Smooth Muscle Pathology and Erectile Dysfunction

Home , Corpus cavernosum penis, Smooth muscle

Smooth muscle pathology and erectile dysfunction

E Wespes1*

1Department of Urology, C.H.U. de Charleroi, Charleroi, Belgium

Penile erection is a vascular phenomenon that results from smooth muscle relaxation, arterial dilation and venous restriction. The atherosclerosis of the penis that occurs with aging causes a decrease in penile oxygen tension. A reduction of smooth muscle cells has been demonstrated in relation with this change in oxygen tension. Changes in the ratio of penile collagen have also been observed and could explain the decrease in penile elasticity and compliance. Chronic ischemia is, therefore, associated with fibrosis but also with nitric oxide (NO)-cyclic guanosine monopho- sphate. The sensitivity of the a-adrenoceptors on the smooth muscle cells increases with aging. All those modifications can explain the prevalence of erectile dysfunction with aging. Low oxygen tension in prostanoid production may also play a role in the mechanism of ischemia-induced cavernosal fibrosis; however, intracavernous injections of prostaglandin E1 do not seem to modify the intracavernous structures by reducing muscular atrophy. The effects of androgen on libido and sexual behavior are well established, but their role in the human erectile mechanism remains unclear. Several studies performed on animals have demonstrated impacts directly on both the physiological function and the trabecular structure of the corpora cavernosa in rats, dogs and rabbits. However, in humans, no study seems to demonstrate a role of testosterone on muscular atrophy or penile neurologic control. Testosterone treatment alters the human behavior but not penile physiologic processes. Further studies are necessary to explain the real role of testosterone not only on the peripheral mechanism of erection but also on the central control. International Journal of Impotence Research (2002) 14, Suppl 1, S17–S21. DOI: 10.1038= sj=ijir=3900792

Keywords: erectile dysfunction; smooth muscle pathology; aging; androgen; testosterone

