Bone mass density selectively correlates with serum markers of oxidative damage in post-menopausal women.

BACKGROUND: Post-menopausal osteoporosis (PO) affecting a large fraction of elderly women, is triggered by the decline in 17ß-estradiol (E2) level. Experimental studies in animal models and cell cultures have suggested that the fall in E2 might contribute to developing oxidative stress (OS) which in turn is believed to play an important role in PO pathogenesis. The scarcity of human studies focusing on this issue prompted us to investigate the effects of the reproductive and post-reproductive phase of women's life on OS and bone health. METHODS: Serum parameters of oxidative challenge (lipid hydroperoxides and protein advanced oxidation products) and antioxidant defence (total serum antioxidants levels) along with bone mineral density (BMD) at femoral neck and lumbar spine were assessed in a sample of 191 women (98 pre- and 93 post-menopausal, of whom 30 osteoporotic). RESULTS: Pearson's correlation analysis unveiled that spinal BMD was negatively correlated with lipid hydroperoxides in overall postmenopausal subsample (r=-0.251, p=0.012), while no significant link between these two variables was detected in women in reproductive age (r=-0.022, p=0.833). Noteworthy, stepwise multiple regression analysis showed that the association found in post-menopausal women retained significance after adjusting for potential confounding factors (p=0.001). CONCLUSIONS: Our data showed that markers of oxidative challenge are associated with bone loss in women in post-menopausal status. We suggest that menopause-related estrogen withdrawal might contribute to make bone more vulnerable to oxidative injury thereby increasing the risk of PO development.

17ß-estradiol levels and oxidative balance in a population of pre-, peri-, and post-menopausal women.

BACKGROUND: The high incidence of various diseases observed in post-menopausal women has been widely associated to the decline of 17ß-estradiol (E2) occurring in correspondence of menopausal transition. One of the mechanisms suggested to explain this link takes into account the ability of E2 to counteract oxidative stress (OS) which is believed to play an important role in several pathogenic processes. AIM: To investigate whether stages of women's life characterized by different levels of E2 influence OS. SUBJECTS AND METHODS: We conducted a cross sectional study of OS markers in 159 women subdivided in 65 pre-menopausal, 36 peri-menopausal, and 58 post-menopausal classified according to the Staging of Reproductive Aging Workshop (STRAW) criteria. E2, follicle-stimulating hormone, and markers of OS including hydroperoxides, thiols, uric acid, total and residual antioxidant power, were assessed. RESULTS: After adjustment for covariates, only total antioxidant power was significantly different according to menopausal status (p <0.01), with lower value in pre- with respect peri- and post-menopausal women. No significant correlations between E2 levels and OS markers were detected. CONCLUSIONS: Endogen E2, and, consequently, its decline during menopausal transition, is not a determinant factor for OS.

Body mass index is a major determinant of abdominal fat accumulation in pre-, peri- and post-menopausal women.

OBJECTIVE: To investigate the role of menopause, body mass index (BMI) and aging on body fat distribution in women. DESIGN: In this population-based cross-sectional study, 335 women (126 in pre-menopause, 75 in peri-menopause and 134 in post-menopause according to Stages of Reproductive Aging Workshop criteria) were evaluated for body mass composition and fat distribution by dual X-ray absorptiometry procedure. A sub-group of 79 women with similar age and BMI was extracted from the sample to examine the relative influence of BMI in body fat distribution. RESULTS: ANCOVA analysis of total sample showed an age-independent increase of total fat mass (p < 0.001) and percentage on total weight (p < 0.001), arms fat mass (p < 0.01), legs fat mass percentage on total fat (p < 0.05) and trunk fat mass (p < 0.001) and percentage (p < 0.05) in peri- and post- with respect to pre-menopausal women. In the sub-sample including age and BMI matched women the difference of regional fat parameters among menopausal status was no more statistically significant. CONCLUSION: BMI, and not age, is the main determinant of the increase of body fat mass (total and abdominal) observed during the menopausal transition.

Oxidative stress, body fat composition, and endocrine status in pre- and postmenopausal women.

