8. Concentration cerebral de estradiol y testosterona 600 400 200 0 MO NA SN CC PO CB Estradiol, pg/g Testosterone/10, pg/g Bixo et al 1995
9. HORMONAS Y FUNCIÓN SEXUAL ESTROGENOS Flujo sanguíneo vaginal Neurotransmision Percepción sensorial Regulación vaginal y clitoridea de la expresión de la oxido nítrico sintasa TESTOSTERONA Deseo sexual y motivación
12. Efetos del hipoestrogenismo Sintomas vasomotores Sequedad vaginal Atrofia urogenital Cambios de humor Aversión al tacto Pérdida de deseo
13. Testosterona Simon JA. (2002) Fertility and Sterility 77, S77-S82 66% Bound to SHBG 31% Bound to Albumin ≤ 3% free = Bioavailable Testosterone +
14. Testosterona 25 30 35 40 45 50 Zumoff et al, 1995 75 50 25 r = -0.54 p < 0.003
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17. Diferencias entre el déficit de estradiol y Testosterone Bachmann G, et al. , Fertil Steril. 2002; 77: 660-665, Dennerstein L, et al. , Obstet Gynecol. 2000; 96: 351-358. Utian W.H, et al ., Menopause. 2002; 9: 402-410, Bachmann G (2004) Menopause 11: 120. Deficit estradiol Sofocos Alteración sueño Camios de humor Sequedad Vaginal Testosterona Deficit Disminución sensación bienestar Disminución de energía Disminución ánimo Pérdida de deseo Disminución excitabilidad Deterioro función sexual
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22. Modelo de Basson (2003) intimidad ESTIMULACIÓN SEXUAL EXCITACIÓN EVALUACIÓN ADECUADA DE LA EXCITACIÓN DESEO EXPERIENCIA SEXUAL SATISFACTORIA INTIMIDAD
23. Ciclo de Respuesta Sexual: Modelos Kaplan HS. The New Sex Therapy Sexual Dysfunctions . New York, NY: Brunner/Mazel; 1974. Motiva la sexualidad mujer neutral Tiempo Deseo Excitación Meseta Tensión Sexual Orgasmo Resolución Intimidad Emocional Satisfacción Emocional & Física Excitación & Deseo Sexual Estímulo Sexual Factores Psicológicos y Biológicos dominan la “ excitabilidad” Excitación Sexual Ciclo tradicional de respuesta sexual Modelo Alternativo del Ciclo de Respuesta Sexual + + Basson R. Obstet Gynecol . 2001;98:350-3.
24. Sand M, and Fisher MA. Women´s endorsement of models of female sexual response: The nurses´sexuality study. J Sex Med 2007;4:708-719.
45. LATENCIA Con Vielle 5.57 minutos Sin Vielle 13.05 minutos INTENSIDAD 68.75% mejoran 31.25% no diferencias
46. Mejoría de la vida sexual con L- Arginina TTO/ TY et al. J Sex Marital T her 2001 73.5 37.2 77 participantes. Doble ciego mejoría de su vida sexual L- Arginina Placebo
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52. TIBOLONE -0.4 0 0.4 0.8 1.2 1.6 sexual attraction libido initiation partner initiat'n responsivity fantasies excitement activity orgasm response pain Tibolone (n=14) Placebo (n=14) Nijland et al. J Sex Med. 2008 LASOFOXIFENE (Laan, Lunsen y Everaed, 2006)
56. Aumento de la actividad sexual satisfactoria total a las 24 semanas mediante SAL INTIMATE SM 1 p=0.0003 % aumento a partir del valor inicial 33% 74% 23% 51% p=0.001 INTIMATE SM 2 0 0.5 1 1.5 2 2.5 Cambio de la frecuencia a las 4 sem a partir del valor inicial Placebo TTP Simon JA et al., J. Clin. Endocrinol. Metab., Sep 2005; 90: 5226 - 5233 Buster JE et al. Obstet Gynecol 2005; 105:944-52
57. Increase in Desire at 24 Weeks from PFSF INTIMATE SM 1 INTIMATE SM 2 p=0.0006 p=0.0006 % increase from baseline 29% 56% 18% 49% 0 2 4 6 8 10 12 14 Mean Change From Baseline (SEM) Simon JA et al. J. Clin. Endocrinol. Metab., Sep 2005; 90: 5226 - 5233 Buster JE et al. Obstet Gynecol 2005; 105:944-52 Placebo + Estrogen Testosterone + Estrogen
58. Mejoría de los aspectos clave de la función sexual mediante PFSF INTIMATE SM 2 Excitación Placer Orgasmo Preocupación Receptividad Autoimagen p =0.0299 p =0.0004 p =0.0016 p =0.0002 p =0.002 p =0.0015 Placebo TTP 0 5 10 15 20 25 30 Buster JE et al. Obstet Gynecol 2005; 105:944-52 Cambio medio a partir del valor inicial
59. Total Satisfying Activity at 24 wks * p<0.05 vs. placebo, # p=0.064 vs. placebo Mean adj. for pooled centers, age, maritial status, baseline scores # * US Study EU/AUS Study 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 Placebo 150 300 450 Placebo 300 Dose of T activities per week + SEM adjusted treatment effect baseline mean level Braunstein G, et al. Arch Intern Med 2005;165:1582-9 Davis SR et al. Menopause 2006; 13:387-396
60. Clinical Relevance of Benefits TST Week Week Week Sexual Desire Distress Total Satisfying Activity * * * * * * * * * * * * * * p< 0.05 Kingsberg and cols. J Sex Med 2007 Placebo Transdermal Testosterone Patch
61. Decreased Distress at 24 Weeks % Decrease From Baseline 40% 65% 48% 68% p =0.0006 p =0.0091 INTIMATE SM 1 INTIMATE SM 2 -30 -25 -20 -15 -10 -5 0 Mean Change From Baseline (SEM) Simon JA et al. J. Clin. Endocrinol. Metab., Sep 2005; 90: 5226 - 5233 Buster JE et al. Obstet Gynecol 2005; 105:944-52 Placebo + Estrogen Testosterone + Estrogen
