Effect of norethisterone acetate on estrogen metabolism in postmenopausal women.

Dominance of estradiol metabolism at the D-ring over the A-ring metabolism may play a role in the pathophysiology of human breast carcinogenesis. Currently, the influence of progestins on breast cancer risk is debated when added to postmenopausal estradiol replacement therapy. However, nothing is known about the action of progestins on estradiol metabolism. Therefore, the effect of oral and transdermal estradiol/norethisterone acetate (NETA) was investigated on the ratio of the main D-ring metabolite 16alpha-hydroxyestrone (16-OHE1) to the main Aring metabolite 2-hydroxyestrone (2-OHE1). The ratio of 16-OHE1 to 2-OHE1 after transdermal hormone replacement therapy (HRT) was 0.43 before treatment, 0.35 after estradiol and 0.52 after estradiol + NETA. The ratio after oral HRTwas 0.94 before treatment, 0.86 after estradiol and 2.30 after estradiol + NETA. Because of the high variations, no statistical significance could be calculated. Since there was a tendency to an increase after oral estradiol + NETA treatment, the individual patient profiles were examined. Here, three patients in the oral treatment group showed a significant increase of the ratio after the estradiol/NETA phase. In conclusion, transdermal NETA in HRT did not elicit any change in estrogen metabolism after 2 weeks' treatment. However, oral NETA may in some cases have an impact on estradiol metabolism which should be further evaluated.     

Kinetics of testosterone metabolism in normal postmenopausal women and women with breast cancer

The constant infusion and single injection techniques were utilized to study the kinetics of ³H-testosterone (T) metabolism in postmenopausal women with and without breast cancer. The metabolic clearance rates (mean ± SEM) for normal postmenopausal women were $\text{578 ± 82}\text{and}\text{644 ±128}\text{1}\text{24}\text{h}$ as obtained by the constant infusion and single injection techniques, respectively. The corresponding results for the women with breast cancer (patients) are $\text{644 ± 25}\text{and}\text{617 ± 106}\text{1}\text{24}\text{h}$. The single injection technique yielded values for rate constants (units) and volumes of distribution (1); k₁ = 37.5 ± 1.6 for the normals and 34.5 ±1.9 for the patients. K₂ = 76.6 ± 5.1 for the normals and 71.1 ± 1.6 for the patients, V₁ = 7.9 ± 2.2 for the normals and 8.7 ± 1.4 for the patients and V₂ = 7.0 ± 1.5 for the normals and 6.4 ± 1.2 for the patients. The constant infusion technique yielded values for the conversion ratios for the transformation of T to several products; 4-androstene-3,17-dione/T of 0.02 ± 0.003 for normals and 0.03± 0.002 for patients, 5α-dihydrotestosterone/T of 0.02 ± 0.002 for normals and 0.03 ± 0.002 for patients, estrone/T of 0.04 ± 0.01 for normals and 0.04 ± 0.01 for patients, estradiol-17β/T of 0.02 ± 0.005 for normals and 0.03 ± 0.005 for patients and estrone sulfate/T of O.16 ± 0.02 for normals and 0.24 ± 0.06 for patients. The T plasma concentrations and production rates were similar for the two groups of subjects. Hence there were no significant differences between the normals and the patients for all the kinetic parameters. It was determined that all the estradiol being produced in postmenopausal women could be coming from circulating T.     

Effect of misoprostol on bone mineral density in women with postmenopausal osteoporosis

OBJECTIVE: To evaluate the effect of misoprostol on bone mineral density in postmenopausal women. MATERIALS AND METHODS: The study was performed in a randomized controlled prospective manner in 90 women with menopause at Süleymaniye Maternity and Women's Diseases Teaching and Research Hospital between January and December 2003. Cases were divided into three groups each consisting of 30 women who were in menopause for at least 1 year and had t-scores less than -1 by dual energy X-ray densitometry (DEXA). Group I was treated with misoprostol and calcium, Group II received tibolone and calcium and Group III was given calcium only and considered as control group. In all patients, bone mineral density in L1-L4 vertebrae, femur neck and Ward triangle were measured by DEXA and t and z scores were calculated. RESULTS: All groups were similar demographically. Bone mineral density in L1-L4 vertebrae, femur neck and Ward triangle in the group treated with misoprostol, increased by 5, 8.1 and 3.6%, respectively. In the tibolone group, bone mineral density in L1-L4 vertebrae, femur neck and Ward triangle increased by 8.3, 5.3 and 7.8%, respectively. There was not a significant difference in t and z-scores and bone mineral density measurements between misoprostol and tibolon groups. CONCLUSION: Misoprostol may be an alternative treatment for patients with osteopenia and osteoporosis who are not suitable for hormone replacement therapy.     

