Erectile Dysfunction and Current Therapies

 Erectile dysfunction is defined as the inability to produce or maintain a penile erection with rigidity sufficient for intercourse. Risk factors include advanced age, diabetes mellitus, hypertension, obesity, dyslipidemia, pharmacologic side effects and cardiovascular disease. The prevalence increases with age and may affect up
to one third of men over the age of 50, representing a significant source of morbidity in an aging population.

 Currently medical therapies for erectile dysfunction are limited to direct manipulation of cavernosal smooth muscle relaxation. Selective pharmacological inhibition of hosphodiesterase-5 enzyme in penile smooth muscle cells prevents breakdown of cGMP leading to higher intracellular levels of this molecule resulting in increased smooth muscle relaxation and erection. Available PDE-5 inhibitors include sildenafil (Viagra), vardenafil (Levitra) and tadalafil (Cialis). Other pharmacologic options for erectile dysfunction include intracavernosal (Caverject) or intraurethral (MUSE) alprostadil delivery.

 The aforementioned therapies each have drawbacks leading to the search for alternative treatment methods. The PDE-5 inhibitors have been the most successful pharmacotherapy class, however up to 50% of diabetic men with erectile dysfunction remain refractory to such agents.

Importantly, while each of the above therapies addresses the mechanical issue of rigidity necessary for penetration and intercourse, none of the above therapies is known to affect sexual desire/libido, an important component to the overall treatment of erectile dysfunction. Thus, there is an unmet medical need to study alternative pathways and agents, such as the melanocortinergic compounds, which may fill in the gaps left by current forms of treatment.

 Complex interactions between the supraspinal, spinal and peripheral nervous system lead to the highly specific and regulated vasculogenic event of penile erection. Of the many neurotransmitters involved, melanocortins appear to play a significant role in regulation of erection, particularly at the supraspinal and spinal levels. MC agents may regulate physiologic erection, and could also have as yet unexplored effects on sexual motivation and libido.

Much knowledge has been gained of MC receptor sites and MC receptor subtypes involved in erection, particularly through the utilization of  novel compounds which activate and/or inhibit specific MC receptors. However, further detailed studies are necessary, particularly if new therapeutic agents are to be developed. The two superpotent synthetic MC agonists, MT-II and PT-141, have been tested in human subjects, with PT-141 showing promise in early clinical trials for treatment of erectile dysfunction.

Spontaneous erections in rodents

 THIQ is a synthetic small molecule hMC4R agonist with moderate bioavailability (14%), rapid absorption (Tmax = 1hr) and a short T1/2 (0.5hrs). THIQ has a >600 selectivity for the MC4R compared with MC3R. Studies by Martin and Van der Ploeg evaluated the effects of THIQ delivered both systemically and intracerebrally in rodents. Systemic administration (1mg/kg) potentiated electrically stimulated erections as well as decreasing mounting and intromission latency mating behaviors in wild type mice. In an ex copula model using male rats, systemic THIQ dose dependently increased total numbers of erections. This effect was blocked by central administration of the non-specific antagonist, AgRP, as well as the MC4R specific antagonist, MBP-10. ICV delivery of 20kg of THIQ increased reflexive penile erections. There are no studies of THIQ in humans to date. Interestingly, and in contradistinction to MT-II, THIQ has not been reported to initiate spontaneous erections in rodents.

 Endogenous and synthetic antagonists have been used to explore melanocortin signaling. When MCR antagonists bind to the MC receptors they either decrease constitutive levels of cAMP production or prevent agonist induced increases in cAMP production. In studies of penile erection, MCR antagonists have been primarily utilized to identify the mechanisms and location of action of MCR agonists as well as parcel out specific receptor subtype activity. These compounds have not been utilized as therapeutic agents.

 Endogenous melanocortin receptor inhibitors include agouti or agouti-related peptide (AgRP). AgRP is a 132 amino acid peptide which competitively antagonizes both MC3R and MC4R. While AgRP has primarily been studied for its role in energy homeostasis, this peptide is principally expressed in the arcuate nucleus of the hypothalamus, a potential site for regulation of melanocortin mediated erection. As mentioned, intracerebral delivery of AgRP (5.5kg) was shown to block erections in rats induced by the MC4R agonist, THIQ. There have been no studies in humans with regard to erection.

 SHU-9119 is a classical inhibitor of both the MC3R and the MC4R. This synthetic cyclic lactam MSH analogue is closely related in structure to MT-II. SHU-9119 actually has agonist properties at MC1R and MC5R, but for the purposes of discussing erection, this compound is considered primarily an antagonist because of the lack of these receptors in the CNS. In rabbits this highly potent compound readily blocked MT-II induced erections when administered systemically. In rats, SHU-9119 blocked erections and grooming/yawning behaviors stimulated by MT-II both at supraspinal and spinal locations. This compound has not been studied in humans.

