The effect of calcium supplements on plasma alkaline phosphatase and urinary hydroxyproline in postmenopausal women

Although calcium supplements are widely used in the treatment of osteoporosis, their beneficial effect is not conclusively established. We now report some effects of a calcium supplement (1 g/day) given for 6 to 12 weeks to 15 postmenopausal osteoporotic women. The mean fasting urinary hydroxyproline/creatinine ratio decreased from 0.021 +/- 0.002 to 0.015 +/- 0.001 (P less than 0.0025), indicating a significant reduction in bone resorption. The mean plasma alkaline phosphatase fell from 123 +/- 5 U/l to 104 +/- 3.1 U/l (P less than 0.01), probably representing some secondary reduction in bone formation following the inhibition of bone resorption. These results support the concept that calcium supplementation is useful in the treatment of postmenopausal osteoporosis.     

Influence of postmenopausal hormone replacement therapy on an estrogen metabolite biomarker of risk for breast cancer.

Whether postmenopausal hormone-replacement therapy (HRT) increases the risk of breast cancer remains controversial, despite numerous epidemiological studies. We approached the question from a biochemical rather than an epidemiological direction - we hypothesized that if estrogen administration increases the risk of breast cancer, it should also alter a known estrogen biomarker of risk towards what has been observed in patients who already have breast cancer. The specific biomarker we studied was the ratio of the urinary excretion of two principal estradiol metabolites, 2-hydroxyestrone and 16 alpha-hydroxyestrone, which is markedly decreased in women with breast cancer and women with familial risk for breast cancer. We studied 34 healthy postmenopausal women not on HRT and 19 women on HRT (Premarin 0.625 mg daily plus Provera, 2.5 mg daily, in women with a uterus and Premarin alone in women without a uterus); treatment duration ranged from 3 months to 15 years. We also studied four women with recently diagnosed, untreated breast cancer. The women with breast cancer showed a significantly lower 2-hydroxyestrone to 16 alpha-hydroxyestrone ratio than control women on HRT (1.35 +/- 0.13 vs. 2.71 +/- 0.84; p < 0.0001). There was no significant difference in the metabolite ratio between healthy women on HRT and women not on HRT (2.82 +/- 0.92 vs. 2.71 +/- 0.84). There was no significant difference between women receiving Premarin alone and women receiving Premarin plus Provera (2.46 +/- 0.84 vs. 3.13 +/- 0.90), and neither differed significantly from women not on HRT (2.71 +/- 0.84). The finding that the ratio of women on HRT was not decreased to or toward the ratio in women with breast cancer can be interpreted, we believe, as a suggestive item of biochemical evidence that HRT is not a risk for breast cancer.     

The effect of ethinyl oestradiol on calcium and bone metabolism in peri- and postmenopausal women

The effects of ethinyl oestradiol on plasma and urinary calcium and other indices of bone turnover have been compared in peri- and postmenopausal women. In postmenopausal women ethinyl oestradiol caused significant decreases in the fasting plasma total and ionised calcium and phosphate concentrations, in alkaline phosphatase activity and in the fasting urinary Ca/Cr and OHPr/Cr ratios. Similar, but less marked, effects were observed in peri-menopausal women, with significant decreases in the fasting plasma phosphate and urinary Ca/Cr ratio. Small decreases in the plasma total and ionised calcium concentrations, in alkaline phosphatase activity and in the urinary OHPr/Cr ratio also occurred but were not statistically significant in our sample. Ethinyl oestradiol therefore appears to reduce bone loss in peri- as well as post-menopausal women, at least in the short term, but the effect is less pronounced in the former group.     

