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Query: UNIPROT:P06889 (Mol)
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Testosterone (T) is the major exogenous stimulus for the growth of prostatic carcinoma. It is believed that the proliferative action of T may be mediated by locally expressed growth modulatory factors. Recent evidence from our laboratory suggests that a LHRH (or a LHRH-like) loop might be expressed in human prostatic tumor cells. To verify this hypothesis, we have studied whether a mRNA for LHRH is expressed in the human androgen-responsive prostatic cancer cell line LNCaP, using the reverse transcription-polymerase chain reaction technique in the presence of a pair of specific oligonucleotide primers. A cDNA band of the expected size was obtained from LNCaP cells; this band hybridized with a 32P-labeled LHRH oligonucleotide probe and its sequence showed a complete match with the reported sequence of the human placental LHRH cDNA. These observations indicate that the mRNA coding for LHRH is expressed in LNCaP cells and suggest that a LHRH (or a LHRH-like) peptide might be produced by these cells. To clarify the possible action of this peptide, LNCaP cells were grown in a steroid-free medium and treated with a LHRH antagonist. The treatment resulted in a significant increase of tumor cell growth. These data clearly indicate that the LHRH system expressed in LNCaP cells plays an inhibitory role on cell proliferation, and that this system seems to be regulated in a negative way by steroids. An EGF/TGF alpha autocrine stimulatory loop (peptides, receptors, intracellular signals) is also functional in these cells. Treatment of LNCaP cells grown in serum-free conditions (i.e. in the absence of exogenous growth factors) with a monoclonal antibody against the EGF receptor, or with immunoneutralizing antibodies against EGF or TGF alpha, resulted in a significant decrease of cell proliferation. T positively regulates this EGF/TGF alpha system by increasing the concentration of EGF binding sites. The present data indicate that an inhibitory LHRH (or LHRH-like) system is expressed in LNCaP cells and participates in the local mechanisms regulating tumor cell proliferation together with an EGF/TGF alpha stimulatory loop. Both systems appear to be modulated by T.
J Steroid Biochem Mol Biol 1994 Jun
PMID:Androgen-dependent prostatic tumors: biosynthesis and possible actions of LHRH. 804 99

The paracrine actions of bovine follistatin (FS), human recombinant activin A and bovine inhibin on progesterone (P), androstenedione (A4) and inhibin production, were investigated using LH-stimulated immature bovine thecal cells. The presence of FS (3-100 ng/ml) alone caused a dose-dependent stimulation of P production by thecal cells induced by bovine LH (10 ng/ml). The stimulatory effect of FS on P production at 10 or 30 ng/ml was reversed to control levels with the addition of activin (10 or 30 ng/ml). Treatment with FS did not significantly effect on A4 production. Activin alone had no consistent effect on A4 production (measured using two different antibodies), but had a dose-dependent inhibitory effect on P production. Treatments of cells with inhibin had no significant effect on the LH-induced production of either P or A4. Testosterone production in FS; activin- or inhibin-treated cells was not different from controls. Northern analysis showed that inhibin beta subunit was not detected in thecal mRNA, whereas there were very faint bands of inhibin alpha subunit and FS which were attributed to contamination of granulosa cells (GC). We conclude that FS in vitro has a stimulatory effect on P production by bovine thecal cells, and that activin has the ability to reverse the stimulatory effect of P production. Unlike the rat and human thecal cells, activin and inhibin had no significant effect on LH-induced androgen synthesis by bovine thecal cells. We propose that FS secreted by the GC acts as a paracrine modulator upon thecal cells to directly stimulate the production of P independently of activin.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1993 Nov
PMID:The effects of follistatin, activin and inhibin on steroidogenesis by bovine thecal cells. 814 2

The influence of steroid hormones on the output of the cyclic nucleotides adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) by porcine granulosa cells was investigated. Both progesterone (100, 1000, 10,000 and 100,000 pg/ml medium) and estradiol (100, 1000, 10,000 and 100,000 pg/ml medium) activated cAMP and cGMP production. Testosterone (100 or 1000 pg/ml medium) also stimulated cAMP output. The stimulating effect of steroid hormones on cyclic nucleotide production may suggest the involvement of cAMP- and cGMP-dependent intracellular mechanisms in the action of steroid hormones on porcine ovarian cells.
J Steroid Biochem Mol Biol 1993 Nov
PMID:Steroid hormones regulate cAMP and cGMP production by porcine granulosa cells in vitro. 824 Sep 79

