J.I. Martínez-Salamancaa, C. Martínez-Ballesterosa, L. Portilloa, I. Moncadab y J. Carballidoa
aHospital Universitario Puerta de Hierro-Majadahonda, Universidad Autónoma de Madrid, Madrid, Spain
bHospital Sanitas-La Zarzuela, Madrid, Spain
Introduction: Radical prostatectomy in all its approaches is the treatment of choice for localized prostate cancer and especially in young, sexually active patients with a desire to keep their sex life. In addition to the well-known and defined postoperative erectile dysfunction, erectile silent period causes, in many patients (9-1%), structural changes, in the penile structure, sometimes irreversible. These tissue changes, resulting in a loss of length and girth, that concern patients.
Objective: To systematically review to date published data in the literature regarding penile changes after radical prostatectomy.
Material and methods: We performed a systematic search in: PubMed, EMBASE, Cochrane, SCOPUS, Science Citation Index period January 1990 to September 2009 for the terms “prostatectomy”, “organ size”, “fibrosis”, “sexual activity”, “erectile dysfunction”, “penile size”, “radical prostatectomy”, “prostatic neoplasms”, “body weights” and “penis measures”. Seven series of patients were selected for analysis.
Results: We described the different measurement methods and their potential biases and differences. Also, we reviewed main physiopathogenic theories to explain this phenomenon. Finally, we detail the results of different series of patients reported.
Conclusions: It seems to be a proven fact that the penis undergoes major changes in its length and girth after radical prostatectomy. Several authors have communicated the data of their series and the different treatment options (5PDE inhibitors, vacuum devices, penile extenders, etc.). Strategies addressed to preserve and protect cavernous tissue and tunica albuginea after the procedure, as well as to increase oxygenation and allow erection to be recovered in the shortest posible time positive will impact on the quality of life of our patients.
Key words: Prostate cancer. Radical prostatectomy. Penile lenght. Penile girth. Penile changes. Erectile dysfunction. Quality of life.
Radical prostatectomy (RP) represents the main therapeutic option in patients with clinically localized prostate cancer 1. Despite continuing improvements in surgical technique, erectile dysfunction (ED) represents a problem to be treated insofar as it affects the quality of life of a large percentage of patients (20-97%) after surgery 2,3. It should also be taken into account that men who suffer from postoperative ED also can perceive loss of length and penile circumference (thickness) 4. Curiously, this aspect has only received marginal attention in the different publications. Several studies have evaluated the outcomes of sexual and urinary function following RP, but only a few have focused on the loss of penile length after surgery 4-7. In these studies, a penile shortening was observed between 9-71% of patients included in different analyzes. This is an important finding because the loss of penile volume can have a significant negative impact on patients’ quality of life, even for those who recover their basal erectile function after surgery, with or without 5-phosphodiesterase inhibitors 5,8.
The pathogenesis of this phenomenon is still under discussion. The hypothesis of a decrease in total urethral length as a result of the removal of the prostate (hence the segment of the prostatic urethra) is not compatible with the pelvic anatomy. The membranous urethra attaches to the urogenital diaphragm and, therefore, is not easily retractable from the pelvic floor. Most authors suggest that mechanisms of fibrosis production that are established in the cavernous tissue during the postoperative period of erectile silence may lead to a reduction in the distensibility and volume of the corpora cavernosa 9-11. Mulhall has recently proposed a hypothesis regarding the genesis of changes in penile length. This author divides the changes and thus their pathophysiological mechanism in two periods. An early and reversible period as a result of a theoretical sympathetic overstimulation and a later period based on the permanent structural alterations resulting from the denervation caused by apoptosis, hypoxia and subsequent collagenation 12. To better elucidate these fascinating hypotheses it would be necessary to perform measurements of penile length immediately after surgery. In addition, if this pathogenic model is valid, changes in the penis should be minimized with a rapid recovery of erectile function.
In this review we have tried to include all the research that to date contribute evidence in the knowledge of this emerging phenomenon.
