Effect of hormone replacement therapy on serum levels of tumor markers in healthy postmenopausal women

Objective: The effect of hormone replacement therapy (HRT) on serum levels of tumor markers is barely defined. The aim of this study was to evaluate the effect of HRT on levels of tumor markers CA 125, CA 15-3, CA 19-9, CEA and -FP. Methods: Retrospective analysis of prospectively collected data in healthy postmenopausal women under oral estrogen replacement therapy (ERT, conjugated equine estrogen (CEE) 0.625 mg (n=21) or estradiol 2 mg (n=31)), and continuous combined estrogen and progesterone regimen (HRT, CEE 0.625 mg plus medroxyprogesterone acetate 2.5 mg (n=34) or estradiol 2 mg plus norethisterone acetate 1 mg (n=37)). One hundred and twenty-three healthy women among a sampled population of 654 postmenopausal patients with complete records, initial normal tumor marker levels, and at least 1 year of follow-up were included into the study. Tumor markers were measured with 1-year interval. Results: Fifty-two (41.5%) patients were under ERT and 71 (58.5%) were under combined HRT. The number of months since menopause, age and age at menopause did not influence tumor marker levels at first admission. All of the tumor marker levels were in normal range after 1 year. Pretreatment CA 125 II, CA 15-3 and CEA levels were significantly low (median and range) 5.0 (1.0–11.8) versus 7.45 (1.0–18.1) U/ml for CA 125, 27.05 (7.3–37.5) versus 32.6 (12.5–37.9) U/ml for CA 15-3, 0.88 (0.58–2.8) versus 1.34 (0.53–2.41) ng/ml for CEA in women with hysterectomy when compared to women without hysterectomy. There was no effect of ERT on CA 125 II, CA 19-9, CEA and -FP levels. E2 led to a significant decrease in post-treatment CA 15-3 levels [32.9 (8.1–34.9) vs. 18.1 (6.7–31.4); P<0.001]. CA 125 levels were only significantly reduced in hysterectomised women using continuously combined HRT [7.9 (2.6–17.7) vs. 5.6 (1.3–19.2) for CEE+MPA, and 7 (1–18.1) vs. 5.8 (1.8–17.4) for E2+NETA; P<0.05]. There was a small, but not significant, increase in CA 125 levels in women under ERT. Conclusion: Although there was a statistically significant decrease in CA 15-3 levels in current E2 and E2+NETA users, and a decrease in CA 125 levels in combined regimens, this change is clinically not relevant in healthy postmenopausal women. This data will be useful for the caregivers in the management and follow-up of cancer survivors who preferred replacement therapy as the only treatment of their postmenopausal symptoms.     

Early effects of continuous low-dosage dl-norgestrel administered alone or with estrogen

Twenty-six postmenopausal women participated in a double-blind trial involving treatment according to a Latin square design with either (i) dl-norgestrel alone (0.075 mg/day) continuously for two cycles, (ii) estradiol-17β alone (1 mg on 25 of 28 days) for two cycles, or (iii) the combined hormones for six cycles. A placebo control cycle followed each hormonal treatment. Plasma triglycerides decreased by an average of 22% during treatment with either dl-norgestrel alone (123 ±11 vs. 160 ±10 mg/dl, n = 25, P < 0.005) or combination therapy (126 ±11 vs. 162 ±11, n = 25, P < 0.005) as compared with control. Plasma total cholesterol fell by 5% during two cycles of treatment with either dl-norgestrel alone (229 ±11 vs. 242 ±10 mg/dl, n = 25, P < 0.02) or combination therapy (233 ± 11 vs. 246 ±10, n = 25, P < 0.05) versus placebo. During the fifth and sixth cycles of combination therapy 94% of cycles were free of flushing (vs. 31% for control, P < 0.01), 64% of cycles were free of spotting not requiring protection (control 75%), 96% of cycles were free of vaginal bleeding (control 100%), endometrial biopsy showed inactive endometrium in nine of the 10 subjects re-biopsied, fasting blood pyruvate decreased by 20% (P < 0.05) and diastolic blood pressure fell by 4% compared with control (P < 0.05), whereas glucose tolerance was unchanged. There was a significant reduction in vasomotor flushing beginning with the third to fourth cycles of combination therapy.     

