Should Metformin therapy continue during pregnancy?

If you become pregnant while taking Metformin, call (513-924-8250), Fax (513-924-8273), or e-mail us (glueckch@healthall.com) IMMEDIATELY.

What blood tests should be done during pregnancy whether or not Metformin is continued?

Background:

The risk of miscarriage in patients with PCOS is considerably higher than in non-PCOS patients. Irrespective of whether Metformin is continued during pregnancy, we believe that pregnancy in women with PCOS should be considered in the same intensive follow-up mode as other "high risk" pregnancies, such as Type I or Type II diabetes, maternal hypertension, or pre-eclampsia. As soon as pregnancy is confirmed, we would suggest that the following blood tests be obtained:

a. Human chorionic gonadotropin
b. Estrone, Estradiol, Estriol
c. Progesterone
d. Testosterone, total and free
e. Luteinizing hormone
f.  Plasminogen Activator Inhibitor-1 and Plasminogen Activator Inhibitor-2
g. Insulin

Abnormal Tests

If the following tests were abnormal, and were abnormal on a repeat sample taken within 1 week, then serious consideration should be given to continuing the Metformin:

a. Low--Human chorionic gonadotropin
b. Low--Estrone, Estradiol, Estriol
c. Low--Progesterone
d. High--Testosterone, total and free
e. High--Luteinizing hormone
f.  High--Plasminogen Activator Inhibitor-1 and Plasminogen Activator inhibitor-2
g. High--Insulin

SCIENTIFIC UPDATE: 3/13/2000, PREGNANCY FAILURE AND PRESERVATION IN WOMEN WITH POLYCYSTIC OVARY SYNDROME: SAFETY AND EFFICACY OF METFORMIN THERAPY CONTINUED THROUGH PREGNANCY

Experimental Biology 2000, San Diego, April 16-18, 2000. CJ Glueck MD, Cholesterol Center, Jewish Hospital, 3200 Burnet Ave, Cincinnati, Ohio 45229. Phone 513-924-8250, Fax 513-924-8273, email glueckch@healthall.com, website uc.edu/~gartsips.

Pregnancy failure and preservation in women with polycystic ovary syndrome. The first, largest reported study of the causes of first trimester miscarriage and its prevention in women with polycystic ovary syndrome, the #1 cause of infertility in American women.

Background 1:  
Polycystic ovary syndrome (PCOS) is a common inherited disorder, affecting about 6% of women. During the reproductive years, it commonly causes infertility, severe obesity, excess hair growth, acne, elevated plasma cholesterol and triglycerides, hypertension, and cystic enlargement of the ovaries. PCOS is the most common cause of infertility. By age 50, 60% of women with PCOS develop type 2 diabetes, and the diabetes, high cholesterol, obesity, hypertension, and reduced ability to dissolve blood clots due to high levels of plasminogen activator inhibitor lead to a 10 fold increase in risk of heart attack and stroke.

Causes of PCOS:         
PCOS is a poster child for insulin resistance syndrome, in which it it difficult to force glucose into the cells of the body. In order to do this, the pancreas must pour out 5-10 times the normal amount of insulin, which brute-forces the glucose into the cells, but with major bad side effects including severe obesity and high levels of male sex hormones (testosterone, androstenedione, DHEAS) produced by the ovaries and adrenal glands, respectively. These high male sex hormones cause the extra body hair, acne, hypertension, and promote obesity and high cholesterol. Worst of all, during the reproductive years, they interfere with the normal release of the pituitary hormones LH and FSH which control the ability of the ovary to provide eggs ready for fertilization and to make the major female hormones, estradiol and progesterone. Hence, women with PCOS are usually amenorrheic (they don't have any menstrual cycles) or oligomenorrheic (they have few cycles), and as a result, they are habitually infertile.

Treatment of PCOS with Metformin:
Using Metformin, a safe and effective drug usually used for type 2 diabetes, a drug which reduces insulin resistance but can be given safely to women with normal blood glucose, we have shown (Metabolism 1999;48:511-519) that 91% of previously amenorrheic women resume normal ovulatory menstrual periods. Once they resume normal periods, then they have the capability of becoming pregnant. Once pregnant, then the issue arises, should the Metformin be continued.

Pregnancy failure in women with PCOS
As reported in San Diego and as recently published (Metabolism 1999;48:1589-1595), pregnancy failure is very common in women with PCOS.

1. We studied risk factors for pregnancy failure in 118 women with PCOS who had 239 pregnancies, and sustained 94 miscarriages (39%).

2. Major determinants of first trimester miscarriage included one of the male sex hormones which is high in women with PCOS, androstenedione, and a protein, plasminogen activator inhibitor activity (PAI-Fx) which reduces the body's ability to dissolve blood clots. Moreover, the higher the PAI-Fx and a second male sex hormone, testosterone, the less likely the women were to have live births. The PAI-Fx appeared to cause miscarriage in women with PCOS by producing reduced blood flow to the placenta (placental insufficiency) through failure to lyse placental blood clots.

3. Treatment of these women with Metformin for an average of 5 months reduced the levels of testosterone and PAI-Fx.

4. Non-teratogenic, safe, Metformin therapy throughout pregnancy, reduces first trimester miscarriage from 45% to 9% in women with PCOS, and lowers PAI-Fx, testosterone, and androstenedione, proably accounting for its ability to be protective during pregnancy in women with PCOS.

 

METFORMIN THROUGHOUT PREGNANCY IN WOMEN WITH POLYCYSTIC OVARY SYNDROME REDUCES FIRST TRIMESTER MISCARRIAGE FROM 39%-58% TO 5%-11%. CJ Glueck, H Phillips, D Cameron, T Tracy, L Sieve-Smith, P Wang. Chol Center, Jewish Hospital, Cincinnati, OH

Introduction 1: Our recent study of 43 previously amenorrheic women with polycystic ovary syndrome (PCOS) (Metabolism 1999;48:511-519) revealed that 39 (91%) resumed normal, regular menstrual cycles when given Metformin 1.5-2.55 g/day for ~6 months. Of  these 43 women, 93% were morbidly obese and 74% had fasting hyperinsulinemia (> 20 uU/ml)

Introduction 2: Metformin-induced improvements in ovarian function were independent of weight loss. The change in fasting serum insulin correlated with the change in testosterone (r=.35, p=.047) and with the change in androstenedione (r=.48, p= .01).

Introduction 3: Patients were more likely than normal controls (83% vs 64%, p=.016) to be heterozygous or homozygous for the 4G polymorphism of the PAI-1 gene, and were also more likely to have high levels of the PAI-1 gene product, plasminogen activator inhibitor activity (PAI-Fx), which controls fibrinolysis. PAI-Fx was high (> 22U/mL in 28% of women with PCOS versus 3% of normals, p=.001).

Introduction 4: In this study of 43 women, we concluded that Metformin (1.5-2.55 g/day)  reduces the endocrinopathy of PCOS , allowing resumption of normal menses in most (91%) previously amenorrheic women with PCOS.

Introduction 5: Many of our original group of 43 women conceived on Metformin, which then raised the difficult question of whether the Metformin should be continued throughout the pregnancy. We knew of the work of Cotzee in South Africa which showed that Metformin was not teratogenic.

Initially, as soon as pregnancy was confirmed, we stopped the Metformin, but were stunned by an ensuing first trimester miscarriage rate >50%, as well as by frequent (~30%) development of pre-eclampsia or eclampsia.

Introduction 6: This led us to retrospectively study the pregnancy outcomes in 41 women with PCOS with at least 1 pregnancy who had conceived without Metformin. Metabolism 1999;48:1589-1595). These 41 women had 77 total pregnancies with 34 miscarriages (44%) and 42 live births (55%).

Introduction 7: By stepwise logistic regression the number of pregnancies (p=.0001) and PAI-Fx (p=.016) were significant explanatory variables for the number of miscarriages. Age, 4G/5G polymorphisms of the PAI-1 gene, the V Leiden and MTHFR gene mutations, androstenedione, testosterone, SHBG, Quetelet, and fasting serum insulin and glucose were not significant variables in the logistic regression model.

Introduction 8: In a separate stepwise logistic regression model in 3 non-overlapping groups of women with worst, intermediate, and best pregnancy outcomes, PAI-Fx was positively associated (p=.05) with the group with the worst pregnancy outcome (> 1 pregnancy, > 1 miscarriage, 0 live births).

Introduction 9: The 41 women with PCOS and at least 1 pregnancy were more likely than normals to have hetero- and homozygosity for the 4G/5G polymorphism of the PAI-1 gene (p=.028), but did not differ from normals in regards to mutations in the factor V Leiden or MTHFR genes.

