Evidence for a prostate cancer susceptibility locus on the X chromosome.

Over 200,000 new prostate cancer cases are diagnosed in the United States each year, accounting for more than 35% of all cancer cases affecting men, and resulting in 40,000 deaths annually. Attempts to characterize genes predisposing to prostate cancer have been hampered by a high phenocopy rate, the late age of onset of the disease and, in the absence of distinguishing clinical features, the inability to stratify patients into subgroups relative to suspected genetic locus heterogeneity. We previously performed a genome-wide search for hereditary prostate cancer (HPC) genes, finding evidence of a prostate cancer susceptibility locus on chromosome 1 (termed HPC1; ref. 2). Here we present evidence for the location of a second prostate cancer susceptibility gene, which by heterogeneity estimates accounts for approximately 16% of HPC cases. This HPC locus resides on the X chromosome (Xq27-28), a finding consistent with results of previous population-based studies suggesting an X-linked mode of HPC inheritance. Linkage to Xq27-28 was observed in a combined study population of 360 prostate cancer families collected at four independent sites in North America, Finland and Sweden. A maximum two-point lod score of 4.60 was observed at DXS1113, theta=0.26, in the combined data set. Parametric multipoint and non-parametric analyses provided results consistent with the two-point analysis. Significant evidence for genetic locus heterogeneity was observed, with similar estimates of the proportion of linked families in each separate family collection. Genetic mapping of the locus represents an important initial step in the identification of an X-linked gene implicated in the aetiology of HPC.

Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancer.

BACKGROUND: Tasquinimod is a quinoline-3-carboxamide derivative with anti-angiogenic activity. Two open-label phase I clinical trials in patients were conducted to evaluate the safety and tolerability of tasquinimod, with additional pharmacokinetic and efficacy assessments. METHODS: Patients with castration-resistant prostate cancer with no previous chemotherapy were enrolled in this study. The patients received tasquinimod up to 1 year either at fixed doses of 0.5 or 1.0 mg per day or at an initial dose of 0.25 mg per day that escalated to 1.0 mg per day. RESULTS: A total of 32 patients were enrolled; 21 patients were maintained for >or=4 months. The maximum tolerated dose was determined to be 0.5 mg per day; but when using stepwise intra-patient dose escalation, a dose of 1.0 mg per day was well tolerated. The dose-limiting toxicity was sinus tachycardia and asymptomatic elevation in amylase. Common treatment-emergent adverse events included transient laboratory abnormalities, anaemia, nausea, fatigue, myalgia and pain. A serum prostate-specific antigen (PSA) decline of >or=50% was noted in two patients. The median time to PSA progression (>25%) was 19 weeks. Only 3 out of 15 patients (median time on study: 34 weeks) developed new bone lesions. CONCLUSION: Long-term continuous oral administration of tasquinimod seems to be safe, and the overall efficacy results indicate that tasquinimod might delay disease progression.

Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search.

Despite its high prevalence, very little is known regarding genetic predisposition to prostate cancer. A genome-wide scan performed in 66 high-risk prostate cancer families has provided evidence of linkage to the long arm of chromosome 1 (1q24-25). Analysis of an additional set of 25 North American and Swedish families with markers in this region resulted in significant evidence of linkage in the combined set of 91 families. The data provide strong evidence of a major prostate cancer susceptibility locus on chromosome 1.

FSH suppression and tumour control in patients with prostate cancer during androgen deprivation with a GnRH agonist or antagonist.

BACKGROUND: Gonadotropin releasing hormone (GnRH) antagonists suppress follicle-stimulating hormone (FSH) to lower levels than GnRH agonists. This may partially explain the differences between these agents on prostate cancer outcomes. In this post-hoc analysis, FSH and prostate specific antigen (PSA) responses and the impact of cross-over from leuprolide to degarelix were evaluated from a 1-year comparative study (CS21) and its extension study (CS21A). MATERIALS AND METHODS: Overall, 610 patients were enrolled in CS21, wherein PSA and FSH levels were evaluated monthly. CS21A evaluated 386 patients, including those previously treated with degarelix (n = 251) who continued to receive degarelix, and those previously treated with leuprolide (n = 135) who crossed-over to receive degarelix. PSA and FSH levels were evaluated in CS21A for 3 months after cross-over. The associations between measurements were assessed using Spearman's correlation coefficient. The impact of class variables on FSH suppression were evaluated using Analysis of Variance. RESULTS: Rapid PSA and FSH suppression was observed and maintained in the degarelix arm (CS21 and CS21A), while patients on leuprolide experienced rising PSA during CS21. Patients crossed-over from leuprolide to degarelix achieved a suppression of FSH and a significant PSA decrease. PSA and FSH levels were significantly (p < .05) correlated at months 1, 3, 6, 12 and 13 in the degarelix arm. CONCLUSIONS: Significant FSH suppression with GnRH antagonists may explain its advantage over GnRH agonists in terms of better prostate cancer control. The effect of profound FSH suppression is analogous to the need for profound testosterone suppression for tumor control.

