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Sexual Dysfunction and Hypogonadism in Men With Diabetes

      Key Messages Regarding Sexual Dysfunction in Men with Diabetes
      • Erectile dysfunction affects approximately 34% to 45% of adult men with diabetes. It has been demonstrated to negatively impact quality of life among those affected across all age strata and may be an early clinical indication of cardiovascular disease.
      • All adult men with diabetes should be regularly screened for erectile dysfunction with a sexual function history.
      • The current mainstay of therapy for erectile dysfunction is phosphodiesterase type 5 inhibitors. They have been shown to have major impacts on erectile function and quality of life, with a low reported side effect profile, and should be offered as first-line therapy to men with diabetes wishing treatment for erectile dysfunction.
      Key Messages Regarding Hypogonadism in Men with Diabetes
      • Hypogonadotropic hypogonadism is common in men with type 2 diabetes, with a prevalence of up to 40%.
      • Hypogonadal men with diabetes have a higher risk for cardiovascular mortality than eugonadal men with diabetes.
      • Screening for symptomatic hypogonadism in men with type 2 diabetes is recommended.
      • Evidence is conflicted as to whether treatment of hypogonadism in men with diabetes can increase quality of life, improve body composition, weight loss and glycemic control.
      • Observational studies assessing the impact of testosterone use on cardiovascular health in hypogonadal men have produced mixed results. Randomized, placebo-controlled studies have been too small or short in duration to adequately answer this question.
      Key Messages for Men with Diabetes
      • Low testosterone is common in men with type 2 diabetes.
      • Symptoms of low testosterone can include: diminished interest in sex, erectile dysfunction, reduced lean body mass, depressed mood and lack of energy.
      • If you are experiencing symptoms of low testosterone, you should talk with your health-care provider.

      Erectile Dysfunction

      Erectile dysfunction (ED) affects approximately 34% to 45% of men with diabetes and has been demonstrated to negatively impact quality of life among those affected across all age strata (
      • Maiorino M.I.
      • Bellastella G.
      • Della Volpe E.
      • et al.
      Erectile dysfunction in young men with type 1 diabetes.
      ), with a greater impact on those with permanent—rather than intermittent—ED (
      • Eardley I.
      • Fisher W.
      • Rosen R.C.
      • et al.
      The multinational Men's Attitudes to Life Events and Sexuality study: The influence of diabetes on self-reported erectile function, attitudes and treatment-seeking patterns in men with erectile dysfunction.
      ,
      • Corona G.
      • Giorda C.B.
      • Cucinotta D.
      • et al.
      The SUBITO-DE study: Sexual dysfunction in newly diagnosed type 2 diabetes male patients.
      ). Recent reports describe up to one-third of newly diagnosed men with diabetes have ED at presentation (
      • Al-Hunayan A.
      • Al-Mutar M.
      • Kehinde E.O.
      • et al.
      The prevalence and predictors of erectile dysfunction in men with newly diagnosed with type 2 diabetes mellitus.
      ), with upward of 50% of men 6 years after diagnosis (
      • Aversa A.
      • Bruzziches R.
      • Vitale C.
      • et al.
      Chronic sildenafil in men with diabetes and erectile dysfunction.
      ,
      • Derosa G.
      • Romano D.
      • Tinelli C.
      • et al.
      Prevalence and associations of erectile dysfunction in a sample of Italian males with type 2 diabetes.
      ). In addition, studies indicate that 40% of men with diabetes greater than 60 years of age have complete ED (
      • Chew K.K.
      • Earle C.M.
      • Stuckey B.G.
      • et al.
      Erectile dysfunction in general medicine practice: Prevalence and clinical correlates.
      ,
      • Maatman T.J.
      • Montague D.K.
      • Martin L.M.
      Erectile dysfunction in men with diabetes mellitus.
      ,
      • Rubin A.
      • Babbott D.
      Impotence and diabetes mellitus.
      ,
      • Kolodny R.C.
      • Kahn C.B.
      • Goldstein H.H.
      • et al.
      Sexual dysfunction in diabetic men.
      ,
      • McCulloch D.K.
      • Campbell I.W.
      • Wu F.C.
      • et al.
      The prevalence of diabetic impotence.
      ,
      • Zemel P.
      Sexual dysfunction in the diabetic patient with hypertension.
      ,
      • McCulloch D.K.
      • Young R.J.
      • Prescott R.J.
      • et al.
      The natural history of impotence in diabetic men.
      ,
      • Bacon C.G.
      • Hu F.B.
      • Giovannucci E.
      • et al.
      Association of type and duration of diabetes with erectile dysfunction in a large cohort of men.
      ,
      • De Berardis G.
      • Pellegrini F.
      • Franciosi M.
      • et al.
      Identifying patients with type 2 diabetes with a higher likelihood of erectile dysfunction: The role of the interaction between clinical and psychological factors.
      ).
      Recent studies have reported that alteration of the cyclic guanosine monophosphate (cGMP)/nitric oxide (NO) pathway among men with diabetes with impaired vascular relaxation is related to endothelial dysfunction (
      • Angulo J.
      • Cuevas P.
      • Fernandez A.
      • et al.
      Enhanced thromboxane receptor-mediated responses and impaired endothelium-dependent relaxation in human corpus cavernosum from diabetic impotent men: Role of protein kinase C activity.
      ,
      • Angulo J.
      • Peiro C.
      • Cuevas P.
      • et al.
      The novel antioxidant, AC3056 (2,6-di-t-butyl-4-((dimethyl-4-methoxyphenylsilyl)methyloxy)phenol), reverses erectile dysfunction in diabetic rats and improves NO-mediated responses in penile tissue from diabetic men.
      ,
      • Angulo J.
      • Gonzalez-Corrochano R.
      • Cuevas P.
      • et al.
      Diabetes exacerbates the functional deficiency of NO/cGMP pathway associated with erectile dysfunction in human corpus cavernosum and penile arteries.
      ). Among men with diabetes, risk factors include increasing age, duration of diabetes, poor glycemic control, cigarette smoking, hypertension, dyslipidemia, androgen-deficiency states (
      • Alexopoulou O.
      • Jamart J.
      • Maiter D.
      • et al.
      Erectile dysfunction and lower androgenicity in type 1 diabetic patients.
      ) and cardiovascular disease (CVD) (
      • Derosa G.
      • Romano D.
      • Tinelli C.
      • et al.
      Prevalence and associations of erectile dysfunction in a sample of Italian males with type 2 diabetes.
      ,
      • McCulloch D.K.
      • Campbell I.W.
      • Wu F.C.
      • et al.
      The prevalence of diabetic impotence.
      ,
      • Zemel P.
      Sexual dysfunction in the diabetic patient with hypertension.
      ,
      • Naliboff B.D.
      • Rosenthal M.
      Effects of age on complications in adult onset diabetes.
      ,
      • Feldman H.A.
      • Goldstein I.
      • Hatzichristou D.G.
      • et al.
      Impotence and its medical and psychosocial correlates: Results of the Massachusetts Male Aging Study.
      ,
      • Ramirez R.
      • Pedro-Botet J.
      • Garcia M.
      • et al.
      Erectile dysfunction and cardiovascular risk factors in a Mediterranean diet cohort.
      ,
      • Glavaš S.
      • Valenčić L.
      • Trbojević N.
      • et al.
      Erectile function in cardiovascular patients: Its significance and a quick assessment using a visual-scale questionnaire.
      ,
      • Pallangyo P.
      • Nicholaus P.
      • Kisenge P.
      • et al.
      A community-based study on prevalence and correlates of erectile dysfunction among Kinondoni District Residents, Dar es Salaam, Tanzania.
      ).
      ED as a marker of potential cardiovascular (CV) events has been reported by numerous investigators (
      • Grover S.A.
      • Lowensteyn I.
      • Kaouache M.
      • et al.
      The prevalence of erectile dysfunction in the primary care setting: Importance of risk factors for diabetes and vascular disease.
      ,
      • Barrett-Connor E.
      Cardiovascular risk stratification and cardiovascular risk factors associated with erectile dysfunction: Assessing cardiovascular risk in men with erectile dysfunction.
      ,
      • Billups K.L.
      Erectile dysfunction as an early sign of cardiovascular disease.
      ,
      • Thompson I.M.
      • Tangen C.M.
      • Goodman P.J.
      • et al.
      Erectile dysfunction and subsequent cardiovascular disease.
      ,
      • Gazzaruso C.
      Erectile dysfunction and coronary atherothrombosis in diabetic patients: Pathophysiology, clinical features and treatment.
      ,
      • Barrett-Connor E.
      Heart disease risk factors predict erectile dysfunction 25 years later (the Rancho Bernardo Study).
      ,
      • Min J.K.
      • Williams K.A.
      • Okwuosa T.M.
      • et al.
      Prediction of coronary heart disease by erectile dysfunction in men referred for nuclear stress testing.
      ,
      • Chiurlia E.
      • D'Amico R.
      • Ratti C.
      • et al.
      Subclinical coronary artery atherosclerosis in patients with erectile dysfunction.
      ,
      • Djordjevic D.
      • Vukovic I.
      • Milenkovic Petronic D.
      • et al.
      Erectile dysfunction as a predictor of advanced vascular age.
      ,
      • Gandaglia G.
      • Salonia A.
      • Passoni N.
      • et al.
      Erectile dysfunction as a cardiovascular risk factor in patients with diabetes.
      ). In fact, ED has been shown to be significantly associated with all-cause mortality and CV events (
      • Araujo A.B.
      • Travison T.G.
      • Ganz P.
      • et al.
      Erectile dysfunction and mortality.
      ,
      • Giugliano F.
      • Maiorino M.I.
      • Bellastella G.
      • et al.
      Adherence to Mediterranean diet and erectile dysfunction in men with type 2 diabetes.
      ,
      • Yamada T.
      • Hara K.
      • Umematsu H.
      • et al.
      Erectile dysfunction and cardiovascular events in diabetic men: A meta-analysis of observational studies.
      ). Diabetic retinopathy has been shown to correlate with the presence of ED (
      • McCulloch D.K.
      • Campbell I.W.
      • Wu F.C.
      • et al.
      The prevalence of diabetic impotence.
      ,
      • McCulloch D.K.
      • Young R.J.
      • Prescott R.J.
      • et al.
      The natural history of impotence in diabetic men.
      ,
      • Klein R.
      • Klein B.E.
      • Lee K.E.
      • et al.
      Prevalence of self-reported erectile dysfunction in people with long-term IDDM.
      ). Organic causes of ED include microvascular and CV disease, and neuropathy. In addition, psychological or situational factors may cause or contribute to ED. In spite of the overwhelming amount of data linking ED and diabetes, it is often neglected by clinicians treating men with diabetes (
      • Grant P.S.
      • Lipscomb D.
      How often do we ask about erectile dysfunction in the diabetes review clinic? Development of a neuropathy screening tool.
      ).
      Compared with the general population, multiple studies have reported that men with diabetes have higher rates of hypogonadism (
      • Alexopoulou O.
      • Jamart J.
      • Maiter D.
      • et al.
      Erectile dysfunction and lower androgenicity in type 1 diabetic patients.
      ,
      • Dhindsa S.
      • Prabhakar S.
      • Sethi M.
      • et al.
      Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes.
      ,
      • Boyanov M.A.
      • Boneva Z.
      • Christov V.G.
      Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency.
      ,
      • Shabsigh R.
      • Rajfer J.
      • Aversa A.
      • et al.
      The evolving role of testosterone in the treatment of erectile dysfunction.
      ,
      • Shabsigh R.
      • Kaufman J.M.
      • Steidle C.
      • et al.
      Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone.
      ,
      • Mazzilli R.
      • Elia J.
      • Delfino M.
      • et al.
      Prevalence of Diabetes Mellitus (DM) in a population of men affected by Erectile Dysfunction (ED).
      ). One report described a correlation between glycemic control and testosterone levels (
      • El-Sakka A.I.
      • Sayed H.M.
      • Tayeb K.A.
      Androgen pattern in patients with type 2 diabetes-associated erectile dysfunction: Impact of metabolic control.
      ). Importantly, phosphodiesterase type 5 (PDE5) inhibitors appear to be less effective in men with diabetes with hypogonadism (
      • Boyanov M.A.
      • Boneva Z.
      • Christov V.G.
      Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency.
      ,
      • Shabsigh R.
      • Kaufman J.M.
      • Steidle C.
      • et al.
      Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone.
      ,
      • Kalinchenko S.Y.
      • Kozlov G.I.
      • Gontcharov N.P.
      • et al.
      Oral testosterone undecanoate reverses erectile dysfunction associated with diabetes mellitus in patients failing on sildenafil citrate therapy alone.
      ,
      • Hadeed N.N.
      • Thanoon I.A.
      • Al-Mukhtar S.B.
      Total testosterone levels and the effect of sildenafil on type 2 diabetics with erectile dysfunction.
      ). In this population, treatment of nonresponders to PDE5 inhibitors with testosterone replacement is successful in roughly 50% of individuals. In addition, ED is a side effect of many drugs commonly prescribed to men with diabetes, such as certain antihypertensives and antidepressants. Obstructive sleep apnea (OSA) is commonly associated with ED and, like diabetes, is an independent risk factor for the presence of ED (
      • Lo W.H.
      • Fu S.N.
      • Wong C.K.
      • et al.
      Prevalence, correlates, attitude and treatment seeking of erectile dysfunction among type 2 diabetic Chinese men attending primary care outpatient clinics.
      ). Screening for OSA in men with obesity with type 2 diabetes and ED should be considered.

