The comments were collated and, together with the recommendations and evidence for the recommendations, were presented at a second all-day meeting for additional review and comments. The task force used an evidence-based approach to acknowledge limitations in the published literature before generating recommendations. We were permitted to include relevant studies published after the search period, while the guideline document was under editorial assessment and in response to peer reviewers’ comments. Reports from meta-analyses, practice guidelines, clinical conferences and major reviews were also examined, and papers were manually searched for additional references. The task force met to identify guideline sections and writing responsibilities, in accordance with their clinical or laboratory knowledge, practice and expertise. Incorporating regenerative therapies in the management of erectile dysfunction and Peyronie’s disease But some medications can have side effects that can cause sexual problems. But shifts in sexual attitudes and risk-taking also can be common signs of bipolar disorder. Knowing how to spot key symptoms and side effects will allow you to work with your doctor to find ways to improve your sexual health. As to ACTH-MSH peptides, several potent analogues that induce penile erection in men are available, but further clinical trials are necessary with these and other analogues to ascertain the absence of severe collateral effects (e.g., priapism) 200,201. In fact, these compounds represent an alternative to apomorphine to be tested in clinical studies for ED. A larger pre-treatment prostate volume was a predictive factor of improvement in LUTS. However, while exogenous testosterone has a beneficial effect on the clinical symptoms of hypogonadism, it inhibits gonadotropin secretion by the pituitary gland, resulting in impaired spermatogenesis and sperm cell maturation . The evidence published so far is poor; all these products are off-label treatments and SERMs, due to their agonistic effect on venous vessels, could predispose men to the development of venous thromboembolism 22,123. Blood collection is best taken at two to four hours after gel application to use the peak level of testosterone absorbed as a reference for adequate therapeutic levels. Local skin adverse effects are limited when compared to those with traditional testosterone patches, but they potentially allow transference of testosterone during close contact with the skin surface. Be mindful of the still possible risks of testosterone replacement therapy Many testosterone formulations are available (Table 459,60 ), and no formulation has superior clinical effects. Development of polycythemia during treatment should lead to cessation of therapy, lowering of the dose, or switching to a lower-risk formulation to avoid increased risk of myocardial infarction, stroke, and venous thromboembolism. Use of supplemental testosterone has been shown to cause a small increase in prostate-specific antigen (PSA) levels,52 but the significance of this increase is questionable. Common side effects included gastrointestinal reactions (nausea, diarrhoea), which occurred at significantly higher rates in the oral TRT group. JATENZO led to statistically significant improvement in sexual and mood symptoms (measured usign the PDQ), comparable to topical TRT. Newer testosterone formulations based on SEDDS bypass the need for high-fat-content meals. TU is partially metabolized in the intestinal wall, absorbed through intestinal lymphatics and converted primarily to 5-dihydro-testosterone. It is crucial to understand that testosterone replacement therapy is designed to restore testosterone levels to a normal range, not to increase them beyond what is considered healthy. TRT is a medical treatment that aims to restore testosterone levels in men who have been diagnosed with low testosterone, also known as hypogonadism. Without adequate testosterone, a man may lose their sex drive, experience erectile dysfunction, feel depressed, have a decreased sense of well-being, fatigue, and have difficulty concentrating. Part of this effort includes the availability of serum-based reference material from pooled sera available from the National Institute for Standards and Technology for testosterone and a hormone standardization program using liquid chromatography/mass spectrometry (LCMS) offered by CDC. The differences in testosterone methodologies have led to considerable effort by a variety of parties including the Centers for Disease Control (CDC) and the College of American Pathologists towards harmonization of assays. It is bound to albumin (50%, loosely-bound), sex hormone-binding globulin (SHBG, 44%, tightly-bound), corticotropin-binding globulin (4%, loosely-bound), and approximately 2% circulates as free testosterone.9 The free and loosely-bound testosterone fractions combined are known as bioavailable testosterone.Testosterone assays are plagued by variability in results. Across the prevalence literature, the cut-off values used to define low testosterone vary widely, heterogeneity exists in the populations studied, the forms of testosterone used to measure testosterone (total and/or free) are not consistent, and the assays utilized to measure testosterone differ. The prevalence of testosterone deficiency in the American male population is difficult to quantify. Modern day, we have several new, exciting, experimental things, such as shockwave therapy of the penis or platelet-rich plasma or stem cell therapy.Testosterone is a hormone produced by the testicles and is responsible for the proper development of male sexual characteristics.Since 2008, there has only been one study that addressed elevated hemoglobin and hematocrit in patients receiving TRT.TU is partially metabolized in the intestinal wall, absorbed through intestinal lymphatics and converted primarily to 5-dihydro-testosterone.According to Harvard Special Health Report Erectile Dysfunction, one study in the European Heart Journal looked at men newly diagnosed with heart disease, but without ED, who started treatment with the beta-blocker atenolol (Tenormin)."Your doctor should also review any other factors that might influence levels, like medication or medical conditions," says Dr. Hayes.In women, testosterone is produced by the ovaries and adrenal glands, and by conversion of proandrogens in peripheral tissues.The aim of pharmacological management of hypogonadism is to increase testosterone levels to normal levels which resolve or improve symptoms of hypogonadism. In men aged 65 years and older, the relative risks (RR) were 2.19 (95% CI 1.27–3.77) for those who received TRT and 1.15 (95% CI 0.83–1.59) for men who received PDE5I. In addition, subject selection was based solely upon T values, rather than in combination with defined clinical symptoms of TD. The predominant criticism of this study was that there was a high prevalence of hypertension, diabetes, hyperlipidemia, obesity, and metabolic syndrome among the participants, with a substantially advanced age. The Testosterone in Older Men (TOM) trial, a double-blind randomized-controlled trial of 209 men of mean age 74 years, was performed to assess the effects of TRT in men with low serum T and limited mobility Basaria et al. 2010. This study then evaluated the effect of TRT on mortality in men in the low T group that was divided into men who did and did not receive TRT. Excluded studies Given the off-label use of these medications, we suggest discussing risks and benefits with the substitute decision maker, with clear documentation. Given possible side effects of these medications, collaboration with a geriatric psychiatrist on management could be useful. If this is the case, consider initiating combination therapy with a safer first-line therapy, with the antipsychotic as a temporary bridge. There is no strong evidence to counter the assumption that these temporal and subjective criteria also apply to men with other sexual orientations or to other sexual situations and activities, e.g., MSM, anal intercourse, oral sex, and masturbation. To qualify as a dysfunction, the patient must not desire delay of ejaculation and he must experience