Metformin and Fertility Treatment: the expanding uses for an age-old drug

We all get excited about new things. But most people remain skeptical when you suggest that something old may be better. In fact, what if something VERY old may be one of the hottest developments in a high tech field like fertility treatment? That’s what has been quietly happening with the medication known as metformin.

Galego officianalis

Metformin has been used since the time of the pharaohs (around 1500 B.C.E.) but it was extracted from the plant Galega officinalis (see image). From then until the discovery of insulin; this was the primary treatment for diabetes. Unfortunately, like many plant extracts there were many other compounds present as well—some with serious and/or troubling side effects. The modern synthesized version of metformin has been purified making it safer and easier to study.

 

The best known use of metformin in reproductive medicine is in the treatment of women with polycystic ovarian syndrome (PCOS). But we’re now learning that there are many other ways that his modern version of an herbal remedy can help improve the outcome of fertility treatment. Although I’m not a fan of lists, the complexity of this treatment is beyond a simple blog post. So here is what you may want to consider when planning your treatment with your doctor:

 

 

In summary, pregnancy is a very multifaceted process. Sometimes, we still have a lot to learn about something that has been around for a long time.

Egg Quality: new insights into why human eggs don’t age well

It has long been accepted that the primary reason that human eggs don’t age well is due to a dysfunction in when and how the chromosomes separate. This reduced chance of becoming pregnant associated with aging as well as the increased miscarriage rates. A new paper has now demonstrated that it’s not just the DNA separation that declines with time but also how the chromosomes are actually sorted and divided.

Within each egg are cable-like structures called microtubules. These microtubules not only help the egg maintain its shape but also are integral in sorting/separating the DNA. They are also in charge of cell division after fertilization is complete. In fact, some of the most powerful cancer fighting drugs are used to deliberately damage microtubules in order to prevent cancers from growing. This new information provides us with further insight into another important aspect of egg quality.

Although we don’t currently have any specific recommendations on what we can do to improve microtubule function; this information does provide us with more diagnostic information for patients that are going through In Vitro Fertilization (IVF). IVF is not only the treatment that provides patients with the highest pregnancy rates but when performed in a high quality setting; it also provides important diagnostic information. There is no accurate test for egg quality except to put a healthy sperm inside and see if/how well the process of fertilization and development takes place. We routinely use this information in discussing treatment options for patients that do not successfully conceive in their first IVF cycle at our center.

Fertile thoughts,

~Robert

Robert Greene, MD, FACOG

Conceptions Reproductive Associates

Why American women are having fewer babies than ever – The Washington Post

Birth rates now are about half of what they were during the height of the “baby boom.” That’s because women are waiting to start their family until they are more settled in their careers, relationships and lifestyles. Unfortunately, this same study also found that about 40% of women between 44 and 50 years of age have had fewer children then they would have preferred. That’s why it is so important that women consider what their family buildings are and consider egg freezing during their mid thirties. Technology now offers women the best of both worlds; delayed reproduction and achieving their ideal family size!   https://www.washingtonpost.com/news/wonk/wp/2016/08/16/why-american-women-are-having-fewer-babies-than-ever/

Omega-3 Fatty Acids: another tool for ovarian rejuvenation

One of the most frustrating questions for women trying to conceive is “what can I do to improve my chances?” Given that women are born with every egg that they will ever have, there are a limited number of ways to optimize the health of the remaining eggs. But for those that are motivated, I have described steps like the use of Acai berry extract and CoQ10 as well as improved sleep and Vitamin D. Now for the first time, there is evidence that some women may be able to improve the responsiveness of their ovaries in as little as one month!

The typical diet of people living in the USA has changed dramatically over the last century. One glaring example has been in the type of fats that we consume on a daily basis. Essential dietary fats—those that we must get from foods because our bodies can’t make them—are typically classified as Omega-6 and as Omega-3 and serve many important physiologic functions. The ideal ratio of Omega-6 to Omega-3 is 1-to-1. However, the typical Western diet—popular amongst most Americans—has a ratio as high as 25-to-1. The result of this unhealthy shift is that many people are eating foods that promote inflammation. This unhealthy shift is associated with a higher risk of heart disease, diabetes, cancer and infertility.

Given that it’s not easy to encourage people to make lasting dietary changes, a recent study looked at the effects of starting a high potency omega-3 fatty acid supplement upon ovarian function and hormone balance. For this study, they put 27 women on a 4 gram supplement and measured their FSH levels before and 30 days after starting this program. Even within this short time frame—effectively one menstrual cycle—they found a dramatic improvement in the omega-6 to omega-3 ratio. Their inflammatory markers improved and their FSH levels dropped. Given that FSH level is considered a marker of ovarian sensitivity; this result is interpreted to mean that their ovaries were more sensitive and thus more fertile.

A cautionary note; they did not find an improved ovarian sensitivity in the women in the study that were obese. It is possible that with longer time and with weight loss, obese women might also experience improved fertility. Obesity has been linked to worsening infertility as well as resistance to some of the treatments offered to normal weight women. It is theorized that obesity itself produces inflammatory chemicals in the body which in turn trigger a state of hormone imbalance. In act, it was discovered that all of the women in the study—including the women that were obese—had improved markers of glucose metabolism. That suggests that the omega-3 fatty acids could help reduce the risk of diabetes and maybe make it easier to lose weight as well.