Regulation of estrogen synthesis in postmenopausal women

The decrease in ovarian estrogen production that occurs at the menopause may lead to an increase in peripheral aromatase activity. While estrogens can have beneficial effects on some body tissues, such as bone and the cardiovascular system, they also have a crucial role in supporting the growth and development of breast tumors. A number of factors, including interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), and prostaglandin E(2) (PGE(2)), which can stimulate aromatase activity, have now been identified. As plasma concentrations of some cytokines increase at the menopause, this may account for the increased peripheral aromatase activity that is detected in older women. Macrophages and lymphocytes which infiltrate breast tissue are now thought to be an important source of cytokines that can stimulate aromatase activity in this tissue. Studies, we have recently carried out, have suggested that the endogenous estrogen metabolite, 2-methoxy-estradiol, may be able to modulate the ability of cytokines and PGE(2) to stimulate aromatase activity. Understanding the role of endogenous estrogen metabolites in regulating estrogen synthesis may give rise to new strategies for the prevention or treatment of breast cancer.     

Effect of estrogen on tendon collagen synthesis, tendon structural characteristics, and biomechanical properties in postmenopausal women

The knowledge about the effect of estradiol on tendon connective tissue is limited. Therefore, we studied the influence of estradiol on tendon synthesis, structure, and biomechanical properties in postmenopausal women. Nonusers (control, n = 10) or habitual users of oral estradiol replacement therapy (ERT, n = 10) were studied at rest and in response to one-legged resistance exercise. Synthesis of tendon collagen was determined by stable isotope incorporation [fractional synthesis rate (FSR)] and microdialysis technique (NH(2)-terminal propeptide of type I collagen synthesis). Tendon area and fibril characteristics were determined by MRI and transmission electron microscopy, whereas tendon biomechanical properties were measured during isometric maximal voluntary contraction by ultrasound recording. Tendon FSR was markedly higher in ERT users (P < 0.001), whereas no group difference was seen in tendon NH(2)-terminal propeptide of type I collagen synthesis (P = 0.32). In ERT users, positive correlations between serum estradiol (s-estradiol) and tendon synthesis were observed, whereas change in tendon synthesis from rest to exercise was negatively correlated to s-estradiol. Tendon area, fibril density, fibril volume fraction, and fibril mean area did not differ between groups. However, the percentage of medium-sized fibrils was higher in ERT users (P < 0.05), whereas the percentage of large fibrils tended to be greater in control (P = 0.10). A lower Young's modulus (GPa/%) was found in ERT users (P < 0.05). In conclusion, estradiol administration was associated with higher tendon FSR and a higher relative number of smaller fibrils. Whereas this indicates stimulated collagen turnover in the resting state, collagen responses to exercise were negatively associated with s-estradiol. These results indicate a pivotal role for estradiol in maintaining homeostasis of female connective tissue.     

