Kazuya Makita

Decreased bone mineral density associated with early menopause progresses for at least ten years: Cross-sectional comparisons between early and normal menopausal women

To establish whether early onset of menopause carries an increased risk of osteoporosis, we compared the bone mineral density (BMD) of the second to fourth lumbar vertebrae (L2-4) between 18 women who had menopause before 43 years of age (early menopause group) and 19 women who had menopause after reaching 43 years of age (normal menopause group). Serum levels of calcium, phosphorus, calcitonin, intact parathyroid hormone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), and alkaline phosphatase activity were measured, and urine samples were analyzed to derive calcium/creatinine, hydroxyproline/creatinine, pyridinoline/creatinine, and deoxypyridinoline/creatinine (D-Pyr/Cr) ratios. Mean BMD was significantly lower in the early menopause group than in the normal menopause group, and individual BMD values in about half of the subjects in the former group were below the fracture threshold for Japanese women. Serum concentrations of LH, FSH, and E2 were slightly, but not significantly, lower in the early menopause group than in the normal menopause group. The D-Pyr/Cr ratio was significantly higher in the early menopause group than in the normal menopause group. There was no correlation between L2-4 BMD and age or the number of years after menopause in the normal menopause group, but both age and the number of years after menopause were negatively correlated with L2-4 BMD in the early menopause group. These results indicate that BMD in women who have early menopause continues to decline for up to 10 years, and that menopause and aging increase the risk of osteoporosis.

Which is more osteoporosis-inducing, menopause or oophorectomy?

The present study was designed to investigate in a comparative manner whether menopause or oophorectomy (OPX) would be a more osteoporosis-inducing factor with regard to sex steroids, bone metabolism and bone mineral density (BMD), including postmenopausal subjects, OPX subjects and age- and body-size-matched premenopausal controls. Serum levels of estradiol (E2), testosterone (TS) and dehydroepiandrosterone (DHEA) were found to decrease in both the postmenopausal and OPX subjects without any significant difference between them, while serum levels of estrone (E1) and androstenedione (delta 4), which have been reported to be related to bone metabolism, were significantly lower in the OPX subjects than in the postmenopausal subjects. According to the indices representing bone formation and bone resorption, as well as the changes in serum levels of Ca-regulating hormones, bone metabolic balance seemed to be slightly more negative in the former than in the latter. However, there was no difference between these two groups of subjects with regard to BMD in lumbar vertebral spongy portion which sensitively reflects the changes in total lumbar BMD and bone metabolism and in which compressive fracture is apt to occur. This fact suggests that these two groups of subjects may be managed in the same way in clinical practice. In other terms, the menopause, a natural event in women, influences BMD as much as OPX, which is the greatest risk factor in osteoporosis, does.

Differences in axial bone mineral density, serum levels of sex steroids, and bone metabolism between postmenopausal and age- and body size-matched premenopausal subjects

The present study was designed to investigate the differences in serum levels of sex steroids, bone metabolism, and bone mineral density (BMD) between 22 premenopausal subjects and 21 age- and body size-matched postmenopausal subjects. Dual photon absorptiometry (DPA) demonstrated total body BMD significantly decreased in postmenopausal subjects. It was also found that not only spinal BMD as assessed by DPA, but also total third lumbar BMD and third lumbar trabecular BMD as measured by quantitative computed tomography (QCT) significantly decreased in these subjects. In postmenopausal subjects, the urinary-hydroxyproline/creatinine ratio increased significantly, which suggested that bone resorption had been stimulated, and serum levels of alkaline phosphatase (ALPase) and osteocalcin also significantly increased, which suggested a stimulation of bone formation. Consequently, the reduction in BMD was thought to result from a negative balance of bone resorption versus bone formation, or a high turnover of bone metabolism. Androgens were not confirmed to participate in these changes in bone metabolism, but the reduction in serum levels of estradiol, as a major factor, and the reduction in serum levels of estrone, as a participating factor, were assumed to result in an increase in bone resorption in excess of bone formation.