Prostatic tumor regrowth after initially successful castration therapy may be related to a decreased apoptotic cell death rate.

Castration of rats transplanted with the androgen-sensitive Dunning R3327-PAP prostatic tumor results initially in a reduction of tumor growth, but after some time, some of the tumors start to grow again. The relapsed, androgen-insensitive PAP tumor shows a dedifferentiated morphology. In the present study, we examined whether this androgen-independent tumor regrowth was due to an increased cell proliferation rate or to a reduction of the number of tumor cells dying by apoptosis. Nine rats (with 18 tumors) were castrated and followed for 16 to 20 weeks. Six of the tumors increased their volume markedly (relapsed), while 12 remained relatively stable (nonrelapsed). The mitotic index and apoptotic index for epithelial cells were examined by light microscopy. Tumor growth rate correlated negatively both to the apoptotic index identified by morphological criteria (RS = -0.82; P < 0.0001) and to the apoptotic index identified by in situ end labeling (RS = -0.83; P < 0.0001). The tumor growth rate percentage did not correlate to the mitotic index, and it was negatively correlated (RS = -0.62; P < 0.01) to the number of cells immunostained for proliferating cell nuclear antigen. It is suggested that one initial event during the androgen-independent prostatic tumor regrowth in the PAP relapse model might be a reduction of the number of tumor cells being depleted by apoptosis, rather than an increase of cell proliferation rate.

Castration induces apoptosis in the ventral prostate but not in an androgen-sensitive prostatic adenocarcinoma in the rat.

Apoptosis in the androgen-sensitive Dunning R3327 PAP prostatic adenocarcinoma was studied during the post castration period of 14 days and compared with the ventral prostate. The mRNA expression of testosterone repressed prostatic message-2 and tissue-type plasminogen activator in the Dunning tumor and in the ventral prostate was analyzed by Northern blot experiments and immunohistochemical procedures. The degree of endonuclease-degraded genomic DNA was examined by gel electrophoresis. Apoptotic tumor epithelial cells were identified with in situ end labeling. Epithelial cells incorporating bromodeoxyuridine (BrdUrd) after castration in the ventral prostate and the Dunning tumors were localized with immunostaining. Androgen ablation resulted in an induction of testosterone repressed prostatic message-2 and tissue-type plasminogen activator transcripts in the normal prostate with a peak at approximately 2 to 5 days post castration. These transcript levels in the Dunning prostatic tumors did not show any induction during the same period. Immunohistochemical staining for sulfated glycoprotein-2 and tissue-type plasminogen activator confirmed this difference between the tumor tissue and the ventral prostate at the transcriptional level. The determination of DNA integrity showed similar results in that the degree of DNA fragmentation in the tumor was much lower than the initial and marked degradation of DNA in the ventral prostate. The number of in situ end-labeled epithelial tumor cells were not increased by castration. BrdUrd immunodetection showed that castration induced an initial increase in the number of BrdUrd-positive epithelial cells in the ventral prostate. In the tumors, castration resulted in a decrease in BrdUrd-positive epithelial cells. It was concluded that in the androgen-sensitive prostatic Dunning R3327 PAP adenocarcinoma, the biochemical cascade leading to apoptosis is not activated by androgen withdrawal, as in the ventral prostate.

Testicular blood flow, vascular permeability, and testosterone production after stimulation of unilaterally cryptorchid adult rats with human chorionic gonadotropin.

