Effects of dutasteride on prostate growth in the large probasin-large T antigen mouse model of prostate cancer.

PURPOSE: We evaluated the effects of dutasteride for preventing or delaying prostate growth and neoplastic changes in a transgenic model of prostate cancer. MATERIALS AND METHODS: Large probasin-large T antigen mice were treated for 4 or 8 weeks with dutasteride. The prostate and seminal vesicles were compared with those from intact and castrated large probasin-large T antigen mice and WT mice. RESULTS: Dutasteride greatly decreased the transgene induced increase in prostate weight but castration caused greater reduction. Dutasteride inhibited type 1 and 2, 5alpha-reductase activities, decreased DNA and protein, and increased apoptotic bodies and TUNEL staining in the dorsolateral prostate. No evidence of poorly differentiated cancer was seen. Dutasteride did not decrease the weight of the androgen dependent levator ani or bulbocavernosus muscle. CONCLUSIONS: Dutasteride inhibited type 1 and 2, 5alpha-reductase activities, and decreased DNA and protein content of the dorsolateral prostate without affecting androgen responsive muscle weight in large probasin-large T antigen mice. These studies provide support for the hypothesis that a 5alpha-reductase inhibitor inhibits the initiation and/or progression of clinical prostate cancers.

Comparison of the growth-promoting effects of testosterone and 7-alpha-methyl-19-nor-testosterone (MENT) on the prostate and levator ani muscle of LPB-tag transgenic mice.

BACKGROUND: 7-alpha-methyl-19-nortestosterone (MENT) is being considered for androgen replacement in testosterone deficient men and as a male contraceptive. Because androgenic effects on the prostate are a major concern, we have evaluated MENT in a transgenic model of prostate cancer. METHODS: LPB-Tag mice were castrated and infused with testosterone (T; 5 or 30 microg/day) or MENT (5 or 30 microg/day) for 4 weeks. Prostate, seminal vesicle, and levator ani muscle (LAM) weights were compared. RESULTS: At an equivalent dose, MENT maintained or stimulated the mean weights of these organs more than T. However, the dorsolateral prostate/LAM ratio of weights did not favor MENT, but DNA/mg tissue and Ki 67 immunostaining suggested that MENT may increase DNA less than T. CONCLUSIONS: MENT is more potent than T in maintaining or stimulating prostate, seminal vesicle, and LAM. Using doses that resulted in comparable stimulation of the levator ani muscle, MENT had similar effect on prostate weight, but increased DNA/mg prostate less than T in this transgenic mouse model of prostate cancer.

Hypogonadism and diabetes.

Clinicians have been aware of the increased prevalence of low testosterone levels in patients with type II diabetes for several years, but how these two conditions are associated is difficult to determine. Older age and obesity may be factors, as both are associated with type II diabetes and both decrease testosterone levels. Sex hormone-binding globulin (SHBG), the major serum carrier protein for testosterone, also may have an impact. SHBG levels fall with obesity and increase with aging. Some studies indicate lower SHBG levels in type II diabetes. Most of the differences in testosterone levels between diabetic and nondiabetic patients may be due to reduced SHBG, rather than reduced testosterone production. However, free testosterone levels fall with increasing age and obesity, rendering many type II diabetic patients testosterone deficient. Testosterone replacement may improve insulin sensitivity in hypogonadal, overweight men with type II diabetes by altering body composition, but studies are conflicting.

Induction of apoptosis in BPH stromal cells by adenoviral-mediated overexpression of caspase-7.

