Women's Health Care Committee, Japan Society of Obstetrics and Gynecology: Annual report-2023.

The Women's Health Care Committee was established in 2010 with the goal of improving women's health. In the current academic year, there are six subcommittees focusing on conducting the following surveys: (1) the current status of pregnancy-associated breast cancer in Japan; (2) surgery for disorders of sex development; (3) diagnosis and treatment of premenstrual syndrome and premenstrual dysphoric disorder; (4) obstetrics and gynecology-based treatment for patients with eating disorders in Japan; (5) multi-drug-resistant bacterial infections in the field of obstetrics and gynecology; and (6) changing the methodology of the treatment of dysmenorrhea and continuing medical education. The activities of each subcommittee are described below. This report is based on the Japanese version of the annual report (Acta Obst Gynaec Jpn 2023;75(6):662-86).

Association between the Change in Blood Pressure during Normotensive Pregnancy and the Development of Hypertension in Later Life.

Introduction: Women who experience maternal complications, including pre-eclampsia, have a higher risk of cardiovascular disease development. Although the mechanism remains unclear, there is a hypothesis that pregnancy would be a stress test for cardiovascular disease. This study aimed to investigate whether changes in blood pressure during pregnancy would be associated with developing hypertension, which is a main risk of cardiovascular disease. Methods: We conducted a retrospective study by collecting Maternity Health Record Books from 735 middle-aged women. Of these, 520 women were selected based on our criteria. 138 were defined as the hypertensive group according to the criteria of receiving antihypertensive medications or blood pressures of >140/90 mmHg at the survey. The rest 382 were defined as the normotensive group. We compared the blood pressures of the hypertensive group with those of the normotensive group during pregnancy and postpartum. Then, 520 women were divided into quartiles (Q1-Q4) according to their blood pressures during pregnancy. After the changes in blood pressure for each gestational month relative to nonpregnant measurements were calculated, the changes in blood pressure were compared among the four groups. Additionally, the rate of developing hypertension was evaluated among the four groups. Results: The average age of the participants was 54.8 years (range: 40-85 years) at the time of the study and 25.9 years (range: 18-44 years) at delivery. There were significant differences in blood pressure during pregnancy between the hypertensive group and the normotensive group. Meanwhile, these two groups did not indicate any differences in blood pressure in postpartum. Higher mean blood pressure during pregnancy was associated with smaller changes in blood pressure during pregnancy. The rate of development of hypertension in each group of systolic blood pressure was 15.9% (Q1), 24.6% (Q2), 29.7% (Q3), and 29.7% (Q4). The rate of development of hypertension in each group of diastolic blood pressure (DBP) was 18.8% (Q1), 24.6% (Q2), 22.5% (Q3), and 34.1% (Q4). Conclusions: Changes in blood pressure during pregnancy are small in women who have a higher risk of hypertension. Levels of blood pressure during pregnancy may be reflected in individual stiffness of blood vessels by the burden of pregnancy. If so, levels of blood pressure would be used to facilitate highly cost-effective screening and interventions for women with a high risk of cardiovascular diseases.

Survey on the Awareness of Menstruation and Menstruation-Related Problems in Athletes among Public High School Physical Education Teachers.

Introduction: In recent years, the activities of female athletes have attracted increasing attention, especially regarding the effect of menstruation on athletic performance. Nevertheless, there are no surveys of these practices among coaches who train non-top-level athletes for general competition. This study aimed to investigate how high school physical education teachers approach the issue of menstruation and the awareness of menstruation-related problems. Methods: This was a questionnaire-based cross-sectional study. The participants were 225 health and physical education teachers from 50 public high schools in the Aomori Prefecture. Participants were asked to answer a questionnaire regarding whether they talk to their female athletes about menstruation, keep track of their menstrual status, or make adjustments for menstruating students. Additionally, we asked for their views on painkiller use and their knowledge of menstruation. Results: The participants included 183 men (81.3%) and 42 women (18.7%); data from 221 participants were analyzed after four teachers were excluded. Teachers of female athletes who communicated with students regarding their menstrual conditions and physical changes were predominantly female (p < 0.01). Regarding the use of painkillers for menstrual pain, more than 70% of respondents said that they recommended their active use. Few respondents reported that they would adjust a game because of athletes with menstrual problems. More than 90% of the respondents knew that there was a change in performance due to the menstrual cycle, and 57% of the respondents understood the relationship between amenorrhea and osteoporosis. Conclusions: Menstruation-related problems are not only issues for top athletes but also important for general competition level athletes. Hence, even in high school clubs, teachers should be educated on how to deal with menstruation-related problems to prevent withdrawal from sports, maximize athletes' abilities, prevent future diseases, and preserve fertility.