Introduction tence tripled from 5.1 to 15%, the probability of moderate impotence doubled from 17 to 34%, whereas the probability of minimal impotence Penile erection is a complex neurovascular phenom- remained constant at 17%. By the age of 70 y, only enon. It involves the coordination of three hemody- 32% portrayed themselves as being free of erectile namic events: increased arterial inflow, sinusoidal dysfunction. smooth muscle relaxation and decreased venous It is estimated that in 1995 there were more than outflow. It also implies the interaction of the brain, 152 million men worldwide who experienced nerves, neurotransmitters and smooth and striated erectile dysfunction; the projection for 2025 shows muscles. An alteration in any of these components a prevalence of 322 million men with erectile may affect the response of the erectile tissue and dysfunction.2 The cause of age-related dysfunction 1 cause erectile dysfunction. is poorly understood and is likely to be multi- The Massachusetts Male Aging Study has re- factorial in origin.3 cently provided a comprehensive epidemiological report on erectile dysfunction, demonstrating the determinant role of age on the physiopathological mechanism of erection. Men between the ages of 40 Can erectile dysfunction be explained by local and 70 y were asked to categorize their erectile structural modifications of the penis? function as potent or either totally, moderately, or minimally impotent.2 In all, 52% of the sample reported some erectile dysfunction. Erectile dys- Using computerized image analysis, the percentage function is an age-dependent disorder: between 40 of smooth muscle cells was measured in patients of and 70 y of age the probability of complete impo- different ages with normal erections. At younger than 40 y, the percentage was 46%, between 41 and *Correspondence: E Wespes, Department of Urology, C.H.U. 60 y it was 40%, and at older than 60 y it was 35%; de Charleroi, Boulevard Zoe¨ Drion 1, 6000 Charleroi, this decrease in smooth muscle content may be Belgium. responsible for the decline in erection in older E-mail: [email protected] men.4 Smooth muscle pathology E Wespes S18 Penile corporal veno-occlusive function is deter- cavernous artery or tissue to a vasoactive drug mined, in part, by the ability of elastic and easily becomes longer with age. These hemodynamic expandable cavernosal tissues to provide adequate alterations can explain the modifications observed compressive and stretching forces on subtunical during nocturnal erections in patients older than draining venules to cause venous outflow resistance. 60 y.14 Aging and vascular risk factors, such as diabetes and hypercholesterolemia, interfere with the histology of penile erectile tissue leading to corporal veno- What is responsible for these alterations? occlusive dysfunction.5,6 The essential factor that determines the ability to achieve normal penile corporal veno-occlusion is the percentage of corpor- Role of ischemic factors al smooth muscle content, whereas the number of elastic fibers or endothelial cells does not seem to correlate with the importance of venous leakage.7 Postmortem studies have revealed that aging is An association has been observed between in- associated with increasing degrees of atherosclerotic creased severity of penile erectile dysfunction and vascular alteration in the arterial bed of the penis.15 altered cavernosal smooth muscle content, and in The exact pathophysiological mechanism of ische- patients with veno-occlusive dysfunction, values of mia-induced fibrosis of the corpus cavernosum is erectile flow rates have been shown to correlate with not clearly understood but it is likely to be caused by percentage of cavernosal smooth muscle content.5,7 hypoxia-induced overexpression of transforming Patients with a low percentage of smooth muscle growth factor beta 1 (TGF-b1).16 TGF-b1isa content exhibited higher flows to maintain the pleotrophic cytokine that has been shown to erection. increase collagen synthesis in corpus cavernosum The flaccid penis is deformable, extensible and smooth muscle cells in vitro. Under ischemia elastic in its longitudinal axis. The length changes of conditions, TGF-b1 induces its own messenger the flaccid penis provoked by a maximum manual RNA (mRNA), leading to a further increase in stretching of the glands have been correlated with TGF-b1 synthesis that reinforces the development age and show a significant decrease.8 of severe fibrosis.16 Measuring the differential Changes of elastic fibers or collagen types can mRNA expression for various growth factors in provoke mechanical alterations of the penis, which young and aging rat penile tissues, it has been reduce its elasticity and compliance. The collagen in demonstrated that TGF-b1 is higher in older rats the corpus cavernosum tissue is predominantly compared with young rats and seems to confirm the types I, III and IV. Type I collagen, which forms role of TGF-b1 and the atrophy of cavernous smooth stiff bands of fibrils, has been shown to be less muscle replaced by fibrosis.17 mRNA expression of compliant than type III collagen, which is found nerve growth factor is reduced in older rat penile predominantly in distensible elastic tissue and is tissues. Therefore, age-related neuronal atrophy may essential for normal tensile strength. The endothe- be caused by the reduced synthesis or availability of lial cells are believed to be responsible for the target-derived neurotrophic factors. secretion of type IV collagen, which forms the In man, a correlation between oxygen tension in basement membrane of blood vessels. In the penis, the penis has been demonstrated with the percen- there is an equal abundance of types I and IV tage of smooth muscle fibers.18 The number of collagen with concomitant diminution of type III.9,10 muscular fibers is therefore dependent on good Although one study reported a decreased ratio of oxygenation of the penis. type III collagen with senescence,9 another study It seems that the histological alterations start did not note a similar significant difference in the distally in the very small penile arteries, which ratios with aging.10 These alterations that are produces replacement of smooth muscle cells by observed with aging in collagen configuration may fibrosis.6 The patient develops a corporeal veno- also be related in another way to advanced glycosy- occlusive dysfunction, whereas the cavernous ar- lation products.11 The elastic fibers are reduced in teries do not demonstrate any pathological alteration the aging penis.12 at the Doppler examination. Later, the pathophysio- All these modifications have a role on penile logical mechanism progress provokes severe arterial hemodynamic changes. A change in arterial flow disease. At this stage, important fibrosis of the velocity in patients with a normal response to corpus cavernosum is observed. Another important pharmacological injection was evaluated. A statisti- role of cavernosal oxygen tension appears to be the cally significant decreasing tendency of peak sys- regulation of prostanoid production in the corpus tolic velocity with age was revealed.13 The greatest cavernosum. It has been shown that low oxygen decrease was observed between patients in the third tension decreases basal and acetylcholine-stimu- and fourth decades of life. These data demonstrate lated production of prostacyclin, thromboxane A2, that cavernous arterial flow during pharmacological prostaglandin F2a and prostaglandin E2 by inhibiting erection decreases, and the response time of the the activity of prostaglandin H synthase.19 Low

