| cytochrome P450 family 19 subfamily A member 1 | OKDB#: 75 |
| Symbols: | CYP19A1 | Species: | human | ||
| Synonyms: | ARO, ARO1, CPV1, CYAR, CYP19, CYPXIX, P-450AROM | Locus: | 15q21.2 in Homo sapiens |
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| General Comment |
Aromatase (EC 1.14.14.1 ), also called estrogen synthetase, is a cytochrome P450 enzyme which catalyzes the formation of aromatic C18 estrogens from C19 androgens; it is symbolized CYP19. Aromatase, or estrogen synthetase, is located in the ovary and placenta and participates in the regulation of reproductive functions. The enzyme is also widely distributed in extragonadal tissues such as muscle, liver, hair follicles, adipose tissue, and brain.
NCBI Summary: This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and catalyzes the last steps of estrogen biosynthesis. Mutations in this gene can result in either increased or decreased aromatase activity; the associated phenotypes suggest that estrogen functions both as a sex steroid hormone and in growth or differentiation. Alternative promoter use and alternative splicing results in multiple transcript variants that have different tissue specificities. [provided by RefSeq, Dec 2016] |
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| General function | Enzyme, Lyase | ||||
| Comment | A randomized, single-blind, prospective trial comparing three different gonadotropin doses with or without addition of letrozole during ovulation stimulation in patients with poor ovarian response. Bastu E et al. (2016) The aim of this randomized controlled trial (RCT) was to investigate whether IVF outcomes would differ between patients with POR who received three different gonadotropin doses with or without the addition of letrozole during ovulation stimulation. Only those who fulfilled two of the three Bologna criteria were included to the study. 95 patients met the inclusion criteria and agreed to participate in the study. In the first group, 31 patients were treated with 450IU gonadotropins. In the second group, 31 patients were treated with 300IU gonadotropins. The third group comprised 33 patients and was treated with 150IU gonadotropins in combination with letrozole. The results indicate that differences in doses of hMG and rFSH in patients with POR result in a similar number of retrieved MII and fertilized oocytes, similar fertilization rates, number of transferred embryos, implantation, cancelation, chemical, clinical, and ongoing pregnancy rates. Increasing the dose of gonadotropins during ovulation stimulation is an intuitively appealing approach when the patient is a poor responder. However, increasing the dose does not necessarily improve the reproductive outcome. Using a mild stimulation with addition of letrozole was as effective as stimulation with higher doses of gonadotropins alone in this patient population.////////////////// Formulation and testing of a non-steroidal aromatase inhibitor intravaginal device for the control of ovarian function in cattle. Yapura J et al. (2015) The study was designed to formulate intravaginal devices that provide biologically active circulating concentrations of an aromatase inhibitor for a minimum of 4 days, and to determine their physiologic effects in cattle. Three compounds with estradiol inhibitory capability (letrozole, anastrozole and fenbendazole) were tested in vitro using bovine granulosa cell culture. Letrozole was found to be the most efficient and potent inhibitor. A wax-based vehicle was selected for further development of a letrozole intravaginal device based on its steady release rate. Cycling heifers were assigned randomly to be given an intravaginal device containing wax plus gel coat (n=4), wax formulation (n=4), no formulation (blank device, control, n=4). Intravaginal devices were inserted on Day 3 (Day 0=ovulation) and kept in place for 8 days. The addition of a letrozole-containing gel coating hastened the initial increase on plasma concentrations, while the letrozole-containing wax-based vehicle maintained prolonged delivery from the intravaginal device. The dominant follicle diameter profile was larger in heifers treated with the wax plus gel coat device (P<0.04), and the interwave interval was prolonged in heifers in the letrozole-treated groups compared to controls (P<0.001). Plasma estradiol concentrations were reduced significantly in the letrozole-treated groups. Plasma progesterone concentrations were lower in the wax letrozole-treated group (P<0.02). We concluded that wax base plus gel coat intravaginal devices are suitable for the development of a letrozole-based protocol for the synchronization of ovulation in cattle. It effectively reduced estradiol production resulting in prolonged dominant follicle growth and lifespan, without adversely affecting progesterone production.