      Screening for Erectile Dysfunction

      All adult men with diabetes should be regularly screened for ED with a sexual function history. Screening for ED in men with type 2 diabetes should begin at diagnosis of diabetes. Validated questionnaires (e.g. International Index of Erectile Function (
      • Rosen R.C.
      • Riley A.
      • Wagner G.
      • et al.
      The international index of erectile function (IIEF): A multidimensional scale for assessment of erectile dysfunction.
      ,
      • Cappelleri J.C.
      • Rosen R.C.
      • Smith M.D.
      • et al.
      Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function.
      ) or Sexual Health Inventory for Men) (
      • Ramanathan R.
      • Mulhall J.
      • Rao S.
      • et al.
      Predictive correlation between the International Index of Erectile Function (IIEF) and Sexual Health Inventory for Men (SHIM): Implications for calculating a derived SHIM for clinical use.
      ) have been shown to be both sensitive and specific in determining the presence of ED and providing a means of assessing response to therapy (
      • Pallangyo P.
      • Nicholaus P.
      • Kisenge P.
      • et al.
      A community-based study on prevalence and correlates of erectile dysfunction among Kinondoni District Residents, Dar es Salaam, Tanzania.
      ). Men with diabetes and ED should be further investigated for hypogonadism (Figure 1).
      Figure 1
      Figure 1Diagnostic workup of hypogonadism (TDS) (modified from reference
      [
      • Morales A.
      • Bebb R.A.
      • Manjoo P.
      • et al.
      Diagnosis and management of testosterone deficiency syndrome in men: Clinical practice guideline.
      ]
      ).
      BAT, calculated bioavailable testosterone; CBC, complete blood count; COPD; chronic obstructive pulmonary disease; FT, free testosterone; FSH, follicle stimulating hormone; LH, luteinizing hormone; PSA, prostate specific antigen; SHBG, sex hormone-binding globulin; TSH, thyroid stimulating hormone.

