Research Articles

Adding a vacuum erection device to regular use of Tadalafil improves penile rehabilitation after posterior urethroplasty

Dong-Liang Zhang, Zhong Chen, Fei-Xiang Wang, Jiong Zhang, Hong Xie, Ze-Yu Wang, Yu-Bo Gu, Qiang Fu, and  Lu-Jie Song

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Abstract

This study aimed to evaluate whether adding a vacuum erection device (VED) to regular use of Tadalafil could achieve better penile rehabilitation following posterior urethroplasty for pelvic fracture-related urethral injury (PFUI). Altogether, 78 PFUI patients with erectile dysfunction (ED) after primary posterior urethroplasty were enrolled and divided into two treatment groups: VED combined with Tadalafil (Group 1, n = 36) and Tadalafil only (Group 2, n = 42). Changes in penile length, testosterone level, International Index of Erectile Function-5 (IIEF-5) questionnaire, Quality of Erection Questionnaire (QEQ), and nocturnal penile tumescence (NPT) testing were used to assess erectile function before and after 6 months of ED treatment. Results showed that the addition of VED to regular use of Tadalafil preserved more penile length statistically (0.4 ± 0.9 vs −0.8 ± 0.7 cm, P < 0.01). IIEF-5 score and QEQ score in Group 1 were higher than Group 2 (both P < 0.05). After treatment, 21/36 (58.3%) Group 1 patients and 19/42 (45.2%) Group 2 patients could complete vaginal penetration. Group 1 patients also had markedly improved testosterone levels (P = 0.01). Unexpectedly, there was no significant difference in NPT testing between two therapies. For PFUI patients with ED after posterior urethroplasty, the addition of VED to regular use of Tadalafil could significantly improve their conditions – improving erection and increasing penile length – thus increasing patient satisfaction and confidence in penile rehabilitation.

The role of vacuum pump therapy to mechanically straighten the penis in Peyronie’s disease

Amr Abdel Raheem, Giulio Garaffa, Tarek Abdel Raheem, Michelle Dixon, Amanda Kayes, Nim Christopher, David Ralph

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Abstract

Objective: To assess the efficacy of vacuum therapy in mechanically straightening the penile curvature of Peyronie’s disease (PD).

Patients and methods: Modelling of the tunica albuginea has been shown to be possible during penile implant surgery and this principle has been applied as an alternative conservative therapy. In all, 31 patients with PD (mean duration 9.9 months; mean age 51 years, range 24-71) completed the study. Over a 12-week period, the patients used a vacuum device (Osbon ErecAid, MediPlus, High Wycombe, UK) for 10 min twice daily. The assessment at study entry and at completion after 12 weeks included the International Index of Erectile Function questionnaire, a perceived pain intensity score, stretched penile length measurement and the angle of penile deformity after an intracavernous injection with prostaglandin E1.

Results: there was a clinically and statistically significant improvement in penile length, angle of curvature and pain after 12 weeks of using the vacuum pump. Of the 31 patients, 21 had a reduction in the angle of curvature by 5-25 degrees, three had worsening of the curvature and there was no change in the remaining seven. The curvature was corrected surgically in 15 patients while the remaining 16 (51%) were satisfied with the outcome.

Conclusion: vacuum therapy can improve or stabilize the curvature of PD, is safe to use in all stages of the disease, and might reduce the number of patients going on to surgery.

Vacuum therapy in penile rehabilitation after radical prostatectomy: review of hemodynamic and antihypoxic evidence

Sheng-Qiang Qian, Liang Gao, Qiang Wei, Jiuhong Yuan

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Abstract

Generally, hypoxia is a normal physiological condition in the flaccid penis, which is interrupted by regular nocturnal erections in men with normal erectile function. [1] Lack of spontaneous and nocturnal erections after radical prostatectomy due to neuropraxia results in persistent hypoxia of cavernosal tissue, which leads to apoptosis and degeneration of cavernosal smooth muscle fibers. Therefore, overcoming hypoxia is believed to play a crucial role during neuropraxia. The use of a vacuum erectile device (VED) in penile rehabilitation is reportedly effective and may prevent loss of penile length. The corporal blood after VED use is increased and consists of both arterial and venous blood, as revealed by color Doppler sonography and blood gas analysis. A similar phenomenon was observed in negative pressure wound therapy (NPWT). However, NPWT employs a lower negative pressure than VED, and a hypoperfused zone, which increases in response to negative pressure adjacent to the wound edge, was observed. Nonetheless, questions regarding ideal subatmospheric pressure levels, modes of action, and therapeutic duration of VED remain unanswered. Moreover, it remains unclear whether a hypoperfused zone or PO 2 gradient appears in the penis during VED therapy. To optimize a clinical VED protocol in penile rehabilitation, further research on the mechanism of VED, especially real-time PO 2 measurements in different parts of the penis, should be performed.

Vacuum therapy in erectile dysfunction–science and clinical evidence

J Yuan, A N Hoang, C A Romero, H Lin, Y Dai, R Wang

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Abstract

Vacuum therapy (VT) utilizes negative pressure to distend the corporal sinusoids and to increase the blood inflow to the penis. Depending on its purpose, VT could be used as vacuum constriction device (VCD), with the aid of an external constricting ring which is placed at the base of penis to prevent blood outflow, maintaining the erection for sexual intercourse. Also, as a vacuum erectile device (VED), without the application of a constriction ring, just increases blood oxygenation to the corpora cavernosa and for other purposes. The emerging of phosphodiesterase 5 inhibitors (PDE(5)I) for the treatment of erectile dysfunction (ED) eclipsed VCD as therapeutic choice for ED; however, widespread usage of VED as part of penile rehabilitation after radical prostatectomy and other purposes rekindle the interest for VT. The underlying hypothesis is that the artificial induction of erections shortly after surgery facilitates tissue oxygenation, reducing cavernosal fibrosis in the absence of nocturnal erections, and potentially increases the likelihood of preserving erectile function. Due to its ability to draw blood into the penis regardless of nerve disturbance, VED has become the centerpiece of penile rehabilitation protocols. Herein, we reviewed the history, mechanism, application, side effects and future direction of VT in ED.

