1. Slide source: www.FemaleSexualDysfunctionOnline.org

2. Testosterone Therapy for Hypoactive Sexual Desire Disorder

3. Slide source: www.FemaleSexualDysfunctionOnline.org Introduction  Rationale for use  Combination estrogen-testosterone therapy  Testosterone use in women – Therapies available and under investigation – Dosing/administration issues – Clinical trials of testosterone use in women – Managing side effects  Patient selection

4. Slide source: www.FemaleSexualDysfunctionOnline.org Rationale for Testosterone Therapy  Testosterone levels in women decline with aging – Women in their 40s have approximately one-half the level of women in their 20s  Women who undergo oophorectomy experience dramatic decreases in the level of testosterone – Level of testosterone decreases to one half of those prior to surgery Zumoff B, et al. J Clin Endocrinol Metab. 1995;80:1429-1430. Judd HL, et al. J Clin Endocrinol Metab. 1974;39:1020-1024.

5. Slide source: www.FemaleSexualDysfunctionOnline.org Rationale for Testosterone Therapy (cont’d)  Testosterone has been linked to sexual desire and coital frequency in menopausal women  Accumulating data indicate that testosterone therapy increases sexual function, including sexual desire, in postmenopausal women McCoy NL, et al. Maturitas. 1985;7:203-210. Shifren JL, et al. N Engl J Med. 2000;343:682-688. Lobo RA, et al. Fertil Steril. 2003;79:1341-1352.

6. Slide source: www.FemaleSexualDysfunctionOnline.org Combination Estrogen- Testosterone Therapy

7. Slide source: www.FemaleSexualDysfunctionOnline.org Impact of Estrogen Deficiency on Sexual Function  Changes in urogenital anatomy – Shortening and loss of elasticity of the vagina – Diminished secretions – Increased pH – Thinning of vaginal epithelial layers  Reduced blood flow  Reduced nerve transmission and discharge  Sleep disruption  Mood alterations Sarrel PM. Obstet Gynecol. 1990;75:26S-30S. Bachmann GA, et al. Menopause. 2004;11:120-130.

8. Slide source: www.FemaleSexualDysfunctionOnline.org Low Estrogen Is Associated With Increased Prevalence of Sexual Problems Sarrel PM. J Womens Health Gend Based Med. 2000;9:S25-S32. Sarrel PM. Obstet Gynecol. 1990;75:26S-30S. Percentage of Women Reporting Problems N=93; significance not reported.

9. Slide source: www.FemaleSexualDysfunctionOnline.org Simon J, et al. Menopause. 1999;6:138-146. N=93; *P≤0.05 EE=esterified estrogens; MT=methyltestosterone Placebo Low-Dose EE High-Dose EE Low-Dose EE + MT High-Dose EE + MT Postplacebo run-in period Month 1 Month 3 * * * ** * * * Efecto de Terapia con Estrógenos and Estrógenos- Andrógenos sobre Síntomas menopaúsicos

10. Slide source: www.FemaleSexualDysfunctionOnline.org Testosterone Use in Women

11. Slide source: www.FemaleSexualDysfunctionOnline.org Testosterone Therapies Available and Under Investigation Testosterone Therapies Available and Under Investigation *  Oral – Methyltestosterone – Testosterone undecanoate  Intramuscular – Testosterone propionate – Testosterone cypionate – Testosterone enanthate  Subcutaneous (implant) – Testosterone propionate pellets – Testosterone crystalline pellets  Transdermal – Transdermal testosterone patch – Testosterone gel – Testosterone emulsion – Testosterone spray  Other – Testosterone-containing vaginal ring – Sublingual testosterone in propylene glycol * Not approved by US Food and Drug Administration for use in women.

12. Slide source: www.FemaleSexualDysfunctionOnline.org Estrógenos y Enantato de Testosterona: Deseo sexual Sherwin BB, et al. Psychosom Med. 1987;49:397-409. Semanas B1234 Estrógeno + TE Control Estrógeno Inyeccion 1 2 3 0 4 5 Niveles medios de Deseo Sexual N=65; TE=testosterona enantato

13. Slide source: www.FemaleSexualDysfunctionOnline.org Davis SR, et al. Maturitas. 1995;21:227-236. Estrogen Estrogen + testosterone Libido Activity Satisfaction Pleasure Fantasy Orgasm Relevancy 5678910 Sexuality Score (Means of 6, 12, 18, and 24 Months) Summary Statistics N=34 Estradiol and Testosterone Implants: Sexual Function

14. Slide source: www.FemaleSexualDysfunctionOnline.org EEEE+MT Treatment difference Total Testosterone (ng/dL) Baseline Change from baseline (mean serum concentration) 20.8  1.1 -0.1  7.4 18.9  8.4 -3.7  6.8 P=0.02 Bioavailable Testosterone (pg/mL) Baseline Change from baseline (mean serum concentration) 3.1  2.7 -0.3  2.4 2.7  1.5 2.0  2.0 P<0.010 Lobo RA, et al. Fertil Steril. 2003;79:1341-1352. EE=esterified estrogens; MT=methyltestosterone Estrogen and Methyltestosterone: Effect on Testosterone Levels N = 111 N = 107

15. Slide source: www.FemaleSexualDysfunctionOnline.org Lobo RA, et al. Fertil Steril. 2003;79:1341-1352. *P<0.02 vs baseline * EE+MT (n = 107) 0 0.3 0.6 0.9 481216 Study Week Mean Change EE (n = 111) Estrogen and Methyltestosterone: Sexual Desire EE=esterified estrogens; MT=methyltestosterone

