Liraglutide 3 mg on weight, body composition, and hormonal and metabolic parameters in women with obesity and polycystic ovary syndrome: a randomized placebo-controlled-phase 3 study.

OBJECTIVE: To study the efficacy and safety of the GLP-1 analog liraglutide 3 mg (LIRA 3 mg) vs. placebo (PL) for reduction of body weight (BW) and hyperandrogenism in women with obesity and polycystic ovary syndrome (PCOS). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Hospital-based outpatient endocrine and metabolic center. PATIENT(S): Women diagnosed with PCOS (NIH criteria) were randomly assigned to LIRA 3 mg (n = 55) or PL (n = 27) once daily for 32 weeks with lifestyle intervention. INTERVENTION(S): Study visits at baseline and 32 weeks included BW and body composition by dual-energy x-ray absorptiometry. Oral glucose tolerance tests were done with sex steroids, free androgen index (FAI), and lipids measured in the fasting sample. MAIN OUTCOME MEASURE(S): The primary end points were changes in BW and FAI. Safety was assessed in all patients who received at least one dose of the study drug. RESULT(S): Change in BW from baseline to week 32 was -5.7% (±0.75) with LIRA 3 mg vs. -1.4% (±1.09) with PL. At week 32, more participants on LIRA 3 mg than on PL achieved at least 5% weight reductions (25 of 44 vs. 5 of 23). Free androgen index significantly reduced with LIRA 3 mg compared with the PL where the mean FAI slightly increased. Gastrointestinal events, which were mostly mild to moderate, were reported in 58.2% of the LIRA 3 mg-subjects and 18.5% of PL subjects. CONCLUSION(S): LIRA 3 mg once daily appears superior to PL in reducing BW and androgenicity and improving cardiometabolic parameters in women with PCOS and obesity. CLINICAL TRIAL REGISTRATION NUMBER: NCT03480022.

Exenatide, Dapagliflozin, or Phentermine/Topiramate Differentially Affect Metabolic Profiles in Polycystic Ovary Syndrome.

CONTEXT: Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors reduce weight and improve insulin sensitivity via different mechanisms. OBJECTIVE: The efficacy of once-weekly exenatide (EQW) and dapagliflozin (DAPA) alone and coadministered (EQW/DAPA), DAPA/extended-release (ER) metformin (DAPA/MET), and phentermine topiramate extended release (PHEN/TPM) on metabolic parameters, body composition, and sex hormones were examined in obese women with PCOS. METHODS: Nondiabetic women (n = 119; aged 18-45 years) with a body mass index (BMI) greater than 30 and less than 45 and polycystic ovary syndrome (National Institutes of Health criteria) were randomly assigned in a single-blinded fashion to EQW (2 mg weekly); DAPA (10 mg daily), EQW/DAPA (2 mg weekly/10 mg daily), DAPA (10 mg)/MET (2000 mg XR daily), or PHEN (7.5 mg)/TPM (46 mg ER daily) treatment for 24 weeks. Study visits at baseline and 24 weeks included weight, blood pressure (BP), waist (WC) measures, and body composition evaluated by dual-energy x-ray absorptiometry (DXA). Oral glucose tolerance tests were conducted to assess glycemia and mean blood glucose (MBG), and compute insulin sensitivity (SI) and secretion (IS) measures. Sex steroids, free androgen index (FAI), and lipid profiles were measured in the fasting sample. RESULTS: EQW/DAPA and PHEN/TPM resulted in the most loss of weight and total body fat by DXA, and WC. Despite equivalent reductions in BMI and WC with PHEN/TPM, only EQW/DAPA and EQW resulted in significant improvements in MBG, SI, and IS. Reductions in fasting glucose, testosterone, FAI, and BP were seen with all drugs. CONCLUSION: Dual therapy with EQW/DAPA was superior to either alone, DAPA/MET and PHEN/TPM in terms of clinical and metabolic benefits in this patient population.

A randomized trial of dapagliflozin and metformin, alone and combined, in overweight women after gestational diabetes mellitus.

