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Showing papers on "Steroid biosynthesis published in 2005"


Journal ArticleDOI
TL;DR: Reincorporation of in vitro transcribed/translated PBR, but not PBR missing the cholesterol-binding domain, into MA-10 mitochondria rescued the ability of the mitochondria to form steroids and the ability to respond to StAR and Tom/StAR proteins.
Abstract: Hormone-induced steroid biosynthesis begins with the transfer of cholesterol from intracellular stores into mitochondria. Steroidogenic acute regulatory protein (StAR) and peripheral-type benzodiazepine receptor (PBR) have been implicated in this rate-determining step of steroidogenesis. MA-10 mouse Leydig tumor cells were treated with and without oligodeoxynucleotides (ODNs) antisense to PBR and StAR followed by treatment with saturating concentrations of human choriogonadotropin. Treatment with ODNs antisense but not missense for both proteins inhibited the respective protein expression and the ability of the cells to synthesize steroids in response to human choriogonadotropin. Treatment of the cells with either ODNs antisense to PBR or a transducible peptide antagonist to PBR resulted in inhibition of the accumulation of the mature mitochondrial 30-kDa StAR protein, suggesting that the presence of PBR is required for StAR import into mitochondria. Addition of in vitro transcribed/translated 37-kDa StAR or a fusion protein of Tom20 (translocase of outer membrane) and StAR (Tom/StAR) to mitochondria isolated from control cells increased pregnenolone formation. Mitochondria isolated from cells treated with ODNs antisense, but not missense, to PBR failed to form pregnenolone and respond to either StAR or Tom/StAR proteins. Reincorporation of in vitro transcribed/translated PBR, but not PBR missing the cholesterol-binding domain, into MA-10 mitochondria rescued the ability of the mitochondria to form steroids and the ability of the mitochondria to respond to StAR and Tom/StAR proteins. These data suggest that both StAR and PBR proteins are indispensable elements of the steroidogenic machinery and function in a coordinated manner to transfer cholesterol into mitochondria.

228 citations


Journal ArticleDOI
TL;DR: Structural and functional evidence is provided supporting the finding that the CRAC domain in the cytosolic carboxyl-terminal domain of PBR might be responsible for the uptake and translocation of cholesterol into the mitochondria.
Abstract: We previously defined a cholesterol recognition/interaction amino acid consensus sequence [CRAC: L/V–X (1–5)–Y–X (1–5)-R/K] in the carboxyl terminus of the peripheral-type benzodiazepine receptor (PBR), a high-affinity drug and cholesterol-binding protein present in the outer mitochondrial membrane protein. This protein is involved in the regulation of cholesterol transport into the mitochondria, the rate-determining step in steroid biosynthesis. Reconstituted wild-type recombinant PBR into proteoliposomes demonstrated high-affinity 2-chlorophenyl)-N-methyl-N-(1-methyl-propyl)-3-isoquinolinecarboxamide and cholesterol binding. In the present work, we functionally and structurally characterized this CRAC motif using reconstituted recombinant PBR and nuclear magnetic resonance. Deletion of the C-terminal domain of PBR and mutation of the highly conserved among all PBR amino acid sequences Y152 of the CRAC domain resulted in loss of the ability of mutant recPBR to bind cholesterol. Nuclear magnetic resonance...

218 citations


Journal ArticleDOI
TL;DR: The zebrafish FTZ-F1 genes are of central interest as they are involved in regulating interrenal development and thereby steroid biosynthesis, as well as that they show expression patterns congruent with reproductive tissue differentiation and function.
Abstract: Sex determination is the process deciding the sex of a developing embryo. This is usually determined genetically; however it is a delicate process, which in many cases can be influenced by environmental factors. The mechanisms controlling zebrafish sex determination and differentiation are not known. To date no sex linked genes have been identified in zebrafish and no sex chromosomes have been identified. However, a number of genes, as presented here, have been linked to the process of sex determination or differentiation in zebrafish. The zebrafish FTZ-F1 genes are of central interest as they are involved in regulating interrenal development and thereby steroid biosynthesis, as well as that they show expression patterns congruent with reproductive tissue differentiation and function. Zebrafish can be sex reversed by exposure to estrogens, suggesting that the estrogen levels are crucial during sex differentiation. The Cyp19 gene product aromatase converts testosterone into 17 beta-estradiol, and when inhibited leads to male to female sex reversal. FTZ-F1 genes are strongly linked to steroid biosynthesis and the regulatory region of Cyp19 contains binding sites for FTZ-F1 genes, further linking FTZ-F1 to this process. The role of FTZ-F1 and other candidates for zebrafish sex determination and differentiation is in focus of this review.

