Triptolide reduces prostate size and androgen level on testosterone-induced benign prostatic hyperplasia in Sprague Dawley rats.

Benign prostatic hyperplasia (BPH) is an age-related disease of unknown etiology, characterized by prostatic enlargement coincident with distinct alterations in tissue histology. In the present study, we investigated whether triptolide can prevent testosterone-induced prostatic hyperplasia in rats. Castration was performed via the scrotal route after urethane aesthesia. BPH was induced in experimental groups by daily subcutaneous injections of testosterone propionate (TP) for two weeks. Triptolide was administered daily by oral gavage at a dose of 100 and 50 µg·kg-1 for 2 weeks, along with the TP injections. On day 14, the animals were humanely killed by cervical dislocation after aesthesia. Prostates were excised, weighed, and used for histological studies. Testosterone and dihydrotestosterone (DHT) levels in serum and prostate were measured. The results showed that triptolide significantly reduced the prostate weight, and the testosterone and DHT levels in both the serum and prostate. Histopathological examination also showed that triptolide treatment suppressed TP-induced prostatic hyperplasia. In conclusion, triptolide effectively inhibits the development of BPH induced by testosterone in a rat model.

NAA-SLR and ICP-AES application in the assessment of mass fraction of 19 chemical elements in pediatric and young adult prostate glands.

The effect of age on the mass fraction of 19 chemical elements in the intact prostate of 50 apparently healthy 0-30-year-old males was investigated by neutron activation analysis with high-resolution spectrometry of short-lived radionuclides and inductively coupled plasma atomic emission spectrometry. Mean values (M ± standard error of the mean) for mass fraction (in milligrams per kilogram, on dry weight basis) of chemical elements were as follows: Al, 77 ± 17; B, 1.31 ± 0.29; Ba, 4.0 ± 1.2; Br, 37.7 ± 4.3; Ca, 1,536 ± 189; Cl, 13,414 ± 949; Cu, 12.3 ± 2.1; Fe, 132 ± 11; K, 11,547 ± 468; Li, 0.064 ± 0.009; Mg, 922 ± 89; Mn, 1.88 ± 0.16; Na, 9,834 ± 411; P, 6,741 ± 335; S, 8,034 ± 251; Si, 199 ± 34; Sr, 1.40 ± 0.19; and Zn, 277 ± 33. The upper limit of mean mass fraction of V was ≤0.24. This work revealed that there is significant tendency for the mass fractions of Ca, K, Mg, and Zn in the prostate tissue of healthy individuals to increase with age from the time of birth up to 30 years. It means that Ca, K, Mg, and Zn mass fractions in prostate tissue are the androgen-dependent parameters. Our finding of a positive correlation between the prostatic Zn and Ca, K, Mg, P, and S mass fractions indicates that there is a special relationship of Zn with some main electrolytes (Ca, K, and Mg) and with P- and S-containing compounds in the prostate. It was shown also that high levels of Al, B, Ba, Br, Cl, Li, Na, and Sr mass fraction in prostate tissue do not indicate a direct involvement of these elements in the reproductive function of the prostate.

Current concepts and significance of estrogen receptor ß in prostate cancer.

An increasing amount of evidence points at important roles for estrogen receptors in prostate carcinogenesis and progression. Of the two estrogen receptors, estrogen receptor ß is the most prominent within the prostate gland. Although there is much yet to be known, the findings from the discovery of the receptor in 1996 until now point at a role of the receptor in maintaining differentiation and reducing cellular proliferation in the prostate. Moreover, estrogen receptor ß is the main target for phytoestrogens, perhaps at least partially explaining the difference in incidence of prostate cancer in the Western world compared to Asia where the intake of soy-based, phytoestrogen-rich food is higher. The tumor suppressive capability of estrogen receptor ß makes it a promising drug target for the treatment and prevention of prostate cancer. This review will focus on different aspects of estrogen receptor signaling and prostate cancer.

Screening for in vivo (anti)estrogenic and (anti)androgenic activities of Tropaeolum majus L. and its effect on uterine contractility.

