BRCA1 mutation carriers have a lower number of mature oocytes after ovarian stimulation for IVF/PGD

Abstract

PurposeThe aim of this study was to determine whether BRCA1/2 mutation carriers produce fewer mature oocytes after ovarian stimulation for in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD), in comparison to a PGD control group.MethodsA retrospective, international, multicenter cohort study was performed on data of first PGD cycles performed between January 2006 and September 2015. Data were extracted from medical files. The study was performed in one PGD center and three affiliated IVF centers in the Netherlands and one PGD center in Belgium. Exposed couples underwent PGD because of a pathogenic BRCA1/2 mutation, controls for other monogenic conditions. Only couples treated in a long gonadotropin-releasing hormone (GnRH) agonist-suppressive protocol, stimulated with at least 150 IU follicle stimulating hormone (FSH), were included. Women suspected to have a diminished ovarian reserve status due to chemotherapy, auto-immune disorders, or genetic conditions (other than BRCA1/2 mutations) were excluded. A total of 106 BRCA1/2 mutation carriers underwent PGD in this period, of which 43 (20 BRCA1 and 23 BRCA2 mutation carriers) met the inclusion criteria. They were compared to 174 controls selected by frequency matching.ResultsThirty-eight BRCA1/2 mutation carriers (18 BRCA1 and 20 BRCA2 mutation carriers) and 154 controls proceeded to oocyte pickup. The median number of mature oocytes was 7.0 (interquartile range (IQR) 4.0–9.0) in the BRCA group as a whole, 6.5 (IQR 4.0–8.0) in BRCA1 mutation carriers, 7.5 (IQR 5.5–9.0) in BRCA2 mutation carriers, and 8.0 (IQR 6.0–11.0) in controls. Multiple linear regression analysis with the number of mature oocytes as a dependent variable and adjustment for treatment center, female age, female body mass index (BMI), type of gonadotropin used, and the total dose of gonadotropins administered revealed a significantly lower yield of mature oocytes in the BRCA group as compared to controls (p = 0.04). This finding could be fully accounted for by the BRCA1 subgroup (BRCA1 mutation carriers versus controls p = 0.02, BRCA2 mutation carriers versus controls p = 0.50).ConclusionsOvarian response to stimulation, expressed as the number of mature oocytes, was reduced in BRCA1 but not in BRCA2 mutation carriers. Although oocyte yield was in correspondence to a normal response in all subgroups, this finding points to a possible negative influence of the BRCA1 gene on ovarian reserve.Electronic supplementary materialThe online version of this article (doi:10.1007/s10815-017-1014-3) contains supplementary material, which is available to authorized users.

Impact of BRCA1 and BRCA2 mutations on ovarian reserve and fertility preservation outcomes in young women with breast cancer

“…It would be of particular interest to assess which is the relevance of these oncologic events as confounding factors in BRCA1/2 women reduced fertility. [13,[15][16][17] The previous six studies related to this topic, addressing ovarian stimulation in BRCA 1/2 subjects, did not analyze in detail the potential role of oncologic history itself, independent of BRCA mutations, as fertility performance determinant [16,[18][19][20][21][22].…”

Crosstalk between PTEN/PI3K/Akt Signalling and DNA Damage in the Oocyte: Implications for Primordial Follicle Activation, Oocyte Quality and Ageing

“…The number of oocytes produced by women with BRCA mutation is lower than without BRCA1 mutation. [160] DNA damage and repair capacity of aged and young buffalo ovaries.…”

Fertility preservation in BRCA mutation carriers—efficacy and safety issues: a review

“…It has been hypothesized that BRCA mutation carriers, especially BRCA1 mutation carriers, are correlated with decreased ovarian reserve, increased fertilityrelated problems and primary ovarian insufficiency. These can all lead to infertility and early menopause [21][22][23][24]. Cumulative evidence has shown that BRCA mutation negatively affect carriers' ovarian reserve and accelerate ovarian aging, impacting reproductive outcomes both quantitatively and qualitatively.…”

“…Based on convincing evidence from in vivo results and prospective studies, women with BRCA1 mutation show accelerated ovarian aging due to function of the intact gene decline. This occurs at an earlier age compared to those with BRCA2 mutation [21,25]. While BRCA1 and BRCA2 are crucial members of the ataxia-telengiectasia mutated (ATM) -mediated double strand break (DSB) repair family of genes, impaired ATM mediated DSB repair act as a cause of aging in human oocytes [26].…”

“…However, some studies have shown that BRCA mutation carriers have a lower number of mature oocytes after ovarian stimulation and have a lower follicle reservation. BRCA mutation carriers also have a lower mean oocyte yield compared to non-carriers [21,25]. This conclusion is very controversial, and despite the fact that carriers have a reduced performance, a reasonable ovarian response can still be expected.…”