Active lifestyle offsets HRT-induced suppression of T cell reactivity to mitogens

Objective. The purpose of the study was to investigate the combined impact of hormone replacement therapy (HRT) and active lifestyle on the phenotypic profile and in vitro activities of specific immune cells in postmenopausal women. Methods. Healthy postmenopausal women aged 45–70 were assigned to one of four groups: (a) HRT/sedentary (n=9); (b) HRT/active (n=12); (c) no HRT/sedentary (n=10); and (d) no HRT/active (n=9). Blood samples were collected from each subject on 3 days within 1 week. The mean value of three samples was used to assess the in vitro response of T lymphocytes to the mitogens phytohemagglutinin and concanavalin A and natural killer cell activity. One of three blood samples was utilized for phenotypic analysis of circulating leukocytes. Results. The mitogenic reactivity of T lymphocytes in whole blood cultures for the groups receiving HRT was lower than from the groups not receiving HRT. There also was a trend for T lymphocyte reactivity to be higher in the active women when compared to the sedentary women. In contrast, the phenotypic profile of leukocytes and natural killer cell activity were not significantly different for samples collected from the four groups. Conclusions. These data suggest that the suppressive effect of HRT on T cell function in postmenopausal women may be attenuated by a physically active lifestyle.     

Testosterone enhances estradiol''s effects on postmenopausal bone density and sexuality

To investigate the role of androgens in increasing bone density and improving low libido in postmenopausal women, we have studied the long-term effects of estradiol and testosterone implants on bone mineral density and sexuality in a prospective, 2 year, single-blind randomised trial. Thirty-four postmenopausal volunteers were randomised to treatment with either estradiol implants 50 mg alone (E) or estradiol 50 mg plus testosterone 50 mg (E&T), administered 3-monthly for 2 years. Cyclical oral progestins were taken by those women with an intact uterus. Thirty-two women completed the study. BMD (DEXA) of total body, lumbar vertebrae (L1–L4) and hip area increased significantly in both treatment groups. BMD increased more rapidly in the testosterone treated group at all sites. A substantially greater increase in BMD occurred in the E&T group for total body (P < 0.008), vertebral L1–L4 (P < 0.001) and trochanteric (P < 0.005) measurements. All sexual parameters (Sabbatsberg sexual self-rating scale) improved significantly in both groups. Addition of testosterone resulted in a significantly greater improvement compared to E for sexual activity (P < 0.03), satisfaction (P < 0.03), pleasure (P<0.01), orgasm (P < 0.035) and relevancy (P < 0.05). Total cholesterol and LDL-cholesterol fell in both groups as did total body fat. Total body fat-free mass (DEXA, anthropometry, impedance) increased in the E&T group only. We concluded that in postmenopausal women, treatment with combined estradiol and testosterone implants was more effective in increasing bone mineral density in the hip and lumbar spine than estradiol implants alone. Significantly greater improvement in sexuality was observed with combined therapy, verifying the therapeutic value of testosterone implants for diminished libido in postmenopausal women. The favourable estrogenic effects on lipids were preserved in women treated with T, in association with beneficial changes in body composition.     

A comparison of the central effects of different progestins used in hormone replacement therapy

Objective: To evaluate the central effect exerted by different progestins used for hormone replacement therapy. Methods: Randomised, placebo-controlled study. One hundred-twenty postmenopausal women on continuous hormonal replacement therapy with transdermal estradiol (50 μg per day) associated, for 10 days every 28 days, with four different progestins: dydrogesterone (DYD; 10 mg per day; n=20), medroxyprogesterone acetete (MPA; 10 mg per day; n=20), nomegestrol acetate (NMG; 5 mg per day; n=20) or norethisterone acetate (NETA; 10 mg per day; n=20). Other 40 women, 10 for each treatment group, were used as controls and were monitored for a single cycle of 28 days during the administration of transdermal estradiol plus placebo. Morning basal body temperature (BBT) was monitored for 28 days. Anxiety, by the state-trait anxiety inventory, and depression, by the self-evaluation depression scale of Zung, were evaluated just prior to and in the last 2 days of the 10-day progestins adjunct. Results: All progestins except DYD increased (P<0.0001) BBT by 0.3–0.5 °C. Anxiety was decreased by DYD (−2.3+1.1; P<0.01) and MPA (−1.5+0.5; P<0.01), but not by NMG or NETA. Depression did not significantly increase during progestins and actually decreased during MPA (−3.0+0.7; P<0.01). Only the effect of DYD on anxiety and that of MPA on depression were significant versus the control group (P<0.05). Conclusions: Different progestins exert different central effects. DYD has the peculiarity of not increasing BBT and of decreasing anxiety, which is also decreased by MPA. Depression is not negatively affected by the tested progestins and it may be ameliorated by MPA. The present data may help to individualise the progestin choice of hormone replacement therapy.     

