Pharmacological Strategies to Delay Ovarian Aging: A Review
By: Olivia Beck
Director’s Note: As the average maternal age at first pregnancy rises, so has interest in methods to delay ovarian aging to maximize fertility and overall health. Through her summary of the article, “Can Ovarian Aging be Delayed by Pharmacological Strategies?” [6] by Zhang et al, former FACTS elective student Olivia Beck reviews potential interventions ranging from antioxidant supplementation to epigenetic strategies. She also highlights how charting with fertility awareness-based methods (FABMs) can help identify effects of ovarian aging earlier and support the management of infertility. To learn more about the role of medications and supplements to address infertility in women and men, join us in Austin April 19-20, to hear from Dr. Christine Hemphill-Jones and Dr Craig Turczynski. Registration closes THIS FRIDAY, so SIGN UP today!
Introduction
The absence of ovarian hormones increases the risk of mortality in women, a fact supported by data from patients in surgical menopause after oophorectomy and observational studies of natural menopause. Physiologic and surgical menopause are independent risk factors for cardiovascular disease, osteoporosis, and cognitive decline. [1][2][3][4] As the world’s population ages, the prevalence of women in postmenopause rises, and a longer duration without ovarian hormones has significant implications on their health. The ovaries age exponentially, with a lifespan predetermined at birth. [5] This presents further challenges as more women now choose to delay childbearing, and many experience fertility difficulties. The ovary’s impact on women’s health and fertility begs the question of whether it is possible to prolong its lifespan.
Antioxidants and Ovarian Aging
Aging is the result of a complex interaction between external environment, lifestyle, genetic factors, cellular events, and poorly understood physiologic processes. One proposed concept for ovarian aging involves the formation of reactive oxygen species (ROS) that damage DNA and mitochondria, leading to cellular apoptosis. ROS are formed through metabolic processes that utilize oxygen, and the body’s natural antioxidant system maintains a balance that limits damage caused by them. Throughout a person’s life, periods of increased stress lead to accumulation of ROS that can result in irreversible cellular damage. Evidence in mice demonstrates that exogenous antioxidants, specifically N-acetylcysteine (NAC), result in increased litter size and better egg quality and counteract the reproductive effects of free radical exposure. [5][6] NAC has also been shown to lengthen telomeres and increase telomerase activity. Telomeres act as protective caps on the ends of chromosomes; they are made of noncoding repeated DNA sequences that limit genetic degradation during replication. Telomerase is the enzyme that builds telomeres. Telomere length has been found to be correlated with life expectancy, oocyte quality, and age of menopause. [5]
“One proposed concept for ovarian aging involves the formation of reactive oxygen species (ROS) that damage DNA and mitochondria, leading to cellular apoptosis.”
More familiar antioxidants include vitamins C and E, which fortify cell membranes against free radical damage. In murine studies, they have been shown to increase the number and quality of oocytes. [6] Turmeric is another common antioxidant. In rat models, turmeric protects ovarian tissue from chemotherapeutic effects, increasing levels of endogenous antioxidants and strengthening the structure of eggs. Other antioxidants found commonly in fruits, vegetables, and tea leaves have also been found to increase ovarian reserve and inhibit oocyte apoptosis.
Coenzyme Q10 (CoQ10) is another potent antioxidant found endogenously within cell membranes and the electron transport chain. It is well-known for its role in the production of ATP within mitochondria. Studies have shown tissue concentrations of CoQ10 decrease with age. More specifically, decreased expression of enzymes involved in CoQ10 synthesis pathways results in phenotypic oocyte outcomes mirroring those found in mice that age naturally. [7] Rescue of these CoQ10-depleted mice with oral supplementation reversed the aging-associated changes in their reproductive system, including fortified ovarian reserve, increased ovulatory capacity, and higher-quality eggs as demonstrated by larger litters.
Through an unknown mechanism, decreasing caloric intake in various mammals has been shown to prolong their lifespan; in rats, it also slows ovarian aging. One proposed explanation involves the reduction of insulin, insulin-like growth factor (IGF-1), and blood sugar as well as renewing the body’s sensitivity to insulin. IGF-1 quantity has an inverse relationship to lifespan. Its receptor has been found mutated in people living past 100 years of age; in animal models, lower IGF-1 levels are associated with longevity. In a study from the United Kingdom, the insulin-sensitizing drug metformin reduced mortality and age-related morbidity in patients with type 2 diabetes. [7] Metformin has also been shown to increase ovulatory function in patients with polycystic ovary syndrome (PCOS). [6]
“Metformin has also been shown to increase ovulatory function in patients with polycystic ovary syndrome (PCOS).”