Effects of continuous conjugated estrogen and micronized progesterone therapy upon lipoprotein metabolism in postmenopausal women

The effects of continuously administering both conjugated equine estrogens (CEE) and micronized progesterone (MP) on the concentration, composition, production and catabolism of very low density (VLDL) and low density lipoproteins (LDL) have not previously been reported. The mechanism of the hormonally induced reductions of plasma LDL cholesterol of S(f) 0;-20 (mean 16%, P < 0.005) and LDL apoB (mean 6%, P < 0.025) were investigated by studying the kinetics of VLDL and LDL apolipoprotein (apo) B turnover after injecting autologous (131)I-labeled VLDL and (125)I-labeled LDL into each of the 6 moderately hypercholesterolemic postmenopausal subjects under control conditions and again in the fourth week of a 7-week course of therapy (0.625 mg/d of CEE + 200 mg/d of MP). The combined hormones significantly lowered plasma LDL apoB by increasing the mean fractional catabolic rate of LDL apoB by 20% (0. 32 vs. 0.27 pools/d, P < 0.03). Treatment also induced a significant increase in IDL production (6.3 vs. 3.7 mg/kg/d, P = 0.028). However, this did not result in an increase in LDL production because of an increase in IDL apoB direct catabolism (mean 102%, P = 0.033). VLDL kinetic parameters were unchanged and the concentrations of plasma total triglycerides (TG), VLDL-TG, VLDL-apoB did not rise as often seen with estrogen alone. Plasma HDL-cholesterol rose significantly (P < 0.02). Our major conclusion is that increased fractional catabolism of LDL underlies the LDL-lowering effect of the combined hormones.     

Codon 325 sequence polymorphism of the estrogen receptor alpha gene and bone mineral density in postmenopausal women

Estrogen receptor alpha (ER alpha) encoding gene is one of the candidate genes to be involved in the development of osteoporosis. Until now correlation between three ER gene polymorphisms (identified with PvuII, XbaI and BstUI) and bone mineral density (BMD) have been investigated. The results of these studies are contradictory. Thus the aim of our work was to search for new, yet unknown, and probably more informative polymorphism(s) of the ER alpha gene. For detection of mutations the whole coding region of the ER alpha gene was screened systematically. In a group of 85 late postmenopausal women all of the eight exons were amplified by polymerase chain reaction (PCR) and fragments were further analyzed by single-stranded conformation polymorphism (SSCP) analysis. Mutations were confirmed by direct DNA sequencing. In the whole coding region of the ER alpha gene two silent mutations in codon 87 and 325, respectively, were found. The silent mutation in codon 85 of exon 1 (GCG-->GCC; A87A) was described previously, as BstUI polymorphism. On the other side, the silent mutation in codon 325 (CCC-->CCG; P325P), located in exon 4, has not been analyzed so far in correlation with BMD. According to the distribution of genotypes CC:CG:GG=49.4:41.2:9.4, we can affirm the existence of genetic polymorphism in codon 325 in our population of late postmenopausal women. The mean femoral neck BMD, but not the lumbar spine BMD, was significantly lower (P=0.029) in the homozygous GG-women with CCG/CCG codon 325 as compared to the homozygous CC-women with the normal codon CCC/CCC. Our results suggest that codon 325 sequence polymorphism of the ER alpha gene might be one of the factors associated with low femoral neck BMD.     

Progestin and estrogen reduce sleep-disordered breathing in postmenopausal women

Women exhibit sleep-disordered breathing syndromes less commonly than men before but not after the age of menopause, suggesting that female hormones may exert a protective effect. We sought to determine whether combined progestin and estrogen treatment decreased sleep-disordered breathing in healthy postmenopausal women. Nine ovarihysterectomized women [50 +/- 2 (SE) yr of age] were studied after 1 wk of treatment with placebo (lactose) or combined progestin and estrogen (medroxyprogesterone acetate, 20 mg tid, and Premarin, 1.25 mg bid). Subjects showed few respiratory disturbances during placebo treatment. Despite this, combined progestin and estrogen administration reduced the number of sleep-disordered breathing episodes in every subject, decreasing the average number of episodes per subject from 15 +/- 4 to 3 +/- 1. The duration of hypopneas also decreased with hormone treatment. Thus the presence of progestin and estrogen may be involved in protecting premenopausal women against sleep-disordered breathing.     

Relation of the estrogen receptor and vitamin D receptor polymorphisms with bone mineral density in postmenopausal Mexican-mestizo women

Background

Since osteoporosis is a complex disease characterized by low bone mineral density (BMD), which is determined by an interaction of genetics with metabolic and environmental factors, the aim of this study was to analyze the possible association among one polymorphism of VDR and two polymorphisms of ESR1; as well as their haplotypes with BMD in postmenopausal Mexican-mestizo women.

