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Comparative uterine response of the selective estrogen receptor modulators (SERMs) Bazedoxifene (BZA), raloxifene (RLX) AND lasofoxifene (LFX) in rodent models
39.1 vs. 26 3.8, P<0.001) levels were significantly higher in the premenopausal group. There were no significant differences with respect to MDA, LDL, triglycerides, Lp (a) and Apo B levels among the groups. Furthermore, serum PON activity was not significanly different between premenopause and ERT groups (204.4 82.1 vs. 178.3 103.6, P¼0.236). BMI and PON activity was negatively correlated (r ¼ 0.33, P¼0.043). Multivariant analysis revealed that age, BMI and Apo A levels were significant predictors for the PON activity. CONCLUSIONS: PON activity was not significantly different among the groups despite the lower HDL, higher BMI and older age of the menopausal group. ERT may increase the PON activity in surgically menopausal women as a results of positive alteration in the lipid and apoprotein levels. However, clinical significance of this association needs further evaluations. Supported by: None.
P-417 ANTISPERMATOGENIC EFFECTS OF TRADITIONALLY USED INDIAN MEDICINAL PLANTS IN MALE ALBINO RATS. P. C. Mali. Reproductive Physiology Section, Centre for Advanced Studies, Department of Zoology, University of Rajasthan, Jaipur, Rajasthan, India. OBJECTIVE: In search of a cheap, safe and orally effective male fertility regulating agent from traditionally used Indian medicinal plants. DESIGN: The 50% ethanolic extracts of Euphorbia neriifolia stem and whole stem of Withania somnifera were administered orally to male albino rats at the dose levels of 50 and 100 mg/kg.b.wt/day for 60 days to evaluate antifertility activities. The animals of control group were received water ad libitum. MATERIALS AND METHODS: The ethanolic extracts were prepared according to the WHO protocol. The colony-bred, fertility proven, adult male rats weighing between 120–200 gm. were distributed into three treatment groups. The animals were maintained under controlled conditionsfed with pallated diet and water was provided ad libitum. A required quantity of the extracts was administered orally in male rats. The body weights of animals were recorded on 61 day and sacrificed under mild ether anesthesia. The testis and accessory reproductive organs were weighed. The sperm motility was accessed. Sperm density was estimated by routine procedure. Serum was separated and stored at 20 C for subsequent analysis. The testis and pieces of accessory reproductive organs were processed for biochemical estimation and histological examinations. The data were analyzed statistically. The study was carried out under the supervision of ethical committee of the Department of Zoology, University of Rajasthan, Jaipur. RESULTS: The weights of testis and accessory reproductive organs were decreased with the treatments. The sperm motility and density were significantly declined in treated rats. The microscopic observations of the testis of rats treated with extracts reveals degenerative changes in the germinal epithelium and germinal elements gradual reduced. The normal seminiferous tubules and mature Leyding cells were decreased, whereas, inter tubular tissue area was elevated. The germinal epithelium of cauda epididymis were degenerated and lumen were appeared empty. There was a significant reduction observed in the biochemical estimation of protein, sialic acid and fructose levels of treated rats. The decreased sperm density after the treatments indicates antispermatogenic effects of the extracts. CONCLUSIONS: The antispermatogenic effects of the treatment caused degenerative changes in germinal elemets, reduced motility and number of spermatozoa the the treated rats. Supported by: The Head, Dept. of Zool, Univ. of Raj., Jaipur for facilities and UGC Bhopal for financial support are gratefully acknowledged.