The mRNA levels for aminolevulinate synthase (ALV-S), the rate-limiting enzyme in porphyrin synthesis, were studied in male and female Syrian hamsters during postnatal development. Sex-associated differences in the expression of ALV-S gene were evident at the end of the third week of postnatal development. Serum levels of luteinizing hormone (LH), testosterone, cortisol, thyroid hormones and insulin-like growth factor were also studied in order to correlate their concentrations with the mRNA levels for ALV-S. Among these hormones, serum LH levels showed a positive correlation with the ALV-S mRNA levels. However, the expected negative correlation with testosterone levels was not clearly observed. Thus, in order to test the effects of testosterone on ALV-S gene expression, 11-day-old male and female Syrian hamsters and adult female hamsters were injected with 50 micrograms of testosterone for 4 days. Testosterone administration decreased the levels of ALV-S mRNA in the adult females but did not influence those of young females. The possible explanation for the insensitivity to testosterone during these postnatal stages might involve the maturational state of androgen receptors in the Harderian glands.
Mol Cell Endocrinol 1993 Jun
PMID:Gender-associated differences in the development of 5-aminolevulinate synthase gene expression in the harderian gland of Syrian hamsters. 834 26

Transgenic mice that express a 10-kilobase human FSH beta (hFSH beta) gene exclusively in pituitary gonadotropes were used to study the regulation of hFSH beta gene expression by gonadal steroids. For comparison, the mouse FSH beta (mFSH beta) gene was studied in parallel in nontransgenic sibling (normal) mice. The hFSH beta gene showed a sexually dimorphic expression pattern, identical to mFSH beta, in the mouse environment. Intact normal and transgenic male mice had elevated (P < 0.05) levels of serum [16 +/- 2 ng/ml (normal); 38 +/- 6 (transgenic)] and pituitary FSH content [2 +/- 0.3 micrograms/mg protein (normal); 36 +/- 6 (transgenic)] and FSH beta mRNA [1.47 +/- 0.10 arbitrary density units (normal); 1.00 +/- 0.23 (transgenic)] compared to the corresponding female mice ([< 2.0 ng/ml (normal and transgenic)] [0.1 +/- 0.01 microgram/mg protein (normal); 0.2 +/- 0.03 (transgenic)] [< 0.03 arbitrary density units (normal and transgenic)]). Serum FSH levels were increased (P < 0.05) 2 weeks after castration of normal (22 +/- 2 ng/ml) and transgenic males (135 +/- 19 ng/ml) and were suppressed (P < 0.05) by testosterone [7 +/- 0.8 ng/ml (normal); 12 +/- 2 (transgenic)] or estradiol [14 +/- 1 ng/ml (normal); 16 +/- 1 (transgenic)] replacement. The increased serum FSH levels were associated with an inverse drop (P < 0.05) in pituitary FSH content to 1 +/- 0.1 microgram/mg protein in normal and 16 +/- 2 in transgenic males. Testosterone replacement further suppressed (P < 0.05) pituitary FSH content in transgenic (3 +/- 0.5 micrograms/mg protein) but not normal (1 +/- 0.1) males.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1993 Jul
PMID:Gonadal steroid hormone regulation of human and mouse follicle stimulating hormone beta-subunit gene expression in vivo. 841 14

Testosterone metabolism was studied in human adult and fetal liver microsomes. In fetal livers 6 beta-hydroxylase (6 beta OH) activity (1-2% of adult activity) and 2 alpha-hydroxylase (2 alpha OH) activity (about 40% of adult activity) were present. Also some fetal livers produced two unknown metabolites. Androstenedione was formed in all fetal livers studied (10-20% of adult activity). Testosterone hydroxylations at 6 beta-, 2 beta-, 15 alpha- and 15 beta-positions were associated with CYP3A isoform(s) in adult liver, because they were strongly inhibited by midazolam, a known substrate for CYP3A4 and by anti-CYP3A4 antibody. Fetal liver activities were consistently inhibited less than the activities in adult livers. The formation of androstenedione was not affected by these inhibitors in fetal or adult liver microsomes. Benzphetamine N-demethylase activity in the fetal livers was about 40% of adult activity. Anti-CYP3A4 antibody had no effect on that activity in fetal or in adult liver microsomes, whereas a monoclonal antibody 1-68-11 (generated against rat CYP2C11) slightly inhibited benzphetamine N-demethylase activity in adult liver. This study indicates that human fetal and adult liver are dissimilar in their testosterone metabolism pattern. The formation of androstenedione from testosterone in fetal liver may have a physiological role. Testosterone hydroxylases are less inhibited by anti-CYP3A4 antibody, midazolam and progesterone in fetal than in adult liver.
J Steroid Biochem Mol Biol 1993 Jan
PMID:The role of cytochrome P450 3A (CYP3A) isoform(s) in oxidative metabolism of testosterone and benzphetamine in human adult and fetal liver. 842 94

