Our first mini article in this fertility series touched on the mechanisms driving reproductive aging. As women age, their reproductive capabilities decline due to ovarian aging, leading to menopause around the age of 50.
This decline not only affects fertility but also has broader health implications, such as increased risks of osteoporosis, cardiovascular diseases, and cognitive decline — further underscoring the need for in-depth studies on reproductive health and longevity. This second article in our series offers a glimpse into reproductive research and potential treatment strategies to address age-related fertility changes.
This article is part two of a five-part series on reproductive aging.
- The Biological Clock: How Female Fertility Declines with Age
- Extending Fertility and Health for Women
- 6 Useful Lifestyle Tips To Promote Ovarian Health
- Primary Drivers of Reproductive Aging: A Deeper Dive
- Current Solutions and Approaches to Reproductive Aging and Longevity
Drug Candidates Targeting Female Reproductive Aging
Understanding potential treatments for reproductive aging can provide hope for many women facing fertility challenges. Here, we explore several promising drug candidates that target female reproductive aging, offering insights into their mechanisms and effectiveness.
1. Antioxidants
Oxidative stress has been suggested as a contributing factor to ovarian aging. Consequently, compounds with antioxidant properties, such as Vitamins C and E, coenzyme Q10 (CoQ10), N-acetyl-L-cysteine (NAC), and certain flavonoids, have been evaluated in rodent models. Antioxidants have shown potential pro-longevity effects in the female reproductive system, leading to varying degrees of improvement in ovarian follicle counts, preservation of ovarian reserve, and increased offspring number.
However, antioxidants have also been linked to adverse effects, including disruptions to ovarian and uterine functions with pharmacological doses of Vitamins C and E. Furthermore, only a limited number of antioxidants have undergone clinical study in women with age-related assisted reproductive technology (ART) failure, and the results have been highly inconsistent.
In some investigations, oral supplementation of certain antioxidants like resveratrol was even associated with reduced pregnancy rates. The effectiveness of antioxidants is not uniform, and both the dosage and treatment duration necessitate further optimization to ensure their safe and effective usage.
2. Hormones (Other Than Estrogens and Progestogens)
Dehydroepiandrosterone (DHEA)
DHEA, an estrogen precursor, has shown potential in enhancing egg and embryo quality for women with diminished ovarian reserve or advanced age. However, while some studies report improvements, they often do not find a significant increase in pregnancy rates, and comprehensive health assessments are lacking. More extensive trials are needed to confirm DHEA’s efficacy.
Genistein
Genistein, a phytoestrogen similar to estradiol, has been observed to slow follicular development in rodent studies, enhancing ovarian reserve and maintaining ovulatory cycles. However, no conclusive improvements in pregnancy outcomes have been reported.
Melatonin
Melatonin, known for its sleep-promoting and antioxidant properties, shows promise in extending reproductive lifespan and improving ovarian markers. Although it consistently improves egg quality and quantity in rodents, clinical studies in women with infertility or IVF failures have shown mixed results. Its wide-ranging metabolic effects complicate its potential clinical use.
3. Mitochondrial Boosters
Mitochondrial dysfunction is a notable hallmark of the aging process and is associated with ovarian aging and infertility. Drug candidates that protect mitochondria, such as CoQ10, Vitamins C and E, and flavonoids, have shown potential in improving ovarian aging.
Recent investigations into NAD+ supplementation, using compounds like nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), have showcased remarkable rejuvenation of eggs in mice, leading to enhanced fertility. These findings highlight the potential of mitochondrial boosters in addressing reproductive aging.
4. Glucose Metabolism Modulators
Modulators of glucose metabolism, notably metformin, have captured substantial attention in longevity research. Metformin has shown potential in counteracting age-associated ovarian fibrosis, improving follicle quantity, and establishing regular ovulatory cycles.
In studies involving IVF repeaters, low-dose metformin has been associated with improved pregnancy rates. However, variations in treatment administration highlight the need for more research to assess metformin’s effects on ovarian function thoroughly.
Another glucose metabolism modulator, 2-deoxyglucose (2-DG), has shown potential for preserving ovarian reserve by inhibiting primordial follicle activation in young mice. However, its cardiotoxicity and increased mortality in male rodents have hindered its clinical advancement.
5. Other Drug Candidates: α-Ketoglutarate (AKG) and Rapamycin
Two other drug candidates, α-ketoglutarate (AKG) and rapamycin, have exhibited promising effects in promoting ovarian longevity in rodent models. AKG plays a crucial role in the Krebs cycle and has shown potential in enhancing protein synthesis, supporting bone growth, and improving antioxidant systems. Long-term use of AKG has been shown to preserve ovarian function and sustain fertility in aged mice.
Rapamycin has been extensively studied for its potential to delay ovarian aging by inhibiting mTOR signaling. While mTOR inhibition can enhance ovarian reserve and extend reproductive lifespan, prolonged use has exhibited certain drawbacks, including disruptions to ovulatory cycles and loss of fertility. Recent research has introduced a more targeted approach, employing brief rapamycin treatments to restore follicular development and ovulatory cycles, leading to improved reproductive capacity and extended ovarian lifespan.
Key Takeaways on Drugs Targeting Reproductive Health
While these drug candidates offer promising avenues for addressing reproductive aging, much of the research has been conducted using rodent models. Further human studies are imperative to translate these findings into practical clinical applications. As we continue to explore these potential treatments, we move closer to providing effective solutions for women facing reproductive aging challenges.
To learn more about possible treatments for reproductive aging, read our full article, Fertility in Focus: Promising Drug Candidates and Lifestyle Strategies. Stay tuned for the next article in our mini series discussing lifestyle interventions to enhance reproductive health.
