炔雌醇对绝经后妇女糖代谢的影响

目的：探讨合成雌激素炔雌醇对绝经后妇女糖代谢的影响。方法：将绝经后妇女１９例随机分为两组，口服炔雌醇（ＥＥ）０．０２５ｍｇ９例为Ａ组，口服ＥＥ０．０５ｍｇ１０例为Ｂ组，共服药３个月。服药前后均进行口服葡萄糖耐量试验和多样本的静脉葡萄糖耐量试验，同时测定血糖、胰岛素和计算曲线下面积（ＡＵＣ）以及胰岛素敏感指数（ＳＩ）。结果：两组均可有效降低空腹血糖、胰岛素水平，明显减少胰岛素ＡＵＣ，提高胰岛素ＳＩ。Ａ组血糖ＡＵＣ无多大变化，Ｂ组血糖ＡＵＣ明显增加。结论：炔雌醇可有效降低绝经后妇女的空腹血糖、胰岛素水平，减弱胰岛素抵抗。０．０５ｍｇＥＥ可损害糖耐量。     

Use of naltrexone in postmenopausal women with exaggerated insulin secretion: a pilot study

OBJECTIVE: To determine the effect of naltrexone (an opiate receptor blocker) on insulin metabolism in postmenopausal women with different insulinemic patterns. DESIGN: Randomized placebo-controlled study. SETTING: Academic research environment. PATIENT(S): Forty-one healthy normoinsulinemic or hyperinsulinemic postmenopausal women. INTERVENTION(S): Oral glucose tolerance test (OGTT) before and after 5 weeks of the opioid antagonist (naltrexone, 50 mg/d orally) or the placebo administration; euglycemic-hyperinsulinemic glucose clamp. MAIN OUTCOME MEASURE(S): Glucose, insulin, and C-peptide plasma levels assessed in fasting condition and during the OGTT. Insulin sensitivity was calculated as total body glucose utilization. RESULT(S): Naltrexone reduced fasting and stimulated insulin response to the glucose load while inducing a significant improvement of the hepatic extraction, only in the hyperinsulinemic patients. No differences were found in the C-peptide pancreatic secretion and in the peripheral insulin sensitivity. No net change in the glycoinsulinemic metabolism was observed in normoinsulinemic patients or in placebo-controlled normoinsulinemic and hyperinsulinemic subjects. CONCLUSION(S): Similar to that reported in premenopausal women, endogenous opioid peptides are involved in the modulation of glycoinsulinemic metabolism in postmenopause. Through a prevalent action on liver insulin metabolism, without any clear improvement of insulin resistance and pancreatic beta-cell function, the chronic administration of naltrexone appears to reduce the hyperinsulinemia in those women with an exaggerated insulin response to the OGTT.     

Effects of oral continuous 17beta-estradiol plus norethisterone acetate replacement therapy on abdominal subcutaneous fat, serum leptin levels and body composition.

AIM: To evaluate the effects of oral continuous 17beta-estradiol plus norethisterone acetate (E2/NETA) replacement therapy on abdominal subcutaneous fat, serum leptin level (SLL) and body composition in postmenopausal women. MATERIALS AND METHODS: A 6-month, prospective, randomized, double-blind and placebo-controlled study was conducted. Forty-three healthy naturally postmenopausal women aged 43-65 years were randomly assigned to receive E2/NETA (2 mg E2 plus 1 mg NETA, n = 22) or placebo (n = 21). Fasting SLL by enzyme-linked immunosorbent assay, subcutaneous abdominal fat thickness (STh) by ultrasound and the anthropometric indices of body weight (BW), body mass index (BMI), waist and hip circumference (WC, HC) and waist-to-hip ratio (WHR) were recorded at the beginning and the end of the study. RESULTS: After 6 months of therapy, BW and SLL increased in the placebo group (p = 0.043 and 0.033, respectively). WC, HC and STh decreased significantly in the E2/NETA group (p = 0.002, 0.006 and 0.000, respectively) and they were also significantly lower in women receiving E2/NETA than in women taking placebo (p = 0.000, 0.034 and 0.000, respectively). At baseline, SLL and STh were positively correlated with all anthropometric indices except WHR. CONCLUSION: Oral continuous combined regimen of E2/NETA significantly reduced central fat accumulation as assessed by WC and STh, and attenuated the increase in SLL. The observed changes in SLL were highly and positively related to changes in STh. The oral continuous combined E2/NETA regimen appears to have protective effects on cardiovascular function and probably on metabolic diseases by its slimming effect upon WC in postmenopausal women.     

