Ethnic differences in levels of bone and cartilage biomarkers and hormonal responsiveness in nine groups of postmenopausal Asian women: the Pan-Asia Menopause (PAM) study.

OBJECTIVE: Significant differences in baseline lipid and reproductive hormone profiles and in responsiveness of lipids to hormone therapy (HT) have previously been found among nine ethnic groups of Asian postmenopausal women participating in the Pan-Asia Menopause (PAM) study. Based on these findings, the primary objective of this study was to test the hypothesis that biomarkers of bone turnover and cartilage degradation and their responsiveness to HT differ among the ethnic groups. METHODS: The PAM study was a prospective, randomized, double-blind clinical trial evaluating 1028 postmenopausal women at 22 clinical centers in 11 Asian countries/territories. Subjects were randomized to one of three continuous combined conjugated estrogens (CE)/medroxyprogesterone acetate (MPA) doses: CE/MPA (in mg/day) = 0.625/2.5; 0.45/1.5; and 0.3/1.5. Following baseline evaluations, subjects received therapy for six continuous 28-day cycles (6 months). Biomarkers for bone resorption (alphaalphaCTX and betabetaCTX, representing newly synthesized and old bone, respectively), bone formation (osteocalcin) and cartilage degradation (CTX-II) were analyzed centrally by state-of-the-art methods. RESULTS: The baseline concentrations of the four biomarkers were significantly associated with ethnicity. This association was independent of age and body mass index (BMI). The biomarker levels varied widely among the ethnic groups, showing ranges of alphaalphaCTX = 0.78-1.14 microg/mmol for Taiwanese vs. Malay women; betabetaTCX = 3.77-4.85 microg/mmol for Korean vs. Pakistani women; osteocalcin = 14.9-24.9 microg/l for Korean vs. Pakistani women; and CTX-II = 300-479 microg/mmol for Vietnamese vs. Indonesian women. The baseline biomarker levels were significantly and independently affected by BMI, but not by age. There was a weak but consistent negative correlation between baseline estradiol levels and baseline biomarkers. Hormone therapy for 6 months significantly lowered the biomarker levels in all ethnic groups, with a few exceptions for CTX-II in the lowest dose group. Ethnicity, but not age or BMI, was significantly associated with the response of the bone markers, whereas ethnicity, age and BMI were significantly associated with the response of the cartilage degradation marker. CONCLUSION: Baseline levels and hormonal responsiveness of two bone resorption markers, a bone formation marker, and a marker of cartilage degradation differ among the ethnic groups of Asian postmenopausal women evaluated in this study. The clinical significance of these findings remains to be investigated.

Estradiol, FSH and LH profiles in nine ethnic groups of postmenopausal Asian women: the Pan-Asia Menopause (PAM) study.

OBJECTIVES: Significant differences in the prevalence of menopausal symptoms and in lipid profiles have previously been reported for nine ethnic groups of postmenopausal Asian women participating in the Pan-Asia Menopause (PAM) study. Based on these findings, we tested the hypothesis that reproductive hormone profiles differ among the nine ethnic groups under investigation in the PAM study. METHODS: Baseline serum samples from postmenopausal women (n=1020) representing nine ethnic groups were analyzed at a central laboratory by electro-chemiluminescence immunoassay methods. Hormone concentrations were measured for estradiol (E2), follicle stimulating hormone (FSH) and luteinizing hormone (LH). RESULTS: The hormone levels for the overall study population (mean+/-SD) were: E2=74.1+/-125.1 pmol/l (n=1015); FSH=81.2+/-31.4 IU/l (n=1013); LH=36.8+/-15.6 IU/l (n=1015). Estradiol levels ranged from 50.0 pmol/l in Chinese women to 106.8 pmol/l in Vietnamese women; FSH ranged from 68.2 IU/l in Korean women to 90.8 IU/l in Malay women; and LH ranged from 30.7 IU/l in Korean women to 44.1 IU/l in Malay women. There was an inverse correlation between log E2 and FSH levels and a positive correlation between FSH and LH levels. The concentrations of E2, FSH and LH were significantly associated with ethnicity after adjustment for age and body mass index. Additionally, the concentrations of all three hormones were significantly associated with body mass index, whereas E2 and LH levels were associated with age, but FSH levels were not. CONCLUSION: The levels of FSH, LH and particularly of E2 differ substantially among ethnic groups of postmenopausal Asian women. The clinical significance, if any, of these differences remains to be investigated. The inverse correlation of E2 and FSH levels suggests that E2 at the postmenopausal state still affects pituitary FSH output.

