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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polycystic ovary syndrome (PCOS) is a very common endocrinopathy of uncertain aetiology in which the most consistent biochemical abnormality is hypersecretion of androgens. In this review, evidence is presented to support the view that a primary abnormality of ovarian androgen biosynthesis provides the basis for the syndrome. PCOS is a familiar disorder and we demonstrate, in molecular genetic studies, that CYP11a, the gene coding for P450 side chain cleavage, is a key susceptibility locus for development of hyperandrogenism.
J Steroid Biochem Mol Biol
PMID:Polycystic ovary syndrome: evidence for a primary disorder of ovarian steroidogenesis. 1041 1

Heme oxygenase (HO)-1 is an oxygen-dependent enzyme that may regulate vascular tone and cell proliferation through the production of carbon monoxide (CO). We tested the hypothesis that HO-1 is upregulated in the lung in chronic hypoxia by exposing male Sprague-Dawley rats to 17,000 feet (395 Torr) for 0, 1, 3, 7, 14, or 21 days. After exposure, blood gases, carboxyhemoglobin (COHb) levels, and hematocrit were measured, and the lungs were either inflation fixed for immunohistochemistry or frozen for later measurement of HO enzyme activity, Western blot for HO-1 protein, and RT-PCR for HO-1 mRNA. The heart was excised and weighed, and the right-to-left heart weight ratio was determined. During hypoxia, the hematocrit increased progressively, reaching significantly higher values than the control value after 3 days. COHb levels increased above the control value after 1 day of hypoxia and increased progressively between 14 and 21 days, whereas arterial PO(2) and arterial PCO(2) did not vary significantly. HO-1 protein determined by Western blot increased for the first 7 days and declined thereafter; however, enzyme activity was elevated only after 1 day. Changes in HO-1 during hypoxia were localized by immunohistochemistry to inflammatory cells (early) and newly muscularized arterioles (later). Lung HO-1 mRNA normalized to glyceraldehyde-3-phosphate dehydrogenase was increased after 1 and 21 days. The data indicate that lung HO-1 protein and activity are upregulated only during early chronic hypoxia, whereas persistent COHb elevations indicate high endogenous CO production rates at nonpulmonary sites. If CO has antiproliferative properties, the lack of HO enzyme activity in the lung may be permissive for pulmonary vascular proliferation in hypoxia.
Am J Physiol Lung Cell Mol Physiol 2000 Apr
PMID:Expression of heme oxygenase-1 in the lung in chronic hypoxia. 1074 58

Previous analysis of germline mutation at highly unstable GC-rich minisatellites with continuous allele size distributions revealed similar meiotic recombinational mechanisms operating at all loci investigated. The insulin minisatellite has been studied intensively due to its associations with diabetes, polycystic ovary syndrome, obesity and birth size. Its bimodal allele size distribution in Caucasians suggests a much lower mutation rate and possible differences in the mutation process compared with highly unstable minisatellites. Mutation at the insulin minisatellite therefore was studied both indirectly from allele diversity surveys and directly by recovering de novo mutants from sperm DNA. Structural analysis of variant repeat distributions in 876 alleles identified 189 different alleles, almost all of which could be assigned to one of three very distinct lineages. Variation within a lineage was minor and due mainly to the gain or loss of one or a few repeat units. These events most probably arise by mitotic replication slippage at a frequency of perhaps 10(-3)per gamete. Sperm DNA analysis revealed a second class of mutation occurring at a frequency of approximately 2 x 10(-5)that involved highly complex intra- and inter-allelic rearrangements very similar to those seen at unstable minisatellites. These complex rearrangements were not seen in somatic DNA and are probably meiotic in origin. Minisatellite homozygosity did not reduce the frequency of these mutants in sperm. The insulin minisatellite therefore appears to evolve by two distinct processes: one involving slippage-like events and the second resulting in complex recombinational turnover of allele structure.
Hum Mol Genet 2000 Mar 22
PMID:Allele diversity and germline mutation at the insulin minisatellite. 1074 78