Oral dehydroepiandrosterone restores ß-endorphin response to OGTT in early and late postmenopause

ß-endorphin is a neuropeptide involved in several brain functions: its plasma levels are higher in obese women and its release increases after oral glucose tolerance test (OGTT) in normal or obese women. The study included 46 healthy women and evaluated the effect of oral dehydroepiandrosterone [DHEA] (50?mg/day) in early postmenopausal women (50–55 years) both of normal weight (group A, n?=?12, BMI = 22.1?±?0.5) and overweight (group B, n?=?12, BMI = 28.2?±?0.5), and late postmenopausal women (60–65 years) both normal weight (group C, n?=?11, BMI = 22.5?±?0.6) and overweight (group D, n?=?11, BMI = 27.9?±?0.4) undergone OGTT, in order to investigate if DHEA could restore/modify the control of insulin and glucose secretion and ß-endorphin release in response to glucose load. The area under the curve (AUC) of OGTT evaluated plasma levels of different molecules. DHEA, DHEAS, and ß-endorphin plasma levels were lower in baseline conditions in older women than younger women. Considering the AUC of ß-endorphin response to OGTT, all groups showed a progressive significant increase after 3 and also after 6 months of treatment in comparison to baseline and 3 months of treatment.     

Insulin resistance in polycystic ovary syndrome: hyperandrogenemia versus normoandrogenemia.

OBJECTIVE: The goal of this study was to evaluate the insulin resistance and glucose tolerance in hyperandrogenemic and normoandrogenemic groups of patients with polycystic ovary syndrome (PCOS). STUDY DESIGN: In this cross-sectional study, 17 hyperandrogenemic and 14 normoandrogenemic, age and weight-matched non-obese women with PCOS were studied. All patients had clinical hyperandrogenism and chronic anovulation with polycystic ovaries on ultrasound. Insulin resistance and glucose tolerance were determined by measuring insulin and glucose concentrations following a 75 g oral glucose tolerance test (OGTT). Fasting glucose to insulin ratio (FG:I ratio), insulin area under the curve (AUC(insulin)) during OGTT, and homeostasis model assessment for insulin resistance (HOMA-IR) were calculated. RESULTS: Hyperandrogenemic group of patients had fasting hyperinsulinemia, lower FG:I ratio, higher AUC(insulin), and HOMA-IR compared with normoandrogenemic group. The differences between two groups were statistically significant. CONCLUSION: PCOS has variable biochemical features. Hyperandrogenemia associated with insulin resistance differs from normoandrogenemia in this syndrome. Fasting insulin concentrations, FG:I ratio, AUC(insulin), and HOMA-IR are convenient markers for determining insulin resistance in PCOS.     

Adiponectin levels in women with polycystic ovary syndrome and severe insulin resistance

OBJECTIVE: Adiponectin is an adipokine that is decreased in obesity and type 2 diabetes. Women with polycystic ovarian syndrome (PCOS) are obese and are at risk for type 2 diabetes. The objective of the current study was to investigate the relationship of adiponectin to obesity and insulin resistance in women with PCOS and severe insulin resistance. METHODS: Thirty women with PCOS and acanthosis nigricans indicating severe insulin resistance were included in the study. Eleven body mass index (BMI)-matched women with normal ovulatory cycles served as controls. Fasting glucose, insulin, and adiponectin levels were measured, and a standard oral glucose tolerance test (OGTT) with insulin levels was performed. To further investigate the role of insulin sensitivity on adiponectin levels, 10 women with PCOS were treated with 4 mg rosiglitazone daily for 6 months and adiponectin levels were measured before and after treatment. RESULTS: Fasting insulin levels (33.5 +/- 3.8 microU/mL; P <.001) and insulin area under the curve (AUC) during OGTT (536.2 +/- 70.5 microU/mL; P <.01) were higher in women with PCOS, while glucose levels were similar to controls. Adiponectin levels were lower (P <.01) in women with PCOS (5.6 +/- 2.6 microg/mL) compared with controls (8.5 +/- 3.9 microg/mL). There was a significant negative correlation between adiponectin levels and fasting insulin levels (r = -0.40, P = .02), insulin AUC during OGTT (r = -0.47, P = .008), fasting glucose levels (r = -0.45, P = .01), and glucose AUC during OGTT (r = -0.51, P = .003). There was no correlation between BMI and serum adiponectin (r = -0.12, P = .508) in women with PCOS, while there was a negative correlation (r = -0.746, P = .013) in controls. There was a significant (P <.01) increase in adiponectin levels when treated with rosiglitazone, despite unchanged BMI. CONCLUSION: These results indicate that in women with PCOS and severe insulin resistance, insulin sensitivity appears to be the major determinant of adiponectin levels rather than adiposity. Low adiponectin levels may predict women with PCOS who are at high risk for developing type 2 diabetes.     

