Dr. Munikrishnappa will discuss the unlabeled use of melanocortin receptor agonists and ion channel gene transfer with hMaxi-K.

Sexual dysfunction in males includes erectile dysfunction, ejaculatory dysfunction and decrease in libido. Erectile dysfunction (ED) is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance.(1) It affects millions of American men including 52% of men aged 40 to 70 years according to the Massachusetts Male Aging Study (MMAS) data.(1),(2) The follow up study of this cohort revealed that there is an age-associated decline in erectile function.(3) This was confirmed by a more recent prospective cohort study by Bacon and colleagues in men aged between 53 to 90 years.(4)

With aging, structural changes in the penis such as decreased concentration of elastic fibers and smooth muscle fibers, as well as certain functional changes, may contribute to ED, independent of diseases, at least in some elderly men.(5) ED is frequently associated with disorders commonly seen in the elderly such as atherosclerosis and diabetes.(6) Thus, aging alone, as well as the diseases that are commonly prevalent among the elderly, predispose elderly men to be at risk for ED.(7)

Erection is an active neuro-hemodynamic process that occurs in a suitable hormonal setting with support from intact organic structural system and appropriate psychological influences. It can broadly occur in three different instances -- nocturnal erections occur during REM sleep, reflexogenic erections occur from genital stimulation [mediated by parasympathetic nervous system (PNS)] and the central or psychogenic one occurs from stimuli such as smell, visual or recalls via sympathetic nervous sytem (SNS).(8)

The penile erectile tissues, mainly the cavernous smooth musculature and the smooth muscles of the arteriolar and arterial walls, play a vital role in the process of erection. When these smooth muscles are tonically contracted, only a small amount of blood sufficient for nutritional purpose is allowed and this results in flaccid penis (which is still a moderate state of contraction and the penis can shrink further as in cold weather).(9) With sexual stimulation, the peripheral mechanism triggered involves the following sequence:(9),(10),(11)

* Shown below is the schematic figure of the peripheral mechanism leading to tumescence and detumescence of penis and the biochemical pathway where phosphodiesterase type 5 (PDE-5) act.

Detumescence begins with smooth muscle contraction (causing transient increase in pressure), slow reopening of venous channels and resumption of basal level of arterial flow, and lastly a rapid pressure decrease with full venous outflow.(9)

Hypothalamus, limbic system and the cerebral cortex control sexual behavior and penile erection via stimulatory or inhibitory impulses to the spinal erectile centers to facilitate or inhibit erection.(9) The major facilitative neurotransmitters (or excitatory) are: dopamine, acetylcholine, oxytocin and serotonin. The major inhibitors are: epinephrine, norepinephrine, serotonine, enkephalins, gamma aminobutyric acid and prolactin.(8)

Risk Factors

Many of the cardiovascular risk factors are strongly associated with ED including diabetes mellitus, hypertension and dyslipidemia. Vascular ED may be a clinical marker for subclinical atherosclerosis and an early warning sign of coronary atherosclerosis independent of traditional risk factors.(12),(13) The clinical importance of this lies in the fact that patients with ED of apparently unknown cause and asymptomatic for cardiovascular symptoms should be screened for cardiovascular disease and its risk factors before initiating treatment for ED, as sexual activity could precipitate cardiac events in some of these individuals.(14) Endothelial dysfunction seems to be the underlying common pathophysiology for vascular ED and cardiovascular disease.

The other risk factors for ED include hypogonadism in association with a number of endocrinologic conditions, drugs, neurogenic disorders, Peyronie's disease, priapism, depression, alcohol ingestion, lack of sexual knowledge, poor sexual techniques, inadequate interpersonal relationships or their deterioration, obesity, smoking and many chronic diseases, particularly renal failure and dialysis.(1) Physical activity and lean body were found to be associated with lower risk for ED, while obesity, smoking, television viewing and alcohol consumption were associated with higher risk for it in the study by Bacon and colleagues.(4) An improvement was noted in a third of obese patients with baseline ED with lifestyle changes.(15) Iatrogenic risk for ED incidence with certain surgeries include: 43-100% from radical prostatectomy, 30-50% from nerve sparing surgery, 29% from perineal prostatectomy for benign disease, 15-100% from abdominal perineal resection and 2 to 49% for external sphincterotomy.(16),(17),(18),(19),(20),(21),(22),(23)

Evaluation -- History, Physical Examination and Investigation

The first clinical step is to ascertain if the primary complaint of the patient is ED or another sexual dysfunction -- ejaculatory dysfunction or decreased libido. Then, as indicated in Table 1, further medical history will provide an insight into etiological and/or risk factors for ED in an individual.