PURPOSE: We hypothesized that expression/activity of critical components of the apoptotic pathway can be used to induce apoptosis of a human prostate cell line derived from benign prostatic hyperplasia (BPH) tissue. MATERIALS AND METHODS: We analyzed the apoptotic pathway in BPH cells treated with the powerful inducer of apoptosis, staurosporine (STS), and adenoviruses overexpressing caspase-3, -7, or the control gene lacZ. RESULTS: Twelve hours post-STS, most BPH cells were floating in the culture medium, TUNEL staining was widespread, and DEVDase activity (the catalytic activity of type II caspases) was increased. The pan-caspase inhibitor, Z-VAD-FMK, prevented STS-induced apoptosis. Based on these observations, we performed immunoblot analysis for the three known group II caspases (that is caspase-2, -3 and -7), but none of them was detected with three commercially available antibodies. Nevertheless, in view of the presence of increased DEVDase activity, we reasoned that a group II caspase must be a critical mediator of apoptosis in this model. If correct, we postulated that overexpression and activation of a type II caspase should cause apoptosis. To test this hypothesis, we coupled the cDNAs encoding caspase-3 and caspase-7 to adenoviral vectors and obtained constructs AvC3 and AvC7. Cells infected with AvC3 or AvC7 overexpressed the protein for caspase-3 or -7 within 24 to 48 hours. Caspase-3 overexpression did not cause apoptosis above that observed in cells receiving the control adenovirus expressing the lacZ cDNA (AvLac-Z). In contrast, caspase-7 overexpression induced massive apoptosis. BPH cells were then infected with increasing multiplicity of infection (MOI) of AvC7 and AvlacZ. A positive correlation was found between the amount of caspase-7 expressed and the level of DEVDase activity measured. AvC7 at MOIs of 25:1 and 50:1 induced apoptosis in about 50% of BPH cells at 72 hours post-infection. This effect was AvC7 specific, because the same MOIs of AvlacZ were not apoptogenic. CONCLUSIONS: Adenoviral-mediated overexpression of caspase-7 induces apoptosis of BPH-derived cells.

Signaling pathway activated during apoptosis of the prostate cancer cell line LNCaP: overexpression of caspase-7 as a new gene therapy strategy for prostate cancer.

We studied the molecular mechanisms of apoptosis in the prostate cancer cell line LNCaP and whether overexpression of caspase activity could force this cell line to undergo apoptosis. The inhibitor of phosphomevalonate decarboxylase, sodium phenylacetate, and the protein kinase inhibitor staurosporine induced (a) release of cytochrome c from the mitochondria to the cytosol; (b) reduction in mitochondrial transmembrane potential; (c) proteolytic processing of caspase-3 and -7 but not -2; (d) cleavage of the DEVD substrate and the death substrates poly(ADP-ribose) polymerase and DNA fragmentation factor; and (e) apoptosis. The panspecific inhibitor of caspase activation N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (z-VAD-FMK) prevented all of these events except release of mitochondrial cytochrome c into the cytosol. None of these apoptotic signaling events were elicited by staurosporine or sodium phenylacetate treatment of LNCaP-Bcl-2 cells that overexpress the oncoprotein Bcl-2. Because caspase-7 is activated in every model of apoptosis that we have characterized thus far, we wished to learn whether overexpression of this protease could directly cause apoptosis of LNCaP cells. By using a replication-defective adenovirus, overexpression of caspase-7 protein in both LNCaP and LNCaP-Bcl-2 cells was accompanied by induction of cleavage of the DEVD substrate and TUNEL. These studies have demonstrated that caspase-7 and -3 are critical mediators of apoptosis in LNCaP cells. Caspase-7 was proteolytically activated in every model of apoptosis that we have developed, and the overexpression of it induced apoptosis of LNCaP and LNCaP-Bcl-2 cells. Thus, adenoviral-mediated transfer of caspase-7 may offer a new effective approach for the treatment of prostate cancer.

Caspase-7 is activated during lovastatin-induced apoptosis of the prostate cancer cell line LNCaP.