Naloxone decreases insulin secretion in hyperinsulinemic postmenopausal women and may positively affect hormone replacement therapy

OBJECTIVE: To evaluate the influence of the opioid system on glyco-regulation in postmenopausal women before and after hormone replacement therapy (HRT). DESIGN: Prospective nonrandomized clinical study. SETTING: Academic research environment. PATIENT(S): Twenty-one healthy normo- or hyperinsulinemic postmenopausal women. INTERVENTION(S): Oral glucose tolerance test (OGTT) (saline study), OGTT with IV injection of naloxone (naloxone study), and hyperinsulinemic euglycemic clamp performed before treatment, after 12 weeks of estrogen replacement therapy (ERT), and after 12 additional weeks of estro-progestin combined therapy (i.e., HRT). MAIN OUTCOME MEASURE(S): Glucose, insulin, and c-peptide plasma levels assessed in fasting condition and during the two OGTTs (area under the curve [AUC]). Evaluation of fractional hepatic insulin extraction (FHIE) and peripheral sensitivity to insulin.RESULT(S): At baseline, there is a greater increase of the FHIE and a more significant reduction of the insulin AUC in the hyperinsulinemic patients during the naloxone study compared with the saline study. In these women, ERT enhanced the c-peptide AUC and improved the FHIE; naloxone infusion mainly increased these two parameters. HRT did not induce any further change. CONCLUSION(S): Endogenous opioid peptides are involved in the modulation of carbohydrate metabolism in menopause in hyperinsulinemic patients more than in other patients. The favorable changes of the glyco-insulinemic metabolism induced by HRT may be partially due to the induction of the opioidergic activity.     

Ultra-low-dose continuous combined estradiol and norethisterone acetate: improved bleeding profile in postmenopausal women.

OBJECTIVE: To evaluate the effect of two ultra-low-dose hormone treatments containing estradiol (E2) 0.5 mg and norethisterone acetate (NETA) 0.1 or 0.25 mg on the endometrium and bleeding. METHODS: A prospective, randomized, placebo-controlled trial of 6 months. Local Ethics Committee approval and informed consent were obtained prior to initiation and enrollment. Out of 577 postmenopausal women randomized, 575 took E2/NETA 0.1 (n = 194), or E2/NETA 0.25 (n = 181) or placebo (n = 200). Endometrial bleeding was monitored by daily diary cards and endometrial thickness by transvaginal ultrasound at baseline and on completion. An endometrial biopsy was obtained when indicated clinically. RESULTS: In months 1-6, the amenorrhea rates with E2/NETA 0.1 were 89%, 89%, 86%, 85%, 89% and 89%, respectively and the no-bleeding rates were correspondingly high: 95%, 94%, 93%, 90%, 95% and 95%. The amenorrhea and spotting-only rates were similar with both ultra-low-dose combinations. The withdrawal rates due to bleeding were very low and the same in all three treatment arms (n = 1; 1%). There was a slight increase in the mean endometrial thickness in all three groups, which remained less than 5 mm. CONCLUSIONS: The ultra-low-dose combination of E2/NETA 0.1 or E2/NETA 0.25 resulted in a high incidence of amenorrhea and no bleeding in postmenopausal women, and a corresponding high level of compliance. Overall, there was no significant change in mean endometrial thickness during 6 months of active treatment or placebo.     