personal distress. In 2010, the 3rd International Consultation on Sexual Dysfunction defined DE as the persistent or recurrent difficulty, delay in, or absence of attaining orgasm after sufficient sexual stimulation, which causes personal distress. Notably, the subgroup analysis exclusively for RCTs published after 2010 demonstrated a significant enhancement in erectile function with TRT (Supplementary Figure 1). In all 28 RCTs, patients were subjected to vigilant and regular monitoring, with a protocol in place to cease treatment promptly upon the detection of signs indicative of prostate cancer or other serious complications. Two researchers extracted data independently such as first author, year, country, therapy, participants, duration, administration, method, characteristics of patients and dosage. Subjects included in this study were screened for medications that affected bone and prostate cancer, but not cardiovascular risks, however the general health of study participants was not reported . As early epidemiological studies suggested that declining function in older men is related to levels of bioavailable testosterone 7, 8, an intervention to improve the health span of older men was proposed in the form of testosterone replacement therapy. The use of testosterone therapy has the potential to increase the risks for developing prostate cancer and or accelerating its progression. This guideline is largely in agreement with the Endocrine Society’s clinical practice guideline on testosterone therapy in men with androgen deficiency syndromes published in 2010,2 which was a thorough, evidence-based assessment using the GRADE system to define the quality of the evidence and the strength of the recommendations. The association between plant-based diet and erectile dysfunction in Chinese men. Santella C, Renoux C, Yin H, Yu OHY, Azoulay L. Testosterone replacement therapy and the risk of prostate cancer in men with late-onset hypogonadism. Saad F, Aversa A, Isidori AM, Zafalon L, Zitzmann M, Gooren L. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Men with ED who also test low for testosterone may be offered a hormone boost, frequently in the form of a rub-on gel applied daily, in addition to an ED drug. But like testosterone, they don't work for about 30% of men who try one. That's because they tend to work more reliably than testosterone, and the response is usually quicker. Also, men with low testosterone and symptoms may experience extra benefits of testosterone replacement, such as more "pep" and more desire for sex in the first place. Based on unique chemistry using a self-emulsifying drug delivery system and lymphatic absorption, JATENZO and TLANDO address some of the limitations of other dosing routes while providing a safe option without evidence of liver dysfunction. A positive family history of venous-thromboembolism should be carefully investigated and the patient counselled with regard to testosterone therapy to avoid/prevent thrombophilia-hypofibrinolysis . Hence, DRE is mandatory in all men at baseline and is recommended to be performed at least annually during testosterone therapy, as long as there is no significant increase in PSA velocity. The correct timing for evaluation of testosterone levels varies according to the type of preparation used (Table 3.5). Two recent reviews on these studies identified nine trials with published results for a total of less than 100 patients included for ED treatment in Phase I and Phase II, and with follow-up periods from 6 to 62 months. Although numerous basic studies are available in rodent models of ED, which support an improving effect of stem cell treatments on ED, very few clinical trials in men are present in the available literature. These treatments aim to find a reliable and long-lasting cure of ED with the recovery of physiological functions by reducing/eliminating the causes underlying the dysfunction rather than providing a symptomatic treatment on demand. This requires the identification of the main cause of the dysfunction, leading to the search of “restorative/regenerative” strategies of erectile function, which vary depending on the main cause(s) of the dysfunction. Yassin 2014 published data only The observed heterogeneity was explained in the predefined sensitivity analysis that excluded studies at high risk of bias. Gilbert 1992 used a sexual questionnaire, and Aydin 1996 did not report measurement tools for erectile function. While Lincoff 2023 used IIEF‐5, we were also unable to use the data for meta‐analysis as the study was nested within the parent trial (inclusion of men with low libido only). The current guideline only included studies in the meta-analysis that used morning total testosterone 411 Meta-analyses of RCTs and cohort studies provide the highest levels of evidence and reliability, followed by individual RCTs, prospective cohorts, retrospective cohorts, and observational studies. To accurately interpret the published testosterone literature, it is important to critically evaluate various aspects of study design, including the population evaluated, study inclusion/exclusion criteria, duration of follow-up, primary endpoints, adverse event reporting, statistical reporting, and clinical relevance of findings. As already recalled, the pro-erectile effect of dopamine agonists is mediated by the stimulation of dopamine receptors of the D2 family located mainly in the PVN, MPOA and nucleus accumbens. Dopamine receptor agonists, excitatory amino acid receptor agonists and oxytocin may also facilitate penile erection and sexual behavior by acting in other brain areas 20,21,22,23,30. As several neurotransmitters and neuropeptides facilitate or inhibit penile erection by activating or inhibiting this oxytocinergic pathway at the PVN level, receptors of these neuromodulators may all be considered targets for ED therapy by centrally acting drugs 21,22,23,30. When activated by neurotransmitters, such dopamine, excitatory amino acids, NO, oxytocin, hexarelin peptide analogues, VGF peptides or by the blockade of CB1 receptors in the PVN, they facilitate penile erection, while when inhibited, for instance by gamma-aminobutyric acid (GABA), opioid peptides and endocannabinoids, this sexual response is reduced. Penile prosthesis has the certain advantage of simulating the natural erection process against the mechanical manual procedures required for the use of vacuum devices (which cause numerous dropouts in the users), but is an irreversible and much more expensive treatment and requires more cautions for its use compared to vacuum devices. Many other studies are required to realize standard protocols and the dosage of cells to be injected and to identify the type of stem cell to be used with ED of different etiology. From what has been discussed above, it is evident that pharmacological strategies aimed at overcoming PDe5 inhibitors’ therapy and their failures have produced very little progress for the therapy of ED so far. Individual pellets consist of 75 mg of testosterone and may be combined to deliver variable doses of testosterone therapy. Men with total testosterone level 315 ng/dL declined from 100% at 4 weeks to 86%, 75%, and 14% by 12, 20, and 24 weeks, respectively.Mean peak total testosterone levels are dose-dependent, with a mean of 746, 866, and 913 ng/dL noted with 8, 10, and 12 pellets administered (not BMI adjusted).446 The duration of effect is similar, however, and is relatively independent of dosing. Administration of 750 mg of IM testosterone undecanoate at weeks 0, 4, and every 10 weeks thereafter maintained total testosterone levels between 300-1,000 ng/dL for 94% of men.438 No men experienced maximal values Adverse Effects. A common cause of disruption in ejaculation or orgasm is failure of the earlier elements of sexual response (e.g., lack of sexual desire and/or ED leading to inadequate genital and subjective excitement). Variations in androgen receptor function (e.g., number of CAG repeats), intracellular trafficking of T bound to the androgen receptor, and the balance among modulators of T receptors determine the final action of T within target tissues. Orgasm is typically experienced at peak sexual