Current status and problems in the diagnosis and treatment of premenstrual syndrome and premenstrual dysphoric disorder from the perspective of obstetricians and gynecologists in Japan.

AIM: To investigate the current status and problems in the diagnosis and treatment of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) from the perspective of obstetricians and gynecologists (OB/GYNs) in Japan, the Japanese Society of Obstetrics and Gynecology (JSOG) conducted a national-wide survey. METHODS: An email survey was sent to all JSOG members (16 732) and a web-based survey was conducted using a Google form between September and November 2021. The current status and problems in PMS/PMDD diagnosis and treatment were surveyed in this cross-sectional study. RESULTS: In total, 1312 respondents (7.8% of all JSOG members) completed the questionnaire. In terms of diagnoses and treatment, OB/GYN was preferred over psychiatrist for PMS (91.4% vs. 45%); however, no differences were noted for PMDD (76.1% vs. 73.7%). A total of 1267 (96.6%) respondents engaged in routine PMS/PMDD treatment. Regarding the general diagnosis procedure, 84.4% respondents answered "only a vague medical interview," 8.4% kept a two-cycle symptom diary, and 10.3% used a screening questionnaire. The most commonly used medication was oral contraceptive pills (OCPs) (98.1%), followed by the Kampo, traditional Japanese herbal medicines, Kamishoyosan (73.6%). Concerning first-line drugs for treatment, OCPs were the most common (76.8%), followed by Kampo medicine (19.5%); selective serotonin reuptake inhibitors (SSRIs) were less frequently used (2.6%). Regarding first-line drugs among OCPs, 65.1% respondents reported drospirenone-ethinylestradriol use. CONCLUSIONS: This study indicates that only a few OB/GYNs practicing PMS/PMDD in Japan use a prospective diary, which is an essential diagnostic criterion for PMS/PMDD. Regarding treatment, SSRIs were used less frequently.

Evaluation of a natural S-equol supplement in treating premenstrual symptoms and the effect of the gut microbiota: An open-label pilot study.

AIM: Premenstrual syndrome causes disturbances in many women's daily activities. Isoflavones might cause changes in the estrogen cycle by their selective estrogen receptor modulator-like activities. Equol, which is a metabolite of a soy isoflavone, has greater biological activity than other soy isoflavones. In this preliminary study, we aimed to examine the effect of a natural S-equol supplement (SE5-OH) on premenstrual symptoms. The gut microbiota has recently been suggested to play an important role in brain function in psychiatric disease, such as depression. Therefore, we further aimed to evaluate the relationship of the effect of SE5-OH and the gut microbiota at preintervention. METHODS: Twenty women who showed premenstrual symptoms and were nonequol producers were enrolled in an open-label, single-arm, clinical study in which they received oral SE5-OH for two period cycles. The Daily Record of Severity of Problems (DRSP) total score was evaluated during the intervention cycles. Before taking SE5-OH, fecal samples were obtained and subjected to terminal restriction fragment length polymorphism analysis. RESULTS: The response rate to treatment (≥50% reduction from baseline in the DRSP total score) was 10.5%. Post hoc analysis showed a significant improvement in the change in the DRSP total score (P = .008) and DRSP scores for four core premenstrual dysphoric disorder symptoms. Multiple regression analysis showed that the percentage improvement of the DRSP total score was positively related to Bifidobacterium and negatively related to Clostridium cluster IV. CONCLUSION: SE5-OH supplementation may be an acceptable treatment for premenstrual symptoms. The intestinal microbiota may have an effect on SE5-OH.

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.

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.

Antidepressive Effects of Kamishoyosan through 5-HT1AReceptor and PKA-CREB-BDNF Signaling in the Hippocampus in Postmenopausal Depression-Model Mice.