ETHNOPHARMACOLOGICAL RELEVANCE: Tropaeolum majus L. (Tropaeolaceae) is a medicinal herb popularly used in Brazil for treatment of inflammatory and cardiovascular diseases. Despite some published data on its efficacy, there are still few toxicological data describing the safety of this plant. The aim of this study was to evaluate the (anti)estrogenic and (anti)androgenic activity of the hydroethanolic extract obtained from Tropaeolum majus L. (HETM), as well as its possible effects on uterine contractility. MATERIALS AND METHODS: Three experimental protocols were performed, (a) uterotrophic assay, (b) Hershberger assay and (c) an ex vivo test to investigate the effects of maternal administration of HETM on uterine contractility at the end of pregnancy. In all protocols three doses of the HETM were administered to Wistar rats: 3, 30 and 300mg/kg. RESULTS: In vivo tests for detection of (anti)androgenic and (anti)estrogenic activities did not show any significant alterations. Similarly, no alterations were observed on uterine contractility induced by oxytocin and arachidonic acid. CONCLUSIONS: HETM was unable to produce (anti)estrogenic or (anti)androgenic activities in the short-term in vivo screening assays performed. In addition, there was no evidence that HETM can affect uterine contractility following gestational exposure of rats.

The combination of Serenoa repens, selenium and lycopene is more effective than serenoa repens alone to prevent hormone dependent prostatic growth.

PURPOSE: Serenoa repens is frequently combined with other natural compounds, such as the carotenoid lycopene and the essential trace element Se, to increase its therapeutic activity in benign prostatic hyperplasia. We noted that the lycopene-Se-Serenoa repens combination has greater, enhanced anti-inflammatory activity, which might be of particular interest for benign prostatic hyperplasia treatment. Testosterone administration in rats is a suitable tool for investigating hormone dependent benign prostatic hyperplasia. We performed a comparison experiment between Serenoa repens and the lycopene-Se-Serenoa repens combination on prostate growth induced in rats by testosterone administration. MATERIALS AND METHODS: Rats were treated daily with testosterone propionate (3 mg/kg subcutaneously) or its vehicle for 14 days. Testosterone administered animals were randomized to receive vehicle, Serenoa repens (25 mg/kg subcutaneously) or the combination of lycopene (3 mg/kg subcutaneously), Se (3 mg/kg subcutaneously) and Serenoa repens for 14 days. The rats were sacrificed and the prostate was removed for analysis. RESULTS: Lycopene-Se-Serenoa repens was more effective than Serenoa repens alone for decreasing prostate weight and hyperplasia, augmenting pro-apoptotic Bax and caspase-9, and blunting anti-apoptotic Bcl-2 mRNA. Lycopene-Se-Serenoa repens also markedly decreased epidermal growth factor and vascular endothelial growth factor expression. CONCLUSIONS: The data indicate that the lycopene-Se-Serenoa repens combination is superior to Serenoa repens alone for decreasing hormone dependent prostatic growth.

17α-Estradiol and genistein inhibit high fat diet induced prostate gene expression and prostate growth in the rat.

PURPOSE: High dietary fat and low phytoestrogen intake are associated with prostate cancer development and progression. Our previous study showed that exposure to a high fat diet significantly increased prostate 5α-reductase-2 mRNA and prostate growth in the rat. In the current experiments we determined the effects of genistein and 17α-estradiol on the modulation of dietary fat induced prostate 5α-reductase-2 and insulin-like growth factor-1 gene expression, and prostate growth. MATERIALS AND METHODS: At weaning male ACI/Seg rats (Harlan® Sprague-Dawley®) were fed a low or a high fat diet, with or without genistein or 17α-estradiol for 2, 4 or 10 weeks. The prostate was dissected and weighed. We determined the levels of prostate 5α-reductase-2 mRNA, insulin-like growth factor-1 mRNA, dihydrotestosterone, and plasma insulin-like growth factor-1, dihydrotestosterone and testosterone. RESULTS: Two-week exposure to a high fat diet significantly increased prostate insulin-like growth factor-1 mRNA without significant changes in plasma insulin-like growth factor-1, which was blocked by genistein and 17α-estradiol. Genistein but not 17α-estradiol also inhibited prostate 5α-reductase-2 mRNA and intraprostatic dihydrotestosterone induced by the high fat diet at 2 weeks. Genistein and 17α-estradiol completely blocked high fat diet induced prostate growth at 10 weeks of dietary treatment. However, neither genistein nor 17α-estradiol had any significant effect when co-administered with the low fat diet. CONCLUSIONS: Results indicate that genistein and 17α-estradiol can inhibit dietary fat induced changes in prostate 5α-reductase-2 and insulin-like growth factor-1 gene expression, and prostate growth in the rat. This may be beneficial to prevent dietary fat associated prostate diseases such as prostate cancer.