arousal and is followed in men by a refractory period during which arousal and sexual climax are not possible.19 The duration of the refractory period tends to become longer with increasing age. Ejaculation is triggered by integration of tactile (e.g., sensation from genital or other peripheral nerves) and non-tactile (e.g., sexually arousing audio and visual inputs) stimuli in the brain. The first of these is orgasm, a sensation of intense pleasure, relaxation, or intimacy that accompanies peak sexual arousal. In the short term, testosterone, when compared to a placebo, shows minor changes in erectile function, sexual quality of life, and cardiovascular mortality.The main causes suggested for functional hypogonadism are obesity, comorbidities and ageing, with the first two accounting for most cases.In addition, more intensive monitoring of PSA while taking testosterone might detect more prostate cancer.The ultimate goal is to improve functional outcomes for men while preventing disease progression and increasing opportunities for therapy.Behavioral or psychological treatment requires an investment in time, typically at least 5-10 sessions, and may not be covered by insurance carriers.Erectile dysfunction drugs, which work by dilating blood vessels to allow more blood to flow through, were first developed to treat high blood pressure.To find out, a team of researchers based at Boston University Medical School conducted a study involving 140 men with low testosterone.In these instances, your doctor may treat the underlying condition or change your medication or dosage to one that would not affect testosterone levels. While all products contain the same medication (testosterone), each product and modality has distinct pharmacokinetic and application attributes based on the excipient agents and the permeator components. The testosterone therapeutic space is relatively unique. Where gaps in the evidence existed, the Panel provides guidance in the form of Clinical Principles or Expert Opinion with consensus achieved using a modified Delphi technique if differences of opinion emerged. Moderate Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is moderate. Strong Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is substantial. By definition, Grade A evidence is evidence about which the Panel has a high level of certainty, Grade B evidence is evidence about which the Panel has a moderate level of certainty, and Grade C evidence is evidence about which the Panel has a low level of certainty. Alternative testosterone therapies included SERMs, hCG, and AIs. The use of vacuum erection devices in the conditions recalled above are supported by studies in animal (rat) models of ED 239,240 and clinical studies in human penile (cavernous and vascular) tissues aimed at characterizing the main effects of the use of the device on physiological markers of erectile function. Since then, a large amount of preclinical studies supporting the main role of oxytocin in erectile function and sexual behavior has appeared and has continued to appear. Despite numerous studies supporting the role of the RhoA/Rho kinase system in improving erectile function in pathological conditions, such as diabetes, hypertension and hypercholesterolemia , and the improving effects of alternative herbal medicine, likely mediated, at least in part, by compounds that inhibit the RhoA/Rho kinase system , no drug capable of inhibiting this system is currently under investigation for ED therapy. A study reported at the 2015 American Heart Association Scientific Sessions involved 1,472 men ages 52 to 63 with low testosterone levels and no history of heart disease. 5.9. Summary of evidence and recommendations on safety and monitoring in testosterone treatment The available evidence indicates that TRT is largely considered to be safe in most men, with a small inherent risk of adverse events in selected high-risk populations of men with multiple medical comorbidities. To date, there are no other long-term studies that have adequately evaluated the potential risk of erythrocytosis from TRT. There were no ‘serious’ patient-centered adverse events (e.g. cerebrovascular accident, vascular occlusive events, venous thromboembolisms) reported during the study period of 36 months Maggio et al. 2013. Since 2008, there has only been one study that addressed elevated hemoglobin and hematocrit in patients receiving TRT. Adverse effects of the intervention Clomiphene has successfully been used in men for treatment of hypogonadism for up to 7 years with no major adverse effects48; however, prior systematic reviews suggested a potential correlation with thrombosis and ocular symptoms due to central retinal vein occlusion (CRVO).49,50 CAC testing should also be considered if additional atherosclerotic cardiovascular disease (ASCVD) risk factors are identified. Reported doses commonly range between 500 and 1000 mg of testosterone per week,7 which is 5–10 times the accepted treatment dose for male hypogonadism.28 There remain little data on TRT relating to long-term OSA outcomes; however, current evidence suggests TRT may transiently worsen objective OSA parameters then resolve. The European Male Aging Study (EMAS)8 studied 3,369 men (mean age 59 years) and culled data on their sexual, physical, and psychological symptoms along with morning total testosterone measurements. A challenge in making the diagnosis of testosterone deficiency is that many of the symptoms reported by patients are non-specific and might be related to conditions other than low testosterone. Total testosterone absence of signs and/or symptoms increases the likelihood of making a false diagnosis and reduces the potential benefit of testosterone therapy. To minimize these effects, two morning draws for testosterone are recommended before any clinical intervention. Acute illnesses should be considered when measuring testosterone levels, the presence of which can affect the accuracy of the test and lead to artificially decreased testosterone measurements. This medicine does not protect you against sexually transmitted diseases (including HIV or AIDS). This condition may require prompt medical treatment to prevent serious and permanent damage to your penis. If you take too much sildenafil or take it together with these medicines, the chance for side effects will be higher. The dose of this medicine will be different for different patients. MAPK/ERK signaling is involved in several important functions in the brain including neurogenesis, differentiation, synaptic plasticity, memory formation, and cell survival (62–65). The data presented here are among the first highlighting the potential efficacy of SARMs for neural endpoints. For example, unlike testosterone, nonsteroidal SARMs are not substrates for aromatase and 5α-reductase and thus do not yield potent estrogen and androgen metabolites (35, 52). ED is a very common condition, especially in men with cardiovascular damage. There are also studies emphasizing the association between CVD and ED 60–62. These diseases share some common biological pathways, and apolipoprotein E is a major risk factor for AD. Coronary artery bypass grafting and transplant surgery, also appear to increase the risk of AD. Research has also shown that high blood pressure, hyperlipidemia, hyperhomocysteinemia and smoking are potentially important risk factors for AD . Several self-reported questionnaires or structural interviews have been developed for screening of hypogonadism. These symptoms are non-specific and need to be recorded and taken in context with the clinical and biochemical state. The main causes suggested for functional hypogonadism are obesity, comorbidities and ageing, with the first two accounting for most cases. So far, the only drugs targeting the central nervous system that have been used for the ED treatment in men are apomorphine (see ), the α2-adrenoceptor antagonists yohimbine and delequamine 113,114,115, the α-melanocyte-stimulating hormone (α-MSH) receptor agonist melanotan II and the serotonin reuptake inhibitor trazodone 117,118. The facilitation of penile erection by drugs acting at the central level is a possible and fascinating, although it is a