Metabolic Effects of a Commonly Used Combined Hormonal Oral Contraceptive in Women With and Without Polycystic Ovary Syndrome.

BACKGROUND: Data on combined hormonal oral contraceptives' (OCs) effects on metabolic changes in women with polycystic ovary syndrome (PCOS) have been conflicting and were predominantly based on OCs with cyproterone acetate (unavailable in the United States) Most studies did not include normal women as controls. We compared metabolic changes before and after an OC commonly used in the United States between women with and without PCOS. METHODS: Ten PCOS and 20 control women took ethinyl estradiol 35 µg and norgestimate 0.18/0.215/0.25 mg. Fasting glucose and insulin, area-under-the-curve (AUC) glucose and insulin, insulin sensitivity (homeostatic model assessment of insulin sensitivity index [HOMA-ISI] and Matsuda index), insulinogenic index (Δinsulin0-30 minutes/Δglucose0-30 minutes), blood pressure, and lipids were evaluated at baseline and after three cycles of OC. RESULTS: At baseline, PCOS women had lower insulin sensitivity (Matsuda index p = 0.0093, HOMA-ISI p = 0.0397), higher fasting insulin (p = 0.0495), fasting glucose (p = 0.0393), AUC insulin (p = 0.0023), and triglycerides (p = 0.0044) versus controls. Baseline AUC glucose did not differ between PCOS women and controls. After 3 months of OC use, glucose tolerance worsened in PCOS women versus controls (p = 0.0468). Higher baseline androgens were predictive of worsened glucose tolerance, and a reduction of AUC insulin during OC use. The insulinogenic index significantly decreased in PCOS women (p < 0.01), while fasting insulin and insulin resistance significantly worsened in control women. CONCLUSION: Women with PCOS exhibited worsened glucose tolerance (demonstrated by AUC glucose) after 3 months of a commonly used OC compared with control women. Larger studies with longer follow-up should confirm these findings.

Effect of Renin-Angiotensin system inhibition on cardiovascular events in older hypertensive patients with metabolic syndrome.

OBJECTIVE: Metabolic syndrome (MetS) is associated with cardiovascular disease (CVD). Insulin resistance has been hypothesized as the underlying feature of MetS. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are widely used antihypertensives that may improve insulin sensitivity. The aim of the study is to evaluate the effect of ACEI/ARB on incident CVD events in older hypertensive patients with MetS. MATERIALS/METHODS: We used the Cardiovascular Health Study, a prospective cohort study of individuals>65years of age to evaluate ACEI/ARB use and time to CVD events (including coronary and cerebrovascular events). The study included 777 subjects who had hypertension and ATP III-defined MetS, but free of CVD and diabetes at baseline. Cox regression models were used to evaluate the effect of ACEI/ARB as compared to other antihypertensives on the time to the first CVD events. RESULTS: ACEI/ARB use was associated with a decreased risk of CVD events (adjusted HR=0.658, 95 % C.I. [0.436-0.993]) compared to other antihypertensives. When CVD endpoints were evaluated separately, use of ACEI/ARB was associated with lower rates of angioplasty and coronary events (HR of 0.129 and 0.530 respectively, with 95 % CI [0.017-0.952] and [0.321-0.875]). CONCLUSIONS: ACEI/ARB use was associated with a lower risk of CVD events in older hypertensive patients with MetS, primarily due to a reduction in coronary events. The potential protective effect of ACEI/ARB on CVD events in older individuals with MetS will need further confirmation from prospective studies.

Effect of combined metformin and oral contraceptive therapy on metabolic factors and endothelial function in overweight and obese women with polycystic ovary syndrome.

In this randomized, double-blind, placebo-controlled study, 19 overweight women with polycystic ovary syndrome were randomized to a 3-month course of either metformin plus combined hormonal oral contraceptive (OC) (n = 9) or OC plus matched placebo (n = 10). After 3 months, both treatments had similar effects on androgen levels, lipid profile, insulin sensitivity, and serum inflammatory markers, but flow-mediated dilatation increased by 69.0% in the metformin plus OC group while it remained unchanged in the OC group. CLINICAL TRIAL REGISTRATION NO: NCT00682890.

Divergent effects of a combined hormonal oral contraceptive on insulin sensitivity in lean versus obese women.

