Reproductive aging refers to the natural process through which the reproductive system undergoes age-related changes and functional declines over time. This process has been closely associated with reduced reproductive capacity and fertility. Still, its impacts are much more far-reaching, and more needs to be done to combat reproductive aging.
In this series of articles, we will discuss what we currently know about reproductive aging – the biological process and its major health impacts, what treatments are available or being studied for it, and, importantly, what we can effectively do about it today.
This is the first article in our three-part “Fertility in Focus” series, where we explore the mechanisms driving reproductive aging, look at the latest treatments, debunk common misconceptions, and examine promising drug candidates and lifestyle interventions.
- Understanding Reproductive Aging
- Reproductive Treatments and Common Misconceptions
- Promising Drug Candidates and Lifestyle Strategies
Table of Contents
- The Biological Clock: How Female Fertility Declines with Age
- The Biology of Ovaries
- The Impacts of Ovarian Aging
- Extending Fertility and Health for Women
The Biological Clock: How Female Fertility Declines with Age
In women, it is widely known that fertility declines with age. After the age of approximately 37, a woman’s ability to become pregnant significantly decreases, and it becomes rare for pregnancy to occur after the age of 45.
Around the age of 50, menopause takes place, which is defined as the permanent cessation of menstrual period that marks the end of a woman’s reproductive stage. Menopause is also a risk factor in many age-related diseases.
The focus on female reproductive aging in scientific research and societal discussions is often more pronounced compared to male reproductive aging. This is mainly because, compared to women who have a finite number of eggs that decline continuously across age, men can produce sperm throughout their lives. Nevertheless, they still experience several age-related changes that can impact their reproductive health and fertility, including a gradual decline in sperm quality, quantity, and motility, reduced testosterone levels, and changes in sexual function.
Though not all men experience these changes, and individual variations exist, these age-related changes can lead to undesirable impacts on a man’s family and personal life, including an increased risk of genetic abnormalities in the offspring, a longer time to achieve pregnancy and lower sexual performance.
While it is important to recognize that male reproductive aging also has many implications, and recent research has been shedding light on this topic, in this series of articles, we will focus on female reproductive aging.
It’s worth noting that women tend to live longer than men in many parts of the world – around 7 years longer in developed countries. The ovaries, which are the female reproductive organs, age much earlier and faster compared to the rest of the body. Every woman is born with about 1-2 million eggs in her ovaries, and this number gradually declines over time. After the age of 31, the decline accelerates, and the quality of the eggs decreases, leading to a gradual loss of fertility. Additionally, the production of estrogen, an important hormone, declines as the number of eggs decreases. When the number of eggs drops below 1000, a woman reaches natural sterility (menopause), which usually happens around the age of 50. (Zhu et al., 2022) (Broekmans et al., 2009)
By medical definition, if a woman over the age of 45 stops having periods for more than 12 months (and is not pregnant), she is considered to have reached menopause. Yet, with even longer lifespans, women spend a significant portion of their lives in menopause.
Before delving into ovarian aging, let’s start by talking about the biology of the ovaries.
The Biology of Ovaries
The ovaries are the central organ in the female reproductive system. Ovaries play a crucial role in regulating menstrual cycles and determining a woman’s reproductive lifespan and overall reproductive health. The ovarian follicles within the ovaries are the key functional units responsible for supporting egg (oocyte) maturation during each menstrual cycle. These eggs are the female gametes that carry genetic information and provide essential nutrients for embryo development upon successful fertilization. A larger pool of ovarian follicles with higher quality indicates a longer reproductive lifespan.
The ovarian follicles consist of specialized cells called granulosa and thecal cells, which surround and support the growth of eggs. These cells serve as an energy source for producing vital reproductive hormones. The thecal cells produce progesterone and androgens, while the granulosa cells produce estrogens. These reproductive hormones, especially estrogens, play a crucial role in maintaining female reproductive health and have beneficial effects on various biological systems.