Another signaling molecule involved in pathways of cell growth and proliferation, mTOR, is also negatively associated with aging. Sirolimus, an mTOR inhibitor, prevents activation of too many ovarian follicles at once, extending longevity of ovarian reserve. Preliminary data suggest that harnessing epigenetic changes may enable control of aging-associated signaling pathways, such as mTOR. Epigenetic modifications alter phenotypic expression of genes without directly changing their DNA sequence. In murine models, use of epigenetic strategies to activate an inhibitor of mTOR improved oocyte quality and strengthened ovarian reserve by decreasing follicle degeneration. [6]
Hormones and Ovarian Aging
Hormones, the diverse set of long-distance chemical directors of complex processes such as puberty and menopause, are also potential targets to delay ovarian aging. Melatonin is produced by the pineal gland and colloquially associated with sleep; it has good evidence of slowing ovarian aging and increasing the quality of oocytes. [8] Levels of melatonin decrease throughout a person’s life alongside menopausal changes and declining ovarian reserve. Melatonin is an effective antioxidant and anti-inflammatory hormone with higher concentrations in healthy Graafian follicles than in blood. Its concentration also rises in calorie-restricted rodents.
“Melatonin … has good evidence of slowing ovarian aging and increasing the quality of oocytes.”
Oral melatonin supplementation is associated with upregulation of progesterone and estrogen production. In mice, melatonin supplementation led to increased follicle count, number of ovulations, and expression of ovarian genes when compared to non-supplemented mice of the same age. A study of women undergoing in vitro fertilization (IVF) found that after only 30 days of pre-treatment with melatonin, fertilization and pregnancy rates were higher compared to the control group. [[8]
Relevance of Fertility Awareness
As the average age at time of pregnancy rises and the population ages, methods to delay ovarian aging to enhance fertility and overall health will become increasingly relevant. In women trained to chart their cycles, ovulatory dysfunction may present with a lack of fertile mucus, limited or no peak days, or a diminished luteal phase. [9] Educating women about fertility awareness-based methods (FABMs) provides valuable insight into the intricate functioning of their reproductive system. Knowledge of FABMs and charting could reveal effects of ovarian aging earlier, enhancing the likelihood of success when managing infertility. The strategies outlined here present potential supportive treatments that could be used to increase fertility and improve health. Initial data is promising, but more human studies are needed to elucidate whether these strategies delay ovarian aging in people, and if the delay truly improves health and fertility outcomes.
References
[1] Mytton, J., Evison, F., Chilton, P., & Lilford, R. (2017). Removal of all ovarian tissue versus conserving ovarian tissue at time of hysterectomy in premenopausal patients with benign disease: study using routine data and data linkage. BMJ, 356-372.
[2] Parker WH, Broder MS, Chang E, et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses’ health study. Obstet Gynecol. 2009;113(5):1027-1037. doi:10.1097/AOG.0b013e3181a11c64.
[3] Cummings, S., Browner, W., Bauer, D., Stone, K., Ensrud, K., Jamal, S., & Ettinger, B. (1998). Endogenous hormones and the risk of hip and vertebral fractures among older women. Study of Osteoporotic Fractures Research Group. New England Journal of Medicine, 733-738.
[4] Rocca, W., Bower, J., Maraganore, D., Ahlskog, J., Grossardt, B., de Andrade, M., & Melton, L. (2007). Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology, 1074-1083.
[5] Park, S., Walsh, L., & Berkowitz, K. (2021). Mechanisms of ovarian aging. Reproduction, R19-R33.
[6] Zhang J, Chen Q, Du D, et al. Can ovarian aging be delayed by pharmacological strategies? Aging (Albany NY). 2019;11(2):817-832. doi:10.18632/aging.101784.
[7] Ben-Meir A, Burstein E, Borrego-Alvarez A, et al. Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging. Aging Cell. 2015;14(5):887-895. doi:10.1111/acel.12368.
[8] Reiter RJ, Sharma R, Romero A, et al. Aging-Related Ovarian Failure and Infertility: Melatonin to the Rescue. Antioxidants (Basel). 2023;12(3):695. Published 2023 Mar 11. doi:10.3390/antiox12030695.
[9] Vigil P, Blackwell LF, Cortés ME. The Importance of Fertility Awareness in the Assessment of a Woman’s Health: A Review. Linacre Q. 2012;79(4):426-450. doi:10.1179/002436312804827109.
ABOUT THE AUTHOR
Olivia Beck
Olivia Beck is a fourth-year medical student at Pacific Northwest University of Health Sciences in Washington state. She completed her undergraduate education at the University of Redlands in California. She was born and raised in rural Alaska and is interested in improving the health outcomes of rural women. She is pursuing residency in obstetrics and gynecology with plans to return home to provide comprehensive care and health education to women in Alaska. As a future physician planning to specialize in women’s health, she enrolled in the FACTS elective from a sense of responsibility to be fully informed about all contraceptive and fertility-based methods of family planning.
