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Asian J Androl 2006; 8 (2): 219–224 .Clinical Experience .
Long-term treatment with intracavernosal injections in diabetic men with erectile dysfunction P. Perimenis, A. Konstantinopoulos, P. P. Perimeni, K. Gyftopoulos, G. Kartsanis, E. Liatsikos, A. Athanasopoulos Department of Urology, University Hospital, 26500 Patras, Greece Aim: To assess the behavior of patients with diabetes mellitus (DM) and erectile dysfunction (ED) during 10 con-
secutive years of treatment with self-injection of vasoactive drugs. Methods: Thirty-eight diabetic men, including 12
with type I and 26 with type II diabetes, were followed up regularly for 10 years after they began self-injecting for
severe ED. Real time rigidity assessment was used for the objective determination of the initial dosage and then doses
were regulated in order to introduce an erection suitable for penetration and maintenance of erection for approximately
30 min. Patients were followed up every two months, and doses were increased only when the treatment response
was not satisfactory. Results: The number of injections used per year by the patients was reduced each year (mean
numbers: 50 in the first year and 22.5 in the 10th) and treatment shifted towards stronger therapeutic modalities
(mixtures of vasoactive drugs instead of prostaglandin E1 alone). Type I diabetic men were standardized to a level of
treatment as early as 5 years after the initiation of treatment. That level was finally reached by type II patients after
another 4-5 years. Conclusion: Treatment with self-injections of vasoactive drugs in diabetic men with severe ED is
a safe and effective alternative in the long term. Diabetic men of both types show the same preferences in quality and
quantity of treatment after 10 years. The key point for maintenance in treatment is the adjustment of the therapeutic
method and dosage to optimal levels for satisfactory erections. (Asian J Androl 2006 Mar; 8: 219–224)
Keywords: diabetes mellitus; erectile dysfunction; impotence; intracavernosal injections; prostaglandin E1; papaverine
be offered to diabetic men, sexual problems, despite theirrelevance, are still seldom investigated by general practitio- The incidence of sexual dysfunction in men with dia- ners and specialists [2]. However, the etiology of diabetic betes mellitus (DM) is approaching 50% and, as diabetes ED has been thoroughly investigated [3, 4] and the thera- is a problem that is increasing at an alarming rate, dia- peutic management became satisfactory with the use of betic men already made up one-quarter of those seeking a wide spectrum of treatments [4–6].
advice for erectile dysfunction (ED) [1]. Although a suc- The natural history of ED indicates the importance cessful impotence assessment and treatment service may of age. In diabetic individuals, ED is more progressiveand usually irreversible. Its etiology is multifactorial, in-cluding neuropathy, vascular disease, metabolic control, Corresponence to: Dr Petros Perimenis, Department of Urology, nutrition, endocrine disorders, psychogenic factors, and University Hospital of Patras, 26500 Rio, Patras, Greece.
Tel: +30-61-999-397, Fax: +30-61-993-981 drugs coadministered for comorbidities, such as antihypertensives. The role of autonomic neuropathy Received 2005-02-03 Accepted 2005-06-23 has been emphasized, and is considered the major factor.
2006, Asian Journal of Andrology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences. All rights reserved.
Erectile dysfunction and diabetes Zhu et al. [7] reported a 50% rate of abnormal pudental investigation with Doppler ultrasonography and tests of evoked potentials, and recently, Xu et al. [8] reported on vasoactive drugs. They were all proposed to start on self- the decrease of nitric oxide (NO) synthase content in injections but six refused treatment. Of the 47 men who corpus cavernosum of diabetic rats. NO synthase is the started on self-injections, nine stopped therapy gradually only enzyme for the synthesis of NO, the neurotransmit- for several reasons, and 38 completed 10 years of treatment.
ter mediating smooth muscle relaxation and introducing Twelve (31.6%) of them had type I diabetes and 26 erection. Although ED is a marker for the development (68.4%) had type II diabetes. The process of enrolment of generalized vascular disease, diabetic arteriopathy may for the studied patients is depicted in detail in Figure 1. The affect blood supply, contributing to the neurogenic fac- patients had acceptable metabolic control. Glycosylated tor [4], but does not appear to result often in entire penile hemoglobin levels ranged between 6% and 8%.