International Journal of Impotence Research Smooth muscle pathology E Wespes S19 oxygen tension in prostanoid production may also Many investigators believe that androgens act play a role in the mechanism of ischemia-induced primarily to stimulate or maintain the activity of the cavernosal fibrosis, because decreased levels of enzyme NOS. Their conclusion is supported by prostaglandin E1 correlated with the increased several investigations. expression of TGF-b1 mRNA in human corpus The intracavernosal pressure increase during cavernosum smooth muscle cells.19 erection in castrated rats is not enhanced by Oxygen tension appears also to be an important systemic administration of nitroglycerin whereas regulator of nitric oxide (NO) synthesis. Because NO pressure is increased in testosterone replacement is one of the major neurotransmitters in erection, rats given the same dose of nitroglycerin.26 low oxygen tension could explain the decrease in NADPH diaphorase staining decreases by more relaxation of smooth muscle fibers as it has been than half in cavernosal nerves 10 days after castra- demonstrated in in vitro studies.20 tion but returns to near normal values following In rats, staining for vasoactive intestinal polypep- testosterone replacement.27 Based on the conversion tide showed no difference among the age groups, of arginine to citrulline to measure NOS activity, whereas a difference was observed for NO synthase there is decreased NOS activity in castrate as (NOS)-containing nerve fibers. The number of NOS compared to intact or testosterone replacement fibers was reduced by half in old rats. These findings animals.28 Measurements of NOS enzyme protein emphasize the role played by NO rather than showed that in castrated animals there is less than vasoactive intestinal polypeptide in erectile phy- half the quantity of NOS protein as in testosterone siology, and a reduction of NOS nerve fibers may be replacement rats.29 the most important neurological factor of age-related In adult rats, the decrease in NOS activity that changes.21,22 followed castration is restored with androgen replacement, whereas no additional NOS activity is observed when intact animals were given additional androgens.30 Role of hormonal factors: testosterone In dogs, castration leads to a decline in the ratio of intracavernosal pressure to peak systolic pressure and there is also evidence of higher outflow rates in Beside the role of oxygen on erectile function, the the castrate animals.31 A decline in the magnitude of concept that androgens affect the male erectile the induced intracavernosal pressure rise during response is still under investigation and incomple- erection is observed but the investigators attributed tely defined. Possible regulatory roles for androgens the lower intracavernosal pressure to be accompa- in penile erection physiology have been mostly nying reduction in mean arterial pressure.31,32 studied in animals, with focus given to the hemo- In rabbits, with strips of cavernosal tissue precon- dynamic characteristics and NO neurotransmission tracted with a-adrenergic agonists, electrical field involved in erectile responses. However, general- stimulation caused a greater degree of relaxation in izations regarding androgen control in the erection strips from castrate than from intact animals.33 The physiology of humans remain uncertain. More contraction in response to norepinephrine may also importantly, the exact molecular mechanism of be hormonally dependent, with strips from intact androgen action in erectile function has not been rabbits showing a greater degree of contraction than described. Using different animals, several investi- tissues from castrates in response to the same gators evaluated the consequences of androgen concentration of the agonist.34 Relaxation in response deprivation (castration) and androgen replacement to field stimulation was greater in castrated than in (testosterone administration following castration) on intact animals, although relaxation in response to NO a range of regulatory features concerning penile donor drugs was not different in the two groups, erection, intracavernosal hemodynamics in vivo and suggesting that basal NOS may be adequate to a1-adrenoceptor expression, neuronal NOS (nNOS) mediate the erectile response. An important differ- expression and activity, phosphodiesterase 5 activ- ence between the rabbit and rat models is the report ity, and smooth muscle amount in isolated corpus that nonadrenergic noncholinergic (NANC) fibers are cavernosal tissue. reduced in castrated rats but are increased in Androgen receptors have been identified in the castrated rabbits.27 cavernosal tissue of most mammalians.23,24 In the Androgen dependence was shown for nerve- rat, cavernosal androgen receptor activity varies stimulated intracavernosal pressures, a1-adrenocep- widely with age, with maximal levels at puberty tor content in corpus cavernosal tissue, and corpus and markedly lower levels thereafter. This age- cavernosal smooth muscle integrity. Androgen le- related reduction in the number of androgen vels had no particular effect on nNOS biochemical receptors is androgen mediated and is not reversi- measurements in the corpus cavernosum. Androgen ble. The age-dependent decline in androgen recep- replacement produced an increased biochemical tor coincides with, and appears to be responsible measurement of phosphodiesterase 5 in the corpus for, the cessation of penile growth.25 cavernosum. The sum of these findings indicates