Physical examination should include local examination of the genitalia-testicular size, asymmetry, mass, consistency suggestive of any malignancy and hypogonadism, palpation of the shaft of penis in the stretched position to determine the presence of fibrous plaques, which may be present at the dorsum or base of the penis (indicative of Peyronie's disease), bulbocavernous reflex, digital rectal examination to check for prostate, anal sphincter tone and perianal sensation. Preserved cremasteric reflex, elicited by stroking the inner thighs and observing ipsilateral contraction of the scrotum, implies intact thoracolumbar erection center integrity.

Systemic examination should be done to assess for cardiovascular risk factors [e.g., obesity, femoral bruits (suggesting pelvic blood flow occlusion), peripheral pulses and hypertension], signs of neurological disorders (e.g., absent bulbocavernous reflex, decreased anal sphincter tone or saddle anesthesia), signs of endocrine disorders (e.g., abnormal visual field defects, thyromegaly, abnormal male secondary sexual characteristics and gynecomastia).(1),(10)

Investigations

Different opinions exist regarding routine tests, especially hormonal, in these patients. However, the following approach is reasonable.

Basic tests aimed at identifying general medical conditions:

• Complete blood count
• urinalysis
• creatinine
• lipid profile
• fasting blood sugar
• and thyroid function studies.

Hormonal Levels

In the study by Slag and colleagues, 10% of 401 men with ED had primary hypogonadism, 9% had secondary hypogonadism, 5% had hypothyroidism, 1% had hyperthyroidism and 4% had hyperprolactinemia.(26) In another study of 1022 men with ED, testosterone and prolactin were measured in those patients with decreased libido or gynecomastia.(31) The prevalence of low testosterone and high prolactin levels were not marked, suggesting no justification for routine measurements. However, this screening strategy missed 40 to 50% of cases that improved with endocrine therapy and the pituitary tumors. This led to the recommendation by this study that before age 50 years testosterone level be determined only in cases of low sexual desire and abnormal physical examination but that it be measured in all men older than 50 years. Furthermore, the study suggested that prolactin should be determined only in cases of low sexual desire, gynecomastia and/or testosterone less than 4 ng/ml.(31)

Testosterone, prolactin, thyroid stimulating hormone (TSH), leutinizing hormone (LH), follicular stimulating hormone (FSH) should be obtained as part of the evaluation of patients with ED, especially for those patients with hypogonadal features.

Nocturnal Penile Tumescence (NPT) Testing

Advances in NPT testing have made it possible to obtain accurate and reproducible data and to use it in clinical decision-making including surgical intervention.(32) If a patient with ED has a normal NPT, psychogenic cause is likely, as compared to a patient with abnormal NPT, who is likely to have either a neurogenic or vascular cause for ED. Duplex Doppler ultrasound or angiography of deep penile arteries may be done in those patients with abnormal NPT to delineate further vascular pathology when surgical intervention is contemplated.(33)

Management of ED

There are several treatment options available and the choice depends on the clinical situation of the patient. The patient and his partner need to make an informed choice after a discussion of risks and benefits with the physician.

The following treatment options are available currently:

Medical

1. PDE Type 5 inhibitors
2. Testosterone
3. Penile injections
4. Psychotherapy and behavioral therapy with or without psychoactive drugs

Non-Medical

1. Topical vacuum pump
2. Inflatable penile implants

Medical Treatment

PDE Type 5 (PDE-5) inhibitors

Since their introduction in 1998 in the form of sildenafil, PDE-5 inhibitors have had tremendous impact on patients with ED.(34) There are presently three drugs in this class that are widely used including sildenafil, vardenafil and tadalafil. Udenafil, a long acting PDE-5 inhibitor, is currently under investigation.(35) About 11 types of PDEs are described in humans. Types 5, 6 and 9 have cGMP as the only substrate.(8) Some of the side effects of these drugs are attributable to their effect on these PDEs in places other than penis.