OBJECTIVE: To evaluate the role of menopause on the regional composition and distribution of fat in women and eventual correlations with the oxidative state. DESIGN: In this observational clinical investigation, 90 women (classified for menopause status according to Stages of Reproductive Aging Workshop criteria) were evaluated for body mass composition and fat distribution by dual-energy x-ray absorptiometry and for oxidative status by determination of serum hydroperoxide levels and residual antioxidant activity. RESULTS: Total body fat mass increases significantly in postmenopause (P < 0.05) by 22% in comparison with premenopause, with specific increases in fat deposition at the level of trunk (abdominal and visceral) (P < 0.001) and arms (P < 0.001). Concomitantly, the antioxidant status increases significantly (P < 0.001) by 17%. When data were adjusted for age by analysis of covariance, statistical significance disappeared for the increase in fat mass, but it was retained for antioxidant status (P < 0.05). Both antioxidant status and hydroperoxide level increased with trunk fat mass, as shown by linear correlation analysis (r = 0.46, P < 0.001 and r = 0.26, P < 0.05, respectively). CONCLUSIONS: The results of our investigation demonstrate that fat content increases in the upper part of the body (trunk and arms) in postmenopause and that age is the main determinant of this increase. During the comparison of premenopausal and postmenopausal women, we also detected a significant increase in antioxidant status. Apparently this change is mainly related to menopausal endocrine and fat changes.

The relation of season of birth to severity of menopausal symptoms.

OBJECTIVE: Season of birth influences the rate of several psychiatric disorders. In this study, we investigated whether climacteric symptoms and, in particular, psychological and somatic symptoms of postmenopausal women were influenced by their season of birth. DESIGN: This retrospective multicenter study was performed on 2,541 women in natural menopause, free of hormone therapy. The score of the Greene Climacteric Scale and of its vasomotor, psychological (anxiety and depression), and somatization subscales were stratified by season of a woman's birth. Data were controlled for possible confounders, such as age, years since menopause, body mass index, education occupation, smoking habits, and season of evaluation. RESULTS: The Greene Climacteric Scale appeared to be associated with the season of birth, with the lowest scores being observed in women born in autumn and the highest scores in women born in spring (+2.11; 95% CI, 0.67-3.56; P = 0.01), and summer (+2.22; CI, 0.82-3.63; P = 0.01). Lowest scores in autumn and highest scores in spring were also observed for psychological symptoms subscaled as anxiety and depression (+1.43; CI, 0.54-2.32; P = 0.01) and somatic symptoms (+0.59; CI, 0.15-1.04; P = 0.01). CONCLUSIONS: In this study, we found a relationship between season of birth and some menopause-associated symptoms. Further study is needed to confirm these relationships and examine possible mechanisms.

Transglutaminase and vascular biology: physiopathologic implications and perspectives for therapeutic interventions.

Consistent clinical and experimental evidence points to the involvement of two enzymatic systems (the matrix metalloproteinases-MMPs and the protein crosslinking enzymes transglutaminases) in prominent physiologic roles of endothelium in the maintenance of vascular wall integrity, regulation of blood flow and clotting, and exchange of molecules and cells between the extra- and the intravascular space. These issues are briefly discussed in relation to differentiation of the endothelium within the vascular system, mechanisms of molecular regulation and the effects of their disruption in pathology. While the roles of MMPs are now understood in detail and represent a promising target for pharmacological interventions, much less is known on the roles of transglutaminases in vascular biology. These last enzymes are expressed at extremely high levels in endothelial cells and are involved in cell matrix interactions important to angiogenesis and apoptosis/cell death of endothelial cells, in the control of blood clotting and and in the transfer of molecules and cells across the vascular walls. On the clinical side, these properties are relevant in vascular inflammatory processes, atherosclerosis and tumor metastasis. We summarise the large body of evidence available in this perspective and discuss its implications for the development of new therapeutic strategies.

Neutral effect of prolonged transdermal hormone therapy on liver function of postmenopausal women with chronic active hepatitis.

