Neuropraxis

, Volume 18, Issue 1, pp 32–45

Een vernieuwende farmacotherapeutische behandeling voor vrouwen met hypoactive sexual desire disorder

  • Saskia Poels
  • Jos Bloemers
  • Kim van Rooij
  • Hans Koppeschaar
  • Berend Olivier
  • Adriaan Tuiten
Artikel
  • 69 Downloads

Samenvatting

Verminderd seksueel verlangen is de meest voorkomende seksuele klacht bij vrouwen. Dit kan seksuele ontevredenheid veroorzaken, wat een negatieve invloed kan hebben op de kwaliteit van leven. Deze klachten zijn in de DSM-IV geclassificeerd als de diagnose Hypoactive Sexual Desire Disorder (HSDD) en sinds kort ondergebracht in de nieuwe diagnose Female Sexual Interest/Arousal Disorder (FSIAD) in de DSM-5. Op dit moment is er nog geen goedgekeurde medicamenteuze behandeling beschikbaar voor vrouwen met HSDD (FSIAD) terwijl er wel grote behoefte aan is. In onze zoektocht naar adequate medische behandelingsmogelijkheden hebben wij een andere wetenschappelijke aanpak gevolgd dan de grote farmaceutische bedrijven. Op basis van een personalized sexual medicine approach hebben we eerst vastgesteld dat er tussen vrouwen verschillen bestaan in oorzakelijke mechanismen die ten grondslag kunnen liggen aan de seksuele klachten. Dit leidde tot twee onderscheidende mechanismen: een ongevoelig systeem voor seksuele stimuli en een overactief seksueel remsysteem. Gebaseerd op deze onderliggende oorzaken van HSDD zijn twee nieuwe on-demand medicamenteuze behandelingen ontwikkeld. De ene behandeling (testosteron gecombineerd met een fosfodiësterase-type-5-remmer) is ontwikkeld voor vrouwen die lijden aan HSDD als gevolg van een relatief ongevoelig systeem voor seksuele prikkels, terwijl de andere behandeling (testosteron gecombineerd met een 5-HT1A -receptoragonist) is ontwikkeld voor vrouwen die lijden aan HSDD als gevolg van overmatige activatie van het seksuele remsysteem.