Prophylaxis of osteoporosis with calcium, estrogens and/or eelcatonin: comparative longitudinal study of bone mass

Objective: To evaluate three different therapeutic regimens for the prevention of osteoporosis in natural and surgical postmenopausal women who had been found to have rapid bone loss in analytical studies. Methods: A total of 104 naturally or surgically postmenopausal women were studied, and subsequently followed-up during 1 year for avoidance of the influence of seasonal variation on bone mass, a factor overlooked in several studies. They were randomized into four groups of 26 patients each: the untreated control group (mean age 50 ± 5 years); the hormonal replacement treatment (HRT) group (mean age 48 ± 6 years), which was treated for 24 days each month with transdermal 17β-estradiol, 50 mg/day, together with medroxiprogesterone, 10 mg during 12 days; the calcium group (mean age 50 ± 4 years), which was treated with elemental calcium, 1 g/day; and the calcitonin group (mean age 50 ± 5 years), which was treated for 10 days each month with eel calcitonin, 40 IU/day and with elemental calcium, 500 mg/day. Full-body bone densitometry, for measuring total body bone mineral content (TBBMC), was carried out in all the women at baseline and 1 year. TBBMC was corrected for body weight by dividing its value by body weight (TBBMC/W). Results: After 1 year TBBMC/W was lower in every group: −2.14% (P < 0.001) in the control group; −0.14% (P = NS) in the HRT group (P < 0.05 vs. controls); −0.18% (P = NS) in the calcium group (P < 0.05 vs. controls); and −0.06% (P = NS) in the calcitonin group (P < 0.01 vs. controls; P < 0.05 vs. calcium and HRT). Conclusions: These findings show that all three treatments are effective in the prevention of postmenopausal loss of bone mass.     

Dietary flour supplementation decreases post-menopausal hot flushes: Effect of soy and wheat

Plants contain compounds with oestrogen — like action called phytoestrogens. Soy contains daidzin, a potent phytoestrogen, and wheat flour contains less potent enterolactones. We aimed to show in 58 postmenopausal women (age 54, range 30–70 years) with at least 14 hot flushes per week, that their daily diet supplemented with soy flour (n = 28) could reduce flushes compared with wheat flour (n = 30) over 12 weeks when randomised and double blind. Hot flushes significantly decreased in the soy and wheat flour groups (40% and 25% reduction, respectively <0.001 for both) with a significant rapid response in the soy flour group in 6 weeks (P < 0.001) that continued. Menopausal symptom score decreased significantly in both groups (P < 0.05). Urinary daidzein excretion confirmed compliance. Vaginal cell maturation, plasma lipids and urinary calcium remained unchanged. Serum FSH decreased and urinary hydroxyproline increased in the wheat flour group.     

Effect of hormone replacement therapy on lipids in perimenopausal and early postmenopausal women