Effects of 1-Year Ipriflavone Treatment on Lumbar Bone Mineral Density and Bone Metabolic Markers in PostmenopausalWomen with Low Bo ne Mass

In vitro studies have shown that ipriflavone affects both bone formation and bone resorption, but the effect in early-stage postmenopausal women with low bone mass and a high turnover of bone metabolism is unknown. In this prospective study, we randomly assigned 60 patients with postmenopausal osteopenia or osteoporosis to receive either 600 mg/day of ipriflavone or 0.8 g/day calcium lactate, and compared the effects on bone mineral density (BMD) from the 2nd to 4th lumbar vertebrae (L2–4) and bone metabolic markers before and after one year of treatment. In the iprifravone-treated (IP) group, L2–4 BMD was similar before and after treatment (0.78 and 0.77 g/cm2, respectively), but in the calcium lactate-treated (CL) group, L2–4 BMD decreased significantly from 0.81 to 0.79 g/cm2 after 1 year of treatment (p < 0.0001). Furthermore, the rate of the decrease in L2–4 BMD was significantly greater in the CL group than in the IP group (p < 0.01). The median deoxypyridinoline (Dpd) level was significantly lower after 1 year of treatment (5.8 mmol/mmol creatinine [Cr]) than the baseline value (10.2 mmol/mmol Cr) in the IP, but not in the CL group, suggesting that IP treatment suppresses bone resorption.

Bone resorption versus estrogen loss following oophorectomy and menopause

OBJECTIVES To investigate if menopause and oophorectomy may represent different risk factors for bone resorption/loss. METHODS The urinary levels of pyridinoline (Pyr) and deoxypyridinoline (D-pyr), the serum levels of type I carboxy-terminal pyridinoline cross-linked telopeptide (ICTP), and lumbar bone mineral density (BMD), were compared in 80 Japanese women after menopause or oophorectomy. These women were divided into four groups of 20 women each as follows: early postmenopausal stage (early physiologic menopause < 3 years before study entry); late postmenopausal stage (physiologic menopause > or = 3 years before study entry); early postoophorectomy stage (oophorectomy < or = 03 years before study entry); or late oophorectomy stage (oophorectomy > 3 years before study entry). RESULTS Lumbar BMD was significantly lower in the late groups compared to their respective early groups and was lowest in the late postoophorectomy group. The ratio of D-pyr/creatinine (Cr) was not significantly different among the four groups. The ratio of Pyr/Cr was significantly higher in the early postoophorectomy subjects compared with either late group. The serum level of ICTP was significantly higher in the early postoophorectomy group compared to all other groups. CONCLUSIONS These findings suggest that serum ICTP may be useful in detecting changes in bone resorption after oophorectomy and that women are at greater risk for bone resorption after oophorectomy than after physiologic menopause, although this difference appears to diminish with time.

Relationship between dermato-physiological changes and hormonal status in pre-, peri-, and postmenopausal women

We previously reported that hormonal changes in perimenopausal women are associated with dermatologic changes. In the present study, we evaluated such dermatologic changes by means of dermato-physiological testing methods in perimenopausal women with various types of hormonal conditions. The study group consisted of 46 consecutive women 41-70 years of age (mean, 54.0 years), attending a climacteric outpatient clinic for a healthy check-up is whom no abnormalities were recognized. The women were divided into four groups according to menstrual history and sex-related steroid hormone values: a premenopausal group (n = 9); a perimenopausal group (n = 8); an early menopausal group, in which 5 years or less had elapsed since menopause (n = 12); and a late menopausal group, in which 6 years or more had elapsed since menopause (n = 17). We found that: (1) after menopause the sebum cutaneum content of the forehead decreased significantly, but that of the subocular region was unchanged; (2) the water content of the stratum corneum of the forehead was significantly higher in the late menopausal group than in the premenopausal group and the perimenopausal group, but there were no significant differences among the four groups at the other sites studied; (3) on psychological stimulation, sweat production was found to decrease significantly after menopause; (4) the skin temperature of the forehead and cheek fell significantly after menopause, but that of the nose, back of the foot, and tips of the toes, did not differ significantly among the four groups; (5) The perimenopausal period was associated with increased skin permeability and vascular responsiveness; (6) fingertip plethysmography revealed significant decreases in peripheral circulatory function in the perimenopausal group and the late menopausal group.

