Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Clinical applications of centrally acting agents in male sexual dysfunction

Abstract

Currently available agents for erectile dysfunction (ED) share the same mechanism of action and pharmacologic properties. Therefore, they share the same limitations, including a principal focus on erection as an end-organ process. One of the relatively unexplored areas of research has been the potential for centrally acting agents to improve male sexual response. A variety of neurohormones and neurotransmitter systems are involved in the male sexual response, including testosterone, dopamine, serotonin and the melanocortin systems. Investigations to determine the utility of centrally acting agents as monotherapy or adjunctive therapy in men with ED or other forms of sexual dysfunction are underway. Bremelanotide, a melanocortin agonist, has been tested in men with ED and may prove to be one of the first centrally acting agents to have clinical utility in male sexual dysfunction.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

References

  1. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA et al. Oral sildenafil in the treatment of erectile dysfunction. N Eng J Med 1998; 338: 1397–1404.

    Article  CAS  Google Scholar 

  2. Raina R, Lakin ML, Agarwal A, Sharma R, Goyal KK, Montague DK et al. Long-term effect of sildenafil citrate on erectile dysfunction after radical prostatectomy: 3-year follow-up. Urology 2003; 62: 110–115.

    Article  PubMed  Google Scholar 

  3. Viagra [package insert]. Pfizer Labs: New York NY, 2006.

  4. Levitra [package insert]. Bayer Pharmaceuticals Corporation: West Haven CT, 2007.

  5. Cialis [package insert]. Lilly ICOS LLC: Indianapolis IN, 2003.

  6. Kendirci M, Walls MM, Hellstrom WJ . Central nervous system agents in the treatment of erectile dysfunction. Urol Clin N Am 2005; 32: 487–501.

    Article  Google Scholar 

  7. Ojumu A, Dobs AS . Is hypogonadism a risk factor for sexual dysfunction? J Androl 2003; 24: S46–S51.

    Article  PubMed  Google Scholar 

  8. Carani C, Bancroft J, Del Rio G, Granata AR, Facchinetti F, Marrama P . The endocrine effects of visual erotic stimuli in normal men. Psychoneuroendocrinology 1990; 15: 207–216.

    Article  CAS  PubMed  Google Scholar 

  9. Seftel A . Testosterone replacement therapy for male hypogonadism: part III. Pharmacologic and clinical profiles, monitoring, safety issues, and potential future agents. Int J Impot Res 2007; 19: 2–24.

    Article  CAS  PubMed  Google Scholar 

  10. Schubert M, Jockenhovel F . Late-onset hypogonadism in the aging male (LOH): definition, diagnostic and clinical aspects. J Endocrinol Invest 2005; 28 (3 Suppl): 23–27.

    CAS  PubMed  Google Scholar 

  11. Rhoden EL, Morgataler A . Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004; 350: 482–492.

    Article  CAS  PubMed  Google Scholar 

  12. Haren MT, Kim MJ, Tariq SH, Wittert GA, Morley JE . Andropause: a quality-of-life issue in older males. Med Clin North Am 2006; 90: 1005–1023.

    Article  CAS  PubMed  Google Scholar 

  13. Lazarou S, Morgentaler A . Hypogonadism in the man with erectile dysfunction: what to look for and when to treat. Curr Urol Rep 2005; 6: 476–481.

    Article  PubMed  Google Scholar 

  14. Bancroft J . The endocrinology of sexual arousal. J Endocrin 2005; 186: 411–427.

    Article  CAS  Google Scholar 

  15. Scepkowski LA, Georgescu M, Pfaus JG . Neuroendocrine factors in sexual desire and motivation. In: Goldstein I, Traish A, Davis S, Meston C (eds). Women's Sexual Function and Dysfunction. Taylor & Francis Ltd: London, 2005, pp 159–168.

    Chapter  Google Scholar 

  16. O′Carroll R, Bancroft J . Testosterone therapy for low sexual interest and erectile dysfunction in men: a controlled study. Br J Psychiatry 1984; 145: 146–151.

    Article  PubMed  Google Scholar 

  17. Frajese G, Lazzari R, Magnani A, Moretti C, Sforza V, Nerozzi D . Neurotransmitter, opiodergic system, steroid-hormone interaction and involvement in the replacement therapy of sexual disorders. J Steroid Biochem Mol Biol 1990; 37: 411–419.

    Article  CAS  PubMed  Google Scholar 

  18. Isidori AM, Giannetta E, Gianfrilli D, Greco EA, Bonifacio V, Aversa A et al. Effects of testosterone on sexual function in men: results of a meta-analysis. Clin Endocrinol (Oxford) 2005; 63: 381–394.

    Article  CAS  Google Scholar 

  19. Both S, Everaerd W, Laan E, Gooren L . Effect of a single dose of levodopa on sexual response in men and women. Neuropsychopharmacology 2005; 30: 173–183.

