Treatment with Insulin Lowering Medications

by Mark Perloe, M.D.

Polycystic ovary syndrome is characterized by anovulation (irregular or absent menstrual periods) and hyperandrogenism (elevated serum testosterone and androstenedione). Patients with this syndrome may complain of abnormal bleeding, infertility, obesity, excess hair growth, hair loss and acne. In addition to the clinical and hormonal changes associated with this condition, vaginal ultrasound shows enlarged ovaries with an increased number of small (6-10mm) follicles around the periphery (Polycystic Appearing Ovaries or PAO). While ultrasound reveals that polycystic appearing ovaries are commonly seen in up to 20% of women in the reproductive age range, PolyCystic Ovary Syndrome (PCOS) is a estimated to affect about half as many or approximately 6-10% of women. The condition appears to have a genetic component and those effected often have both male and female relatives with adult-onset diabetes, obesity, elevated blood triglycerides, high blood pressure and female relatives with infertility, hirsutism and menstrual problems.

As of yet, we do not understand why one woman who demonstrates polycystic appearing ovaries on ultrasound has regular menstrual cycles and no signs of excess androgens while another develops PCOS. One of the major biochemical features of polycystic ovary syndrome is insulin resistance accompanied by compensatory hyperinsulinemia (elevated fasting blood insulin levels). There is increasing data that hyperinsulinemia produces the hyperandrogenism of polycystic ovary syndrome by increasing ovarian androgen production, particularly testosterone and androstenedione and by decreasing the serum sex hormone binding globulin concentration. The high levels of androgenic hormones interfere with the pituitary ovarian axis, leading to increased LH levels, anovulation, amenorrhea, and infertility. Hyperinsulinemia has also been associated high blood pressure and increased clot formation and appears to be a major risk factor for the development of heart disease, stroke and type II diabetes.

There is little agreement when it comes to how PCOS is diagnosed. Most physicians will consider this diagnosis after making sure you do not have other conditions such as Cushing’s disease (overactive adrenal gland), thyroid problems, congenital adrenal hyperplasia or increased prolactin production by the pituitary gland. TSH, 17-hydroxyprogesterone, prolactin and a dexamethasone suppression test may be advisable. After reviewing your medical history, your physicians will determine which tests are necessary. If you have irregular or absent menstrual periods, clues from the physical exam will be considered next. Your height and weight will be noted along with any increase facial or body hair or loss of scalp hair, acne and acanthosis nigricans (a discoloration of the skin under the arms, breasts and in the groin). Elevated androgen levels (male hormones) androstenedione, DHEAS or testosterone confirm the diagnosis. A fasting insulin and glucose level will be obtained. Many physicians tell their patients that insulin values are normal, when in fact the value indicates that insulin may be playing a role in stimulating the development of PCOS. Most labs report levels less than 25-30 miu/ml as normal, while in fact, levels over 10miu/ml on a fasting blood sample suggests that PCOS may be related to hyperinsulinism. As women with polycystic ovary syndrome may be a greater risk for other medical conditions, testing for blood lipids, diabetes and PAI-1 (a blood factor that promotes abnormal clotting).

Traditional treatments have been difficult, expensive and have limited success when used alone. Infertility treatments include weight loss diets, ovulation medications (clomiphene, follistim, Gonal-F), ovarian drilling surgery and IVF. Other symptoms have been managed by anti-androgen medication (birth control pills, spironolactone, flutamide or finasteride).

Ovarian drilling can be performed at the time of laparoscopy. A laser fibre or electrosurgical needle is used to puncture the ovary 10-12 times. This treatment results in a dramatic lowering of male hormones within days. Studies have shown that up to 80% will benefit from such treatment. Many who failed to ovulate with clomiphene or metformin therapy will respond when rechallenged with these medications after ovarian drilling. Interestingly, women in these studies who are smokers, rarely responded to the drilling procedure. Side effects are rare, but may result in adhesion formation or ovarian failure if the procedure is performed by an inexperienced surgeon.