Likewise, progesterone, often referred to as the “pregnancy hormone,” was traditionally believed to impact only the reproductive system, but it has now been found to be involved in neuro-regeneration and take a protective role in brain and breast tissue. Since the number of ovarian follicles is determined at birth in girls and represents their ovarian reserve for a lifetime, the irreversible decline in both the quantity and quality of follicles as women age ultimately leads to the end of their reproductive lifespan and a decline in overall health. Consequently, women born with a limited number of ovarian follicles or those experiencing accelerated follicle depletion will reach menopause earlier.
Menopause is a stage where the number of eggs in the ovaries is so low that there isn’t enough estrogen to stimulate the uterus and cause regular menstrual bleeding. Unfortunately, 1% of women experience premature ovarian insufficiency (POI), which means they go through menopause before the age of 40 due to a premature and irreversible loss of eggs (Laven et al., 2015). It’s important to note that several chronic diseases are influenced by the onset of menopause. These include increased risks of neurocognitive decline, cardiovascular diseases, metabolic issues, muscle loss, insulin resistance, osteoporosis, and sexual dysfunction.
The Impacts of Ovarian Aging
The most direct impact of reproductive aging in women is reduced fertility, which increases the likelihood of miscarriage and birth defects, making age the most significant risk factor for infertility. In fact, other risk factors for infertility, such as medical conditions including polycystic ovarian syndrome (PCOS), endometriosis, uterine fibroids and hormonal imbalances, have also been found to be age-related. However, the impacts of ovarian aging entail more than a mere decline in fertility because follicle depletion also leads to the loss of protective female sex hormones. Here, we list four major impacts of ovarian aging on a woman’s general well-being.
1. Perimenopausal symptoms
Perimenopause is a critical phase in a woman’s life. The term “perimenopause,” meaning “around menopause,” signifies the natural transition to menopause, characterized by a gradual cessation of reproductive function and the end of the menstrual cycle. Typically commencing in the late 40s, this stage sees a decrease in estrogen and progesterone production by the ovaries, resulting in irregular periods and various accompanying symptoms. Common complaints during perimenopause include hot flashes (sudden sensations of intense heat), night sweats, sleep disturbances, mood swings, and vaginal dryness. Although the biological mechanisms behind these symptoms are not entirely understood, they are largely attributed to hormonal level reductions.
Hot flashes and night sweats are believed to be linked to changes in the brain’s hypothalamus, the body’s temperature regulator, which can be disrupted by declining estrogen levels. Hormonal fluctuations may also impact the activity of neurotransmitters like serotonin, leading to mood swings and emotional changes that contribute to feelings of irritability, anxiety, and depression. Likewise, perimenopausal hormonal shifts can disturb the sleep-wake cycle and affect sleep-regulating brain regions, causing sleep disturbances such as difficulty falling and staying asleep, as well as non-restorative sleep. Night sweats can further exacerbate sleep quality (Finch et al., 2014).
Beyond symptoms related to the central nervous system, diminishing estrogen levels can induce vaginal dryness, along with thinning and reduced elasticity of vaginal tissues. This decrease in natural lubrication can result in discomfort, pain, and irritation during sexual activity and may heighten the risk of urinary tract infections. These perimenopausal symptoms can persist with varying intensity even after women transition into postmenopause (i.e., after menopause) (Gimenez et al., 2013).
2. Bone loss
Another major impact of menopause on women’s health is bone loss. Estrogen is crucial in maintaining bone health by promoting bone formation and inhibiting bone resorption. The receptors for estrogen (ER) are found in musculoskeletal tissues, and estrogen stimulates the activation and growth of muscle stem cells during repair (Khosla et al., 2012).
