Effects of oestradiol and oestroprogestin on erythrocyte antioxidative enzyme system activity in postmenopausal women

OBJECTIVE: Data concerning the relationship between sex steroid hormones and the cellular antioxidative enzyme system are controversial. We investigated the effects of oestradiol deficiency after menopause and the influence of transdermal oestradiol therapy (ET) and hormonal (oestradiol plus medroxyprogesterone) replacement therapy (HT) on erythrocyte superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT). GSH and selenium (Se) concentrations were also estimated. Serum lipid peroxide (LPO) levels were measured as an indicator of free-radical production and lipid peroxidation. PATIENTS: The study group consisted of 80 postmenopausal women, divided into two subgroups: 26 women with surgically induced menopause (ET1) and 54 women with physiological menopause (HT1). Forty premenopausal healthy volunteers were controls (C group). RESULTS: LPO was higher in postmenopausal women and decreased after both ET and HT. GSH-Px and GSH were lower in the postmenopausal groups but increased significantly after both types of therapy. Se concentrations did not differ significantly among the groups. CAT activities were similar in all groups and decreased after ET and HT. SOD activities in postmenopausal women were similar to those in the C group and did not change significantly after treatment. CONCLUSIONS: The administration of natural oestrogens to postmenopausal women diminishes oxidative stress and increases antioxidative cell potency.     

THE RELATIONSHIP BETWEEN 17β-HYDROXYSTEROID DEHYDROGENASE ACTIVITY AND OESTROGEN CONCENTRATIONS IN HUMAN BREAST TUMOURS AND IN NORMAL BREAST TISSUE

The activity of 17 beta-hydroxysteroid dehydrogenase (17 beta HSD) was measured in human breast tumours and in normal breast tissue from premenopausal, perimenopausal and postmenopausal women. Enzyme activity was higher in tumour tissue than in normal tissue from the same breast and under the conditions of the assay the oxidation of oestradiol was higher than the reduction of oestrone. The physiological status of the women in the study did not relate to the activity of the enzyme in either normal or tumour tissue although fibroadenomas had less activity than adenocarcinomas. In postmenopausal women tumour tissue oestrogens were 2-3 fold higher than in normal tissue from the same breast. Furthermore, tumour tissue concentrations of oestradiol tended to be higher than those of oestrone although in normal tissue the two oestrogens were present in similar concentrations. In plasma from the same women oestrone was the predominant oestrogen. There appears to be no direct relationship between 17 beta HSD activity and oestrogen concentrations but the enzyme may play a part in determining the balance between oestrone and oestradiol according to substrate and cofactor availability.     

Endogenous oestrogens are related to cognition in healthy elderly women

OBJECTIVE: To investigate whether levels of endogenous hormones, in particular circulating oestrogens and SHBG, are associated with cognition in healthy postmenopausal women. DESIGN: Cross-sectional study. PATIENTS: Four hundred and two healthy postmenopausal women aged 50-74 years between 8 and 30 years after menopause, none taking oestrogen. MEASUREMENTS: Serum concentration of oestradiol, oestrone, and sex hormone binding globulin (SHBG) determined by immunoassay. Cognition assessed using the mini-mental state examination questionnaire (MMSE). RESULTS: In this group, 149 individuals had a MMSE score < 27, while only 89 individuals had a MMSE score < 26, indicating a relatively healthy population with regard to cognitive ability. Cognition decreased with age, time since menopause and blood pressure, and was better with higher age at menopause. Serum oestrogens and SHBG levels were not related to age, age at menopause, or time since menopause, and oestrogen levels were positively associated with blood pressure. After adjustment for mean arterial pressure and SHBG, the frequency of mild cognitive impairment decreased significantly with higher oestradiol and oestrone serum levels [ORs Q5 vs. Q1: 0.41 (95% CI 0.20-0.84) and 0.51 (95% CI 0.20-0.99) for oestradiol and oestrone, respectively]. CONCLUSIONS: Postmenopausal women with higher remaining circulating oestradiol levels appear less likely to suffer from cognitive impairment. This effect is independent of age at menopause, time since menopause and BMI. These findings support the hypothesis that endogenous oestrogens may protect against cognitive decline with ageing.     

