BRCA1 mutation carriers have a lower number of mature oocytes after ovarian stimulation for IVF/PGD
Derks-Smeets, Inge A P; van Tilborg, T. C.; van Montfoort, A.P.; Smits, L.; Torrance, H. L.; Meijer-Hoogeveen, M.; Broekmans, F.; Dreesen, J. C.F.M.; Paulussen, Aimee D C; Tjan-Heijnen, Vivianne C G; Homminga, I.; van Den Berg, M. M.J.; Ausems, M. G.E.M.; de Rycke, M.; de Die-Smulders, Christine E M; Verpoest, W.; van Golde, R.
(2017) Journal of Assisted Reproduction and Genetics, volume 34, issue 11, pp. 1475 - 1482
(Article)
Abstract
Purpose: The 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. Methods: A retrospective, international, multicenter cohort study was performed on data of first
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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. Results: Thirty-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). Conclusions: Ovarian 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.
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Keywords: Adult, BRCA1 Protein/genetics, BRCA2 Protein/genetics, Female, Fertilization in Vitro, Follicle Stimulating Hormone, Gonadotropins/administration & dosage, Heterozygote, Humans, In Vitro Oocyte Maturation Techniques, Mutation, Oocytes/growth & development, Ovarian Reserve/genetics, Ovulation Induction/methods, Pregnancy, Pregnancy Rate, Preimplantation Diagnosis/methods, Journal Article
ISSN: 1058-0468
Publisher: Springer New York
Note: Funding Information: IDS, VTH, CDS, WV, and RvG were involved in the conception of the study and, together with TvT, AvM, LS, HT, and FB, in the study design. IDS, TvT, AvM, JD, AP, IH, MvdB, and WV collected the data. Data analysis was performed by IDS and LS. IDS wrote the first version of the manuscript. All authors were involved in the data interpretation, contributed to the critical revision of the manuscript, approved the final version, and agreed to be accountable for all aspects of the work. The study was approved by the Institutional Review Boards of Maastricht University Medical Center (METC 14-4-163) and Universitair Ziekenhuis Brussel (2014/383). All couples gave their written informed consent for IVF/PGD treatment and the usage of their PGD data for scientific research. Funding Information: Study funding This study was financially supported by a personal grant for I. Derks-Smeets, kindly provided by the Dutch Cancer Society (grant number 2011-5249). The sponsor had no role in the conduct of the study and/or preparation of the article, i.e., no involvement in study design; the collection, analysis, and/or interpretation of the data; the writing of the report; and/or the decision to submit the article for publication. Publisher Copyright: © 2017, The Author(s).
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