////////////////// Research Resource: Small RNA-seq of human granulosa cells reveals miRNAs in FSHR and aromatase genes. Velthut-Meikas A et al. The granulosa cells in the mammalian ovarian follicle respond to gonadotropin signalling and are involved in the processes of folliculogenesis and oocyte maturation. Studies on gene expression and regulation in human granulosa cells are of interest due to their potential for estimating the oocyte viability and IVF success. However, the post-transcriptional gene expression studies on microRNA (miRNA) level in the human ovary have been scarce. The current study determined the miRNA profile by deep sequencing of the two intrafollicular somatic cell types: mural and cumulus granulosa cells (MGC and CGC, respectively) isolated from women undergoing controlled ovarian stimulation and in vitro fertilization. Altogether 936 annotated and nine novel miRNAs were identified. Ninety of the annotated miRNAs were differentially expressed between MGC and CGC. Bioinformatic prediction revealed that TGF? ErbB signalling and heparan sulphate biosynthesis were targeted by miRNAs in both granulosa cell populations, while extracellular matrix remodelling, Wnt and neurotrophin signalling pathways were enriched among miRNA targets in MGC. Two of the novel miRNAs found were of intronic origin: one from the aromatase and the other from the FSH receptor gene. The latter miRNA was predicted to target the activin signalling pathway. In addition to revealing the genome-wide miRNA signature in human granulosa cells, our results suggest that post-transcriptional regulation of gene expression by miRNAs could play an important role in the modification of gonadotropin signalling. miRNA expression studies could therefore lead to new prognostic markers in assisted reproductive technologies. DNA Methylation Is Not Involved in Preovulatory Down-Regulation of CYP11A1, HSD3B1, and CYP19A1 in Bovine Follicles But May Play a Role for Permanent Silencing of CYP19A1 in Large Granulosa Lutein Cells. Vanselow J et al. The luteinizing hormone-induced morphological and physiological reorganization of the bovine follicle is preceded by a profound and well-orchestrated modulation of gene expression. In the present study, the cell type-specific methylation profiles of CYP11A1, HSD3B1, and CYP19A1, genes that encode key enzymes of steroid hormone biosynthesis, were analyzed to elucidate whether epigenetic parameters such as DNA methylation might be involved in gene regulation during luteinization. Transcript abundance and DNA methylation levels were determined in granulosa and theca of large dominant and late preovulatory follicles and in large granulosa lutein cells isolated from corpora lutea cyclica and graviditatis. Levels of the steroid hormones progesterone and estradiol-17beta were monitored to assess the physiological status of individual follicles. From our results, we conclude that (1) individual, even closely neighboring, CpG dinucleotides can show very different methylation levels; (2) proximal (< 300 bp from the respective transcription start sites) but not distal CpGs show cell type-specific methylation levels; (3) higher methylation levels suggestively preclude high levels of gene expression; (4) DNA methylation is not involved in the transient (HSD3B1 and CYP11A1), respectively permanent (CYP19A1) down-regulation of gene expression in late preovulatory follicles; (5) DNA methylation may play a role in the permanent shutdown of promoter 2-directed CYP19A1 expression in large (granulosa derived) lutein cells. Aromatase inhibitors in women with clomiphene citrate resistance: a randomized, double-blind, placebo-controlled trial. Kamath MS et al. In 36 women with polycystic ovary syndrome and clomiphene citrate resistance, letrozole, an aromatase inhibitor, statistically significantly increased the ovulation rate by 33.3% in the treatment group, indicating that letrozole can be used as an effective and simple alternate ovulation-inducing agent in these women. | ||||
| Cellular localization | Cytoplasmic | ||||