A novel synthetic androgen receptor ligand, S42, works as a selective androgen receptor modulator and possesses metabolic effects with little impact on the prostate.

We identified a novel synthetic steroid, S42, as a promising candidate of selective androgen receptor (AR) modulator. Results of the whole-cell binding assay using COS-7 cells exogenously expressing various steroid receptors indicated that S42 specifically binds to AR and progesterone receptor. When orchiectomized Sprague Dawley rats were administered with S42 for 3 wk, the muscle weight of the levator ani was increased as markedly as that induced by 5alpha-dihydrotestosterone (DHT), but the weight of the prostate was not elevated at any doses in contrast to DHT. The plasma concentrations of gonadotropin and adiponectin, those down-regulated by DHT, were unaffected by S42. In addition, although the plasma triglyceride level was unaffected by DHT, it was significantly reduced by S42. This effect of S42 was associated with suppression of the SRBP-1c-mediated lipogenic and insulin-desensitizing pathway in the liver and visceral fat. Taken together, S42 works as an AR agonist in muscle and as an AR antagonist in the prostate, pituitary gland, and liver, accompanying beneficial potentials on lipid metabolism.

Banana peel extract suppressed prostate gland enlargement in testosterone-treated mice.

A methanol extract of banana peel (BPEx, 200 mg/kg, p.o.) significantly suppressed the regrowth of ventral prostates and seminal vesicles induced by testosterone in castrated mice. Further studies in the androgen-responsive LNCaP human prostate cancer cell line showed that BPEx inhibited dose-dependently testosterone-induced cell growth, while the inhibitory activities of BPEx did not appear against dehydrotestosterone-induced cell growth. These results indicate that methanol extract of banana peel can inhibit 5alpha-reductase and might be useful in the treatment of benign prostate hyperplasia.

A critical review of the pharmacology of the plant extract of Pygeum africanum in the treatment of LUTS.

Despite an unremitting increase in the number of patients presenting symptoms of benign prostate hyperplasia (BPH), the viable treatment options remain relatively limited when compared to other disorders of aging. This has spurred an interest in so-called alternative medicines, many of which continue to be used in spite of the more recent emergence of rationally targeted therapies. Nonetheless, in the case of plant extracts, the vast majority of these have not been subjected to the same rigorous pre-clinical pharmacological testing and large-scale clinical trials now required by health authorities. Furthermore, demonstration of their clinical efficacy in BPH has been hindered by trials of limited duration with a high placebo response. Beginning with a preliminary demonstration of in vitro inhibition of growth factor-mediated fibroblast proliferation with Pygeum africanum extract, a detailed series of in vitro and in vivo studies on prostate growth and bladder function were undertaken. These studies, reviewed herein, have permitted the identification of putative molecular targets of Pygeum africanum extract affecting both growth factor-mediated prostate growth as well as specific parameters of bladder function. These results, corroborated in part by short-term clinical efficacy, set the stage for a large-scale clinical trial to investigate the efficacy of Pygeum africanum extract in the treatment of lower urinary tract symptoms.

Pumpkin seed oil and phytosterol-F can block testosterone/prazosin-induced prostate growth in rats.

