A polymorphic tetranucleotide repeat in the CYP19 gene and male breast cancer

The CYP19 gene codes for the aromatase enzyme that is involved in the synthesis of oestrogens. This case–control study examines the relationship between a tetranucleotide repeat sequence in the CYP19 gene and the development of male breast cancer. No significant differences were found between male breast cancer cases and controls. © 2000 Cancer Research Campaig

Analysis of aromatase (CYP19) gene in Iranian women with endometriosis

Endometriosis is a chronic, inflammatory, estrogen dependent disease that affects up to 10% of all women of fertile age. It is characterized by the presence and proliferation of functional endometrial glands and stroma outside the uterine cavity. The aim of this study was to assess whether intron 4 (TTTA)n repeat and TCT deletion/insertion polymorphisms of CYP19 gene are associated with endometriosis in northern Iran. This study involved 110 patients with endometriosis and 200 healthy controls, who were genotyped for (TTTA) repeats in the fourth intron of the CYP19 gene. Genomic DNA from patients and controls was genotyped by polymerase chain reaction (PCR). A total of eight alleles were observed in our study population, ranging from 7 repeats to 13 repeats. (TTTA) repeat lengths of 69 were classified as short (S), and those P10 were classified as long (L). Compared to women who possessed the S/S genotype, those who carried L/L (OR, 5.56; 95% CI, 3.33–9.29) had significantly increased risk of endometriosis. There was a significant trend between L/L genotype and higher stage of endometriosis (P <0.001). In conclusion, a significant association was identified between endometriosis and the CYP19 gene polymorphism, with endometriosis having longer CYP19 repeat lengths than control subjects. The strong association of CYP19 gene polymorphism with high-stage endometriosis suggests that CYP19 may have a prognostic implication.Keywords: CYP19; Aromatase; Endometriosis; Gene polymorphismThe Egyptian Journal of Medical Human Genetics (2013) 14, 165–16

Polimorfismos do gene CYP19 : associação com cancro da mama e com concentrações séricas de hormonas sexuais em mulheres pós-menopáusicas

Dissertação de mestrado em Ginecologia Oncológica, apresentada à Faculdade de Medicina da Universidade de Coimbr

The molecular genetics of polycystic ovary syndrome.

