CLINICAL DIABETES
VOL. 14 NO. 5 SEPTEMBER/OCTOBER 1996

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Erectile Dysfunction in Diabetes

Aaron Vinik, MD,PhD, FCT, FACP, and Donald Richardson, MD

 Erectile dysfunction (ED) is the consistent inability to attain and maintain an erection adequate for sexual intercourse. The term impotence implies failure of the individual and should be abandoned in favor of terms such as penile failure or penile unreliability, or even ED, thus placing the responsibility with the offending organ and not the person.

An estimated 10-15 million men in the United States (more than 10%) have ED. One in every three men will experience the problem. The prevalence of ED in men with diabetes has been estimated to be between 35 and 75%.^1,2

Figure 1 shows the major causes of ED in the United States. Diabetes accounts for 30%, and vascular disease, of which diabetes is the dominant contributor, for 40%. Surgery to the prostate and urogenital area, spinal cord injuries, and multiple sclerosis combined account for about 24%, and endocrine disorders for only about 3-6%.

After the age of 70 years, two-thirds of the general male population have ED. The incidence of ED in men with diabetes between the ages of 20-29 years is 9%, but it rises to 95% by age 70 years. In fact, it may be the presenting symptom of diabetes. Indeed, the later the onset of diabetes, the earlier the onset of ED. It may herald the development of diabetes and even precede abnormalities in glucose tolerance. More than 50% of men with diabetes notice the onset of ED within 10 years of the onset of diabetes.

Nevertheless, a large segment of the public and many health professionals remain uninformed or misinformed about ED. This lack of information, added to the reluctance of physicians to deal candidly with their patients' sexual problems, has resulted in patients being denied treatment despite a variety of therapeutic options.

Before discussing treatment options, however, let us consider the reasons for concern for patients with ED. Erectile dysfunction is a marker for the development of generalized vascular disease and premature demise from myocardial infarction. It has been said that the penis is a divining rod capable of identifying individuals at risk for a vascular catastrophe long before it occurs. As a corollary, the prevalence of diabetes in men with ED is 50%, compared with 7% in an age-matched non-diabetic population. ED is associated with elevated total and low-density lipoprotein (LDL) cholesterol, low high-density lipoprotein (HDL) cholesterol, and reduced levels of dehydroepiandrosterone sulfate (DHEA-S), known risk factors for coronary vascular disease. 

Pathophysiology of ED in Diabetes
Normal gonadal function is required for phenotypically male development of the genital tract and for maintenance of some elements of male sexual behavior. The most clearly androgen-dependent aspects include libido, sexual activity, and spontaneous erections.

In normal, young males rendered hypogonadal with a gonadotropin-releasing hormone (GnRH) antagonist, sexual acts, fantasies, and desire were significantly diminished, both clinically and statistically.³ Spontaneous erections also decreased by approximately 40% within 6 weeks.³

Replacement with testosterone prevented these changes, suggesting that an intact male gonadal system is required to maintain sexual function. However, visual and possibly tactile stimulus-bound erections are not impaired in men rendered hypogonadal after infancy. This implies that androgen action is not required to maintain the capacity for erection. 

Figure 1. Major causes of erectile dysfunction in the United States.

Hypogonadism and Diabetes
Type I diabetes occasionally has been associated with hypogonadism. Most cases seem to be due to the hypogonadism of malnutrition and respond to improved control. Some specific conditions associated with diabetes mellitus, such as hemachromatosis, and the Laurence-Moon Biedl, Alstrom, and Cushing syndromes, also typically produce hypogonadism (Table 1).

The vastly more common type II diabetes seems to have a frequent concomitant hypogonadism not related to poor control.^4,5 This can best be ascribed to the truncal obesity so closely tied to type II diabetes, rather than to the abnormalities of glucose metabolism.^6-8 It seems to be due to a lower output of pulsatile GnRH, both in amplitude and frequency of pulses, and, consequently, of luteinizing hormones.⁹

This decrease in central gonadotropin output is mediated by elevated levels of estrogens (estrone and estradiol) produced by the aromatase enzyme found in fat of both sexes, and is derived from adrenal (androstenedione) and testicular (testosterone) androgen. How much this contributes to ED in diabetes is still uncertain, but it should be recognized and, if it is of sufficient magnitude, considered for treatment.

Physiology of Erection
An erection is dependent upon the orchestrated actions of the muscles, nerves, and blood vessels of the penis. It is a hemodynamic event governed by the integrity of smooth muscles in the arteriolar wall and sinusoids of the corpora cavernosa. It requires intact blood flow and sphincteric competence, both regulated by the nervous system.

The corporeal parenchyma is a trabecular framework of bundles of smooth muscle fibers intertwined in a collagen matrix. The blood supply is derived from branches of the cavernous arteries that give rise to the helicene arteries. The corporeal smooth muscle surrounds a complex vascular network consisting of endothelial cell-lined sinuses, or lacunae, and the helicene arteries.

