Management of postmenopausal women: Collège National des Gynécologues et Obstétriciens Français (CNGOF) and Groupe d'Etude sur la Ménopause et le Vieillissement (GEMVi) Clinical Practice Guidelines.

AIM: The aim of these recommendations is to set forth an individualized approach to the management of early postmenopausal women (i.e., within the first 10 years after natural menopause) covering all aspects of lifestyle and therapeutic management, with or without menopause hormone therapy (MHT). MATERIALS AND METHODS: Literature review and consensus of French expert opinion. Recommendations were graded according to the HAS methodology and levels of evidence derived from the international literature, except when there was no good-quality evidence. SUMMARY RECOMMENDATIONS: The beginning of menopause is an ideal time for each woman to evaluate her health status by assessing her bone, cardiovascular, and cancer-related risk factors that may be amplified by postmenopausal estrogen deficiency and by reviewing her lifestyle habits. Improving lifestyle, including nutrition and physical activity, and avoiding risk factors (notably smoking), should be recommended to all women. MHT remains the most effective treatment for vasomotor symptoms but it could be also recommended as first-line treatment for the prevention of osteoporosis in early postmenopausal women at low to moderate risk for fracture. The risks of MHT differ depending on its type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used. There is reasonable evidence that using transdermal estradiol in association with micronized progesterone or dydrogesterone may limit both the venous thromboembolic risk associated with oral estrogens and the risk of breast cancer associated with synthetic progestins. Treatment should be individualized to each woman, by using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of its benefit-risk balance. For bothersome genitourinary syndrome of menopause (GSM) symptoms, vaginal treatment with lubricants and moisturizers is recommended as first-line treatment together with low-dose vaginal estrogen therapy, depending on the clinical course. No recommendation of an optimal duration of MHT can be made, but it must take into consideration the initial indication for MHT as well as each woman's benefit-risk balance. Management of gynecological side-effects of MHT is also examined. These recommendations are endorsed by the Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVI) and the Collège National des Gynécologues-Obstétriciens Français (CNGOF).

Bone mineral density at menopause does not predict breast cancer incidence.

UNLABELLED: In this prospective study in 2,137 perimenopausal and early postmenopausal women who were followed over a 13.1-year period of time, we observed no association between bone mineral density measured at the beginning of menopause and the subsequent risk of breast cancer. INTRODUCTION: This study aimed to investigate the relationship between BMD and the risk of breast cancer (BC) in young postmenopausal women. METHODS: As part of a clinical research program, 2,137 women who were perimenopausal or within their 5 first postmenopausal years were scanned between 1988-1990 and reviewed on average 13.1 years after their initial examination. Ninety-eight incident BC cases were recorded throughout the follow-up. RESULTS: Women with incident BC significantly differed from those who had never had BC with regard to age at menarche, age of birth of 1st child, familial history of BC and postmenopausal hormone therapy (PHT) use. There was no significant difference between the two groups for baseline DXA of the spine. There was a trend for BC cases for having lower femoral neck BMD compared to women without BC. However, women with low BMD were more likely to have taken PHT by the end of the study. In Cox multivariate analyses the relationship between BC risk and femoral neck BMD no longer existed. CONCLUSIONS: There was no relationship between BMD measured within the first postmenopausal years and the risk of BC, which makes unlikely the possibility of using BMD as a predictor factor for BC in early postmenopausal women.

Withdrawal of hormone replacement therapy is associated with significant vertebral bone loss in postmenopausal women.