INTRODUCTION: This study was undertaken to investigate the effects of pumpkin seed oil alone or combined with Phytosterol-F on testosterone/prazosin-induced (T-P) prostate growth in rats. MATERIALS AND METHODS: Forty adult Wistar rats were divided into five groups, including: one control group, rats treated with vehicle only, one group treated with T-P, and two groups of T-P-treated rats, one receiving orally pumpkin seed oil alone and one group receiving orally pumpkin seed oil combined with Phytosterol-F. Two weeks later, the prostatic weight-to-body weight ratio was determined after sacrifice. The total protein concentration was measured by using a protein assay. Some ventral prostatic tissues were histologically examined after hematoxylin-eosin staining. RESULTS: Histological sections of the ventral prostate showed that the architecture of the prostate glands became hyperplastic in the T-P rats, but not in the control or vehicle-treated animals. As compared with the control or vehicle group, T-P rats had a significantly higher prostatic weight-to-body weight ratio for the ventral prostate (p=0.05 and p=0.007, respectively), but not for the dorsolateral prostate (p=0.53 and p=0.73, respectively). The T-P rats had significantly higher protein levels within both lobes (ventral lobe, p=0.02 and p<0.0001, respectively; dorsolateral lobe, p=0.06 and p=0.005, respectively). As compared with the T-P-alone rats, the TP rats treated with pumpkin seed oil alone or pumpkin seed oil combined with Phytosterol-F had a significantly lower weight ratio for the ventral prostate (p=0.01 and p=0.004, respectively) and significantly lower protein levels within both lobes (p=0.03 and p=0.003, respectively; p=0.007 and p=0.002, respectively). In addition, Phytosterol-F had some additive effect on the total protein synthesis within the ventral prostate (p=0.02). CONCLUSION: Pumpkin seed oil alone or combined with Phytosterol-F can block the T-P-induced increases in prostatic weight-to-body weight ratio and protein synthesis.

Anti-androgenic activities of Ganoderma lucidum.

The inhibitory effects of methanol extracts of 19 edible and medicinal mushrooms on 5alpha-reductase activity were examined. The extract of Ganoderma lucidum Fr. Krast (Ganodermataceae) showed the strongest 5alpha-reductase inhibitory activity. The treatment of the fruit body of Ganoderma lucidum or the extract prepared from it significantly inhibited the testosterone-induced growth of the ventral prostate in castrated rats. These results showed that Ganoderma lucidum might be a useful ingredient for the treatment of benign prostatic hyperplasia (BPH).

Lycopene reduced gene expression of steroid targets and inflammatory markers in normal rat prostate.

Epidemiological evidence links consumption of lycopene, the red carotenoid of tomato, to reduced prostate cancer risk. We investigated the effect of lycopene in normal prostate tissue to gain insight into the mechanisms, by which lycopene can contribute to primary prostate cancer prevention. We supplemented young rats with 200 ppm lycopene for up to 8 wk, measured the uptake into individual prostate lobes, and analyzed lycopene-induced gene regulations in dorsal and lateral lobes after 8 wk of supplementation. Lycopene accumulated in all four prostate lobes over time, with all-trans lycopene being the predominant isoform. The lateral lobe showed a significantly higher total lycopene content than the other prostate lobes. Transcriptomics analysis revealed that lycopene treatment mildly but significantly reduced gene expression of androgen-metabolizing enzymes and androgen targets. Moreover, local expression of IGF-I was decreased in the lateral lobe. Lycopene also consistently reduced transcript levels of proinflammatory cytokines, immunoglobulins, and immunoglobulin receptors in the lateral lobe. This indicates that lycopene reduced inflammatory signals in the lateral prostate lobe. In summary, we show for the first time that lycopene reduced local prostatic androgen signaling, IGF-I expression, and basal inflammatory signals in normal prostate tissue. All of these mechanisms can contribute to the epidemiologically observed prostate cancer risk reduction by lycopene.

Sonic hedgehog-patched Gli signaling in the developing rat prostate gland: lobe-specific suppression by neonatal estrogens reduces ductal growth and branching.