Normal secretion of the incretin hormones glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 during gestational diabetes mellitus.

BACKGROUND AND AIM: Gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (DM2) are suggested to be caused by the same metabolic disorder. Defects in gut hormone-dependent regulation of beta-cell function (entero-insular axis) have been proposed to contribute to the pathogenesis of DM2. The aim of study was to evaluate whether an impaired secretion of glucagon-like peptide-1 (GLP-1) and/or glucose-dependent insulinotropic polypeptide (GIP) could play a role in the development of carbohydrate disorders during pregnancy. SUBJECTS AND METHODS: The study group (GDM) consisted of 13 gestational women with diabetes mellitus in whom GDM was diagnosed according to the World Health Organization criteria (75-g oral glucose tolerance test (OGTT)). The control group consisted of 13 pregnant women with normal glucose tolerance (NGT), matched according to age and duration of pregnancy. For all patients, plasma glucose, insulin, GLP-1 and GIP concentrations were evaluated after an OGTT, i.e. at 0, 30, 60, 90 and 120 min after glucose load. RESULTS: Fasting plasma glucose concentrations were similar in both groups, but the 0-120 min area under the curve (AUC) for glucose was significantly greater in the GDM group than in the NGT group (p < 0.0005). Fasting insulin concentration was higher (p < 0.05) and the 2-h insulin response (AUCtotal) was significantly greater (p = 0.01) in the GDM group than in the NGT group. Insulin resistance was significantly higher in GDM compared with control women (homeostasis model assessment, p = 0.003). Fasting GLP-1 concentrations were higher in the GDM group (p = 0.05), but no differences were observed in GLP-1 response (AUC) between the studied groups. Fasting and stimulated GIP response did not differ between groups at any time of the study (p > 0.05). Positive correlations were observed between fasting GLP-1 and insulin concentration (r = 0.56, p < 0.004) and between fasting GLP-1 and insulin resistance (r = 0.43, p < 0.029). CONCLUSION: An impaired secretion of GLP-1 and GIP does not seem to play a major role in the pathogenesis of GDM.     

Neutral effect of ultra-low-dose continuous combined estradiol and norethisterone acetate on mammographic breast density.

OBJECTIVE: To compare the effects of two different ultra-low doses of continuous combined hormone therapy and placebo on mammographic breast density in postmenopausal women. METHODS: A subpopulation of 255 postmenopausal women from the CHOICE trial were randomly assigned to 0.5 mg 17beta-estradiol (E2) + 0.25 mg norethisterone acetate (NETA), 0.5 mg E2 + 0.1 mg NETA, or placebo. Women using hormone replacement therapy (HRT) up to 2 months prior to the study were excluded; 154 women fulfilled the inclusion criteria. Mammograms were performed at baseline and after 6 months. Breast density was evaluated by visual classification scales and a computer-assisted digitized technique. RESULTS: No significant differences were detected between the active treatment groups and the placebo group in the digitized quantification. The mean baseline values for density around 20% were unchanged after 6 months. Also, visual classifications showed no increase in breast density in any study group. CONCLUSION: In contrast to currently available bleed-free regimens, the new ultra-low-dose combination of 0.5 mg E2 and 0.1 mg NETA seems to have very little or even a neutral effect on the breast. Both digitized quantification and visual assessment of breast density were unchanged after 6 months. Larger prospective studies should be performed to confirm this new finding.     

Comparison of various simple insulin sensitivity and beta-cell function indices in lean hyperandrogenemic and normoandrogenemic young hirsute women

