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BRCA mutations and Ovarian ageing in women applying for in vitro fertilization and preimplantation genetiC diAgnosis


- candidate number19165
- NTR NumberNTR4703
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR25-jul-2014
- Secondary IDs14-175 UMC Utrecht
- Public TitleBRCA mutations and Ovarian ageing in women applying for in vitro fertilization and preimplantation genetiC diAgnosis
- Scientific TitleBRCA mutations and Ovarian ageing in women applying for in vitro fertilization and preimplantation genetiC diAgnosis
- ACRONYMBROCA-2
- hypothesisThe main hypothesis is that normo-ovulatory women with a deleterious BRCA mutation have lower levels of AMH compared to normal controls, with at least a difference of 0.90 ng/ml, suggesting an effect size of approximately five years in menopausal age.
- Healt Condition(s) or Problem(s) studiedBRCA1/2, Pregnancy, Ovarian reserve
- Inclusion criteriaCase group (BRCA mutation carriers)
- Female age > 18 years and < 40 years
- Regular menstrual cycles (i.e. mean cycle length of 21-35 days)
- First IVF with ICSI and PGD treatment cycle due to a female pathogenic BRCA mutation
- Written informed consent

Controle group (non suspected for BRCA mutation):
- Female age > 18 years and < 40 years
- Regular menstrual cycles (i.e. mean cycle length of 21-35 days)
- First IVF with ICSI and PGD treatment cycle due to an indication unsuspected for reduced ovarian reserve status
- Written informed consent
- Exclusion criteriaCase group (BRCA mutation carriers)
- Ovarian surgery
- Chemo therapy
- Radiation therapy to the pelvis, lower abdomen or total body radiation
- Known female endocrine or autoimmune abnormalities (i.e. Cushing syndrome, type I Diabetes Mellitus, hypothyroidism, hyperprolactinemia, adrenal insufficiency, hypoparathyriodism, myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus)
- Body Mass Index > 35 kg/m2
- Polycystic Ovarian Syndrome (Rotterdam criteria)
- Early follicular FSH > 15 IU/L
- Known Human immunodeficiency virus (HIV) infection
- Known female genetic abnormalities suspected for subfertility (structural or numerical abnormalities of the X-chromosome (i.e. Turner¡¯s syndrome, fragile X syndrome), or abnormalities of human autosomal functionally relevant genes, other than a BRCA mutation, suspected for subfertility

Controle group (non suspected for BRCA mutation):
- Ovarian surgery
- Chemo therapy
- Radiation therapy to the pelvis, lower abdomen or total body radiation
- Known female endocrine or autoimmune abnormalities (i.e. Cushing syndrome, type I Diabetes Mellitus, hypothyroidism, hyperprolactinemia, adrenal insufficiency, hypoparathyriodism, myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus)
- Body Mass Index > 35 kg/m2
- Polycystic Ovarian Syndrome (Rotterdam criteria)
- Early follicular FSH > 15 IU/L
- Known HIV infection
- Known genetic abnormalities, suspected for subfertility (structural or numerical abnormalities of the X-chromosome (i.e. Turner¡¯s syndrome, fragile X syndrome), or abnormalities of human autosomal functionally relevant genes suspected for subfertility
- mec approval receivedyes
- multicenter trialyes
- randomisedno
- groupParallel
- TypeSingle arm
- Studytypeobservational
- planned startdate 1-aug-2014
- planned closingdate1-aug-2017
- Target number of participants155
- Interventionsblood sample
- Primary outcomeSerum AMH level
- Secondary outcome- AFC
- Amount of poor response (less than 4 oocytes at retrieval or cancellation due to insufficient follicle growths, i.e. < 4 dominant follicles sized ¡İ14 mm growing)
- Number of retrieved oocytes (total amount and MII) after first cycle COH
- Ongoing pregnancy rate
- TimepointsThe aim is to investigate a total of 31 BRCA mutation positive women and 124 controls in a period of approximately 2.5 years. Data analysis and publishing results will take ½ year, resulting in a total study duration of approximately 3 years.
- Trial web siteN/A
- statusplanned
- CONTACT FOR PUBLIC QUERIESProf. dr. F.J. Broekmans
- CONTACT for SCIENTIFIC QUERIESProf. dr. F.J. Broekmans
- Sponsor/Initiator University Medical Center Utrecht (UMCU), Maastricht University Medical Center (MUMC+), University Medical Center Groningen (UMCG), Academic Medical Center (AMC), Amsterdam, Universitair Ziekenhuis Brussel
- Funding
(Source(s) of Monetary or Material Support)
- PublicationsN/A
- Brief summaryRationale:
The study proposal aims to confirm the observation of a reduced quantity of the follicle pool in BRCA (Breast Cancer) mutation-positive women. If confirmed, advanced ovarian ageing in BRCA mutated women will have a major impact on their general health and fertility prospects. Furthermore, identification of genes that contribute to the endowment and wastage of follicles in the ovaries and thus timing of menopause will add to the understanding of the physiological mechanism of the ovarian ageing process.
In the current study we will be able to study the effect of BRCA mutations on the ovarian ageing process, by comparing serum anti-Müllerian hormone (AMH) levels between cohorts of BRCA mutation-positive women and normal controls, applying for in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD).
The main hypothesis is that normo-ovulatory women with a deleterious BRCA mutation have lower levels of AMH compared to normal controls, with at least a difference of 0.90 ng/ml, suggesting an effect size of approximately five years in menopausal age.

Objective:
To demonstrate the presence of a reduced age specific ovarian reserve status in BRCA mutation carriers by:
1.using serum AMH as ovarian reserve test
2.using the antral follicle count (AFC) as ovarian reserve test
3.using ovarian response to ovarian hyperstimulation for IVF as proxy variable of ovarian reserve status

Study design: The study is designed as an observational prospective cohort study in exposed and non-exposed women during their first IVF with ICSI and PGD treatment cycle

Study population: Couples, with normo-ovulatory women between 18 and 41 years old, applying for their first IVF with ICSI and PGD treatment cycle in view of their status as carrier of a female BRCA mutation will be asked to participate. Normo-ovulatory women between 18 and 41 years old, who visit the department of Reproductive Medicine for their first IVF, with ICSI and PGD treatment cycle unsuspected for reduced ovarian reserve, are asked to participate as control group.

Main study endpoints: The main study endpoint will be advanced ovarian ageing measured by serum AMH levels.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The nature and extent of the burden and risks associated with participation can be stated as negligible. Participating is not associated with (medical) benefits.
- Main changes (audit trail)
- RECORD25-jul-2014 - 17-aug-2014


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