John E. Nestler

EFFECTS OF METFORMIN ON SPONTANEOUS AND CLOMIPHENE-INDUCED OVULATION IN THE POLYCYSTIC OVARY SYNDROME

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 microU 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.

Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome.

BACKGROUND Insulin resistance and increased ovarian cytochrome P450c17 alpha activity are both features of the polycystic ovary syndrome. P450c17 alpha, which is involved in androgen biosynthesis, has both 17 alpha-hydroxylase and 17,20-lyase activities. Increased activity of this enzyme results in exaggerated conversion of progesterone to 17 alpha-hydroxyprogesterone in response to stimulation by gonadotrophin. We hypothesized that hyperinsulinemia stimulates ovarian P450c17 alpha activity. METHODS We measured fasting serum steroid concentrations and the response of serum 17 alpha-hydroxyprogesterone to leuprolide, a gonadotrophin-releasing hormone agonist, and performed oral glucose-tolerance tests before and after oral administration of either metformin (500 mg three times daily) or placebo for four to eight weeks in 24 obese women with the polycystic ovary syndrome. RESULTS In the 11 women given metformin, the mean (+/- SE) area under the serum insulin curve after oral glucose administration decreased from 9303 +/- 1603 to 4982 +/- 911 microU per milliliter per minute (56 +/- 10 to 30 +/- 6 nmol per liter per minute) (P = 0.004). This decrease was associated with a reduction in the basal serum 17 alpha-hydroxyprogesterone concentration from 135 +/- 21 to 66 +/- 7 ng per deciliter (4.1 +/- 0.6 to 2.0 +/- 0.2 nmol per liter) (P = 0.01) and a reduction in the leuprolide-stimulated peak serum 17 alpha-hydroxyprogesterone concentration from 455 +/- 54 to 281 +/- 52 ng per deciliter (13.7 +/- 1.6 to 8.5 +/- 1.6 nmol per liter) (P = 0.01). The serum 17 alpha-hydroxyprogesterone values increased slightly in the placebo group. In the metformin group, the basal serum luteinizing hormone concentration decreased from 8.5 +/- 2.2 to 2.8 +/- 0.5 mlU per milliliter (P = 0.01), the serum free testosterone concentration decreased from 0.34 +/- 0.07 to 0.19 +/- 0.05 ng per deciliter (12 +/- 3 to 7 +/- 2 pmol per liter) (P = 0.009), and the serum sex hormone-binding globulin concentration increased from 0.8 +/- 0.2 to 2.3 +/- 0.6 microgram per deciliter (29 +/- 7 to 80 +/- 21 nmol per liter) (P < 0.001). None of these values changed significantly in the placebo group. CONCLUSIONS In obese women with the polycystic ovary syndrome, decreasing serum insulin concentrations with metformin reduces ovarian cytochrome P450c17 alpha activity and ameliorates hyperandrogenism.

Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone

OBJECTIVE To determine whether metformin treatment increases the ovulation and pregnancy rates in response to clomiphene citrate (CC) in women who are resistant to CC alone. DESIGN Randomized, double-blind, placebo-controlled trial. SETTING Multicenter environment. PATIENT(S) Anovulatory women with the polycystic ovary syndrome (PCOS) who were resistant to CC. INTERVENTION(S) Participants received placebo or metformin, 500 mg three times daily, for 7 weeks. Information on reproductive steroids, gonadotropins, and oral glucose tolerance testing was obtained at baseline and after treatment. Metformin or placebo was continued and CC treatment was begun at 50 mg daily for 5 days. Serum P level > or =4 ng/mL was considered to indicate ovulation. With ovulation, the daily CC dose was not changed, but with anovulation it was increased by 50 mg for the next cycle. Patients completed the study when they had had six ovulatory cycles, became pregnant, or experienced anovulation while receiving 150 mg of CC. MAIN OUTCOME MEASURE(S) Ovulation and pregnancy rates. RESULT(S) In the metformin and placebo groups, 9 of 12 participants (75%) and 4 of 15 participants (27%) ovulated, and 6 of 11 participants (55%) and 1 of 14 participants (7%) conceived, respectively. Comparisons between the groups were significant. CONCLUSION(S) In anovulatory women with PCOS who are resistant to CC, metformin use significantly increased the ovulation rate and pregnancy rate from CC treatment.

