Fertility in Women Carrying BRCA Gene Abnormality

Fertility in Women Carrying BRCA Gene Abnormality

Fertility in women carrying BRCA gene abnormality may be reduced

Women carrying BRCA gene abnormality frequently consult with reproductive endocrinologists for fertility treatment or preservation.  Women referred to test the BRCA gene for mutations based on ancestry, family history and type of cancer diagnosed in her family. If a mutation is found the lifetime risk for breast cancer is 70% and ovary cancer is 40%.

Fertility in women with BRCA mutations maybe reduced in reproductive age women because of the mutation itself, procedures used to reduce the risk of cancer or cancer treatment if they develop cancer.


BRCA mutation and Fertility

BRCA mutation and Fertility

Ovarian Reserve and Response to Ovarian Stimulation

Women carrying a BRCA mutation may require ovarian stimulation using fertility medications for

  1. Preservation of fertility through egg freezing or embryo freezing prior to prophylactic removal of both ovaries,
  2. Preservation of fertility after the diagnosis of breast cancer and before chemotherapy or
  3. An incidental fertility problem unrelated to BRCA mutation.

Ovarian reserve and response to fertility medication is one of the most determinants of success of fertility treatment or preservation.

Although it was suggested that women with BRCA mutations respond more modestly to fertility medications, this was not proven. When women carrying these mutations were compared to relatives with no mutations, there were no differences in the number of deliveries and the need for fertility treatment. Also in a study of 260 Ashkenazi Jewish women with ovarian cancer and 331 controls, unselected for age or family history of the disease. Pregnancy success was similar for 96 mutation carrier and 164 non-carrier cases and controls.

Fertility & fertility treatment

Its unlikely that fertility or fertility treatment will increase the risk for breast cancer in women with BRCA mutations. 1380 women diagnosed with breast cancer and carrying BRCA mutations were matched 1380 women without breast cancer and carrying BRCA mutations. 16% reported fertility problems, 4% used fertility medications and 1% used IVF. There was no difference between women who developed breast cancer and those who did not regarding history of infertility and the use of fertility medication. The type of fertility medicine-oral or injection medication also did not change the risk for breast cancer, irrespective if women had children before or not.

Interestingly, there is significant excess of females among the offspring of female carriers of BRCA1 and BRCA2 mutations-higher female to male ratio.

Avoiding BRCA transmission to babies (PGD)

Women interested in getting pregnant should be counseled to the risk of transmission of mutation to future children. Both men and women carrying the mutation are at a significantly increased risk of cancer. It is very possible to prevent this transmission if the eggs or embryos are tested before replacement into the uterus in women undergoing in vitro fertilization – IVF Eggs are tested by polar body biopsy (this is a small cell attached to the egg and carry chromosomes representative to those of the egg). Embryos are tested by testing one cell of a 6 to 8 cell embryo. Testing has many medical and ethical dimensions and is better handled by providers specializing in these areas.


The risk of breast cancer may increase with multiple pregnancies and deliveries in women carrying BRCA2 mutations. In BRCA1 mutation carriers, late menarche and breast feeding reduces the risk for breast cancer. The effect of pregnancy on cancer risk though was not confirmed in multiple studies.

Read more to learn about different methods for preserving fertility after BRCA diagnosis.

Egg Reserve and Infertility

Egg Reserve and Infertility

Egg reserve means the number and quality of eggs remaining in the ovaries at a given age. It reflects the fertility potential of a woman irrespective of the cause of infertility, even male factor.

Benefits of Testing for Egg Reserve

Testing for egg reserve results should be interpreted with caution. Abnormal values should not be a cause for denying fertility treatment because the predictive power for pregnancy with own eggs is modest. For women, ovarian reserve tests give women insight into the chance of pregnancy with there own eggs. It also may indicate the need to promptly avoid delay in seeking fertility treatment.  For reproductive endocrinologists, the tests have value in designing fertility treatment and selecting the most appropriate fertility treatment protocol. They predict response to fertility medications and allow infertility specialists to select treatment protocol and gonadotropin dose. Egg reserve also predicts the number of eggs retrieved for IVF or egg freezing.

