FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 338:1876-1880 June 25, 1998 Number 26 Next

Abstract PDF Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Obese women with the polycystic ovary syndrome are relatively unresponsive to the induction of ovulation by clomiphene. We hypothesized that reducing insulin secretion by administering metformin would increase the ovulatory response to clomiphene.

Methods We performed oral glucose-tolerance tests before and after the administration of 500 mg of metformin or placebo three times daily for 35 days in 61 obese women with the polycystic ovary syndrome. Women who did not ovulate spontaneously were then given 50 mg of clomiphene daily for five days while continuing to take metformin or placebo. Serum progesterone was measured on days 14, 28, 35, 44, and 53, and ovulation was presumed to have occurred if the concentration exceeded 8 ng per milliliter (26 nmol per liter) on any of these days.

Results Twenty-one women in the metformin group and 25 women in the placebo group were given clomiphene because they did not ovulate spontaneously during the first phase of the study. Among the 21 women given metformin plus clomiphene, the mean (±SE) area under the serum insulin curve after oral glucose administration decreased from 6745±2021 to 3479±455 µU per milliliter per minute (40.5±12.1 to 20.9±2.7 nmol per liter per minute, P=0.03), but it did not change significantly in the 25 women given placebo plus clomiphene. Nineteen of the 21 women (90 percent) who received metformin plus clomiphene ovulated (mean peak serum progesterone concentration, 23.8±3.4 ng per milliliter [7.6±10.9 nmol per liter]). Two of the 25 women (8 percent) who received placebo plus clomiphene ovulated (P<0.001). Overall, 31 of the 35 women (89 percent) treated with metformin ovulated spontaneously or in response to clomiphene, as compared with 3 of the 26 women (12 percent) treated with placebo.

Conclusions The ovulatory response to clomiphene can be increased in obese women with the polycystic ovary syndrome by decreasing insulin secretion with metformin.

Clomiphene citrate, an antiestrogenic drug, is the primary therapy used for ovulation induction in women with the polycystic ovary syndrome.^13,14,15 However, obese women with the syndrome often require multiple courses and high doses of clomiphene, and there is a positive correlation between obesity and the dose of clomiphene required to induce ovulation.¹⁵ Since increasing obesity is associated with increasing hyperinsulinemia,¹⁶ the high degree of hyperinsulinemia in obese women with the polycystic ovary syndrome may account for their poor responsiveness to clomiphene.¹³ Hyperinsulinemia could adversely affect folliculogenesis and ovulation by increasing intraovarian androgen production,^6,8,17,18,19 altering gonadotropin secretion,^8,9,20,21,22 or directly affecting follicular development.

The aim of this study was to determine whether reducing hyperinsulinemia with metformin would increase the ovulatory response to clomiphene in obese women with the polycystic ovary syndrome.

Methods

Subjects

We studied 61 obese women (body-mass index [the weight in kilograms divided by the square of the height in meters], >28) with polycystic ovary syndrome in the United States, Venezuela, and Italy. All had oligomenorrhea (fewer than six menstrual periods in the preceding year) and hyperandrogenemia (elevated serum free testosterone concentrations, determined at local clinics), and none had diabetes mellitus. All had normal serum prolactin concentrations and normal thyroid-function tests. Late-onset adrenal hyperplasia was ruled out by the finding of a morning serum 17-hydroxyprogesterone concentration below 200 ng per deciliter (6 nmol per liter). All the women had findings on ultrasonography of the ovaries consistent with the diagnosis of the polycystic ovary syndrome.²³ Thirty-one women had received clomiphene previously, but none had taken it or any other medication for at least two months before the study. The study was approved by the institutional review board at each study site, and each woman gave informed consent.

Experimental Protocol

At the time of entry into the study, all the women were in the equivalent of the follicular phase of the menstrual cycle, as documented by a serum progesterone concentration below 2 ng per milliliter (6.4 nmol per liter), and their last episode of menstrual bleeding had been at least two months earlier.

On day 0, the women came to the hospital after a 12-hour overnight fast, at which time their weight, height, and waist-to-hip ratio were measured. Blood samples were drawn at 8:30, 8:45, and 9 a.m., and equal volumes of serum were pooled for the measurement of insulin, glucose, steroid hormones, and sex hormone–binding globulin. At 9 a.m. 75 g of glucose was given orally, and blood samples were collected after 60 and 120 minutes for the determination of serum glucose and insulin concentrations.

Findings from a previous study⁸ suggested that metformin might increase spontaneous ovulation. Given that a goal of the study was to have an equal number of women in the metformin and placebo groups during the administration of clomiphene, more women were randomly assigned to receive metformin. Thirty-five women were assigned to take 500 mg of metformin (Glucophage, Bristol-Myers Squibb, Princeton, N.J.; Glafornil, North Medicamenta, Caracas, Venezuela; or Metforal, Laboratori Guidotti, Pisa, Italy) orally three times daily, and the remaining 26 women were assigned to receive placebo. The women were asked to abstain from sexual intercourse or to use a barrier method of contraception during the study.

The women took metformin or placebo alone on days 1 to 34 to allow sufficient time for metformin to exert its putative insulin-sensitizing effects. Serum progesterone was measured on days 14, 28, and 35, and ovulation was presumed to have occurred if the value exceeded 8 ng per milliliter (25.6 nmol per liter) on any of these days. All tests performed at base line (day 0) were repeated on day 35.

The 21 women in the metformin group and the 25 women in the placebo group who did not ovulate and had serum progesterone concentrations below 2 ng per milliliter between days 0 and 35 were given 50 mg of clomiphene citrate (Serophene, Teva Pharmaceuticals, Jerusalem, Israel) daily for five days (days 35 to 39), while continuing to receive metformin or placebo through day 53. Serum progesterone was measured on days 44 and 53 to assess the ovulatory response to clomiphene.

