INTRODUCTION:
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.
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.
HYPERINSULIN & PCOS?
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 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, recurrent pregnancy loss, 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.
DIAGNOSIS
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), DHEAS or testosterone help make the diagnosis. A two hour insulin and glucose tolerance test 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 cardiovascular risk factors such as blood lipids, homocysteine, CRP and PAI-1 (a blood factor that promotes abnormal clotting) will also be carried out.
NEWER METHODS OF TREATMENT
Traditional treatments have been difficult, expensive and have limited success when used alone. Infertility treatments include weight loss diets, ovulation medications (clomiphene,letrozole, 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 letrozole 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.
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, reduction in cardiovascular risk factors, normal fertility, and a reduced risk of miscarriage. 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, diet and exercise 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 syndrome 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.
ARE THESE MEDICATIONS SAFE?
Side effects are rare. Although metformin, rosiglitazone and pioglitazone lower elevated blood sugar levels in diabetics, when given to nondiabetic 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. Surprisingly, we have found that the extended release version, Glucophage XR seems to be associated with less weight loss as compared to the generic preparation. Patients with reduced renal function (creatinine >1.5 or creatinine clearance <60%)>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.
BIBLIOGRAPHY
1. Velazquez EM, Mendosa S, Hamer T, Sosa F, Glucck CJ. Metformin therapy in women with polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating menstrual regularity and pregnancy. Metabolism 1994,43:647655.
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 1996,335:617623.
3. Utiger RD. Insulin and the polycystic ovary syndrome. New England J Medicine 1996,335:657658
4. Dunaif A, Scott D, Finegood D, Quintana ma B, Whitcomb R. The insulin sensitizing agent Troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome Endocrinol Metab 1996;81:32993306
5. Coetzee EJ, Jackson WP. The management of non-insulin-dependent diabets during pregnancy. Diabetes Res Clin Pract 1985-86;1:281-287
6. Homburg R. Polycystic ovary syndrome: induction of ovulation. Ballieres Cllinical Endocrinologys & Metabolism 1996; 10:281-292
7. Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L. Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with polycystic ovary syndrome. Metabolism 1999; 48:1-10.
8. Tulppala M, Stenman UH, Cacciatore B, Ylikorkala O. Polycystic ovaries and levels of gonadotropins and androgens in recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum Reprod 1994;9:1328-32.
HYPERINSULIN & PCOS?
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 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, recurrent pregnancy loss, 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.
DIAGNOSIS
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), DHEAS or testosterone help make the diagnosis. A two hour insulin and glucose tolerance test 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 cardiovascular risk factors such as blood lipids, homocysteine, CRP and PAI-1 (a blood factor that promotes abnormal clotting) will also be carried out.
NEWER METHODS OF TREATMENT
Traditional treatments have been difficult, expensive and have limited success when used alone. Infertility treatments include weight loss diets, ovulation medications (clomiphene,letrozole, 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 letrozole 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.
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, reduction in cardiovascular risk factors, normal fertility, and a reduced risk of miscarriage. 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, diet and exercise 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 syndrome 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.
ARE THESE MEDICATIONS SAFE?
Side effects are rare. Although metformin, rosiglitazone and pioglitazone lower elevated blood sugar levels in diabetics, when given to nondiabetic 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. Surprisingly, we have found that the extended release version, Glucophage XR seems to be associated with less weight loss as compared to the generic preparation. Patients with reduced renal function (creatinine >1.5 or creatinine clearance <60%)>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.
BIBLIOGRAPHY
1. Velazquez EM, Mendosa S, Hamer T, Sosa F, Glucck CJ. Metformin therapy in women with polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating menstrual regularity and pregnancy. Metabolism 1994,43:647655.
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 1996,335:617623.
3. Utiger RD. Insulin and the polycystic ovary syndrome. New England J Medicine 1996,335:657658
4. Dunaif A, Scott D, Finegood D, Quintana ma B, Whitcomb R. The insulin sensitizing agent Troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome Endocrinol Metab 1996;81:32993306
5. Coetzee EJ, Jackson WP. The management of non-insulin-dependent diabets during pregnancy. Diabetes Res Clin Pract 1985-86;1:281-287
6. Homburg R. Polycystic ovary syndrome: induction of ovulation. Ballieres Cllinical Endocrinologys & Metabolism 1996; 10:281-292
7. Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L. Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with polycystic ovary syndrome. Metabolism 1999; 48:1-10.
8. Tulppala M, Stenman UH, Cacciatore B, Ylikorkala O. Polycystic ovaries and levels of gonadotropins and androgens in recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum Reprod 1994;9:1328-32.
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