PCOS Articles - Metformin and PCOS treatment




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Violet30
05-04-2004, 04:58 PM
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If you have polycystic ovary syndrome (PCOS), there's a good chance your doctor has prescribed a drug called metformin (brand name "Glucophage" or "Glucophage XR"). Metformin offers both benefits and risks. They are summarized below. We also offer some suggestions if you are now taking metformin.

A small number of medical studies are mentioned in this article in order to give you some context for understanding the benefits and risks of metformin. Some of the purported benefits of metformin are controversial or unproven, and the studies cited below are not conclusive proof of benefits. Other relevant studies have not been included because of lack of space.

What Is Metformin?

Metformin is a drug that has been used to help control blood glucose levels in people with Type 2 Diabetes. Although metformin has been used in Europe for over 25 years, it was not available in the US until 1995. The FDA has approved metformin only for the treatment of Type 2 Diabetes. Consequently, some physicians don't have much clinical experience with metformin, or are reluctant to use it unless the patient has diabetes.(1)

Metformin appears to work in three ways. First, it decreases the absorption of dietary carbohydrates through the intestines.

Second, it reduces the production of glucose by the liver.(2) The liver uses the raw material in your food to create a reserve supply of blood sugar. When your body experiences stress, the liver releases the reserve glucose to supply your brain and muscles with an immediate source of energy to cope with the stress. Metformin suppresses the production of this reserve fuel.

Third, and perhaps most importantly, metformin increases the sensitivity of muscle cells to insulin.(2) Insulin is the hormone that delivers glucose into your cells to be burned as fuel, or stored. Women with PCOS frequently have "insulin resistance", a condition where excessive amounts of insulin are required in order to get blood glucose moved into cells, where it belongs. Metformin helps your body to transport glucose with relatively less insulin, thus lowering your insulin levels. Chronically high levels of either glucose or insulin in your blood contributes to obesity, heart disease, infertility, and certain cancers, as well as the development of diabetes.

Metformin is available in three different forms:
Generic Metformin Hcl
Glucophage (brand name)
Glucophage XR (brand name)

Metformin is available in 500 mg, 850 mg, or 1,000 mg tablets. The usual dose is 850-1,000 mg twice daily. The maximum safe dose is thought to be 850 mg three times daily. To minimize GI upset or diarrhea, it's recommended that you start with a low dosage and work your way up to the recommended dose.

Glucophage XR, an extended-release version of Glucophage, allows you to take only one dose a day. The slower release of long-acting Glucophage XR may help to reduce stomach upset that may occur with the regular Glucophage or metformin.

Recent prices for sixty 500 mg tablets of metformin at drugstore.com are:
Generic Metformin Hcl - $33.22
Glucophage (brand name) - $46.78
Glucophage XR (brand name) - $41.77.
Glucophage is chemically identical to generic metformin, so you can save money by using generic metformin.

Benefits of Metformin:

LOWERING OF INSULIN, TESTOSTERONE, AND GLUCOSE LEVELS. Quite a number of studies indicate metformin reduces insulin, testosterone and glucose levels -- which reduces acne, hirsutism, abdominal obesity, amenorrhea and other symptoms. In one study conducted at Virginia Commonwealth University, 24 obese PCOS women were given metformin or placebo. The 11 women who received the metformin experienced a reduction in insulin levels, which slowed the activity of an enzyme in the ovaries that stimulates excess production of testosterone. As a result, testosterone levels also dropped.(3)

Metformin appears to do the same for non-obese PCOS women, according to a study from the University of Medical Sciences in Poznan, Poland. Thirty nine PCOS women were given metformin for 12 weeks. They had improvements in insulin, testosterone, hirsutism and acne. (4)

PREVENTION OR DELAY OF ONSET OF DIABETES. Metformin may help to prevent diabetes, according to a study at George Washington University.(5) In this study, 3,234 non-diabetics with elevated blood glucose were given metformin, placebo, or lifestyle recommendations. The incidence of diabetes in the metformin group was 31% less than in the placebo group.

