Melatonin: a novel and safe therapeutic to delay and counteract the effects of ovarian aging on your fertility
Posted By Braverman IVF & Reproductive Immunology | 18-September-2018
A recent review published in the journal Current Drug Targets showed the beneficial role of Melatonin on delaying ovarian aging by preventing or minimizing its detrimental effects on oocyte quality and fertility. We will take this opportunity to remind you the different aspects of the ovarian aging process (increased oxidative stress, mitochondrial dysfunction) and explain you how melatonin, with its many benefits, can delay its onset.
1- Ovarian aging
a- What fertility parameters are disrupted with age?
Women are endowed with a finite number of oocytes at birth, each enclosed by a single layer of granulosa cells in a primordial follicle (1-2). The ovarian lifespan is defined by the number of primordial follicles, able to develop and grow to give rise to an oocyte (or egg) during each menstrual cycle (3). Fertility is associated with the ovarian function and decreases with age (4).
By 35, and even more after the age of 38, the oocyte quantity and quality declined (2), with increased risk for embryo aneuploidy reaching 50% at ages 42–43, and 100% at 45 (5). Ovarian aging is a natural process that will lead inevitably to menopause (6-7) but it can be dramatically accelerated by genetic factors (as seen in Premature Ovarian Failure), the microenvironment (inflammation, oxidative stress) or different pathologies (endometriosis, PCOS).
b- Oxidative stress and ovarian aging
Oxidative stress is a natural process, present in all cell types and is part of a normal function of the female reproductive system. It is defined by the production of Reactive oxygen species (ROS). In the ovary, reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced by the developing oocyte (egg) and the surrounding granulosa cells supporting its development. As a result, the follicular fluid (FF) contains abundant levels of reactive species that are crucial for regulating the ovarian function influencing the development of follicles, the oocyte maturation, the production of steroids (8). Nevertheless, these reactive species are highly reactive with other cell components such as proteins, lipids or DNA (9) which could alter their function and lead to potent oxidative stress damaging the oocyte quality (10) by impacting DNA (11).
Higher levels of oxidative stress in the follicular microenvironment accelerates ovarian aging (12) and ROS levels in the follicular fluid is used as a marker to measure ovarian age and follicular metabolic age (13).
c- Mitochondrial dysfunction and ovarian aging Mitochondria are small energy producing organelle, present in the oocyte that play a key role in supporting the early step of embryo development. Mitochondrial dysfunction triggers ovarian dysfunction, infertility, and ovarian aging (14). Moreover, oxidative damage is much more prominent in mitochondria and can disrupt its function.
2- Melatonin benefits on Fertility
a- What is Melatonin?
Melatonin is a hormone secreted by the pineal gland that controls the wake/sleep cycles, circadian rhythms and reproduction (15) During the follicle development (leading to a mature and fertilizable egg), very high levels of melatonin have been found in the follicular fluid (16) which may, thanks to its free radical scavenger properties, protect the developing oocyte against oxidative stress (10), one of the multiple causes of ovarian aging.
b- Melatonin: a potent anti-oxidant
Antioxidants have been used to prevent the ovary from aging.
They protect the oocytes by allowing nuclear maturation, promoting functional mitochondria, supporting spindle morphology and DNA integrity (17). Melatonin is by nature an agent able to pass through any cellular membranes.
It is a potent anti-oxidant that prevents oxidative stress induced by reactive oxygen species. While melatonin has a direct effect on oxidative stress by scavenging ROS and RNS (18), its metabolites (product of its degradation) are also active and act indirectly by inducing the production of anti-oxidative enzymes and lowering the synthesis of pro-oxidative molecules (19) leading to an overall reduction of oxidative stress. In the FF, melatonin eliminates free radicals and stimulates antioxidant enzymes in addition to promote sex steroid hormone production by granulosa cells which support follicle development leading to ovulation (20). Melatonin plays also a key role during the luteal phase protecting the luteal granulosa cells from oxidative damage leading to apoptosis and preventing the occurrence of a premature new menstrual cycle. It maintains progesterone production by the corpus luteum which supports the luteal phase.
c- Melatonin improves women fertility
There are many clinical studies assessing the use of melatonin during IVF cycles although most of them have been conducted with patients as their own controls and not through a randomized, double blinded comparison between treated patients “melatonin group” and proper controls “placebo group”. A study (21) assessing the effects of oral administration of melatonin (3mg/day) in patients from day 5 until oocyte collection showed significant increase in fertilization rates as compared to the precedent cycle for the same patients (50% vs 20.2%).
A small randomized study (22) with N=60 patients where melatonin was orally administrated (3mg/day) from day 3-5 until hCG administration (oocyte collection) showed:
- a higher number of total oocytes (11.5 vs 6.9)
- higher number of mature oocyte (9% vs 4.4%)
- higher rate of embryos transferred (69.3% vs 44.8%)
These results were confirmed in another independent trial (23).
Although not detailed in this blog, Melatonin targets many other processes involved in ovarian aging such as autophagy, telomere length and genes of the Sirtuin family and is able to delay ovarian aging as demonstrated in a mice study (24).
Melatonin use is safe and did not show any teratogenic effects in both human and animal (25-26) as well as no toxicity (27) even at very high dose (5-20mg/day). Given the potential clinical benefits of melatonin and its safety, it is a target of choice to minimize the effects of aging on women fertility, counteract oxidative stress and enhance oocyte/embryo quality.
As pioneer in the field of Reproductive Immunology, it is with the greatest care, that we studied any scientific evidences showing beneficial effects of different ingredients on women fertility.
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