What role should rosiglitazone play?

By Raymond W. Ke, MD, and William H. Kutteh, MD, PhD

While insulin-sensitizing agents like metformin have proven useful in managing this disorder, mounting evidence indicates that rosiglitazone can also help induce ovulation and improve the metabolic profile in these patients.

Polycystic ovarian syndrome affects 5% to 7% of reproductive-aged women and often causes infertility. In addition to having to cope with chronic anovulation and mild hyperandrogenism, a large proportion of these women also experience peripheral insulin resistance. And while this resistance is made worse when a patient is obese, it's actually independent of weight.¹

Insulin resistance usually leads to hyperinsulinemia as the ß-islet cells in the pancreas secrete increased amounts of insulin in an attempt to maintain glucose homeostasis. This compensatory mechanism contributes to the ovarian hyperandrogenism and may directly interfere with ovulation.² Insulin resistance may also increase a PCOS patient's risk of pregnancy loss.^3,4

Obese PCOS patients with insulin resistance are also more likely to suffer from metabolic defects, which is why they are at increased risk for dyslipidemia, type 2 diabetes, hypertension, and coronary heart disease.⁵ The theory that insulin resistance is at least partially responsible for PCOS is supported by the fact that insulin-sensitizing agents like metformin can correct clinical and endocrinologic abnormalities in these women.^2,6,7

Anovulation-induced infertility is common among women with PCOS. When this occurs, the first line of defense is ovulation induction using clomiphene citrate (CC). Unfortunately, a significant number of patients don't respond to this approach, leaving exogenous gonadotropins as the only alternative, an expensive alternative that carries the risk of higher-order multiple pregnancy and ovarian hyperstimulation.

With these dangers in mind, researchers have turned their attention to the correction of hyperinsulinemia as a way to induce ovulation, particularly in obese women who are very insulin insensitive. While metformin, a biguanide normally employed to treat type 2 diabetes, has become popular for this purpose, another class of insulin sensitizers, the thiazolidinediones, has recently attracted attention.² In a large, placebo-controlled trial of PCOS women, troglitazone, the first drug in this group, increased spontaneous ovulation while lowering hirsutism scores, free testosterone, and dehydroepiandrosterone sulfate (DHEA-S).⁸

Diagnosing PCOS

PCOS, which generally surfaces in the first year or two after puberty, remains a diagnosis of exclusion. There is tremendous heterogeneity in the clinical picture of PCOS, with the classic symptoms of amenorrhea, hirsutism, and obesity evident in only 65% to 75% of affected women. While present in 60% to 80% of women with PCOS, the simple presence of multi- or polycystic ovaries alone cannot be used to diagnose the syndrome.⁹ Ovarian cysts result from incomplete follicular development and can be found in a variety of disorders characterized by anovulation.

Obesity is present in 60% to 80% of women with PCOS and is typically android with an increased waist:hip ratio. Signs of hyperandrogenism are mild and often include hirsutism, acne, and less commonly, alopecia.¹⁰ When masculinization—characterized by clitoromegaly, male-pattern alopecia, shrunken breasts, and increased muscle mass—is evident, then PCOS becomes a less likely diagnosis. Women with PCOS usually have a very irregular menstrual pattern, with varying periods of amenorrhea followed by episodes of excessive bleeding. While this pattern usually indicates anovulation, some patients may present with regular menstrual cycles and erratic occurrences of spontaneous ovulation resulting in pregnancy.

The differential diagnosis includes hyperprolactinemia, thyroid dysfunction, adult-onset or non-classic adrenal hyperplasia, and hypothalamus-pituitary-ovarian axis immaturity. In general, consider PCOS when a patient presents with the signs and symptoms of both hyperandrogenism and chronic anovulation.

Endocrinological features associated with PCOS include elevated free testosterone, elevated androstenedione, decreased sex hormone- binding globulin (SHBG), an LH:FSH ratio greater than 2, elevated DHEA-S, and elevated total testosterone, although you won't see all these abnormalities in all patients. In many cases, the patient's clinical and endocrinological features will be accompanied by metabolic abnormalities such as insulin resistance and compensatory hyperinsulinemia.

Measuring insulin resistance

It can be very time-consuming and expensive to accurately measure insulin resistance. Since a single fasting serum insulin is not sensitive enough, some experts say it would be more accurate to take three measurements within 10 minutes. In general, values between 10 and 14 µU/L indicate mild resistance, while values greater than 14 µU/L suggest severe resistance. An obese patient is more likely to have abnormal laboratory values.

