The Translational Role of Animal Models for Estrogen-Related Functional Bladder Outlet Obstruction and Prostatic Inflammation.

The prevalence of LUTS and prostatic diseases increases with age both in humans and companion animals, suggesting that a common underlying cause of these conditions may be age-associated alterations in the balance of sex hormones. The symptoms are present with different and variable micturition dysfunctions and can be assigned to different clinical conditions including bladder outlet obstruction (BOO). LUTS may also be linked to chronic non-bacterial prostatitis/chronic pelvic pain syndrome (CP/CPPS), but the relationship between these conditions is unknown. This review summarizes the preclinical data that supports a role for excessive estrogen action in the development of obstructive voiding and nonbacterial prostatic inflammation. Preclinical studies that are emphasized in this review have unequivocally indicated that estrogens can induce functional and structural changes resembling those seen in human diseases. Recognizing excessive estrogen action as a possible hormonal basis for the effects observed at multiple sites in the LUT may inspire the development of innovative treatment options for human and animal patients with LUTS associated with functional BOO and CP/CPPS.

Morphology of plantar interdigital neuroma: a comparative cadaveric study of elderly Finnish and Japanese individuals.

To examine morphological differences in Morton's interdigital neuroma between two elderly human populations, we conducted comparative study using 40 Japanese (27 males, 13 females; mean age, 81.2 years) and 21 Finnish (6 males, 15 females; mean age, 80.5 years) cadavers. We defined the neuroma as a thickening of the nerve of at least two-fold relative to the non-pathological proximal part. The incidence of this neuroma was 25% (10/40) in the Japanese and 33.3% (7/21) in the Finnish cadavers. Moderate or severe hallux valgus (with an angle of more than 20 degrees) was seen in half of the 40 Japanese cadavers (7 males, 13 females), but was absent in the Finnish cadavers. Such hallux valgus was present in 7 (5 males, 2 females) of the 10 Japanese cadavers with neuroma. Moreover, in 2 Japanese cadavers, a paper-like, specialized type of neuroma was associated with the deformity. Pathogenesis of Morton's neuroma might be different between human populations with or without hallux valgus.

Voiding effects mediated by α2-adrenoceptors in the anaesthetized male rat.

OBJECTIVE: To study the role of α(2)-adrenoceptors (α(2)-AR) in micturition of anaesthetized male rats, with specific focus on the effects on the electrical activity (by electromyography, EMG) of the rhabdosphincter, and actual urinary flow rate, as the effects mediated by α(2)-ARs on sphincter activity and urethral pressures have not been established. MATERIALS AND METHODS: Adult anaesthetized male Noble rats were used; intravesical pressure, rhabdosphincter EMG and urinary flow rate from the distal urethra were recorded. After baseline recordings, an α(2)-AR agonist (dexmedetomidine, DEX) or α(2)-AR antagonist (atipamezole), were injected intravenously. RESULTS: DEX treatment significantly decreased the maximum bladder pressure and urinary flow rate, and the amplitude of rhabdosphincter EMG was significantly reduced. Intraluminal pressure high-frequency oscillations, usually observed during rat voiding were abolished. The effects of DEX were fully reversed within 31 min. Atipamezole treatment significantly increased actual urinary flow rates and rhabdosphincter EMG amplitude, but the number of times flow was interrupted was increased during the voiding cycle, leading to increased overall micturition time. CONCLUSION: Stimulation and blockade of α(2)-ARs have a significant effect on lower urinary tract function. If the data from this rat model are also valid in humans, a study of the effects of atipamezole on urethral sphincter activity and urethral pressures in humans would be of interest, and might show therapeutic potential of the drug.

Assessment of information to substantiate a health claim on the prevention of prostate cancer by lignans.