Egg Reserve: Egg Number

Although the number of eggs in the ovaries decrease with age there is significant individual variation in initial number endowed in the ovaries and the rate of decrease. Some young women has low egg number and older with large number of eggs. Ovarian reserve tests are used to estimate this number.

Egge reserve: the number of eggs in the ovaries drops with age

Egge reserve: the number of eggs in the ovaries drops with age


Medical history may indicate low egg reserve in women with prior excision of ovarian cysts, endometriosis of the ovaries,  women who smoke and with family history of early menopause

Antral follicle count

The number of antral follicles in the ovaries (the structures that contain the eggs) can be seen and counted using vaginal ultrasound. Performed by an experienced reproductive endocrinologist, it can accurately estimate ovarian reserve. Low count e.g <10 in both ovaries points to low reserve.

Day 3 FSH, Estradiol

FSH is produced by the master gland in the base of the brain. Estradiol is made by the follicles themselves. Measured in the second or third day of menstrual cycle, high FSH (>12) of high estradiol (>75) points to low egg reserve.

Antimullerian Hormone (AMH)

AMH is produced by the cells surrounding the eggs in small follicles and is a more direct measure of egg reserve than FSH. It can be accurately measured any day in the cycle with  little variations in between cycles. Levels <1.5 ng/dL generally indicates low egg reserve. It correlates well with antral follicle count.

Genetic Screening

Low egg reserve in few women is due to a genetic cause. Fragile X syndrome is a genetic disease that causes low egg reserve and mental deficiency in newborn males. Chromosomal abnormalities e.g Turner syndrome, translocations are also associated with low egg reserve. Genetic screening is performed using a simple blood test before starting fertility treatment.

Egg Reserve: Egg Quality

What does egg quality means ?

Good quality eggs are chromosomaly normal (has 23 chromosomes). The most important factor that prevents the achievement of pregnancy or leads to early miscarriage is an abnormal egg (has extra or missing chromosome or piece of a chromosome). Many eggs at any age in any woman are abnormal and the normal eggs are the ones that are successful in being fertilized with sperm, implant and achieve a pregnancy. These errors takes place when the original cell that produce the eggs divide to reduce the number of chromosomes to half. The division (meiosis) is many times unequal leading to an egg with an extra or missing chromosome.

Age and egg quality

The ovary releases better quality age earlier in life and lower quality age later, for unknown reason. Female age is the most important indicator for egg quality, chance for spontaneous pregnancy and after fertility treatment. Older women need to try longer to achieve pregnancy and at an increased risk for miscarriage, ectopic pregnancy and delivering a baby with chromosomal abnormalities e.g Down Syndrome. This effect of age become clinically evident at age 30 or even earlier. Age is more important than the number of eggs in the ovaries. Young women with few eggs in the ovary are more successful in getting pregnant than older women with many eggs in the ovary.



Testing for egg quality: PGD

Age is the only available noninvasive method to estimate egg quality. Healthy eggs cannot be identified using any non invasive method. It is possible to identify chromosomal errors in the egg during IVF fertility treatment after biopsy of the first polar body of unfertilized egg or after removing one cell from an embryo after the egg is fertilized then test this material for chromosomal abnormality. This process is called PGD or preimplantation genetic diagnosis. It is important to remember that PGD is not proven so far as method of enhancing fertility potential. It simply detects if the egg or embryo is chromosomaly normal or not but will not make an unhealthy egg healthy.

Read more about ovarian reserve and low response to ovarian stimulation in my review here.

Egg Quality and Fertility Treatment Success

Egg Quality and Fertility Treatment Success

What does egg quality means?

Good quality eggs are mature eggs that are able to fertilize, develop into normal embryos that are able to implant and progress to a healthy baby. Good quality eggs have normal chromosomes. A normal egg contains 23 chromosomes and when fertilized with a sperm produce a zygote that has 46 chromosomes.

How is egg quality tested?