The ability of the sex hormones progesterone, testosterone and estradiol-17 beta and the glucocorticoid dexamethasone to modulate expression of the interleukin-5 (IL-5) gene in T cell lines has been investigated. The T cell lines used show analogous regulation of IL-5 gene expression to that occurring in T-lymphocytes, in that IL-5 mRNA levels are undetectable unless the cells are induced with phorbol myristate acetate (PMA). Progesterone and testosterone were as effective as PMA in inducing IL-5 mRNA levels in the T cell hybrid NIMP-TH1 and induced IL-5, -3 and -2 mRNA accumulation in the T cell lymphoma EL-4. Estradiol-17 beta also induced IL-5 mRNA accumulation but less effectively than testosterone. Nuclear run-on experiments suggested that the effects of progesterone, testosterone and PMA on IL-5 gene expression were mediated at the level of transcription. The presence of the protein synthesis inhibitor cycloheximide completely prevented PMA-induced synthesis of IL-5 mRNA by both NIMP-TH1 and EL-4 cells, indicating that induction of IL-5 mRNA via PMA stimulation requires de novo synthesis of a presumptive trans-acting factor(s). PMA-, testosterone- and progesterone-induced expression of the IL-5 gene was completely blocked by the anti-inflammatory steroid dexamethasone. Stimulation of IL-5 expression by PMA was relatively resistant to the immuno- suppressive drug cyclosporin A although inhibition did occur at very high levels. Testosterone- and progesterone-induced IL-5 gene expression was not inhibited by cyclosporin A. The in vivo significance of these findings are not yet clear but the results show that sex hormones have the potential to regulate cytokine gene expression in cells possessing the appropriate steroid receptors.
J Steroid Biochem Mol Biol 1993 Mar
PMID:Sex hormones and dexamethasone modulate interleukin-5 gene expression in T lymphocytes. 846 Dec 54

Androgen aromatase was found to also be estrogen 2-hydroxylase. The substrate specificity among androgens and estrogens and multiplicity of aromatase reactions were further studied. Through purification of human placental microsomal cytochrome P-450 by monoclonal antibody-based immunoaffinity chromatography and gradient elution on hydroxyapatite, aromatase and estradiol 2-hydroxylase activities were co-purified into a single band cytochrome P-450 with approx. 600-fold increase of both specific activities, while other cytochrome P-450 enzyme activities found in the microsomes were completely eliminated. The purified P-450 showed M(r) of 55 kDa, specific heme content of 12.9 +/- 2.6 nmol.mg-1 (+/- SD, n = 4), reconstituted aromatase activity of 111 +/- 19 nmol.min-1.mg-1 and estradiol 2-hydroxylase activity of 5.85 +/- 1.23 nmol.min-1.mg-1. We found no evidence for the existence of catechol estrogen synthetase without concomitant aromatase activity. The identity of the P-450 for the two different hormone synthetases was further confirmed by analysis of the two activities in the stable expression system in Chinese hamster ovarian cells transfected with human placental aromatase cDNA, pH beta-Aro. Kinetic analysis of estradiol 2-hydroxylation by the purified and reconstituted aromatase P-450 in 0.1 M phosphate buffer (pH 7.6) showed Km of 1.58 microM and Vmax of 8.9 nmol.min-1.mg-1. A significant shift of the optimum pH and Vmax, but not the Km, for placental estrogen 2-hydroxylase was observed between microsomal and purified preparations. Testosterone and androstenedione competitively inhibited estradiol 2-hydroxylation, and estrone and estradiol competitively inhibited aromatization of both testosterone and androstenedione. Estrone and estradiol showed Ki of 4.8 and 7.3 microM, respectively, for testosterone aromatization, and 5.0 and 8.1 microM, respectively, for androstenedione aromatization. Androstenedione and testosterone showed Ki of 0.32 and 0.61 microM, respectively, for estradiol 2-hydroxylation. Our studies showed that aromatase P-450 functions as estrogen 2-hydroxylase as well as androgen 19-, 1 beta-, and 2 beta-hydroxylase and aromatase. The results indicate that placental aromatase is responsible for the highly elevated levels of the catechol estrogen and 19-hydroxyandrogen during pregnancy. These results also indicate that the active site structure holds the steroid substrates to face their beta-side of the A-ring to the heme, tilted in such a way as to make the 2-position of estrogens and 19-, 1-, and 2-positions of androgens available for monooxygenation.
J Steroid Biochem Mol Biol 1993 Mar
PMID:Multiple functions of aromatase and the active site structure; aromatase is the placental estrogen 2-hydroxylase. 847 62

