KatCarney

Insulin and Oral Antidiabetic Agents for Treatment of Polycystic Ovary Syndrome

Naci K. Kuscu, MD, and Faik M. Koyuncu, MD
Medscape General Medicine 4(4), 2002. © 2002 Medscape

Posted 09/13/2002

Abstract
Insulin plays a major role in polycystic ovary syndrome (PCOS). Insulin resistance and resultant hyperinsulinemia stimulate both the ovary and adrenal to produce androgens. Oral antidiabetic agents have been used to alleviate the symptoms and to induce ovulation in women with PCOS. This review focuses on the relation between insulin and PCOS and discusses the use of oral antidiabetic agents.

Introduction
Polycystic ovary syndrome (PCOS) is characterized by chronic menstrual irregularity (amenorrhea or oligomenorrhea), hirsutism, hyperinsulinemia, and infertility, and affects nearly 6% of women of reproductive age.[1] The exact pathogenesis is still unknown, but oligomenorrhea and infertility result from anovulation, and hirsutism is the result of both ovarian and adrenal hyperactivity. About 40% to 70% of patients with PCOS have increased levels of adrenal androgens.[2] Hyperresponsiveness of adrenal to corticotropin (ACTH), increased ACTH production, decreased endogenous opioids, hypersecretion of catecholamines, or hyperprolactinemia may contribute to the increased adrenal activity.[3] Obesity does not seem to affect pathophysiology of PCOS.[4]

What is the relation between hyperandrogenism and hyperinsulinemia? Does an elevated androgen level cause hyperinsulinemia or vice versa? One study has shown that gonadotropin-releasing hormone agonist (GnRHa) therapy suppressed androgens in subjects with PCOS, but no change in insulin resistance was observed[5]; when hyperinsulinemia is reduced, however, androgen levels fall,[6] indicating that it is insulin that induces hyperandrogenism.


PCOS and Insulin
Insulin, androgen, and body mass index (BMI) are related in women with and without PCOS.[20] Although fasting insulin and glucose levels may be normal in both lean and obese women with PCOS, they manifest an exaggerated serum insulin response to an oral glucose tolerance test (OGTT), as compared with weight-matched controls. According to Acien and colleagues,[20] there are at least 3 types of disorders associated with PCOS: (1) simple, hyperinsulinemic, nonhyperandrogenic obesity; (2) typical PCOS, probably with hyperactivity of steroidogenic enzymes but without hyperinsulinemia; (3) insulin-resistant PCOS resulting from anomalies in the genes involved in the secretion and action of insulin. The latter type is considered to have the highest metabolic, renal, and cardiovascular risks.

Insulin resistance associated with PCOS was reported by Chang and colleagues in 1983.[7] This resistance, which is independent of obesity, causes hyperinsulinemia.[8,13] More than 50% of obese women with PCOS are insulin resistant compared with age- and weight-matched controls.[10] In addition, in women with insulin resistance, the causative defect in insulin secretion is more prevalent and severe in those with a family history of non-insulin-dependent diabetes mellitus (NIDDM, or type 2), diabetes.[9]

Insulin and insulin-like growth factor-I (IGF-I) receptors found in the ovary,[11] androgen production stimulated by insulin in ovarian theca and stromal cell cultures from hyperandrogenic and normal women,[12] and reduction of serum androgen with short-term suppression of serum insulin with diazoxide in some patients[6] all point to a role for insulin in the pathophysiology of PCOS. Plasma insulin correlates with androgen levels, and hyperinsulinemia may itself induce higher androgen production in both the ovary[14,15] and the adrenal.[16]

In vitro studies have shown that the direct ovarian effect of insulin is to increase androgen precursors from theca cells[17] and aromatization in granulosa cells.[18] In a recent study in rats, we demonstrated that insulin may act to change ovarian structure in a manner similar to hyperthecosis.[19] We injected insulin daily to one group of rats and insulin + hCG into another group for 4 weeks to see whether we could observe a polycystic appearance in the ovaries. In the rats treated with insulin only, follicular structure was completely damaged and stromal dominance was observed. We concluded that insulin may directly play a role in follicular arrest in addition to elevating levels of androgens in the microenvironment.

