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Comment |
Pregnancy-associated changes of Peroxisome Proliferator-Activated Receptor Delta (PPARD) and Cytochrome P450 Family 21 Subfamily A Member 2 (CYP21A2) expression in the bovine corpus luteum. Sakumoto R et al. (2020) We investigated gene expression profiles of the corpus luteum (CL) at the time of maternal recognition to evaluate the functional changes of the CL during early pregnancy in cows and help improve reproductive efficiency and avoid defective fetuses. Microarray analyses using a 15 K bovine oligo DNA microarray detected 30 differentially expressed genes and 266 differentially expressed genes (e.g., PPARD and CYP21A2) in the CL on pregnancy days 15 (P15) and 18 (P18), respectively, compared with the CL on day 15 (NP15) of non-pregnancy (n = 4 for each group). PPARD expression was the highest while the CYP21A2 expression was the lowest in P15 and P18 compared with that of NP15. These microarray results were validated by quantitative real-time PCR analysis. The addition of interferon-τ (IFNT) and supernatants derived from homogenized fetal trophoblast (FMP) increased ISG15 and MX1 expressions in the cultured luteal tissue (P < 0.01), but did not affect PPARD and CYP21A2 expressions. PPARD expression in the luteal tissue was stimulated (P < 0.05) by GW0742, known as a selective PPARD agonist, and PPARD ligands (i.e., arachidonic, linoleic and linolenic acids). In contrast, CYP21A2 mRNA expression was not affected by both agonist and ligands. The concentration of prostaglandin (PG) E2 and PGF2α decreased after GW0742 stimulation and increased after arachidonic acid stimulation (P < 0.05). The addition of GW0742 and arachidonic acid increased progesterone (P4) concentration. Collectively, these findings suggest that high expression levels of PPARD and low expression levels of CYP21A2 in the CL during early pregnancy may support P4 production by bovine luteal cells.//////////////////
21-Hydroxylase-Derived Steroids in Follicles of Nonobese Women Undergoing Ovarian Stimulation for in Vitro Fertilization (IVF) Positively Correlate With Lipid Content of Luteinized Granulosa Cells (LGCs) as a Source of Cholesterol for Steroid Synthesis. Amin M 2014 et al.
Context: Mineralocorticoid synthesis by the nonhuman primate periovulatory follicle enhances luteinization. Whether a similar event occurs in women undergoing in vitro fertilization (IVF) is unknown. Objective: The objective of the study was to determine whether human luteinized granulosa cells (LGCs) produce mineralocorticoids derived from 21-hydroxylase activity and also express mRNA for 21-hydroxylase and the mineralocorticoid receptor. Design: This was a prospective cohort study. Setting: The study was conducted at an academic center. Patients: LGC lipid content and follicle fluid (FF) hormone analysis was performed on 27 nonobese IVF women. LGCs from six additional nonobese IVF women were used for gene expression studies. Intervention: At oocyte retrieval, FF was aspirated from the first follicle (=16 mm in size) of each ovary and pooled LGCs were collected. Main Outcome Measures: FF steroid analysis was performed by liquid chromatography-tandem mass spectrometry. LGCs were stained with lipid fluorescent dye BODIPY FL C16 to estimate lipid content by confocal microscopy as a cholesterol source for steroidogenesis in vivo. Quantitative real-time PCR was performed using LGCs to detect 21-hydroxylase and mineralocorticoid receptor mRNA expression. Pearson correlation coefficients determined associations between FF steroid levels and LGC lipid content. Results: FF levels of the 21-hydroxylase-derived steroids, 11-deoxycorticosterone (39.97, median (13.94-63.02) ng/mL) and 11-deoxycortisol 11-deoxycorticosterone, 2.07 (0.69-5.01) ng/mL, along with the 21-hydroxylase precursor 17-hydroxyprogesterone (1268.21 (493.26-3558.39) ng/mL), positively correlated with LGC lipid content (84 ? 43 fluorescent units/sample) (P = .05, all steroids). 21-Hydroxylase and mineralocorticoid receptor mRNA expression was detected in LGCs. Conclusions: Human LGCs likely synthesize 21-hydroxylase-derived mineralocorticoids from cholesterol-containing lipid in vivo to promote postovulatory luteinization via mineralocorticoid receptor-mediated events.