BACKGROUND: Women with a history of gestational diabetes mellitus are at a substantially increased risk of gestational diabetes mellitus recurrence and type 2 diabetes. Weight gain, particularly increased central adiposity after delivery, is strongly associated with deterioration of pancreatic beta cell compensation for insulin resistance. Weight management after gestational diabetes mellitus could have a significant benefit in these women who are at a high risk of developing type 2 diabetes. OBJECTIVE: This study aimed to evaluate the treatment efficacy of dapagliflozin and metformin, alone and in combination, on body weight and anthropometric, cardiovascular, and metabolic parameters in overweight women with a recent history of gestational diabetes mellitus. STUDY DESIGN: This was a prospective, single-blind, randomized, outpatient clinical trial with 3 parallel treatment groups. Overweight or obese (body mass index>25) females (n=66; ≥18-45 years) with gestational diabetes mellitus in pregnancy in the past 12 months were randomized in a single-blind manner to dapagliflozin, metformin, or dapagliflozin-metformin for 24 weeks. Body weight, height, body mass index, waist circumference, waist-to-height ratio, and blood pressure were determined at baseline and trial completion. Oral glucose tolerance tests were performed at baseline and 24 weeks to assess glycemia and mean blood glucose and calculate insulin sensitivity and secretion measures. Plasma lipid fractions, thyroid-stimulating hormone, and liver enzymes were also assessed in the fasting sample at the beginning and completion of the study trial. RESULTS: The study was completed by 49 participants (74%). Significant reduction of weight, waist circumference, and waist-to-height ratio and improved glycemia and insulin sensitivity index derived from oral glucose tolerance test were found with dapagliflozin-metformin vs metformin monotherapy. Both dapagliflozin and dapagliflozin-metformin therapy were superior to metformin in increasing high-density lipoprotein levels, reducing triglyceride concentrations, lowering the triglyceride-to-high-density lipoprotein cholesterol ratio, and improving glucose excursion after an oral glucose tolerance test. The early insulin response to a glucose challenge significantly improved with only dapagliflozin-metformin compared with single-drug treatments. CONCLUSION: This is the first report comparing the efficacy of a sodium-glucose cotransporter 2 inhibitor alone and in combination with metformin in this patient population. We found that combination dapagliflozin-metformin treatment over a 24-week period had a greater positive effect on body weight, waist circumference, and glycemic, cardiovascular, and metabolic parameters than metformin monotherapy in overweight or obese at-risk women with a recent history of gestational diabetes mellitus.

Postpartum treatment with liraglutide in combination with metformin versus metformin monotherapy to improve metabolic status and reduce body weight in overweight/obese women with recent gestational diabetes: A double-blind, randomized, placebo-controlled study.

BACKGROUND: Gestational diabetes (GDM) imparts a high risk of developing diabetes postpartum. Insulin resistance appears to be the major contributor. Liraglutide, a glucagon-like peptide-1 analogue, improves peripheral glucose disposal and reduces body weight. We evaluated whether liraglutide in combination with metformin (MET-LIRA) is more effective than metformin monotherapy (MET-P) in improving insulin action and reducing body weight in overweight prior GDM (pGDM) women. METHODS: Women (n = 153; body mass index (BMI) ≥25 kg/m2; 18-45 y; GDM within 12 months) with metabolic abnormalities were randomized to MET-LIRA (MET-2000 mg, LIRA 1.8 mg SC QD) or MET-P (MET-2000 mg, Placebo QD). Study visits at baseline, 36-40, 56-60 and 80-84 weeks included body weight (BW), BMI, waist circumference and waist-to-height ratio measures. Oral glucose tolerance tests (OGTTs) were performed to assess glycemia, mean blood glucose (MBG), lipids, and compute insulin sensitivity and secretion measures. FINDINGS: Seventy-two (47%) participants completed the study. MET-LIRA therapy was significantly better in improving MBG and insulin sensitivity indices [SIOGTT MET-LIRA from 4.6 (3.2) to 5.9 (2.9) vs. MET-P 5.5 (3.0) to 5.4 (3.2)] and reducing BW and central adiposity [BMI MET-LIRA from 37.2 (8.3) to 33.8 (5.2) vs MET-P 33.8(5.2) to 32.8(6)]. MET-LIRA therapy but not MET-P decreased triglycerides (TRG) and TRG/high density lipoprotein cholesterol (HDL-C) ratios. INTERPRETATION: MET-LIRA treatment demonstrated superior efficacy in correcting the metabolic status of pGDM women over 84 weeks of therapy. The addition of liraglutide to metformin therapy resulted in a more dramatic decrease in BW and central adiposity than metformin alone. FUNDATION: Supported by an unrestricted investigator initiated grant from Novo Nordisk, Inc. awarded to K.E.H. MEETING PRESENTATION: The results from preliminary analyses of this study were presented at 76th meeting of the American Diabetes Association, June 10-14, 2016 New Orleans, LA, and 77th meeting of the American Diabetes Association, June 9-12, 2017San Diego, CA.