 Two other synthetic MC receptor antagonists that have been utilized in studies of erectogenisis include MPB-10 and HS014. Both of these compounds preferentially block the MC4 receptor. Their use in animal studies has primarily been related to determination of receptor specification as described in the following section. These compounds have not been studied in humans.

 Of the 5 melanocortin receptor subtypes, only the MC3R and MC4R have been identified in CNS regions associated with activation of penile erection, particularly the PVN of the hypothalamus. Many of the more commonly studied compounds, such as MT-II and MSH, activate both MC3 and MC4 receptor subtypes to some degree. This lack of receptor specificity has limited our understanding of each receptor’s contribution toward erectile behaviors and has prompted studies utilizing receptor specific agonists and antagonists as well as receptor knock out mouse models. Contrary evidence has pointed to each receptor as the principle subtype mediating erection. Although the weight of evidence leans towards MC4R activation being responsible for activation of erection, the debate remains unresolved.

Evidence of MC3Rs participation in sexual stimulation and erection comes from a series of studies in the late 1990s utilizing an MC4R specific antagonist, HS014. Vergoni et al. administered ACTH and MSH into the lateral ventricle of adult male SpragueDawley rats and showed predictable responses with grooming, stretching, yawning and erections. Co-administration of these compounds with HS014 completely blocked grooming, stretching and yawning behaviors, but only partially reduced erections.

Argiolas  et al. studied this effect further with ACTH,  MSH and HS014 microinjections into regions surrounding the 3rd ventricle of adult rats. The effect was a dose dependent elicitation of yawns, grooms and erections when only ACTH and MSH were administered. Co-administration of these compounds with HS014 significantly blocked yawns and grooms but erections were unaffected. This evidence suggested that the MC4R was not involved in the sexual response to ACTH and MSH. As the only other MC receptor in the region, the MC3R was attributed partial Table 2. Sample of Melanocortin Receptor Binding Agents Studied with Erection Structure Preferential MCR Binding MC3R affinity Ki (nM)* MC4R affinity Ki (nM)* Agonists ACTH 39 amino acid peptide.

Penile Implant

A 58-year-old heterosexual man was referred to our clinic for control visit. He had previously undergone penile implant surgery at 2000, for erectile dysfunction because of arterial vascularisation failure which had developed after transurethral prostatectomy in 1999, and which was unresponsive to medical therapy. He and his partner were satisfied with the penile implant. However, he had begun using home-made herbal remedies in February 2003 to obtain normal physiological erection because he felt himself sentenced to artificial erection evoked by the implant. After 2 months, he perceived that spontaneous full, rigid erections upon sexual arousal, without activation of the implant were adequate for vaginal penetration and satisfying sexual intercourse. He stated that since then, he had been activating the implant only once per month to prevent malfunction of the implant and had been regularly achieving sexual intercourse with spontaneous erection without activation of the implant.

We wanted to confirm radiologically this urological entity by magnetic resonance imaging technique. The images of flaccid penis and artificial erection evoked by the implant were obtained. On the following day, 50 mg sildenafil was given orally to the patient with the inactivated implant, for achievement of penile erection to demonstrate whether the penis still contains erectile tissue. One hour later, rigid penile erection was obtained. The glans and corpus spongiosum are also involved.

However, erection was not resolved spontaneously and semirigid erection persisted with minimal pain. The erection lasted for 6 h and, resolved with oral terbutaline, the application of ice pack to the genitalia and intermittent activation of the implant until detumescence. We did not attempt to stick a needle into cavernous body for diagnostic or therapeutic purposes during prolonged erection, because of the presence of an intracavernous implant. Routine haematological, biochemical and urine tests were normal.

Although the latest pharmacological developments have revolutionised the management of erectile dysfunction, penile implant surgery remains one of the most effective treatments for all types of erectile dysfunction. Nevertheless, it is a common belief that erectile tissue is destroyed utterly during dilatation of corporeal space in penile implant surgery and the penis thus loses its erectile function permanently. Even special penile implants (soft or fenestrated) have been developed with the aim at avoiding this adverse event and the fact remains that spontaneous tumescence or even erection was achieved with these devices in accordance with the expectations. Regular spontaneous tumescence is not surprising in men with specially designed implants, because these devices restore erectile function by the initiation of a new haemodynamic status in the corpora cavernosa which are dilated lesser than that of standard procedure.

The remaining functional cavernous tissue between the cylinder of implant and the tunica albuginea plays a pivotal role in men who experienced spontaneous tumescence, with this special penile implant. However, the same condition was not expected theoretically in men with three-piece hydraulic implants. Surprisingly, Manning et al. reported spontaneous tumescence without activation of the device in 50% of patients with three-piece inflatable device in their retrospective study including 32 patients.

