Fertility in Focus: Reproductive Treatments and Common Misconceptions

Before we can decelerate, halt, or potentially even reverse reproductive aging, we must look at the fundamental mechanisms propelling this process. Ovarian aging constitutes a multifaceted progression of gradual decline and eventual depletion of ovarian functional units, namely the follicles and ovarian functions. This intricate journey involves continuous interplay with various other bodily components, notably the brain. While only partially understood, numerous underlying factors have been postulated, and in this article, we will cover some of the more extensively explored ones.

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This is the second 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.

1. Understanding Reproductive Aging
2. Reproductive Treatments and Common Misconceptions
3. Promising Drug Candidates and Lifestyle Strategies

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Table of Contents

• The Driving Factors of Reproductive Aging
  • Endocrine Changes 
  • Oxidative Stress
  • Inflammation
  • Mitochondrial Dysfunction
• Reproductive Aging: A Look at Current Solutions and Approaches 
  • Hormone Replacement Therapy (HRT)
  • Assisted Reproduction Technologies (ART)
• Additional Misconceptions About Ovarian Aging

The Driving Factors of Reproductive Aging

1. Endocrine Changes 

The physiological process of ovarian aging is characterized by endocrine changes (hormonal changes), with a pivotal role played by the hypothalamic–pituitary–ovarian (HPO) axis. Within the HPO axis, the hypothalamus releases gonadotropin-releasing hormone (GnRH), which travels to the pituitary gland, triggering the secretion of two hormones: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). 

These hormones then travel to the ovaries through the bloodstream, stimulating the development of ovarian follicles and the synthesis of estrogen and progesterone (two important hormones in the female body) during the follicular and luteal phases of the menstrual cycle. 

Estrogen levels progressively rise through a positive feedback mechanism, culminating in an LH surge from the anterior pituitary gland, which serves as a trigger for ovulation. In a youthful ovary, multiple dormant primordial follicles with immature eggs activate and progress, and typically, only one follicle ultimately releases the mature egg/ovum (ovulation) as the dominant follicle. Both the developing follicles and those that have ruptured release sex hormones to contribute to the proper functioning of the ovaries. However, in an aging ovary or instances of premature ovarian insufficiency, the diminished number of ovarian follicles results in an estrogen deficiency, known as hypoestrogenism. 

Estrogen is a hormone essential for maintaining the regular functions of the female reproductive system. Despite a wealth of evidence showcasing the involvement of both the ovary and the HPO axis in the process of reproductive aging, ongoing debates persist regarding which of these factors serves as the primary driver (Neal-Perry et al., 2010). Notably, attempts to restore estrus cycles (similar to menstrual cycles in human women) by transplanting ovaries from young rats and mice into older ones proved unsuccessful (Peng, et al., 1972). This implies that ovarian aging cannot be attributed solely to ovarian function, leading to the hypothesis that the HPO axis plays a significant role in reproductive aging. Furthermore, clinical evidence indicates impaired LH surge responses in older women compared to their younger counterparts. (Park et al., 2002)

Disruptions in gonadotropin secretion, particularly FSH, were discernible before observable menstruation or ovulation failure (Ebbiary et al., 1994). While the precise trigger for HPO axis dysfunction and associated endocrine changes remains incompletely understood, neurotransmitters like glutamate, GABA, and kisspeptin may be involved.

As mentioned earlier, the reduction in ovarian follicles leads to the absence of estrogen, which impacts the reproductive process. Estrogen provides protective benefits for cardiovascular, musculoskeletal, and neurocognitive health. The epidemiological link between chronic illnesses and the onset of menopause suggests that women of reproductive age are less likely to experience these health issues than men. Consequently, as estrogen levels decline after menopause, women become more vulnerable to chronic conditions like osteoporosis, atherosclerosis, sarcopenia, and dementia.