SHORT-TERM SITAGLIPTIN-METFORMIN THERAPY IS MORE EFFECTIVE THAN METFORMIN OR PLACEBO IN PRIOR GESTATIONAL DIABETIC WOMEN WITH IMPAIRED GLUCOSE REGULATION.

OBJECTIVE: Our pilot study examined the effectiveness of sitagliptin-metformin (SITA-MET), metformin (MET), and placebo (P) therapy on fasting and post-glucose challenge glucose levels in postpartum women with prior gestational diabetes mellitus (GDM) and impaired glucose regulation. METHODS: Prediabetic women (N = 36, age 18 to 42 years) with recent GDM were randomized to P (one pill twice a day), MET (1,000 mg twice a day), or SITA-MET (50 mg SITA, 1,000 mg MET twice a day) for 16 weeks in a single-blind fashion. An individualized diet and exercise plan were provided to all participants. At baseline and 16 weeks, oral glucose tolerance tests were performed to assess glycemia, mean blood glucose (MBG), and calculate insulin sensitivity (IS) and secretion (SI) indexes. Lipid profile, thyroid-stimulating hormone level, and pregnancy test were performed in the baseline sample. RESULTS: Thirty-three (92%) participants completed the study. At study end, 15 participants had normal glycemia (SITA-MET vs. MET, P; P = .035). MBG, IS, IS-SI index, and waist to height ratio were significantly improved with SITA-MET compared with MET and P treatment. SITAMET therapy was more effective in lowering body mass index and waist circumference compared to P treatment. CONCLUSION: Our pilot study is the first to evaluate the use of a dipeptidyl peptidase 4 inhibitor combined with MET in glucose-impaired women with a history of GDM. In this investigation, combination SITA-MET was found to be superior to MET and P in improving glycemia and metabolic measures in this prediabetic population. ABBREVIATIONS: BID = twice a day; BMI = body mass index; BP = blood pressure; BW = body weight; CHOL = cholesterol; DI = disposition index; DM = diabetes mellitus; DPP-4i = dipeptidyl peptidase 4 inhibitor; FBG = fasting blood glucose; GDM = gestational diabetes mellitus; GLP-1 = glucagon-like peptide 1; HDL-C = high-density-lipoprotein cholesterol; HOMA-IR = homeostasis model assessment of insulin resistance; IGI = insulinogenic index; IGR = impaired glucose regulation; IGT = impaired glucose tolerance; IR = insulin resistance; IS = insulin sensitivity; LDL-C = low-density-lipoprotein cholesterol; MBG = mean blood glucose; MET = metformin; OGTT = oral glucose tolerance test; P = placebo; SI = insulin secretion; SIOGTT = Matsuda's insulin sensitivity index; TRG = triglycerides; WC = waist circumference; WHR = waist to hip ratio; WHtR = waist to height ratio.

Short-term therapy with combination dipeptidyl peptidase-4 inhibitor saxagliptin/metformin extended release (XR) is superior to saxagliptin or metformin XR monotherapy in prediabetic women with polycystic ovary syndrome: a single-blind, randomized, pilot study.