Assays

Blood samples were centrifuged as soon as they were obtained, and the serum was stored at –20°C until assayed. Serum hormones and sex hormone–binding globulin (measured as protein) were assayed as previously described,^6,24,25 except for serum free testosterone, the concentration of which was calculated according to the method of Sodergard et al.²⁶ and was predicated on the assumption of a constant serum albumin concentration of 4.0 g per deciliter. To avoid variation between assays, all samples from an individual woman were analyzed in duplicate in a single assay for each hormone. The intraassay coefficient of variation was 5.5 percent for the insulin assay and less than 10 percent for all steroid hormone assays.

Statistical Analysis

We analyzed the serum glucose and insulin responses to oral glucose administration by calculating the areas under the response curves by the trapezoidal rule using absolute values. Fisher's exact test was used to analyze the differences in ovulation rates between the metformin and placebo groups. For other variables, we compared results within a group by testing for normality with the Wilk–Shapiro test and then using Student's two-tailed paired t-test or the Wilcoxon signed-rank test, and we compared results between groups with Student's two-tailed unpaired t-test or the Mann–Whitney rank-sum test.

Results

Treatment with Metformin or Placebo Alone

On entry into the study (day 0), the metformin and placebo groups did not differ with respect to history of clomiphene treatment, anthropometric variables, and biochemical values (Table 1).

View this table: [in this window] [in a new window]   Table 1. Base-Line Characteristics of Women with the Polycystic Ovary Syndrome.

 
In the metformin group, the mean (±SE) area under the serum insulin curve during the oral glucose-tolerance test decreased from 6598±1267 to 3764±317 µU per milliliter per minute (39.6±7.6 to 22.6±1.9 nmol per liter per minute, P=0.002), whereas this value did not change significantly in the placebo group (P=0.20). There was also a small but significant decrease in the waist-to-hip ratio during testing (from 0.89±0.01 to 0.88±0.01, P<0.001) in the metformin group, but not in the placebo group (P=0.60). In neither group was there any change in the body-mass index, serum insulin or glucose concentrations during fasting, or the area under the serum glucose curve during the oral glucose-tolerance test.

During the first 35 days of treatment, serum total testosterone concentrations did not change significantly in either the metformin group (P=0.84) or the placebo group (P=0.53). Serum sex hormone–binding globulin concentrations increased in both the metformin group (from 2.0±0.2 to 2.7±0.3 µg per deciliter [69±7 to 93±10 nmol per liter], P= 0.01) and the placebo group (2.7±0.4 to 3.6±0.5 µg per deciliter [94±13 to 124±17 nmol per liter], P=0.06). As a result, serum free testosterone concentrations decreased in the metformin group, from 1.0±0.1 to 0.8±0.1 ng per deciliter (347±35 to 278±35 pmol per liter, P=0.07), and in the placebo group, from 0.8±0.1 to 0.6±0.1 ng per deciliter (278±35 to 208±35 pmol per liter, P=0.04).

Twelve of the 35 women (34 percent) in the metformin group ovulated spontaneously during treatment with metformin alone, as compared with only 1 of the 26 women (4 percent) in the placebo group (P<0.001). The mean peak serum progesterone concentration in the 12 women in the metformin group who ovulated was 13.0±1.0 ng per milliliter (41.6±3.2 nmol per liter). Two other women in the metformin group had peak serum progesterone concentrations between 4 and 8 ng per milliliter (12.8 to 25.6 nmol per liter) and were not included in the second phase of the study. Figure 1 shows the number of women who had serum progesterone concentrations above 8 ng per milliliter (indicative of ovulation) on days 14, 28, and 35 in the metformin and placebo groups.

View larger version (7K): [in this window] [in a new window]   Figure 1. Number of Women with a Serum Progesterone Concentration above 8 ng per Milliliter on Each Day of the Study on Which It Was Measured. During days 1 to 34 the women were treated with metformin or placebo alone. On day 35, ovulation induction with clomiphene was started while metformin or placebo was continued. Only women whose serum progesterone concentrations were less than 2 ng per milliliter throughout the first phase of the study were included in the ovulation-induction phase of the study.

 
Treatment with Clomiphene and Metformin or Placebo

Twenty-one women in the metformin group and 25 women in the placebo group continued into the second phase of the study, during which they received concurrent clomiphene treatment. The two groups had not differed on study day 0 with respect to the area under the serum insulin curve (6745±2021 µU per milliliter per minute [40.5±12.1 nmol per liter per minute] in the group given metformin and clomiphene, as compared with 6574±1072 µU per milliliter per minute [39.4±6.4 nmol per liter per minute] in the group given placebo and clomiphene; P=0.83), but on day 35, before clomiphene treatment was started, this value was significantly lower in the group given metformin and clomiphene (P=0.03) (Table 2). The difference was due to a 48 percent decrease (P=0.03) in the value in the 21 women in the group given metformin and clomiphene between days 0 and 35, from 6745±2021 to 3479±455 µU per milliliter per minute (40.5±12.1 to 20.9±2.7 nmol per liter per minute). On day 35 the two groups did not differ with respect to history of clomiphene treatment, anthropometric variables, or biochemical values (Table 2).

View this table: [in this window] [in a new window]   Table 2. Characteristics of Women with the Polycystic Ovary Syndrome on Initiation of Ovulation Induction with Clomiphene after the Administration of Metformin or Placebo for 35 Days.

 
Nineteen of the 21 women (90 percent) who received combined metformin and clomiphene ovulated; the mean peak serum progesterone concentration in these 19 women was 23.8±3.4 ng per milliliter (76.1±10.9 nmol per liter). In contrast, only 2 of the 25 women (8 percent) in the group given placebo and clomiphene ovulated (P<0.001); 2 other women in this group had serum progesterone concentrations between 4 and 8 ng per milliliter. Figure 1 shows the number of women who had serum progesterone concentrations above 8 ng per milliliter on days 44 and 53 in the two groups.

Discussion

We conducted this study to determine whether decreasing insulin secretion in obese women with the polycystic ovary syndrome would facilitate the induction of ovulation by clomiphene. We found that treatment with metformin, but not placebo, significantly decreased the serum insulin response to oral glucose administration. Simultaneously with the reduction in serum insulin, the women given metformin had marked increases in both spontaneous ovulation and clomiphene-induced ovulation, as compared with the women given placebo. Thirty-one of the 35 women treated with metformin (89 percent) ovulated either spontaneously or in response to clomiphene, as compared with only 3 of the 26 women in the placebo group (12 percent). These findings support the idea that hyperinsulinemia impedes ovulation in obese women with the polycystic ovary syndrome and that decreasing insulin secretion facilitates both spontaneous ovulation and the induction of ovulation by clomiphene.