The role of vacuum erection devices in penile rehabilitation after radical prostatectomy

T Lehrfeld, D I Lee

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Abstract

Even nerve-sparing radical prostatectomy damages the cavernous nerves and leads to temporary erectile dysfunction (ED) in men recovering from prostate cancer surgery. Historically, patients recovering from prostate cancer surgery have been advised that the return of erectile function (EF) can take from 6 to 18 months, or even longer. Unfortunately, the return of sexual function in these patients remains variable, but is generally thought to be dependent on the individual patient’s pre-surgery EF, as well as the degree of cavernous nerve disruption during prostate removal. Recently, there has been a growing movement to proactively treat patients postoperatively for presumed nerve damage to stimulate nerve recovery and possibly reduce the degree of irreversible damage. This would reduce the on-demand therapy these patients would require, and hopefully remove the requirement for an implantable prosthesis. The underlying hypothesis is that the artificial induction of erections shortly after surgery facilitates tissue oxygenation, reducing cavernosal fibrosis in the absence of nocturnal erections, potentially increasing the likelihood of preserving EF. Vacuum erection devices (VED), because of their ability to draw blood into the penis regardless of nerve disturbance, have become the centerpiece of penile rehabilitation protocols. This review will discuss the pathophysiology of radical prostatectomy induced ED and the rationale for rehabilitation. It will then discuss current protocols, including those involving the VED.

High levels of circulating testosterone are not associated with increased prostate cancer risk: A pooled prospective study

 Pär Stattin, Sonja Lumme, Leena Tenkanen, Henrik Alfthan, Egil Jellum, Göran Hallmans, Steinar Thoresen, Timo Hakulinen, Tapio Luostarinen, Matti Lehtinen, Joakim Dillner, Ulf-Håkan Stenman, Matti Hakama

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Abstract

Androgens stimulate prostate cancer in vitro and in vivo. However, evidence from epidemiologic studies of an association between circulating levels of androgens and prostate cancer risk has been inconsistent. We investigated the association of serum levels of testosterone, the principal androgen in circulation, and sex hormone‐binding globulin (SHBG) with risk in a case‐control study nested in cohorts in Finland, Norway and Sweden of 708 men who were diagnosed with prostate cancer after blood collection and among 2,242 men who were not. In conditional logistic regression analyses, modest but significant decreases in risk were seen for increasing levels of total testosterone down to odds ratio for top vs. bottom quintile of 0.80 (95% CI = 0.59–1.06; p_trend = 0.05); for SHBG, the corresponding odds ratio was 0.76 (95% CI = 0.57–1.01; p_trend = 0.07). For free testosterone, calculated from total testosterone and SHBG, a bell‐shaped risk pattern was seen with a decrease in odds ratio for top vs. bottom quintile of 0.82 (95% CI = 0.60–1.14; p_trend = 0.44). No support was found for the hypothesis that high levels of circulating androgens within a physiologic range stimulate development and growth of prostate cancer.

Testosterone Replacement Therapy in Hypogonadal Men at High Risk for Prostate Cancer: Results of 1 Year of Treatment in Men With Prostatic Intraepithelial Neoplasia

Ernani Luis Rhoden, Abraham Morgentaler

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Abstract

Purpose:

One of the greatest concerns among clinicians regarding testosterone replacement therapy (TRT) is the fear of causing or promoting prostate cancer. We evaluated prostatic changes in hypogonadal men with and without high grade prostatic intraepithelial neoplasia (PIN), which is considered a prostatic precancerous lesion, after 1 year of TRT.

Materials and Methods:

A total of 75 hypogonadal who completed 12 months of TRT were studied. All underwent prostate biopsy prior to initiating treatment. Of the men 55 had benign prostate biopsies (PIN−) and 20 had PIN without frank cancer (PIN+). All men with PIN underwent repeat biopsy to exclude cancer prior to the initiation of testosterone treatment. Prostate specific antigen (PSA), and total and free testosterone were determined prior to treatment and at 1 year. Repeat biopsy was performed for a change noted on digital rectal examination or for a PSA increase of 1 ng/l or greater.

PSA was similar at baseline in men with and without PIN (1.49 ± 1.1 and 1.53 ± 1.6 ng/dl, p >0.05) and after 12 months of TRT (1.82 ± 1.1 and 1.78 ± 1.6 ng/dl, respectively, p >0.05). A slight, similar increase in mean PSA was noted in the PIN− and PIN+ groups (0.25 ± 0.6 and 0.33 ± 0.6 ng/dl, p >0.05). One man in the PIN+ group had cancer after biopsy was performed due to abnormal digital rectal examination. Four additional men in the PIN− group and 2 in the PIN+ group underwent re-biopsy for elevated PSA and none had cancer. No differences were noted between the PIN− and PIN+ groups with regard to total and free testosterone at baseline and at 1 year (p = 0.267).

Conclusions:

After 1 year of TRT men with PIN do not have a greater increase in PSA or a significantly increased risk of cancer than men without PIN. These results indicate that TRT is not contraindicated in men with a history of PIN.