The goals of this work were to establish a reproducible and effective model of apoptosis in a cell line derived from advanced prostate cancer and to study the role of the caspase family of proteases in mediating apoptosis in this system. The study involved the use of the prostate cancer cell line LNCaP. Apoptosis was induced using the hydroxymethyl glutaryl CoA reductase inhibitor, lovastatin, and was evaluated by agarose gel electrophoresis of genomic DNA, morphological criteria, and terminal deoxynucleotidyl transferase-mediated nick end labeling. Caspases were studied by catalytic activity, mRNA induction, and protein processing. Lovastatin (30 microM) was an effective inducer of apoptosis, causing changes that were evident after 48 h and essentially complete after 96-120 h of treatment. These effects were prevented by the simultaneous addition of mevalonate (300 microM) to the culture medium. Lovastatin induced a proteolytic activity that was able to cleave the enzyme poly(ADP-ribose) polymerase and the substrate Z-DEVD-AFC, which is modeled after the P1-P4 amino acids of the poly(ADP-ribose) polymerase cleavage site. Caspase-7, but not caspase-3, underwent proteolytic activation during lovastatin-induced apoptosis, an effect prevented by mevalonate. Caspase-7 was the only detected interleukin 1beta converting enzyme family protease with DEVD cleavage activity that exhibited lovastatin-induced mRNA up-regulation. Again, mevalonate blocked this effect. Lovastatin-induced apoptosis also was prevented when the caspase inhibitors Z-DEVD-CH2F or Z-VAD-CH2F (100 microM) where added to the medium. These studies have identified lovastatin as a powerful inducer of apoptosis in the cell line LNCaP. Caspase activation was a necessary event for LNCaP cells to undergo apoptosis during treatment with lovastatin. Of the caspases tested, only caspase-7 underwent proteolytic activation after stimulation with lovastatin. Identification of caspase-7 as a potential mediator of lovastatin-induced apoptosis broadens our knowledge of the molecular events associated with programmed cell death in a cell line derived from prostatic epithelium.

Androgen and sleep-related erections.

Sleep-related penile erections provide a unique opportunity to objectively study erectile physiology in man. Testosterone is one of several factors involved in normal sexual function and testosterone reduction can be achieved by administering luteinizing-hormone releasing-hormone agonists (LHRH-A). In this study, ten healthy, young adult males were administered LHRH-A or placebo for a 12-week period. Subjects taking LHRH-A had a marginally significant decline in sleep-related erection duration at week 4 and significant reductions at weeks 8 and 12. By contrast, no statistically reliable change was found for the number of erections over the course of study. Maximum circumference increase during sleep erections showed mixed results. These results indicate that, whereas androgen reduction adversely affects sleep-related erections, it does not eliminate them over a 12-week trial in healthy young adult men. Further study in a larger sample is needed. Nonetheless, these preliminary findings support androgen having an important role in sleep-related erections.

Lovastatin-induced apoptosis in prostate stromal cells.

Benign prostatic hyperplasia (BPH) is a common disease of aging men. Current medical treatment for this condition is only partially effective, therefore many patients must undergo surgery for symptomatic relief. BPH is caused by an increase in prostate epithelial and stromal cells, especially the latter. Since BPH stromal cells have a long life span and are not very responsive to androgen withdrawal, cultured BPH stromal cells were used to explore the feasibility of pharmacologically inducing apoptosis in these cells. We obtained BPH tissue during surgery, and stromal cells were isolated and maintained in culture. After cells achieved confluence, we induced apoptosis with the HMGCoA reductase inhibitor, lovastatin (30 micromol/L). The effects of testosterone (100 micromol/L), dihydrotestosterone (DHT; 100 micromol/L) and finasteride (100 micromol/L) on lovastatin-induced apoptosis were studied on cells grown in media containing charcoal stripped serum. Similarly, we examined the effect of the cholesterol pathway metabolites, mevalonic acid (30 micromol/L), geranyl geraniol (30 micromol/L), farnesol (10 micromol/L), squalene (30 micromol/L) and 7-ketocholesterol (3 micromol/L) on lovastatin-induced apoptosis. We demonstrated apoptosis by DNA laddering in agarose gels, by fluorescence microscopy following acridine orange staining, and by flow cytometry after end-labeling of DNA strand breaks with biotin-16-dUTP using deoxynucleotidyl exotransferase (TdT). Lovastatin at 30 micromol/L, but not at lower concentrations, induced apoptosis in BPH prostate stromal cells. This was seen (by flow cytometry) in 16.6 +/- 7.3% (mean +/- SD) of BPH cells treated with lovastatin at 72 h vs. 2.5 +/- 1.2% of cells treated with ethanol. Lovastatin-induced apoptosis was not increased in stripped serum or by the addition finasteride, and was not inhibited by testosterone or DHT. Only mevalonate and geranyl geraniol, prevented lovastatin-induced apoptosis whereas farnesol, squalene, or 7-ketocholesterol did not. We conclude that lovastatin can induce apoptosis in BPH stromal cells in vitro, and this is not affected by androgen withdrawal or stimulation. It is unlikely that lovastatin, per se, will be an effective treatment for BPH in vivo, but it does provide a means for inducing apoptosis in vitro. Understanding the apoptotic process in BPH stromal cells ultimately may lead to new therapeutic strategies for BPH.