62. Sexual Desire and Distress at Month 6 (Panay, Al-Azzawi, Bouchard, Davis, Eden Lodhi, Rees, Rodenberg, Rymer, Schwenkhagen, Sturdee, 2009) P<0.0007 P<0.0032 ITT Non-HRT Mean Change from Baseline p=0.0024 p=0.0137 ITT Non-HRT Mean Change from Baseline Increased Desire Decreased Distress 0 2 4 6 8 10 12 14 16 Placebo TTP -30 -25 -20 -15 -10 -5 0 Placebo TTP
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69. Efficacy in open-label phase Mean number of SSE/month Mean desire score/month ∆ from week 0 baseline ∆ from week 0 baseline Weeks 2.6 events 13.2 units Mean (SE); Desire score – Indicate your most intense level of sexual desire in the last 24 hours/since your last visit, from 0 (no desire) to 3 (strong desire) Goldfischer ER, et al. ISSWSH annual meeting, 21-24 February 2008, San Diego, USA. Oral presentations 14 & 15. Baseline mean = 12.2 Baseline mean = 2.7
70. Efficacy in open-label phase PGI of Improvement Mean, FAS, full analysis set; LOCF, last observation carried forward Goldfischer ER, et al. 60 th Institute on Psychiatric Services Meeting, 2-5 October 2008, Chicago, USA. Poster presentation NR71
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Hinweis der Redaktion
Key Learning Points The chemical nature of circulating testosterone.
Key Learning Points
In the INTIMATE SM1 study, the sexual desire (a domain of the PFSF) score was significantly increased in the T group vs. baseline (56%) and vs. placebo (11.85 vs. 6.90 points, p=0.0006). In the INTIMATE SM2 study, the sexual desire (a domain of the PFSF) score was significantly increased in the T group vs. baseline (49%) and vs. placebo (10.6 vs. 4.3 points, p=0.0006). Note that secondary endpoints (PFSF and PDS) are measured as the change from baseline to weeks 21-24.
I don’t konow why, however at 450 we have no significant differences In the US study there was a statistically significant 30% increase in the frequency of total satisfying sexual activity vs. placebo (p=0.0493) and an 81% increase vs. baseline (p<0.05). The linear dose effect was marginally significant. The 150 group was similar to placebo. There was no advantage of the 450 group over the 300 group. In the EU/AUS study, there was a 43% increase in the frequency of total satisfying sexual activity (p=0.06) and a 110% increase over baseline (p<0.05).
We can see significartive differences in all the variables and as claim Kingsber and cols there are clinical relevance Objective: The Testosterone Patch increases sexual activity significantly after 8 weeks of treatment, the positive effect on sexual desire and distress can be seen as early as 4 weeks of treatment. Key points: Looking at the time course of effect in total satisfying activity, sexual desire and distress there can be seen a significant change in sexual activity in comparison to placebo as of 8 weeks. The changes in sexual desire and associated distress differ significantly from placebo after 4 weeks of treatment. The changes remain statistically significant over the subsequent time points throughout the study. Personal distress continued to decreases during the duration of the study. All patients were oophorectomised women receiving concomitant estrogen (transdermal or oral)
Remind why this is going in opposite direction. This indicates the impact on the patient. Emphasize clin. relevance. Make point of what the baseline distress was ~60, corresponding to “often being distressed about lack of interest in sex”. Changes in Distress associated with having low sexual desire at 24 Weeks of treatment are shown on this slide. Again highly significant changes over placebo were seen in the decrease of distress associated with treatment. Patients in both trial had similar improvements associated with their improved libido. (Not give numbers unless asked) Study 133-Unadjusted Mean Change from Baseline Placebo -15.07 TTP -22.77 Study 134-Unadjusted Mean Change from Baseline Placebo -16.05 TTP -22.72
Falta de deseo se debe a 5HT2 antagonismo. No ocurre si existe efecto adrenérgico y con agonismo 5HT1
Falta de deseo se debe a 5HT2 antagonismo. No ocurre si existe efecto adrenérgico y con agonismo 5HT1
Total monthly desire score = 28 x (sum of the daily desire score) / (sum of number of entries). Total monthly SSE = 28 x (sum of the number of SSE) / (sum of number of days entered). Desire score/month increased from 12.2 at baseline to 25.4 at the end of the open-label phase. 1 The number of SSE/month increased from 2.7 at baseline to 5.3 at the end of the open-label phase. 1 Reference Goldfischer ER, et al. ISSWSH annual meeting, 21-24 February 2008, San Diego, USA. Oral presentations 14 & 15.
The majority of patients felt that flibanserin improved their condition by week 8. 1 Categories were collapsed into three groups reflecting patients who felt that treatment with flibanserin improved (rating 1–3) or worsened (rating 5–7) their condition and those patients who felt the treatment made no difference (rating 4). Reference Goldfischer ER, et al. 60 th Institute on Psychiatric Services Meeting, 2-5 October 2008, Chicago, USA. Poster presentation NR71.