Introduction 10: We knew from 3 previous studies (1994-1997) that PAI-Fx was significantly lowered by Metformin 1.5-2.55 g/day in women with PCOS. We concluded from our study of miscarriage in women with PCOS that PAI-Fx with attendant hypofibrinolysis was a predominant, independent, significant, positive, and probably reversible risk factor for miscarriage in women with PCOS.

Study Design 1: The present study is ongoing in 41 pregnant women with PCOS who had conceived on Metformin and remained on Metformin. The.study is open label, Metformin dose 1.5-2.55 g/day, single center, type I or II diabetes excluded, with followup > once/month throughout the pregnancy. Most pregnancies were followed with a standard obstetrical high risk pregnancy protocol. All women took prenatal vitamins with > 1 g folic acid/day

Study Design 2: Seventeen of the 41 women with PCOS came from our previously published cohort of 41 amenorrheic women with PCOS (Metabolism 1999;48:511-519); 24 came from women with PCOS, receiving Metformin 1.5-2.55 g/day on our protocol, in the USA.

Study Design 3: Major outcome variables included the number of first trimester miscarriages, fetal loss in the 2nd and 3rd trimester, development of pre-eclampsia, eclampsia, abruptio placentae, intrauterine growth retardation,  birth defects, rate of intrauterine fetal development by sonography, and infants' Apgar score and physical examination at birth.

In 41 previously oligo-amenorrheic, non-diabetic women with polycystic ovary syndrome (PCOS), who conceived on Metformin (MET) (1.5-2.55 g/day), we assessed whether MET throughout pregnancy would reduce 1st trimester (T) miscarriage (MISC).

Characteristics of Previous pregnancies without Metformin, n=19:
Before MET, 19 of these 41 women had 38 previous pregnancies,  with 22 1st T MISC (58%).

Results 1, Current pregnancies on Metformin, n=19: In their current pregnancies on MET, these 19 women had 2 1st T MISC (11%, chi^2=10.9, p=.0008), 8 normal, term, live births (42%), and 9 ongoing pregnancies (47%). Eight of these 9 ongoing pregnancies are currently uneventfully past 16 weeks gestation.

Results 2, Reduction of First Trimester Miscarriage, Live Births, on Metformin, n=41: In all 41 women with PCOS who conceived on and remained on MET, there were 2 1st T MISCs (5%), 11 live births, and 28 ongoing pregnancies, currently at a median of 24 weeks gestation (24 past 14 weeks gestation). This 5% 1st T MISC rate on MET was 11 times lower than in the subset of 19 women without MET  (58%), chi^2 =23.7, p=.001.

Results 3, Absence of birth defects on Metformin, n=41:  There were no congenital defects in the 11 term live births of women who conceived on and remained on MET; no congenital defects have been visualized by sonography in the fetuses in the 28 ongoing pregnancies (median of 24 weeks gestation).

Results 4, Normal fetal growth and development on Metformin, n=41:  The 11 infants' length, weight, and physical examination at birth were within normal limits, and sonography has shown normal fetal development in the 28 ongoing pregnancies where MET has been continued.

Conclusions 1, Metformin reverses endocrinopathy, allows ovulatory cycles in 91% of women with PCOS: MET reverses the endocrinopathy of PCOS, allowing 91% of previously oligo-amenorheic women to achieve regular ovulatory cycles, and thus facilitates conception.

Conclusions 2, Metformin reduces Plasminogen activator inhibitor activity, thus  reducing first trimester miscarriages by reducing placental insufficiency: During pregnancy in women with PCOS, by lowering the hypofibrinolytic plasminogen activator inhibitor activity (PAI-Fx),  MET,  a non-teratogenic agent, sharply reduces 1st trimester MISC, probably by reducing the likelihood of PAI-Fx driven placental insufficiency.

In press, J Invest Med 4/2000

Summary:

It is always very difficult to give medical advice when there are not enough data to allow an unequivocal decision, as is the case of continued use of Metformin during pregnancy. The final decision should be made by your ob/gyn doctor, yourself, and your family doctor. We have provided the information above to try to help everyone make the best informed decision, based on what we know today.

Miscarriage and complications of pregnancy in women with and without PCOS. Scientific update, 1/11/99, Cholesterol Center, Jewish Hospital

E-mail: glueckch@healthall.com or cglueck@fuse.net Fax: 513-924-8273

Background:

1. It has been known for many years that the thrombophilic antiphospholipid antibodies (anticardiolipin antibody [ACLA], the Lupus Anticoagulant) are causally associated with recurrent miscarriage.

2. Women with Polycystic Ovary Syndrome (PCOS) have up to a 44% first trimester miscarriage rate. Speculative causes for this high miscarriage rate include high levels of plasminogen activator inhibitor (with reduced blood clot lysis), high levels of testosterone, androstenedione, or DHEAS, and low levels of progesterone.

New Data. Kupperminc MJ, Eldor A, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. New Eng J Med 1999;340:9-13.

a. 110 women with either severe preeclamsia, abruptio placentae, fetal growth retardation, or stillbirth compared to 110 women with > 1 normal pregnancy.
b. Women tested several days after delivery for genetic thrombophilia including the Factor V Leiden, MTHFR, and prothrombin gene mutations; 2-3 months after delivery, women were tested for protein C or protein S deficiency, and for ACLA.
c. Factor V Leiden mutation found in 20% of women with obstetrical complications vs 6% of controls (p=.0003).
d. Homozygosity for the MTHFR mutation were found in 22% of women with obstetrical complications vs 8% of controls (p=.0005).
e. Mutation of the prothrombin gene was found in 10% of women with obstetrical complications vs 3% of controls (p=.03).
f. Overall, 52% of women with obstetrical complications had an thrombophilic mutation vs 17% of normal women (p<.001).
g. Deficiency of proteins S, C, or Antithrombin III or anticardiolipin antibodies were detected in an additional 13% of women with obstetrical complications vs 1% of normal women (p<.001).

Conclusions: Women with serious obstetrical complications have increased incidence of inherited thrombophilia.

Speculation: Thrombophilic mutations which predispose to thrombosis may be major risk factors for inadequate maternal-fetal circulation.

TAKE ACTION: Women with severe complications of pregnancy and one or more miscarriages should be tested for markers of thrombophilia. These tests should include PCR cDNA tests for 3 common thrombophilic mutations, Factor V Leiden, MTHFR, and Prothrombin gene, and blood coagulation tests for proteins S, C, anticardiolipin antibodies, and the Lupus Anticoagulant. Call MDL (513-475-6631) or email (fontaine@mdl-labs.com) to arrange for the PCR cDNA tests.

[HOME] [PCOS]

Treatment of PCOS

E-mail: glueckch@healthall.com or cglueck@fuse.net Fax: 513-924-8273

Summary: There are now 8 original data papers which show that reduction of insulin resistance with Metformin (1-5, 8) or Troglitazone (6,7) with subsequent reduction of hyperinsulinemia can, to a large degree, ameliorate the endocrinopathy of PCOS, and provide a novel therapy for PCOS. All of these studies show that in addition to resolving the endocrinopathy of PCOS, the treatments should reduce risk of coronary artery disease, which is known to be high in PCOS. This reduction in risk for coronary artery disease is mediated by improved lipid profiles, weight loss (on Metformin), reduction in blood pressure, and reduction in the otherwise high levels of plasminogen activator inhibitor activity, which, when high, reduces the body's ability to lyse thrombi (blood clots).Metformin, the leading oral drug used in the treatment of mature onset diabetes is a standard, approved drug, and is universally available. Its major side effect is stomach upset and/or diarrhea, usually worse in the first week of its use, with gradual resolution of symptoms over time. It is taken three times/day with food.

Troglitazone, another oral drug used for the treatment of diabetes, and with a biochemical action much like Metformin, has recently been released to the market.

Current approaches to treat Polycystic Ovary Syndrome:

• Major weight loss in women who are obese. Weight loss can be facilitated by Metformin (500 or 850 mg, three times/day with meals)*  
• Methods to ameliorate infertility: Clomiphene, various assisted-reproduction procedures, partial ovarian resection, Metformin (500 or 850 mg, three times/day with meals)*.
• To reduce the clinical manifestations of androgen excess and restore normal menstrual bleeding:

a. Antiandrogen (spironolactone or cyproterone, or both)
b. oral contraceptive therapy.
c. Metformin (500 or 850 mg, three times/day with meals)*.

