Paper Urol. int. 1982;37:160-171 How Important Are Prostaglandins in the Urology of Man? D. H. Bach Walker Department of Urology, University of Bonn, FRG Key Words Prostaglandins Male genital tract Steroid hormones Prolactin Abstract Although the discovery of prostaglandins (PGs) is to be attributed to investigations into the semen plasma and the accessory sex glands, it has been the female genital function and its relationship to the PGs rather than the male genital function which has been the subject of intensive research in the past. This survey is intended to provide some idea of which known PGs play a part in the function of the male genital tract and of the urinary bladder. PGs, above all PGE, occur in testicle tissue, have a modulating effect on the LH-dependent steroid synthesis and possibly influence sperm density and sperm function. The PGs certainly play a part in the motility of the vas deferens and participate decisively in blood flow regulation in male genitals. The basal tone and contractility of the testicle capsule are partly controlled by PGs. Connections between reduced PGE levels in semen plasma and infertility are discussed. PGs are partly responsible for the basal tone and the emptying mechanism in the urinary bladder, and are transmitters acting between the nervous system and the muscular stimulus response. The significance to be attributed to PGs and the effect of urinary bladder carcinomas on their synthesis is still largely unclear. Animal studies and in vitro investigations reveal interesting aspects. The seminal vesicle synthesizes very large amounts of PGs, which probably display their action in the semen plasma and with this also in the female genital tract; there is a close relationship between the steroid and prolactin effects and PGs in the prostate gland. Together with prolactin, PGs are modulators of the stimulatory effects of steroids on this organ, on the other hand, the PGs formed in the prostate gland also exert a certain ‘remote action’ in semen and in the urinary bladder. The importance of PGs in inflammatory changes in the prostate gland and the therapeutic possibilities for these clinical symptoms which may result from influencing PGs can be seen from some studies, but it is not yet possible to draw a final conclusion at this point in time. Dr. H. Walker, Hessenring 29, D-3440 Eschwege (FRG) Prostaglandins in Urology 161 Downloaded by: Vanderbilt University Library 18.104.22.168 - 10/27/2017 11:05:05 AM Introduction The history of prostaglandins starts with the observation that substances which cause functional changes in an entire organism and above all in the female genital tract occur in seminal fluid. The fundamental discovery was made by Kurzrok and Lieb  in 1930: strips of human uteri relaxed under the influence of samples of human semen. Some strips, however, were also made to contract by the same sample of semen. Moreover, the authors even established that the uteri of fertile women reacted to semen samples with relaxation, and the uteri of infertile women reacted with contraction. This discovery thus led to the conclusion that substances which can influence both the male and the female reproductive system must exist in human semen. Goldblatt  and von Euler  were able to define this group of substances further and to demonstrate their biological action. A suitable model was the effect of human seminal fluid extracts (alcohol and acetone extracts) on the blood pressure of cats and rabbits. These extracts led to a drop in blood pressure, independently of atropine and anaesthesia. Boiling was able to annul this effect. The source of this substance, whether the prostate gland or seminal vesicle, could not be further differentiated by Goldblatt . In 1935, von Euler  described special extraction processes for this group of substances occurring in the seminal fluid, defined their hypotensive action, established their origins in the prostate gland and seminal vesicle and proposed the name ‘prostaglandins’ for this class of substances. When investigations into the physiological and pharmacological significance of prostaglandins were renewed after a long interval, the male genital system was by no means at the centre of scientific interest. The uterus, Fallopian tube and ovary, and overall the role of prostaglandins in the female reproductive system, were the subject of extensive and extremely detailed investigations, as can be seen worldwide from a number of comprehensive reviews [44, 45, 48, 50, 65, 67]. The knowledge of the biological properties prostaglandins display in the female genital system increased at the same rate at which prostaglandins became available by semi-synthetic synthesis. In vitro findings were tested in vivo and showed that prostaglandins provided a substance with which obstetric procedures can be influenced and, for example, termination of pregnancy by medicaments is possible at any time. Parallel