artery occlusion. The psychological component has alsobeen emphasized. The results of the largest study evalu- 2.2 Treatment for ED and follow-up ating quality of life in diabetic patients with ED provide Each patient was initially examined in privacy under clear evidence that ED is associated with higher levels of discrete conditions. The response to intracavernosal in- diabetes-specific health distress and worse psychologi- jections was evaluated in real time by Rigiscan (Dacomed, cal adaptation to diabetes, which are, in turn, related to Minneapolis, MN, USA). The device was applied for worse metabolic control. Erectile problems are also as- 30 min after the injection with simultaneous audiovisual sociated with a dramatic increase in the prevalence of stimulation. The aims of this test were to assess tumes- severe depressive symptoms and lower scores in mental cence and rigidity and to determine the proper drug and components [2].
dosage for the achievement of an erection for up to Diabetic men are more likely to achieve a satisfac- 30 min. A response was considered objectively satisfac- tory response to intracavernosal injections than those with tory if there was a 30-mm or more increase in circum- other types of ED [9]. Moreover, diabetic patients ac- ference and a rigidity of 70% or more, both for at least cept self-injecting more easily and comply better with 10 min. To determine the response to vasoactive drugs treatment for ED compared to non-diabetics [10].
and the therapeutic dose, all patients were initially in- However, in general, the frequency of non-compliance jected with 5–10 µg PGE1 and the non-responders were with self-injecting is high, approaching 50%, and is prob- given 15–20 µg PGE1 after 1 week. A few patients, ably the most common event in clinical practice [11]. In who did not respond to the higher dose of PGE1 (20 µg), this study we assessed the main characteristics of long- needed a further mixture of PGE1 and papaverine (PAP).
term treatment with self-injection of vasoactive drugs in The drugs were prepared and given in the clinic at diabetic men with ED.
follow-up, and dosages were regulated to provide an erec- 2 Materials and methods
2.1 Study recruitment Only diabetic patients with ED who had completed 10 years of treatment with self-injection of vasoactivedrugs were included in this study. In 1993 and 1994, 78men with DM and ED were referred or presented to oursexual dysfunction clinic. A detailed history was ob-tained from all patients, who filled out a questionnaireabout their sexual activities. Most of them underwentlaboratory tests and all had a simple test of intracavernosalinjection with 10 mg prostaglandin E1 (PGE1). Of them,25 men achieved satisfactory erections responding toconservative treatment and psychosexual counsellingduring the assessment period and were not managed Figure 1. Enrolment process of patients in our study of diabetic further. The remaining 53 patients underwent a detailed men with erectile dysfunction (ED).
Asian J Androl 2006; 8 (2): 219–224 tion suitable for penetration and maintenance of approxi- duration, this group represents a typical sample of men mately 30 min. The patients were asked to complete a with ED [12]. Seventeen men (32%) had abnormal pe- consent form because the drugs used were not licensed nile Doppler assessments (maximum penile systolic ve- for intracavernosal treatment, and approval was required locity < 25 cm/s). Overall, during initial real-time Rigiscan for possible scientific publication of the data. The pa- evaluation, 19 men responded to low and 12 to high PGE1 tients were taught how to self-inject and were advised to doses, whereas four men responded to low and three to use injections not more than once per week, alternating high MIX doses. Treatment with self-injections was safe between the two sides of the penis. They were also asked and well tolerated. Five patients noticed fibrosis in the cor- to record the results of their attempts for intercourse, to pora without bend. Episodes of prolonged erections or bring back the unused injections (in order to record the priapism were not recorded during the treatment period.
frequency of sexual activity and to verify the number of The majority of patients responded initially to PGE1, recorded attempts), and to report any complications especially to low doses, but with time they needed in- immediately. All data of the patients' follow-up were pro- creasing doses of PGE1, and later, increasing doses of spectively entered into the departmental database.