OBJECTIVE: To evaluate the effects of a commonly used combined hormonal oral contraceptive (OC) on carbohydrate metabolism in obese as compared with lean women. DESIGN: 6-month prospective study. SETTING: Clinical research center at an academic medical center. PATIENT(S): Premenopausal nondiabetic women with body mass index <25 kg/m(2) (n = 15) or >30 kg/m(2) (n = 14). INTERVENTION(S): Ethinyl estradiol (35 µg) and norgestimate (0.18/0.215/0.25 mg) for 6 cycles. MAIN OUTCOME MEASURE(S): Insulin sensitivity by frequent sampling intravenous glucose tolerance test; other indices of insulin sensitivity (homeostatic model assessment of insulin sensitivity index [ISI HOMA], the Matsuda index); fasting lipid panel. RESULT(S): Insulin sensitivity changed from 6.62 ± 3.69 min(-1)/mIU/L (baseline) to 8.23 ± 3.30 min(-1)/mIU/L (6 months) in lean women, and from 4.36 ± 2.32 to 3.82 ± 2.32 min(-1)/mIU/L in obese women. Divergent effects on insulin sensitivity were also observed with ISI HOMA and the Matsuda index. Low-density lipoprotein increased by approximately 20 mg/dL in both the lean and obese groups. CONCLUSION(S): Lean and obese women exhibit differential changes in insulin sensitivity when given 6 months of a commonly used oral contraceptive. The mechanisms of these differences and whether these divergent effects persist in the long term require further investigation.

Long-term effect of metformin on metabolic parameters in the polycystic ovary syndrome.

Insulin resistance is a central feature of the PCOS and may increase cardiovascular risk. Owing to insulin resistance, the metabolic syndrome is more prevalent in women with PCOS compared with unaffected women. Metformin improves the metabolic profile in PCOS in short-term studies. In this study, we evaluated the long-term effect of metformin on metabolic parameters in women with PCOS during routine care without a controlled diet.We performed a retrospective medical chart review of 70 women with PCOS receiving metformin from an academic endocrine clinic. Metabolic risk factors were compared before and after metformin treatment. Time trends of these metabolic parameters were also analysed. After a mean follow-up of 36.1 months with metformin treatment, improvements were observed for BMI (-1.09 +/- 3.48 kg/m2, p = 0.0117), diastolic blood pressure (-2.69 +/- 10.35 mmHg, p = 0.0378), and HDL cholesterol (+5.82 +/- 11.02 mg/dL, p <0.0001).The prevalence of metabolic syndrome decreased from 34.3% at baseline to 21.4% (p = 0.0495). The course of BMI reduction during metformin treatment was significantly more pronounced in women with PCOS with metabolic syndrome at baseline, compared with those without the metabolic syndrome (p = 0.0369 for interaction). In conclusion, metformin improved the metabolic profile of women with PCOS over 36.1 months, particularly in HDL cholesterol, diastolic blood pressure and BMI.

Insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator correlates with insulin sensitivity in women with polycystic ovary syndrome.

Some actions of insulin are mediated by inositolphosphoglycan (IPG) mediators. Deficient release of a putative D-chiro-inositol-containing (DCI) IPG mediator may contribute to insulin resistance in women with polycystic ovary syndrome (PCOS). Previously, we demonstrated that oral DCI supplementation improved ovulation and metabolic parameters in women with PCOS. However, whether oral DCI mediates an increase in the release of the DCI-IPG mediator and an improvement in insulin sensitivity in women with PCOS is unknown. We conducted a randomized controlled trial of DCI supplementation vs placebo in 11 women with PCOS who were assessed at 2 time points 6 weeks apart. Plasma DCI, DCI-IPG release during oral glucose tolerance test (AUC(DCI-IPG)), and insulin sensitivity (S(i)) by frequently sampled intravenous glucose tolerance test were assessed at baseline and end of study. The study was terminated early because of a sudden unavailability of the study drug. However, in all subjects without regard to treatment assignment, there was a positive correlation between the change in AUC(DCI-IPG)/AUC(insulin) ratio and the change in S(i) during the 6-week period (r = 0.69, P = .02), which remained significant after adjustment for body mass index (P = .022) and after further adjustment for body mass index and treatment allocation (P = .0261). This suggests that, in women with PCOS, increased glucose-stimulated DCI-IPG release is significantly correlated with improved insulin sensitivity. The significant relationship between DCI-IPG release and insulin sensitivity suggests that the DCI-IPG mediator may be a target for therapeutic interventions in PCOS.