Imperial Users onl

Estudio citogenético y molecular en personas con conducta transexual

[Resumen]La transexualidad es un desorden de la identidad de género con etiología multifactorial en donde están implicados tanto factores del neurodesarrollo como genéticos. En esta investigación se analizó la vulnerabilidad genética de la transexualidad en un grupo de transexuales FtM (female to male) y MtF (male to female) mediante el estudio del cariotipo y el análisis de cuatro regiones polimórficas de los genes ERβ, AR, CYP19A1 y CYP17A1 en una población de 715 transexuales y 844 controles. Resultados: No se encontró una alteración cariotípica específica de la transexualidad, aunque la aneuploidía fue 4,5 veces mayor en la población transexual (2,4%) que en la población general (0,53%) (p = 1E-06). La prevalencia del síndrome de Klinefelter fue significativamente mayor que la esperada (p = 0,022031). El polimorfismo del ERβ fue significativamente más largo en FtM que en el grupo control femenino (p = 0,002). La probabilidad de desarrollo de la transexualidad fue mayor en los individuos FtM homocigotos LL (odds ratio: 2,001 [1,15-3,46]). El polimorfismo CYP17 MspA1 mostró una distribución alélica dependiente del sexo en la población transexual FtM>MtF (p = 0,041), al contrario que la población control, lo que indica una asociación entre este polimorfismo y la transexualidad.[Resumo]A transexualidade é unha desorde da identidade de xénero con etioloxía multifactorial onde están implicados tanto factores do neurodesenvolvemento coma xenéticos. Nesta investigación analizouse a vulnerabilidade xenética da transexualidade nun grupo de transexuais FtM (female to male) e MtF (male to female), a través do estudo citoxenético do cariotipo e da análise molecular de catro rexións polimórficas dos xenes ERβ, AR, CYP19A1 e CYP17A1 nunha populación de 715 transexuais e 844 controis. Resultados: Non foi encontrada unha alteración cariotípica específica da transexualidade, mais a prevalencia da aneuploidía foi 4,5 veces superior na populación transexual (2,4%) que na populación xeral (0,53%) (p = 1E-06). A síndrome de Klinefelter mostrou unha prevalencia significativamente maior que a esperada (p = 0,022031). Canto á análise molecular, o número de repeticións do polimorfismo ERβ foi significativamente maior en FtM que no grupo control feminino (p = 0,002) e a probabilidade de desenvolvemento da transexualidade foi maior nos individuos FtM homocigotos para o alelo longo (LL) (odds ratio: 2,001 [1,15-3,46]). A respecto do polimorfismo CYP17 MspA1, foi achada unha distribución alélica dependente do sexo FtM>MtF (p = 0,041), ao contrario do que na populación control, o que indica unha asociación entre este polimorfismo e a transexualidade.[Abstract]Transsexualism is a gender identity disorder with a multifactorial etiology. Both neurodevelopmental and genetic factors seem to be implicated. The aim of this study was to investigate the possible influence of genetic factors on the etiology of FtM (female to male) and MtF (male to female) transsexualism by analysing the karyotypes and performing the molecular analysis of four polymorphisms on genes ERβ, AR, CYP19A1 and CYP17A1. We carried out the analysis in 715 transsexuals and 844 controls. Results: No karyotype aberration has been linked to transsexualism but aneuploidy prevalence (2.4%) appears to be higher than in the general population (0.53%) (p = 1E-06). The prevalence of Klinefelter syndrome is also significantly higher (p = 0.022031) than in the general population. FtMs differed from control females with respect to ERβ (p = 0.002). Repeats in ERβ were significantly higher in FtMs than in female controls, and the likelihood of developing transsexualism was higher in the subjects (LL) (odds ratio: 2.001 [1.15-3.46]). Regarding CYP17 MspA1, the allelic frequencies differed significantly between FtMs and MtFs (p = 0.041) but were not sex-dependent in the control population. The data support the association between this polymorphism and transsexualism

Understanding Aromatase: A Mechanistic Basis for Drug Interactions and New Inhibitors

Indiana University-Purdue University Indianapolis (IUPUI)Aromatase is the cytochrome P450 enzyme that converts androgens to estrogens. Aromatase is the target of the aromatase inhibitor class of drugs widely used to treat estrogen-mediated conditions including breast cancer. Little is known about the role of this enzyme in drug metabolism or in drug interactions. Since this lack of knowledge has been an impediment to optimal therapy, it is important to understand these roles of aromatase. Therefore, a comprehensive series of studies was carried out to characterize its ability to metabolize drugs and its susceptibility to inhibition by xenobiotics. The overall objective of this work was to better understand the interactions of small molecules with aromatase and to use this new knowledge to predict aromatase-mediated drug interactions and anticipate novel molecular structures that interact with the enzyme. Aromatase was shown to be a drug metabolizing enzyme able to metabolize methadone both in vitro (Km of 314 μM) and in vivo (22% of methadone clearance). A number of novel aromatase inhibitors that employ diverse kinetic mechanisms were identified. These include a potent competitive inhibitor: norendoxifen (Ki of 35 nM), two non-competitive inhibitors: endoxifen (Ki of 4.0 μM) and N-desmethyl-tamoxifen (Ki of 15.9 μM), a mechanism-based inhibitor: methadone (KI of 40.6 ± 2.8 μM; kinact of 0.061 ± 0.001 min-1), and a stereoselective inhibitor: naringenin (IC50s of 2.8 μM for (R)-enatiomer and 1.4 μM for (S)-enatiomer). Through investigation of the structure-potency relationships so discovered, a series of new biochemical structures to be exploited as aromatase inhibitors were identified. These studies have identified new roles for aromatase as a catalyst for methadone metabolism and as a mediator of the effects of tamoxifen by demonstrating that a number of its metabolites can act as aromatase inhibitors. This work also provides a new mechanistic framework for the design of novel aromatase inhibitors that can be used in breast cancer. Overall, the data suggest ways to more consistently treat breast cancer with current medications, to better anticipate drug interactions, and therefore to improve the quality of life of patients in ways that minimize side effects, while optimizing therapeutic benefits, in each person treated