Lignans and their in vivo metabolites, especially enterolactone (ENL), have attracted substantial interest as potential chemopreventive agents for prostate cancer. Preclinical and clinical interventions performed with lignan-rich flaxseed that use surrogate biomarkers as endpoints suggest that lignans may attenuate prostate carcinogenesis in individuals with increased risk or with diagnosed cancer. No unequivocal prostate cancer risk reduction has been found for lignans in epidemiological studies, suggesting that lignan concentrations found in populations consuming a regular non-supplemented diet are not chemopreventive in prostate cancer. Presumably, the main obstacles in assessing the efficacy of food lignans is limited knowledge of the serum and tissue lignan concentrations required for the putative prevention. Further clinical studies performed with the purified compounds are required to substantiate a health claim.

Inflammation and epithelial alterations in rat prostate: impact of the androgen to oestrogen ratio.

Chronic non-bacterial prostatitis may offer new insights into the pathogenesis of human benign prostatic hyperplasia and prostate cancer and the strategies for their treatment and prevention. The potential significance of androgen replacement therapy in terms of the reversal of oestradiol (E(2))-induced inflammatory reaction was studied in the dorsolateral prostate (DLP) of the Noble rat. Castrated Noble rats were treated with E(2) and different doses of androgens [dihydrotestosterone (DHT) and testosterone (T)] to achieve an elevated concentration of E(2) and a wide range of the androgen-to-oestradiol ratios in serum. After the 3-week treatment, inflammatory changes in the DLP were classified and counted. Oestrogen receptor alpha (ER alpha), progesterone receptor (PR), fos-related antigen-2 (Fra2), Ki-67 and P63 were immunocytochemically stained. T, E(2) and prolactin concentrations in serum were measured and the relative weights of the seminal vesicles and pituitary glands and microscopic structures of the DLP and seminal vesicle ducts were determined. Hypoandrogenic doses of DHT (judged on the basis of seminal vesicle weight gain), dose-dependently increased the number of perivascular and stromal inflammatory infiltrates. T and DHT were anti-inflammatory at the doses which normalized or over stimulated the growth of the seminal vesicles. As signs of anti-oestrogenicity, androgens dose-dependently decreased the number and distribution of the ER alpha and PR-positive cells at proinflammatory concentrations. Anti-inflammatory concentrations were needed to reduce the expression of Fra2, E(2)-increased prolactin concentration in serum and pituitary weight. The androgen concentrations required to prevent proinflammatory and epithelial responses to E(2) in the presence of elevated E(2) concentrations may subject the accessory sex glands to more intense androgenic stimulation than is normal for the male. The androgen-resistant endpoints of oestrogen action (body weight reduction and hyperplasia of seminal vesicle ducts) further indicate limitations in the possible preventive effects of androgen-replacement therapy.

Fispemifene [Z-2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)-phenoxy]ethoxy}-ethanol], a novel selective estrogen receptor modulator, attenuates glandular inflammation in an animal model of chronic nonbacterial prostatitis.

The anti-inflammatory and antiestrogenic action of fispemifene [Z-2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}-ethanol], a novel selective estrogen receptor modulator (SERM), was tested on the Noble rat model of chronic nonbacterial prostatic inflammation with cellular composition and inflammation patterns similar to those described in human prostatitis. Inflammation was assessed by counting perivascular and stromal infiltrates and the number of inflamed acini. Furthermore, the aggressiveness of inflammation was assessed on the basis of the relation of lymphocytes to the acinar epithelium. The immunohistochemical expression of progesterone receptor (PR) and Fos-related antigen 2 (Fra2), prolactin concentration in serum, and the weights of the seminal vesicles and pituitary glands were used as endpoints of estrogen action. Fispemifene significantly attenuated the glandular form of inflammation induced in the dorsolateral prostatic lobes (DLP) in the hormonal milieu of the decreased androgen/estrogen ratio. The anti-inflammatory action was seen in the decreased number of acini containing intraluminal neutrophils. As signs of antiestrogenic action, fispemifene blocked estrogen-induced expression of PR and Fra2 in the acinar epithelium of the DLP, and it decreased prolactin concentration in serum and the relative weights of the seminal vesicles and pituitary glands. Because fispemifene exhibited both antiestrogenic and anti-inflammatory action in the prostate, this experimental study suggests that SERMs could be considered as a new therapeutic option in the treatment and prevention of prostatic inflammation.