| Comment | CYP19A1 Gene Expression in Patients with Polycystic Ovarian Syndrome. Panghiyangani R et al. (2020) Polycystic ovarian syndrome (PCOS) is a common endocrine system disorder among the women of reproductive age, yet the etiology of PCOS remains unclear. Infertility in females with PCOS can be caused by anovulation, high luteinizing hormone levels, and hyperandrogenism. This research analyzed the role of the aromatase gene (CYP19A1) in PCOS pathogenesis. This study used an observational, cross-sectional design. A total of 110 research participants (55 PCOS patients and 55 non-PCOS patients) were included in the study. A real-time quantitative polymerase chain reaction was used to analyze the mRNA expression for aromatase in granulosa cells. The relative expression of aromatase mRNA is lower in women with PCOS compared to those without PCOS (P < 0.05). Relative expression of CYP19A1 (aromatase) mRNA in PCOS group was 0.38 ± 0.25, whereas in non-PCOS group was 1.00 ± 0.00. The decline in aromatase activity contributes to an increase in testosterone level. This condition has a role in hyperandrogenism which is a typical characteristic of PCOS women. Granulosa cells in polycystic ovary undergo disturbance in the development and cannot respond to follicle-stimulating hormone (FSH) stimulation. Lack of stimulation of FSH causes induction inadequacy to aromatase enzyme activity in the aromatization process. The decline in FSH activity is caused by various factors that are associated with typical characteristics of PCOS. There is a decrease in the relative expression rate of granulosa cells' aromatase mRNA in women with PCOS compared to the non-PCOS.////////////////// | ||||
| Ovarian function | Follicle development, Initiation of primordial follicle growth, Preantral follicle growth, Antral follicle growth, Cumulus cell differentiation, Follicle atresia, Ovulation, Steroid metabolism, Luteinization | ||||
| Comment | Compensatory Increase in Ovarian Aromatase in Older Regularly Cycling Women. Shaw ND et al. (2015) Serum estradiol (E2) levels are preserved in older reproductive-aged women with regular menstrual cycles despite declining ovarian function. To determine whether increased granulosa cell aromatase expression and activity account for preservation of E2 levels in older, regularly cycling women. Daily blood sampling and dominant follicle aspirations at an academic medical center during a natural menstrual cycle. Healthy, regularly cycling older (36-45 yrs; n=13) and younger (22-34 yrs; n=14) women. Hormone levels were measured in peripheral blood and follicular fluid aspirates and granulosa cell CYP19A1 (aromatase) and FSH-R mRNA expression was determined. Older women had higher FSH levels than younger women during the early follicular phase with similar E2 but lower inhibin B and AMH levels. Late follicular phase serum E2 was also similar in the two groups. Follicular fluid E2 (O = 960.0 IQR 765.0-1419.0]; Y = 994.5 [647.3-1426.5] ng/ml, p=1.0), E1 (O = 39.6 [29.5-54.1]; Y = 28.8 [22.5-42.1] ng/ml, p=0.3), and the E2/T ratio (O = 109.0±41.9; Y = 83.0±18.6, p=0.5) were preserved in older women. Granulosa cell CYP19A1 expression was increased 3-fold in older compared with younger women (p< 0.001) with no difference in FSH-R expression. Ovarian aromatase expression increases with age in regularly cycling women. Thus, upregulation of aromatase activity appears to compensate for the known age-related decrease in granulosa cell number in the dominant follicle to maintain ovarian estrogen production in older pre-menopausal women.////////////////// Tissue-specific promoter methylation and histone modifications regulate CYP19 gene expression during folliculogenesis and luteinization in buffalo ovary. [Monga R et al. Aromatase, the key enzyme of estrogen biosynthesis, is encoded by the CYP19 gene. The expression of CYP19 gene is regulated in species- and tissue-specific manner by alternate use of different promoters. We have previously, cloned and characterized the tissue-specific promoter and tissue-specific transcripts in preovulatory (granulosa cells) and postovulatory (corpus luteum) structure of buffalo ovary. The present study was aimed to understand if epigenetic gene regulation through DNA methylation and histone modifications is involved in tissue-specific CYP19 gene regulation during folliculogenesis and luteinization in buffalo ovary. Methylation analysis of five CpG dinucleotides of ovary specific proximal promoter II showed hypo-methylation in large follicle while hyper-methylation in corpus luteum. However, PI.1, the exclusive promoter responsible for residual CYP19 gene expression in corpus luteum, was found to be hypermethylated. Analysis of histone modifications using ChIP assay revealed that the distal promoter (PI.1) of CYP19 gene is ~40-fold more enriched with acetylated Histone H3 in corpus luteum than in the