3,3′-Diindolylmethane Dose-Dependently Prevents Advanced Prostate Cancer

Yufei Li, Nathaniel W. Mahloch, Nicholas J.E. Starkey, Mónica Peña-Luna, George E. Rottinghaus, Kevin L. Fritsche, Cynthia Besch-Williford, Dennis B. Lubahn

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Abstract

3,3’-Diindolylmethane (DIM) is an acid-derived dimer of indole-3-carbinol, found in many cruciferous vegetables, such as broccoli, and has been shown to inhibit prostate cancer (PCa) in several in vitro and in vivo models. We demonstrated that DIM stimulated both estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) transcriptional activities and propose that ERβ plays a role in mediating DIM’s inhibition on cancer cell growth. To further study the effects of DIM on inhibiting advanced PCa development, we tested DIM in TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate) mice. The control group of mice were fed a high fat diet. Three additional groups of mice were fed the same high fat diet supplemented with 0.04%, 0.2% and 1% DIM. Incidence of advanced PCa, poorly differentiated carcinoma (PDC), in the control group was 60%. 1% DIM dramatically reduced PDC incidence to 24% (p=0.0012), while 0.2% and 0.04% DIM reduced PDC incidence to 38% (p=0.047) and 45% (p=0.14) respectively. Though DIM did affect mice weights, statistical analysis showed a clear negative association between DIM concentration and PDC incidence with p=0.004, while the association between body weight and PDC incidence was not significant (p=0.953). In conclusion, our results show that dietary DIM can inhibit the most aggressive stage of prostate cancer at concentration lower than previously demonstrated, possibly working through an estrogen receptor mediated mechanism.

Testosterone Therapy and Cardiovascular Risk: Advances and Controversies

Abraham Morgentaler, MD; Martin M. Miner, MD; Monica Caliber, MSc; Andre T. Guay, MD; Mohit Khera, MD; Abdulmaged M. Traish, PhD

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Abstract

Two recent studies raised new concerns regarding cardiovascular (CV) risks with testosterone (T) therapy. This article reviews those studies as well as the extensive literature on T and CV risks. A MEDLINE search was performed for the years 1940 to August 2014 using the following key words: testosterone, androgens, human, male, cardiovascular, stroke, cerebrovascular accident, myocardial infarction, heart attack, death, and mortality. The weight and direction of evidence was evaluated and level of evidence (LOE) assigned. Only 4 articles were identified that suggested increased CV risks with T prescriptions: 2 retrospective analyses with serious methodological limitations, 1 placebo-controlled trial with few major adverse cardiac events, and 1 meta-analysis that included questionable studies and events. In contrast, several dozen studies have reported a beneficial effect of normal T levels on CV risks and mortality. Mortality and incident coronary artery disease are inversely associated with serum T concentrations (LOE IIa), as is severity of coronary artery disease (LOE IIa). Testosterone therapy is associated with reduced obesity, fat mass, and waist circumference (LOE Ib) and also improves glycemic control (LOE IIa). Mortality was reduced with T therapy in 2 retrospective studies. Several RCTs in men with coronary artery disease or heart failure reported improved function in men who received T compared with placebo. The largest meta-analysis to date revealed no increase in CV risks in men who received T and reduced CV risk among those with metabolic disease. In summary, there is no convincing evidence of increased CV risks with T therapy. On the contrary, there appears to be a strong beneficial relationship between normal T and CV health that has not yet been widely appreciated.

Testosterone does not adversely affect fibrinogen or tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in 46 men with chronic stable angina

A M Smith, K M English , C J Malkin, R D Jones, T H Jones, and K S Channer

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Abstract

Objective: In women, sex hormones cause increased morbidity and mortality in patients with coronary heart disease (CHD) and adversely affect the coagulation profile. We have studied the effect of physiological testosterone replacement therapy in men on coagulation factor expression, to determine if there is an increased risk of thrombosis.

Methods: Double-blind, randomized, placebo-controlled trial of testosterone in 46 men with chronic stable angina. Measurements of free, total and bioavailable testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH), estradiol, plasminogen activator inhibitor-1 (PAI-1), fibrinogen, tissue plasminogen activator (tPA) and full blood count were made at 0, 6 and 14 weeks.

Results: Bioavailable testosterone levels were: 2.58^0.58 nmol/l at baseline, compared with 3.35^0.31 nmol/l at week 14 (P , 0.001) after treatment compared with 2.6^0.18 nmol/l and 2.44^0.18 nmol/l in the placebo group (P was not significant). There was no change in fibrinogen (3.03^0.18 g/l at baseline and 3.02^0.18 g/l at week 14, P ¼ 0.24), tPA activity (26.77^4.9 Iu/ml and 25.67^4.4 Iu/ml, P ¼ 0.88) or PAI-1 activity (0.49^0.85 Iu/ml and 0.36^0.06 Iu/ml, P ¼ 0.16) with active treatment and no differences between the groups (at week 14, P value 0.98, 0.59 and 0.8 for fibrinogen, PAI-1 and tPA respectively). Haemoglobin concentration did not change over time, in the testosterone group (1.44^0.02 g/l and 1.45^0.02 g/l, P ¼ 0.22).

Conclusion: Physiological testosterone replacement does not adversely affect blood coagulation status.