RESTORATION OF NORMAL MENSTRUAL CYCLE. A number of studies have shown that menstruation can be restored in many women with PCOS. For example, in a study at Jewish Hospital in Cincinnati, 43 women who were not having periods took metformin, and 39 of them resumed normal menses.(6) In another study at Jewish Hospital, 11 teenage girls with PCOS were put on metformin and a high-protein, low-carbohydrate diet. Ten of the 11 girls resumed regular periods.(7)

IMPROVED CHANCE OF PREGNANCY. A study of 48 women with PCOS and infertility was conducted at the Baylor College of Medicine. They were first given metformin and 19 of them resumed menstruating and showed indications of ovulation. But 10 required clomiphene (a fertility drug) in addition to metformin in order to show evidence of ovulation. Twenty women of the 48 (42%) became pregnant. However, 7 of the 20 miscarried.(8)

REDUCED RISK OF MISCARRIAGE. Another aspect of PCOS-related infertility is the tendency for repeated miscarriages. A study from the Hospital de Clinicas Caracas in Venezuela looked at 65 women who received metformin during their pregnancies vs. 31 who did not. The early pregnancy (first trimester) loss rate in the metformin group was 8.8% as compared to a 41.9% loss in the untreated group. Of those women who previously had miscarried, 11.1% of the metformin group miscarried again, while 58.3% of the untreated group again miscarried. (9)

REDUCED RISK OF GESTATIONAL DIABETES. In another study at Jewish Hospital in Cincinatti, gestational diabetes risk was evaluated in two groups of PCOS women. The first group was 33 non-diabletic women who had conceived while taking metformin or took metformin during their pregnancy. This group was compared to a group of 39 PCOS women who did not take metformin. Only 3% of the metformin group developed gestational diabetes as compared to 31% in the non-metformin group.(10)

WEIGHT LOSS AND OTHER BENEFITS. Metformin may contribute to weight loss in some diabetics.(11) However, weight loss does not appear to be one of its primary benefits. Metformin may also be of some value improving success with in vitro fertilization, lowering cholesterol, and improving energy.

Side Effects of Metformin:

MALAISE. 10%- 25% of women who take metformin just don't feel well. They experience a general malaise, fatigue and occasional achiness that lasts for varying lengths of time. Malaise a signal for the physician to closely monitor body systems affected by metformin, including liver, kidneys, and GI tract. A blood count should be taken from time to time, because metformin can induce B vitamin insufficiencies that can lead to a form of anemia.

GI DISTURBANCE. About one third of women on metformin experience gastrointestinal disturbances, including nausea, occasional vomiting and loose, more frequent bowel movements, or diarrhea. This problem occurs more often after meals rich in fats or sugars. The symptoms lessen over time, so if you can tolerate the GI upset for a few weeks, it may go away. Some women have found it helps to start with a very low dose and gradually increase it. One "benefit" of these unpleasant symptoms is that you find yourself eating less and thus losing some weight.

VITAMIN B12 MALABSORPTION. Of patients who take metformin, 10%-30% show evidence of reduced vitamin B12 absorption. A substance formed in the stomach called "intrinsic factor" combines with B12 so that it can be transferred into the blood. Metformin interferes with the ability of your cells to absorb this intrinsic factor-vitamin B12 complex.(12)

Over the long term, vitamin B12 insufficiency is a significant health risk. B12 is essential to the proper growth and function of every cell in your body. It's required for synthesis of DNA and for many crucial biochemical functions. There is also a link between B12 insufficiency and cardiovascular disease.

At least one study raises the concern that even if metformin is withdrawn, the vitamin B12 malabsorption may continue in some people.(13) The apparent cause is continued problems with availability of intrinsic factor, which is required for B12 absorption.

ELEVATED HOMOCYSTEINE. People who take metformin tend to have higher homocysteine levels.(14) Women with PCOS also tend to have elevated homocysteine.(15)

Homocysteine is an amino acid in the blood. A normal amount is OK. But an elevated level means that your metabolic processes are not working properly. Elevated homocysteine is associated with coronary artery disease, heart attack, chronic fatigue, fibromyalgia,(16) cognitive impairment.(17), and cervical cancer. (18)

Vitamin B12, along with vitamin B6 and folic acid (another B vitamin), is responsible for metabolizing homocysteine into less potentially harmful substances (19). Therefore, when metformin reduces absorption of vitamin B12, you lose one of the nutrients needed to reduce homocysteine and thus reduce your risk of cardiovascular disease.