    Article  CAS  PubMed  Google Scholar 

  20. Lal S, Ackman D, Thavundayil JX, Kiely ME, Etienne P . Effect of apomorphine, a dopamine receptor agonist, on penile tumescence in normal subjects. Prog Neuropsychopharmacol Biol Psychiatry 1984; 8: 695–699.

    Article  CAS  PubMed  Google Scholar 

  21. Heaton JP, Morales A, Adams MA, Johnston B, el-Rashidy R . Recovery of erectile function by the oral administration of apomorphine. Urology 1995; 45: 200–206.

    Article  CAS  PubMed  Google Scholar 

  22. Mirone VG, Stief CG . Efficacy of apomorphine SL in erectile dysfunction. BJU Int 2001; 88 (s3): 25–29.

    Article  CAS  PubMed  Google Scholar 

  23. Dula E, Bukofzer S, Perdok R, George M, the Apomorphine SL Study Group. Double-blind, crossover comparison of 3 mg apomorphine SL with placebo and with 4 mg apomorphine SL in male erectile dysfunction. Eur Urol 2001; 39: 558–564.

    Article  CAS  PubMed  Google Scholar 

  24. Broderick GA . Oral pharmacotherapy and the contemporary evaluation and management of erectile dysfunction. Rev Urol 2003; 5 (Suppl 7): S9–S20.

    PubMed  PubMed Central  Google Scholar 

  25. Perimenis P, Markou S, Gyftopoulos K, Giannitsas K, Athanasopoulos A, Liatsikos E et al. Efficacy of apomorphine and sildenafil in men with nonarteriogenic erectile dysfunction. A comparative crossover study. Andrologia 2004; 36: 106–110.

    Article  CAS  PubMed  Google Scholar 

  26. Perimenis P, Gyftopoulos K, Giannitsas K, Markou SA, Tsota I, Chrysanthopoulou A et al. A comparative, crossover study of the efficacy and safety of sildenafil and apomorphine in men with evidence of arteriogenic erectile dysfunction. Int J Impot Res 2004; 16: 2–7.

    Article  CAS  PubMed  Google Scholar 

  27. Eardley I, Wright P, MacDonagh R, Hole J, Edwards A . An open-label, randomized, flexible-dose, crossover study to assess the comparative efficacy and safety of sildenafil citrate and apomorphine in men with erectile dysfunction. Andrology 2004; 93: 1271–1275.

    CAS  Google Scholar 

  28. Porst H, Bebre HM, Jungwirth A, Burkart M . Comparative trial of treatment satisfaction, efficacy, and tolerability of sildenafil versus apomorphine in erectile dysfunction. An open, randomized cross-over study with flexible dosing. Eur J Med Res 2007; 12: 61–67.

    CAS  PubMed  Google Scholar 

  29. Maggi I, Filippi S, Ledda F, Magini A, Forti G . Erectile dysfunction: from biochemical pharmacology to advances in medical therapy. Eur J Endocrinol 2000; 143: 143–154.

    Article  CAS  PubMed  Google Scholar 

  30. Ernst E, Pittler MH . Yohimbine for erectile dysfunction: a systematic review and meta-analysis of randomized clinical trials. J Urol 1998; 159: 433–436.

    Article  CAS  PubMed  Google Scholar 

  31. Uckert S, Fuhlenriede MH, Becker AJ, Stief CG, Scheller F, Knapp WH et al. Is serotonin significant for the control of penile flaccidity and detumescence in the human male? Urol Res 2003; 31: 55–60.

    PubMed  Google Scholar 

  32. Clayton AH, Pradko JF, Croft HA, Montano CB, Leadbetter RA, Bolden-Watson C et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry 2002; 63: 357–366.

    Article  PubMed  Google Scholar 

  33. Rosen RC, Lane RM, Menza M . Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol 1999; 19: 67–85.

    Article  CAS  PubMed  Google Scholar 

  34. Kugaya A, Seneca NM, Snyder PJ, Williams SA, Malison RT, Baldwin RM et al. Changes in human in vivo serotonin and dopamine transporter availabilities during chronic antidepressant administration. Neuropsychopharmacology 2003; 28: 413–420.

    Article  CAS  PubMed  Google Scholar 

  35. Waldinger MD . The neurobiological approach to premature ejaculation. J Urol 2002; 168: 2359–2367.

    Article  PubMed  Google Scholar 

  36. Damsa C, Bumb A, Bianchi-Demicheli F, Vidailhet P, Sterck R, Andreoli A et al. ‘Dopamine-dependent’ side effects of selective serotonin reuptake inhibitors: a clinical review. J Clin Psychiatry 2004; 65: 1064–1068.

    Article  CAS  PubMed  Google Scholar 

  37. Zisook S, Rush AJ, Haight BR, Clines DC, Rockett CB . Use of bupropion in combination with serotonin reuptake inhibitors. Biol Psychiatry 2006; 59: 203–210.

    Article  CAS  PubMed  Google Scholar 

  38. Clayton A, Keller A, McGarvey EL . Burden of phase-specific sexual dysfunction with SSRIs. J Affect Disord 2006; 9: 27–32.