* Metformin is a widely available, safe, effective drug used for treatment of adult onset diabetes. It can be given safely to subjects with normal blood glucose levels because it will not lower them. Metformin should not be used in patients with substantially reduced renal function (serum creatinine >1.5, creatinine clearance < 60%) because of increased risk of a rare side effect, lactic acidosis. Use of Metformin solely for the treatment of polycystic ovary syndrome should currently be considered experimental, and it should be optimally used following an approved Institutional Review Board protocol with signed informed consent, as is done at the Cholesterol Center, Jewish Hospital of Cincinnati. It is possible to enroll patients in our outpatient clinical research protocol following a single 3 hour visit to our Cholesterol Center in Cincinnati. We will be glad to make our approved clinical research protocol available for use in other clinical research centers. 

When the clinical research avenue is not available, however, carefully supervised "off label" use of Metformin can probably be done, provided that a structured sequence of evaluations and followup is in place.

METFORMIN-INDUCED RESUMPTION OF NORMAL MENSES IN 19 OF 23 (83%) PREVIOUSLY AMENORRHEIC WOMEN WITH POLYCYSTIC OVARY SYNDROME.

CJ Glueck, T Tracy, P Wang, L Sieve-Smith, R. N. Fontaine, A Gupta. Cholesterol Center, Jewish Hospital, Cincinnati Ohio. J Investigative Med 1998:46(#3):208A.

In 24 amenorrheic women with polycystic ovary syndrome (PCOS), 70% of whom had fasting hyperinsulinemia (> 20uU/ml), our specific aim was determine whether Metformin (1.5 g/day) would reverse the endocrinopathy of PCOS, allowing resumption of normal menses. A second specific aim was to assess associations between PCOS and 4G/5G polymorphisms in the promoter sequence of the plasminogen activator inhibitor gene (PAI-1) and with plasminogen activator inhibitor activity (PAI-Fx). Non insulin dependent mature onset diabetes was present in 3/24 (13%) women. Metformin, a biguanide drug which reduces hyperinsulinemia, thus initiating reversal of the endocrinopathy of PCOS, was given for 6.2 + 6.9 months (range 1.8-28 months). On Metformin, 19/23 patients (83%) resumed normal menses. Weight fell from 219 + 41 pounds at study entry to 211 + 42 pounds on Metformin (p=.014). Weight loss occurred in 64% of the patients, ranging from 2 to 54 pounds, with 27% of patients having weight loss > 12 pounds. Serum estradiol rose from 52 + 39 pg/ml at study entry to 140 + 162 pg/ml (p=.009) on Metformin. Patients were much more likely than normal controls (91% vs 64%, p=.008) to be hetero- or homozygous for the 4G polymorphism of the PAI gene, a polymorphism associated with hyperinsulinemia and with high PAI-1. Patients were also much more likely than normal controls to have high PAI-Fx (> 28.3 U/L, 58% vs 0%), X²=29.8, p=.001. The 4G polymorphism of the PAI-1 gene, accompanied by high PAI-Fx and hyperinsulinemia, characterizes PCOS. Metformin facilitates resumption of normal menses in most (83%) previously amenorrheic women with PCOS, restoring fertility, promoting weight loss, and reversing the endocrinopathy of PCOS.

Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome.

Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith, L. Metabolism 1999;48: 511-519 (#4, April, 1999)

In 43 amenorrheic women with polycystic ovary syndrome (PCOS), 31 (74%) with fasting hyperinsulinemia (³ 20 m U/ml), our specific aim was to determine whether Metformin, which reduces hyperinsulinemia, would reverse the endocrinopathy of PCOS, allowing resumption of regular, normal menses. A second specific aim was to assess effects of weight loss vs other Metformin-induced effects on ovarian function, and to determine if there were different responses to Metformin between those who lost weight and those who did not. A third specific aim was to assess associations between PCOS, 4G/5G polymorphisms in the promoter sequence of the plasminogen activator gene (PAI-1 gene), and plasminogen activator inhibitor activity (PAI-Fx). Of the 43 women, 40 (93%) had normal fasting blood glucose and 37 had normal HgA1C; only 3 (7%) had Type 2 diabetes mellitus. Metformin (1.5-2.25 g/day) was given for 6.1 ± 5.1 months, range 1.5-24 months, to 16 patients for <3 months, to 12 for 3 to 6 months, and to 15 for ³ 6 months. On Metformin, 39 of 43 patients (91%) resumed normal menses. The percentage of women resuming normal menses did not differ among treatment duration groups (p>0.1) or among dose groups (p>0.1). Body mass index fell from 36.4 + 7 at study entry to 35.1 + 6.7 on Metformin (p=.0008). Of the 43 patients, 28 (67%) lost weight (1-69 pounds), with 9 (21%) losing ³ 12 pounds. On Metformin, median fasting serum insulin fell from 26 m U/ml to 22 (p=.019), testosterone fell from 61 ng/dl to 47 (p=.003), and estradiol rose from 41 pg/ml to 71 (p=.0001). Metformin-induced improvements in ovarian function were independent of weight loss (testosterone fell [p<.002], estradiol rose [p<.0004]). Change in response variables on Metformin did not differ (p>0.05) between those who lost weight and those who did not, excepting Lp(a) which rose 4 mg/dl in those who lost weight and fell 9 mg/dl in those who did not, p=.003. Change in response variables on Metformin did not differ among the 5 quintiles of weight loss, excepting fasting glucose (p<.05) which rose 6 mg/dl in those who lost the least weight on Metformin vs those in the 60th to 80th percentile for weight loss, whose glucose fell 33 mg/dl. Although pre-treatment, fasting serum insulin was not significantly correlated with testosterone (r=.24, p=.13) or androstenedione (r=.27, p=.09), on Metformin, change in insulin correlated positively with change in testosterone (r=.35, p=.047), and with change in androstenedione (r=.48, p=.01). Patients were more likely than normal controls (83% vs 64%, p=.016) to be hetero- or homozygous for the 4G polymorphism of the PAI-1 gene and were also more likely to have high PAI-Fx (³ 22 U/Ml), 28% vs 3%, X²=10.1, p=.001. Metformin reduces the endocrinopathy of PCOS, allowing resumption of normal menses in most (91%) previously amenorrheic women with PCOS.

If you live near a medical library, you should be able to find the medical journal "Metabolism" there. If you cannot find a copy, send $5 to cover shipping and handling to The Cholesterol Center, Attn: Dr. Charles Glueck, 3200 Burnet Ave., Cincinnati, OH 45229. Dr. Glueck also plans to post an order form for reprints on his web site (http://www.uc.edu/~gartsips).

METFORMIN SAFELY AND EFFECTIVELY FACILITATES WEIGHT LOSS IN OBESE NON-DIABETIC AND DIABETIC HYPERLIPIDEMIC PATIENTS. 

P McCullough, CJ Glueck, P Wang, J Lang, T Tracy, L Sieve-Smith. Cholesterol Cent, Jewish Hospital, Cincinnati Ohio.

In 35 hyperlipidemic, obese, white patients, 22 without and 13 with non-insulin dependent, mature onset diabetes, our specific aim was to assess the effectiveness and safety of Metformin Rx (1.5-2.55 g/day) for weight loss. Quetelet indices ([QI] kg/cm²) were >LRC 90th percentile in 71% of the 24 men and in 73% of the 11 women, with mean (SD) QI 3.18 + 0.33 in men and 3.62 + 1.01 in women. Mean + SD weight pre-Metformin Rx was 212 + 37 pounds, increasing to 219 + 38 (p=.0002) despite serial dietary instruction. In the 22 non-diabetic patients, pre-Rx weight was 222 + 44 pounds, falling after 9 + 6.6 months on Rx to 213 + 35 (p=.002). In the 13 diabetic patients, pre-Rx weight was 213 + 25 pounds, falling after 14 + 9 months on Rx to 205 + 23 (p=.004). On Rx, of the 35 patients, weight loss was 1-5 pounds in 5, 5-10 in 8, 10-20 in 8, 20-30 in 4, and >30 pounds in 4 (-31,-40,-43,-46). On Rx, weight did not change in 1 patient and rose in 5 (1,2,2,3,5 pounds). On Rx, median triglycerides fell in the 35 patients from 224 to 165 mg/dl (p=.0001). In the 14 non-diabetic patients with measures of pre-Rx fasting serum insulin (40 + 21 uU/ ml), insulin fell on Rx to 29 + 14 uU/ml, p=.03. Aside from sporadic diarrhea, Metformin was well tolerated, without adverse changes in laboratory safety tests. In obese, hyperlipidemic patients, who, despite conventional diets, gain weight, Metformin, by reducing hyperinsulinemia, safely and effectively facilitates weight loss.

Metformin, coronary heart disease risk factors, and resumption of normal menses in amenorrheic women with polycystic ovary syndrome. 