Effects of endogenous estrogen on renal calcium and phosphate handling in elderly women

High postmenopausal endogenous estrogen concentrations are an important determinant of preservation of bone mass and reduced fracture in elderly women. Calcium supplementation can also reduce bone loss in these patients, suggesting an interaction between estrogen deficiency and calcium balance. Potential mechanisms of estrogen on calcium transport include direct effects on the bone, the kidney, and the bowel. Previous studies have demonstrated effects of estrogen on renal phosphate handling. We have used a cross-sectional, population-based analysis of biochemical data obtained from ambulant elderly women to determine the association of endogenous estradiol with urine calcium and phosphorus excretion. The subjects were 293 postmenopausal women >70 yr old. Factors associated with renal calcium and phosphate excretion were measured, including the filtered calcium and phosphate load, parathyroid hormone (PTH), estradiol, and sex hormone-binding globulin (SHBG). The free estradiol concentration (FE) was calculated from a previously described formula. A high plasma estradiol concentration (r(2) = 0.023, P = 0.01) and a high FE (r(2) = 0.045, P = 0.001) were associated with reduced renal calcium excretion. The estradiol and FE effect on renal calcium excretion remained significant after adjusting for calcium filtered at the glomerulus and serum PTH. A high FE was associated with a reduced renal phosphate threshold in univariate analysis (r(2) = 0.023, P = 0.010). The effect remained significant after adjustment for serum PTH. The size of the effect of the FE was of the same order of magnitude as the effect of PTH on reducing renal calcium excretion and increasing renal phosphate excretion. These data support in vitro and animal data demonstrating an effect of estradiol on renal calcium and phosphate handling and indicate that, in elderly postmenopausal women, the effect is of a similar magnitude to the well-recognized effects of PTH on these physiologically regulated parameters.     

A comparison of biochemical indices of bone turnover in elderly institutionalized and free-living subjects

Plasma concentrations of calcium-phosphate, alkaline phosphatase, 25-hydroxyvitamin D (25(OH)D) and albumin, and fasting urinary sodium/creatinine (Na/Cr), calcium/creatinine (Ca/Cr) and hydroxyproline/creatinine (HPr/Cr) were measured in a survey of 208 Chinese elderly subjects living in chronic care institutions, and compared with values from free-living elderly subjects. Plasma parathyroid hormone estimations were also performed on a subpopulation of women living in an institution.Subjects in institutions had higher urinary HPr/Cr ratios in both men and women, as well as higher urinary Ca/Cr ratios in women, suggesting increased bone resorption. These values show significant variation depending on the degree of mobility. Factors which could contribute to the increased bone loss among institutionalized subjects are: reduced physical activity, reduced exposure to sunlight and hence reduced plasma 25(OH)D concentrations, low calcium intake, protein caloric malnutrition and possibly higher sodium intake. Correction of these factors may reduce the risk of fractures among the elderly living in chronic care institutions.     

Clinical opinion: the biologic and pharmacologic principles of estrogen therapy for symptomatic menopause

The endocrinology of the menopausal transition involves a complex interaction of molecular and tissue-specific hormone receptors, enzymes, and moderating cofactors that determine the functional expression of a given organ. The synthesis and metabolism of estrogen in estrogen-sensitive organs continue postmenopausally, albeit at levels substantially reduced from those of reproductive women. The postmenopausal production of estrogen is genetically determined. Thus, symptoms of estrogen deprivation will vary among menopausal women, although all will cease to menstruate. All prescribed estrogens have a similar class effect and exert their estrogenicity through similar genomic and nongenomic pathways. However, the source, chemical structure, and composition of the estrogens most commonly prescribed for menopausal complaints--conjugated equine estrogens (CEE), micronized 17beta estradiol (E2), and ethinyl estradiol (EE)--vary in content, pharmacokinetics, and pharmacodynamics. These variables are further influenced by dosage and route of administration. The net clinical effect depends on the type and amount of free bioavailable estrogen derived exogenously combined with the respective organ's endogenous synthesis of estrogen. Extrapolation of population- and group-based randomized clinical trials that evaluate a fixed dose of a standard estrogen preparation over a predetermined period of time may not be applicable to other products or to individual women whose biology differs from that of the study population. The decision to prescribe estrogen therapy for menopausal symptoms should be considered within the context of the woman's total quality of life healthcare needs and adjusted over time to ensure maximal efficacy with minimal risk.     

Measurement of bone mineral density (BMD) with quantitative computed tomography (QCT) in postmenopausal osteoporosis: effect of estrogen.