P-418 A RANDOMIZED, DOUBLE-BLIND, MULTIPLE DOSE ESCALATION STUDY OF THE EFFECT OF THE CHINESE HERBAL MEDICINE PREPARATION DANG GUI BUXUE TANG ON MENOPAUSAL SYMPTOMS IN HONG KONG CHINESE WOMEN. C. J. Haines, P. M. Lam, T. K. H. Chung, P. C. Leung. Obstetrics and Gynaecology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, NT, Hong Kong; Institute of Chinese Medicine, Chinese University of Hong Kong, Shatin, NT, Hong Kong. OBJECTIVE: Many postmenopausal women are now using alternative or complementary medicines instead of standard menopausal hormone therapy. We have previously shown that the Chinese herbal preparation (Dang Gui Buxue Tang) (DBT) was superior to placebo in controlling mild vasomotor
FERTILITY & STERILITYÒ
symptoms in postmenopausal Chinese women. In the present study we examined the effect of different doses of this DBT preparation on vasomotor symptoms. DESIGN: This was a randomized, double-blind, multiple dose escalation study of the effect of the Chinese herbal medicine preparation Dang Gui Buxue Tang on vasomotor symptoms. MATERIALS AND METHODS: The preparation was made in a ratio of 1:5 Dang Gui (Radix Angelicae) to Huangqi (Radix Astragali). Doses of 1.5 g, 3 g and 6 g were administered daily. Symptoms were assessed using the Greene Climacteric Scale and the vasomotor domain of the MENQOL. Subjects were randomly assigned to receive one of the three trial doses and were assessed at baseline and then at monthly intervals for 4 months. RESULTS: Using the Greene Climacteric Scale, hot flushes significantly decreased with the middle dose compared with baseline (P<0.01) and also compared with the other dose groups (P<0.01). Night sweats significantly decreased in both the middle and low dose groups compared with baseline (P<0.01). In the vasomotor domain of the MENQOL, hot flushes were significantly reduced in all groups, with the greatest effect being in the medium dose group (54%). For night sweats, there was a significant reduction in all dose groups, with the greatest effect also being in the medium dose group (47%). CONCLUSIONS: This study found that a dose of 3 g Dang Gui Buxue Tang daily was the most effective in reducing vasomotor symptoms. Vasomotor symptoms decreased by 30–50% in women using this preparation. We have now completed recruitment for this study and are awaiting the final results. Supported by: This study was supported through an Area of Excellence grant from the Research Grants Committee of Hong Kong for ‘‘Chinese Medicine Research and Further Development’’.
P-419 COMPARATIVE UTERINE RESPONSE OF THE SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs) BAZEDOXIFENE (BZA), RALOXIFENE (RLX) AND LASOFOXIFENE (LFX) IN RODENT MODELS. B. S. Komm, P. V. N. Bodine, H. A. Harris, Y. Kharode. WHMSB, Wyeth Research, Collegeville, PA. OBJECTIVE: The desired clinical profile of SERMs was for the treatment of menopausal symptoms and maintenance of bone mass, with no stimulatory effect on the uterus or mammary gland. To date, no SERM has achieved this goal. Although all SERMs function via estrogen receptors, differences in their chemical structures result in distinct pharmacologic profiles. These studies explored the preclinical uterine activation profiles of 3 SERMs: BZA, RLX, and LFX. DESIGN: Preclinical studies in immature and mature ovariectomized (OVX) rats. MATERIALS AND METHODS: Immature and mature OVX rats were treated daily for 3 days or 6 weeks, respectively, with BZA, RLX, and LFX compared to saline control and ethinyl estradiol (EE). Uterine and endometrial endpoints were evaluated, including wet weight, endometrial epithelial cell height, and other histologic parameters. RESULTS: The data reveal distinct differences between BZA, RLX, and LFX. In the highly sensitive immature rat model, the effect of BZA on uterine wet weight was less than that of RLX or LFX. Similarly, BZA more effectively antagonizes the stimulatory effect of EE on the uterus in comparison with RLX and LFX (rank order, BZA < RLX < LFX). BZA was the only SERM that completely reversed EE-induced uterine stimulation, as the maximal effect of RLX and LFX converged to their independent stimulatory level (rank order, BZA < RLX < LFX). These increases in wet weight occurred at very low doses, and leveled off with increased dose. The same rank order (BZA < RLX < LFX) of uterine stimulation was observed in the mature OVX rat model. Histologic evaluation demonstrated that BZA did not stimulate a significant increase in luminal epithelial cell height vs. control, whereas RLX and LFX stimulated 2- and 5-fold increases, respectively. The rates of myometrial hypertrophy and epithelial apoptosis correlated with rates of endometrial hypertrophy. When BZA was co-administered with RLX, BZA antagonized the stimulatory effect of RLX on these uterine endpoints. CONCLUSIONS: BZA demonstrated the lowest degree of uterine stimulation of the SERMs evaluated and results show how these molecules distinguish themselves on the presented endpoints. These data support the endometrial safety of BZA observed in phase III trials for the prevention and treatment of postmenopausal osteoporosis. Supported by: Wyeth Research, Collegeville, PA.