The corpora are enclosed by a dense nondistensible fibrous sheath, the tunic albuginea, and communicate with each other via a medial septum. Subtunical vessels provide the venous drainage of the corpora and coalesce to form the emissary veins that pierce the tunica and drain into the dorsal vein. The innervation of the penis is mainly from the thoracolumbar sympathetic and parasympathetic sacral spinal cord segments. Somatosensory innervation is via the pudendal nerve.

In the flaccid state, the corporeal smooth muscle is tonically contracted, allowing only a small amount of blood to enter the penis. In the proper hormonal milieu, with either psychic stimuli or physical stimulation of the genital organs, autonomic nerves are activated. This releases a variety of neurotransmitters, causing vasodilatation of the helicine arteries and relaxation of the corporeal smooth muscle, both of which produce large increases in penile blood flow and causing trabecular engorgement.

The parasympathetic nervous system is of paramount importance. Increasing cholinergic and noncholinergic neurotransmitters, neuromodulators, and hormones, with simultaneous reduction in adrenergic tone, is responsible for stimulating increased blood flow. The endothelium play an important role, inasmuch as cholinergic activation is dependent upon endothelial release of the potent vasodilators, nitric oxide and prostacyclin, while neuropeptides such as vasoactive intestinal polypeptide (VIP) may be released from the nerves per se.

A number of endothelial-derived peptides and amines have been implicated in modulating erectile function by inducing vasodilatation (erection) or vasoconstriction (detumescence) (Table 2). As the trabeculae fill, the subtunical vessels are compressed against the tunica in a veno-occlusive mechanism, thereby further increasing the turgidity of the corpora. Contraction of the bulbocavernosis and bulbospongiosus muscles adds to the rigidity.

Both penile nitric oxide synthetase (NOS) and the spinal motor neurons innervating the striated erectile muscles are androgen-dependent, and in diabetes the principal vasodilator nitric oxide (NO) is depressed in direct correlation with testosterone.¹⁰ Thus, there appears to be two mechanisms outside the brain supporting an extra-libidinous role for androgens in penile tumescence.

Detumescence is heralded by the return of tone to the corporeal smooth muscle, with reduction of size of the vascular sinuses and release of the compression of the subtunical vessels allowing the corpora to drain and become flaccid. The major regulator of detumescence is norepinephrine acting via post-synaptic alpha 1 adrenergic nerves modulated by presynaptic alpha 2 receptor activity.

For this reason, detumescence can be achieved with infusion of an alpha adrenergic agonist such as phenylephrine, and erection can be achieved with an alpha adrenergic blocking drug such as phentolamine. Exceptions to this rule abound, and people with severe autonomic adrenergic insufficiency do not have priapism, suggesting once again that there are alternate modulators of corporeal detumescence. A recent candidate is endothelin, which is a potent smooth muscle contractor.

The partnership between the sympathetic and parasympathetic nervous system, the endothelium, and smooth muscle function may be disrupted by diseases of blood vessels or nerves, such as occur in diabetes. The development of autonomic neuropathy is partly responsible for the loss of cholinergic activation of the erectile process. In the penis, acetylcholine acts upon the vascular endothelium to release NO and prostacyclin, both of which are defective in diabetes. There is also evidence that nonadrenergic/noncholinergic nerve function is hampered with decreased penile content of VIP, substance P, and other vasodilator neurotransmitters (Table 2).

The association of diabetes with atherosclerosis and microvascular disease further compounds the problem. Recent data indicate that circulating levels of endothelin may be increased in diabetes. Thus, ED in diabetes is no simple matter, and derives from a host of abnormalities.

Evaluation of ED
Initial assessment of a patient with ED should include the patient's significant other or sexual partner, if possible. The clinician should try to obtain an impression of the overall relationship and the impact that return of erections will have on it. A thorough work-up will include medical and sexual history; physical and psychological evaluations; blood tests for diabetes and for levels of testosterone, prolactin, and thyroid hormones; tests to assess penile, pelvic, and spinal nerve function; tests to assess penile blood supply and blood pressure; and tests for nocturnal erections. 

Patient History
A careful history will invariable lead to the correct diagnosis. The flow chart shown in Figure 2 can help define the problem.

It is important to establish the type of problem. For example, is there partial erectile failure or is there a complete loss of rigidity? The natural sequence in diabetes is for a slow progression from poor quality of the erection, culminating often many years later in total failure. There is no loss of libido, which should alert practitioners to the possibility of coexistence of an endocrine or psychogenic component.

With psychogenic ED, the onset is often sudden and maximal ab initio, occurs with a particular partner, and is associated with persistence of morning, nocturnal, and reflex erections due to a distended bladder. In contrast, ED in diabetes occurs with all partners; includes loss of morning, nocturnal, or reflex erections; and is progressive. It is, therefore, important to evaluate past and present relationships.