Objective: To determine the effects of oral sequential hormone replacement therapy (HRT) on lipid-profile in perimenopausal and early postmenopausal women. Methods: We performed a single-center, randomized, placebo-controlled trial. The trial was double blind with respect to 17β-estradiol/desogestrel (17β-E-D) and placebo and open with respect to conjugated estrogens/norgestrel (CEE-N). A total of 125 healthy perimenopausal and early postmenopausal women, aged 43–58 years, were recruited from the general population in Zoetermeer, the Netherlands. The intervention consisted of 6 months treatment with 1.5 mg 17β-estradiol/0.15 mg desogestrel (n=53), 0.625 mg conjugated estrogens/0.15 mg norgestrel (n=36) or placebo (n=36). At baseline, cycle 1, 3 and 6, overnight fasting blood samples were obtained in which lipids were determined. We used linear regression analysis to calculate differences in mean change from baseline in lipids in the active treatment groups compared to placebo. Results: In both treatment groups significant (P<0.05) falls in low-density-lipoprotein (LDL)-cholesterol (17β-E-D: −7.8% and CEE-N: −8.4%) and lipoprotein(a) (17β-E-D: −11.7% and CEE-N: −28.3%) were found compared to placebo. Apolipoprotein A1 (17β-E-D: 6.8% and CEE-N: 7.3%) and HDL-cholesterol (17β-E-D: 6.4% and CEE-N: 8.0%) significantly increased compared to placebo. No significant changes were found in the other lipids. Mean changes from baseline in total cholesterol, LDL-cholesterol and apolipoprotein B were significantly more pronounced in postmenopausal women compared to perimenopausal women, adjustment for age-differences did not change the results. Conclusion: Treatment of perimenopausal and early postmenopausal women with 17β-E-D or CEE-N changes their lipid-profile in a potentially anti-atherogenic direction. Changes appear to be more pronounced in postmenopausal women compared to perimenopausal women.     

Ovarian testosterone secretion during perimenopause

Objective: The aim of the study was to investigate ovarian testosterone secretion during the last few years of reproductive life and after menopause. Materials and methods: Ovarian and peripheral venous levels of total testosterone were analyzed in 52 women aged 42–69 years (mean 51) undergoing hysterectomy with adnexal removal for benign indications at the Department of Obstetrics and Gynecology at Tampere University Hospital, Finland. The study population was divided into pre- (n=19), peri- (n=18) and postmenopausal (n=15) women in addition to the classical division according to menstrual cycle. Corresponding serum estradiol, progesterone and gonadotropin levels were measured, and the degree of ovarian stromal hyperplasia was analyzed. Results: The levels of all steroid hormones were higher in the ovarian vein than in the periphery. A significant positive correlation was found between age and ovarian vein testosterone levels (r=0.3, P=0.01). In premenopausal women, it was 1.5 nmol/l (median; range 0.78–6.0), in perimenopausal women 2.2 nmol/l (range 0.9–13.6), and 2.5 nmol/l (range 0.6–26.6) in postmenopause, respectively. Peripheral testosterone level did not increase with age. Ovarian stromal hyperplasia was significantly associated with increased testosterone secretion (P=0.009). Conclusion: The ovary seems to increase the secretion of testosterone into circulation during the menopausal transition period, as the highest levels were measured in postmenopausal women. High testosterone levels in the ovarian vein, however, were not reflected in the peripheral venous blood.     

Bone turnover and its relationship with bone mineral density in pre- and postmenopausal women with or without fractures

Objective: This work was carried out in order to investigate possible relationships between bone turnover rate, as evaluated by bone biomarkers and skeletal mass, as evaluated by bone mineral density (BMD). Method: Fifty-eight normal women and 30 female patients with osteoporotic fractures were enrolled. Three groups were defined: (1) fertile subjects (n=24), mean age 33.7±8.1 years; (2) postmenopausal women (n=32, including 11 patients with fractures) whose BMD values, in terms of T score, were less than −2.5 S.D. below the young adult mean obtained in our laboratory (mean age 61.7±7.9 years; and years since menopause (ysm), 12.6±8.3); (3) postmenopausal women (n=32, including 19 patients with fractures) whose BMD values in terms of T score, were below −2.5 S.D. (mean age 62.9±8.6 years; and ysm 15.9±9.0). Groups II and III characterised, by inclusion criteria, by significant different mean BMD values, were similar as far as chronological and menopausal age were considered. Metabolic tests included a short urine collection to determine calcium, hydroxyproline, cross-linked N-telopeptides of type I collagen (NTx) and creatinine (Cr); half-way through this collection, a blood sample was taken for the measurement of total alkaline phosphatase activity (ALP) and tartrate-resistant acid phosphatase activity (TRAP). BMD at lumbar spine was evaluated. Results: There were significant differences amongst the three groups in mean ALP (P<0.001, by analysis of variance) TRAP (P<0.006) and NTx/Cr (P<0.001) values, but not as far as mean values of calcium/Cr or hydroxyproline/Cr ratios were concerned. Considering the group as a whole, there were significant inverse correlations between NTx/Cr, ALP, TRAP and BMD controlling for both age (r=−0.392, P<0.001; r=−0.447, P<0.001 and r=−0.327, P<0.002, respectively) and ysm (r=−0.374, P<0.001; r=−0.474, P<0.001 and r=−0.333, P<0.002). Conclusions: Our results indicate, that, even after controlling for both ageing and oestrogen status, there is an inverse relationship between bone mass (that at a given time represents the balance of all previous metabolic events) and a biochemical marker (which reflects bone turnover at the time of examination). These findings are in line with the belief that increased bone turnover should be regarded as a risk factor for osteoporosis. Furthermore, our results indicate that, unless there is no increase of hepatic isozyme, total ALP still maintains a possible role as a first analysis to evaluate bone turnover before requesting markers with greater specificity, sensitivity but also more expensive and whose analysis is sometimes time-consuming.     