Women's Health Care Committee, Japan Society of Obstetrics and Gynecology: Annual report-2022.

The Women's Health Care Committee was instituted in 2010 with the goal of improving women's health. In the current academic year, there are 6 subcommittees focusing on conducting the following surveys: (1) Current status of pregnancy-associated breast cancer in Japan; (2) Surgery for disorders of sex development; (3) Diagnosis and treatment of premenstrual syndrome and premenstrual dysphoric disorder; (4) Obstetrics and gynecology-based treatment for patients with eating disorders in Japan; (5) Multi-drug-resistant bacterial infections in the field of obstetrics and gynecology; and (6) Changing methodology of treatment of dysmenorrhea and continuing medical education. The activities of each subcommittee are detailed below. This report is based on the Japanese version of the annual report (Acta Obst Gynaec Jpn 2022;74(6): XXX-XXX).

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Investigate the Effects of Kamishoyosan, a Traditional Japanese Medicine, on Menopausal Symptoms: The KOSMOS Study.

OBJECTIVE: The KOSMOS study, a multicenter, randomized, double-blind, placebo-controlled trial, investigated the effects and safety of kamishoyosan (TJ-24), a traditional Japanese medicine, in the treatment of climacteric disorder. METHODS: Japanese women with climacteric disorder were administered a placebo during a 4-week run-in period, after which they were classified as placebo responders (R group) if their score on the modified Questionnaire for the Assessment of Climacteric Symptoms in Japanese Women (m-QACS) with excitability and irritability as the primary outcome improved by ≥ 3 points and as placebo nonresponders (NR group) otherwise. Members of the NR group were randomly allocated to receive either TJ-24 or placebo. After 12 weeks, their m-QACS scores, anxiety and depression, sleep, and overall quality of life (QOL) were compared. RESULTS: The TJ-24 and placebo arms in the NR group included 20 patients each. The change in the m-QACS scores of members of the NR group for excitability and irritability at 12 weeks versus baseline was -3.1 ± 1.7 in the TJ-24 arm, a significant decrease, but compared with -2.7 ± 2.2 in the placebo arm, no significant difference was between two arms. However, the proportion of participants whose score improved by ≥3 points was significantly higher in the TJ-24 arm. In the subgroup analysis of premenopausal women, the changes in the score for excitability and irritability were significantly larger in the TJ-24 arm. The incidence of adverse drug reactions or adverse events did not differ between the two arms, and no serious events were reported. CONCLUSION: Although no significant difference was identified for the primary outcome, a significantly higher proportion of patients who received TJ-24 displayed improvement. Its high level of safety and effects on excitability and irritability in premenopausal women suggest that TJ-24 may be a useful treatment.

Subcutaneous abscess caused by Streptococcus pneumoniae serotype 28F in an infant: a case report.

BACKGROUND: Invasive pneumococcal disease (IPD) is defined by the detection of Streptococcus pneumoniae on culture from samples obtained from a normally sterile site. Pneumococcal conjugate vaccines (PCV) have been developed for the prevention of IPD that is caused by highly virulent serotypes. Despite the effective reduction of IPD caused by vaccine serotypes after the introduction of PCV, there has been a rapid increase in the incidence of IPD caused by non-vaccine serotypes, and serotype replacement has become a global issue. CASE PRESENTATION: We report a previously healthy 4-month-old girl presenting with a large subcutaneous abscess caused by S. pneumoniae, identified as non-vaccine serotype 28F. The patient had received routine vaccination, including PCV vaccination. After the incision and drainage of the subcutaneous abscess, the patient was treated with antibiotics. She was discharged on Day 7 of hospitalization without any residual sequelae. CONCLUSIONS: Subcutaneous abscess is a common pediatric skin and soft tissue infection, whereas pneumococcal subcutaneous abscesses are quite rare. As the pneumococcal serotype 28F caused a subcutaneous abscess, this serotype possibly has a high virulence. The incidence of IPD caused by non-vaccine serotypes, such as 28F, is expected to increase in the future. The consolidation of international data on pneumococcal serotypes is important for the development of novel PCV.

Effects of Kamishoyosan, a Traditional Japanese Medicine, on Menopausal Symptoms: A Randomized, Placebo-Controlled, Double-Blind Clinical Trial.