Testicular blood flow, testosterone production, and the formation of testicular interstitial fluid (IF) were studied in unilaterally cryptorchid rats, basally, 8 h and 24 h after treatment with 200 IU human CG (hCG). Testicular blood flow was lower in the abdominal testis in both control rats and hCG-treated rats than in the scrotal testis within the same treatment group. The scrotal testicular blood flow increased significantly 24 h after hCG treatment, but not after 8 h. In the abdominal testis, there was a significant increase of blood flow 8 h after hCG, but not 24 h after. The formation of IF was subnormal in the abdominal testes of control rats, but this was corrected in hCG-treated rats, where there was a significant increase of IF in both abdominal and scrotal testes. The total endothelial surface of small blood vessels was decreased in abdominal testes. Testosterone concentration in the spermatic vein was significantly lower on the abdominal side than on the scrotal side in both control and hCG-treated rats. The concentration of testosterone was lower in IF on the abdominal side in control rats, but after hCG the testosterone concentration was similar in both scrotal and abdominal testes, indicating a trapping of testosterone in the abdominal testis. The outflow of testosterone in the spermatic vein was significantly increased at both 8 and 24 h after hCG from both the scrotal and abdominal testes, although it was always smaller from the abdominal testis. The lower secretion of testosterone from the abdominal testis after hCG was mainly due to reduced blood flow and not to any disability of the Leydig cells of abdominal testes to produce testosterone.

Are leukocytes involved in the human chorionic gonadotropin-induced increase in testicular vascular permeability?

Adult male rats were given a single sc injection of human CG (hCG). The volume density of polymorphonuclear leukocytes (PMNs) located in blood vessels or in the interstitial space was determined by morphometry. The volume of testicular interstitial fluid (IF) was also measured. hCG in doses from 50-800 IU increased the IF volume 8 h after treatment and resulted in migration of PMN into the interstitial space. In contrast, treatment with 12.5 IU hCG, although increasing intratesticular testosterone to about 50% of the maximal value, did not increase the volume of IF, and no leukocytes appeared in the interstitial space. Treatment with 50 IU hCG sc increased the volume of IF at 8, 16, and 32 h after treatment. The increase in IF volume, which is a reliable estimator of changes in the vascular permeability, was preceded by an intravascular accumulation of PMNs. Four hours after hCG treatment, there was a 6-fold increase in the volume density of intravascular PMNs. Later, leukocytes migrated into the interstitial space reaching a maximal concentration 8 h after hCG treatment (at that time 6.4 +/- 0.7 X 10(-5) of the total testis volume was composed of leukocytes). The number of interstitial PMNs declined thereafter and by 32 h they were no longer observed. It is suggested that leukocytes could be involved in mediating the hCG-induced increase in vascular permeability in the testis.

Differences in the regulation of steroidogenesis and tropic hormone receptors between the scrotal and abdominal testes of unilaterally cryptorchid adult rats.

Rats were made unilaterally cryptorchid by cutting the gubernaculum testis at birth. At 100 days age, the rats were injected with 600 IU/kg hCG. A biphasic testosterone response was seen in the scrotal (Scr) testis in response to hCG, with maxima at 1 h and 3 days after injection. The acute peak of testosterone was of similar magnitude in the abdominal (Abd) testis, but the secondary peak was not present. The response of testicular progesterone concentration to hCG stimulation showed a maximum at 1 day in both gonads, but it was 10- to 20-fold higher (P less than 0.01) in the Abd testis. The content of LH, FSH, and PRL receptors per testis was decreased on the Abd side. After hCG injection, the loss of available LH receptors was faster in the Abd testis. Likewise, the recovery of binding was faster in the Abd testes; at day 10 of the experiment, it was 102 +/- 5% of the starting levels compared to 52 +/- 4% on the Scr side (P less than 0.01). hCG did not affect FSH binding of the Scr testes, but induced a transient drop of 25-35% on day 1 on the Abd side (P less than 0.05). Thereafter, on days 3-10, the FSH binding of the Abd testes was 20-40% higher than on the Scr side (P less than 0.05-0.01). In PRL binding, similar heterologous down-regulation of 50-80% was found in both testes between 12-24 h. Thereafter, the Abd testis PRL receptors showed a transient elevation of 25-70% (P less than 0.05-0.01) on day 3, which was not seen in the Scr testes. In conclusion, the Abd testis displays a dramatically enhanced blockade of C21 steroid side-chain cleavage upon gonadotropin stimulation. The kinetics of changes in testicular LH receptors after hCG stimulation is faster in the Abd testis. Only Abd testes displayed hCG-induced changes in FSH binding and transient up-regulation of PRL receptors. The altered tropic regulation of Leydig and Sertoli cells of the Abd testis are indicative of direct functional changes in these cells in the elevated intra-Abd temperature and/or of changes in the paracrine component of testicular regulation.