Glueck CJ, Tracy T, Wang P, Sieve-Smith L, Fontaine R. Circulation 1998 (suppl) 98 #17, I-43, 211A.

Presented, National American Heart Association Meeting, Dallas, 11/9/1998

In 37 amenorrheic women with polycystic ovary syndrome (PCOS), 27 (75%) with fasting hyperinsulinemia (³ 20 ug/ml), our specific aim was to determine whether Metformin would ameliorate coronary heart disease risk factors and reverse the endocrinopathy of PCOS, allowing resumption of normal menses. A second specific aim was to assess associations between PCOS and 4G/5G polymorphisms in the plasminogen activator gene (PAI-1 gene), and with plasminogen activator inhibitor activity (PAI-Fx). Mature onset diabetes was present in 3 of 37 (8%) of the women. Metformin (1.5-2.25 g/day) was given for 6.2 ± 5.2 months, range 1.5 -24 months, to 12 patients for <3 months, to 12 for 3 to 6 months, and to 13 for ³ 6 months. On Metformin, 34 of 37 patients (92%) resumed normal menses. Weight fell from 218 ± 43 pounds at study entry to 210 ± 43 on Metformin (p=.0009). Of the 37 patients, 24 (67%) lost weight (1-69 pounds), with 25% patients losing ³ 12 pounds. Mean ± SD serum insulin fell from 43 ± 51 uU/ml to 27 ± 18 on Metformin. Testosterone fell from 68 ± 39 ng/dl to 54 ± 27 (p=.024), and triglyceride fell from 149 ± 103 mg/dl to 119 ± 78 (p=.008). Serum estradiol rose from 46 ± 34 pg/ml to 82 ± 51 pg/ml (p=.0001) on Metformin. Patients were more likely than normal controls (80% vs 64%, p=.058) to be hetero- or homozygous for the 4G polymorphism of the PAI-1 gene and were also more likely than normal controls to have high PAI-Fx (³ 22 U/L), 30% vs 3%, X²=10.8, p=.001. Metformin ameliorates major CHD risk factors and facilitates resumption of normal menses in most (92%) previously amenorrheic women with PCOS, reversing the endocrinopathy of PCOS, promoting weight loss, and restoring fertility. (ahapcos.abs)

References:

1. Velazquez EM, Mendosa S, Hamer T, Sosa F, Glueck CJ. Metformin theraoy in women with polycystic ovarysyndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating menstrual regularity and pregnancy. Metabolism 1994;43:647- 655.
2. Velazquez EM, Mendoza SG, Wang P, Glueck CJ. Metformin therapy is associated with a decrease in plasmaplasminogen activator inhibitor-1, lipoprotein (a), and immunoreactive insulin levels in patients with polycystic ovary syndrome. Metabolism 1997;46:454-457.
3. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. New England J Medicine 1996;335:617-623. 
4. Utiger RD. Insulin and the polycystic ovary syndrome. New England J Medicine 1996;335:657-658 
5. Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R. The insulin sensitizing agent Troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab 1996;81:3299-3306
6. Ehrmann DA, Schneider DJ, Sobel BR, et al. Troglitazone improves defects insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol and Metab. 1997;82:2108-2116.
7. Velazquez E, Acosta A, Mendoza SG. Menstrual cyclicity after Metformin therapy in polycystic ovary syndrome. Obstet. Gynecol. 1997 90:392-395.

PCOS SCIENTIFIC UPDATE, 6/2/98, CJ GLUECK MD, JEWISH HOSPITAL CHOLESTEROL CENTER.

E-mail: glueckch@healthall.com or cglueck@fuse.net Fax: 513-924-8273

INSULIN SENSITIZING DRUGS, A REVOLUTION IN THE TREATMENT OF PCOS

Eight previous studies^{3-6,10,11,14,15} using Metformin (1.5 g/day) in obese women with PCOS (mean BMI [in 6 studies] , 27.7⁵, 29.1⁴, 26.7⁶, 31.5¹⁴, 33.6¹⁵, 34.1³, ) have shown significant improvements in insulin sensitivity, reduction of hyperinsulinemia, and, to varying degrees, weight loss, reductions in hyperandrogenemia and in PAI-1. The women in our study had even greater relative ponderosity^3-6,15 with mean BMI of 36.9. More importantly, these 8 previous studies^{3-6,10,11,14,15} have, to varying degrees, shown improvements in ovulatory function, development of normal menses, and restoration of fertility. As many as 21 of 22 (96%) previously oligo-amenorrheic obese (mean BMI 27.7) women with PCOS had restoration of menstrual cyclicity with Metformin therapy for ³ 6 months⁵. In a recent study of 20 obese Finnish women with PCOS¹⁴, Morin-Papunen et al reported that 11 (69% of those with menstrual disturbances) experienced more regular cycles during therapy with Metformin, 1.5 g/day. On Metformin, fasting serum insulin fell, testosterone fell at 2 months but returned close to starting levels at 6 months, while free testosterone fells fell significantly¹⁴. There were no significant changes in hirsutism, body mass index, or blood pressure. Recently, Diamanti-Kandarakis et al¹⁵ reported resumption of normal menses in 44% of 16 women with PCOS on Metformin, accompanied by increased glucose utilization (p=.0001) measured by the two-step euglycaemic-hyperinsulinemic clamp. Response to Metformin in PCOS patients, has not, however, been entirely uniform^7,12. Ehrmann et al¹², in very obese women with PCOS (mean BMI 39.0), gave 2.55 g Metformin/day for 12 weeks, and reported no changes in insulin, hormones, BMI, or fat distribution. Similarly, Acbay et al⁷, gave 2.55 g Metformin/day for 10 weeks to obese women with PCOS (mean BMI 29.8) and noted no changes in insulin metabolism, hormones, BMI, or waist/hip ratio.

A second insulin-sensitizing agent, Rezulin (200/400 mg/day for 12 weeks⁸, 400 mg/day for 12 weeks⁹), has been reported to be efficacious in two studies of very obese women with PCOS (mean BMI 42⁸, 39.9⁹). In both studies^8,9 there were improvements in insulin metabolism, androgens, SHBG, and PAI-1⁹, without changes in BMI. In one study⁸, two women resumed ovulatory menses.  (This drug is no longer available).

In aggregate, hyperinsulinism and resultant hyperandrogenism chronically alter gonadotropin secretion, increasing LH^1-19, disrupting the normal pituitary-ovarian axis, leading to oligo-amenorrhea and infertility. Hyperinsulinism, in conjunction with hyperandrogenemia, also leads to morbid obesity, hirsutism, acne, frequent hypertension, hyperlipidemia, and increased levels of hypofibrinolytic PAI-1, which together increase risk for myocardial infarction and stroke later in life^1-21. Hyperinsulinemia, independent of other risk factors for coronary heart disease (CHD), is a major CHD risk factor^20,21. Insulin resistance-hyperinsulinemia is also a risk factor for noninsulin-dependent, mature onset diabetes^4-6, common in PCOS.

We have previously shown in PCOS patients that the decrement in fasting serum insulin on Metformin is a significant, independent, positive determinant of the reduction in both total and free serum testosterone⁴. Metformin-induced restoration of menstrual cyclicity and fertility probably reflects Metformin-driven reduction in serum insulin with consequent decrements in androgens and unblocking of the normal pituitary-ovarian feedback system^{3-6,10,11,14-17}. Metformin⁵ and Rezulin^8,9, by reducing PAI-1, and (for Metformin), reducing weight, triglycerides, and blood pressure, should also reduce the increased risk to atherothrombosis which characterizes PCOS patients in later adulthood^1,3-6,14-21. By promoting regular menses, Metformin or Rezulin therapy should also reduce risk of endometrial carcinoma²². Insulin resistance and consequent hyperinsulinemia are probably central in the pathogenesis of PCOS^1-21.