OBJECTIVE: To assess and compare various simple insulin sensitivity and beta-cell function indices in lean, hirsute, young women. DESIGN: Prospective study. SETTING: Departments of endocrinology and metabolism at a university and a state hospital. PATIENT(S): Seventy-one hirsute young women were classified as hyperandrogenemic or normoandrogenemic. MAIN OUTCOME MEASURE(S): Insulin sensitivity and beta-cell function indices derived from a single sample and an oral glucose tolerance test (OGTT). RESULT(S): Lean hyperandrogenemic hirsute women have insulin resistance and increased beta-cell function. The most sensitive indices of insulin resistance were total and 1-hour and 2-hour post-challenge insulin levels during OGTT. When a cut-off value of 3.2 or greater for homeostasis model assessment of insulin resistance (HOMA-IR) was accepted, 46% of hyperandrogenemic women and 30% of normoandrogenemic women were insulin resistant. Fasting insulin level was best correlated with the fasting insulin resistance index, HOMA-IR, and Quicky index. The HOMA-IR was best correlated with fasting insulin level and the hepatic insulin sensitivity index (ISI(HOMA)). CONCLUSION(S): Insulin levels based on OGTT are the most useful index of insulin resistance and beta-cell function index in hirsute women. The HOMA-IR may be a proposed global test for insulin resistance; it correlated well with both OGTT-derived insulin resistance and beta-cell function indices and with global insulin resistance indices derived from a single sample (such as ISI (HOMA), Quicky index, FIRI(-1), fasting Belfiore index, and glucose/insulin ratio).     

Evaluation of the effects of various gestagens on insulin sensitivity, using homeostatic model assessment, in postmenopausal women on hormone replacement therapy.

The objective of the present study was to compare the effects of various gestagens on insulin sensitivity in postmenopausal women on hormone replacement therapy (HRT). This prospective study enrolled 156 postmenopausal women who had menopausal status for at least 6 months. Group 1 was treated with 17 beta-estradiol (E2; 2 mg) plus norethisterone acetate (NETA; 1 mg); Group 2 was given E2 (2 mg) plus medroxyprogesterone acetate (MPA; 2.5 mg); Group 3 was given E2 (2 mg) plus dydrogesterone (DG; 10 mg); and Group 4 was given E2 (2 mg) plus micronized progesterone (MP; 100 mg). Group 5 was the surgical menopausal group and was given only E2 (2 mg) continuously. All 156 subjects completed the 3-month follow-up on the trial. The patients were analyzed by using homeostatic model assessment (HOMA) for insulin sensitivity before treatment and 3 months after treatment, comparing the effects of various HRT regimens on insulin sensitivity. No significant differences were found in the baseline characteristics of the patients (p > 0.05). There were no significant differences in mean values of HOMA before HRT among the five groups (p > 0.05). There were statistically significant differences in mean values of HOMA only in Group 1 (E2 + NETA) and Group 3 (E2 + DG) after HRT (p > 0.05). E2 + NETA and E2 + DG were found to improve insulin sensitivity in postmenopausal women after 3 months of treatment, whereas E2 + MPA, E2 + MP and E2 only did not show such an effect in postmenopausal women.     

The effects of estrogen therapy and estrogen combined with different androgenic progestins on carbohydrate and lipid metabolism in overweight–obese younger postmenopausal women

Objective. The aim of the present study was to compare the effect of three different progestins with differing androgenicity on carbohydrate and lipid metabolism in overweight–obese younger postmenopausal women. Additionally, the relationship between testosterone and insulin resistance was assessed.

Methods. The study included 125 postmenopausal women. Estradiol (E₂) 2 mg/day was given to 20 hysterectomized women and the remaining 105 women were randomized into three treatment groups: E₂ 2 mg/day plus dienogest 2 mg/day (n=35); E₂ 2 mg/day plus norethisterone acetate (NETA) 1 mg/day (n=35); E₂ 2 mg/day plus medroxyprogesterone acetate (MPA) 2.5 mg/day (n=35). A 75-g oral glucose tolerance test was performed at the initial and 3-month visit. Serum glucose, insulin, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides were measured before and after treatment.

Results. A significant treatment-related increase was observed only in the E₂/MPA group for insulin resistance (p=0.031). When the change in the insulin/glucose ratio was compared, the E₂ group was significantly different from the E₂/MPA and E₂/NETA groups (p=0.008 and 0.02, respectively). Only the E₂/dienogest group showed a treatment-related increase in fasting glucose level (p=0.037). A decrease in total cholesterol and LDL-C levels was observed in all groups (p=0.004 and 0.012, respectively). The only significant decrease in HDL-C level was observed in the E₂/NETA group (p=0.005).

Conclusion. Estrogen therapy had a positive effect on carbohydrate and lipid metabolism in overweight–obese postmenopausal women. The addition of progestin to estrogen therapy attenuated estrogen's positive effects slightly; however, the biological actions of the three different androgenic progestins used did not result in any variation.     