ELEVATED HOMOCYSTEINE & PREGNANCY COMPLICATIONS. Pre-eclampsia is a complication of pregnancy characterized by increasing blood pressure and edema. If left untreated, pre-ecampsia can lead to eclampsia, a serious condition that puts you and your baby at risk. In a study conducted at the Center for Perinatal Studies at Swedish Medical Center in Seattle, a second trimester elevation of homocysteine was associated with a 3.2 fold increased risk of pre-eclampsia.(20)

The Dept. of Obstetrics and Gynecology, Nijmegen, The Netherlands, reviewed a series of studies on the linkage between elevated homocysteine and early pregnancy loss. They concluded that high homocysteine levels are a risk factor for recurrent early pregnancy loss.(21)

Ovarian follicular fluid contains detectable amounts of homocysteine along with B12, B6, and folic acid. The follicular fluid provides nourishment to the egg by facilitating transport of nutrients from blood plasma. High levels of homocysteine as well as an insufficiency of B vitamins may adversely influence the process of fertilization and early fetal development.(22)

NOTE: We are suggesting that elevated homocysteine, not metformin itself, could contribute to pregnancy complications in some women. However, metformin does contribute to increased homocysteine levels.

PREGNANCY WARNING. Many women use metformin in their pursuit of a successful pregnancy. However, metformin is a category B drug, meaning its safety for use while pregnant has not been established. Metformin is found in breast milk so it's not advisable to breast feed while taking metformin.

ANEMIA. By preventing optimal absorption of vitamins B12 and folic acid, metformin could induce or contribute to megaloblastic anemia.(23) Megaloblastic anemia occurs when your bone marrow doesn't have enough B vitamins to manufacture red blood cells. Your bone marrow then releases immature and dysfunctional red blood cells into circulation.

Although anemia is not common among people taking metformin, it remains a risk for those whose B12 and folic acid levels were already low when metformin therapy was started.

LIVER OR KIDNEY PROBLEMS. If you have liver or kidney problems of any kind, metformin could pose a problem, because metformin alters liver function and is excreted through the kidneys. A healthy liver and kidneys will improve your outcome with metformin. Liver and kidney function should be assessed before starting metformin and rechecked at least once a year while taking metformin. A blood chemistry screen and a complete blood count will tell your physician how well your system is doing with this drug.

MULTIPLE MEDICATIONS. You may be at risk for health problems or symptoms if you take metformin in addition to other medications. The more drugs you take, and the higher the dosage, the greater the probability there will be some kind of interaction between the drugs or some unexpected effect from the combined drugs. The effect of combined drugs also depends on the state of your health, your genetic uniqueness, and your diet and lifestyle. Always consult with your doctor if you add or change any medication, or if you develop any symptoms.

HAIR LOSS. Metformin may contribute to male pattern hair loss at the temples and top of head. Although there's nothing in the medical literature to support this linkage, some women have reported that hair loss was made worse by metformin.(24)

LACTIC ACIDOSIS. About 3 of every 100,000 people who take metformin will develop a medical emergency called "lactic acidosis". Lactic acid is a metabolic byproduct that can become toxic if it builds up faster than it is neutralized. Lactic acidosis is most likely to occur in people who with diabetes, kidney or liver disease, multiple medications, dehydration, or severe chronic stress.

Lactic acidosis can gradually build up. Symptoms to watch for include a need to breathe deeply and more rapidly, a slow, irregular pulse, a feeling of weakness, muscle pain, sleepiness, and a sense of feeling very sick. Treatment requires intravenous administration of sodium bicarbonate. Contact your doctor or go immediately to a hospital emergency room if you have these symptoms.

BILE ABNORMALITIES. Bile is produced by the liver, stored in the gallbladder, and secreted into the intestines in order to absorb fats into the bloodstream. One possible reason for the GI problems is that metformin reduces normal reabsorption of bile from the intestines back into the bloodstream, which causes elevated bile salt concentrations in the colon.(25) Most studies suggest that colonic bile salts cause free radical damage to DNA and may contribute to colon cancer.(26,27)

In addition, bile acids may stimulate cells in the colon to produce leukotriene B4 (LTB4), a highly inflammatory substance. LTB4 would be a contributor to any intestinal inflammatory condition.(28) Byproducts of bacterial action on bile salts may lead to intestinal cell damage and absorption of "foreign" molecules such as food or bacteria particles into the bloodsteam, possibly causing allergies and other immune responses.(29)

Moreover, many PCOS women have switched to a high-protein diet. If that protein consists of beef and other meats, bile acid concentration in the intestines is increased.(30) A diet high in meats is also linked to a higher risk of colon cancer.