large follicle. This indicates that PI.1 chromatin was more accessible for transcription in corpus luteum as compared to large follicles. The chromatin accessibility for the proximal promoter (PII) in the preovulatory stage tends to be higher than the luteal tissue. However, the difference was not found to be significant. In vitro experiments showed the similar results. In conclusion, results of the present study suggests that tissue-specific methylation status of PII and chromatin remodeling through histone modifications of PI.1, coincides with the changes in expression of CYP19 gene and thus are the regulatory mechanism controlling its tissue-specific expression and promoter activity during folliculogenesis and luteinization. Estrogen Promotes the Development of Mouse Cumulus Cells in Coordination with Oocyte-Derived GDF9 and BMP15. Sugiura K et al. The differentiation and function of cumulus cells depend upon oocyte-derived paracrine factors, but studies on the estrogen receptor knockout mice suggested that estrogen also participates in these processes. This study investigates the possible coordination of estrogen and oocytes in the development and function of cumulus cells using cumulus expansion and the expression of transcripts required for expansion as functional endpoints. Preantral granulosa cell-oocyte complexes developed in vitro with 17?estradiol (E2) exhibited increased levels of cumulus expansion and Has2 transcripts, encoding hyaluronan synthase 2, compared with those developed without E2. Moreover, cumulus cell-oocyte complexes (COCs) isolated from antral follicles and maintained in culture without E2 exhibited reduced cumulus expansion and Has2 mRNA levels compared with freshly isolated COCs. Exogenous E2, provided during the maintenance culture, alleviated these deficiencies. However, when oocytes were removed from COCs, E2 supplementation did not maintain competence to undergo expansion; the presence in culture of either fully grown oocytes or recombinant growth differentiation factor 9 (GDF9) was required. Recombinant bone morphogenetic protein 15, but not fibroblast growth factor 8, augmented the GDF9 effect. Oocytes or GDF9 suppressed cumulus cell levels of Nrip1 transcripts encoding nuclear receptor-interacting protein 1, a potential inhibitor of estrogen receptor signals. Therefore, E2 and oocyte-derived paracrine factors GDF9 and bone morphogenetic protein 15 coordinate to promote the development of cumulus cells and maintain their competence to undergo expansion. Furthermore, suppression of Nrip1 expression in cumulus cells by oocyte may be one mechanism mediating cross talk between oocyte and E2 signals that promotes follicular development. The isolation and cloning of a full-length cDNA insert complementary to mRNA encoding human aromatase system cytochrome P-450 was reported by Corbin et al. (1988) The insert contains an open reading frame encoding a protein of 503 amino acids. This gene is a member of the cytochrome P-450 gene superfamily, because the sequence contains regions of marked homology to those of other members, notably a putative membrane-spanning region, I helix, Ozols, and heme-binding regions. | ||||
| Expression regulated by | FSH, LH, Steroids, Growth Factors/ cytokines, Eicosanoids, activin, progestin melatonin | ||||
| Comment | Transcriptional regulation of CYP19 by cohesin-mediated chromosome tethering in human granulosa cells. Kotomura N et al. (2021) Human CYP19 spans a region of chromosome 15 of approximately 130 kb and encodes aromatase, an enzyme required for estrogen synthesis. In the human granulosa cell-line KGN, there are seven open chromatin regions within the CYP19 locus. In this study, we demonstrate that two of these regions ~40 kb upstream and ~15 kb downstream of the CYP19 promoter are cohesin-loading sites, physically interacting with the promoter to negatively and positively regulate transcription, respectively. These observations suggest that CYP19 expression is controlled by a balance between the upstream silencer and downstream enhancer. When cohesin is depleted, CYP19 expression is elevated since the silencer is 2.5-fold further from the promoter than the enhancer and most likely depends on cohesin-mediated tethering to influence expression.