Sex-specific association of the androgen to oestrogen ratio with adipocytokine levels in older adults: the Rancho Bernardo Study

OBJECTIVE: Androgens and oestrogens have opposing effects on some adipocyte functions. Thus, the androgen to oestrogen balance may be as important as the individual hormones in determining the biological interaction between endogenous sex hormones and adipocyte-derived factors such as adiponectin and leptin. We tested this hypothesis by evaluating the sex-specific, cross-sectional association of sex hormones and androgen to oestrogen ratios with serum adiponectin and leptin in older men and postmenopausal women. DESIGN: Cross-sectional. PARTICIPANTS: A total of 1510 community dwelling men and postmenopausal women aged 50-92 years. MEASUREMENTS: Serum leptin, adiponectin and sex hormone levels. RESULTS: Adiponectin and leptin levels were higher in women than men (P < 0.001). In both sexes, adiponectin concentrations were lower, and leptin levels higher, with increasing BMI and waist girth (all P < 0.001). Although the ratio of total testosterone to total oestradiol was significantly associated with both adipocytokines in both sexes, the strongest and most consistent hormone-adipocytokine associations were observed when the androgen to oestrogen ratio was expressed as total testosterone to bioavailable oestradiol. In linear regressions, the testosterone to bioavailable oestradiol ratio was positively related to adiponectin and inversely related to leptin, with nearly identical standardized beta-coefficients for men and women (all P < 0.001). The strength of the hormone ratio-adipocytokine associations was reduced, but not eliminated, after adjustment for age, adiposity and cardiovascular disease risk factors, including insulin resistance. CONCLUSIONS: The striking similarity of the hormone ratio-adipocytokine associations for men and women, despite wide differences in sex hormone and adipocytokine levels, suggests these results reflect underlying physiological mechanisms common to both sexes.     

Blood growth hormone-binding protein levels in premenopausal and postmenopausal women: roles of body weight and estrogen levels

A substantial proportion of GH circulates bound to high affinity GH-binding protein (GHBP), which corresponds to the extracellular domain of the GH receptor. Current evidence indicates that nutritional status has an important role in regulating plasma GHBP levels in humans. In the present study the relationship among plasma GHBP levels, body composition [by bioelectrical impedance analysis (BIA) and dual energy x-ray absorptiometry (DEXA)] and serum estradiol (E(2)) was evaluated in premenopausal (n = 92) and postmenopausal (n = 118) healthy women with different body weight [three groups according to body mass index (BMI): normal, 18.5-24.99; overweight, 25-29.99; obese, 30-39.99 kg/m(2)]. Plasma GHBP levels were measured by high pressure liquid chromatography gel filtration. GH and insulin-like growth factor I levels were determined by immunoradiometric assay and RIA, respectively. GHBP levels were significantly higher in premenopausal women with BMI above 25 kg/m(2) (overweight, 3.789 +/- 0.306 nmol/L; obese, 4.372 +/- 0.431 nmol/L) than those observed in postmenopausal women (overweight, 1.425 +/- 0.09 nmol/L; obese, 1.506 +/- 0.177 nmol/L). No significant differences were found between normal weight premenopausal (1.741 +/- 0.104 nmol/L) and postmenopausal (1.524 +/- 0.202 nmol/L) women. In premenopausal women GHBP levels correlated positively with BMI (r = 0.675; P < 0.001), fat mass (FM; r = 0.782; P < 0.001; by BIA; r = 0.776; P < 0.001; by DEXA), truncal fat (TF; r = 0.682; P < 0.001), waist to hip circumference ratio (WHR; r = 0.551; P < 0.001), and E(2) (r = 0.298; P < 0.05), whereas no significant correlation was found in postmenopausal women between GHBP levels and BMI, FM, TF, WHR, or E(2). In normal weight pre- and postmenopausal women GHBP levels did not change between the ages of 20 and 69 yr. No statistically significant correlation was found between GHBP and age for all groups studied. Moreover, in two distinct subgroups of pre- and postmenopausal women, aged 40-49 yr, the direct relationship between GHBP levels and all indexes of adiposity were only observed in premenopausal women [BMI: r = 0.836; P < 0.001; FM: r = 0.745 (BIA) and r = 0.832 (DEXA); P < 0.001; TF: r = 0.782; P < 0.001; WHR: r = 0.551; P < 0.05], but not in postmenopausal women. In conclusion, the present data indicate a strong direct correlation between GHBP and body fat in premenopausal, but not in postmenopausal women, whereas they failed to detect a relationship between GHBP and age. Therefore, these results suggest that endogenous estrogen status may be an important determinant of the changes in GHBP levels in women with different body weights.     