176 citations


Journal ArticleDOI
TL;DR: Critical research needs are identified that will help determine the significance of PPARs in phthalate-induced effects in the rat male reproductive tract and the relevance of toxicity to humans.

151 citations


Journal ArticleDOI
TL;DR: It is shown that mitochondria must be energized, polarized, and actively respiring to support Leydig cell steroidogenesis and alterations in the state of mitochondria may be involved in regulating steroid biosynthesis.
Abstract: The first and rate-limiting step in the biosynthesis of steroid hormones is the transfer of cholesterol into mitochondria, which is facilitated by the steroidogenic acute regulatory (StAR) protein. Recent studies of Leydig cell function have focused on the molecular events controlling steroidogenesis; however, few studies have examined the importance of the mitochondria. The purpose of this investigation was to determine which aspects of mitochondrial function are necessary for Leydig cell steroidogenesis. MA-10 tumor Leydig cells were treated with 8-bromo-cAMP (cAMP) and site-specific mitochondrial disrupters, pro-oxidants, and their effects on progesterone synthesis, StAR expression, mitochondrial membrane potential (delta psi(m)) and ATP synthesis were determined. Dissipating delta psi(m) with CCCP inhibited progesterone synthesis, even in the presence of newly synthesized StAR protein. The electron transport inhibitor antimycin A significantly reduced cellular ATP, inhibited steroidogenesis, and reduced StAR protein expression. The F0/F1 ATPase inhibitor oligomycin reduced cellular ATP and inhibited progesterone synthesis and StAR protein expression, but had no effect on delta psi(m). Disruption of pH with nigericin significantly reduced progesterone production and StAR protein, but had minimal effects on delta psi(m). Sodium arsenite at low concentrations inhibited StAR protein but not mRNA expression and inhibited progesterone without disrupting delta psi(m). The mitochondrial Ca2+ inhibitor Ru360 also inhibited StAR protein expression. These results demonstrate that delta psi(m), ATP synthesis, delta pH and [Ca2+]mt are all required for steroid biosynthesis, and that mitochondria are sensitive to oxidative stress. These results suggest that mitochondria must be energized, polarized, and actively respiring to support Leydig cell steroidogenesis and alterations in the state of mitochondria may be involved in regulating steroid biosynthesis.

137 citations


Journal ArticleDOI
TL;DR: This review focuses on the significant findings that have been made with regards to the regulation of StAR expression and also on the clinical and endocrinological consequences of a non-functioning StAR gene.
Abstract: Steroid hormones are synthesized in steroidogenic cells of the adrenal, ovary, testis, placenta and brain and are essential for normal reproductive function and bodily homeostasis. The rate-limiting and regulated step in steroid biosynthesis is the intramitochondrial transport of cholesterol, a process that is mediated by the steroidogenic acute regulatory (StAR) protein. The importance of StAR has been illustrated by analyses of patients with lipoid congenital adrenal hyperplasia (lipoid CAH), an autosomal recessive disorder that markedly disrupts the synthesis of all gonadal and adrenal steroids. Molecular and physio-pathological analyses have demonstrated that alterations in the StAR gene are the only known cause of lipoid CAH. Furthermore, StAR knockout mice have been generated and display a phenotype that is essentially identical to the human condition. Recent advances in tissue-specific and hormone-induced expression of the StAR protein provide insights into a number of human endocrinological health issues including developmental and reproductive abnormalities. Several factors and processes have been demonstrated to influence StAR expression in steroidogenic cells and there is increasing evidence that a transcription factor-binding site-rich region present in the proximal region of the StAR promoter is highly instrumental in StAR gene expression. In this review we focus on the significant findings that have been made with regards to the regulation of StAR expression and also on the clinical and endocrinological consequences of a non-functioning StAR gene.