Females are well known to suffer disproportionately more than males from stress-related neuropsychiatric disorders, especially during perimenopausal and postmenopausal periods. In addition to a decline in serum estradiol levels, environmental stress and social stress likely contribute to the development of neuropsychiatric symptoms in perimenopausal and postmenopausal women. Kamishoyosan (KSS) is a traditional Japanese Kampo medicine, composed of a specified mixture of 10 crude compounds derived from plant sources, widely used for various neuropsychiatric symptoms in perimenopausal and postmenopausal women. However, the molecular mechanisms underlying KSS-mediated attenuation of neuropsychological symptoms and stress-response behaviors in perimenopausal and postmenopausal women remain unknown. In the present study, we first established a mouse model for postmenopausal depression-like signs using chronic water-immersion and restraint-stressed ovariectomized (OVX) mice to investigate the underlying molecular mechanism of KSS. We found that continuous administration of KSS to these mice normalized the activation of the hypothalamic-pituitary-adrenal (HPA) axis, ameliorated stress-induced depressive behavior, and prevented a decrease of neurogenesis in the hippocampus. As previous studies have implicated dysfunction of the hippocampal 5-HT1A receptor (5-HT1AR) in depressive disorders, we also evaluated the effect of KSS on 5-HT1AR expression and the protein kinase A- (PKA-) cAMP response element-binding- (CREB-) brain-derived neurotrophic factor (BDNF) signaling pathway in the hippocampus in this model. The level of 5-HT1AR in the hippocampus decreased in chronic stress-exposed OVX mice, while KSS treatment normalized the stress-induced decrease in 5-HT1AR expression in the hippocampus of chronic stress-exposed OVX mice. Furthermore, we found that KSS treatment upregulated the expression levels of phosphorylated PKA (p-PKA), phosphorylated CREB (p-CREB), and BDNF in the hippocampus in chronic stress-exposed OVX mice. These results suggest that KSS improves neuropsychiatric symptoms through 5-HT1AR and PKA-CREB-BDNF signaling in the hippocampus in postmenopausal women.

[Effects of Immune Checkpoint Inhibitor Combined with Dendritic Cell Therapy and Hyperthermia].

In this study, 97cancer patients were treated with combined immune checkpoint inhibitor therapy and dendritic cell thera- py between June 2015 and April 2018. We administered nivolumab with 2-3mg/kg bw every 2-3weeks. The rate of progress in cases where nivolumab was administered more than 3 times was 55.2%. Dendritic cell therapy enhanced the immune checkpoint inhibitor therapy. In cases where the effect of combined immune checkpoint inhibitor therapy and dendritic cell therapy was restricted, hyperthermia and radiation therapy are useful for the recovery of combined therapy.

[Enhancing Antitumor Effects Using Hyperthermia(Including Immune Checkpoint Inhibitor)].

Hyperthermia enhances the efficacies of radiotherapy, chemotherapy, immunotherapy, and molecular targeted therapy. In this study, we investigated whether hyperthermia enhanced the efficacy of immune check point inhibitor therapy. The LLC tumor inoculated in mouse was heated and immunostained, which showed increase in PD-L1 staining post-heating. PD-L1 and HLA class I staining increased after heating samples derived from a case of analinvasion of rectalcancer associated with Lynch syndrome.

Effectiveness of natural S-equol supplement for premenstrual symptoms: protocol of a randomised, double-blind, placebo-controlled trial.

INTRODUCTION: Premenstrual syndrome (PMS) comprises a range of mood, behavioural and physical symptoms, and impairs many women's quality of life. Isoflavones are expected to stabilise the natural fluctuation of the oestrogen cycle through their selective oestrogen receptor modulator-like activities that alleviate PMS symptoms. Equol, a metabolite of a soy isoflavone converted from daidzein by specific gut bacteria, has a greater bioavailability compared with other soy isoflavones. We aim to examine the effect of natural S-equol supplements on premenstrual symptoms. METHODS AND ANALYSIS: This study will enrol 124 women (aged 20-45 years) who have PMS symptoms and are non-equol producers in a double-blind, parallel, randomised, placebo-controlled trial, in which they will receive natural S-equol supplement (equol 10 mg a day) or placebo, orally, twice daily, for three menstrual cycles. The primary outcome measure (Daily Record of Severity of Problems total score) will be assessed during intervention cycles. To compare the primary outcomes between the S-equol group and the placebo group, the mean differences in the Daily Record of Severity of Problems total score between the two groups will be determined. The p values will be determined using Student's t-test, where the significance level is 5% (two-sided). ETHICS AND DISSEMINATION: The institutional review board at Kindai University approved the study. The findings of this trial will be submitted to an international peer-reviewed journal. Abstracts will be submitted to national and international conferences. TRIAL REGISTRATION NUMBER: UMIN000031815.

Royal Jelly Supplementation Improves Menopausal Symptoms Such as Backache, Low Back Pain, and Anxiety in Postmenopausal Japanese Women.