OBJECTIVE: Kampo medicine, a traditional Japanese medicine, is widely used in Japan, especially in the field of menopause medicine. However, few studies have shown evidence-based effects. This study aimed to confirm the effects of kamishoyosan on menopausal symptoms with a randomized, placebo-controlled, double-blind clinical trial. METHODS: Subjects were randomly allocated to groups that received either kamishoyosan (n = 101) or a placebo resembling kamishoyosan (n = 104). The primary outcomes were the change in the number of hot flashes, depression scores, improvements of anxiety, quality of life (QOL), and menopausal symptoms before and 4 and 8 weeks after initiation of treatment with the study drug. The secondary outcome was drug safety. RESULTS: After 8 weeks, the number of hot flashes decreased after treatment in both groups, but there was no significant difference between the two groups. The changes in SDS scores showed the same results. Moreover, no significant differences were observed between the two groups in assessments with the STAI, SF-36, and JSOG menopausal index. No serious adverse effect was reported. CONCLUSIONS: This first placebo-controlled double-blind randomized trial with kamishoyosan demonstrated that it was safe and had some effects on climacteric symptoms, but not significant compared with placebo. Some problems, such as placebo effects, in the study of Kampo therapy for menopausal symptoms, were revealed. This trial is registered with the trial registration number. UMIN 000006042.

Single-dose toxicity study by intra-arterial injection of 10BSH entrapped water-in-oil-in-water emulsion for boron neutron capture therapy to hepatocellular carcinoma.

We developed a mixing medical device by attaching Shirasu porous glass Millipore membrane to prepare water-in-oil-in-water (WOW) emulsion in a shorter time to be applied as 10B-entrapped WOW emulsion for hepatocellular carcinoma (HCC) treatment. Single-dose toxicity studies by intra-arterial injection of 10BSH-entrapped WOW were performed in rabbits and pig, and no side effects were observed. We hope to proceed to the preclinical and clinical studies for further evaluation of 10B compound as multidisciplinary treatments for HCC.

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. Bone metabolism of women in primary amenorrhea.]

For development of the bone during adolescence, the increased estrogen plays an important role especially in young women as well as GH/IGF-Ⅰ system. Although primary amenorrhea can be caused by various pathological factors, almost of cases have a dysfunction of estrogen secretory systems. For Turner syndrome, which is well-known disease with primary amenorrhea,it is generally recommended that the estrogen therapy is started at adolescence and gradually increased up to adult dose level. Recently studies about the adequate dose of estrogen and the adequate age of adult dose in Turner syndrome revealed that intervention with adult dose of estrogen is required as soon as possible for gaining better bone mineral. In the point of view for bone fragility at the future, early diagnosis and adequate intervention for primary amenorrhea is important.

Blood pressure during pregnancy is a useful predictive maker for hypertension and dyslipidemia later in life, a population-based, cross-sectional study.

OBJECTIVE: Pregnancy is an opportunity for women to become aware of their risk of cardiovascular disease (CVD), because physiologic responses to dynamic hemodynamic changes can be observed during pregnancy. Accordingly, we hypothesized that blood pressure levels during pregnancy may be associated with the risk of CVD later in life. STUDY DESIGN: We used data from the Iwaki Health Promotion Project and designed a population-based, cross-sectional study. In this study, Maternity Health Record Books were collected from women over 40 years of age in order to obtain reliable data regarding past pregnancies. Of a total of 642 women, 432 were selected according to the study criteria. MAIN OUTCOME MEASURES: The associations between blood pressure levels during pregnancy and major CVD risk factors (hypertension and dyslipidemia) were analyzed retrospectively. RESULTS: A 10 mmHg increase in the mean diastolic blood pressure level between gestational weeks 12 and 42 conferred a 1.70- and 1.55-fold increase in the risk of hypertension and dyslipidemia, respectively, in later life. CONCLUSIONS: Blood pressure levels during pregnancy may be associated with CVD risk and could therefore be a useful predictive marker.

Role of antimüllerian hormone as a biomarker of the menopausal transition.