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P-417 ANTISPERMATOGENIC EFFECTS OF TRADITIONALLY USED INDIAN MEDICINAL PLANTS IN MALE ALBINO RATS. P. C. Mali. Reproductive Physiology Section, Centre for Advanced Studies, Department of Zoology, University of Rajasthan, Jaipur, Rajasthan, India. OBJECTIVE: In search of a cheap, safe and orally effective male fertility regulating agent from traditionally used Indian medicinal plants. DESIGN: The 50% ethanolic extracts of Euphorbia neriifolia stem and whole stem of Withania somnifera were administered orally to male albino rats at the dose levels of 50 and 100 mg/kg.b.wt/day for 60 days to evaluate antifertility activities. The animals of control group were received water ad libitum. MATERIALS AND METHODS: The ethanolic extracts were prepared according to the WHO protocol. The colony-bred, fertility proven, adult male rats weighing between 120–200 gm. were distributed into three treatment groups. The animals were maintained under controlled conditionsfed with pallated diet and water was provided ad libitum. A required quantity of the extracts was administered orally in male rats. The body weights of animals were recorded on 61 day and sacrificed under mild ether anesthesia. The testis and accessory reproductive organs were weighed. The sperm motility was accessed. Sperm density was estimated by routine procedure. Serum was separated and stored at 20 C for subsequent analysis. The testis and pieces of accessory reproductive organs were processed for biochemical estimation and histological examinations. The data were analyzed statistically. The study was carried out under the supervision of ethical committee of the Department of Zoology, University of Rajasthan, Jaipur. RESULTS: The weights of testis and accessory reproductive organs were decreased with the treatments. The sperm motility and density were significantly declined in treated rats. The microscopic observations of the testis of rats treated with extracts reveals degenerative changes in the germinal epithelium and germinal elements gradual reduced. The normal seminiferous tubules and mature Leyding cells were decreased, whereas, inter tubular tissue area was elevated. The germinal epithelium of cauda epididymis were degenerated and lumen were appeared empty. There was a significant reduction observed in the biochemical estimation of protein, sialic acid and fructose levels of treated rats. The decreased sperm density after the treatments indicates antispermatogenic effects of the extracts. CONCLUSIONS: The antispermatogenic effects of the treatment caused degenerative changes in germinal elemets, reduced motility and number of spermatozoa the the treated rats. Supported by: The Head, Dept. of Zool, Univ. of Raj., Jaipur for facilities and UGC Bhopal for financial support are gratefully acknowledged.