Glucose intolerance in polycystic ovary syndrome--a position statement of the Androgen Excess Society.

OBJECTIVES: Women with polycystic ovarian syndrome (PCOS) are at increased risk for developing glucose intolerance and type 2 diabetes mellitus (DM). Recommendations for the timing and method of screening have varied. The purpose of this statement is to determine the optimal screening method, timing of screening, and treatment modalities for impaired glucose tolerance (IGT) among women with PCOS. PARTICIPANTS: The expert panel was appointed by the Androgen Excess Society (AES) to review the literature and make recommendations based on the available evidence. Meetings were open, and there was no funding for the panel. EVIDENCE: A systematic review was conducted of the published, peer-reviewed medical literature using MEDLINE to identify studies that addressed the prevalence, risk factors, testing, and treatment for IGT in both adults and adolescents with PCOS. Unpublished data were not considered. CONSENSUS PROCESS: The panel held meetings to review the literature and draft the statement as a committee. The AES board members reviewed and critiqued the manuscript, and changes were made based on their comments. CONCLUSIONS: The panel recommends that all patients with PCOS be screened for IGT with a 2-h oral glucose tolerance test. A few members of the AES board recommend alternatively screening women with PCOS for IGT and type 2 DM using an oral glucose tolerance test only in patients with a body mass index of 30 kg/m2 or greater or in lean patients with additional risk factors. Patients with normal glucose tolerance should be rescreened at least once every 2 yr, or more frequently if additional risk factors are identified. Those with IGT should be screened annually for development of type 2 DM. PCOS patients with IGT should be treated with intensive lifestyle modification and weight loss and considered for treatment with insulin-sensitizing agents.

Effect of macronutrient composition on postprandial peptide YY levels.

BACKGROUND: Peptide YY (PYY) is released from the distal small intestine and colon after meals and reduces appetite by increasing satiety. The amount of PYY released is proportional to calories ingested. Fat ingestion has also been reported to stimulate PYY release. OBJECTIVE: The objective of the study was to determine whether macronutrient composition influences postprandial serum PYY levels by comparing 1 wk of a weight-maintenance low-carbohydrate, high-fat (LCHF) diet with a low-fat, high-carbohydrate (LFHC) diet. METHODS: In this randomized crossover study, 18 obese subjects (14 females, 4 males, mean body mass index 35.6 +/- 2.9 kg/m(2)) were randomly assigned initially to 1 wk of a weight-maintenance LCHF or LFHC diet, after which a test meal of identical composition was given and serum PYY levels were assessed for 2.5 h postprandially. After a 1-wk washout period, subjects were crossed over and retested. RESULTS: After 1 wk, mean postprandial area under the curve PYY after the LCHF test meal was 1.5-fold greater than after the LFHC test meal (P < 0.001). The LCHF diet led to 55% higher levels of postprandial serum PYY levels, compared with the LFHC diet (P = 0.005). CONCLUSIONS: These data show that a LCHF diet stimulates PYY secretion more than a LFHC diet in obese individuals.

The metabolic syndrome in polycystic ovary syndrome.

Approximately one-third to one-half of all women and adolescent girls with polycystic ovary syndrome (PCOS) has the metabolic syndrome, associated with increased risk for cardiovascular disease and type 2 diabetes. Evidence suggests that insulin resistance is the likely link between PCOS and the metabolic syndrome. Early screening for impaired glucose tolerance, even in adolescents, is recommended. Lifestyle modification with increased physical activity and weight reduction remains first-line therapy. Insulin-sensitizing drugs may also ameliorate features of the metabolic syndrome in PCOS but long-term prospective studies are needed to determine the role of these drugs in the prevention of the metabolic syndrome.

Dermatology of androgen-related disorders.