Another approach is to measure the serum insulin response during an oral glucose tolerance test (OGTT). It's very likely that a patient is insulin resistant if peak insulin levels are greater than 100 µU/L. Although accurate, the OGTT is time-consuming and expensive. A simple and useful screening test for insulin resistance in obese women with PCOS is the fasting glucose to fasting insulin ratio (G:I). A ratio less than 4.5 in Caucasians or 5.0 in Hispanics is abnormal, and has a sensitivity of 95%, specificity of 84%, positive predictive value of 87%, and a negative predictive value of 94%.¹¹

Insulin sensitization therapy

Figure 1 outlines the basic evaluation and treatment of chronic anovulation. For all PCOS patients, the management goals should include regulation of menses, correction of hyperandrogenism, and correction of insulin resistance.

In the past, the treatment for PCOS focused on steroid hormone correction, but recently the emphasis has shifted to correcting or minimizing insulin resistance. Decreasing serum insulin levels will help lower androgen levels, which in turn may eventually induce ovulation and hence, produce regular menses and correct infertility.

Hyperinsulinemia seems to be associated with excessive androgen production from both the ovary and adrenal gland, although the mechanism is unclear.^7,12,13 Ovarian hyperandrogenism arrests follicular development, which subsequently interferes with ovulation. Insulin also inhibits hepatic production of SHBG, thus worsening the hyperandrogenic picture.^12,14 As we mentioned previously, insulin resistance is usually worse in obese PCOS patients. Weight loss is a fundamental, and for some, an extremely difficult way to improve peripheral insulin sensitivity. Clearly, the most important recommendation for all women suffering from PCOS is to attempt to normalize their body weight.¹⁵

As we said earlier, the realization that insulin resistance contributes to PCOS has sparked interest in insulin-sensitizing medications.¹⁶ Metformin, a biguanide that inhibits hepatic gluconeogenesis and stimulates peripheral uptake of glucose, is the most widely researched of these agents.¹⁷ In women with PCOS, it reduces ovarian production of androgens, attenuates insulin levels, and seems to enhance both spontaneous and clomiphene-induced ovulation.¹⁸ In a randomized, double-blinded trial, Nestler and colleagues showed that metformin induces ovulation in obese women with PCOS.² Treatment improved insulin sensitivity, and ovulation was induced in 34% of patients treated with metformin alone and in 90% among those given metformin and CC. Recently, Vandermolen and associates studied the effects of metformin in PCOS patients who were resistant to clomiphene.¹⁹ Compared to CC with placebo, women randomized to CC with metformin had a significantly higher rate of ovulation, with over half conceiving during the trial.

What role should rosiglitazone play?

Although troglitazone has been shown effective in PCOS, it's not available in the United States. When used in patients with type 2 diabetes, it has been linked to a rare but fatal form of hepatotoxicity; that has led to its withdrawal from the market. Rosiglitazone and pioglitazone, two of the other members of this class of drugs, improve insulin sensitivity without stimulating insulin secretion. Rosiglitazone binds to the transcription factor peroxisome proliferator-activated receptor-

(PPAR

) found in hepatic, skeletal, and adipose tissues. PPAR

promotes synthesis of glucose transporters and up-regulates expression of multiple genes. These drugs also promote differentiation of adipocytes in subcutaneous depots in preference to the visceral compartment. The result is improved glycemic control and reduced circulating insulin levels.^20,21 In a randomized trial involving PCOS patients, combining rosiglitazone with clomiphene was more effective in inducing ovulation than clomiphene alone. Furthermore, the addition of rosiglitazone improved insulin sensitivity, although serum LH and free testosterone did not differ between groups. ²²

Recently, we conducted a randomized clinical trial with rosiglitazone in obese women with PCOS-related infertility.²³ All 25 subjects were hyperandrogenic, anovulatory, and CC-resistant. Patients were all started on 4 mg bid of rosiglitazone, then randomized to either CC (up to 100 mg per day) or a placebo. Overall, 14 of 25 (56%) women previously resistant to CC successfully ovulated within 8 weeks of treatment. In patients taking rosiglitazone alone, four of 12 patients (33.3%) ovulated. The addition of moder-ate doses of CC to rosiglitazone enhanced the response, with 10 of 13 women (77%) achieving ovulation within two treatment cycles (vs. rosiglitazone alone: P=0.04). Three patients became pregnant, resulting in two successful live births and one first-trimester spontaneous abortion. The experiment showed that insulin sensitization therapy with rosiglitazone can induce ovulation in obese women with PCOS when clomiphene alone has failed.

