Hyperinsulinemia in nonobese women reporting a moderate weight gain at the beginning of menopause: a useful early measure of susceptibility to insulin resistance.

OBJECTIVE: At menopause, the frequent weight gain excess could be related to insulin resistance. This study evaluated the prevalence of hyperinsulinemia in nonobese women reporting a moderate increase in weight at the beginning of menopause. METHODS: Women who were postmenopausal for 1 to 5 years and reporting a weight gain of 5 to 15 kg were evaluated for weight, eating habits, physical activity, body circumferences, fasting blood glucose level, insulin level, and lipid profile. An oral glucose tolerance test was performed in subgroups of 21 hyperinsulinemic women and 21 normoinsulinemic women matched for age, weight, height, body mass index, and hysterectomy. RESULTS: Among 279 postmenopausal women reporting a weight gain of 8.7 +/- 4.4 kg, insulin level was increased in 49 (17.6%) women as compared with normoinsulinemic women (108.53 +/- 31.35 vs 58.96 +/- 14.52 pmol/L, respectively; P < 0.001). Differences were also found for glucose (5.24 +/- 0.37 vs 5.05 +/- 0.42 mmol/L, respectively; P = 0.003), insulin resistance as estimated by homeostasis model assessment HOMA-2-IR (2.01 +/- 0.53 vs 1.10 +/- 0.27, respectively; P < 0.001), weight (72.6 +/- 8.0 vs 69.9 +/- 7.1 kg, respectively; P = 0.023), body mass index (28.3 +/- 2.3 vs 27.2 +/- 2.3 kg/m2, respectively; P = 0.003), and waist circumference (89.8 +/- 5.8 vs 86.0 +/- 6.5 cm, respectively; P < 0.001). Triglyceride levels were higher (1.47 +/- 0.66 vs 1.17 +/- 0.61 mmol/L, respectively; P = 0.002) and high-density lipoprotein cholesterol level was lower (1.54 +/- 0.35 vs 1.72 +/- 0.42 mmol/L, respectively; P = 0.007) in the hyperinsulinemic and normoinsulinemic groups. Although insulin levels were higher in 21 hyperinsulinemic women at all times that oral glucose tolerance tests were performed, levels of glucose were also above those of 21 matched normoinsulinemic women at 1 and 2 hours and remained greater than 6.0 mmol/L at 2 hours. CONCLUSIONS: Because insulin resistance is frequently associated with weight gain in nonobese women at menopause, the measurement of fasting insulin, along with glucose, lipids, and waist circumference, may help to identify those who are at higher risk of developing glucose intolerance, metabolic syndrome, diabetes, and cardiovascular diseases and to implement early preventive measures.

Flaxseed on cardiovascular disease markers in healthy menopausal women: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Due to its high content of lignans, alpha-linolenic acid and fiber, flaxseed may reduce cardiovascular disease risk in humans. The present study evaluated the effect of flaxseed on markers of cardiovascular disease risk in healthy menopausal women. METHODS: One hundred ninety-nine women were randomly assigned to consume 40 g daily of flaxseed or wheat germ placebo for 12 mo. Fatty acids, apolipoproteins A-1 and B, lipoprotein(a), low-density lipoprotein particle size, fibrinogen, C-reactive protein, insulin, and glucose were measured at baseline and at 12 mo. RESULTS: In total 179 women were available for the intention-to-treat analysis. Flaxseed increased plasma alpha-linolenic (P < 0.0001), docosapentaenoic (P = 0.001), and total omega-3 fatty (P = 0.0004) acids. Differences between flaxseed and wheat germ were observed for apolipoprotein A-1 (-0.10 +/- 0.26 g/L, P = 0.011) and apolipoprotein B (-0.05 +/- 0.16 g/L, P = 0.047). From baseline, flaxseed raised apolipoproteins A-1 and B by 4.4% (P = 0.006) and 3% (P = 0.054), whereas wheat germ increased these apolipoproteins by 11.6% (P < 0.0001) and 7% (P = 0.0001), respectively. Both treatments increased lipoprotein(a) (P < 0.0001) and decreased low-density lipoprotein peak particle size (P < 0.0001). CONCLUSION: In this large, long-term, placebo-controlled trial in healthy menopausal women, flaxseed increased some omega-3 fatty acids in plasma and had a limited effect on apolipoprotein metabolism.

