What does scientific research say about improving oocyte/egg quality?

Oocyte quality is the most important determinant of IVF success. As a result of aging more chromosomal and spindle abnormalities accumulate in oocytes leading to increased incidence of infertility, foetal loss and birth defects like trisomy 21 or Down syndrome. Eggs obtained from younger women carry less genetic abnormalities and hence have higher chance of implanting and becoming a healthy baby. This is evident by the fact that women even after their menopause are able to get pregnant and carry the baby to term using donor eggs obtained from younger women.

When a woman undergoing IVF faces repeated failure, naturally the issue of egg quality crops up in the mind of infertility specialist and the patient. Unfortunately even after dramatic improvement in ART techniques, there is no sure way of saying whether an egg is competent enough (without genetic abnormalities) to produce an embryo which will subsequently implant and produce a baby. Although embryologists are able to select good embryos by observing their morphology under the microscope it doesn’t guarantee that the embryos are without abnormalities. A beautiful looking embryo of an older woman has more chance of being genetically defective than that of a younger woman. 

As a result older women as well as younger women who undergo repeated IVF failures are desperately searching for ways which would increase their egg quality and give them their most wanted wish-a baby! Infertility bulletin boards are filled with women who are determined to find a cure for their bad quality eggs. DHEA, metformin, melatonin, myo-inositol, wheat grass, anti-oxidants, fish oil, co-enzyme Q10, vitamins, especially vitamin D and other nutritional supplements are now-a-days extensively used by women to improve egg quality. Some of these substances used have scientific proof but some not. Selling supplements to improve egg quality is growing into a huge market as many businessmen are trying to make cash of our desperate situation. This led me to screen the scientific literature to find out what does science say really! Most of the experiments concerning oocyte quality are conducted in mice as it is difficult to do such experiments in humans for a number of reasons. 

Anti-oxidants

Oxidative stress contributes to somatic aging and it is also implicated in reproductive aging. So experiments were done to see whether using anti-oxidants improve egg quality and reproductive parameters. The researchers supplemented mice with pharmacological doses of vitamin C and E (both are well-known antioxidants) during their early or late life. They found that administration of oral anti-oxidants counteracted the negative effects of female aging on oocyte number and quality (PMID: 11835584). Good news right! Please do not rush to the pharmacy. Their research finding is not yet complete! Even though they found a positive effect of these supplements on the oocyte level they also found that oral administration of pharmacological doses of vitamin C and E reduced reproductive fitness and impaired ovarian and uterine function of female mice. They also said that the antioxidant diet decreased the frequency of litters, litter size, total number of offspring born and survival of male pups to weaning (PMID:12054212). Shocking or? A very recent publication suggested that, when mice are given low concentration of N-acetyl-L-cysteine the quality of fertilized oocytes and early embryo development improved. It also improved the quality of oocytes in older mice (PMID: 22357770). 

Now the question is how seriously we should take these experiments? First we should keep in mind that these experiments are performed in mice. The next thing to remember is ‘nothing equals a good diet’. Do you feel that you are not able to eat enough vegetables and fruits a day? Is your medical condition preventing you from getting appropriate amounts of nutrition from your diet? Supplementing with a good vitamin pill is a nice thing to do. Otherwise the best way is to add colour to your life by eating different coloured vegetables and fruits. Remember darker their colour more is the anti-oxidant content in them. 

DHEA

I am sure most of you will be aware of DHEA. If you google you will find lots of information about DHEA. Please visit CHR (Center for Human Reproduction) website for further details. DHEA was found to increase oocyte production (PMID: 16169414). The mechanism behind it is not so clear. DHEA is used in mice to induce PCOS phenotype in previously normal ovaries (PMID: 16514202). DHEA supplementation was also shown to decrease embryo aneuploidy (genetic defects) (PMID: 21067609). 

I have seen women who swear on DHEA for their IVF success. Many women even achieved natural pregnancies after taking DHEA. Will DHEA work for me? It might work. It worked for many but we should not also forget that it didn’t work for so many others. I am not trying to be negative, just trying to be cautiously optimistic. Try to monitor your thyroid levels and insulin levels when on DHEA (as it is found to affect both either in a positive or negative manner). Please remember that it is a steroid hormone and it is wise to be safe than sorry! 

Melatonin and Myo-inositol

Melatonin is a hormone produced in our body and it regulates circadiac rhythm. It has very powerful anti-oxidant properties and is found to protect nuclear and mitochondrial DNA (hence less genetic abnormalities) (PMID: 16217125). A recent publication concluded that melatonin is likely to improve oocyte and embryo quality in women undergoing IVF or ICSI but they found no statistical significance between the treated and non-treated group (PMID: 21770829). Melatonin was found to significantly improve thyroid function, reduce gonodotrophin levels, and in some women it helped in the re-acquisition of normal menstrual cycle. Furthermore, an abrogation of menopause-related depression, amelioration of hot-flashes and improvement of quality and duration of sleep has been reported. Myo-inositol is involved in several aspects of human reproduction. Elevated concentrations of myo-inositol in human follicular fluids appear to play a positive role in follicular maturity and also act as a marker for good quality oocytes. (I got this information from clinical trials.gov identifier: NCT01115127)

Should I try it?