The health of the partner also must be considered. Deteriorating physical and psychological health of the female companion can wreak havoc on the sexual performance of the male, as can deterioration of the relationship. Performance anxiety and marital disharmony are major causes of ED that may be neglected if the patient has diabetes. Such problems can perpetuate an organic disorder and sabotage treatment if not addressed.

Depression is rife among patients with diabetes, especially those with complications such as neuropathy, retinopathy, and nephropathy. It can place an additional burden on sexual performance.

It is also important to find out if there has been surgery, trauma, or radiation to the pelvis and especially to ask about symptoms of prostatism and the ramifications of treatment with surgery, radiation, orchidectomy, and antiandrogens.

A history of sexual development, stages of androgenization (e.g. deepening of the voice, and growth of beard and pubic hair), and changes in penile and scrotal development, need to be pursued in younger people with type I diabetes. Other endocrine conditions associated with ED include hyper- and hypothyroidism, and it is well to ask about heat and cold intolerance.

The association of vascular disease of the penis and generalized vascular disease requires an inquiry into angina, myocardial infarction, strokes, claudication, and amputations for vascular insufficiency.

Because the major cause of ED in diabetes is autonomic insufficiency it behooves clinicians to ask about the symptom complexes of autonomic neuropathy, such as loss of appetite, nausea, vomiting, bloating with meals, constipation, diarrhea, urinary incontinence, dizziness on standing, gustatory sweating, and night blindness (the inability to drive at night because of the failure of pupillary adaptation to oncoming headlights).

Physical Examination
The physical examination should establish the level of sexual development, with emphasis on the size of the penis, the maturity of the scrotal sac, and the size of the testes. Evidence of virilization should be sought (e.g. the presence of pubic hair, a beard, a thyroid cartilage, and deepening of the voice). If hypogonadism is apparent, then testing for sense of smell, optic fundus examination, breast exam, measurement of arm span to height ratio, and inspection of the hands for klinedactylly may identify the rarer genetic forms of sexual infantilism, such as Laurence-Moon Biedl syndrome.

Vascular status must be evaluated with measurement of blood pressure, cardiac exam, presence of pulses or bruits over vessels, and, if suspicious, a penile brachial index measured using Doppler ultrasound. An index of < 0.7 suggests significant compromise of penile blood flow.

Finally, and probably most important, is a thorough examination of the somatic and autonomic nervous systems.¹¹ Autonomic neuropathy causing ED is almost always accompanied by loss of ankle jerks and absence or reduction of vibration sense over the large toes. More direct evidence of impairment of penile autonomic function can be obtained by demonstrating normal perianal sensation, assessing the tone of the anal sphincter during a rectal exam, and ascertaining the presence of an anal wink when the area of the skin adjacent to the anus is stroked or contraction of the anus when the glans penis is squeezed.

These measurements are easily and quickly done at the bedside and reflect upon the integrity of sacral outflow segments S2, 3, and 4, which represent the sacral parasympathetic divisions. More sophisticated testing of the autonomic nervous system can be done by measuring the change in postural blood pressure and the change in heart rate with deep breathing.

At this point, the cause of ED is usually obvious, and there is no need for further testing. When there are subtleties in the presentation, hormonal measurement of free testosterone and prolactin, as well as gonadotropins and thyrotropin (TSH) is the next step.

The value of a sophisticated sleep study is debatable. In many institutions, the decision is simply to administer intracavernous prostaglandin. A normal response to a small dose indicates the presence of neuropathy with competent vasculature and dictates the treatment options. Resistance to the low dose or absence of an erection is compatible with vascular insufficiency and indicates a need to consider higher doses of the intrapenile drugs, vacuum de-vices, or prostheses. Distinguishing psychogenic from organic nocturnal penile tumescence (NPT) can be done either in a sleep lab or with the NPT portable device.

Nocturnal Penile Tumescence
In measuring NPT, we seek to determine the ability to achieve nocturnal erections and also the change in the diameter and rigidity over the length of the penis. Measuring NPT is not so simple. For patients, it is much like having a sphygmomanometer cuff inflate over the penis many times while trying to have a normal night's sleep. Patients may have to be given the device for several nights before one has a reliable estimate of the failure of NPT.

Ackerman and associates reported that self-reported sexual functioning is highly predictive of the response to NPT measurement,¹² and NPT may be abnormal regardless of daytime sexual function.¹³ Because of the lack of consensus on the value of NPT measurement, more sophisticated tests of penile function have been developed.

Pharmaco-Diagnostic Testing
The discovery of pharmacologically inducible erection by intracavernosal injection (ICI) of vasoactive compounds was a major breakthrough in ED diagnosis. Three vasoactive agents have been used: papaverine, papaverine/

phentolamine, and prostaglandin E1 (PGE1). Other drugs, such as calcitonin gene-related peptide, nitric oxide donors, and vasoactive intestinal polypeptide, or a combination of these, are also being investigated.