Low-dose oral combination of 17beta-estradiol and norethisterone acetate in postmenopausal women decreases factor VII, fibrinogen, antithrombin and plasminogen activator inhibitor-1.

OBJECTIVE: Controversies still persist concerning hormone replacement therapy (HRT) and its effects upon blood coagulation and fibrinolysis. This study was carried out to evaluate possible effects of continuously administered low-dose 17beta-estradiol (E2) and norethisterone acetate (NETA) on coagulation and fibrinolytic factors. METHODS: We conducted a randomized double-blind, placebo-controlled, 1-year study in 120 healthy postmenopausal women. The three groups consisted of a placebo group (n = 40), a group receiving oral continuous combined E2 1 mg and NETA 0.25 mg (n = 40) and a group receiving oral continuous combined E2 1 mg and NETA 0.5 mg (n = 40). RESULTS: The two low doses of E2-NETA induced significantly lower plasma levels of factor VII, fibrinogen, antithrombin and plasminogen activator inhibitor-1 (PAI-1), compared with placebo treatmen CONCLUSIONS: Low-dose E2 (1 mg) in combination with NETA resulted in favorable changes of factor VII activity and fibrinogen, compared with placebo. The lower plasma levels of PAI-1 may lead to increased fibrinolytic activity. These findings suggest a decreased risk of developing coronary heart disease. Antithrombin activity was also reduced, which may increase the risk of developing venous thromboembolism. The clinical significance of the lower levels of these factors remains to be clarified.     

Insulin sensitivity during postmenopausal hormone replacement with transdermal estradiol and intrauterine levonorgestrel.

BACKGROUND: The study was devised to measure the effect of intrauterinely delivered levonorgestrel and transdermal estradiol on insulin sensitivity in postmenopausal women and compare this effect with that induced by transdermal estradiol alone. METHODS: An open, prospective, comparative study of healthy postmenopausal women without earlier use of hormone replacement therapy. The estrogen therapy group consisted of eight hysterectomized women, who used a transdermal patch delivering a daily dose of 50 microg of estradiol continuously for 6 months. The estrogen-progestin therapy group consisted of 13 women with an intact uterus, who received a simultaneous combination of a transdermal patch and a levonorgestrel (20 microg/day) intrauterine system for the same length of time. Fasting plasma concentrations of glucose, insulin and C-peptide and an insulin tolerance test were used to measure glucose metabolism and insulin sensitivity. RESULTS: Neither therapy changed the fasting plasma levels of glucose, insulin or C-peptide. Transdermal estrogen improved insulin sensitivity by 22%, as measured by an insulin tolerance test, while a small increase of 3.6% was observed using the combination therapy. CONCLUSIONS: Transdermal estradiol improves insulin sensitivity in healthy postmenopausal women. Combining intrauterine levonorgestrel to transdermal estradiol reverses this effect. This combination does not, however, seem to induce insulin resistance.     

Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity

OBJECTIVE: To determine whether insulin-sensitizing drugs would improve ovulation and T levels in women with polycystic ovary syndrome (PCOS), without clinical or biochemical criteria indicating insulin resistance and whether the combination of two distinct insulin-sensitizing drugs would be of any benefit over either drug alone. DESIGN: Randomized controlled double-blind trial. SETTING: A referral center in Caracas, Venezuela. PATIENT(S): One hundred twenty-eight nonobese PCOS women with normal indices of insulin sensitivity-that is, normal glucose tolerance, fasting insulin, peak insulin during an oral glucose tolerance test (OGTT), and fasting glucose-to-insulin ratio. Twenty-eight women were lost to follow-up initially and did not receive any intervention. INTERVENTION(S): One hundred women received twice daily one of the following for 6 months: metformin (850 mg), rosiglitazone (4 mg), combination of both drugs, or at least one placebo. MAIN OUTCOME MEASURE(S): Frequencies of ovulation and serum free T after 6 months. RESULT(S): Frequencies of ovulation were higher after treatment with an insulin-sensitizing drug (ovulations per subject in 6 months: metformin, 3.3; rosiglitazone, 2.4; and combination, 3.4) than with placebo (0.4). Ovulatory frequencies increased significantly more with metformin than rosiglitazone, and the combination was not more potent. After treatment, serum free-T levels were comparable among all active treatment groups (metformin: 2.34 pg/mL, rosiglitazone: 3.06 pg/mL, and combination: 2.39 pg/mL) and were significantly lower than in the placebo group (7.26 pg/mL). Compared with placebo, fasting insulin levels, area under the insulin curve during OGTT, the homeostatic model assessment of insulin sensitivity, and OGTT-derived insulin sensitivity index improved significantly after metformin or combination therapies but not after rosiglitazone. CONCLUSION(S): These findings suggest that insulin-sensitizing drugs increase ovulatory frequency and ameliorate hyperandrogenemia, even in nonobese women with PCOS who appear to have normal insulin sensitivity.     