Safety and efficacy of normalizing fasting glucose with bedtime NPH insulin alone in NIDDM.

OBJECTIVE: To examine the safety and overall clinical effects of normalizing the fasting plasma glucose (FPG) level with bedtime NPH insulin alone in patients with non-insulin-dependent diabetes mellitus (NIDDM) that is poorly controlled with maximal doses of sulfonylureas. RESEARCH DESIGN AND METHODS: Twelve obese male NIDDM subjects were treated for 16 weeks with bedtime insulin after a 4-week sulfonylurea washout. The insulin dosage was increased until the FPG level was normalized. The 24-h plasma glucose profiles and lipid and HbA1c levels were measured at the beginning and end of the study, and the incidence and severity of hypoglycemic episodes were closely monitored. In addition, hyperglycemic clamp studies were performed to assess insulin secretion and provide an indirect measurement of insulin sensitivity. RESULTS: FPG (14.6 +/- 0.9 mmol/l at week 0) was normalized ( < 6.4 mmol/l) within 6 weeks (5.9 +/- 0.6 mmol/l) and remained at target levels until the end of the study (4.0 +/- 0.03 mmol/l at week 16, P < 0.001). The insulin dose was 80 +/- 9 U/day (0.86 +/- 0.10 U/kg). Improved glycemic control was confirmed by a reduction in HbA1c (10.9 +/- 0.05 vs. 7.2 +/- 0.2%, P < 0.001) and mean 24-h glucose (17.2 +/- 0.2 vs. 7.4 +/- 0.2 mmol/l, P < 0.001). The incidence of mild or moderate hypoglycemic episodes was 3.4 +/- 1/patient for the entire 16-week study, and no patient experienced severe hypoglycemia. Bedtime insulin significantly improved total cholesterol, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and triglyceride levels (P < 0.01). Weight gain was 2.4 +/- 0.7 kg, and blood pressure was unchanged. During the hyperglycemic clamp, there was an improvement in the first phase (P < 0.001) and in the second phase (P < 0.01) of insulin secretion. There also was an increase in the rate of exogenous glucose infused (M) (P < 0.01) and in the M/C-peptide ratio (P < 0.02), suggesting enhanced insulin sensitivity. CONCLUSIONS: NPH insulin given at bedtime in amounts sufficient to achieve a normal FPG level does not cause excessive or severe hypoglycemia and does lead to good glycemic and lipid control in NIDDM. Bedtime insulin therapy also is accompanied by improved insulin secretion and insulin sensitivity. We conclude that a single dose of insulin alone at bedtime merits consideration as a therapeutic strategy in patients with poorly controlled NIDDM.

Inhibition of steroid 5 alpha-reductase with finasteride: sleep-related erections, potency, and libido in healthy men.