Patients with hyperandrogenism manifest increased ovarian cytochrome P450c17alpha activity, which is involved in androgen biosynthesis. Increased activity of this enzyme also results in an exaggerated serum 17-hydroxyprogesterone (17-OHP) response to GnRHa therapy.[23,24] Treatment of hyperandrogenism in PCOS was not found to improve insulin resistance; thus, the resistance may be an intrinsic feature of PCOS rather than secondary to androgen excess.[21] Besides increasing ovarian androgen production, hyperinsulinemia decreases sex hormone binding globulin (SHBG) level, which further stimulates hyperandrogenism.[6,12,22] However, it is not insulin resistance but the elevation of circulating insulin that stimulates ovarian androgen production and suppresses serum SHBG. When insulin release is inhibited by diazoxide, androgen and SHBG levels return to normal.[6]

Insulin receptors are found in the pituitary tissue,[25] and insulin is capable of increasing the release of luteinizing hormone (LH).[26,27] In the peripheral glucose-utilizing tissues, insulin binds to its receptor, and tyrosine autophosphorylation is activated with consequent phosphorylation of intermediary proteins and glucose uptake into the cells. If the receptor is serine phosphorylated, downstream actions are blocked.[28] Insulin receptors are reported to be normal in women with PCOS,[29] and the defect in insulin signal transduction is considered to be at postreceptor level.[30,31] One study of obese women with PCOS has shown that in half, the defect was found to be in autophosphorylation of the receptor, with basal phosphorylation occurring on serine residues instead of tyrosine.[32]

The pancreas compensates insulin resistance by secreting additional insulin, but at a certain point, when the capacity for secretion is exceeded, postprandial glucose levels rise. When inadequate suppression of hepatic glucose production is added, fasting glucose levels also rise. The end result is impaired glucose intolerance and finally NIDDM. About 40% of obese women with PCOS develop either glucose intolerance or diabetes.[33]


PCOS and Possible Complications
PCOS is usually regarded as a menstrual disorder by both gynecologists and family physicians. But to our view, it is an enigma with unknown etiology and must be accepted as a multisystem problem. Patients with PCOS are at risk for early-onset NIDDM,[9,33] gestational diabetes, and dyslipidemia,[34] which has been found to be associated with insulin resistance rather than obesity.[35] The latter was demonstrated in a study showing that the dyslipidemia profile (hypertension and increased triglycerides, total and LDL-cholesterol with decreased HDL-cholesterol levels) is not different between women with and without PCOS if the data are adjusted for body weight.[36] In addition, another study found that women with PCOS were not hypertensive compared with control subjects matched for body composition even if they were significantly insulin resistant.[37] However, a higher rate of hypertension was reported in the postmenopausal period of women with a prior history of PCOS, as compared with controls.[38] Thus, hyperinsulinemia may accelerate the development of coronary and other vascular disease,[39-41] and patients with PCOS should be closely monitored their whole lives and their healthcare should be tailored to decrease their risk of cardiovascular disease.

If the patient does not seek assistance for infertility problems, a primary care physician or a family physician can supervise her healthcare with routine follow-up. Here the question arises, what should be included in routine follow-up? The patient is at risk for early atherosclerosis; therefore, annual checking for hypertension and monitoring her lipid profile seems reasonable. In addition, if the patient has a family history for diabetes, she can be treated for insulin resistance, which may be diagnosed most easily by calculating the fasting glucose:insulin ratio. A value below 4.5 suggests insulin resistance. Dysfunctional uterine bleeding must be stopped to prevent the development of endometrial hyperplasia.


PCOS and Oral Antidiabetic Agents
Metformin
Oral antidiabetic agents are usually used by internists and endocrinologists to treat NIDDM. But for the past decade, these drugs have become familiar in gynecologic practice. Metformin was the first drug used for alleviation of the symptoms of PCOS. Its major action is suppression of glucose output,[42] but it also improves insulin's action without affecting its secretion.[43] Various studies with metformin have evaluated the changes in both insulin and androgen levels. Some report the drug is effective while others report no benefit. For example, Velazquez and colleagues[44] found a decrease in androgen level accompanied with weight loss in patients treated with metformin, suggesting that the effect may be primarily due to weight loss rather than the drug itself. In another study, similar results -- ie, no apparent drug effect -- were found when weight loss only was compared with weight loss and metformin therapy.[45] Acbay and Gundogdu[46] reported that insulin resistance and associated metabolic and hormonal abnormalities did not improve in patients with PCOS who were given metforminfor 10 weeks. BMI did not change during the therapy, so these patients did not have the beneficial effect of weight loss.