very complicated strategy for the ED treatment. Prostaglandin E1 activates the AC/cAMP pathway, thus increasing cAMP levels, which activates protein kinase A, facilitating Ca2+ mobilization from intracellular stores and the relaxation of cavernous smooth muscles . Prostaglandins exert numerous effects on cavernous smooth muscles, depending on the type of prostaglandin. Similar results are obtained with other α1-adrenergic receptor antagonists, such as phenoxybenzamine and moxisylite , but phentolamine is the only α1-adrenergic receptor antagonist used in the intracavernous therapy of ED, usually in combination with other drugs (i.e., prostaglandin E1, alprostadil and/or papaverine) (see below). There is limited evidence to suggest that combination of life-style interventions and testosterone therapy in symptomatic hypogonadal men might result in better outcomes .Adverse effects specific to topical preparations include application site reactions (3-16% erythema or rash), and risk of transference.The risk was even higher when a haematocrit threshold of 54% was considered whilst no risk was observed when a 50% threshold was applied .If you have bipolar disorder and notice changes in your sexual health, you're not alone.While including many of the same RCTs, our review differs in the inclusion only of those studies in which participants presented with a baseline complaint of sexual dysfunction (although they may also have had other complaints). Combined therapy with Continuous Positive Airway Pressure (CPAP) and testosterone gel was more effective than CPAP alone in the treatment of obstructive sleep apnoea . With testosterone therapy an elevated haematocrit is more likely to occur if the baseline level is toward the upper limit of normal prior to initiation. Any elevation above the normal range for haematocrit usually becomes evident between three and twelve months after testosterone therapy initiation. An elevated haematocrit is the most common adverse effect of testosterone therapy. Management of cardiovascular risk factors is recommended in men who have ED but no known CVD.49,50 Because diagnosing ED can help identify men at higher risk of CVD, use of the IIEF-5 is also recommended during CVD risk assessment. In this regard, SARMs like RAD140 can be better alternatives to T because they are only partial agonists or antagonists to androgenic regulation of prostate while still having androgenic effects on other tissues such as muscle and brain. The promise of selective androgen treatment has been realized in animal models, with SARMs shown to promote muscle and bone health in the absence of prostate growth (33, 52, 54, 55). RAD140 treatment resulted in a nonsignificant increase in the weights of seminal vesicles and prostate, which were still significantly lower than weights observed in the sham-GDX and GDX+T groups. The prevalence of symptoms consistent with DE increase at progressively lower serum T levels.232 Given the relationship between many domains of male sexual function and serum T concentration, the Panel supports morning T testing as recommended by the AUA Guideline on the Management of Testosterone Deficiency.233 Clinicians should counsel men considering surgical treatment for PE that there is a paucity of data concerning circumcision with or without dorsal penile neurectomy or HA injection; the risks and benefits of dorsal penile neurectomy and HA injection are not known; and there may be as yet undefined chronic disabilities resulting from dorsal penile neurectomy or HA injection. These medical agents are discussed in more detail in the Future Directions section as they may have utility for medical practitioners caring for PE patients pending further clinical study. Some studies have shown that men with moderate chronic cardiac failure may benefit from low doses of testosterone, which achieve mid-normal range testosterone levels 165,179,180. The findings could be considered sufficiently reliable for at least a three-year course of testosterone therapy, after which no available study can exclude further or long-term CV events 177,178. The results showed that testosterone therapy was noninferior to placebo with respect to the incidence of MACE. Clinical trials of dapoxetine have included men with PE and mild ED per international index of erectile function (IIEF) criteria. ED pharmacotherapy alone or in combination with PE pharmacotherapy may be considered for the treatment of lifelong and acquired PE in men with co-morbid ED. Invasive therapies (e.g., intracavernous injection, prosthesis placement) are appropriate for properly-counselled patients with ED not responsive to other therapies but should not be considered standard of care in patients whose principle concern is PE and in patients with PE and ED who are satisfied with non-invasive ED treatments. Providers should strive to limit the number of pharmaceutical interventions required to optimize sexual function. However, a more nuanced and clinically appropriate strategy is to determine primacy of incidence and bother for both ED and PE and to treat according to which condition is most sexually disabling and/or primary. Corona G, Bianchini S, Sforza A, Vignozzi L, Maggi M. Hypogonadism as a possible link between metabolic diseases and erectile dysfunction in aging men. In this meta-analysis of RCTs, TRT could improve the erectile function of hypogonadal men. Additionally, differences in the measurements of testosterone levels contributed to potential heterogeneity in the results. This results could provide more evidence for the clinical utilization of TRT for treating LOH and guiding the dietary recommendations for LOH patients. However, a meta-analysis reported that TRT had no effect on the cardiovascular events (64). In addition, although subjects with cardiovascular risks such as unstable angina and uncontrolled hypertension, as well as diseases such as heart failure or myocardial infarction, were excluded, the study did not provide information on the health of the enrolled subjects. These findings were in line with an earlier 3-year study by Snyder and colleagues that demonstrated a significant increase in lean mass and a decrease in fat mass in 54 men with baseline levels of serum testosterone below 350 ng/dL treated with 144 mg/day testosterone delivered in the form of a scrotal patch . Although the study screened subjects and excluded those with major cardiovascular and other risk factors, the health of the recruited subjects was not described. In the study by Srinivas-Shankar et al., 138 older community-dwelling intermediate-frail and frail men over 65 years of age received testosterone treatment in the form of a transdermal patch at a dose of 50 mg/day for 6 months . Meanwhile, the prevalence of hypogonadism, defined by early morning serum testosterone levels below 280 ng/dL, in older men over 65 years of age is approximately 16–18% 17, 18. It is approved in some countries for treatment of testosterone deficiency but is not currently approved in the US. Methyltestosterone is an oral androgen modified at the 17-alpha position resulting in decreased first pass hepatic clearance and is approved in the US for treatment of testosterone deficiency. A larger study that examined the contraceptive efficacy of testosterone-induced azoospermia in men was conducted by the WHO Task Force on Methods for the Regulation of Male Fertility.385 A total of 271 healthy, fertile men across 7 countries were given 200 mg IM testosterone enanthate every week for 12 months. Testosterone patches consist of a mixture of testosterone, penetration agents, and a gelatinous matrix separated from the skin by a microporous membrane. Liquids and gels should be applied to clean, dry skin, and the treatment site should not be washed until the time of next application to optimize delivery. In analyzing the literature, it is imperative to determine whether or not statistically significant results are clinically meaningful. Beyond statistical significance, clinical relevance is another key factor. One important aspect of study design is the specific endpoints and objective measures used to identify outcomes. Similar increases in hematocrit and hemoglobin might occur with