In a multicenter study comparing papaverine, papaverine/phentolamine, and PGE1, PGE1 emerged as the most accurate diagnostic drug, with an overall erection rate of 74% and a prolonged erection rate of only 0.1%. Prolonged erection during diagnostic work-up occurred in 9.5% with papaverine, 5.3% with papaverine/phentolamine, and 2.4% with PGE.¹⁴

In patients with psychogenic impotence, erections can be obtained virtually 100% of the time. Similarly, in neurogenic impotence, the response to ICI is about 95%. Failure of response implies vascular insufficiency, which can be arterial or venous incompetence.

Not surprisingly, patients with diabetes respond to ICI about 65-70% of the time. This is in keeping with the predominantly neurogenic cause of their ED and compatible with a significant arterial component (i.e., a normal erectile response implies normal veno-occlusive, but not necessarily arterial function).

A negative response may reflect anxiety in the office setting, however. It is, therefore, advisable on initial ICI testing to administer the drug in the office and allow the patient to go home and report on the quality of erection. Re-dosing is in order with increasing doses to overcome the vascular resistence to vasodilitation of people with diabetes because of the arterial element.

Simultaneous evaluation of penile blood flow with synchronized pharmaco-penile-duplex ultrasonography (PPDU), cavernosometry, and enhancement of the erectile response by genital self-stimulation, vibratory stimulation, visual erotic stimulation, or application of a penoscrotal tourniquet may overcome the element of anxiety and embarrassment. When testing younger patients and those with suspected psychogenic cause of ED, it may be prudent to start with a lower dose.

Since Gaskell and associates introduced Doppler for evaluating penile blood flow, it has been combined with pharmacodynamic testing to assess anatomic and functional parameters of ED.¹⁵ However, PPDU¹⁶ has replaced duplex ultrasound as a means of evaluating veno-occlusive function and pudendal angiography and cavenosometry are second-line tests reserved for patients in whom surgical repair is being considered. For the most part, this is not applicable to diabetes patients.

Treatment Options
There are three treatment options for the men with diabetes and ED: 1) no treatment, with withdrawal from offending medications and psychosexual counseling, 2) medical treatment, 3) surgery.

 1. No Treatment
The option of no treatment will usually be selected for patients with long-standing disorder who have given up the thought of sexual relations and have transferred their energies to other avenues of reward. It may also be wise for patients who have serious underlying vascular or other diseases who should not pursue the level of exertion required to generate sexual satisfaction.

Every effort should be made to have patients withdraw from drugs likely to promote ED (Table 3). Antihypertensive and antidepressant medications, when necessary, should also be chosen on the basis of the least offensive agent (Tables 4 and 5).

It is important to establish the alternative techniques to intercourse the couple has established and, if necessary, to educate them about how to jointly achieve satisfaction despite ED. Psychosexual counseling is mandatory in these situations. Sexual therapy is vital for people with diabetes and ED since the chronic condition is fraught with situational stresses, performance anxiety, and relationship problems.

Psychological counseling for and, if necessary, pharmacologic management of diabetes-related depression may also enhance sexual performance.

 2. Medical Treatment
Several drugs have been shown to have some measure of success in patients with ED. These include:

Yohimbine. This alpha 2-adrenergic blocker has been reported to help patents with ED 14-30% of the time.^18,19 It may be taken continuously or only before intercourse. The transdermal ointment may be effective in ED of recent onset and in young people with ED. However, it is not approved by the Food and Drug Administration for this use.

Apomorphine. This short-acting dopamine receptor agonist has been used successfully in one-third of the patients tried in a very small series,²⁰ but more research is needed.

Trazodone. This tricyclic antidepressant with few anticholinergic effects has been used preferentially to treat ED in depressed patients. It has been used alone or in combination with moxisylyte. Once again further work is necessary.²¹

Pentoxyfylline. Attempts to enhance blood flow to the penis with the rheologic agent, pentoxifylline have been disappointing, as have agents designed to enhance the vasodilating capacity of the corpora cavernosal vessels with the nitric oxide donor nitroglycerine or the topical application of the alpha adrenergic antagonist minoxidil.

Androgens. While there are many reasons other than correction of erectile dysfunction to use androgens in hypogonadal men, ²¹ most patients seeking assistance in this regard are not worried about bone density, hand-grip strength, or hematocrit. Unfortunately, the track record for testosterone replacement therapy in diabetes patients is not stellar.

Direct replacement with testosterone enanthate (200 mg given intramuscularly every 2 weeks) improved long-term sexual function in only 17% of 78 obese men with type II diabetes. Alternately, correction of the underlying excess estrogenic feedback of the obesity using clomiphene citrate, allowing total and free testosterone to rise to normal, did not produce any meaningful improvement in subjective and objective measures of sexual activity. Even subnormal concentrations (8.9 pmol/L), as is found in obese males, allowed normal sexual function,³ militating against hormone augmentation in these individuals.

Androgen replacement therapy does, however, provide a return to normal sexual function for many hypogonadal men without diabetes. In hypo- or hypergonadotropic hypogonadal men, testosterone given by any of several routes results in a two- to threefold increase in measures of nocturnal penile tumescence and sexual activity.³,²¹ Clearly, any deficiency of androgens related to diabetes is of concern for those who provide for patients with erectile dysfunction.