However, metformin reduces the resistance and dyslipidemia when given to patients with NIDDM. These findings suggest that the mechanism for insulin resistance in PCOS is different from that in NIDDM.[32] In a 12-week trial of metformin in 14 obese nondiabetic women with PCOS, no improvement in hyperinsulinemia and androgen excess was noted.[47] In this study, neither BMI of patients nor insulin sensitivity changed during the trial. The authors concluded that metformin had no effect on hyperinsulinemia or hyperandrogenemia independent of weight loss. The subjects in this study were extremely obese, however, and therefore either the drug itself or the dosage used was not sufficient to produce a beneficial effect. In addition, in an in vitro study, metformin had no effect on insulin-stimulated theca cell androgen production.[48]

However, there are studies that report good results with metformin therapy in women with PCOS. One randomized placebo-controlled trial showed that metformin therapy administered for 4-8 weeks resulted in decreased levels of insulin, 17-OHP, and free testosterone levels and increased SHBG levels, without a change in BMI.[27] Reduction of serum insulin levels also decreased ovarian cytochrome P450c17alpha activity, which is responsible for exaggerated serum 17-OHP response in patients with PCOS.[23,24] In another placebo-controlled study, metformin improved hyperinsulinemia and reduced androgen levels in nonobese women with PCOS within 4-6 weeks.[4] No change was seen in the control group, and the authors concluded that reduction of insulin with metformin decreased P450c17alpha activity and thus ameliorated hyperandrogenism. But on the contrary, in another study, metformin administration did not decrease adrenal androgen secretion[49]: subjects with elevated adrenal androgens had less improvement of menstrual cycle irregularity, and no change in hirsutism was noted with metformin treatment of 12 weeks' duration.[50] In this study, response of adrenal gland was found to have a major negative impact on metformin therapy.

In a 6-month trial of 22 oligoamenorrheic women with PCOS, metformin restored menstrual cyclicity in 95%, and ovulation occurred in 87% who had regular menses.[51] Fasting and integrated insulin response to the glucose load, LH/FSH ratio, and BMI decreased as well. Improvement in ovulatory rates with metformin have been reported by different authors.[52-54] In light of these studies, can metformin be used as an adjunctive therapy in ovulation induction? (see below) In a placebo-controlled study considering this question, an ovulation rate of 90% was achieved in the study group, compared with a rate of 8% in the control group.[55] Of note, the serum insulin curve decreased in the metformin group, which may have helped the increase in ovulatory response.

We know that metformin does not primarily act on insulin and that the reduction of insulin level is a secondary effect following reduced gluconeogenesis. In a study conducted in obese women with PCOS, metformin treatment for 6 months was compared with ethinyl estradiol (35 micrograms)-cyproterone acetate (2 mg) oral contraceptive pills.[56] Although similar results were obtained in both groups for hyperandrogenism, metformin decreased fasting free fatty acids and insulin concentrations and improved oxidative glucose utilization. Reduction in the release of fatty acids from the adipose tissue helped to reduce hyperinsulinemia by blocking the competition of fatty acids with glucose for oxidation in the skeletal muscle. Metformin could be an alternative to oral contraceptives, as regular menstrual cycles were observed after the therapy.

Abdominal obesity and hyperinsulinemia may have complementary effects in the pathogenesis of PCOS. Metformin vs placebo treatment for 6 months in addition to hypocaloric diet in obese patients with and without PCOS showed that metformin led to a greater decrease in body weight and abdominal fat and a more consistent decrease of serum insulin, testosterone, and leptin levels, which were all associated with amelioration of hirsutism and menstrual disorders.[57] Decrease in BMI values was noted in women with or without PCOS in the metformin group.

In 8 trials demonstrating efficacy of the drug, BMI decreased in 4 and did not change in 3 trials; the eighth trial involved nonobese patients. In 3 trials demonstrating no efficacy, BMI did not change. It seems that the drug exerts its action primarily through weight loss, but on the basis of the other positive results, we can conclude that metformin not only acts through weight loss but also stimulates resolution of the symptoms by itself. When there was a reduction in serum insulin, serum testosterone levels also decreased. This might be proof of the role of insulin in stimulating androgen production in patients with PCOS.