This study aimed to assess the changes in vertebral bone mineral density (BMD) after cessation of hormone replacement therapy (HRT) in postmenopausal women who had been treated on a long-term basis. Fifty healthy postmenopausal women who had been followed both during the course of HRT and after cessation of treatment in our menopause clinic were included in this study. All women had started HRT within the first 3 years after the postmenopause and had received HRT (either 1.5 mg/day of 17 beta-estradiol given percutaneously or 50 micrograms/day of 17 beta-estradiol given as a transdermal patch, combined in all women with natural progesterone or a 19-norprogesterone derivative) for a mean 5 +/- 2.4 years. In all women, vertebral BMD was assessed during the course of HRT up to the last 6 months before estrogen withdrawal, then at least once within the first 18 months after cessation of treatment. Of the initial population, 30 women were additionally reviewed later on and up to 8 years after cessation of treatment (mean duration of follow-up for the whole population: 3.9 +/- 1.7 years). Rates of changes in vertebral BMD were compared with those determined in a group of healthy untreated women who had been followed within the first years of postmenopause during the same time period as the study population. In the study group, bone loss was found to accelerate within the first 2 years after HRT withdrawal and the annual rate of loss was identical to that which occurs within the first 2 years of postmenopause in untreated women (-1.64% +/- 1.3% vs -1.52 +/- 0.9%, NS). Beyond this first 2-year time period, the annual rate of bone loss decreased as a function of time following cessation of treatment, as was observed following the menopause in untreated women (between 3 and 5 years: -0.83% + 1.35% in the study group vs -0.70% +/- 0.8% in the control group, NS). On average, 3 years after cessation of HRT mean vertebral BMD when expressed as a Z-score was significantly higher (-0.13 vs -0.89, p < 0.01) than at baseline, before HRT was started, which suggested a lasting beneficial effect on bone mass. However, even though our findings do not support the hypothesis that bone loss might continue to be accelerated several years after cessation of treatment we cannot fully address the question as to whether any residual benefit on bone mass over a longer period of time may be observed. In conclusion, the pattern of bone loss observed after cessation of estrogen therapy was found to be comparable to that which occurs in younger women within the first years after the menopause. Such a pattern needs to be kept in mind when the decision to stop HRT is taken, especially in women who were given HRT to prevent osteoporosis. The issue of assessing their risk of fracture several years after cessation of treatment thus needs to be addressed.

Ability of peripheral DXA measurements of the forearm to predict low axial bone mineral density at menopause.

The aim of this study was to evaluate the ability of peripheral dual-energy X-ray absorptiometry (pDXA) measurement of the forearm to predict low axial bone mineral density (BMD) as defined according to the WHO classification. Two hundred and thirty-four healthy women aged 45-60 years were investigated. BMD was measured at the proximal and distal radius + ulna by pDXA and at the lumbar spine and femoral neck by DXA. There was a significant but moderate correlation between peripheral and axial BMD measurements, with r values ranging from 0.4 to 0.6 (SEE: 13.5-17%). The cutoff values for the proximal and distal radius BMD that allow the identification with 95% sensitivity of postmenopausal women with either a lumbar spine or femoral neck T-score < -1, corresponded to a T-score of +0.5 (proximal radius) and +1 (distal radius). More than 90% of the whole population had a peripheral T-score below these thresholds. Using an axial T-score < or = -2.5 as the definition of abnormality reduced to 48% (proximal radius) to 66% (distal radius) the number of women who would have required DXA axial measurements (i.e., with a pDXA T-score below the cutoff value of -0.7). Of the 33 women (14%) with a proximal radius T-score < or = -2.5 (osteoporosis), only 1 had a lumbar spine and femoral neck T-score > or = -1 (normal). Conversely, of the 50% (proximal radius) to 65% (distal radius) of the women with normal forearm measurement, 5% (proximal radius) to 9% (distal radius) were found to be osteoporotic and an additional 57% (proximal radius) to 59% (distal radius) could be classified as osteopenic (T-score between -1 and -2.5) at either the lumbar spine or femoral neck. In conclusion, use of pDXA forearm measurement as a prescreening tool in early postmenopausal women should allow the direct identification of about 50% of the women with no axial osteoporosis. However, this study highlights the difficulties in using a unique T-score that could be applied to different sites to diagnose osteoporosis.

Effect of hormone replacement therapy on age-related increase in carotid artery intima-media thickness in postmenopausal women.