Methods

We studied 742 postmenopausal Mexican-mestizo women. A structured questionnaire for risk factors was applied and BMD was measured in the lumbar spine and total hip by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. One polymorphism of VDR (rs11568820) and two of ESR1 (rs2234693 and rs9340799) were studied. Real-time PCR allelic discrimination was used for genotyping. The differences between the means of the BMDs according to genotype were analyzed with covariance. Hardy–Weinberg equilibrium was tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r²; haplotype analysis was conducted.

Results

Rs9340799 of ESR1 and one haplotype formed by the two polymorphisms of the ESR1 were significantly associated with FN-BMD variations. Moreover, analysis of the genotype of rs11568820 of VDR and the rs2234693 of ESR1 showed no significant differences with BMD variations.

Conclusions

Our results showed that rs9340799 and one haplotype of ESR1 were significantly associated with BMD only at the femoral neck and this association remained after adjusting for covariates.     

Lipoprotein, apolipoprotein, and lipolytic enzyme changes following estrogen administration in postmenopausal women

To test whether estrogen can modulate the cholesterolemic response to an Occidental diet, six healthy postmenopausal women were studied for 84 days while ingesting a solid food diet of constant composition high in cholesterol content (995 mg/d). In the middle of the study, estrogen (17 alpha-ethinyl estradiol, 1 microgram/kg per day) was administered orally. Ingestion of the diet for the initial 28 days did not alter lipoprotein lipid or apolipoprotein (apo) levels. However, with just 4 days of estrogen use there were significant decreases in apoE (-36%), low density lipoprotein cholesterol (-26%), and postheparin plasma hepatic triglyceride lipase activity (HTGL) (-61%), and an increase in high density lipoprotein (HDL) triglyceride (72%). These changes persisted throughout the estrogen use. The percent change in HTGL with 4 days of estrogen correlated inversely with the percent change in HDL triglyceride (rs = -0.94). After 28 days of estrogen there were also significant increases in HDL cholesterol (21%), HDL2 cholesterol (42%), apoA-I (37%), and apoA-II (9%), and a decrease in apoB (-11%). The level of apoE at this juncture correlated inversely with the level of HDL cholesterol (rs = -0.90), and the levels of HTGL and apoA-I correlated with HDL2 cholesterol (rs = -0.89 and rs = 0.89, respectively). Thus, HTGL may play a role in both the early estrogen-related changes in HDL triglyceride and apoE and the late estrogen-related changes in HDL cholesterol, apoA-I, and apoA-II.     

Evaluation of high-dose estrogen and high-dose estrogen plus methyltestosterone treatment on cognitive task performance in postmenopausal women

OBJECTIVES: To investigate the cognitive effects of high-dose oral estrogen alone or in combination with oral methyltestosterone in postmenopausal women. METHODS: Participants were tested with a randomized, double-blind design on the Identical Pictures, Cube Comparisons, Building Memory and Shape Memory tasks before and after 4 months of hormone treatment. RESULTS: Women receiving estrogen and methyltestosterone maintained a steady level of performance on the Building Memory task, whereas those receiving estrogen alone showed a decrease in performance. CONCLUSIONS: These results indicate that the addition of testosterone to high-dose estrogen replacement exerts a protective effect on memory performance in postmenopausal women.     