OBJECTIVE: To evaluate efficacy with the dipeptidyl peptidase-4 inhibitor saxagliptin (SAXA), metformin extended release (MET), and combination (SAXA-MET) in patients with polycystic ovary syndrome (PCOS) and impaired glucose regulation. DESIGN: Prospective, randomized, single-blind drug study. SETTING: Outpatient clinic. PATIENT(S): Patients (n = 38) with PCOS (aged 18-42 years) and prediabetic hyperglycemia determined by a 75-gram oral glucose tolerance test. INTERVENTION(S): Patients were randomized to SAXA-MET (5 mg/2,000 mg), SAXA (5 mg), or MET (2,000 mg) for 16 weeks. MAIN OUTCOME MEASURE(S): Fasting and mean blood glucose, insulin sensitivity, insulin secretion, and insulin secretion-sensitivity index (IS-SI) by oral glucose tolerance tests. Free androgen index and lipid levels, average menstrual interval, and anthropometric measurements (body mass index, waist circumference, and waist/height ratio). RESULT(S): The study was completed by 34 patients. Nineteen patients had normal glucose tolerance: 3 of 12 (25%) on MET; 6 of 11 (55%) on SAXA; and 10 of 11 (91%) on SAXA-MET (SAXA-MET statistically superior to MET) at study completion. Body mass index, waist circumference, waist/height ratio, free androgen index, insulin sensitivity, IS-SI, and menses improved in all groups; however, IS-SI and menstrual regularity were significantly better with SAXA-MET vs. MET treatment. Triglyceride, triglyceride/high-density lipoprotein cholesterol ratio and mean blood glucose significantly declined in the SAXA-MET and SAXA groups only. CONCLUSION(S): This pilot work provides the first evidence regarding the effects of a dipeptidyl peptidase-4 inhibitor alone and in combination with MET in this patient population. Treatment with SAXA-MET was superior to either drug alone in terms of clinical and metabolic benefits in prediabetic patients with PCOS. CLINICAL TRIAL REGISTRATION NUMBER: NCT02022007.

Prepregnancy obesity and periodontitis among pregnant females with and without gestational diabetes mellitus.

BACKGROUND: This study explored whether there is an association between prepregnancy obesity and periodontitis among pregnant females. METHODS: A retrospective cohort study was conducted by using data from a previous case-control study at Woman's Hospital, Baton Rouge, Louisiana. One hundred fifty-nine pregnant females were recruited at their prenatal care visits. Periodontal status was assessed through dental examinations performed at an average of 31 weeks gestation. Periodontitis was defined as the presence of one or more sites exhibiting probing depth ≥4 mm or clinical attachment level ≥4 mm. A Poisson regression with robust error variance was used to estimate risk ratio (RR) and 95% confidence interval (CI). RESULTS: Prepregnancy obesity was statistically significantly associated with periodontitis during pregnancy, with obese females at 1.7 times higher risk compared with under/normal-weight females (RR = 1.7, 95% CI = 1.2 to 2.3, P <0.01). There is no difference in the association between maternal obesity and periodontitis between females with gestational diabetes mellitus (GDM) and females without GDM. CONCLUSION: There is a positive association between prepregnancy obesity and periodontitis among pregnant females.

Change of periodontal disease status during and after pregnancy.

BACKGROUND: This study explored whether there is any change of periodontal disease status during and after pregnancy. We also examined whether the change is different between females with a history of gestational diabetes mellitus (GDM) and females without GDM during pregnancy. METHODS: A follow-up study was conducted at Woman's Hospital, Baton Rouge, Louisiana. Thirty-nine females who were previously enrolled in a case-control study during pregnancy were followed an average of 22 months postpartum. Periodontal status was assessed through dental examinations performed both during and after pregnancy. Clinical periodontal parameters included bleeding on probing (BOP), mean probing depth (PD), and mean clinical attachment level (CAL). Periodontitis was defined as the presence of ≥1 sites exhibiting PD ≥4 mm or CAL ≥4 mm. We used generalized estimating equation analysis to examine the change of periodontal status. RESULTS: Mean number and percentage of sites with BOP decreased from 10.7 ± 11.6 (mean ± SD) and 6.5% ± 7.0% during pregnancy to 7.1 ± 8.8 and 4.3% ± 5.3% at 22 months postpartum (P <0.05), respectively. Mean levels of PD and CAL decreased from 1.8 ± 0.4 mm and 1.9 ± 0.3 mm to 1.6 ± 0.3 mm and 1.6 ± 0.3 mm (P <0.01), respectively. The prevalence of periodontitis decreased from 66.7% to 33.3% (P <0.01, adjusted risk ratio = 2.1, 95% confidence interval = 1.3 to 3.4). There was no difference in the change of periodontal status between females with GDM and females without GDM during pregnancy. CONCLUSIONS: Pregnancy may be associated with an increased risk of periodontal disease. The association is not different between females with GDM and females without GDM during pregnancy.