Why not? Both melatonin and myo-inositol are naturally synthesized in our body and supplementing them won’t be a bad idea (but please read about the side-effects of melatonin supplementation). But better way is to optimize your health and get sound sleep.

Vitamin D

A search for vitamin D and oocyte quality did not give any appropriate pubmed result. I am sure many publications will come in the future on this topic. But searching for vitamin D and fertility gave some interesting information. Human sperms express vitamin D. Serum concentration of vitamin D is positively associated with sperm motility (PMID: 21427118). It is also found to regulate a large number of genes in reproductive tissue (PMID: 22047005). Animal data show that low vitamin D status is connected with impaired fertility, endometriosis and polycystic ovary syndrome (PMID: 10232622). 

Are you living in a country where winter is harsh and there is very less sunlight? It is advisable to take vitamin D supplements. There is lot of contradictions regarding safe vitamin D dosage. According to the new guidelines the tolerable upper limit is 4000 IU for ages 9 and above. Vitamin D at very high doses is found to cause calcification of soft tissues including brain tissue and several other complications. Published cases of toxicity, for which serum levels and dose are known, all involve intake of ≥ 40000 IU (1000 mcg) per day (search in google for Vitamin D Council for further information).

In summary are you living in a country where you get ample sunlight? Then just roam around with no sunscreen and expose your skin to sun’s rays. Exposure to sun rays for 10 minutes will help your body synthesize 10,000 IU of vitamin D. You can do this without the fear of vitamin D toxicity because your skin has a built in mechanism to prevent vitamin D toxicity. Take vitamin D supplements if you live in a country where there are very less sunny days and monitor your serum vitamin D levels at appropriate intervals. 

Diet or calorie restriction

This section is the most interesting part of this article. I found a very high quality publication on this topic and this is means it is more reliable. Calorie restriction in the absence of malnutrition is found to slow down the aging process and extend lifespan. If calorie restriction can slow down the aging process of somatic cells does it has the ability to slow down oocyte aging too? The research says YES. Recently a publication in PNAS, which is a reputed, high-ranked journal, showed that calorie restriction showed striking beneficial effects on chromosomal, spindle and mitochondrial dynamics in mature oocytes of adult female mice at ages normally associated with poor reproductive parameters. The study said that calorie restriction vastly improved fertility in aged animals. When initiated during adulthood calorie restriction significantly extended reproductive lifespan and increased the survival rate of offsprings conceived by aging females. This study clearly states that old age induced oocyte aneuploidy and spindle defects can be safely circumvented using calorie restriction (PMID:21730149). The study is well-designed and very promising. Rhesus monkey maintained on calorie restriction diet into advanced age showed the same health benefits as in mice.

Should I start a calorie restricted diet?

Why not? But you should also remember that this study is done in mice. Sometimes animal studies cannot be translated to humans. Please remember to take a good nutritional supplement (especially folic acid) when you are on a calorie restricted diet. Our ancestors are wise enough to starve themselves (do a fast) atleast once a week. Calorie restriction comes with an added benefit, who wouldn’t love to look younger than their real age!!!

Metformin

Metformin is a calorie restriction mimetic. It induces a dietary restriction like state (PMID: 20090912). It extends life span and is considered to be an anti-aging drug. It possesses anti-tumour properties. It activates genes which are induced during calorie restriction. So if calorie restriction preserves oocyte quality metformin can also do it! Hyperinsulinemic conditions are detrimental for oocyte quality. Metformin reduces insulin levels by decreasing insulin resistance and hence increases the egg quality of women suffering with PCOD.

Should I start metformin?

Are you diagnosed with PCOD? Do you have insulin resistance? Are you having poor egg quality because of PCOD? Metformin is for you. Do you have diminished ovarian reserve? Are you struggling to produce enough eggs? Then metformin is not for you. Metformin is known to reduce antral follicle count and when you are undergoing IVF number of eggs collected matters too!

Does lowering FSH and increasing AMH help me if I have poor egg quality?

FSH and AMH help to determine our ovarian reserve (egg quantity) and not egg quality (

PMID:

 21133869), (

PMID:

2073613). But as you age both egg quantity and egg quality starts to decrease simultaneously. This does not mean that egg quantity and quality are related. I think egg quantity and quality are two different events which has no connection to each other. This can be substantiated by the fact that younger women with diminished ovarian reserve are more likely to get pregnant and carry the baby to term even though they produce less amount of eggs during IVF stimulation (

PMID:

21602123). On the other hand older women with low ovarian reserve are less likely to conceive. So both FSH and AMH should be just looked as markers for poor ovarian reserve and nothing more. This can be understood if the actual modes of action of these two hormones are studied in detail. Egg quality is something to do with our genetic machinery which has no connection to these two hormones. Decreasing FSH or increasing AMH is also less likely to increase follicle numbers. Actually increasing AMH artificially can bring down your antral follicle count. 

These are some of the important scientific information which every woman undergoing multiple IVFs should understand. I wish this will reduce their tension about what supplements to take and what not to take, what is realistic and what is not. But at the end if you think taking certain supplements (because your friend took a supplement and fell pregnant miraculously!) increases your confidence level go ahead and take it, provided it should be from a reliable pharmaceutical company. You should also know for sure that the particular supplement does not have any negative side-effects that will compromise your health. Good luck for every woman who is searching frantically for that single good egg which will make their dream come true!