References

1. Sattar N, Hopkinson ZEC, Greer IA. Insulin-sensitizing agents in polycystic-ovary syndrome. Lancet 1998;351:305-307
2. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications of pathogenesis. Endocrine Rev 1997;18:774-800.
3. Nestler JE, Jakubowicz D. Decrease in ovarian cytochrome P450c17a activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 1996;335:617-23.
4. Velazquez EM, Mendoza SG, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinaemia insulin resistance, hyperandrogenemia and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43:647-54.
5. Velazquez EM, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol 1997;90:392-5.
6. Velazquez EM, Mendoza SG, Wang P, Glueck CJ. Metformin therapy is associated with decreased plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with polycystic ovary syndrome. Metabolism 1997;46:454-57.
7. Acbay O, Gundogdu S. Can metformin reduce insulin resistance in polycystic ovary syndrome? Fertil Steril 1996;65:946-49.
8. Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R. The insulin sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovarian syndrome. J Clin Endocrinol Metab 1996;81:3299-306.
9. Ehrmann D, Schneider DJ, Sobel BE, et al. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J. Clin Endocrinol Metab 1997;82:2108-16.
10. Casimirri F, Biscotti M, Gambineri A, Calzoni F, Eliana B, Pasquali R. Metformin improves insulin, body fat distribution, and androgens in obese women with and without the polycystic ovary syndrome (abstract). Int J Obesity 1997;21(suppl 2):S61.
11. Van der Spuy ZM, Dhansay R, Nugent FA. Adjuvant therapy with metformin to improve the therapeutic outcome in anovulatory hyperinsulinaemic women with polycystic ovary syndrome. Hum Reprod 1996;11:167.
12. Ehrmann DA, Cavaghan M, Imperial J, Sturis J, Rosenfield R, Polonsky KS. Effects of metformin on insulin secretion, insulin action and ovarian steroidogenesis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997;82:524-30.
13. Crave JC, Fimbel S, Lejeune H, Cugnardey N, Dechaud H, Pugeat M. Effects of diet and metformin administration on sex hormone-binding globulin, androgens and insulin in hirsute and obese women. J Clin Endocrinol Metab 1995;80:2057-62.
14. Morin-Papunen LC, Koivunen RM, Ruokonen A, Martikainen HK. Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertility and Sterility 1998;69:691-696.
15. Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A. Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome. Eur J Endocrinol 1998;138:269-274.
16. Diamanti-Kandarakis E, Dunaif A. New perspectives in polycystic ovary syndrome. Trends Endocrinol Metab 1996;7:267-271.
17. Pasquali R, Filicori M. Insulin sensitizing agents and polycystic ovary syndrome. Eur J Endocrinol 1998;138:253-254.
18. Legro RS, Dunaif A. The role of insulin resistance in polycystic ovary syndrome. The Endocrinologist 1996;6:307-321.
19. Dunaif A. Molecular mechanisms of insulin resistance in the polycystic ovary syndrome. Semin Reprod Endocrinol 1994;12:15-20.
20. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988;37:1595-1607.
21. Wild RA. Cardiovascular disease risks, insulin resistance, and androgen excess. Semin Reprod Endocrinol 1994;12:38-44.
22. Dahlgren E, Friberg LG, Johannsson S, Lindstrom B, Oden A, Samsioe G. Endometrial carcinoma. Ovarian-dysfunction-a risk factor in young women. Eur J Obstet Gynecol Reprod Biol 1991;41:143-150.

REGISTRY FOR PREGNANCY IN WOMEN WITH POLYCYSTIC OVARY SYNDROME (PCOS). 

Charles J. Glueck MD, Cholesterol Center, Jewish Hospital, ABC Building, 3200 Burnet Ave, Cincinnati OH 45229. 

E-mail: glueckch@healthall.com or cglueck@fuse.net Fax: 513-924-8273

Background:

There is now abundant evidence that Metformin, an insulin sensitizing drug, can reverse the endocrinopathy of PCOS, with ~90% of women resuming normal menstrual cycles.^1-4 Metformin-induced reduction of insulin resistance with reduction of hyperinsulinemia and subsequent reduction of hyperandrogenemia appears to be central to reversal of endocrinopathy in PCOS.^1-6 Many (probably most) women with PCOS are now able to conceive while taking Metformin.

Before Metformin therapy, unfortunately, from 20 to 50% of women with PCOS experienced first trimester miscarriage. High levels of plasminogen activator inhibitor (PAI-Fx), the major inhibitor of fibrinolysis, have recently been shown to be a major, independent cause of miscarriage in PCOS, causing thrombosis and placental insufficiency.⁷ We know^1,4 that Metformin usually normalizes high PAI-Fx in women with PCOS, and as such, should be protective against the high rate of first trimester miscarriage in PCOS.⁷ Metformin is known not to be teratogenic^8,9, i.e., it does not produce birth defects in infants. Although we do not yet have placebo-controlled trial data, our current clinical experiences suggests that pregnancy outcomes in women with PCOS are much better when Metformin is continued throughout the pregnancy than when Metformin is discontinued. However, we need to accumulate more data on pregnancy in women with PCOS, particularly on the use of Metformin during pregnancy. Within this frame of reference, we are setting up a worldwide, internet-based, confidential registry of pregnancy in women with PCOS, with and without Metformin use.

References

1. Glueck CJ, Tracy T, Wang P, Sieve-Smith L, Fontaine R, Gupta A. Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with polycystic ovary syndrome. Metabolism 1999;48:511-519
2. Velazquez EM, Mendoza SG, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43:647-54.
3. Velazquez EM, Acosta A, Mendoza SG. Menstrual cyclicity after Metformin therapy in polycystic ovary syndrome. Obstet Gynecol 1997;90:392-5.
4. Velazquez EM, Mendoza SG, Wang P, Glueck CJ. Metformin therapy is associated with decreased plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with polycystic ovary syndrome. Metabolism 1997;46:454-57.
5. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of Metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. New Eng J Med 1998; 338:1876-1880.
6. Nestler JE, Jakubowicz D. Decrease in ovarian cytochrome P450c17a activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Eng J Med 1996;335:617-23.
7. Glueck CJ, Wang P, Fontaine FR, Sieve-Smith L, Tracy T. Plasminogen activator inhibitor activity: an independent cause of the high miscarriage rate during pregnancy in women with polycystic ovary syndrome. Metabolism, In Press, 5/99
8. Coetzee EJ, Jackson WP. Metformin in management of pregnant insulin-dependent diabetics. Diabetalogia 16:241-245, 1979
9. Coetzee EJ, Jackson WP. The management of non insulin-dependent diabetes during pregnancy. Diabetes Res Clin Pract 1:281-7, 1985-86 

Reproductive and Blood Clotting History Questionaire

PREGNANCY REGISTRY IN POLYCYSTIC OVARY SYNDROME (PCOS).

Please download the Questionnaire below. Print it, fill out the answers, and mail to

CJ Glueck MD, Cholesterol Center,
ABC Building, Jewish Hospital,
3200 Burnet Ave, Cincinnati, OH 45229.

Or Fax (513-924-8273).

Your information will be treated with the same absolute security restrictions as any usual patient-physician communication and can only be released to your designee, following our receipt of your original signature-bearing request, sent to us by snail mail.

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Metformin: The treatment of choice in Polycystic Ovary Syndrome

Scientific Update (9/5/2000): CJ Glueck MD, Cholesterol Center, Alliance Hospitals, ABC Building, 3200 Burnet Ave, Cincinnati OH, 45229.

E-mail: glueckch@healthall.com or cglueck@fuse.net Fax: 513-924-8273

Polycystic ovary syndrome (PCOS) is common, affecting 5-10% of the population, and is characterized by chronic anovulation with oligo-amenorrhea and infertility, and by clinical (hirsutism, acne) and biochemical hyperandrogenism.^1-16 Many women with PCOS also have morbid obesity,  excessive skin pigmentation (acanthosis nigricans), insulin resistance syndrome, and type 2 diabetes mellitus.^1-16  Commonly, insulin resistance with resultant hyperinsulinemia leads to abnormal ovarian and adrenal androgen secretion^1-16 which, in turn, leads to abnormal LH and FSH release and subsequent oligo-amenorrhea. During adolescence and childbearing years,^10-14 before the advent of Metformin therapy,^1,3-9,15 treatment of PCOS was directed (with only modest success) at the presenting clinical features, chronic anovulation with oligo-amenorrhea, infertility, hyperandrogenism, and (frequently) morbid obesity. In adulthood,^{1,2,5-7,15-18} PCOS appears to be associated with increased risk of coronary heart disease (CHD), mediated through Type 2 diabetes mellitus, hyperlipidemia, hyperandrogenemia, hypertension, morbid obesity, hyperinsulinemia, and insulin-induced elevations of plasminogen activator inhibitor (PAI-Fx), the major inhibitor of fibrinolysis.^1,2,5-7 The high levels of PAI-Fx, commonly present in subjects with PCOS, are in part inherited (the gene product of the 4G/5G polymorphism of the PAI-1 gene),^1,2,5,7 and are also associated with hyperinsulinemia.^1,2,5,7