135 citations


Journal ArticleDOI
TL;DR: It is demonstrated that basal activities of both PKC and PKA play important roles in the constitutive steroidogenic characteristics of R2C cells and the requirement for submaximal doses of cAMP to produce steroids in Leydig cells.
Abstract: This study investigated the roles of the protein kinase C (PKC) and protein kinase A (PKA) pathways in regulating constitutive steroidogenesis and steroidogenic acute regulatory (STAR; herein designated by its common name, StAR) protein in R2C Leydig tumor cells. Inhibition of PKC and phospholipase C resulted in significant decreases in steroid production, phosphorylation of cAMP-responsive element binding (CREB) protein, and Star gene transcription under basal conditions in R2C cells. These observations were corroborated in MA-10 and mLTC-1 Leydig tumor cell lines, in which activation of PKC by phorbol-12-myristate-13-acetate (PMA, 10 nM) increased CREB phosphorylation and total StAR (tot-StAR) protein expression. However, induction of StAR protein by PMA did not result in the expected concomitant increase in steroids because PKC failed to phosphorylate StAR, the biologically active form of the protein. However, in conjunction with PMA, minor increases in PKA activity using submaximal doses of (...

107 citations


Journal ArticleDOI
TL;DR: Data support the model that StAR activity requires a pH-dependent molten globule transition on the OMM, and the correct folding and positioning of the disulfide bonds was confirmed.

80 citations


Journal ArticleDOI
TL;DR: Differential responses to retinol and retinoids in normal and PCOS theca suggest that altered retinoic acid synthesis and action may be involved in augmented CYP17 gene expression and androgen production in PCOS.
Abstract: Context: Polycystic ovary syndrome (PCOS) is characterized by ovarian androgen excess and infertility. Recent experiments have suggested that several genes involved in retinoic acid synthesis may be differentially expressed in PCOS theca cells and may contribute to excessive theca-derived androgen production. Objective: The study was performed to examine whether there are differential effects of retinol and retinoids on normal and PCOS theca cell function. Design: We used in vitro assays. Setting: The study was conducted at the university laboratory. Patients: We studied theca interna cells isolated from normal-cycling women and women with PCOS. Interventions: Theca cells were treated with all-trans-retinoic acid (atRA), 9-cis retinoic acid (9-cis RA), or the retinoic acid precursor retinol. Main Outcome Measure(s): We measured dehydroepiandrosterone, testosterone, and progesterone biosynthesis as well as cytochrome P450 17α-hydroxylase (CYP17), cytochrome P450 cholesterol side-chain cleavage, and steroid...

73 citations


Journal ArticleDOI
TL;DR: The synthesis and binding studies of new 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamides as selective Peripheral Benzodiazepine Receptor (PBR) ligands are reported and a subset of the novel compounds showing high affinity for PBR was tested for their ability to modulate the steroid biosynthesis in C6 glioma cells.

48 citations


Journal ArticleDOI
01 Jul 2005-Steroids
TL;DR: The reinstatement of serum estradiol, progesterone, and PI during the therapy demonstrates its favorable effect on both reproductive functions and the psychosomatic stability of the patients.

Journal ArticleDOI
TL;DR: The results of the present study suggest that two distinct steroid biosynthesis sites exist in the ovary and that cells at the two sites differ functionally.
Abstract: Androgen plays an important role in the developing ovaries of female fish. However, little is known regarding either the sites of production of androgen or its functional roles. In the present study, we investigated immunohistochemically the localization of cholesterol-side-chain-cleavage (P450scc) and cytochrome P45011β-hydroxylase (P45011β) with antibodies P450scc and P45011β in the ovary of the female honeycomb grouper Epinephelus merra during its reproductive cycle. Clusters of strongly immunopositive cells, with 100–1000 cells in each cluster, against both P450scc and P45011β, were observed throughout the annual reproductive cycle in tissue near blood vessels in the tunica ovary surrounding the outer periphery of the ovary. The ultrastructural characteristics of these cells showed that they were steroid-producing cells. In contrast, immunopositive cells against P450scc but not against P45011β were localized in the theca layer surrounding the outer periphery of oocytes. These results suggest that two distinct steroid biosynthesis sites exist in the ovary and that cells at the two sites differ functionally. The only cells that biosynthesize 11-ketotestosterone are found in clusters in the vicinity of blood vessels; they possibly play a physiological role in oocyte growth and gonadal restructuring during the sex change of individuals of this species.