Randomized trial comparing low-dose hormone replacement therapy and HRT plus 1α-OH-vitamin D3 (alfacalcidol) for treatment of postmenopausal bone loss

We conducted a prospective, randomized, multicenter, open-label 2-year trial with 76 postmenopausal women aged ≥60 years with low (T-score less than −1) lumbar bone mineral density (BMD). The hormone replacement therapy (HRT) group received a low dose of conjugated estrogen (CEE) at a dose of 0.31 mg/day ± medroxyprogesterone acetate (MPA) 2.5 mg/day. Group HRT/D received the same dose of HRT together with alfacalcidol in a daily dose of 1.0 µg/day. Changes in lumbar BMD measured by dual energy X-ray absorptiometry (DXA) were followed every 6 months for 2 years. The lumbar BMD of group HRT increased 3.37% [95% confidence interval (CI) 1.6%–5.2%], 4.00% (95%CI 1.6%–6.4%), and 2.32% (95%CI −0.7% to 5.3%) at 12, 18, and 24 months, respectively, when the baseline value was taken as 0%. Lumbar BMD of group HRT/D showed a significant increase beyond 6 months. The percent increases for this group at 6, 12, 18, and 24 months were 6.18 (95%CI 1.3%–6.6%), 6.18% (95%CI 3.9%–8.5%), 7.17% (95%CI 4.3%–10.0%), and 8.75% (95%CI 6.0%–11.5%), respectively. In addition, there was a significant difference in the changes of the lumbar BMD between the two groups at 24 months, suggesting that the combination of HRT and alfacalcidol is more effective than HRT alone in terms of the BMD effect. This study is the first prospective trial demonstrating an additive effect of alfacalcidol on lumbar BMD in postmenopausal women receiving low-dose HRT. It suggests that the combination therapy can be considered to be a promising mode of treatment for bone loss after menopause.

Influence of bilateral oophorectomy upon lipid metabolism

OBJECTIVES Reduction in serum level of estrogen has been thought to result in hyperlipidemia which triggers atherosclerosis, and even to lead to cardiovascular diseases, in postmenopausal women. The present study was designed to investigate the influence of bilateral oophorectomy (OPX), which induces as much reduction in serum estrogen level as menopause, upon lipid metabolism, especially the serum levels of total cholesterol. METHODS In 31 OPX subjects and 31 age- and body size-matched premenopausal controls, the serum levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein (VLDL-C), apoprotein-A1 (Apo-A1), apoprotein-B (Apo-B), lipoprotein lipase (LPL) and lipoprotein-a [LP(a)] were measured as indices of lipid metabolism and the index of arteriosclerosis was calculated. RESULTS TC level was significantly higher in the OPX group than in the premenopausal control group, being 8995 +/- 244 (mean +/- S.E.) mmol/l and 7757 +/- 228 mmol/l, respectively. LDL-C and Apo-B levels and the index of arteriosclerosis were all significantly higher in the OPX group than in the premenopausal control groups. However, there were no significant intergroup differences with regard to HDL-C, Apo-A1, LPL and LP(a). CONCLUSIONS The above results demonstrated that, in spite of no reduction in HDL-C, the blood levels of Apo-B, LDL-C and TC change due to OPX. These changes suggest OPX induces cardiovascular diseases and, therefore, follow-up of the changes in lipid metabolism is required, paying special attention to Apo-B and LDL-C.

Relation between climacteric symptoms and ovarian hypofunction in middle-aged and older Japanese women.

Objective: To gain insight into the characteristics and current status of climacteric symptoms reported by middle-aged and older women in Japan, we surveyed women presenting at our menopause clinic. Design: The participants included 1,069 women, ranging in age from 40 to less than 60 years (mean age, 50.2 y). Climacteric (indefinite) symptoms were objectively assessed with the use of the Keio questionnaire, which grades the severity of 40 types of symptoms classified into 20 subgroups. The total scores obtained for the 40 symptoms were used to calculate symptom prevalence and severity. To evaluate ovarian function, concentrations of estradiol and follicle-stimulating hormone (FSH) in sera were measured. Results: The most frequent symptom was general fatigue, reported by 88.2% of the women. Shoulder stiffness was the symptom rated to be severe by the highest percentage of women (38.1%). The prevalence and severity of hot flushes (and sweats) were slightly higher in perimenopausal and early postmenopausal women than in premenopausal and late postmenopausal women. The prevalence and severity of hot flushes and sweats were higher in women with estradiol < 25 pg/mL and FSH > 40 mIU/mL than in those with estradiol ≥ 25 pg/mL and FSH ≤ 40 mIU/mL. Conclusion: General fatigue and shoulder stiffness, symptoms with low hormone dependence, are the two most frequent climacteric symptoms in our clinic. Hot flushes and sweats, symptoms with high hormone dependence, are also common symptoms.

Status of climacteric symptoms among middle-aged to elderly Japanese women: Comparison of general healthy women with women presenting at a menopausal clinic

Aim: To examine the status and characteristics of climacteric symptoms reported by generally healthy middle‐aged to elderly women in Japan, those living in Saitama Prefecture were surveyed .