| 
  • If you are citizen of an European Union member nation, you may not use this service unless you are at least 16 years old.

View
 

Sexual Dysfunction in Diabetes

Page history last edited by willbrant@gmail.com 11 years, 11 months ago

 

The Web diabetesmanager

 

 

Sexual Dysfunction in Diabetes

 

Tom F Lue, M.D.

William Brant, MD

Alan Shindel, MD

Anthony J. Bella, M.D.

 

Last Author Revision:  2009

 

 

 


 

 

Introduction

 

Diabetes mellitus (DM) may lead to disruption of normal sexual function in both men and women via diabetic induced damage to the nerves and blood vessels essential for normal function of the genital organs.  Additionally, the presence of poorly controlled diabetes may increase the morbidity associated with the treatment of erectile dysfunction (ED) in men. In the Endotext chapter “Medical and Surgical Therapy of Erectile Dysfunction”, Bochinski, et al review the pathophysiology, work-up, and treatments for erectile dysfunction of any cause. In this chapter, we will focus specifically on sexual dysfunction in diabetics, with particular emphasis on practical information for practicing clinicians.

 

Epidemiology

 

Erectile dysfunction is a common clinical problem and a serious detriment to quality of life for men and their partners. While the incidence of ED increases with age this is driven not so much by age in and of itself but by comorbid conditions associated with aging.  Examples include smoking, heart disease, high blood pressure, high cholesterol, and diabetes.[1] The incidence of ED in men with diabetes is approximately three-fold higher than in the general population.[2][3][4] ED may also be the presenting symptom for DM and may predict later neurologic sequelae.[5]

 

Pathogenesis

 

The pathophysiology of ED in DM is multifactorial, consisting of vascular and neurologic insults. There is impaired relaxation of the corpus cavernosal smooth muscle in diabetics in response to neuronal- and endothelial-derived nitric oxide, which may be due to the accumulation of glycosylation products .[6][7][8][9]  New evidence has suggested that in addition to problems with the arteries and nerves supplying the penis, men with diabetes may be at increased risk of low testosterone levels (aka hypogonadism).[10] [11] While the precices mechanism of this effect has not been entirely elucidated it may be secondary in some cases to a decline in the levels of pituitary hormones responsible for stimulating testicular production of testosterone.[12]  Low levels of testosterone may lead to a decline in sexual desire and, directly or indirectly, erectile dysfunction.[13]

 

 

Treatment of ED with phosphodiesterase type 5 inhibitors (PDE5i)

 

The treatment of ED in general was revolutionized by the availability of sildenafil (Viagra), followed by tadalafil (Cialis) and vardenafil (Levitra). The three medications work by a similar pathway. Sexual stimulation provokes the release of nitric oxide (NO), leading to increased cellular concentrations of cyclic guanosine monophosphate (cGMP) and subsequent penile smooth muscle relaxation. This process is reversed by the conversion of cGMP to guanosine monophosphate, which is mediated by phosphodiesterase type 5 (PDE5)- the predominant functional PDE type found in the penis. PDE5i act at this step to maintain elevated levels of cGMP and continued smooth muscle relaxation. Since the release of NO is a neurologically-mediated event, neuropathy (as may occur with diabetes) may blunt the efficacy of PDE5i. This is indeed borne out clinically, as diabetics have a poorer response overall to PDE5i than men with ED of other causes.

 

A prospective, multi-center, randomized, double-blinded (RCDB) trial of vardenafil in diabetics was carried out by Goldstein, et al [14]. The study consisted of 430 men with chronic ED, a hemoglobin A1c (HbA1c) of <12%, and no other serious confounding causes of ED (e.g. radical pelvic surgery, spinal cord injury, etc). Additionally, patients were excluded if they had unstable coronary disease or other contraindications to PDE5i use. The patients were evaluated using the erectile function (EF) domain of the 15 item International Index of Erectile Function (IIEF), 2 diary questions regarding the patient’s ability to penetrate (SEP2) and have successful intercourse (SEP3), and a global assessment question (GAQ) about whether or not the treatment had improved their erections. There were statistically and clinically significant improvements in all of the evaluated endpoints, with most of the improvements demonstrating a dose-relation. With 20 mg of vardenafil, the EF score was 19 (out of a total possible of 25) and 54% of men were able to complete intercourse, with an overall responder rate (as measured by the GAQ) of 72%. The effect was attenuated in patients with severe underlying ED but improvement remained significant. There was no correlation noted between different strata of HgA1c levels. The drug was well-tolerated with few patients discontinuing the study due to adverse side-effects.

