The Impact of BRCA1- and BRCA2 Mutations on Ovarian Reserve Status

Abstract

This study aimed to investigate whether female BRCA1- and BRCA2 mutation carriers have a reduced ovarian reserve status, based on serum anti-Mullerian hormone (AMH) levels, antral follicle count (AFC) and ovarian response to ovarian hyperstimulation. A prospective, multinational cohort study was performed between October 2014 and December 2019. Normo-ovulatory women, aged 18-41 years old, applying for their first PGT-cycle for reason of a BRCA mutation (cases) or other genetic diseases unrelated to ovarian reserve (controls), were asked to participate. All participants underwent a ICSI-PGT cycle with a long-agonist protocol for controlled ovarian hyperstimulation. Linear and logistic regression models were used to compare AMH, AFC and ovarian response in cases and controls. Sensitivity analyses were conducted on BRCA1- and BRCA2 mutation carrier subgroups. Thirty-six BRCA mutation carriers (18 BRCA1- and 18 BRCA2 mutation carriers) and 126 controls, with mean female age 30.4 years, were included in the primary analysis. Unadjusted median AMH serum levels (IQR) were 2.40 (1.80-3.00) ng/ml in BRCA mutation carriers and 2.15 (1.30-3.40) ng/ml in controls (p = 0.45), median AFC (IQR) was 15.0 (10.8-20.3) and 14.5 (9.0-20.0), p = 0.54, respectively. Low response rate was 22.6% among BRCA mutation carriers and 9.3% among controls, p = 0.06. Median number of retrieved oocytes was 9 (6-14) in carriers and 10 (7-13) in controls, p = 0.36. No substantial differences were observed between BRCA1- and BRCA2 mutation carriers. Based on several biomarkers, no meaningful differences in ovarian reserve status were observed in female BRCA mutation carriers compared to controls in the context of ICSI-PGT treatment.

Keywords: Anti-Müllerian hormone; BRCA gene mutations; BRCA1; BRCA2; Ovarian reserve; Ovarian response.

Fig. 1

Study flowchart. a Flowchart for primary analyses, including only participants who completely fulfilled all in/exclusion criteria. b Flowchart for secondary (full) analyses, including subjects with protocol violations PGT, pre-implantation genetic testing; PCOS, polycystic ovarian syndrome; AMH, anti-Mullerian hormone; AFC, antral follicle count; FSH, follicle-stimulating hormone

Fig. 2

Scatterplot and boxplot representing serum AMH levels. PGT, preimplantation genetic testing; AMH, anti-Mullerian hormone. a Scatterplot representing serum AMH level (ng/ml) on a logarithmic scale by age (in years) in BRCA1 mutation carriers (n = 18, blue dots), BRCA2 mutation carriers (n = 18, pink dots) and controls (n = 126, white squares). The visualized lines are fit lines for BRCA1 mutation carriers (blue regression line, AMHBRCA1 = 7.58–0.17*age), BRCA2 mutation carriers (pink regression line, AMHBRCA2 = 7.54–0.15*age) and controls (black/dotted regression line, AMHcontrol = 4.63–0.07*age). b Boxplot representing median and interquartile ranges of female AMH serum levels (ng/ml) on a logarithmic scale in couples with PGT indication due to BRCA1-, BRCA2- and female/male non-BRCA gene mutations. BRCA1 mutation carriers are presented in blue, BRCA2 mutation carriers in pink and controls in grey