable vaginal cytology Futter JCEM 1986;62:16-21, Hickok Obstet Gynecol 1993;82:919-24, Lobo Fertil Steril 2003;79:1341-52, Sarrel J Reprod 199843;847-56
Breast Cancer Risk • Epidemiology: May be a relationship between high endogenous T and breast cancer • Hyperandrogenism associated with metastasis • Physiology: Androgen receptors found in 50-90% of breast tumors and may stimulate breast epithelium via aromatization • Women: No reports of breast cancer with exogenous T treatment Ballerini Breast Cancer Res Treat 1993;26:1-6. Secreto, Eur J Cancer 1994;30A:1629. Endogenous Hormones and Breast Cancer Group, J National Cancer Institute 2003
Other Possible Effects of Testosterone in Women • Liver Function • Men: High dose of alkylated androgens have been associated with hepatotoxicity and hepatic adenomas • Women: No evidence of abnormal LFT with lower doses either pellets or transdermal • Fluid retention • Minimal Basaria JCEM 2001;86:5108-17. Barrett-Connor J Reprod Med 1999;44:1012-20; Shifren NEJM 2000;343:682-88
Anger and Hostility • Clinical presentation: Difficult to measure • Physiology: Androgen and estrogen receptors in the brain • Men: Some questionable data on testosterone and violent behavior in men • Women: Increase in hostility scores in women given high doses • No evidence in lower doses Bagatell, JCEM 1994;79:561-567, Sherwin, Psychoneuroneuroendorinology 1985:10:325-335
Outline of Safety Concerns of Testosterone Administration to Women • Androgenic effects • Cardiovascular • Lipids • Vascular • Glucose tolerance • Hematopoietic • Endometrial and breast effects • Recommendations
Contraindications of T Treatment • Absolute • Pregnancy, lactation • Endometrial cancer of unexplained vaginal bleeding • Breast cancer • Relative • Moderate-severe acne or hirsutism • Androgenic alopecia • Severe insulin resistance • Anger management disorders Basaria and Dobs, Mayo Clin Proc 2004 Apr;79(4 Suppl):S25-32
Monitoring of Women on Testosterone Treatment • Acne and hirsutism – at each visit • Virilization - at each visit • Anger and hostility – at each visit • Breast exams and serial mammograms – annually • Ensure regular OB/GYN exams • Discontinue if vaginal bleeding • Hematocrits – after 3 mos. and then annually • Serum lipids – as indicated • Serum total testosterone – 6 weeks and every 6 mos.???
Remaining Questions About the Safety of Testosterone Therapy • Long-term effects on androgenic signs and symptoms • Conceptual difficulties with endogenous T vs. exogenous treatment and CV risk • Testosterone alone vs. in combination with estrogens and progestins • Risk on breast and uterine tissue