//////////////////Melatonin stimulates aromatase expression and estradiol production in human granulosa-lutein cells: relevance for high serum estradiol levels in patients with ovarian hyperstimulation syndrome. Cheng JC et al. (2020) Ovarian hyperstimulation syndrome (OHSS) is one of the most life-threatening and potentially fatal complications associated with controlled ovarian hyperstimulation (COH) during in vitro fertilization (IVF) treatment. Although the pathogenesis of OHSS remains unclear, elevated serum estradiol (E2) levels before human chorionic gonadotropin (hCG) administration are associated with the risk of OHSS. The pineal hormone melatonin and its receptors are expressed in human granulosa cells and have been shown to stimulate E2 production. However, the effect of melatonin on the expression of aromatase, an enzyme responsible for a key step in the biosynthesis of E2, in human granulosa cells remains to be determined. Here, we demonstrate that melatonin upregulates aromatase expression in primary cultured human granulosa-lutein (hGL) cells through the melatonin receptor-mediated PKA-CREB pathway. Using a mouse model of OHSS, we demonstrate that administration of the melatonin receptor inhibitor luzindole inhibits the development of OHSS. In addition, the expression of ovarian aromatase and serum E2 levels are upregulated in OHSS mice compared to control mice, but this upregulation is attenuated by inhibition of the function of melatonin. Moreover, clinical results reveal that aromatase expression levels are upregulated in hGL cells from OHSS patients. Melatonin and E2 levels in the follicular fluid are significantly higher in OHSS patients than in non-OHSS patients. Furthermore, melatonin levels are positively correlated with E2 levels in follicular fluid. This study helps to elucidate the mechanisms mediating the expression of aromatase in hGL cells and provides a potential mechanism explaining the high E2 levels in patients with OHSS.////////////////// The effects of levonorgestrel on FSH-stimulated primary rat granulosa cell cultures through gene expression profiling are associated to hormone and folliculogenesis processes. Lira-Albarrán S et al. (2016) Levonorgestrel (LNG), a synthetic progestin, is used in emergency contraception (EC). The mechanism is preventing or delaying ovulation at the level of the hypothalamic pituitary unit; however, little knowledge exists on LNG effects at the ovary. The aim of this study was to identify the effects of LNG on FSH-induced 17β-estradiol (E2) production, including LNG-mediated changes on global gene expression in rat granulosa cells (GC). Isolated GC from female Wistar rats were incubated in vitro in the presence or absence of human FSH and progestins. At the end of incubations, culture media and cells were collected for E2 and mRNA quantitation. The results showed the ability of LNG to inhibit both hFSH-induced E2 production and aromatase gene expression. Microarray analysis revealed that LNG treatment affects GC functionality particularly that related to folliculogenesis and steroid metabolism. These results may offer additional evidence for the mechanisms of action of LNG as EC.////////////////// Activin stimulates CYP19A gene expression in human ovarian granulosa cell-like KGN cells via the Smad2 signaling pathway. Surnamenomura G et al. Activin, a transforming growth factor ?family member, has a wide range of physiological roles during embryonic development and organogenesis. In the ovary, activin, secreted from ovarian granulosa cells, not only acts on the pituitary gland to regulate the gonadotropin secretion from the pituitary gland in an endocrine manner but also acts on granulosa cells in a paracrine/autocrine manner to regulate folliculogenesis. Previously, we showed that activin signals through activin type IB receptor (ActRIB) and up-regulates follicle-stimulating hormone receptor expression and P450 aromatase activity in human ovarian granulose cell-like KGN cells. In the current study, we demonstrate the direct involvement of Smad2 as a downstream signal mediator of ActRIB in the transcriptional regulation of the P450 aromatase gene (CYP19A) in KGN cells. Upon activin stimulation, Smad2 activation and an increase in P450 aromatase messenger RNA (mRNA) were observed in KGN cells. Interestingly, Smad2 phosphorylation correlated well with the increase in P450 aromatase mRNA. Reciprocally, knockdown of Smad2 mRNA in KGN cells led to a decrease in the P450 aromatase mRNA expression, suggesting that Smad2 regulates CYP19A gene expression. Further analysis of CYP19A promoter activity revealed that the 5' upstream region between -2069 and -1271 bp is required for the activation by Smad2. Finally, we provide compelling evidence that Smad2 shows follicular stage-specific expression, which is high in granulosa cells of preantral or early antral follicles in mice. Our results suggest that activin