to the clinical investigations, fully developed and in some cases expensive analytical processes provided and provide new knowledge relating to the regulatory processes in genitals of women. There is scarcely any area of the female reproductive system in which it has not been established that prostaglandins, by themselves or modulating other processes, can affect the function. In contrast, summary references to the role of prostaglandins in the male genitals and in the efferent urinary tract occupy a modest place in the reviews [44, 45, 48]. Whilst the discovery of physiological and pathophysiological viepoints in connection with prostaglandins in the urological area has led to comprehensive new information relating to the excretory and endocrinological function of the kidneys , statements regarding their significance for the urinary bladder, prostate gland, seminal vesicle and testicles remain rather fragmentary. An attempt will now be made to demonstrate, with the aid of selected examples, the 162 Bach/Walker Downloaded by: Vanderbilt University Library 22.214.171.124 - 10/27/2017 11:05:05 AM occurrence, physiological and pathophysio-logical significance and therapeutic possibilities of prostaglandins in the male urogenital system, excluding the kidney. Testicles, Epididymis, Sperm The composition and fertility-determining factors of sperm depend on age, it being possible to influence these changes by exoge-nously supplying prostaglandins  or modulation of the prostaglandins. This report shows that the prostaglandins must participate at the central point of the generative and endocrine testicle function. On the one hand, examination of the sperm fluid and, on the other hand, tissue analyses and tissue incubation can provide the relevant information. The results obtained by the latter method must certainly be viewed more critically than is the case for analyses carried out under in vivo experimental conditions. Prostaglandins of groups Eι, E2, E3, F[α and F2α were first extracted from human semen and separated by chromatography by Samuelsson  in 1963. In 1966, Hamberg and Samuelsson  identified a total of 13 different prostaglandins in human semen plasma. It was particularly striking that the 19-hydroxy derivatives were present in four times the concentration of, for example, PGE2. Aspirin doses led to a drastic reduction in the concentration of PGE and PGF in the ejaculate of test persons . The place of origin of the prostaglandins and the physiological significance of these findings were not the subject of detailed consideration when they were first discovered. However, that the testicle itself is capable of forming prostaglandins and of metabolizing these substances is proved by the findings of Carpenter et al. : human testicle homogenate – in this case specifically the microsome fraction – is capable of synthesizing prostaglandin from endogenous and exogenous substrate. Furthermore, the testicle tissue is also involved in the prostaglandin turnover. In further differentiating the places of origin of prostaglandins in the testicle, Gerozissis and Dray  found PGE and PGF in the testic-ular parenchyma of rats in quantities which depend on age. Furthermore, copious amounts of thromboxane B2 and 6-ketoPGF ια were found in almost all the portions of testicle tissue investigated, above all in prepubertal rats. Particularly high concentrations were found in the testicle capsule. The considerable differences between species were striking and indicate the need for care when interpreting results from animal studies in relation to humans. The same authors investigated the relationship between steroid production in the testicle and the production rate of PGE2 and PGF2α. A significant correlation was found between the two parameters investigated. However, the biological value of this relationship is not completely clear. If normal, intact rats are injected with HCG, the production of PGF2α and PGE2 in the testicle increases 50-fold. There is a time lag between this rise and the rise in testosterone production. Haour et al.  concluded from this that the prostaglandins in the rat testicle cannot be directly connected with testosterone formation . In these investigations, however, it was striking that the number of LH-HCG receptors induced by HCG was significantly lower when the prostaglandin level was high. If the animals were also treated with indomethacin, the HCG-induced release of prostaglandins was suppressed, the amount of testosterone was reduced and supProstaglandins in Urology 163 Downloaded by: Vanderbilt University Library 126.96.36.199 - 10/27/2017 11:05:05 AM pression of the HCG receptor regulation was interrupted for 6 h. Direct HCG stimulation of Leydig cells (from pigs) in a cell culture resulted in a rise in testosterone, but without a simultaneous change in prostaglandin production. PGF2α caused a drop in HCG receptors in a cell culture in