Prostatic inflammation and obstructive voiding in the adult Noble rat: impact of the testosterone to estradiol ratio in serum.

BACKGROUND: The age-related decline of the testosterone to estradiol (T-to-E(2)) ratio in serum is associated with the increased prevalence of prostatic inflammation and lower urinary tract symptoms suggesting obstructive voiding. The impact of the T-to-E(2) ratio on the development and reversal of non-bacterial prostatic inflammation and obstructive voiding was tested in adult Noble rats. METHODS: Adult male Noble rats (n = 16) were treated with estradiol (83 microg/day) and two different doses (280 and 830 microg/day) of testosterone to cause hypoandrogenic and hyperandrogenic states with elevated estrogen. After the 13-week hormonal treatment, urodynamical measurements and electrical activity recording of the rhabdosphincter muscle were performed under anesthesia. Testosterone, estradiol, and prolactin concentrations in serum were measured and inflammatory changes in the dorsolateral prostate were classified and counted. RESULTS: Histopathological and urodynamical analyses indicated that the hypoandrogenic animals with a decreased T-to-E(2) ratio (10 versus > 300 in control) developed prostatic inflammation and non-obstructive voiding. The hyperandrogenic state with decreased T-to-E(2) ratio of 50 decreased the aggressiveness of the inflammation and the number of inflamed acini in the prostate and caused urethral obstruction associated with rhabdosphincter dysfunction. CONCLUSIONS: Different responses of the prostatic inflammation and voiding function to the change in T-to-E(2) ratio imply that non-bacterial prostatic inflammation is not a sufficient condition for the development of obstructive voiding. The present study finds no support for the idea that age- and/or obesity-related hypoandrogenic state with a decreased ratio of T-to-E(2) would cause urethral obstruction.

Histopathological evidence for an association of inflammation with ductal pin-like lesions but not with ductal adenocarcinoma in the prostate of the noble rat.

BACKGROUND: Chronic inflammation may contribute to the development of prostate cancer. The goal of this study was to determine the possible association of prostatic inflammation, prostatic intraepithelial neoplasia (PIN)-like lesion, and prostate cancer, and to assess the androgen and estrogen dependency of the early steps of carcinogenesis. METHODS: Noble rats were treated with testosterone and estradiol implants for 13, 18, or 26 weeks. Hormone dependency of the lesions was studied in a subset of animals by removing hormone implants for 3 weeks after 15 weeks treatment time. RESULTS: After treatment for 13 weeks, acute and chronic inflammation was found in the dorsolateral prostate lobes and both inflammation and PIN-like lesions were present in the periurethal area of the prostate in all animals (n = 8). Following hormone exposure for 18 and 26 weeks, inflammation in the prostate remained, and adenocarcinomas in the periurethal prostate area with no adjacent inflammation were observed in all 18 animals studied. When both hormone implants were removed after 15 weeks, PIN-like lesions progressed further to adenocarcinoma only in two of seven animals. When only the estradiol implants were removed, three of five animals developed adenocarcinomas. CONCLUSIONS: Even though adenocarcinomas were not morphologically associated with inflammation, PIN-like lesions preceding adenocarcinoma were found in close association with inflammation, pointing towards a possible initiator role of inflammation in the early steps of prostatic carcinogenesis. Further, these results indicate that both androgens and estrogens together play a significant role in the induction of inflammation and prostatic cancer in this model.

Hydroxymatairesinol and sesaminol act differently on tocopherol concentrations in rats.