mixtures of PGE1 and PAP to achieve a satisfactory Drug doses were increased only when the treatment erection. After 7 years of treatment, none was treated response was not satisfactory. The doses of PGE1 were with low doses of PGE1. After 5 years the majority increased by 5–10 µg, and PAP by 8–16 mg. The use of needed a mixture of the vasoactive drugs, and particu- 20 µg PGE1 without satisfactory response was the cri- larly after 7 years the majority needed high doses of MIX.
terion for switching to a drug mixture. The mixtures During the first year of treatment, 31 patients used pros- were combinations of PGE1 20 µg and various doses of taglandins only and seven used mixture treatments. In PAP. For practical reasons, treatment with self-injec- the 10th year, however, only two patients used prostag- tions was classified as low PGE1, high PGE1, low MIX landins and the majority, 36, used mixtures.
and high MIX. This classification is shown in detail in Without taking into consideration the type of DM, Table 1. Patients were followed up every 2 months to there was a statistically significant (aP < 0.001) turn in reassess their erectile function.
the patients towards stronger treatments (mixtures) af-ter 10 years. The changes in treatment in the long term 2.3 Statistics are depicted analytically in Figure 2. In the 10th year of The McNemar testa, Pearson's χ2-testb, the Wilcoxon treatment, the type of diabetes was not related to the signed-ranks test for paired observationsc, and the Mann– treatment used, as there was no statistically significant Whitney U-testd were applied for statistical evaluation of relation between the two variables (bP = 0.324). All DM the data where appropriate, using a designated statistical type I patients (12/12) used mixtures, as did almost all package (SPSS 12.0 for Windows, SPSS Inc., Chicago, DM type II patients (24/26). But in the first year, the Illinois, USA). Statistical significance was set at P < 0.05.
type of diabetes was significantly related to the kind oftreatment: patients with DM type II used only prostag- 3 Results
landin and patients with DM type I used prostaglandinand mixtures almost equally, 5 of 12 and 7 of 12, re- Patients' demographic characteristics at baseline are spectively (bP < 0.001). This relationship between the shown in Table 2. According to age and dysfunction type of diabetes and treatment began to weaken as earlyas the sixth year and lost its significance in the ninth year(bP = 0.151). By definition, bP values estimate the sta- Table 1. Classification of treatment with self-injections of vasoac-tive drugs in diabetic men with erectile dysfunction (ED). PAP, tistical significance of the difference between the ob- papaverine; PGE1, prostaglandin E1; MIX, combinations of 20 µgPGE1 and various doses of papaverine.
Table 2. Patient demographics at the beginning of our study of men with diabetes mellitus (DM) and erectile dysfunction (ED).
20 µg PGE1 + 8–16 mg PAP DM duration (year) 20 µg PGE1 + > 16 mg PAP ED duration (year) Erectile dysfunction and diabetes Table 3. Relationship between patients' type of diabetes mellitus (DM) and the treatment used for erectile dysfunction. *bP < 0.001;**bP = 0.151. PGE1, prostaglandin E1; MIX, combinations of 20 µg PGE1 and various doses of papaverine; Count, number of patients;Expected count, number of patients according to the null hypothesis.
First year* (ninth year**) Figure 2. Treatment methods over 10 years applied to the wholestudy group of 38 diabetic men with erectile dysfunction (ED).
prostaglandin E1 (PGE1) low, 5–10 µg PGE1; PGE1 high, 15–20 µg PGE1; MIX low, 20 µg PGE1 + 8–16 mg papaverine (PAP);MIX high, 20 µg PGE1 + > 16 mg PAP.
served and the expected counts of patients in each treat-ment method (Table 3).