the absence of HCG. From this, it can be concluded that steroid formation and prostaglandin production in the testicle are only indirectly related to one another, probably via desensitization of the HCG receptors and via control of the HCG receptor formation in the Leydig cells. The findings of Chantharaksi and Fuchs [ 17] are interpreted somewhat differently but give a similar result. In rats, exogenously supplied PGF2α inhibits the testicular testicular production of testosterone by influencing the effect of LH on the Leydig cells. Endogenous PGF2α probably plays a decisive role in local negative feedback regulation of the effects of LH in the testicle tissue. However, impressive as the role of prostaglandins in the endocrine regulation of testicle function has been shown to be, daily administration of PGE2 or PGF2α does not influence fertility, the amount of semen, sperm motility or the percentage of living sperms in the ejaculate . Nevertheless, the sperm transportation rate can be significantly influenced by prostaglandins [2, 7, 41]. This is probably due to the regulating effect which prostaglandins exert during neuromus- cular transfer in the vas deferens . Kelly  attributes the following effects to prostaglandins in semen: With inexplicable and considerable differences between the species (humans and primates have a very high prostaglandin level), the prostaglandins play a certain role in the motility in the vas deferens. However, in this connection, in vitro studies cannot necessarily be compared with in vivo conditions. Furthermore, the prostaglandins in semen plasma have actions – and sometimes contrasting actions – in all parts of the female genitals, as was also confirmed impressively by Eliasson and Posse . Moreover, it is to be assumed that there are a number of prostaglandin actions directly affecting the sper-matozoal function and the sperm density. In addition, the effect of prostaglandins on the testicle capsule and the blood supply of the testicle must also be mentioned. Ellis et al.  and Hargrove et al.  demonstrated that PGE can reduce the autorhythmic contractions and the basal tone of the testicle capsule of the rabbit to complete inhibition as a function of the dose, whilst PGF displays the opposite effect. Furthermore, prostaglandins play a decisive role in testicular blood flow, PGF being capable of causing very severe vasoconstriction. In this connection, investigations into the effect of PGI and throm-boxane would be interesting. The possible effects which pathological changes in prostaglandin synthesis or in prostaglandin metabolism can have on the male reproductive function in humans has been described by Bygdeman and Samuelsson  and Bygdeman et al. . Differences in the PGF2α content in human semen show no correlation at all with the fertility of the particular males. Nevertheless, significantly more males in the infertile group had a markedly lower PGE level than in the group shown to be fertile. Needless to say, conclusions from the findings obtained remain hypotheses. An effect of prostaglandins on female genitals is assumed to be most probable. It is certainly not futile to determine PGE in semen plasma if all the other test parameters should prove to be normal. 164 Bach/Walker Downloaded by: Vanderbilt University Library 188.8.131.52 - 10/27/2017 11:05:05 AM Urinary Bladder The hollow muscular bladder with its various components has a certain basal tonus and is capable of contracting under adequate stimulation. Nervous control of these processes is known. If 100 times the concentration of hyoscine which would be necessary to inhibit reaction of the bladder to exogenous acetylcholine in rats is administered, the contraction response to nervous stimulation in this test animal is inhibited by up to 50–60%. The response to stimulus after administration of troxypyrrolidinium or hemicholinium 3 is similar. In contrast, local anaesthetics are capable of completely blocking the bladder contraction. Indomethacin reduces the response to stimulation by about 30% . From these findings, Choo and Mitchelson  concluded that PGE and PGF can function as transmitters for the contraction of the rat bladder in the presence of hyoscine or troxypyrrolidinium. Further investigations carried out after prostaglandins have been supplied exogenously have shown that pros-taglandin-induced contractions proceed slowly and are prolonged, whilst the response of the bladder to nervous stimulation was rapid. As a result, it can be assumed that prostaglandins are modulators of stimulus transfer, either by increasing the release of transmitters or by increasing the effectiveness of the transmitters, as has been described several times for the ileum of guinea pigs [8, 42, 43]. Larsson  comes to the same result, also on the basis of animal studies. Electrically induced bladder contractions (in vitro and in vivo) are increased by the prostaglandins formed in