# Presentation: 759165

## 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

## 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

## Hirsutism Scores in Women on Estrogens and Androgens

*Barrett-Connor, J Reprod Med 1999*

- % of Women

## Outline of Safety Concerns of Testosterone Administration to Women

- Androgenic effects
- Cardiovascular
- Lipids
- Vascular
- Glucose tolerance
- Hematopoietic
- Endometrial and breast effects
- Recommendations

## Odds Ratio of Cardiovascular Events by Quartile of Endogenous Hormone Levels

- Rexrode, Circulation 2003;108:1688-93

- n=200
- Women’s Health Study

## 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

## % Change in Lipids in Women Randomized to Estrogen vs. with Estrogen and Methyltestosterone 

- Dobs, JCEM, 2002

- *

- *

##  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

## Effect of T on the Vasculature Reactivity in Women

- Worbys, JCEM 2001;86;158-61

- p<0.05

- p<0.05

## 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

- 20, 25

- Buckler. Clin Endocrinol 1998;49:173-8.
- Shahidi, NEJM 1973;289:72-80.
- Barrett-Connor J Reprod Med 1999;44:1012-20.

## 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

## 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

## 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