General Characteristics of PDE-5s

• Often the first-line of therapy
• All of them require sexual arousal to cause erection unlike the penile injection methods
• Need to be taken at least an hour prior to sexual activity
• Act by inhibiting phosphodiesterase enzyme leading to decreased breakdown of and increased accumulation of cGMP within the penis
• In hypogonadal non-responders to the drug, combining with testosterone improved erections(36)
• Half-life of PDE-5s are affected by inducers and inhibitors of the CYP3A4
• Contraindications/Cautions:
  1. Some retinitis pigmentosa patients have PDE-6 gene defect, so these drugs are contraindicated in retinitis pigmentosa patients.(10)
  2. Another contraindication is nitrate therapy, as severe hypotension may be caused. Nitrates should not be given within 24 hours of sildenafil or vardenafil and within 48 hours of tadalafil.(37),(39) If there is concomitant renal or hepatic impairment, nitrates and these medications should be used further apart in duration. Sildenafil is relatively safe in stable angina patients controlled on medications, as shown by meta-analysis, but there is an increased risk of precipitating myocardial infarction (MI) and death in those coronary artery disease patients who engaged suddenly in sexual physical activity.(38),(40) All patients, therefore, need to be questioned regarding their exercise tolerance and whether they have been active or relatively inactive before prescribing these medications. The cardiovascular metabolic cost of sexual activity is probably 3 to 5 metabolic equivalents; consequently, patients who achieve 5 to 6 metabolic equivalents without ischemic changes are probably at low risk.(38) Sexual activity increases the chances of MI by a factor of 2x and some patients seem to accept this risk for the quality life that they are able to appreciate in return.(38)
  3. Caution needs to be exercised in benign prostatic hyperplasia (BPH) patients, as the combination of α₁-adrenergic antagonist medications with PDE-5 inhibitors can lead to precipitous hypotension.(10) See below the specific considerations for each PDE-5 inhibitor.
  4. Rarely, non-arteritic ischemic optic neuropathy (NAION) is reported in patients (especially with concomitant presence of autonomic or vascular risk factors) taking sildenafil and tadalafil but conclusive evidence linking it to these drugs is lacking.(41),(42)
  5. Lower doses should be used in patients with neuropathic ED (e.g., spinal cord trauma), as they could be at increased risk for priapism.(39)

Sildenafil

• Preferably take on an empty stomach
• Dose is 25 to 100 mg, may start with 50 mg and titrate up or down depending on clinical condition/s. Most people respond to 75 mg. Dose adjustment may be needed in the elderly.(14)
• Onset of action: 30 to 60 minutes, so patients need to take it an hour prior to sexual activity; Duration: 4 h.(10)
• Side effects: Many are secondary to the drug effect on PDEs elsewhere in the body.(43) Headache, flushing, dyspepsia, diarrhea, rhinitis and nausea. Blue-tinged vision, unique to sildinafil, occurs in 3%, lasts two to three hours, likely caused by PDE-6 activation in the retina, resolves with discontinuation of the drug or spontaneously.(39),(43),(44) Hypotension occurs by about 8 mm Hg and much greater with nitrates.(39)
• Sildenafil at doses more than 25 mg should not be taken within 4 hours of any α₁ - adrenergic antagonist medications.(10)
• All patients may not respond equally: only 56% of diabetic men had improved erections;(45) approximately 50% of men with prostate cancer after treatment with prostatectomy or radiation therapy had improvement and the outcomes were better in men who had a nerve-sparing surgery.(46),(47),(48)

Vardenafil and tadalafil have similar profiles as sildenafil but are more selective and potent. The important differences include:

Vardenafil(10)

• Take with or without food
• Doses: 2.5, 5, 10 and 20 mg; dose adjustment not necessary in the elderly
• Side effects: back pain, myalgias and arthralgias
• Contraindicated with any α₁-adrenergic antagonist medications. The drug is thought to prolong the QT interval, although slightly, which is not clinically important except that it should not be used in men who have congenital QT prolongation or in those who are on antiarrhythmics, e.g., quinidine and amiodarone.(49)

Tadalafil(10)

• Take with or without food
• Doses: 5, 10 and 20 mg; dose adjustment not necessary in the elderly
• Onset of action: 30 min; Duration of action: 24 to 36 h
• Contraindicated with any α₁-adrenergic antagonist medications except tamsulosin at the 0.4-mg dose.(50)

Patients who failed PDE-5 inhibitors or those who cannot take them, could consider other treatment modalities including intraurethral alprostadil and penile injection therapy. However, these are not options for patients with penile deformity, blood dyscrasias (e.g., sickle cell disease), leukemia or multiple myeloma.(10) No adequate safety data is available for combining both PDE-5 and these modalities.(10)

Intraurethral Alprostadil(10)

• Inserted into the tip of the penis
• Effective in all ages
• Side effects: syncope (health professional needs to observe first dose), local pain, priapism

Intracavernosal Penile Injections

• The most effective medical therapy for ED(10)
• Alprostadil can be used to treat with papverine and phentolamine (triple therapy) to reduce side effects, e.g., pain, penile corporal fibrosis, fibrotic nodules, hypotension and priapism(1)
• Mechanism: alprostadil and papverine relax the cavernous smooth muscle and penile blood vessels, and phentolamine blocks α-adrenoreceptors causing increased penile blood flow(10)
• Side effects: scarring, pain and priapism but generally safe(51),(52)
• Priapism lasting 36 hours may be treated with adrenergic agents and puncture whereas after 48 hours glandulacavernous shunts were needed. The risk of fibrosis was greater with the shunts(1),(53)
• Liver function tests in papverine treated patients
• Not FDA approved but in use(1)