International Journal of Impotence Research Smooth muscle pathology E Wespes S20 that androgen deprivation causes functional and=or testosterone on the human mechanism of erection structural changes in the corpus cavernosum un- has to be established. The actual treatments at our related to adrenergic or nNOS-based mechanisms, at disposal can improve erectile rigidity but do not least in the rabbit, that affect penile erection.35 cure erectile impotence. New, potentially useful In normal men, testosterone treatment does not therapeutic modalities need to be developed and the increase the frequency of nocturnal penile tumes- application of gene therapy might produce a new cence (NPT) episodes but does increase the rigidity option for the treatment of erectile dysfunction. of their erections, suggesting that testosterone acts on the cavernosal arterioles to control blood flow into the sinuses.36 References The episodes of NPT and the quality of sponta- neous erections are diminished in older men and 1 Lue TF, Tanagho EA. Physiology of erection and pharmaco- hypogonadal men and treatment with gonadotropin logical management of impotence. J Urol 1987; 137: 829 – 833. or testosterone improves the quality of erection and 2 Feldman HA et al. Impotence and its medical and psychoso- NPT frequency. Testosterone replacement is impor- cial correlates: results of the Massachussetts Male Aging tant for sleep-associated erections but not for Study. J Urol 1994; 151:54– 61. erection in response to fantasy or visual erotic 3 Aytaç IA, McKinlay JB, Krane RJ. The likely worldwide 37 increase in erectile dysfunction between 1995 and 2025 and stimulation. some possible policy consequences. Br J Urol Int 1999; 84:50– Although androgens are known to be essential for 56. libido, further investigations are still needed to 4 Wespes E, Moreira de Goes P, Schulman CC. Age-related resolve their role in the regulation of human penile changes in the qualification of the intracavernous smooth muscles in potent men. J Urol 1998; 159: 379 (abstract). erection. 5 Nehra A et al. Mechanisms of venous leakage: a prospective clinicopathological correlation of corporeal function and structure. J Urol 1996; 156: 1320 – 1329. Can the intracavernous structures be improved 6 Wespes E et al. Corporeal veno-occlusive dysfunction: a distal or restored? arterial pathology? J Urol 1998; 160: 2054 – 2057. 7 Wespes E et al. Corporeal veno-occlusive dysfunction predominantly intracavernous muscular pathology. J Urol 1997; 157: 1678 – 1680. Hypoxia in patients with impotence of vascular 8 Bondil P et al. Clinical study of the longitudinal deformation origin induces the expression of TGF-b1, which of the flaccid penis and of its variations with aging. Eur Urol produces collagen synthesis in the corpus caverno- 1992; 21: 284 – 286. sum and, therefore, fibrosis of the penis.16 Prosta- 9 Padma-Nathan H et al. The effects of aging, diabetes, and glandins seem to be able to suppress this collagen vascular ischemia on the biochemical composition of collagen found in the corpora and tunica of potent and impotent men. synthesis in primary cultures of human corpus Int J Impot Res 1990; 2:75– 76. cavernosum smooth muscle cells and may have the 10 Luangkhot R et al. Collagen alterations in the corpus potential to prevent fibrotic lesions associated with cavernosum of men with sexual dysfunction. J Urol 1992; vasculogenic impotence. Intracavernous prostaglan- 148: 467 – 471. 11 Jiaan DB et al. Age-related increase in an advanced glycation din E1 (PGE1) injection would result in oxygenation end product in penile tissue. World J Urol 1995; 13: 369 – 375. of the corpora cavernosa and perhaps remodeling of 12 Akkus E et al. Structural alterations in the tunica albuginea of the penile connective tissue. However, no increase the penis: impact of Peyronie’s disease, ageing and impotence. in the percentage of smooth cells quantified on Br J Urol Int 1997; 79:47– 53. biopsies performed during treatment has been 13 Chung WS, Park YY, Kwon SW. The impact of aging on penile hemodynamics in normal responders to pharmacological observed in patients treated by intracavernous injection: a Doppler sonographic study. J Urol 1997; 157: 38 PGE1 injection. It is well known that what is 2129 – 2131. observed in vitro cannot always be applied in vivo. 14 Zimmern P, Leach GE, Yao J, Wolde-Tsadik G. Crite`res de 1 Improvement in the erectile quality in patients normalite´ de Rigiscan chez l’homme aˆge´. Prog Urol 1999; 9: 37 – 44. treated with intracavernous PGE1 injection would 15 Bossart MI, Spjut HJ, Scott FB. Ultrastructural analysis of be due to psychogenic effects rather than modifica- human penile corpus cavernosum. Urology 1980; 15: 448 – tions of the intracavernous structures. 456. Gene therapy may be applied to human erectile 16 Moreland RB. Is there a role of hypoxemia in penile fibrosis: a tissues and several approaches have been pro- viewpoint presented to the Society for the Study of Impotence. 39,40 Int J Impot Res 1998; 10: 113 – 120. posed. 17 Dahiya R et al. Differential gene expression of growth factors in young and old rat penile tissues is associated with erectile dysfunction. Int J Impot Res 1999; 11: 201 – 206. Conclusions 18 Sattar AA et al. Cavernous oxygen tension and smooth muscle fibers: relation and function. J Urol 1995; 154: 1736 – 1739. 19 Moreland RB et al. PGE1 suppresses the induction of collagen Organic erectile dysfunction results from alterations synthesis by transforming growth factor-b1 in human corpus cavernosum smooth muscle. J Urol 1995; 153: 826 – 834. of the intracavernous structures, mainly smooth 20 Kim N et al. Oxygen tension regulates the nitric oxide muscle atrophy, and could be explained by athero- pathway: physiological role in penile erection. J Clin Invest sclerotic lesions and ischemic factors. The role of 1993; 91: 437 – 442.