Journal ArticleDOI
TL;DR: There are two broad groups of uterine leiomyomata associated with an alteration of tuberin and glucocorticoid receptor, and one group is associated with upregulation of human mobility group gene A2 and steroid receptor cofactors.

Journal ArticleDOI
15 Dec 2005-Steroids
TL;DR: Tributyltin at concentrations higher than 100 nM suppressed all steroid biosynthesis in the adrenal cells, and this suppression was closely correlated to the decrease in steroidogenic acute regulatory protein.

Journal ArticleDOI
TL;DR: A novel homozygous single nucleotide insertion in exon 11 (codon A589fs) produces a frame shift in the open reading frame predicting for premature termination of translation 17 amino acids downstream, the first frame shift mutation in the LH receptor gene ever reported to date.
Abstract: Leydig cell hypoplasia (LCH) is a rare autosomal recessive condition that interferes with normal development of male external genitalia in 46,XY individuals and is caused by inactivating mutations of the LH receptor gene. The clinical and biochemical diagnostic parameters of LCH are not always specific and may therefore show significant overlap with other causes of insufficient testicular steroid biosynthesis. We have studied a 46,XY newborn with completely female external genitalia and palpable testes. Due to an increased basal serum ratio of androstenedione/testosterone, 17 beta-hydroxysteroid dehydrogenase type 3 (17 beta-HSD 3) deficiency was initially suspected. DNA analysis of the corresponding HSD17B3 gene, however, showed no abnormalities in the entire coding region. In contrast, direct sequencing of the LH receptor gene revealed a novel homozygous single nucleotide insertion in exon 11 (codon A589fs) producing a frame shift in the open reading frame predicting for premature termination of translation 17 amino acids downstream. From the genetic perspective, this mutation represents the first frame shift mutation in the LH receptor gene ever reported to date. From the clinical standpoint, LCH should always be considered in the differential diagnosis as steroid profiles may not be informative. Therefore, molecular genetic analysis should be warranted for androgen biosynthesis defects in all cases.

Journal ArticleDOI
TL;DR: Modeling human POR on the X‐ray crystal structure of rat POR shows that these mutant activities correlate well with their locations in the structure, and is a new disease, distinct from the craniosynostosis syndromes caused by FGFR mutations.
Abstract: Microsomal P450 enzymes, which metabolize drugs and catalyze steroid biosynthesis require electron donation from NADPH via P450 oxidoreductase (POR). POR knockout mice are embryonically lethal, but we found recessive human POR missense mutations causing disordered steroidogenesis and Antley-Bixler syndrome (ABS), a skeletal malformation syndrome featuring craniosynostosis. Dominant mutations in exons 8 and 10 of fibroblast growth factor receptor 2 (FGFR2) cause phenotypically related craniosynostosis syndromes and were reported in patients with ABS and normal steroidogenesis. Sequencing POR and FGFR2 exons in 32 patients with ABS and/or hormonal findings suggesting POR deficiency showed complete genetic segregation of POR and FGFR2 mutations. Fifteen patients carried POR mutations on both alleles, four carried POR mutations on 1 allele, nine carried FGFR2/3 mutations on one allele and no mutation was found in three patients. The 34 affected POR alleles included 10 with A287P, 7 with R457H, 9 other missense mutations and 7 frameshifts. These 11 missense mutations and 10 others identified by database mining were expressed in E. coli, purified to apparent homogeneity, and their catalytic capacities were measured in four assays: reduction of cytochrome c, oxidation of NADPH, and support of the 17alpha-hydroxylase and 17,20 lyase activities of human P450c17. As assessed by Vmax/Km, 17,20 lyase activity provided the best correlation with clinical findings. Modeling human POR on the X-ray crystal structure of rat POR shows that these mutant activities correlate well with their locations in the structure. POR deficiency is a new disease, distinct from the craniosynostosis syndromes caused by FGFR mutations.