Our findings are consistent with those of previous studies that noted an increased frequency of menstruation or ovulation in women with the polycystic ovary syndrome during treatment with metformin^7,8,9 or troglitazone.^11,12 However, the specific effect of insulin reduction on ovulation was not assessed in those studies. In a recent study, several previously infertile women with the polycystic ovary syndrome who were treated with metformin for six months became pregnant.²⁷ However, the study was uncontrolled and was not specifically designed to monitor ovulation, and nearly half the women recruited did not complete the study. None of the studies examined the effect of the reduction in insulin secretion on the induction of ovulation by clomiphene.^{7,8,9,11,12,27}

To assess clomiphene-induced ovulation, we purposefully chose to administer a low daily dose of only 50 mg of clomiphene, because few obese women with the polycystic ovary syndrome would be expected to have a response to this dose.^13,15 For example, in a study of women with the polycystic ovary syndrome who weighed more than 91 kg (200 lb), 50 mg of clomiphene daily for five days resulted in an ovulatory rate of only 20 percent.¹⁵ The rate of clomiphene-induced ovulation was lower in our placebo group, most likely because half the women had not had a response to previous clomiphene therapy.

We chose to use metformin because several previous studies had documented its ability to decrease serum insulin in women with the polycystic ovary syndrome.^7,8,9,10,28 It is classified as a category B drug, which means that no teratogenic effects have been demonstrated in vitro. It is commonly given to premenopausal women with type II diabetes mellitus and simply discontinued when they become pregnant. Metformin was administered to a limited number of South African women with diabetes throughout their pregnancies,²⁸ and no teratogenic effects were reported. It is not known to influence hypothalamic, pituitary, or ovarian function independently, but this possibility cannot be ruled out.

There are two main limitations to our study. First, pregnancy was not an outcome measure, and we do not know whether the increased frequency of ovulation would be accompanied by an increased pregnancy rate or birth rate. Second, we do not know whether the improved ovulatory function in the women given metformin was due to a decrease in intraovarian androgen production, normalization of spontaneous or clomiphene-induced gonadotropin secretion, diminution of the potential direct effects of insulin on ovarian folliculogenesis, or a combination of these processes.

In summary, the frequency of spontaneous ovulation and ovulation induced by clomiphene can be increased in obese women with the polycystic ovary syndrome by decreasing serum insulin concentrations with metformin.

Supported by grants from the National Institutes of Health (R01HD35629 and R01CA64500 [to Dr. Nestler] and M01RR00847). Dr. Nestler is a consultant to Bristol-Myers Squibb, which manufactures metformin, and owns 300 shares of Bristol-Myers Squibb stock.

Source Information

From the Departments of Medicine at the Medical College of Virginia, Virginia Commonwealth University, Richmond (J.E.N.); Hospital de Clinicas Caracas, Caracas, Venezuela (D.J.J.); the University of Virginia, Charlottesville (W.S.E.); and the University of Bologna, Bologna, Italy (R.P.).

Address reprint requests to Dr. Nestler at the Medical College of Virginia, P.O. Box 980111, Richmond, VA 23298-0111.

References

1. Franks S. Polycystic ovary syndrome. N Engl J Med 1995;333:853-861. [Erratum, N Engl J Med 1995;333:1435.] [Free Full Text]
2. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989;38:1165-1174. [Abstract]
3. Carmina E, Koyama T, Chang L, Stanczyk FZ, Lobo RA. Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet Gynecol 1992;167:1807-1812. [Medline]
4. Ehrmann DA, Sturis J, Byrne MM, Karrison T, Rosenfield RL, Polonsky KS. 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.
5. Apter D, Butzow T, Laughlin GA, Yen SS. Metabolic features of polycystic ovary syndrome are found in adolescent girls with hyperandrogenism. J Clin Endocrinol Metab 1995;80:2966-2973. [Free Full Text]
6. Nestler JE, Barlascini 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;68:1027-1032. [Free Full Text]
7. Velazquez EM, Mendoza S, 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;43:647-654. [CrossRef][Medline]
8. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 activity and serum free testosterone after reduction in insulin secretion in polycystic ovary syndrome. N Engl J Med 1996;335:617-623. [Free Full Text]
9. Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 activity and serum androgens. J Clin Endocrinol Metab 1997;82:4075-4079. [Free Full Text]
10. Velazquez EM, Mendoza SG, Wang P, Glueck CJ. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism 1997;46:454-457. [CrossRef][Medline]
11. 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. [Free Full Text]
12. 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. [Abstract]
13. Shepard MK, Balmaceda JP, Leija CG. Relationship of weight to successful induction of ovulation with clomiphene citrate. Fertil Steril 1979;32:641-645. [Medline]
14. O'Herlihy C, Pepperell RJ, Brown JB, Smith MA, Sandri L, McBain JC. Incremental clomiphene therapy: a new method for treating persistent anovulation. Obstet Gynecol 1981;58:535-542. [Medline]
15. Lobo RA, Gysler M, March CM, Goebelsmann U, Mishell DR Jr. Clinical and laboratory predictors of clomiphene response. Fertil Steril 1982;37:168-174. [Medline]
16. DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14:173-194. [Abstract]
17. Barbieri RL, Makris A, Randall RW, Daniels G, Kistner RW, Ryan KJ. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab 1986;62:904-910. [Free Full Text]
18. Bergh C, Carlsson B, Olsson JH, Selleskog U, Hillensjo T. Regulation of androgen production in cultured human thecal cells by insulin-like growth factor I and insulin. Fertil Steril 1993;59:323-331. [Medline]
19. Nahum R, Thong KJ, Hillier SG. Metabolic regulation of androgen production by human thecal cells in vitro. Hum Reprod 1995;10:75-81. [Free Full Text]
20. Prelevic GM, Wurzburger MI, Balint-Peric L. LH pulsatility and response to a single s.c. injection of buserelin in polycystic ovary syndrome. Gynecol Endocrinol 1990;4:1-13. [Medline]
21. Adashi EY, Hsueh AJW, Yen SSC. Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology 1981;108:1441-1449. [Free Full Text]
22. Yen SS, Laughlin GA, Morales AJ. Interface between extra- and intraovarian factors in polycystic ovarian syndrome. Ann N Y Acad Sci 1993;687:98-111. [CrossRef][Medline]
23. Yeh HC, Futterweit W, Thornton JC. Polycystic ovarian disease: US features in 104 patients. Radiology 1987;163:111-116. [Free Full Text]
24. 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. [Free Full Text]
25. Nestler JE, Beer NA, Jakubowicz DJ, Beer RM. Effects of a reduction in circulating insulin by metformin on serum dehydroepiandrosterone sulfate in nondiabetic men. J Clin Endocrinol Metab 1994;78:549-554. [Abstract]
26. Sodergard R, Backstrom T, Shanbhag V, Carstensen H. Calculation of free and bound fractions of testosterone and estradiol-17 to human plasma proteins at body temperature. J Steroid Biochem 1982;16:801-810. [CrossRef][Medline]
27. Velazquez E, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol 1997;90:392-395. [CrossRef][Medline]
28. Coetzee EJ, Jackson WPU. Metformin in management of pregnant insulin-independent diabetics. Diabetologia 1979;16:241-245. [CrossRef][Medline]