While prostate gland development is dependent on androgens, other hormones including retinoids and estrogens can influence this process. Brief exposure to high-dose estrogen during the neonatal period in rats leads to permanent, lobe-specific aberrations in the prostate gland, a phenomenon referred to as developmental estrogenization. We have previously shown that this response is mediated through alterations in steroid receptor expression; however, further downstream mechanisms remain unclear. Herein, we examined Sonic hedgehog (Shh)-patched (ptc)-gli in the developing rat prostate gland, its role in branching morphogenesis, and the effects of neonatal estrogens on its expression and localization to determine whether a disturbance in this signaling pathway is involved in mediating the estrogenized phenotype. Shh was expressed in epithelial cells at the distal tips of elongating ducts in discreet, heterogeneous foci, while ptc and gli1-3 were expressed in the adjacent mesenchymal cells in the developing gland. The addition of Shh protein to cultured neonatal prostates reduced ductal growth and branching, decreased Fgf10 transcript, and increased Bmp4 expression in the adjacent mesenchyme. Shh-induced growth suppression was reversed by exogenous Fgf10, but not noggin, indicating that Fgf10 suppression is the proximate cause of the growth inhibition. A model is proposed to show how highly localized Shh expression along with regulation of downstream morphogens participates in dichotomous branching during prostate morphogenesis. Neonatal exposure to high-dose estradiol suppressed Shh, ptc, gli1, and gli3 expressions and concomitantly blocked ductal branching in the dorsal and lateral prostate lobes specifically. In contrast, ventral lobe branching and Shh-ptc-gli expression were minimally affected by estrogen exposure. Organ culture studies with lateral prostates confirmed that estradiol suppressed Shh-ptc-gli expression directly at the prostatic level. Taken together, the present findings indicate that lobe-specific decreases in Shh-ptc-gli expression are involved in mediating estradiol-induced suppression of dorsal and lateral lobe ductal growth and branching during prostate morphogenesis.

Effect of Pygeum africanum tadenan on micturition and prostate growth of the rat secondary to coadministered treatment and post-treatment with dihydrotestosterone.

OBJECTIVES: Pretreatment with oral tadenan (TAD) has been shown to possess a protective effect on bladder dysfunction-induced obstruction. We evaluated the functional influence of cotreatment and post-treatment with oral TAD on the frequency/volume characteristics of micturition of conscious rats stimulated with exogenous dihydrotestosterone (DHT) to induce experimental prostate growth. METHODS: Studies were done on 36 adult Sprague-Dawley male rats, treated daily for 6 weeks and grouped as follows: group 1, sesame oil during weeks 1 and 2, peanut oil during weeks 3 to 6; group 2, DHT (1.25 mg/kg subcutaneously) dissolved in sesame oil as vehicle during weeks 1 and 2 and peanut oil during weeks 3 to 6; group 3, DHT (1.25 mg/kg subcutaneously) dissolved in sesame oil as vehicle and TAD (100 mg/kg orally) in peanut oil during weeks 1 and 2 and TAD during weeks 3 to 6; and group 4, DHT in sesame oil during weeks 1 and 2 and TAD in peanut oil during weeks 3 to 6. The characteristics of frequency/volume were monitored biweekly and at the sixth week. RESULTS: Controls showed no significant changes from baseline values in volume or frequency during the entire study period. DHT treatment produced a significant increase in frequency (1.9 +/- 0.3 to 3.0 +/- 0.4/hr) and a significant decrease in volume (1.8 +/- 0.3 to 1.2 +/- 0.1 mL). In groups 3 and 4, no significant changes occurred in frequency or volume. By the sixth week of observation, the effects of DHT treatment decreased to control values in all groups. A significant increase in prostatic weight (1191 +/- 11 to 1434 +/- 17 mg/kg) was produced by DHT treatment and TAD cotreatment suppressed growth to 1390 +/- 8.4 mg/kg. CONCLUSIONS: TAD cotreatment or post-treatment suppressed the effects of DHT on micturition, and TAD cotreatment regressed a developing increase in prostatic weight. Post-treatment TAD administration did not reduce already established growth.

Genistein alters growth but is not toxic to the rat prostate.