We have previously reported that sesame seed with the tetrahydrofurofuran type lignans sesamin and sesaminol (SeOH) produced higher tocopherol concentrations, while flaxseed with the dibenzylbutyrolactone type lignans did not cause higher tocopherol concentrations in rats. Sesame seeds also contain the dibenzylbutyrolactone type lignan 7-hydroxymatairesinol (HMR). To clarify whether or not the tocopherol elevating effect is affected by the chemical structure of lignans, the effect of HMR isolated from Norway spruce, was compared with SeOH, isolated from sesame seed. The lignans were added to a low alpha-tocopherol (10 mg/kg) diet, and rats were maintained on these diets for 8 wk. The experimental diet containing 0.2% SeOH elevated alpha-tocopherol content in the plasma liver, kidney, and brain, but HMR (0.2% or 0.5%) had no effects. Dietary HMR and SeOH (both in concentrations of 0.2%) were further compared in rats fed on a gamma-tocopherol (50 mg/kg) containing diet. SeOH produced significantly higher g-tocopherol content in the plasma and tissues, and significantly lower 2,7,8-trimethyl-2(2'-carboxyethyl)-6-hydroxychroman (gamma-CEHC, a gamma-tocopherol metabolite) content in the urine. However, HMR did not show such effects. These results suggest that the sesame lignan SeOH increases tocopherol concentrations in animals by suppressing the conversion of gamma-tocopherol to gamma-CEHC. HMR, a structurally different plant lignan, does not have such properties. Further studies are needed to show the potential health effects associated with an increased tocopherol concentration in the body.

Hydroxymatairesinol and its mammalian metabolite enterolactone reduce the growth and metastasis of subcutaneous AH109A hepatomas in rats.

Both epidemiological and experimental evidence is accumulating to show that a lignan-rich diet may reduce the risk of human breast cancer. Possible anti-cancer effects of dietary lignans on hepatomas or hepatoma cells have not been the topic of earlier studies. In the present study, we examined the effect of 7-hydroxymatairesinol (HMR) and its mammalian metabolite, enterolactone (ENL), on AH109A hepatoma cell proliferation and invasion in vitro. HMR and ENL inhibited the proliferation and invasion of AH109A hepatoma cells in vitro. The 50% inhibitory concentration (IC50) of hepatoma cell proliferation was lower for ENL (10 microM) than HMR (> 200 microM). Likewise, IC50 of hepatoma cell invasion was lower for ENL (9 microM) than HMR (144 microM). ENL suppressed hepatoma cell proliferation by accumulating cells in G1 phase and elongating doubling time of these cells, and by increasing the rate of apoptosis. Subsequently, we investigated in vivo the effect of dietary HMR and ENL on growth and metastasis of AH109A hepatomas in rats. Both of these compounds reduced the growth and metastasis of solid AH109A hepatomas in rats. These in vitro and in vivo findings suggest that HMR has inhibitory activities on tumor growth and metastasis in the hepatoma-bearing rats, and that this anti-tumor effect is mediated at least partially by ENL, a metabolite of HMR.

Urodynamic changes in a noble rat model for nonbacterial prostatic inflammation.

BACKGROUND: Chronic nonbacterial prostatitis (CP) associated with voiding dysfunction is a poorly understood clinical phenomenon. The goal of the present study was to induce prostatic inflammation with estrogen and androgen treatment and to record associated urodynamic changes in Noble rats. METHODS: Rats were treated with estradiol and testosterone implants to increase estradiol concentration in serum while testosterone concentration was maintained at or slightly above the control level. The urodynamical recordings were performed under anesthesia after the hormone treatments for 3 and 6 weeks. The dorsolateral lobes of the prostates were removed for histopathological analysis after recordings. RESULTS: After the 3-week treatment, lymphocytes, mainly T-cells, were located around the capillaries. During the following 3 weeks lymphocytes migrated into stroma and acini. Cytotoxic T-cells were seen intraepithelially, and neutrophiles inside the acini. Removal of estrogen implant or treatment with anti-estrogen diminished inflammation. No changes in voiding pattern were seen after the 3-week treatment. Three weeks later, bladder weight and capacity were increased, and the micturition time was prolonged. CONCLUSIONS: Elevated estrogen concentration was essential for the gradual development of prostatic inflammation. The profile and location of inflammatory cells suggest that prostatic vasculature is one of the sites of estrogen action. Urodynamic changes which developed in association with glandular inflammation indicated abnormal bladder function, reflecting an incipient obstruction.

The soy effect in the disease models of nonbacterial prostatitis and obstructive voiding.