International Journal of Impotence Research Smooth muscle pathology E Wespes S21 21 Garban H et al. Effect of aging on nitric oxide-mediated penile 31 Muller SC, Hsieh JT, Lue TF, Tanagho EA. Castration and erection in rats. Am J Physiol 1995; 268: 467 – 475. erection: an animal study. Eur Urol 1988; 15: 118 – 124. 22 Carrier S et al. Age decreases nitric oxide synthase-containing 32 Lin SN et al. Castration may not affect the penile erection nerve ﬁbers in the rat penis. J Urol 1997; 157: 1088 – 1092. ability in terms of peripheral neurocavernous mechanism in 23 Horwitz KB, Horwitz LD. Canne vascular tissues are targets for dogs. J Urol 1990; 143: 172 – 174. androgens, estrogens, progestins, and glucocorticoids. J Clin 33 Holmquist F, Persson K, Bodker A, Anderson KE. Some pre- Invest 1982; 69: 750 – 758. and post-junctional effects of castration in rabbit isolated 24 Takane KK, Wilson JD, McPhaul MJ. Decreased levels of the corpus cavernosum and urethra. J Urol 1994; 152: 1011 – 1016. androgen receptor in the mature rat phallus are associated 34 Baba K. Effects of testosterone on smooth muscle in the with decreased levels of androgen receptor messenger ribonu- isolated rabbit corpus cavernosum penis. Jpn J Urol 1993; 84: cleic acid. Endocrinology 1991; 129: 1093 – 1100. 1783 – 1790. 25 Takane KK, George FW, Wilson JD. Androgen receptor of rat 35 Traish AM et al. Effects of castration and androgen replace- penis is down-regulated by androgen. Am J Physiol 1990; 258: ment on erectile function in a rabbit model. Endocrinology E46 – E50. 1999; 140: 1861 – 1868. 26 Mills TM, Wiedmeier VT, Stopper VS. Androgen maintenance 36 Carani C, Scuteri A, Marrama P, Bancroft J. The effects of of erectile function in the rat penis. Biol Reprod 1992; 46: testosterone administration and visual erotic stimuli on 342 – 348. nocturnal penile tumescence in normal men. Horm Behav 27 Zvara P et al. Nitric oxide mediated erectile activity is a 1990; 24: 435 – 441. testosterone dependent event: a rat erection model. Int J Impot 37 Zini D et al. Sexual behavior of men with isolated hypogona- Res 1995; 7: 209 – 219. dotropic hypogonadism or prepubertal anterior panhypopitui- 28 Lugg J, Rajfer J, Gonzalez-Cadavid NF. Dihydrotestosterone is tarism. Horm Behav 1990; 24: 174 – 185. the active androgen in the maintenance of nitric oxide- 38 Wespes E, Sattar AA, Noe¨l JC, Schulman CC. Does prosta- mediated penile erection in the rat. Endocrinology 1995; 136: glandin E1 therapy modify the intracavernous musculature? 1495 – 1501. J Urol 2000; 163: 464 – 466. 29 Chammes SL et al. The effect of androgen on nitric oxide 39 Champion HC et al. Gene transfer of endothelial nitric oxide synthase in the male reproductive tract of the rat. Fertil Steril synthase to the penis augments erectile responses in the aged 1995; 63: 1101 – 1107. rat. Proc Natl Acad Sci USA 1999; 96: 11648 – 11652. 30 Garban H et al. Restoration of normal adult penile erectile 40 Wessells H, Williams SK. Endothelial cell transplantation into response in aged rats by long-term treatment with androgens. the corpus cavernosum: moving towards cell-based gene Biol Reprod 1995; 53: 1365 – 1372. therapy. J Urol 1999; 162: 2162 – 2164.

