title: Serum AMH levels in healthy women from BRCA1/2 mutated families: are they reduced?
abstract: Do BRCA1/2 mutation carriers have a compromised ovarian reserve compared to proven non-carriers, based on serum anti-Müllerian hormone (AMH) levels?
  
  
  
  BRCA1/2 mutation carriers do not show a lower serum AMH level in comparison to proven non-carriers, after adjustment for potential confounders.
  
  
  
  It has been suggested that the BRCA genes play a role in the process of ovarian reserve depletion, although previous studies have shown inconsistent results regarding the association between serum AMH levels and BRCA mutation status. Hence, it is yet unclear whether BRCA1/2 mutation carriers may indeed be at risk of a reduced reproductive lifespan. STUDY DESIGN, SIZE, DURATION: A multicenter, cross-sectional study was performed between January 2012 and February 2015 in 255 women. We needed to include 120 BRCA1/2 mutation carriers and 120 proven non-carriers to demonstrate a difference in AMH levels of 0.40 µg/l (SD ± 0.12 µg/l, two-sided alpha-error 0.05, power 80%).
  
  
  
  Healthy women aged 18-45 years who were referred to the Clinical Genetics Department and applied for predictive BRCA1/2 testing because of a familial BRCA1/2 mutation were asked to participate. A cross-sectional assessment was performed by measuring serum AMH levels and filling out a questionnaire. Multivariate linear regression analyses adjusted for age, current smoking and current hormonal contraceptive use were performed on log-transformed serum AMH levels.
  
  
  
  Out of 823 potentially eligible women, 421 (51.2%) were willing to participate, and of those, 166 (39%) did not meet our inclusion criteria. Two hundred and fifty-five women were available for analyses; 124 BRCA1/2 mutation carriers and 131 proven non-carriers. The median [range] AMH level in carriers was 1.90 µg/l [0.11-19.00] compared to 1.80 µg/l [0.11-10.00] in non-carriers (P = 0.34). Adjusted linear regression analysis revealed no reduction in AMH level in the carriers (relative change = 0.98 (95%CI, 0.77-1.22); P = 0.76).
  
  
  
  Participants were relatively young. Power was insufficient to analyze BRCA1 and BRCA2 mutation carriers separately. AMH levels may have been influenced by the use of hormonal contraceptives, though similar proportions of carriers and non-carriers were current users and adjustments were made to correct for potential confounding in our analysis.
  
  
  
  Limitations of the current analysis and limitations of the existing literature argue for prospective, well-controlled follow-up studies with recurrent AMH measurements to determine whether carriers might be at risk for low ovarian reserve and to definitively guide care.
  
  
  
  This study was partially financially supported by a personal grant for Inge A.P. Derks-Smeets, kindly provided by the Dutch Cancer Society (Grant Number UM 2011-5249). Theodora C. van Tilborg, Inge A.P. Derks-Smeets, Anna M.E. Bos, Jan C. Oosterwijk, Christine E. de Die-Smulders, Lizet E. van der Kolk, Wendy A.G. van Zelst-Stams, Maria E. Velthuizen, Marinus J.C. Eijkemans and Margreet G.E.M. Ausems have nothing to disclose. Ron J. van Golde has received unrestricted research grants from Ferring and Merck Serono, outside the submitted work. Annemieke Hoek received an unrestricted educational grant from Ferring pharmaceutical BV, The Netherlands and a speaker's fee for post graduate education from MSD pharmaceutical company, outside the submitted work. Joop S.E. Laven has received unrestricted research grants from Ferring, Merck Serono, Merck Sharpe & Dome, Organon, and Schering Plough, outside the submitted work. Frank J.M. Broekmans is a member of the external advisory board for Merck Serono (The Netherlands), outside the submitted work.
  
  
  
  NTR no. 4324.
authors.affiliation: Department of Reproductive Medicine, University Medical Center Utrecht, Heidelberglaan 100, Room F05.126, PO Box 85500, 3508 GA Utrecht, The Netherlands ctilborg@umcutrecht.nl.
authors.forename: Theodora C
authors.initials: TC
authors.lastname: van Tilborg
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Center+, PO Box 5800, 6202 AZ Maastricht, The Netherlands.|GROW, School for Oncology and Developmental Biology, Maastricht University, PO Box 616, 6200 MD Maastricht,  The Netherlands.
authors.forename: Inge A P
authors.initials: IA
authors.lastname: Derks-Smeets
authors.affiliation: Department of Reproductive Medicine, University Medical Center Utrecht, Heidelberglaan 100, Room F05.126, PO Box 85500, 3508 GA Utrecht, The Netherlands.
authors.forename: Anna M E
authors.initials: AM
authors.lastname: Bos
authors.affiliation: Department of Genetics, Groningen University, University Medical Center, PO Box 30.001, 9700 RB Groningen, The Netherlands.
authors.forename: Jan C
authors.initials: JC
authors.lastname: Oosterwijk
authors.affiliation: GROW, School for Oncology and Developmental Biology, Maastricht University, PO Box 616, 6200 MD Maastricht,  The Netherlands.|Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Maastricht University Medical Center+, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
authors.forename: Ron J
authors.initials: RJ
authors.lastname: van Golde
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Center+, PO Box 5800, 6202 AZ Maastricht, The Netherlands.|GROW, School for Oncology and Developmental Biology, Maastricht University, PO Box 616, 6200 MD Maastricht,  The Netherlands.
authors.forename: Christine E
authors.initials: CE
authors.lastname: de Die-Smulders
authors.affiliation: Family Cancer Clinic, Netherlands Cancer Institute, PO Box 90203, 1066 CX Amsterdam, The Netherlands.
authors.forename: Lizet E
authors.initials: LE
authors.lastname: van der Kolk
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Wendy A G
authors.initials: WA
authors.lastname: van Zelst-Stams
authors.affiliation: Department of Genetics, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Velthuizen
authors.affiliation: Department of Reproductive Medicine, Groningen University, University Medical Center, PO Box 30.001, 9700 RB Groningen, The Netherlands.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Hoek
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands.
authors.forename: Marinus J C
authors.initials: MJ
authors.lastname: Eijkemans
authors.affiliation: Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Joop S E
authors.initials: JS
authors.lastname: Laven
authors.affiliation: Department of Genetics, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands.
authors.forename: Margreet G E M
authors.initials: MG
authors.lastname: Ausems
authors.affiliation: Department of Reproductive Medicine, University Medical Center Utrecht, Heidelberglaan 100, Room F05.126, PO Box 85500, 3508 GA Utrecht, The Netherlands.
authors.forename: Frank J M
authors.initials: FJ
authors.lastname: Broekmans
mesh_terms: D000328:Adult; D054304:Anti-Mullerian Hormone / Q000097:blood*; D019313:BRCA1 Protein / Q000235:genetics*; D003430:Cross-Sectional Studies; D005260:Female; D006579:Heterozygote; D006801:Humans; D011446:Prospective Studies; D016387:Women's Health
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D054304:Anti-Mullerian Hormone
keywords: BRCA mutation; anti-Müllerian hormone; genes; ovarian aging; ovarian reserve