Abstract PDF Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

This article has been cited by other articles:

• Aubuchon, M., Lieman, H., Stein, D., Cohen, H. W., Isaac, B., Adel, G., Weitzman, V., Tetrokalashvili, M., Polotsky, A. J., Santoro, N. (2009). Metformin Does Not Improve the Reproductive or Metabolic Profile in Women With Polycystic Ovary Syndrome (PCOS). Reproductive Sciences 16: 938-946 [Abstract]  
• Rice, S., Pellatt, L., Ramanathan, K., Whitehead, S. A., Mason, H. D. (2009). Metformin Inhibits Aromatase via an Extracellular Signal-Regulated Kinase-Mediated Pathway. Endocrinology 150: 4794-4801 [Abstract] [Full Text]  
• Aigner, E., Bachofner, N., Klein, K., De Geyter, C., Hohla, F., Patsch, W., Datz, C. (2009). Retinol-Binding Protein 4 in Polycystic Ovary Syndrome--Association with Steroid Hormones and Response to Pioglitazone Treatment. J. Clin. Endocrinol. Metab. 94: 1229-1235 [Abstract] [Full Text]  
• Palomba, S., Falbo, A., Zullo, F., Orio, F. Jr. (2009). Evidence-Based and Potential Benefits of Metformin in the Polycystic Ovary Syndrome: A Comprehensive Review. Endocr. Rev. 30: 1-50 [Abstract] [Full Text]  
• Moll, E., Korevaar, J.C., Bossuyt, P.M.M., van der Veen, F. (2008). Does adding metformin to clomifene citrate lead to higher pregnancy rates in a subset of women with polycystic ovary syndrome?. Hum Reprod 23: 1830-1834 [Abstract] [Full Text]  
• Baillargeon, J.-P., Nestler, J. E., Ostlund, R. E., Apridonidze, T., Diamanti-Kandarakis, E. (2008). Greek hyperinsulinemic women, with or without polycystic ovary syndrome, display altered inositols metabolism. Hum Reprod 23: 1439-1446 [Abstract] [Full Text]  
• Nestler, J. E. (2008). Metformin for the Treatment of the Polycystic Ovary Syndrome. NEJM 358: 47-54 [Full Text]  
• Moll, E., van der Veen, F., van Wely, M. (2007). The role of metformin in polycystic ovary syndrome: a systematic review. Hum Reprod Update 13: 527-537 [Abstract] [Full Text]  
• Trolle, B., Flyvbjerg, A., Kesmodel, U., Lauszus, F.F. (2007). Efficacy of metformin in obese and non-obese women with polycystic ovary syndrome: a randomized, double-blinded, placebo-controlled cross-over trial. Hum Reprod 22: 2967-2973 [Abstract] [Full Text]  
• Barbieri, R. L. (2007). Clomiphene Versus Metformin for Ovulation Induction in Polycystic Ovary Syndrome: The Winner Is ..... J. Clin. Endocrinol. Metab. 92: 3399-3401 [Full Text]  
• Kim, Y.-W., Park, S.-Y., Kim, J.-Y., Huh, J.-Y., Jeon, W.-S., Yoon, C.-J., Yun, S.-S., Moon, K.-H. (2007). Metformin Restores the Penile Expression of Nitric Oxide Synthase in High-Fat-Fed Obese Rats. J Androl 28: 555-560 [Abstract] [Full Text]  
• Gambineri, A., Patton, L., De Iasio, R., Palladoro, F., Pagotto, U., Pasquali, R. (2007). Insulin-Like Factor 3: A New Circulating Hormone Related to Luteinizing Hormone-Dependent Ovarian Hyperandrogenism in the Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 92: 2066-2073 [Abstract] [Full Text]  
• Seow, K.-M., Juan, C.-C., Hsu, Y.-P., Hwang, J.-L., Huang, L.-W., Ho, L.-T. (2007). Amelioration of insulin resistance in women with PCOS via reduced insulin receptor substrate-1 Ser312 phosphorylation following laparoscopic ovarian electrocautery. Hum Reprod 22: 1003-1010 [Abstract] [Full Text]  
• Seow, K.-M., Juan, C.-C., Ho, L.-T., Hsu, Y.-P., Lin, Y.-H., Huang, L.-W., Hwang, J.-L. (2007). Adipocyte resistin mRNA levels are down-regulated by laparoscopic ovarian electrocautery in both obese and lean women with polycystic ovary syndrome. Hum Reprod 22: 1100-1106 [Abstract] [Full Text]  
• Legro, R. S., Barnhart, H. X., Schlaff, W. D., Carr, B. R., Diamond, M. P., Carson, S. A., Steinkampf, M. P., Coutifaris, C., McGovern, P. G., Cataldo, N. A., Gosman, G. G., Nestler, J. E., Giudice, L. C., Leppert, P. C., Myers, E. R., the Cooperative Multicenter Reproductive Medicine, (2007). Clomiphene, Metformin, or Both for Infertility in the Polycystic Ovary Syndrome. NEJM 356: 551-566 [Abstract] [Full Text]  
• Guzick, D. S. (2007). Treating the Polycystic Ovary Syndrome the Old-Fashioned Way. NEJM 356: 622-624 [Full Text]  
• Legro, R. S. (2007). A 27-Year-Old Woman With a Diagnosis of Polycystic Ovary Syndrome. JAMA 297: 509-519 [Abstract] [Full Text]  
• Gambineri, A., Patton, L., Vaccina, A., Cacciari, M., Morselli-Labate, A. M., Cavazza, C., Pagotto, U., Pasquali, R. (2006). Treatment with Flutamide, Metformin, and Their Combination Added to a Hypocaloric Diet in Overweight-Obese Women with Polycystic Ovary Syndrome: A Randomized, 12-Month, Placebo-Controlled Study. J. Clin. Endocrinol. Metab. 91: 3970-3980 [Abstract] [Full Text]  