Type 2 Diabetes and Testosterone Therapy

Geoffrey Hackett

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Abstract

A third of men with type 2 diabetes (T2DM) have hypogonadotrophic hypogonadism (HH) and associated increased risk of cardiovascular and all-cause mortality. Men with HH are at increased risk of developing incident T2DM. We conducted MEDLINE, EMBASE, and COCHRANE reviews on T2DM, HH, testosterone deficiency, cardiovascular and all-cause mortality from May 2005 to October 2017, yielding 1,714 articles, 52 clinical trials and 32 randomized controlled trials (RCT). Studies with testosterone therapy suggest significant benefits in sexual function, quality of life, glycaemic control, anaemia, bone density, fat, and lean muscle mass. Meta-analyses of RCT, rather than providing clarification, have further confused the issue by including under-powered studies of inadequate duration, multiple regimes, some discontinued, and inbuilt bias in terms of studies included or excluded from analysis.

Bio-available testosterone levels fall acutely following myocardial infarction in men: association with fibrinolytic factors

Peter J Pugh, Kevin S Channer, Helen Parry, Tom Downes, T Hugh Jone

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Abstract

The effect of acute myocardial infarction on plasma levels of testosterone in men is unclear. No previous studies have evaluated the bio-available fraction of testosterone. Low plasma testosterone levels have been associated with several risk factors for myocardial infarction, including an unfavorable fibrinolytic profile. In a prospective, case control study, we examined changes in plasma levels of sex hormones, including bio-available testosterone, in patients with acute myocardial infarction and in control subjects. In addition, changes in hormone levels in patients were compared with alterations in the fibrinolytic profile. Thirty male patients admitted with chest pain were studied. Twenty two had acute myocardial infarction and eight had non-specific chest pain. Plasma levels of total and bio-available testosterone, 17beta-estradiol, sex hormone binding globulin and insulin were measured at baseline and throughout admission. In addition, fibrinolytic factors (plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and fibrinogen) were measured in patients who received fibrinolysis. Height and weight, and the subsequent development of heart failure or myocardial dysfunction were also recorded. Patients had lower levels of bio-available testosterone (2.07 +/- 0.75 nmol/L vs. 5.3 +/- 1.7 nmol/L, p < 0.05) and higher levels of 17beta-estradiol (87.9 +/- 39.5 pmol/L vs. 48.1 +/- 18.4 pmol/L, p < 0.001) than controls. Total and bio-available testosterone levels fell acutely following myocardial infarction (11.9 +/- 3.8 nmol/L to 9.7 +/- 3.3 nmol/L, p < 0.05; 1.95 +/- 0.76 nmol/L to 1.55 +/- 0.67 nmol/L, p < 0.05). This reduction was associated with elevation of PAI-I activity and reduction of tPA activity, independent of changes in plasma insulin levels. Patients with lower baseline levels of testosterone and higher levels of 17beta-estradiol had a relatively pro-thrombotic fibrinolytic profile and increased risk of complications. In conclusion, total and bio-available levels of testosterone fall following acute myocardial infarction in men, in association with adverse changes in fibrinolytic profile. It is not clear whether this association represents a direct effect of testosterone on thrombotic tendency but warrants further investigation.

The Testosterone Controversy

With references adapted from an article posted by William Faloon of Life Extensions

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Abstract

Testosterone levels are high in young men, but plummet during aging. Despite compelling findings of efficacy, conventional doctors still question the value of testosterone replacement in maturing men. This oversight is causing needless heart attacks and strokes. Low testosterone is associated with excess abdominal fat,1-4 loss of insulin sensitivity,5,6 andatherosclerosis.7,8 A critically important role of testosterone is to enable HDL to remove excess cholesterol from the arterial wall and transport it to the liver for disposal. This effect of enhancing HDL is termed “reverse cholesterol transport” and is vital to preventing arterial occlusion.9,10 Cardiologists routinely prescribe statin drugs to lower LDL, a lipoprotein that transports cholesterol from the liver to the arteries. These same doctors, however, fail to maintain sufficient testosterone levels in their patients to enable HDL to remove cholesterol buildup in the arteries. This is one reason why statin drugs have not always been shown to work in older men, who require functional HDL to keep arterial linings free of excess cholesterol. 11,12 Numerous studies document the vital role that testosterone plays in maintaining youthful metabolic processes throughout the body.6,7,13-21 A large new study confirms the deadly impact of low testosterone in older men.22 What’s scary are clinical trials designed by doctors who have no idea how to achieve youthful hormone levels. Men who enroll in these studies are subjected to lethal dangers because testosterone and estrogen blood levels are not properly balanced. Cells throughout a man’s body are laden with receptor sites that are activated by the hormone testosterone. When testosterone is available to bind to these receptor sites, good things happen such as elevated mood and improved cognition in response to plentiful testosterone being available to the brain.23-25 Be it muscle, bone, vascular, or nerve tissue, testosterone provides critical command signals for your cells to behave in a youthful manner.8,26-33 As testosterone levels diminish, degenerative processes set in.

Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial

Prof Gary Wittert, MD, Karen Bracken, PhD , Kristy P Robledo, PhD , Prof Mathis Grossmann, PhD , Prof Bu B Yeap, PhD , Prof David J Handelsman, MD , et al.

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Background

Men who are overweight or obese frequently have low serum testosterone concentrations, which are associated with increased risk of type 2 diabetes. We aimed to determine whether testosterone treatment prevents progression to or reverses early type 2 diabetes, beyond the effects of a community-based lifestyle programme.

Regulation of Bone Metabolism by Sex Steroids

Sundeep Khosla and David G. Monroe

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Abstract

Osteoporosis is a significant public health problem, and a major cause of the disease is estrogen deficiency following menopause in women. In addition, considerable evidence now shows that estrogen is also a major regulator of bone metabolism in men. Since the original description of the effects of estrogen deficiency on bone by Fuller Albright more than 70 years ago, there has been enormous progress in understanding the mechanisms of estrogen and testosterone action on bone using human and mouse models. Although we understand more about the effects of estrogen on bone as compared with testosterone, both sex steroids do play important roles, perhaps in a somewhat compartment-specific (i.e., cancellous vs. cortical bone) manner. This review summarizes our current knowledge of sex steroid action on bone based on human and mouse studies, identifies both agreements and potential discrepancies between these studies, and suggests directions for future research in this important area.