Periodontal disease as a potential risk factor for the development of diabetes in women with a prior history of gestational diabetes mellitus.

OBJECTIVE: To examine if periodontal disease is associated with later development of impaired glucose metabolism in women with a recent history of gestational diabetes (GDM). METHODS: Women with (n = 19) and without (n = 20) a history of GDM were prospectively followed at 22 months postpartum. All subjects underwent: a) a 75-gram oral glucose tolerance test (OGTT); and b) an oral examination for measuring periodontal disease. Insulin sensitivity and pancreatic ß-cell secretory capacity derived from fasting (HOMA-IR) and glucose-stimulated measures (SI(OGTT) and IGI/HOMA-IR) were determined. Periodontitis was defined as the presence of any site with a probing depth ≥ 4 mm or a clinical attachment loss ≥ 4 mm. RESULTS: Compared to women without a history of GDM, prior GDM women had significantly higher fasting glucose and insulin concentrations, increased insulin resistance and decreased ß-cell function. Although not statistically significant, prior GDM women had a higher prevalence of periodontal disease (42.1%) than women without a history of GDM (25.0%). Women with periodontal disease showed greater insulin resistance and lower ß-cell function. Women with both prior GDM and periodontal disease had the most impaired glucose metabolism; the insulin secretion-sensitivity index was significantly lower in women with both prior GDM and periodontal disease (208.20 ± 2.60) than in women without prior GDM and periodontal disease (742.93 ± 1.78) (P < 0.05). CONCLUSIONS: Women with prior GDM show reduced insulin sensitivity and inadequate ß-cell secretory function at 22 months postpartum. Periodontal disease may contribute to their impaired glucose metabolism and future risk of developing diabetes.

Periodontal disease is associated with gestational diabetes mellitus: a case-control study.

BACKGROUND: Few studies have specifically examined the relationship between periodontal disease and gestational diabetes mellitus (GDM). The objective of this study was to examine whether maternal periodontal disease is associated with GDM. METHODS: A case-control study was conducted of 53 pregnant women with GDM and 106 pregnant women without GDM at Woman's Hospital, Baton Rouge, Louisiana. The periodontal examinations were performed by a calibrated dentist who was masked to the diabetic status of the pregnant women. Periodontitis was defined as the presence of any site with a probing depth (PD) >or=4 mm or a clinical attachment loss (AL) >or=4 mm. The severity of periodontal disease was measured in quartiles of PD and clinical AL. Univariable analysis and multivariable logistic regression were used to examine the relationships between periodontal disease and GDM. RESULTS: The percentage of periodontitis was 77.4% in women with GDM and 57.5% in women without GDM, with an odds ratio (OR) of 2.5 and a 95% confidence interval (CI) of 1.2 to 5.3. After adjusting for confounding variables of maternal age, parity, race, marital status, education, family income, smoking, alcohol consumption, systemic antibiotics during pregnancy, family history of diabetes, income, dental insurance coverage, and body mass index, the adjusted OR (95% CI) was 2.6 (1.1 to 6.1). The adjusted ORs (95% CIs) of GDM comparing the highest-to-lowest quartiles of PD and clinical AL were 3.8 (1.0 to 14.0) and 4.5 (1.2 to 16.9). CONCLUSION: This study supports the hypothesis of an association between periodontal disease and GDM.

Improved glycemic control and reduction of cardiometabolic risk factors in subjects with type 2 diabetes and metabolic syndrome treated with exenatide in a clinical practice setting.