the detrusor muscle, i.e. the prostaglandins have a modulating effect on the stimulus transfer in the bladder in that they increase the effectiveness or the release of the transmitter. This effect may not be restricted to the cholinergic transmitter, but possibly includes another transmitter, which is unknown. There would certainly also be a direct stimulatory effect of the prostaglandins on the bladder muscle. Using bladder muscle sections from various animal species, including humans, Hills [38, 39] and Bultitude et al. [ 13] have found that prostaglandins are partly responsible for the basal tone and for the spontaneous activity of the bladder. Moreover, it was possible to demonstrate that spontaneously contracting strips of bladder muscle release PGE2, but not PGF2α. When supplied exogenously, however, PGF2α acts in the same way as PGE2. Furthermore, the findings clearly show that acetylcholine and prostaglandin are necessary for the contraction. These in vitro studies provided the basis for preliminary clinical trials for the above group of authors . In these trials, it was found that 30 min after intravesical instillation of PGE2, two thirds of the patients felt the desire to urinate although the volume of the urinary bladder was significantly reduced. Surprisingly, after PGE2 instillation, the therapeutic effect in the form of an increase in tonus and, above all, a reduction in residual urine continued for the entire observation period of 2 years in three quarters of the successfully treated patients. In the remainder of this group of patients, a second instillation of PGE2 into the bladder was carried out after 3 months, after which the effect also continued for a long period. The reason for the long-term effect of the prostaglandins, which are known to be extremely ‘short-lived’, is not clear. A certain ‘learning effect’ in the patients possibly plays a part. However, this ‘learning effect’ would then also have to occur similarly after the action of carbachol, which is apProstaglandins in Urology 165 Downloaded by: Vanderbilt University Library 184.108.40.206 - 10/27/2017 11:05:05 AM proximately as acute. This is not the case. Patients who do not respond to the therapeutic effect of PGE2 are found to be those, above all, with neurological lesion of the bladder, i.e. patients in whom acetylcholine is absent. In their clinical experiments, Khaíafet al.  also came to the conclusion that prostaglandins participate in the vesico-urethral function and certainly play a central role in facilitating urination. In this context, it is particularly emphasised that prostaglandins are responsible for complete emptying of the bladder by coordination of bladder contraction and sphincteral and urethral function. This effect of prostaglandins can also be seen from the fact that prostaglandins are released from the bladder into the venous blood on spontaneous emptying of the bladder. Grünberger and Tul∑er  administered PGE2 intravesically to 25 random female patients with postoperative ischuria. 6 h after administration of the PGE2 (0.75 or 1.5 mg), 8 of the 25 women were able to empty the urinary bladder completely, and on the following day a further 3 women were free from residual urine. After this period, 12 other cases showed a significant improvement compared with their starting condition. These results clearly show that intravesical administration of PGE2 can be successfully used for the postoperative urological complication described above. A further aspect of the relationship between the urinary bladder and prostaglandins should not go without mention: human bladder tumour cell lines produce and secrete large amounts of PGE2 in vitro. This prosta-glandin formation can be inhibited by indo-methacin. If purified peripheral lymphocytes of a healthy donor are supplied to these tumour cells, the PGE2 synthesis is increased. The accumulation of c-AMP caused by PGE2 in the lymphocytes appears to be responsible for the fact that these cells lose a large proportion of their cytotoxicity towards the tumour cells. On the other hand, the cytotoxicity can be increased by adding indomethacin, an effective prostaglandin cyclooxygenase inhibitor. It can thus be said that, with the aid of prostaglandins, these tumour cells suppress the cellular immune response towards themselves and thus protect themselves from lym-phocytic attack . Plescia et al.  found similar results. In their in vivo tumour test system, PGE2 had an immunosuppressive action, and blockade of prostaglandin synthesis led to a slowing down in tumour growth. The cellular immune response can thus probably proceed undisturbed, without inhibition by prostaglandins. Summarising, it can be said that prostaglandins exert a decisive control on the bladder wall, sphincteral and urethral functions. Further investigations are required to provide details of the action mechanism, since it is not yet known whether complete