Subcutaneous Testosterone Anastrozole Therapy in Men: Rationale

Rebecca L. Glaser, MD Anne E. York, MS

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Abstract

This analysis was designed to determine the efficacy of anastrozole, an aromatase inhibitor, combined with testosterone in a subcutaneous implant in preventing elevated estradiol levels and the subsequent side effects of excess estrogen associated with testosterone therapy. It also allowed for the establishment of normative ranges of serum testosterone levels on subcutaneous implant therapy. The study participants were 344 men who were accrued to an institutional review board-approved cohort study between April 2014 and 2017. Efficacy of the subcutaneous combination implant in maintaining low estradiol levels was evaluated. Serum levels of testosterone and estradiol were measured throughout the implant cycle, at week 4, and when symptoms returned. Correlations between patient demographics, dosing, and serum levels on therapy were evaluated. Mean testosterone dose was 1827 + 262 mg. Mean anastrozole dose was 15.3 + 3.2 mg with the majority of men receiving 16 mg of subcutaneous anastrozole. The mean interval of insertion was 4.8 months. Low estradiol levels were maintained throughout the implant cycle. Mean T level at week 4 was 1183 + 315 ng/dl and 553 + 239 ng/dl when symptoms returned. Levels of testosterone on therapy inversely correlated with body mass index. There were no adverse events attributed to testosterone or anastrozole therapy. Subcutaneous anastrozole delivered simultaneously with testosterone allowed for higher dosing of testosterone and less frequent intervals of insertion. Low- dose anastrozole released from the combination implant maintained low estradiol levels throughout the implant cycle and prevented clinical side effects attributed to excess estrogen.

A Harvard expert shares his thoughts on testosterone-replacement therapy

An interview with Abraham Morgentaler, M.D.

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It could be said that testosterone is what makes men, men. It gives them their characteristic deep voices, large muscles, and facial and body hair, distinguishing them from women. It stimulates the growth of the genitals at puberty, plays a role in sperm production, fuels libido, and contributes to normal erections. It also fosters the production of red blood cells, boosts mood, and aids cognition.

Over time, the testicular “machinery” that makes testosterone gradually becomes less effective, and testosterone levels start to fall, by about 1% a year, beginning in the 40s. As men get into their 50s, 60s, and beyond, they may start to have signs and symptoms of low testosterone such as lower sex drive and sense of vitality, erectile dysfunction, decreased energy, reduced muscle mass and bone density, and anemia. Taken together, these signs and symptoms are often called hypogonadism (“hypo” meaning low functioning and “gonadism” referring to the testicles). Researchers estimate that the condition affects anywhere from two to six million men in the United States. Yet it is an underdiagnosed problem, with only about 5% of those affected receiving treatment.

Studies have shown that testosterone-replacement therapy may offer a wide range of benefits for men with hypogonadism, including improved libido, mood, cognition, muscle mass, bone density, and red blood cell production. But little consensus exists on what constitutes low testosterone, when testosterone supplementation makes sense, or what risks patients face. Much of the current debate focuses on the long-held belief that testosterone may stimulate prostate cancer.

Dr. Abraham Morgentaler, an associate professor of surgery at Harvard Medical School, the director of Men’s Health Boston, and a member of Perspectives’ editorial board, specializes in treating prostate diseases and male sexual and reproductive difficulties. He has developed particular expertise in treating low testosterone levels. In this interview, Dr. Morgentaler shares his views on current controversies, the treatment strategies he uses with his own patients, and why he thinks experts should reconsider the possible link between testosterone-replacement therapy and prostate cancer.

Not giving up: Testosterone promotes persistence against a stronger opponent

Hana H. Kutlikova, Shawn N. Geniole, Christoph Eisenegger, Claus Lamm, Gerhard Jocham, Bettina Studer

Abstract

Recent research suggests that when we lack a sense of control, we are prone to motivational failures and early quitting in competitions. Testosterone, on the other hand, is thought to boost competitiveness. Here we investigate the interaction between these factors, testing the testosterone’s potential to enhance persistence in a competition against a stronger opponent, depending on experimentally manipulated perceived control. Healthy participants were administered a single dose of testosterone or placebo. They first underwent a task designed to either induce low or high perceived control and then entered a costly competition against a progressively stronger opponent that they could quit at any time. In the placebo group, men with low perceived control quitted twice as early as those with high perceived control. Testosterone countered this effect, making individuals with low control persist in the competition for as long as those with high perceived control, and did so also despite raising participants’ explicit awareness of the opponents’ advantage. This psychoendocrinological effect was not modulated by basal cortisol levels, CAG repeat polymorphism of the androgen receptor gene, or trait dominance. Our results provide the first causal evidence that testosterone promotes competitive persistence in humans and demonstrate that this effect depends on the psychological state elicited prior to the competition, broadening our understanding of the complex relationships between testosterone and social behaviors

Can Low-Intensity Extracorporeal Shockwave Therapy Improve Erectile Function? A 6-Month Follow-up Pilot Study in Patients with Organic Erectile Dysfunction

Yoram Vardi, Boaz Appel, Giris Jacob, Omar Massarwi, Ilan Gruenwald

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Abstract

Background: Low-intensity extracorporeal shockwave therapy (LI-ESWT) is currently under investigation regarding its ability to promote neovascularization in different organs.