The goal of this study was to improve the understanding of the potential significance of dietary soy for human health by investigating its effects in the animal models of nonbacterial prostatitis and urethral obstruction. Nonbacterial prostatitis was induced in adult Noble rats with the combined treatment of testosterone and 17beta-estradiol. The inflammatory foci categorized into three forms were counted and correlated with expression of an estrogen-responsive gene, progesterone receptor (PR), in the dorsolateral lobes of the rats on soy (+) and soy (-) diets. Development of obstructive voiding after neonatal estrogenization of Noble rats (NeoDES rats) was followed with urodynamic measurements in rats on soy (+) and soy (-) diets. The amounts of genistein and daidzein, two major soy-derived isoflavones, were measured in the urine of Noble rats by the high-performance liquid chromatography-photodiodearray method. Dietary soy decreased the total number of inflammatory foci while no demonstrable effects were seen on the cellular composition of the infiltrates. Soy did not increase the weights of the pituitary gland, testes, or sex accessory glands, but it did increase the number of PR-positive epithelial cells in the dorsolateral prostate. It also decreased the bladder pressures in NeoDES rats but did not increase the flow rates. The soy effects may be mediated by the strong estrogen influence involved in the animal models. Dietary soy had anti-inflammatory effects in the prostate but only marginal effects on the development of obstructive voiding in Noble rats. The anti-inflammatory effects of soy may contribute to the lower prevalence of prostatitis-like symptoms and the historically lower risk of benign prostatic hyperplasia in Japan; however, no evidence was found that regular consumption of soy influences the age-related development of lower urinary tract symptoms or decline of flow rate.

COX-1 and -2 expressions in sex-related organs of neonatally estrogen-treated rats and in activated and nonactivated macrophage RAW264.7 cells with phytoestrogen.

Cyclooxygenase (COX)-2 is an inducible isoform, expressed in inflamed leukocytes and cancer cells. It is known that estrogen causes prostate dysplasia, but little is known about COX-2 expression and its influence on male reproductivity. In this study, we show that COX-2 was abolished in the distal end of the vas deferens in neonatally estrogenized (diethylstilbestrol, NeoDES) Sprague-Dawley (SD) rats at age of 15 mo, but the control normal rats were found to remain constitutive expression at the same age, while the levels of COX-1 in these rats remained intact. Furthermore, BAX, an indicator of sperm quality, was observed in the endothelium of vas deferens and sperm of the aged rats. However, COX-2 was not detected in the inflamed lesions of NeoDES rat's prostate by immunohistochemistry. In addition to estrogen, hydroxymatairesinol (HMR), a phytoestrogen, was analyzed in vitro for possible regulation on COX-2. Through Western blot analysis, HMR was shown to have no inhibitory affect on COX-2 expression. These results indicated that estrogen treatment strongly influences the expression of COX-2 that is associated with fertility, but no induction of COX-2 by estrogen may not exclude COX-2's role in prostatitis, and the anti-tumor mechanism of HMR largely remains elusive.

Division of the male rat rhabdosphincter into structurally and functionally differentiated parts.

In order to understand the structure-function relationship in the male rat rhabdosphincter, the 3D structure of the striated muscle and associated dense connective tissue was reconstructed from representative serial sections cut from the proximal urethra harboring the muscle. The 3D structure was correlated with electromyography (EMG) of the rhabdosphincter, urodynamic parameters (bladder pressure and flow rate), and longitudinal contraction force of the proximal urethra. The muscular component of the rhabdosphincter consisted of a homogeneous population of the fast-twitch-type fibers. In the cranial part, striated muscle formed a complete ring encircling the urethra, deferent ducts, and ducts from seminal vesicles and prostatic lobes. Toward the middle part, the amount of densely packed connective tissue lacking type III collagen increased anteriorly and posteriorly and penetrated the muscular ring that became divided first posteriorly and then anteriorly into two symmetrical halves. In the caudal part, a thin midsagittal dense connective tissue septum remained posteriorly. EMG recordings suggested that the rhabdosphincter muscle was functionally divided into two parts. Unlike the cranial and middle parts, the caudal part did not show the first depolarization peak. It appears that rapid oscillatory oblique-to-circular muscular contractions proceeding in craniocaudal direction in the cranial and middle part draw the anterior wall supported by arch-like dense connective tissue closer to the posterior wall supported by a more rigid rhomboidal raphe. Longitudinal contractions of the urethra are possibly evoked from the proximal and caudal parts of rhabdosphincter. These could lead to simultaneous increase in urethral pressure ensuring rapid urine flow rate. The caudal part could augment the opening of urethral lumen during oscillatory voiding.