To determine the efficacy of the estrogen replacement therapy (ERT) on the bone mineral density (BMD) measured with quantitative computed tomography (QCT) in postmenopausal osteoporosis 16 women aged 46-72 were examined. They were divided into two groups: 8 women treated with conjugated estrogens (Group I) and 8 who did not received ERT (Group II). In all 16 patients the serum hormonal concentrations (LH, FSH and estradiol) were measured with radioimmunological methods. The bone densitometry was performed in all of them using the single-energy computed tomography (QCT) with the computer Picker 1200. Bone mineral density was measured in three lumbar vertebra (L1-L3) and expressed in milligrams K2HPO4 per ml. The bone mineral density (BMD) was statistically significantly higher in the estrogen treated group (Group I) in every vertebra compared with that of controls (Group II). The serum FSH concentration was statistically significantly lower in the ERT group (Group I) and a statistically significant correlation between FSH level and average BMD (Lmean) was present. In conclusion: 1. the ERT is very efficacious in preventing bone loss in postmenopausal women; 2. measurement of BMD in lumbar vertebra L1 or L3 may be a sufficiently reliable and accurate, cost-effective and time-saving method of screening for osteoporosis; 3. the serum FSH determination seems to be useful in monitoring of the estrogen therapy for postmenopausal osteoporosis.     

Effect of Late Night Calcium Supplements on Overnight Urinary Calcium Excretion in Premenopausal and Postmenopausal Women

The overnight urinary calcium/creatinine ratio is higher in the early years after the menopause than before it. However, the increment of urinary calcium/creatinine after a late evening calcium supplement is less in early postmenopausal than in premenopausal women. It is suggested that calcium therapy in postmenopausal osteoporosis may be best administered as a single late evening dose rather than in divided doses throughout the day.     

Effects of estrogen on gender-related autonomic differences in humans

Our previous studies demonstrated that premenopausal women have dominant vagal and subordinate sympathetic activity compared with age-matched men. This study was designed to investigate the role of estrogen in gender-related autonomic differences. We evaluated the heart rate variability of four healthy groups: age-matched postmenopausal women without hormone replacement therapy (PM), postmenopausal women on conjugated estrogen replacement therapy (PME), men, and non-age-matched premenopausal women (PreM). Frequency-domain analysis of short-term and stationary R-R intervals was performed to evaluate low-frequency power (LF; 0.04-0.15 Hz), high-frequency power (HF; 0.15-0.40 Hz), the ratio of LF to HF (LF/HF), and LF in normalized units (LF%). No gender-related autonomic differences existed between the PM and men groups, but they did exist between the PME and men group. Compared with the PreM group, the PM group had a lower HF and higher LF% and LF/HF. Compared with the PM group, the PME group had a higher HF but lower LF% and LF/HF. These results suggest that conjugated estrogen replacement therapy may facilitate vagal and attenuate sympathetic regulation of heart rate in postmenopausal women. In addition, estrogen may play an important role in gender-related autonomic differences.     

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.     

Postmenopausal estrogen replacement therapy and increased rates of cholecystectomy and appendectomy

BACKGROUND: Several studies have indicated that estrogen may prime inflammatory and nociceptive pathways, leading to symptoms that mimic cholecystitis. We set out to confirm the relation between recent estrogen use and cholecystectomy in postmenopausal women and to test the novel hypothesis that a similar relation exists for appendectomy. METHODS: We developed a retrospective cohort using prescribing and surgical procedure information from health administrative databases for approximately 800,000 female residents of Ontario who were over 65 years of age between July 1, 1993, and Mar. 31, 1998. We compared the incidence of cholecystectomy and appendectomy among women recently prescribed estrogen replacement therapy, levothyroxine and dihydropyridine calcium-channel antagonists (DCCA) using age-adjusted Cox proportional hazards models. Patients were followed for a mean of 540 (standard deviation [SD] 449) days. RESULTS: Compared with women taking DCCA, those who had recently begun taking estrogen were significantly more likely to undergo cholecystectomy (age-adjusted risk ratio [aRR] 1.9, 95% confidence interval [CI] 1.6-2.2) and appendectomy (aRR 1.8, 95% CI 1.1-3.0). No significant difference in either outcome measure was found between the levothyroxine users and the DCCA users. INTERPRETATION: This study identifies an increased risk of cholecystectomy and appendectomy among postmenopausal women who have recently begun estrogen replacement therapy.     