Effect of three doses of conjugated estrogens/medroxyprogesterone acetate on biomarkers of bone turnover and cartilage degradation in postmenopausal women: The Pan-Asia Menopause (PAM) study.

OBJECTIVE: To assess the effects of three doses of continuously combined conjugated estrogens (CE) and medroxyprogesterone acetate (MPA) on bone turnover and cartilage degradation markers in early postmenopausal Asian women (mean age 53.6 years). METHODS: A total of 1028 women were randomly allocated to receive treatment with either 0.625/2.5, 0.45/1.5, or 0.3/1.5 mg CE/MPA for 6 months. End-points were the percent change from baseline in markers of bone resorption (alpha alpha CTX, beta beta CTX), bone formation (osteocalcin), and cartilage degradation (CTX-II). RESULTS: The 0.45/1.5 mg and the 0.625/2.5 mg doses elicited comparable responses as measured by the biomarkers. Women with high rates of bone or cartilage turnover at baseline responded with larger changes to the effects of CE/MPA. CONCLUSIONS: Lowering the commonly used dose of 0.625 mg CE + 2.5 mg MPA to 0.45 mg CE + 1.5 mg MPA does not significantly alter the inhibitory effect on bone and cartilage turnover in Asian women.

Distinct lipid/lipoprotein profiles and hormonal responsiveness in nine ethnic groups of postmenopausal Asian women: the Pan-Asia Menopause (PAM) study.

BACKGROUND: Lipid/lipoprotein profiles, among other factors, are associated with risk of cardiovascular disease. Because cardiovascular disease varies in Asian countries, we hypothesized that lipid profiles differ in ethnic groups of postmenopausal Asian women. To add to the limited body of information currently available, we also investigated the effects of estrogen/progestin therapy on lipid/lipoprotein profiles in postmenopausal Asian women. METHODS: The Pan-Asia Menopause (PAM) study was a prospective, randomized, double-blind clinical trial evaluating 1028 postmenopausal women at 22 investigational centers in 11 Asian countries/territories. Subjects were randomly assigned to one of three doses of continuous combined conjugated estrogens (CE)/medroxyprogesterone acetate (MPA): CE/MPA (in mg/day) = 0.625/2.5, 0.45/1.5 or 0.3/1.5. The treatment period, following baseline evaluations, consisted of six continuous 28-day cycles. Analysis of lipid profiles was a secondary objective of the PAM study. Total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), very low density cholesterol (VLDC-C), triglycerides and lipoprotein(a) were analyzed at a central laboratory by state-of-the-art methods. RESULTS: Mean concentrations of total cholesterol, LDL-C, VLDL-C and triglycerides differed significantly among the nine ethnic groups of postmenopausal women. This difference was independent of body mass index and age, two factors that also influenced lipid/lipoprotein profiles. Mean HDL-C concentrations also differed, but this difference was influenced by body mass index in a weak interaction. All three doses of CE/MPA significantly lowered total cholesterol. Treatment with the high and middle doses significantly lowered LDL-C, and increased HDL-C, VLDL-C and triglycerides. The high dose produced a significant decrease in lipoprotein(a). CONCLUSIONS: The different lipid/lipoprotein profiles in the nine ethnic groups of postmenopausal Asian women evaluated here suggest a relationship to differences in the prevalence of cardiovascular disease reported for different regions in Asia. However, the reported prevalence data on cardiovascular disease morbidity and mortality in the regions corresponding to the nine ethnic groups are insufficient to allow qualitative comparisons with the lipid profiles shown in our study. The lipid/lipoprotein changes in response to estrogen/progestin therapy observed here are consistent with those reported for Western women.

Differential prevalence of quality-of-life categories (domains) in Asian women and changes after therapy with three doses of conjugated estrogens/medroxyprogesterone acetate: the Pan-Asia Menopause (PAM) study.

