K. Hashimoto

The chronological change of vertebral bone loss following oophorectomy using dual energy X-ray absorptiometry: the correlation with specific markers of bone metabolism.

The changes of vertebral bone mineral density (BMD; g/cm2) following oophorectomy were studied, using dual energy X-ray absorptiometry (DEXA) in 38 premenopausal and 244 oophorectomized women. Two biochemical indices of bone remodeling, urinary deoxypyridinoline (DPyr) for bone resorption and serum intact human osteocalcin (hOC) for bone formation, were also measured at the same time. The rate of bone loss in the first year after oophorectomy was 10.7%, while that in the second year was 5.7% (rapid phase), followed by a slow phase at the rate of 1.1%. The bone mass finally reached an osteoporotic level (BMD < 0.767 g/cm2) at 12 years after oophorectomy. The DPyr increased to reach a peak level in the first year, whereas the hOC increased and reached its peak level in the second year after surgery. The maximal bone loss in the first year is considered to be caused by the remarkable increase of bone resorption and the biological delay of the maximal increase in bone formation.

Changes in coagulation factors and fibrinolytic components of postmenopausal women receiving continuous hormone replacement therapy

OBJECTIVE The effect of hormone replacement therapy (HRT) on coagulation factors and fibrinolytic components in postmenopausal women was studied for 6 months to elucidate whether continuous HRT has an influence on thrombosis. METHODS One hundred and thirty-four postmenopausal women were divided into three groups according to treatment: 39 women who had undergone hysterectomy and oophorectomy received 0.625 mg/day of conjugated equine estrogen (CEE) continuously (CEE therapy), 48 postmenopausal women received both 0.625 mg/day of CEE and 2.5 mg/day of medroxyprogesterone acetate (MPA) continuously (CEE/MPA therapy) and 47 postmenopausal women received placebo as control. The following variables were measured before treatment as well as after 1, 3 and 6 months of treatment: factor VII activity, protein C activity, fibrinogen level, antithrombin III activity, plasminogen activator inhibitor-1 (PAI-1) level and the plasma concentration of tissue-type plasminogen activator (t-PA). RESULTS After 1 month of treatment, protein C activity increased by 9.6% and 11.4% of the initial value (p < 0.05), fibrinogen level decreased by 7.8% and 6.1% of the initial value (p < 0.05) and PAI-1 decreased by 19.4% and 14.3% of the initial value (p < 0.05) in the CEE therapy group and the CEE/MPA therapy group, respectively. Factor VII activity increased by 10.1% of the initial value (p < 0.05) in the CEE therapy group only. Antithrombin III and t-PA levels did not change throughout either treatment. CONCLUSION Except for an increase in factor VII activity in the case of continuous CEE therapy, continuous HRT had no unfavorable effects on either coagulation factors or fibrinolytic components.

Urinary excretion of pyridinium crosslinks of collagen in oophorectomized women as markers for bone resorption

To detect increased bone resorption in estrogen-deficient women, the urinary excretion of hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP), which are intermolecular crosslinkings of collagen fibers, were measured and their chronological changes were evaluated following oophorectomy. Seventy-five women were divided into three groups; 15 premenopausal women (mean age 44.0 years), 15 postmenopausal women (mean age 54.2 years) and 45 surgically menopausal women who had a normal menstrual cycle before surgery (mean age 42.2 years). There was a significant increase in HP and LP of the postmenopausal women (P < 0.001). In the oophorectomized women, both HP and LP were three times higher than those of premenopausal women within 1 year after oophorectomy, and decreased to the same level of the postmenopause between 2 and 3 years after surgery. In the six oophorectomized women after the administration of estrogen, HP and LP both decreased remarkably in all cases. The present study thus indicates that an increase of bone resorption which was evaluated by urinary HP and LP occurs in the early stage after oophorectomy. It may, therefore, be good to begin estrogen replacement therapy as soon as possible after oophorectomy.

Treatment of bone loss in oophorectomized women with a combination of ipriflavone and conjugated equine estrogen.

