4 research outputs found
Direct Steroidal Regulation and Inhibitory Mode of Action of Gonadotropin-inhibitory Hormone (GnIH or RFRP-3) in Immortalized Hypothalamic Cell Models
Fertility is dependent on the precisely orchestrated communication of an array of effectors within the reproductive axis, all of which impinge on gonadotropin-releasing hormone (GnRH) neurons. A novel reproductive inhibitor was identified in avian species and growing evidence suggests that the functional mammalian homologue, RFamide-related peptide-3 (RFRP-3 or GnIH) can inhibit GnRH neuronal activity and gonadotropin release. To date, the regulation and effects of RFRP-3 at the hypothalamic level are poorly understood. We established an Rfrp-expressing neuronal cell model to investigate the mechanisms of transcriptional regulation of the genes for RFRP and the RFRP receptor, GPR147 by dexamethasone and estradiol. We show that the RFRP system is a direct target for stress-associated transcriptional regulation. Further, employing a novel GnRH-secreting cell line, we report that GnRH neurons express Gpr147 and RFRP-3 represses the transcription of GnRH. These data further our understanding of the level and regulatory effects at which RFRP-3 modulates reproduction.MAS
The Screen Project: Guided Direct-To-Consumer Genetic Testing for Breast Cancer Susceptibility in Canada
There is limited information of the outcomes of direct-to-consumer testing for BRCA1 and BRCA2 mutations. The Screen Project was initiated in 2017 to offer BRCA1 and BRCA2 genetic screening to all Canadians over the age of 18 who wish to know their mutation status. Patients enrolled in the study from 2017 to 2019 and were followed for one year after the receipt of a genetic test result. Study subjects registered online and were sent a saliva sample kit, which was shipped to the reference laboratory. Pre-test genetic counselling and counselling for mutation-negative subjects was optional and at the individual’s discretion. There were 1269 tested individuals between March 2017 and January 2019. A total of 1157 (93%) were women and 87 (7%) were men. Sixty-six percent had a first- or second-degree relative with breast or ovarian cancer. Of the 1269 tested individuals, 30 (2.4%) had a pathogenic mutation in BRCA1 or BRCA2 (20 women and 10 men). Seventy-five percent of the female mutation carriers underwent a bilateral mastectomy and/or salpingo-oophorectomy within a year of receiving a positive result. Genetic counselling was available at no cost to all participants but was requested by only 5% of the non-carriers. The study subjects expressed a high degree of satisfaction with the process
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Contraceptive use and the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation
Background BRCA1 and BRCA2 (BRCA) mutation carriers face a high lifetime risk of developing ovarian cancer. Oral contraceptives are protective in this population; however, the impact of other types of contraception (e.g. intrauterine devices, implants, injections) is unknown. We undertook a matched case-control study to evaluate the relationship between type of contraception and risk of ovarian cancer among women with BRCA mutations. Methods A total of 1733 matched pairs were included in this analysis. Women were matched according to year of birth, date of study entry, country of residence, BRCA mutation type and history of breast cancer. Detailed information on hormonal, reproductive and lifestyle exposures were collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with each contraceptive exposure. Results Ever use of any contraceptive was significantly associated with reduced risk of ovarian cancer (OR = 0.62; 95% CI 0.52-0.75; P < 0.0001), which was driven by significant inverse associations with oral contraceptives (OR = 0.66; 95% CI 0.54-0.79; P < 0.0001) and contraceptive implants (OR = 0.30; 95% CI 0.12-0.73; P = 0.008). We observed a similar effect with use of injections (OR = 0.37; 95% CI 0.10-1.38; P = 0.14), but this did not achieve significance. No significant associations were observed between patterns of intrauterine device use and risk of ovarian cancer. Conclusions These findings support a protective effect of oral contraceptives and implants on risk of ovarian cancer among women with BRCA mutations. The possible protective effect of injections requires further evaluation