Objective: To evaluate the effect of LI-ESWT on men with erectile dysfunction (ED) who have previously responded to oral phosphodiesterase type 5 inhibitors (PDE5-I). Design, setting, and participants: We screened 20 men with vasculogenic ED who had International Index of Erectile Function ED (IIEF-ED) domain scores between 5–19 (average: 13.5) and abnormal nocturnal penile tumescence (NPT) parameters. Shockwave therapy comprised two treatment sessions per week for 3 wk, which were repeated after a 3-wk no-treatment interval.

Intervention: LI-ESWT was applied to the penile shaft and crura at five different sites. Measurements: Assessment of erectile function was performed at screening and at 1 mo after the end of the two treatment sessions using validated sexual function questionnaires, NPT parameters, and penile and systemic endothelial function testing. The IIEF-ED questionnaire was answered at the 3- and 6-mo follow-up examinations.

Results and limitations: We treated 20 middle-aged men (average age: 56.1 yr) with vasculogenic ED (mean duration: 34.7 mo). Eighteen had cardiovascular risk factors. At 1 mo follow-up, significant increases in IIEF-ED domain scores were recorded in all men (20.9 5.8 vs 13.5 4.1, p < 0.001); these remained unchanged at 6 mo. Moreover, significant increases in the duration of erection and penile rigidity, and significant improvement in penile endothelial function were demonstrated. Ten men did not require any PDE5-I therapy after 6-mo follow-up. No pain was reported from the treatment and no adverse events were noted during follow-up.

Conclusions: This is the first study that assessed the efficacy of LI-ESWT for ED. This approach was tolerable and effective, suggesting a physiologic impact on cavernosal hemodynamics. Its main advantages are the potential to improve erectile function and to contribute to penile rehabilitation without pharmacotherapy. The short-term results are promising, yet demand further evaluation with larger sham-control cohorts and longer follow-up.

Low intensity extracorporeal shockwave therapy for erectile dysfunction: a study in an Indian population

Vasan Satya Srini, MD, Rahul Kumar Reddy, MD, Tamar Shultz, PhD, Bela Denes, MD

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Abstract

Erectile dysfunction (ED) has been shown to be associated with a number of physical conditions and affects not only physical but also psychosocial health. Currently oral, on-demand phosphodiesterase type 5 inhibitors (PDE5i) are preferred first line treatment. Though effective, these drugs have limitations and are associated with significant non-compliance, side effects and do not reverse the underlying pathology. Non-invasive low intensity shockwave therapy (LISWT) has been shown to significantly improve erectile function in men previously PDE5i dependent. We describe our experience and results with this therapy in an Indian population of men with ED. This study assessed the efficacy of low intensity extracorporeal shockwave therapy (LI-ESWT) on Indian men with organic ED who had previously responded to PDE5i.

Initial experience with linear focused shockwave treatment for erectile dysfunction: a 6-month follow-up pilot study

Y Reisman, A Hind, A Varaneckas and I Motil

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Abstract

Vasculogenic erectile dysfunction (ED) is defined as inability to get or keep an erection firm enough for satisfying sexual intercourse and is maybe originated by diseases, such as diabetes mellitus (DM) and atherosclerotic vascular occlusive disease. Current methods for treating vasculogenic ED aim at reducing symptoms instead of reversing the source of the dysfunction, which in the majority of the patients is due to arterial or inflow disorders.1 It has been demonstrated that shockwaves can enhance intrinsic angiogenesis and are used to treat ischemic heart disease.2 Low-intensity shockwaves (LISW) have been evaluated for treating ED in both pilot and randomized sham-controlled studies. The encouraging results that were seen in these studies were the first to show the effect of LISW on ED symptoms,3–4 but have never been evaluated elsewhere. Recently published study conducted on rats with DM-associated ED showed that low-energy shockwave therapy (LESWT) significantly restored erectile function to levels almost similar to normal levels of controls. The therapeutic efficacy of LESWT is possibly mediated by increased recruitment of mesenchymal stem cells (MSCs) that promote the regeneration of DM-damaged erectile tissues.5 The present study was aimed to assess the safety and efficacy of a new dedicated shockwave device, ‘Renova’, which was designed to achieve substantially superior organ coverage, compared with the existing devices and hence produces positive results with a shorter protocol in a multicenter study.

Tadalafil once daily and extracorporeal shock wave therapy in the management of patients with Peyronie’s disease and erectile dysfunction: results from a prospective randomized trial

A. Palmieri, C. Imbimbo, M. Creta, P. Verze, F. Fusco and V. Mirone

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Abstract

Extracorporeal shock wave therapy improves erectile function in patients with Peyronie’s disease. However, erectile dysfunction still persists in many cases. We aimed to investigate the effects of extracorporeal shock wave therapy plus tadalafil 5 mg once daily in the management of patients with Peyronie’s disease and erectile dysfunction not previously treated. One hundred patients were enrolled in a prospective, randomized, controlled study. Patients were randomly allocated to receive either extracorporeal shock wave therapy alone for 4 weeks (n = 50) or extracorporeal shock wave therapy plus tadalafil 5 mg once daily for 4 weeks (n = 50). Main outcome measures were: erectile function (evaluated through the shortened version of the International Index of Erectile Function), pain during erection (evaluated through a Visual Analog Scale), plaque size, penile curvature and quality of life (evaluated through an internal questionnaire). Follow-up evaluations were performed after 12 and 24 weeks. In both groups, at 12 weeks follow-up, mean Visual Analog Scale score, mean International Index of Erectile Function score and mean quality of life score ameliorated significantly while mean plaque size and mean curvature degree were unchanged. Intergroup analysis revealed a significantly higher mean International Index of Erectile Function score and quality of life score in patients receiving the combination. After 24 weeks, intergroup analysis revealed a significantly higher mean International Index of Erectile Function score and mean quality of life score in patients that received extracorporeal shock wave therapy plus tadalafil. In conclusion extracorporeal shock wave therapy plus tadalafil 5 mg once daily may represent a valid conservative strategy for the management of patients with Peyronie’s disease and erectile dysfunction.

