Japan Society of Obstetrics and Gynecology and Japan Society for Menopause and Women's Health 2017 guidelines for hormone replacement therapy.

Hormone replacement therapy (HRT) plays a large part in maintaining and improving the quality of life (QOL) of postmenopausal women. Despite this obvious role, the use of HRT has stagnated in Japan as well as the United States, since the interim report of the HRT trial of Women's Health Initiative study was published in 2002. The Japan Society of Obstetrics and Gynecology and Japan Society for Menopause and Women's Health formulated the Guidelines for Hormone Replacement Therapy in 2009, which was subsequently revised in 2012, with the aim of organizing perceptions about HRT and allowing people to provide or receive HRT with a sense of security. Later on, in light of changes in indications for HRT and attitudes toward its impact on cancer risks, amendments were made again in 2017. With the establishment of the 2017 guidelines, practitioners in Japan are able to address various issues related to HRT with more appropriate judgment. Moreover, the practice of reliable, safe and effective HRT is expected to promote further efforts toward improvement or maintenance of QOL in patients.

[Calcium and bone metabolism across women's life stages. Nutritive therapy for improvement of bone and calcium metabolism according to life stage in women.]

Postmenopausal osteoporosis is mainly caused by decreased estrogen levels, and progression of disease is associated with irreversible changes. It is therefore extremely important to maintain or improve healthy bone and calcium metabolism during and before the climacteric from a preventive medicine viewpoint. The specific preventive measures are appropriate calcium intake and regular physical exercise. In recent years, women in their twenties are considerably thinner and have a lower calcium intake than women in other age groups, which may lead to a further increase in the number of women with osteoporosis in the future. From the aspect of female hormone secretion, women are at higher risk for osteoporosis than men at any given age. Aggressive intervention should therefore be undertaken to prevent osteoporosis according to life stage in women.

Changes in migraine before and after menopause in Japanese climacteric women.

Introduction We conducted a questionnaire survey of Japanese women with migraine who presented at neurology and gynecology headache clinics to assess how the frequency and severity of migraine in pre-, peri-, and postmenopausal women changed as compared with what they experienced in their 20s and 30s. Methods The study group comprised 171 women with migraine (mean age 48.5) at the time of the survey. They were requested to fill out a self-administered questionnaire. Results (1) The current frequency and severity of migraine were claimed to be higher than that in their 20s and 30s. (2) More than 50% of postmenopausal women responded that migraines were currently less frequent than in their 20s and 30s. (3) The largest proportion of postmenopausal women responded that migraine was currently less severe than during any other period. Conclusions Our survey demonstrated that there are trends toward fewer migraine attacks and milder symptoms in postmenopausal Japanese women.

Symptoms and effects of physical factors in Japanese middle-aged women.

OBJECTIVE: The aim of the study was to clarify the prevalence and severity rates of symptoms and investigate whether symptoms varied in relation to body mass index (BMI). METHODS: The study group composed of 1,969 women, aged 40 to 60 years, who presented at our department from 1993 through 2014. The participation rate was 98%. The presence or absence of symptoms was evaluated by having the participants complete the Keio Questionnaire, a self-administered questionnaire. To allow the results to be compared according to ovarian function, serum levels of follicle-stimulating hormone and estradiol were measured. Participants were classified into three groups according to BMI: underweight, normal weight, and overweight. Symptoms were also compared among these subgroups. RESULTS: The most common symptom was general fatigue. Vasomotor symptoms differed significantly between pre- and postmenopause status. When symptoms were analyzed according to BMI, the severity rates of the following symptoms were significantly higher in the overweight group than in the normal weight and underweight groups: hot flushes, sweats, joint pain, numbness, and incontinence. On the contrary, the underweight group had significantly higher severities of cold constitution, nervousness, and wrinkled skin than did the other groups. In addition, an increase in BMI was associated with an increased severity of vasomotor symptoms. CONCLUSIONS: The prevalence and severities of shoulder stiffness, considered a characteristic symptom in Japanese women, were high. Increased BMI was shown to be associated with a higher severity of vasomotor symptoms, joint pain, nervousness, and urinary symptoms.