Literatuur

  1. 1.
    Aleman, A., Bronk, E., Kessels, R.P., Koppeschaar, H.P., Honk J. van (2004). A single administration of testosterone improves visuospatial ability in young women. Psychoneuroendocrinology, 29, 612–617.Google Scholar
  2. 2.
    American Psychiatric Association (2000). Diagnostic and Statistical Manual of Mental Disorders. Text Revision. Fourth ed. Washington, DC: American Psychiatric Association;.Google Scholar
  3. 3.
    American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders. Fifth ed. Washington, DC: American Psychiatric Association.Google Scholar
  4. 4.
    Anders, S.M. van, Hamilton, L.D., Schmidt, N. & Watson, N.V. (2007). Associations between testosterone secretion and sexual activity in women. Hormones and Behavior, 51, 477–482.Google Scholar
  5. 5.
    Auger A. (2004). Steroid receptor control of reproductive behavior. Hormones and Behavior, 45, 168–72.Google Scholar
  6. 6.
    Baglietto, L., Severi, G., English, D.R., Krishnan, K., Hopper, J.L., McLean, C. et al. (2010). Circulating steroid hormone levels and risk of breast cancer for postmenopausal women. Cancer Epidemiology, Biomarkers and Prevention, 19, 492–502.Google Scholar
  7. 7.
    Basson, R. & Brotto, L.A. (2003). Sexual psychophysiology and effects of sildenafil citrate in oestrogenised women with acquired genital arousal disorder and impaired orgasm: a randomised controlled trial. BJOG, An International Journal of Obstetrics and Gyneacology, 110, 1014–1024.Google Scholar
  8. 8.
    Beauregard, M., Levesque, J. & Bourgouin, P. (2001). Neural correlates of conscious self-regulation of emotion. The Journal of Neuroscience, 21, RC165.Google Scholar
  9. 9.
    Bloemers, J., Gerritsen, J., Bults, R., Koppeschaar, H., Everaerd, W., Olivier, B. et al. (2010). Induction of sexual arousal in women under conditions of institutional and ambulatory laboratory circumstances: a comparative study. Journal of Sexual Medicine, 7, 1160–1176.Google Scholar
  10. 10.
    Bloemers, J., Rooij, K. van, Poels, S., Goldstein, I., Everaerd, W., Koppeschaar, H. et al. (2013). Toward personalized sexual medicine (part 1): integrating the ‘dual control model’ into differential drug treatments for Hypoactive Sexual Desire Disorder and female sexual arousal disorder. Journal of Sexual Medicine, 10, 791–809.Google Scholar
  11. 11.
    Bos, P.A., Panksepp, J., Bluthe, R.M. & Honk, J.V. (2011). Acute effects of steroid hormones and neuropeptides on human social-emotional behavior: A review of single administration studies. Frontiers in Neuroendocrinology.Google Scholar
  12. 12.
    Brand, J.S., Schouw, Y.T. van der (2010). Testosterone, SHBG and cardiovascular health in postmenopausal women. International Journal of Impotence Research, 22, 91–104.Google Scholar
  13. 13.
    Braunstein, G.D. (2007). Safety of testosterone treatment in postmenopausal women. Fertility and Sterility, 88, 1–17.Google Scholar
  14. 14.
    Braunstein, G.D., Sundwall, D.A., Katz, M., Shifren, J.L., Buster, J.E., Simon, J.A. et al. (2005). Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial. Archives of Internal Medicine, 165, 1582–1589.Google Scholar
  15. 15.
    Chamberlain, N.L., Driver, E.D. & Miesfeld, R.L. (1994). The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Research, 22, 3181–3186.Google Scholar
  16. 16.
    Childress, A.R., Ehrman, R.N., Wang, Z., Li, Y., Sciortino, N., Hakun, J. et al. (2008). Prelude to passion: limbic activation by ‘unseen’ drug and sexual cues. PLoS One, 3, e1506.Google Scholar
  17. 17.
    Clayton, A.H. (2010). The pathophysiology of hypoactive sexual desire disorder in women. International Journal of Gynecology and Obstetrics, 110, 7–11.Google Scholar
  18. 18.