Effects of menopause and hormone replacement therapy on plasma lipids, lipoproteins and LDL-receptor activity

A cross-sectional study of ninety six women was conducted to examine the effect of menopause and hormone replacement therapy (HRT) on plasma lipids, lipoproteins and oxidation of low density lipoproteins. The sample consisted of 26 premenopausal women, 26 postmenopausal women taking no replacement hormones and 43 postmenopausal women on hormone replacement therapy. Postmenopausal women not taking replacement hormones had significantly higher plasma cholesterol, low density lipoprotein (LDL) cholesterol and lipoprotein[a] (Lp[a]) levels compared to premenopausal women or postmenopausal women on HRT [6.00±0.15, 5.36±0.17 (P<0.01), 5.63±0.13 (P<0.05) mmol/l, respectively for total cholesterol; 4.13±0.15, 3.64±0.15 (P<0.05), 3.82±0.12 (P<0.05) mmol/l, respectively for LDL-cholesterol; 48.19±9.90, 26.59±5.53 (P<0.03), 25.12±4.62 (P<0.03) mg/dl, respectively for Lp[a]]. The differences in LDL cholesterol concentrations were inversely related to changes in LDL receptor activity (r=−0.27, P<0.01). HRT use was found to be associated with a significantly smaller LDL particle size. Plasma triglyceride was significantly higher in women on HRT (1.16±0.07 mmol/l) than in the premenopausal group (0.96±0.07) or postmenopausal group not using HRT (0.87±0.06). There were no differences in LDL oxidation between the groups when LDL was oxidised in the presence of copper. Nor was there any difference in the uptake of copper-oxidised or macrophage-modified LDL into J774 macrophages. These results confirm the effect of menopause and exogenous hormones on plasma lipids and lipoproteins, and suggest that HRT modifies the activity of the LDL receptor. Hormone replacement did not appear to protect LDL from oxidation.     

Haemodynamic and hormonal effects of short-term oestradiol treatment in postmenopausal women

Haemodynamic changes during a 3-wk treatment with oestradiol valerianate (2 mg/day orally) were studied in 12 postmenopausal women by isotope ¹¹³In^m radiocardiography.

Systolic blood pressure measured in the supine position decreased during oestradiol treatment by 3% (P < 0.05) and the diastolic blood pressure decreased by 4% (P < 0.01). The heart rate decreased by 15% (P < 0.001).

Blood volume increased during oestrogen treatment by 5% (P < 0.05) whereas cardiac output decreased by 9% (P < 0.05). Stroke volume increased by 13% (P < 0.001) due to concomitant decrease in heart rate.

Changes in plasma oestrone and oestradiol concentrations during oestradiol valerianate substitution showed a positive correlation with the changes of blood volume.     

