Редактирование: BRCA2

Breast cancer type 2 susceptibility protein (Fanconi anemia group D1 protein) [FACD] [FANCD1]

==Publications==

{{medline-entry
|title=BRCA-related [[ATM]]-mediated DNA double-strand break repair and ovarian aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31822904
|abstract=Oocyte aging has significant clinical consequences, and yet no treatment exists to address the age-related decline in oocyte quality. The lack of progress in the treatment of oocyte aging is due to the fact that the underlying molecular mechanisms are not sufficiently understood. [[BRCA1]] and 2 are involved in homologous DNA recombination and play essential roles in ataxia telangiectasia mutated ([[ATM]])-mediated DNA double-strand break (DSB) repair. A growing body of laboratory, translational and clinical evidence has emerged within the past decade indicating a role for BRCA function and [[ATM]]-mediated DNA DSB repair in ovarian aging. Although there are several competing or complementary theories, given the growing evidence tying BRCA function and [[ATM]]-mediated DNA DSB repair mechanisms in general to ovarian aging, we performed this review encompassing basic, translational and clinical work to assess the current state of knowledge on the topic. A clear understanding of the mechanisms underlying oocyte aging may result in targeted treatments to preserve ovarian reserve and improve oocyte quality. We searched for published articles in the PubMed database containing key words, BRCA, [[BRCA1]], [[BRCA2]], Mutations, Fertility, Ovarian Reserve, Infertility, Mechanisms of Ovarian Aging, Oocyte or Oocyte DNA Repair, in the English-language literature until May 2019. We did not include abstracts or conference proceedings, with the exception of our own. Laboratory studies provided robust and reproducible evidence that [[BRCA1]] function and [[ATM]]-mediated DNA DSB repair, in general, weakens with age in oocytes of multiple species including human. In both women with BRCA mutations and BRCA-mutant mice, primordial follicle numbers are reduced and there is accelerated accumulation of DNA DSBs in oocytes. In general, women with [[BRCA1]] mutations have lower ovarian reserves and experience earlier menopause. Laboratory evidence also supports critical role for [[BRCA1]] and other [[ATM]]-mediated DNA DSB repair pathway members in meiotic function. When laboratory, translational and clinical evidence is considered together, BRCA-related [[ATM]]-mediated DNA DSB repair function emerges as a likely regulator of ovarian aging. Moreover, DNA damage and repair appear to be key features in chemotherapy-induced ovarian aging. The existing data suggest that the BRCA-related [[ATM]]-mediated DNA repair pathway is a strong candidate to be a regulator of oocyte aging, and the age-related decline of this pathway likely impairs oocyte health. This knowledge may create an opportunity to develop targeted treatments to reverse or prevent physiological or chemotherapy-induced oocyte aging. On the immediate practical side, women with BRCA or similar mutations may need to be specially counselled for fertility preservation.
|mesh-terms=* Aging
* Animals
* Ataxia Telangiectasia
* BRCA1 Protein
* BRCA2 Protein
* DNA Breaks, Double-Stranded
* DNA Repair
* Female
* Fertility
* Fertility Preservation
* Humans
* Mice
* Oocytes
* Ovarian Follicle
* Ovarian Reserve
* Ovary
|keywords=* 
          BRCA
        
* 
          BRCA1/2
        
* DNA repair
* anti-Mullerian hormone
* chemotherapy
* mutations
* oocyte
* ovarian aging
* ovarian reserve
* ovarian response
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935693
}}
{{medline-entry
|title=Do [[BRCA1]] and [[BRCA2]] gene mutation carriers have a reduced ovarian reserve? Protocol for a prospective observational study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31772111
|abstract=[[BRCA1]]/2 gene mutations increase risk of breast and/or ovarian cancer and may have implications for reproductive health. Indirect biomarkers of the ovarian primordial follicle pool (anti-Müllerian hormone ([[AMH]])) and one small study in female cadavers suggest that ovarian reserve may be reduced in BRCA mutation carriers, but findings are conflicting and association between circulating [[AMH]] and primordial follicle number is not established. The aim of this study is to measure primordial follicle density in premenopausal ovarian tissue samples from women with [[BRCA1]]/2 gene mutations versus age-matched comparison group. Prospective observational study measuring associations between BRCA gene mutation status, premenopausal ovarian primordial follicle density and serum [[AMH]] concentrations versus age-matched premenopausal women from the general population. Primordial follicle density will be measured in cortical sections from ovarian tissue collected at the time of risk-reducing bilateral salpingo-oophorectomy (RRBSO) in 88 [[BRCA1]] gene mutation carriers, 65 [[BRCA2]] gene mutation carriers and 157 non-mutation carriers. Primordial follicle density will be determined by counting follicles in a known volume of ovarian cortical tissue using light microscopy. Follicles will be identified by immunohistochemical staining for oocyte marker mouse vasa homologue. To inform the mechanisms underlying reduced ovarian reserve, the proportion of follicles containing oocytes with DNA damage will be determined by immunohistochemical staining for phosphorylated histone [[H2AX]] and terminal deoxynucleotidyl transferase dUTP nick end labelling assay to identify apoptotic cells. Follicle density will be correlated with circulating [[AMH]] concentrations quantified in the same cohort, using an electrochemiluminescence immunoassay on an automated platform. Ethics approval has been granted by Peter MacCallum Cancer Centre to access biobanks, including; The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab-HREC#97_27) and the What Happens after Menopause? (HREC12PMCC24-12/90) and Melbourne IVF.