• De Leo, V., Musacchio, M.C., Morgante, G., Piomboni, P., Petraglia, F. (2006). Metformin treatment is effective in obese teenage girls with PCOS. Hum Reprod 21: 2252-2256 [Abstract] [Full Text]  
• Blank, S.K., McCartney, C.R., Marshall, J.C. (2006). The origins and sequelae of abnormal neuroendocrine function in polycystic ovary syndrome. Hum Reprod Update 12: 351-361 [Abstract] [Full Text]  
• Moll, E., Bossuyt, P. M M, Korevaar, J. C, Lambalk, C. B, van der Veen, F. (2006). Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ 332: 1485- [Abstract] [Full Text]  
• Gambineri, A., Vicennati, V., Genghini, S., Tomassoni, F., Pagotto, U., Pasquali, R., Walker, B. R. (2006). Genetic Variation in 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Predicts Adrenal Hyperandrogenism among Lean Women with Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 91: 2295-2302 [Abstract] [Full Text]  
• Sohrabvand, F., Ansari, Sh., Bagheri, M. (2006). Efficacy of combined metformin-letrozole in comparison with metformin-clomiphene citrate in clomiphene-resistant infertile women with polycystic ovarian disease. Hum Reprod 21: 1432-1435 [Abstract] [Full Text]  
• Tang, T., Glanville, J., Orsi, N., Barth, J. H., Balen, A. H. (2006). The use of metformin for women with PCOS undergoing IVF treatment. Hum Reprod 21: 1416-1425 [Abstract] [Full Text]  
• Eisenhardt, S., Schwarzmann, N., Henschel, V., Germeyer, A., von Wolff, M., Hamann, A., Strowitzki, T. (2006). Early Effects of Metformin in Women with Polycystic Ovary Syndrome: A Prospective Randomized, Double-Blind, Placebo-Controlled Trial. J. Clin. Endocrinol. Metab. 91: 946-952 [Abstract] [Full Text]  
• Kim, Y.-W., Kim, J.-Y., Park, Y.-H., Park, S.-Y., Won, K.-C., Choi, K.-H., Huh, J.-Y., Moon, K.-H. (2006). Metformin Restores Leptin Sensitivity in High-Fat-Fed Obese Rats With Leptin Resistance. Diabetes 55: 716-724 [Abstract] [Full Text]  
• Mohlig, M., Spranger, J., Ristow, M., Pfeiffer, A. F H, Schill, T., Schlosser, H. W, Moltz, L., Brabant, G., Schofl, C. (2006). Predictors of abnormal glucose metabolism in women with polycystic ovary syndrome. Eur J Endocrinol 154: 295-301 [Abstract] [Full Text]  
• Homburg, R. (2005). Clomiphene citrate--end of an era? a mini-review. Hum Reprod 20: 2043-2051 [Abstract] [Full Text]  
• Abbott, D.H., Barnett, D.K., Bruns, C.M., Dumesic, D.A. (2005). Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome?. Hum Reprod Update 11: 357-374 [Abstract] [Full Text]  
• Gambineri, A., Patton, L., De Iasio, R., Cantelli, B., Cognini, G. E., Filicori, M., Barreca, A., Diamanti-Kandarakis, E., Pagotto, U., Pasquali, R. (2005). Efficacy of Octreotide-LAR in Dieting Women with Abdominal Obesity and Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 90: 3854-3862 [Abstract] [Full Text]  
• Checa, M.A., Requena, A., Salvador, C., Tur, R., Callejo, J., Espinos, J.J., Fabregues, F., Herrero, J., (Reproductive Endocrinology Interest Group of the, (2005). Insulin-sensitizing agents: use in pregnancy and as therapy in polycystic ovary syndrome. Hum Reprod Update 11: 375-390 [Abstract] [Full Text]  
• Legro, R. S., Chiu, P., Kunselman, A. R., Bentley, C. M., Dodson, W. C., Dunaif, A. (2005). Polycystic Ovaries Are Common in Women with Hyperandrogenic Chronic Anovulation but Do Not Predict Metabolic or Reproductive Phenotype. J. Clin. Endocrinol. Metab. 90: 2571-2579 [Abstract] [Full Text]  
• van Santbrink, E. J P, Hohmann, F. P, Eijkemans, M. J C, Laven, J. S E, Fauser, B. C J M (2005). Does metformin modify ovarian responsiveness during exogenous FSH ovulation induction in normogonadotrophic anovulation? A placebo-controlled double-blind assessment. Eur J Endocrinol 152: 611-617 [Abstract] [Full Text]  
• Ehrmann, D. A. (2005). Polycystic Ovary Syndrome. NEJM 352: 1223-1236 [Full Text]  
• Sepilian, V., Nagamani, M. (2005). Effects of Rosiglitazone in Obese Women with Polycystic Ovary Syndrome and Severe Insulin Resistance. J. Clin. Endocrinol. Metab. 90: 60-65 [Abstract] [Full Text]  
• Seow, K.-M., Juan, C.-C., Hsu, Y.-P., Ho, L.-T., Wang, Y.-Y., Hwang, J.-L. (2005). Serum and follicular resistin levels in women with polycystic ovarian syndrome during IVF-stimulated cycles. Hum Reprod 20: 117-121 [Abstract] [Full Text]  
• Cibula, D., Fanta, M., Vrbikova, J., Stanicka, S., Dvorakova, K., Hill, M., Skrha, J., Zivny, J., Skrenkova, J. (2005). The effect of combination therapy with metformin and combined oral contraceptives (COC) versus COC alone on insulin sensitivity, hyperandrogenaemia, SHBG and lipids in PCOS patients. Hum Reprod 20: 180-184 [Abstract] [Full Text]  