Transdermal estrogen replacement therapy and plasma lipids in 693 French women

Objectives: The cardiovascular effects of transdermal estrogen are not so well established than those induced by oral estrogen. In a representative sample of French postmenopausal women, we assessed plasma lipid changes induced by transdermal 17β-estradiol. Methods: This cross-sectional study was carried out among the population sample of the third MONICA survey on cardiovascular risk factors. We selected 693 postmenopausal women according to the followed criteria; women with intact uterus and no menstruation for more than 12 months, women with bilateral oophorectomy, hysterectomized women older than 55 years and hysterectomized women who had followed hormone replacement therapy. We used multivariate linear regression models, taking into account confounding variables, to assess lipid changes induced by estrogen. Results: We compared 192 women currently taking transdermal 17β-estradiol (27 unopposed estrogen and 165 estrogen plus progestin) with 501 women without any hormonal treatment. After adjustment for living area, education level, income tax, smoking, alcohol consumption, physical activity, age and body mass index, transdermal estrogen replacement therapy (ERT) was significantly associated with lower levels of serum total cholesterol [6.10 (S.E., 0.11) vs 6.35 (0.09) mmol/l, P<0.01], triglycerides [1.06 (0.06) vs 1.23 (0.05) mmol/l, P<0.001], LDL-cholesterol [3.93 (0.11) vs 4.13 (0.09) mmol/l, P<0.05], VLDL-cholesterol [0.48 (0.03) vs 0.56 (0.02) mmol/l, P<0.001] and apolipoprotein B [1.20 (0.03) vs 1.26 (0.02) g/l, P<0.01]. Levels did not differ significantly for HDL-cholesterol [1.68 (0.05) vs 1.66 (0.04) mmol/l] and apolipoprotein A1 [1.79 (0.03) vs 1.81 (0.02) g/l]. Conclusion: Transdermal ERT may confer a cardiovascular protection by lowering atherogenic lipoproteins.     

Plasma leptin levels in obese and non-obese postmenopausal women before and after hormone replacement therapy

Objective: the aim of this study was to investigate the effect of hormone replacement therapy (HRT) on plasma leptin levels in postmenopausal women, and the relationship between the plasma leptin levels and obesity. Methods: premenopausal women with normal cycles (n=30; mean ages, 35.4±8.3 years) and postmenopausal women (n=45; mean ages, 49.5±4.7 years) were randomly selected. Women were classified as obese (BMI>27 kg/m²) and as non-obese (BMI<27 kg/m²). Blood samples were obtained from the premenopausal women at the beginning of cycle, and from the postmenopausal women before and 6 months after HRT. Plasma leptin levels were measured by radioimmunassay. Results: plasma leptin levels were significantly higher in premenopausal women than in postmenopausal women (18.60±5.0; 3.67±2.44 ng/ml, respectively, P<0.001). Obese premenopausal women (n=15) had significantly higher plasma leptin levels (24. 60±7.81 ng/ml) in comparison with the levels of the non-obese premenopausal women (n=15; 12.50±4. 63 ng/ml) (P<0.001). Although there was no significant difference in the plasma leptin levels between obese (n=25) and non-obese (n=20) postmenopausal women before HRT, plasma leptin levels were significantly elevated in both obese and non-obese postmenopausal women after HRT (P<0.001), and the obese women had significantly higher plasma leptin levels than the non-obese (29.05±10.53; 14.78±6.76 ng/ml, respectively, P<0.001). Conclusion: HRT is effective in the elevation of the plasma leptin levels in postmenopausal women, and in obese women the increase of the plasma leptin levels are more marked than the non-obese women after HRT.     

Association between urinary incontinence and urinary tract infections, and fractures in postmenopausal women

Objective: The association between urinary disorders, such as ongoing urinary incontinence (UI), history of urinary incontinence (HIST-UI) and urinary tract infactions (UTI), and fractures in peri- and postmenopausal women was assessed in an epidemiological study. Subjects and methods: The sample consisted of 10 000 women from seven birth cohorts, born between 1900 and 1940, who were investigated regarding urinary disorders, fractures and reproductive history by means of a postal questionnaire. Results: The overall response rate was 74.6%. The respondents (n = 7459) represented 53% of the total population from the respective birth cohorts. There was a significant independent correlation between UI, HIST-UI and UTI, respectively, and fractures after the age of 30. In subjects with HIST-UI, tobacco smokers compared to non-smokers had significant more fractures in both the 1930 and 1940 birth cohorts (P < 0.01). Logistic multiple regression in the 1930 and 1940 cohorts demonstrated that age (P < 0.001), HIST-UI (P < 0.001) and tobacco smoking (P < 0.05), respectively, had an independent explanatory value for fractures. Conclusion: The prevalence of fractures increased with increasing age, in smokers compared to non-smokers and in women with a history of UI.     