Material and methods
We performed a systematic search in PubMed, EMBASE, Cochrane, SCOPUS, Science Citation Index during the period from January 1990 to September 2009 for the terms “prostatectomy”, “organ size”, “fibrosis”, “sexual activity”, “erectile Dysfunction, penile size, radical prostatectomy, prostatic neoplasms, body weights and penis measures. We analyzed all the articles according to the different levels of evidence according to the Center for Evidence-Based Medicine, Oxford. The total number of studies analyzed are level 3b (individual case-control studies) and 4 are case series and cohort studies and low-quality cases and controls.
Methodology and controversies in penile measurement
McCullough, in a very interesting review 10,11, states that after having made countless assessments of the length of the post-RP penis can state several facts. It is important to make different observations at multiple times. The exact nature of the measurement should be clearly identified. Some studies have used penis length in stretching (PLS) and others length in erection (EL) after injection with vasoactive agents. Wessels et al13 clearly demonstrate that PLS correlates with EL. The technique of measuring penis length is also important. Authors should indicate whether they have used a tape measure or rigid rule and whether the tissue-supra pubic fat pad (Tables 1 and 2) has been included.
Although the degree of penile stretching may seem to affect the results, interobserver observations at the University of New York varied just under 20mm. McCullough claims to have discovered that measurements that included glans length tend to be more variable, unlike measurements up to the preputial balane groove. The glans seems more malleable and therefore more able to be distorted than the body of the penis. In a longitudinal study of penile length after RP, the length of the penis with a rigid rule from the symphysis (including the fat pad) to the preputial balane groove was measured and lengths comparable to those published previously. 11
Supposedly, the penis glans is more or less comparable in length to the fat pad. The circumference of the penis is more difficult to measure in the state of flaccidity than in the elongation due to the redundancy of the skin when the penis is flaccid. The erect circumference is much easier to measure reliably, since the redundant skin is stretched as an effect of the same erection.
For this group, the ambient temperature is not a confusing factor, since they assure that most of the offices are uniform in temperature in winter or summer. 11 Also, these investigators carry out PES / EL measurements both by the physician and the female nursing staff. The interobserver variation was less than 20 mm. Therefore, the sex of the observers does not seem to make any significant difference.
In contrast, Gontero et al claim that any minimal variability in the environment, the temperature of the room and even the sex of the evaluator can influence the final value of the measurement. 14
Numerous methodological aspects should be considered when evaluating the effects of RP on penile morphology. The number of patients should be adequate to the power sought in the study, and most studies so far include a limited number of patients. Also important are the two points used to define the length of the penis.
The classic point used is from the tip of the glans to the pubic symphysis, however, other researchers exclude the measurement to the bone with the idea of excluding the thickness of the prepubic fat. This fat pad may have been resized during the 12 months following surgery, although it is unlikely that it has changed much in the days between surgery and removal of the catheter.
Variations in the technique of measuring pre and postoperative penile length may also affect the results. In addition, the person who takes the measurements of the penis is of vital importance and should be the same in both periods, pre and post-surgery. Likewise, the timing of the postoperative measurement is also likely to affect outcomes. Finally, it is important to collect the comorbidity profiles of the patients. Although in Gontero’s work 80% of the patients had preoperative DE, it could be inferred that they were not healthy; however, an international low erectile function index score does not necessarily indicate an organic etiology. This issue is especially important when attempting to extrapolate this data to individual clinical practice15.
Bases and pathogenic theories
The data obtained with animal models of lesion of the cavernous nerve show histological and morphological changes of the tunica albuginea, which can represent the substrate of the overall final damage of the penis. The changes can be mitigated with the administration of 5-PDE inhibitors in the postoperative period. There appears to be an increasing number of evidence showing the morphological changes occurring during the neuropraxia period after RP with neurovascular preservation, resulting in the final structural damage of the organ. The histological changes that occur appear to reflect large morphometric changes of the penis, although no study has prospectively and simultaneously examined the histological changes of the corpus cavernosum and morphometrics of the penis. Morphometric changes appear to be worse in men who suffer the highest degree of postoperative ED. 11
Although there is evidence that penile rehabilitation strategies can cause long-term functional improvement, but not so penile rehabilitation strategies post-prostatectomy can avoid morphological changes occurring within the corpora cavernosa or loss of length and thickness of the penis. More prospective, randomized studies are needed to elucidate the best surgical technique (open, laparoscopic or robotic) and penile rehabilitation strategy to maximize functional recovery and minimize damage to the cavernous tissue after surgery.