signaling through the ActRIB-Smad2 pathway plays a pivotal role in CYP19A expression and thus in follicular development. Changes in Histone Modification and DNA Methylation of the StAR and Cyp19a1 Promoter Regions in Granulosa Cells Undergoing Luteinization during Ovulation In Rats. Lee L et al. The ovulatory LH surge induces rapid up-regulation of steroidogenic acute regulatory (StAR) protein and rapid down-regulation of aromatase (Cyp19a1) in granulosa cells (GCs) undergoing luteinization during ovulation. This study investigated in vivo whether epigenetic mechanisms including histone modifications are involved in the rapid changes of StAR and Cyp19a1 gene expression. GCs were obtained from rats treated with equine chorionic gonadotropin (CG) before (0 h) and after human (h)CG injection. StAR mRNA levels rapidly increased after hCG injection, reached a peak at 4 h, and then remained higher compared with 0 h until 12 h. Cyp19a1 mRNA levels gradually decreased after hCG injection and reached their lowest level at 12 h. A chromatin immunoprecipitation assay revealed that levels of histone-H4 acetylation (Ac-H4) and trimethylation of histone-H3 lysine-4 (H3K4me3) increased whereas H3K9me3 and H3K27me3 decreased in the StAR promoter after hCG injection. On the other hand, the levels of Ac-H3 and -H4 and H3K4me3 decreased, and H3K27me3 increased in the Cyp19a1 promoter after hCG injection. Chromatin condensation, which was analyzed using deoxyribonuclease I, decreased in the StAR promoter and increased in the Cyp19a1 promoter after hCG injection. A chromatin immunoprecipitation assay also showed that binding activities of CAATT/enhancer-binding protein ?to the StAR promoter increased and binding activities of phosphorylated-cAMP response element binding protein to the Cyp19a1 promoter decreased after hCG injection. These results provide in vivo evidence that histone modifications are involved in the rapid changes of StAR and Cyp19a1 gene expression by altering chromatin structure of the promoters in GCs undergoing luteinization during ovulation. The pre-ovulatory luteinizing hormone surge is followed by down-regulation of CYP19A1, HSD3B1, and CYP17A1 and chromatin condensation of the corresponding promoters in bovine follicles. Nimz M et al. The pre-ovulatory luteinizing hormone (LH) surge induces an extensive molecular, physiological, and morphological reorganization of the bovine follicle. This study was designed to elucidate if chromatin modulation is involved in the LH-induced gene regulation. Granulosa and theca of well-characterized large bovine follicles were isolated before and after the LH surge. CYP19A1, HSD3B1, and CYP17A1 transcripts, which encode key enzymes of steroid hormone biosynthesis, were quantified by real-time PCR (qPCR) and the degree of chromatin condensation was determined by DNase I protection assays. After LH, granulosa-specific CYP19A1 and theca-specific CYP17A1 transcripts were almost completely down-regulated. Also, the abundance of HSD3B1 transcripts was reduced. The promoter chromatin of HSD3B1 and particularly of CYP19A1 was significantly less accessible to DNAse I in both cell types after LH, whereas the chromatin accessibility of the CYP17A1 promoter changed only in the theca. Correlation analysis revealed partly, highly significant negative correlations between transcript abundance and protection from DNase I digestion of the corresponding chromatin. The data strongly suggest that LH induces cell type- and gene-specific chromatin condensation in the pre-ovulatory bovine follicle. This epigenetic mechanism might be involved in the pre-ovulatory down-regulation of genes. Mol. Reprod. Dev. ? 2010 Wiley-Liss, Inc. Different Promoter Usage for CYP19 Gene Expression In Buffalo Ovary And Placenta. Deepti A et al. Aromatase is the key enzyme for estrogen biosynthesis and is coded by CYP19 gene. The expression of CYP19 gene is regulated in tissue-specific manner by alternate use of different promoters. In this study, we have analyzed tissue-specific expression and their regulation of CYP19 gene in preovulatory and postovulatory stages of buffalo (Bubalus bubalis) ovary and placenta. RT-PCR analysis showed that the CYP19 gene expression was significantly (p<0.05) higher in granulosa cells of large follicles as compared to the other tissues. The transcript analysis and transcriptional start site identified by 5' RLM RACE for CYP19 expression indicated different transcriptional start sites within the different sized follicles during folliculogenesis. Sequence analysis showed that the transcription start site of