      Treatment of ED

      While no randomized clinical trials have demonstrated that interventions that improve glycemic control also reduce the incidence and progression of ED, the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS) showed that intensive glycemic control was effective for primary prevention of and secondary intervention for neuropathy, a condition that can impair sensory feedback from the penis, leading to reduced erectile function (
      • Valiquette L.
      • Montorsi F.
      • Auerbach S.
      First-dose success with vardenafil in men with erectile dysfunction and associated comorbidities: RELY-I.
      ,
      The Diabetes Control and Complications Trial Research Group
      The effect of intensive diabetes therapy on the development and progression of neuropathy.
      ,
      The Diabetes Control and Complications Trial Research Group
      The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.
      ). The current data are controversial as they relate to diet, glycemic control and ED, with both positive and negative studies (
      • Giugliano F.
      • Maiorino M.I.
      • Bellastella G.
      • et al.
      Adherence to Mediterranean diet and erectile dysfunction in men with type 2 diabetes.
      ,
      UK Prospective Diabetes Study (UKPDS) Group
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
      ,
      • Azad N.
      • Emanuele N.V.
      • Abraira C.
      • et al.
      The effects of intensive glycemic control on neuropathy in the VA cooperative study on type II diabetes mellitus (VA CSDM).
      ,
      • El-Sakka A.I.
      • Hassoba H.M.
      • Sayed H.M.
      • et al.
      Pattern of endocrinal changes in patients with sexual dysfunction.
      ). Based on these conflicting data, a prudent clinician should encourage optimal glycemic control as a potential factor in maintaining erectile function (
      • Giugliano F.
      • Maiorino M.I.
      • Bellastella G.
      • et al.
      Adherence to Mediterranean diet and erectile dysfunction in men with type 2 diabetes.
      ,
      • Giagulli V.A.
      • Carbone M.D.
      • Ramunni M.I.
      • et al.
      Adding liraglutide to lifestyle changes, metformin and testosterone therapy boosts erectile function in diabetic obese men with overt hypogonadism.
      ,
      • Wong L.
      • Chen H.M.
      • Lai S.Q.
      • et al.
      Effects of sulfonylurea as initial treatment on testosterone of middle-aged men with type 2 diabetes: A 16-week, pilot study.
      ).
      Dyslipidemia and hypertension are also risk factors for ED. A meta-analysis of statin use in older men, many of whom had diabetes, suggests a benefit from statin treatment on erectile function. Diabetes-specific data are lacking (
      • Kostis J.B.
      • Dobrzynski J.M.
      The effect of statins on erectile dysfunction: A meta-analysis of randomized trials.
      ). A small study of losartan in combination with tadalafil in men with type 2 diabetes showed an improved ED response rate compared to tadalafil monotherapy (
      • Chen Y.
      • Cui S.
      • Lin H.
      • et al.
      Losartan improves erectile dysfunction in diabetic patients: A clinical trial.
      ).
      The current mainstay of treatment for ED in men with diabetes is therapy with PDE5 inhibitors (
      • Balhara Y.P.
      • Sarkar S.
      • Gupta R.
      Phosphodiesterase-5 inhibitors for erectile dysfunction in patients with diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials.
      ,
      • Walsh T.J.
      • Hotaling J.M.
      • Smith A.
      • et al.
      Men with diabetes may require more aggressive treatment for erectile dysfunction.
      ,
      • Santi D.
      • Granata A.R.
      • Guidi A.
      • et al.
      Six months of daily treatment with vardenafil improves parameters of endothelial inflammation and of hypogonadism in male patients with type 2 diabetes and erectile dysfunction: A randomized, double-blind, prospective trial.
      ). They have been reported to have a major impact on erectile function and quality of life, and should be offered as first-line therapy to men with diabetes wishing treatment for ED (
      • Fonseca V.
      • Seftel A.
      • Denne J.
      • et al.
      Impact of diabetes mellitus on the severity of erectile dysfunction and response to treatment: Analysis of data from tadalafil clinical trials.
      ,
      • Rendell M.S.
      • Rajfer J.
      • Wicker P.A.
      • et al.
      Sildenafil for treatment of erectile dysfunction in men with diabetes: A randomized controlled trial.
      ,
      • Boulton A.J.
      • Selam J.L.
      • Sweeney M.
      • et al.
      Sildenafil citrate for the treatment of erectile dysfunction in men with type II diabetes mellitus.
      ,
      • Goldstein I.
      • Young J.M.
      • Fischer J.
      • 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.
      ,
      • Sáenz de Tejada I.
      • Anglin G.
      • Knight J.R.
      • et al.
      Effects of tadalafil on erectile dysfunction in men with diabetes.
      ,
      • Carson C.C.
      • Lue T.F.
      Phosphodiesterase type 5 inhibitors for erectile dysfunction.
      ) (see Figure 2). There is evidence that scheduled daily therapy is effective within the population with diabetes and ED (
      • Hatzichristou D.
      • Gambla M.
      • Rubio-Aurioles E.
      • et al.
      Efficacy of tadalafil once daily in men with diabetes mellitus and erectile dysfunction.
      ,
      • Buvat J.
      • van Ahlen H.
      • Schmitt H.
      • et al.
      Efficacy and safety of two dosing regimens of tadalafil and patterns of sexual activity in men with diabetes mellitus and erectile dysfunction: Scheduled use vs. on-demand regimen evaluation (SURE) study in 14 European countries.
      ), and may improve efficacy with lower rates of side effects, may reduce lower urinary tract symptoms and has the potential for endothelial benefits (
      • Konstantinopoulos A.
      • Giannitsas K.
      • Athanasopoulos A.
      • et al.
      The impact of daily sildenafil on levels of soluble molecular markers of endothelial function in plasma in patients with erectile dysfunction.
      ). Additionally, among PDE5 inhibitor failure patients, use of a vacuum constriction device may salvage a significant percentage of men with erectile function and should be considered (
      • Canguven O.
      • Bailen J.
      • Fredriksson W.
      • et al.
      Combination of vacuum erection device and PDE5 inhibitors as salvage therapy in PDE5 inhibitor nonresponders with erectile dysfunction.
      ,
      • Pajovic B.
      • Dimitrovski A.
      • Fatic N.
      • et al.
      Vacuum erection device in treatment of organic erectile dysfunction and penile vascular differences between patients with DM type I and DM type II.
      ).
      Contraindications for the use of PDE5 inhibitors include unstable angina or untreated cardiac ischemia and concomitant use of nitrates (
      • Aversa A.
      • Bruzziches R.
      • Vitale C.
      • et al.
      Chronic sildenafil in men with diabetes and erectile dysfunction.
      ,
      • Briganti A.
      • Salonia A.
      • Gallina A.
      • et al.
      Drug Insight: Oral phosphodiesterase type 5 inhibitors for erectile dysfunction.
      ,
      • DeBusk R.
      • Drory Y.
      • Goldstein I.
      • et al.
      Management of sexual dysfunction in patients with cardiovascular disease: Recommendations of The Princeton Consensus Panel.
      ). Interestingly, men with diabetes appear to have lower rates of side effects with PDE5 inhibitors than the general population. This is believed to be a result of altered vasomotor tone or other factors (
      • Brock G.
      • Glina S.
      • Moncada I.
      • et al.
      Likelihood of tadalafil-associated adverse events in integrated multiclinical trial database: Classification tree analysis in men with erectile dysfunction.
      ).
      Referral to a specialist in ED should be offered to men who do not respond to PDE5 inhibitors or for whom the use of PDE5 inhibitors is contraindicated (see Figure 2). Second-line therapies (e.g. vacuum constriction devices [
      • Sun L.
      • Peng F.L.
      • Yu Z.L.
      • et al.
      Combined sildenafil with vacuum erection device therapy in the management of diabetic men with erectile dysfunction after failure of first-line sildenafil monotherapy.
      ], intracorporal injection therapy with prostaglandin E1 [PGE1] alone or in combination with papaverine and phentolamine [triple therapy], or intraurethral therapy using PGE1) or third-line therapy (penile prosthesis) may be considered for these men (
      • Carson C.C.
      • Mulcahy J.J.
      • Govier F.E.
      Efficacy, safety and patient satisfaction outcomes of the AMS 700CX inflatable penile prosthesis: Results of a long-term multicenter study. AMS 700CX Study Group.
      ,
      • Redrow G.P.
      • Thompson C.M.
      • Wang R.
      Treatment strategies for diabetic patients suffering from erectile dysfunction: An update.
      ).
      Figure 2
      Figure 2Management of erectile dysfunction in men with diabetes.
      PDE5, phosphodiesterase type 5.

      Ejaculatory Disorders

      Ejaculatory disorders are a common disorder of sexual function in men with diabetes, occurring in 32%–67% of that population (
      • Isidro M.L.
      Sexual dysfunction in men with type 2 diabetes.
      ,
      • Fedder J.
      • Kaspersen M.D.
      • Brandslund I.
      • et al.
      Retrograde ejaculation and sexual dysfunction in men with diabetes mellitus: A prospective, controlled study.
      ). They range in scope from retrograde ejaculation, usually secondary to autonomic neuropathy with incomplete closure of the bladder neck during ejaculation, to premature or retarded ejaculation. Their recognition as an important component in sexual quality of life makes inquiry about ejaculatory function important.

