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Ulipristal (UPA), a selective progesterone receptor modulator, has both agonistic and antagonistic effects on progesterone receptors. UPA suppresses ovulation by inhibiting the luteinizing hormone (LH) surge from the pituitary gland; however, the direct effect of UPA on ovarian tissue remains poorly studied. In the present study, we examined the effects of UPA on the ovaries of rats. Rats were treated for 28 d with 4, 20, and 100 mg/kg UPA. UPA treatment increased the number of primordial follicles at each treatment group, with the highest number found in the 4 mg/kg group, and the number of primordial follicles decreasing with increasing dose. The number of primary and antral follicles tended to increase with increasing UPA levels. Furthermore, the decrease in primary follicle number could be attributed to the exhaustion of follicles, but the examination of proliferation markers, oxidative stress markers, and cell death markers revealed no remarkable toxic effects on ovarian tissues. These results suggest that UPA treatment promotes follicle development at each stage but inhibits ovulation by suppressing the LH surge, resulting in an increase in atretic follicles or unruptured luteinized cysts. UPA may not have toxic effects on the ovary because the expression of antioxidant genes and cell death markers was not dramatic in follicles treated with UPA. Taken together, these results suggest that UPA may not have a direct local effect on ovarian follicles. Hence, we hypothesized that prolonged UPA treatment in patients with uterine fibroids may not be harmful and may not decrease future fecundity.

Cerebellar neurons such as Purkinje cells (PCs) and granule cells (GCs) are differentiated from neural progenitors expressing proneural genes. Zebrafish mutants of proneural genesptf1aandneurogenin1showed a reduction or loss of PCs, GABAergic interneurons (INs), and reduced expression of GC progenitor genesatoh1a/b/c. Lineage tracing revealed that theptf1a-expressing progenitors gave rise to PCs, INs, and a part of GCs in zebrafish. These data indicate that theptf1a/neurognin1-expressing neural progenitors can generate a variety of cerebellar neurons. In this study, we found that genes encoding transcriptional regulators Foxp1b and Foxp4, as well as Skor1b and Skor2, which are reportedly expressed in PCs, were not expressed inptf1a;neurogenin1mutants.foxp1b;foxp4mutants showed a strong reduction in PCs, whileskor1b;skor2mutants completely lacked PCs but instead displayed an increase in immature GCs. Misexpression ofskor2in GC progenitors expressingatoh1csuppressed GC fate. These data indicate that Foxp1b/4 and Skor1b/2 function as key transcriptional regulators in the initial step of PC differentiation fromptf1a/neurogenin1-expressing neural progenitors, while Skor1b and Skor2 control PC differentiation by suppressing their differentiation into GCs.

Endometriosis is linked to asymptomatic atherosclerosis and increases the risk of cardiovascular disease (CVD). Vascular function tests are used to assess atherosclerosis, an important indicator of CVD development. In this study, we aimed to evaluate atherosclerosis-related biomarkers, such as vascular function tests and laboratory data, in perimenopausal women with endometriosis.This prospective cohort study enrolled 207 women (≥40 years old) with endometriosis. Laboratory data, ankle brachial index (ABI), and cardio-ankle vascular index (CAVI) were evaluated.The mean age, CAVI, and ABI of the participants at the initial examination were 45.02 years, 6.9 ± 0.6, and 1.07 ± 0.06, respectively. In multiple regression analysis, no factor was associated with CAVI, but ABI was significantly correlated with elevated total cholesterol (TC), low-density lipoprotein cholesterol, and estradiol (partial regression coefficient [β] = -0.00074, p = 0.017; β = -0.00075, p = 0.033; and β = -0.00022, p = 0.015, respectively). The annual rate of change in CAVI showed a positive correlation with TC and pentosidine and a negative correlation with history of hormone therapy. Neither correlation was strong. In a comparison of three groups classified by the annual rate of change in CAVI, the group with the severe change had a higher level of pentosidine. In adjusted multinomial logistic regression analysis, high pentosidine levels were a risk factor for increased rate of change in CAVI.The association between CAVI and serum markers related to lipid metabolism and ovarian function was mild. Longitudinal analysis of CAVI showed an association with pentosidine, which may be helpful in assessing atherosclerosis risk in women with endometriosis during perimenopause.

