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Breast cancer drug olaparib depletes the storage of immature eggs in mouse ovaries



Breast cancer drug olaparib depletes the storage of immature eggs in mouse ovaries

No DNA damage is detected in normal mouse primordial eggs (stained green). However, in addition to killing the primordial egg, olaparib causes DNA damage in some surviving eggs, suggesting that the eggs die sooner or are too poor in quality to produce a healthy baby. doing. Credit: Human Reproduction

Australian researchers first showed that a new drug used to treat breast cancer patients damages a reservoir of immature eggs in the ovaries of mice.

Author of the study announced today Human reproduction, One of the world’s leading journals of reproductive medicine, the drug olaparib not only treats young people, With breast It is caused by mutations in the BRCA1/2 gene, but its effects on fertility are unknown.

Their study shows that olaparib destroys a significant proportion (36%) of immature eggs contained in a structure called the primitive follicle. Females are born with a limited number of follicles in the ovaries, and during the reproductive life some eggs (or oocytes) are released from the ovaries and begin to grow to the point where they can be fertilized by sperm. Therefore, the loss of follicle store due to damage from It may affect female fertility.

Olaparib is not used This study in mice is an important indicator of its effect, as it is long enough to see how it affects their fertility.

“We’re pleased to announce that Dr. Amy Winship, a lead researcher at Monash University’s Biomedicine Discovery Institute (Melbourne, Australia), is the lead author of the study. “There are differences in species, such as the number of eggs ovulated during the menstrual cycle, but many important similarities that make mice an excellent model for studying the human ovary: preservation and activation of primordial follicles, The processes of growth and ovulation are all the same.

“Infertility is often overlooked in many safety studies in animal models and preclinical studies. New anti-cancer drug. However, we know that this is an important and valid concern for young cancer patients and survivors, especially as survival rates for many cancers have improved. We have shown for the first time that olaparib is detrimental to immature eggs stored in the ovaries and produces the mature eggs needed to maintain fertility and normal hormone levels. “

Olaparib inhibits DNA repair by blocking the action of a family of enzymes called poly(ADP-ribose) polymerase or PARP. Therefore, this drug is used to prevent cancer cells from repairing themselves and continuing to replicate and grow. Approved for use of olaparib in 2018 For BRCA1/2 breast cancer that has spread (metastasized) to other parts of the body. OlympiA, a randomized controlled trial, is currently investigating its use in women with early, potentially curable BRCA1/2 breast cancer who have not yet metastasized. Many of these are young women who have not yet begun or completed a family.

Breast cancer drug olaparib depletes the storage of immature eggs in mouse ovaries

The ovaries of this normal mouse show two healthy primordial follicles, including eggs (control, left). However, after olaparib, it is rich in primitive egg follicle debris, suggesting that this new breast cancer drug kills eggs. Credit: Human Reproduction

The researchers gave mice a single dose of chemotherapy (cyclophosphamide, doxorubicin, carboplatin, or paclitaxel) or placebo, followed by olaparib or placebo daily for the next 28 days. The mouse was then humanely killed and the researchers counted the number of ovarian primitive and growing follicles. They also counted the remaining number of follicles in which the eggs were destroyed.

“We found that olaparib significantly reduced primordial follicles by 36% compared to the ovaries of drug-free mice,” said Dr. Winship. “In mice receiving olaparib, a significant accumulation of residual primordial follicles was detected, but these were barely detected in the ovaries of naive mice.

“If a drug kills a growing egg, ovulation and fertilization can be temporarily affected, but more eggs are activated from an immature primitive stockpile and ovulation resumes normally. In contrast, when the primordial egg is killed, this is more serious, which can lead to complete infertility and premature menopause if the stockpiles are exhausted. “Olaparib kills the primitive, but the eggs and follicles do not grow.”

Although mice treated with chemotherapy had reduced numbers of primordial follicles in the ovaries, researchers found that olaparib did not exacerbate this loss compared to mice that received chemotherapy but not olaparib. I found that.

In their paper, the researchers conclude: Numbers are impossible in women, our data presented here have important clinical implications. Female cancer patients may have clinically regular menstrual cycles and serum AMH levels within the normal range after treatment with olaparib, but unknowingly have a markedly reduced ovarian reserve of primordial follicles. I will. Poor ovarian reserve leads to infertility and premature menopause. Therefore, fertility counseling should be considered for young female patients prior to olaparib treatment. “

Anti-Muller Hormone (AMH) is often used to assess the reserve of ovarian follicles in women, but AMH levels are not affected by olaparib and give false reassurance between women and their fertility physicians. May lead to.

Professor Kerry Ann Phillips is an oncologist and author of the article at the Peter McCallum Cancer Center in Melbourne, Australia. She said: “Olaparib’s Olympia A trial includes young women with early-stage breast cancer, but the drug is currently approved for use only in metastatic women People who have inadequate storage of fertility treatments. However, in the future, olaparib and similar drugs may be approved for use in young women for the purpose of curing the disease, and for these women, maintaining fertility is an important consideration. .. Therefore, understanding the effects on ovarian function is very important and encourages researchers to consider measuring ovarian function and fertility in future clinical trials.

Maintaining fertility includes removing and freezing ovarian tissue, follicles, or mature eggs prior to treatment with chemotherapy. Or other anti-cancer treatments that may damage the ovaries and ..

Olaparib maintenance prolongs PFS for an estimated 3 years in advanced ovarian cancer

For more information:
Amy L Winship et al., PARP Inhibitor olaparib Depletes Ovarian Reserve in Mice: Impact on Fertility Maintenance, Human reproduction (2020). DOI: 10.1093 / humrep / deaa128

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