transcript isolated from buffalo granulosa cells of small follicles was 37 bases upstream of the transcript isolated from granulosa cells of large follicles. However, both the transcripts were found to be derived from proximal promoter II. Difference in the transcriptional start site indicates the different promoter sequence usage in granulosa cells of different sized follicles. Further, in silico analysis of the difference in promoter sequence based on the 5'UTRs isolated from granulosa cells of small follicles (151 bases) and large follicles (114 bases) showed that consensus sequence for certain important trans-elements (viz., TATA Binding Protein, E2F and CAAT Binding Protein) would lie in the promoter sequence isolated from the granulosa cells of large follicles. These transcription factors may be involved in regulation of CYP19 gene expression in ovary, either directly or indirectly. The difference in the size of 5'UTR among the granulosa cells of ovary reflects the possible mechanism for the differential regulation of CYP19 gene during development. The transcripts isolated from buffalo corpus luteum and placental cotyledons were having same 5'UTR comprises of 168 bases and found to be derived from PI.1. Estimates of CYP19 gene transcript concentration in the different tissues revealed that the CYP19 gene expression in granulosa cells is predominantly regulated by PII and to a minor extent by PI.1. However, PI.1 is almost exclusively responsible for CYP19 gene expression in placenta and residual expression in corpus luteum. In order to understand the complex CYP19 gene regulation in these tissues, further studies are needed to elucidate the activity of different promoters and define regulatory elements for binding of transcription factors. | ||||
| Ovarian localization | Oocyte, Cumulus, Granulosa, Theca, Luteal cells | ||||
| Comment | Estrogen Is Not Directly Required for Oocyte Developmental Competence Huynh K, et al . Oocyte maturation and ovulation require a coordinated interaction between gonadotrophins, steroid hormones and growth factors. The extent to which estrogen is required in this process, however, remains unclear. To better understand the role of estrogen in maintaining developmental competence of mammalian oocytes, we studied the aromatase knockout (ArKO) mouse which has been genetically engineered to be incapable of synthesising endogenous estrogen. Previous studies have established that ArKO female mice are anovulatory with ovaries that progressively degenerate, developing haemorrhagic cystic follicles. In young ArKO females, however, apparently healthy follicles and oocytes have been observed. We investigated if these oocytes could be induced to ovulate, then mature, fertilise and develop in vitro. Following a standard superovulation protocol, ArKO oocytes did not ovulate. When recovered manually from the ovary, however, ArKO oocytes successfully progressed through in vitro maturation, fertilisation and development to the blastocyst stage, at the same rate as wildtype and heterozygote littermates. Therefore it appears that estrogen is not required for the production and growth of oocytes capable of maturation and complete pre-implantation development but is required for continued follicle growth and feedback regulation of ovulation. | ||||
| Follicle stages | Primordial, Secondary, Antral, Preovulatory, Corpus luteum | ||||
| Comment | Development of Steroid Signaling Pathways during Primordial Follicle Formation in the Human Fetal Ovary. Fowler PA et al. Context: Ovarian primordial follicle formation is critical for subsequent human female fertility. It is likely that steroid, and especially estrogen, signaling is required for this process, but details of the pathways involved are currently lacking. Objective: The aim was to identify and characterize key members of the steroid-signaling pathway expressed in the second trimester human fetal ovary. Design: We conducted an observational study of the female fetus, quantifying and localizing steroid-signaling pathway members. Setting: The study was conducted at the Universities of Aberdeen, Edinburgh, and Glasgow. Patients/Participants: Ovaries were collected from 43 morphologically normal human female fetuses from women undergoing elective termination of second trimester pregnancies. Main Outcome Measures: We measured mRNA transcript levels and immunolocalized key steroidogenic enzymes and steroid receptors, including those encoded by ESR2, AR, and CYP19A1. Results: Levels of mRNA encoding the steroidogenic apparatus and steroid receptors increased across the second