Nine studies in adult women with PCOS using the insulin-sensitizing drug, Metformin,^1,3-9,15 have revealed improvements in insulin sensitivity, reduction in hyperinsulinemia, and amelioration of risk factors for CHD. Most of these studies have also reported Metformin-driven weight loss, and often, but not uniformly, normalization of circulating androgens, LH, FSH, sex hormone binding globulins, and PAI-Fx.^1,3-9,15 Most importantly, Metformin commonly leads to resumption of normal, ovulatory menses and, often, to reversal of infertility.^1,3-9,15 Metformin^1,3-9,15 provides a safe, effective, and physiologically rational approach to the treatment of the metabolic and endocrine abnormalities of PCOS in adult women with PCOS. A second insulin-sensitizing drug, Rezulin, although now withdrawn because of hepatotoxicity, was also effective in adult women with PCOS.^17,18

Nine previous studies in adult women with PCOS^1,3-9,15 using Metformin (³1.5 g/day) have reported significant improvements in insulin sensitivity, reduction of hyperinsulinemia, and, to varying degrees, weight loss, reductions in hyperandrogenemia, and decrements in PAI-Fx. Metformin use in adult women with PCOS has been safe, without reported lactic acidosis.^1,3-9,15 In adult women with PCOS, Metformin has restored menstrual cyclicity in 44% to 96%,^1,6,8,9 and ovulatory cycles in 34%³ and 79%.¹⁵ Metformin-induced improvements in ovarian function have been associated with restoration of normal menstrual cycles in 91% of 43 previously amenorrheic American women with PCOS.¹ Twenty-one of 22 (96%) previously oligo-amenorrheic obese (mean BMI 27.7) Venezuelan Mestizo women with PCOS had restoration of menstrual cyclicity on Metformin (1,500 mg/day) for ³6 months.⁶ In 20 obese Finnish women with PCOS,⁸ 11 (69% of those with menstrual disturbances) experienced more regular cycles during therapy with Metformin, 1,500 mg/day for 6 months. Diamanti-Kandarakis et al⁹ reported resumption of normal menses in 44% of 16 Greek women with PCOS on Metformin (1,700 mg/day for 6 months), accompanied by increased glucose utilization (p=.0001). After 35 days on Metformin (1,500 mg/day) in 35 obese women with PCOS, Nestler et al³ reported that 12 (34%) ovulated vs 1 of 26 (4%) given placebo, p<.001. Subsequently, 21 women continued on Metformin and 25 on placebo, with both groups being given 50 mg Clomiphene for 5 days³.  Of the 21 women on Metformin and Clomiphene, 19 (90%) ovulated vs 2 of 25 (8%) on placebo and Clomiphene (p<.001).³ Moghetti et al¹⁵ reported that in 10 adult women whose menses became regular on Metformin 1.5 g/day, 79% of menstrual cycles assessed were ovulatory. By restoring normal menstrual cycles,^1,4-7,15 Metformin may also reduce the likelihood of endometrial hyperplasia and carcinoma associated with PCOS.²⁵

Response to Metformin in adult women with PCOS, has not, however, been entirely uniform.^26,27 Ehrmann et al,²⁷ in very obese women with PCOS (mean body mass index [BMI] 39.0), gave 2.55 g Metformin/day for 12 weeks, and reported no changes in insulin, hormones, BMI, or fat distribution. Similarly, Acbay et al²⁶ gave 1.7 g/day of Metformin for 10 weeks to obese women with PCOS (mean BMI 29.8) and noted no changes in insulin metabolism, hormones, BMI, or waist/hip ratio.

A second insulin-sensitizing agent, Rezulin (200/400 mg/day for 12 weeks,¹⁷ 400 mg/day for 12 weeks¹⁸), has been reported to be efficacious in two studies of very obese women with PCOS (mean BMI 42,¹⁷ 39.9¹⁸). In both studies^17,18 there were improvements in insulin metabolism, androgens, SHBG, and PAI-Fx, without changes in BMI. Due to idiopathic hepatotoxicity associated with Rezulin,²⁸ and its withdrawal from use, Metformin is currently the insulin-sensitizer of choice in PCOS.

Hyperinsulinism and resultant hyperandrogenism in PCOS chronically alter gonadotropin secretion, increasing LH,^{1,3-9,15,17,18} disrupting the normal pituitary-ovarian axis, leading to oligo-amenorrhea and infertility.  Hyperinsulinemia in conjunction with hyperandrogenemia also may lead to morbid obesity, hirsutism, acne, frequent hypertension, hyperlipidemia, and increased levels of hypofibrinolytic PAI-Fx, which together increase risk for myocardial infarction and stroke later in life.^{1,3-9,16-18,29-32}

Hyperinsulinemia, independent of other risk factors for CHD, is a major CHD risk factor.^29-31 Metformin,^1,5,7 by reducing insulin, insulin resistance, PAI-Fx, weight, triglycerides, and blood pressure, should also reduce the increased CHD risk which characterizes PCOS patients in later adulthood.^1,16,29-33

PAI-1 gene 4G/4G homozygosity is a risk factor for venous and arterial thrombosis.²³ PAI-1 gene 4G/4G homozygosity, by producing hypofibrinolysis and placental insufficiency, also appears to be a major, significant, independent cause of the high first trimester miscarriage rate in women in PCOS.² Our recent pilot study has shown that continuation of Metformin throughout pregnancy in women with PCOS does not appear to be teratogenic and reduces the risk of first trimester miscarriage from 73% to 10%.³⁰

Ovarian dysfunction in obese oligomenorrheic women with PCOS can be improved by weight loss alone.35,36 Without Metformin, weight loss (through caloric restriction and increased exercise) in PCOS patients is exceptionally difficult to achieve and maintain,^35,36 due to the countervailing, weight preserving, anabolic effects of high insulin,³¹ androstenedione, testosterone, and DHEAS. In our experience,^1,5,7 most teenage and adult women with PCOS cannot, despite heroic efforts with formal dietary and exercise instruction, lose enough weight to ameliorate their endocrinopathy and/or CHD risk factor status, and to suggest otherwise sets up an unattainable, disheartening goal.  

We postulate that further confirmation of beneficial effects of Metformin^1,3-9,15 on the endocrinopathy of PCOS may revolutionize its treatment, and, as primary prevention in adolescents with PCOS, should also reduce the increased risk of developing coronary heart disease, type 2 diabetes, and endometrial cancer  in adulthood.