Patient preference for monthly bisphosphonate versus weekly bisphosphonate in a cluster-randomized, open-label, crossover trial: Minodroate Alendronate/Risedronate Trial in Osteoporosis (MARTO).

Minodronate is a potent nitrogen-containing bisphosphonate that can be administered according to a monthly (every 4 weeks) dosing regimen. A 6-month, cluster-randomized, open-label, multicenter, crossover trial was conducted to test the preference of Japanese patients with osteoporosis for monthly bisphosphonate versus weekly bisphosphonate. One hundred and forty-seven patients (postmenopausal women and men) with primary osteoporosis were recruited at eight outpatient clinics. The clinics were randomized into two groups according to the dosing protocol-monthly minodronate followed by weekly alendronate or risedronate for a total of 24 weeks, or weekly alendronate or risedronate followed by monthly minodronate for 24 weeks. Patient preference for either the monthly or weekly bisphosphonate regimen was evaluated using a preference questionnaire. One hundred and fifteen patients (78.2 %) who completed the trial were processed for the analyses. Significantly more patients preferred the monthly bisphosphonate regimen (65.2 %) than the weekly bisphosphonate regimen (15.7 %) (P = 0.007). 'Dosing schedule fits lifestyle better' was the most common reason given for the patient preference for both the monthly (32.0 %) and weekly bisphosphonate (33.3 %) regimens. Significantly more patients found the monthly bisphosphonate regimen to be more convenient (73.0 %) than the weekly bisphosphonate regimen (13.9 %) (P < 0.0001). The safety profiles of the two regimens were similar. The present trial demonstrated a strong patient preference for and the convenience of the monthly bisphosphonate regimen over the weekly bisphosphonate regimen in Japanese patients with osteoporosis.

Polymorphisms of estrogen metabolism-related genes ESR1, UGT2B17, and UGT1A1 are not associated with osteoporosis in surgically menopausal Japanese women.

INTRODUCTION: Bilateral salpingo-oophorectomy (BSO) is a risk factor for osteoporosis. Previous studies have reported an association between genetic polymorphisms and the risk of developing osteoporosis. However, the relationship between osteoporosis and genetic polymorphisms in Japanese women treated with BSO is not well understood. To improve the quality of life for post-BSO patients, it is important to determine the genetic factors that influence their risk for osteoporosis. The aim of this study was to investigate the association between gene variations of estrogen metabolism-related genes and osteoporosis in surgically menopausal patients, which may improve their quality of life. MATERIAL AND METHODS: This study included 203 menopausal women treated with BSO because of gynecologic disorders. One hundred and twenty-six women with artificial (surgical) menopause, who had undergone BSO in the premenopausal period, were compared with 77 women with natural menopause, who had undergone BSO in the postmenopausal period. The women were tested for bone mineral density to diagnose osteoporosis. Polymorphisms of estrogen receptor 1 (ESR1) and UDP-glucuronosyl transferase (UGT) genes UGT2B17 and UGT1A1 were analyzed, and their association with bone mass and osteoporosis was statistically evaluated. RESULTS: No significant association was found between osteoporosis and polymorphisms in ESR1, UGT2B17, or UGT1A1 in both groups, suggesting that BSO might be a more significant physiological factor in influencing bone mass density compared to genetic variations. CONCLUSIONS: These results suggest that the ESR1, UGT2B17, and UGT1A1 polymorphisms are not genetic factors affecting osteoporosis in postmenopausal Japanese women.

Osteoporosis is less frequent in endometrial cancer survivors with hypertriglyceridemia.

We previously reported an association between dyslipidemia and endometrial cancers. Osteoporosis is also reported to relate with some cancers. A common etiologic event has been proposed between dyslipidemia and osteoporosis. However, the pattern of interrelationships among dyslipidemia, osteoporosis and endometrial cancer is not well understood. To improve the quality of life of endometrial cancer survivors, these relationships should be determined. This study included 179 Japanese menopausal women who underwent bilateral salpingo-oophorectomy, including 114 women with incident endometrial cancer and 65 without endometrial cancer. The women were categorized according to dyslipidemia status. Bone mineral density was measured and compared between groups. Osteoporosis was statistically more frequent in women with hypertriglyceridemia who did not have endometrial cancer. In contrast, osteoporosis was statistically less frequent in women with hypertriglyceridemia who had endometrial cancer. In this cross-sectional study in a Japanese population, osteoporosis was associated with hypertriglyceridemia in post-menopausal women without endometrial cancer, but was less frequent in endometrial cancer survivors with hypertriglyceridemia.