To find an explanation for the possible working mechanism of laparoscopic ovarian electrocautery for the treatment of anovulation in polycystic ovarian syndrome (PCOS), we evaluated the distribution of steroidogenic enzymes involved in the synthesis of ovarian androgens in surgical pathology specimens of entire polycystic ovaries. A total of 13 formalin-fixed and paraffin-embedded samples of the ovaries of patients with clinically proven PCOS were immunostained with specific antibodies against cholesterol side-chain-cleavage enzyme (P450scc), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), 17alpha-hydroxylase (P450c17) and adrenal 4-binding protein (Ad4BP), a transcription factor of steroidogenic enzymes. Follicular theca cells of all ovaries demonstrated marked immunoreactivity for Ad4BP, P450scc, 3beta-HSD and P450c17. Granulosa cells of seven ovaries expressed Ad4BP, while granulosa cells of three ovaries also showed P450scc. In the granulosa cells of all ovaries, 3beta-HSD and P450c17 immunoreactivity was not observed. In the stroma, luteinized cells of most ovaries demonstrated Ad4BP, P450scc, 3beta-HSD and P450c17 immunoreactivity, but at a much lower level compared with the follicular theca cells. Non-luteinized stromal cells sporadically demonstrated Ad4BP, P450scc, 3beta-HSD and P450c17 immunoreactivity. The stromal steroidogenic cells were mainly located in the ovarian cortex, except for some hilus steroidogenic cells. These data demonstrate that in polycystic ovaries, androgens are mainly produced in the follicular theca cells and to some extent in luteinized stromal cells. This suggests that the working mechanism of laparoscopic electrocautery of the ovary is primarily explained through the reduction of ovarian hyperandrogenism by coagulation of follicular theca cells and concomitant stroma.
Mol Hum Reprod 2000 May
PMID:Distribution of steroidogenic enzymes involved in androgen synthesis in polycystic ovaries: an immunohistochemical study. 1077 48

Strong evidence for a link between the follistatin gene and polycystic ovary syndrome (PCOS) has recently been found in a well-designed large-scale study. Follistatin binds to activin and affects its functions, e.g. stimulation of FSH synthesis and secretion. Thus, it may play a role in the functional impairment of the FSH-granulosa cell axis in PCOS. In this study, we screened 64 Chinese patients with PCOS for mutations in the entire coding region (including the region encoding alternative carboxy-terminals) of the follistatin gene using polymerase chain reaction (PCR)-based single-stranded conformational polymorphism (SSCP) and DNA sequencing. However, we could not identify a single mutation of either the activating or inhibiting type, using these techniques. Therefore, it would appear that PCOS in the local Chinese population is not caused by mutations in the coding regions of the follistatin gene.
Mol Hum Reprod 2000 Jul
PMID:Preliminary investigation of follistatin gene mutations in women with polycystic ovary syndrome. 1087 44

A central role for nuclear factor-kappaB (NF-kappaB) in the induction of lung inflammatory injury is emerging. We hypothesized that NF-kappaB is a critical early regulator of the inflammatory response in lung ischemia-reperfusion injury, and inhibition of NF-kappaB activation reduces this injury and improves pulmonary graft function. With use of a porcine transplantation model, left lungs were harvested and stored in cold Euro-Collins preservation solution for 6 h before transplantation. Activation of NF-kappaB occurred 30 min and 1 h after transplant and declined to near baseline levels after 4 h. Pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of NF-kappaB, given to the lung graft during organ preservation (40 mmol/l) effectively inhibited NF-kappaB activation and significantly improved lung function. Compared with control lungs 4 h after transplant, PDTC-treated lungs displayed significantly higher oxygenation, lower PCO(2), reduced mean pulmonary arterial pressure, and reduced edema and cellular infiltration. These results demonstrate that NF-kappaB is rapidly activated and is associated with poor pulmonary graft function in transplant reperfusion injury, and targeting of NF-kappaB may be a promising therapy to reduce this injury and improve lung function.
Am J Physiol Lung Cell Mol Physiol 2000 Sep
PMID:Attenuation of lung reperfusion injury after transplantation using an inhibitor of nuclear factor-kappaB. 1095 28