Journal ArticleDOI
TL;DR: The CYP17 MspA1 polymorphism is probably not associated with endometriosis in either the UK or the Japanese population, and no significant differences in allele or genotype frequencies were seen.
Abstract: Endometriosis is a complex trait, which means that multiple susceptibility genes interact with one another and the environment to produce the phenotype. One of the genes previously implicated in the disease is CYP17; this encodes the enzyme P450c17α, which plays a vital role in steroid biosynthesis in the ovary. The presence of a single nucleotide polymorphism (T→C) in the 5′-promoter region of the gene creates a new recognition site for the restriction enzyme MspA1 producing a mutant allele (A2), which affects circulating estrogen levels. In this study, we compared the frequency of the CYP17 MspA1 polymorphism in two different ethnic populations. DNA was obtained from (1) 94 women with revised American Fertility Society (rAFS) stage III–IV endometriosis and 97 male blood donors in the UK, and (2) 130 women with rAFS stage III–IV endometriosis and 179 female newborn infants in Japan. No significant differences in allele or genotype frequencies were seen in either population. The genotype distribution in t...

Journal ArticleDOI
TL;DR: Women with epilepsy apparently have a higher incidence of polycystic ovary syndrome (PCOS) than do women without epilepsy, although the underlying disease or the antiepileptic drug (AED) treatment is unknown.
Abstract: Summary: Purpose: Women with epilepsy apparently have a higher incidence of polycystic ovary syndrome (PCOS) than do women without epilepsy. Whether the underlying disease or the antiepileptic drug (AED) treatment is responsible for this increased risk is unknown, although clinical reports implicate valproic acid (VPA) as a potential cause. The steroidogenic enzymes 3βHSDII (3β-hydroxysteroid dehydrogenase) and P450c17 (17α-hydroxylase/17,20 lyase) are essential for C19 steroid biosynthesis, which is enhanced during adrenarche and in PCOS. Methods: To determine whether the AEDs VPA, carbamazepine (CBZ), topiramate (TPM), or lamotrigine (LYG) directly affect the activities of human 3βHSDII and P450c17, we added them to yeast expressing human P450c17 or 3βHSDII and assayed enzymatic activities in the microsomal fraction. Results: Concentrations of VPA ≤10 mM had no effect on activities of P450c17; however, VPA inhibited 3βHSDII activity starting at 0.3 mM (reference serum unbound concentration, 0.035–0.1 mM) with an IC50 of 10.1 mM. CBZ, TPM, and LTG did not influence 3βHSDII or P450c17 activities at typical reference serum unbound concentrations, but did inhibit 3βHSDII and P450c17 at concentrations >10-fold higher. Conclusions: None of the tested AEDs influenced 3βHSDII or P450c17 activities at concentrations normally used in AED therapy. However, VPA started to inhibit 3βHSDII activity at concentrations 3 times above the typical reference serum unbound concentration. Because inhibition of 3βHSDII activity will shift steroidogenesis toward C19 steroid production when P450c17 activities are unchanged, very high doses of VPA may promote C19 steroid biosynthesis, thus resembling PCOS. CBZ, TPM, and LTG influenced 3βHSDII and P450c17 only at toxic concentrations.

Journal ArticleDOI
TL;DR: It is concluded that mitochondrial cytochrome P450 systems are a source of mitochondrial ROS production and can play a role in the induction of mitochondrial apoptosis.
Abstract: Mitochondrial cytochrome P450 systems are an indispensable component of mammalian steroid biosynthesis; they catalyze regio- and stereo-specific steroid hydroxylations and consist of three protein entities: adrenodoxin reductase (AdR), adrenodoxin (Adx), and a mitochondrial cytochrome P450 enzyme, e.g., CYP11A1 (P450 side chain cleavage, P450scc). It is known that the latter two are able to generate reactive oxygen species (ROS) in vitro . In this study, we investigated whether this ROS generation also occurs in vivo and, if so, whether it leads to the induction of apoptosis. We found that overexpression of either human or bovine Adx causes a significant loss of viability in 11 different cell lines. This loss of viability does not depend on the presence of the tumor suppressor protein p53. Transient overexpression of human Adx in HCT116 cells leads to ROS production, to a disruption of the mitochondrial transmembrane potential (DeltaPsi), to cytochrome c release from the mitochondria, and to caspase activation. In contrast, the effect of transient overexpression of human CYP11A1 on cell viability varies in different cell lines, with some being sensitive and others not. We conclude that mitochondrial cytochrome P450 systems are a source of mitochondrial ROS production and can play a role in the induction of mitochondrial apoptosis.