The use of androgens in men with normal testosterone levels is not recommended, but replacement therapy for those with a documented low level of testosterone may be worth a trial, especially if the patient has loss of libido as well as ED. Administration of androgens to people with ED and normal gonadal function is usually not beneficial.^3,21,22

Before giving testosterone to a diabetes patient, clinicians must take great care to be sure there is no prostatic hypertrophy and levels of prostate specific antigen < 2 U/ml. Testosterone also should not be administered to those at risk for congestive heart failure or stroke because of the increased red cell mass.

Androgen use may accentuate the high triglycerides and low HDL cholesterol in type II diabetes. So men with an established lipid disorder who use androgens may require modification of drug therapy for the dyslipidemia to avoid increasing the risk of a macrovascular event. However, several studies suggest that androgens may actually improve lipoprotein profiles, or at least not worsen them.²¹ It is wise nonetheless to at least determine the lipoprotein profile before and 6 months after starting treatment with an androgen.

Androgens that can be used are long- or short-acting and can be given transcutaneously. One form is a scrotal patch. These are expensive, however, and patches require shaving the scrotum and produce higher levels of dihydrotestosterone, which is responsible for lowering HDL cholesterol and stimulating the prostate.

Favored androgens are those without a methyl group and include testosterone cypionate and enanthate. Doses vary with the individual and the degree of insufficiency. Patients can usually sense whenever the drug is wearing off in anything from 2 weeks to a month. The frequency of dosing can be adjusted according to libido and sex drive and the general feeling of well being, strength, and vitality. Elderly men or those with some enlargement of the prostate should be treated initially with a lower dose. Prostatic hypertrophy rarely progresses with this approach.

The patient's clinical status is the best indication of effectiveness of androgen therapy. Increased libido, energy, and strength occur within days, and physical features may take several months. Prepubertal men will have profound physical and psychological changes and so require counseling for both patient and significant other before starting treatment.

In older men, examination of the prostate is mandatory before starting therapy and at intervals of 6 months with treatment. PSA should be measured at 6-month intervals, but a doubling of the value can be due to testosterone itself and is not cause for panic. There is no need to measure testosterone or gonadotropin levels serially.

An added benefit often occurs in patients with pain due to neuropathy, with the pain improving with correction of the hypogonadism. Serum levels of testosterone do decline with age and may contribute to the loss of libido and muscle strength and mass. Preliminary studies suggest that androgen therapy may restore lean body mass, muscle strength, and libido and decrease bone turnover. However, treating older men with androgens simply on the basis of these possible benefits without clear documentation of hypogonadism cannot be justified.

Patients with low or high gona-dotropins and low testosterone levels (i.e., those with secondary hypogonadism due to obesity) may undergo a trial of therapy as long as the prostate exam, PSA, or voiding symptoms do not preclude treatment. If, as usual, minimal long-term benefit is shown, the trial can be discontinued in 6-12 weeks, unless other compelling reasons, such as osteoporosis, mandate permanent treatment.

Bromocriptine. When hypogonadism is due to elevated levels of prolactin, the treatment of choice is bromocriptine mesylate. The impact on orthostatic blood pressures should be examined periodically, and the patient given guidelines for prevention of syncope when arising too rapidly from the horizontal position or after taking hot baths.

Hormone replacement therapy. If hypogonadism is secondary to a pituitary tumor or hypopituitarism, replacement therapy with hydrocortisone in divided doses may be helpful. Thyroid replacement may also be necessary. It is not clear that any additional benefit can be derived from treating people with growth hormone, although it does appear to be required for optimal action of testosterone in young men.

Self injection therapy. There have been a number of recent reports of intracavernosal treatment of ED with a wide variety of drugs. Of these, the vasoactive agents papaverine, phentolamine, and PGE1 (alprostadil) are currently in use. These substances stimulate the natural erectile process by inhibiting sympathetic tone and relaxing corporeal smooth muscle. Alprostadil and papaverine relax the smooth muscle of the corpora cavernosa, and phentolamine is a competitive inhibitor of alpha-adrenergic receptors. Because of the vascular cross-communication between the corporal bodies, injection into one causes bilateral tumescence.

Papaverine causes arterial dilatation, sinusoidal relaxation, and venous constriction, thereby increasing the blood retained in the corpora. The dose required to initiate and maintain and erection varies with age and cause of ED. The major problem with papaverine is corporeal fibrosis, which may resemble a Peyronie's type deformity and is usually the result of repeated injections. Systemic adverse events include vasovagal reactions with bradycardia, hypotension, dizziness, and flushing. These are uncommon and can be treated with atropine. Their complications include local infections, hematomas, and pain and occasionally systemic effects with abnormalities of liver functions are encountered, which revert with discontinuation of the drug.