Anovulation in women with polycystic ovary syndrome (PCOS) is characterised by arrested growth of antral follicles. A relative lack of FSH may contribute to the persistence of anovulation but is unlikely, by itself, to be a major cause of it. Granulosa cells from anovulatory women with polycystic ovaries hypersecrete oestradiol, compared with size-matched follicles from normal ovaries or polycystic ovaries from ovulatory women. This phenomenon appears to reflect a condition of advanced maturation of medium-sized antral follicles. The underlying basis for the abnormalities in anovulatory PCOS remains uncertain, but it is possible that there are intrinsic differences in folliculogenesis between polycystic and normal ovaries which affect preantral as well as antral follicles. An alternative - but not mutually exclusive - explanation of this disorder is the abnormal endocrine environment. Hypersecretion of both LH and insulin are typical of anovulatory women with PCOS. Studies in isolated granulosa cells, have shown, that insulin greatly augments the action of LH on steroidogenesis but this interaction may compromise further growth of medium-sized antral follicles by generation of 'preovulatory' concentrations of cAMP within the granulosa cell and thereby leading, prematurely, to terminal differentiation of granulosa cells.
Mol Cell Endocrinol 2000 May 25
PMID:Follicular dynamics in the polycystic ovary syndrome. 1096 73

Polycystic ovarian syndrome (PCOS) is often associated with obesity and insulin resistance, both of which are features that are linked to the leptin and leptin receptor (LEPR) genes. Analysis of the leptin gene by sequencing samples from 38 well-characterized patients with PCOS revealed no mutations of the coding exons. In single-stranded conformational polymorphism (SSCP) analysis and subsequent sequencing of the LEPR gene revealed previously identified amino acid variants in exons 2, 4 and 12 as well as the pentanucleotide insertion in the 3'-untranslated region (3'-UTR). The allele frequencies of these polymorphisms did not differ from those in the general population, as assessed in 122 female controls. Compared with non-carriers, serum insulin concentrations tended to be lower in the carriers of the variant LEPR exon 12 allele as well as in the carriers of the variant LEPR 3'-UTR allele, a marker previously suggested to be associated with serum insulin concentrations. In conclusion, PCOS is not commonly a consequence of mutations of the leptin or LEPR genes. However, our data support the hypothesis that variations in the LEPR gene locus have an effect on insulin regulation.
Mol Hum Reprod 2000 Oct
PMID:No evidence for mutations of the leptin or leptin receptor genes in women with polycystic ovary syndrome. 1100 14

Polycystic ovarian syndrome (PCOS) involves follicular atresia, formation of multiple ovarian cysts and is frequently associated with a higher abortion rate. Follicular development, ovulation, formation of corpus luteum and its regression involve extensive tissue remodelling. Mammalian ovaries express a number of matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP). We assessed the differences in production of MMP-2, MMP-9 and TIMP-1 by cultured luteinized granulosa cells from women with PCOS and normal ovulatory women after ovarian stimulation for IVF treatment. In follicular fluid from women with PCOS, levels of MMP-9 and MMP-2 were higher than the normal group, as was the basal production of these proteins by cultured cells. Basal production of TIMP-1 by cultured cells was not different between PCOS and normal groups. A time-dependent increase in the production of MMP-9 was observed in cells from both normal and PCOS women, although the increase was more pronounced in the latter. Thus the MMP-TIMP balance is shifted toward greater MMP activity in luteinized granulosa cells from women with PCOS.
Mol Hum Reprod 2001 Apr
PMID:The balance between MMP-9 and MMP-2 and their tissue inhibitor (TIMP)-1 in luteinized granulosa cells: comparison between women with PCOS and normal ovulatory women. 1127 94

Insulin-like growth factor-I (IGF-I) has been implicated in a wide variety of physiological processes including ovarian function. To better understand the ovarian role of IGF-I, transgenic mice harbouring a human IGF-I cDNA (hIGF-I) under the control of the mouse LH receptor promoter were generated. Expression of the hIGF-I, determined by Northern blot, was found to occur in the gonad tissues of these transgenic mice. The hIGF-I protein was also detectable by radioimmunoassay in ovarian extracts as well as in the plasma. The fertility of mating transgenic females, as estimated by the number of implantation sites post-coitum, did not appear to be affected. However, transgenic females who failed to mate and produce offspring were found to possess polycystic ovaries. Evaluation of testosterone, estradiol, and LH levels revealed that transgenic animals had significantly elevated circulating levels of testosterone compared to their non-transgenic littermates, while LH levels in transgenic females were significantly lower. Yet, estradiol appeared to be unaffected. These results support the contention that the IGF system plays an important role in ovarian function and that an imbalance in this system may result in ovarian pathology.
Mol Reprod Dev 2001 Jun
PMID:Ovarian expression of human insulin-like growth factor-I in transgenic mice results in cyst formation. 1138 52


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