OBJECTIVE: To test whether transdermal hormone therapy can be safely administered to postmenopausal women with chronic viral hepatitis B and/or C. DESIGN: Eighty-one postmenopausal women with chronic viral hepatitis B and/or C and with severe vasomotor symptoms were treated for 5 years with transdermal estradiol (50 microg/day) continuously and with transdermal norethisterone (250 microg/day) for 14 days of every 28-day cycle. Another 95 women with viral chronic hepatitis but without climacteric symptoms were used as controls. Liver enzymes (glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase, gamma-glutamine-transferase, and alkaline phosphatase) were measured every year. RESULTS: At baseline, liver enzymes were similar in the two groups, with the exception of gamma-GT, which was slightly higher in untreated women (P < 0.01). Liver enzymes did not significantly vary with time in hormone-treated and untreated women. No significant difference was observed between the two groups. CONCLUSIONS: Transdermal estradiol and norethisterone can be safely administered for a prolonged period to postmenopausal women with chronic viral B and/or C hepatitis.

Management of the menopausal disturbances and oxidative stress.

Women frequently seek gynaecologic medical advice at menopause and require pharmacologic interventions to control subjective vasomotor complaints and to prevent late severe organic complications, which may effect the genitourinary tract, the skeletal, the cardiovascular and the nervous system. Depending on the severity of the presentation and the involvement of additional systems beyond the reproductive tract, physicians have several distinct therapies available, which should be carefully evaluated and administered in a "patient-personalised" fashion: they include organ-oriented drugs, available for selective treatment in patients which do not display major direct endocrine symptoms, as well as endocrine therapies (administration of native estrogens; or synthetic selective hormonal drugs, i.e. SERMs and SEEMs). Much interest is now focusing on new kinds of plant estrogen-like compounds, mostly isoflavones, which by one hand display estrogen-like (or antagonistic) effects, by the other are powerful antioxidising agents. In our survey, we discuss extensively the enormous amount of data available in the literature, underlining by one side that most of the formulations currently in use for the overall therapy of menopausal complaints have structure features also characteristic of antioxidising agents, by the other that there are wide evidences of increased oxidative damage occurs in women during the postmenopausal life. These observations suggest the possibility of a contribution of antioxidising activity of the administered drugs to the beneficial clinical effects on the patients, in agreement with the demonstrated estrogen intrinsic antioxidising activity in vitro. This stresses the requirement of further basic and clinical studies on the relevance of oxidative damage during postmenopausal female life.

Interaction with heparin protects tissue transglutaminase against inactivation by heating and by proteolysis.

The considerable affinity of tissue transglutaminase for heparin was the basis for use of heparin-based affinity matrices for enzyme purification. Interaction of transglutaminase with heparin might mimic the physiological binding to membrane heparan sulfates, accounting for the limited but significant fraction of enzyme exposed at cell surface to crosslink ECM proteins. Exploring effects of heparin on transglutaminase activity and stability, we have noted that heparin only slightly affects activity in vitro, but the protein against heat treatment and proteolysis.

Season of birth influences the timing of menopause.

BACKGROUND: Seasons may influence prenatal growth and future fertility. This study investigated whether season and month of birth influenced the timing of menopause in a group of women attending three Italian menopause clinics. METHODS AND RESULTS: Age at menopause of 2822 post-menopausal women (>12 months of amenorrhoea) was stratified by month and season of birth. Mean age at menopause was 49.42 years (SEM: 0.78 years). Menopause occurred earlier for women born in the spring (age 49.04+/-0.15 years) than in the autumn (49.97+/-0.14 years). The earliest menopause was found in women born in March (48.9+/-0.25 years) and the latest in women born in October (50.3+/-0.25 years). The effect of season of birth on age at menopause remained even when considering factors that in our analysis were capable of significantly interfering with the timing of menopause, such as age at menarche, body mass index, smoking habit, level of education and type of job. CONCLUSIONS: Taking into consideration the retrospective design of the study, and a possible recall bias, the present data seem to suggest that environmental factors linked to seasons are capable of interfering with the timing of a woman's ovarian exhaustion by an action exerted in the prenatal period.

Effect of low-dose transdermal E2/NETA on the reduction of postmenopausal bone loss in women.