The mortality of clinical prostate cancer is lower in Asian populations than in American or European men. Asian men typically consume more soy than their Western counterparts, leading to the investigation of individual components, particularly phytoestrogens, as protective factors against prostate cancer. Genistein, the predominant isoflavone in soy, has been reported to reduce the incidence of prostate cancer in animal models, but the underlying biological action remains to be elucidated. The purpose of this investigation was to identify the effects of the phytoestrogen, genistein and the synthetic estrogen diethylstilbestrol (DES), as a control, on development and function of the rat dorsolateral prostate (DLP) when given in the diet. The effects of testosterone and dihydrotestosterone (DHT) injections were also tested. Analysis of individual lobes of the DLP revealed that 1000 mg/kg, but not 250 mg/kg, of a genistein AIN-76A diet slightly reduced lateral prostate type 1 (LP1) bud perimeter. However, expression of the secretory dorsal protein 1 (DP1) and 5alpha-reductase type II activity were not altered in the prostate. This suggested that prostate differentiation, and not toxicity, had occurred. DES in the diet reduced and testosterone injections elevated relative prostate weights and perimeters of the dorsal, LP1, lateral prostate type 2 and DP1 expression. DHT increased relative prostate weights but did not significantly increase individual lobe perimeter. Unlike DES, maximally tolerated doses of genistein in the diet were not toxic to the rat prostate.

Selective estrogen receptor modulators for the chemoprevention of prostate cancer.

The ability to interfere with prostate carcinogenesis, and as a consequence, prevent prostate cancer with drugs is the basis for chemoprevention. The prostate contains estrogen receptors in both the stroma and epithelium. Both animal models and human epidemiologic studies have implicated estrogens as an initiator of prostate cancer. In the aging male, prostate cancer occurs in an environment of rising estrogen and decreasing androgen levels. Selective estrogen receptor modulators (SERMs) have shown the ability to prevent (GTx-006 [acapodene]) and treat (GTx-006 and arzoxifene) prostate cancer, suggesting that they may be used in prostate cancer chemoprevention. A phase 2 clinical trial using GTx-006 for prostate cancer chemoprevention is currently being conducted.

The in vivo effect of red clover diet on ventral prostate growth in adult male mice.

The incidence of clinically significant prostate disease in Asian men is lower than in Western men and appears to be influenced by dietary and environmental factors. The aim of this study was to examine the effect of dietary isoflavones on prostate growth in intact male mice using an extract of red clover. The results demonstrated that prostate, but not testis, size was significantly reduced over 28 days of a red clover isoflavone supplemented diet. Histological examination revealed an increase in apoptotic cells, rather than a reduction in proliferative activity in the epithelium. These findings support the hypothesis that dietary red clover isoflavones can induce apoptosis and lead to a reduction in prostate size.

Functional evaluation of Tadenan on micturition and experimental prostate growth induced with exogenous dihydrotestosterone.

OBJECTIVES: To evaluate the effect of Tadenan (TAD; Pygeum africanum extract) pretreatment on the micturition characteristics of conscious and anesthetized rats consequent to dihydrotestosterone (DHT) administration and to examine the influence of such treatment on the growth of the prostate. METHODS: Studies using 40 adult Sprague-Dawley male rats were performed during a 7-week period. These animals were treated with DHT 1.25 mg/kg subcutaneously dissolved in peanut oil and/or TAD 100 mg/kg orally dissolved in sesame oil, except for the controls, which received vehicle only. Rats were divided into four groups: group 1 (control), vehicle only; group 2, DHT administered during weeks 3 and 4; group 3, TAD pretreatment, administered during weeks 1 and 2, followed by the combined administration of DHT and TAD during weeks 3 and 4 and TAD only during weeks 5 to 7; and group 4, continuous TAD treatment for 7 weeks. Micturition of conscious rats was evaluated in metabolic chambers, and in anesthetized rats, cystometrograms were done at the end of 7 weeks. RESULTS: DHT or DHT plus TAD did not produce significant changes in the volume but did reduce the frequency of micturition. TAD given alone significantly increased the volume of micturition and the rate of urine production. Cystometrographic studies in anesthetized rats revealed that DHT produced micturition characteristics similar to obstruction. The DHT plus TAD and TAD pretreatment data showed no significant difference from controls, suggesting that in the presence of TAD, the effects of DHT were negated. The total prostate weight of DHT and DHT plus TAD pretreated rats increased, and in the TAD group, these values decreased to lower than controls; growth of the ventral lobes was suppressed in the presence of TAD. CONCLUSIONS: These results demonstrate that TAD pretreatment significantly reduces the "obstructive" effects of DHT on micturition, counteracts the hormone-induced enlargement of the prostate, and reduces prostate weight in the ventral but not the dorsal lobe.