inhibition of prostaglandin synthesis, for example by indomethacin, can impair the basal tonus or contractility of the urinary bladder in healthy humans. The role played by prostaglandins in bladder tumour growth and the spread of tumours in vivo and the extent to which it is possible to influence these parameters by blockade of the prostaglandin synthesis should be clarified in controlled studies. Seminal Vesicle, Prostate Gland Prostaglandins occur throughout the entire animal kingdom. It is assumed that, on the basis of the synthesis output of almost every living cell – with the exception of the insect kingdom – they are central stimulus 166 Bach/Walker Downloaded by: Vanderbilt University Library 220.127.116.11 - 10/27/2017 11:05:05 AM transmitters for the cellular function. Particularly high concentrations are found incer-tain types of coral [12, 19], and as a result large amounts of prostaglandins were extracted from coral in the initial phase of pros-taglandin isolation. In addition, prostaglandins, above all from the seminal vesicle, are synthesized from the corresponding precursors [12, 30]. As a result, it was possible to isolate large amounts of prostaglandins after incubation of sheep seminal vesicles with arachidonic acid, which then provided the knowledge of the mode of action and the possibilities of therapeutic use of these substances. No accurate details of the quantitative synthesis output of human seminal vesicles are known. Hamberg  was able to demonstrate qualitatively the prostaglandin formation in the seminal vesicle homogenate, but quantitative information cannot be obtained with this experimental design. Furthermore, Eliasson  found by examining fractionated human ejaculate that the seminal vesicle is the chief, and in his opinion the only, prostaglandin source of the semen plasma. Like Hamberg , the author concludes that the prostate gland and testicle are not intended to play a part in prostaglandin formation, which can be measured in semen plasma. The physiological part played by prostaglandins formed in the seminal vesicle of humans has as yet not been completely explained. It is suggested that concomitant prostaglandins from the seminal vesicle which are present in seminal plasma are important for the sperm function . On the other hand, there is, of course, the possibility that these prostaglandins are decisive for male or female fertility as a result of their action on the female genital tract which has been described above. However, further studies on this theme would be absolutely necessary. In contrast to the studies by Hamberg  and Eliasson  quoted above, a number of other groups of workers were able to extract prostaglandins from prostate gland tissue [9–11, 21, 66] and to demonstrate the prostaglandin synthesis output of prostate gland tissue [21, 56]. Human prostate gland epithelial cells in a tissue culture form 6-keto-PGFlα, thromboxane B2 and, above all, PGE2 from an arachidonic acid substrate . The synthesis output of older cells is significantly lower than that of fresh cell cultures. Incorporation of arachidonic acid into the cellular lipid stores is quantitatively the same in all cell types of a wide variety of organs investigated, only the determination to give the particular prostaglandin differs considerably from cell type to cell type. Other hormonal parameters probably play a decisive role, above all in the prostate gland region, in the preferential formation of certain prostaglandins (PGE2). As well as the prostaglandin synthesis output which has been demonstrated in the prostate gland tissue, a certain degree of prostaglandin metabolization also takes place in the prostate gland . It should thus be regarded as proved that the prostate gland is capable of prostaglandin synthesis and that the prostaglandins in this gland, as also in other tissues, can exert a modulating influence on the specific organ function. The extent to which prostaglandins are influenced by other hormones (androgens and prolactin) in the prostate gland and how prostaglandins can influence other hormonal actions can be seen from some studies which have illuminated, above all, the pathogenetic mechanism of benign prostate gland hypertrophy [29, 61, 66]. 