|mesh-terms=* Adolescent
* Adult
* Aging
* BRCA1 Protein
* BRCA2 Protein
* Female
* Germ-Line Mutation
* Heterozygote
* Humans
* Immunohistochemistry
* Middle Aged
* Observational Studies as Topic
* Ovarian Follicle
* Ovarian Reserve
* Prospective Studies
* Research Design
* Young Adult
|keywords=* BRCA
* DNA repair
* fertility
* follicle
* germline mutation
* oocyte
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887091
}}
{{medline-entry
|title=Analysis of somatic mutations identifies signs of selection during in vitro aging of primary dermal fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31385397
|abstract=Somatic mutations are critical for cancer development and may play a role in age-related functional decline. Here, we used deep sequencing to analyze the prevalence of somatic mutations during in vitro cell aging. Primary dermal fibroblasts from healthy subjects of young and advanced age, from Hutchinson-Gilford progeria syndrome and from xeroderma pigmentosum complementation groups A and C, were first restricted in number and then expanded in vitro. DNA was obtained from cells pre- and post-expansion and sequenced at high depth (1656× mean coverage), over a cumulative 290 kb target region, including the exons of 44 aging-related genes. Allele frequencies of 58 somatic mutations differed between the pre- and post-cell culture expansion passages. Mathematical modeling revealed that the frequency change of three of the 58 mutations was unlikely to be explained by genetic drift alone, indicative of positive selection. Two of these three mutations, [[[[CDKN2A]]]] c.53C>T (T18M) and [[ERCC8]] c.*772T>A, were identified in cells from a patient with [[XPA]]. The allele frequency of the [[[[CDKN2A]]]] mutation increased from 0% to 55.3% with increasing cell culture passage. The third mutation, [[BRCA2]] c.6222C>T (H2074H), was identified in a sample from a healthy individual of advanced age. However, further validation of the three mutations suggests that other unmeasured variants probably provide the selective advantage in these cells. Our results reinforce the notions that somatic mutations occur during aging and that some are under positive selection, supporting the model of increased tissue heterogeneity with increased age.