Effect of prenatal vitamin D (calcitriol) exposure on the growth and development of the prostate.

BACKGROUND: We previously found that in the absence of testosterone (T), calcitriol promotes proliferation of normal prostatic stroma, while in the presence of T, it has a differentiating effect on prostatic epithelium. The present study was conducted to determine the effect of calcitriol exposure in utero on the postnatal development of the normal prostate. METHODS: Pregnant rats were injected subcutaneously with either 1.25 microg of calcitriol or vehicle alone on alternate days till delivery. Calcitriol-exposed and control pups were sacrificed at age 25 days (prepuberty), 63 days (postpuberty), or 102 days (adults), and their prostates and seminal vesicles were harvested and weighed. RESULTS: Pups prenatally exposed to calcitriol and sacrificed before puberty (25 days) had a 35% greater mean prostatic weight than controls (0.0314 vs. 0.0422 g, P < 0.007), and calcitriol-exposed adult rats (102 days) had a 68% greater mean prostatic weight than controls (0.1365 vs. 0.2304 g, P < 0.005). No differences were observed in seminal vesicle weights, and in serum calcium and testosterone levels. A disproportionately high mortality rate from sudden death (71%) was observed at puberty in uncastrated male rats prenatally exposed to calcitriol. CONCLUSIONS: These findings suggest that high-dose calcitriol exposure in utero may uniquely influence subsequent prostatic growth. Nonandrogenic steroids such as calcitriol may also be involved in genetic imprinting of the prostate.

Growth regulation of prostatic stromal cells by prostate-specific antigen.

BACKGROUND: Prostate-specific antigen (PSA) is a serine protease that can cleave insulin-like growth factor-binding protein-3 (IGFBP3), thereby decreasing its affinity for insulin-like growth factor-I (IGF-I). Dissociation of the IGF-I-IGFBP3 complex renders IGF-I available to bind to its receptor and stimulates cellular proliferation. We evaluated the potential for PSA to modulate the effects of IGF-I and IGFBP3 on the proliferation of human benign prostatic hyperplasia (BPH)-derived fibromuscular stromal cells in primary cultures. METHODS: We cultured BPH-derived stromal cells for 48 hours in serum-free RPMI-1640 medium supplemented with 0.2% bovine serum albumin and studied the effects of IGF-I, IGFBP3, PSA, and ZnCl(2) at varying concentrations. Differences in cell growth between control and treated cultures were evaluated by use of Dunnett's test. Concentration-related trends were evaluated by linear regression of log-transformed concentrations of test reagents on BPH-derived stromal cell number responses. Statistical tests were two-sided. RESULTS: We observed a concentration-dependent proliferative response of BPH-derived stromal cells to IGF-I. IGFBP3 inhibited this response in a concentration-dependent fashion. IGFBP3 alone had no effect on stromal cell proliferation. When stromal cells were incubated with PSA alone or with PSA, IGF-I, and IGFBP3, an increase in stromal cell numbers that was dependent on PSA concentration was evident in both instances. Zinc, an endogenous inhibitor of PSA enzymatic activity, was able to attenuate the stimulatory effect of PSA at intraprostatic physiologic concentrations. CONCLUSIONS: These results are consistent with the idea that PSA can modulate in vitro interactions between IGF-I and IGFBP3 and suggest that PSA may play a role in the regulation of human prostatic fibromuscular cell growth.