    Article  Google Scholar 

  39. Masand PS, Ashton AK, Gupta S, Frank B . Sustained-release bupropion for selective serotonin reuptake inhibitor-induced sexual dysfunction: a randomized, double-blind, placebo-controlled, parallel-group study. Am J Psychiatry 2001; 158: 805–807.

    Article  CAS  PubMed  Google Scholar 

  40. Clayton AH, Croft HA, Horrigan JP, Wightman DS, Krishen A, Richard NE et al. Bupropion extended release compared with escitalopram: effects on sexual functioning and antidepressant efficacy in 2 randomized, double-blind, placebo-controlled studies. J Clin Psychiatry 2006; 67: 736–746.

    Article  CAS  PubMed  Google Scholar 

  41. DeBattista C, Solvason B, Poirier J, Kendrick E, Loraas E . A placebo-controlled, randomized, double-blind study of adjunctive bupropion sustained release in the treatment of SSRI-induced sexual dysfunction. J Clin Psychiatry 2005; 66: 844–848.

    Article  CAS  PubMed  Google Scholar 

  42. Taylor MJ . Strategies for managing antidepressant-induced sexual dysfunction: a review. Curr Psychiatry Rep 2006; 8: 431–436.

    Article  PubMed  Google Scholar 

  43. Voisey J, Carroll L, van Daal A . Melanocortins and their receptors and antagonists. Curr Drug Targets 2003; 4: 586–597.

    Article  CAS  PubMed  Google Scholar 

  44. Van der Ploeg LH, Martin WJ, Howard AD, Nargund RP, Austin CP, Guan X et al. A role for the melanocortin 4 receptor in sexual function. Proc Nat Acad Sci 2002; 99: 11381–11386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rosen RC, Diamond LE, Earle DC, Shadiack AM, Molinoff PB . Evaluation of the safety, pharmacokinetics and pharmacodynamic effects of subcutaneously administered PT-141, a melanocortin receptor agonist, in healthy male subjects and in patients with an inadequate response to Viagra. Int J Impot Res 2004; 16: 135–142.

    Article  CAS  PubMed  Google Scholar 

  46. Diamond LE, Earle DC, Rosen RC, Willett MS, Molinoff PB . Double-blind, placebo-controlled evaluation of the safety, pharmacokinetic properties and pharmacodynamic effects of intranasal PT-141, a melanocortin receptor agonist, in healthy males and patients with mild-to-moderate erectile dysfunction. Int J Impot Res 2004; 16: 51–59.

    Article  CAS  PubMed  Google Scholar 

  47. Diamond LE, Earle DC, Garcia WD, Spana C . Co-administration of low doses of intranasal PT-141, a melanocortin receptor agonist, and sildenafil to men with erectile dysfunction results in an enhanced erectile response. Urology 2005; 65: 755–759.

    Article  CAS  PubMed  Google Scholar 

  48. Kaminetsky J, Zinner N, Gittleman M, Auerbach S, Fischkoff S . Phase IIb study of bremelanotide in the treatment of ED in non-diabetic males. Proceedings of the American Urology Association Annual Meeting; 19–24 May 2007; Anaheim, USA.

  49. Althof SE, Pereman MA, Rosen RC, Fischkoff S, Earle D . Improvement in sexual relationship satisfaction, confidence, and self-esteem in erectile dysfunction patients treated with bremelanotide. Proceedings of the American Urology Association Annual Meeting; 19–24 May 2007; Anaheim, USA.

  50. Hellstrom WJ, Gittelman M, Zinner N, Hallam T, Harning R, Dworaczyk DA et al. Randomized, double-blind, placebo-controlled, at-home study to evaluate the efficacy and safety of intranasal bremelanotide in men with erectile dysfunction with and without diabetes mellitus. Proceedings of the European Society for Sexual Medicine (ESSM) Annual Meeting; 3–6 December 2006; Vienna, Austria.

  51. Diamond LE, Earle DC, Heiman JC, Rosen RC, Perelman MA, Harning R . An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist. J Sex Med 2006; 3: 628–638.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from Palatin Technologies, Inc. Editorial support for the development of this paper was provided by Kevin Kehres.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to W J G Hellstrom.

Additional information

Disclosure

Dr Hellstrom serves as a consultant/advisor, lecturer and/or clinical trial investigator for the following: VIVUS, Mentor, Bayer, Pfizer, Johnson & Johnson, Auxilium, King, Palatin, American Medical Systems, Medtronic, GlaxoSmithKline, Coloplast and Sanofi-Synthelabo.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hellstrom, W. Clinical applications of centrally acting agents in male sexual dysfunction. Int J Impot Res 20 (Suppl 1), S17–S23 (2008). https://doi.org/10.1038/ijir.2008.18

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijir.2008.18

Keywords

  • male sexual dysfunction
  • erectile dysfunction
  • treatment
  • bremelanotide

This article is cited by

Search

Quick links