Can metformin prevent embryo aneuploidy?

A dividing cell - microtubules in 'green' and chromosomes in 'red'

Metformin is an anti-diabetic drug used to treat type II diabetes alongside diet and exercise. It functions by increasing the sensitivity of our body’s cells to insulin (decreases insulin resistance) and thus by helps in the proper utilization of glucose.  It has no direct effect on insulin secretion from pancreas and so it does not alter the insulin level in our body. Hence the risk of dangerous hypoglycemic episodes is very low when compared to other anti-diabetic drugs. Metformin has a very high safety record and is used in clinical practice for more than 50 years. 

Metformin is now used widely used for treating Polycystic Ovarian Disease (PCOD). Insulin resistance and obesity are common among women with PCOD. They have high levels of androgens in their body. They suffer from absence of ovulation and hence lack regular menstrual cycles too. Metformin treatment of PCOD women decreased circulating insulin levels, corrected hyperandrogenism (presence of high level of androgens) and helped in the resumption of regular ovulation. As a result many PCOD women are able to conceive with the help of metformin. Continuation of metformin during the first trimester reduced miscarriage rates in women having PCOD (women with PCOD are prone to miscarriages) and continuation of metformin throughout pregnancy prevented gestational diabetes.  PCOD is a multifaceted disease and the exact mode of metformin action in helping PCOD patients is still unknown. Another interesting information regarding metformin is, it is touted as a gerosuppressant (anti-aging drug) and it prevented reproductive aging too (estrous cycle in mouse treated with metformin remained regular even in older age while in control animals estrous cycle became irregular with age!) (PMID: 18728386).  Metformin works as a calorie restriction mimetic.

Several studies have been carried out to find whether metformin treatment of women with and without PCOD increases the implantation rate and pregnancy rate during IVF treatment. Some studies found that metformin increased egg quality, pregnancy rate and implantation rate in women with PCOD and some failed to show any benefit. But metformin treatment of women with PCOD during IVF was found to prevent ovarian hyperstimulationsyndrome. A multi-centre, prospective, randomized, double-blind study conducted in 2011 showed that metformin treatment of non-obese PCOD women undergoing ART cycles improved pregnancy rate and live birth rate but the clinical pregnancy rate remained the same between the metformin treated and the placebo group.

The exact mode of action of metformin in preventing miscarriages, improving pregnancy and live birth rates remains unknown. It is hypothesized that decreased insulin and androgen levels contribute to this beneficial effect. It is known that more that 60% of miscarriages happen because of embryo aneuploidy (a form of genetic aberration leading to abnormal chromosome number in the embryo). So the question arises whether metformin does something to prevent embryo aneuploidy. To answer this question I tried to look into the signaling pathway activated by metformin and its effect on cell division. 

 Metformin activates a signaling pathway called AMP Kinase. AMP Kinase is called the energy sensor of the cell. When the energy level is low within the cell AMP Kinase senses this energy deficit and switches on activities within the cell which produces more energy and switches off activities which consumes energy. AMP Kinase also functions as a tumour suppressor and metformin which activates AMP Kinase has been proved to posses anti-cancer properties. Interestingly it was found that, AMP Kinase is necessary for proper cell division in drosophila and lack of functional AMP Kinase subunits lead to abnormal chromosome segregation during mitosis (which is the reason for chromosomal abnormalities or aneuploidy) and increased polyploid cells. It was also found that AMP kinase regulates the stability of spindlemicrotubules, the structures responsible for proper chromosomal segregation during cell division. Another publication stated that AMP Kinase activators like metformin can selectively induce apoptosis in aneuploid cells. 

A couple of studies were also done by adding metformin to the culture medium in which embryos of experimental animals were grown. They observed increased blastocyst formation when metformin is present in the culture medium containing insulin (PMID: 16107611). When AMP Kinase was activated using metformin in mouse embryos there was decreased apoptosis and increased pregnancy rates (PMID:17575082).

Can the beneficial effect of metformin (decreased miscarriage rates) in human reproduction be due to the result of metformin’s ability to prevent cell division errors by activating AMP Kinase? Isn’t aneuploidy the major reason for miscarriages? Are laboratory culture conditions (like excess nutrients in the culture medium, over activation of IGF-1 pathway as a result and complete supression of AMP Kinase pathway) a culprit for producing lot of aneuploid embryos? Can adding metformin to embryo culture medium prevent aneuploidies arising due to mitosis? Does metformin uptake by women improve reproductive outcome by reducing aneuploidy in their oocytes? There are many unanswered questions and perhaps research in this area will help in finding the plausible connection between metformin use and embryo anueploidy prevention!