• Kashyap, S., Wells, G. A., Rosenwaks, Z. (2004). Insulin-sensitizing agents as primary therapy for patients with polycystic ovarian syndrome. Hum Reprod 19: 2474-2483 [Abstract] [Full Text]  
• Norman, R. J. (2004). Metformin--Comparison with Other Therapies in Ovulation Induction in Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 89: 4797-4800 [Full Text]  
• Palomba, S., Orio, F. Jr., Nardo, L. G., Falbo, A., Russo, T., Corea, D., Doldo, P., Lombardi, G., Tolino, A., Colao, A., Zullo, F. (2004). Metformin Administration Versus Laparoscopic Ovarian Diathermy in Clomiphene Citrate-Resistant Women with Polycystic Ovary Syndrome: A Prospective Parallel Randomized Double-Blind Placebo-Controlled Trial. J. Clin. Endocrinol. Metab. 89: 4801-4809 [Abstract] [Full Text]  
• Gambineri, A., Pelusi, C., Manicardi, E., Vicennati, V., Cacciari, M., Morselli-Labate, A. M., Pagotto, U., Pasquali, R. (2004). Glucose Intolerance in a Large Cohort of Mediterranean Women With Polycystic Ovary Syndrome: Phenotype and Associated Factors. Diabetes 53: 2353-2358 [Abstract] [Full Text]  
• Brettenthaler, N., De Geyter, C., Huber, P. R., Keller, U. (2004). Effect of the Insulin Sensitizer Pioglitazone on Insulin Resistance, Hyperandrogenism, and Ovulatory Dysfunction in Women with Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 89: 3835-3840 [Abstract] [Full Text]  
• Mioni, R., Chiarelli, S., Xamin, N., Zuliani, L., Granzotto, M., Mozzanega, B., Maffei, P., Martini, C., Blandamura, S., Sicolo, N., Vettor, R. (2004). Evidence for the Presence of Glucose Transporter 4 in the Endometrium and Its Regulation in Polycystic Ovary Syndrome Patients. J. Clin. Endocrinol. Metab. 89: 4089-4096 [Abstract] [Full Text]  
• Ganie, M. A., Khurana, M. L., Eunice, M., Gulati, M., Dwivedi, S. N., Ammini, A. C. (2004). Comparison of Efficacy of Spironolactone with Metformin in the Management of Polycystic Ovary Syndrome: An Open-Labeled Study. J. Clin. Endocrinol. Metab. 89: 2756-2762 [Abstract] [Full Text]  
• Kjotrod, S.B., von During, V., Carlsen, S.M. (2004). Metformin treatment before IVF/ICSI in women with polycystic ovary syndrome; a prospective, randomized, double blind study. Hum Reprod 19: 1315-1322 [Abstract] [Full Text]  
• van Dam, E. W. C. M., Roelfsema, F., Veldhuis, J. D., Hogendoorn, S., Westenberg, J., Helmerhorst, F. M., Frolich, M., Krans, H. M. J., Meinders, A. E., Pijl, H. (2004). Retention of estradiol negative feedback relationship to LH predicts ovulation in response to caloric restriction and weight loss in obese patients with polycystic ovary syndrome. Am. J. Physiol. Endocrinol. Metab. 286: E615-E620 [Abstract] [Full Text]  
• Garg, A. (2004). Acquired and Inherited Lipodystrophies. NEJM 350: 1220-1234 [Full Text]  
• Jakubowicz, D. J., Essah, P. A., Seppala, M., Jakubowicz, S., Baillargeon, J.-P., Koistinen, R., Nestler, J. E. (2004). Reduced Serum Glycodelin and Insulin-Like Growth Factor-Binding Protein-1 in Women with Polycystic Ovary Syndrome during First Trimester of Pregnancy. J. Clin. Endocrinol. Metab. 89: 833-839 [Abstract] [Full Text]  
• Sheehan, M. T. (2004). Polycystic Ovarian Syndrome: Diagnosis and Management. Clin Med Res 2: 13-27 [Abstract] [Full Text]  
• The Rotterdam ESHRE/ASRM-sponsored PCOS consensus, (2004). Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 19: 41-47 [Abstract] [Full Text]  
• Seow, K.-M., Juan, C.-C., Wu, L.-Y., Hsu, Y.-P., Yang, W.-M., Tsai, Y.-L., Hwang, J.-L., Ho, L.-T. (2004). Serum and adipocyte resistin in polycystic ovary syndrome with insulin resistance. Hum Reprod 19: 48-53 [Abstract] [Full Text]  
• Coffler, M. S., Patel, K., Dahan, M. H., Yoo, R. Y., Malcom, P. J., Chang, R. J. (2003). Enhanced Granulosa Cell Responsiveness to Follicle-Stimulating Hormone during Insulin Infusion in Women with Polycystic Ovary Syndrome Treated with Pioglitazone. J. Clin. Endocrinol. Metab. 88: 5624-5631 [Abstract] [Full Text]  
• Eagleson, C. A., Bellows, A. B., Hu, K., Gingrich, M. B., Marshall, J. C. (2003). Obese Patients with Polycystic Ovary Syndrome: Evidence that Metformin Does Not Restore Sensitivity of the Gonadotropin-Releasing Hormone Pulse Generator to Inhibition by Ovarian Steroids. J. Clin. Endocrinol. Metab. 88: 5158-5162 [Abstract] [Full Text]  
• Lord, J. M, Flight, I. H K, Norman, R. J (2003). Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 327: 951- [Abstract] [Full Text]  
• De Leo, V., la Marca, A., Petraglia, F. (2003). Insulin-Lowering Agents in the Management of Polycystic Ovary Syndrome. Endocr. Rev. 24: 633-667 [Abstract] [Full Text]  
• Ibanez, L., de Zegher, F. (2003). Flutamide-Metformin Therapy to Reduce Fat Mass in Hyperinsulinemic Ovarian Hyperandrogenism: Effects in Adolescents and in Women on Third-Generation Oral Contraception. J. Clin. Endocrinol. Metab. 88: 4720-4724 [Abstract] [Full Text]  