 

A similar RCDB trial of tadalafil in diabetics was performed by Saenz de Tejada, et al .[15] A total of 191 patients completed this study; evaluated parameters were very similar to the vardenafil study above. Exclusion criteria were also similar to the vardenafil study, except that patients with hypertension and hypercholesterolemia were also excluded in the tadalafil study. As in the vardenafil study, statistically and clinically significant improvements were noted in all of the evaluated parameters for men using tadalafil, regardless of severity of underlying DM or level of HgA1c, with an overall responder rate (as assessed by GAQ) of 64% by those using 20 mg. The drug was also well-tolerated with few discontinuations.

 

A unique study from Denmark attempted to assess the “real-life” use of sildenafil in diabetics in terms of how many patients wanted to try an agent, how many were eligible to do so, and how efficacious the medicine was . [16]Examining a diabetes outpatient clinic population of 326 men, 192 (59%) self-reported ED and 187 of these were over 40 years old. Of these 187 patients, 79 (42%) were excluded because of medical or pharmacologic contraindications to sildenafil use. A further 63 patients either declined to participate in the study or did not respond. This left 45 patients for the study (23% of those patients with self-reported ED). Of these, 10 dropped out due to lack of sexual partner and 2 others without recorded reason. Sixty-one percent of the remaining patients self-titrated to a maximum dose of 100 mg. Of the 33 patients remaining, 36% noted consistent improvement, 27% noted variable improvement, and 36% felt they had no improvement; overall, 54% felt that the medicine had met their expectations. If we consider that 18 patients total felt that the medicine met their expectations and that the starting pool was 187 patients with self-reported ED, this leaves less than 10% of patients with a satisfactory outcome, thus pointing out that PDE5i, while efficacious under normal study conditions, do not represent a panacea.

 

In 2008 the US Food and Drug Administration (FDA) approved low-dose (2.5-5 mg) tadalafil as a daily treatment for ED.  Hatzichristou et al. enrolled 298 men with diabetes (89% type 2) and ED in a RCDB lasting 12 weeks and assessed clinical response using the sexual encounter profile questions 2 and 3.  At baseline 38%, 42%, and 32% of men reported the ability to attain an erection sufficient for vaginal penetration (SEP2) in the placebo, 2.5 mg, and 5 mg groups, respectively. The percentages of men in the same groups able to maintain erection until the completion of satisfactory intercourse (SEP3) were 20%, 20% and 16%, respectively.  At the completion of the study, men treated with either the 2.5 mg or 5 mg dose of tadalafil manifested greater improvements in SEP 2 (increase from baseline of 5%, 20%, and 29%) and SEP3 (28%, 46%, 41%).  The lower success rate in the 5 mg group was likely accounted for by relatively worse diabetic disease at baseline in that group.  Patients treated with tadalafil reported improvements in erection (based on IIEF scores) irrespective of baseline IIEF scores.  Patients were significantly more likely to prefer tadalafil treatment compared to placebo.[17]

 

In addition to daily dosing as an alternative to on-demand dosing for PDE5i, there has been great interest in recent years in the use of PDE5i not just as a therapy to produce erections but as a means to halt or even reverse the penile tissue damage that leads to ED.  Studies in animals with a form of experimentally induced diabetes most similar to Diabetes mellitus type 1 have demonstrated enhancement of erectile function and preservation of penile tissue health when treated with either vardenafil or SK-3530 (a novel PDE5i that has not yet been approved for routine in humans).[18],[19]  A preliminary study of routine dose sildenafil vs. placebo for 4 weeks in 292 men with type 2 diabetes and ED revealed some improvements in blood tests used to measure oxidative stress in men treated with sildenafil.  Unfortunately, there were some differences between the placebo and sildenafil group at baseline and there were no significant erectile function differences after the 4 week course of daily treatment was completed.[20] Another study in 20 men with type 2 diabetes but no ED indicated that treatment with sildenafil 25 mg three times a day led to improved vascular function and a decline in blood markers for various types of inflammation and oxidative stress; the ultimate clinical relevance of these findings is however unclear.[21] These encouraging preliminary results will require further assessment before the routine use of PDE5i for reversal of tissue damage can be recommended routinely.  A degree of caution is required since, despite a series of encouraging pre-clinical animals studies, routine dose PDE5i for the management of ED related to pelvic surgery has not at this time been proven to be of benefit.[22]