Figure 3. Mean number (±SD) of self-injections of vasoactive drugs The mean number of injections required by the pa- in the whole study group of 38 diabetic patients over 10 years.
tients as a whole was 50 in the first year and 22.5 in the10th year. The number of injections, regardless of thetype of diabetes, was significantly reduced year by year 4 Discussion
(cP < 0.001), with a temporary weakening of significancebetween the fourth and fifth years (cP = 0.035). The num- The treatment of severe ED with self-injection of ber of injections per year is depicted in Figure 3. Both vasoactive drugs in diabetic patients has been a very com- groups of diabetic patients significantly reduced the num- mon alternative. The mixtures of vasoactive drugs in ber of injections (cP = 0.001 for each of the groups).
particular, which use different mechanisms of action and Between the second and fourth years, type I diabetic men exert pharmacological synergism, are an effective and safe used fewer injections than the type II patients (dP < 0.05), treatment for severe diabetic ED. Self-injection is also a but after the fifth year the type II patients began to close safe treatment, especially in terms of concerns about the the gap, standardizing to 22.42 ± 2.67 (mean ± SD) injec- perceived risk of priapism. It has been reported that pri- tions at the 10th year. The mean number of injections apism never occurred during the long-term treatment phase used per year by both groups is depicted in Figure 4.
of experienced patients [13]. Although the majority of pa- Asian J Androl 2006; 8 (2): 219–224 patient, to solve practical problems regarding the injec-tions and to encourage patients and their partners to con-tinue and comply with the treatment. The adjustment ofdosage to appropriate levels is also very important, par-ticularly for the patient treated with injections. The pa-tient must be reassured that the treatment works, and to beconfident that when an increase in the dose is needed, it isnecessary to go along with his physician's advice. Menwith type I (insulin-dependent) DM are more familiar withself-injecting on a daily basis. On the other hand, menwith type II DM, who end up using injections, are gen-erally patients who have used oral treatment in the pastunsuccessfully and injections seem the last option leftbefore penile implantation.
The erectile tissue and penile musculature is not modified negatively or positively by intracavernosal in-jections [16], but the biochemical and ultrastructuralchanges by DM, as well as aging, affect it in a negativeway [17, 18]. These factors could play a major role inthe observed increased need for stronger remedies (higher Figure 4. Mean number of self-injections of vasoactive drugs per doses of PGE1 or more effective mixtures of PGE1 and year for each type of diabetes mellitus (DM).
PAP). It is well established that the combination of lowor reasonable doses of vasoactive drugs are more effec- tients with ED strongly prefer oral therapeutic compounds, tive than high doses of PGE1 to achieve an erection suit- which represent the first-line treatment because of the po- able for penetration, with a lower incidence of pain [19].
tential benefits and lack of invasiveness [14], diabetic men In our study, in the 10th year of treatment, there who have started self-injecting are not likely to switch suc- was no difference between the two groups of diabetic cessfully to oral treatment [15]. Therefore self-injection patients in the number of injections or the kind of treat- should be considered at this time a long-term therapeutic ment they used. Insulin-treated men proceeded earlier option and these patients should be advised accordingly.
than the others towards the final standardization of their In this study of men who started therapy before, but treatment. Because they were more familiar with the continued within, the Phosphodiesterase 5 inhibitors era, possibility of ED, they may compromise quickly with we attempted to assess the behaviour of patients with lower expectations for sexual life, so they find their either type I or type II DM, towards continuing treat- quantitave and qualitative balance earlier. DM type II ment with intracavernosal self-injections of vasoactive patients continued for longer to make more effort for drugs. The group presented here are the non-respond- successful intercourse, which actually meant more in- ers to oral treatment after the launch of PDE5 inhibitors.
jections per year, but ended up reaching the same levels Thus continuing injections, they complied with treatment of effort as the DM type I group. The obvious decrease because of satisfaction with the response, the quality of of injection frequency per year for both groups may also erections and the care undertaken for the treatment show tiredness by time of having to self-inject and an attempt to minimize side-effects.
