M. Tagliabue, G.M. Molinatti
Dipartimento di Medicina Interna, Universita degli Studi di Torino, Ospedale Molinette, Torino, Italy
The existence of sexual disorders in diabetes mellitus has long been recognized. In the pre-insulin era, impotence was considered one of the commonest symptoms of diabetes, being present in both severe and milder forms of the disease. However, only now are sexual function problems receiving their rightful attention, as the medical professional has moved from a mere 'survivalist' approach to diabetes and its more invalidating complications towards care for the diabetic individual in all his or her complexity.
Today, diabetology is no longer satisfied to keep diabetics in reasonably good health, but also addresses everything that may affect the individual's quality of life and, from this standpoint, sexuality cannot fail to occupy a role of primary importance. In the diabetic male, it is sexuality in the narrowest sense, namely what is conventionally designated 'potentia coeundi', that is compromised and it is precisely in relation to that situation that a comprehensive overview of this condition can provide the diabetic patient with the answer he seeks.
Erectile dysfunction is 3 times more common among diabetics than in the healthy control population. However, the complication is still considered occult since it is often unreported by patients. In the various studies published, the incidence of this dysfunction in diabetics varies from 28 to 59%. The predictive factors are: age, duration of the disease, degree of metabolic com pensation, the presence of microvascular complications (especially retinopathy) and neuropathy, high blood pressure and the drugs taken for that condition, smoking and alcohol abuse. The age factor is particularly important. The very earliest epidemiological studies showed that the incidence of impotence in diabetic males rose from 1.5% in the under-40s to 25% in the 40-60 age group. More recently, others have reported incidences rising from 15% in the under-40 group to 55% at 60. The trend revealed by the Wisconsin Epidemiologic Study in particular is highly significant (p<0.0001), rising from 1.1% in the 21-30 age group to 47.1% among insulin-dependent diabetics over 43 years old. Klein himself confirms that significance when he analyses the duration of diabetes: men with a more than 35-year history of the disease are 7.2 times more likely to present this complication than those with only a 10- to 14-year history. However, the link between erectile dysfunction and disease duration is not inevitable, since the erectile disorder occasionally appears before the clinical onset of the diabetes. In addition, diabetic erectile dysfunction is also related to HbA1c levels which indicate the ability to metabolize glucose, the risk of impotence tripling in those worst affected (HbA1c >9.8%). That increased risk is explained when we consider the treatment needed to control diabetes - restrictive diets and drugs to lower blood sugar and/or insulin -that are most aggressive in the most metabolically compromised patients. Both diabetic retinopathy, especially if severe, and neuropathy, both peripheral and autonomic, are related to a higher incidence of erectile dysfunction which is 5.3 times more likely to occur in such patients. High blood pressure is an additional risk factor especially when treated by certain drugs such as P-blockers, methyldopa and particularly diuretics. Finally, excessive drinking and smoking intensify the risk of erectile dysfunction in diabetics.
A recent Italian study of 9,868 diabetic patients reported a 35.8% incidence of erectile dysfunction and confirms the reported literature data: incidence increasing with age, duration of diabetes, severity of failure to metabolize glucose, complexity of diabetic therapy, diabetic complications (angiopathy, retinopathy, kidney disease, neuropathy) as well as cardiovascular disease and the use of certain drugs in its treatment and finally habitual smoking.
Apart from erectile dysfunction, diabetes can also produce problems with ejaculation, especially retrograde ejaculation as the so-called 'dry orgasm' (a dysfunction of the autonomic and somatic nervous system) which occurs in 1-4% of male diabetics, most particularly in those with the longest history of the disease and those who are most metabolically compromised.
Ejaculation without orgasm and indeed failure to achieve ejaculation (reflecting a compromised sympathetic nervous system) are also commoner among diabetics than in the general population, accounting for 8% of ejacula-tory disorders. By contrast, the incidence of premature ejaculation is almost
Table 1. Possible causes of erectile dysfunctions in diabetics
Psychological causes Poor glycaemic control
Vascular alterations (macro-/microangiopathies and venous) Autonomic neuropathy
Endothelial alterations (reduced NO secretion) Concomitant pathologies and related drugs identical in the diabetic and the healthy populations, a finding that confirms the psychosomatic pathogenesis of that disorder.