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Mutations in Women with Polycystic Ovary Syndrome (PCOS). Settas N et al. The question of the contribution of CYP21A2 heterozygosity to the development of polycystic ovary syndrome (PCOS) has repeatedly been raised in the literature. The available data, however, do not offer a satisfactory answer. The discrepancy must be attributed, primarily, to the small number of subjects in the various studies, the type of selected phenotype, and the number of searched mutations. The aim of the study was to define the contribution of CYP21A2 heterozygous mutations to the pathogenesis of PCOS. We searched for 14 molecular defects of the CYP21A2 gene in 197 PCOS women, employing allele specific PCR. Androgen levels were determined at baseline by appropriate methodology in the follicular phase. PCOS women with 17-hydroxyprogesterone (17OHP) basal values >2 ng/ml and/or post-ACTH >10 ng/ml were excluded. Appropriate controls were included. The frequency of the CYP21A2 heterozygous mutations in PCOS women and in controls was 7.6% and 5.9%, respectively [p-value (PCOS vs. controls): 0.663]. Homozygosity for CYP21A2 gene defects was not detected. In conclusion, the contribution of CYP21A2 heterozygous mutations to the pathogenesis of PCOS is not substantiated by our data. Moreover, 17-hydroxyprogesterone values of < 10 ng/ml post-ACTH exclude homozygosity of CYP21A2 mutations.
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Mutations |
1 mutations
Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Non-Classic Adrenal Hyperplasia due to the Deficiency of 21-Hydroxylase and Its Relation to Polycystic Ovarian Syndrome. Pignatelli D 2013 et al.
Non-classic adrenal hyperplasia (NCAH) is a disease in which a partial deficiency of the steroidogenic enzyme 21-hydroxylase produces mild to moderate hyperandrogenemia, hirsutism, polycystic ovaries, oligomenorrhea or amenorrhea, insulin resistance, male pattern baldness and subfertility. The resemblances between NCAH and polycystic ovary syndrome (PCOS) are manifest, and a relation between the two has been sought by many authors trying to identify subtle alterations in the CYP21 gene transcription end-products as the cause or a contributing cause of PCOS. On the other hand, the differences that may differentiate these two diseases have also been the focus of research by many groups, searching for clinical markers that might help to distinguish the two conditions. Insulin resistance or the polycystic ovarian morphology once thought to be hallmarks of PCOS have been proven to exist also in NCAH. Obesity, not being a diagnostic criterion of either but being very prevalent in PCOS women is also present in many NCAH women, and hence is not helpful in the distinction between the two. And if it is a fact that women with NCAH have a higher prevalence of normal ovulation and lower likelihood of having an LH/FSH ratio >2 or polycystic ovaries, in comparison to PCOS, it is also true that even in those parameters overlap does exist. Besides 17-OH-progesterone, progesterone, androstenedione and testosterone are elevated in most NCAH cases, similarly to what occurs in PCOS patients. The only exception in fact is the level of 17-OH-progesterone and progesterone that are not significantly elevated in PCOS, at least not to the levels attained in NCAH. Our recommendation, thus, is that NCAH should be excluded in all women presenting with hirsutism, oligomenorrhea and infertility. A basal follicular phase 17-hydroxyprogesterone level should be used as a screening tool, regardless of the presence of polycystic ovaries or metabolic dysfunction; in the case of doubt, an ACTH stimulation test is recommended. Levels above 10 ng/ml (30 nmol/l), either basal or after stimulation should be considered as diagnostic of NCAH, and some of those patients, particularly the ones that are planning to conceive, should be genotyped, mainly with the purpose of genetic counseling. Treatment of NCAH women normally requires the use of the same anti-androgenic weapons as PCOS but some may benefit from the administration of small doses of glucocorticoids. Curiously, some studies have demonstrated that PCOS cases too may benefit from the administration of glucocorticoids.
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