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In the human prostate, various androgen-metabolizing enzymes are present. Among these enzymes, testosterone 5 alpha-reductase seems to be dominant. However, androstenedione is also a potential substrate of the prostatic 5 alpha-reductase. To address the question of to what extent the reduction of androstenedione to androstanedione occurs, the present study describes in detail the kinetic characteristics (Km and Vmax) and possible age-dependent alterations of this enzymatic step in epithelium and stroma of the human prostate. In normal prostate (NPR), the mean Km (nM) and Vmax (pmol/mg protein.h) were about twofold higher in stroma (Km, 211; Vmax, 130) than in epithelium (Km, 120; Vmax, 56), whereas in the benign prostatic hyperplasia (BPH), the mean Km (nM; mean +/- SEM) and Vmax (pmol/mg protein.h; mean +/- SEM) were about sixfold higher in stroma (Km, 668 +/- 121; Vmax, 415 +/- 73) than in epithelium (Km, 120 +/- 10; Vmax, 73 +/- 8). In BPH, those differences between epithelium and stroma were highly significant (p < 0.001). However, the efficiency ratios (Vmax/Km) of neither BPH nor NPR showed any significant differences between epithelium (NPR, 0.47; BPH, 0.62 +/- 0.06) and stroma (NPR, 0.70; BPH, 0.63 +/- 0.05). With respect to age-related changes, only stroma showed a significant increase of Km (p < 0.01) and Vmax (p < 0.05) with age. In summary, in both epithelium and stroma of the human prostate, a 5 alpha-reductase converts in measurable amounts androstenedione to androstanedione. The kinetic data were, in part, different between epithelium and stroma; the reason for this difference remains unclear. In comparison to other metabolic conversions, such as testosterone to dihydrotestosterone and androstenedione to testosterone, it is unlikely that, in the human prostate, the adrenal androgen androstenedione contributes significantly to the formation of testosterone and, further, of dihydrotestosterone.
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PMID:Kinetic analysis of androstenedione 5 alpha-reductase in epithelium and stroma of human prostate. 943 53

To assess the long-term efficacy and use of fenofibrate together with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor ("statin") in the treatment of elevated levels of triglycerides and low-density lipoprotein (LDL) cholesterol, we conducted a study that compared a before- and after-case series. The study involved 80 patients with a diagnosis of combined hyperlipidemia and existing coronary artery disease (81% of patients) or outpatients with > or = 3 risk factors for coronary artery disease who had been receiving treatment at a tertiary care center. Fasting biochemical measures were obtained at baseline during monotherapy with a statin consisting of pravastatin 20 mg once daily or simvastatin 10 mg once daily (39 patients) or fenofibrate 300 mg once daily (41 patients), and during a 2-year period of combination therapy. This combination therapy comprised fenofibrate 300 mg once daily or micronized fenofibrate 200 mg once daily taken together with pravastatin 20 mg once daily (63 patients) or simvastatin 10 mg once daily (17 patients). The main outcome measures were: (1) absolute and percent change in total cholesterol, triglycerides, LDL cholesterol, and high-density lipoprotein (HDL) cholesterol; (2) percentage of patients with alanine aminotransferase > or = 2x the upper limits of normal on any occasion; (3) percentage of patients with creatinine kinase > or = 3 times the upper limits of normal on any occasion; (4) absolute changes in alanine aminotransferase and creatinine phosphokinase; and (5) months on combination therapy. Patients receiving combination therapy had a mean total cholesterol (+/- standard error of the mean [SEM]) that was significantly decreased by 26+/-1%, triglycerides by 41+/-3%, and LDL cholesterol by 28+/-2%, and mean HDL cholesterol that was significantly increased by 22+/-6%. These changes correspond to mean absolute changes of total cholesterol: -75+/-5 mg/dL; triglycerides: -94+/-13 mg/dL; LDL cholesterol: -52+/-5 mg/dL; and HDL cholesterol: 5+/-1 mg/dL. During combination treatment, alanine aminotransferase increased by 2+/-2 U/liter (not significant) and creatinine phosphokinase decreased by 4+/-13 U/liter (not significant). During treatment, 8 patients (10%) had transitory isolated elevations in alanine aminotransferase levels > or = 2 times the upper limits of normal and 2 patients (2.5%) had an isolated and transitory elevation of creatinine kinase (> or = 3x but < 6x upper limits of normal) without associated muscle symptoms. Patient-years on combination therapy equaled 220.6 (average 2.06 years per patient). The results demonstrated that combination treatment with fenofibrate and low-dose simvastatin or pravastatin is generally safe and effective for the treatment of combined hyperlipidemia in patients with normal hepatic and renal function.
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PMID:Long-term efficacy and safety of fenofibrate and a statin in the treatment of combined hyperlipidemia. 952 16