Imbalance in the peritoneal levels of interleukin 1 and its decoy inhibitory receptor type II in endometriosis women with infertility and pelvic pain.

OBJECTIVE: To evaluate the levels of interleukin-1beta (IL1beta) and its inhibitory soluble interleukin-1 receptor type II (IL1R2) in the peritoneal fluid (PF) of normal women and patients with endometriosis suffering from pelvic pain and infertility. DESIGN: Retrospective study using ELISA to measure peritoneal fluid IL1beta and soluble IL1R2. SETTING: Gynecology clinic and human reproduction research laboratory. PATIENT(S): Sixty-eight normal women and 154 women with endometriosis. INTERVENTION(S): Peritoneal fluid samples were obtained at laparoscopy. MAIN OUTCOME MEASURE(S): IL1beta and soluble IL1R2 concentrations in the PF samples. RESULT(S): This study showed a marked decrease in peritoneal soluble IL1R2 levels in women with endometriosis compared to normal women and a concomitant increase in the levels of IL1beta. Both fertile and infertile women with endometriosis had lower soluble IL1R2 and higher IL1beta concentrations than fertile women having a normal gynecological status, but the difference was more significant in infertile endometriosis patients. Compared with normal controls, the decrease in soluble IL1R2 levels was less significant in women with endometriosis than without pelvic pain, whereas the increase in IL1beta concentrations was statistically significant only in women with endometriosis reporting pelvic pain. CONCLUSION(S): This study revealed an imbalance between IL1beta and its decoy inhibitory receptor type 2 in women with endometriosis, which was particularly obvious in those who were infertile, and suggests that a defect in the local control of IL1 may be involved in the pathophysiology of endometriosis and related infertility.

An indirect quantitative method for the assessment of angiogenesis in human tissues.

We set up an ELISA that measures the concentration of von Willebrand factor (vWF) in human endometrial tissue and found a significant correlation with the mean vessel counts in vWF- and CD31-immunostained tissue sections. This ELISA allows an objective and quantitative evaluation of the vascular state in the endometrium and could be used as a method to evaluate the angiogenic state in other tissues.

Estradiol and interleukin-1beta exert a synergistic stimulatory effect on the expression of the chemokine regulated upon activation, normal T cell expressed, and secreted in endometriotic cells.

Endometriosis, commonly associated with intraperitoneal inflammation, is estrogen dependent. Possible links between the immunoinflammatory and endocrine changes observed in endometriotic women have been poorly understood. In this study, we report that estradiol (E(2)) and IL-1beta exert a synergistic stimulatory action on RANTES (regulated upon activation, normal T cell expressed, and secreted) expression by endometriotic cells. Treatment of endometriotic cells with IL-1beta had a dose-dependent effect on RANTES protein secretion and mRNA steady state levels, whereas cell treatment with E(2) or progesterone had no detectable effect. Interestingly, treatment of endometriotic cells with E(2) before stimulation with IL-1beta resulted in a further increase in RANTES protein secretion and mRNA steady state levels, compared with IL-1beta alone, whereas treatment with progesterone did not significantly affect cell responsiveness to IL-1beta. Assessment of RANTES mRNA half-life revealed that cell pretreatment with E(2) enhanced RANTES mRNA stability and increased gene transcription as shown by run-on analysis. Immunohistochemical analysis of RANTES in endometriotic tissue showed immunostaining to be predominant in the stroma with no noticeable differences in tissues from the proliferative and secretory phase of the menstrual cycle. This appears to be consistent with the cell culture data and indicates that RANTES expression in endometriotic tissue is not subject to cyclic variation. These findings reveal a new regulatory mechanism by which IL-1beta produced by activated macrophages can in synergy with ovarian and locally produced E(2) lead to enhanced macrophage and T-lymphocyte recruitment, thereby exacerbating the local immunoinflammatory process. Furthermore, the findings provide a further evidence for a close relationship between the endocrine and immunological changes observed in endometriosis.