OBJECTIVE: To assess the efficacy of a continuous-combined transdermal patch (estradiol/ norethisterone acetate [E(2)/NETA] 25/125; Estragest TTS, Novartis, Basel, Switzerland) in the reduction of bone loss in postmenopausal women. DESIGN: In a 96-week, double-blind, randomized, multicenter, parallel study, 124 healthy women with an intact uterus more than 4 years after menopause received either transdermal continuous-combined E(2)/NETA (0.025/0.125 mg/day) or placebo patch for 24 treatment cycles; diet was normalized for calcium intake. Lumbar spine bone mineral density (BMD) ranged from 0.969 to 0.805 g/cm2 with a mean annual BMD decrement ranging from 3% to 8% within the last 24 months. BMD at lumbar spine L(2)-L(4) (postero-anterior) and femur were assessed by dual energy x-ray absorptiometry after 6, 12, and 24 cycles. Efficacy variables included measurement of biochemical markers of bone turnover (3, 6, 12, and 24 months). RESULTS: BMD at lumbar spine was significantly higher at all time points in the E(2)/NETA group than in the placebo group (P < 0.0001). Significant increases in BMD (P < 0.0008) from baseline were observed at all sites after 24 months in the E(2)/NETA group compared with placebo, which demonstrated a decrease from baseline. At endpoint, statistically significant decrements in the values of bone remodeling markers were observed (P < 0.05) with E(2)/NETA. CONCLUSIONS: E(2)/NETA 25/125 Estragest TTS was more effective than placebo in reducing the activation frequency of bone remodeling and in preventing bone loss at the spine and hip. Effects on the hip were similar to those observed for higher doses of estrogen.

Simvastatin, transdermal patch, and oral estrogen-progestogen preparation in early-postmenopausal hypercholesterolemic women: a randomized, placebo-controlled clinical trial.

Hormone replacement therapy (HRT) seems to have a favorable influence on the plasma lipid profile. Only a few investigations have examined the effects of HRT versus hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors. We compared the relative effects of different hypolipidemic strategies on lipoproteins and coagulative parameters in women with recent-onset spontaneous menopause. In this 24-week, placebo-controlled trial, 60 consecutive healthy women aged >/= 45 years, with amenorrhea from 6 to 60 months (mean, 1.9 +/- 1.4 years), serum follicle stimulating hormone (FSH) greater than 40 U/L, and slight to moderate hypercholesterolemia (low-density lipoprotein-cholesterol [LDL-C] 160 to 250 mg/dL, high-density lipoprotein-cholesterol [HDL-C] < 75 mg/dL, and triglycerides < 200 mg/dL) were enrolled and randomized to dietetic advice (placebo group), simvastatin 10 mg, 0.625 mg of conjugated equine estrogen (CEE), or 50 microg estrogen transdermal patch (ETP). In the latter 2 cases, the progestative nomegestrol was added to estrogens (days 17 to 28 of the cicle). Lipoprotein parameters were evaluated after separating very-low-density lipoproteins (VLDLs) by ultracentrifugation, while fasting glucose and insulin, homocysteine, and hemocoagulative parameters were determined in plasma. Fifty-four patients completed the trial. Total cholesterol (TC) and LDL-C significantly decrased in the simvastatin (-62 mg/dL [-20%] and -72 mg/dL [-30%], respectively), CEE (-42 mg/dL [-13%] and -45 mg/dL [-18%]), and ETP (-30 mg/dL [-10%] and -26 mg/dL [-11%]) groups compared to baseline, but only simvastatin showed an effect significantly superior to diet alone. Apolipoprotein (Apo) B was decreased by simvastatin (-25%, P <.001) and by CEE (-10%, P <.05); again, simvastatin was more effective than either diet or ETP. Triglyceride concentration and VLDL-C were unmodified by treatments. HDL-C and Apo A-I significantly increased in the simvastatin group (+18% and +8%, respectively), while HDL-C was unmodified by both HRT regimens and Apo A-I was reduced by ETP treatment (-17%); lipoprotein[a] (Lp[a]) was decreased by both HRTs (-38%, P <.05, and -22%, P =.07, for CEE and ETP, respectively). Among coagulative parameters, plasminogen activator inhibitor-1 (PAI-1) was significantly reduced by CEE (-29%, P <.05) but not ETP treatment (+16%, P = not significant), while fibrinogen, antithrombin, and homocysteine were unaffected by therapy. Thus, HRT, particularly CEE, seems well tolerated and moderately effective in improving the lipid pattern and, perhaps, the coagulative/fibrinolytic balance in postmenopausal hypercholesterolemic women; it may represent a therapeutic option in slightly dyslipidemic subjects. Statins are preferred in case of more severe disease.