Sep. 22, 2012 New research offers hope to women whose fertility has been compromised by the side-effects of cancer therapy or by premature menopause.
In a study published in Molecular Cell, researchers from the Walter and Eliza Hall Institute (WEHI), Monash University and Prince Henry's Institute of Medical Research found that two proteins, PUMA and NOXA, cause the death of egg cells in the ovaries. Blocking the activity of the proteins may lead to new strategies to protect women's fertility.
The team, including Associate Professor Jeffrey Kerr from Monash, Associate Professor Clare Scott, Dr Ewa Michalak and Professor Andreas Strasser from WEHI and Dr Karla Hutt and Professor Jock Findlay from PHI, focused their studies on egg cells called primordial follicle oocytes, which provide each woman's lifetime supply of eggs. Low numbers of these egg cells can also cause early menopause.
Associate Professor Clare Scott, an oncologist at The Royal Melbourne and Royal Women's hospitals, said the research showed that when the DNA of egg cells is damaged following exposure to radiation or chemotherapy, PUMA and NOXA trigger the death of the damaged eggs, leading to infertility in many female cancer patients.
"PUMA and NOXA can trigger cell death, and have been found to be necessary for the death of many different cell types in response to DNA damage," Associate Professor Scott said.
"This removal of damaged cells is a natural process that is essential to maintaining health but, for women undergoing cancer treatment, can be devastating when it leads to infertility."
Associate Professor Kerr said that when these egg-producing cells were missing the PUMA protein they did not die after being exposed to radiation therapy.
"This might ordinarily be cause for concern because you want damaged egg cells to die so as not to produce abnormal offspring," he said.
"To our great surprise we found that not only did the cells survive being irradiated, they were able to repair the DNA damage they had sustained and could be ovulated and fertilised, producing healthy offspring. When the cells were also missing the NOXA protein, there was even better protection against radiation."
Future treatments could block the function of PUMA, preventing egg cell death in patients undergoing chemotherapy or radiation.
Professor Jock Findlay, head of the Female Reproductive Biology Group at PHI, said the study could also have implications for delaying menopause.
"We know that the timing of menopause is influenced by how many egg cells a female has," he said. "Interventions that slow the loss of egg cells from the ovaries could delay premature menopause, prolonging female fertility, such a treatment could have the potential to reduce menopause-associated health conditions, such as osteoporosis and heart disease."
The research was supported by National Health and Medical Research Council, Cancer Council Victoria, the Victorian Cancer Agency, the US Leukemia and Lymphoma Society, the US National Cancer Institute, the American Cancer Society, and the Victorian Government.
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- Jeffrey B. Kerr, Karla J. Hutt, Ewa M. Michalak, Michele Cook, Cassandra J. Vandenberg, Seng H. Liew, Philippe Bouillet, Alea Mills, Clare L. Scott, Jock K. Findlay, Andreas Strasser. DNA Damage-Induced Primordial Follicle Oocyte Apoptosis and Loss of Fertility Require TAp63-Mediated Induction of Puma and Noxa. Molecular Cell, 2012; DOI: 10.1016/j.molcel.2012.08.017
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