Impact of the mass-reductive therapy with orlistat on 25-(OH)-D3 and PTH concentration in sera of obese, menopausal women

Epidemiological studies suggest a protective influence of obesity against postmenopausal bone loss. Lower risk of osteoporotic fractures was described in obese patients. However there were only a few studies which examined the effect of weight reduction on bone metabolism and results of these studies are controversial. The aim of the study was to evaluate the influence of weight reduction program using Orlistat on bone metabolism in perimenopausal women. Twenty obese women with simple obesity and without concomitant diseases (BMI 37.1 +/- 3.0 kg/m2, mean age 49.8 +/- 4.6 yrs) were enrolled into this study. The control group consisted of 20 healthy women (mean age 53.5 +/- 5.4 yrs, BMI 24.1 +/- 2.2 kg/m2). All patients have participated in a 3-month weight reduction therapy that consisted of: a 1000-1200 kcal/ day balanced diet (daily calcium consumption about 500mg), Orlistat 3 x 120mg a day and regular physical exercises. Before the weight reduction therapy and after 10% reduction of body weight, serum concentrations of PTH, 25-(OH)-D3, total calcium and phosphorus, total cholesterol were assessed. Dual energy x-ray absorptiometry (DEXA method) of lumbar spine and femoral neck, measuring BMD was performed once, after a 3-month weight reduction therapy using Lunar DPXL. All these measurements were performed only once in control subjects. After a 3-month weight reduction program in patients treated with Orlistat the mean weight loss was 11.6 +/- 5.1 kg which is 12.1 +/- 4.78 %. BMI decreased from 37.1 +/- 3.0 kg/m2 at baseline to 32.6 +/- 2.7 kg/m2 post-treatment. The body weight reduction resulted in significant decrease of body fat and total cholesterol concentration. In obese subjects serum concentration of 25-(OH)-D3 was significantly lower and serum concentration of PTH was significantly higher in comparison to healthy controls, both before and after weight reduction therapy. Serum concentration of PTH, 25-(OH)-D3, total calcium and phosphorus did not change significantly after therapy with Orlistat. Conclusion: 3-month weight reduction program using Orlistat did not influence significantly bone metabolism.     

Dose dependent response of symptoms,pituitary, and bone to transdermal oestrogen in postmenopausal women.

The effect of the plasma oestradiol concentration on climacteric symptoms, gonadotrophin release, and bone resorption was studied in three groups of postmenopausal women given 0.025 mg, 0.05 mg, or 0.1 mg transdermal oestradiol daily. There was a dose related reduction in symptoms, plasma follicle stimulating hormone concentration, and urinary calcium and hydroxyproline excretion. The relation of the response to plasma oestradiol values was similar for each variable with an initial large reduction and little change in response to increases in the plasma oestradiol concentration above 150 pmol/l (41 pg/ml). Hormone replacement therapy producing an effect equivalent to higher oestradiol concentrations is likely to increase the risk of side effects without conferring any additional benefit.     

Relationship of plasma leptin and adiponectin concentrations with menopausal status in Tunisian women

To evaluate the effect of menopausal status and body mass index (BMI) on circulating leptin and adiponectin concentrations and investigate whether there is an influence of menopausal transition on the relationships of these adipokines and leptin to adiponectin (L/A) ratio with lipid profile and insulin resistance in a sample of Tunisian women. One hundred ninety-six premenopausal (mean age 35.3 ± 7.6 years) and 180 postmenopausal women (mean age 53.4 ± 6.2 years) were included in the study. Participants were stratified into obese and normal weight groups based upon their baseline BMI. Fasting glucose, HDL-cholesterol (HDL-C), triglycerides (TG), total cholesterol (TC), insulin, leptin, and adiponectin concentrations were measured. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Premenopausal women had significantly higher leptin and L/A ratio and lower adiponectin levels than postmenopausal women. Menopause had no effect on the mean values of BMI, insulin or HOMA-IR, HDL-C, and TG. Using a multiple linear regression model, menopausal status was identified, as significant independent predictor for leptin and adiponectin levels. Irrespective of the menopausal status, obese women exhibited higher leptin and L/A ratio and lower adiponectin levels compared to those with normal weight. Comparison between the two menopausal stages in obese and normal weight groups showed that leptin and L/A ratio decreased, while adiponectin increased from pre- to postmenopausal stage only in obese group. The L/A ratio correlated better with lipid profile and HOMA-IR in postmenopausal stage. The present study showed a significant interaction between menopause and BMI on leptin and adiponectin secretion. Menopausal transition affects the relationships of these adipokines with lipids and insulin resistance.     