|mesh-terms=* Adolescent
* Aged, 80 and over
* Cells, Cultured
* Cellular Senescence
* Child
* Child, Preschool
* DNA
* Female
* Fibroblasts
* Humans
* Male
* Mutation
* Sequence Analysis, RNA
* Skin
|keywords=* aging cell
* cell mosaicism
* genome instability
* molecular biology of aging
* positive selection
* somatic mutation
* tissue heterogeneity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826141
}}
{{medline-entry
|title=Klotho gene polymorphisms are associated with healthy aging and longevity: Evidence from a meta-analysis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30633899
|abstract=Klotho gene polymorphisms have been implicated in healthy aging, but inconsistences in findings from previous case-control studies have raised concerns regarding the associations between KLOTHO gene polymorphisms and susceptibility to aging-related diseases and longevity. Hence, this meta-analysis was performed. We assessed the associations between two polymorphisms (G-395 A/rs1207568 and F352 V/rs9536314) and five parameters (urolithiasis, cognitive impairment, cardiovascular disease, cancer, and longevity) by calculating pooled odds ratios with 95% confidence intervals. According to the pooled results, the G allele of the G-395 A polymorphism conferred a significantly higher risk of urolithiasis; G-395 A was related to the susceptibility to cardiovascular disease under allele, dominant, and recessive models. There was no significant association between the G-395 A polymorphism and cognitive impairment among the elderly. The F allele of the F352 V polymorphism protected against breast and ovarian cancer susceptibility. Interestingly, based on the results of the subgroup analysis, the F352 V polymorphism was associated with the overall risk of neoplasms in [[BRCA1]] mutation carriers but not in [[BRCA2]] mutation carriers. Moreover, the F allele played a protective role in determining human longevity. In conclusion, Klotho G-395 A polymorphisms were associated with urolithiasis and cardiovascular disease but not with cognitive impairment. Additionally, Klotho F352 V polymorphisms were associated with cancers and longevity.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Cardiovascular Diseases
* Case-Control Studies
* Cognitive Dysfunction
* Female
* Glucuronidase
* Healthy Aging
* Humans
* Longevity
* Male
* Middle Aged
* Neoplasms
* Polymorphism, Genetic
* Urolithiasis
|keywords=* Aging
* Gene polymorphisms
* Klotho
* Meta-Analysis
|full-text-url=https://sci-hub.do/10.1016/j.mad.2018.12.003
}}
{{medline-entry
|title=The replicative senescent mesenchymal stem / stromal cells defect in DNA damage response and anti-oxidative capacity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30008586
|abstract=Replicative senescence and potential malignant transformation are great limitations in the clinical application of bone marrow-derived mesenchymal stem / stromal cells (MSCs). An abnormal DNA damage response may result in genomic instability, which is an integral component of aging and tumorigenesis. However, the effect of aging on the DNA damage response in MSCs is currently unknown. In the present study, we evaluated the DNA damage response induced by oxidative stress and DNA double-strand breaks in human bone marrow-derived MSCs. After long-term cell culture, replicative senescent MSCs (sMSCs) were characterized by a poor proliferation rate, high senescence-associated β-galactosidase activity, and enhanced expression of P53 and P16. Features of the DNA damage response in these sMSCs were then compared with those from early-passage MSCs. The sMSCs were more sensitive to hydrogen peroxide and bleomycin treatment with respect to cell viability and apoptosis induction. Combined with the comet assay, γH2AX foci characterization and reactive oxygen species detection were used to demonstrate that the antioxidant and DNA repair ability of sMSCs are attenuated. This result could be explained, at least in part, by the downregulation of anti-oxidation and DNA repair genes, including Cu/Zn-SOD, GPX, [[CAT]], [[OGG1]], [[XRCC1]], Ku70, [[BRCA2]] and [[XRCC4]]. In conclusion, MSCs aging is associated with a reduction in the DNA repair and anti-oxidative capacity.
|mesh-terms=* Cell Proliferation
* Cells, Cultured
* Cellular Senescence
* DNA Damage
* DNA Repair
* DNA-Binding Proteins
* Gene Expression Regulation
* Humans
* Mesenchymal Stem Cells
* Oxidative Stress
|keywords=* DNA damage response
* DNA double-strand breaks
* Replicative senescence
* mesenchymal stem cells
* oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036081
}}
{{medline-entry
|title=Faulty [[BRCA1]], [[BRCA2]] genes: how poor is the prognosis?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29017890
|abstract=We take a critical look at the meaning behind the number 87% given to 25-year-old Sophie, a [[BRCA1]] and [[BRCA2]] carrier. Sophie has been told she has an 87% chance of getting breast cancer. She is contemplating a preventive double mastectomy after genetic counseling and her physician's advice. Some 92% of British general practitioners are in favor of prophylactic mastectomy as a treatment option for women similar to Sophie. The treatment decision results, to a very large extent, from the size of the number (87%) alone. The central argument of this study is that physicians, their patients, and the public need a much better understanding on what is meant by probability estimates of 0.87. The figure on its own does not tell us much, and we need to be very cautious in its interpretation. It is important to know that the very same genetic and statistical models, and observed data, resulting in a verdict of an 87% lifetime chance of getting breast cancer, based on [[BRCA1]], [[BRCA2]], and familial information, simultaneously show Sophie to have a greater than 99% chance of surviving beyond the next 5 years cancer free. If she succeeds-the chances are overwhelmingly in her favor-then, given that fact, her chances of surviving a further 5 years are once again greater than 98%. Her chances of not dying due to breast cancer over the next 20 years are greater than 97%, a percentage that changes little if instead of 20 we write the number 30. In a word, although the diagnosis of a faulty BRAC gene may be a disappointment, there is no immediate peril and no need for undue alarm. Sophie, and her primary care providers, can carefully consider her options without feeling that they are under any kind of acute pressure. Whatever the threat, it is not an imminent one.