Why metformin is successful in some studies and not in others is a concern, however. Obesity, variation in the dose, genetic background, and duration of therapy may be major factors in patient response. It may take 4-6 months to improve menstrual cyclicity and ovulation rates when metformin is used as a single agent. Patients should be aware of this time interval to avoid expecting a positive result too soon. Side effects encountered during the therapy include nausea, abdominal discomfort, diarrhea, and anorexia. Blood glucose levels of patients who use metformin decrease without a hypoglycemia risk. Besides suppressing glucose output and improving the action of insulin, metformin increases utilization of glucose by skeletal muscle, reduces plasma glucagon levels, and decreases intestinal absorption of glucose. In addition, it acts on lipoproteins, accelerating transformation of very low density lipoprotein (VLDL) to HDL, and decreases atherogenic effect of cholesterol.

Major contraindications to metformin include organic or functional renal failure with serum creatinine level higher than 1.4 ng/dL, alcoholism, hepatic disease, and chronic cardiopulmonary dysfunction. Metformin is a class B drug and has been used in the first trimester to decrease spontaneous abortion rate (SAB) related to high plasminogen activator inhibitor levels that occur in women with PCOS.[58] The pilot study by Glueck and colleagues showed that SAB decreased from 73% to 10% in 10 pregnant women whose previous pregnancies without metformin treatment were compared with current pregnancies during metformin therapy. The drug did not seem to be teratogenic.

Metformin for Ovulation Induction in PCOS
Metformin has been used as an adjuvant agent for ovulation induction in women with PCOS. When used alone, 40% (19/48) of patients in one study resumed regular cycles and ovulation.[59] Addition of clomiphene citrate (CC) to nonresponders increased ovulation rate to 67%. The combination of metformin and CC seems to be synergistic, but metformin alone was also effective as an inducer in this study. Conception rate was 69% in ovulatory patients. In another study, a 28.2% ovulation rate and 4.2% pregnancy rate were achieved with CC in 24 women with PCOS.[60] But when metformin was added to the induced cycles, ovulation and pregnancy rates increased to 57.9% and 65.2%, respectively. The mean time to achieve conception was 4.3 months. The most striking result of this study was the high pregnancy rate. In general, approximately half of women who ovulate in response to CC become pregnant, but adding metformin raises this ratio. Therefore, besides inducing a higher ovulation rate, metformin may increase pregnancy rate as well.

In 2 double-blind, placebo-controlled studies, pretreatment with metformin in CC-resistant patients with PCOS improved ovulation rates.[61,62] Vandermolen and colleagues[61] used 500 mg metformin 3 times daily for 7 weeks in the study group and then both study and control groups received 50 mg CC for 5 days. In anovulatory patients, the CC dose was increased by 50 mg for the next cycle. Patients were given this regimen for up to 6 cycles to achieve either ovulation or pregnancy or both. Ovulation and pregnancy rates were significantly higher in the study group (ovulation rates: 75% vs 27%; pregnancy rates 55% vs 7%). Although fasting serum insulin and glucose:insulin ratio did not change during the treatment, the authors related higher response to the insulin-sensitizing effect of metformin.

Kocak and coworkers[62] compared metformin with placebo before induction with CC in their study. They used 850 mg metformin twice daily during the first cycle and then added 100 mg CC for the subsequent cycle. In addition to a significant decrease in total testosterone, LH level, LH/FSH ratio, insulin resistance, and mean BMI in the study group, the ovulation rate was significantly higher in the study group than in the control group (77% vs 14%). The pregnancy rate did not differ significantly, but the total number of pregnancies in the metformin group was significantly higher.

This is another report revealing beneficial effects of metformin with regard to not only ovulation but also conception. The authors hypothesize that metformin could alter follicular steroidogenesis. But the factor responsible for higher ovarian androgen production in these patients is actually hyperinsulinemia, which activates IGF-I receptors in theca cells and augments androgen production, not insulin resistance. Despite a decrease in insulin resistance at the end of the study, the authors did not find a change in fasting insulin levels. Therefore, the decrease in androgen levels and improvement in folliculogenesis cannot be solely related to the effect of lower insulin levels on ovarian androgen production. However, higher ovulation rates may be the advantage of metformin treatment whether or not it reduces fasting insulin levels.

