PCOS and Insulin Resistance: Part 8 Fertility Treatments

Medical science, particularly in the field of fertility, has advanced by leaps and bounds. Fertility stimulation therapies such as the use of clomiphene, IUI (intrauterine insemination) and IVF (in-vitro fertilization) have been a blessing for many families, including those whose women have suffered with PCOS (Polycystic Ovary Syndrome). Fertility treatments, such as IVF, in fact have been shown to be extremely successful for women with PCOS, more so even than for those who don’t suffer from PCOS, like women with tubal infertility. This advantage is in part due to the fact that women with PCOS tend to have an increased number of oocytes (immature eggs), at least up until the age of 40 or so 1. It would seem then that IVF and fertility treatments are the answer to the “prayers” of every woman with PCOS trying to conceive… or are they…?

I gather that stimulation fertility treatments for women with PCOS may in fact be a “double-edged sword”, rather than a blessing. A wanted baby is always a welcomed miracle…but at what “cost”? I myself reached out for fertility support when trying to conceive with both of my children. My body was not ovulating. I couldn’t (or so I thought) conceive spontaneously. When we completed the first round of clomiphene, unsuccessfully, my husband refused to go on to more intrusive procedures, like IVF. Intuitively (leave it to the male in the relationship to be more intuitive one 😊 ) he said, if your/our bodies don’t “want to get pregnant” it’s because we have to “fix” something, not “force” it to get pregnant through artificial measures. Looking back now, I am in awe of his wisdom. Of course, for some couples, fertility treatments or adoption may be the only option, but that is not necessarily the case for women with PCOS. How do I know that? Because I am a woman with PCOS and I conceived twice, without IVF. First, with dietary and lifestyle changes, and the second time around, with the help of metformin. Metformin is not an ovulatory stimulant, per se, although it’s mechanism of action can help women with PCOS conceive and ensure a pregnancy with less chances of complications (2). If we can understand the science behind this, we can understand how other lifestyle measures may also be as useful (if not more).

First, let us look at the advantages and disadvantages of fertility treatments, specifically for women with PCOS.

ADVANTAGES

Obvious, duh! A BABY...

DISADVANTAGES

Straight from the source, another very wise man, in his own words, Dr. Fung has shared with me his thoughts on this:

“IVF is mostly a waste of money because it doesn't address the root cause. There may be some risk (and) yes, IVF can get you a baby, but because you still have hyperinsulinemia, you have not improved your own health and may be putting the health of your future child at risk. Better instead to save your money, improve your health, and then have a healthy baby.” BRILLIANT.

Let’s first address what the potential risks of IVF and other stimulation fertility treatments might be, for PCOS women specifically. The most common and worrisome of all is OHSS. Ovarian hyperstimulation syndrome (OHSS) is a medical condition that can occur in some women, particularly women with PCO (Polycystic Ovaries) who take fertility medication to stimulate egg growth. These medications stimulate follicle development. Even though most cases are mild, this condition can vary from mild to moderate, severe or even critical (lethal). The symptoms often observed with these enlarged ovaries can range from mild abdominal distention, pain, gastrointestinal discomfort (diarrhea and nausea), to thrombosis, oliguria (decreased urinary production), breathing difficulties and even death which can develop before pregnancy and into early pregnancy.

Women who become pregnant while plagued with PCOS are at a significant higher risk of developing gestational diabetes, pregnancy-induced hypertension, pre-eclampsia and pre-term birth when compared to normal women or those who have overcome PCOS (3). Another significantly greater risk is spontaneous abortion, likely related to the higher prevalence of obesity in women with PCOS (another issue that should be overcome prior to pregnancy) (4). Lastly, women with PCOS who successfully conceive, are also more likely to deliver by Caesarian section, which in of itself comes with complications.

Unfortunately, the mothers with PCOS are not the only ones negatively affected here. The offspring born to these mothers are also at a significant higher risk of developing neonatal complications and metabolic consequences later in life. This is not as widely known and relayed to women as it should be. Women care quite a bit more about the health outcome of their children when compared to their own. Although many women will engage in recreational use of alcohol, drugs and tobacco, most will take the necessary measures to cease this behaviour prior to and during pregnancy. The known detrimental effects of these substances on their babies is the primary motivation. If more women knew that getting pregnant with PCOS, obesity and insulin resistance would greatly and negatively impact their babies as well, they would ensure appropriate attempts at resolving these issues prenatally (if and when the opportunity was available).