Dienogest (DNG) is widely used to treat dysmenorrhea associated with estrogen-dependent diseases such as endometriosis and adenomyosis. DNG becomes unnecessary after menopause when estrogen secretion declines drastically. However, there are no clear criteria for when to halt DNG in perimenopausal patients. Menstruation and dysmenorrhea often resume after discontinuation due to approaching menopause. This case-control study used serum estradiol and follicle-stimulating hormone (FSH) levels to predict whether menstruation would resume in perimenopausal women after discontinuation of DNG. The study enrolled patients aged ≥40 years with endometriosis and/or adenomyosis and who had either completed oral DNG therapy (DNG group) or had spontaneous menopause without hormone therapy (control group). We assessed estradiol and FSH values before DNG termination or the final menstrual period. DNG group members that resumed menstruation after DNG termination (D (+) group, n = 17) had significantly higher estradiol and lower FSH levels than those who did not (D (-) group, n = 22) up to four months before DNG termination but not from four to 12 months. Estradiol and FSH levels were not significantly different between the D (-) and control groups. Receiver operating characteristic curves created from the estradiol and FSH values indicated that menstruation resumed when levels were ≥17 pg/mL and100 mIU/mL, respectively. In contrast, menstruation did not resume in cases of estradiol ≤20 pg/mL and FSH80 mIU/mL. The study results provide useful criteria for deciding when to terminate DNG in perimenopausal patients that consider their tolerance for resuming menstruation. Applications to menopause-inducing therapy for uterine fibroids and other conditions are anticipated. Further large-scale studies are needed.

Background In women with endometriosis, the association between ovarian function, hormones, and bone mineral density (BMD) is unclear. Therefore, this study aimed to elucidate the correlation between changes in bone mineral density (BMD) in perimenopausal women with endometriosis and clinical data, such as ovarian reserves. Methods In this prospective study, we evaluated 207 female patients who visited the Department of Obstetrics and Gynecology at the University of Tokyo Hospital between December 2015 and December 2020. We included patients aged ≥ 40 years with a history of endometriosis or who presented with endometriosis lesions. Patients with a history of smoking, steroid administration, autoimmune diseases, dyslipidaemia, and heart disease were excluded. During the study period, patients who underwent two tests, an initial and a follow-up test (n = 142, average age: 45.02 years, average BMD: 1.16 g/cm2), were evaluated at regular intervals based on the annual rate of change in BMD. Results There was a negative correlation between the follicle-stimulating hormone (FSH) and BMD, and a positive correlation between the anti-Müllerian hormone (AMH) and BMD. The annual rate of change in BMD correlated only with thyroid-stimulating hormone (TSH) levels. A large decline in BMD was associated with high TSH levels and higher average age at menopause. Patients with higher TSH exhibited a higher rate of decrease in BMD than those without. Conclusions High FSH or low AMH levels are associated with decreased BMD. Decreased ovarian reserve is associated with decreased BMD in perimenopausal women with endometriosis. High TSH levels increase the risk of BMD loss. This finding may help manage osteoporosis and BMD loss in perimenopausal women with endometriosis by predicting BMD loss from ovarian reserve and TSH levels.

Background In women with endometriosis, the association between ovarian function, hormones, and bone mineral density (BMD) is unclear. Therefore, this study aimed to elucidate the association between changes in bone mineral density (BMD) and clinical data, such as ovarian reserves, in perimenopausal women with endometriosis. Methods In this prospective study, we evaluated 207 female patients who visited the Department of Obstetrics and Gynecology at the University of Tokyo Hospital between December 2015 and December 2020. We included patients aged ≥ 40 years with a history of endometriosis or who presented with endometriosis lesions. Patients with a history of smoking, steroid administration, autoimmune diseases, dyslipidaemia, and heart disease were excluded. During the study period, patients who underwent two tests, an initial and a follow-up test (n = 142, average age: 45.02 years, average BMD: 1.16 g/cm2), were evaluated at regular intervals based on the annual rate of change in BMD. Results There was a weak negative correlation between the follicle-stimulating hormone (FSH) and BMD and a weak positive correlation between the anti-Müllerian hormone (AMH) and BMD. The annual rate of change in BMD showed a very weak correlation with thyroid-stimulating hormone (TSH) levels. A large decline in BMD was associated with high TSH levels and higher average age at menopause. Patients with higher TSH exhibited a higher rate of decrease in BMD than those without. Conclusions High FSH or low AMH levels are associated with decreased BMD. Decreased ovarian reserve is associated with decreased BMD in perimenopausal women with endometriosis. High TSH levels increase the risk of BMD loss. This finding may suggest that women with endometriosis should undergo bone scanning to rule out the possibility of reduced bone mass and subsequent increased risk of fracture.