OBJECTIVE: The objectives of this study were to clarify changes in antimüllerian hormone (AMH) concentrations during the menopausal transition and to determine whether AMH may serve as a marker to predict the onset of menopause. METHODS: Blood samples were collected annually for 6 years from 595 women living in Iwaki, Japan. We selected 44 women according to strict criteria: those older than 40 years at first participation; those who had their regular menstruation; those whose menstrual cycle had changed from regular to irregular or those who met the final menstrual period; and those who did not take medication that may affect the menstrual cycle. Serum AMH concentrations were determined by the newly developed AMH Gen II assay kit. Stage of the menopausal transition was defined according to the Stages of Reproductive Aging Workshop. RESULTS: Among the 44 women who participated in the study, 29 experienced menopause during the study (group A), whereas the remainder developed irregular menstrual cycles (group B). AMH was consistently found to be undetectable for 3 years before menopause, suggesting that AMH is a sensitive marker for predicting the onset of menopause. In addition, serum AMH was detectable at low levels in women from group B until menstrual cycles became irregular, suggesting that AMH serves as a marker for diagnosing the menopausal transition. CONCLUSIONS: When AMH levels fall below detectable levels, women at the menopausal transition will progress to menopause within 3 years.

Urinary pentosidine and plasma homocysteine levels at baseline predict future fractures in osteoporosis patients under bisphosphonate treatment.

To clarify what kind of risk factors predict incident fractures in patients treated with bisphosphonates, the authors investigated the relationship between baseline characteristics and incident vertebral fracture in Japanese osteoporosis patients undergoing bisphosphonate treatment. This was a multi-center follow-up study conducted at three centers, in which a total of 251 Japanese patients with osteoporosis (mean age 70.5 years) from the three centers were followed for 3.2 ± 2.0 years. Baseline data, including pre-existing fractures, bone mineral density in the lumbar spine (LBMD), bone metabolic markers, urinary pentosidine, and plasma homocysteine, were evaluated. Changes in LBMD, bone turnover markers, and incident fractures after the treatment were followed. Sixty-one patients developed incident vertebral fractures; this group of patients was older and had lower LBMD, a higher prevalent vertebral fracture number, and higher homocysteine and pentosidine levels than patients who did not develop incident vertebral fractures. Changes in LBMD, urinary N-terminal telopeptides of type I collagen (NTX), and bone-derived alkaline phosphatase showed no significant association with the occurrence of vertebral fractures. Cox's proportional hazard model demonstrated that age, prevalent fracture, pentosidine, and homocysteine were independent predictors of the incident vertebral fracture rate under bisphosphonate treatment. Higher baseline levels of pentosidine and homocysteine in osteoporosis patients are potential risk factors for incident vertebral fractures when these patients are treated with bisphosphonates. Further clarification is needed to explain why such patients have higher fracture susceptibility.

A Case of Ovarian Clear Cell Carcinoma Simultaneously Producing Parathyroid Hormone-related Protein and Granulocyte Colony-Stimulating Factor.

We describe the first report of an ovarian clear cell carcinoma simultaneously producing parathyroid hormone-related protein (PTHrP) and granulocyte colony-stimulating factor (G-CSF). A 64-year-old woman complained of general fatigue, loss of appetite, nausea, vomiting and constipation. The results of blood and biochemistry tests were white blood cell count of 21,060 /ml and calcium of 18.0 mg/dl, indicating an increase in the number of leukocytes and hypercalcemia. A computerized tomography scan showed a tumor in the lower abdomen with a maximum diameter of 16 cm and containing both cystic and solid parts. There was a remarkable elevation of the tumor marker CA 19-9, to 1611 IU/ml, and serum level of PTHrP was elevated to 25.9 pmol/ml. The PTH-intact level was 14 pg/ml, which was at the lower limit of the normal range. In addition, the G-CSF level was also elevated to 73 pg/ml (normal range: <38 pg/ml). Since hypercalcemia caused by tumor PTHrP production was suspected, and as this required elimination of the primary disease, extirpation of the tumor was carried out. Serum calcium levels promptly returned to 11.1 mg/ml on the first day following surgery, and PTHrP also dropped to its normal level on the same day. Histological and immunohistochemical examinations revealed that the tumor was clear cell adenocarcinoma which was partially positive for PTHrP and positive for G-CSF, indicating the tumor simultaneously producing PTHrP and G-CSF.

Septic shock induced by Lecythophora mutabilis in a patient with mitochondrial encephalomyopathy.

Invasive fungal infection (IFI) caused by Lecythophora mutabilis occasionally occurs in patients with impaired host immunity; such patients had eosinophilia at onset, and surviving patients were treated with fungal cell-membrane-targeted drugs. An 18-year-old man with mitochondrial encephalomyopathy accompanied with refractory anaemia and chronic renal failure developed septic shock caused by L. mutabilis, which was detected from a blood culture, and was identified morphologically and genetically. During the course of the infection, he had eosinophilia, although beta-d-glucan levels were within the normal range. He was treated with micafungin, but deteriorated and died, despite his treatment being changed to liposomal amphotericin B. On the basis of this we suggest that IFI caused by L. mutabilis should be suspected when a compromised host develops infection and eosinophilia, and that antifungal drugs that target beta-d-glucan are not advisable.