Studies on osteoporosis X. Effect of estrogen-progestin combination on heparin-induced osteoporosis

Neutron activation analysis was employed to determine total body calcium in C₃H/St(Ha) female mice. As 99% of body calcium is in bone, loss of calcium was used as an index of bone loss (osteoporosis). Heparin (500 U/kg b.i.d. caused bone loss in 3 months. Premarin (2 mg/kg q.d.) or norethindrone (40 mg/kg q.d.) alone prevented this osteoporosis. A Premarin-norethindrone combination (2 mg – 10 mg q.d. respectively) appeared to be somewhat more effective than either agent alone, but this difference was not significant at the 5% level. Combinations of estrogen and progestins may prevent metabolic bone disease at the same time reducing the danger of estrogen induced neoplasia.     

Urinary excretion of glycosaminoglycans in patients with postmenopausal osteoporosis.

The organic bone matrix contains glycosaminoglycans (GAG) of which the precise function and importance in bone mineralisation are still unclear. We examined 85 persons--35 healthy women (25 premenopausal [preMP] mean aged 40.7 years; 10 menopausal [MP] mean aged 59.3 years) and 50 patients with postmenopausal osteoporosis [PMOP] at a mean age 60.4 years. The dynamic of urinary excretion of GAG was measured in 24-hour collected urine by precipitation with cetylpyridinum chloride and spectrophotometry at 560 nm, corrected for the level of excretion of creatinine. There was a significant increase in GAG excretion in patients with PMOP compared with healthy persons (8.25 mg/g and 9.53 mg/g vs 24.11 mg/g; p < 0.0001). A significant positive correlation was established between GAG and calcium urinary excretion and a negative one between GAG and serum estradiol levels. During the treatment with calcitonin the excretion of GAG was decreased which can be used for monitoring the changes of bone metabolism.     

Plasma estrone-sulfate: assessment of reduced estrogen production during treatment of metastatic breast carcinoma

Highly sensitive and specific estrogen assays are required to monitor the hormonal effects of surgical adrenalectomy or pharmacologic estrogen suppression in postmenopausal women with breast carcinoma. Because the levels of plasma estrone-sulfate are 10-fold higher than its unconjugated counterpart, we developed a radioimmunoassay for estrone-sulfate to quantitate the minimal estrogen concentrations expected under conditions of endocrine gland ablation. After establishing normal ranges, we compared plasma estrone- sulfate levels and urinary conjugated estrone basally and after surgical adrenalectomy or aminoglutethimide (estrogen suppression) therapy in 23 postmenopausal women with breast carcinoma. In response to either therapy, the plasma levels of estrone-sulfate fell by 63.5-79.2% (p less than .01) and conjugated urinary estrone by 85-94.5% (p less than .01) in all study days over a 12-week period. Correlation analyses yielded r values of 0.77-0.94 between conjugated plasma and urinary estrone concentrations in the surgical adrenalectomy and aminoglutethimide-treated groups, respectively. No significant differences in estrone-sulfate levels were observed when comparing spontaneously menopausal and surgically castrate patients.     