From the histological point of view, apoptosis has been demonstrated in rats after penile denervation, 16 and the subsequent phenomena of fibrosis in the cavernous tissue have recently been evaluated and described, changes that could contribute to ulterior penile shortening 9.
Mulhall et al reflect on this mechanism and base the changes on four basic principles:
- Structural anatomy of the penis.
- Cavernous nerve injury and its associated changes.
- Hypoxia of the cavernous tissue and its consequences.
- Hyperactivation in sympathetic innervation. 12
The corpora cavernosa are composed of two different tissues: the trabecular smooth muscle and the tunica albuginea. The smooth muscle of the penis is subject to contractile and relaxation forces. Relaxation is achieved through the release of nitric oxide (NO) and the generation of second messengers, such as GMPc and AMPc17. The smooth muscle has an overall contractility tone and is under the control of erectolytic neurotransmitters, such as adrenaline. Some of the factors that result in decreased NO secretion (as occurs in patients with lower motor neuron lesions, for example, diabetic or after RP) lead to relaxation or decrease in smooth muscle compliance and can lead to loss of length. It is assumed that even in the best scenarios of bilateral neurovascular preservation in expert hands, some type of damage (neurapraxia) occurs on the cavernous nerve. It has also been suggested that the tunica albuginea may undergo structural changes after RP, but, except for some data on Peyronie’s disease after RP, there is currently no evidence to support structural alterations in the albuginea9.
It has been shown that nerve damage leads to structural alterations in the organs or terminal tissues. Carrier et al18 in 1995 demonstrated that in a murine model with bilateral section of the cavernous nerve there was a significant reduction in NO synthesis as fast as 3 weeks after injury and that these reductions were maintained at 6 months.
Klein et al16 demonstrated that after injuring the cavernous nerve, the smooth muscle underwent apoptotic changes, and these results were confirmed by User et al 19 the latter group showed that the penis weight and the DNA content were significantly reduced and more intense when the nerve section was bilateral. In particular, apoptosis was more evident in the subalbugal zone of smooth muscle19.
Leungwattanaki et al20 also demonstrated that cavernous neurotomy leads to the supregulation of fibrogenic cytokines and the subsequent collagenization of the trabecular smooth muscle.
Similarly, it is postulated that the chronic absence of erectile activity (erectile silence after surgery) leads to a state of hypoxia in the cavernous tissue. In a flaccid state, the corpora cavernosa21 have a venous pO2 that favors the secretion of fibrogenic cytokines, such as TGF-β. During erection, the smooth muscle is oxygenated and this results in the secretion of endogenous prostaglandins 1, which in turn inhibit the production of fibrogenic cytokines21.
Therefore, the health of the erectile tissue is based to a certain extent on the balance between erection and sagging. In the patient who does not have erectile activity, as is often the case in the early stages after RP, the balance is tilted in favor of hypoxia and the production of collagen, which, if not avoided, will produce definitive damage to the cavernous tissue.
Sattar et al22 demonstrated that there may be a correlation between smooth muscle content and intracavernous pO2 levels. Moreland et al 21,23,24 published in cell culture models that cavernous smooth muscle cells when exposed to hypoxic conditions preferentially secrete TGF-β, and this alters the release of endogenous prostaglandins 1 once the cells are exposed to normoxia conditions.
Finally, the concept of sympathetic hyperinervation refers to the ability of autonomic sympathetic fibers (inhibit erection-decrease size in flaccidity) as opposed to parasympathetic (favor erection-enlargement in flaccidity) to regenerate more rapidly after injury. This leads to an increase in sympathetic tone, which gives the penis smaller size25.