      Hypogonadism

      Hypogonadotropic hypogonadism has a reported prevalence of 30% to 40% in men with type 2 diabetes (
      • Ho C.H.
      • Jaw F.S.
      • Wu C.C.
      • et al.
      The prevalence and the risk factors of testosterone deficiency in newly diagnosed and previously known type 2 diabetic men.
      ,
      • Hackett G.
      • Kirby M.
      • Sinclair A.J.
      Testosterone deficiency, cardiac health, and older men.
      ,
      • Liu R.T.
      • Chung M.S.
      • Wang P.W.
      • et al.
      The prevalence and predictors of androgen deficiency in Taiwanese men with type 2 diabetes.
      ). One study noted a prevalence of 30% in men with prediabetes, compared to 13.6% of age-matched controls (
      • Rabijewski M.
      • Papierska L.
      • Piatkiewicz P.
      Late-onset hypogonadism among old and middle-aged males with prediabetes in Polish population.
      ). In contrast to type 2 diabetes, the prevalence of hypogonadism in men with type 1 diabetes is similar to the general male population (
      • Holt S.K.
      • Lopushnyan N.
      • Hotaling J.
      • et al.
      Prevalence of low testosterone and predisposing risk factors in men with type 1 diabetes mellitus: Findings from the DCCT/EDIC.
      ,
      • Ng Tang Fui M.
      • Hoermann R.
      • Cheung A.S.
      • et al.
      Obesity and age as dominant correlates of low testosterone in men irrespective of diabetes status.
      ). Although the pathophysiology may be related to numerous factors, including age, insulin resistance, glycemic control, concomitant sleep apnea and obesity, the most significant predictor is theorized to be the degree of central or visceral obesity (
      • Ho C.H.
      • Jaw F.S.
      • Wu C.C.
      • et al.
      The prevalence and the risk factors of testosterone deficiency in newly diagnosed and previously known type 2 diabetic men.
      ,
      • Liu R.T.
      • Chung M.S.
      • Wang P.W.
      • et al.
      The prevalence and predictors of androgen deficiency in Taiwanese men with type 2 diabetes.
      ,
      • Ng Tang Fui M.
      • Hoermann R.
      • Cheung A.S.
      • et al.
      Obesity and age as dominant correlates of low testosterone in men irrespective of diabetes status.
      ,
      • Saboor Aftab S.A.
      • Kumar S.
      • Barber T.M.
      The role of obesity and type 2 diabetes mellitus in the development of male obesity-associated secondary hypogonadism.
      ). Insulin resistance is correlated with a reduction of sex hormone-binding globulin (SHBG). Measurement of total testosterone may be affected by low SHBG levels, giving the false impression of biochemical hypogonadism when bioavailable or free testosterone levels are still normal.
      Biochemical testing should be by analysis of total testosterone levels drawn before 11 am or within 3 hours of awakening (
      • Morales A.
      • Bebb R.A.
      • Manjoo P.
      • et al.
      Diagnosis and management of testosterone deficiency syndrome in men: Clinical practice guideline.
      ). Due to the natural variability of serum testosterone levels, repeat testing is often helpful to clarify the diagnosis. In men with diabetes with symptoms of hypogonadism but with total testosterone levels still in the lower normal range, measurement of bioavailable testosterone may be helpful.
      Common symptoms of hypogonadism include fatigue, muscle weakness or muscle cramps, loss of sleep-related erections, low libido, night sweats or mood changes, such as depressive affect or irritability. A recent systematic review of male hypogonadism provides a more detailed discussion regarding diagnosis and treatment of testosterone deficiency (
      • Morales A.
      • Bebb R.A.
      • Manjoo P.
      • et al.
      Diagnosis and management of testosterone deficiency syndrome in men: Clinical practice guideline.
      ).
      Many men with type 2 diabetes and hypogonadism are asymptomatic, and treatment should be reserved for those who are biochemically hypogonadal and symptomatic. Some causes of secondary hypogonadism are potentially reversible, such as sleep apnea and obesity. Significant weight reduction is generally associated with an increase in testosterone in hypogonadal men with diabetes (
      • Grossmann M.
      Low testosterone in men with type 2 diabetes: Significance and treatment.
      ,
      • Corona G.
      • Rastrelli G.
      • Monami M.
      • et al.
      Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: A systematic review and meta-analysis.
      ). In some instances, this can restore the eugonadal state without the need for testosterone replacement (
      • Grossmann M.
      Low testosterone in men with type 2 diabetes: Significance and treatment.
      ,
      • Corona G.
      • Rastrelli G.
      • Monami M.
      • et al.
      Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: A systematic review and meta-analysis.
      ).
      Conflicting evidence suggests that testosterone therapy in hypogonadal men with type 2 diabetes may increase quality of life or improve sexual function (
      • Mazzilli R.
      • Elia J.
      • Delfino M.
      • et al.
      Prevalence of Diabetes Mellitus (DM) in a population of men affected by Erectile Dysfunction (ED).
      ,
      • Hackett G.
      • Cole N.
      • Bhartia M.
      • et al.
      Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: The BLAST study.
      ,
      • Gianatti E.J.
      • Dupuis P.
      • Hoermann R.
      • et al.
      Effect of testosterone treatment on constitutional and sexual symptoms in men with type 2 diabetes in a randomized, placebo-controlled clinical trial.
      ,
      • Hackett G.
      • Cole N.
      • Bhartia M.
      • et al.
      Testosterone replacement therapy with long-acting testosterone undecanoate improves sexual function and quality-of-life parameters vs. placebo in a population of men with type 2 diabetes.
      ,
      • Hackett G.
      • Cole N.
      • Bhartia M.
      • et al.
      The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study).
      ,
      • Brooke J.C.
      • Walter D.J.
      • Kapoor D.
      • et al.
      Testosterone deficiency and severity of erectile dysfunction are independently associated with reduced quality of life in men with type 2 diabetes.
      ). Studies assessing whether testosterone treatment in hypogonadal men with diabetes can reduce glycated hemoglobin (A1C) values have also produced mixed results (
      • Corona G.
      • Rastrelli G.
      • Monami M.
      • et al.
      Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: A systematic review and meta-analysis.
      ,
      • Hackett G.
      • Cole N.
      • Bhartia M.
      • et al.
      Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: The BLAST study.
      ,
      • Cai X.
      • Tian Y.
      • Wu T.
      • et al.
      Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials.
      ,
      • Grossmann M.
      • Hoermann R.
      • Wittert G.
      • et al.
      Effects of testosterone treatment on glucose metabolism and symptoms in men with type 2 diabetes and the metabolic syndrome: A systematic review and meta-analysis of randomized controlled clinical trials.
      ,
      • Corona G.
      • Rastrelli G.
      • Maggi M.
      Diagnosis and treatment of late-onset hypogonadism: Systematic review and meta-analysis of TRT outcomes.
      ,
      • Taylor S.R.
      • Meadowcraft L.M.
      • Williamson B.
      Prevalence, pathophysiology, and management of androgen deficiency in men with metabolic syndrome, type 2 diabetes mellitus, or both.
      ,
      • Gianatti E.J.
      • Dupuis P.
      • Hoermann R.
      • et al.
      Effect of testosterone treatment on glucose metabolism in men with type 2 diabetes: A randomized controlled trial.
      ,
      • Haider A.
      • Yassin A.
      • Doros G.
      • et al.
      Effects of long-term testosterone therapy on patients with “diabesity”: Results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes.
      ). A nonrandomized, ongoing, observational study of testosterone-treated men with hypogonadism with (40%) or without diabetes showed reductions in weight, visceral obesity, abdominal circumference, as well as decreased hypertension and insulin resistance over a 5-year study interval (
      • Haider A.
      • Saad F.
      • Doros G.
      • et al.
      Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: An observational study.
      ,
      • Saad F.
      • Yassin A.
      • Doros G.
      • et al.
      Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity classes I-III: Observational data from two registry studies.
      ).
      Hypogonadism has been associated both with risk factors of CVD, including carotid intimal medial changes in men with type 2 diabetes (
      • Farias J.M.
      • Tinetti M.
      • Khoury M.
      • et al.
      Low testosterone concentration and atherosclerotic disease markers in male patients with type 2 diabetes.
      ), and an increased risk of myocardial infarction (MI) and increased CV mortality (
      • Daka B.
      • Langer R.D.
      • Larsson C.A.
      • et al.
      Low concentrations of serum testosterone predict acute myocardial infarction in men with type 2 diabetes mellitus.
      ,
      • Muraleedharan V.
      • Jones T.H.
      Testosterone and mortality.
      ). A 3-year randomized, placebo-controlled study of testosterone use in men with hypogonadism age 60 years or older showed no significant change in either carotid artery intimal medial thickness or coronary artery calcium scores. However, only 15% of this cohort had diabetes (
      • Basaria S.
      • Harman S.M.
      • Travison T.G.
      • et al.
      Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: A randomized clinical trial.
      ). Hypogonadism also predicted an increased CV risk in men (27% of whom had type 2 diabetes) with known coronary artery disease (CAD) (
      • Chmiel A.
      • Mizia-Stec K.
      • Wierzbicka-Chmiel J.
      • et al.
      Low testosterone and sexual symptoms in men with acute coronary syndrome can be used to predict major adverse cardiovascular events during long-term follow-up.
      ). Several nonrandomized, observational studies have produced conflicting results in regards to cardiac risk vs. benefit from testosterone replacement (
      • Corona G.
      • Rastrelli G.
      • Maggi M.
      Diagnosis and treatment of late-onset hypogonadism: Systematic review and meta-analysis of TRT outcomes.
      ,
      • Muraleedharan V.
      • Jones T.H.
      Testosterone and mortality.
      ,
      • Muraleedharan V.
      • Marsh H.
      • Kapoor D.
      • et al.
      Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes.
      ).
      As men with type 2 diabetes are high risk for CV events, any positive or negative impact could, therefore, potentially have a very significant clinical impact due to the high CVD event rate in this population. Until future studies clarify the effect of testosterone on CVD, it is prudent to discuss the issue with men with diabetes prior to initiating testosterone treatment.
      To date, no large, randomized, placebo-controlled study has shown an increased risk of prostate cancer in men treated with testosterone. Monitoring for prostate cancer both prior to initiation of testosterone therapy and while on therapy is recommended.