To objectively measure the effects of a 5 alpha-reductase inhibitor on erectile function, we studied 20 sexually active men (aged 41-64 yr) during double blind, randomized administration of 5 mg/day finasteride (F) or placebo (P). Serum testosterone and dihydrotestosterone (DHT) were measured every 4 weeks. Sleep-related erections were assessed with comprehensive polysomnography for 2 nights before randomization (session 1) and at week 12 (session 2). Sexual function questionnaires were administered weekly. Serum DHT levels at week 0 were 1.47 +/- 0.11 and 1.16 +/- 0.27 nmol/L (P > 0.05) in the P and F groups, respectively. F group levels fell to 31% and 28% of control values at week 4 and 12. Penile tip peak tumescence time increased on second nights more in the P than the F group at 12 weeks, producing a session main effect (P < 0.02) and a group X session interaction (P < 0.05). No significant group X session interactions were found for any sleep erection measures in a best night analysis or for self-reported sexual activity. Thus, F did not consistently suppress sleep-related erections compared to P. F primarily inhibits type 2 5 alpha-reductase activity; however, type 1 5 alpha-reductase is the major enzyme in the central nervous system. Therefore, DHT involvement in the maintenance of libido and potency is not excluded. Nonetheless, these data support the feasibility of using a type 2 inhibitor to treat benign prostatic hyperplasia without impairing erectile function.

Anti-androgen effects of the aromatase inhibitor, atamestane.

Prostatic hyperplasia can be induced in both intact and castrated dogs and in intact cynomolgus monkeys by the administration of androgenic steroids. Estrogenic steroids potentiate this effect in dogs. These changes also can be induced by androstenedione, which increases androgen and estrogen levels. Atamestane (ATA; 1-methyl-3,17-dione-androsta-1,4-diene), a potent aromatase inhibitor, inhibits some of the androstendione-induced effects; however, the nonsteroidal aromatase inhibitor, CGS-16949A, has been reported to decrease serum estradiol levels in adult rats but to have no effect on androgen-dependent organ weights. To examine the mechanisms by which ATA affects the rat prostate, in vivo and in vitro studies were conducted using adult rat ventral prostate (VP). Intact Sprague-Dawley rats were injected daily for 14 days with sesame seed oil, ATA (70 mg/kg/day), finasteride (FIN; 5 mg/kg/day), a 5 alpha-reductase inhibitor, or the combination of FIN plus ATA. A fifth group was castrated (CASTR) on day 1. The mean +/- standard error VP weight of the controls was 350 +/- 19 mg. It was reduced 17% (P < 0.05) by ATA, 29% (P < 0.001) by FIN, 48% (P < 0.001) by FIN plus ATA, and 86% (P < 0.001) by CASTR. The DNA/VP was reduced 22% (not significant) by ATA, 18% by FIN (not significant), 35% (P < 0.01) by FIN plus ATA, and 60% (P < 0.001) by CASTR. More significant changes were observed in RNA and protein. The mRNA for prostatein C3 was reduced by each of the treatments, but only CASTR increased the mRNA for TRPM-2, a marker of apoptosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of 4-MAPC, a 5 alpha-reductase inhibitor, and cyproterone acetate on regrowth of the rat ventral prostate.

Inhibitors of 5 alpha-reductase activity cause less involution of the rat ventral prostate (VP) than does castration. Studies were conducted in adult Sprague Dawley rats to evaluate the effects of a potent 5 alpha-reductase inhibitor, 4-MAPC, and the antiandrogen, cyproterone acetate (CA), on DNA synthesis and apoptosis. In experiment 1, VP weight fell 33%, 53%, and 83%, and DNA per ventral prostate was reduced 24%, 46%, and 71%, by 4-MAPC, CA, and castration, respectively. In experiment 2, adult rats were castrated, and the VP involuted for 7 days prior to 3 daily injections of testosterone propionate (TP; 1 mg/kg/d) +/- 10 mg/kg/d of 4-MAPC or CA. 3H-thymidine incorporation into VP DNA was increased in castrated animals treated with TP, and 4-MAPC and CA reduced uptake. In experiment 3, animals were treated for 14 days with the same protocol as that used in experiment 2. VP weight was increased in all animals treated with TP when compared with castration, and was reduced by both 4-MAPC and CA. DNA in rats treated with TP was similar to that in intact animals. DNA was not reduced by 4-MAPC, but was reduced by CA. The mRNA for TRPM-2, a marker of apoptosis, was increased only in untreated castrated rats. It appears that CA has a greater inhibitory effect than 4-MAPC on DNA synthesis. A major reason why castration reduces DNA more than either 4-MAPC or CA is that neither of these agents was able to increase programmed cell death to the degree seen with castration.