To synthesize these concepts into a working hypothesis, changes in penile length can be divided into early and late. In relation to the immediate changes, the response to neural damage that occurs during PR, the nerves of the cavernous body undergo Wallerian degeneration, and in the early phase, when the sympathetic nerve function is increased, the penis is a Hypertonic organ, showing sympathetic hyperactivation. Given that the smooth muscle of the penis is very contractile in response to adrenergic tone, the result is a penis that patients often refer to as buried. Mulhall12 states that it has been his experience that this hypertonic state is most pronounced within the first 3-6 months after surgery.
Late structural changes are the result of true irreversible structural alterations in the smooth muscle of the cavernous body. These structural changes are most likely a combination of factors:
- Denervation of apoptosis associated with neural lesions.
- Cavernous collagenation induced by hypoxia in patients who suffer delayed return of erectile function.
Different series of cases and treatments
Gontero et al14 monitor changes in the penis after RP by taking measurements at various intervals from the time of catheter withdrawal to 1 year after surgery. They also evaluate whether surgery with neurovascular preservation and recovery of sexual function may have some effect on the final size of the penis. These authors demonstrate that neurovascular preservation and recovery from erectile function were independent predictors of loss of penile length 12 months after surgery. This group is the first to demonstrate in its multivariate analysis that the state of erectile function after surgery is a predictor of loss of length14 (Tables 1 and 2)
Mulhall15 reports that the various published studies indicate that permanent structural alterations in the first 4 months after surgery are less frequent26, but Gontero’s work finds that the maximum reduction in penile length occurs at the time of withdrawal from the probe. This same author has not been able to satisfactorily explain the mechanism of such spectacular loss of length in such a short period; this could be related to the percentage of nerve preservation in his series14.
On the other hand, these same authors affirm that the degree of neurovascular preservation predicts the degree of venous leakage as well as the period of time until the beginning of this15. Another possible explanation for the phenomenon observed by Gontero would be the reduction of force applied to the penis at the time of removal of the probe. This hypothesis would be supported by the absence of involvement in the penile circumference values at that time.
Dalkin et al27 carried out a study to see if early intervention after RP with a DV could prevent changes in penile erectile tissue, such as shortening. This study presents a total of 42 patients undergoing RP with neurovascular preservation with good preoperative sexual function who were submitted to penile measurement by a single preoperative investigator and 3 months after surgery. Daily use of DV was initiated the day after catheter removal and continued for 90 days. A decrease of greater than or equal to 1.0cm in penile length was considered significant. Thirty-nine of the 42 men completed the study. In men (36) who used DV at least 50% of possible days, only 1 (3%) had a decrease of 1.0cm. Of the three men who used it less days, two (67%) had a reduction of 1.0cm. When compared to previous studies, where 48% of men post-surgery had a significant reduction in penile length, it appears that early intervention with daily use of a DV results in a significantly lower risk of loss of length Penis (p <0.0001)27.
Zippe et al28 demonstrate that patients successfully use DV after PR, confirming their safety and tolerability. Numerous studies have been published demonstrating that patients have had good-quality erections using DV in 84-95% of cases29-34. Most patients report an improvement in sexual life31, observed by an increase in quality and frequency of intercourse and orgasm. As a result, there was an improvement in marital relationships and in the self-esteem of patients 30-32,35.
Colombo et al36 published a series of 52 patients in which daily use of DV without constriction ring, regardless of coitus, resulted in an improvement in spontaneous erections in 60% of the men studied.
Raina et al37 showed that the use of DV after RP (with and without neurovascular preservation) improved the results of the international erectile function index, patients experienced preservation of penile length and rapid return of spontaneous erections38.
The changes that occur in the penis after prostatectomy appear to be the result of a multifactorial process in stages, which is directly related to nerve damage and absence of erection (hypoxia). It also represents one more objective in the complex process of sexual rehabilitation and is a permanent complaint in a large majority of patients.
Strategies to preserve and protect cavernous tissue and tunica albuginea after the procedure, as well as those that increase oxygenation and allow recovery of erection in the shortest possible time will have a positive impact on the quality of our patients.
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