OBJECTIVES: To assess the prevalence of four categories (domains) of menopausal symptoms as markers for quality of life in nine ethnic groups of Asian women. To evaluate changes in quality of life (MENQOL scores) in Asian women following hormone therapy. METHODS: A prospective, randomized, double-blind, multinational clinical trial in 1028 healthy postmenopausal women of nine ethnic groups from 11 Asian countries/regions. Following 2 weeks of baseline observation, the women received one of three conjugated estrogens (CE)/medroxyprogesterone acetate (MPA) doses (in mg) daily for 24 weeks: 0.625/2.5, 0.45/1.5, or 0.3/1.5. At baseline and at the end of weeks 4, 12 and 24 following the start of therapy, the study participants were asked to record, on a menopause-specific quality of life (MENQOL) questionnaire, 29 menopausal symptoms, as experienced during the preceding month. The symptoms were categorized into four domains: vasomotor, psychosocial, physical and sexual. RESULTS: The baseline (pretreatment) symptom scores in each of the four domains varied substantially among the different ethnic groups, ranging from 2.21 to 5.71 in the vasomotor, 2.37-5.96 in the psychosocial, 2.66-5.39 in the physical, and 2.11-6.55 in the sexual domain. Overall, Vietnamese and Pakistani women had the highest baseline scores, i.e. were most afflicted by each set of symptoms in a given domain, and Indonesian, Malay, Taiwanese and Thai women were least afflicted. In the overall population, intervention resulted in statistically significant decreases in the scores of all four domains within 4 weeks of intervention. The beneficial effects were similar in the three dose groups. CONCLUSIONS: The prevalence of four domains of menopausal symptoms, representative of quality of life as recorded on a MENQOL questionnaire, varies considerably among ethnic groups of Asian women. The MENQOL scores in the overall population were significantly lowered in the course of the study, indicating an improvement in quality of life. In the absence of a placebo group, the relative contribution of hormones and placebo in our intervention is unknown.

Dose of human menopausal gonadotropin influences the outcome of an in vitro fertilization program.

This study compares outcomes of in vitro fertilization (IVF) in two groups of 57 patients when either 2 (group 1) or 3 (group 2) ampules of human menopausal gonadotropin (hMG) were administered daily. Treatment began on day 3 of the cycle and was discontinued when at least 2 follicles attained diameters greater than or equal to 1.5 cm. Human chorionic gonadotropin (hCG) was given either 24 or 48 hours after the last dose of hMG. Although serum estradiol levels were lower in group 1, the average number of oocytes retrieved (3.2 versus 2.9), fertilized (1.9 versus 2.0), and cleaved (1.7 versus 1.8) per completed cycle did not differ between groups 1 and 2. Likewise, the number of oocytes that fertilized abnormally was similar in both groups (0.5 versus 0.3/cycle). However, the number of atretic oocytes (0.03 versus 0.5/cycle) and the percent of oocytes recovered from the cul-de-sac (0 versus 7.2%) were significantly (P less than 0.05) lower in group 1. In group 1, administration of hCG 48 hours after the last dose of hMG was associated with a higher number of cleaving embryos (2.1 versus 1.5/cycle) and a higher pregnancy rate (34.8 versus 14.7%; P less than 0.05) when compared with injection at 24 hours. In group 2, the interval between hMG and hCG did not influence these results. Together, the associations between fewer oocytes that were atretic or recovered from the cul-de-sac, and a trend toward a higher pregnancy rate, suggest that follicular recruitment with 2 ampules of hMG is more appropriate than 3 ampules in an IVF program.

Cervical mucus changes in relationship to urinary luteinizing hormone.

In order to evaluate the relationship between the urinary luteinizing hormone (LH) surge as detected by the OvuSTICK (Monoclonal Antibodies, Inc., Mountain View, CA) method and daily cervical mucus parameters, ten spontaneously ovulating women undergoing infertility evaluation were followed during their cycles with twice daily urinary LH testing as well as daily ultrasound, mucus evaluation, and hormonal assays of serum LH, progesterone (P), and estradiol (E2). Maximal cervical mucus scores, as determined using a modified Insler score, were noted to coincide consistently with the urinary LH surge as detected by twice daily testing and to precede ultrasound evidence of ovulation by 0 to 24 hours. Mucus scores rapidly declined in the 24-hour period following the urinary LH surge. Detection of the urinary LH surge may therefore help identify that period of time during which cervical mucus parameters are optimal and therefore facilitate the timing of artificial insemination, intercourse, or postcoital testing.

The zona-free hamster egg penetration assay as a prognostic indicator in a human in vitro fertilization program.

The present study was designed to test the validity of the hamster egg penetration assay as a prognostic indicator of male fertility in 54 patients undergoing in vitro fertilization. Human oocyte fertilization, cleavage, and pregnancy were compared with the results of this bioassay. Good correlation was found between hamster egg penetration and oocyte fertilization. Conversely, a definite lower limit of hamster egg penetration to define absolute male infertility could not be established because human oocyte fertilization, cleavage, and even pregnancy occurred in spite of low hamster egg penetration.