    Corbin, J. & Francis, S. (1999). Cyclic GMP phosphodiesterase-5: Target of sildenafil. Journal of Biological Chemistry, 274, 13729–13732.Google Scholar
  19. 19.
    Cottingham, S.L. & Pfaff, D. (1986). Interconnectedness of steroid-binding hormones: existence and implications. In: Gauten, D., editor. Current Topics in Endocrinology. Berlin: Springer, pp. 223–240.Google Scholar
  20. 20.
    Dabbs, J.D.M., editor (2000). Heroes, rogues, and lovers: Testosterone and behavior. New York: McGraw-Hill.Google Scholar
  21. 21.
    Davis, S., Papalia, M.A., Norman, R.J., O’Neill, S., Redelman, M., Williamson, M. et al. (2008). Safety and efficacy of a testosterone metered-dose transdermal spray for treating decreased sexual satisfaction in premenopausal women: a randomized trial. Annals of Internal Medicine, 148, 569–577.Google Scholar
  22. 22.
    Davis, S.R, Moreau, M., Kroll, R., Bouchard, C., Panay, N., Gass, M. et al. (2008). Testosterone for low libido in postmenopausal women not taking estrogen. New England Journal of Medicine, 359, 2005–2017.Google Scholar
  23. 23.
    Davis, S.R., Braunstein, G.D. (2012). Efficacy and safety of testosterone in the management of hypoactive sexual desire disorder in postmenopausal women. Journal of Sexual Medicine, 9, 1134–1148.Google Scholar
  24. 24.
    Davis, S.R., Hirschberg, A.L., Wagner, L.K., Lodhi, I., Schoultz, B. von (2009). The effect of transdermal testosterone on mammographic density in postmenopausal women not receiving systemic estrogen therapy. Journal of Clinical Endocrinology & Metabolism, 94, 4907–4913.Google Scholar
  25. 25.
    Davis, S.R., Wolfe, R., Farrugia, H., Ferdinand, A. & Bell, R.J. (2009). The incidence of invasive breast cancer among women prescribed testosterone for low libido. Journal of Sexual Medicine, 6, 1850–1856.Google Scholar
  26. 26.
    Davison, S.L. & Davis, S.R. (2011). Androgenic hormones and aging − the link with female sexual function. Hormones and Behavior, 59, 745–753.Google Scholar
  27. 27.
    Eisenegger, C., Haushofer, J. & Fehr, E. (2011). The role of testosterone in social interaction. Trends in Cognitive Sciences, 15, 263–271.Google Scholar
  28. 28.
    El-Hage, G., Eden, J.A. & Manga, R.Z. (2007). A double-blind, randomized, placebo-controlled trial of the effect of testosterone cream on the sexual motivation of menopausal hysterectomized women with hypoactive sexual desire disorder. Climacteric, 10, 335–343.Google Scholar
  29. 29.
    Fogle, R.H., Stanczyk, F.Z., Zhang, X. & Paulson, R.J. (2007). Ovarian androgen production in postmenopausal women. Journal of Clinical Endocrinology & Metabolism, 92, 3040–3043.Google Scholar
  30. 30.
    Hamilton, L.D. & Meston, C.M. (2010). The effects of partner togetherness on salivary testosterone in women in long distance relationships. Hormones and Behavior, 57, 198–202.Google Scholar
  31. 31.
    Hayes, D.J. & Greenshaw, A.J. (2011). 5-HT receptors and reward-related behaviour: a review. Neuroscience and Biobehavioral Reviews, 35, 1419–1449.Google Scholar
  32. 32.
    Hermans, E.J., Bos, P.A., Ossewaarde. L., Ramsey, N.F., Fernandez, G. & Honk J. van (2010). Effects of exogenous testosterone on the ventral striatal BOLD response during reward anticipation in healthy women. Neuroimage, 52, 277–283.Google Scholar
  33. 33.
    Hermans, E.J., Putman, P. & Honk, J. van (2006). Testosterone administration reduces empathetic behavior: a facial mimicry study. Psychoneuroendocrinology, 31, 859–866.Google Scholar
  34. 34.
    Hermans, E.J., Putman, P., Baas, J.M, Gecks, N.M., Kenemans, J.L. & Honk J. van (2007). Exogenous testosterone attenuates the integrated central stress response in healthy young women. Psychoneuroendocrinology, 32, 1052–1061.Google Scholar