References

1. 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;511-519.
2. Glueck CJ, Wang P, Fontaine FR, et al: Plasminogen activator inhibitor activity: an independent risk factor for the high miscarriage rate during pregnancy in women with polycystic ovary syndrome. Metabolism1999;48:1589-1595.
3. Nestler JE, Jakubowicz DJ, Evans WS, et al: Effects of Metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. New Eng J Med 1998; 338:1876-1880.
4. Nestler JE, Jakubowicz D.  Decrease in ovarian cytochrome P450c17α activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome.  N Engl J Med 1996;335:617-23.
5. Velazquez EM, Mendoza SG, Hamer T, et al:  Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy.  Metabolism 1994;43:647-54.
6. Velazquez EM, Acosta A, Mendoza SG.  Menstrual cyclicity after metformin therapy in polycystic ovary syndrome.  Obstet Gynecol 1997;90:392-5.
7. Velazquez EM, Mendoza SG, Wang P, et al:  Metformin therapy is associated with decreased plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with polycystic ovary syndrome.  Metabolism 1997;46:454-57.
8. Morin-Papunen LC, Koivunen RM, Ruokonen A, et al:  Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertility and Sterility 1998;69:691-696.
9. Diamanti-Kandarakis E, Kouli C, Tsianateli T, et al:  Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome. Eur J Endocrinol 1998;138:269-274.
10. Van Hooff MH, Voorhorst FJ, Kaptein MB et al: Endocrine features of polycystic ovary syndrome in a random population sample of 14-16 year old adolescents. Hum Reprod 1999;14:2223-9
11. Pasquali R, Gambineri A, Anconetani B et al: The natural history of the metabolic syndrome in young women with the polycystic ovary syndrome and the effect of long-term oestrogen-progestagen treatment. Clinical Endocrinol 1999;50:517-527.
12. Gordon CM. Menstrual disorders in adolescents. Excess androgens and the polycystic ovary syndrome. Pedatr Clin North Am 1999;46:519-543.
13. Kahn JA, Gordon CM. Polycystic ovary syndrome. Adolesc Med 1999;10:321-326.
14. De Leo V, Lanzetta D, D'Antona D, et al: Hormonal effects of flutamide in young women with polycystic ovary syndrome. J Clin Endocrinol Metal 1998;83:99-102.
15. Moghetti P, Castello R, Negri C, et al: Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 2000;85:139-146.
16. Mather KJ, Kwan F, Corenblum B. Hyperinsulinemia in polycystic ovary syndrome correlates with increased cardiovascular risk independent of obesity. Fertil Steril 2000;73:150-156.
17. Dunaif A, Scott D, Finegood D, et al: The insulin sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovarian syndrome.  J Clin Endocrinol Metab 1996;81:3299-306.
18. Ehrmann D, Schneider DJ, Sobel BE et al:  Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome.  J. Clin Endocrinol Metab 1997;82:2108-16.
19. Ferriman D, Gallwey JD.  Clinical Assessment of body hair growth in women.  J Clin Endocrinol Metab 1961;21:1440-1447.
20. Isojarvi JI, Ratta J, Myllyla VV, et al: Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy. Ann Neurol 1998;43:446-451.
21. The Lipid Research Clinics Population Studies Data Book, Vol 1.  The prevalence study.  US DHHS, public Health Service NIH.  NIH publication 80-1527, 1980.
22. Franks S.  Polycystic ovary syndrome: A changing perspective. Clin Endocrinol 1989;31:87-120.
23. Glueck CJ, Fontaine RN, Gruppo R, et al: The plasminogen activator inhibitor-1 gene, hypofibrinolysis, and osteonecrosis. Clinical Orthopedics 1999;366:133-146.
24. Snedecor GW, Cochran WG: Statistical methods (ed 7). Ames, IA. Iowa State University Press, 1980.
25. Dahlgren E, Friberg LG, Johannsson S, et al:  Endometrial carcinoma. Ovarian-dysfunction-a risk factor in young women. Eur J Obstet Gynecol Reprod Biol 1991;41:143-150.
26. Acbay O, Gundogdu S.  Can metformin reduce insulin resistance in polycystic ovary syndrome?  Fertil Steril 1996;65:946-49.
27. Ehrmann DA, Cavaghan M, Imperial J, et al: Effects of metformin on insulin secretion, insulin action and ovarian steroidogenesis in women with polycystic ovary syndrome.  J Clin Endocrinol Metab 1997;82:524-30.
28. Kohlroser J, Mathai J, Reichheld J, et al: Hepatotoxicity due to troglitazone: report of two cases and review of adverse events reported to the United States Food and Drug Administration. Am J Gastroenterol 2000;95:272-29.
29. Cibula D, Cifkova R, Fanta M, et al: Increased risk of non-insulin dependent diabetes mellitus, arterial hypertension, and coronary artery disease in perimenopausal women with a history of the polycystic ovary syndrome. Hum Reprod 2000; 15:787-789.
30. Amowitz LL, Sobel BE. Cardiovascular consequences of polycystic ovary syndrome. Endocrinol Metab Clin North Am 1999;28:439-458.
31. Glueck CJ, Lang JE, Tracy T, et al: Contribution of fasting hyperinsulinemia to prediction of atherosclerotic disease status in 293 hyperlipidemic patients. Metabolism 1999;48:1437-1444.
32. Birdsall MA, Farquhar CM, White HD. Association between polycystic ovaries and extent of coronary artery disease in women having cardiac catheterization. Ann Intern Med 1997;126:32-35.
33. Pasquali R, Filicori M.  Insulin sensitizing agents and polycystic ovary syndrome.  Eur J Endocrinol 1998;138:253-254.
34. Glueck CJ, Phillips H, Cameron D, et al: Continuing Metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first trimester spontaneous abortion: A pilot study. Fertility and Sterility 2000; In Press.
35. Crave JC, Fimbel S, Lejeune H, et al: Effects of diet and metformin administration on sex hormone-binding globulin, androgens, and insulin in hirsute and obese women.  J Clin Endocrinol Metab 1995;80:2057-62.   
36. Kiddy DS, Hamilton-Fairley D, Bush A, et al: Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxford) 1992;36:105-111.

[HOME][PCOS]

Scientific Update, 9/11/00.

Our newest data (summarized below), shows conclusively that Metformin (1.5-2.55 g/day), continued through pregnancy, protects against first trimester miscarriage, and is safe for the mother and fetus. 

CONTINUING METFORMIN THROUGHOUT PREGNANCY IN WOMEN WITH POLYCYSTIC OVARY SYNDROME SAFELY REDUCES FIRST TRIMESTER MISCARRIAGE FROM 64% TO 5%, WITHOUT TERATOGENICITY.

CJ Glueck, H Phillips, D Cameron, L Sieve-Smith, P Wang. Ping Wang. The Cholesterol Center, Jewish Hospital, Cincinnati Ohio

E-mail: glueckch@healthall.com or cglueck@fuse.net Fax: 513-924-8273

Journal of Investigational Medicine 2000;48:25, In Press, Fertility and Sterility

Our specific aim was to prospectively determine whether Metformin would safely reduce first trimester miscarriage without teratogenicity in 45 women with polycystic ovary syndrome (PCOS) who conceived and remained on Metformin throughout pregnancy. We assessed 45 previously oligo-amenorrheic non-diabetic women with PCOS who conceived on Metformin (1.5-2.55 g/day) and continued it throughout pregnancy. Metformin was continued throughout pregnancy (1.5-2.55 g/day). Outcome measures included first trimester miscarriage and teratogenicity. Before receiving Metformin, 21 of these 45 women had 39 previous pregnancies with 25 first trimester miscarriages (64%). In their current pregnancies on Metformin, including live births and pregnancy > the first trimester, only 5% had first trimester miscarriages, a ten-fold reduction from 64% in their previous pregnancies without Metformin. In the total cohort of 45 women, there have been 14 normal term live births without congenital defects (31%) and 2 (4.4%) first trimester miscarriages. Sonography has shown normal fetal development without congenital defects in the 29 ongoing pregnancies (currently at a median of 25 weeks gestation) where Metformin has been continued. There have been no adverse maternal side effects.

When Metformin is continued through pregnancy in women with PCOS, it effects a ten-fold reduction in first trimester miscarriage and does not appear to have any adverse effects on fetal development.

Molecular Diagnosis of Risk Factors for venous and arterial thrombi, and for atherosclerosis. Jewish Hospital Cholesterol Center and Molecular Diagnostics Laboratories (MDL)

Metformin safely reduces the development of gestational diabetes in women with polycystic ovary syndrome when continued throughout pregnancy.

METFORMIN THERAPY THROUGHOUT PREGNANCY IN WOMEN WITH POLYCYSTIC OVARY SYNDROME REDUCES DEVELOPMENT OF GESTATIONAL DIABETES FROM 32-56% TO 3%. CJ Glueck, P Wang, S Kobayashi, H Phillips, L Sieve-Smith.Cholesterol Center, Jewish Hospital, Cincinnati, OH

Journal Invest Med 2001;49:299A, Circulation 2001, In Press. Presented, CSCR (Chicago 9/8/01), national American Heart Association (Anaheim 11/11/01).

In 33 non-diabetic women with well documented polycystic ovary syndrome (PCOS) who conceived on the insulin-sensitizing drug, Metformin (MET) (2.55 g/day), 28 of whom continued it through delivery (34 live births), and in 35 non-diabetic women with PCOS with 53 live births without MET, our specific aim was to assess whether MET would reduce the development of gestational diabetes (GD). Mean [SD] body mass index [BMI] in the cohorts of 33 and 35 women, respectively 33.3 [7.5] and 33.5 [7.6] did not differ. Before MET, the women with PCOS were hyperinsulinemic, insulin resistant (IR), and had high insulin secretion in response to IR. In the groups of 33 and 35 women, median fasting serum insulin was 22.5 and 18 uU/ml (57% and 46% high [? 20 uU/ml]), and median HOMA insulin resistance was 5.1 and 4.8 (40% and 37% high [? 5.54]). GD developed in 1/33 (3%) pregnancies in the 33 women who conceived on MET (3%) versus 5/9 (56%) previous pregnancies without MET (p<.0001) in those 7 of 33 women who were able to conceive without MET. GD developed in 17/53 (32%) pregnancies in the cohort of 35 women with PCOS who conceived without MET, versus 1/33 (3%) in the 33 women with PCOS who conceived on MET (p=.0013). Without MET, women with PCOS commonly develop GD (32%-56%) with consequent worsening of pregnancy outcomes. Without MET, GD is common in women with PCOS in part because of age (older than non-PCOS women because of infertility), morbid obesity, hyperinsulinemia, and IR. In women with PCOS, MET effects a > ten-fold reduction in GD, apparently by reducing IR and insulin secretion, thus lowering secretory demands imposed on pancreatic beta cells by IR and by pregnancy.