 

Treatment of ED with other modalities

 

Intracavernosal alprostadil injection therapy in diabetics was evaluated in a large, multicenter trial by Heaton, et al[23] . Over 300 men entered the trial, 83% completing the titration period and proceeding to home use. Of those patients using the medication at home, 79% required 30 micrograms/dose or less, and 72% remained satisfied with the initial dose during the followup period (6 months). There were 2 instances of priapism (sustained erection of greater than 4 hours unaccompanied by sexual stimuli) neither of which required intervention, 1 patient developed a penile nodule, and 24% of patients reported penile pain with injection; the pain led to patient drop-out in 5% of the treatment group. A smaller, more recent study with longer followup (10 years) found that diabetic patients tended to shift towards decreased frequency of use but preferred stronger agents (mixtures of alprostadil with other vasodilators such as papavarine and phentolamine), with type 1 diabetics stabilizing their doses within 5 years and type 2 diabetics stabilizing within 9-10 years.[24]

 

In patients for whom injection therapy does not work vacuum erection devices (VED) may be useful. There is a paucity of data specifically evaluating the use of VED in diabetics but the drop-out rate for patients is generally quite high, even for patients who are able to achieve a rigid erection with the device. One subset analysis found that despite a good response (i.e. rigid erection) using VED, only 50% of those couples found the treatment to be satisfactory . This may be due to the “unnaturalness” of the devices, as well as the fact that they may have several local side effects, including petechiae (small red dots from broken capillaries), a feeling of having a cold penis, and abnormal sensation of ejacuation.

[25]

 

Penile Prosthetics

 

When there is lack of efficacy or dissatisfaction with other modalities, penile prostheses are often the best alternative for erectile dysfunction in diabetics. Unlike the other modalities, prosthesis surgery is irreversible in that the corporal tissue is permanently altered such that physiologic erections are no longer possible. If the prosthesis has to be removed, there will be complete ED. While a variety of exotic materials, flaps , and grafts have been used, most contemporary prostheses are hydraulic or semi-rigid.[26][27]Of all modalities for management of ED, prostheses have the highest satisfaction rates, with 2 large studies demonstrating greater than 95% satisfaction.[28][29] While this high rate of satisfaction is encouraing it must be understood that the population of men who are motivated enough to undergo surgery for erectile function may not be representative of the larger population of ED patients.

 

Although some studies suggest that elevated HbA1c levels may predict a higher rate of infections in diabetics having penile prosthesis surgery, more recent studies refute this.[30] A large study from Wilson, et al demonstrated that neither diabetic status nor preoperative HgA1c were risk factors for prosthesis infection. A more recent study also finds that elevated HbA1c is not a risk factor for infection but notes that short-term poor glucose control (as defined by morning fast glucose levels >200 ng/ml) is, although that data is hampered by very low numbers of patients within that set.[31][32]

 

Treatment of low testosterone levels

 

Although there is some controvery over what constitutes a true "low" testosterone level and the best way to measure it, well designed studies have indicated that men with low levels of testerone and symptoms of hypogonadism (such as decreased libido, decreased energy, depression, anxiety, fatigue, weight gain, etc) may benefit from testosterone replacement therapy.   To our knowledge there have not been specific studies of sexual function in hypogonadal, diabetic men treated with testosterone.  However, the general efficacy of testosterone in improving sexual function (particularly sexual desire and response to PDE5i in cases of initial failure to respond) in appropriately selected patients is well known.[33] In addition to improving sexual symptoms in these men, testosterone supplementation may have beneficial effects with respect to lean body mass and insulin sensitivity in diabetic men with hypogonadism.[34][35]