      Evaluation of hypogonadal symptoms

      Biochemical testing is recommended in men with diabetes who are symptomatic. In the absence of symptoms of hypogonadism, biochemical testing is not indicated. OSA is very common in people with type 2 diabetes and obesity (
      • Foster G.D.
      • Sanders M.H.
      • Millman R.
      • et al.
      Obstructive sleep apnea among obese patients with type 2 diabetes.
      ). Increasing age and obesity are risk factors (
      • Foster G.D.
      • Sanders M.H.
      • Millman R.
      • et al.
      Obstructive sleep apnea among obese patients with type 2 diabetes.
      ). When hypogonadotrophic hypogonadism is diagnosed in men with type 2 diabetes, the presence of underlying OSA should be considered.

      Treatment of hypogonadism

      There is no evidence that 1 preparation of testosterone is superior to another in the relief of hypogonadal symptoms or the prevention of hypogonadism-related complications. The selection of a testosterone preparation should consider the benefits and risks of testosterone therapy in addition to patient preference. Monitoring the effects of testosterone should be done in accordance with national guidelines, such as those recommended by the Endocrine Society or the Diagnosis and management of testosterone deficiency syndrome in men: Clinical Practice Guideline (
      • Morales A.
      • Bebb R.A.
      • Manjoo P.
      • et al.
      Diagnosis and management of testosterone deficiency syndrome in men: Clinical practice guideline.
      ).
      Recommendations
      • 1.
        All adult men with diabetes should be regularly screened for ED with a sexual function history [Grade D, Consensus].
      • 2.
        A PDE5 inhibitor should be offered as first-line therapy to men with diabetes and ED in either an on-demand [Grade A, Level 1A (
        • Fonseca V.
        • Seftel A.
        • Denne J.
        • et al.
        Impact of diabetes mellitus on the severity of erectile dysfunction and response to treatment: Analysis of data from tadalafil clinical trials.
        ,
        • Rendell M.S.
        • Rajfer J.
        • Wicker P.A.
        • et al.
        Sildenafil for treatment of erectile dysfunction in men with diabetes: A randomized controlled trial.
        ,
        • Boulton A.J.
        • Selam J.L.
        • Sweeney M.
        • et al.
        Sildenafil citrate for the treatment of erectile dysfunction in men with type II diabetes mellitus.
        ,
        • Goldstein I.
        • Young J.M.
        • Fischer J.
        • 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.
        ,
        • Sáenz de Tejada I.
        • Anglin G.
        • Knight J.R.
        • et al.
        Effects of tadalafil on erectile dysfunction in men with diabetes.
        ,
        • Carson C.C.
        • Lue T.F.
        Phosphodiesterase type 5 inhibitors for erectile dysfunction.
        ,
        • Hatzichristou D.
        • Gambla M.
        • Rubio-Aurioles E.
        • et al.
        Efficacy of tadalafil once daily in men with diabetes mellitus and erectile dysfunction.
        )] or daily-use [Grade B, Level 2 (
        • Hatzichristou D.
        • Gambla M.
        • Rubio-Aurioles E.
        • et al.
        Efficacy of tadalafil once daily in men with diabetes mellitus and erectile dysfunction.
        ,
        • Buvat J.
        • van Ahlen H.
        • Schmitt H.
        • et al.
        Efficacy and safety of two dosing regimens of tadalafil and patterns of sexual activity in men with diabetes mellitus and erectile dysfunction: Scheduled use vs. on-demand regimen evaluation (SURE) study in 14 European countries.
        )] dosing regimen.
      • 3.
        Men with diabetes and ED who do not respond to PDE5 inhibitors should be investigated for hypogonadism with measurement of a morning serum total testosterone level drawn before 11 am [Grade D, Level 4 (
        • Alexopoulou O.
        • Jamart J.
        • Maiter D.
        • et al.
        Erectile dysfunction and lower androgenicity in type 1 diabetic patients.
        ,
        • Dhindsa S.
        • Prabhakar S.
        • Sethi M.
        • et al.
        Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes.
        ,
        • Boyanov M.A.
        • Boneva Z.
        • Christov V.G.
        Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency.
        ,
        • Shabsigh R.
        • Kaufman J.M.
        • Steidle C.
        • et al.
        Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone.
        )].
      • 4.
        Referral to a specialist in ED should be considered for eugonadal men who do not respond to PDE5 inhibitors or for whom the use of PDE5 inhibitors is contraindicated [Grade D, Consensus].
      • 5.
        Men with diabetes and ejaculatory dysfunction who are interested in fertility should be referred to a health-care professional experienced in the treatment of ejaculatory dysfunction [Grade D, Consensus].
      Abbreviations:
      A1C, glycated hemoglobin; CV, cardiovascular; CVD, cardiovascular disease; CAD, coronary artery disease; ED, erectile dysfunction; NO, nitrous oxide; PDE5, phosphodiesterase type 5; OSA, obstructive sleep apnea; SHBG, sex hormone-binding globulin.

      Other Relevant Guidelines

      • Cardiovascular Protection in People With Diabetes, p. S162
      • Screening for the Presence of Cardiovascular Disease, p. S170
      • Diabetes in Older People, p. S283
      Unlabelled image
      *Excluded based on: population, intervention/exposure, comparator/control or study design.
      From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097 (
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • et al.
      Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement.
      ).
      For more information, visit www.prisma-statement.org.

      Author Disclosures

      Dr. Brock reports personal fees from Lilly, Pfizer, Astellas, Ferring, Boston Scientific, and Paladin, outside the submitted work. No other author has anything to disclose.