Transgenic mice expressing p450 aromatase as a model for male infertility associated with chronic inflammation in the testis.

Our previous studies have shown that transgenic male mice expressing human P450 aromatase (AROM+) are infertile. In the present study, we followed the testis phenotype up to 15 months of age in these mice. The testes of the old AROM+ mice showed Leydig cell hypertrophy and hyperplasia, as indicated by the staining for steroidogenic enzymes and androgen and estrogen receptors. However, the Leydig cell adenomas did not show signs of malignization. In contrast, we observed a marked increase in the number of activated macrophages in the testicular interstitium of the aging AROM+ mice. The macrophages were further shown to express high levels of CD68 (a monocyte/macrophage marker) and secrete TNFalpha, indicating strong activation, presumably by estrogen exposure. The increased activity of the macrophages was associated with Leydig cell depletion (analyzed at the age of 9 and 15 months) and an increased number of mast cells and fibrosis in the testicular interstitium. Interestingly, similar findings have been made in testes of infertile men. Hence, the aging AROM+ males present with a phenocopy of inflammation-associated infertility in men, providing a model for further studies on the putative link among estrogens, orchitis, and infertility.

Activation of NF-kappaB in association with prostate carcinogenesis in noble rats.

There is an increasing interest in the role of chronic nonbacterial prostatitis in the development of prostate cancer. The aim of the study was to explore the role of NF-kappaB in the prostate of Noble rats treated with testosterone (T) and 17beta-estradiol (E(2)), a widely used model for prostate carcinogenesis. NF-kappaB-positive epithelial cells appeared in both inflamed and noninflamed glands and ducts at 13 weeks after hormone implantation in hypoandrogenemic, hyperestrogenemic rats. Both nuclear and cytoplasmic staining were observed. When daily dose of T was increased to give serum concentration above the level of control animals, dysplastic lesions and ductal carcinomas with NF-kappaB-positive cells were induced at 13 weeks and 26 weeks. The number of acini with NF-kappaB-positive cells decreased and no nuclear staining was observed. Surprisingly, no inflammation was seen in the periurethral region where ductal carcinomas developed. In conclusion, no unequivocal evidence was obtained to support the idea that NF-kappaB would be activated in association with inflammation in the development of ductal carcinomas. The hormonal control of NF-kappaB in the prostate warrants further studies.

A dose-dependent dual effect of oestrogen on voiding in the male mouse?

OBJECTIVES: To explore the effect of different degrees of oestrogenization on male voiding, by treating adult castrated and 5alpha-dihydrotestosterone (DHT)-maintained male mice with different doses of oestrogens, as exposure of male mice to excessive amounts of oestrogens can cause bladder outlet obstruction (BOO); in addition, male mice lacking oestrogen receptor (ER)alpha (ERKO) or ERbeta (BERKO) were studied to assess the importance of ER subtypes. MATERIALS AND METHODS: Castrated, DHT-maintained adult mice were treated with 17beta-oestradiol (E(2); 50 and 250 microg/kg) or oestrone (E(1); 5, 50 and 500 microg/kg) daily for 10 days. Control mice were treated only with the vehicle. BERKO and ERKO mice, and their wild-type littermates used as their controls, remained untreated. Under anaesthesia, the bladder and distal urethra were exposed to record simultaneously the bladder pressure and urinary flow rate from the distal urethra. RESULTS: E(2)-treated mice showed obstructive voiding, seen as increased bladder pressure, decreased average flow rate and prolonged micturition time. This was also evident when a high dose (500 microg/kg) of E(1) was used. After treatment with a dose of 50 microg/kg, the urodynamic variables were similar to those in the control mice. Surprisingly, after treatment with a low dose (5 microg/kg) all urodynamic variables improved. There was a minor increase in the bladder pressure in BERKO mice; ERKO mice had a significantly lower urinary flow rate. CONCLUSIONS: High doses of oestrogens caused BOO in castrated, DHT-maintained male mice. A small dose of E(1) had a positive effect on voiding, suggesting that oestrogens are needed for normal male voiding. Reduced urinary flow rates in ERKO mice suggest that oestrogen effects on voiding are mediated at least partly via ERalpha.