  35. 35.
    Hermans, E.J., Ramsey, N.F. & Honk, J. van (2008). Exogenous testosterone enhances responsiveness to social threat in the neural circuitry of social aggression in humans. Biological Psychiatry, 63, 263–270.Google Scholar
  36. 36.
    Hobbs, A. & Ignarro, L. (1996). Nitric oxide cyclic GMP signal transduction system. Nitric Oxide, Pt B, 269, 134–148.Google Scholar
  37. 37.
    Hofling, M., Hirschberg, A.L, Skoog, L., Tani, E., Hagerstrom, T., Schoultz, B. von (2007). Testosterone inhibits estrogen/progestogen-induced breast cell proliferation in postmenopausal women. Menopause, 14, 183–190.Google Scholar
  38. 38.
    Honk, J. van, Peper, J.S. & Schutter, D.J. (2005). Testosterone reduces unconscious fear but not consciously experienced anxiety: implications for the disorders of fear and anxiety. Biological Psychiatry, 58, 218–225.Google Scholar
  39. 39.
    Honk, J. van, Schutter, D.J, Hermans, E.J, Putman, P., Tuiten, A. & Koppeschaar, H. (2004). Testosterone shifts the balance between sensitivity for punishment and reward in healthy young women. Psychoneuroendocrinology, 29, 937–943.Google Scholar
  40. 40.
    Honk, J. van, Schutter, D.J. (2007). Testosterone reduces conscious detection of signals serving social correction: implications for antisocial behavior. Psychological Science, 18, 663–667.Google Scholar
  41. 41.
    Hull, E.M. & Dominguez, J.M. (2007). Sexual behavior in male rodents. Hormones and Behavior, 52, 45–55.Google Scholar
  42. 42.
    Joseph, R. (1999). Environmental influences on neural plasticity, the limbic system, emotional development and attachment: a review. Child Psychiatry and Human Development, 29, 189–208.Google Scholar
  43. 43.
    Kaaks, R., Rinaldi, S., Key, T.J., Berrino, F., Peeters, P.H., Biessy, C. et al. (2005). Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocrine-Related Cancer, 12, 1071–1082.Google Scholar
  44. 44.
    Karama, S., Lecours, A.R., Leroux, J.M., Bourgouin, P., Beaudoin, G, Joubert, S. et al. (2002). Areas of brain activation in males and females during viewing of erotic film excerpts. Human Brain Mapping, 16, 1–13.Google Scholar
  45. 45.
    Kenemans, P. & Mooren, M.J. van der (2012). Androgens and breast cancer risk. Gynecological Endocrinology, 28 Suppl 1, 46–49.Google Scholar
  46. 46.
    Laumann, E.O., Paik, A. & Rosen, R.C. (1999). Sexual dysfunction in the United States: prevalence and predictors. JAMA, 281, 537–544.Google Scholar
  47. 47.
    Lobo, R.A., Rosen, R.C., Yang, H.M., Block, B., Hoop, R.G. van der (2003). Comparative effects of oral esterified estrogens with and without methyltestosterone on endocrine profiles and dimensions of sexual function in postmenopausal women with hypoactive sexual desire. Fertility and Sterility, 79, 1341–1352.Google Scholar
  48. 48.
    Made, F. van der, Bloemers, J., Ham, D. van, El Yassem, W., Kleiverda, G., Everaerd, W. et al. (2009a). Childhood sexual abuse, selective attention for sexual cues and the effects of testosterone with or without vardenafil on physiological sexual arousal in women with sexual dysfunction: a pilot study. Journal of Sexual Medicine, 6, 429–439.Google Scholar
  49. 49.
    Made, F. van der, Bloemers, J., Yassem, W.E., Kleiverda, G., Everaerd, W., Ham, D. van et al. (2009b). The influence of testosterone combined with a PDE5-inhibitor on cognitive, affective, and physiological sexual functioning in women suffering from sexual dysfunction. Journal of Sexual Medicine, 6, 777–790.Google Scholar
  50. 50.
    Mendel, C. (1989). The Free Hormone Hypothesis – a Physiologically Based Mathematical-Model. Endocrine Reviews, 10, 232–274.Google Scholar
  51. 51.