Influence of exogenous melatonin on catecholamine levels in postmenopausal women prior and during oestradiol replacement

OBJECTIVE: In young individuals melatonin administration reduces circulating norepinephrine. Some effects of melatonin are reduced in elderly women and are modulated by gonadal steroids. Accordingly, the influence of melatonin on catecholamine levels was investigated in postmenopausal women without and with oestradiol replacement. DESIGN: Prior to and after 2 months of transdermal oestradiol (50 microg/day), women were studied on two consecutive days, on which they received placebo or 1 mg of melatonin orally in a randomised and double-blind fashion. PATIENTS: Fourteen healthy postmenopausal women. MEASUREMENTS: Resting levels of epinephrine and norepinephrine and their responses to both a cold stimulus, performed by placing a hand in a basin of water and ice for 2 minutes, and to 10 minutes of upright position (upright test). RESULTS: Prior to oestradiol, melatonin did not modify baseline or stimulated catecholamine levels. In contrast, during oestradiol, melatonin tended to reduce, although not significantly, baseline norepinephrine levels (P = 0.053), and significantly reduced peak values (P = 0.0061) and integrated norepinephrine response (P = 0.0076) to the cold stimulus. Responses of norepinephrine to the upright test were not modified, while those of epinephrine were increased (P = 0.042). During, but not prior to oestradiol replacement, modifications induced by melatonin (melatonin day-placebo day) in the norepinephrine response to the cold (r2 = 0. 457; P = 0.0079) and the upright (r2 = 0.747; P = 0.0001) tests were linearly and inversely related to the responses of the placebo day. CONCLUSIONS: Melatonin does not modulate adrenergic activity in postmenopausal women without hormone replacement therapy. Oestradiol replacement restores the capability of melatonin to modulate adrenergic activity, particularly the norepinephrine response to stimuli.     

Serum oestradiol and oestrogen-receptor gene polymorphism are associated with bone mineral density independently of serum testosterone in normal males

OBJECTIVES: The physiological effects of oestrogens on bone in men were largely unanticipated until recently, when oestrogen deficiency in males with aromatase deficiency and oestrogen resistance was found to cause osteoporosis and delayed fusion of epiphyses despite sufficient serum testosterone. This raises the possibility that in normal men oestrogens rather than androgens are of physiological importance in bone maturation. In the present study, we examined the association of serum oestradiol (E2) compared to that of free testosterone (FT) with bone mineral density (BMD) in normal men. The effect of oestrogen receptor (ER) gene polymorphism on BMD in men was also addressed. SUBJECTS: Eighty-one Thai men aged 20-79 years. All were healthy and did not take medication which may affect calcium and bone metabolism. BMD was assessed by DEXA. Dietary calcium was assessed by a 3-day dietary record. Serum E2 and FT concentrations were measured by radioimmunoassay. Polymorphism at intron 1 of the alpha isoform of ER gene was determined by PCR-RFLP. Small p represents the presence of the restriction site while capital P indicates the absence of the restriction site. RESULTS: Serum FT decreased with increasing age (r = -0.58, P < 0.0001) while E2 did not. However, there was a positive association between E2 and FT (r = 0.28, P < 0.05). Serum FT was related to BMD at femoral neck (r = 0.26, P < 0.05) and Ward's triangle (r = 0.30, P < 0.01) while E2 was related to BMD at anteroposterior (AP) lumbar spine (r = 0.29, P < 0.05), femoral neck (r = 0.23, P < 0.05) and femoral trochanter (r = 0.27, P < 0.05). Besides FT and E2, age, body weight, fat mass and fat-free mass were also correlated to BMD at various skeletal sites. Using stepwise multiple linear regression to control for the confounding effects among these factors, fat-free mass was found to be strongly associated with BMD at most skeletal sites. Serum E2 was related to BMD independently of other factors including FT at AP lumbar spine (r = 0.22, P < 0.05), femoral neck (r = 0.26, P < 0.01), femoral trochanter (r = 0.22, P < 0.05) and Ward's triangle (r = 0.26, P < 0.01) while serum FT was not associated with BMD at any site after controlling for E2 and other related factors. Concerning ER alpha gene polymorphism, 27 (33.3%) of the subjects had pp genotype, while 42 (51.9%) and 12 (14.8%) Pp and PP genotypes, respectively. After controlling for age, body weight, fat mass, fat-free mass, calcium intake, FT and E2, the presence of P allele was associated with higher BMD at AP L2-L4 (P < 0.05). CONCLUSIONS: Serum oestradiol is more related to bone mass than free testosterone in normal men. Oestrogen-receptor gene polymorphism is also associated with bone mass in men independently of oestradiol levels. Serum oestradiol together with oestrogen-receptor genotype may partly determine bone mass in males.     