TRT, which is more pronounced with a high dose of testosterone . If a male subject has recently suffered from heart disease, he is recommended to withhold male hormone-replacement therapy . Cardiovascular adverse events were first mentioned in a study by Vigen et al . They also reported that the changes in PV after 12 months were likely related to aging rather than testosterone therapy.One trial with three years of follow-up showed near linear, time-dependent improvements in BMD.202 These findings are similar to other prospective, controlled data, which report an estimated 5% per year increase in BMD in men on testosterone therapy.309 Declining bone density may necessitate additional medical intervention, such as weight bearing exercise, calcium, vitamin D, or bisphosphonate medications.Venous drainage of the erectile bodies occurs via postcavernous venules that coalesce to form large emissary veins that pierce the tunica albuginea before draining into the deep dorsal vein.3Another meta-analysis also demonstrated that TRT has no significant effect on cardiovascular events, but TRT would result in an increase in hemoglobin and hematocrit and a decrease in HDL cholesterol (65).Additionally, some of the studies that were included in the qualitative analysis did not report any primary outcomes.Outcome of therapy with long-acting TU in men with type 2 diabetes and hypogonadism (Birmingham, Lichfield, Atherstone, Sutton and Tamworth, BLAST) Hackett et al. 2014. The IIEF is designed to be a self-administered measure of erectile dysfunction, but it also assesses a patient's function in other phases of sexual function. Once a concern with the patient's sexual function is identified, the next step is to differentiate erectile dysfunction from other sexual problems, such as loss of libido or ejaculatory problems. Aging is an independent risk factor, and although the incidence of erectile dysfunction increases steadily with age, it is not an inevitable consequence of aging. Most causes of erectile dysfunction were once considered to be psychogenic, but current evidence suggests that up to 80 percent of cases have an organic cause.1 Organic causes are subdivided into vasculogenic, neurogenic and hormonal etiologies. The presence of ASCVD risk factors is not a contraindication to starting testosterone therapy; however, the optimization of modifiable risk factors in such patients using lifestyle and medical management strategies is recommended and may be best addressed by the patient's primary care provider. Patients with testosterone deficiency who maintain testosterone levels in the normal range while on testosterone therapy should have their PSA levels tested, utilizing a shared decision-making approach, in accordance with the AUA's Early Detection of Prostate Cancer Guideline. If SHBG levels are low/free testosterone levels are high, dose adjustment of the testosterone therapy should be considered. Longitudinal population studies have reported that men with testosterone in the upper quartile of the normal range have a reduced number of CV events compared to men with testosterone in the lower three quartiles . Limited data are available in the literature, with most case series not providing sufficient data to draw definitive conclusions (e.g., insufficient follow-up, small samples, lack of control arms, heterogeneity in study population and treatment regimen, etc.) . Meta-analyses have not found significant changes in LUTS between patients treated with testosterone or placebo . Likewise, while some literature suggests that food ingestion might affect testosterone levels, the evidence is particularly weak, and the Panel does not recommend that clinicians insist on fasting prior to testing.Circadian Rhythm. One strategy is to further evaluate patients using adjunctive tests, which might strengthen an argument for a short-term trial of testosterone therapy. However, as the testosterone literature uses absolute values to define low testosterone, the absolute value is ultimately the most important factor to determine whether patients may expect to achieve benefits with testosterone therapy. A review by Millar et al.4 searched MEDLINE and Embase databases from January 1966 to July 2014 for studies that compared clinical indication of low testosterone along with a measurement of serum testosterone in men. For example, a particular study might show that testosterone therapy is correlated with a statistically significant improvement in the IIEF scores in a given population; however, the clinician may not feel that this has any clinical meaning for the patient in terms of his QoL or sexual function. At the end of the study, serum testosterone levels rose in those men receiving testosterone therapy; however, no rise in testosterone levels were seen within the prostate tissue itself. It is the opinion of this Panel that until there is definitive evidence demonstrating that testosterone therapy is not safe for use in prostate cancer patients, the decision to commence testosterone therapy in men with a history of prostate cancer is a negotiated decision based on the perceived potential benefit of treatment. While the FDA retains a warning regarding the potential risk of prostate cancer in patients who are prescribed testosterone products ("patients treated with androgens may be at increased risk for prostate cancer"), there is accumulating evidence against a link between testosterone therapy and prostate cancer development. Secondary hypogonadism is characterised by low or inappropriately normal gonadotropin levels; therefore, the rationale is to substitute the gonadotropin deficiency with simultaneously FSH and LH analogues, if fertility is desired . A positive family history for venous thromboembolism requires further analysis to exclude a condition of undiagnosed thrombophilia-hypofibrinolysis . Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) represents the most accurate method for sex steroid evaluation; however, standardised automated platform immuno-assays for total testosterone assessment demonstrate a good correlation with LC-MS/MS . Testosterone levels are produced in a circadian variation, which may persist in ageing men 63,64. Testicular and penile size, as well the presence of sexual secondary characteristics can provide useful information regarding overall androgen status. The long-term effectiveness of testosterone treatment (beyond 2 years) is questionable based on the few controlled long-term treatment studies. In general, it is good practice, at the present time, to avoid treating patients with significant cardiovascular and cerebrovascular disease history, hypercoagulable states, prostate cancer, and overtly symptomatic benign prostatic hypertrophy. Therefore, it appears that testosterone effects in older men may be heavily dependent on pre-existing comorbidities and risk factors. Current knowledge obtained from recent clinical trials in older men over the age of 60 years, and with a duration of therapy no shorter than 6 months, is reported in Table 1. Clinicians should be aware that a period of time should elapse after RT and before initiating testosterone therapy in order to allow the patient adequate time to regain functional endogenous testosterone production. There is also a dearth of data evaluating the safety of testosterone therapy in men treated with radiation therapy (RT). Product labels for all testosterone formulations explicitly state that their use is contraindicated in men with a history of prostate cancer, which results from Huggins' precept that testosterone therapy feeds prostate cancer cell proliferation. Since Huggins' work, subsequent research has failed to definitively link testosterone therapy to a progression of prostate cancer in the untreated patient or recurrence in the treated patient. The estimated likelihood of adverse effects of long-term TRT is still essentially unknown, as overall high-quality evidence based upon prospective randomized trials to recommend for or against its use in most men with testosterone deficiency (TD) is lacking.Ultimately, the AUA and the Testosterone Panel were committed to creating a Guideline that ensures that men in need of testosterone therapy