PRE-PREGNANCY REDUCTIONS IN WEIGHT, INSULIN, AND INSULIN RESISTANCE EFFECTED BY METFORMIN THERAPY IN WOMEN WITH POLYCYSTIC OVARY SYNDROME ARE MAINTAINED THROUGHOUT PREGNANCY, LEADING TO A TEN-FOLD REDUCTION IN GESTATIONAL DIABETES MELLITUS. CJ Glueck, P Wang, S Kobayashi, H Phillips, L Sieve-Smith.Cholesterol Center, Jewish Hospital, Cincinnati, OH

Journal Invest Med 2001;49:299A. Presented, CSCR (Chicago 9/8/01)

In 20 non-diabetic women with well documented polycystic ovary syndrome (PCOS) who conceived on the insulin-sensitizing drug, Metformin (MET) (2.55 g/day), 15 of whom had repeated follow-ups through delivery , our specific aim was to assess whether pre-pregnancy, MET-induced reductions in weight, insulin, and insulin resistance (IR) would be maintained throughout pregnancy, thus reducing the development of gestational diabetes mellitus (GDM). Pre-pregnancy, before MET, the 20 women with PCOS were hyperinsulinemic, insulin resistant, and morbidly obese. From pre-pregnancy without MET, to the last visit on MET before conception, median weight fell from 207 to 192 pounds (p<.0001), BMI fell from 33.5 to 29.2 (p <.0001), fasting serum insulin fell from 23 to 14 uU/ml (p=.006), and IR fell from 5.33 to 2.87 (p=.004). In the 15 patients who had follow-ups and on MET throughout pregnancy, median weight and BMI pre-pregnant and during pregnancy did not differ (194 vs 195 pounds, 29.2 vs 31.1), nor did fasting serum insulin (15 vs 15 uU/ml), glucose (86 vs 84 mg/dl), or IR (3.18 vs 3.03) (p>0.05 for all). The 20 non-diabetic women with PCOS came from a larger cohort of 33 non-diabetic women with PCOS who conceived on MET (2.55 g/day), 28 of whom continued MET through delivery (34 live births). The development of GDM was assessed in these 33 women on MET and in a separate cohort of 35 PCOS women without MET during pregnancy. GDM developed in 1 of 33 (3%) pregnancies in the women on MET, in 5 of 9 (56%) of their previous pregnancies without MET (p<.0001), and in 17 of 53 (32%) pregnancies without MET in the cohort of 35 PCOS women (p=.0013). In women with PCOS, before pregnancy, MET effects reductions in weight, insulin, and IR, and safely maintains these effects without teratogenicity throughout pregnancy. Also, MET effects a greater than ten-fold reduction in GDM, apparently by maintaining reduced insulin and insulin resistance, and restricting weight gain, thus lowering secretory demands imposed on pancreatic beta cells by insulin resistance and by pregnancy.

Metformin remarkably effective in PCOS in adolescents. Data suggest that therapy with Metformin starting in the teenage years, at the earliest diagnosis of the endocrinopathy of PCOS may prevent the development of many of the most serious features of this disorder: morbid obesity, amenorrhea, oligomenorrhea, anovulation, hirsutism.

1: J Adolesc Health 2001 Sep;29(3):160-169

Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome (PCOS)(1).

Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L.

Cholesterol Center, Jewish Hospital and Molecular Diagnostics Laboratories, Cincinnati, Ohio, USA

Purpose: To describe our clinical experience in using Metformin combined with a high protein-low carbohydrate diet to restore normal menstrual cycles in teenaged females with polycystic ovary syndrome (PCOS).Methods: To enter the study, patients had to have well-documented PCOS, be oligo- (six cycles or less in the preceding year) or amenorrheic (absence of menstrual cycles for 1 year), and not have exclusionary diseases or drugs. Accompanying a high protein-low carbohydrate diet, Metformin (1.5-2.55 g/day) was given for 10.5 +/- 6.4 months (range, 4.5-26.5 months). Follow-up every 8-10 weeks for >/=6 months was scheduled with interval history, review of menstrual status, assessment of any Metformin-related side effects, brief physical examination, and determination of weight and blood pressure.Results: All 11 girls had normal fasting blood glucose and glycohemoglobin. Pre-Metformin, five girls were amenorrheic, three had only one menstrual cycle in the previous year, and three had >/=6 cycles/year. With Metformin, 10 of 11 girls (91%) resumed regular normal menses; 39% of 38 follow-up visits with regular normal menstrual cycles were ovulatory with normal luteal-phase serum progesterone (>/=2.3 ng/mL). Of the 11 girls, nine (82%) lost weight; five girls lost >/=11 lb and seven lost >/=5 lb. After adjusting for weight reduction, with Metformin, estradiol and progesterone rose (p =.0014,.027, respectively) (changes consistent with resumption of regular normal menses), total plasma cholesterol fell (p =.026), and there was a downward trend in testosterone (p =.068).Conclusion: Metformin safely ameliorates the endocrinopathy of PCOS in previously oligo-amenorrheic teenage females with PCOS, facilitating resumption of normal menses in most girls.

PMID: 11524214 [PubMed - in process]

Metformin effective in facilitating weight loss in morbidly obese non-diabetic subjects without concurrent caloric restriction.

1: Metabolism 2001 Jul;50(7):856-861

Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30.

Glueck CJ, Fontaine RN, Wang P, Subbiah MT, Weber K, Illig E, Streicher P, Sieve-Smith L, Tracy TM, Lang JE, McCullough P.

Cholesterol Center, Jewish Hospital, and Molecular Diagnostics Laboratories, Cincinnati, OH 45229, USA.

We studied 31 nondiabetic, habitually (> or =5 years) morbidly obese subjects (mean +/- SD body mass index [BMI] 43 +/- 8.7, median 43). Our specific aim was to determine whether metformin (2.55 g/d for 28 weeks) would ameliorate morbid obesity and reduce centripetal obesity; lipid and lipoprotein cholesterol, insulin, and leptin levels; and plasminogen activator inhibitor activity (PAI-Fx), risk factors for coronary heart disease (CHD). The patients were instructed to continue their prestudy dietary and exercise regimens without change. After 2 baseline visits 1 week apart, the 27 women and 4 men began receiving metformin, 2.55 g/d, which was continued for 28 weeks with follow-up visits at study weeks 5, 13, 21, and 29. Daily food intake was recorded by patients for 7 days before visits then reviewed with a dietitian. Kilocalories per day and per week were calculated. At each visit, fasting blood was obtained for measurement of lipid profile, insulin, leptin, and PAI-Fx. The mean +/- SD kilocalories consumed per day, 1,951 +/- 661 at entry, fell by week 29 to 1,719 +/- 493 (P =.014) but did not differ at weeks 5, 13, and 21 from that at week 29 (P >.2). Weight fell from 258 +/- 62 pounds at entry to 245 +/- 54 pounds at week 29 (P =.0001). Girth was reduced from 51.8 +/- 6.2 to 49.2 +/- 4.5 inches (P =.0001). Waist circumference fell from 44.0 +/- 6.4 inches to 41.3 +/- 5.9 (P =.0001). The waist/hip ratio fell from 0.85 +/- 0.09 to 0.84 +/- 0.09 (P =.04). Fasting serum insulin, 28 +/- 15 microU/mL at entry, fell to 21 +/- 11 microU/mL at week 29 (P =.0001), and leptin fell from 79 +/- 33 ng/mL to 55 +/- 27 ng/mL (P =.0001). On metformin, there were linear trends in decrements in weight, girth, waist circumference, waist/hip ratio, insulin, and leptin throughout the study period (P <.007). Low-density lipoprotein (LDL) cholesterol, 126 +/- 34 mg/dL at study entry, fell to 112 +/- 43 mg/dL at week 29 (P =.001), with a linear trend toward decreasing levels throughout (P =.036). By stepwise linear regression, the higher the entry weight, the larger the reduction in weight on metformin therapy (partial R(2) = 31%, P =.001). The greater the reduction in kilocalories consumed per day, the greater the decrease in weight on metformin therapy (partial R(2) = 15%, P =.011). The higher the waist/hip ratio at entry, the greater its reduction on metformin therapy (partial R(2) = 11%, P =.004).

The higher the entry serum leptin, the greater its reduction on metformin therapy (partial R(2) = 29%, P =.002). The greater the reduction in insulin on metformin, the greater the reduction in leptin (partial R(2) = 8%, P =.03). The higher the entry PAI-Fx, the greater the reduction in PAI-Fx on metformin (partial R(2) = 43%, P =.0001). Metformin safely and effectively reduces CHD risk factors (weight, fasting insulin, leptin, LDL cholesterol, centripetal obesity) in morbidly obese, nondiabetic subjects with BMI > 30, probably by virtue of its insulin-sensitizing action. Copyright 2001 by W.B. Saunders Company.

PMID: 11436194 [PubMed - indexed for MEDLINE]

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