EFA Medical Conference 2017: "Fertility Preservation to BRCA Mutations" Presentation by Dr. Kutluk Oktay

Dr. Kutluk Oktay from the Yale University School of Medicine discussed the molecular mechanisms that cause aging within the ovaries, which ultimately leads to a decrease in fertility.

Key Points

Highlights:

• Dr. Kutluk Oktay from the Yale University School of Medicine presented the molecular mechanisms that cause decreased fertility over time at the EFA 2017 Medical conference.

Importance:

• Fertility is a concern for women suffering from cancer and endometriosis. 

Key points:

• Women are born with a set number of eggs, also called primordial follicles, which are initially inactive but later start growing through an undetermined process.
• Anti-Müllerian hormone is a marker that is used to determine ovarian reserve.
• As women age, the million or so eggs present in the body, decrease. This decrease is steep once a woman is 37-38. By the time a woman is 50 usually nothing left in her reserve.  From a million of eggs, she only ovulates about 500 throughout her life. 37 also is the age at which a lot of declines are noticed especially concerning natural fecundity or fertility and IVF success rate. Furthermore, there is also a sharp decline in the percent of oocytes with normal chromosomes.
• In patients with breast cancer, Aromatase inhibitors are used instead of ovarian stimulation to keep estrogen levels low while trying to obtain viable oocytes for fertility preservation. Aromatase inhibitors have also been used in endometriosis treatment.
  • Using aromatase inhibitors for fertility preservation yielded fewer eggs for individuals with the BRCA mutation. There are two BRCA genes, on chromosomes 13 and 17 respectively, and they have a role in DNA repair.
• A double strand DNA break is more severe than a single strand break because there is not a template DNA for the repair.
• Oocytes use a process called homologous recombination where a sister chromatid is copied and then used for repair; however, this process can lead to severe mutations. This complex pathway includes the following key players:
  • MRE11 is part of the MRN complex, and it works by sensing the DNA damage
  • BRCA1 and BRCA2 genes work on repairing the damage - Women that have a BRCA1 mutation were also found to have fewer follicles in their ovarian reserve.
  • ATM is an orchestrator that directs other molecules
  • Histone H2AX protein marks the location of the injury. The stains that bind to H2AX to show the extensiveness of the damage. Follicles in older women have higher levels of H2AX.
• Over time there is a decline in critical DNA repair genes, including BRCA1. That being said, there was no significant decline over time for BRCA2; but it declines significantly only after a woman’s reproductive years had passed.
• Studies show that the homologous recombination DNA repair mechanism may play a big part in ovarian aging.

• Is it possible to manipulate the oocyte DNA repair mechanism?
  • Chemicals like interfering RNA (siRNA) can be injected into cells to block genes individually. cDNA and mRNA can also be inserted to produce more of the enzymes of interest.
  • When genes are blocked, DNA damage and cell death increase whereas survival decreases.
  • Injecting cDNA was found to increase oocyte survival to levels that were comparable to that of a young oocyte.
  • An individual that carries the BRCA mutation has decreased density of primordial follicles. Additionally, these women have a faster rate of decline of their follicles and an increased rate of DNA damage accumulation. The conclusion is, "the women with the BRCA mutation experience accelerated aging in their ovaries".
• Overall, as women age, their DNA repair mechanism is not as efficient. The BRCA gene cannot function as well as it did before. The resulting oocytes are more susceptible to death, or a baby with many abnormalities could be produced. Less of these cells are available with age as the body’s survival mechanism works hard to get rid of these damaged oocytes.
• A similar pattern has been seen in sperm. Sperm from a BRCA mutant male has more DNA damage and is less likely to implant.

Lay Summary

Dr. Kutluk Oktay is the Director of the Laboratory of Molecular Reproduction & Fertility Preservation as well as a Professor of OBGYN at Yale University School of Medicine. Dr. Oktay also presented at the EFA 2017 Medical Conference, and his presentation was titled “Fertility Preservation to BRCA Mutations: A Path to Discovering Mechanisms and Manipulation Ovarian Aging.”

Dr. Oktay begins his presentation by stating that a woman has a set number of eggs at birth. This amount decreases over time, but there is a significant and steep decrease at the age of 37. 37 is also the age at which there is a decrease in natural fertility, IVF success, and percent of oocytes with normal chromosomes. Dr. Oktay proceeds to speak briefly about fertility preservation protocol that is used for women with breast cancer. In fact, the aromatase inhibitors used for fertility preservation in breast cancer patients are very similar to the treatment prescribed for individuals suffering from endometriosis. Thus another link is drawn between breast cancer and endometriosis.

In the latter part of his lecture, Dr. Oktay focuses on the molecular mechanisms that drive this oocyte aging. Dr. Oktay begins by describing the problems associated with double-strand breaks and the process of homologous recombination that is used to fix the double-strand break. He explains critical players in this process including MRE11, BRCA1, BRCA2, ATM, and Histone H2AX. Dr. Oktay then proceeds to delineate various studies related to aging and fertility. Some of these studies look at the levels of different genes and molecules in oocytes as a woman ages, whereas others hope to reverse the process. In short, the process of aging is accompanied by less efficient DNA repair mechanisms. Some of this loss of functionality can be attributed to the decreased effectiveness of genes like BRCA1. As a result, these faulty older oocytes cannot survive, or the baby conceived has a higher risk of having various abnormalities. A similar pattern is also seen with male aging in that an old sperm is more likely to have DNA damage and is less likely to implant.

Dr. Oktay’s entire presentation can be found at the following link: https://www.endofound.org/video/fertility-preservation-to-brca-mutations-a-path-to-discovering-mechanisms-and-manipulation-of-ovarian-aging-kutluk-oktay-md-phd-facog/1562.