trimester. CYP19A1 transcript increased 4.7-fold during this period with intense immunostaining for CYP19A detected in pregranulosa cells around primordial follicles and somatic cells around oocyte nests. ESR2 was localized primarily to germ cells, but androgen receptor was exclusively expressed in somatic cells. CYP17A1 and HSD3B2 were also localized to oocytes, whereas CYP11A1 was detected in oocytes and some pregranulosa cells. Conclusions: The human fetal ovary expresses the machinery to produce and detect multiple steroid signaling pathways, including estrogenic signaling, with the oocyte acting as a key component. This study provides a step-change in our understanding of local dynamics of steroid hormone signaling during the key period of human primordial follicle formation. Estrogen Actions on Follicle Formation and Early Follicle Development. Britt KL, et al . Estradiol 17beta (E2) affects late follicular development whilst primordial follicle differentiation and early activation are thought to be independent of E2. To test this hypothesis we compared numbers of primordial and primary follicles in wildtype and E2 deficient, Aromatase knockout (ArKO) mice, and the immunohistochemical staining or mRNA expression of Mullerian inhibiting substance (MIS), Wilms tumour 1 (WT-1), and growth differentiation factor (GDF9), known to effect early follicular differentiation. Proliferating cell nuclear antigen (PCNA) staining was a marker of proliferative index. The effects of E2 replacement for 3 wk in 7 wk old ArKO and wildtype mice on these parameters were also tested. ArKO mice had reduced numbers of primordial and primary follicles compared to wildtype (63%, p<0.001 and 60%, p=0.062 respectively). This reduction was not corrected by E2 treatment, suggesting that E2 affects the initial formation or activation of primordial follicles. There was a significant increase in the diameters of the oocytes in primordial follicles of ArKO mice compared to wildtype. There were no differences in the immunostaining of MIS, WT-1 and PCNA in primordial and primary follicles between wildtype and ArKO mice. The only difference was as a consequence of Sertoli and Leydig cells which develop in ovaries of ArKO mice. GDF9 mRNA expression was markedly increased in ArKO ovaries. E2 treatment restored the ovarian follicular morphology in ArKO mice, and consequently the immunostaining patterns, but had no effect on early follicle numbers. In conclusion, E2 has a role in controlling the size of the oocyte and primordial follicle pool in mice. Identification of regulatory elements in the Cyp19 proximal promoter in rat luteal cells. Stocco C et al. The cytochrome P450 aromatase (Cyp19) gene encodes an enzyme of crucial importance in the synthesis of estradiol. Estradiol is luteotropic in the rat. In this species, luteal Cyp19 expression increases progressively during pregnancy and falls before parturition. The mechanisms that control these changes are unknown. Using gel shift assays, we sought to identify the promoter regions that control Cyp19 expression in the rat corpus luteum (CL). The Cyp19 promoter contains a cAMP response element-like sequence (CLS), two nuclear receptor elements half sites (NREs), a GATA binding site, a Yin Yang-1 (YY1) response element, and an activation protein 3 (AP3) binding site. Nuclear extracts were obtained from CL of rats on days 4, 15, and 23 of pregnancy and from the ovaries of immature rats treated with vehicle or a hormone that induces Cyp19 expression in the follicles. CLS was active in immature ovaries but inactive in the CL of pregnant rats, whereas binding to NREs and GATA was observed in both tissues. YY1 was inactive in all samples tested. In the CL, AP3 binding was higher on day 15 of pregnancy when compared with day 4 and day 23 but it was absent in ovaries of immature rats, whereas luteinization increased AP3 binding activity. Mutation of the AP3 site blunted the stimulation of Cyp19 promoter activity in granulosa cells. Our results indicate that CLS is active only in follicles; whereas in the CL, binding to the GATA, NRE, and AP3 sites associates with changes in Cyp19 expression, suggesting that they control Cyp19 promoter activity in luteal cells. | ||||
| Phenotypes |
PCO (polycystic ovarian syndrome) |
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| Mutations |
8 mutations
Species: human
Species: mouse
Species: rat
Species: human
Species: human
Species: human
Species: mouse
Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | July 22, 1999, midnight | by: |
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