Be that as it may, the organic character of diabetes and its complications should not lead us to forget the influence of psychological factors which may at times be preponderant.
Diabetic erectile dysfunction is often a complex problem given its psychogenic and organic components, the latter linked to the failure to metabolize glucose and the related organic complications, not to mention the pathological conditions known to be caused by the drugs used to treat those complications (table 1). However, many studies have confirmed that erectile dysfunction is primarily organic in origin, since the dysfunction is rarely reversible. In monitoring the nocturnal erections associated with REM sleep, researchers have found fewer REM sleep-erections in diabetic males, a finding which supports the view that impotence in diabetics is more likely to be organic than psychological in origin. Nevertheless, the role of hormonal abnormalities in the physiopathology of organic erectile dysfunction remains controversial. It is therefore vital to examine the fundamental psychological and organic factors involved in the sexual function of diabetics.
There is substantial evidence to suggest that erectile dysfunction in diabetes is often psychological in origin. The main contributory factors are: awareness of suffering from a chronic condition, relationship problems and the fear of failure during sexual intercourse as a result of that situation. It is not clear whether such psychological factors are greater in the diabetics affected than in the general population of people with erectile dysfunctions, though diabetics with the problem appear more stressed than those unaffected. Accord ing to some authors, diabetic patients are more fearful of developing erectile dysfunctions as a complication of their condition than of going blind, but however great their concern, they are unlikely to discuss it with their doctor. In fact only 50% of erectile dysfunction sufferers report it to their physician.
It is important for the correct management of diabetic erectile dysfunction to repair any severe metabolic disorder the patient may be suffering from. Patients may recover normal erectile function, as soon as insulin injections to correct their impaired glucose metabolism are started. The impaired delivery of oxygen to the tissue, caused by the formation of glycosylated haemoglobin which has a greater affinity for oxygen increases vascular permeability, depositing lipoprotein on the vessel wall and this may be the cause of the vascular damage.
Vascular disorders cause impotence in 18% of diabetic males. Haemo-dynamic disturbances in diabetics may be either arterial (macro- and/or micro-angiopathies) or venous given the direct communication between the two vascular systems.
Macroangiopathy causes major arterosclerotic obstructions of the large, medium-sized and small arterial blood vessels which cut off the blood flow to the corpora cavernosa. Many authors claim that the primary cause of impotence in diabetics is of vascular origin and atherosclerosis is, in fact, the earliest lesion on the peripheral arteries of the penis. Histological findings of pathological alterations to the small arteries are also reported to occur before any neurological damage. Later, neurological damage caused by the same atherosclerotic processes appears on the vasa nervorum. Such vascular alterations are the result of proliferating endothelial and intimal cells, fragmentation of the endothelium, calcium deposits, and perivascular fibrosis. Perineural fibrosis may occur without causing any direct damage to the nerve fibres.
There is an equally close link between ischaemic heart disease and diabetic erectile dysfunction, both being caused by the ischaemic vasculopathy affecting both areas. Diabetic microangiopathies produce alterations and irregularities in the local microvascular blood flow. Those alterations concern: endothelial cell metabolism and function; the basal membrane of vessel walls, which are thickened; oxygen transportation; the characteristics of blood flow and haemostasis.
In the venous system the uncontrolled blood flow and the failure of the arteriovenous anastomoses may also contribute to the erectile dysfunction. Finally, venous occlusions in diabetes may be due to a structural alteration in the fibroelastic components of the trabeculae.