More interestingly, one patient had claimed regular, full, rigid spontaneous erections that were adequate for sexual intercourse in their study. The authors finally stated that the destruction of cavernous tissue during dilatation was incomplete and tumescence, even with three-piece hydraulic implants, was not completely prevented.

Our report includes the complete case history of a penile implant patient who is regularly achieving sexual intercourse with spontaneous erection upon sexual arousal without activation of the three-piece implant. This extremely rare condition becomes more interesting with the occurrence of prolonged drug-induced erection in the patient with penile implant because of arteriogenic erectile dysfunction. The same has not yet been reported in terms of the presence of both spontaneous and prolonged drug-induced erection.

The most important question that needs to be answered in this subject is, how the penis which was unresponsive to medical therapy before penile implant surgery, spontaneously achieves an erection after penile implant. Several hypotheses were proposed to explain the phenomenal aspect. Our case, particularly with the occurrence of prolonged drug-induced erection supports the hypothesis proposed by Goldstein et al. They stated that elevated pre-load of likely compressed rather than destructed cavernous tissue and easier venous compression is the underlying mechanism of spontaneous tumescence with penile implants.

In addition, the herbal remedies used by the patient may have played a role in occurrence of this interesting phenomenon because some naturopathic remedies have significant hormonal content, even though this issue has not yet been clearly elucidated.

PT-141 (Bremelanotide)

 PT-141 (Bremelanotide) is currently the most studied melanocortinergic compound with regard to therapeutic potential for treatment of erectile dysfunction. PT-141 is a synthetic heptapeptide. It is a deaminated derivative and likely metabolite of MT-II. This compound has strong binding to MC receptors 1, 3 and 4, with a higher affinity for MC4R over MC3R. Application of PT-141 to HEK-293 cells expressing MC4R increases cAMP production, indicating that this compound, like MT-II, acts as an agonist.

 Studies with adult male Sprague-Dawley rats indicate pro-erectile responses through multiple modes of delivery. Intranasal injection of 50?g/kg PT-141 produced a significant increase in spontaneous erections compared with saline controls in rats observed over a 30-minute period. As well, 100% of the drug treated rats had at least one erection. In this study the pro-erectile effect of PT-141 was attributed to hypothalamic stimulation of MC3R and/or MC4R. Two hours after PT-141 (50?g/kg IN) administration, immunostaining for FOS, a measure of neural activation, showed increased expression in the paraventricular nucleus compared with rats administered saline.

 Preliminary trials in humans have established both safety and efficacy of PT-141. A phase 1 randomized doubleblind placebo controlled trial involved 24 healthy male subjects without erectile dysfunction. Intranasal doses of 4 to 20mg were delivered to patients in the absence of visual sexual stimulation (VSS). Safety and tolerability were monitored revealing no significant hemodynamic changes or side effects, including priapism. Serum concentration of drug was dose dependent and peaked at 30 minutes in the maximum dose group. Serum half-life was measured at 120 minutes. Rigi-Scan monitoring of erectile response revealed a significantly increased duration of rigid erections of 140 minutes compared to 22 minutes in the placebo group. Time to onset of erection ranged from 34 to 63 minutes.

Erections were considered rigid if they were more than 60% of base rigidity. 

Based on the above results, phase II studies were initiated in patients with mild to moderate ED who showed positive erectile response to PDE-5 inhibitors [44]. RigiScan monitoring in the presence of VSS detected a 3-fold increase in erectile activity with PT-141 (20mg intranasal) administration. The duration of base rigidity was significantly increased utilizing both a 60% and 80% cut-off versus placebo [43]. Timing of erections corresponded well to visual stimulation indicating a potential acilitator mechanism of drug action.

 In a first Phase IIB at home study, PT-141 induced dose dependent improvements in erectile function as assessed by the International Index of Erectile Function (IIEF). Of the patients who completed at least 3 at home attempts (n = 203), the mean IIEF erectile function domain score increased in a dose dependent fashion (p < 0.05 for 10, 15, and 20 mg). Normal erectile function (EF>26) was achieved by 10, 30, 36, 53, and 50% of patients in the placebo, 5, 10, 15, and 20 mg groups respectively.

Improved erections as defined by a global assessment question were reported by 17, 49, 67, 66, and 66% of patients in the placebo, 5, 10, 15, and 20 mg groups respectively. There were no episodes of syncope or hypotension. The only serious adverse event reported in this study occurred in one patient who reported a rolonged erection that was painless and required no treatment. Gastrointestinal side-effects were the primary reasons for discontinuation in the higher two higher dose groups.