are treated effectively and safely.It is typical for men to have some control over the timing of ejaculation during a sexual encounter.Guidelines cannot include evaluation of all data on emerging technologies or management, including those that are FDA-approved, which may immediately come to represent accepted clinical practices.The Panel recommends shared decision-making as fundamental in the management of disorders of ejaculation; involvement of sexual partner(s) in decision making, when possible, may allow for optimization of outcomes.Each class is believed to have somewhat unique anabolic and/or androgenic effects.26 However, not all men with biochemically low T levels suffer from DE, and not all men with the DE have low T levels. The Panel is supportive of clinicians offering appropriately selected and counseled patient’s pharmacotherapies that have a physiologic rationale for benefit in DE treatment. Well-designed, appropriately powered studies are needed to better define efficacy and safety of pharmacotherapies for DE. The prescribing physician(s) and possibly a pharmacist should be advised of the potential issue with the prescribed medication; the decision on cessation and dose adjustment must be made using shared decision-making involving all parties after careful consideration of risks and benefits. The IIEF also establishes a reliable baseline that can be used to monitor changes related to treatment. ”11 Depending on the initial response, more focused questions may provide information on the patient's social and sexual relationships. In other instances, the topic can be brought up in a nonthreatening way during the standard review of systems by asking questions such as, “Are you currently sexually active? For example, you could say “Many men (insert a condition that affects the particular patient, such as diabetes, hypertension, medication, recent heart attack, etc.) experience sexual problems. Many studies have reported the benefit of TRT for LOH (8). Given the paucity of data, it is difficult to draw clinical conclusions from our analyses comparing TRT to phosphodiesterase‐5 inhibitors (PDE5I) or TRT as an add‐on to PDEI5I versus PDE5I alone. Given that men are typically treated for years, and that cardiovascular risk factors are common in these men, these limitations should have important implications for patient counseling and monitoring. Importantly, we know much less about the long‐term effects of TRT compared to placebo. There is probably little to no effect on treatment withdrawal due to adverse events, prostate‐related events, or lower urinary tract symptoms (LUTS). To date, the literature has been conflicting, suggesting TRT has either no beneficial effect on reduction of cardiovascular morbidity or mortality, or even a detrimental effect. Abstracts and book chapters were excluded from the search, yet relevant case studies were included in the search given the specificity and nature of the search topics. TD has been identified concomitantly with many comorbid health conditions in men, including cardiovascular disease (CVD), metabolic syndrome, diabetes mellitus, hypertension, and dyslipidemia, while positing an associative relationship. Drugs that potentiate relaxation or reduce contraction mechanisms are suitable candidates for ED treatment. When sexual (visual, auditory, olfactory, tactile, and even imaginative in men) stimuli reach the central nervous system, they activate neural pathways, which are to date still unknown, mediating penile erection and sexual activity. When sexual stimuli reach the central nervous system, neural pathways are activated that convey sexual information from the higher brain centers through the spinal cord and the autonomous nervous system to the genital apparatus to induce penile erection (2,7,8 and references therein) (Figure 1). Until there is definitive evidence proving an association between testosterone therapy and subsequent MACE, the Panel recommends that clinicians counsel patients that the current scientific literature does not definitively demonstrate that testosterone therapy increases risk. A study by Pastuszak et al. (2015)355 found a significant increase in biochemical recurrence in high-risk patients who received testosterone therapy after RT or RT/ADT. Available studies are retrospective in nature but have suggested that post-RT patients (with or without ADT exposure) placed on testosterone therapy do not experience recurrence of prostate cancer. Currently published studies have not demonstrated an increased risk of biochemical cancer recurrence in post-RP patients who are on testosterone therapy, nor does it define the optimal timing for commencement of testosterone therapy. Another meta-analysis by Calof et al.190 (2005) pooled data from 19 RCTs to determine the number of all-cause prostate events in men who were on exogenous testosterone treatment as compared to men who were on placebo. In this clinical scenario, an argument can be made to continue testosterone therapy. If patients achieve target testosterone levels, but do not feel that they have sufficient improvement in their symptoms, clinicians should question whether testosterone deficiency is the etiology of their symptoms. As mentioned above, combination therapy with low dose hCG has been described as a means to maintain intratesticular testosterone levels394 and preserve spermatogenesis336 for men on exogenous testosterone. It is the opinion of the Panel that testosterone therapy, with close monitoring to ensure appropriate dosing and safety surveillance, may be considered in these patients after a three to six month waiting period. The currently available literature does not provide enough evidence to offer clear guidance on the use of testosterone therapy in men with existing, stable atherosclerotic CVD and/or a remote history of a myocardial infarction or a cerebrovascular accident. However, the lack of a full spectrum of testosterone bioactivity strongly limits its long-term use 22,123. For all new oral TU formulations a mild increase in arterial blood pressure has been reported. Accordingly, data derived from RCTs showed only an improvement of fat mass and lean mass of the same amount without any modifications in body weight . While circadian rhythm of serum testosterone peaks during the early morning hours, the actual serum levels fluctuate approximately every 90 min, representing a burst-like secretory pattern . This review is aimed at discussing the possible benefits and complications of testosterone replacement therapy in older men over 60 years of age. While prescription sales of testosterone have increased from $150 million in 2000 to $1.8 billion in 2011, a significant portion of men prescribed testosterone replacement therapy did not meet the laboratory criteria for hypogonadism. Treatment method should take into consideration patient preference, pharmacokinetics, potential for medication interactions, formulation-specific adverse effects, treatment burden, and cost. However, normal nocturnal erections do not always correlate with sexually relevant erections, and this test may be unreliable in older or anxious patients.66 Both TLANDO and JATENZO and a new self-injectable medication, testosterone enanthate (XYOSTED®; Antares Pharma, Ewing, NJ, USA) have shown elevations in ambulatory blood pressure compared with the treatment arm. Previous trials using TRT for hypogonadism did not address the cardiovascular risk with adequate power. TLANDO® (Lipocine Inc., Salt Lake City, UT, USA), another oral formulation of TU using SEDDS, has recently been approved by the FDA for the treatment of male hypogonadism.44 As this formulation does not require dose titration, patients do not need to have regular blood work, making use and follow-up easier. The 24-hour data correlated very well with single-point testosterone concentrations (between hours 4 and 6 after oral TU administration), which is typically used in the outpatient setting. With the increased release of new data and the elucidation of answers to remaining clinical questions, it is anticipated that this guideline will be revised within the next three to five years. Prominent among controversial issues are concerns