One man's joy is another man's sorrow

Erectile dysfunction can be severely limiting. The same applies to the opposite: if an erection persists permanently, it can become really dangerous. What to do when erectile tissue does not behave as it should? And what is the actual benefit of testosterone substitution in old age?

What does andrology practice look like in the last 15 years? “Thematic choices for a presentation would include erectile dysfunction (ED), penile curvature, priapism, premature ejaculation, or hypogonadism,” said Ian Eardley, MD, Teaching Hospital Trust, Urology, Leeds (UK). “In the meantime, we have learned, for example, that although erectile dysfunction is (usually) well treatable with oral PDE5 inhibitors, the overall cardiovascular picture of the affected patient must not be forgotten in the routine process. In addition, diagnosis and awareness of the issue of testosterone deficiency increased. New medical therapies for premature ejaculation and Peyronie’s disease were introduced, but met with limited response in international practice. In addition, many new guidelines were again released in 2018.”

Erectile dysfunction after prostatectomy

Among other things, there is a sentence in the new American guidelines (AUA) on erectile dysfunction [1] that calls into question the practice of one or the other urologist or even primary care provider (who follows up on the patients): Early use of PDE5 inhibitors after radical prostatectomy or radiation probably does not improve the ability to achieve spontaneous erection-this should be communicated to patients (level of evidence C). In principle, a contradiction to the Italian study from 1997, with which the chapter of the so-called “penile rehabilitation” began: At that time it could be shown that the spontaneous erectile function of 30 operated men was significantly improved with intracavernosal injections of alprostadil three times a week compared to no intervention in the long-term course [2]. The idea behind this, which would become established in the practice of many physicians in subsequent years, was a preventive one: early, repeated oxygenation of erectogenic tissue reduces fibrosis induced by hypoxia (Fig. 1) [3]. For example, patients were advised to take a PDE5 inhibitor at daily intervals three to four times per week (or even every night) approximately one month after radical prostatectomy. In a 2011 survey of approximately 600 AUA members, 86% reported using some form of penile rehabilitation, with just over half making it available (undifferentiated) to all of their patients. PDE5 inhibitors were by far the first choice. Studies such as the one by Padma-Nathan and colleagues in 2008 [4], which showed low overall response rates and therefore had to be stopped early, may have played a role in the perception of PDE5 inhibitors as a preventive drug, but nevertheless found a clear advantage of sildenafil over placebo (27% vs. 4%) in spontaneous erections after almost one year.

Now, it is the case that the aforementioned first study is easily criticized because of its limited size and the fact that preoperative erectile status did not play a role. Spontaneous erectile functionality was not objective in the patients, i.e., standardized resp. validated, have been determined. And while it quickly became clear in subsequent years that PDE5 inhibitors were efficient and safe in the treatment of ED, their use in prevention (i.e., for the long-term induction of spontaneous erections even after the end of therapy) came increasingly into doubt. In addition to the 2008 study mentioned above, there was another from 2013 on sildenafil [5], as well as one on vardenafil (2008) [6] and tadalafil (2014) [7] – two of which, incidentally, were conducted by the same author as the study in the mid-1990s. They all clearly missed their primary rehabilitation endpoint at the end of therapy, but were able to demonstrate superiority over placebo during the intake phase, ultimately the therapeutic (rather than preventive) approach. For this, an as-needed use of the drug is probably sufficient. It is clear that about one third of all those operated on are capable of spontaneous erections again after a good year. Within this period, about half of the patients respond again to PDE5 inhibitors.

Today, it can be said that the evidence on penile rehabilitation for both intracavernosal and intraurethral alprostadil and vacuum/vibration techniques comes from small, problematic studies with no clearly demonstrated benefit, whereas the factual situation with regard to PDE5 inhibitors appears to be at least mixed, with the vast majority again failing to demonstrate benefit. “Therefore, the caution of the new Guidelines is appropriate at this point,” the speaker explained. “The same is true for a new technique being studied in the ED, called low-intensity extracorporeal shock wave therapy (Li-SWT).” In the European (EAU) and American (AUA) guidelines, the procedure is still considered experimental, and clear recommendations cannot be given (at most, weak indications for use in mild organic ED or in the absence of response to PDE5 inhibitors). Nevertheless, research in the field of “low-intensity extracorporeal shock wave therapy” is currently more intensive than in other areas of ED therapy.

Li-SWT first appeared on the professional scene in 2010, when indications of effective therapy, and even possible cure, of ED through this procedure emerged. Compared to the use for kidney stones, the energy used for this purpose is again significantly lower and lies in the range of 0.09 ^mJ/mm2. Today there are numerous forms resp. Li-SWT study protocols, this ranges from different devices (linear or focused shock wave devices), to different number and type of shock waves per session, to different session frequencies per week. So far, the studies have been of varying quality and some have been suspected of bias, which is why the evidence – including corresponding meta-analyses [8], which showed a rather clear benefit – is still viewed rather critically [9]. The presumed mechanism behind this: Targeted waves into erectile tissue are intended to stimulate neoangiogenesis and thus ultimately restore erectile function in the long term. If the whole thing doesn’t turn out to be “false hype,” this would actually be the first potential cure for ED.