Testosterone stimulates angiogenesis and vascular regrowth in the ventral prostate in castrated adult rats.

The castration-induced regression and testosterone stimulated regrowth of the vasculature in the rat ventral prostate lobe were studied using stereological techniques. Seven days after castration, the endothelial cell proliferation rate (bromodeoxyuridine labeling index); the total weights of blood vessel walls, blood vessel lumina, endothelial cells, glandular epithelial cells; and total organ weight were all decreased. Within 2 days after sc treatment with testosterone, the total weights of blood vessel walls, endothelial cells, and vascular lumina, as well as the endothelial cell proliferation rate, were all normalized. In contrast to the rapid response of the vasculature, the total weight of glandular epithelium and total organ weight were not normalized during the 4 days of testosterone treatment. Growth of the vasculature apparently precedes growth of the glandular epithelium. The testosterone- dependent factors stimulating the vasculature are unknown, but factors derived from epithelial cells, mast cells (which accumulate in the prostate during the first day of testosterone treatment), and tissue macrophages could all be involved. Castration-induced regression and testosterone-stimulated regrowth of the prostatic vasculature can be used as an experimental model to study factors regulating angiogenesis and organ growth in the prostate.

Relationship between symptom severity and hormone changes in women with premenstrual syndrome.

The relationship between symptoms and plasma hormone levels was investigated during 2 consecutive cycles in 18 women with the premenstrual tension syndrome (PMS). The women were asked to provide daily symptom ratings using a previously described and tested rating scale, and blood samples were taken daily during the luteal phase and most of the follicular phase for plasma estradiol, progesterone, FSH, and LH measurements. The symptom scores during the premenstrual phase were compared within each woman and between cycles with higher luteal phase and cycles with lower luteal phase plasma estradiol, progesterone, FSH, and LH concentrations. The results indicated that higher adverse premenstrual scores occurred in cycles with high luteal phase plasma estradiol and progesterone concentrations. In particular, a high luteal phase plasma estradiol concentration was related to higher premenstrual scores for adverse symptoms and lower scores for positive mood symptoms. The women experienced more severe PMS in cycles with high luteal phase plasma estradiol and progesterone levels. The results contradict the hypothesis that progesterone deficiency plays a part in the etiology of PMS.

Risk perception, screening practice and interest in genetic testing among unaffected men in families with hereditary prostate cancer.

Approximately 5-10% of prostate cancer cases are caused by dominantly inherited susceptibility to the disease. Although advances have been made in research concerning the genetic mechanisms of hereditary prostate cancer, little is known about the psychological consequences for men at high risk of developing the disease. The aims of the present study were to examine risk perception, interest in genetic investigations, cancer-specific worry, and screening practice among unaffected men, aged 40-72 years old, with a pedigree consistent with hereditary prostate cancer and an estimated lifetime risk of prostate cancer of 35-45%. A questionnaire was sent by mail to 120 subjects, of whom 110 responded. Most of the men (n = 90, 82%) worried about having an inherited susceptibility to prostate cancer, and 34 (31%) claimed that worry about prostate cancer affected their daily life (3 (3%) fairly much, 31 (28%) slightly). As many as 40% of the study subjects perceived their lifetime risk of prostate cancer as 67% or more. Perceived high risk was associated with symptoms of depression and with cancer worry affecting daily living. Two-thirds of the men aged 50 years old or more were regularly screened for prostate cancer. Subjects with high levels of cancer-specific stress, as measured by the avoidance subscale of the Impact of Event Scale, were less likely to opt for screening. Almost all of the men (94%) were interested in presymptomatic genetic testing (84 (76%) "definitely yes" and 20 (18%) "probably yes"). We conclude that hereditary susceptibility to prostate cancer has significant psychological consequences although it rarely causes psychiatric morbidity. The present study underlines the importance of giving thorough, repeated information to men at high risk of prostate cancer.