[Estrogens for treatment of osteoporoses].

It has been noted that estrogens have strong effects for suppression of bone absorption and prevention of fracture. Although WHI reports emphasized on adverse events of hormone replacement therapy (HRT) too much to avoid this therapy for osteoporosis, recently there are several statements for HRT with positive assessment. Those mentioned that considering risk factor of HRT and age factor, it is possible to use estrogens safely. There is the evidence that estrogens prevent bone fractures in not only osteoporotic women but also healthy women. It is a unique effect that only estrogen has among antiosteoporotic drugs. Taking these characters into consideration, it seems that estrogen therapy is useful for prevention of fractures in perimenopausal women irrespective of bone condition.

[Evidence of hormone replacement therapy for osteoporosis].

Postmenopausal bone estrogen deficiency causes rapid bone loss. Therefore hormone replacement therapy (HRT) has been considered as a rational therapy for postmenopausal not only for osteopenia but also osteoporosis. The results of Women's Health Initiative (WHI) hormone trial had given the strong restriction on HRT. However recent closer analyses have shown that HRT initiated for early menopausal women brings many benefits without elevation of the risks, and that the appropriate selection of dose level or a way to apply can also reduce the risks of HRT. HRT has many physiological effects that were not seen in other drugs and so HRT can be considered as one of the most effective treatment for postmenopausal osteoporosis.

[Daily practice using the guidelines for prevention and treatment of osteoporosis. Recent evidence of estrogen therapy for osteoporosis].

Results of WHI hormone trial have given the strong restriction on HRT. But recently the conception of adverse events of HRT is getting changed. Generally, it is considered that HRT under 60 years aged or early menopausal women make many benefits without elevation of risk of adverse events and selection of dose level or way to apply can also vary the risk of disease. Because any kind of estrogens has exact effects suppressing bone resorption and fracture, we can use them for osteopenia or osteoporotic women in climacteric state cost-effectively by taking age, dose level and application methods into consideration.

4-Methylumbelliferone inhibits hyaluronate synthesis in human uterine cervical fibroblasts.

AIM: Hyaluronate plays an important role in the regulation of cervical function during parturition. In our previous study we showed that 4-methylumbelliferone (MU) suppresses hyaluronate synthesis by cultured human skin fibroblasts. The present study investigated the effects of MU on fibroblasts obtained from the human uterine cervix and assessed the possibility of controlling cervical ripening with MU. METHODS: Human uterine cervical fibroblasts were collected from uterine cervices obtained from the uteri of three patients who had a total hysterectomy for uterine myoma at Hirosaki University Hospital. The fibroblasts were cultured in Dulbecco's modified Eagle's medium until confluence. They were then cultured in medium containing [3H]glucosamine (0.074 MBq/mL) with various MU doses. Hyaluronate synthesis was evaluated by assessing the incorporation of [3H]glucosamine into the soluble fraction of hyaluronate. Three independent studies were carried out on each specimen to clarify whether MU causes compositional changes or promotes hyaluronate degradation, whether the inhibitory effects of MU on hyaluronate synthesis are dose-dependent, and whether the effects of MU are reversible. RESULTS: MU added to the medium of the cultured cells reduced the synthesis of hyaluronate in a dose-dependent manner. After MU was removed from the medium, hyaluronate synthesis recommenced, and the amount of [3H]hyaluronate synthesized was similar to the control level. CONCLUSIONS: MU inhibits the synthesis of hyaluronate in human uterine cervical fibroblasts.

[Hormone replacement Up-to-date. Effect of estrogen therapy (EP) and estrogen-progestogen therapy (EPT) on the bone metabolism].

Estrogen depletion after menopause become involved with postmenopausal bone loss, therefore ET (estrogen therapy) and EPT (estrogen-progestogen therapy) have been considered as first-line therapy for postmenopausal osteopenia and osteoporosis. However, after WHI (Women's Health Initiative) reports, use of estrogen for treatment of osteopenia and osteoporosis is limited. Because estrogen plays indispensable roles in maintaining female physiological functions including bone metabolism, use of estrogens would elicit much benefits when administered properly.