Androgens exert important biological effects on the brain, and 5alpha-reductase plays a crucial role in androgen metabolism. Therefore, we investigated the expression of the two isozymes of 5alpha-reductase in the human temporal lobe to determine the predominant isoform and to elucidate the existence of possible sex differences and differences between children and adults. We studied biopsy materials from the temporal lobe of 34 women, 32 men, and 12 children. Quantification of 5alpha-reductase 1 and 2 messenger ribonucleic acid (mRNA) was achieved by competitive RT-PCR. 5Alpha-reductase activity was determined in tissue homogenates using [1,2-3H]androstenedione as the substrate. Only 5alpha-reductase 1 mRNA was expressed in human temporal lobe tissue; 5alpha-reductase 2 mRNA was not expressed. 5Alpha-reductase 1 mRNA concentrations did not differ significantly in the cerebral cortex of women [25.9+/-7.9 arbitrary units (aU); mean +/-SEM] and men (20.4+/-2.8 aU) or in the cerebral cortex (23.3+/-4.4 aU) and the subcortical white matter of adults (32.6+/-5.6 aU), but they were significantly higher in the cerebral cortex of adults than in that of children (6.4+/-2.3 aU; P < 0.005). The apparent Km of 5alpha-reduction did not show significant differences between the two sexes. In conclusion, 5alpha-reductase 1 mRNA is expressed in the temporal lobe of children and adults, but 5alpha-reductase 2 mRNA is not. 5Alpha-reductase 1 mRNA concentrations did not differ significantly in the sexes, but they were significantly higher in specimens of adults than in those of children.
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PMID:Expression of 5alpha-reductase in the human temporal lobe of children and adults. 976 77

Changes in plasma 25-hydroxyvitamin D (25-OHD) were used as an index of vitamin D status of cats. Plasma 25-OHD concentration of kittens given a purified vitamin D-free diet and exposed to direct summer sun for 15 h/wk declined at a similar rate as kittens given the same diet kept indoors. Similarly, plasma 25-OHD of kittens exposed to ultraviolet (UV) lamps declined at a similar rate as kittens not exposed, and these kittens developed clinical signs of vitamin D deficiency. Eight weaned kittens were given the vitamin D-free purified diet until their plasma concentrations of 25-OHD were < 5 nmol/L. They then had the hair on their backs clipped at weekly intervals and were paired on the basis of skin color and exposed to UV light for 2 h/d. One member of each pair was given an inhibitor of 7-dehydrocholesterol (5, 7-cholestradien-3beta-ol)-delta7-reductase (EC 1.3.1.21) in the diet. Cats receiving the inhibitor had a progressive increase in 25-OHD concentration of plasma with time to 91 +/- 22 nmol/L (mean +/- SEM), whereas cats not receiving the inhibitor had plasma 25-OHD concentrations that were not detectable (P < 0.001). Biopsy samples of skin from cats receiving the inhibitor had more than five times the concentration of 7-dehydrocholesterol (P < 0.001) than the skin of control cats. Low concentration of 7-dehydrocholesterol (presumably due to high activity of the reductase) in the skin of cats is the major impediment to effective vitamin D synthesis. Analysis of wild caught potential prey of cats indicated that these animals could supply adequate vitamin D to meet the requirement of growing kittens.
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PMID:Ineffective vitamin D synthesis in cats is reversed by an inhibitor of 7-dehydrocholestrol-delta7-reductase. 1020 68

