Melanocortin receptor agonists in the treatment of male and female sexual dysfunctions: results from basic research and clinical studies

Erection is basically a spinal reflex that can be initiated by recruitment of penile afferents, both autonomic and somatic, and supraspinal influences from visual, olfactory, and imaginary stimuli. Several central transmitters are involved in the erectile control. Dopamine, acetylcholine, nitric oxide (NO), and peptides, such as oxytocin and adrenocorticotropin/α-melanocyte-stimulating hormone, have a facilitatory role, whereas serotonin may be either facilitatory or inhibitory, and enkephalins are inhibitory. The balance between contractant and relaxant factors controls the degree of contraction of the smooth muscle of the corpora cavernosa (CC) and determines the functional state of the penis. Noradrenaline contracts both CC and penile vessels via stimulation of α₁-adrenoceptors. Neurogenic NO is considered the most important factor for relaxation of penile vessels and CC. The role of other mediators, released from nerves or endothelium, has not been definitely established. Erectile dysfunction (ED), defined as the "inability to achieve or maintain an erection adequate for sexual satisfaction," may have multiple causes and can be classified as psychogenic, vasculogenic or organic, neurologic, and endocrinologic. Many patients with ED respond well to the pharmacological treatments that are currently available, but there are still groups of patients in whom the response is unsatisfactory. The drugs used are able to substitute, partially or completely, the malfunctioning endogenous mechanisms that control penile erection. Most drugs have a direct action on penile tissue facilitating penile smooth muscle relaxation, including oral phosphodiesterase inhibitors and intracavernosal injections of prostaglandin E₁. Irrespective of the underlying cause, these drugs are effective in the majority of cases. Drugs with a central site of action have so far not been very successful. There is a need for therapeutic alternatives. This requires identification of new therapeutic targets and design of new approaches. Research in the field is expanding, and several promising new targets for future drugs have been identified.

The melanocortin system consists of melanocortin peptides derived from the proopiomelanocortin gene, five melanocortin receptors, two endogenous antagonists, and two ancillary proteins. This review provides an abbreviated account of the basic biochemistry, pharmacology, and physiology of the melanocortin system and highlights progress made in four areas. In particular, recent pharmacological and genetic studies have affirmed the role of melanocortins in pigmentation, inflammation, energy homeostasis, and sexual function. Development of selective agonists and antagonists is expected to further facilitate the investigation of these complex physiological functions and provide an experimental basis for new pharmacotherapies.

Women's sexual dysfunction includes reduced interest/incentives for sexual engagement, difficulties with becoming subjectively and/or genitally aroused, difficulties in triggering desire during sexual engagement, orgasm disorder, and sexual pain. To update the recommendations published in 2004, from the 2nd International Consultation on Sexual Medicine (ICSM) pertaining to the diagnosis and treatment of women's sexual dysfunctions. A third international consultation in collaboration with the major sexual medicine associations assembled over 186 multidisciplinary experts from 33 countries into 25 committees. Twenty one experts from six countries contributed to the Recommendations on Sexual Dysfunctions in Women. Expert opinion was based on grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate. A comprehensive assessment of medical, sexual, and psychosocial history is recommended for diagnosis and management. Indications for general and focused pelvic genital examination are identified. Evidence based recommendations for further revisions of definitions for sexual disorders are given. An evidence based approach to management is provided. Extensive references are provided in the full ICSM reports. There remains a need for more research and scientific reporting on the optimal management of women's sexual dysfunctions including multidisciplinary approaches.