Phentolamine is an alpha 1 and 2 adrenergic antagonist, which increases blood flow to the corpora primarily by decreasing arterial resistance and increasing arterial blood flow. It is usually given with papaverine to decrease the likelihood of fibrosis and prolonged erection. To avoid fibrosis, these drugs should not be used more than once a week.

Alprostadil is a prostaglandin derived from polyunsaturated fats and is naturally occurring in the body. With alpha adrenergic blocking properties, it dilates blood vessels, and it relaxes smooth muscle directly via a prostacyclin receptor. Prolonged erections can occur with its use, but fibrosis is rare. The major side effect appears to be pain at the site of injection, but this is not sufficient to preclude its use for ED except in 1% of people. Alprostadil has actions that may minimize the development of fibrosis. It does cause local reactions and hematomas if abused or injected directly into a vessel.

A number of studies have now reported on the effects of alprostadil in diabetes patients.^23-25 A new formulation of alprostadil, viz. alprostadil sterile powder was specifically formulated for treatment of ED²⁵ and its effects examined prospectively in a total of 683 patients, 104 of whom were diabetic (49 type I and 55 type II). The starting dose of alprostadil was 5-10 mg with escalating doses until an erection was obtained and that dose was then used 1.5 times a week for 6 months. Men with diabetes required higher mean doses (21 mg vs. 17 mg), fewer self-injected in the home use phase and fewer completed the study. However, in those who actually administered the drug the overall response rate, duration of erection and erectile response per injection was similar to non-diabetic subjects. Ninety-one percent had satisfactory intercourse at least once during the home phase as did 88% of the partners. There were no differences in the rate in type I diabetes vs. type II diabetes. A significant number of diabetics dropped out of the study because of intercurrent medical events, in addition to a higher frequency of penile pain (65 vs. 48%), hematomas (8 vs. 4%) and fibrosis (5 vs. 2%). Intensity of pain was higher in diabetic males. Priapism and prolonged erections lasting > 4-6 hours were more frequent among the people with diabetes. They conclude that diabetic men were less responsive to alprostadil and experienced a higher frequency of adverse events compares with the non-diabetic patients.

The commonly used mixture is alprostadil, papaverine, and phentolamine, commonly referred to as trimix. Although urologists have used these drugs for a decade or more, the FDA only approved alprostadil for this use in 1995.

While pain may be more frequent with alprostadil than the mixture, the incidences of prolonged erection (5%) and priapism (1%) are rare and make it the drug of choice. Recent attempts to solve this problem with the introduction of a medicated urethral system whereby alprostadil is administered in a topical gel via the urethra have not met with similar success.^{26, 27} As successful as intracavernous therapy has become, up to 50% of men discontinue eventually because of pain, loss of effect, or lack of interest.^28,29

Caveats for self-injection therapy. Ideal candidates for self-injection therapy are lean individuals with recent onset ED, in whom the cause is predominantly neuropathic, who seek help with the problem, are not on anticoagulants, and whose sexual partners do not mind the procedure.

Of the three most common drugs for this therapy, priapism is most frequently seen with papaverine. Treatment of priapism with adrenergic agents can be hazardous in those receiving mono-amine-oxidase inhibitors. Use of penile vasodilators can also be problematic in patients who cannot tolerate transient hypotension, who have severe psychiatric disease, who have poor manual dexterity, who have poor vision, or who are on anticoagulants. Liver functions should be checked in those on papaverine.

Prostaglandin can be used to decrease side effects such as pain, corporeal fibrosis, fibrotic nodules, hypotension, and priapism. The drugs are contraindicated in men with gross obesity and those taking anticoagulants.

The first injection is always given in the consulting rooms and allows for dose titration if necessary and for treatment of any complications such as prolonged erection or priapism. The patient can then be instructed on dose escalation and the use of enhancing procedures. Application of a constriction band to the base of the penis can enhance the quality of the erection, while some people require provocative visual images to elicit an appropriate response. The quality of the erection is almost always better at home than in the inhibiting circumstances found in most ambulatory care settings.

Patients must be warned to immediately call if an erection persists for longer than 4 hours. Patient should also receive written instructions on what to do under those circumstances so that the treatment can be administered by another doctor if necessary. Simple measures such as immersion in a cold bath or exercising may be effective. If these fail, decompression can be achieved by injecting an alpha adrenergic agonist such as metaraminol or phenylephrine. If this fails, withdrawal of 20-70 ml of blood from the corpus cavernosum is the next step.

Vacuum devices. When medical treatment fails, vacuum tumescence devices will work regardless of the cause of the ED. Erection is induced by negative pressure drawing blood into the corpora. It is maintained by retaining the blood in the penis with a constriction band to the base of the penis to obstruct venous drainage.

The apparatus consists of a plastic cylinder, to which a vacuum pump is attached. The constriction band is made of soft transparent silicone rubber and is rolled over the cylinder and left in place at the base of the penis during intercourse. The band should not be left in place for more than 30 minutes. 

