Dados do Trabalho

Title

THE ROLE OF BRCA GENE MUTATION IN INFERTILITY PATIENTS

Objective

The objective of the present study was to assess existing scientific evidence of the impacts of mutation in the BRCA gene and infertility.

Methods

This bibliographic review was elaborated through a search in the PUBMED database from the descriptors “fertility”; “infertility”, “BRCA” and “ovarian reserve”, from the last 5 years, which included reviews, clinical trials, and randomized controlled trials.

Results

Evidence demonstrates that when compared with controls, women who carry a mutation in the BRCA1 gene produced fewer oocytes 7.4 (95% CI, 3.1–17.7) versus 12.4 (95% CI, 10.8–14.2); p = 0.025), indicating that the BRCA gene may be related to gametogenesis. It has also been shown that their oocytes not only have a higher frequency of impaired repair mechanisms, but also accelerated DNA double strand breakage. This condition may be associated with a decreased ability to neutralize genotoxic stress, leading to an accelerated loss of ovarian reserve after the accumulation of these DNA breaks in the oocyte, and consequently, premature ovarian failure. Furthermore, after adjusting for age and BMI, significantly lower levels of anti-Mullerian hormone (AMH), a biomarker that represents a woman's reproductive competence, were found in carriers of the mutated BRCA1 gene (P=0.02), but not in carriers of the mutated BRCA2 gene (P=0.94) when compared to controls. However, the study states that low serum concentrations of AMH have not been shown to affect natural fecundity and fertility in BRCA mutation carriers below 30 years of age, affecting only older patients. With regard to preservation of fertility, it has been shown that after ovarian stimulation, carriers of the mutation in the BRCA gene had a lower number of mature oocytes and follicular reserve. It was also demonstrated that the average number of oocyte production in these patients is lower when compared to non-mutation carriers. Furthermore, studies show that BRCA mutation carriers have higher rates of poor ovarian response compared to BRCA mutation negative patients undergoing ovarian hyperstimulation. It is also important to mention that studies point to ovarian aging induced by chemotherapy, which occurs by inducing the breakage of DNA double strand repair in primordial follicular oocytes and thus triggers massive apoptotic death. Despite this, it is noteworthy that recent studies have shown that many follicles can remain free of apoptosis, suggesting that there is reversal of chemoinduction.

Conclusion

In conclusion, it was observed that women with a BRCA1 gene mutation produced smaller numbers of oocytes and faster double-strand DNA breaks, which resulted in loss of ovarian reserve after the accumulation of these breaks and consequently premature ovarian failure. The low concentrations of AMH have not been shown to affect natural fecundity and fertility in patients with a BRCA mutation younger than 30 years old, affecting only patients with more advanced age. Moreover, it has been shown that after ovarian stimulation, patients with a mutation in the BRCA gene have a lower number of mature oocytes and follicular reserve. However, it is important to understand the limitations of studies in healthy women with BRCA mutations, as they may represent only a small part of a larger, complex problem. Women who develop cancer as a result of a mutation in the BRCA gene and receive chemotherapy have ovaries aging due to induction of DNA double-stranded repair breakage in primordial follicular oocytes resulting in massive apoptotic death.

Keywords

“fertility”;”infertility”; “BRCA” and “ovarian reserve”.