Metformin for the Treatment of the Polycystic Ovary Syndrome

A 23-year-old woman with known polycystic ovary syndrome visits her family physician. She has taken oral contraceptive pills in the past but did not tolerate them and is not currently receiving any treatment. She has three or four menstrual periods per year and is not interested in becoming pregnant now, but she will be getting married in a year. She has heard that the polycystic ovary syndrome is associated with diabetes and is concerned because both her mother and father have type 2 diabetes. Her bodymass index (the weight in kilograms divided by the square of the height in meters) is 32, her waist circumference is 38 in. (96.5 cm), her serum total testosterone level is elevated at 0.9 ng per milliliter (90 ng per deciliter, or 2.9 nmol per liter), her plasma high-density lipoprotein cholesterol level is 35 mg per deciliter (0.9 mmol per liter), and her triglyceride level is 190 mg per deciliter (2.1 mmol per liter). Her serum glucose level 2 hours after the ingestion of 75 g of dextrose is 138 mg per deciliter (7.7 mmol per liter). The physician wonders whether treatment with metformin would be beneficial and refers the patient to an endocrinologist. T h e C l i nic a l Probl e m The polycystic ovary syndrome is a clinical diagnosis characterized by the presence of two or more of the following features: chronic oligo-ovulation or anovulation, androgen excess, and polycystic ovaries. 1 It affects 5 to 10% of women of childbearing age 2,3 and is the most common cause of anovulatory infertility in developed countries. Common clinical manifestations include menstrual irregularities and signs of androgen excess such as hirsutism, acne, and alopecia. The polycystic ovary syndrome is associated with important metabolic derangements. The prevalence of type 2 diabetes in the United States is 10 times as high among young women with the polycystic ovary syndrome as among normal women, 4,5 and impaired glucose tolerance or overt type 2 diabetes develops by the age of 30 years in 30 to 50% of obese women with the polycystic ovary syndrome. 4‑6 The prevalence of the metabolic syndrome is two to three times as high among women with the polycystic ovary syndrome as among normal women matched for age and body-mass index, and 20% of women with the polycystic ovary syndrome who are younger than 20 years of age have the metabolic syndrome. 7 Although outcome data specifically for women with the polycystic ovary syndrome are lacking, the risk of fatal myocardial infarction is twice as high among women with severe oligomenorrhea, most of whom would be expected to have the polycystic ovary syndrome, as among women with eumenorrhea. 8 This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the author’s clinical recommendations.

Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome

OBJECTIVE Insulin resistance and its compensatory hyperinsulinemia play a key pathogenic role in the infertility of the polycystic ovary syndrome. Numerous studies indicate that insulin-sensitizing drugs can be used to enhance spontaneous ovulation and the induction of ovulation in the syndrome. The aim of this review is to summarize the studies in which insulin-sensitizing drugs were used to increase ovulation rate or improve fertility in women with the PCOS and to translate the information into practical guidelines for the use of these drugs by reproductive endocrinologists. DESIGN Review and critique of studies in which an insulin-sensitizing drug was used to increase ovulation rate or improve infertility in women with the polycystic ovary syndrome. MAIN OUTCOME MEASURE(S) Ovulation rate and pregnancy rate. RESULT(S) Studies have demonstrated that insulin-sensitizing drugs can increase spontaneous ovulation, enhance the induction of ovulation with clomiphene citrate, and increase clinical pregnancy rates. CONCLUSION(S) An algorithmic approach is provided for the use of insulin-sensitizing drugs to treat the anovulation and infertility of women with the polycystic ovary syndrome.

Cardiometabolic Aspects of the Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder amongst women of reproductive age and is associated with various metabolic perturbations, in addition to chronic anovulation and factors related to androgen excess. In general, women live longer than men and develop cardiovascular disease at an older age. However, women with PCOS, as compared with age- and body mass index-matched women without the syndrome, appear to have a higher risk of insulin resistance, hyperinsulinemia, glucose intolerance, dyslipidemia, and an increased prothrombotic state, possibly resulting in a higher rate of type 2 diabetes mellitus, fatty liver disease, subclinical atherosclerosis, vascular dysfunction, and finally cardiovascular disease and mortality. Further alterations in PCOS include an increased prevalence of sleep apnea, as well as various changes in the secretion and/or function of adipokines, adipose tissue-derived proinflammatory factors and gut hormones, all of them with direct or indirect influences on the complex signaling network that regulates metabolism, insulin sensitivity, and energy homeostasis. Reviews on the cardiometabolic aspects of PCOS are rare, and our knowledge from recent studies is expanding rapidly. Therefore, it is the aim of the present review to discuss and to summarize the current knowledge, focusing on the alterations of cardiometabolic factors in women with PCOS. Further insight into this network of factors may facilitate finding therapeutic targets that should ameliorate not only ovarian dysfunction but also the various cardiometabolic alterations related to the syndrome.

Inhibition of accelerated coronary atherosclerosis with dehydroepiandrosterone in the heterotopic rabbit model of cardiac transplantation.

BackgroundAccelerated coronary atherosclerosis has become a critical problem in cardiac transplantation. Although the pathogenesis of this disease is unknown, hypercholesterolemia has been shown to be a major risk factor. Methods and ResultsTo study this problem, a hypercholesterolemic rabbit model of heterotopic cardiac transplantation was developed to study accelerated graft atherosclerosis. Based on suggestions in the literature, it was hypothesized that dehydroepiandrosterone (DHEA) may retard the progression of the disease. Using semiquantitative light microscopy, a predilection for the development of small vessel occlusive disease in the transplanted hearts was found. Chronic DHEA administration produced a 45% reduction in the number of significantly stenosed vessels in the transplanted hearts (p<0.05) compared with controls and a 62% reduction in the nontransplanted hearts (p<0.05), yielding an overall 50% reduction in the number of significantly stenosed vessels in both the transplanted and nontransplanted hearts. This reduction in luminal stenosis was observed in the absence of any significant alterations in lipid profiles. ConclusionsIt is concluded that chronic DHEA administration in a hypercholesterolemic rabbit model of heterotopic cardiac transplantation significantly retards the progression of accelerated atherosclerosis in both the transplanted heart and in the native heart.

