Metformin
The preferred drug for reducing Insulin Resistance is Metformin. Although this drug has been in use for the treatment of Type 2 diabetes for upward of 50 years, it is only now that we have some understanding of its mode of action. It apparently acts at a key metabolic step in the cell to eventually increase insulin receptor numbers, their efficiency of signaling, reduces glucose production by the liver, as well as reduces the levels of free fatty acids. It reverses many of the metabolic characteristics of PCOS predicated on insulin resistance. It helps in weight reduction and other symptoms of PCOS such as fatigue, disturbed sleep and hypoglycemia afterwards.
It works equally well in both overweight individuals with PCOS as well as those of normal weight.
Metformin is very cheap. Even where a dispensing fee is factored in, it is much cheaper to have Metformin on a private prescription than obtaining a prescription for which the patient pays a set fee.
How Metformin acts
Metformic activates AMPK in liver and muscle to improve glucose and lipid metabolism. Metformin mediates its action by stimulating adenosine monophosphate-activated protein kinase (AMPK), a critical enzyme. It also reduces enzymatic pathways involved in incraesing fatty acid production by the liver. (ACC = acteyl-CoA carboxylase; SREPB-1 = sterol-regulatory-element-binding-protein-1) In this manner it reduces storage of fat in the liver and in the blood carrier protein (VLDL or very low density lipoprotein) that shuttles triglycerides (trigs) and the body. Diagram adapted from Alice Y.Y. Cheng, I. George Fantus, 'Oral antihyperglycemic therapy for type 2 diabetes mellitus' Canadian Medical Association Journal 172(2),2005 pp213-226.
Usage
We recommend a start with a single dose of Metformin (500 mg or even 250 mg), with the FIRST bite of dinner. If well tolerated, a similar dose can be introduced after breakfast after 7 – 10 days. In another 7 – 10 days, a third dose may be introduced at lunch. This easing in of Metformin will minimize side effects, which in most people are transitory. Side effects include metallic taste, wind, loose bowels and, sometimes, nausea. A very small number of patients cannot tolerate Metformin at all, and alternative treatment may have to be found.
With reduction of weight loss and improvement in insulin resistance, regular periods resume. Ovulation may become more predictable, and in most patients serum testosterone and LH falls. The latter development is not, however, necessarily always the case and may well reflect differences between individuals in the degree of insulin resistance and the involvement of other factors in PCOS. It is, therefore, not always possible to promise a woman who has achieved ideal body weight and who continues with exercise that she would do equally well if she came off Metformin.
Metformin can interfere with the absorption of Vitamin B12 in a small percentage of patients. Serum B12 concentration should, therefore, be checked twice a year. Apparently, increasing dietary intake of calcium prevents Metformin influence on B12 absorption. Blood tests for liver function should also be checked at least yearly. Very unusual individuals experience sensitivity to sunlight when taking metformin. It is not a problem that a good sunscreen will not solve.
A few patients who adhere to the program of low glyceamic eating, exercise, Metformin and stress management fail to lose a significant amount of weight, even though they may feel symptomatically better. Some individuals who cannot tolerate regular Metformin may do better on the slow release form. Slow release Metformin (850 mg) is, however, not available in the UK at this time.
Metformin during pregnancy
In view of the high reported rate of EPL (40%) in PCOS, we advocate that women who fall pregnant continue to take Metformin through the first 12 weeks of pregnancy. Other doctors discontinue Metformin once pregnancy has occurred, whereas others yet suggest that Metformin be taken throughout the pregnancy. There are currently no controlled studies to favor any of the recommendations. The endometrium of women with PCOS is inefficient in making substances e.g. glycodelin that inhibit the endometrial immune response to the implantation of the early embryo and that play an important role in infloatation and maintaining the pregnancy. Metformin increases the production of endometrial glycodelin, perhaps explaining how it reduces EPL rates.
To share our experience with you, over the last 23 months, 41 women with PCOS became pregnant after adopting our program of low GI, exercise and metformin. There were 40 live births, one EPL and no baby with birth defects, even though the average age among the women was 33.5 years.
If you have followed our program and become pregnant, we would like to hear from you!
Although Metformin is a category A drug (no information available that it does not cause congenital malformation), there is no evidence to show that it harms the fetus.