Assessment of ovarian reserve and reproductive outcomes inBRCA1orBRCA2mutation carriers

Abstract

IntroductionThe clinical impact on fertility in carriers of BRCA1 and BRCA2 mutations remains unclear. The aim of this study was to assess ovarian reserve as measured by anti-mullerian hormone levels in BRCA1 or BRCA2 mutation carriers, as well as to investigate the impact of anti-mullerian hormone levels on reproductive outcomes.MethodsThe study involved a cohort of women who tested positive for BRCA1 and BRCA2 screening or were tested for a BRCA1 or BRCA2 family mutation. Blood samples were collected for anti-mullerian hormone analysis and the reproductive outcomes were analyzed after a mean follow-up of 9 years. Participants were classified into BRCA mutation-positive versus BRCA mutation-negative. Controls were healthy relatives who tested negative for the family mutation. All patients were contacted by telephone to collect data on reproductive outcomes. Linear regression was used to predict anti-mullerian hormone levels by BRCA status adjusted for a polynomial form of age.ResultsResults of anti-mullerian hormone analysis and reproductive outcomes were available for 135 women (BRCA mutation-negative, n=66; BRCA1 mutation-positive, n=32; BRCA2 mutation-positive, n=37). Anti-mullerian hormone curves according to BRCA status and adjusted by age showed that BRCA2 mutation-positive patients have lower levels of anti-mullerian hormone as compared with BRCA-negative and BRCA1 mutation-positive. Among the women who tried to conceive, infertility was observed in 18.7% of BRCA mutation-negative women, in 22.2% of BRCA1 mutation-positive women, and in 30.8% of BRCA2 mutation-positive women (p=0.499). In the multivariable analysis, there were no factors independently associated with infertility.DiscussionBRCA2 mutation-positive carriers showed more diminished anti-mullerian hormone levels than BRCA1 mutation-positive and BRCA mutation-negative women. However, these differences do not appear to have a negative impact on reproductive outcome. This is important to consider at the time of reproductive counseling in women with BRCA1 or BRCA2 mutations.

Ovarian reserve of women with and without BRCA pathogenic variants: A systematic review and meta-analysis

“…One study apparently fulfilling inclusion criteria, categorized women as low risk due to a negative family history for breast and/or ovarian cancer, without a confirmation BRCA test, therefore it was excluded [ 23 ]. At the end of the screening, ten studies resulted eligible and were included in the meta-analysis [ 5 , 6 , 10 , [24] , [25] , [26] , [27] , [28] , [29] , [30] ]. The group populations of the ten selected studies, considered as upper limit 40 [ [24] , [25] , [26] ], 42 [ 6 ], and 45 years old [ 5 , [27] , [28] , [29] , [30] ].…”

Reproductive issues in carriers of germline pathogenic variants in the BRCA1/2 genes: an expert meeting

“…A major concern among BRCA1/2 pathogenic variant carriers is the potential higher risk of premature ovarian insufficiency (POI) [22,23]. Most of the available preclinical evidence suggests that BRCA mutations could directly accelerate ovarian aging, reducing the ovarian reserve both quantitatively and qualitatively [24][25][26][27][28][29]. BRCA1 and 2 are known to be involved in DNA repair mechanism, through ATM-mediated regulation of the DNA double-strand breaks (DSBs) repair [23,30].…”

“…Levels of anti-Müllerian hormone (AMH) are considered a quantitative marker of ovarian reserve, although not predictive of chances of spontaneous pregnancy [37]. In some studies, the levels of AMH were found to be significantly lower in women carrying pathogenic variants in BRCA1 [24][25][26]30] or BRCA2 [27,29] or both genes [28], while other studies reported no significant difference with controls [36,38]. Clinical studies describing a decreased oocyte quality in human carriers of BRCA pathogenic variants (i.e., an increase in aneuploidies) are still lacking, while age at natural menopause among BRCA carriers is difficult to ascertain, because of various types of selection bias, diverse control groups, and the small population of the studies [39][40][41][42].…”

Fertility preservation in patients with BRCA mutations or Lynch syndrome

“…In our search, 11 articles [17][18][19][20][21][22][23][24][25][26][27] considered anti-Mullerian hormone and antral follicular count as indexes of ovarian function in BRCA mutation carriers compared with wild-type controls (Table 1). In fact, anti-Müllerian hormone levels and antral follicular count are considered predictors of ovarian response during in vitro fertilization techniques, with lower levels suggestive of a poor response.…”

“…Several studies have validated anti-Müllerian hormone as a direct biomarker for ovarian aging, which reflects the decline in reproductive capacity. 29 30 In our search, we considered 11 studies [17][18][19][20][21][22][23][24][25][26][27] evaluating anti-Müllerian hormone levels as an index of the ovarian reserve, comparing BRCA carriers with wild-type controls. Four studies concluded that BRCA mutation carriers had lower levels of anti-Müllerian hormone compared with BRCA wild-type patients 17 20 22 23 while five studies had the opposite results, reporting BRCA patients who had higher anti-Müllerian hormone levels compared with BRCA wild-type patients.…”