In addition to the ways in which metformin was used in these studies, it has been used in conjunction with gonadotropins for ovulation induction.[63,64] Yarali and colleagues[63] did not observe an improvement in either insulin sensitivity or ovarian response in CC-resistant PCOS patients when pretreated with metformin 850 mg twice daily and then induced with recombinant FSH. Although insulin sensitivity did not change during the 6-week metformin trial, the investigators noticed an increase in spontaneous ovulation rate. Metformin treatment did not affect ovarian response with rFSH. The dose and treatment period may be the limiting factors in this study, and other authors have not observed beneficial effect of the drug despite a treatment period of 10-12 weeks. In addition, BMI, an important factor for insulin resistance, did not change in those reports nor in the study by Yarali and colleagues. Lean patients with PCOS may also be insulin resistant, but metformin is thought to act principally by inducing weight loss, which is not considered in these studies.

On the contrary, Stadtmauer and coworkers[64] reported improvement in IVF and pregnancy rates in CC-resistant PCOS patients pretreated with metformin. The protocol in their study was administration of 1000-1500 mg metformin daily for 1 cycle before induction with gonadotropins. Fertilization and clinical pregnancy rates were higher in patients who received metformin. Although metformin was used for a shorter period (1 cycle). In this study, the authors observed a better response when metformin was used in combination with rFSH.

These studies support the use of metformin as an adjunctive treatment in CC-resistant PCOS patients. Treatment period and dosage may vary, but the usual dosage is 500 mg twice daily or single 850 mg for normal-weight subjects and 500 mg 3 times daily or 850 mg twice daily for obese subjects. Maximum dosage should not exceed 3 g/day.

Troglitazone
Troglitazone is an insulin-sensitizing agent with a direct action at the insulin receptor[65] and thus improves peripheral glucose uptake.[66] Activation of tyrosine kinase leads to tyrosine phosphorylation on the beta-subunit of the insulin receptor. Marked improvement in insulin sensitivity without weight changes has been observed.[67,68] Troglitazone increases both insulin secretion from the beta-cells of the pancreas[69] and its action in the periphery. In a 3-month trial of troglitazone, total body insulin action improved, resulting in lower circulating insulin levels.[70] The authors concluded that improving insulin sensitivity, independent of weight loss, could ameliorate hyperandrogenism in insulin-resistant, hyperandrogenic women. Concomitant with decreases in androgen levels during therapy was an increase in SHBG levels, which demonstrates the negative effect of insulin on SHBG.

Insulin sensitivity and beta-cell function increased in extremely obese patients with PCOS during a 12-week trial of troglitazone administration.[71] Both metabolic and hormonal derangements of the PCOS were ameliorated. In 2 other studies, troglitazone either alone or combined with CC induced ovulation in insulin and/or clomiphene-resistant patients with PCOS.[72,73] Ovulatory and pregnancy rate were 83% and 39% in 18 CC-resistant patients, and in most of the patients, ovulation was achieved with troglitazone alone or in combination with low doses of CC. Major side effects of troglitazone were elevated liver enzymes and hepatic necrosis, and it was withdrawn from the market by FDA because of these effects. However, a newer derivative of the drug, pioglitazone, is reported to have no major hepatotoxic effects and may be useful in women with PCOS.


Conclusion
We have seen that the effects of oral antidiabetic agents are to increase rates of ovulation and pregnancy. This type of therapy could be an alternative to gonadotropins, especially for those who consider the cost of parenteral injections too high. Oral antidiabetic agents do not seem to be superior to oral contraceptives in terms of hyperandrogenism and menstrual regulation. Further studies are needed to determine the best protocol for insulin-sensitizing agents in PCOS: Is it better to use them as a pretreatment drug, or as an adjunctive therapy during ovulation induction? Another issue is to determine whether these drugs can replace oral contraceptives for long-term use. When hyperinsulinemia is reduced, can the patients be protected from metabolic complications of the disease? If yes, how long will patients be able to use the drug without experiencing major side effects? Diet and exercise seem to be the most prudent initial step, especially in overweight patients, and adding an oral antidiabetic agent as if the patient has NIDDM may be the gold standard for restoring insulin sensitivity.