The penile nerve system is both autonomic and somatic and the relaxation of the smooth muscle tissue of the corpus cavernosum results from the interaction of three systems: adrenergic, cholinergic and VIPergic. Other factors like nitric oxide (NO) initially called endothelium-derived relaxing factor (EDRF) and produced by constitutive nitric oxide synthetase (cNOS) which increases the concentration of intracellular cyclic guanosine monophosphate (cGMP) may well be involved in the relaxation of the smooth muscle in the corpus cavernosum. As we know, the earliest studies into NO production by cNOS were carried out on bioptic samples taken from the corpus cavernosum tissue of impotent diabetics who presented reduced acetylcholine vasodilation. The reduced NO production and consequent reduction in intracellular cGMP probably leads to an increase in intracytosolic calcium that is responsible for the contraction in smooth muscle cells. In diabetics there may well also be a reduction in the noradrenaline, VIP and acetylcholine content of the corpus cavernosum and both the cholinergic fibres and their ability to synthesize acetylcholine may be reduced over time, as may the VIPergic pathways. Cho-linergic stimulation is certainly known to increase NO production. This would compromise both the neurogenic and the endothelial mechanisms dependent on the relaxation of the cavernosal smooth muscle. Increased levels of endoth-elin-1, a powerful vasoconstrictor released by the endothelial cells, have also been found in patients with erectile dysfunction, especially those with diabetes. That finding suggests that endothelial dysfunction may contribute to erectile dysfunction and that in the absence of any significant vascular element the increase in plasmatic endothelin-1 may be related to early atherosclerosis. The autocrine role of this peptide, which causes the smooth muscle cells of the corpus cavernosum to proliferate and/or contract, has been confirmed in experimentally induced diabetes mellitus.
Somatic and autonomic neuropathy (bladder dysfunction) is often associated with impotence in diabetes and is responsible for 67% of cases, according to recent statistics. The disease causes axonal degeneration of the nerves in the penis (and other parts of the body) together with thickening of the basal membrane.
The biochemical abnormalities encountered in diabetic patients can be somewhat improved if their glucose metabolism problem is carefully controlled.
Researchers have also found a lack of coordination in the electrical activity of the corpus cavernosum in diabetics with a consequent loss of the diminished or absent activity that is normal in the tumescent or erectile phase.
Total basal testosterone levels have been found to be normal or low and researchers have also documented a diminished response in terms of absolute testosterone increases after HCG stimulation. Some reports describe a decrease in the free fraction of testosterone and estradiol, which they attribute to a marked increase and/or enhanced binding capacity in SHBG and/or inappropriate gonadotropin secretion. In addition, there also appears to be an alteration in gonadic response to tropine stimulation with a tendential rise in basal LH and a more protracted increase after GnRH stimulation.
The evidence on circulating gonadotropin and prolactin is conflicting. Some report an increase in urinary LH among diabetics with primary organic impotence, as well as a reduction in levels of free testosterone. Diabetes and obesity often go together and increased aromatization of testerostene in the adipose tissue produces an increase in oestrogen levels that contributes to erectile failure.
In actual fact, there is increasing doubt about the role of steroids and other hormones in the aetiopathology of sexual disorders in the diabetic male and the variations that may be found do not appear to play a particularly important part in the genesis of this complication.
The most frequently encountered alteration in spermatogenesis is reduced spermatozoa motility which appears to be closely linked to the metabolic disorders and the presence of autonomic neuropathy. Functional damage to the seminal vesicles is probably a major contributory factor. Studies conducted on rats with streptozotocin-induced diabetes revealed an alteration in the animals' sexual behaviour and a reduction in the weight of their secondary sex glands, in their production of androgens and in spermatogenesis as a result of altered gonadotropin pulsatility.
Erectile dysfunction is diagnosed in diabetics in much the same way as in their healthy counterparts and diagnosis therefore includes anamnestic assessment, objective examination, laboratory tests and instrumental investigation (table 2). Both the rigidity and the duration of penile erections are affected (reduced arterial blood flow and altered control of the autonomic nervous system over the penile circulation) while, at least initially, the libido remains unaffected.
