Melatonin Use in IVF

What is melatonin?

Melatonin is a hormone, which is naturally found in the body. This hormone is produced by the pineal gland and plays a role in regulating the circadian rhythm or sleep-wake cycle, fetal development, and fertility. Synthetic melatonin is also available in the form of nutritional supplements.  

Aside from influencing sleep, women who are undergoing in vitro fertilization (IVF) treatment tend to improve their ability to get pregnant because of melatonin supplementation. Melatonin is known to be involved in many factors of human reproduction such as ovulation and regulation of female reproductive hormones. It also affects the levels of other hormones such as estrogen, luteinizing hormone (LH), androgens, progesterone, prolactin, and thyroid hormones. However, melatonin supplementation may interfere with ovulation in some patients.

It has been evident from the research done in animal models that melatonin is important when it comes to oocyte maturation and development. Melatonin is said to influence a number of events that occur within the developing mammalian follicle. The human follicular fluid contains melatonin and the largest follicle contains the highest concentration of melatonin.

During an IVF cycle, the follicular fluid obtained from human and animal models showed melatonin at highest concentration in mature follicles. Thus, it is thought that eggs may be protected by melatonin from oxidative stress. There are ongoing studies regarding melatonin supplementation in women and IVF. Majority of them are with other supplements such as myo-inositol, vitamin E, and folic acid. Prior to an IVF cycle, reports tend to show low or poor oocyte quality.

Melatonin supplementation has shown an improvement in:

• Oocyte quality and maturity
• Fertilization rate
• Reduction in the fragmentation of embryos
• Rates of implantation
• Rates of pregnancy
• Number of high-quality embryos

However, it is still unclear if women who do not undergo IVF treatment would also benefit from melatonin supplementation. 

The effects of an oral dose of 3 mg melatonin at bedtime on oocyte quality have been most commonly studied. However, the duration of melatonin treatment to improve the quality of the oocyte is yet to be determined. Melatonin appears to be nontoxic and a safe supplement at typical doses. Before taking melatonin, discuss with your doctor about any other current medications you are taking. Some common side effects associated with melatonin supplementation include vivid dreams, nausea, irritability, nightmares, and fatigue. 

Poor egg quality is one of the causes of female infertility. It poses several problems such as improper division of the egg or missing chromosomes. Due to age and certain medical conditions such as the polycystic ovary syndrome (PCOS), the quality of the eggs deteriorates. One research presented at the World Congress on Fertility and Sterility in Munich found out that egg quality may be improved in IVF if women are treated with melatonin.

The presence of 8-OHdG, an oxidizing agent in follicular fluids, was measured by a group at Yamaguchi University Graduate School of Medicine led by Associate Professor Hiroshi Tamura. If this oxidizing agent is present in high levels, then it indicates poor egg quality. It was found that as the level of the concentration of melatonin increased, the levels of 8-OHdG also decreased. This led the group to believe that there was a link between melatonin and stressing oxidizing agents. Melatonin is also known to have antioxidizing effects. This study was done in mice to learn the effects of melatonin. With the addition of melatonin, the damage caused to the egg by an oxidizing agent seemed to reduce.

A trial was conducted on a group of women at the Yamaguchi University Graduate School of Medicine for IVF treatment. They failed to become pregnant due to poor oocyte quality. They were divided into groups of three after the first cycle of IVF. Before the next IVF cycle, 56 women were given a dose of 3 mg melatonin while the rest of the women received a standard IVF cycle without melatonin treatment. They found out that there was a significant reduction in the concentration of the damaging 8-OHdG with melatonin treatment. Those who received melatonin treatment also had an increase in intrafollicular melatonin concentrations. 

Moreover, 50 percent of the eggs could be successfully fertilized in this group. After transplantation, 19 percent of the women could become pregnant. In the control group, the rate of fertilization of the eggs was only 22.8 percent and the probability of pregnancy was only 10 percent after transplantation. 

This study showed that melatonin can counter the effects of the oxidizing agents on the quality of the oocytes. In a clinical trial, it was shown that melatonin supplementation led to higher rate of fertilization due to an improved oocyte quality. In women with poor oocyte quality and unable to become pregnant, this first clinical application showed that melatonin can be a significant option to improve their oocyte quality and chances of pregnancy. 

The effects of reactive oxygen species on oocytes and the action of melatonin in reducing oxidative stress on oocytes are still being studied.