P-418 A RANDOMIZED, DOUBLE-BLIND, MULTIPLE DOSE ESCALATION STUDY OF THE EFFECT OF THE CHINESE HERBAL MEDICINE PREPARATION DANG GUI BUXUE TANG ON MENOPAUSAL SYMPTOMS IN HONG KONG CHINESE WOMEN. C. J. Haines, P. M. Lam, T. K. H. Chung, P. C. Leung. Obstetrics and Gynaecology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, NT, Hong Kong; Institute of Chinese Medicine, Chinese University of Hong Kong, Shatin, NT, Hong Kong. OBJECTIVE: Many postmenopausal women are now using alternative or complementary medicines instead of standard menopausal hormone therapy. We have previously shown that the Chinese herbal preparation (Dang Gui Buxue Tang) (DBT) was superior to placebo in controlling mild vasomotor
FERTILITY & STERILITYÒ
symptoms in postmenopausal Chinese women. In the present study we examined the effect of different doses of this DBT preparation on vasomotor symptoms. DESIGN: This was a randomized, double-blind, multiple dose escalation study of the effect of the Chinese herbal medicine preparation Dang Gui Buxue Tang on vasomotor symptoms. MATERIALS AND METHODS: The preparation was made in a ratio of 1:5 Dang Gui (Radix Angelicae) to Huangqi (Radix Astragali). Doses of 1.5 g, 3 g and 6 g were administered daily. Symptoms were assessed using the Greene Climacteric Scale and the vasomotor domain of the MENQOL. Subjects were randomly assigned to receive one of the three trial doses and were assessed at baseline and then at monthly intervals for 4 months. RESULTS: Using the Greene Climacteric Scale, hot flushes significantly decreased with the middle dose compared with baseline (P<0.01) and also compared with the other dose groups (P<0.01). Night sweats significantly decreased in both the middle and low dose groups compared with baseline (P<0.01). In the vasomotor domain of the MENQOL, hot flushes were significantly reduced in all groups, with the greatest effect being in the medium dose group (54%). For night sweats, there was a significant reduction in all dose groups, with the greatest effect also being in the medium dose group (47%). CONCLUSIONS: This study found that a dose of 3 g Dang Gui Buxue Tang daily was the most effective in reducing vasomotor symptoms. Vasomotor symptoms decreased by 30–50% in women using this preparation. We have now completed recruitment for this study and are awaiting the final results. Supported by: This study was supported through an Area of Excellence grant from the Research Grants Committee of Hong Kong for ‘‘Chinese Medicine Research and Further Development’’.
P-419 COMPARATIVE UTERINE RESPONSE OF THE SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs) BAZEDOXIFENE (BZA), RALOXIFENE (RLX) AND LASOFOXIFENE (LFX) IN RODENT MODELS. B. S. Komm, P. V. N. Bodine, H. A. Harris, Y. Kharode. WHMSB, Wyeth Research, Collegeville, PA. OBJECTIVE: The desired clinical profile of SERMs was for the treatment of menopausal symptoms and maintenance of bone mass, with no stimulatory effect on the uterus or mammary gland. To date, no SERM has achieved this goal. Although all SERMs function via estrogen receptors, differences in their chemical structures result in distinct pharmacologic profiles. These studies explored the preclinical uterine activation profiles of 3 SERMs: BZA, RLX, and LFX. DESIGN: Preclinical studies in immature and mature ovariectomized (OVX) rats. MATERIALS AND METHODS: Immature and mature OVX rats were treated daily for 3 days or 6 weeks, respectively, with BZA, RLX, and LFX compared to saline control and ethinyl estradiol (EE). Uterine and endometrial endpoints were evaluated, including wet weight, endometrial epithelial cell height, and other histologic parameters. RESULTS: The data reveal distinct differences between BZA, RLX, and LFX. In the highly sensitive immature rat model, the effect of BZA on uterine wet weight was less than that of RLX or LFX. Similarly, BZA more effectively antagonizes the stimulatory effect of EE on the uterus in comparison with RLX and LFX (rank order, BZA < RLX < LFX). BZA was the only SERM that completely reversed EE-induced uterine stimulation, as the maximal effect of RLX and LFX converged to their independent stimulatory level (rank order, BZA < RLX < LFX). These increases in wet weight occurred at very low doses, and leveled off with increased dose. The same rank order (BZA < RLX < LFX) of uterine stimulation was observed in the mature OVX rat model. Histologic evaluation demonstrated that BZA did not stimulate a significant increase in luminal epithelial cell height vs. control, whereas RLX and LFX stimulated 2- and 5-fold increases, respectively. The rates of myometrial hypertrophy and epithelial apoptosis correlated with rates of endometrial hypertrophy. When BZA was co-administered with RLX, BZA antagonized the stimulatory effect of RLX on these uterine endpoints. CONCLUSIONS: BZA demonstrated the lowest degree of uterine stimulation of the SERMs evaluated and results show how these molecules distinguish themselves on the presented endpoints. These data support the endometrial safety of BZA observed in phase III trials for the prevention and treatment of postmenopausal osteoporosis. Supported by: Wyeth Research, Collegeville, PA.
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