References
Franks S. Polycystic ovary syndrome. N Engl J Med. 1995;333:853-861.
Hoffman DI, Klove K, Lobo RA. The prevalence and significance of elevated dehydroepiandrosterone sulfate levels in anovulatory women. Fertil Steril. 1984;42:76-81.
Azziz R, Black V, Hines GA, et al. Adrenal androgen excess in the polycystic ovary syndrome: sensitivity and responsivity of the hypothalamic-pituitary-adrenal axis. J Clin Endocrinol Metab. 1998;83:2317-2323.
Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17alpha activity and serum androgens. J Clin Endocrinol Metab. 1997;82:4075-4079.
Geffner ME, Kaplan SA, Bersch N, et al. Persistence of insulin resistance in polycystic ovarian disease after inhibition of ovarian steroid secretion. Fertil Steril. 1986;45:327-333.
Nestler JE, Baralascani CO, Matt DW, et al. Suppression of serum insulin by diazoxide reduces serum testosterone levels in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1989;66:1027-1032.
Chang RJ, Nakamura RM, Judd HL, et al. Insulin resistance in non-obese patients with polycystic ovarian disease. J Clin Endocrinol Metab. 1983;57:356-359.
Dunaif A, Segal KR, Futterweit W, et al. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38:1165-1174.
Ehrmann D, Struris J, Byrne M, et al. Insulin secretory defects in polycystic ovary syndrome: relationship to insulin sensitivity and family history of non-insulin dependent diabetes mellitus. J Clin Invest. 1995;96:520-527.
Legro RS, Finegood DT, Dunaif A. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1998;183:2694-2699.
Poretsky L, Grigorescu F, Seibel M, et al. Distribution and characterization of insulin and insulin-like growth factor-1 receptors in normal human ovary. J Clin Endocrinol Metab. 1985;61:728-734.
Barbieri RL, Makris A, Randall W, et al. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab. 1986;62:904-910.
Buyalos RP, Geffner ME, Bersch N, et al. Insulin and insulin-like growth factor-I responsiveness in polycystic ovarian syndrome. Fertil Steril. 1992;57:796-803.
Stuart CA, Peters EJ, Prince MJ, et al. Insulin resistance with acanthosis nigricans: the role of obesity and androgen excess. Metabolism. 1986;35:197-205.
Dunaif A, Segal KR, Shelley DR, et al. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes. 1992;41:1257-1266.
Moghetti P, Castello R, Negri C, et al. Insulin infusion amplifies 17 alpha-hydroxycorticosteroid intermediates response to adrenocorticotropin in hyperandrogenic women: apparent relative impairment of 17,20-lyase activity. J Clin Endocrinol Metab. 1996;81:881-886.
Willis D, Mason H, Gilling-Smith C, et al. Modulation by insulin of follicle stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries J Clin Endocrinol Metab. 1996;81:302-309.
McAllister JM, Byrd W, Simpson ER. The effects of growth factors and phorbol esters on steroid biosynthesis in isolated human theca interna and granulosa-lutein cells in long term culture. J Clin Endocrinol Metab. 1994;79:106-112.
Kuscu NK, Koyuncu FM, Ozbilgin K, Inan S, Tuglu I, Karaer O. Insulin: Does it induce follicular arrest in rat ovary? Gynecol Endocrinol. (In press)
Acien P, Quereda F, Matallin P, et al. Insulin, androgens, and obesity in women with and without polycystic ovary syndrome: a heterogeneous group of disorders. Fertil Steril. 1999;72:32-40.
Dunaif A, Green G, Futterweit W, et al. Suppression of hyperandrogenism does not improve peripheral or hepatic insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab. 1990;70:699-704.
Nestler JE, Powers LP, Matt DW, et al. A direct effect of hyperinsulinemia on serum sex hormone binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 1991;72:83-89.
Rosenfield RL, Barnes RB, Ehrman DA. Studies of the nature of 17-hydroxyprogesterone hyperresponsiveness to GnRHa challenge in functional ovarian hyperandrogenism. J Clin Endocrinol Metab. 1994;79:1686-1692.
White D, Leigh A, Wilson C, et al. Gonadotrophin and gonadal steroid response to a single dose of a long-acting agonist of GnRH in ovulatory and in anovulatory women with the polycystic ovary syndrome. Clin Endocrinol (Oxf). 1995;42:475-481.