The aim of this study was to determine the changes in carotid artery intima-media thickness as measured by B-mode ultrasound in postmenopausal women receiving hormone replacement therapy (HRT) or not. One hundred and fifty-nine healthy postmenopausal women aged 45-65 years were recruited from our menopause clinic. All the selected women were free of cardio-vascular diseases and had no cardio-vascular risk factors. None of the women were receiving lipid-lowering or antihypertensive drugs. Because carotid artery intima-media thickness was shown to be strongly and positively correlated with age in women aged 55 years and older but not before, women were divided into four groups according to age (<55 vs. > or =55 years) and use of HRT (current users vs. never users). All the treated women received non-oral 17beta-estradiol with a non-androgenic progestin and had started HRT within the first year after menopause. Scanning of the right common carotid artery was performed with a B-mode ultrasound imager and thickness of the intima-media complex as well as luminal diameter of the artery were determined using an automated computerized procedure. Within each age group (i.e. <55 or > or =55 years), women had comparable demographic characteristics and only differed by HRT use. Long-term treated women had significantly lower total cholesterol levels than untreated women (P=0.005). Triglycerides, low-density lipids (LDL)-cholesterol and high-density lipids (HDL)-cholesterol levels, systolic and diastolic blood pressure were not significantly different between users and non-users. In women <55 years, no significant difference in carotid intima-media thickness was found between current users (mean 2.5+/-1.4 years) and non users. In older women, the mean values of carotid intima-media thickness were significantly smaller in current users (mean 6.9+/-3.3 years) than in never treated women: 0.50+/-0.05 versus 0.56+/-0.07 mm, P<0.0001. Carotid artery intima-media thickness was significantly correlated to age in never users (r=0.5, P<0.0001) but not in women who were currently receiving HRT (r=0.2, ns). These findings suggest an apparent protective effect of long-term HRT on age-related thickening of the intima-media of the right common carotid artery. This may contribute to explain the apparent cardio-protective effect of HRT after the menopause.

Coronary heart disease risk factors and menopause: a study in 1684 French women.

This study aimed to assess the relationship between menopause and various risk factors for coronary heart diseases (CHD) in a large sample of French women aged 45 65 years. One thousand six hundred and eighty-four consecutive healthy women who received a systematic check-up in our Menopause Unit were included in this study. All the women answered a computer-assisted questionnaire which comprised 156 items, 72 questions being exclusively related to the identification of familial and personal cardio-vascular risk factors. Biological measurements were performed to evaluate lipid-lipoprotein profile and fasting glucose levels. Women, none of whom were treated with hormonal replacement therapy, were classified as postmenopausal according to the date of their last menses and levels of serum FSH and estradiol (n = 1200). Perimenopausal women were further subdivided into two subgroups according to the regularity of their menstrual cycles and FSH levels (early (n = 143) and late (n = 341) perimenopause). 12% (n = 205) of the women were currently receiving lipid-lowering drugs (84.4% postmenopausal vs. 15.6% perimenopausal). When all women were considered, menopause was associated with a higher prevalence of hypertension and hypercholesterolemia (serum total cholesterol level > 250 mg/dl + LDL cholesterol level > 160 mg/dl). This higher prevalence in postmenopausal women was also found when the analysis was restricted to women aged 45 55 years, which rather suggests an effect of menopause than of age. Of the women not receiving hypolipidemic treatments, postmenopausal women had significantly higher serum levels of total cholesterol, LDL , VLDL cholesterol, triglycerides and apolipoprotein B and lower levels of HDL cholesterol than perimenopausal women. Multivariate analysis indicated that these effects were independent of age, body mass index and years since menopause. The prevalence of other metabolic disturbances was much more lower. On average, perimenopausal women had significantly less CHD risk factors than postmenopausal women (P < 0.0001). Fifty-two per cent of the perimenopausal women had none of the risk factors studied as compared with 39% of the postmenopausal women (P < 0.0001). This study shows that menopause was associated with a higher prevalence of risk factors for CHD.

Effect of estrogens on bone and other systems and hormonal substitute treatment.