As women reach menopause, the decrease in estrogen levels results in increased bone resorption by osteoclasts, the cells responsible for breaking down old bone tissue. Simultaneously, the formation of new bone by osteoblasts, the cells responsible for forming, growing, and healing bones, becomes less efficient (Krum et al., 2008). Although this complex effect has not been fully elucidated yet, this process is thought to be facilitated by a factor called RANKL, a cytokine involved in bone resorption, which is normally suppressed by estrogen. It has been found that changes in the TGFβ signaling pathway with an immunomodulatory effect from lymphocytes (a type of white blood cells) may be involved too (Streicher et al., 2017). Over time, a decrease in estrogen results in a loss of bone mass and density, causing bones to become more porous and weaker. Studies on female ERα knockout mice have shown significant bone loss similar to that observed in rodents whose ovaries have been surgically removed (Yousefzadeh, et al., 2020).
The loss of bone mass during menopause can result in a condition called osteoporosis, characterized by fragile and brittle bones prone to fractures, even with minor trauma. Osteoporosis increases the risk of fractures in various body parts, including the spine, hip, and wrist. Women typically experience accelerated bone loss during the first few years after menopause, and the rate of bone loss may slow down but continue throughout the postmenopausal years.
This period of rapid bone loss highlights the critical importance of managing bone health during and after menopause. Particularly, postmenopausal women often experience a negative calcium balance that gradually stabilizes over time but remains tilted towards calcium loss. The malabsorption of calcium can compound the onset of osteoporosis. NOVOS Core includes calcium, an essential nutrient for bone strength. Adequate calcium intake, combined with sufficient vitamin D, is crucial for effective calcium absorption from the gut, supporting overall bone health.
3. Cardio-metabolic risk
Recent studies have shed light on increased cardiovascular and metabolic risks in women after menopause, in contrast to their premenopausal counterparts. This has been linked to disrupting the balance of sex hormones in the body, leading to significant implications for obesity and glucose regulation.
Sex hormones are known to regulate the distribution of visceral fat in humans, and in particular, estrogen appears to have a protective effect on cardiovascular health in premenopausal women. Experimental models indicate that estrogen is an anti-inflammatory agent, retarding the onset and progression of cardiovascular disease (CVD)(Babiker et al., 2004). This clarifies why premenopausal women have lower CVD risk than men and postmenopausal women (Lerner et al. 1986). With a decline in sex hormone levels, postmenopausal women have shown disrupted lipid profiles, including changes in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglycerides (TGs), and total cholesterol (TC), alongside impaired glucose tolerance (Lorga et al., 2017) (Knowlton et al., 2012). Moreover, postmenopausal women risk developing insulin resistance, a condition of reduced responsiveness to pancreatic insulin in target tissues, which results in type 2 diabetes (Kirtikar et al., 2020).
4. Neurocognitive risk
It is more common for women to complain about cognitive function issues compared to men, especially in postmenopausal women rather than premenopausal women. The risk of developing dementia is also consistently higher in females. Additionally, women going through menopausal transition may experience a decline in cognitive function, such as memory loss. Neuroimaging studies show menopause significantly predicts neurobiological changes associated with Alzheimer’s disease (AD), including brain volume reduction, decreased glucose metabolism, β-amyloid deposition, and synaptic loss.
Adjusted for age, postmenopausal cognitive performance, especially in verbal delayed memory and executive function, tends to be lower than during pre- and perimenopausal periods, potentially due to changing estrogen levels.
Studies indicate extended estrogen exposure throughout a woman’s life correlates with better cognitive outcomes. Reduced estrogen levels in menopause may affect systems like the basal forebrain cholinergic, dopaminergic, and mitochondrial bioenergetic systems, potentially leading to cognitive decline. Estrogen also modulates mitochondrial activity cellular respiration, and reduces inflammation (Russell et al., 2019) (Siddiqui et al., 2016). Although a deeper understanding of estrogen’s influence on cognition is needed, these findings suggest a strong link between menopausal estrogen changes and cognitive deterioration.