 

A number of different testosterone formulations are available.  Patients can discuss available options with their health care providers

 

Ejaculatory dysfunction

 

Men with diabetes may have sexual disorders other than erectile dysfunction. Examples include diminished sexual desire, lack of ejaculation with sexual climax (anejaculation or retrograde ejaculation), and premature ejaculation. Successful antegrade ejaculation depends on the coordination of three neurologic events: seminal emission, bladder neck closure, and contraction of the muscles of the pelvic floor (e.g. bulbocavernous, ischiocavernous, etc.). In diabetes, derangements of the nerves controlling closure of the connection between the bladder and urethra may disrupt normal ejaculation.  In this situation ejaculate is deposited in the innermost portion of the urethra but the connection between the bladder and urethra does not close.  Since the bladder neck is open, some or all of the ejaculate may leak backwards into the bladder during the muscle contractions that normally expel the semen from the penis.  In the most severe cases there may be total lack of seminal emission. Either of these conditions will impact fertility.  It may also be a source of psychological disturbance to the man; indeed, some men report that they are not able to fully enjoy orgasm in the absence of ejaculation. From a fertility standpoint, sperm may be retrieved from post-ejaculate urine and then used for artificial insemination. Alternative strategies to overcome retrograde ejaculation generally focus on attempts to help the bladder neck close.  A variety of pharmacologic agents have also been used, including anticholinergics, antihistamines, and alpha-adrenergics .[36][37] 

 

Female Sexual Dysfunction

 

Our understanding of the medical and physiological aspects of females sexual function is poor relative to our understanding of men's sexual physiology and function. It is recognized that diabetes can be detrimental to female sexuality in a multifactorial manner, including both psychologic and physiologic dimensions. [38][39]The best studied  class of female sexual dysfunctions (at least with respect to medicophysiological research) is arousal disorder; physiologically, this is accompanied by vasodilation and engorgement of the female external genitalia.[40] Given that the processes involved in female genital engorgement are governed by many of the same molecular processes that occur duing male genital engorgement, Caruso et al [41]undertook a RCDB trial of 100 mg sildenafil in type 1 diabetic women with sexual dysfunction. Of the 28 women who completed the trial, significant improvement was seen in both subjective and objective parameters. Subjectively, arousal, orgasm and dyspareunia were all improved in those taking sildenafil in comparison to baseline and those taking placebo. Color Doppler ultrasonography was performed on the clitoral arteries, revealing an increase in blood flow in these women. However, it should be noted that the use of ultrasonography in the evaluation of women with sexual dysfunction is not routine and these results should be interpreted with caution.

 

The importance of managing lifestyle factors in treating sexual problems in diabetes

 

As with most aspects of diabetes care, routine exercise, careful monitoring of glucose levels, and usage of appropriate therapies to prevent hyperglycemia are key to preventing progression of diabetes-induced sexual problems.  Weight management and dietary prudence are also critical in the management of diabetes.  There is evidence to suggest weight loss may reverse erectile dysfunction in some men.  In a study of 65 obese men with ED and the Metabolic Syndrome (MetS, obesity with at abnormalities of blood pressure, abnormal glucose level/diabetes, and abnormal cholesterol levels), eating a "Mediterranean diet" (emphasizing fresh fruit and vegetables) for two years led to normalization of erectile function (as determined by an International Index of Erectile function score greater than 22) in 13 of 35 men compared to 2 of 30 men in the group that did not have dietary manipulation.[42]  A similar study in women with sexual dysfunction and MetS showed a significant improvement in mean sexual function (mean increase on the Female Sexual Function Index from 19.7 to 26.1 in the treatment group vs. no change from baseline in the control group).  Also noted in both of these studies were improvements in serum insulin and glucose level in men and women who ate the Mediterranean diet.[43] 

  

Conclusion

 

Sexual dysfunctions are common in people with diabetes and may arise from a variety of vascular, neurologic, and hormonal derangements. While PDE5i do not work as well in diabetics as in other populations, they still represent a good first-line treatment. If their use is unsatisfactory, intracorporal injections and implantable prosthesis are excellent alternatives. Vacuum devices represent another viable alternative, although satisfaction is generally not as high. Beyond erectile difficulties, men may complain of ejaculatory symptoms which arise from neuropathy of sympathetic nerves. Female sexual dysfunctions may be underreported in diabetics but further clinical advances may lead to increased hope and more efficacious treatments for these disorders.