Antiinflammatory mechanisms are important in ovulation and may be regulated by cortisol (F). We previously showed that after administration of human (h)CG for ovulation induction, luteinized granulosa cells (LGC) abundantly express 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) messenger RNA but not 11betaHSD type 2 (11betaHSD2) messenger RNA. 11ssHSD1 is responsible for the reversible formation of antiinflammatory F from its inactive precursor cortisone (E), whereas 11betaHSD2 unidirectionally converts F to E through 11-oxidation. This pattern of gene expression predicts that LGC from periovulatory follicles would show increased activation of E to F, compared with granulosa cells from immature follicles (IGC), and that follicular fluid concentrations of E and F would alter accordingly. To test this hypothesis, we isolated IGC, thecal cells (TC), and follicular fluid, from ovaries of cyclic women, removed during surgery for benign gynecological disease. LGC and follicular fluid were aspirated from periovulatory follicles, 35 h after hCG injection, in patients undergoing in vitro fertilization treatment. In an 11betaHSD assay based on interconversion of tritiated E and F by cell suspensions in vitro, IGC (% conversion, 0.6 +/- 0.4, mean +/- SEM) and collagenase-dispersed TC (0.2 +/- 0.1%) were unable to convert E to F, whereas LGC (36.3 +/- 3.7%) were highly efficient at this reaction. Immature granulosa cells, LGC, and (to a lesser extent) TC were all able to convert F to E. Correspondingly, follicular fluid concentrations of total F and F:E ratios were significantly higher in periovulatory follicles, compared with immature follicles. Culturing IGC for 48 h in the presence of hFSH resulted in increased 11betaHSD1 reductase activity, paralleling stimulation of estrogen (aromatase activity) and progesterone biosynthesis. Similar treatment with hLH did not influence 11betaHSD1 reductase activity, except in a patient with more mature IGC, which also showed a significant increase in E-to-F conversion, as well as progesterone synthesis in response to hLH. These data confirm that 11betaHSD activity in the human ovary is developmentally regulated and gonadotropin responsive, favoring metabolism of F to E in immature follicles and E to F in periovulatory follicles. Increased formation of F by LGC in periovulatory follicles is consistent with an antiinflammatory function for this glucocorticoid at ovulation.
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PMID:Development-related increase in cortisol biosynthesis by human granulosa cells. 1113 35

Intrahepatic calculi, highly prevalent in the Far East, including Japan, are characterized clinically by chronic proliferative cholangitis with frequent stone recurrences. Intrahepatic calculi consist of 2 groups, i.e., brown pigment stones, including a high cholesterol content, and cholesterol stones, with the former predominating. To gain insights into the pathogenesis of intrahepatic calculi, cholesterol and bile acid biosynthesis, as well as alterations in intracellular transport and/or canalicular secretion of phospholipid and bile acid were investigated in liver of patients with intrahepatic calculi. Enzyme activities of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase were increased (12.8 +/- 1.9 pmol/min/mg protein, mean +/- SEM vs. 5.5 +/- 0.4 in controls; P < .01) and cholesterol 7 alpha-hydroxylase activities were decreased (1.3 +/- 0.4 vs. 4.9 +/- 0.6; P < .01) in liver specimens of patients with brown pigment stones. In addition, messenger RNA (mRNA) levels of multidrug resistance P-glycoprotein 3 (MDR3 Pgp) and phosphatidylcholine transfer protein (PCTP) were markedly low in the liver specimens compared with the levels in specimens of control subjects, gallbladder stone patients, and patients with obstructive cholestasis. The protein levels and the immunohistochemical staining were decreased for MDR3 Pgp and PCTP in the liver. Consistently, the concentrations of phospholipid were markedly reduced in the hepatic bile from both affected and unaffected hepatic segments. In patients with intrahepatic calculi, biliary cholesterol supersaturation and the formation of cholesterol-rich brown pigment as well as cholesterol stones may be attributed to decreased hepatic transport and biliary secretion of phospholipids, in the setting of increased cholesterogenesis and decreased bile acid synthesis.
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PMID:Etiologic significance of defects in cholesterol, phospholipid, and bile acid metabolism in the liver of patients with intrahepatic calculi. 1134 49