Oestrogens prevent the increase of human serum soluble interleukin-6 receptor induced by ovariectomy in vivo and decrease its release in human osteoblastic cells in vitro

OBJECTIVE: Interleukin-6 (IL-6) seems to be a key mediator of the increased bone loss that follows loss of ovarian function. Based on this and on evidence that oestrogen deficiency may also increase cell sensitivity to IL-6, we studied the effects of ovariectomy and of oestrogen replacement therapy on the serum levels of IL-6 and of soluble IL-6 receptor (sIL-6R) in vivo. DESIGN AND PATIENTS: Thirty-seven fertile women undergoing surgery for benign uterine diseases were divided into 3 groups and monitored for 12 months: hysterectomized women (n = 9), ovariectomized untreated women (n = 12) and ovariectomized women starting treatment with transdermal estradiol (E2, 50 microg/d) 1 month after surgery (n = 16). RESULTS: Hysterectomy alone caused no significant changes of sIL6R whereas serum levels of sIL-6R rose progressively after ovariectomy (mean +/- SEM: 31 +/- 9% and 38 +/- 7% over baseline, at 6 and 12 months, respectively; P < 0.01). Oestrogen replacement therapy prevented the increase of sIL6R over a 1-year period. A similar pattern was also found for serum IL-6 but the changes did not reach statistical significance. In ovariectomized (OVX) women there were significant correlations between serum sIL-6R levels and FSH (r = 0.59; P < 0. 01), oestradiol (r = - 0.43; P < 0.01), testosterone (r = - 0.41; P < 0.05), osteocalcin (r = 0.42; P < 0.05) and bone alkaline phosphatase (r = 0.44; P < 0.05). To examine whether oestrogen directly regulates sIL-6R secretion by bone cells, we studied in vitro the basal and phorbol ester (PMA) stimulated release of sIL-6R in a human osteoblastic cell-line (MG-63) and in a tumour-derived osteoclastic cell line (GCT-51). Osteoblastic (but not osteoclastic) cells spontaneously produced considerable amounts of sIL-6R and the protein kinase-C activator PMA (10-8 M) increased the release of sIL-6R by osteoblasts more than 3-fold. More strikingly, 17beta E2 (but not 17alpha) significantly inhibited both the spontaneous- and PMA-induced release of sIL-6R by osteoblastic cells (P < 0.05). CONCLUSIONS: These results indicate that oestrogen loss causes alterations of the IL-6 system, and that sIL-6R is under the direct inhibitory control of oestrogens both in vivo and in vitro.     

Oestrogen has no short-term effect on intestinal strontium absorption in healthy postmenopausal women

OBJECTIVE: Impaired intestinal calcium absorption in postmenopausal women is often indirectly linked to decreased serum 1,25(OH)2D or to intestinal resistance to its action rather than directly to low circulating oestrogen levels following the menopause. The purpose of this clinical study was to investigate the short-term effect of oral 17 beta-oestradiol on intestinal calcium absorption, with strontium as a marker. DESIGN AND PATIENTS: Twenty-five healthy postmenopausal women participated in this randomised double blind placebo controlled clinical trial. Twelve women received oestradiol therapy (2 mg/day) and thirteen placebo for 2 months. Fractional strontium absorption (Fc240) was assessed at baseline and after 2 months of oestradiol/placebo therapy. RESULTS: Intestinal strontium absorption (Fc240) was unchanged after treatment with 17 beta-oestradiol (10.1 +/- 5.0 vs. 10.2 +/- 3.8(%)). Serum total calcitriol (1,25(OH)2D) was unchanged after treatment with placebo (88 +/- 22 vs. 79 +/- 21 (pmol/l)) but increased after treatment with oestradiol (88 +/- 30 vs. 116 +/- 33 (pmol/l); P < 0.005). Serum vitamin D binding protein (DBP) increased after oestradiol but not after placebo treatment. The free serum 1,25(OH)2D index was calculated. This index did not change after oestrogen therapy (1.6 +/- 0.5 vs. 1.8 +/- 0.5). CONCLUSION: In healthy postmenopausal women, short-term suppletion with exogenous oral oestrogen did not influence intestinal calcium absorption as measured by the strontium absorption test.     