The effects of the constant infusion with mini-osmotic pumps of several steroid hormones on body weight, energy balance and protein/lipid/water composition in young female rats has been studied for a period of 15 days. Despite unchanged food consumption, progesterone strongly induced fat deposition, with higher protein accrual efficiency coupled with lowered energy losses through thermogenesis. Estrogens lowered body weight but maintained higher protein levels and protein accrual rates; beta-estradiol induced the loss of lipid and diminished food intake. Heat production was unchanged or lower in all estrogen-treated animals; beta-estradiol had a more marked effect on body weight (through food intake, heat production and lipid mobilization/storage combined) than estrone. Testosterone and 5-androstenediol increased the proportion of protein, but none of them had a significant effect on lipid deposition or heat production. Nortestosterone, increased energy expenditure, fuelled in part by a higher food ingestion, a trait shared by 4-androstenedione, but not by the other androgens. The effect of androgens on body weight may thus be a combination of their actions on a) food intake, b) efficiency of protein deposition and c) activation of heat production or of lipid (energy) storage. Practically all increased the efficiency of protein deposition. Nortestosterone increased heat production. Androstenedione increased lipid storage. Dehydroepiandrosterone did not decrease body weight or metabolic rate. Cortisol depressed heat production and food intake, with a net loss of weight. Cortisol and cortisone did not increase protein deposition, but corticosterone did; deoxycorticosterone showed a high efficiency of protein deposition and increased the size of fat stores, also increasing the metabolic rate by a mean 26% versus controls, compared with a reduction of about the same magnitude induced by cortisol. The data presented suggest that cortisol-cortisone and corticosterone may represent two distinct groups of glucocorticoids.
Biochem Mol Biol Int 1993 Feb
PMID:Effect of chronic intravenous injection of steroid hormones on body weight and composition of female rats. 849 17

Two androgens, testosterone and dihydrotestosterone, are required for the development of the male urogenital tract in the rat. Testosterone is secreted by the fetal testes and is thought to elicit differentiation of the Wolffian ducts into seminal vesicles, vas deferens, and epididymides. Testosterone is converted into dihydrotestosterone by steroid 5 alpha-reductase in the urogenital tract, and this conversion is necessary for the differentiation of the prostate and external genitalia. Genes encoding two 5 alpha-reductase isozymes, designated type 1 and type 2, have been identified. We examined the expression and regulation of these genes on days 17-21 in the urogenital tracts of male and female fetuses. Expression of the type 1 gene predominated in epithelial cells, whereas type 2 gene expression was limited to mesenchymal cells. Surprisingly, this expression pattern was detected in both testosterone-dependent and dihydrotestosterone-dependent anlagen of the urogenital tract and was the same in both male and female fetuses. Furthermore, transcripts encoding the two isozymes were present in their respective cell types before the overt differentiation of internal genitalia. Androgens stimulated expression of the type 2 gene in the urogenital tracts of both sexes, but did not effect expression of the type 1 gene or the cell type-specific expression patterns of the 5 alpha-reductase genes. In the adult prostate, 5 alpha-reductase gene expression is under feedforward control, in which the product of the enzyme, dihydrotestosterone, stimulates the expression of the gene. However, no evidence for feedforward regulation of either 5 alpha-reductase gene was detected in the fetus.
Mol Endocrinol 1995 Nov
PMID:Expression and regulation of steroid 5 alpha-reductase in the urogenital tract of the fetal rat. 858 33


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