Survey of the utility of once-monthly bisphosphonate treatment for improvement of medication adherence in osteoporosis patients in Japan.

Prescription of a bisphosphonate (BP) with monthly dosing has recently been approved in Japan. The value of this approach for improvement of medication adherence was investigated in patients undergoing drug therapy for osteoporosis. A questionnaire was distributed to patients receiving treatment for osteoporosis at 8 medical facilities (5 orthopedic, 2 gynecology, and one internal medicine). Responses were collected from 1,300 patients. After exclusion of those who missed an item on the questionnaire or took drugs other than oral drugs, responses from 1,151 patients were analyzed. The most frequently used drug for treatment of osteoporosis was a once-weekly BP. Of the 1,151 patients, 38.4 % reported forgetting to take their current drug. The most frequent concern was 'I cannot feel an effect', but 73.2 % answered 'I have no concerns'. Regarding the most appropriate dosing regimen for long-term treatment, 60.3 % selected once-weekly and 24 % selected once every 4 weeks. Based on a recommendation by a physician of a drug to be taken monthly, 32.5 % wanted to switch, 31.8 % were undecided, and 35.7 % wanted to continue with their current drug. The desire for a change was higher among patients currently taking a once-weekly BP (52.3 %) than among patients taking a daily BP (29.5 %) or a SERM (19.4 %). This survey revealed patients' preferences in osteoporosis drug therapy. It is important to select a drug for osteoporosis based on the efficacy and the drug regimen preferred by the individual patient.

Family history and BRCA1/BRCA2 status among Japanese ovarian cancer patients and occult cancer in a BRCA1 mutant case.

BACKGROUND: This study aimed to examine family history among Japanese ovarian cancer patients and to investigate the TP53 status of fallopian tube epithelial and ovarian cancer cells in a Japanese BRCA1 mutant case that may be associated with the transformed state in hereditary ovarian cancer. METHODS: One hundred and two primary ovarian cancer patients were retrospectively evaluated in this cross-sectional study. The family history of cancer was determined in probands. In a BRCA1 mutant case, p53 immunostaining and direct sequencing, followed by laser-capture microdissection, were performed for the fallopian tube, considered the origin of ovarian cancer. RESULTS: Nine of 102 (8.8%) families were regarded as having hereditary breast-ovarian cancer syndrome, two families (2.0%) were diagnosed with Lynch syndrome and six patients harbored BRCA1 or BRCA2 mutations. One case underwent risk-reductive salpingo-oophorectomy as a BRCA1 mutant carrier was retrospectively diagnosed as occult cancer. Common TP53 mutations were detected in cancer and fallopian tube epithelial cells in the case. CONCLUSIONS: Here, we integrate family cancer history and histology in ovarian cancer cases as well as TP53 status in a BRCA1 mutant case into a discussion regarding carcinogenesis in a Japanese population. The TP53 status for the BRCA1 mutant case examined here supports the recently proposed theory that ovarian cancer develops because of BRCA1 or BRCA2 inactivation and/or TP53 mutations.

Polymorphisms in the UGT1A1 gene predict adverse effects of irinotecan in the treatment of gynecologic cancer in Japanese patients.

Irinotecan is a key chemotherapeutic drug used to treat many tumors, including cervical and ovarian cancers; however, irinotecan can cause toxicity, particularly in the presence of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphisms, which are associated with reduced enzyme activity. Here, we investigated the prevalence of three different variants of UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28) and their relationships with irinotecan-induced adverse events in patients with gynecologic cancer, who are treated with lower doses of irinotecan than patients with other types of solid tumors. Fifty-three female patients treated with irinotecan and 362 female patients not treated with irinotecan were screened for UGT1A1*6, UGT1A1*27 and UGT1A1*28. Homozygosity for UGT1A1*6 or heterozygosity for UGT1A1*6/*28 was associated with a high risk of severe absolute neutrophil count decrease or diarrhea (odds ratios: 16.03 and 31.33, respectively). In contrast, serum bilirubin levels were not associated with irinotecan toxicity. Homozygosity for UGT1A1*6/*6 and heterozygosity for UGT1A1*6/*28 were associated with an increased risk of absolute neutrophil count and/or diarrhea in Japanese gynecologic cancer patients, despite the lower doses of irinotecan used in these patients. UGT1A1*6 and UGT1A1*28 are potential predictors of severe absolute neutrophil decrease and diarrhea caused by low-dose irinotecan in gynecologic cancer patients.