Babies born to women with PCOS are at a greater risk for spontaneous abortion as mentioned above. Further, there is a higher chance of both reduced fetal growth and birth weight (SGA-small for gestational age) as well as the other end on the spectrum: fetal overgrowth and adiposity (LGA-large for gestational age), likely due to increased nutrient availability because of their mothers’ insulin status. Both ends of the spectrum are associated with metabolic complications later in life for the infants (type 2 diabetes, obesity and hypertension) (5). There is a significantly higher risk of admissions to the NICU (neonatal intensive care unit) and perinatal mortality for these babies (6).

PCOS is an endocrine-metabolic disorder with strong familial aggregation. Likely there is also a genetic factor at play. “Parents and brothers of PCOS women exhibit insulin resistance and related metabolic defects”, while sisters and first cousins of women with PCOS are more likely to also express the condition. Sons of women with PCOS are more likely to develop obesity throughout infancy into adulthood and express other signs of insulin resistance which places them at a higher risk for developing type 2 diabetes and cardiovascular disease (7). Daughters born to women with PCOS have an increased serum AMH (Anti-Mullerian hormone) concentration, altered follicular development, hyperandrogenemia and higher likelihood of developing PCOS. Both sons and daughters of women with PCOS inherit insulin resistance from their PCOS mothers often expressing itself in later stages of puberty (8). Over the past 20 years, in the USA as well as other countries, there has been a significant increase in the rates of type 2 diabetes and a parallel increase in obesity. Although all age groups seem to be affected, “the most dramatic increases have occurred in adolescents. The relationship between decreased maternal insulin sensitivity and fetal overgrowth particularly in obese women and women with gestational diabetes may help explain the increased incidence of adolescent obesity and related glucose intolerance in the offspring of these women.” The most shocking of all, is the fact that these metabolic experiences in utero by the fetus may affect his/her intellectual and psychomotor development primarily thought to be due to excessive insulin secretion in utero (9).

Even though PCOS accounts for “80% of anovulatory infertility cases” and is the most common endocrine (hormonal) pathology in women resulting in poor quality of life during their reproductive years and significantly higher morbidity and mortality post-menopause (type 2 diabetes, cardiovascular disease, obesity, cancer), I must agree that most primary health care providers do not commonly appreciate the severity of this syndrome and its complications to the woman and her eventual offspring (10).

I haven’t yet mentioned the prohibitive costs and discomfort associated with more intrusive fertility treatments, such as IVF, but that goes without saying. It’s an obvious disadvantage.

So then, what to do? Do we just “castrate” all women with PCOS? Obviously not (or I myself would have been robbed of the pleasure and pain of motherhood). Why is metformin so successful in both improving reproductive function as well as positively affecting pregnancy outcomes? Can this effect be replicated without medication (or in conjunction with medication)? I believe that it can. First off, metformin has been shown to significantly reduce the risk of OHSS (ovarian hyperstimulation syndrome) (11). Obese women especially seem to benefit from a 3-month prenatal treatment with metformin (significant higher pregnancy rates and reduction in early miscarriage) (12) as well as lower rates of severe complication during pregnancy (Gestational Diabetes, Pregnancy-induced hypertension and Pre-eclampsia) and post-partum (13) without adversely affecting the infant. I’ll go as far as to say that metformin may even help to attenuate the metabolic complications of children born to mothers with PCOS (although there aren’t enough studies to support this).

What is the MoA (mechanism of action) of Metformin, and again, can this action be replicated without the use of medications (many people have mild to severe adverse effects to metformin). “Metformin has been shown to have encouraging effects on several metabolic aspects of polycystic ovarian syndrome, such as insulin sensitivity, plasma glucose concentration and lipid profile and since women with PCOS are more likely than healthy women to suffer from pregnancy-related problems like early pregnancy loss, gestational diabetes mellitus and hypertensive states in pregnancy, the use of metformin therapy in these patients throughout pregnancy may have beneficial effects on early pregnancy loss and development of gestational diabetes.” Basically, Glumetza (metformin hydrochloride) is an oral antihyperglycemic drug, primarily used in the treatment of type 2 diabetes, but it’s use in the USA, Canada and worldwide, to help women with PCOS conceive has grown. I was prescribed Metformin in Mozambique in 2012. It’s MoA then: “Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.” Pretty impressive. This will, in turn, help women with PCOS conceive, prevent pregnancy complications, and potentially spare children the burden of metabolic disease. WOW.

The truth of the matter is, some women with PCOS will unfortunately not get pregnant even with the aid of metformin (sorry to burst your bubble), even though many sing its praises. Ultimately the take-home message here is that reducing glucose absorption and improving insulin sensitivity will be as good a method as any to help women with PCOS conceive and spare them, and their children, the negative outcomes of a PCOS pregnancy. I know something else that can do this, utilizing a similar MoA as metformin, but to a much greater degree and extent: Intermittent Fasting and a Low Carb Diet!