To keep a patient satisfied in the long term with a In conclusion, the self-injection of vasoactive drugs semi-invasive treatment, such as the penile injection, is continues to be, in the long term, a highly effective and not easy. This issue may be mainly responsible for the safe treatment for ED in men with DM. The key point high rate of non-compliance with self-injecting in the for maintaining the treatment is the adjustment of the thera- general population of men with ED. Thus, we conclude peutic method and dosage to optimal levels for satisfactory that it is very important for the physician to have a erections. For this reason, systematic follow-up of these constant, personal, face-to-face communication with the cases is of the utmost importance. Diabetic men de- Erectile dysfunction and diabetes crease the number of self-injections over time, set realis- 1996; 13: 84–9.
tic expectations and create a baseline of satisfactory sexual 10 Perimenis P, Gyftopoulos K, Athanasopoulos A, Barbalias G.
life with aging.
Diabetic impotence treated by intracavernosal injections: hightreatment compliance and increasing dosage of vaso-activedrugs. Eur Urol 2001; 40: 398–403.
11 Althof SE, Turner LA, Levine SB, Risen C, Kursh E, Bodner D, et al. Why do so many people drop out from auto-injectiontherapy for impotence? J Sex Marital Ther 1989; 15: 121–9.
Guay AT. Sexual dysfunction in the diabetic patient. Int J 12 Markou S, Perimenis P, Gyftopoulos K, Athanasopoulos A, Impot Res 2001; 13: S47–50.
Barbalias G. Vardenafil (Levitra) for erectile dysfunction: a De Berardis G, Franciosi M, Belfiglio M, Di Nardo B, systematic review and meta-analysis of clinical trial reports.
Greenfield S, Kaplan SH, et al. Erectile dysfunction and qua- Int J Impot Res 2004; 16: 470–8.
lity of life in type 2 diabetic patients. A serious problem too 13 Perimenis P, Athanasopoulos A, Geramoutsos I, Barbalias G.
often overlooked. Diabetes Care 2002; 25: 284–91.
The incidence of pharmacologically induced priapism in the Bemelmans BLH, Meuleman EJH, Doesburg WH, Notermans diagnostic and therapeutic management of 685 men with erec- SLH, Debruyne FMJ. Erectile dysfunction in diabetic men: tile dysfunction. Urol Int 2001; 66: 22–6.
the neurological factor revisited. J Urol 1994; 151: 884–9.
14 Aversa A, Fabbri A. New oral agents for erectile dysfunction: Veves A, Webster L, Chen TF, Payne S, Boulton AJM.
what is changing in our practice? Asian J Androl 2001; 3: 175– Aetiopathogenesis and management of impotence in diabetic males: four years experience from a combined clinic. Diabetic 15 Perimenis P, Markou S, Gyftopoulos K, Athanasopoulos A, Med 1995; 12: 77–82 Giannitsas K, Barbalias G. Switching from long-term treat- Heaton JP, Lording D, Liu SN, Litonjua AD, Guangwei L, ment with self-injections to oral sildenafil in diabetic patients Kim SC, et al. Intracavernosal alprostadil is effective for the with severe erectile dysfunction. Eur Urol 2002; 41: 387–91.
treatment of erectile dysfunction in diabetic men. Int J Impot 16 Wespes E, Sattar AA, Noel JC, Schulman CC. Does prostag- Res 2001; 13: 317–21.
landin E1 therapy modify the intracavernous musculature? J Vickers MA, Satyanarayana R. Phosphodiesterase type 5 Urol 2000; 163: 464–6.
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nitric oxide synthase I and activity of nitric oxide synthase in Zhu GY, Shen Y. Application of pudental evoked potentials rat penis. Asian J Androl 2003; 5: 117–20.
in diagnosis of erectile dysfunction. Asian J Androl 1999; 1: 18 Lu YL, Shen ZJ, Wang H, Chen SW, Zhou XL, Chen ZD.
Ultrastructural changes of penile tunica albuginea in diabetic Xu ZS, Fu Q, Zhao ST, Liu HN. Effect of diabetes and insulin rats. Asian J Androl 2004; 6: 365–8.
treatment on nitric oxide synthase content in rat corpus 19 Bechara A, Casabe A, Cheliz G, Romano S, Fredotovich N.
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