Two methods

  1. Non invasive: asking a woman about her age. Age is the most important determinant of fertility. All women have abnormal eggs and well as normal ones. With advance in age the proportion of normal eggs decrease because the ovary ovulates the healthier eggs earlier in life. Older women have less eggs and more abnormal eggs. Apart from age and ovarian reserve testing there are no other noninvasive methods to test for egg quality. Couples may present with unexplained infertility, minor abnormalities or repeated unsuccessful fertility treatment. Other indicators of lower egg quality are recurrent early first trimester pregnancy loss (biochemical pregnancy), pregnancy loss in the first trimester when chromosome analysis of products of conception is abnormal. Ectopic pregnancies are more common with chromosomally abnormal embryos.
  2. Invasive method: the eggs can be retrieved and DNA analyzed via PGD, before or after fertilization to detect the number and structure of chromosomes. This is usually done during actual fertility treatment.
Advance in maternal age is associated with lower chance for conception due to lower number of eggs with normal chromosomes

Advance in maternal age is associated with lower chance for conception due to lower number of eggs with normal chromosomes


How can we improve egg quality during fertility treatment?

Strategies employed to improve egg quality during fertility treatment include

  1. Random increase in the number of eggs produced: Ovarian stimulation can increase the number of eggs produced increasing the odds that one or more of those eggs have normal chromosomes. This random increase in the number of eggs is employed in IUI and IVF cycles. We do not know if any of the eggs are normal but generally the more eggs you make the higher the likelihood that one or more are normal.
    Human eggs retrieved after ovarian stimulation

    Human eggs retrieved after ovarian stimulation

  2. Tweaking of ovarian stimulation protocol: Many changes to the stimulation protocol can improve response and egg quality including, choosing an agonist or antagonist based protocol, the addition of an oral agents like clomid or letrozole, reducing the dose of gonadotropins, changing the timing for the trigger shot hCG.
  3. Embryo selection using morphology: Healthy embryos divide and double the number of cells every 24 hours or less (8 to 10 cells on day 3). Healthy embryos have equal cells and each has a single nucleus. Healthy embryos are not fragmented (due to cell breakdown). These embryos are identified under the microscope. The problem with morphology is that many unhealthy embryos are good looking. the prediction ability of morphology in detecting chromosomally normal embryos is probably 60% or less. Morphology, however is non invasive and cheep. Extended vulture is used to push embryos to day 5 to observe which embryo will reach the blastocyst stage and select it for transfer. Blstocysts have generally higher implantation rates than day 3 embryos because of the ability to select the better embryos. Extended culture is employed when many embryos are available on day 3 (usually five or more).
  4. Genetic analysis of eggs or embryos: The most important point to know about genetic analysis of eggs and embryos is that PGD does not create a new potential or improve the overall success for fertility treatment for a given stimulation cycle. It just detects fairly accurately (not 100% accurate) the chromosome makeup of eggs or embryos. The potential advantage of PGD is to directly select the embryo, out of available cohort, that is most likely to implant instead of selecting based on morphology. Thus it maybe helpful for women with large number of embryos available on day 3 and day 5. In other words if you have two embryos available on day 3 and you are transferring two embryos, there is no point in testing them. On the other hand if you have eight embryos on day 3 and you will only transfer 1-2 embryos, then PGD may makes sense to go directly to the embryos most likely to work.

The potential disadvantages of PGD are the need for embryo biopsy that potentially may harm the embryo. PGD assumes that the cell obtained represents the whole embryo while sometimes that cell chromosomes maybe different than the embryo. The method for analysis used is not 100% accurate. In other words the method may misdiagnose a healthy embryo as abnormal or vice versa or on occasions fail to diagnose the embryo at all. PGD is expensive requiring embryo biopsy and embryo genetic analysis.

So far no large scientific studies are available and reproduced by many centers indicating increase in fertility potential of IVF. Because of all these factors, PGD is selectively applied to select patients and not a universal step in all IVF cycles.

Other methods suggested as supplements as well experimental methods as mitochondrial transfer still lack scientific evidence that they work.