Effects of administration of 17beta-oestradiol on serum leptin levels in healthy postmenopausal women

OBJECTIVE: Women have higher leptin levels than men at a certain degree of adiposity. The role of oestrogens in the regulation of serum leptin levels remains inconclusive. The aim of the present study was to investigate the effect of unopposed oestrogen replacement therapy, during two months, on serum leptin levels in postmenopausal women. DESIGN: A double-blind, placebo-controlled, randomized study. SUBJECTS: Twenty-five healthy postmenopausal women were studied (mean (+/- SD) age: 52.9 +/- 2.7 years, range of age: 48.7-57.4 years; mean body mass index (BMI): 26.4 +/- 4.2 kg/m2, range of BMI: 21.0-39.0 kg/m2). Twelve of these women were treated with 2 mg 17beta-oestradiol daily, and 13 postmenopausal women received placebo. MEASUREMENTS: Before and at the end of a 2-month study period, anthropometric and bio-electrical impedance measurements were performed, and fasting blood samples were taken, to determine serum levels of sex hormones and leptin. RESULTS: During the 2-month study period, body weight had increased significantly in the placebo group compared with the treatment group, but no significant changes were observed in percentage of body fat or the amount of body fat in kg between the groups. Following administration of 17beta-estradiol, the median leptin level increased from 17.6 microg/l to 24.1 microg/l after 2 months (P = 0. 008 compared with baseline). This increase was significantly different from the placebo group (P = 0.019), which showed no change in circulating leptin levels. CONCLUSION: This study demonstrates that unopposed oestrogen replacement therapy during 2 months in postmenopausal women slightly, but significantly, increases total serum leptin levels. This observation suggests a role for oestrogens in the regulation of leptin.     

Adjuvant oestrogen therapy does not improve disease activity in postmenopausal patients with rheumatoid arthritis.

OBJECTIVE--To investigate whether oestrogens can be used as treatment to diminish disease activity in women with rheumatoid arthritis. METHODS--Forty postmenopausal female patients with active rheumatoid arthritis participated in a placebo-controlled, double-blind study on the possible beneficial effect of adjuvant treatment of oestradiol on disease activity. RESULTS--Thirty three patients completed 52 weeks of treatment with 2 mg oestradiol-valerate or placebo. No statistically significant difference was found in and between both treatment groups with regard to articular indices, pain score by visual analogue scale, erythrocyte sedimentation rate and health questionnaire on daily activities before, during and at the end of the study. CONCLUSION--This first randomised prospective placebo-controlled study shows no beneficial effect of oestrogens on disease activity in postmenopausal female patients with rheumatoid arthritis.     

Oestrogen and colorectal cancer: mechanisms and controversies

Aim

The role of oestrogen metabolism and action in colorectal cancer (CRC) is controversial. An extensive review of the current literature, encompassing epidemiological evidence, systemic and peripheral oestrogen concentrations, 17β-hydroxysteroid dehydrogenase (17β-HSD) and aromatase in CRC, steroid sulphatase (STS)/oestrone sulphotransferase (EST) and in vitro and in vivo genomic effects was therefore undertaken.

Methods

A literature search (key words: colorectal cancer, oestrogen, oestrogen receptor, 17β-HSD, STS, organic anion transporter) was performed using Embase, Medline, and Pubmed and papers were evaluated on scientific relevance on an individual basis.