Other factors like age at first period (menarche), age at menopause, and reproductive history can affect neuropsychological test performance in postmenopausal individuals. There are mixed findings on the relationship between these reproductive factors and cognitive decline or dementia risk (Zárate et al., 2017). Surgical removal of ovaries (oophorectomy) before menopause increases the risk of cognitive impairment and dementia (Georgakis et al., 2019), while progesterone, another sex hormone, has shown potential benefits for neuro-regeneration and protection (Sitruk-Ware et al. 2013). However, the effects of Hormone Replacement Therapy (HRT) on neurocognitive function and dementia risk remain inconclusive and warrant further research.
Extending Fertility and Health for Women
The projected average lifespan has steadily increased to approximately 72.6 years (and 79.4 years in developed regions) for humans (United Nations, 2019). However, this progress has not been matched by a corresponding advancement in healthspan. Older individuals often contend with frailty and age-related health conditions affecting various organs. This predicament is further accentuated by ovarian or reproductive aging. In modern times, women have an extended post-reproductive lifespan, yet they face infertility and health risks due to the absence of sex hormones, resulting in an unchanged healthspan.
The divergence between healthspan and lifespan has underscored the idea that, particularly for individuals beyond a certain age, typically around 65 years old, the primary focus should extend beyond just prolonging life. Therefore, it’s crucial to determine when to intervene in women’s health to improve their reproductive and overall well-being. This may involve imitating the beneficial effects of estrogen after menopause while minimizing any negative consequences. This is a key aspect of reproductive longevity research, which aims to extend the time women can have children while enhancing their overall health and lifespan.
Reproductive longevity research has become more important due to longer lifespans and the growing trend of delaying marriage and having children later. For example, in many developed countries, the average age for having children has increased by about one year per decade.
However, pregnancies in women of higher maternal age are associated with an elevated likelihood of maternal obstetrical complications such as gestational diabetes, pre-eclampsia, and hypertension. Additionally, there are increased fetal risks, including aneuploidy (such as Down syndrome) and other birth defects (Pinheiro et al., 2019). These risks stem from the declining quality of ovarian follicles, which leads to the production of eggs of reduced quality as maternal age advances.
Considering these challenges, reproductive longevity research has two key objectives: extending the duration of fertility and improving reproductive and overall healthspan.
In our upcoming article, we will explore the current landscape of treatments targeting reproductive aging.
Lu DONG is a reproductive aging scientist affiliated with the Centre for Healthy Longevity at the National University of Singapore (NUS). She is currently pursuing her PhD in the field of drug repurposing and natural products for female reproductive longevity, working under the supervision of Prof. Brian Kennedy.
Lu was honored with the Singapore Agency for Science, Technology, and Research (A*STAR) Undergraduate Scholarship and earned her Bachelor of Science (Pharmacy) degree with first-class honors from the National University of Singapore in 2020. Upon graduation, she was awarded the prestigious Integrative Sciences and Engineering Programme Scholarship in NUS for her PhD journey. Lu has given talks on female reproductive aging at international conferences such as the Bia-Echo Asia Centre for Reproductive Longevity and Equality (ACRLE) Conference 2022. She has also published a review article: “Unraveling female reproductive senescence to enhance healthy longevity” in Cell Research.
- Mills, M. C. & Tropf, F. C. The Biodemography of Fertility: A Review and Future Research Frontiers. Kolner Z Soz Sozpsychol 67, 397-424, doi:10.1007/s11577-015-0319-4 (2015).
- Khosla, S., Oursler, M. J. & Monroe, D. G. Estrogen and the skeleton. Trends Endocrinol Metab 23, 576-581, doi:10.1016/j.tem.2012.03.008 (2012).
- Babiker, F. A. et al. 17beta-estradiol antagonizes cardiomyocyte hypertrophy by autocrine/paracrine stimulation of a guanylyl cyclase A receptor-cyclic guanosine monophosphate-dependent protein kinase pathway. Circulation 109, 269-276, doi:10.1161/01.Cir.0000105682.85732.Bd (2004).
- Battaglia, D. E., Goodwin, P., Klein, N. A. & Soules, M. R. Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Hum Reprod 11, 2217-2222, doi:10.1093/oxfordjournals.humrep.a019080 (1996).