Objective: We previously reported that 0.625 mg/day of conjugated equine estrogen (CEE) could not prevent acute bone loss in the first year after oophorectomy. The effect of additional administration of ipriflavone on bone mineral density (BMD) and biochemical indices of bone remodeling were studied to investigate whether concurrent use of CEE and ipriflavone prevent acute bone loss in the early stages following surgical menopause. Methods: One‐hundred and sixteen oophorectomized women were randomly divided into four groups according to treatment; group 1: placebo, n=30; group 2: CEE (0.625 mg/day), n=29; group 3: ipriflavone (600 mg/day), n=30; group 4: CEE (0.625 mg/day) plus ipriflavone (600 mg/day), n=27. Vertebral BMD was measured using dual energy X‐ray absorptiometry (DEXA) and two biochemical indices of bone metabolism, urinary pyridinoline (Pyr) and serum intact human osteocalcin (hOC), were also measured before, 24 weeks, and 48 weeks after initiation of treatment. Results: BMD was reduced 48 weeks after treatment by 6.1, 3.9 and 5.1% in groups 1–3, respectively, but by only 1.2% in group 4. Pyr decreased by 49.5, 32.0 and 41.5% in groups 2–4, respectively. hOC also decreased by 45.2 and 21.6% in groups 2 and 4, but increased by 40.5% in group 3, suggesting an inhibitory action of CEE and ipriflavone on the turnover of bone metabolism and stimulatory action of ipriflavone on bone formation. Conclusion: Concomitant use of ipriflavone with CEE from an early stage after oophorectomy inhibited bone loss and was considered to be effective in maintaining bone mass after oophorectomy.

Medroxyprogesterone acetate inhibits proliferation of colon cancer cell lines by modulating cell cycle-related protein expression.

Objective: To investigate the effects of medroxyprogesterone acetate on colon cancer cells in vitro. Design: HT29 and HCT116 human colon cancer cell lines were used in this study. Cell growth and WST-1 assays were performed to investigate the antiproliferative effect of medroxyprogesterone acetate. Cell cycle analysis was performed to investigate the effects of medroxyprogesterone acetate on cell cycle distribution. Western blot, immunoprecipitation, and a cyclin-dependent kinase assay were performed to investigate changes in the levels of cell cycle proteins. Results: Medroxyprogesterone acetate inhibited proliferation of the cancer cells by inducing accumulation in the G0/G1 fraction. Medroxyprogesterone acetate decreased expression of cyclin E, increased expression of p21WAF1/CIP1, and enhanced interaction of p21WAF1/CIP1 with cyclin-dependent kinase 2, eventually inhibiting its activity. Conclusions: Medroxyprogesterone acetate exerts its antiproliferative effect by modulating cell cycle-related protein expression and cyclin-dependent kinase 2 activity. These results should help to elucidate the protective effect of medroxyprogesterone acetate on colon cancer risk.

Differential time-related effects of conjugated equine estrogen on bone metabolism in oophorectomized women

Objective: The effects of conjugated equine estrogen (CEE) on bone mineral density (BMD) and biochemical indices of bone remodeling in oophorectomized women were studied for 3 years during estrogen replacement therapy (ERT) to investigate whether 0.625 mg/day of CEE alone prevent acute bone loss in the early stage of surgical menopause. Methods: We divided the subjects into three groups according to interval between oophorectomy and the start of ERT (group 1: less than 2 years after surgery, n = 31; group 2: 2–5 years after surgery, n = 29; and group 3: more than 5 years after surgery, n = 27). Vertebral BMD was measured using dual energy X‐ray absorptiometry (DEXA). Two biochemical indices of bone metabolism, urinary deoxypyridinoline (DPyr) and serum intact human osteocalcin (hOC) were also measured. Results: In group 1, continuous ERT with 0.625 mg/day of CEE could not prevent a BMD decrease within the first year. However, by the end of the second year, BMD was restored to the pre‐ERT. The same dosage of CEE significantly increased BMD in groups 2 and 3 by the end of the first year. DPyr and hOC levels both decreased dramatically in the initial 6 months of therapy and were stable thereafter. Conclusion: In the initial 2‐year period after oophorectomy, 0.625 mg/day of CEE alone could not prevent acute bone loss suggesting that additional therapy for the prevention of osteoporosis may be needed.