Anamnesis is the first step. In diabetics, erectile dysfunction usually arises insidiously, evolving slowly but inexorably. Physicians should pay particular
Table 2. Main diagnostic procedures for erectile dysfunction in diabetics
Anamnesis (physiology, pathology, pharmacology, sexual) Clinical examination
Blood chemical analyses (HbA1c, T, PRL, TSH)
Instrumental investigations (penile biothesiometry and cardiovascular tests) Vascular evaluation (office-intracavernosal injection test)
attention to their patient's smoking and drinking habits and to the presence of any concomitant pathologies (high blood pressure and dyslipidaemias are common) and the drugs they are being treated with, since these often have a negative impact on sexual activity itself. In the case of diabetes mellitus, it is essential to know type, duration and treatment, how far glucose metabolism is compromised and whether or not the patient presents with micro/macroangi-opathic and/or neuropathic complications.
In order to obtain a full diagnostic picture, the investigation of organic factors must be accompanied by investigation of learning, intrapsychic, dyadic, systemic and sociocultural factors.
The sexual anamnesis will cover aspects like the presence or absence of sexual desire, the presence of spontaneous erections on awakening and/or in response to visual stimuli and/or erotic thoughts and/or physical stimulation by a partner, as well as the quality and frequency of sexual intercourse, the presence of any significant changes in recent months and the description of the sexual intercourse itself.
The instrumental investigations indicated include those used to examine the vascular system (ultrasound scans or basal and dynamic Doppler echo-sonography) which usually involves the intracavernosal injection of prosta-glandin (PGE1) and penobrachial plethysmography. Others examine neurological aspects (vibration and heat perception thresholds, autonomic cardiovascular tests, peroneal motor conduction velocity and sural sensitivity tests; possibly also sacral evoked potential tests). Then there are urological tests (cavernosography, cavernosometry, bulbocavernosus reflex). A new minimally invasive test has recently been proposed and has been tested on type 2 diabetics with no vascular disease in whom basal penile tumescence was assessed using the Rigiscan technique and found to be related to autonomic nerve damage.
An easy-to-use protocol for the diagnosis of level I erectile dysfunctions in diabetics was proposed by the Italian Diabetology Society's 'Diabetic Neuropathy' Study Group in 1996:
Anamnestic screening Targeted questionnaire
Penile biothesiometry Cardiovascular tests
PGE1 drug stimulation Patients < 40 years old: 5 ^g Patients >40 years old: 10 ^g
If the erectile response is absent: repeat after 1 week with 10 or 20 ^g PGE1 persistently absent: refer to your andrology unit for further investigation (Rigiscan, Ultrasound, Doppler ultrasonography, invasive vascular tests)
If the erectile response is present: oral and/or intracavernosal and/or psychological treatment.
The protocol proposed by Japanese authors is more complex. In it, vascular investigations, Rigiscan and audiovisual sexual stimulation precede intracavernosal drug stimulation. If there is no erectile response, nocturnal penile erectile tumescence is monitored, which, if found, allows us to label our patient as 'not suffering from any organic disorder'.
The treatment for erectile dysfunction in diabetics (table 3) is primarily based on rectifying the glucose-metabolizing disorder by diet and/or drug treatment and by persuading the patient to abstain from risk factors like smoking and alcohol abuse. In addition, every possible effort will be made to find substitutes for any drugs with a negative impact on sexual function.
Psychotherapy can help to minimize anxiety and modify the couple's sexual habits in a helpful fashion. Even so, 'psychological problems' appear to be no more common among diabetics than among the general population.
Treatment with a2-antagonists (yohimbine) or arantagonists (doxazosin, terazosin, etc.) can enhance penile vasodilation but cannot alone induce and
Table 3. Treatment of erectile dysfunction
Psycho- or behavioural therapy
Drug treatment Yohimbine aj-antagonists Local nitroderivatives Sildenafil
Intracavernosal injection Papaverine Alprostadil Phentolamine Moxisylyte
External mechanical support Vacuum device
Penile prosthesis maintain erection. These drugs are indicated in patients with high blood pressure and certain prostate pathologies. Moderate success has been obtained with topical nitroderivatives that are rapidly absorbed through the skin (nitroglycerin). These act directly by stimulating the release of the adenylase cyclase which relaxes the smooth muscle tissue.