      References

        • Maiorino M.I.
        • Bellastella G.
        • Della Volpe E.
        • et al.
        Erectile dysfunction in young men with type 1 diabetes.
        Int J Impot Res. 2017; 29: 17-22
        • Eardley I.
        • Fisher W.
        • Rosen R.C.
        • et al.
        The multinational Men's Attitudes to Life Events and Sexuality study: The influence of diabetes on self-reported erectile function, attitudes and treatment-seeking patterns in men with erectile dysfunction.
        Int J Clin Pract. 2007; 61: 1446-1453
        • Corona G.
        • Giorda C.B.
        • Cucinotta D.
        • et al.
        The SUBITO-DE study: Sexual dysfunction in newly diagnosed type 2 diabetes male patients.
        J Endocrinol Invest. 2013; 36: 864-868
        • Al-Hunayan A.
        • Al-Mutar M.
        • Kehinde E.O.
        • et al.
        The prevalence and predictors of erectile dysfunction in men with newly diagnosed with type 2 diabetes mellitus.
        BJU Int. 2007; 99: 130-134
        • Aversa A.
        • Bruzziches R.
        • Vitale C.
        • et al.
        Chronic sildenafil in men with diabetes and erectile dysfunction.
        Expert Opin Drug Metab Toxicol. 2007; 3: 451-464
        • Derosa G.
        • Romano D.
        • Tinelli C.
        • et al.
        Prevalence and associations of erectile dysfunction in a sample of Italian males with type 2 diabetes.
        Diabetes Res Clin Pract. 2015; 108: 329-335
        • Chew K.K.
        • Earle C.M.
        • Stuckey B.G.
        • et al.
        Erectile dysfunction in general medicine practice: Prevalence and clinical correlates.
        Int J Impot Res. 2000; 12: 41-45
        • Maatman T.J.
        • Montague D.K.
        • Martin L.M.
        Erectile dysfunction in men with diabetes mellitus.
        Urology. 1987; 29: 589-592
        • Rubin A.
        • Babbott D.
        Impotence and diabetes mellitus.
        J Am Med Assoc. 1958; 168: 498-500
        • Kolodny R.C.
        • Kahn C.B.
        • Goldstein H.H.
        • et al.
        Sexual dysfunction in diabetic men.
        Diabetes. 1974; 23: 306-309
        • McCulloch D.K.
        • Campbell I.W.
        • Wu F.C.
        • et al.
        The prevalence of diabetic impotence.
        Diabetologia. 1980; 18: 279-283
        • Zemel P.
        Sexual dysfunction in the diabetic patient with hypertension.
        Am J Cardiol. 1988; 61: 27h-33h
        • McCulloch D.K.
        • Young R.J.
        • Prescott R.J.
        • et al.
        The natural history of impotence in diabetic men.
        Diabetologia. 1984; 26: 437-440
        • Bacon C.G.
        • Hu F.B.
        • Giovannucci E.
        • et al.
        Association of type and duration of diabetes with erectile dysfunction in a large cohort of men.
        Diabetes Care. 2002; 25: 1458-1463
        • De Berardis G.
        • Pellegrini F.
        • Franciosi M.
        • et al.
        Identifying patients with type 2 diabetes with a higher likelihood of erectile dysfunction: The role of the interaction between clinical and psychological factors.
        J Urol. 2003; 169: 1422-1428
        • Angulo J.
        • Cuevas P.
        • Fernandez A.
        • et al.
        Enhanced thromboxane receptor-mediated responses and impaired endothelium-dependent relaxation in human corpus cavernosum from diabetic impotent men: Role of protein kinase C activity.
        J Pharmacol Exp Ther. 2006; 319: 783-789
        • Angulo J.
        • Peiro C.
        • Cuevas P.
        • et al.
        The novel antioxidant, AC3056 (2,6-di-t-butyl-4-((dimethyl-4-methoxyphenylsilyl)methyloxy)phenol), reverses erectile dysfunction in diabetic rats and improves NO-mediated responses in penile tissue from diabetic men.
        J Sex Med. 2009; 6: 373-387
        • Angulo J.
        • Gonzalez-Corrochano R.
        • Cuevas P.
        • et al.
        Diabetes exacerbates the functional deficiency of NO/cGMP pathway associated with erectile dysfunction in human corpus cavernosum and penile arteries.
        J Sex Med. 2010; 7: 758-768
        • Alexopoulou O.
        • Jamart J.
        • Maiter D.
        • et al.
        Erectile dysfunction and lower androgenicity in type 1 diabetic patients.
        Diabetes Metab. 2001; 27: 329-336
        • Naliboff B.D.
        • Rosenthal M.
        Effects of age on complications in adult onset diabetes.
        J Am Geriatr Soc. 1989; 37: 838-842
        • Feldman H.A.
        • Goldstein I.
        • Hatzichristou D.G.
        • et al.
        Impotence and its medical and psychosocial correlates: Results of the Massachusetts Male Aging Study.
        J Urol. 1994; 151: 54-61
        • Ramirez R.
        • Pedro-Botet J.
        • Garcia M.
        • et al.
        Erectile dysfunction and cardiovascular risk factors in a Mediterranean diet cohort.
        Intern Med J. 2016; 46: 52-56
        • Glavaš S.
        • Valenčić L.
        • Trbojević N.
        • et al.
        Erectile function in cardiovascular patients: Its significance and a quick assessment using a visual-scale questionnaire.
        Acta Cardiol. 2015; 70: 712-719
        • Pallangyo P.
        • Nicholaus P.
        • Kisenge P.
        • et al.
        A community-based study on prevalence and correlates of erectile dysfunction among Kinondoni District Residents, Dar es Salaam, Tanzania.
        Reprod Health. 2016; 13: 140
        • Grover S.A.
        • Lowensteyn I.
        • Kaouache M.
        • et al.
        The prevalence of erectile dysfunction in the primary care setting: Importance of risk factors for diabetes and vascular disease.
        Arch Intern Med. 2006; 166: 213-219
        • Barrett-Connor E.
        Cardiovascular risk stratification and cardiovascular risk factors associated with erectile dysfunction: Assessing cardiovascular risk in men with erectile dysfunction.
        Clin Cardiol. 2004; 27: I8-13
        • Billups K.L.
        Erectile dysfunction as an early sign of cardiovascular disease.
        Int J Impot Res. 2005; 17: S19-S24
        • Thompson I.M.
        • Tangen C.M.
        • Goodman P.J.
        • et al.
        Erectile dysfunction and subsequent cardiovascular disease.
        JAMA. 2005; 294: 2996-3002
        • Gazzaruso C.
        Erectile dysfunction and coronary atherothrombosis in diabetic patients: Pathophysiology, clinical features and treatment.
        Expert Rev Cardiovasc Ther. 2006; 4: 173-180
        • Barrett-Connor E.
        Heart disease risk factors predict erectile dysfunction 25 years later (the Rancho Bernardo Study).
        Am J Cardiol. 2005; 96: 3m-7m
        • Min J.K.
        • Williams K.A.
        • Okwuosa T.M.
        • et al.
        Prediction of coronary heart disease by erectile dysfunction in men referred for nuclear stress testing.
        Arch Intern Med. 2006; 166: 201-206
        • Chiurlia E.
        • D'Amico R.
        • Ratti C.
        • et al.
        Subclinical coronary artery atherosclerosis in patients with erectile dysfunction.
        J Am Coll Cardiol. 2005; 46: 1503-1506
        • Djordjevic D.
        • Vukovic I.
        • Milenkovic Petronic D.
        • et al.
        Erectile dysfunction as a predictor of advanced vascular age.
        Andrology. 2015; 3: 1125-1131
        • Gandaglia G.
        • Salonia A.
        • Passoni N.
        • et al.
        Erectile dysfunction as a cardiovascular risk factor in patients with diabetes.
        Endocrine. 2013; 43: 285-292
        • Araujo A.B.
        • Travison T.G.
        • Ganz P.
        • et al.
        Erectile dysfunction and mortality.
        J Sex Med. 2009; 6: 2445-2454
        • Giugliano F.
        • Maiorino M.I.
        • Bellastella G.
        • et al.
        Adherence to Mediterranean diet and erectile dysfunction in men with type 2 diabetes.
        J Sex Med. 2010; 7: 1911-1917
        • Yamada T.
        • Hara K.
        • Umematsu H.
        • et al.
        Erectile dysfunction and cardiovascular events in diabetic men: A meta-analysis of observational studies.
        PLoS ONE. 2012; 7 (e43673)
        • Klein R.
        • Klein B.E.
        • Lee K.E.
        • et al.
        Prevalence of self-reported erectile dysfunction in people with long-term IDDM.
        Diabetes Care. 1996; 19: 135-141
        • Grant P.S.
        • Lipscomb D.
        How often do we ask about erectile dysfunction in the diabetes review clinic? Development of a neuropathy screening tool.
        Acta Diabetol. 2009; 46: 285-290
        • Dhindsa S.
        • Prabhakar S.
        • Sethi M.
        • et al.
        Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes.
        J Clin Endocrinol Metab. 2004; 89: 5462-5468
        • Boyanov M.A.
        • Boneva Z.
        • Christov V.G.
        Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency.
        Aging Male. 2003; 6: 1-7
        • Shabsigh R.
        • Rajfer J.
        • Aversa A.
        • et al.
        The evolving role of testosterone in the treatment of erectile dysfunction.
        Int J Clin Pract. 2006; 60: 1087-1092
        • Shabsigh R.
        • Kaufman J.M.
        • Steidle C.
        • et al.
        Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone.
        J Urol. 2004; 172: 658-663
        • Mazzilli R.
        • Elia J.
        • Delfino M.
        • et al.
        Prevalence of Diabetes Mellitus (DM) in a population of men affected by Erectile Dysfunction (ED).
        Clin Ter. 2015; 166: e317-e320
        • El-Sakka A.I.
        • Sayed H.M.
        • Tayeb K.A.
        Androgen pattern in patients with type 2 diabetes-associated erectile dysfunction: Impact of metabolic control.
        Urology. 2009; 74: 552-559
        • Kalinchenko S.Y.
        • Kozlov G.I.
        • Gontcharov N.P.
        • et al.
        Oral testosterone undecanoate reverses erectile dysfunction associated with diabetes mellitus in patients failing on sildenafil citrate therapy alone.
        Aging Male. 2003; 6: 94-99
        • Hadeed N.N.
        • Thanoon I.A.
        • Al-Mukhtar S.B.
        Total testosterone levels and the effect of sildenafil on type 2 diabetics with erectile dysfunction.
        Oman Med J. 2014; 29: 46-50
        • Lo W.H.
        • Fu S.N.
        • Wong C.K.
        • et al.
        Prevalence, correlates, attitude and treatment seeking of erectile dysfunction among type 2 diabetic Chinese men attending primary care outpatient clinics.
        Asian J Androl. 2014; 16: 755-760
        • Rosen R.C.
        • Riley A.
        • Wagner G.
        • et al.
        The international index of erectile function (IIEF): A multidimensional scale for assessment of erectile dysfunction.
        Urology. 1997; 49: 822-830
        • Cappelleri J.C.
        • Rosen R.C.
        • Smith M.D.
        • et al.
        Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function.
        Urology. 1999; 54: 346-351
        • Ramanathan R.
        • Mulhall J.
        • Rao S.
        • et al.
        Predictive correlation between the International Index of Erectile Function (IIEF) and Sexual Health Inventory for Men (SHIM): Implications for calculating a derived SHIM for clinical use.
        J Sex Med. 2007; 4: 1336-1344
        • Valiquette L.
        • Montorsi F.
        • Auerbach S.
        First-dose success with vardenafil in men with erectile dysfunction and associated comorbidities: RELY-I.
        Int J Clin Pract. 2006; 60: 1378-1385
        • The Diabetes Control and Complications Trial Research Group
        The effect of intensive diabetes therapy on the development and progression of neuropathy.
        Ann Intern Med. 1995; 122: 561-568
        • The Diabetes Control and Complications Trial Research Group
        The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.
        N Engl J Med. 1993; 329: 977-986
        • UK Prospective Diabetes Study (UKPDS) Group
        Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
        Lancet. 1998; 352: 837-853
        • Azad N.
        • Emanuele N.V.
        • Abraira C.
        • et al.
        The effects of intensive glycemic control on neuropathy in the VA cooperative study on type II diabetes mellitus (VA CSDM).
        J Diabetes Complications. 1999; 13: 307-313
        • El-Sakka A.I.
        • Hassoba H.M.
        • Sayed H.M.
        • et al.
        Pattern of endocrinal changes in patients with sexual dysfunction.
        J Sex Med. 2005; 2: 551-558
        • Giagulli V.A.
        • Carbone M.D.
        • Ramunni M.I.
        • et al.
        Adding liraglutide to lifestyle changes, metformin and testosterone therapy boosts erectile function in diabetic obese men with overt hypogonadism.
        Andrology. 2015; 3: 1094-1103
        • Wong L.
        • Chen H.M.
        • Lai S.Q.
        • et al.
        Effects of sulfonylurea as initial treatment on testosterone of middle-aged men with type 2 diabetes: A 16-week, pilot study.
        J Diabetes Investig. 2015; 6: 454-459
        • Kostis J.B.
        • Dobrzynski J.M.
        The effect of statins on erectile dysfunction: A meta-analysis of randomized trials.
        J Sex Med. 2014; 11: 1626-1635
        • Chen Y.
        • Cui S.
        • Lin H.
        • et al.
        Losartan improves erectile dysfunction in diabetic patients: A clinical trial.
        Int J Impot Res. 2012; 24: 217-220
        • Balhara Y.P.
        • Sarkar S.
        • Gupta R.
        Phosphodiesterase-5 inhibitors for erectile dysfunction in patients with diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials.
        Indian J Endocrinol Metab. 2015; 19: 451-461
        • Walsh T.J.
        • Hotaling J.M.
        • Smith A.
        • et al.
        Men with diabetes may require more aggressive treatment for erectile dysfunction.
        Int J Impot Res. 2014; 26: 112-115
        • Santi D.
        • Granata A.R.
        • Guidi A.
        • et al.
        Six months of daily treatment with vardenafil improves parameters of endothelial inflammation and of hypogonadism in male patients with type 2 diabetes and erectile dysfunction: A randomized, double-blind, prospective trial.
        Eur J Endocrinol. 2016; 174: 513-522
        • Fonseca V.
        • Seftel A.
        • Denne J.
        • et al.
        Impact of diabetes mellitus on the severity of erectile dysfunction and response to treatment: Analysis of data from tadalafil clinical trials.
        Diabetologia. 2004; 47: 1914-1923
        • Rendell M.S.
        • Rajfer J.
        • Wicker P.A.
        • et al.
        Sildenafil for treatment of erectile dysfunction in men with diabetes: A randomized controlled trial.
        JAMA. 1999; 281: 421-426
        • Boulton A.J.
        • Selam J.L.
        • Sweeney M.
        • et al.
        Sildenafil citrate for the treatment of erectile dysfunction in men with type II diabetes mellitus.
        Diabetologia. 2001; 44: 1296-1301
        • Goldstein I.
        • Young J.M.
        • Fischer J.
        • 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: 777-783
        • Sáenz de Tejada I.
        • Anglin G.
        • Knight J.R.
        • et al.
        Effects of tadalafil on erectile dysfunction in men with diabetes.
        Diabetes Care. 2002; 25: 2159-2164
        • Carson C.C.
        • Lue T.F.
        Phosphodiesterase type 5 inhibitors for erectile dysfunction.
        BJU Int. 2005; 96: 257-280
        • Hatzichristou D.
        • Gambla M.
        • Rubio-Aurioles E.
        • et al.
        Efficacy of tadalafil once daily in men with diabetes mellitus and erectile dysfunction.
        Diabet Med. 2008; 25: 138-146
        • Buvat J.
        • van Ahlen H.
        • Schmitt H.
        • et al.
        Efficacy and safety of two dosing regimens of tadalafil and patterns of sexual activity in men with diabetes mellitus and erectile dysfunction: Scheduled use vs. on-demand regimen evaluation (SURE) study in 14 European countries.
        J Sex Med. 2006; 3: 512-520
        • Konstantinopoulos A.
        • Giannitsas K.
        • Athanasopoulos A.
        • et al.
        The impact of daily sildenafil on levels of soluble molecular markers of endothelial function in plasma in patients with erectile dysfunction.
        Expert Opin Pharmacother. 2009; 10: 155-160
        • Canguven O.
        • Bailen J.
        • Fredriksson W.
        • et al.
        Combination of vacuum erection device and PDE5 inhibitors as salvage therapy in PDE5 inhibitor nonresponders with erectile dysfunction.
        J Sex Med. 2009; 6: 2561-2567
        • Pajovic B.
        • Dimitrovski A.
        • Fatic N.
        • et al.
        Vacuum erection device in treatment of organic erectile dysfunction and penile vascular differences between patients with DM type I and DM type II.
        Aging Male. 2016; : 1-5
        • Briganti A.
        • Salonia A.
        • Gallina A.
        • et al.
        Drug Insight: Oral phosphodiesterase type 5 inhibitors for erectile dysfunction.
        Nat Clin Pract Urol. 2005; 2: 239-247
        • DeBusk R.
        • Drory Y.
        • Goldstein I.
        • et al.
        Management of sexual dysfunction in patients with cardiovascular disease: Recommendations of The Princeton Consensus Panel.