Appendix able shrinkage of the penis within 2 y. You can measure it. So the shrinkage is due to a decrease of the smooth muscle cells. Otherwise, you can Open discussion following Dr Wespes’ presentation objectively measure the shrinkage of the penis when you make a depletion of androgens in prostate cancer. Dr Porst: In your relatively small study you found Dr Hatzichristou: When you say that testosterone that androgen depletion did not have an impact on seems not to modify penile erection in man, you are the concentration of smooth muscle cells. On the talking about its action on the corpora cavernosa. other hand, there are publications that have proven You’re not talking about erection. When we say that with castration we see an apoptosis of smooth erection, we do know that we need testosterone for muscle cells. Thus, these findings are contradictory the whole erectile process. The question I have is the to your finding. following: Did you notice the decrease in the Dr Nehra: And that castration was done in very amount of smooth muscle at the site of the corpora young rats. used for self-injections? Dr Wespes: There are several studies concerning Dr Wespes: In the corpora, we expect to have less testosterone. We have very few receptors of testos- and less smooth muscle over time. terone inside the human penis. When you do all the Dr Hatzichristou: How can you explain that we have in vitro studies and when you inject testosterone, patients who have been in injection therapy for there is no modification of the answer. So it seems more than 10 y who have not needed their dosages of that in the in vitro study testosterone does not the vasoactive drugs increased? influence the answer. I’ve shown, of course, in a Dr Wespes: Most of the time the patient does the small study of patients with hypogonadism, a injection at the same level on the same site, even if resultant decrease of percentage of smooth muscle you ask him to change. So, in fact, you have only a cells. local restriction of the smooth muscle. Dr Porst: But these patients who have withdrawal of androgens due to prostate cancer have a consider-

International Journal of Impotence Research