This article reviews recent advances in the effects of estrogen on bone and other body systems. The effect of estrogen use for the prevention of osteoporosis is no longer a matter of debate. Some issues are still discussed, however, especially with regard to the magnitude of its protection (especially for hip fracture), which would be dependent on the time at which estrogen therapy is initiated with respect to menopause as well as its total duration of use. The mechanisms of estrogen's action on bone also remains poorly understood. Controversy persists concerning the specific contribution of an indirect action through the modulation of calciotropic hormones and a direct action on bone cells in which estrogen receptors have been identified. Estrogens have been shown to reduce osteoclastogenesis by modulating the production of cytokines (interleukins, tumor necrosis factor) and transforming growth factor from bone marrow and bone cells. In addition to its effects on bone, a great number of observational studies have evaluated the relationship between estrogen use and coronary heart disease. The overall risk of coronary disease is estimated to be reduced by 50% in women who use estrogen replacement therapy. This reduction would be even greater in women with previous atherosclerosis. Moreover, recent data suggest that estrogen use could be associated with delayed onset and reduced risk for Alzheimer's disease. Overall, estrogen treatment in postmenopausal women has several proven benefits. Conversely, the potential risks of long-term estrogen therapy include a slightly increased risk of breast cancer, which would be associated with long-term use. Although the individual decision for a postmenopausal woman to start estrogen replacement therapy must take into account this risk:benefit ratio, current evidence suggests a clear advantage for estrogen's benefits over its risks.

Relative influence of age and menopause on total and regional body composition changes in postmenopausal women.

OBJECTIVE: We measured total and regional body composition to evaluate the differences in body composition associated with menopause and to determine whether the changes in fat distribution were more related to age or to menopause. STUDY DESIGN: Two hundred five healthy white women who had never received estrogen replacement therapy were studied according to menopausal status and age. Bone mass and body composition were measured by dual x-ray absorptiometry. The proportions of android and gynoid fat were calculated in all women and differences were sought by statistical analysis. RESULTS: Compared with premenopausal women, postmenopausal women were characterized by a significant increase in the proportion of android fat and the ratio trunk fat/leg fat, whereas the absolute amount of body fat mass did not significantly change. The different variables of android fat distribution tended to correlate better with years since menopause than with age. In multiple linear regression, years since menopause was a predictor of body fat mass and fat trunk, whereas age was not a predictor of any of the fat distribution variables. CONCLUSIONS: This study underlines the early changes in body fat distribution with a shift of body fat toward a more central location in postmenopausal women. This change in fat distribution appears to be more related to menopause than to age and might, together with other factors, contribute to explain the increased cardiovascular risk reported in postmenopausal women.

A prospective two-year study of progestin given alone in postmenopausal women: effect on lipid and metabolic parameters.

OBJECTIVE: A controlled study was conducted to assess the long-term effect of a progestin with very low androgenic potency given alone on serum lipoprotein profile, serum renin substrate, sex hormone-binding globulin levels, and serum antithrombin III activity in early postmenopausal women. STUDY DESIGN: Thirty-five early postmenopausal women who had not received any form of hormonal treatment after menopause were randomly assigned to a 2-year regimen of 500 micrograms of a progestin derived from 19-norprogesterone (promegestone) or a placebo for 21 days of a 28-day treatment cycle. Serum lipid and lipoprotein levels and other biochemical parameters were measured in the two groups, and differences were sought by statistical analysis. RESULTS: After 2 years of treatment the women in the two groups showed no statistically significant variation from baseline values in the concentrations of any of the biochemical parameters studied. CONCLUSIONS: The results show that a progestin with very low androgenic activity given alone has no influence on lipid profile and hepatic synthesis of several proteins in early postmenopausal women.

Vertebral postmenopausal bone loss is reduced in overweight women: a longitudinal study in 155 early postmenopausal women.