Excretion and metabolism of desogestrel in healthy postmenopausal women

The metabolism of desogestrel (13-ethyl-11-methylene-18,19-dinor-17-pregn-4-en-20-yn-17-ol), a progestagen used in oral contraceptives and hormone replacement therapy, was studied in vivo after a single oral administration of 150 μg [¹⁴C]-labeled desogestrel and 30 μg ethinylestradiol under steady state conditions to healthy postmenopausal women. After this oral administration, desogestrel was extensively metabolized. The dosed radioactivity was predominantly (60%) excreted via urine, while about 35% was excreted via the feces. Desogestrel was metabolized mainly at the C3-, C5-, C6- and C13-CH₂CH₃ positions. At the C3-position, the 3-keto moiety was found and in addition, 3β-hydroxy and 3-hydroxy groups were observed in combination with a reduced Δ⁴-double bond (5-H). Hydroxy groups were introduced at the C6- (6β-OH), the C13-ethyl (C13-CH₂CH₂OH) and possibly the C15- (15-OH) position of desogestrel. Conjugation of the 3-hydroxy moiety with sulfonic acid and conjugation with glucuronic acid were also major metabolic routes found for desogestrel in postmenopausal women. The 3-keto metabolite of desogestrel (the biologically active metabolite) was the major compound present in plasma at least up to 24 h after administration of the radioactive dose. Species comparison of the metabolic routes of desogestrel after oral administration indicates that in rats and dogs desogestrel is also mainly metabolized at the C3-position, similar to what is now found for postmenopausal women. Most other metabolic routes of desogestrel were found to differ between species. Finally, major metabolic routes found in the present study in postmenopausal women are in line with outcome of previous in vitro metabolism studies with human liver tissue (microsomes and postmitochondrial liver fractions) and intestinal mucosa.     

Genome-wide association study of circulating estradiol, testosterone, and sex hormone-binding globulin in postmenopausal women

Genome-wide association studies (GWAS) have successfully identified common genetic variants that contribute to breast cancer risk. Discovering additional variants has become difficult, as power to detect variants of weaker effect with present sample sizes is limited. An alternative approach is to look for variants associated with quantitative traits that in turn affect disease risk. As exposure to high circulating estradiol and testosterone, and low sex hormone-binding globulin (SHBG) levels is implicated in breast cancer etiology, we conducted GWAS analyses of plasma estradiol, testosterone, and SHBG to identify new susceptibility alleles. Cancer Genetic Markers of Susceptibility (CGEMS) data from the Nurses' Health Study (NHS), and Sisters in Breast Cancer Screening data were used to carry out primary meta-analyses among ~1600 postmenopausal women who were not taking postmenopausal hormones at blood draw. We observed a genome-wide significant association between SHBG levels and rs727428 (joint β = -0.126; joint P = 2.09 × 10(-16)), downstream of the SHBG gene. No genome-wide significant associations were observed with estradiol or testosterone levels. Among variants that were suggestively associated with estradiol (P<10(-5)), several were located at the CYP19A1 gene locus. Overall results were similar in secondary meta-analyses that included ~900 NHS current postmenopausal hormone users. No variant associated with estradiol, testosterone, or SHBG at P<10(-5) was associated with postmenopausal breast cancer risk among CGEMS participants. Our results suggest that the small magnitude of difference in hormone levels associated with common genetic variants is likely insufficient to detectably contribute to breast cancer risk.     

Effects of estrogen replacement therapy on abdominal fat compartments as related to glucose and lipid metabolism in early postmenopausal women.

The effects of estrogen replacement therapy on lipid and glucose metabolism as related to abdominal fat distribution were investigated in fifty-one healthy postmenopausal women aged 52-53 years. They were randomized to treatment with either estradiol 2 mg or placebo daily for three months in a double-blind design. Forty-six women continued with estradiol for another nine months in an open design with the addition of medroxyprogesterone for ten days every three months. Intra-abdominal and subcutaneous abdominal fat, and intrapelvic and subcutaneous pelvic fat was estimated by computed tomography before and after one year of estrogen treatment. Euglycemic hyperinsulinemic clamp, oral glucose tolerance test and analyses of blood lipids were performed after 3 and 12 months of treatment. Estrogen replacement therapy decreased body fat mass as well as intra-abdominal and intrapelvic fat, but not the subcutaneous fat compartments. LDL cholesterol decreased and HDL cholesterol increased, whereas triglycerides were not changed by one year of estrogen treatment. Insulin sensitivity and glucose tolerance were not affected by estrogen treatment. In postmenopausal women estrogen treatment for one year decreased intra-abdominal and intrapelvic fat compartments, but this was not related to changes in plasma lipid levels. Insulin sensitivity and plasma triglycerides were not affected by estrogen treatment.