OBJECTIVES: This study aimed to evaluate the effect of Royal Jelly (RJ) at a dose of 800 mg/day on menopausal symptoms in healthy Japanese postmenopausal women with placebo-controlled design. MATERIAL AND METHODS: A total of 42 healthy Japanese postmenopausal women have been recruited for this study. The subjects were randomized to oral treatment with either 800 mg of protease-digested lyophilized powder of RJ (enzyme-treated RJ) or placebo (800 mg of dextrin) daily for 12 weeks. The level of menopausal symptoms has been evaluated every 4 weeks, using menopausal symptoms questionnaire of Japanese women. Independent t-test was used to evaluate statistical significance of the treatment effects between the two groups. RESULTS AND CONCLUSION: All of the 42 women have completed the trial. There were significant differences related to the anxiety score (P = 0.046) and backache and low back pain score (P = 0.040) between 800 mg/day enzyme-treated RJ and placebo-treated groups after 12 weeks of administration, and no significant differences were found between the two groups in 4 weeks after intervention. No side effects were observed in either group. This study demonstrates that enzyme-treated RJ supplementation with doses of 800 mg/day is effective in relieving menopausal symptoms such as anxiety, backache, and low back pain in Japanese postmenopausal women.

Questionnaire-Based Development of an Educational Program of Traditional Japanese Kampo Medicine.

Traditional Japanese Kampo medicine has been widely used in clinical practice in Japan. Though it is a compulsory subject in Japanese medical schools, a standard educational program in Kampo medicine does not exist. Tohoku University has incorporated Kampo medicine into clinical education via didactic lectures since 2003; however, student evaluations have been lower for Kampo than for all other clinical specialties. We administered a questionnaire about a Kampo medicine course for fifth-year students from 2009 to 2012 and developed an educational program based on feedback obtained. The questionnaire consisted of nine questions (a clear training plan; opportunities for learning, practice, and patient contact; acquisition of medical knowledge and physical examination; learning professionalism; understanding the specialty; overall assessment) that were rated on a 5-point Likert scale along with open-ended questions about the course's strengths and weaknesses. The students responded to the questionnaire after clinical practice in Kampo medicine and other clinical specialty courses. Scores for Kampo medicine and the average of other clinical specialties were compared. All 389 students who participated in Kampo clinical practice answered the questionnaire. In 2009, scores for Kampo medicine for nine questions were lower than for the average of the other clinical specialties. After curriculum reformation involving hands-on training in 2012, all scores except "opportunities to learn about clinical cases" and "opportunities to practice involvement" were higher than the average of all other clinical specialties. In conclusion, we have successfully developed a Kampo medicine educational program for our university through this survey study.

The Kampo Medicine Yokukansan Decreases MicroRNA-18 Expression and Recovers Glucocorticoid Receptors Protein Expression in the Hypothalamus of Stressed Mice.

It is well known that glucocorticoid receptor (GR) signaling regulates the hypothalamic-pituitary-adrenal (HPA) axis, and GR expression level is associated with HPA axis activity. Recent studies revealed that microRNA- (miR-) 18 and/or 124a are candidate negative regulators of GR in the brain. The Kampo medicine Yokukansan (YKS) can affect psychological symptoms such as depression and anxiety that are associated with stress responses. In this study, we evaluated the effect of YKS on miR-18 and 124a and GR levels in mice exposed to stress. We found that YKS pretreatment normalized elevated plasma corticosterone levels in stress-exposed mice. In addition, GR mRNA levels were downregulated in the brain following stress exposure. While miR-124a expression levels were not altered in the hypothalamus of stress-exposed mice, miR-18 levels decreased in the hypothalamus of YKS-pretreated mice after stress exposure. Finally, GR protein levels in the paraventricular nucleus (PVN) of the hypothalamus after stress exposure recovered in YKS-pretreated mice. Collectively, these data suggest that YKS normalizes GR protein levels by regulating miR-18 expression in the hypothalamus, thus normalizing HPA axis activity following stress exposure.

Proliferative effect of Hachimijiogan, a Japanese herbal medicine, in C2C12 skeletal muscle cells.