Low-intensity Extracorporeal Shock Wave Treatment Improves Erectile Function: A Systematic Review and Meta-analysis

Zhihua Lu, Guiting Lin, Amanda Reed-Maldonado, Chunxi Wang, Yung-Chin Lee, Tom F. Lue

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Abstract

Context: As a novel therapeutic method for erectile dysfunction (ED), low-intensity extracorporeal shock wave treatment (LI-ESWT) has been applied recently in the clinical setting. We feel that a summary of the current literature and a systematic review to evaluate the therapeutic efficacy of LI-ESWT for ED would be helpful for physicians who are interested in using this modality to treat patients with ED.

Objective: A systematic review of the evidence regarding LI-ESWT for patients with ED was undertaken with a meta-analysis to identify the efficacy of the treatment modality.

Evidence acquisition: A comprehensive search of the PubMed and Embase databases to November 2015 was performed. Studies reporting on patients with ED treated with LIESWT were included. The International Index of Erectile Function (IIEF) and the Erection Hardness Score (EHS) were the most commonly used tools to evaluate the therapeutic efficacy of LI-ESWT.

Evidence synthesis: There were 14 studies including 833 patients from 2005 to 2015. Seven studies were randomized controlled trials (RCTs); however, in these studies, the setup parameters of LI-ESWT and the protocols of treatment were variable. The meta-analysis revealed that LI-ESWT could significantly improve IIEF (mean difference: 2.00; 95% confidence interval [CI], 0.99–3.00; p < 0.0001) and EHS (risk difference: 0.16; 95% CI, 0.04–0.29; p = 0.01). Therapeutic efficacy could last at least 3 mo. The patients with mildmoderate ED had better therapeutic efficacy after treatment than patients with more severe ED or comorbidities. Energy flux density, number of shock waves per treatment, and duration of LI-ESWT treatment were closely related to clinical outcome, especially regarding IIEF improvement.

Conclusions: The number of studies of LI-ESWT for ED have increased dramatically in recent years. Most of these studies presented encouraging results, regardless of variation in LI-ESWT setup parameters or treatment protocols. These studies suggest that LI-ESWT could significantly improve the IIEF and EHS of ED patients. The publication of robust evidence from additional RCTs and longer-term follow-up would provide more confidence regarding use of LI-ESWT for ED patients. Patient summary: We reviewed 14 studies of men who received low-intensity extracorporeal shock wave treatment (LI-ESWT) for erectile dysfunction (ED). There was evidence that these men experienced improvements in their ED following LI-ESWT.

Impact of aging and comorbidity on the efficacy of low-intensity shock wave therapy for erectile dysfunction

Shin-ichi Hisasue, Toshiyuki China, Akira Horiuchi, Masaki Kimura, Keisuke Saito, Shuji Isotani, Hisamitsu Ide, Satoru Muto, Raizo Yamaguchi and Shigeo Horie

Abstract

Objectives: To evaluate the efficacy of low-intensity shock wave therapy and to identify the predictive factors of its efficacy in Japanese patients with erectile dysfunction.

Methods: The present study included 57 patients with erectile dysfunction who satisfied all the following conditions: more than 6-months history of erectile dysfunction, sexual health inventory for men score of ≤12 without phosphodiesterase type-5 inhibitor, erection hardness score grade 1 or 2, mean penile circumferential change by erectometer assessing sleep related erection of <25 mm and non-neurological pathology. Patients were treated by a low-energy shock waves generator (ED1000; Medispec, Gaithersburg, MD, USA). A total of 12 shock wave treatments were applied. Sexual health inventory for men score, erection hardness score with or without phosphodiesterase type-5 inhibitor, and mean penile circumferential change were assessed at baseline, 1, 3 and 6 months after the termination of low-intensity shock wave therapy.

Results: Of 57 patients who were assigned for the low-intensity shock wave therapy trial, 56 patients were analyzed. Patients had a median age of 64 years. The sexual health inventory for men and erection hardness score (with and without phosphodiesterase type-5 inhibitor) were significantly increased (P < 0.001) at each timepoint. The mean penile circumferential change was also increased from 13.1 to 20.2 mm after low-intensity shock wave therapy (P < 0.001). In the multivariate analysis, age and the number of concomitant comorbidities were statistically significant predictors for the efficacy.

Conclusions: Low-intensity shock wave therapy seems to be an effective physical therapy for erectile dysfunction. Age and comorbidities are negative predictive factors of therapeutic response.

Low-Intensity Extracorporeal Shock Wave Therapy—A Novel Effective Treatment for Erectile Dysfunction in Severe ED Patients Who Respond Poorly to PDE5 Inhibitor Therapy

Ilan Gruenwald, MD, Boaz Appel, MD, and Yoram Vardi, MD

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Abstract

Introduction. Low-intensity shock wave therapy (LI-ESWT) has been reported as an effective treatment in men with mild and moderate erectile dysfunction (ED).

Aim. The aim of this study is to determine the efficacy of LI-ESWT in severe ED patients who were poor responders to phosphodiesterase type 5 inhibitor (PDE5i) therapy.