Change in body weight after hormone replacement therapy in postmenopausal women is dependent on basal circulating leptin

Objective: To address the effect of leptin in the modulation of change in body weight after hormone replacement therapy (HRT), we prospectively examined the responses of body weight and serum leptin after estrogen–progestin replacement in postmenopausal women. Patients: Subjects consisted of 63 postmenopausal women aged 54–82 years on HRT for osteoporosis. Design: Thirty three of the subjects received 0.3 mg of conjugated equine estrogen (CEE) (group 1) while 30 were on 0.625 mg of CEE daily (group 2). All subjects also took 5 mg of medrogestone acetate and 750 mg elemental calcium supplement daily. Measurements: Fasting serum leptin was measured by RIA at baseline, 1 and 3 months after treatment. Data were expressed as mean±S.E.M. Results: Serum leptin was highly related to body weight both at baseline (r=0.40, P<0.001) and after 3 months of HRT (r=0.42, P<0.001). When divided the subjects into three equal groups according to baseline leptin levels, it was found that serum leptin significantly decreased in subjects with high baseline leptin at 3 months (−9.4±5.7%, P<0.05) while it increased in subjects whose baseline leptin levels were in the lowest tertile at 1 month (33.2±8.3%, P<0.001) and 3 month (27.8±8.3%, P<0.01). In regards to body weight, those with leptin in the highest tertile demonstrated a reduction of body weight at 3 (−1.9±0.6%, P<0.05) and 12 months (−3.2±0.5%, P<0.05) after HRT while those whose serum leptin levels were in the lowest and middle tertiles did not demonstrate change in body weight. By repeated measured analysis of variance, it was found that the decrease in body weight in subjects with high serum leptin was independent of the doses of estrogen. Conclusion: Postmenopausal hormone replacement does not cause weight gain. However, it results in a small reduction in body weight particularly in subjects with higher basal leptin concentrations.     

Inhibin A and B in peri- and postmenopause

Objective: The aim of the study was to investigate the origin of inhibin A and B during the last years of the reproductive age and after menopause by measuring their levels in the ovarian and peripheral venous blood. Methods: The study population consisted of 43 women, aged 42–69 years (mean 50), who underwent hysterectomy with ovarian removal for a benign disease. A total of 24 of them were in follicular phase, 11 in luteal phase, and eight were postmenopausal. Peripheral and ovarian venous blood was collected for measurement of inhibin A and B. In addition, sex steroid hormone and gonadotropin levels were measured. Results: Ovarian venous inhibin B correlated significantly with ovarian estradiol secretion (r=0.5, P=0.001). The levels of inhibin B were significantly higher in the ovarian vein than in the peripheral vein (P=0.006). The highest inhibin B concentrations were detected in the mid-proliferative (mid-follicular) phase (median 31.6 pg/ml range 25.9–47.9). In postmenopausal women, inhibin B was not detectable. No correlation between FSH and ovarian inhibin B was found. Inhibin A rose rapidly in late proliferative (late follicular) phase (median 28.5, range <2–51.8) and dominated in the circulation throughout the luteal phase (median 20.9, range 8.8–60). For inhibin A, no concentration gradient existed between the ovarian and peripheral vein. Unlike inhibin B, inhibin A was detectable in ovarian and peripheral blood in postmenopausal women. A significant negative correlation between ovarian and peripheral inhibin A and FSH was found (r=−0.386, P=0.015; r=−0.345, P=0.034, respectively). Conclusion: Inhibin B correlates with ovarian estradiol secretion and seems to reflect follicular function. Inhibin A dominates in circulation during the luteal phase but is detectable at low concentrations both in follicular phase and even in postmenopause. Our findings suggest that inhibin A may play a role in FSH suppression in the female reproduction. In addition to the ovary, there may be extragondal source(s) of inhibin A.     