 In summary, PT-141 is a potent initiator of erection with minimal side effects, a rapid onset of action and a sufficiently long duration of action. Notably, the recent Phase II studies confirm that the erectile responses are augmented by sexual stimulation. With its central mechanism of action, PT-141 may act independent or synergistically with PDE-5 inhibitors and provide a useful alternative therapy for erectile dysfunction, both from organic and psychogenic origin. A randomized prospective lacebocontrolled study compared treatement of ED with sildenafil alone verses sildenafil with 7.5mg intranasal PT-141. Co-administration of the two agents resulted in significantly prolonged time of increased base rigidity (>60%) compared with sildenafil alone during a 2.5 hour monitoring session. The combination of drugs was well
tolerated with no significantly increased side-effects over either sildenafil or PT-141 alone. The ability of the peptide to safely and effectively induce high quality erections allowed Palatin Technologies to initiate a second Phase IIB study in 2006 and propose Phase III studies in 2007.

Endogenous Receptor Agonists

 ACTH, MSH are the known endogenous agonists of the MC system. Each hormone is a product of posttranslational modification of the POMC gene transcript and
contains the sequence of His-Phe-Arg-Trp, considered to be the “core” of agonist activity. Only ACTH and MSH have shown the ability to generate sexual stimulation and penile erection in various animal species including rats, rabbits, cats, dogs and monkeys. These pro-erectile effects appear to be androgendependent as castration abolishes the aforementioned response.

Notably, many of the synthetic MC agonists contain the “core” sequence present in ACTH and  MSH, particularly the agents MT-II and PT-141.

MT-II is a synthetic cyclic heptapeptide that was initially designed as an artificial tanning agent. Its structure is based on an earlier linear peptide, Melanotan-I, however cyclization was introduced to prevent degradation and allow both N and C terminal truncation of the peptide. The pro-erectile activity of
MT-II was reported as a significant unexpected reaction during a phase-I human trial of human tanning. MT-II contains a seven amino acid sequence with homology to receptor binding portions of MSH and ACTH. The compound is thought to cross the blood brain barrier and has high affinity for the MC1R, MC3R and MC4R. MT-II has a similar affinity for MC4R compared with MC3R and may be considered “superpotent” because of its relatively high affinity for MC4R compared with the endogenous
peptides MSH and ACTH (10-100 fold difference).

 The pro-erectile activity of MT-II appears to be both forebrain and spinally mediated, with little, if any, peripheral effect. Dose dependent increases in spontaneous erections in awake Long-Evans rats were noted with administration of MT-II intracerebrally, intrathecally and intravenously.

Increases in yawning and grooming behaviors paralleled erectile activity with intracerebral administration but not spinal administration. As discussed previously, when the non-selective MCR antagonist SHU-9119 was given spinally, it blocked spinal MT-II induced erections, however intrathecal SHU-9119 failed to block intracerebral MT-II induced erections. This indicates potentially independent sites of melanocortin action along the CNS axis with intracerebral sites activating multiple downstream pathways including those independent of melanocortinergic activation.

 In parallel with the above observations, Vemulapalli et al found that isolated corpus cavernosal strips from rabbits had no relaxation in response to electrical field stimulation in the presence or absence of MT-II. As well, MT-II associated elevations in intracavernosal pressure were abolished when anesthetized rabbits underwent bilateral pudendal nerve ablation. Inhibition of NOsynthase enzymes with L-NAME also blocked the erectile effect of systemic MT-II. These pieces of data indicate that MT-II exerts direct actions through CNS brain and spinal activation, which is then mediated peripherally through established NO vasodilatory pathways.

 A double blind placebo-controlled crossover study by Wessells  et al. demonstrated the safety and pro-erectile activity of subcutaneous MT-II in humans. In the absence of erotic stimulation, 10 men with psychogenic (non-organic) erectile dysfunction received subcutaneous doses ranging from 0.025 to
0.157 mg/kg, while erections were monitored by RigiScan over a 6-hour period. Eight of the 10 men developed clinically apparent erections with greater than 80% rigidity of an average duration of 38 minutes compared with 3 minutes for placebo controls. The time to onset ranged from 15 to 270 minutes. Side effects were dose
dependent included nausea, stretching, yawning and decreased appetite. At the preferred dose of 0.025 mg/kg side effects were mild.

 The above study documented erectogenic effects of MT-II in men with presumed normal underlying physiology. A subsequent study of MT-II was carried out on men with organic ED. In a similar double blind, placebo-controlled crossover study, 10 men received 2 subcutaneous doses of 0.025 mg/kg MT-II and 2 doses of vehicle. MT-II initiated subjectively reported erections following 63% of the drug injection verses 5% of the placebo injections. The mean rigidity score of the responders was 6.9 on a scale of 0 to 10.

 Mean duration of tip rigidity greater than 80% was 45 minutes with Melanotan II compared to two minutes for placebo. There was increased subjective reporting of sexual desire after MT-II administration compared with placebo, although the question used to assess desire was not designed specifically to measure desire in men not engaging in sexual intercourse.