Testosterone

It is reasonable to screen for serum testosterone levels in those who show hypogonadal features or who fail PDE-5 inhibitor therapy, as the penile nitric oxide pathway is testosterone dependent (also a reason to combine these therapies).(10),(54) Hypogonadism is diagnosed by symptoms such as decreased libido, cognitive decline, muscle weakness and low testosterone level. Testosterone replacement therapy has not been shown to improve erectile function in men with normal levels of testosterone.(55) In patients for whom replacement therapy is indicated, the added testosterone increases libido, nocturnal erections and frequency of sexual intercourse.(10),(54),(56),(57) Increasing evidence shows that combining testosterone and PDE-5 inhibitors is effective in patients who failed with testosterone or PDE-5 inhibitors alone.(36)

Therapy with testosterone has potential adverse effects. For instance, hepatic neoplasms, fulminant hepatitis and cholestatic jaundice may be associated with prolonged, high-dose usage of orally active 17-α-alkyl androgens such as methyl-testosterone.(10) However, according to one clinical review by Rogol and Yesalis III, serious side-effects are few, especially for the commonly used injectable testosterone esters, taken intermittently in the usual quantities.(58) Other potential adverse effects of exogenous testosterone therapy include gynecomastia, decreased high density lipoprotein, erythropoietin-mediated polycythemia, edema, sleep apnea, hypertension, infertility and BPH.(10) Supplemental testosterone may not cause prostate carcinoma but it might augment the growth of existing occult cancer.(1),(10),(56)

Thus, prior to starting replacement therapy, any history of the above mentioned diseases should be elicited and serum prostate specific antigen (PSA), digital rectal examination for prostate, baseline complete blood count, liver function tests and lipid profile should be obtained.

Testosterone is available by injection, skin patch, buccal oral tablets and topical gel. As early as two weeks later, one can reassess the testosterone level. The therapeutic response and testosterone level are reassessed at 3 months to decide whether treatment should be continued or dosage adjusted. The goal is to bring the testosterone level to low or middle-normal range.

PSA should be measured and prostatic symptoms assessed at 6 months and then annually. If the PSA is either elevated or is increasing, testosterone should be stopped. Hematocrit and lipids should be monitored every 6 months for 18 months and then yearly.(59) If the hematocrit is more than 50%, testosterone should be decreased or discontinued.(59)

Psychotherapy and Behavioral Therapy with or without Psychoactive Drugs

Patients with psychogenic causes of ED such as depression and anxiety benefit from psychotherapy (with or without psychoactive drugs) but caution needs to be exercised, as some of the antidepressants themselves cause ED. Evidence exists to try yohimbine, a presynaptic α-2 adrenergic receptor blocker, in those patients suspected of psychogenic ED who respond to it initially and tolerate its side effects.(60) Combination of l-arginine glutamate and yohimbine has been shown to improve erection in ED in some studies.(61),(62) Side effects such as tachycardia and hypertension limit its use in heart disease patients.

Non-Medical Therapy

A topical vacuum pump creates a vacuum around the penis causing the blood flow into the penis. Once engorged, a ring is placed over the base of the penis and the pump is removed. Vacuum limiters should be used to avoid the injury from negative pressure.

If all medical treatments fail, surgical interventions including penile prosthesis could be considered. Inflatable prostheses may appear more physiological compared to the semi-rigid and malleable varieties but careful attention should be paid to other aspects of this treatment such as a high rate of infection, especially in diabetics, and a need for re-operation because of a higher rate of failure.(1) Vascular surgical interventions including venous ligation in patients with venous leakage, arterial revascularization in congenital or traumatic vascular abnormality have limited roles and are best done in medical centers with investigational setting.

What's Ahead?

We need to better understand the molecular mechanisms, especially the neurotransmitters, involved in triggering NO release. Randomized controlled studies to assess the effectiveness of combination therapies and their performance across the age spectrum need to be further pursued. For a substantial number of patients, who either do not respond to or tolerate PDE-5 inhibitors, other therapies that do not target the vascular system will be required. Melanocortin receptor agonists are a new class of drugs that are currently being explored in this direction. Bremelanotide is the first compound in this class that appears promising in early clinical studies. Gene transfer therapy is another potential alternative therapy that is being pursued. Early human trials have been conducted using ion channel gene transfer with hMaxi-K and further investigation is ongoing.(63)