But recently promising new treatment options have become available. Drs. Velazquez, Nestler and Dunaif have shown that lowering serum insulin concentrations with metformin (Glucophage 1500 mg a day) or troglitazone (troglitazone, Rezulin has recently been withdrawn from the market because of lifethreatening side effects) ameliorates hyperandrogenism, by reduction of ovarian enzyme activity that results in male hormone production.

For women in the reproductive age range, polycystic ovary syndrome is a serious, common cause of infertility, because of the endocrine abnormalities which accompany elevated insulin levels. There is increasing evidence that this endocrine abnormality can be reversed by treatment with widely available standard medications which are leading medicines used in this country for the treatment of adult onset diabetes, metformin (Glucophage 500 or 850 mg three times per day or 1000mg twice daily with meals), pioglitazone (Actos 15-30 mg once a day), rosiglitazone (Avandia 4-8 mg once daily) or a combination of these medications. These medications have been shown to reverse the endocrine abnormalities seen with polycystic ovary syndrome within two or three months. They can result in decreased hair loss, diminished facial and body hair growth, normalization of elevated blood pressure, regulation or menses, weight loss and normal fertility. We have seen pregnancies result in less than two months in woman who conceived in their very first ovulatory menstrual cycle. By six months over 90% of women treated with insulin-lowering agents will resume regular menses.

The medical literature suggests that the endocrinopathy in most patients with polycystic ovary syndrome can be resolved with insulin lowering therapy. This is clinically very important because the therapy reduces hirsutism, obesity, blood pressure, triglyceride levels, elevated blood clotting factors and facilitates reestablishment of the normal pituitary*ovarian cycle, thus often allowing resumption of normal ovulatory cycles and pregnancy. We know the polycystic ovary disease is associated with increased risk of heart attack and stroke because of the associated heart attack and stroke risk factors, hypertension, obesity, hyperandrogenism, hypertriglyceridemia, and these are to a large degree resolved by therapy with these medications.

Side effects are rare. Although metformin, rosiglitazone and troglitazone lower elevated blood sugar levels in diabetics, when given to non*diabetic patients, they only lower insulin levels. Blood sugar levels will not change. In fact, episodes of “hypoglycemic attacks” appear to be reduced.