 

 

Footnotes

  1. Feldman, H.A., et al., Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol, 1994. 151(1): p. 54-61.
  2. Parazzini, F., et al., Frequency and determinants of erectile dysfunction in Italy. Eur Urol, 2000. 37(1): p. 43-9.
  3. Fedele, D., et al., Erectile dysfunction in diabetic subjects in Italy. Gruppo Italiano Studio Deficit Erettile nei Diabetici. Diabetes Care, 1998. 21(11): p. 1973-7.
  4. Fedele, D., et al., Erectile dysfunction in type 1 and type 2 diabetics in Italy. On behalf of Gruppo Italiano Studio Deficit Erettile nei Diabetici. Int J Epidemiol, 2000. 29(3): p. 524-31.
  5. McCulloch, D.K., et al., The natural history of impotence in diabetic men. Diabetologia, 1984. 26(6): p. 437-40.
  6. Seftel, A.D., et al., Advanced glycation end products in human penis: elevation in diabetic tissue, site of deposition, and possible effect through iNOS or eNOS. Urology, 1997. 50(6): p. 1016-26.
  7. Angulo, J., et al., Diabetes impairs endothelium-dependent relaxation of human penile vascular tissues mediated by NO and EDHF. Biochem Biophys Res Commun, 2003. 312(4): p. 1202-8.
  8. Cartledge, J.J., I. Eardley, and J.F. Morrison, Advanced glycation end-products are responsible for the impairment of corpus cavernosal smooth muscle relaxation seen in diabetes. BJU Int, 2001. 87(4): p. 402-7.
  9. Saenz de Tejada, I., et al., Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med, 1989. 320(16): p. 1025-30.
  10. Diaz-Arjonilla M et al. Obesity, low testosterone levels, and erectile dysfunction. Int J Impot Res 2008 Oct 9 [E-pub ahead of print]
  11. Kapoor D, et al. Erectile dysfunction is associated with low bioactive testosterone levels and visceral adiposity in men with type 2 diabetes. Int J Androl. 2007 Dec;30(6):500-507
  12. Dandona P, et al. Hypogonadotrophic hypogonadism in type 2 diabetes. Aging Male. 2008 Sep;11(3):107-17
  13. Morelli A, et al. Which patients with sexual dysfunction are suitable for testosterone replacement therapy. J Endocrinol Invest. 2007 Nov;30(10):880-888
  14. Goldstein, I., et al., Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes: a multicenter double-blind placebo-controlled fixed-dose study. Diabetes Care, 2003. 26(3): p. 777-83.
  15. Saenz de Tejada, I., et al., Effects of tadalafil on erectile dysfunction in men with diabetes. Diabetes Care, 2002. 25(12): p. 2159-64.
  16. Behrend, L., J. Vibe-Petersen, and H. Perrild, Sildenafil in the treatment of erectile dysfunction in men with diabetes: demand, efficacy and patient satisfaction. Int J Impot Res, 2005. 17(3): p. 264-9.
  17. Hatzichristou D, et al. Efficacy of tadalafil once daily in men with diabetes mellitus and erectile dysfunction. Diabet Med. 2008 Feb;25(2):138-46
  18. Park K, et al. Chronic treatment with a type 5 Phosphodiesterase inhibitor suppresses apoptosis of corporal smooth muscle by potentiating Akt signaling in a rat model of diabetic erectile dysfunction. Eur Urol. 2008;53:1282-1289
  19. DeYoung LX, et al. Endothelial rehabilitation: the impact of chronic PDE5 inhibitors on erectile function and protein alteration in cavernous tissue of diabetic rats. Eur Urol. 2008;54:213-220
  20. Burnett AL, et al. Serum biomarker measurements of endothelial function and oxidative stress after daily dosing of sildenafil in type 2 diabetic men with erectile dysfunction. J Urol. 2009;181:245-251.
  21. Aversa A, et al. Chronic administration of Sildenafil improves markers of endothelial function in men with Type 2 diabetes. Diabet Med. 2008 Jan;25(1):37-44