70 patients with clinically demonstrated Prostaglandins in Urology 167 Downloaded by: Vanderbilt University Library 18.104.22.168 - 10/27/2017 11:05:05 AM benign prostate gland hypertrophy, in some cases dysuric and in some cases with acute retention of urine, were treated with bromocriptine for 15 days. Prolactin in the periphery and PGE2 in the bladder and urethra were measured before and during therapy. Rolland et al. [61 ] found that, under this treatment, the urodynamic parameters were significantly improved in 75% of the cases, whilst the prostate gland hypertrophy, i.e. the enlargement of the prostate gland, was not affected. The release of PGE2 from the prostate gland decreased under the bromocriptine treatment. This study thus shows that the PGE2 content of the prostate gland primarily has nothing to do with the size of this organ and the degree of severity of the disease. The improvement in the clinical symptoms, however, can certainly be correlated with the drop in PGE2 under bromocriptine treatment. It is thus to be assumed that, with the aid of prolactin, prostaglandin synthesis in the prostate gland is reduced, which leads to ‘normalization’ in the area of the urinary bladder function by changing the prostaglandin production in the prostate gland has also been described for other methods of treatment with medicaments [summary in 66]. However, why the bladder function is significantly improved in spite of the reduction in the amount of PGE2 in the urine is not clear, since sufficient amounts of prostaglandins are doubtless partly responsible for the normal basal tone and spontaneous activity of the bladder [1, 3, 4, 13, 18, 38, 47, 54]. The ‘normalization’ of the relative proportions of the various prostaglandins is possibly of great importance for controlling the mechanical function of the bladder. In this connection  the impairment caused by PGF2α and PGI2 is unknown. The increase in PGI2 synthesis by, for example, sterols which has been demonstrated on strips of human uteri possibly plays a decisive part [Zahradnik et al.: unpublished results]. This problem must be clarified by further studies. It should, therefore, be regarded as proved that the prostaglandins formed in the prostate gland (physiologically or pathologically?) can affect the urinary bladder. The role which prostaglandins play in the prostate gland itself must be considered more closely. The human prostate gland is an extremely active steroid-metabolizing organ. The 5-α-reductase activity in the prostate gland tissue is decidedly high , which may explain the fact that, probably, the relatively high dihy-drotestosterone concentration in the seminal plasma originates from the prostate gland. Furthermore, the prostate gland appears to be a target organ for prolactin, which is specifically bonded in the prostate gland, and probably potentiates the effect of testosterone on this organ and is released into the seminal plasma via the prostate gland [5, 6]. Moreover, as also in other organs, prolactin stimulates prostaglandin synthesis [40, 57–59] by stimulating the phospholipase A activity in the cell membrane, as was first detected in vitro in mammary gland tissue . Furthermore, however, it is also known that exoge-nously supplied prostaglandin can increase the bonding of steroids to human prostate gland tissue as a function of the dose; this effect is neither antagonistic nor additive to the same effect of prolactin . Stroma hy-perplasia and/or inflammation increases the sensitivity of the tissue to this prostaglandin effect. It thus becomes probable that prostaglandins are the mediators of the prolactin effect influencing androgens in the prostate gland tissue. However, prolactin itself in turn modulates prostaglandin synthesis in the prostate gland tissue. 168 Bach/Walker Downloaded by: Vanderbilt University Library 22.214.171.124 - 10/27/2017 11:05:05 AM Whether prostaglandins play a part in the development of benign prostate gland hypertrophy at all and by what interactions is completely unclear, although measures which are associated with a reduction in the formation of prostaglandins in the prostate gland are capable of improving the clinical symptoms of this disease [61, 66]. It is certain that the growth of the prostate gland in dogs and humans, either normally or pathologically, is a process brought about by hormones formed in the testicle . It is furthermore known that benign prostate gland hypertrophy does not develop after castration . It is also known that tissue from a benign nodular prostate gland hyperplasia metabolizes significantly more testosterone to give dihydrotestosterone than normal or cancerous prostate gland tissue . If the above relationships between steroids and prostaglandins and between prostaglandins and prolactin are viewed critically, the conclusion is drawn that prostaglandins formed in the prostate gland on the one hand have a modulating effect on the stimulatory steroid actions on this organ, and on the other hand can also exert a certain ‘remote action’ in the semen plasma and in the urinary bladder. The importance of prostaglandins in inflammatory changes of the prostate gland and the therapeutic possibilities which could result from influencing the prostaglandins would have to be shown by further studies. Acknowledgement The authors are most grateful to Priv. Doz. Dr. H.P. Zahradnik, Department of Clinical Endocrinology, Obstetrics and Gynaecology, University of Freiburg, FRG, who encouraged and helped us. We are also grateful to him for critical reading of the manuscript. 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