Journal ArticleDOI
TL;DR: This study identified genes with recognized roles in CL regression, genes with potential roles in this process and genes whose function have yet to be defined in this event.

Journal ArticleDOI
TL;DR: The results reinforce the idea that the subcellular localisation of PBR defines its function and that this receptor could be a possible target for new strategies against cancer.

Journal ArticleDOI
TL;DR: Pitx1 stimulates the rat LHbeta gene promoter via two Pitx1 DNA-regulatory regions via two pituitary homeobox 1 sites, which further the understanding of the molecular mechanisms that regulate expression of this critical reproductive gene promoter.
Abstract: Luteinizing hormone (LH) plays a central role in the reproductive axis, stimulating both gonadal steroid biosynthesis and the development of mature gametes. Over the past decade, significant progress has been made in characterizing the transcription factors and associated DNA-regulatory sites which mediate expression of the LH -subunit gene (LH). One of these factors, pituitary homeobox 1 (Pitx1), has been shown to stimulate LH gene promoter activity, both alone and in synergy with the orphan nuclear receptor, steroidogenic factor-1 (SF-1), and the early growth response gene 1 (Egr-1). Prior reports have attributed the Pitx1 response to a cis-element located at position �101 in the rat LH gene promoter. While investigating the role of Pitx1 in regulating rat LH gene expression, we observed a small, but significant, residual Pitx1 response despite mutation or deletion of this site. In the studies presented here, we identify the presence of a second functional Pitx1 region spanning positions �73 to �52 in the rat LH gene promoter. Based on electrophoretic mobility shift assay, Pitx1 binds to both the initially described 58Pitx1 site as well as this putative 38Pitx1 region. In transient transfection analysis, mutation of the LH-38Pitx1 site significantly blunted Pitx1 responsiveness, with elimination of the Pitx1 response in a construct containing mutations in both Pitx1 cis-elements. We also analyzed the importance of each of these Pitx1 sites for providing functional synergy with SF-1 and with Egr-1. We observed a markedly decreased synergistic response with mutation of the 58Pitx1 site with further loss following mutation of the 38Pitx1 site. In contrast, functional interaction between Pitx1 and Egr-1 persisted with mutation of both Pitx1 regions. We conclude that Pitx1 stimulates the rat LH gene promoter via two Pitx1 DNA-regulatory regions. These results further our understanding of the molecular mechanisms that regulate expression of this critical reproductive gene promoter.

Journal ArticleDOI
TL;DR: Data indicate that stimulation of the cAMP-PKA-CREB pathway enhances rat SR-BIpr activity and substantiate the role of CREB as an intermediary in this process.

Journal ArticleDOI
TL;DR: The results indicated that arctiin might not exert significant modifying effect on prostate carcinogenesis in SV 40 Tag TG rats at least under the present experiment.

Journal ArticleDOI
01 Oct 2005-Alcohol
TL;DR: It is demonstrated that ethanol is capable of inhibiting FSH-induced ovarian StAR and thus, contributing to suppressed E2 secretion, at least in part, through an inhibitory action on the COX-2-PGE2 pathway.

Journal ArticleDOI
TL;DR: The reinstatement of progesterone, P3alpha5alpha, and P3beta5beta serum levels demonstrates the favorable effect of detoxification therapy on both reproductive functions and the psychosomatic stability of premenopausal women treated for alcohol addiction.
Abstract: BACKGROUND Alcohol abuse is associated with menstrual irregularities related to the inhibition of progesterone secretion involved in regulation of the menstrual cycle. Reduced progesterone metabolites, including pregnanolone isomers (PIs), are efficient neuromodulators. The authors attempted to evaluate whether levels of PIs reflect impairment in progesterone biosynthesis in premenopausal women treated for alcohol addiction and whether alcohol detoxification therapy contributes to the restoration of their reproductive functions and psychosomatic stability by influencing steroid biosynthesis. METHODS Serum allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one; P3alpha5alpha), pregnanolone (P3alpha5beta), isopregnanolone (P3beta5alpha), epipregnanolone (P3beta5beta), progesterone, pregnanolone sulfate (PregS), pregnanolone, and estradiol were measured in 20 women during therapy (at start, three days, 14 days, one month, and four months) by gas chromatography-mass spectrometry or radioimmunoassay. The results were evaluated by a linear mixed model for longitudinal data, with stage of the treatment and subject as categorical factors, phase of the menstrual cycle as a time-varying covariate, and age of the subject as a covariate and by regression in individual stages of the menstrual cycle. RESULTS During detoxification treatment, progesterone increased in the luteal phase. P3alpha5alpha, P3beta5alpha, and P3beta5beta rose in both phases of the menstrual cycle. DISCUSSION Given the similar mechanism in the effects of alcohol and steroids in activating gamma-aminobutyric acid A receptors, the restoration of progesterone and PIs during therapy could be explained by an adaptation to increasing requests for gamma-aminobutyric acid A-receptor activating substances owing to the cessation of alcohol intake or by the regeneration of progesterone formation. In conclusion, the reinstatement of progesterone, P3alpha5alpha, and P3beta5beta serum levels demonstrates the favorable effect of detoxification therapy on both reproductive functions and the psychosomatic stability of premenopausal women treated for alcohol addiction.