Sildenafil, a selective inhibitor of type V cyclic phosphodiesterase in the corpus cavernosus, prevents the breakdown of cGMP and therefore acts on the NO mechanism (NO/cGMP) that plays a dominant part in the relaxation of smooth muscle tissue and hence penile erection. This is a rapidly absorbed drug that is taken 60 min before intercourse and has an effect lasting about 4 h. It does not trigger erection as such but improves its quality by promoting the smooth muscle relaxation initiated by NO release. It is important to remember that Sildenafil is contraindicated in men taking nitrates, given the risk of significant reductions in blood pressure caused by intensification of the vasodilatory effects of such drugs. Caution must also be exercised in a number of other clinical conditions (kidney or liver problems) and/or when the patient is taking other drugs which might interfere with absorption kinetics.
In doses of 25-100 mg, Sildenafil has proved effective in 59% of diabetic patients with erectile dysfunction (placebo 15%). It is well tolerated and the side effects reported in this population are: headache, dyspepsia and flushing. Other side effects described are temporary and relate to the perception of colours, sensitivity to light and fuzzy vision.
Alprostadil (a synthetic preparation of PGEj), also appears as a compound that is incorporated into pellets for intraurethral application (MUSE: Medical Urethral System for Erection). Patients have to be taught how to use the applicator which delivers a microsuppository into the urethra at an average dose of 500-1,000 ^g. The side effects are penile pain, stranguria and slight bleeding. MUSE is contraindicated without the use of a condom in intercourse with a partner who is pregnant or liable to conceive. It is not widely used in Italy and may be contraindicated in diabetics with their greater risk of infections.
Intracavernosal pharmacoprosthesis is currently one of the most widely used treatments and enjoys good patient compliance, especially among diabetics who get a satisfactory response in 66% of cases compared to only 23% in nondiabetics with erectile dysfunction. Vasodilatory substances either alone or in combination (papaverine, alprostadil, phentolamine and atropine) are inoculated directly into the corpus cavernosum. The patient has to be trained in the inoculation procedure and doses must be carefully selected in order to avoid prolonged erections or priapism. Erection occurs about 10 min after inoculation of the substance. The incidence of complications depends on the type of drug used. Pain on the inoculation site is rare, but penile fibrosis or priapism may develop over time. The most commonly used drug is alprostadil because of its minimal side effects and the dose varies from 5 to 20 ^g. This prostaglandin produces cAMP which acts with cGMP to relax the smooth musculature. Both are metabolized by the type V phosphodiesterase found in both the penile smooth muscle tissue and the eyes. Moxisylyte is a selective a1 drug used in 10- to 20-^g doses. Its minimal side effects include penile pain and prolonged erections. Vasointestinal peptide combined with phentolamine is now in the advanced research stage. Its side effects are flushing and tachycardia and, rarely, penile pain.
A patient who prefers not to use drugs can employ a so-called 'vacuum device'. This is a cylinder into which the penis is inserted. The cylinder is pressed against the abdominal wall and a mechanical or electric pump is activated to create a vacuum which draws blood into the corpus cavernosum thereby producing a penile erection. The erection is maintained by a rubber ring around the base of the penis for as long as the ring remains in situ.
Patient compliance with this system is generally good. However the device should not be used for more than 30 min at a time, since it can create a feeling of chill in the penis. Furthermore, ejaculation is generally impeded and this may make for a less satisfying orgasm. The vacuum device can be used to potentiate the effect of drug treatment.
Where erectile dysfunction is caused by vascular disease, both venous and arterial revascularization procedures are a possibility.
Diabetic patients with irreversible penile dysfunctions are candidates for penile implants, which, however, expose them to the risk of local infections.
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Prof. G.M. Molinatti, Dipartimento di Medicina Interna, Universitá degli Studi di Torino, Ospedale Molinette, I-10126 Torino (Italy)
Tel. +39 (0)11 6635318, Fax +39 (0)11 6634751, E-Mail [email protected]
Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment. Basel, Karger, 2000, pp 229-240
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