Treatment with flutamide improves hyperinsulinemia in women with idiopathic hirsutism.

OBJECTIVE: To investigate insulin metabolism and its modifications induced by the administration of flutamide, a specific antiandrogen compound, in women with idiopathic hirsutism (IH) and in nonobese women with polycystic ovary syndrome (PCOS). DESIGN: Prospective, randomized trial. SETTING: Endocrinological Centre of the Department of Obstetrics and Gynecology, University of Caligari, Caligari, Italy. PATIENT(S): Thirty-two women with normal body mass index participated in the study: 11 with clinical and hormonal features of PCOS and 21 age- and weight-matched normally cycling women with IH (n = 11) and without IH (n = 10, controls). INTERVENTION(S): Each subject with PCOS or IH was assigned randomly to receive either flutamide tablets (250 mg twice a day) or placebo for > or =5 months. Twelve subjects (6 with PCOS, 6 with IH) received flutamide and 10 (5 with PCOS, 5 with IH) received placebo. All subjects ingested 75 g of glucose and then underwent an oral glucose tolerance test (OGTT), 3-7 days after spontaneous or medroxyprogesterone acetate (5 mg daily for 5 days)-induced menses. In women with PCOS or IH, the OGTT was repeated at the fourth month of treatment. MAIN OUTCOME MEASURE(S): Fasting and OGTT-stimulated levels of glucose, insulin, and C peptide. RESULT(S): Both fasting and OGTT-stimulated levels of insulin and C peptide were significantly higher in women with PCOS and in those with IH than in controls. Placebo did not modify parameters of glucose metabolism. Flutamide was capable of significantly blunting fasting and OGTT-stimulated secretion of insulin only in women with IH. CONCLUSION(S): Hyperinsulinemia exists in women with IH as well as in nonobese women with PCOS. Treatment with flutamide can completely reverse hyperinsulinemia only in women with IH, which suggests that the efficacy of the drug is dependent on peripheral androgen hyperactivity.     

Effects of menopausal hormone therapy on hemostatic parameters,blood pressure,and body weight: Open-label comparison of randomized treatment with estradiol plus drospirenone versus estradiol plus norethisterone acetate

Objectives

Clinical studies have reported changes in hemostatic parameters in women taking menopausal hormone therapy (HT) and a small increased risk of venous thromboembolism. We compared the effects of two different HTs on hemostatic parameters in postmenopausal women.

Study design

An open-label, randomized study conducted at two centers in Germany compared continuous 28-week combined HT with 17β-estradiol 1 mg plus drospirenone 2 mg (E2/DRSP) daily versus E2 1 mg plus norethisterone acetate 0.5 mg (E2/NETA) daily in healthy postmenopausal women. Changes in D-dimer levels from baseline to the end of treatment, as well as effects on further parameters of coagulation, fibrinolysis, and global hemostasis, and effects on bleeding pattern, blood pressure, and body weight were evaluated.

Results

D-dimer levels increased by 9.1% (median change) with E2/DRSP (n = 29) and by 15.1% with E2/NETA (n = 30). Other hemostatic parameters showed <10% median change from baseline in both treatment groups, except for tissue plasminogen activator antigen (E2/DRSP, −1.9%; E2/NETA, −24.2%). Systolic blood pressure decreased from baseline by 6.4 mmHg in the E2/DRSP group compared with 0.1 mmHg in the E2/NETA group at final examination. Body weight remained stable in the E2/DRSP group (+0.18 kg) compared with a slight increase (+1.00 kg) in the E2/NETA group. In nonhysterectomized women, the mean number of bleeding/spotting days was 5.2 (2.0 bleeding/3.2 spotting) in the E2/DRSP and 8.2 (4.4 bleeding/3.8 spotting) in the E2/NETA group. Most nonhysterectomized women, however, remained amenorrheic during the study period (E2/DRSP, 68%; E2/NETA, 62%).