    Mifsud, A., Ramirez, S. & Yong, E. (2000). Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries. Journal of Clinical Endocrinology & Metabolism, 85, 3484–3488.Google Scholar
  52. 52.
    Miller, S.L. & Maner, J.K. (2010). Scent of a woman: men’s testosterone responses to olfactory ovulation cues. Psychological Science, 21, 276–283.Google Scholar
  53. 53.
    Nachtigall, L., Casson, P., Lucas, J., Schofield, V., Melson, C. & Simon, J.A. (2011). Safety and tolerability of testosterone patch therapy for up to 4 years in surgically menopausal women receiving oral or transdermal oestrogen. Gynecological Endocrinology, 27, 39–48.Google Scholar
  54. 54.
    Nathorst-Boos, J., Floter, A., Jarkander-Rolff, M., Carlstrom, K. & Schoultz, B. (2006). Treatment with percutaneous testosterone gel in postmenopausal women with decreased libido-effects on sexuality and psychological general well-being. Maturitas, 53, 11–18.Google Scholar
  55. 55.
    Okazawa, H., Yamane, F., Blierm P, & Diksic, M. (1999). Effects of acute and chronic administration of the serotonina(1A) agonist buspirone on serotonin synthesis in the rat brain. Journal of Neurochemistry, 72, 2022–2031.Google Scholar
  56. 56.
    Pineyro, G. & Blier, P. (1999). Autoregulation of serotonin neurons: Role in antidepressant drug action. Pharmacological Reviews, 51, 533–591.Google Scholar
  57. 57.
    Poels, S., Bloemers, J., Rooij, K. van, Goldstein, I., Gerritsen, J., Ham, D. van et al. (2013). Toward personalized sexual medicine (part 2): testosterone combined with a PDE5 inhibitor increases sexual satisfaction in women with HSDD and FSAD, and a low sensitive system for sexual cues. Journal of Sexual Medicine, 10, 810–823.Google Scholar
  58. 58.
    Postma, A., Meyer, G., Tuiten, A., Honk, J. van, Kessels, R.P. & Thijssen, J. (2000). Effects of testosterone administration on selective aspects of object-location memory in healthy young women. Psychoneuroendocrinology, 25, 563–575.Google Scholar
  59. 59.
    Roney, J.R., Lukaszewski, A.W. & Simmons, Z.L. (2007). Rapid endocrine responses of young men to social interactions with young women. Hormones and Behavior, 52, 326–333.Google Scholar
  60. 60.
    Rooij, K. van, Bloemers, J., Leede, L. de, Goldstein, I., Lentjes, E., Koppeschaar, H. et al. (2012). Pharmacokinetics of three doses of sublingual testosterone in healthy premenopausal women. Psychoneuroendocrinology, 37, 773–781.Google Scholar
  61. 61.
    Rooij, K. van, Poels, S., Bloemers, J., Goldstein, I., Gerritsen, J., Ham, D. van et al. (2013). Toward personalized sexual medicine (part 3): testosterone combined with a Serotonin1A receptor agonist increases sexual satisfaction in women with HSDD and FSAD, and dysfunctional activation of sexual inhibitory mechanisms. Journal of Sexual Medicine, 10, 824–837.Google Scholar
  62. 62.
    Schutter, D.J. & Honk, J. van (2004). Decoupling of midfrontal delta-beta oscillations after testosterone administration. International Journal of Psychophysiology, 53, 71–73.Google Scholar
  63. 63.
    Secreto, G., Venturelli, E., Meneghini, E., Carcangium M.L., Paolini, B., Agresti, R. et al. (2012). Androgen receptors and serum testosterone levels identify different subsets of postmenopausal breast cancers. BMC Cancer, 12, 599,2407-12-599.Google Scholar
  64. 64.
    Sherwin, B.B., Gelfand, M.M. & Brender, W. (1985). Androgen enhances sexual motivation in females: a prospective, crossover study of sex steroid administration in the surgical menopause. Psychosomatic Medicine, 47, 339–351.Google Scholar
  65. 65.
    Shifren, J..L, Braunstein, G.D., Simon, J.A., Casson, P.R., Buster, J.E., Redmond, G.P. et al. (2000). Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. New England Journal of Medicine, 343, 682–688.Google Scholar