16. Slide source: www.FemaleSexualDysfunctionOnline.org Estrogen and Methyltestosterone: Frequency of Interest/Desire Lobo RA, et al. Fertil Steril. 2003;79:1341-1352. *P<0.02 vs baseline; † P<0.01 vs baseline Study Week EE+MT (n = 107) EE (n = 111) * † † EE=esterified estrogens; MT=methyltestosterone

17. Slide source: www.FemaleSexualDysfunctionOnline.org Estrogen and Methyltestosterone: Sexual Functioning Sarrel PM, et al. J Reprod Med. 1998;43:847-856. EE=esterified estrogens; MT=methyltestosterone

18. Slide source: www.FemaleSexualDysfunctionOnline.org Estrogen and Testosterone Patch: Free and Bioavailable Testosterone Levels Shifren JL, et al. N Engl J Med. 2000;343:682-688. N=75; *P<0.001 for comparison with placebo Endocrine Sciences normal range for cycling women Placeb o Regimen (+CEE) 0 Regimen (+CEE) 1 2 3 4 5 6 7 8 Free T (pg/mL) * * 0 2 4 6 8 10 12 14 Bioavailable T (ng/dL) * * Baseline 300 mcg150 mcg CEE=conjugated equine estrogens; T=testosterone

19. Slide source: www.FemaleSexualDysfunctionOnline.org N=75; *P<0.05 for comparison with placebo Baseline 300 mcg 150 mcg Placebo Thoughts/ Desires Frequency Pleasure/ Orgasm Problems Percentage of Normative Mean 40 50 60 70 80 90 100 110 120 * * Arousal Shifren JL, et al. N Engl J Med. 2000;343:682-688. Oral Estrogen and Testosterone Patch: Sexual Function

20. Slide source: www.FemaleSexualDysfunctionOnline.org Oral Estrogen and Testosterone Patch: Effect on Sexual Function Author (Year)Population (N) Treatment (Dose) Outcome (at 24 Weeks) Braunstein (2003) SM, HSDD (N=447) T patch (150, 300, 450 mcg/d) Placebo patch  Desire  Activity Davis (2003)SM, HSDD (N=77) T patch (300 mcg/d) Placebo patch  Desire  Activity Braunstein GD, et al. In: Program and abstracts of the 14th annual meeting of the North American Menopause Society; September 17-20, 2003; Miami Beach, Fla. Abstract 60. Davis S, et al. Fertil Steril. 2003;80(suppl 3):76. SM=surgically menopausal; HSDD=hypoactive sexual desire disorder; T=testosterone

21. Slide source: www.FemaleSexualDysfunctionOnline.org Oral Estrogen and Testosterone Patch: Effect on Sexual Function (cont’d) Author (Year)Population (N) Treatment (Dose) Outcome (at 24 Weeks) Simon (2004) SM, HSDD (N=562) T patch (300 mcg/d) Placebo patch  Desire  Activity Buster (2004) SM, HSDD (N=533) T patch (300 mcg/d) Placebo patch  Desire  Activity Simon JA, et al. Obstet Gynecol. 2004;103(suppl):64S. Buster J, et al. In: Program and abstracts of the 86th annual meeting of the Endocrine Society; June 16- 19, 2004; New Orleans, La. Abstract OR44-6. SM=surgically menopausal; HSDD=hypoactive sexual desire disorder; T=testosterone

22. Slide source: www.FemaleSexualDysfunctionOnline.org Floter A, et al. Climacteric. 2002;5:357-65. N=50; EV-estradiol valerate; TU-testosterone undecanoate *P<0.05 vs EV at 24 weeks Estrogen and Testosterone Undecanoate: Sexual Function McCoy Sex Scale Score (Mean) * EV Baseline * * EV + TU Enjoyment of Sex Satisfaction With Frequency of Sex Interest in Sex

23. Slide source: www.FemaleSexualDysfunctionOnline.org Potential Side Effects With Testosterone Therapies  Hirsutism  Acne  Voice deepening  Alopecia  Liver toxicity  Negative effects on lipoproteins  Clitoromegaly

24. Slide source: www.FemaleSexualDysfunctionOnline.org Side Effects in Studies With Testosterone Therapies  Few side effects are reported in studies  Increased doses are associated with – Facial hair – Acne/oily skin  Oral preparations – Decreases in high-density lipoprotein Not seen with transdermal preparations

25. Slide source: www.FemaleSexualDysfunctionOnline.org N=75; *P<0.05 for comparison with placebo 0.0 0.5 1.0 1.5 2.0 2.5 Hirsutism (Lorenzo Scale) Acne (Palatsi Scale) Facial Depilation (Times/Month) Mean Score (SEM) Baseline 300 mcg * 150 mcg Placebo Shifren JL, et al. N Engl J Med. 2000;343:682-688. Estrogen and Testosterone Patch: Safety

26. Slide source: www.FemaleSexualDysfunctionOnline.org Estrogen and Methyltestosterone: Safety EEEE+MT Hirsutism score (Lorenzo scale) Baseline score Change from baseline at week 16 2.3  2.5 0.0  1.9 2.9  3.3 -0.4  2.2 Acne score (Palatsi scale) Baseline score Change from baseline at week 16 0.1  0.4 0.2  0.5 0.1  0.5 Lobo RA, et al. Fertil Steril. 2003;79:1341-1352. EE=esterified estrogens; MT=methyltestosterone

27. Slide source: www.FemaleSexualDysfunctionOnline.org Patient Selection  Testosterone therapy, in conjunction with estrogen therapy, may be indicated in women with: – Surgical menopause – Decreased libido – Diminished sense of well-being