Total testosterone assays in women with polycystic ovary syndrome: Precision and correlation with hirsutism

CONTEXT There is no standardized assay of testosterone in women. Liquid chromatography mass spectrometry (LC/MS) has been proposed as the preferable assay by an Endocrine Society Position Statement. OBJECTIVE The aim was to compare assay results from a direct RIA with two LC/MS. DESIGN AND SETTING We conducted a blinded laboratory study including masked duplicate samples at three laboratories--two academic (University of Virginia, RIA; and Mayo Clinic, LC/MS) and one commercial (Quest, LC/MS). PARTICIPANTS AND INTERVENTIONS Baseline testosterone levels from 596 women with PCOS who participated in a large, multicenter, randomized controlled infertility trial performed at academic health centers in the United States were run by varying assays, and results were compared. MAIN OUTCOME MEASURE We measured assay precision and correlation and baseline Ferriman-Gallwey hirsutism scores. RESULTS Median testosterone levels were highest with RIA. The correlations between the blinded samples that were run in duplicate were comparable. The correlation coefficient (CC) between LC/MS at Quest and Mayo was 0.83 [95% confidence interval (CI), 0.80-0.85], between RIA and LC/MS at Mayo was 0.79 (95% CI, 0.76-0.82), and between RIA and LC/MS at Quest was 0.67 (95% CI, 0.63-0.72). Interassay variation was highest at the lower levels of total testosterone (≤50 ng/dl). The CC for Quest LC/MS was significantly different from those derived from the other assays. We found similar correlations between total testosterone levels and hirsutism score with the RIA (CC=0.24), LC/MS at Mayo (CC=0.15), or Quest (CC=0.17). CONCLUSIONS A testosterone RIA is comparable to LC/MS assays. There is significant variability between LC/MS assays and poor precision with all assays at low testosterone levels.

EFFECTS OF D-CHIRO-INOSITOL IN LEAN WOMEN WITH THE POLYCYSTIC OVARY SYNDROME

OBJECTIVE To determine whether the administration of D-chiro-inositol, a putative insulin-sensitizing drug, would affect the concentration of circulating insulin, the levels of serum androgens, and the frequency of ovulation in lean women with the polycystic ovary syndrome. METHODS In 20 lean women (body mass index, 20.0 to 24.4 kg/m 2) who had the polycystic ovary syndrome, treatment was initiated with either 600 mg of D-chiro-inositol or placebo orally once daily for 6 to 8 weeks. We performed oral glucose tolerance tests and measured serum sex steroids before and after therapy. To monitor for ovulation, we determined serum progesterone concentrations weekly. RESULTS In the 10 women given D-chiro-inositol, the mean (+/- standard error) area under the plasma insulin curve after oral administration of glucose decreased significantly from 8,343 +/- 1,149 mU/mL per min to 5,335 +/- 1,792 mU/mL per min in comparison with no significant change in the placebo group (P = 0.03 for difference between groups). Concomitantly, the serum free testosterone concentration decreased by 73% from 0.83 +/- 0.11 ng/dL to 0.22 +/- 0.03 ng/dL, a significant change in comparison with essentially no change in the placebo group (P = 0.01). Six of the 10 women (60%) in the D-chiro-inositol group ovulated in comparison with 2 of the 10 women (20%) in the placebo group (P = 0.17). Systolic (P = 0.002) and diastolic (P = 0.001) blood pressures, as well as plasma triglyceride concentrations (P = 0.001), decreased significantly in the D-chiro-inositol group in comparison with the placebo group, in which these variables either increased (blood pressure) or decreased minimally (triglycerides). CONCLUSION We conclude that, in lean women with the polycystic ovary syndrome, D-chiro-inositol reduces circulating insulin, decreases serum androgens, and ameliorates some of the metabolic abnormalities (increased blood pressure and hypertriglyceridemia) of syndrome X.

Insulin sensitizers for polycystic ovary syndrome.

The findings that insulin resistance has important implications in the pathogenesis of the polycystic ovary syndrome (PCOS) and that insulin-sensitizing drugs are a useful therapeutic approach are relatively recent. Nevertheless, multiple well-designed clinical trials have been published in the past decade, and there is now sufficient evidence in the literature to support clinical recommendations. The management of PCOS includes short-term objectives, such as treatment of infertility and control of androgen excess, as well as long-term considerations, such as prevention of endometrial cancer and management of the dysmetabolic syndrome with its associated risks of type 2 diabetes and cardiovascular disease. The present review will address the rationale for the use of insulin-sensitizing drugs to treat both the short-term and long-term issues in PCOS. Since it has been only sparsely reviewed in the literature, we will emphasize the importance of preventing the long-term risks associated with PCOS, if possible, when choosing a pharmacologic therapy.