Sympathoadrenal response of postmenopausal women prior and during prolonged administration of estradiol

Objective: Cardiovascular disease seems to increase after the menopause and is thought to be reduced by estrogen replacement therapy. Among the many studies which have tried to define the multifactorial mechanisms of estrogens cardiovascular prevention, very few have focused on their possible modulation of adrenergic activity. In the present study we investigated whether prolonged estradiol replacement via transdermal patches is able to modulate cardiovascular and adrenergic responses to stimuli. Methods: Baseline and responses to a cold stimulus and to the upright position of catecholamines (epinephrine and norepinephrine), heart rate, systolic and diastolic blood pressure were investigated in 15 healthy volunteer postmenopausal women both prior to and after 2 months of treatment with patches rated to deliver 50 μg/day of estradiol. Results: Basal norepinephrine levels (P<0.005), as well as their integrated responses to the cold stimulus (P<0.02) were lower during estradiol. By contrast, responses of norepinephrine to the upright test, as well as basal and responses to stimuli of epinephrine and circulatory parameters were not different before and during estradiol. Conclusions: Estradiol replacement at low doses significantly decreases overall sympathetic output, both in basal conditions and under specific stimuli. These effects whether maintained or magnified in the long term may play a role in the prevention of the postmenopausal cardiovascular risk.     

Worsening of depressive symptoms 6 months after an acute coronary event in older adults is associated with impairment of cardiac autonomic function

Background: Depression increases mortality of coronary patients, and autonomic dysfunction has been proposed as an explanation for this association. Methods: In a sample of 38 adults ≥ 60 years with myocardial infarction or unstable angina, we studied depression (presence of a major depressive episode and 21-item Hamilton depression score) and heart rate variability (HRV) of 550 normal beats shortly after admission to the coronary care unit (CCU). Thirty patients were alive at 6 months and were studied at that time as well. Spectral HRV measurements included power in the high-frequency range (HF, 0.15—0.55 Hz, a measure of parasympathetic activity) and low-frequency range (LF, 0.03—0.15 Hz). Nonspectral HRV measurements included standard deviation of normal beats (SDNN) and two measures of vagal activity: percentage of adjacent cycles differing by >50 ms (pNN50) and the root-mean-square of differences in successive beats (rMSNN). Results: Patients who died within 6 months (n=8) had a higher Hamilton-D score than survivors (13.9±6.5 vs. 18.4±5.6, P=0.039) and were more likely to have an episode of major depression upon admission to the CCU (71 vs. 27%, P=0.027). An increase in Hamilton-D score at 6 months correlated with a decrease in total (r=–0.48, P=0.014), high-frequency (r=–0.49, P=0.007), and low-frequency HRV (r=–0.46, P=0.014). Limitations: Patients belonged to a single institution and there was a small proportion of men. Conclusions: Progression of mood symptoms 6 months after an acute coronary event is associated with an impairment of autonomic control of the heart in elderly individuals.     

Endometrial safety and tolerability of AERODIOL(R) (intranasal estradiol) for 1 year

Objective: the purpose of this study was to assess the endometrial safety and patient acceptability of a pulsed estrogen therapy provided by S21400 (intranasal 17 β-estradiol) in the treatment of postmenopausal symptoms. Design: postmenopausal women (n=408) entered an open-label, community based, multicentre trial. Patients received S21400 plus sequential (>90% of patients) or continuous progestogen. Treatment was initiated with a standard daily dose of 300 μg but dose adaptation was possible every 3 months from 150 to 600 μg daily. Endometrial biopsies were performed at entry and at 12 months, and bleeding patterns were recorded at 3-monthly intervals throughout the trial. Results: 71% of patients received 300 μg per day S21400 throughout the study, 3% had their dose decreased, 19% had their dose increased and 7% had their dose both decreased and increased. Three hundred and eleven biopsies were obtained after 12 months of treatment, there were no cases of endometrial hyperplasia. The 95% confidence interval [CI] for the rate of incidence was 0–1.2%. Cyclical bleeding occurred in 82% of sequential treatment cycles. Unexpected bleeding occurred in 5% of the treatment cycles. Presence of unexpected bleeding varied according to the treatment regimen, 15 and 4% of the cycles with combined continuous and sequential regimen, respectively. Unexpected bleeding was mostly spotting. Nasal treatment was well accepted. Nasal symptoms (itching sensation, rhinorrhea and sneezing) were mostly mild in intensity and they led to treatment withdrawal in approximately 3% of patients. The rate of treatment continuation was 85% at 1 year. Conclusions: S21400, in combination with continuous or sequential progestogen, exhibits good endometrial safety and patient acceptability in postmenopausal women.