Unger JW, Livingston JN, Hossa M. Insulin receptors in the central nervous system: localization, signalling mechanisms and functional aspects. Prog Nuerobiol. 1991;36:343-362.
Adashi EY, Hsveh AJW, Yen SSC. Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology. 1981;108:1441-1449.
Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome N Engl J Med. 1996;335:617-623.
Dunaif A. Hyperandrogenic anovulation (polycystic ovary syndrome): a unique disorder of insulin action associated with an increased risk of non-insulin-dependent diabetes mellitus. Am J Med. 1985;98(Suppl 1A):33S-39S.
Talbot JA, Bicknell EJ, Rajkhowa M, et al. Molecular scanning of the insulin receptor gene in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1996;81:1979-1983.
Ciaraldi TP, El-Roeiy A, Madar Z, et al. Cellular mechanisms of insulin resistance in polycystic ovary syndrome. J Clin Endocrinol Metab. 1992;75:577-583.
Dunaif A. Insulin resistance and ovarian dysfunction. The Endocrinologist. 1992;2:248-260.
Dunaif A, Xia J, Book CB, et al. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle: a potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest. 1995;96:801-810.
Dunaif A, Graf M, Mandeli J, et al. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab. 1987;65:499-507.
Wild RA, Painter PC, Coulson PB, et al. Lipoprotein lipid concentrations and cardiovascular risk in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1985;61:946-951.
Robinson S, Henderson AD, Gelding SV, et al. Dyslipidemia is associated with insulin resistance in women with polycystic ovaries. Clin Endocrinol (Oxf). 1996;44:277-284.
Graf MJ, Richards CJ, Brown V, et al. The independent effects of hyperandrogenemia, hyperinsulinemia, and obesity on lipid and lipoprotein profiles in women. Clin Endocrinol. 1990;33:119-131.
Zimmermann S, Phillips RA, Dunaif A, et al. Polycystic ovary syndrome: lack of hypertension despite profound insulin resistance. J Clin Endocrinol Metab. 1992;75:508-513.
Dahlgreen E, Janson P, Johansson S, et al. Polycystic ovary syndrome and risk for myocardial infarctus. Acta Obstet Gynecol Scand. 1992;71:599-604.
Guzick D, Talbott E, Sutton-Tyrell K, et al. Carotid atherosclerosis in women with polycystic ovary syndrome: initial results from a case-control study. Am J Obstet Gynecol. 1996;174:1224-1232.
Talbott E, Guzick D, Clerici A, et al. Coronary heart disease risk factors in women with polycystic ovary syndrome. Arterioscler Thromb Vasc Biol. 1995;15:821-826.
Birdsall M, Farquhar C, White H. Association between polycystic ovaries and extent of coronary heart disease in women having cardiac catheterization. Ann Intern Med. 1997;126:32-35.
Bailey CJ. Metformin - an update. Gen Pharmacol. 1993;24:1299-1309.
Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334:574-579.
Velazquez EM, Mendoza S, 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;43:647-654.
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;80:2057-2062.
Acbay O, Gundogdu S. Can metformin reduce insulin resistance in polycystic ovary syndrome? Fertil Steril. 1996;65:946-949.
Ehrmann DA, Cavaghan MK, 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;82:524-530.
Duleba AJ, Pawelczyk LA, Ho Yuen B, et al. Insulin actions on ovarian steroidogenesis are not modulated by metformin. Hum Reprod. 1993;8:1194-1198.
Unluhizarci K, Kelestimur F, Sahin Y, Bayram F. The treatment of insulin resistance does not improve adrenal cytochrome p450c17alpha enzyme dysregulation in polycystic ovary syndrome. Eur J Endocrinol. 1999;140:56-61.
Kolodziejczyk B, Duleba AJ, Spaczynski RZ, et al. Metformin therapy decreases hyperandrogenism and hyperinsulinemia in women with polycystic ovary syndrome. Fertil Steril. 2000;73:1149-1154.
Velazquez ME, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol. 1997;90:392-395.
Glueck CJ, Wang P, Fontaine R, et al. Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome. Metabolism. 1999;48:511-519.