about the diagnostic accuracy of laboratory tests, and cardiovascular and prostate health. It was of considerable interest that 61% of the respondents (including a portion of those who considered themselves comfortable with the diagnosis and management of testosterone deficiency) agreed to be part of a follow-up study. In 2012, the European Association of Urology published a guideline on male hypogonadism that was developed by European genitourinary surgeons.28 The levels of evidence were graded in accordance with a rating scheme adapted from the Oxford Centre for Evidence-Based Medicine’s levels of evidence. The algorithms and the abridged recommendations constitute a readily available resource for most professionals whose clinical practice includes a sizable number of men over 50 years of age, among whom testosterone deficiency syndrome is most prevalent. Behre 2012 published data only To obtain pooled overall MD and 95% CIs for outcomes, we used a random-effects model published by DerSimonian and Laird . In studies that did not report standard deviation, we applied an estimate of pooled standard deviation of two groups. Articles that were finally included in this study were chosen based on inclusion and exclusion criteria followed by an evaluation discussion among all investigators. And being aware of possible side effects may make a man more likely to recognize them as abnormal.Conversely, a population-based retrospective case-control study utilizing a UK clinical database of 19,215 patients with confirmed VTE showed that there was increased risk of VTE in the first 6 months of testosterone therapy.Urologist Tobias Kohler, M.D., answers the most frequently asked questions about erectile dysfunction.Patients who are on long-acting IM testosterone (testosterone undecanoate) should have blood work tested once steady state levels have been achieved.Methyltestosterone is an oral androgen modified at the 17-alpha position resulting in decreased first pass hepatic clearance and is approved in the US for treatment of testosterone deficiency.The FDA has mandated that testosterone product manufacturers conduct a large-scale randomized controlled trial specifically to determine cardiovascular risk,38 but results of any such trial would not be available for years.Although the absolute risks of POME and anaphylaxis require ongoing study, data from 342 patients undergoing 3,022 injections (1,000 mg in 4 mL) over a period of 3.5 years demonstrated that POME occurred after 1.9% of injections (12% of patients experienced at least one POME), with coughing episodes lasting 1-10 minutes in duration.443 All episodes were managed conservatively in the clinic, with no supplemental oxygen required. Table Four highlights pharmacotherapy options applicable to men with likely SSRI-induced DE. Use of drugs as adjunct therapies (e.g., bethanecol, cyproheptadine)244, 245 have also been reported. Cessation of these medications should be considered patients who present with troublesome DE, particularly if the onset of DE coincides with initiation of the medication. A variety of medications have been clearly linked to disruption of orgasmic function in both men and women. We downgraded the certainty of evidence for serious study limitations (‐1) and serious indirectness (‐1). Due to the resulting higher certainty of evidence, this sensitivity analysis became the basis of the summary of findings table (Table 1). The observed heterogeneity was explained in the predefined sensitivity analyses that excluded studies at high risk of bias. We downgraded the certainty of evidence for serious study limitations (–1) and serious indirectness (‐1). Due to the resulting higher certainty of evidence, the sensitivity analysis became the basis of the summary of findings table (Table 1). However, when patients were requested to assess their global impression of change regarding energy level, men receiving testosterone were significantly more likely to rate changes as a little or much better compared to placebo (approximately 15% more in testosterone cohort). There are conflicting results in the literature as to whether testosterone therapy has a significant impact on these symptoms. Men who seek medical care for possible testosterone therapy often present with non-specific symptoms, such as low energy and fatigue, which can be manifestations of other conditions, such as chronic stress, chronic fatigue, and depression. Studies reporting optimal testosterone levels yielded a mean 2.2 kg increase in lean body mass compared to a non-significant 0.8 kg increase when suboptimal levels of testosterone were achieved. These studies are supported by a meta-analysis that concluded that hypogonadism is a risk factor for cardiovascular morbidity and mortality . Evidence from RCTs of testosterone therapy in men with MetS and/or T2DM demonstrates some benefit in CV risk, including reduced central adiposity, insulin resistance, total cholesterol and LDL-cholesterol and suppression of circulating cytokines 29-31,36,152,153. Although it is mandatory to avoid testosterone administration in men with advanced PCa, insufficient long-term prospective data on the safety of testosterone therapy in PCa survivors , should prompt caution in choosing to treat symptomatic hypogonadal men in this setting. In conclusion, recent literature does not support an increased risk of PCa in hypogonadal men undergoing testosterone therapy. Anderson and colleagues retrospectively searched electronic medical records between 1996 and 2011 to identify 5695 men who had a low initial TT level, a subsequent testosterone level, and up to 3 years of follow up Anderson et al. 2014a. In the testosterone-treated group, 7% had a recurrence of stroke in 2 years versus 16.6% in the control group, with 28% of the treated men returning to work versus 6% of the control group. In the quartile at greatest risk, there was a significant reduction in events and mortality. BEHAVIOR THERAPY Further individualization may be considered based on trough testosterone levels at the end of a 10-week injection cycle. In contrast to topical agents where a percentage of men have difficulty achieving therapeutic levels within standard dosing ranges, injectable testosterone preparations are able to achieve therapeutic levels in almost any clinical scenario. Historically, testosterone levels have been measured mid-cycle (day three to four); however, such a measurement protocol misses the ability to define peak and trough levels. The pharmacokinetics of short-acting testosterone therapy depends on the dose, interval, and method of delivery (SQ versus IM). Removal of the system results in a rapid drop in testosterone levels.433 In another retrospective national cohort study, testosterone replacement also increased the risk of death, myocardial infarction, and stroke in older men with a pre-existing cardiac condition and those who underwent cardiac angiography . A greater proportion of men in the testosterone group than in the placebo group reported that they had received a diagnosis of hyperlipidemia or were taking a statin. In that study, both control and treatment groups had a high prevalence of hypertension, obesity, diabetes, hyperlipidemia, and pre-existing cardiovascular disease. Most studies enrolled middle‐aged (aged 40 years and over) participants with sexual dysfunction. We defined sexual dysfunction as acquired symptoms of decreased libido (or desire to engage in sexual activity) and/or erectile dysfunction, referring to the inability to attain or maintain an erection sufficient to permit satisfactory sexual performance (Khera 2016a; Lunenfeld 2013; Wang 2009). Additionally, we excluded ill or fragile older men who were not appropriate for the pharmacotherapy of sexual dysfunction. Therefore, in this review, we have focused on men with sexual dysfunction (i.e. testosterone‐related symptoms) regardless of serum testosterone level, to determine the role of TRT in the population without certain medical conditions. Reduced gonadotropin secretion decreases intratesticular and peripheral testosterone levels, which can cause adverse effects such as testicular atrophy, oligospermia, azoospermia, and other sperm abnormalities (Fronczak 2012). It is the opinion of this Panel that serum PSA levels should be measured prior to the commencement of testosterone therapy in patients over 40 years of age in order to minimize the risk of prescribing testosterone therapy to men with occult prostate cancer. Clinicians should discuss the cessation of testosterone therapy three to six months after commencement of treatment in patients who experience normalization of total testosterone levels but fail to achieve symptom or sign improvement. Prior to initiating treatment, clinicians should counsel patients that, at this time, it cannot be stated definitively whether testosterone therapy increases or decreases the risk of cardiovascular events (e.g., myocardial infarction, stroke, cardiovascular-related death, all-cause mortality). Clinical trials discussed in this review were selected based on a duration of testosterone replacement therapy of no less than 6 months, with several follow-up time points, and which reported statistically significant increases in testosterone levels upon the initiation of treatment and throughout the timeframe of the clinical trial. Although this study confirms that electrical stimulation of the cavernous nerve induces penile erection, these results have been obtained in an intraoperative condition, and it is unknown if this kind of intervention also will work in early prostatectomized patients. In this regard, a recent study has described the intraoperative implant of a two-dimensional flexible electrode array that covers the entire plexus area, ensuring that at least one of the electrodes will be in optimal contact with the cavernous nerve, without the need of intraoperative identification, in 24 patients enrolled for radical prostatectomy. However, their application is complicated by the paucity of criteria for patients selection, by the intrinsic difficulties in the procedures themselves that need high expertise in vascular microsurgery and nerve graft reconstruction, and by the fact that, even when the cause of ED is well known, it is difficult to identify the procedure which would produce the best results in terms of erectile function recovery. Nonetheless, the available studies with microarterial bypass surgery with or without a stent suggest that these procedures may be extremely effective as a long-lasting treatment of focal vasculogenic ED only in young men (age lower than 55 years) without other vascular risk factors 238,252,260. Positive results have been reported with these procedures in a few number of selected patients with an age not higher than 55 years and those who did not present other vascular risk factors 238,252. Men who have a history of chronic corticosteroid use have been shown to be at risk for low testosterone levels. Men who have had exposure of their testes during radiation therapy, either through direct or scatter radiation, are possibly at risk for low testosterone and the Panel recommends total testosterone measurement in such patients. BMD increased in patients treated with testosterone therapy leading the authors to conclude that younger testosterone deficient men may benefit from having routine DEXA scans performed, particularly those with concomitant low E2 and low BMI.89 Specifically, the odds ratio for developing ED in men with total testosterone 6 used a single question to define ED and also showed an increase in ED risk as total testosterone levels decreased. Point estimates that measure the difference in testosterone levels between men with and without ED may appear statistically significant, but these estimates are not always clinically meaningful. Holmang S, Marin P, Lindstedt G, Hedelin H. Effect of long-term oral testosterone undecanoate treatment on prostate volume and serum prostate-specific antigen concentration in eugonadal middleaged men. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels, low bone mass, and physical frailty. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. Via a case study, Thompson describes how carers employ effective body language, appropriate physical contact, and banter to de-escalate a potentially violent situation on an inpatient unit. Of note, the participants stressed the relevance of having appropriate physical and social environments in both maintaining wellbeing and dealing with risky behaviours. Kitwood developed a tool for assessing wellbeing and personhood called Dementia Care Mapping (DCM37); this is an important measure, which was reflected in its use being strongly recommended by the participants in the current study. Participants recommended the use of highly personalised forms of care in order to prevent and de-escalate agitation, and to manage risky behaviours. The discussion will first focus on “macro-features”, which are typically clinical pathways, care plans, formulations and “named” therapies. Using very lenient study selection criteria (all types of trials, including observational), Corona et al.325 identified improvements in total cholesterol, triglycerides, and high-density lipoproteins (HDL). A second large RCT by Snyder et al.319 used the Functional Assessment of Chronic Illness Therapy-Fatigue scales (range 0-52) in 474 men treated with testosterone for 12 months. Duration of studies and mode of administration did not appear to impact outcomes. If baseline DEXA demonstrate bone density loss, imaging should be repeated one to two years after testosterone initiation. These studies have revealed that stem cell treatment has a good efficacy on ED in the tested animal models and a safe profile, but studies on the protocols and dosages of the different type of stem cells to be injected, and mechanism of action as well, are still lacking. The majority of studies that have used these regenerative treatments for ED have been made with stem cells of different type (e.g., mesenchymal stem cells, placental-matrix-derived stem cells, mesenchymal-stem-cell-derived exosomes, adipose-derived stem cells, bone-marrow-derived mononuclear stem cells, umbilical cord tissue or blood stem cells, and urine derived stem cells) (202,203,204,205,206,207,208,209,210,211,212,213 and references therein). These new therapies (at the moment, experimental only) are based on the use of stem cells, platelet-rich plasma, gene transfer and tissue engineering for the restoration of viable cavernous muscle, vascular and endothelial cells, and nerves leading to the recovery of erectile function. The pharmacological therapies reviewed above are aimed at providing symptomatic relief to ED, thus providing a temporary resolution of the problem rather than a cure aimed at resolving the cause of the dysfunction. Thus, when pharmacological treatments are found scarcely efficacious or totally inefficacious in restoring the erectile response, other strategies must be used in order to attempt to overcome ED, at least if using of the old vacuum erection device or the surgical implant of a technologically advanced penile prosthesis is not an available option. RCTs have failed to categorically define if testosterone therapy increases the incidence of MACE when compared to placebo. Men who are on testosterone therapy should be advised to report the occurrence of any possible cardiovascular symptoms, such as chest pain, shortness of breath, dizziness, or transient loss of consciousness, during routine follow-up visits. The risk corresponded to an additional 10 cases per 10,000 person-years, which, while low in absolute terms, raised concern about using testosterone therapy in men who may be at increased risk for VTE prior to commencement of therapy.362 Compared to placebo, no significant changes were noted with testosterone therapy, including when the data were evaluated as a continuous or dichotomous (≥4 point change) variable. Another meta-analysis of RCTs performed by Cai324 concluded that testosterone therapy in diabetic men improved fasting glucose levels (mean difference -1.1 points), fasting serum insulin levels (mean difference -2.73), and HbA1c (mean difference -0.87). Despite the absence of definitive evidence, the Panel recommends that patients with these symptoms be counseled regarding the possibility of improvement on testosterone therapy.