Hyperandrogenism in women can be caused by various conditions, the most prevalent of which is polycystic ovary syndrome. Common dermatologic manifestations of hyperandrogenism include hirsutism, acne, acanthosis nigricans, and androgenic alopecia. Hirsute women often have increased activity of 5 alpha-reductase, the enzyme that converts the androgen testosterone to its active metabolite, in hair follicles. Likewise, androgens affect the formation of acne by increasing sebum production from sebaceous glands in the skin. The diagnosis of polycystic ovary syndrome includes a complete history, physical examination with emphasis on evidence of androgen excess, and appropriate laboratory investigation to exclude other causes of hyperandrogenism. Treatments for the dermatologic conditions of hyperandrogenism include lifestyle modification, oral contraceptives, antiandrogens, and insulin-sensitizing medications.

Metabolic syndrome in women with polycystic ovary syndrome.

The prevalence of the metabolic syndrome in polycystic ovary syndrome (PCOS) is high across all age groups. Dyslipidemia, particularly a decreased high-density lipoprotein cholesterol level, also is common in women with PCOS.

Effects of short-term and long-term metformin treatment on menstrual cyclicity in women with polycystic ovary syndrome.

The purpose of this retrospective study was to compare the frequency of menstrual cyclicity between two groups of patients with polycystic ovary syndrome: women who were followed while on metformin for 3-6 months and those who were followed for >6 months. The results showed that metformin is highly effective in normalizing menstrual cyclicity in women with polycystic ovary syndrome (the overall response rate was 69%, with 88% of responders achieving normal cyclicity), especially with a treatment duration of 6 months or longer (the response rate was 40% higher for women who were treated with metformin for >6 months vs. 3-6 months, 77% vs. 55%).

Evidence for metabolic and reproductive phenotypes in mothers of women with polycystic ovary syndrome.

Dyslipidemia is a feature of polycystic ovary syndrome (PCOS), but its pathogenesis remains controversial. We performed this study of mothers of women with PCOS to test the hypothesis that dyslipidemia is a heritable trait in families of women with PCOS and to investigate the impact of age on reproductive and metabolic phenotypes. Fasting blood was obtained in 215 non-Hispanic white mothers of women with PCOS and 62 control women. The prevalence of metabolic syndrome was compared with that in non-Hispanic white women of comparable age from the National Health and Nutrition Examination Survey III. Mothers had higher total (P < 0.001) and low-density lipoprotein (LDL) cholesterol levels (P = 0.007), whereas high-density lipoprotein and triglyceride levels did not differ compared with control women. The only predictors of LDL levels in mothers were their daughters' LDL levels (r2 = 0.11, P < 0.001) and their own unbound testosterone levels (r2 = 0.04, P = 0.03). The prevalence of metabolic syndrome was increased in obese (body mass index > or = 30 kg/m2) mothers compared with obese non-Hispanic white women from the National Health and Nutrition Examination Survey III (P = 0.04). Thirty-one percent of mothers reported a history of menstrual irregularity. These mothers had higher androgen levels, markers of insulin resistance, and LDL levels than mothers with regular menses. LDL levels are increased in mothers of women with PCOS, suggestive of a heritable trait. A history of menstrual irregularity identifies mothers with features of PCOS. Obese mothers have a very high prevalence of metabolic syndrome. These findings suggest that both the reproductive and metabolic abnormalities persist with age in PCOS.

Association between the current use of low-dose oral contraceptives and cardiovascular arterial disease: a meta-analysis.

CONTEXT: The long-term cardiovascular safety of widely used oral contraceptives (OCs) is still debated, and no meta-analysis assesses the modern use of OCs and the associated cardiovascular risks. OBJECTIVE: We aimed to assess the risk of cardiovascular diseases associated with current use of low-dose combined OCs. DATA SOURCES: All studies published between January 1980 and October 2002 were searched using MEDLINE, BIOSIS, and Scientific Citations. STUDY SELECTION: Original studies were selected independently by two investigators (J.P.B., P.A.E.) based on inclusion criteria: low-dose combined OC (<50 mug of ethinyl-estradiol); more than 10 cases in low-dose users; clear definition of cases; concurrent controls; and control for age. A third investigator (J.E.N.) adjudicated disagreements. From 2715 identified articles, 14 independent studies were included. DATA EXTRACTION: All data were abstracted by one investigator (J.P.B.) in a systematic manner. Classification of OCs and types of exposure were directly abstracted from studies. Current use was defined as use at the time of the event or within 3 months. Only peer-reviewed studies with definition of events as definite or possible, based on prespecified criteria, were included. DATA SYNTHESIS: The summary risk estimates associated with current use of low-dose OCs were 1.84 [95% confidence interval (CI) = 1.38, 2.44] for myocardial infarctions and 2.12 (95% CI = 1.56, 2.86) for ischemic strokes. The overall summary odds ratio for both outcomes was 2.01 (95% CI = 1.63, 2.48). Second generation OCs were associated with a significant increased risk of both myocardial infarction and ischemic stroke events [1.85 (95% CI = 1.03,3.32) and 2.54 (95% CI = 1.96,3.28), respectively]; and third-generation OCs, for ischemic stroke outcome only [2.03 (95% CI = 1.15,3.57)]. CONCLUSIONS: In conclusion, a rigorous meta-analysis of the literature suggests that current use of low-dose OCs significantly increases the risk of both cardiac and vascular arterial events, including a significant risk of vascular arterial complications with third generation OCs.

Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome.

The polycystic ovary syndrome (PCOS) is characterized by insulin resistance with compensatory hyperinsulinemia. Insulin resistance also plays a role in the metabolic syndrome (MBS). We hypothesized that the MBS is prevalent in PCOS and that women with both conditions would present with more hyperandrogenism and menstrual cycle irregularity than women with PCOS only. We conducted a retrospective chart review of all women with PCOS seen over a 3-yr period at an endocrinology clinic. Of the 161 PCOS cases reviewed, 106 met the inclusion criteria. The women were divided into two groups: 1) women with PCOS and the MBS (n = 46); and 2) women with PCOS lacking the MBS (n = 60). Prevalence of the MBS was 43%, nearly 2-fold higher than that reported for age-matched women in the general population. Women with PCOS had persistently higher prevalence rates of the MBS than women in the general population, regardless of matched age and body mass index ranges. Acanthosis nigricans was more frequent in women with PCOS and the MBS. Women with PCOS and the MBS had significantly higher levels of serum free testosterone (P = 0.002) and lower levels of serum SHBG (P = 0.001) than women with PCOS without the MBS. No differences in total testosterone were observed between the groups. We conclude that the MBS and its components are common in women with PCOS, placing them at increased risk for cardiovascular disease. Women with PCOS and the MBS differ from their counterparts lacking the MBS in terms of increased hyperandrogenemia, lower serum SHBG, and higher prevalence of acanthosis nigricans, all features that may reflect more severe insulin resistance.

Reduced serum glycodelin and insulin-like growth factor-binding protein-1 in women with polycystic ovary syndrome during first trimester of pregnancy.

The polycystic ovary syndrome (PCOS) is associated with an increased rate of early pregnancy loss (EPL). Hyperinsulinemia is an independent risk factor for EPL and has been found to decrease levels of glycodelin and IGF binding protein-1 (IGFBP-1), two major endometrial proteins. We hypothesized that serum glycodelin IGFBP-1 concentrations would be reduced in women with PCOS during the first trimester of pregnancy. Fasting serum insulin, glycodelin, and IGFBP-1 were measured, and oral glucose tolerance tests were performed in 72 women with PCOS and 62 normal women. Each woman was seen once and assigned to one of three gestational groups: wk 3-5, 6-8, and 9-11. The insulin sensitivity index during oral glucose tolerance test was lower in women with PCOS compared with normal women throughout the first trimester (P < 0.0001). Both serum glycodelin and IGFBP-1 were markedly lower in women with PCOS (for glycodelin: wk 3-5, P < 0.0001; wk 6-8, P = 0.03; wk 9-11, P = 0.19; and for IGFBP-1: wk 3-5 and 6-8, P < 0.0001; wk 9-11, P = 0.0003). Comparing women with PCOS who experienced EPL with those who did not, serum glycodelin was significantly lower during wk 3-8 (P < 0.02) and serum IGFBP-1 during wk 9-11 (P = 0.003). During the first trimester, serum glycodelin and IGFBP-1 concentrations are markedly decreased in PCOS, implicating endometrial epithelial and stromal dysfunction during periimplantation and early pregnancy as a possible mechanism for EPL in PCOS. These decreases are likely to be secondary to hyperinsulinemia and reduced insulin sensitivity.