Results

Epidemiological data highlights that premenopausal women, or postmenopausal women taking hormone replacement therapy, are significantly less likely than males to develop CRC. This implies that oestrogen signalling is most likely involved in CRC physiology and aetiology. Little is known about oestrogen metabolism in the colon. However, the expression of 17β-HSD, STS, and EST, enzymes involved in oestrogen metabolism, have shown prognostic significance. Evidence also suggests that protective effects are modulated through oestrogen receptor beta, although which metabolite of oestrogen, oestradiol (E₂) or oestrone (E₁), is more active remains undefined. To complicate matters, the changes in the peripheral ratios of these enzymes, oestrogens and receptors most likely influences CRC progression.

Conclusion

Epidemiological evidence, now supported by in vitro and in vivo studies, strongly associates oestrogen action and metabolism with CRC. Initially protective against CRC, once developed, results suggests that oestrogens increase proliferation. Consequently, hormone-ablation therapy, already successful against breast and prostate cancer, may be effective against CRC.     

Transdermal 17 beta-estradiol combined with oral progestogen increases plasma levels of insulin-like growth factor-I in postmenopausal women.

In order to evaluate the effect of postmenopausal estrogen replacement therapy on the plasma levels of the insulin-like growth factor-I (IGF-I) 12 postmenopausal women aged 44 to 59 years were studied. The control group consisted of 15 healthy premenopausal women aged 20-44 years. In the postmenopausal women the plasma levels of IGF-I, gonadotrophins and sex hormones were determined before and after 3 and 6 months cyclic replacement therapy with transdermal 17 beta-estradiol (E2 100 micrograms patches applied twice weekly) combined with oral chlormadinone acetate (2 mg daily for 7 days in each cycle). Basal levels of estradiol (E2), IGF-I, dehydroepiandrosterone sulphate (DHEA-S), testosterone and androstenedione were lower, but gonadotropin levels were higher in postmenopausal than in premenopausal women. In all the women studied age was inversely correlated with IGF-I levels (r = -0.793, p less than 0.001) and with DHEA-S concentrations (r = -0.435, p less than 0.02). In postmenopausal women transdermal estradiol administration restored the circulating E2 levels to the early follicular range and increased the IGF-I levels (from 76.4 +/- 9.2 micrograms/l to 141.8 +/- 20.8 micrograms/l; p less than 0.01). Transdermal estradiol decreased gonadotrophin levels without changes in concentration of DHEA-S, testosterone, androstenedione and SHBG. In postmenopausal women before and during replacement therapy a positive correlation was found between estradiol and IGF-I concentrations (r = -0.439, p less than 0.01). These results suggest that cyclic replacement therapy with transdermal 17 beta-estradiol in combination with chlormadinone acetate given orally increase the plasma levels of IGF-I in postmenopausal women.     

Modulation of endometrial redox balance during the menstrual cycle: relation with sex hormones

This study aimed to evaluate the effects of changes in sex hormones occurring during the menstrual cycle on the redox balance and lipid peroxidation in normal human endometrial cells. Forty women, ages 21-41 yr, who were admitted to the Department of Gynecology and Obstetrics of the University of Bari for routine checkups or were treated for benign uterine disease, underwent endometrial biopsy and venipuncture. On the basis of histological examination, patients were allocated as follows: 10 in the early proliferative phase, 12 in the late proliferative phase, 8 in the early secretory phase, and 10 in the late secretory phase. LH, FSH (immunoradiometric essay), estradiol (E2), and progesterone (P(4)) (RIA) were determined in plasma samples. On the endometrial specimens, total glutathione (GSH), oxidized GSH (GSSG), malondialdehyde, and GSH peroxidase activity (GSH-Px) were determined. Significant cycle-dependent changes in endometrial GSH-Px (P < 0.0001), GSH (P < 0.001), and GSSG as a percentage of GSH (P < 0.0001) were observed. Malondialdehyde did not show significant differences. A linear regression model correlating sex hormone changes with redox indexes was performed. A significant positive correlation was observed between E2 and GSH-Px (r = 0.74; P = 0.0001), E2 and GSSG, as percentage of total (r = 0.84; P < 0.0001); a negative correlation was found between E2 and GSH (r = -0.57; P = 0.0001). No significant correlation was found between P(4) or FSH and oxidative balance. LH was found to be correlated with GSH-Px (r = 0.66; P = 0.0001) and GSSG as percentage of GSH (r = 0.5; P < 0.001). We conclude that the hormonal pattern is involved in maintaining the optimal redox balance in endometrium, mainly through modulation of GSH level and metabolism.     