The SOGC statement on the WHI report on estrogen and progestin use in postmenopausal women.

The recent Women's Health Initiative study report evaluated the long-term benefits and risks of hormone replacement therapy among healthy postmenopausal women. The report showed that the risk-benefit profile of continuous combined hormone replacement therapy was not consistent with the primary prevention of coronary heart disease. The Women's Health Initiative study of continuous combined hormone replacement therapy is a landmark study and the results provide valuable information for patients and clinicians. However, the most common indication for hormone replacement therapy is menopausal symptoms, for which it is effective, not prevention of disease, and the most common use is for less than three years. Nevertheless, even short-term use has small effects on some outcomes. This statement discusses how the findings of the Women's Health Initiative study can be applied to reach appropriate clinical decisions.

The relevance of the Women's Health Initiative results on combined hormone replacement therapy in clinical practice.

The results of the Women's Health Initiative's (WHI) large prospective randomized controlled study on the benefits and risks of combined hormone replacement therapy (HRT) have been reported earlier than expected, due to the findings of a small excess in cases of breast cancer, myocardial infarction, cerebrovascular accident, and venous thrombosis, in conjunction with a slight diminution of the number of cases of bone fracture and colon cancer. These results were obtained in a population of women with a mean age of 63 +/- 7 years, many of whom were already presenting relative risks of diseases at randomization. The results provide the best evidence available at present on HRT for prevention of heart disease, and indicate that combined HRT is not indicated for this purpose in the studied population, thus contradicting the reported beneficial effects of HRT on coronary heart disease (CHD) in previous observational studies. Some comments need to be made, particularly with regard to the relevance of the WHI study results to the traditional use of HRT at the beginning of menopause. The results, obtained from a population having a wide age range (50 to 79 years), with only 33% being between the ages of 50 and 59, taking 0.625 mg/day conjugated equine estrogens combined with 2.5 mg/day medroxyprogesterone acetate or placebo, are presented without stratification according to the various decades. Further, 73.9% of the women never took HRT before entering the study; rather, they began HRT several years after menopause. Thus, the age distribution and late start of HRT in the women in the WHI study do not correspond to the traditional use of HRT. The studied population presented numerous risks of diseases related to aging, in particular cardiovascular disease. Except for venous thrombosis, the confidence intervals for outcomes are near the limit of statistical significance, which disappears after adjustment. The accrual of breast cancer cases appearing during the fourth year of observation is similar to that found in previous studies, and remains inferior to the increases related to lifestyle factors reported in other studies. The overall results are being applied to women aged 50 to 60 without specific data for this age group, who are usually considered to be at no or low risk for the traditional use of HRT. There are no data to compare the various formulations actually approved as class labelling (estrogens or estradiol associated or not with a progestin or natural progesterone by the oral or transdermal route) in the various outcomes of the WHI study. Results of the ongoing WHI study on estrogen alone will have to be considered when they become available. The results of the WHI study do not put into question the validity of prescribing combined HRT in early menopause. They are likely to modify somewhat the recommendations of published consensus cautioning the use of HRT. HRT remains an effective and safe intervention when it is prescribed to palliate the signs and symptoms related to estrogen deficiency, mainly in women soon after menopause, but also in women presenting risk factors for osteoporosis but without actual risk factors of cardiovascular disease and without a family history of breast cancer. New mid-term and long-term randomized studies need to be conducted on women starting various formulations of HRT before the age of 60, to evaluate their impact on risk factors and events of cardiovascular disease.

Flaxseed dietary supplement versus hormone replacement therapy in hypercholesterolemic menopausal women.