BACKGROUND: Type 2 diabetes mellitus (T2DM) with the presence of metabolic syndrome (MetS) carries increased risk for cardiovascular disease. Adjunctive exenatide treatment in patients with T2DM is associated with improvements in glycemic control coupled with progressive weight reduction. We evaluated exenatide use on glycosylated hemoglobin A1c (HbA(1c)) and cardiometabolic risk factors in patients with T2DM and MetS in a single clinical practice setting. METHODS: A retrospective analysis of clinical data extracted from the records of 176 adult patients with T2DM and MetS (106 women, 70 men) who received exenatide along with existing therapeutic regimes from 2005 to 2007 was performed. HbA(1c), lipid profiles, blood pressure, and anthropometric measures were evaluated at baseline and after 16 (+/-4) weeks of exenatide therapy. RESULTS: Mean HbA(1c) was significantly reduced from baseline in 16 weeks (P < 0.001), with 68% of patients achieving HbA(1c) <7%. Total, high-density lipoprotein-, and low-density lipoprotein-cholesterol levels decreased significantly. This decline was not attributable to changes in lipid-lowering agents. Significant reductions were also noted in body mass index, mean body weight, and abdominal girth (AG) with the addition of exenatide. Additional analyses showed 76% of subjects lost weight. Lessening of AG was much more pronounced in female compared with male subjects with diabetes (P < 0.032). No consistent changes in blood pressure were observed. CONCLUSIONS: We found that addition of exenatide to an existing treatment regimen in patients with T2DM and MetS resulted in significant reductions in HbA(1c) along with decline in lipids, AG, and body weight. This indicates improvement in these patients' metabolic profiles.

Exenatide use in the management of metabolic syndrome: a retrospective database study.

OBJECTIVE: To evaluate the effect of exenatide therapy on cardiometabolic risk factors and anthropometric parameters in patients with metabolic syndrome. METHODS: From June 2005 to June 2007, we performed a retrospective analysis of data extracted from the records of adult patients with metabolic syndrome being treated with exenatide. Diagnosis of any type of diabetes mellitus was exclusionary. Patients were initiated on exenatide therapy, 5 mcg, 1 hour before their morning and evening meals for the first month and were instructed to titrate up to 10 mcg. Cardiometabolic risk factors (total cholesterol, high-density lipoprotein cholesterol, triglycerides, calculated low-density lipoprotein cholesterol, and blood pressure) and anthropometric parameters (absolute body weight, body mass index, and abdominal girth) were measured at baseline and at 16 +/- 4 weeks after initiating exenatide therapy. Data collected also included age, sex, metabolic syndrome diagnosis, and other concomitant medication used in the management of endocrine disorders. RESULTS: The study population consisted of 299 patients (259 women, 40 men) with an age range of 18 to 74 years. Exenatide treatment was associated with significant reductions in mean body weight (P<.001) and body mass index (P<.001). Weight loss in 76.6% of patients was concomitant with a significant reduction in mean abdominal girth (P<.001). Further analysis revealed significant decreases in mean triglycerides (P<.001), total cholesterol (P<.01), and both systolic (P<.01) and diastolic blood pressure (P<.03). Approximately 60.2% of patients used metformin concomitantly, and half either decreased or discontinued metformin therapy. CONCLUSIONS: This is the first report examining the effect of exenatide on patients with metabolic syndrome. We observed a significant improvement in cardiometabolic risk factors and anthropometric parameters as a result of exenatide over the treatment interval.

The predictive value for in vitro fertility delivery rates is greatly impacted by the method used to select the threshold between normal and elevated basal follicle-stimulating hormone.

OBJECTIVE: To evaluate the predictive accuracy of different methodologies for selecting a basal FSH threshold level that prognosticates live birth after IVF. DESIGN: Retrospective. SETTING: Academic private practice. PATIENT(S): Eight thousand nineteen patients who had their basal FSH levels determined by the program's endocrinology laboratory. INTERVENTION(S): Thresholds between normal and elevated basal FSH levels were calculated by using six different methodologies. MAIN OUTCOME MEASURE(S): Live birth rate per initiated IVF cycle. RESULT(S): The thresholds selected by using the manufacturer's normal range or using 95% confidence intervals of a fertile population, the infertile population, or distinct age groups within the infertile population all proved unsatisfactory. The live birth rates for patients in whom there had been a previously elevated FSH level were

Contraceptive vaginal ring use for women has less adverse metabolic effects than an oral contraceptive.