3. Surgery
Penile prostheses. A variety of prosthetic devices have been used for those who fail medical therapy. Semirigid or malleable rods can be implanted into the corpora cavernosa. However, this results in a constantly erect penis. Inflatable prostheses have a pump housed in the scrotal sac, and an inflatable portion in the corpora.

The main problems are mechanical failure, infection, and erosions. Men with diabetes, spinal cord injuries, or urinary tract infections have an increased risk of prosthesis-associated infection, which in most instances requires removal of the device.

Before the advent of injection therapy, we were enthusiastic about the use of penile prostheses. But with vacuum therapy and penile injection now available, we almost never insert a prosthesis.

Revascularization. Although most patients with diabetes have ED secondary to autonomic neuropathy, some people do have severely compromised blood flow. Dynamic infusion pharmaco-cavernosometry and cavernosonography (DICC), duplex ultrasonography, and possibly arteriography may be needed to diagnose these individuals and are best left to those expert in these procedures.

In these cases, the inferior artery can be anastomosed to the dorsal artery of the penis or the deep cavernosal artery. When venous incompetence prevails, venous leakage can be treated by ligation of the deep dorsal vein of the penis and circumflex arteries.

These procedures are not all that successful, and the severity and extent of vascular disease in men with diabetes renders revascularizing procedures even less successful.³⁰ The only person we would now consider for revascularization is a young person with recent onset diabetes in whom it is likely that fairly localized insufficiency is at the root of the ED.

 New Insights and More Questions
What is the role of nonadrenergic/noncholinergic modulators of erection, and what will be the role of the endothelial-derived modulators of corporal blood flow? At this point in time, their function is not clear. New oral agents that can affect the production of these modulators by the endothelium are being tested in phase 2 studies, raising interesting possibilities for the future.

What is the potential for reversing neuropathy, the major cause of ED in men with diabetes? Exciting developments are on the horizon for the use of aldose reductase inhibitors, linolenic acid, and aminoguanidine. The agents may overcome the impact of metabolic abnormalities in diabetes that have not been prevented by glycemic control. And, they show promise for reversing established neuropathy.

Possibly the most exciting is the development of various growth factors (e.g., nerve growth factor [NGF]), that are capable of causing regeneration of autonomic nerves, thereby restoring the normal physiologic regulation of erection. ³¹

Finally, a component of diabetic neuropathy is related to autoimmune destruction of nerve fibers. New therapies aimed at treating the autoimmunity may prove helpful in this regard.³²

References

¹McCulloch DK, Campbell IW, Wu FC, Prescott RJ, Clarke BF: The prevalence of diabetic impotence. Diabetologia 18:279-83, 1980.

²Vinik AI, Mitchell BD, Leichter SB, Wagner AL, O'Brian JT, Georges L-P: Epidemiology of the Complications of Diabetes. In: Diabetes: Clinical Science in Practice. Leslie RDG, Robbins DC, Eds. Cambridge: Cambridge University Press, 1995, p.221-87.

³Guay AT, Bansal S, Heatly GJ: Effect of raising endogenous testosterone levels in impotent men with secondary hypogonadism: double blind placebo-controlled trial. J Clin Endocrinol Metab 80:3546-52, 1995.

⁴Barrett-Connor E, Khaw KT, Yen SSC: Endogenous sex hormones in older adult men with diabetes mellitus. Am J Epidemiol 132:895-901, 1990.

⁵Andersson B, Marin P, Lissner L, Vermeulen A, Bjorntorp P: Testosterone concentrations in women and men with type 2 diabetes. Diabetes Care 17:405-11, 1994.

⁶Seidell JC, Bjorntorp P, Sjostrom L, Kvist H, Sannerstedt R: Visceral fat accumulation is positively associated with insulin, glucose and C-peptide levels but negatively with free testosterone levels. Metabolism 39:897-901, 1990.

⁷Khaw KT, Chir MBB, Barrett-Connor E: Lower endogenous androgens predict central adiposity in men. Am J Epidemiol 77:675-82, 1992.

⁸Tchernof A, Despres JP, Belanger A, Dupont A, Prud'homme D, Moorjani S, Lupien PJ, Labrie F: Reduced testosterone and adrenal C19 steroid levls in obese men. Metabolism 44:513-19, 1995.

⁹Giagulli VA, Kaufman JM, Vermeulen A: Pathogenesis of decrease androgen levels in obese men. J Clin Endocrinol Metab 79:1310-16, 1994.

¹⁰Vernet D, Cai L, Garban H, Babbitt ML, Murray FT, Rajfer J, Gonzalez-Cadavid NF: Reduction of penile nitrogen oxide synthase in diabetic BB/WOR (Type 1) and BBZ/WOZ (Type II) rats with erectile dysfunction. Endocrinology, 136:5709-17, 1995.