Pretreatment p53 immunoreactivity does not infer radioresistance in prostate cancer patients.

PURPOSE: To test, in a clinical context, the hypothesis that p53 aberrations, assessed by immunoreactivity, are related to radioresistance as suggested by several experimental studies. METHODS AND MATERIALS: Sixty patients with prostate cancer who underwent transurethral resection of the prostate or biopsy prior to definitive external beam therapy were retrospectively identified. The endpoint in the study was cancer specific survival. The nuclear accumulation of the aberrant p53 protein was evaluated by immunohisto-chemistry with the pantropic, monoclonal Ab-6 anti-p53 antibody (clone DO-1) on pretreatment biopsies. Immunoreactivity was related to stage, grade, and cancer-specific survival. RESULTS: There was a correlation between p53 immunoreactivity and low tumor stage (p < 0.001), but no relation between p53 status and grade was found. Moreover, no significant difference was found in cancer-specific survival between the p53 positive tumors (109 months) and the p53 negative tumors (99 months). CONCLUSIONS: No disadvantage regarding survival was seen for patients with p53 immunoreactive tumors, implicating that p53 immunoreactivity does not infer radioresistance in prostate cancer. This suggests that the p53 inactivation may be a less important determinant of tumor response to radiotherapy in some human cancers than in the previously studied experimental situations. Thus, other mechanisms may be more important in determining outcome after radiation. However, the series is small and data should be interpreted with caution.

Combined castration and fractionated radiotherapy in an experimental prostatic adenocarcinoma.

PURPOSE: The present study using the Dunning R3327-PAP rat prostatic adenocarcinoma model was designed to study the effect on tumor growth of castration prior to or after irradiation with 20-25 Gy as compared with either irradiation or castration alone. METHODS AND MATERIALS: Rats were bilaterally orchidectomized. During the irradiation procedure the nonanesthetized animals were held in a metallic frame with a strong cotton net and they were observed by means of a video camera. The suboptimal irradiation dose was given once daily with a 4-MeV linear accelerator, 4-5 Gy/fraction, during 5 consecutive days. Tumor volumes and rat weights were followed. At the end point of the study the animals were sacrificed and the tumors were morphometrically analyzed. RESULTS: The combination of irradiation and castration delayed tumor regrowth better than irradiation alone with the same suboptimal dose. Castration before irradiation delayed tumor regrowth more efficiently than castration after irradiation. However, castration alone delayed tumor regrowth even more effectively than suboptimal irradiation doses combined with castration. CONCLUSIONS: In combination with suboptimal irradiation neoadjuvant androgen deprivation was more inhibitory to rat prostatic adenocarcinoma regrowth than adjuvant androgen deprivation. Irradiation with suboptimal doses combined with castration may cause an earlier relapse to androgen-independent tumor growth than castration alone.

Soy and rye diets inhibit the development of Dunning R3327 prostatic adenocarcinoma in rats.

Two experiments were conducted to investigate the effect of soy and rye on the development of Dunning R3327 prostatic adenocarcinoma in rats.

Relationship between human chorionic gonadotrophin-induced changes in testicular microcirculation and the formation of testicular interstitial fluid.

The relationship between testicular vascular permeability and testicular microcirculation as measured by laser Doppler flowmetry was studied in adult rats. In untreated control animals there was an oscillatory testicular blood-flow pattern with a frequency of 10.6 +/- 0.8 pulses/min and the amount of testicular interstitial fluid (IF) collected was 61.5 +/- 2.2 microliter/g testis. Treatment of the rats with 25-200 i.u. human chorionic gonadotrophin (hCG) s.c. 8 h before the experiment resulted in a change in the testicular flow pattern from pulsatile to continuous and an increase in IF volume. Treatment with hCG (50 i.u., s.c.) changed the testicular blood-flow pattern from oscillatory to continuous 4, 8 and 16 h after treatment. The flow pattern returned to being pulsatile 32 h after treatment with hCG. The IF information was increased at those times when the blood-flow pattern was continuous. No effects on blood flow or IF formation were observed with 12.5 i.u. hCG s.c. The present study shows a dose- and time-dependent covariation between the increase in testicular IF volume and the disappearance of the pulsatile flow in testicular microcirculation. It appears that a continuous flow pattern favours the transport of fluid from blood vessels to the interstitium.