2. Oxidative Stress 

The classical theory of aging, known as the free radical theory, postulates that the aging process is propelled by the gradual accumulation of oxidative stress within cells. According to this theory, the buildup of reactive oxygen species (ROS) leads to increased oxidative stress within the ovaries, which subsequently leads to modifications in the ovarian microenvironment. Consequently, this initiates cellular senescence and contributes to a decline in the quality and quantity of eggs. (Sasaki  et al., 2019)(Yan et al., 2022)

Indeed, scientific evidence has established a correlation between oxidative stress and the deterioration of eggs associated with aging. Prior research indicates that factors such as age, smoking, high-sugar diets, stress, superovulation, chemotherapy, and environmental pollutants can intensify ovarian aging by exacerbating oxidative stress (Dabbagh Rezaeiyeh et al., 2022). Earlier studies have also shown that older women undergoing in vitro fertilization (IVF) have higher levels of harmful ROS (reactive oxygen species) and lower levels of protective antioxidants in their eggs. (Appasamy et al., 2018) This phenomenon is also associated with the lack of success in assisted reproductive techniques (ART). (Becatti et al., 2018)

It’s worth noting that while the free radical theory was once thought to fully explain the aging process, it has since been found to be just one of the many contributors that we discuss.

3. Inflammation 

Prolonged and persistent inflammation contributes to accelerated aging within the body. A substantial body of evidence underscores the close association between chronic inflammation and ovarian aging and associated symptoms. 

The increased likelihood of women developing chronic inflammatory conditions such as osteoporosis and atherosclerosis after menopause can be attributed to reduced estrogen levels. Estrogen directly interacts with specific receptors in the body, known as ERα or ERβ (for more details on these receptors, refer to the first article in this series). This interaction prompts these receptors to relocate into the nucleus of cells, where they target specific genes responsible for regulating inflammation. Through this process, estrogen helps prevent a chain reaction of events that lead to inflammation. This interruption in the chain reaction impacts the generation and release of specific molecules that promote inflammation, such as TNFα, IL6, and IL1β. (Broekmans et al., 2009)

Studies have found that women with lower estrogen levels, like those experiencing premature ovarian insufficiency, tend to have higher levels of these molecules in their blood. (Lliberos et al., 2021) Additionally, estrogen can also influence how certain immune cells, called macrophages, respond on the cell surface. This is important because macrophages play a significant role in the inflammatory process by releasing certain signaling molecules. Consequently, as estrogen levels diminish post-menopause, women become more prone to chronic inflammatory conditions like osteoporosis, atherosclerosis, and sarcopenia. (Zavatta et al., 2023) This is consistent with the epidemiological correlation between chronic inflammatory ailments and the onset of menopause, suggesting a lower susceptibility to these coexisting health conditions in women of reproductive age when contrasted with men.

4. Mitochondrial Dysfunction

Mitochondria are like powerhouses in our cells, providing the energy needed for normal cell functions. The connection between mitochondrial dysfunction and cellular aging is widely recognized. In the context of ovarian function and fertility, mitochondria are highly significant since eggs contain a substantial number of them. As we age, changes happen in our mitochondria, like the accumulation of mutations in their DNA (mtDNA), disruptions in their energy production, and problems with their structure.

For instance, irregular mitochondrial DNA quantity, coupled with reduced mitochondrial content, has been connected with ovarian aging. Additionally, mutation rates in mitochondrial DNA have also been associated with ovarian aging and the ability to form embryos. These alterations interfere with the normal functioning of mitochondria and are thought to be a factor in the manifestations of ovarian aging. (Larbata et al., 2019)

Furthermore, it’s important to note that mitochondria’s role in producing ATP (adenosine triphosphate), a crucial energy molecule, is significant. In the context of in vitro fertilization (IVF), variations in ATP levels within human eggs can impact embryo development and the potential for successful implantation. Issues with mitochondrial function may also lead to the disruption of the spindle in mouse eggs, potentially increasing the risk of aneuploidy. (Van et al., 1995) (Zhang et al., 2006)

Additionally, another essential molecule in mitochondrial metabolism, NAD+, is believed to decrease as ovarian aging progresses (Yang et al., 2020). NMN, like the one found in NOVOS Boost, is a naturally occurring molecule used to make NAD+. 

The factors discussed here are not exhaustive and require further research. Other age-related changes that cause ovarian aging include shortening of telomeres, interplay of apoptosis and autophagy, accumulation of DNA damage, and aneuploidy. These changes are all interconnected and likely work together to affect how our reproductive system ages. There’s still a lot more to learn, and scientists are continuing to study these processes.

So, what current options are available to address female reproductive aging in the market?