|mesh-terms=* BRCA1 Protein
* BRCA2 Protein
* Breast Neoplasms
* Decision Support Techniques
* Female
* Genes, BRCA1
* Genes, BRCA2
* Humans
* Life Expectancy
* Mastectomy
* Prognosis
|keywords=* BRCA1
* BRCA2
* Breast cancer
* Genetics
* Probability
* Risk
|full-text-url=https://sci-hub.do/10.1016/j.annepidem.2017.09.005
}}
{{medline-entry
|title=Ovarian Aging in Women With BRCA Germline Mutations.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28938488
|abstract=Recent clinical and laboratory studies suggested that women with BRCA mutations have lower ovarian reserve and their primordial follicle oocytes may be more prone to DNA damage; however, direct proof is lacking. To determine whether women with germline BRCA mutations have reduced primordial follicle reserve and increased oocyte DNA damage. A comparative laboratory study of ovarian tissue obtained from unaffected BRCA mutation carriers (BMCs) vs age-matched organ donor cadavers. Two academic centers. Of the 230 ovarian specimens from BMCs, 18 met the study inclusion criteria. Healthy ovaries from 12 organ donor cadavers served as controls. Histology and immunohistochemical analysis on paraffin-embedded ovarian sections. Primordial follicle density and the percentage of DNA double-strand break (DSB)-positive primordial follicle oocytes. Ovaries from BMCs had significantly lower primordial follicle densities than those of controls (11.2 ± 2.0 vs 44.2 ± 6.2 follicles/mm3; P = 0.0002). BRCA mutations were associated with increased DNA DSBs in primordial follicle oocytes (62% ± 5.2% vs 36% ± 3.4%; P = 0.0005). In subgroup analyses, both [[BRCA1]] and [[BRCA2]] mutations were associated with lower primordial follicle density (P = 0.0001 and 0.0030, respectively), and [[BRCA1]] mutations were associated with higher DNA DSBs (P = 0.0003) than controls. The rates of follicle decline (R2 = 0.74; P = 0.0001) and DNA DSB accumulation (R2 = 0.70; P = 0.0001) appeared to be accelerated, particularly in primordial follicle oocytes of BMCs over age 30 years. We provide direct evidence of diminished ovarian reserve as well as accelerated primordial follicle loss and oocyte DNA damage in women with BRCA mutations. These findings may further our understanding of ovarian aging, and be useful when counseling BMCs.
|mesh-terms=* Adult
* Aging
* BRCA1 Protein
* Biopsy
* Cadaver
* Case-Control Studies
* DNA Damage
* Female
* Genetic Carrier Screening
* Germ-Line Mutation
* Humans
* Oocytes
* Ovarian Follicle
* Ovarian Reserve
* Ovary
* Young Adult

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630253
}}
{{medline-entry
|title=The expected benefit of preventive mastectomy on breast cancer incidence and mortality in BRCA mutation carriers, by age at mastectomy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28914396
|abstract=Preventive breast surgery is offered to unaffected BRCA mutation carriers to prevent breast cancer incidence and mortality. The clinical benefit of preventive mastectomy can be measured in several ways, including extension of life expectancy (mean years of life gained) and by estimating the probability of surviving until age 80. We sought to estimate the expected benefit of a preventive mastectomy at various ages, using these indices of mortality, by simulating hypothetical cohorts of women. The age-specific annual risks of developing breast cancer were used to estimate the actuarial risk of developing breast cancer by age 80 for women with a [[BRCA1]] or [[BRCA2]] mutation. The probability of developing breast cancer before age 80 was then modified to include competing causes of death, including from ovarian cancer. The mortality rate from breast cancer after a diagnosis of breast cancer was set at 2% annually for the first 10 years and then 1% annually for years ten to twenty. The incidence rate and mortality rate from ovarian cancer were based on published literature. We assumed that preventive mastectomy was associated with complete protection against subsequent breast cancer. A series of simulations was conducted to evaluate the reduction in the probability of death (from all causes) until age 80, according to the age at mastectomy. The actuarial risk of developing breast cancer until age 80 was estimated to be 70.8%. The actual risk (incorporating competing risks) was 64.0%. The probability of being alive at age 80 by having a mastectomy at age 25 increased by 8.7% (from 42.7 to 51.3%). The estimated benefit declined with age at mastectomy; for surgery done at age 50 the improvement in survival to age 80 was much more modest (2.8% at age 80, from 42.7 to 45.5%). Among BRCA mutation carriers, the mortality benefit of preventive mastectomy at age 25 is substantial, but the expected benefit declines rapidly with increasing age at surgery.