BACKGROUND: Hachimijiogan (HJG), Ba-Wei-Di-Huang-Wan in Chinese, is one of the most popular herbal medicines in Japanese Kampo. HJG is often prescribed for the prevention and treatment of age-related diseases. Muscle atrophy plays an important role in aging-related disabilities such as sarcopenia. The purpose of this study was to investigate the possible beneficial effect of HJG on skeletal muscle. METHODS: Cells of murine skeletal muscle myoblast cell line C2C12 were used as an in vitro model of muscle cell proliferation and differentiation. The effect of HJG on C2C12 cell proliferation and differentiation was assessed. We counted the number of myotubes morphologically to assess the degree of differentiation. RESULTS: HJG treatment (200 µg/mL) for 3 days significantly increased C2C12 cell number by 1.23-fold compared with that of the control. HJG promoted the proliferation of C2C12 cells through activation of the ERK1/2 signaling pathway without affecting the Akt signaling pathway. HJG did not affect the differentiation of C2C12 cells. CONCLUSION: HJG had beneficial effects on skeletal muscle myoblast proliferation. These findings may provide a useful intervention for the prevention and treatment of sarcopenia.

[The effect of immunotherapy and hyperthermia on patients with advanced or recurrent cancer - analyses by cancer type and recurrence form].

We treated 1,939 patients with advanced or recurrent cancer using hyperthermia and or immunotherapy between July 2005 and November 2013. Standard therapy showed no effect or was refused by these patients. There were 309(15.9%)patients who experienced a clinical benefit(complete response[CR], partial response[PR], and long-term stable disease[SD], >6 months), including 52 CR cases. The effective rate of immunotherapy increased from 9.9%to 19.1%using hyperthermia. The effective rate for patients with hyperthermia-alone was 3.6%, and skin and regional lymph node metastases disappeared. Immunotherapy alone was effective for liver or lung metastases. Combined hyperthermia and immunotherapy had a beneficial effect on multiple metastases observed in important plural solid organs. Ovarian cancer had the highest effective rate (25.0%), followed by prostate cancer.

[The effect of immunotherapy and hyperthermia for advanced or recurrent head and neck cancer - 74 clinical cases].

We treated 74 patients with advanced or recurrent head and neck cancer using hyperthermia and/or immunotherapy between July 2005 and November 2013. Standard therapy showed no effect or was refused by these patients. Fifteen(21.4%) patients experienced a clinical benefit(complete response[CR], partial response[PR], and long-term stable disease[SD], >6 months), including 4 CR cases. Hyperthermia alone was effective for one patient only. A combination of dendritic cell therapy and hyperthermia was beneficial for the remaining 14 patients. One patient was effectively treated with cetuximab, and γδ lymphocytes and dendritic cell therapy.

[The effect of immunotherapy and hyperthermia on advanced or recurrent ovarian and uterine cancer - 229 clinical cases].

We treated 116 advanced or recurrent ovarian cancer and 102 uterine cancer patients with hyperthermia and/or immunotherapy(2005/7-2013/11). Of these, 63, 31, and 8 patients had cervical cancer, endometrial cancer, and uterine sarcoma, respectively. Standard therapy showed no effect or was refused by these patients. Twenty-nine(25.0%)ovarian cancer patients experienced a clinical benefit(complete response[CR], partial response[PR], and long-term stable disease[SD], >6 months). The effective rate of a combination of therapies including activated lymphocyte therapy, dendritic cell therapy, and hyperthermia was 47.5%. Thirteen(12.7%)uterine cancer patients experienced a clinical benefit. The effective rates for cervical cancer, endometrial cancer, and uterine sarcoma were 7.9%, 22.5%, and 12.5%, respectively. Both hyperthermia and immunotherapy were administered to successfully treat these patients.

[The effect of immunotherapy and hyperthermia on patients with advanced or recurrent breast cancer].

We treated 172 patients with advanced or recurrent breast cancer using hyperthermia or immunotherapy between July 2005 and September 2012. In these patients, standard therapy showed no results, or it was refused. Clinical benefit( complete response [CR], partial response[PR], and long stable disease [SD] for more than 6 months) was observed in 30 patients( 17.4%), including CR in 5 patients. The effective rate of immunotherapy increased from 7.7% to 26.0% using hyperthermia. The effective rate of hyperthermia was only 5.1%. The standard therapy had not been altered in 23 of the 30 patients in whom clinical benefit was observed. Thus, immunotherapy or hyperthermia had benefited these 23 patients. Of the 23 effectively treated patients, skin or regional lymph node metastases disappeared in 3 patients treated with hyperthermia alone, and lung metastases disappeared and carcinomatous pleuritis improved in 1 patient treated with immunotherapy alone. In the remaining 19 effectively treated patients, multiple metastases were observed in important solid organs such as the liver, lung, bone, and brain. Combined hyperthermia and immunotherapy was used to treat these 19 patients to good effect.