• Harborne, L., Fleming, R., Lyall, H., Sattar, N., Norman, J. (2003). Metformin or Antiandrogen in the Treatment of Hirsutism in Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 88: 4116-4123 [Abstract] [Full Text]  
• Legro, R. S. (2003). Polycystic Ovary Syndrome and Cardiovascular Disease: A Premature Association?. Endocr. Rev. 24: 302-312 [Abstract] [Full Text]  
• Ibanez, L., Ong, K., Ferrer, A., Amin, R., Dunger, D., de Zegher, F. (2003). Low-Dose Flutamide-Metformin Therapy Reverses Insulin Resistance and Reduces Fat Mass in Nonobese Adolescents with Ovarian Hyperandrogenism. J. Clin. Endocrinol. Metab. 88: 2600-2606 [Abstract] [Full Text]  
• Bloomgarden, Z. T. (2003). American Association of Clinical Endocrinologists (AACE) Consensus Conference on the Insulin Resistance Syndrome: 25-26 August 2002, Washington, DC. Diabetes Care 26: 1297-1303 [Full Text]  
• Zangeneh, F., Kudva, Y. C., Basu, A. (2003). Insulin Sensitizers. Mayo Clin Proc. 78: 471-479 [Abstract]  
• Gunton, J. E., Delhanty, P. J. D., Takahashi, S.-I., Baxter, R. C. (2003). Metformin Rapidly Increases Insulin Receptor Activation in Human Liver and Signals Preferentially through Insulin-Receptor Substrate-2. J. Clin. Endocrinol. Metab. 88: 1323-1332 [Abstract] [Full Text]  
• George, S. S., George, K., Irwin, C., Job, V., Selvakumar, R., Jeyaseelan, V., Seshadri, M.S. (2003). Sequential treatment of metformin and clomiphene citrate in clomiphene-resistant women with polycystic ovary syndrome: a randomized, controlled trial. Hum Reprod 18: 299-304 [Abstract] [Full Text]  
• Dolfing, J.G., Tucker, K.E., Lem, C.M., Uittenbogaart, J., Verzijl, J.C., Schweitzer, D.H. (2003). Low 11-deoxycortisol to cortisol conversion reflects extra-adrenal factors in the majority of women with normo-gonadotrophic normo-estrogenic infertility. Hum Reprod 18: 333-337 [Abstract] [Full Text]  
• Morin-Papunen, L., Vauhkonen, I., Koivunen, R., Ruokonen, A., Martikainen, H., Tapanainen, J. S. (2003). Metformin Versus Ethinyl Estradiol-Cyproterone Acetate in the Treatment of Nonobese Women with Polycystic Ovary Syndrome: A Randomized Study. J. Clin. Endocrinol. Metab. 88: 148-156 [Abstract] [Full Text]  
• Cermik, D., Selam, B., Taylor, H. S. (2003). Regulation of HOXA-10 Expression by Testosterone in Vitro and in the Endometrium of Patients with Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 88: 238-243 [Abstract] [Full Text]  
• Ibanez, L., de Zegher, F. (2003). Low-dose combination of flutamide, metformin and an oral contraceptive for non-obese, young women with polycystic ovary syndrome. Hum Reprod 18: 57-60 [Abstract] [Full Text]  
• Welt, C. K., Taylor, A. E., Martin, K. A., Hall, J. E. (2002). Serum Inhibin B in Polycystic Ovary Syndrome: Regulation by Insulin and Luteinizing Hormone. J. Clin. Endocrinol. Metab. 87: 5559-5565 [Abstract] [Full Text]  
• Stadtmauer, L. A., Wong, B. C., Oehninger, S. (2002). Should patients with polycystic ovary syndrome be treated with metformin?: Benefits of insulin sensitizing drugs in polycystic ovary syndrome--beyond ovulation induction. Hum Reprod 17: 3016-3026 [Abstract] [Full Text]  
• Seli, E., Duleba, A. J. (2002). Should patients with polycystic ovarian syndrome be treated with metformin?. Hum Reprod 17: 2230-2236 [Abstract] [Full Text]  
• Nestler, J. E. (2002). Should patients with polycystic ovarian syndrome be treated with metformin?: An enthusiastic endorsement. Hum Reprod 17: 1950-1953 [Abstract] [Full Text]  
• Cahill, D J, Wardle, P G (2002). Management of infertility. BMJ 325: 28-32 [Full Text]  
• Elter, K., Imir, G., Durmusoglu, F. (2002). Clinical, endocrine and metabolic effects of metformin added to ethinyl estradiol-cyproterone acetate in non-obese women with polycystic ovarian syndrome: a randomized controlled study. Hum Reprod 17: 1729-1737 [Abstract] [Full Text]  
• Ibanez, L., Valls, C., Ferrer, A., Ong, K., Dunger, D. B., de Zegher, F. (2002). Additive Effects of Insulin-Sensitizing and Anti-Androgen Treatment in Young, Nonobese Women with Hyperinsulinism, Hyperandrogenism, Dyslipidemia, and Anovulation. J. Clin. Endocrinol. Metab. 87: 2870-2874 [Abstract] [Full Text]  
• Bloomgarden, Z. T. (2002). Neuropathy, Womens' Health, and Socioeconomic Aspects of Diabetes. Diabetes Care 25: 1085-1094 [Full Text]  
• Legro, R. S., Bentley-Lewis, R., Driscoll, D., Wang, S. C., Dunaif, A. (2002). Insulin Resistance in the Sisters of Women with Polycystic Ovary Syndrome: Association with Hyperandrogenemia Rather Than Menstrual Irregularity. J. Clin. Endocrinol. Metab. 87: 2128-2133 [Abstract] [Full Text]  