- Broekmans, F. J., Soules, M. R. & Fauser, B. C. Ovarian Aging: Mechanisms and Clinical Consequences. Endocrine reviews 30, 465-493, doi:10.1210/er.2009-0006 (2009).
- Finch, C. E. The menopause and aging, a comparative perspective. J Steroid Biochem Mol Biol 142, 132-141, doi:10.1016/j.jsbmb.2013.03.010 (2014).
- Iorga, A. et al. The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy. Biol Sex Differ 8, 33, doi:10.1186/s13293-017-0152-8 (2017).
- Iorga, A. et al. Rescue of Pressure Overload-Induced Heart Failure by Estrogen Therapy. J Am Heart Assoc 5, doi:10.1161/jaha.115.002482 (2016).
- Kirtikar, U., Kajale, N., Patwardhan, V., Khadilkar, V. & Khadilkar, A. V. Cardiometabolic Risk in Pre- and Post-Menopausal Women with Special Reference to Insulin Resistance: A Cross-Sectional Study. J Midlife Health 11, 22-26, doi:10.4103/jmh.JMH_65_19 (2020).
- Knowlton, A. A. & Lee, A. R. Estrogen and the cardiovascular system. Pharmacol Ther 135, 54-70, doi:10.1016/j.pharmthera.2012.03.007 (2012).
- Lerner, D. J. & Kannel, W. B. Patterns of coronary heart disease morbidity and mortality in the sexes: A 26-year follow-up of the Framingham population. American Heart Journal 111, 383-390, doi:https://doi.org/10.1016/0002-8703(86)90155-9 (1986).
- Mesiano, S. & Jones, E. E. in Medical physiology. 3rd ed. (eds WF Boron & EL Boulpaep) (Elsevier, 2017).
- Pellestor, F., Anahory, T. & Hamamah, S. Effect of maternal age on the frequency of cytogenetic abnormalities in human oocytes. Cytogenetic and Genome Research 111, 206-212, doi:10.1159/000086891 (2005).
- Richardson, S. J. & Nelson, J. F. Follicular Depletion during the Menopausal Transition. Annals of the New York Academy of Sciences 592, 13-20, doi:10.1111/j.1749-6632.1990.tb30312.x (1990).
- Russell, J. K., Jones, C. K. & Newhouse, P. A. The Role of Estrogen in Brain and Cognitive Aging. Neurotherapeutics 16, 649-665, doi:10.1007/s13311-019-00766-9 (2019).
- Siddiqui, A. N. et al. Neuroprotective Role of Steroidal Sex Hormones: An Overview. CNS Neurosci Ther 22, 342-350, doi:10.1111/cns.12538 (2016).
- Sitruk-Ware, R. & El-Etr, M. Progesterone and related progestins: potential new health benefits. Climacteric 16 Suppl 1, 69-78, doi:10.3109/13697137.2013.802556 (2013).
- Vitale, C., Mendelsohn, M. E. & Rosano, G. M. C. Gender differences in the cardiovascular effect of sex hormones. Nature Reviews Cardiology 6, 532-542, doi:10.1038/nrcardio.2009.105 (2009).
- Wilkinson, H. N. & Hardman, M. J. The role of estrogen in cutaneous ageing and repair. Maturitas 103, 60-64, doi:10.1016/j.maturitas.2017.06.026 (2017).
- Yang, X. P. & Reckelhoff, J. F. Estrogen, hormonal replacement therapy and cardiovascular disease. Curr Opin Nephrol Hypertens 20, 133-138, doi:10.1097/MNH.0b013e3283431921 (2011).21 Zárate, S., Stevnsner, T. & Gredilla, R. Role of Estrogen and Other Sex Hormones in Brain Aging. Neuroprotection and DNA Repair. Front Aging Neurosci9, 430-430, doi:10.3389/fnagi.2017.00430 (2017).