|mesh-terms=* Adult
* Age Factors
* Aged
* Aged, 80 and over
* BRCA1 Protein
* BRCA2 Protein
* Breast Neoplasms
* Female
* Humans
* Life Expectancy
* Middle Aged
* Mutation
* Ovarian Neoplasms
* Ovariectomy
* Prophylactic Mastectomy
|keywords=* BRCA
* Breast cancer
* Mastectomy
* Ovarian cancer
|full-text-url=https://sci-hub.do/10.1007/s10549-017-4476-1
}}
{{medline-entry
|title=A Multigene Test Could Cost-Effectively Help Extend Life Expectancy for Women at Risk of Hereditary Breast Cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28407996
|abstract=The National Comprehensive Cancer Network recommends that women who carry gene variants that confer substantial risk for breast cancer consider risk-reduction strategies, that is, enhanced surveillance (breast magnetic resonance imaging and mammography) or prophylactic surgery. Pathogenic variants can be detected in women with a family history of breast or ovarian cancer syndromes by multigene panel testing. To investigate whether using a seven-gene test to identify women who should consider risk-reduction strategies could cost-effectively increase life expectancy. We estimated effectiveness and lifetime costs from a payer perspective for two strategies in two hypothetical cohorts of women (40-year-old and 50-year-old cohorts) who meet the National Comprehensive Cancer Network-defined family history criteria for multigene testing. The two strategies were the usual test strategy for variants in [[BRCA1]] and [[BRCA2]] and the seven-gene test strategy for variants in [[BRCA1]], [[BRCA2]], [[TP53]], [[PTEN]], [[CDH1]], [[STK11]], and [[PALB2]]. Women found to have a pathogenic variant were assumed to undergo either prophylactic surgery or enhanced surveillance. The incremental cost-effectiveness ratio for the seven-gene test strategy compared with the [[BRCA1]]/2 test strategy was $42,067 per life-year gained or $69,920 per quality-adjusted life-year gained for the 50-year-old cohort and $23,734 per life-year gained or $48,328 per quality-adjusted life-year gained for the 40-year-old cohort. In probabilistic sensitivity analysis, the seven-gene test strategy cost less than $100,000 per life-year gained in 95.7% of the trials for the 50-year-old cohort. Testing seven breast cancer-associated genes, followed by risk-reduction management, could cost-effectively improve life expectancy for women at risk of hereditary breast cancer.
|mesh-terms=* Adult
* Age Factors
* Aged
* Aged, 80 and over
* Biomarkers, Tumor
* Breast Neoplasms
* Cost-Benefit Analysis
* Decision Support Techniques
* Early Detection of Cancer
* Female
* Gene Expression Profiling
* Genetic Predisposition to Disease
* Genetic Testing
* Health Care Costs
* Heredity
* Humans
* Life Expectancy
* Magnetic Resonance Imaging
* Mammography
* Mastectomy
* Middle Aged
* Models, Economic
* Patient Selection
* Phenotype
* Predictive Value of Tests
* Prognosis
* Quality-Adjusted Life Years
* Risk Assessment
* Risk Factors
* Watchful Waiting
|keywords=* BRCA
* breast cancer
* cost-effectiveness
* multigene panel testing
|full-text-url=https://sci-hub.do/10.1016/j.jval.2017.01.006
}}
{{medline-entry
|title=Serum [[AMH]] levels in healthy women from [[BRCA1]]/2 mutated families: are they reduced?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27907901
|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