Reproductive Aging: A Look at Current Solutions and Approaches 

To address reproductive aging in women, two main approaches are commonly employed: adjunct technologies for assisted reproduction (ART) and hormone replacement therapy (HRT). These approaches aim to counteract the two major impacts of ovarian aging, namely the decline in fertility and the loss of health-protective effects from estrogen. We’ll look below at the effectiveness and limitations of these strategies based on research findings, most of which are derived from clinical data.

1. Hormone Replacement Therapy (HRT)

HRT involves providing women with hormones that diminish during the menopausal transition, alleviating associated symptoms. While HRT is applicable to perimenopausal and early postmenopausal women, it also finds use in addressing premature ovarian insufficiency and, in certain cases, polycystic ovarian syndrome (PCOS). 

Conventional HRT seeks to replicate the natural hormonal balance of the human ovary by incorporating both estrogen and progesterone components. Estrogen therapies encompass a range of options, including those naturally produced by the ovary, like estradiol and estriol. Another option is conjugated equine estrogen (CEE), widely prescribed in the United States. The term “progestogen” often appears, encompassing not only naturally occurring progesterone but also synthetic compounds known as “progestins.” 

In HRT, a woman with an intact uterus combines a progestogen with estrogen to protect the uterine lining against abnormal growth that could lead to endometrial issues. While estrogen prompts endometrial lining growth, progestogens help regulate it. Progesterone stands out for its potential to alleviate symptoms like sleep disturbances and mood swings, along with possible protective effects for breast tissue. HRT is not intended for lifelong use. Most women can gradually discontinue HRT with a reduced dosage after their menopausal symptoms subside, a process taking 2-5 years. (Mehta et al., 2021)

The effectiveness of HRT in preventing cardiovascular diseases (CVD) in postmenopausal women remains a topic of debate. While some studies suggest a lowered risk, others indicate no benefits or even heightened risks. The protective effect of HRT against cognitive decline is also inconclusive, with some trials suggesting potential detriments. Initial observational studies hinted at a protective effect against dementia, with a meta-analysis indicating a 34% risk reduction (Nelson et al., 2002). However, the Women’s Health Initiative Memory Study (WHIMS) raised concerns about increased dementia risk associated with the use of oral estrogen alone or combined with medroxyprogesterone acetate (MPA) (Shumaker et al., 2004). 

The protective effects of HRT on cardiometabolic health and cognition are inconclusive, but its bone health benefits appear more evident. Findings from the Women’s Health Initiative (WHI) investigations suggest that menopausal HRT may decrease the occurrence of bone fractures among postmenopausal women. (Lorentzon et al., 2022) Recent research indicates that HRT for several years could have a lasting effect on fracture reduction. (Papadakis et al., 2016)

However, HRT may elevate risks in various health conditions, such as ischemic stroke, venous thromboembolism, and breast cancer (Boardman, et al., 2015) (D’Alonzo et al., 2019)(Vinogradova et al., 2020) . Risk levels may differ based on formulations and age groups. HRT is contraindicated for women with a known, suspected, or historical presence of breast cancer or an active or historical history of multiple thrombotic diseases. Therefore, when considering menopausal hormone replacement therapy (HRT) for better bone and muscle health, it’s important to carefully assess the risks of increased chances of breast cancer and stroke, even with short-term and low-dose usage. (Fait, T., 2019) (Lobo, R.A., 2017)

Despite controversies, HRT remains essential for women with premature and early ovarian insufficiency, offering direct benefits in areas like cardiovascular health, brain aging, and osteoporosis protection.

2. Assisted Reproduction Technologies (ART)

Assisted reproductive technology (ART), primarily utilizing the in vitro fertilization (IVF) technique developed in the latter part of the 20th century, has experienced a surge in popularity and accessibility. While it is usually employed when natural methods of conception prove unsuccessful due to various factors, including low sperm count or quality, it serves as a solution to fertility challenges arising from the direct impact of diminished egg quantity and/or quality, as well as obstacles in fertilization and embryogenesis due to reproductive aging. IVF involves fertilizing an egg with sperm outside the human body within a laboratory environment. This process encompasses several key stages: ovarian stimulation, egg retrieval, sperm collection, fertilization, embryo culture, embryo transfer, and pregnancy testing.