  66. 66.
    Shifren, J.L., Monz, B.U., Russo, P.A., Segreti, A. & Johannes, C.B. (2008). Sexual problems and distress in United States women: prevalence and correlates. Obstetrics & Gynecology, 112, 970–978.Google Scholar
  67. 67.
    Simon, J., Braunstein, G., Nachtigall, L., Utian, W., Katz, M., Miller, S. et al. (2005). Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder. The Journal of Clinical Endocrinology & Metabolism, 90, 5226–5233.Google Scholar
  68. 68.
    Slatcher, R.B., Mehta, P.H. & Josephs, R.A. (2011). Testosterone and self-reported dominance interact to influence human mating behavior. Social Psychological and Personality Science, 2, 531–539.Google Scholar
  69. 69.
    Snabes, M.C., Berry, S., Zborowski, J. & White, W. (2012). Libigel (R) (Testosterone Gel) Safety Study Completes Enrollment and Continues with a Low Cv Event Rate. Journal of Sexual Medicine, 9, 166-.Google Scholar
  70. 70.
    Snabes, M.C., Zborowski, J. & Simes, S. (2012). Libigel (R) (Testosterone Gel) does Not Differentiate from Placebo Therapy in the Treatment of Hypoactive Sexual Desire Disorder in Postmenopausal Women. Journal of Sexual Medicine, 9, 171-.Google Scholar
  71. 71.
    Staa, T.P. van & Sprafka, J.M. (2009). Study of adverse outcomes in women using testosterone therapy. Maturitas, 62, 76–80.Google Scholar
  72. 72.
    Stoleru, S., Gregoire, M.C., Gerard, D., Decety, J., Lafarge, E., Cinotti, L. et al. (1999). Neuroanatomical correlates of visually evoked sexual arousal in human males. Archives of Sexual Behavior, 28, 1–21.Google Scholar
  73. 73.
    Tops, M., Russo, S., Boksem, M.A. & Tucker, D.M. (2009). Serotonin: modulator of a drive to withdraw. Brain and Cognition, 71, 427–436.Google Scholar
  74. 74.
    Tuiten, A., Honk, J. van, Koppeschaar, H., Bernaards, C., Thijssen, J. & Verbaten, R. (2000). Time course of effects of testosterone administration on sexual arousal in women. Archives of General Psychiatry, 57, 149–153; discussion 155–156.Google Scholar
  75. 75.
    Tuiten, A., Honk, J. van, Verbaten, R., Laan, E., Everaerd, W. & Stam, H. (2002). Can sublingual testosterone increase subjective and physiological measures of laboratory-induced sexual arousal? Archives of General Psychiatry, 59, 465466.Google Scholar
  76. 76.
    Tuiten, A., Laan, E., Panhuysen, G., Everaerd, W., Haan, E. de, Koppeschaar, H. et al. (1996). Discrepancies between genital responses and subjective sexual function during testosterone substitution in women with hypothalamic amenorrhea. Psychosomatic Medicine, 58, 234–241.Google Scholar
  77. 77.
    Woolcott, C.G., Shvetsov, Y.B., Stanczyk, F.Z., Wilkens, L.R., White, K.K, Caberto, C. et al. (2010). Plasma sex hormone concentrations and breast cancer risk in an ethnically diverse population of postmenopausal women: the Multiethnic Cohort Study. Endocrine-Related Cancer, 17, 125–134.Google Scholar
  78. 78.
    Zhang, X., Tworoger, S.S., Eliassen, A.H. & Hankinson, S.E. (2013). Postmenopausal plasma sex hormone levels and breast cancer risk over 20 years of follow-up. Breast Cancer Research and Treatment, 137, 883–892.Google Scholar

Copyright information

© Bohn, Stafleu van Loghum 2014

Authors and Affiliations

  • Saskia Poels
    • 1
    • 2
  • Jos Bloemers
    • 1
    • 2
  • Kim van Rooij
    • 1
    • 2
  • Hans Koppeschaar
    • 1
  • Berend Olivier
    • 2
    • 3
  • Adriaan Tuiten
    • 1
    • 2
  1. 1.Emotional Brain B.V.AlmereNetherlands
  2. 2.Utrecht Institute for Pharmaceutical Sciences en Rudolf Magnus Institute of NeuroscienceUniversiteit UtrechtUtrechtNetherlands
  3. 3.Yale University School of MedicineNew HavenUSA

Personalised recommendations