CONSULT WITH YOUR PHYSICIAN TO MINIMIZE RISK. Your physician should always do a thorough medical history and metabolic assessment before putting you on metformin. You should be re-checked at least once a year for as long as you take this drug. Make sure to ask your physician what the unique benefits and risks of metformin will be for you. If you doctor prescribes metformin without a careful review of your health status and without involving you in the decision, find another doctor.

What to Do if You Are Taking Metformin:

IMPROVE YOUR DIET AND INCREASE EXERCISE. If you improve your diet and increase your level of exercise, you may be able to reduce or eventually eliminate your metformin therapy.

According to recently published results from the Diabetes Prevention Program, exercise and diet changes are more effective than metformin in preventing diabetes.(5) This study divided 3,234 non-diabetics with elevated blood glucose into 3 groups. One group was given metformin but no diet or lifestyle education and support. The second group was given only diet and lifestyle education and support (no metformin). The third group received a placebo and no diet or lifestyle support.

After 2.8 years in the study, the incidence of diabetes in the placebo group was 11 per 100 people. In the metformin group, the incidence was only 7.8 per 100 people. But the diet/lifestyle group had the best results of all: only 4.8 of every 100 developed diabetes. In other words, diet and exercise were 38% more effective than metformin in preventing diabetes in high-risk people.

Other studies have shown that reducing weight and increasing exercise improves ovulation rates and reduces male hormone levels. There's no question that healthy diet, exercise and lifestyle habits will significantly improve PCOS-related health problems, as well as reduce the risk of diabetes and cardiovascular disease.

CONSIDER SPECIAL NUTRIENT THERAPY. There are herbs, vitamins and minerals, and other specialty natural foods and supplements that have effects similar to metformin. These nutrients have an excellent safety record and are a valuable complement to regular exercise and healthy diet.

As a first step, we suggest you protect yourself from the potential malabsorption and loss of B vitamins that are needed to control homocysteine and to keep you healthy by taking a high-quality B-complex vitamin.

Blood sugar levels, insulin resistance, and male hormone levels can be favorably influenced by chromium, vitamin E, certain fish oils, magnesium, CoQ10, zinc, conjugated linoleic acid (CLA), biotin, certain amino acids, and soluble fiber from particular plants.(31-35)

An important potential alternative to metformin is d-chiro-inositol, although it is not yet on the market. A form of the B vitamin niacin, d-chiro-inositol increases the action of insulin in women with polycystic ovary syndrome. It improves ovulatory function and decreases male hormones, triglycerides and blood pressure.(36)

While on metformin, you should take a good quality multiple vitamin & mineral supplement as well as extra calcium (37), magnesium and vitamin D.

Specific details about special nutrient therapy are beyond the scope of this article, but we hope to go into more detail in future newsletters.

BOTTOM LINE: There are several important reasons why a more "holistic" approach using physical activity, healthy diet, stress management, and special nutrients should be considered.
A healthy diet and lifestyle is more effective than metformin alone.
You may be able to reduce your dosage of metformin or eliminate it altogether.
A healthy diet and lifestyle is less expensive than metformin.
A holistic approach builds your health whereas metformin does not.
A holistic approach does not have drug side effects and is safer than metformin.

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FOOTNOTES

(1) Thatcher, S, PCOS: The Hidden Epidemic, Perspectives Press, 2000, p.156

(2) Damico, C et al, eds., Nursing 2002, Drug Handbook, 22nd Ed, Springhouse Publishers, 2002, p.779

(3) Nestler, JE et al, Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome, N Engl J Med, 1996, 335(9):657-8

(4) Kolodziejezyk, B et al, Metformin therapy decreases hyperandrogenism and hyperinsulinemia in women with polycystic ovary syndrome, 2000, Fertil Steril, 73(6):1149-54

(5) Knowler, WC et al, Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin, N Engl J Med, 2002, 346(6):393-403

(6) Glueck, CJ et al, Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with polycystic ovary syndrome, Metabolism, 1999, 48:511-519

(7) Glueck, CJ et al, Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary sundrome (PCOS), J Adolesc Health, 2001, 29(3):160-9

(8) Heard, MJ et al, Pregnancies following use of metformin for ovulation induction in patients with polycystic ovary syndrome, Fertil Steril, 2002, 77(4):669-73

(9) Jakubowicz, DJ et al, Effects of metformin on early pregnancy loss in the polycystic ovary syndrome, J Clin Endocrinol Metab, 2002, 87(2):524-9

(10) Glueck, CJ et al, Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome, Fertil Steril, 2002, 77(3):520-5

(11) Greenway, F, Obesity medications and the treatment of type 2 diabetes, Diabetes Technol Ther, 1999, 1(3):277-87.