OBJECTIVE: To assess serum lipid changes by a phytoestrogen dietary supplement compared with oral estrogen-progesterone replacement in hypercholesterolemic menopausal women. METHODS: Twenty-five menopausal patients with total cholesterol greater than 6.2 mmol/L (240 mg/dL), a cholesterol/high-density lipoprotein-cholesterol ratio greater than 4.5 and triglycerides less than 3.5 mmol/L (310 mg/dL) after a 4-month diet, were randomized to add 40 g/day of crushed flaxseed to their diet or to take daily 0.625 mg of conjugated equine estrogens alone (hysterectomy, n = 10) or combined with 100 mg of micronized progesterone (intact uterus, n = 15). After 2 months of treatment, both groups continued the diet alone during a 2-month washout period before crossing over to the alternate treatment for 2 more months. RESULTS: Differences were found between hormone replacement therapy and flaxseed respectively for decrease of low-density lipoprotein cholesterol (3.8 +/- 0.2 versus 4.4 +/- 0.2 mmol/L) (148 +/- 8 versus 170 +/- 8 mg/dL) (P =.10), increase of high-density lipoprotein cholesterol (1.6 +/- 0.04 versus 1.3 +/- 0.03 mmol/L) (62 +/- 1 versus 50 +/- 1 mg/dL) (P =.001), and increase of apolipoprotein A-1 (1.71 +/- 0.07 versus 1.42 +/- 0.05 g/L) (P =.003). These changes were not related to modifications in diet, exercise, or anthropometric measurements evaluated in parallel. Both treatments produced similar decreases in menopausal symptoms and in glucose and insulin levels. Only hormone replacement therapy as compared with flaxseed induced an elevation of sex hormone binding globulin (P =.004), lowered fibrinogen (P =.08), and plasminogen activator inhibitor type 1 (P =.01). CONCLUSION: Although 40 g of flaxseed is as effective as oral estrogen-progesterone to improve mild menopausal symptoms and to lower glucose and insulin levels, only hormone replacement therapy significantly improves cholesterol profile in hypercholesterolemic women and favorably modifies markers related to cardiovascular health.

Oral contraceptives as anti-androgenic treatment of acne.

Although acne is seldom associated with high serum levels of androgens, it has been shown that female acne patients have definite increases in ovarian and adrenal androgen levels when compared to appropriate controls. As shown in several pilot and in multiple open and comparative studies, oral contraceptives (OCs) are effective in causing a significant regression of mild to moderate acne. These results have been confirmed by multicentre randomized trials where low-dose OCs did not cause side effects different from those of the placebo-controlled group. The beneficial effect of OCs is related to a decrease in ovarian and adrenal androgen precursors; to an increase in sex hormone-binding globulin (SHBG), which limits free testosterone; and to a decrease in 3a-androstenediol glucuronide conjugate, the catabolite of dihydrotestosterone (DHT) formed in peripheral tissues. The estrogen-progestin combination containing cyproterone acetate (CPA) is particularly effective in treating acne, since this progestin also has a direct peripheral anti-androgenic action in blocking the androgen receptor. Only two open studies and one randomized study on small numbers of patients have reported some efficacy of spironolactone used alone or in combination with an OC in the treatment of acne. The new non-steroidal anti-androgens flutamide and finasteride are being evaluated for the treatment of hirsutism. Oral antibiotics are prescribed to patients with inflammatory lesions, where they are effective in decreasing the activity of microbes, the activity of microbial enzymes, and leukocyte chemotaxis. Concomitant intake of an OC and an antibiotic usually prescribed for acne does not impair the contraceptive efficacy of the OC. A second effective contraceptive method should be used whenever there would be decreased absorption or efficacy of the OC (digestive problems, breakthrough bleeding), lack of compliance and use of a type or dose of antibiotic different from that usually prescribed for acne.Overall, the various approaches for the treatment of acne depend on the needs of the patient and on the therapeutic objectives. Low-dose OCs are effective in improving acne and have side effects similar to placebo. They can be used alone or in combination with other anti-acne agents. The physician prescribing an OC as an anti-androgen intervention should take into account the multiple factors involved in acne and be familiar with current non-hormonal agents for treating mild to moderate acne. Individuals presenting with moderate to severe acne, or not responding to an estrogen-progestin combination, should be referred to a dermatologist.