IVF can be combined with other advanced techniques to augment the likelihood of successful pregnancy and the delivery of healthy infants. For instance, egg or embryo cryopreservation, commonly known as egg/embryo freezing, empowers women to preserve and store their eggs for future use. While initially utilized by women wishing to preserve their eggs before undergoing medical treatments that could impact their reproductive health, more women opt to freeze their eggs at a younger age to bolster the potential of having a biological child later in life, even as their fertility declines. (Argyle et al., 2016) (Lussig et al., 2019)

Furthermore, current research is concentrating on optimizing embryo culture media to increase the chances of successful embryo development and pregnancy.  (Terao et al., 2019) The composition of embryo culture media varies considerably, and a consensus has yet to be reached. In addition to essential nutrients, recent studies have shown promising outcomes in egg maturation and embryo development by supplementing the media with potential longevity-enhancing substances such as vitamin C, fisetin (both found in NOVOS Core) and NAD+ precursors like the NMN (found in NOVOS Boost). Other ART techniques, like intracytoplasmic sperm injection (injecting a single sperm into an egg) and artificial insemination (introducing sperm directly into the uterus), address male infertility.

IVF and its complementary methods have evolved, increasing usage and success rates. Nonetheless, these approaches have limitations as they work around, rather than directly address, the fundamental cause of fertility decline – ovarian aging. Therefore, while they provide women with the opportunity to pursue conception, these strategies cannot guarantee reproductive success due to the continuous decline in egg quality associated with aging. 

Advanced maternal age, in particular, emerges as a dominant and irreversible factor influencing IVF outcomes. (George, K. & Kamath, M. S., 2010) In reality, despite undergoing invasive and time-consuming procedures, most women experience success rates of around 20-35% per cycle, with the likelihood of pregnancy decreasing with each successive round as costs escalate. Ultimately, about 60% of cases do not result in success. (Bhattacharya et al., 2013) Additionally, ART fails to fully restore or sustain the levels and protective benefits of ovarian gonadal hormones, such as estrogens.

As a scientist dedicated to researching female reproductive aging, I have encountered several instances where some individuals mistakenly view IVF as a silver bullet for infertility. However, as discussed, IVF is not a guaranteed remedy for all cases of infertility, with a success rate of approximately one-third and advanced maternal age as the greatest and irreversible limiting factor. Financial concerns, psychological burdens, and risks of associated complications, such as hyperstimulation syndrome (which can be life-threatening), surgical injuries, bleeding, and anesthesia-related issues, are additional considerations to manage.

Additional Misconceptions About Ovarian Aging

“Menopause symptoms only hit at about 50 years old.”

Typically, perimenopause begins about ten years before actual menopause. It can start in the early to mid-40s and, in some cases, even earlier. As discussed, perimenopause and postmenopause (which can continue for several years after menopause) come with various symptoms. The duration and intensity of these symptoms vary widely among individuals. Experiencing menopause before the age of 40 is known as premature menopause, which occurs in 4.9%–9.4% of women (doi: 10.3346/jkms.2020.35.e97) and requires medical attention.

“Reproductive aging is only about infertility.”

As discussed, reproductive aging has two significant impacts: a decline in fertility and the loss of health-protective effects from sex hormones. While the former leads to the termination of a woman’s reproductive lifespan, the latter profoundly affects her overall healthspan. Thus, reproductive aging is not solely confined to infertility.

“Reproductive aging can’t be slowed.”

Advances in our understanding of the aging process and its mechanisms have paved the way for multiple research strategies aimed at slowing down aging and promoting healthier aging. Although reproductive aging is a relatively specialized area that has garnered increased attention in recent years, its underlying mechanisms remain partially understood. Yet, similar to general aging research, promising drug candidates demonstrate positive outcomes in preserving ovarian follicles and functions across various animal models. 

Moreover, the first human study of a drug for aging ovaries called the VIBRANT study (Validating Benefits of Rapamycin for Reproductive Aging Treatment), just started at Columbia University. The realm of aging research is intricate and continuously evolving. With ongoing discoveries and advancements, the potential to decelerate or reverse reproductive aging becomes increasingly feasible.

In our next and final installment in our Female Reproductive Aging series, we discuss what science has found you can do now to slow down your reproductive aging.

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