        Am J Cardiol. 2000; 86: 175-181
        • Brock G.
        • Glina S.
        • Moncada I.
        • et al.
        Likelihood of tadalafil-associated adverse events in integrated multiclinical trial database: Classification tree analysis in men with erectile dysfunction.
        Urology. 2009; 73: 756-761
        • Sun L.
        • Peng F.L.
        • Yu Z.L.
        • et al.
        Combined sildenafil with vacuum erection device therapy in the management of diabetic men with erectile dysfunction after failure of first-line sildenafil monotherapy.
        Int J Urol. 2014; 21: 1263-1267
        • Carson C.C.
        • Mulcahy J.J.
        • Govier F.E.
        Efficacy, safety and patient satisfaction outcomes of the AMS 700CX inflatable penile prosthesis: Results of a long-term multicenter study. AMS 700CX Study Group.
        J Urol. 2000; 164: 376-380
        • Redrow G.P.
        • Thompson C.M.
        • Wang R.
        Treatment strategies for diabetic patients suffering from erectile dysfunction: An update.
        Expert Opin Pharmacother. 2014; 15: 1827-1836
        • Isidro M.L.
        Sexual dysfunction in men with type 2 diabetes.
        Postgrad Med J. 2012; 88: 152-159
        • Fedder J.
        • Kaspersen M.D.
        • Brandslund I.
        • et al.
        Retrograde ejaculation and sexual dysfunction in men with diabetes mellitus: A prospective, controlled study.
        Andrology. 2013; 1: 602-606
        • Ho C.H.
        • Jaw F.S.
        • Wu C.C.
        • et al.
        The prevalence and the risk factors of testosterone deficiency in newly diagnosed and previously known type 2 diabetic men.
        J Sex Med. 2015; 12: 389-397
        • Hackett G.
        • Kirby M.
        • Sinclair A.J.
        Testosterone deficiency, cardiac health, and older men.
        Int J Endocrinol. 2014; 2014: 143763
        • Liu R.T.
        • Chung M.S.
        • Wang P.W.
        • et al.
        The prevalence and predictors of androgen deficiency in Taiwanese men with type 2 diabetes.
        Urology. 2013; 82: 124-129
        • Rabijewski M.
        • Papierska L.
        • Piatkiewicz P.
        Late-onset hypogonadism among old and middle-aged males with prediabetes in Polish population.
        Aging Male. 2015; 18: 16-21
        • Holt S.K.
        • Lopushnyan N.
        • Hotaling J.
        • et al.
        Prevalence of low testosterone and predisposing risk factors in men with type 1 diabetes mellitus: Findings from the DCCT/EDIC.
        J Clin Endocrinol Metab. 2014; 99: E1655-E1660
        • Ng Tang Fui M.
        • Hoermann R.
        • Cheung A.S.
        • et al.
        Obesity and age as dominant correlates of low testosterone in men irrespective of diabetes status.
        Andrology. 2013; 1: 906-912
        • Saboor Aftab S.A.
        • Kumar S.
        • Barber T.M.
        The role of obesity and type 2 diabetes mellitus in the development of male obesity-associated secondary hypogonadism.
        Clin Endocrinol (Oxf). 2013; 78: 330-337
        • Morales A.
        • Bebb R.A.
        • Manjoo P.
        • et al.
        Diagnosis and management of testosterone deficiency syndrome in men: Clinical practice guideline.
        CMAJ. 2015; 187: 1369-1377
        • Grossmann M.
        Low testosterone in men with type 2 diabetes: Significance and treatment.
        J Clin Endocrinol Metab. 2011; 96: 2341-2353
        • Corona G.
        • Rastrelli G.
        • Monami M.
        • et al.
        Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: A systematic review and meta-analysis.
        Eur J Endocrinol. 2013; 168: 829-843
        • Hackett G.
        • Cole N.
        • Bhartia M.
        • et al.
        Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: The BLAST study.
        J Sex Med. 2014; 11: 840-856
        • Gianatti E.J.
        • Dupuis P.
        • Hoermann R.
        • et al.
        Effect of testosterone treatment on constitutional and sexual symptoms in men with type 2 diabetes in a randomized, placebo-controlled clinical trial.
        J Clin Endocrinol Metab. 2014; 99: 3821-3828
        • Hackett G.
        • Cole N.
        • Bhartia M.
        • et al.
        Testosterone replacement therapy with long-acting testosterone undecanoate improves sexual function and quality-of-life parameters vs. placebo in a population of men with type 2 diabetes.
        J Sex Med. 2013; 10: 1612-1627
        • Hackett G.
        • Cole N.
        • Bhartia M.
        • et al.
        The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study).
        Int J Clin Pract. 2014; 68: 203-215
        • Brooke J.C.
        • Walter D.J.
        • Kapoor D.
        • et al.
        Testosterone deficiency and severity of erectile dysfunction are independently associated with reduced quality of life in men with type 2 diabetes.
        Andrology. 2014; 2: 205-211
        • Cai X.
        • Tian Y.
        • Wu T.
        • et al.
        Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials.
        Asian J Androl. 2014; 16: 146-152
        • Grossmann M.
        • Hoermann R.
        • Wittert G.
        • et al.
        Effects of testosterone treatment on glucose metabolism and symptoms in men with type 2 diabetes and the metabolic syndrome: A systematic review and meta-analysis of randomized controlled clinical trials.
        Clin Endocrinol (Oxf). 2015; 83: 344-351
        • Corona G.
        • Rastrelli G.
        • Maggi M.
        Diagnosis and treatment of late-onset hypogonadism: Systematic review and meta-analysis of TRT outcomes.
        Best Pract Res Clin Endocrinol Metab. 2013; 27: 557-579
        • Taylor S.R.
        • Meadowcraft L.M.
        • Williamson B.
        Prevalence, pathophysiology, and management of androgen deficiency in men with metabolic syndrome, type 2 diabetes mellitus, or both.
        Pharmacotherapy. 2015; 35: 780-792
        • Gianatti E.J.
        • Dupuis P.
        • Hoermann R.
        • et al.
        Effect of testosterone treatment on glucose metabolism in men with type 2 diabetes: A randomized controlled trial.
        Diabetes Care. 2014; 37: 2098-2107
        • Haider A.
        • Yassin A.
        • Doros G.
        • et al.
        Effects of long-term testosterone therapy on patients with “diabesity”: Results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes.
        Int J Endocrinol. 2014; 2014: 683515
        • Haider A.
        • Saad F.
        • Doros G.
        • et al.
        Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: An observational study.
        Obes Res Clin Pract. 2014; 8: e339-e349
        • Saad F.
        • Yassin A.
        • Doros G.
        • et al.
        Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity classes I-III: Observational data from two registry studies.
        Int J Obes. 2016; 40: 162-170
        • Farias J.M.
        • Tinetti M.
        • Khoury M.
        • et al.
        Low testosterone concentration and atherosclerotic disease markers in male patients with type 2 diabetes.
        J Clin Endocrinol Metab. 2014; 99: 4698-4703
        • Daka B.
        • Langer R.D.
        • Larsson C.A.
        • et al.
        Low concentrations of serum testosterone predict acute myocardial infarction in men with type 2 diabetes mellitus.
        BMC Endocr Disord. 2015; 15
        • Muraleedharan V.
        • Jones T.H.
        Testosterone and mortality.
        Clin Endocrinol (Oxf). 2014; 81: 477-487
        • Basaria S.
        • Harman S.M.
        • Travison T.G.
        • et al.
        Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: A randomized clinical trial.
        JAMA. 2015; 314: 570-581
        • Chmiel A.
        • Mizia-Stec K.
        • Wierzbicka-Chmiel J.
        • et al.
        Low testosterone and sexual symptoms in men with acute coronary syndrome can be used to predict major adverse cardiovascular events during long-term follow-up.
        Andrology. 2015; 3: 1113-1118
        • Muraleedharan V.
        • Marsh H.
        • Kapoor D.
        • et al.
        Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes.
        Eur J Endocrinol. 2013; 169: 725-733
        • Foster G.D.
        • Sanders M.H.
        • Millman R.
        • et al.
        Obstructive sleep apnea among obese patients with type 2 diabetes.
        Diabetes Care. 2009; 32: 1017-1019
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • et al.
        Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement.
        PLoS Med. 2009; 6: e1000097