Protective Role of Melatonin

During the process of ovulation, reactive oxygen species (ROS) are produced within the ovarian follicles, which may impair oocyte maturation. Melatonin is detected in the human follicular fluids and it is a scavenger of these potent free radicals. This research was undertaken to study the relationship between poor oocyte quality and oxidative stress. Moreover, the aim of the study was to find out if melatonin supplementation could protect the oocyte from radical cytotoxicity and improve the quality of the oocytes. 

Eighty-five follicular fluids from 85 patients were taken as samples at the oocyte retrieval during in vitro fertilization and embryo transfer (IVF-ET) program. Superoxide dismutase (SOD), glutathione (GSH), and melatonin were determined as antioxidants and intrafollicular concentrations of 8-OHdG were determined as oxidative stress markers. No correlation was found between SOD, GSH, and follicular growth. However, a negative correlation was found between melatonin and 8-OHdG. No correlation was also found between SOD and GSH. Thus, it was believed that melatonin was an important antioxidant in the follicle. 

Women who failed to become pregnant in the treatment of IVF-ET were given 3 mg melatonin tablets in the next IVF-ET. A group of 115 patients was split into two groups. Fifty-six patients received melatonin treatment and 59 were kept as controls, who did not receive melatonin treatment. A comparison was done between the fertilization and pregnancy rate with the previous IVF-ET. With melatonin treatment, the fertilization and pregnancy rates improved compared to the previous cycle, which only had 20.2 percent. In a melatonin treatment cycle, the fertilization rate was 50 percent.

Melatonin in IVF Success and Egg Quality

Women in their 30s to 40s may achieve success using IVF with melatonin treatment. A study showed that prior to IVF, women who took 3 mg of melatonin at bedtime for a particular period may show a double success rate compared to the ones who did not take melatonin. It was concluded that in fertile women, melatonin treatment increases intrafollicular melatonin concentrations, reduces intrafollicular oxidative damage, and increases both fertilization and pregnancy rates. Melatonin may also help those who are trying to naturally conceive. With melatonin treatment, the oocyte quality can be improved by preventing free radical damage.

Studies have also shown that melatonin possesses strong regenerative action on self-repair mechanism, which may help in healthy cell division and prevents damage to the cellular DNA. Thus, melatonin has also become a center of focus for research in cancer treatment since it is known to keep the cells free from cancer. The same mechanism can be used to protect the oocyte during cell division.

Melatonin naturally fights against free radicals and prevents the healthy cells from getting damaged. Melatonin scavenges the free radicals that damage the oocyte and sperm. Hence, its role is believed to be more effective and protective. It is able to stimulate other antioxidants.

Higher levels of antioxidants in the follicular fluid are linked to a higher rate of fertilization. Thus, it could be the reason why the Mediterranean diet seems to improve fertility since this particular diet is rich in antioxidants. With melatonin supplementation, the antioxidative capacity also increases. For the first time, melatonin had been measured in this capacity.

Side Effects of Melatonin

Few side effects have been associated with melatonin supplementation. It was described in one study called Melatonin and Reproduction Revisited that melatonin is an uncommonly safe molecule and did not demonstrate toxicity when given in higher doses throughout the pregnancy. However, melatonin should not be taken before driving or operating any machinery since it can make a person feel very sleepy.

Melatonin usage up to 3 months has been studied in clinical trials and found that melatonin had no adverse effects. Side effects such as headache, nausea, and dizziness were equally found in groups who received melatonin including the placebo group. Some studies have also found grogginess and irritability as its side effects. However, there has been no evidence that melatonin might interfere with reproduction or lower follicle-stimulating hormones.

Studies on older people show some noted side effects such as skin pigmentation, restless legs, and thrombosis.

Interactions

Melatonin should be avoided by patients who are taking the following medications:

• Blood thinners or anticoagulants
• CNS depressants or sedative medications
• Medications for diabetes
• Immunosuppressants
• Angiotensin-converting enzyme (ACE) inhibitors

Bottom Line

In a double blind, randomized trial in older women undergoing IVF, it has been found that melatonin supplementation improves the oocyte quality and the quality of the embryo, but not the clinical rate of pregnancy. Studies have shown that melatonin protects the ovaries and testes from oxidative stress, stops the synthesis of prostaglandin, and stimulates the secretion of progesterone.