Hypertriglyceridemia is frequent in endometrial cancer survivors.

OBJECTIVE: Previous studies have reported an association between endometrial cancer and the risk of metabolic syndrome; however, the pattern of endometrial cancer-associated dyslipidemia is not well understood. The standard therapy for endometrial cancer is total abdominal hysterectomy and bilateral salpingo-oophorectomy. Premenopausal bilateral salpingo-oophorectomy may cause adverse events, including dyslipidemia. Gynecologists have to care dyslipidemia in endometrial cancer survivors at cancer follow-up clinic. METHODS: This study included 693 patients who had undergone bilateral salpingo-oophorectomy, and included 412 women with incident endometrial cancer and 281 controls. We divided the patients into two categories according to whether they had a premenopausal or postmenopausal bilateral oophorectomy. Serum lipid levels were measured and statistically analyzed. RESULTS: Hypertriglyceridemia was statistically more frequent in patients who had undergone bilateral salpingo-oophorectomy both before and after menopause than in the corresponding non-endometrial cancer controls. High levels of low-density lipoprotein cholesterol and a high low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio were statistically more frequent in patients who had undergone bilateral salpingo-oophorectomy before menopause than in non-endometrial cancer controls. CONCLUSIONS: Our report highlights the importance of the relationship between endometrial cancer and lipid metabolism, which may aid in preventing cerebrovascular or cardiovascular diseases due to dyslipidemia and improving the quality of life in endometrial cancer survivors.

Experience of risk-reducing salpingo-oophorectomy for a BRCA1 mutation carrier and establishment of a system performing a preventive surgery for hereditary breast and ovarian cancer syndrome in Japan: our challenges for the future.

BACKGROUND: Risk-reducing salpingo-oophorectomy is currently regarded as the most certain primary method for preventing ovarian cancer among BRCA1/2 mutation carriers with hereditary breast and ovarian cancer syndrome. However, risk-reducing salpingo-oophorectomy has rarely been performed in Japan. METHODS: We developed the first system in Japan for performing risk-reducing salpingo-oophorectomy for BRCA1/2 mutation carriers at our university hospital in 2008. RESULTS: The indication for risk-reducing salpingo-oophorectomy for patients with hereditary breast/ovarian cancer syndrome is currently limited in Japan. This situation may be because of the limited number of genetic counseling units, the limited number of facilities that can perform BRCA1/2 genetic testing and the fact that prophylactic surgery is not covered by health insurance in Japan. CONCLUSIONS: Recent treatment guidelines for breast cancer in Japan recommended risk-reducing salpingo-oophorectomy for BRCA1/2 mutation carriers. Risk-reducing salpingo-oophorectomy should be performed in the framework of the standard therapeutic modality for BRCA1/2 mutation carriers in the near future.

Antipsychotic-induced hyperprolactinemia inhibits the hypothalamo-pituitary-gonadal axis and reduces bone mineral density in male patients with schizophrenia.