Book ChapterDOI
TL;DR: 1α,25-dihydroxyvitamin D4 is a promising therapeutic agent for osteoporosis, skin disease and immune disorders, and the importance of the side chain structure is suggested.
Abstract: We synthesized active forms of naturally occurring vitamin D analogues (vitamin D2, D3, D4, D5, D6 and D7) and investigated the biological activities and metabolism (especially for 1α,25-dihydroxyvitamin D4). 1α,25-Dihydroxyvitamin D4 showed the same affinity for vitamin D receptor as 1α,25-dihydroxyvitamin D3, but it had stronger affinity for vitamin D binding protein and more efficient biological activities, such as activation of vitamin D receptor and effect on cellular growth and differentiation than 1α,25-dihydroxyvitamin D3. 1α,25-Dihydroxyvitamin D4 increased total bone mass content in animal models of osteoporosis without elevating plasma calcium level. The pharmacokinetic study on 1α,25-dihydroxyvitamin D4 showed longer T1/2, higher Cmax and AUC values than those of 1α,25-dihydroxyvitamin D3. According to the metabolism study, 1α,25-dihydroxyvitamin D4 is metabolized in a similar manner to 1α,25-dihydroxyvitamin D2 but differently from 1α,25-dihydroxyvitamin D3, suggesting the importance of theside chain structure. The results indicate that 1α,25-dihydroxyvitamin D4 is a promising therapeutic agent for osteoporosis, skin disease and immune disorders. The synthetic procedure developed for active forms of vitamin D analogues was applied to the synthesis of biologically active steroids such as dictyosterol possessing the neurite outgrowth activity and the intermediates in steroid biosynthesis.

Journal ArticleDOI
TL;DR: The concept that the placenta and fetus, in concert with the mother, consists of a unit for hormonal synthesis and metabolism derived from the work of Diczfalusy et al., plays a unique role in the regulation of steroid hormone production in pregnancy.

Journal ArticleDOI
TL;DR: It is suggested that although DDT and DDE may affect ovarian androgen synthesis under some conditions, under the conditions of the present study, they do not impact on overall rates of gonadal estrogen synthesis.

Journal ArticleDOI
TL;DR: The ovaries of Hipposideros speoris were observed throughout the reproductive cycle from July 2001 to 2002 and the interstitial cells or so called "epithelial cords" showed variations in their distribution, morphology and association with other ovarian structures.
Abstract: The ovaries of Hipposideros speoris were observed throughout the reproductive cycle from July 2001 to 2002. The interstitial cells or so called "epithelial cords" showed variations in their distribution, morphology and association with other ovarian structures. These cords appear to be formed in the ovarian cortex by the transformation of granulosa ceils of primordial follicles and small preantral follicles whose ova regress and disappear. Mostly, these cords were conspicuous, hypertrophied, abundant and in clusters or in zones occupying major portion of the cortex during 4-5 months of gestation and also during lactation period. The accumulation of sudanophilic lipid droplets in these cords suggests their role in steroid biosynthesis, most probably the progestins. An increase in lipid droplets parallels the development of alkaline phosphatase reactivity. The origin and the fate of the cords were not determined but their absence or reduction in number suggests their transformation into stroma during non-pregnancy.