Activation of phospholipase D following perturbation of the human T lymphocyte antigen receptor/CD3 complex is dependent upon protein kinase C.

Perturbation of the T lymphocyte antigen receptor/CD3 complex or phorbol ester stimulation leads to activation of phospholipase D in the Jurkat T lymphocyte cell line. These observations suggested that phospholipase D activation might result from activation of protein kinase C. In other systems, phospholipase D activity has been shown to be under G-protein or protein kinase C control. Studies detailed here demonstrate that commonly used inhibitors of protein kinase C had unrelated, diverse effects on phospholipase D activity in T lymphocytes. However, protein kinase C down-regulation resulting from prolonged cellular exposure to phorbol esters led to abrogation of anti-CD3-stimulated phospholipase D activation. The results presented underline the complexity of studies employing inhibitors of protein kinase C, suggest interesting approaches to isolation of phospholipase D dependent signalling pathways, confirm that T cell antigen receptor-linked activation of phospholipase D is dependent upon protein kinase C activity and suggest that distant events of T lymphocyte activation are dependent upon the establishment of a positive feedback loop involving protein kinase C and phospholipase D which would result in the prolonged activation of protein kinase C required for certain lymphokine production.

Effects of finasteride on the rat ventral prostate.

The objectives of this study were to compare changes in the ventral prostate (VP) of young adult Sprague Dawley rats after 28 days of treatment with finasteride (F), a potent 5 alpha-reductase inhibitor, with those caused by castration (Cx). VP concentrations of DHT were reduced to 20.2% and 6.6% of controls (1,947 +/- 207 pg/VP, mean +/- SE) by F (5 or 20 mg/kg/day) and to 2.6% of controls by Cx. VP weights were reduced 49% and 54% by F and 88% by Cx. DNA/VP fell 25% and 15% with F treatment and 72% after Cx, whereas RNA and protein/VP were reduced 37-51% by F and 91-93% by Cx. The RNA/DNA and the protein/DNA ratios fell to 30-36% of controls after F treatment and to 70% of controls after Cx. The mRNA concentrations of the C3 subunit of prostatein 28S ribosomal RNA fell after treatment with F (5 mg/kg/day) and after Cx, whereas the mRNA for TRPM-2, an androgen-suppressed protein associated with apoptosis, was increased only after castration. To examine further the effects of F on the rate of DNA synthesis, 7-day regressed adult rats were treated for 3 days with testosterone propionate +/- F, and incorporation of 3H-thymidine in minced ventral prostates was determined. F inhibited 3H-thymidine incorporation. We conclude that Cx causes a greater reduction in cell number/VP and a greater reduction in RNA and protein cell than F and that the differences between F treatment and castration probably result from differences in prostatic concentrations of T.(ABSTRACT TRUNCATED AT 250 WORDS)

Activation of phospholipase D: a signaling system set in motion by perturbation of the T lymphocyte antigen receptor/CD3 complex.