Liposome-mediated macrophage depletion: an experimental approach to study the role of testicular macrophages in the rat.

Liposome-entrapped dichloromethylene diphosphonate was injected locally into the right testes of adult rats. This treatment, which has been found to deplete resident macrophages in some other organs, reduced the number of testicular macrophages by at least 90%. Testicular weight and seminiferous tubule morphology were unaffected by liposome treatment. Leydig cell testosterone secretion gradually declined in the macrophage-depleted testes, and there was a compensatory increase in Leydig cell size and testosterone secretion in the contralateral saline-injected testes. These observations suggest that macrophages influence Leydig cell function locally. It is concluded that liposome-mediated depletion of testicular macrophages may serve as an experimental model with which to study the physiological role of these cells.

The human chorionic gonadotrophin-induced inflammation-like response is enhanced in macrophage-depleted rat testes.

Liposome-entrapped dichloromethylene diphosphonate (Cl2MDP) was injected locally into the right testes of adult rats in order to deplete testicular macrophages. The number of testicular macrophages in the treated testes was reduced by at least 90% at 7 and 14 days after treatment. Unilaterally testicular macrophage-depleted animals were treated with 100 IU human chorionic gonadotrophin (hCG) subcutaneously and the inflammatory response was compared in the macrophage-depleted and intact contralateral testis. Four hours after hCG treatment, intratesticular testosterone was similarly increased in intact and macrophage-depleted testes. In macrophage-depleted testes there was a large increase in the number of leukocytes in testicular blood vessels and numerous leukocytes had migrated into the interstitial tissue. This response was greater than in the intact contralateral testis. It was concluded that testicular macrophages are probably not the origin of the inflammatory mediator secreted in the rat testis after hCG treatment. On the contrary, it appears that testicular macrophages may secrete factors inhibiting hCG-induced testicular inflammation.

Effects of oestradiol-17 beta on testicular microcirculation in rats.

The effect of oestradiol-17 beta on testicular microcirculation in intact and hypophysectomized rats was studied before and after treatment with human chorionic gonadotrophin (hCG). Treatment of intact rats with oestradiol-17 beta for 5 days did not influence vasomotion but decreased testicular interstitial fluid volume (IFV). Treatment of intact rats with 50 IU hCG 8 h before the experiment began induced an increase in testicular IFV, abolished vasomotion and increased the accumulation of polymorphonuclear leucocytes in the testicular venules and interstitium. These changes were unaffected by pretreatment with oestradiol-17 beta, despite the decreased testosterone production. However, pretreatment with oestradiol-17 beta potentiated the hCG-induced migration of polymorphonuclear leucocytes to the interstitium. The interstitial fluid volume and number of polymorphonuclear leucocytes in blood vessels were decreased in hypophysectomized rats, and vasomotion was abolished. Daily treatment with 5 IU hCG increased the IFV and the number of polymorphonuclear leucocytes in blood vessels, and preserved vasomotion. Treatment of hypophysectomized rats with oestradiol-17 beta decreased testosterone production but did not influence basal IFV, vasomotion or the changes in IFV and vasomotion induced by 5 IU hCG. The present study shows that the regulation of testicular vascular permeability and vasomotion may not be directly related to testicular steroidogenesis, and that oestrogens are probably not involved as a mediator of the hCG-induced changes in testicular microcirculation.

Leucocytes mediate the hCG-induced increase in testicular venular permeability.

Human chorionic gonadotrophin (hCG) treatment of adult male rats induces microvascular changes in the testis consisting of abolished vasomotion, an accumulation of leucocytes in postcapillary venules and increased vascular permeability. To study the role of leucocytes, rats were made leucopenic with a specific antineutrophil serum (ANS). Testicular interstitial fluid volume was decreased in leucopenic rats. Leucopenic rats also failed to show an hCG-induced increase in venular permeability as in saline-treated rats. The normally pulsatile blood flow pattern (vasomotion) persisted in leucopenic rats but was abolished after hCG treatment both in saline-treated and leucopenic rats. Plasma testosterone concentration after hCG treatment was not affected by elimination of circulating polymorphonuclear (PMN) leucocytes. It is concluded that PMN leucocytes mediate in part the hCG-induced increase in testicular venular permeability but not the hCG-induced inhibition of vasomotion.