(12) Adams, JF et al, Malabsorption of vitamin B12 and intrinsic factor secretion during biguanide therapy, Diabetologia, 1983, 24(1):16-8

(13) McCarty, MF, Toward practical prevention of type 2 diabetes, Med Hypotheses, 2000, 54(5):786-93

(14) Desouza, C et al, Drugs affecting homocysteine metabolism: impact on cardiovascular risk, Drugs, 2002, 62(4):605-16

(15) Vrbikova, J et al, Homocysteine and steroids levels in metformin treated women with polycystic ovary sundrome, Exp Clin Endocrinol Diabetes, 2002, 110(2):74-6

(16) Regland B, et al, Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome, Scand J Rheumatol, 1997; 26(4):301-7.

(17) Parsons RB, et al, In vitro effect of the cysteine metabolites homocysteic acid, homocysteine and cysteic acid upon human neuronal cell lines, Neurotoxicology, 1998. 19(4-5):599-603.

(18) Weinstein, SJ et al, Elevated serum homocysteine levels and increased risk of invasive cervical cancer in U.S. women, Cancer Causes Control, 2001, 12(4):317-24

(19) Selhub, J, Folate, vitamin B12 and vitamin B6 and one carbon metabolism, J Nutr Health Aging, 2002, 6(1):39-42

(20) 31. Sorensen TK, et al, Elevated second-trimester serum homocyst(e)ine levels and subsequent risk of preeclampsia, Gynecol Obstet Invest, 1999, 48(2):98-103

(21) Nelen, WL, et al, Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis, Fertil Steril, 2000, 74(6):1196-9

(22) 30. Steegers-Theunissen RP, et al, Study on the presence of homocysteine in ovarian follicular fluid, Fertil Steril, 1993, 60(6):1006-10

(23) Callaghan, TS et al, Megaloblastic anaemia due to vitamin B12 malabsorption associated with long-term metformin treatment, Br Med J, 1980, 280(6225):1214-5

(24) Boss, A et al, Living With PCOS, Addicus Books, 2001, p. 58

(25) Scarpello, JH et al, Effects of metformin on bile salt circulation and intestinal motility in type 2 diabetes mellitus, Diabet Med, 1998, 15(8):651-6

(26) Allgayer, H et al, Effects of bile acids on base hydroxylation in a model of human colonic mucosal DNA, Cancer Detect Prev, 2002, 26(1):85-9

(27) Barone, M et al, Demonstration of a direct stimulatory effect of bile salts on rat colonic epithelial cell proliferation, Scand J Gastroenterol, 2002, 37(1):88-94

(28) Dias, VC et al, Bile salts determine leukotriene B4 synthesis in a human intestinal cell line (CaCo-2), Dig Dis Sci, 1994, 39(4):802-8

(29) Fegundes-Neto, U et al, Bile salt-enhanced rat jejunal absorption of a macromolecular tracer, Lab Invest, 1981, 44(1):18-26

(30) Goldin, BR et al, Modern Nutrition in Health and Disease, 1994, Lea & Beger, pp. 577-80

(31) Linday, LA, Trivalent chromium and the diabetes prevention program, Med Hypotheses, 1997, 49(1):47-9

(32) McCarty, MF, Exploiting complementary therapeutic strategies for the treatment of type II diabetes and prevention of its complications, Med Hypotheses, 1997, 49(2):143-52

(33) McCarty, MF, Hepatothermic therapy of obesity: rationale and an inventory of resources, Med Hypotheses, 2001, 57(3):324-36

(34) Fulghesu, AM et al, N-acetyl-cysteine treatment improves insulin sensitivity in women with polycystic ovary syndrome, Fertil Steril, 2002, 77(6):1128-35

(35) Kelly, GS, Insulin resistance: lifestyle and nutritional interventions, Altern Med Rev, 2000, 5(2):109-32

(36) Nestler JE et al, Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome, N Engl J Med, 1999, 29;340(17):1314-20

(37) Bauman, WA et al, Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin, Diabetes Care, 2000, 23(9):1227-31

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