A number of cellular signaling systems are called into play by interaction of the T lymphocyte antigen receptor/CD3 complex with its cognate antigen. Well-described signaling systems include phosphoinositide turnover, tyrosine phosphorylation, protein kinase C activation, and increased cytosolic calcium. We have explored the possibility that another recently described signaling system, activation of phospholipase D, may be operative. Data presented here demonstrate that stimulation of Jurkat T cells with anti-CD3 antibodies or phorbol esters resulted in activation of phospholipase D, as measured by production of phosphatidylethanol and phosphatidic acid. The combination of anti-CD3 antibody plus phorbol ester led to a greater than additive production of phosphatidylethanol and to the additive production of phosphatidic acid (in the absence of ethanol). Phorbol esters as a second stimulus with anti-CD3 antibody led to a additive increase in cellular diacylglycerol content but provided no increased production of inositol phosphates, suggesting that diacylglycerol production in these cells results from hydrolysis of noninositol containing lipids as well as from phosphinositides. Exogenous addition of phosphatidic acid led to increases in cytosolic calcium that, depending on the concentration used, resulted from release of an intracellular store of calcium and influx of extracellular calcium. Changes in cytosolic calcium occurred in the absence of inositol phosphates production. These studies establish a role for increased phospholipase D activity in T lymphocyte activation.

4-MAPC, a 5 alpha-reductase inhibitor, reduces rat ventral prostate weight, DNA, and prostatein concentrations.

Several compounds, such as 4-MAPC (4-methyl-3-oxo-4-aza-5 alpha-pregnane-20- carboxylate), that inhibit conversion of testosterone (T) to dihydrotestosterone (DHT) by 5 alpha-reductase have been demonstrated to reduce prostate size in rats and dogs. The current studies were undertaken to determine if this effect is due to a reduction in cell number, in epithelial cell synthetic activity, or both. Eight-week-old intact rats were treated daily for 14 days with sesame seed oil, 4-MAPC (10 mg/kg), 4-MAPC + testosterone propionate (TP, 1 mg/kg), or 4-MAPC + TP (3 mg/kg). Rats were killed 24 hours after the last injection. In the animals treated only with 4-MAPC, ventral prostate weight was reduced 37%, but the 14% reduction in total DNA was not significant. The mean intraprostatic concentration of prostatein, a major secretory protein, was reduced 45% (P less than 0.05). The 3 mg/kg dose of TP increased ventral prostate weight, prostatein concentrations, and acid phosphatase activity, even though DNA/ventral prostate was similar to that in control animals. These observations indicate that the reduction in ventral prostate weight in adult rats is due in part to a reduction in cell number, but the primary effect was due to a reduction in synthetic activity, and possibly atrophy of the epithelial cells. Furthermore, TP in pharmacologic doses increased ventral prostate weight and synthetic activity without increasing DNA.

Abnormal growth hormone dynamics in chronic liver disease do not depend on severe parenchymal disease.

Abnormal basal serum levels of growth hormone (GH) and abnormal GH dynamics have been observed in patients with alcoholic cirrhosis (AC). To further characterize these abnormalities, patients with AC or schistosomal hepatic fibrosis (SHF) were evaluated. The former patients have parenchymal liver disease, portal hypertension, and portosystemic shunting. SHF, in contrast, is characterized by periportal fibrosis with minimal or no parenchymal cell disease, portal hypertension, and portosystemic shunting. We studied 20 patients with SHF and normal stature and 15 patients with AC. In these two groups of patients, basal serum GH was higher than normal (P less than .01). A paradoxical increase in GH was observed during the oral glucose tolerance test (OGTT) in 55% of SHF and in 40% of AC patients. Significant GH elevation followed thyrotropin-releasing hormone (TRH) administration in 80% of SHF and 66% of AC patients, but not in normals. Serum nonsuppressible insulin-like activity (NSILA) and serum somatomedin C (Sm-C) levels were reduced significantly in both groups. In SHF patients, the paradoxical increase in GH during OGTT correlated inversely with Sm-C (r = -.6, P less than .05). We conclude that (1) abnormal GH secretion occurs in both SHF and AC, (2) serum Sm-C and NSILA are diminished in both forms of liver disease, and (3) portosystemic shunting of blood appears to be the important pathology shared by both forms of liver disease.