METFORMIN (Glucophage):
When first starting this medication, people will often experience upset stomach or diarrhea which usually resolves after the first week. This side effect can be minimized by taking metformin with a meal and starting with a low dose. I recommend that our patients start with one 500 mg pill daily the first week and increase to twice a day during the second week. If after the second week GI side effects are minimal, the dose is increased to 850 mg twice daily. Patients with reduced renal function (creatinine >1.5 or creatinine clearance <60%) are at a higher risk for a rare side effect of metformin therapy called lactic acidosis, and the drug should be given cautiously, if at all, to such patients. Patients taking metformin should notify their physician and discontinue the medication: 48 hours before surgery 48 hours before an IVP Xray study or other Xrays where an intravenous dye is administered If you experience shortness of breath, severe muscle weakness or chest pain If you use alcohol excessively TROGLITAZONE, (Rezulin) PIOGLITAZONE, (Actos), ROSIGLITAZONE, (Avandia): These medications belong to a class of medications called PPAR gamma agonists. They enhance the ability of smooth muscle to metabolize sugar, thereby reducing insulin resistance. The FDA has recently reviewed the safety of troglitazone ( and reports that 35 patients out of approximately 1.5 million have either died or required liver transplant.) Therefore Rezulin has been removed from the market. As the new alternatives to troglitazone, (Rezulin), Rosiglitaone (Avandia) and pioglitazone (Actos) are metabolized by different liver enzymes experience has shown that these medications appear to pose less risk of hepatotoxicity. HOW DO WE MONITOR THERAPY? BBT charts are monitored and reviewed to determine if you are ovulating. With metformin, you will be asked to return three months after initiating therapy. If you have ovulated, therapy may be continued another three months to see if you will conceive. Women taking rosiglitazone or pioglitazone will be seen at two month intervals for monitoring liver function tests (ALT). BBT charts will be reviewed after four months. Re-evaluation will include measurements of lab tests that were abnormal at the initial evaluation. C-peptide levels, a measure of insulin secretion, may also be tested. If the laboratory studies are still abnormal, metformin may be increased up to 850 mg three times daily or rosiglitazone may be added. If the laboratory studies are normal but ovulation has not occured, a repeat trial of clomiphene may be considered. We have seen that women who were unable to ovulate on up to 250 mg ovulate when 50 mg of clomiphene is used in conjunction with metformin or PPARgamma therapy. Laparoscopic ovarian drilling may be considered for those women where other indications for laparoscopy are present. PREGNANCY While safety during pregnancy has not yet been established, three patients who continued on metformin during their entire pregnancy and one who remained on troglitazone have delivered normal babies. There are no reports of abnormal babies in women who conceived using metformin and all resulting babies were normal. Metformin is a category B medication. This means that insufficient human data is available but no credible animal data suggesting a teratogenic (could produce birth defects) risk. Although to the best of our present knowledge the risk of birth defects would be small, it must also be noted that maternal diabetes has been associated with an increased risk of birth defects and the underlying elevated insulin levels may lead to birth defects if not corrected. While the most prudent policy may be to avoid the use of these medications during pregnancy until more data on pregnancy outcome is available, the risk of miscarriage may be reduced by continuing metformin during the pregnancy. We ask our PCOS patients taking insulin-lowering medications to monitor their basal body temperatures if pregnancy is a possibility. When the temperature remains elevated for more than 16 days, pregnancy is likely and a home pregnancy test should be performed. If positive, a medical consultation with the physician is scheduled. If the EPT is negative the BBT chart is reviewed by the physician or nurse to determine the appropriate course to follow. MISCARRIAGE & PCOS Women with PCOS who conceive either spontaneously or after ovulation induction have a much higher risk of miscarriage. Liddell has shown that polycystic appearing ovaries (on ultrasound) are more frequently seen in women with recurrent pregnancy loss, the presence of PCO on ultrasound did not predict the outcome in subsequent pregnancies. Hypersecretion of LH was thought to cause chromosomally abnormal eggs leading to an increased risk of miscarriage. But a Japanese study found that PCOS was more common in women whose prior loss was associated with normal chromosomes. Others have suggested that high androgen levels may be a contributory factor. Homburg has shown that miscarriage rates after ovulation induction or IVF is decreased when women are pretreated with a GnRH-agonist such as Synarel, Lupron or Zoladex. Hyperinsulinemia may be a contributing factor in the higher rate of miscarriage. Elevated levels of insulin interfere with the normal balance between factors promoting blood clotting and those promoting breakdown of the clots. Increases in plasminogen activator inhibitor activity (PAI-Fx) associated with high insulin levels may result in increased blood clotting at the interface between the uterine lining (endometrium) and the placenta. This could lead to placental insufficiency and miscarriage. There are no placebo-controlled clinical trials to indicate whether pregnancy outcomes are improved in pregnancies that result from the use of insulin-lowering medications or whether pregnancy outcomes are better in those who continue metformin throughout the pregnancy or those who discontinue. Coetzee has shown that use of metformin to manage non-insulin dependent diabetes during pregnancy can be accomplished safely. We have initially noted that women who conceive following metformin or troglitazone therapy have an unacceptably high (>30%) risk of miscarriage. Dr. Glueck notes similar increased risk of miscarriage following metformin therapy. He notes that the risk of miscarriage is increased in those patients with a prior history of miscarriage, those with high LH, high androgen levels, hyperinsulinemia or elevated PAI-Fx. Initial findings in a non-ramdomized trial suggest a decreased risk of miscarriage if metformin is continued throughout the pregnancy. At present there is insufficient data to routinely advise continuation of metformin during pregnancy. As an alternative to continuing metformin therapy, those women with increased risk of abnormal blood clotting may benefit from baby aspirin, folate supplementation and low dose heparin therapy. Pregnancy loss is a troubling concern. This information is provided to enable you work with your ob/gyn physician to make an informed decision about your care.

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2. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450cl7alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. New England J Medicine 1996,335:617*623.

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