Vaginal microbial diversity among postmenopausal women with and without hormone replacement therapy

Urogenital infections in postmenopausal women remain problematic. The use of estrogen replacement therapy has been shown to lower these infection rates, corresponding to increasing colonization by Lactobacillus species. Despite the gut's 500 microbial species and the proximity of the anus to the vagina, only a relatively few microbial strains appear to be able to colonize the urogenital area. In the present study, the sparsity of microbes in the vagina was confirmed by denaturing gradient gel electrophoresis analysis of swabs taken at time zero and monthly for 3 months from 40 postmenopausal subjects receiving Premarin (conjugated equine estrogen in combination with progesterone) hormone replacement therapy (HRT) and 20 who were not on HRT. Lactobacilli were recovered from the vagina of 95% or more women in both groups, but in the HRT group, Lactobacillus were more often the dominant and only colonizers and significantly fewer bacteria with pathogenic potential were found. The incidence of bacterial vaginosis was significantly lower in the HRT group than in the non-HRT-treated women (5.6% versus 31%). The use of HRTs has recently come under criticism. The ability of drugs such as Premarin to help recover the lactobacilli vaginal microbiota appears to be at least one benefit of HRT use. In women not using HRTs, use of probiotics may be the only way to restore a nonpathogen-dominated flora.     

Treatment with high-dose estrogen (diethylstilbestrol) significantly decreases plasma estrogen and androgen levels but does not influence in vivo aromatization in postmenopausal breast cancer patients

While growth factors and hormones are known to influence aromatase expression in experimental systems, little is know about potential factors influencing peripheral aromatization in postmenopausal women. The fact that peripheral aromatase activity is higher in old compared to young women and the finding of relatively high tissue estradiol (E₂) concentrations after the menopause suggests peripheral aromatization could be influenced by estrogen concentration. To test this hypothesis, we determined plasma hormone levels (n = 9) and in vivo aromatization (n = 3) in postmenopausal women suffering from advanced breast cancer before and during treatment (4 weeks) with diethylstilbestrol (DES) 5 mg three times daily. Plasma levels of cortisol (C), corticosteroid-binding globulin (CBG), and sex hormone binding globulin (SHBG) were significantly increased in all patients (P < 0.05 for all). While we found no change in total body aromatization and plasma estrone (E₁) levels, estradiol (E₂) and estrone sulfate (E₁S) were suppressed by a mean of 48.8 and 68.2%, respectively (P = 0.043 and 0.008). Surprisingly, plasma levels of androstenedione (A), testosterone (T), dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) were also suppressed by a mean in the range of 32.1 to 52.6% (P < 0.05 for all androgens). In contrast, no change in plasma progesterone or 17-hydroxyprogesterone was found. Thus, one possible explanation to our findings could be that DES administered in high doses reduces 17,20-lyase activity in the adrenal gland.     

Change of bone mass in postmenopausal Caucasian women with and without hormone replacement therapy is associated with vitamin D receptor and estrogen receptor genotypes

Our purpose is to assess whether genotypes of the vitamin D receptor (VDR) and estrogen receptor (ER) and their interaction influence changes in bone mass in postmenopausal Caucasian women with and without hormone replacement therapy (HRT). A population of 108 US Mid-West women who participated in a study of low-dose continuous estrogen/progestin was genotyped at the VDR BsmI site and the ER XbaI and PvuII sites. Adequate vitamin D and calcium nutritional intakes were assured in all the study subjects. For the 3.5-year duration of the study, we analyzed changes in bone mineral density (BMD) at the spine, femoral neck, distal radius, and the total body (total body bone mineral content, tbBMC). We adjusted for confounding factors, such as age and weight, in the analysis. We found that VDR and/or ER genotypes and/or their interaction generally had significant effects on the changes in the bone mass measurements in both the placebo and HRT groups. When a significant gene-by-gene interaction exists between VDR and ER genotypes, failure to account for them in analyses may yield nonsignificant results, even if significant genotypic effects exist. The amount of variation in changes in bone mass measurements explained by the total genotypic effects of the VDR and ER loci varies from ∼1.0% (for the tbBMC changes in combined placebo and HRT groups) to ∼18.7% (for the spine BMD changes in the HRT group). These results suggest that individual genotypes are important factors in determining changes in bone mass in the elderly with and without HRT and thus may need to be considered with respect to the treatment to preserve bone mass in elderly Caucasian women. Received: 31 July 1998 / Accepted: 11 September 1998