Thiols like glutathione may serve as reducing cofactors in the production of nitric oxide (NO) and protect NO from inactivation by radical oxygen species. Depletion of thiol compounds reduces NO-mediated vascular effects in vitro and in vivo. The mechanisms underlying these actions are not clear, but may involve decreased synthesis of NO and/or increased degradation of NO. This study investigates the effect of glutathione depletion on the response to NO-mediated vasodilation induced by acetylcholine (Ach, 10 micrograms/kg), endothelial NO synthase (eNOS) activity and potential markers of vascular superoxide anion (O2.-) production in conscious chronically catheterized rats. Thiol depletion induced by buthionine sulfoximine (BSO, 1 g i.p. within 24 h) decreased the hypotensive effect of Ach by 30% (MAP reduction before BSO 27 +/- 3 mmHg, 19 +/- 3 mmHg after BSO, (mean +/- SEM), p < .05, n = 8). The impaired effect of Ach was associated with a significant reduction in eNOS activity (control: 7.7 +/- 0.8, BSO: 3.9 +/- 0.4 pmol/min/mg protein (p < .05), n = 6). In contrast, neither NADH/NADPH driven membrane-associated oxidases nor lucigenin reductase activity were significantly (p < .05) affected by BSO (BSO: 4415 +/- 123, control: 4105 +/- 455 counts/mg; n = 6) in rat aorta. It is concluded that in vivo thiol depletion results in endothelial dysfunction and a reduced receptor-mediated vascular relaxation. This effect is caused by reduced endothelial NO formation.
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PMID:Endothelium-dependent vasorelaxation in inhibited by in vivo depletion of vascular thiol levels: role of endothelial nitric oxide synthase. 1169 35

The effects of newly synthesized cholesterol availability on bile acid synthesis are largely unknown, particularly in humans. The present study was aimed to study the changes induced on bile acid synthesis by simvastatin, a competitive inhibitor of hydroxymethyl glutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme of cholesterol synthesis, during pharmacologic interruption of the enterohepatic circulation. Six patients with primary hypercholesterolemia were studied in basal conditions, after treatment with the bile acid binding resin cholestyramine alone (8-16 g/d for 6-8 weeks) and subsequently in combination with simvastatin (40 mg/d for 6-8 weeks). Cholesterol 7alpha-hydroxylation rate, a measure of total bile acid synthesis, was assayed in vivo by tritium release analysis. Serum lathosterol levels were assayed by gas chromatography-mass spectrometry as a measure of cholesterol synthesis. Serum total and low-density lipoprotein-cholesterol were reduced significantly after cholestyramine (by 26% and 30%, respectively) and during combined treatment (by 47% and 55%). 7alpha-hydroxylation rates increased nearly 4-fold with cholestyramine alone; addition of simvastatin induced a significant decrease of hydroxylation rates (cholestyramine alone, 1,591 +/- 183 mg/d; plus simvastatin, 1,098 +/- 232 mg/d; mean +/- SEM; P <.05). Hydroxylation rates significantly correlated with serum lathosterol/cholesterol ratio (r = 0.79, P <.05). In conclusion, in conditions of chronic stimulation bile acid synthesis may be affected by changes in newly synthesized cholesterol availability. The finding might relate to the degree of substrate saturation of microsomal cholesterol 7alpha-hydroxylase; alternatively, newly synthesized cholesterol might induce a stimulatory effect on cholesterol 7alpha-hydroxylase transcription.
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PMID:Influence of newly synthesized cholesterol on bile acid synthesis during chronic inhibition of bile acid absorption. 1451 81