To study the influence of excess body weight on vertebral postmenopausal bone loss, 155 healthy early postmenopausal women were divided into 2 groups according to their body mass index (BMI = weight/height2) and prospectively followed over a mean 31-month period. Spinal (L2-L4) bone mineral density was measured by dual photon absorptiometry. The annual rate of vertebral bone loss (percentage) was significantly reduced (-0.54 +/- 1.1% vs. -1.46 +/- 1.6%; P < 0.05) in the overweight group (BMI, > or = 25; n = 40) compared to that in the normal weight group (BMI, < 25; n = 115). At baseline, a significant decrease in the urinary calcium/creatinine ratio was observed in the overweight group, which suggested a decrease in bone turnover. A significant correlation was found between the annual rate of bone loss and the BMI (r = 0.21; P < 0.05), but not the body weight. The positive correlation between vertebral postmenopausal rate of bone loss and BMI was confirmed after adjustment for age and time since menopause. Moreover, plasma dehydroepiandrosterone sulfate levels were higher in the high BMI group than in the normal BMI group (P < 0.05). We conclude that within the first years after menopause, moderate excess body weight significantly reduces vertebral postmenopausal bone loss. This effect is probably related to excess adipose tissue through increased conversion of estrogen from adrenal precursors and/or increased production of adrenal androgens.

Progesterone and promegestone stimulate human bone cell proliferation and insulin-like growth factor-2 production.

Recent clinical studies suggest that progesterone may be involved in the regulation of bone turnover and could promote bone formation. This study was undertaken to evaluate whether progesterone and promegestone (a 19 nor-PG derivative) may have a direct effect on human bone cells and, if so, whether growth factor production could be involved in promoting this effect. The osteosarcoma cell line TE85 and untransformed normal human osteoblastic cells derived from iliac crest were used as in vitro model systems. Progesterone and promegestone were found to significantly increase [3H]thymidine incorporation in TE85 cells in a dose-dependent manner at concentrations ranging from 10(-12) to 10(-8) mol/l after four days of cultivation (p less than 0.01, ANOVA). Consistent with this response in the TE85 cells, progesterone and promegestone increased cell number in human osteoblastic cells after six days of treatment (p less than 0.05, ANOVA). To determine whether this effect on cell proliferation was mediated by the insulin-like growth factor (IGF) regulatory system, the levels of IGF-1, IGF-2 and IGF binding protein (IGFBP) were measured in the conditioned media of both TE85 and human osteoblast cells. While no significant changes in IGF-1 levels were found in the conditioned media of progesterone and promegestone treated cultures, progesterone and promegestone at the concentration of 5 nmol/l significantly increased IGF-2 levels 2.4 and 1.5-fold respectively, at 48 h in the conditioned medium of TE85 cells as compared to control. Similarly, a 4.1 and 1.9-fold increase in IGF-2 levels was found upon treatment with progesterone and promegestone in human osteoblastic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin-like growth factor II and transforming growth factor beta 1 regulate insulin-like growth factor I secretion in mouse bone cells.

Bone cells in culture produce and respond to growth factors, suggesting that local as well as systemic factors regulate bone volume. Previous studies have shown that IGF-I is the major mitogen produced by mouse bone cells and that its production is regulated by systemic agents such as PTH and estrogen. Because IGF-II and transforming growth factor beta 1 have been shown, respectively, to increase and decrease MC3T3-E1 cell proliferation, we tested the hypothesis that these two growth factors modulate the production of IGF-I in this cell line. In order to eliminate artifacts owing to IGF binding proteins, conditioned media samples were pretreated with IGF-II before measurement of IGF-I by RIA. After 24 h treatment at a density of 2.5 x 10(4) cells/cm2, IGF-II (10 micrograms/l) induced a 2.2-fold increase compared with untreated control (9.5 +/- 1.5 vs 4.2 +/- 0.44 pg/micrograms protein, p less than 0.001), whereas transforming growth factor beta 1 (1 microgram/l) caused a 66% decrease in IGF-I production (1.5 +/- 0.3 vs 4.2 +/- 0.44 pg/micrograms protein, p less than 0.001). Both IGF-II and transforming growth factor beta 1 regulated IGF-I production in a dose-, time- and cell density-dependent manner. The lowest effective doses for IGF-II and transforming growth factor beta 1 were 1 and 0.01 microgram/l, respectively. These results support a role for IGF-II and transforming growth factor beta 1 as potent modulators of IGF-I secretion in mouse bone cells.(ABSTRACT TRUNCATED AT 250 WORDS)