Methods. This was an open-label single-arm prospective study on ED patients with an erection hardness score (EHS) 2 at baseline. The protocol comprised two treatment sessions per week for 3 weeks, which were repeated after a 3-week no-treatment interval. Patients were followed at 1 month (FU1), and only then an active PDE5i medication was provided for an additional month until final follow-up visit (FU2). At each treatment session, LI-ESWT was applied on the penile shaft and crus at five different anatomical sites (300 shocks, 0.09 mJ/mm2 intensity at120 shocks/min). Each subject underwent a full baseline assessment of erectile function using validated questionnaires and objective penile hemodynamic testing before and after LI-ESWT.

Main Outcome Measures. Outcome measures used are changes in the International Index of Erectile Functionerectile function domain (IIEF-ED) scores, the EHS measurement, and the three parameters of penile hemodynamics and endothelial function.

Results. Twenty-nine men (mean age of 61.3) completed the study. Their mean IIEF-ED scores increased from 8.8 1 (baseline) to 12.3 1 at FU1 (P = 0.035). At FU2 (on active PDE5i treatment), their IIEF-ED further increased to 18.8 1 (P < 0.0001), and 72.4% (P < 0.0001) reached an EHS of 3 (allowing full sexual intercourse). A significant improvement (P = 0.0001) in penile hemodynamics was detected after treatment and this improvement significantly correlated with increases in the IIEF-ED (P < 0.05). No noteworthy adverse events were reported.

Conclusions. Penile LI-ESWT is a new modality that has the potential to treat a subgroup of severe ED patients. These preliminary data need to be reconfirmed by multicenter sham control studies in a larger group of ED patients.

Penile Low Intensity Shock Wave Treatment is Able to Shift PDE5i Nonresponders to Responders: A Double-Blind, Sham Controlled Study

Noam D. Kitrey, Ilan Gruenwald, Boaz Appel, Arik Shechter, Omar Massarwa and Yoram Vardi

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Abstract

Purpose: We performed sham controlled evaluation of penile low intensity shock wave treatment effect in patients unable to achieve sexual intercourse using PDE5i (phosphodiesterase type 5 inhibitor).

Materials and Methods: This prospective, randomized, double-blind, sham controlled study was done in patients with vasculogenic erectile dysfunction who stopped using PDE5i due to no efficacy. All patients had an erection hardness score of 2 or less with PDE5i. A total of 58 patients were randomized, including 37 treated with low intensity shock waves (12 sessions of 1,500 pulses of 0.09 mJ/mm2 at 120 shock waves per minute) and 18 treated with a sham probe. In the sham group 16 patients underwent low intensity shock wave treatment 1 month after sham treatment. All patients were evaluated at baseline and 1 month after the end of treatment using validated erectile dysfunction questionnaires and the flow mediated dilatation technique for penile endothelial function. Erectile function was evaluated while patients were receiving PDE5i.

Results: In the low intensity shock wave treatment group and the sham group 54.1% and 0% of patients, respectively, achieved erection hard enough for vaginal penetration, that is an EHS (Erection Hardness Score) of 3 (p <0.0001). According to changes in the IIEF-EF (International Index of Erectile FunctionErectile Function) score treatment was effective in 40.5% of men who received low intensity shock wave treatment but in none in the sham group (p ¼ 0.001). Of patients treated with shock waves after sham treatment 56.3% achieved erection hard enough for penetration (p <0.005).

Conclusions: Low intensity shock wave treatment is effective even in patients with severe erectile dysfunction who are PDE5i nonresponders. After treatment about half of them were able to achieve erection hard enough for penetration with PDE5i. Longer followup is needed to establish the place of low intensity shock wave treatment in these challenging cases.

Does Low Intensity Extracorporeal Shock Wave Therapy Have a Physiological Effect on Erectile Function? Short-Term Results of a Randomized, Double-Blind, Sham Controlled Study

Yoram Vardi, Boaz Appel, Amichai Kilchevsky and Ilan Gruenwald

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Abstract

Purpose: We investigated the clinical and physiological effect of low intensity extracorporeal shock wave therapy on men with organic erectile dysfunction who are phosphodiesterase type 5 inhibitor responders.

Materials and Methods: After a 1-month phosphodiesterase type 5 inhibitor washout period, 67 men were randomized in a 2:1 ratio to receive 12 sessions of low intensity extracorporeal shock wave therapy or sham therapy. Erectile function and penile hemodynamics were assessed before the first treatment (visit 1) and 1 month after the final treatment (followup 1) using validated sexual function questionnaires and venoocclusive strain gauge plethysmography.

Results: Clinically we found a significantly greater increase in the International Index of Erectile Function-Erectile Function domain score from visit 1 to followup 1 in the treated group than in the sham treated group (mean
SEM 6.7
0.9 vs 3.0
1.4, p 0.0322). There were 19 men in the treated group who were initially unable to achieve erections hard enough for penetration (Erection Hardness Score 2 or less) who were able to achieve erections sufficiently firm for penetration (Erection Hardness Score 3 or greater) after low intensity extracorporeal shock wave therapy, compared to none in the sham group. Physiologically penile hemodynamics significantly improved in the treated group but not in the sham group (maximal post-ischemic penile blood flow 8.2 vs 0.1 ml per minute per dl, p 0.0001). None of the men experienced discomfort or reported any adverse effects from the treatment.

Conclusions: This is the first randomized, double-blind, sham controlled study to our knowledge that shows that low intensity extracorporeal shock wave therapy has a positive short-term clinical and physiological effect on the erectile function of men who respond to oral phosphodiesterase type 5 inhibitor therapy. The feasibility and tolerability of this treatment, coupled with its potential rehabilitative characteristics, make it an attractive new therapeutic option for men with erectile dysfunction.