BACKGROUND: This study compared metabolic, hormonal and lipid profiles before and during use of a contraceptive vaginal ring (RING) releasing 15 mcg ethinyl estradiol (EE) and 120 mcg etonogestrel per day NuvaRing, Organon USA Inc., Roseland, NJ versus a low-dose oral contraceptive (PILL) containing 20 mcg EE and 100 mcg levonorgestrel daily (Aviane, Barr Pharmaceuticals Inc., Pomona, NY). STUDY DESIGN: Sixty-five women were randomized to either the RING or PILL treatment for five cycles. In the pretreatment cycle (Cycle Days 2-5) and during Weeks 2 and 3 of the fifth treatment cycle, a 75-g oral glucose tolerance test (OGTT) was performed. Baseline samples were used to evaluate basal hormonal, metabolic and lipid levels. RESULTS: Forty-two women completed the study. Basal insulin resistance (HOMA-IR) was slightly decreased, whereas a significant reduction in the insulin sensitivity index (IS(OGTT)) was found in women on PILL therapy compared to those in the RING group (p<.035). Pancreatic beta-cell function was not significantly altered with either treatment. CONCLUSION: The lower-dose, nonoral hormonal RING had a lesser impact on carbohydrate metabolism and greater reduction of free androgen and dehydroepiandrosterone sulfate levels than PILL treatment.

Thiazolidinediones for the therapeutic management of polycystic ovary syndrome : impact on metabolic and reproductive abnormalities.

Polycystic ovary syndrome (PCOS) is a diagnosis made between late adolescence and the menopause in 5-10% of women. PCOS is a heterogeneous disorder of unknown etiology characterized by hyperandrogenic chronic anovulation. This syndrome consists of a diverse constellation of signs and symptoms, such as hirsutism, acne, acanthosis nigricans, obesity, menstrual irregularities, anovulation, and/or infertility. Features of the metabolic syndrome, including obesity, insulin resistance, and dyslipidemia, are common in this patient population. Recent insights into the pathophysiology of PCOS have shown insulin resistance and hyperinsulinemia to play a substantial role. Insulin resistance is increasingly recognized as a chronic, low-level, inflammatory state. Recent studies show that serum levels of inflammatory mediators, such as tumor necrosis factor-alpha and interleukin-6, are increased in the insulin-resistant conditions of obesity and PCOS. The optimal modality for long-term treatment should have positive effects on androgen synthesis, sex hormone-binding globulin production, the lipid profile, insulin sensitivity, inflammatory mediators, and clinical symptoms including acne, hirsutism, and irregular menstrual cycles. Treatment with insulin-sensitizing agents is a relatively new therapeutic strategy in women with PCOS. Current research has shown that the use of diabetes mellitus management practices aimed at reducing insulin resistance and hyperinsulinemia (such as weight reduction and the administration of oral antidiabetic drugs) can not only reverse testosterone and luteinizing hormone abnormalities and restore menstrual cycles, but can also improve glucose, insulin, proinflammatory cytokine, and lipid profiles.Clinical treatment with troglitazone, a member of the thiazolidinedione family, for the management of PCOS complications such as insulin resistance, hyperandrogenism, and anovulation was found to have beneficial effects; however, it was taken off the market over concerns of hepatotoxicity. Although troglitazone is no longer available in the US, numerous clinical trials have established the role of thiazolidinediones in the treatment of women with PCOS. Clinical data emerging regarding the utility of two of the newer, safer thiazolidinediones, pioglitazone and rosiglitazone, for this patient population, consistently demonstrate effective improvements of endocrine and ovulatory performance in women with PCOS. The benefit and importance of lifestyle modification and weight reduction, when it can be achieved, is still an important component in the long-term treatment of PCOS. Pharmacologic reduction in insulin levels using thiazolidinediones appears to offer another therapeutic modality for PCOS, which may ameliorate the progress of both hyperinsulinemia and hyperandrogenism. However, additional studies of patients so treated are necessary before these agents can be considered first-line treatment for PCOS. Convincing data from randomized controlled trials with sufficient power to detect both the benefits and risks of long-term treatment with thiazolidinediones in women with PCOS remain to be obtained.

Conception rates in clomiphene citrate cycles with and without hormone supplementation: a pilot study.