¹¹Vinik AI, Suwanwalaikorn S, Holland MT, Liuzzi FJ, Colen LB, Stansberry KB: Diagnosis and management of diabetic autonomic neuropathy. In: Current Management of Diabetes Mellitus. DeFronzo RA, ed. St. Louis: Mosby-Year Book, Inc., 1996. In press

¹²Ackerman MD, D'Attilioo JP, Antoni MH, Campbell BM: Assessment of erectile dysfunction in diabetic men: the clinical revelance of self-reported sexual functioning. J Sex & Marital Ther 17:191-202, 1991.

¹³Nofzinger EA, Reynolds CF 3d, Jennings JR, Thase ME, Frank E, Yeager A, Kupfer DJ: Results of nocturnal penile tunescence studies are abnormal in sexually functional diabetic men. Arch Int Med 152:114-18, 1992.

¹⁴Junemann KP, Alken P: Pharmacotheraphy of ED: a review. Int J Impot Res 1:71, 1989.

¹⁵Gaskell P. The importance of penile blood pressure in cases of impotence. Can Med Assoc J 105:1047, 1971.

¹⁶Lue TF, Hricak H, Marich KW, Tanagho EA: Vasculogenic impotence evaluated by high-resolution ultrasonography and pulsed Doppler analysis. Radiology 155:777, 1985.

¹⁷Saenz de Tejada I, Goldstein I, Azadzoi K, Krane RJ, Cohen RA. Impaired neurogenic and endothelium-dependent relaxation of human penile smooth muscle from diabetic men with impotence. New Eng J Med 320:1025, 1989.

¹⁸Susset JG, Tessier CD, Wineze J, Bansal S, Malhotra C, Schwacha MG: Effect of yohimibine hydrochloride on erectile impotence: a double blind study. J Urol 141:1360-63, 1989.

¹⁹Canale D, Cilurzo P, Giorgi PM, Menchini-Fabriss GF: Transdermal therapy of erectile insufficiency. Arch Ital Urol ^{Nefrol Androl 64:263-66, 1992.}

²⁰Lal S, Tesfaye Y, Thavandayil JX, Thompson TR, Kiely ME, Nair NP, Grassino A, Dubrovsky B: Apomorphine: clinical studies on erectile impotence and yawning. Prog Neuropsychopharmacol Biol Psychiatry 13:329-39, 1989.

²¹Bondil P: The combination of oral trazodone-moxisylyte: diagnostic and therapeutic value in impotence: report of 110 cases. Prog Urol 2:671-74, 1992.

²²Hubert W: Psychotropic effects of testosterone. In: Testosterone: Action, Deficiency, Substitution. Nieschlag EB, Behre HM, Eds. Berlin, Germany: Springer-Verlag, 1990, p. 51-71.

²³Oblak C, Ravnik-Oblak M: Intracavernous injection of prostaglandin E1 in impotent diabetic men. Int J Impot Res 2:263-64, 1990.

²⁴Burgess TR, Earle CM, Glatthaar C, Keogh EJ, Cherry DJ, Lord DJ: Intracavernosal vasoactive agents: comparison of diabetic and non-diabetic impotent men. Int J Impot Res 2:236-37, 1990.

²⁵Linet OI, Ogrinc FG, Alprostadil Study Group: Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction. New Engl J Med 334:873-77, 1996.

²⁶Padma-Nathan H, Bennett A, Gesundheit N, Hellstrom W, Henry D, Lue T, Morley J, Peterson C, Prendergast JJ, Tam P, Teresi A, Place V, and the VIVUS-MUSE Study Group of Menlo Park, Calif.: Treatment of erectile dysfunction by the medicated urethral system for erection (MUSE). Abstract. J Urol 153:472A, 1995.

²⁷Kim ED, McVary KT: Topical prostaglandin-E1 for the treatment of erectile dysfunction. J Urol 153:1828-30, 1995.

²⁸Lakin MM, Montague DK, VanderBrug-Medendorp S, Tesar L, Schover LR: Intracavernous injection therapy: analysis of results and complications. J Urol 143:1138-41, 1990.

²⁹Gerber GS, Levin LA: Pharmacological erection program using prostaglandin E-1. J Urol 146:786-89, 1991.

³⁰Wiles PG: Erectile impotence in diabetic men: aetiology, investigation and management. Diabetic Med 9:888-92, 1992.

³¹Vinik AI, Newlon PG, Lauterio TJ, Liuzzi FJ, Depto AS, Pittenger GL, Richardson DW: Nerve survival and regeneration in diabetes. Diabetes Reviews 3:139-57, 1995.

³²Pittenger GL, Liu D, Vinik AI: The toxic effects of serum from patients with Type I diabetes mellitus on mouse neuroblastoma cells: a new mechanism for development of diabetic autonomic neuropathy. Diabetic Med 10:925-32, 1993.

Aaron Vinik MD, PhD, FCP, FACP, is a professor of internal medicine and anatomy/neurobiology and director of the Diabetes Research Institute at the Eastern Virginia Medical School in Norfolk, Va. Donald Richardson, MD, is an associate professor of internal medicine at the Diabetes Institute and Center for Endocrinology and Metabolism at the same institution.Granuloma

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