• Arslanian, S. A., Lewy, V., Danadian, K., Saad, R. (2002). Metformin Therapy in Obese Adolescents with Polycystic Ovary Syndrome and Impaired Glucose Tolerance: Amelioration of Exaggerated Adrenal Response to Adrenocorticotropin with Reduction of Insulinemia/Insulin Resistance. J. Clin. Endocrinol. Metab. 87: 1555-1559 [Abstract] [Full Text]  
• Homburg, R. (2002). Should patients with polycystic ovarian syndrome be treated with metformin?: A note of cautious optimism. Hum Reprod 17: 853-856 [Abstract] [Full Text]  
• Fleming, R., Hopkinson, Z. E., Wallace, A. M., Greer, I. A., Sattar, N. (2002). Ovarian Function and Metabolic Factors in Women with Oligomenorrhea Treated with Metformin in a Randomized Double Blind Placebo-Controlled Trial. J. Clin. Endocrinol. Metab. 87: 569-574 [Abstract] [Full Text]  
• Yarali, H., Yildiz, B. O., Demirol, A., Zeyneloglu, H. B., Yigit, N., Bukulmez, O., Koray, Z. (2002). Co-administration of metformin during rFSH treatment in patients with clomiphene citrate-resistant polycystic ovarian syndrome: a prospective randomized trial. Hum Reprod 17: 289-294 [Abstract] [Full Text]  
• Ibanez, L., Valls, C., Ferrer, A., Marcos, M. V., Rodriguez-Hierro, F., de Zegher, F. (2001). Sensitization to Insulin Induces Ovulation in Nonobese Adolescents with Anovulatory Hyperandrogenism. J. Clin. Endocrinol. Metab. 86: 3595-3598 [Abstract] [Full Text]  
• Ng, E. H. Y., Wat, N. M. S., Ho, P. C. (2001). Effects of metformin on ovulation rate, hormonal and metabolic profiles in women with clomiphene-resistant polycystic ovaries: a randomized, double-blinded placebo-controlled trial. Hum Reprod 16: 1625-1631 [Abstract] [Full Text]  
• Fedorcsak, P., Dale, P. O., Storeng, R., Tanbo, T., Abyholm, T. (2001). The impact of obesity and insulin resistance on the outcome of IVF or ICSI in women with polycystic ovarian syndrome. Hum Reprod 16: 1086-1091 [Abstract] [Full Text]  
• Peppard, H. R., Marfori, J., Iuorno, M. J., Nestler, J. E. (2001). Prevalence of Polycystic Ovary Syndrome Among Premenopausal Women With Type 2 Diabetes. Diabetes Care 24: 1050-1052 [Abstract] [Full Text]  
• Azziz, R., Ehrmann, D., Legro, R. S., Whitcomb, R. W., Hanley, R., Fereshetian, A. G., O’Keefe, M., Ghazzi, M. N. (2001). Troglitazone Improves Ovulation and Hirsutism in the Polycystic Ovary Syndrome: A Multicenter, Double Blind, Placebo-Controlled Trial. J. Clin. Endocrinol. Metab. 86: 1626-1632 [Abstract] [Full Text]  
• Parulkar, A. A., Pendergrass, M. L., Granda-Ayala, R., Lee, T. R., Fonseca, V. A. (2001). Nonhypoglycemic Effects of Thiazolidinediones. ANN INTERN MED 134: 61-71 [Abstract] [Full Text]  
• (2001). Tackling polycystic ovary syndrome. DTB 39: 1-5 [Abstract] [Full Text]  
• Matthaei, S., Stumvoll, M., Kellerer, M., Häring, H.-U. (2000). Pathophysiology and Pharmacological Treatment of Insulin Resistance. Endocr. Rev. 21: 585-618 [Abstract] [Full Text]  
• Martens, J. W. M., Geller, D. H., Arlt, W., Auchus, R. J., Ossovskaya, V. S., Rodriguez, H., Dunaif, A., Miller, W. L. (2000). Enzymatic Activities of P450c17 Stably Expressed in Fibroblasts from Patients with the Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 85: 4338-4346 [Abstract] [Full Text]  
• De Leo, V., la Marca, A., Morgante, G., Ciotta, L., Mencaglia, L., Cianci, A., Petraglia, F. (2000). Clomiphene citrate increases insulin-like growth factor binding protein-1 and reduces insulin-like growth factor-I without correcting insulin resistance associated with polycystic ovarian syndrome. Hum Reprod 15: 2302-2305 [Abstract] [Full Text]  
• Ibáñez, L., Valls, C., Potau, N., Marcos, M. V., de Zegher, F. (2000). Sensitization to Insulin in Adolescent Girls to Normalize Hirsutism, Hyperandrogenism, Oligomenorrhea, Dyslipidemia, and Hyperinsulinism after Precocious Pubarche. J. Clin. Endocrinol. Metab. 85: 3526-3530 [Abstract] [Full Text]  
• Morin-Papunen, L. C., Vauhkonen, I., Koivunen, R. M., Ruokonen, A., Martikainen, H. K., Tapanainen, J. S. (2000). 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. 85: 3161-3168 [Abstract] [Full Text]  
• Moghetti, P., Castello, R., Negri, C., Tosi, F., Perrone, F., Caputo, M., Zanolin, E., Muggeo, M. (2000). 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. 85: 139-146 [Abstract] [Full Text]  
• la Marca, A., Egbe, T. O., Morgante, G., Paglia, T., Ciani, A., De Leo, V. (2000). Metformin treatment reduces ovarian cytochrome P-450c17{alpha} response to human chorionic gonadotrophin in women with insulin resistance-related polycystic ovary syndrome. Hum Reprod 15: 21-23 [Abstract] [Full Text]