Isoflavones found in soybeans are nonsteroidal phytoestrogenic and antioxidative diphenolic compounds with potential roles in the prevention of chronic diseases, including hormone dependent cancer cardiovascular diseases, osteoporosis, and postmenopausal syndrome. Japanese consume 40–100 mg/day from various kind of soy foods, and it may contribute to the low incidence of above diseases. S(–)-equol, a metabolite of daidzein by the intestinal microflora, shows the strongest estrogenic activity among isoflavones. Epidemiology, metabolism and measurements, animal and in vitro experiments, randomized clinical study and metaanalysis, supplements, and safety are reviewed.

Background/Aim: Guaiazulene (1,4-dimethyl-7-isopropylazulene) is present in several essential oils of medicinal and aromatic plants. There exist few studies that investigated the anticancer activity of guaiazulenes. We investigated the relative cytotoxicity of 10 alkylaminoguai-azulene derivatives towards both cancer and normal cells.Materials and Methods: Cytotoxicity towards four human oral squamous cell carcinoma (OSCC) cell lines and five types of human normal oral cells (gingival fibroblasts, periodontal ligament fibroblasts, pulp cells and keratinocytes, gingival epithelial progenitors) was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor specificity (TS) was evaluated as the ratio of the mean 50% cytotoxic concentration against normal oral cells to that against OSCC cell lines. Apoptosis-inducing activity was evaluated by cleavage of poly ADP-ribose polymerase and caspsase-3 with western blot analysis. Results: Validity of the present TS measurement method was confirmed using methotrexate. With increasing length of the alkyl group of alkylaminoguaiazulene derivatives, cytotoxicity increased.Introduction of oxygen, nitrogen or sulfur atom into the alkyl group slightly reduced cytotoxicity. Most compounds had very low TS, no synergistic action with methotrexate and doxorubicin, nor did they induce apoptosis of OSCC cells. On the other hand, compound [10], containing a morpholino group, induced apoptosis of OSCC cells.Conclusion: The cytotoxicity of alkylaminoguaiazulenes is not always coupled with TS and apoptosis-inducing activity., This article is freely accessible online / Permission has been acquired by e-mail from publisher

Antioxidative flavonoids, ubiquitously included in vegetables, fruits and teas, are expected to prevent degenerative diseases. It is unclear, however, whether flavonoids can enter the cellular nuclei and suppress the oxidative damage of DNA. Here, several flavonoids at the physiological concentration of 10 μM were dosed to 2.5 × 107 HepG2 cells. The nuclei were isolated and determined in the incorporated flavonoid levels, and simultaneously exposed to reactive oxygen generated from 25 mM of 2,2′-azobis(2-amidinopropane) dihydrochloride. Most of the tested flavonoids were incorporated into the cells in the range between 1000 and 1600 pmol/107 cells, and were in the nuclei at 250–450 pmol/107 cells at the maximum incorporation after 30 min of cell incubation. In the cells, 23% of quercetin (3,5,7,3′,4′-OH) and 8% of luteolin (5,7,3′,4′-OH) were the original aglycone forms and the others were the methylated and gulucuronide/sulfate conjugates, while 72% of kaempferol (3,5,7,4′-OH) and 85% of apigenin (5,7,4′-OH) were aglycones and located in the nuclei at the similar ratio of metabolites. Quercetin and luteolin significantly suppressed the formation of 8-oxo-7,8-dihydrodeoxyguanosine by 25% and 15%, respectively, compared to those in 0-time incubated cells with the flavonoids. Under such conditions of low level and hydroxyl-masked in the nuclei, the limited flavonoids were bioavailable antioxidants to prevent genetic damage and they were B-ring catechols such as quercetin and luteolin.