Effect of methyl testosterone administration on plasma viscosity in postmenopausal women

BACKGROUND: Coronary heart disease (CHD) is the leading cause of mortality in women, with an incidence that increases after menopause, hence suggesting a cardioprotective role of oestrogen. Menopause also results in a decline in androgen levels with resulting symptoms of decreased libido and sexual dysfunction. Recently, there has been a growing interest in the treatment of postmenopausal women with androgens. However, no data are available on plasma viscosity and fibrinogen levels in postmenopausal women on combined oestrogen/androgen therapy. METHODS: We conducted a randomized, double-blind, parallel-group 16-week study evaluating the effects of methyltestosterone supplementation on plasma viscosity and fibrinogen levels in postmenopausal women already on oestrogen replacement therapy (ERT) for at least 3 months. Women 21 years and older who were menopausal (natural or surgical) for at least 12 months were enrolled in the study. Participants were randomized to (1) an oestrogen-only group taking 1.25 mg esterified oestrogen (E-group) and (2) an oestrogen plus methyltestosterone (1.25 mg esterified oestrogen and 2.5 mg methyltestosterone) group (EA-group). Progesterone was not administered during the study period and women with intact uteri were given medroxyprogesterone 10 mg daily for 14 days at the completion of the study. RESULTS: After 16 weeks of treatment, both groups had a significant increase in serum oestradiol levels from baseline. The levels of total oestrogen were significantly higher in the E-group compared to the EA-group (P < 0.001). There was a greater decrease in the LH and SHBG levels in the EA-group (P = 0.01). There was no difference in total testosterone; however, free testosterone levels were significantly higher in the EA-group (P = 0.01). At the end of the study, there was a significant decrease in plasma viscosity only in the EA-group (P = 0.01). Fibrinogen levels increased in both the groups, reaching significance only in the EA-group (P = 0.006). Baseline weight, body mass index (BMI) and the duration of menopausal status did not have any significant impact on the changes in plasma viscosity or fibrinogen. Women in the EA-group showed significant reductions in total cholesterol (P = 0.009), high density lipoprotein (HDL) (P < 0.001) and triglyceride (TG) levels (P = 0.001). There was no significant change in these parameters in the E-group. CONCLUSION: This prospective study shows that the treatment of postmenopausal women on oestrogen with low-dose oral methyltestosterone results in a significant reduction in plasma viscosity. This lowering of plasma viscosity was achieved despite an increase in fibrinogen levels. Significant lowering of lipoproteins, especially TG levels, might have been responsible for this benefit. The combination regimen did not result in major side-effects. Based on these results, we feel confident in recommending low-dose androgens to postmenopausal women with a history of sexual dysfunction and decreased libido.     

Plasma cholesteryl ester fatty acid composition, insulin sensitivity, the menopause and hormone replacement therapy

This study was designed to determine the effect of menopause and hormone replacement therapy (HRT) on plasma cholesteryl ester fatty acid (CEFA) composition and insulin sensitivity and the relationships between these variables in perimenopausal women (aged 40-55 years) including 49 who were premenopausal and 32 who were postmenopausal. Plasma cholesteryl ester proportions of dihomo-gamma-linolenic acid (20:3 n-6) were correlated significantly with insulin sensitivity index (r=-0.319, P=0.005), fasting serum insulin levels (r=0.230, P=0.038), body mass index (r=0.242, P=0.03) and per cent body fat (r=0.329, P=0.003) in perimenopausal women (n=81). Similar associations were observed in premenopausal women. Regression analysis suggested the relationships between 20:3 n-6 proportions and indices of insulin action may be partly mediated by levels of adiposity. In postmenopausal women, 6 months of HRT significantly (P=0.008) increased the ratio of arachidonic acid (20:4 n-6) to linoleic acid (18:2 n-6), which is an indicator of activity in the pathway of 20:4 n-6 synthesis, compared with placebo. These findings suggest that the type of fat in the diet indicated by plasma CEFA composition is linked to adiposity and insulin action. They also suggest that in postmenopausal women, HRT may increase the synthesis of 20:4 n-6, which is the precursor for eicosanoids with important cardiovascular functions.     