OBJECTIVE: An inhibitory effect of hyperprolactinemia on the hypothalamo-pituitary-gonadal axis has been suggested as a mechanism of bone loss in schizophrenia, but this has not been confirmed. In this study, which was conducted in Tokyo, Japan, from February to May 2005, we examined the possible causes of reduced bone mineral density (BMD) in male patients with schizophrenia. METHOD: The BMD of the radius of 74 male patients (aged 31-78 years) who met the diagnostic criteria for DSM-IV schizophrenia was measured by dual-energy x-ray absorptiometry. Levels of prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, estradiol, and 1,25-dihydroxy vitamin D (VitD) were also measured. Pedometers were used to measure the impact of exercise. RESULTS: Study subjects showed lower BMD in all age groups compared with reference values in healthy persons. There was no significant difference in the Z score among low, medium, and high exercise groups. 87% of the subjects had hyperprolactinemia, and VitD levels were normal in all subjects except 1. The high PRL group had lower levels of FSH and LH, and significantly lower levels of estradiol (p < .05), compared with the normal PRL group. In the high PRL group, there was a significant negative correlation between the duration of treatment and the Z score (p < .05). CONCLUSION: Male patients with schizophrenia had lower BMD than normal individuals irrespective of the amount of exercise or the level of VitD. The results support the hypothesis that inhibition of the hypothalamo-pituitary-gonadal axis by hyperprolactinemia contributes to the mechanism of the bone loss and suggest that the longer the duration of hyperprolactinemia, the greater the reduction in BMD.

Randomized trial comparing low-dose hormone replacement therapy and HRT plus 1alpha-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 > or =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 microg/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.

Analysis of fatty acid composition in human bone marrow aspirates.

In the present study, the fatty acid composition of bone marrow aspirates and serum phospholipids in nine patients with hematologic diseases was investigated, and the effect of fatty acids on osteoblast differentiation in ST2 cells was examined. The concentrations of oleic acid and palmitic acid were significantly higher in bone marrow aspirates than in serum phospholipids, but the concentrations of other fatty acids did not differ. The rate of alkaline phosphatase positive ST2 cells induced by BMP2 was significantly increased by oleic acid, but was unaffected by the presence or absence of palmitic acid. We conclude that the fatty acid composition of bone marrow aspirates differs from that of serum phospholipids. This difference may affect osteoblast differentiation in the bone marrow microenvironment.

Long-term effects on bone mineral density and bone metabolism of 6 months' treatment with gonadotropin-releasing hormone analogues in Japanese women: comparison of buserelin acetate with leuprolide acetate.

Our objective was to assess the effects of 6 months' treatment with two types of gonadotropin-releasing hormone (GnRH) analogues on lumbar bone mineral density (BMD) and bone metabolism. We studied 27 women who had been given a diagnosis of endometriosis or uterine myoma. The subjects received drug therapy for 6 months and were subsequently followed up for 1 year. The BMD of the lumbar spine (L2, L3, L4) was measured by dual energy X-ray absorptiometry four times: at baseline, after 6 months, after 12 months, and after 18 months. The serum concentrations of sex steroids and bone metabolic markers were measured at the same times as BMD. Compared with the baseline value, the mean decrease in the buserelin group L2-4 BMD was 3.7% at 6 months, 1.7% at 12 months, and 0.4% at 18 months. In the leuprolide group, L2-4 BMD decreased respectively by 5.1%, 6.2%, and 4.3%. Serum concentrations of calcium increased significantly after 6 months of treatment (P < 0.05) and returned to the baseline level at 12 months in both groups. In the leuprolide group, the intact osteocalcin concentration after 6 months was significantly higher than the baseline value, and after 12 months, it decreased to the baseline level. Our results indicate that the effect on BMD of 6 months' treatment with GnRH analogues virtually resolves by 1 year after treatment, provided that drugs affecting bone metabolism are not given during this period.

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 . METHODS: The subjects comprised 398 women ranging in age from 40 to <60 years (mean age, 50.5 years). Climacteric symptoms were objectively assessed using the Keio questionnaire. The total scores obtained for the 40 symptoms were used to calculate symptom prevalence and severity. RESULTS: (i) The most frequent symptom was poor memory, reported by 88.7% of the women. (ii) Lumbar-sacral back pain was rated as a severe symptom by the highest percentage of women (15.3%). (iii) The prevalence and severity of poor memory and lumbar-sacral back pain did not differ with menopausal status. (iv) Hot flashes and sweats were slightly higher in peri- and early postmenopausal women than in premenopausal women. CONCLUSIONS: The present study showed that healthy women who do not consult physicians because of climacteric symptoms are primarily concerned with age-related symptoms, such as poor memory, loss of hair, and forgetfulness.

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 > or = 25 pg/mL and FSH < or = 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.