Conclusion

Both E2/DRSP and E2/NETA were associated with a minor increase in fibrinolytic activity and a slight change in the concentration of some coagulation factors. Both HTs were well tolerated. The decrease in systolic blood pressure and stable body weight in the E2/DRSP group are consistent with DRSP's anti-aldosterone properties.     

Bleeding profile and endometrial safety of continuous combined regimens 1 mg 17beta-estradiol/trimegestone versus 1 or 2 mg 17beta-estradiol/norethisterone acetate in postmenopausal women.

OBJECTIVE: To compare the bleeding profile and endometrial safety of continuous combined 1 mg 17beta-estradiol (17beta-E2) and 0.125 mg trimegestone (TMG) with those of two continuous combined 17beta-E2 and norethisterone acetate (NETA) regimens. STUDY DESIGN: This was a double-blind, randomized, multicenter study conducted in 12 European countries and Israel over a 2-year period. Healthy postmenopausal women with an intact uterus were given either 1 mg 17beta-E2/0.125 mg TMG, 2 mg 17beta-E2/1 mg NETA or 1 mg 17beta-E2/0.5 mg NETA for up to 26 cycles, each of 28 days. RESULTS: The percentage of amenorrheic women was greater in most cycles up to cycle 13 in the 1 mg 17beta-E2/0.125 mg TMG group than in the comparator groups. The mean number of bleeding days was similar in the 1 mg 17beta-E2/0.125 mg TMG and the 1 mg 17beta-E2/0.5 mg NETA groups, but greater in the 2 mg 17beta-E2/1 mg NETA group. No endometrial hyperplasia was observed for any group. CONCLUSION: Continuous combined 1 mg 17beta-E2/0.125 mg TMG exhibits a more favorable bleeding profile than 1 mg 17beta-E2/0.5 mg NETA up to 1 year, while providing an adequate protective effect on the endometrium.     

Effects of two different regimens of continuous hormone replacement therapy on endometrial histopathology and postmenopausal uterine bleeding

Objective: To compare the effects of frequently used two different regimens of combined continuous hormone replacement therapy; 0.625 mg conjugated equine estrogen (CEE) + 2.5 mg medroxyprogesterone acetate (MPA) and 1 mg 17β estradiol (E2) + 0.5 mg norethindrone acetate (NETA), on endometrial histopathology and postmenopausal uterine bleeding. Materials and methods: Two hundred and forty-six outpatient subjects aged 41–57 years were enrolled in the study conducted at the menopause clinic between November 2003 and November 2004. One hundred and thirty-nine patients were assigned to receive 0.625 mg conjugated equine estrogen + 2.5 mg medroxyprogesterone acetate (CEE/MPA), whereas 107 patients were to receive 17β estradiol + 0.5 mg norethindrone acetate (E2/NETA). Inclusion criteria of the study were: normal values of endometrial thickness at basal evaluation, women with intact uterus, at least 12 months of amenorrhea, normal vaginal smear, bilateral mammography and biochemical blood parameters. All women were questioned every 3 months for vaginal bleeding/spotting. Endometrial sampling was performed by Pipelle catheter in the 12th month of therapy. Results: For the first 3 months, vaginal bleeding/spotting rate for the CEE/MPA group was 38.7%, whereas it was higher (45%) in the E2/NETA group. For the second 3-month period, vaginal bleeding/spotting frequencies were 41.1 and 37.8%, respectively. In the third 3-month period 30.6 and 29.6%, and in the fourth 3-month period, 18.5 and 12.5% of the patients reported vaginal bleeding or spotting. None of the results of endometrial sampling have shown findings of cancer histopathology. Conclusion: Compared to CEE/MPA regimen, E2/NETA therapy has not shown more favorable effects on postmenopausal bleeding abnormalities. Irregular endometrial proliferation was seen more with the E2/NETA regimen.