  22. Montorsi F, Brock G, Lee J, Shapiro J, van Poppel H, Graefen M, et al. Effect of nightly versus on-demand vardenafil on recovery of erectile function in men following bilateral nerve-sparing radical prostatectomy. Eur Urol. 2008;54:924-931
  23. Heaton, J.P., et al., Intracavernosal alprostadil is effective for the treatment of erectile dysfunction in diabetic men. Int J Impot Res, 2001. 13(6): p. 317-21
  24. Perimenis, P., et al., Long-term treatment with intracavernosal injections in diabetic men with erectile dysfunction. Asian J Androl, 2006. 8(2): p. 219-24.
  25. Ryder, R.E., et al., Impotence in diabetes: aetiology, implications for treatment and preferred vacuum device. Diabet Med, 1992. 9(10): p. 893-8.
  26. Akoz, T., et al., The use of iliac bone flap as a penile stiffener in a diabetic patient with erectile dysfunction. Plast Reconstr Surg, 1999. 103(7): p. 1975-8.
  27. Mulcahy, J.J., et al., The penile implant for erectile dysfunction. J Sex Med, 2004. 1(1): p. 98-109.
  28. Levine, L.A., C.R. Estrada, and A. Morgentaler, Mechanical reliability and safety of, and patient satisfaction with the Ambicor inflatable penile prosthesis: results of a 2 center study. J Urol, 2001. 166(3): p. 932-7.
  29. Montorsi, F., et al., AMS three-piece inflatable implants for erectile dysfunction: a long-term multi-institutional study in 200 consecutive patients. Eur Urol, 2000. 37(1): p. 50-5.
  30. Bishop, J.R., et al., Use of glycosylated hemoglobin to identify diabetics at high risk for penile periprosthetic infections. J Urol, 1992. 147(2): p. 386-8.
  31. Wilson, S.K., et al., Quantifying risk of penile prosthesis infection with elevated glycosylated hemoglobin. J Urol, 1998. 159(5): p. 1537-9; discussion 1539-40.
  32. Cakan, M., et al., Risk factors for penile prosthetic infection. Int Urol Nephrol, 2003. 35(2): p. 209-13.
  33. Buvat J et al. Significance of hypogonadism in erectile dysfunction. World J Urol. 2006 Dec;24(6):657-67.
  34. Kapoor D et al. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006 Jun;154(6):899-906
  35. Kapoor D, et al. The effect of teststerone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes. Eur j Endocrinol. 2007 May;156(5):595-602
  36. Kamischke, A. and E. Nieschlag, Update on medical treatment of ejaculatory disorders. Int J Androl, 2002. 25(6): p. 333-44.
  37. Tomasi, P.A., G. Fanciulli, and G. Delitala, Successful treatment of retrograde ejaculation with the alpha1-adrenergic agonist methoxamine: case study. Int J Impot Res, 2005. 17(3): p. 297-9.
  38. Koch, P.B. and E.W. Young, Diabetes and female sexuality: a review of the literature. Health Care Women Int, 1988. 9(4): p. 251-62
  39. Grandjean C, Moran B. The impact of diabetes mellitus on female sexual well-being. Nurs Clin North Am. 2007 Dec;42(4):581-92;
  40. Yang, C.C., et al., Sexually responsive vascular tissue of the vulva. BJU Int, 2006. 97(4): p. 766-72.
  41. Caruso, S., et al., Sildenafil improves sexual functioning in premenopausal women with type 1 diabetes who are affected by sexual arousal disorder: a double-blind, crossover, placebo-controlled pilot study. Fertil Steril, 2006
  42. Esposito K, et al. Mediterranean diet improves erectile function in subjects with the metabolic syndrome. Int J Impot Res. 2006 Jul-Aug;18(4):405-10.
  43. Esposito K, et al. Mediterranean diet improves sexual function in women with the metabolic syndrome. Int J Impot Res. 2007 Sep-Oct;19(5):486-91.

Comments (0)

You don't have permission to comment on this page.