These results were achieved despite the fact that patients had received the medication for a relatively short time: between 4 to 12 weeks.²³ With rosiglitazone therapy, fasting insulin levels declined over 40% from 29.4 ± 13.8 µU/mL before the study to 17.3 ± 7.8 µU/mL after therapy (P=0.003). This normalized the mean glucose-to-insulin ratio. In addition, while subjects experienced only a small decrease in serum total testosterone and androstenedione, there was a significant increase in SHBG levels, resulting in a marked decline in androgenicity. There was also a decrease in luteinizing hormone (LH) during the study from 9.4 ± 6.3 µU/mL to 7.2 ± 3.7 µU/mL (P=0.01). No significant differences in liver or renal function parameters, FSH, TSH, or prolactin occurred. There was a significant decline in hematocrit with rosiglitazone therapy, dropping from 40.3% ± 3.1% before the study to 38.0% ± 2.9% after completion (P=0.008). One subject complained of swollen fingers and another of mild headaches but both completed the study without sequelae.

An important consideration in choosing an insulin-sensitizing agent is its side-effect profile. The adverse effects of rosiglitazone are a consequence of its fluid-retaining properties and include peripheral edema and a dilutional decrease in hematocrit, which was observed in our study.²³ However, unlike troglitazone, after 3 years of clinical experience in the US, rosiglitazone did not cause hepatotoxicity. In addition, rosiglitazone is not associated with the gastrointestinal side effects commonly reported with metformin that often limit patient compliance. Weight loss is supposed to be a beneficial secondary effect of metformin but the effect isn't very consistent. Although not observed in our study, weight gain has been documented with rosiglitazone despite improvement in insulin sensitivity.^21,23,24 The weight gain may be due to a combination of fluid retention, increased appetite, or increased subcutaneous adipocyte differentiation.^25-27

Because rosiglitazone causes fluid retention, it's contraindicated in patients with anemia, congestive heart failure, hypertension, and any conditions where excessive body fluid volume is inadvisable. To be safe, patients with abnormal renal or liver function should not take rosiglitazone. For all women starting therapy, liver function should be reassessed every 8 weeks for the first year of therapy.

Rosiglitazone is classified as pregnancy category C due to animal evidence of growth retardation in mid-to-late gestation, so at present, it cannot be recommended for unrestricted use in pregnancy. There is no evidence of teratogenicity, however, in either preclinical or clinical trials.²⁸ It is currently recommended that women who conceive while taking rosiglitazone discontinue the drug upon confirmation of pregnancy.

Conclusions

In summary, short-term rosiglitazone therapy enhances both spontaneous and clomiphene-induced ovulation in overweight and obese women with PCOS. The drug improves insulin sensitivity and decreases hyperandrogenemia, primarily through an increase in SHBG. It appears to be well tolerated and is a promising adjunct treatment in the management of PCOS-associated insulin resistance and anovulation.

REFERENCES

1. Dale PO, Tanbo T, Vaaler S. Body weight, hyperinsulinemia and gonadotropin level in PCOS: evidence of two distinct populations. Fertil Steril. 1992;58:487-491.

2. 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.

3. Jakubowicz DJ, Iuorno MJ, Jakubowicz S, et al. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87:524-529.

4. Craig LB, Ke RW, Kutteh WH. Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss. Fertil Steril. 2002;78:487-490.

5. Wild R. Cardiovascular and lipoprotein abnormalities in androgen excess. In: Androgen Excess Disorders in Women. Azziz R, Nestler J, Dewailly D, eds. Philadelphia, Pa: Lippincott-Raven; 1997:681-688.

6. Ehrmann DA, Schneider DJ, Sobel BE, et al. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovarian syndrome. J Clin Endocrinol Metab. 1997;82:2108-2116.

7. 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;81:3299-3306.

8. Azziz R, Ehrmann D, Legro RS, et al. Troglitazone improves ovulation and hirsutism in the polycystic ovarian syndrome: a multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab. 2001;86:1626-1632.

9. Farquhar CM, Birdsall M, Manning P, et al. The prevalence of polycystic ovaries on ultrasound scanning in a population of randomly selected women. Aust N Z J Obstet Gynaecol. 1994;34:67-72.