Another important benefit of omega-3 fatty acids is that they can reduce oxidative stress. That means that consuming these healthy dietary fats can reduce the risk of DNA damage to a woman’s eggs—another important fertility promoting benefit. So although this was a small study and needs to be confirmed in a longer time period, you don’t need to wait. Make this health promoting change in your fertility promoting plan now. Here are a few practical suggestions:

  • Switch to a low-fat diet plan taking care to avoid animal fats when possible
  • Use products at home that include healthy omega-3 fatty acids instead of butter
  • Incorporate more olive oil, Flax seeds and tree nuts into your daily diet
  • Start taking a daily supplement—preferably a plant based one (rather than fish oil) like those made by Life’s DHA
  • IMPORTANT NOTE TO MEN: Emerging evidence suggests that increasing your omega-3 fatty acid consumption can improve sperm shape (teratospermia) as well!!

Women Getting Pregnant Later AND Aging at a Slower Rate; a review of the data

Most women are aware that their fertility declines more rapidly than other—often more visible—signs of aging. In fact, the ovaries have very unique properties. They begin a prolonged hibernation-like state from infancy until the start of puberty. During this ten to fourteen year period, the ovaries remain inactive; producing neither hormones nor mature eggs. However, there are still biological signs of aging taking place within the resting ovary but at a much slower pace than after the menstrual cycles begin. Then throughout the reproductive years a group of eggs is lost each month. In some women—depending on their diet and lifestyle—eggs may be lost at a faster pace. This happens for instance in women that use tobacco products. As I’ve written about previously, the blood test for the hormone AntiMullerian Hormone (AMH) is considered by most fertility specialists today to be the most reliable assessment of a woman’s ovarian reserve (the approximate number of immature eggs that she has available at any given time). Now there are also new ways to actually measure how we age physiologically as well.

One study recently demonstrated that people do age at variable rates. They quantified the aging process by measuring various physiologic and genetic markers over a 12 year period in 954 individuals beginning at age 26. They correlated their findings with each test subject’s appearance and their quality of life. They found that those that appeared to be aging faster also had measureable changes in their physiology, cognition and physical complaints consistent with their appearance. The researchers also analyzed their DNA. Their analysis supported that some individuals were aging faster than others and that diet and lifestyle seemed to be a major influence on the rate of aging. In fact, some people seemed to age 3 years for each 1 year that passed on the calendar while others didn’t seem to be aging at all during the 12 years of the project. So taking steps to improve your health and wellness may in fact slow your rate of aging. However, there are still some changes taking place that can’t be delayed indefinitely.

In most species, females are able to conceive throughout their natural lifespan. Humans are unique from most other mammals in that women typically live about half of their life after their fertility has ceased. It has also been reported that women that conceive later in life tend to live longer. Efforts to look at the genetic relationship have found that there are 17 genetic markers that explain about 30% of the occurrence of premature ovarian failure. That means that most ovarian aging is related to other factors including damage to the egg’s DNA (telomere length) that naturally occurs over time. There are also changes that occur in the egg’s power house, the mitochondria. Each egg has 20,000 to 800,000 of these important power units. Each mitochondrion has its own small strand of DNA. We inherit all of our mitochondria from our mother. As women age, the DNA of mitochondria within the eggs becomes damaged. This damage cannot be repaired. As a result, the mitochondria are intimately linked to egg quality. They not only impact the chance that an egg will fertilize and grow successfully but also the health of the child that results. There are also other ways that delaying pregnancy may influence the child’s health but in a more positive way. There is considerable evidence that children born to older mothers may have more positive cognitive and behavioral outcomes.

There is a growing trend for women to delay childbearing. Doing so is associated with higher socioeconomic status, increased educational achievement, higher income level and smaller family size. It may be due to any or all of these reasons or it may be due to greater readiness for pregnancy or more that children of older mothers tend to fair better when it comes to cognitive and behavioral measures. Others feel that it may due to a more mature mother-child interaction. Whatever the reason the benefits are present without any elevated risks in psychiatric problems.  So even though cause and effect cannot be established in the available studies, advanced maternal age seems to have a protective effect upon the psychological and cognitive development of children. Now there is also evidence that carrying a pregnancy may in turn have healthy implications on the aging of the mother as well.

A new series of investigations is finding that a healthy pregnancy may slow aging process. In animal studies, it has been a consistent finding that pregnancy has a rejuvenating effect upon mother through a process called parabiosis (connecting the circulation between the young and the old). In humans, studies have found measureable benefits including improved liver functioning, improved reparative abilities within the central nervous system and protective effects upon the heart following a healthy pregnancy. There is also data suggesting that unhealthy pregnancies can identify women at risk of age-related conditions like diabetes, stroke and heart disease—possibly identifying those at risk so that preventive measures can be initiated. So it seems that healthy women have a longer opportunity to conceive and that when women in their later years get pregnant that they remain healthier longer.

In summary, the links between fertility and healthy aging are far more complicated than previously believed. We can reassure women that taking steps during their younger years to live a healthy lifestyle should optimize their opportunities for pregnancy. We can not only track a woman’s fertility status through ovarian reserve testing but now we can also freeze/store eggs to extend their reproductive years. Then, by taking steps to optimize a women’s health during pregnancy, women may both have a healthier child as well as slow their own aging.