Priapism

What some have too little of, others have too much of: according to the new EAU guidelines, the (painful) permanent erection of the penis, called priapism, can be treated with a penile prosthesis after a minimum of 36 hours of existence or failure of the other measures. When priapism with ischemia persists for up to 12 hours, trabecular edema is still minimal; however, with increasing duration, early endothelial damage and interstitial edema are found. The defects on the endothelium become progressively larger with more than 24 hours of erection until they finally reach their peak with necrosis and transformation of the smooth muscle and fibrosis of the trabecular system after approximately two days. The persistent congestion changes the blood (blood gas analysis): The carbon dioxide content increases, and at the same time the oxygen content and the pH value decrease.

The therapy is therefore about removing the congested oxygen-depleted blood from the corpora cavernosa as quickly as possible. Conservative treatment is initially with local anesthesia and with an aspirate of cavernous blood (corpus cavernosum puncture); cavernous irrigation with saline-heparin solution is then possible. Intracavernosal therapies include the injection of adrenoceptor agonists such as phenylephrine (Firstline), and finally surgical options such as shunting or penile prosthesis. The results of shunting, i.e., surgically created arteriovenous connections (corpora cavernosa and corpus spongiosum), vary depending on the duration of its existence: the longer ischemic priapism persists, the more difficult it is to resolve with a shunt, and the more frequent is severe long-term erectile dysfunction thereafter. Therefore, from the critical threshold of more than 36 hours of priapism, according to the European guidelines, penile prosthesis can be considered, which retrospectively showed a better outcome (i.e., better patient satisfaction, smaller revision rate, and decreased subjective penile reduction), provided that it was inserted early (median 7 days) [10]. The same applies if other therapeutic approaches failed. Despite the recommendation, current practice in Switzerland is unlikely to change: Penile prostheses are not reimbursable in this country.

Testosterone deficiency

While the AUA guidelines clarify that low testosterone levels are a risk factor for cardiovascular disease and patients with testosterone deficiency must be informed accordingly (level of evidence B), they consider the current evidence base insufficient to definitively postulate positive or negative effects of testosterone therapy on rates of cardiovascular events. Thus, the patient could not be advised in one direction or the other. The EAU makes a similar statement, but focuses on serious adverse cardiovascular events (MACE), which have not been validly demonstrated within the normal physiologic range with testosterone substitution (1a). Rather, in men with hypogonadism, testosterone therapy has shown a beneficial effect on cardiovascular risk (1b). In the diagnosis of a testosterone deficiency both guidelines agree so far, there must be a minimum of two tests of a morning sample with biochemical indications of a deficiency (AUA: total testosterone <10.4 nmol/l, EAU: basically <12.1 nmol/l “abnormal”; in the lower gray zone of 8-12 nmol/l, however, measure free testosterone) and corresponding symptoms.

One thing is certain: testosterone decreases over the course of a man’s life. A good fifth of all men over 60 have total testosterone levels below the range of a healthy young man. Such a defect is likely to be at the level of the hypothalamic-pituitary axis, and chronic diseases such as obesity, type 2 diabetes, hypertension or hyperlipidemia also play a role. While the vast majority of studies show that low testosterone is associated with increased cardiovascular risk, the crucial question remains: Are low endogenous testosterone levels genuinely partly responsible for the aforementioned increase in risk, or is the decline with age and chronic disease merely an adaptive response of the body to another cause (i.e., ultimately a marker)? That the latter is true, that it is an independent biomarker of cardiovascular risk, as in ED, is largely clear from looking at the evidence. However, whether testosterone deficiency is really a cause of cardiovascular disease/mortality has not been conclusively determined.

It may seem strange that, in addition to some retrospective studies that showed a clear benefit of testosterone therapy on all-cause mortality, there are also prospective and retrospective studies that found exactly the opposite, namely a (sometimes significant) increase in cardiovascular risk. In 2016, the FDA pointed to numerous limitations of these studies that did not allow a definitive conclusion. Meta-analyses also do not come to a clear conclusion, while one sees the risk increased by 54% (OR 1.54), the other contradicts (OR 1.01) [11,12] – new studies again tend in a positive direction [13–15].

In view of the confusing situation of studies, the following can be stated:

The evidence that low testosterone is a biomarker of increased cardiac risk is good.
Mixed evidence, on the other hand, is found on the risk from intervention in older men with testosterone deficiency.

Testosterone therapy in older men without a history of cardiovascular disease does not appear to be a problem so far, Eardley said of his own practice. In all others, the diagnosis should be carefully considered, well clarified and carefully monitored, and an intermediate position in normal testosterone levels should be targeted.

Source: 74th Annual Meeting of the Swiss Society of Urology, September 5-7, 2018, Lausanne.

Literature:

Burnett AL, et al: Erectile Dysfunction: AUA Guideline. The Journal of Urology 2018; 200(3): 633-641.
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Hatzimouratidis K, et al: Phosphodiesterase type 5 inhibitors in postprostatectomy erectile dysfunction: a critical analysis of the basic science rationale and clinical application. Eur Urol 2009 Feb; 55(2): 334-347.
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