[Immunotherapy and hyperthermia for the treatment of patients with advanced or recurrent colorectal cancer].

We treated 226 patients with advanced or recurrent colorectal cancer using hyperthermia or immunotherapy between July 2005 and September 2012. Clinical benefit (complete response [CR], partial response [PR], and long stable disease [SD] for more than 6 months) was observed in 30 patients (13.3%), including CR in 5 patients. The effective rate of immunotherapy increased from 14.3% to 16.1% using hyperthermia. The effective rate of hyperthermia was 3.9%. Of the 30 effectively treated patients, liver metastases disappeared in 2 patients treated with hyperthermia alone, and lung metastases disappeared in 2 patients treated with immunotherapy alone. In the remaining 26 effectively treated patients, multiple metastases were observed in solid organs. Both hyperthermia and immunotherapy were administered and were found to be effective in the treatment of patients with advanced or recurrent colorectal cancer.

[Immunotherapy with hyperthermia for advanced or recurrent breast cancer patients in whom standard therapy showed no effect or was refused].

We treated 168 advanced or recurrent breast cancer patients with hyperthermia or immunotherapy (2005/7-2011/12). In these cases, standard therapy showed no effect or was refused. Clinical benefit( complete response: CR, partial response, and long stable disease) was observed in 26 cases; CR occurred in 4 cases. The effective rate of immunotherapy increased from 9.1% to 23.9% using hyperthermia. Both hyperthermia and immunotherapy needed to be used together to be effective in 20 cases with distant metastases to solid organs.

Development of a questionnaire for the diagnosis of Qi stagnation.

The objective of this study was to develop a questionnaire for the diagnosis of Qi stagnation. At first, we made the preliminary version of the questionnaire from 30 symptoms most frequently mentioned about Qi stagnation in classic books of Oriental Medicine. Two hundred and seven participants completed the preliminary version of the questionnaire rating the severity of 30 symptoms. Those participants were assessed for Qi stagnation by 2 physicians. Logistic regression analysis was performed between the physicians' assessment of Qi stagnation and the severity of symptoms in the preliminary questionnaire. The final version of the questionnaire was developed with 23 symptoms that had significant odds ratios. The Cronbach's α coefficient was 0.83. The area under the curve was 0.90 and cut-off value for diagnosis of Qi stagnation was 28.5 in receiver operating characteristic (ROC) analysis. Sensitivity and specificity were 0.83 and 0.80, respectively. The Spearman's correlation coefficient was 0.72 in the test-retest. This questionnaire would enable standardization and objective verification of the diagnosis of Qi stagnation.

Perceptions and attitudes of Japanese gynecologic cancer patients to Kampo (Japanese herbal) medicines.

BACKGROUND: Kampo (Japanese herbal) medicine is the complementary and alternative medicine that is most frequently used by Japanese doctors. We studied the perceptions and attitudes of Japanese gynecologic cancer patients to Kampo medicines and analyzed the characteristics of the backgrounds of Kampo users. METHODS: A total of 476 patients with gynecologic cancer completed a self-reported questionnaire on Kampo medicine. State anxiety and trait anxiety were also assessed using the State-Trait Anxiety Inventory. RESULTS: It was confirmed that 22.9% of the women had used Kampo medicine. Kampo users were more likely to have had chemotherapy and were more likely to have experienced uncomfortable side effects of cancer treatment. Kampo users were more likely to believe that 'Kampo offers relief of symptoms,' 'fewer side effects than Western-style medicine,' and 'is not less effective than Western-style medicine' than nonusers. Kampo users expressed a stronger attitude of 'I want to take Kampo medicine.' Multiple risk ratio regression analysis revealed that chemotherapy (RR, 1.82; 95% CI, 1.14-2.91), lower state anxiety (RR, 0.76; 95% CI, 0.58-1.00), and higher trait anxiety (RR, 1.46; 95% CI, 1.11-1.92) were independently associated with Kampo use. CONCLUSIONS: This study showed that slightly less than one-fourth of Japanese gynecologic cancer patients take Kampo medicine. Kampo users made more favorable comments on Kampo medicine than nonusers. Our findings suggest that the psychological characteristics of individual patients is one of the factors that can influence the usage of Kampo.