OBJECTIVE: A trial was conducted to examine the effects of a timed sequence of hormone supplementation (HS) with oral estradiol (E(2)) and vaginal progesterone (P) following clomiphene citrate (CC) therapy to determine if this regimen can increase pregnancy rates in CC cycles. METHODS: This study was a randomized, open-label study. Seventy-one oligo-ovulatory women were randomized into one of two groups; those who received CC plus HS (n = 34) and those who received no HS (n = 37). All subjects received 100 mg CC orally from cycle days 3 to 7. Subjects randomized to HS started oral E(2) at a dose of 1.5 mg BID on cycle day 8. All subjects monitored urine luteinizing hormone (LH) levels starting on cycle day 10; additionally, intercourse was encouraged starting on cycle day 10. Subjects receiving HS discontinued E(2) with LH surge and started using vaginal progesterone gel (Prochieve 8%) daily for 2 weeks starting 3 days after LH surge. All subjects had a pregnancy test (Assure) 2 weeks after LH surge. If pregnancy occurred, the subject continued using vaginal progesterone gel daily for an additional 10 weeks. RESULTS: Sixty-five (65) subjects (31 CC plus HS and 34 no HS) completed the study. Fifty of the 65 subjects (77%) (23 [74%] CC plus HS, 27 [79%] no HS) who completed the study ovulated. The mean (range) progesterone (P) concentration for these 50 subjects was 1662.6 (340 to 5690) ng/dL, and mean and median P levels were slightly higher, but not statistically significant, in the HS group compared with the no HS group. Pregnancy rates were clinically, but not statistically, different between the treatment groups. Of the 50 responders, 12% became pregnant (17% CC plus HS, 7% no HS). CONCLUSION: These findings show a potential supportive effect on pregnancy rates in the CC plus oral estradiol and vaginal progesterone gel group compared to CC alone that needs to be confirmed in a larger study.

Concurrent ganirelix and follitropin beta therapy is an effective and safe regimen for ovulation induction in women with polycystic ovary syndrome.

OBJECTIVE: To evaluate controlled ovarian stimulation cycles using the GnRH antagonist ganirelix in combination with the recombinant FSH, follitropin-beta, in women with polycystic ovary syndrome (PCOS). DESIGN: Prospective, nonrandomized clinical study. SETTING: Hospital-based infertility practice. PATIENT(S): Twenty women with PCOS planning to undergo ovarian stimulation. INTERVENTION(S): Fasting glucose and insulin levels were used to calculate insulin resistance ratios (FG/I). After pretreatment with oral contraceptives, serum LH levels were determined, and 250 microg ganirelix was administered on cycle day 2. Upon suppression of LH, concurrent ganirelix and follitropin-beta therapy (morning ganirelix and evening follitropin-beta) was started and continued until the day of hCG. MAIN OUTCOME MEASURES: Days of stimulation, dose of follitropin-beta, pregnancy, and ongoing pregnancy were compared based on FG/I ratios. RESULTS: One dose of ganirelix effectively suppressed LH levels in all patients. All patients ovulated as documented by a rise in progesterone. Significant differences were observed between the insulin-resistant and non-insulin-resistant groups for both days of stimulation and dose of follitropin-beta. The overall clinical pregnancy rate was 44.4%, with an ongoing pregnancy rate of 27.8%. CONCLUSIONS: In this preliminary study, we demonstrate the effectiveness of a concurrent ganirelix and follitropin-beta therapy for ovarian stimulation in women with PCOS.

Sequential hormonal supplementation with vaginal estradiol and progesterone gel corrects the effect of clomiphene on the endometrium in oligo-ovulatory women.

BACKGROUND: We investigated the possibility of correcting the endometrial alterations induced with clomiphene citrate (CC) by vaginal hormonal supplementation (HS) with estradiol (E2) and progesterone gel. METHODS: Oligo-ovulatory women were prospectively randomized into four groups receiving either 50 mg (groups 1 and 2) or 100 mg (groups 3 and 4) of CC from cycle day 3-8. Groups 2 and 4 also received vaginal E2 cream 0.1 mg twice daily from day 8 until the LH surge and vaginal progesterone gel, starting 3 days after ovulation. All participants had an endometrial biopsy performed 10 +/- 1 days after ovulation. RESULTS: All biopsies in the HS groups (2 and 4) showed complete predecidual changes, and were 'in-phase' with findings normally made 10 days post-ovulation (+/- 2 days of clinical dating). However, without HS (groups 1 and 3), only 4/6 and 3/6 biopsies showed predecidual changes in women receiving 50 and 100 mg of CC. CONCLUSION: The addition of vaginal E2 and progesterone to CC ovulation induction regimens normalizes the alterations in endometrial morphology. Hormonal treatment combining vaginal E2 and progesterone may improve endometrial receptivity in CC cycles and ultimately yield higher pregnancy rates.