Erythrocyte membrane phospholipid composition as a biomarker of dietary fat

BACKGROUND/AIMS: In a cross-sectional study, we investigated the relationship between erythrocyte membrane phospholipid fatty acid composition and dietary fat; we also investigated roles of menopausal status, age, body mass index (BMI) and waist-to-hip ratio (WHR) in interindividual variation of the biomarker. METHODS: Study participants were 204 women, aged 39-65 years, drawn from the ORDET cohort and selected as controls in a study of breast cancer. Membrane composition was assessed using capillary gas chromatography. Dietary fat composition was evaluated using a food frequency questionnaire. RESULTS: In pre- and postmenopausal women, erythrocyte membrane phospholipid levels of linoleic acid, oleic acid, and mono-unsaturated fatty acids were significantly associated with corresponding dietary measures (partial correlation coefficients: 0.23 and 0.39; 0.45 and 0.47; 0.40 and 0.48; respectively, in pre- and postmenopausal women). Among postmenopausal women, membrane poly-unsaturated fatty acids were correlated with the corresponding dietary measure (r=0.39, p<0.001). Membrane eicosapentanoic and docosahexanoic acid levels were significantly correlated with intake of fish/shell fish : r=0.21 and r=0.43 (premenopausal), and r=0.41 and r=0.44 (postmenopausal). Age, BMI and WHR had independent effects on membrane lipid composition. Age was associated with delta-6 desaturase activity in postmenopausal women (r=0.25, p<0.05). BMI was negatively associated with delta-9 desaturase activity in both pre- and postmenopausal women (r=-0.29, p=0.01 and r=-0.22, p<0.01, respectively). WHR was negatively associated with delta-5 desaturase activity in pre-menopausal women (r=-024, p<0.05). CONCLUSIONS: Erythrocyte membrane levels of some specific fatty acids can be used as biomarkers of these fatty acids as proportions of dietary fat.     

COMPARISON OF THE EFFECTS OF ETHINYL OESTRADIOL AND CONJUGATED EQUINE OESTROGENS IN OOPHORECTOMIZED WOMEN

Seventeen oophorectomized women were treated for 3 month periods, in random sequence, with ethinyl oestradiol 20 and 50 mug daily and conjugated equine oestrogens (Premarin)0-625 and 1-25 mg daily. The serum cholesterol, clot lysis time, plasma fibrinogen, platelet adhesiveness and activated partial thromboplastin time remained unchanged throughout the different oestrogen regimes. There was a significant rise of serum triglyceride levels on both doses of ethinyl oestradiol but no significant change with Premarin. Serum luteinizing hormone levels were depressed most by ethinyl oestradiol 50 mug daily, although no down to the levels in premenopausal women.     

Neutrophil glutathione peroxidase activity in iron deficiency anaemia

Neutrophil glutathione peroxidase (GSH-Px) activity was studied in 30 children with nutritional iron deficiency anaemia and 25 healthy age-matched controls. Initially GSH-Px in iron deficient anaemic children was significantly (p less than 0.001) low compared to the control group. All patients were subjected to iron therapy but only 8 returned for follow-up. The GSH-Px activity in all 8 cases rose to normal levels after therapy. These results suggest a relationship between iron and GSH-Px activity.     

Effect of raloxifene on salivary sex steroid concentrations in premenopausal women

Raloxifene is a selective oestrogen receptor modulator used clinically for the treatment and the prevention of osteoporosis in postmenopausal women. The drug has been evaluated in the Study of Tamoxifen and Raloxifene as an agent to reduce breast cancer incidence in postmenopausal women at high risk. However, about 30% of women who develop breast cancer do so in their premenopausal years. In this pilot study, salivary oestradiol and progesterone were determined throughout the menstrual cycle for a total of 22 subjects, 14 of whom completed pre- and postraloxifene (60 mg daily) salivary collections. The mean concentration of oestradiol during the menstrual cycle when subjects were taking raloxifene was significantly greater (P<0.001) than during baseline cycles. Neither salivary progesterone and cortisol nor menstrual cycle length were affected by raloxifene treatment. These data demonstrate that raloxifene administered to premenopausal women increases the concentration of oestradiol that diffuses into the salivary glands, and which presumably represents the concentration available to other organs as well. The results reflect increases in serum oestradiol reported earlier.