Sex specific expression of progesterone receptor in mouse lower urinary tract.

Progesterone receptor (PR) was investigated immunohistochemically in the lower urinary tract of the male and female mouse. Estrogen receptor (ER)-subtype-deficient mice (ERKO, BERKO) were used to determine the possible regulation of PR expression in an ER-subtype-specific manner. PR was found to be co-expressed with ERalpha in cell nuclei of urothelium, lamina propria fibroblasts and smooth muscle cells in the female urethra. Only few PR positive cells were seen in female ERKO mice. Ovariectomy reduced and estrogen treatment restored the urethral PR expression in female wild type and BERKO mice. Thus, the expression of PR in the female urethra is estrogen-inducible via ERalpha. In male urethra, PR was co-expressed with ERbeta in the rhabdosphincter. In male, no evidence was obtained for the ER-linked control of the PR expression. No PR-positive cells were observed in the body of the bladder of either sex or any strain.

The role of the rhabdosphincter in female rat voiding.

OBJECTIVES: To obtain information on the mechanisms of female rat micturition using a model in which pressure was measured in the bladder and distal part of the urethra corresponding to the location of the rhabdosphincter, providing information on the role of the sphincter in opening and closing the urethral lumen. MATERIALS AND METHODS: A micturition reflex was induced in adult anaesthetized (chloral hydrate and urethane) female rats by filling the bladder with saline. Bladder pressure (BP), urethral pressure (UP), electromyography (EMG) of the middle part of the rhabdosphincter, and urinary flow rate in the distal urethra were simultaneously recorded. RESULTS: There were four phases of the micturition contraction, the second characterized by intraluminal pressure high-frequency oscillations (IPHFOs) of BP. When a non-oscillatory micturition contraction started, the BP increased and exceeded UP for the rest of the micturition contraction. Even though the BP increased during this first phase, the urethral lumen stayed closed. Its opening was indicated by a simultaneous decrease in BP and increase of UP as the fluid flowed from the bladder to the urethra. When the rhabdosphincter closed, as indicated by an EMG-burst of the muscle, the UP declined, bladder pressure increased and the flow ceased. Because of momentary contractions of the rhabdosphincter, the UP and urine flow rate had the same periodicity as the IPHFOs of BP. CONCLUSIONS: The simultaneous recording of the BP, UP, EMG of the rhabdosphincter and urinary flow rate showed the sequence of events during micturition. The rhabdosphincter acts as an 'on-off' switch, causing interruptions in the urinary flow rate.

Chemopreventive effects of hydroxymatairesinol on uterine carcinogenesis in Donryu rats.

Hydroxymatairesinol (HMR), obtained from the heartwood of spruce (Picea abies), has been demonstrated to exert chemo-preventive effects on the development of mammary tumors in rats. To examine the influence of HMR on uterine carcinogenesis, adult Donryu rats were initiated with a single intrauterine treatment of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) at 11 weeks of age and fed thereafter 0, 200, or 600 ppm HMR mixed in the soy-containing diet until 15 months of age. Incidences of uterine adenocarcinoma in both 200 and 600 ppm HMR-dosed groups were significantly reduced to 11% and 15%, respectively, less than 50% of 0 ppm, at the end of the experiment (P < 0.05). A delay in the start of persistent estrus by HMR was observed at 8 months of age compared with controls given carcinogen alone. From urinalysis, HMR was metabolized mainly to enterolactone and hydroxyenterolactone. These findings suggest that HMR or its metabolites exert chemo-preventive effects in the rat ENNG-uterine carcinogenesis model.