Moghetti P, Casello 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.
Vandermolen DT, Ratts VS, Evans WS, et al. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril. 2001;75:310-315.
Nestler JE, Jakubowicz DJ, Evans WS, et al. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med. 1998;338:1876-1880.
Morin-Papunen LC, Vauhkonen I, Koivunen RM, et al. Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproterone acetate in obese women with polycystic ovary syndrome: a randomized study. J Clin Endocrinol Metab. 2000;85:3161-3168.
Pasquali R, Gambineri A, Biscotti D, et al. Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab. 2000;85:2767-2774.
Glueck CJ, Phillips H, Cameron D, Sieve-Smith L, Wang P. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot-study. Fertil Steril. 2001;75:46-52.
Heard MJ, Pierce A, Carson SA, Buster JE. Pregnancies following use of metformin for ovulation induction in patients with polycystic ovary syndrome. Fertil Steril. 2002;77:669-673.
Batukan C, Baysal B. Metformin improves ovulation and pregnancy rates in patients with polycystic ovary syndrome. Arch Gynecol Obstet. 2001;265:124-127.
Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma SW, Nestler JE. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone.Fertil Steril. 2001;75:310-315.
Kocak M, Caliskan E, Simsir C, Haberal A. Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome. Fertil Steril. 2002;77:101-106.
Yarali H, Yildiz BO, Demirol A, et al. Co-administration of metformin during rFSH treatment in patients with clomiphene citrate-resistant polycystic ovarian syndrome: a prospective randomized trial. Hum Reprod. 2002;17:289-294.
Stadtmauer LA, Toma SK, Riehl RM, Talbert LM. Metformin treatment of patients with polycystic ovary syndrome undergoing in vitro fertilization improves outcomes and is associated with modulation of the insulin-like growth factors. Fertil Steril. 2001;75:505-509.
Kellerer M, Kroder G, Tippner S, et al. Troglitazone prevents glucose-induced insulin resistance of insulin receptor in rat-1 fibroblasts. Diabetes. 1994;43:447-453.
Inzucchi SE, Maggs DG, Spollett GR, et al. Efficacy and metabolic effects of metformin and troglitazone in type in type II diabetes mellitus. N Engl J Med. 1998;338:867-872.
Hofmann CA, Colca JR. New oral thiazolidinedione anti-diabetic agents act as insulin sensitizers. Diabetes Care. 1992;15:1075-1078.
Nolan JJ, Ludvik B, Beerdsen P, et al. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med. 1994;331:1188-1193.
Cavaghan M, Ehrmann D, Byrne M, et al. Treatment with the oral anti-diabetic agent troglitazone improves beta-cell responses to glucose in subjects with impaired glucose tolerance. J Clin Invest. 1997;100:530-537.
Dunaif A, Scott D, Finegood D, et al. The insulin sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab. 1996;81:3299-3306.
Ehrmann DA, 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;82:2108-2116.
Hasegawa I, Murakawa H, Suzuki M, et al. Effect of troglitazone on endocrine and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome. Fertil Steril. 1999;71:323-327.
Mitwally MF, Kuscu NK, Yalcinkaya TM. High ovulatory rates with use of troglitazone in clomiphene-resistant women with polycystic ovary syndrome. Hum Reprod. 1999;14:2700-2703.


Naci K. Kuscu, MD, is Assistant Professor in the Department of Obstetrics and Gynecology, Celal Bayar University, School of Medicine, Manisa, Turkey.

Faik M. Koyuncu, MD, is Associate Professor, in the Department of Obstetrics and Gynecology, Celal Bayar University, School of Medicine, Manisa, Turkey.

Naci K. Kuscu, MD, and Faik M. Koyuncu, MD, have no significant financial interests to disclose.

Kuscu NK, Koyuncu FM. Insulin and Oral Antidiabetic Agents for Treatment of Polycystic Ovary Syndrome. MedGenMed 4(4), 2002 [formerly published in Medscape Women's Health eJournal 7(5), 2002]. Available at: http://www.medscape.com/viewarticle/440584.

__________________