Older men, particularly those with low serum testosterone (T) levels, might benefit from T therapy to improve bone mineral density (BMD) and reduce fracture risk. Concerns exist, however, about the impact of T therapy on the prostate in older men. We hypothesized that the combination of T and finasteride (F), a 5 alpha-reductase inhibitor, might increase BMD in older men without adverse effects on the prostate. Seventy men aged 65 yr or older, with a serum T less than 12.1 nmol/liter on two occasions, were randomly assigned to receive one of three regimens for 36 months: T enanthate, 200 mg im every 2 wk with placebo pills daily (T-only); T enanthate, 200 mg every 2 wk with 5 mg F daily (T+F); or placebo injections and pills (placebo). Low BMD was not an inclusion criterion. We obtained serial measurements of BMD of the lumbar spine and hip by dual x-ray absorptiometry. Prostate-specific antigen (PSA) and prostate size were measured at baseline and during treatment to assess the impact of therapy on the prostate. Fifty men completed the 36-month protocol. By an intent-to-treat analysis including all men for as long as they contributed data, T therapy for 36 months increased BMD in these men at the lumbar spine [10.2 +/- 1.4% (mean percentage increase from baseline +/- SEM; T-only) and 9.3 +/- 1.4% (T+F) vs. 1.3 +/- 1.4% for placebo (P < 0.001)] and in the hip [2.7 +/- 0.7% (T-only) and 2.2 +/- 0.7% (T+F) vs. -0.2 +/- 0.7% for placebo, (P < or = 0.02)]. Significant increases in BMD were seen also in the intertrochanteric and trochanteric regions of the hip. After 6 months of therapy, urinary deoxypyridinoline (a bone-resorption marker) decreased significantly compared with baseline in both the T-only and T+F groups (P < 0.001) but was not significantly reduced compared with the placebo group. Over 36 months, PSA increased significantly from baseline in the T-only group (P < 0.001). Prostate volume increased in all groups during the 36-month treatment period, but this increase was significantly less in the T+F group compared with both the T-only and placebo groups (P = 0.02). These results demonstrate that T therapy in older men with low serum T increases vertebral and hip BMD over 36 months, both when administered alone and when combined with F. This finding suggests that dihydrotestosterone is not essential for the beneficial effects of T on BMD in men. In addition, the concomitant administration of F with T appears to attenuate the impact of T therapy on prostate size and PSA and might reduce the chance of benign prostatic hypertrophy or other prostate-related complications in older men on T therapy. These findings have important implications for the prevention and treatment of osteoporosis in older men with low T levels.
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PMID:Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. 1476 52

Smith-Lemli-Opitz syndrome is a condition of impaired cholesterol synthesis that is caused by mutations in DHCR7 encoding 7-dehydrocholesterol-Delta7 reductase. Birth defects and mental retardation are characteristic. Deficient plasma and tissue cholesterol and excess cholesterol precursors 7 and 8 dehydrocholesterol (7DHC and 8DHC) contribute to the pathogenesis. Cholesterol is transported to tissues via lipoproteins. We measured the effect of dietary cholesterol (egg yolk) on plasma lipoproteins to evaluate this potential treatment. We used the enzymatic method to measure total sterols in lipoproteins (n=12) and plasma (n=16). In addition, we analyzed individual plasma sterols by a gas chromatographic method. Samples were evaluated after 3 wk of a cholesterol-free diet and after 6-19 mo of dietary cholesterol. We also analyzed the distribution of sterols in lipoproteins and the apolipoprotein E genotype. Dietary cholesterol significantly increased the total sterols in plasma (2.22 +/- 0.13 to 3.10 +/- 0.22; mean +/- SEM; p < 0.002), in LDL (0.98 +/- 0.13 to 1.52 +/- 0.17 mM), and in HDL (0.72 +/- 0.04 to 0.92 +/- 0.07). Plasma cholesterol increased (1.78 +/- 0.16 to 2.67 +/- 0.25 mM; p < 0.007) and plasma 7DHC decreased in 10 children, but the mean decrease was not significant. The distribution of individual sterols in each lipoprotein fraction was similar to the distribution in plasma. The baseline cholesterol and the response to dietary cholesterol was the same in children with 3/3 and 3/4 apolipoprotein E genotypes. Dietary cholesterol increased total sterols in plasma, LDL, and HDL in children with Smith-Lemli-Opitz syndrome. These favorable increases in the lipoproteins are potentially therapeutic for this condition.
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PMID:Effects of dietary cholesterol on plasma lipoproteins in Smith-Lemli-Opitz syndrome. 1549 12


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