10. Farah L, Azziz R. Polycystic ovary syndrome. Female Patient. 1999;24(July):79-85.

11. Legro RS, Finegood D, 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;83:2694-2698.

12. Nestler JE, Barlascini CO, Matt DW, et al. Suppression of serum insulin by diazoxide reduces serum testosterone levels in obese women with polycystic ovarian syndrome. J Clin Endocrinol Metab. 1989;68:1027-1032.

13. Barbieri RL, Makris A, Randall RW, et al. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab. 1986;62:904-910.

14. 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.

15. Huber-Buchholz MM, Carey DG, Norman RJ. Restoration of reproductive potential by lifestyle modifications in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab. 1999;84:1470-1474.

16. 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.

17. Inzucchi SE, Maggs DG, Spollett GR, et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med. 1998;338: 867-872.

18. Ehrmann DA, Cavaghan MK, Imperial J, et al. Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovarian syndrome. J Clin Endocrinol Metab. 1997;82:524-530.

19. Vandermolen DT, Ratts VS, Evans WS, et al. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovarian syndrome who are resistant to clomiphene citrate alone. Fertil Steril. 2001;75:310-315.

20. Adams M, Montague CT, Prins JB, et al. Activators of peroxisome proliferator-activated receptor-

have depot-specific effects on human preadipocyte differentiation. J Clin Invest., 1997:100:3149-3153.

21. Lehmann JM, Moore LB, Smith-Oliver TA, et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma. J Biol Chem. 1995;270:12953-12956.

22. Shobokshi A, Shaarawy M. Correction of insulin resistance and hyperandrogenism in polycystic ovarian syndrome by combined rosiglitazone and clomiphene citrate therapy. J Soc Gynecol Investig. 2003;10:99-104.

23. Ghazeeri G, Kutteh WH, Bryer-Ash M, et al. Effect of rosiglitazone on spontaneous and clomiphene citrate- induced ovulation in polycystic ovarian syndrome. Fertil Steril. 2003;79:562-566.

24. Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance in type II diabetes. Diabetes. 1996;45:1661-1669.

25. Day C. Thiazolidinediones: a new class of antidiabetic drugs. Diabet Med. 1999;16:179-192.

26. Shimizu H, Tsuchiya T, Sato N, et al. Troglitazone reduces plasma leptin concentration but increases hunger in NIDDM patients. Diabetes Care. 1998;21:1470-1474.

27. Chiasson JL, Josse RG, Gomis R, et al. Acarbose for preventing type 2 diabetes mellitus: The STOP-NIDDM randomized trial. Lancet. 2002;359:2072-2077.

28. Avandia drug insert. In: Physicians Desk Reference 2001. (55th Ed.). Montvale, NJ: Thomson Healthcare.

Dr. Ke is Associate Professor, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Tennessee Health Science Center, Memphis, Tenn.

Dr. Kutteh is Professor, Department of Obstetrics and Gynecology, and Director of Reproductive Endocrinology, University of Tennessee Health Science Center, Memphis Tenn.

Series Editor: Richard S. Legro, MD, is Associate Professor, Department of Obstetrics and Gynecology, Penn State Milton S. Hershey Medical Center, Hershey, Pa. Previous installments in the PCOS series appeared in the January, March, and July 2003 issues of Contemporary OB/GYN.

Key points

• Rosiglitazone and pioglitazone both improve insulin sensitivity, reduce circulating insulin levels, and improve glycemic control. In a randomized PCOS trial, rosiglitazone plus clomiphene was more effective in inducing ovulation than clomiphene alone.

• Rosiglitazone can lower fasting insulin levels by more than 40% and normalize the mean glucose-to-insulin ratio. In one trial, patients had only a small decrease in serum total testosterone and androstenedione, and significantly increased SHBG levels markedly reduced androgenicity. No significant differences in liver or renal function parameters, FSH, TSH, or prolactin occurred.

• Rosiglitazone's adverse effects are a consequence of its fluid-retaining properties and include peripheral edema and a dilutional decrease in hematocrit. But, unlike troglitazone, after 3 years of clinical experience in the US, rosiglitazone did not cause hepatotoxicity.

• Because rosiglitazone causes fluid retention, it's contraindicated in patients with anemia, congestive heart failure, hypertension, and any conditions where excessive body fluid volume is inadvisable. Anyone with abnormal renal or liver function should not take the drug. Reassess liver function every 8 weeks for the first year of therapy.

William Kutteh, Raymond Ke. What role should rosiglitazone play?

Contemporary Ob/Gyn

Mar. 1, 2004;49:33-48.