Recurrent Serous Borderline Tumor After Fertility-Sparing Surgery Following Twin Pregnancy and Resumption of Menstruation.

Gynecologic malignancies sometimes affect women before menopause. Aggressive treatments, such as surgery, chemotherapy, and/or radiotherapy, often lead to premature menopause. Hormone replacement therapy (HRT), typically used for managing menopause-associated health issues, may be limited by tumor sensitivity to estrogen. Here, we present a case of a 37-year-old woman seeking fertility, who was diagnosed with a serous borderline ovarian tumor (BOT). Fertility-preserving surgery and in-vitro fertilization resulted in a twin pregnancy. During a postpartum amenorrheic period, there was no recurrence. However, she experienced a rapid recurrence of the disease following the resumption of menstruation and underwent radical surgery. This rapid recurrence after menstruation resumed suggests potential estrogen sensitivity. Close postoperative monitoring has been ongoing without HRT.

Inhibitory effects of estetrol on the invasion and migration of immortalized human endometrial stromal cells.

Endometriosis, a common gynecological disorder characterized by the growth of endometrial gland and stroma outside the uterus, causes several symptoms such as dysmenorrhea, hypermenorrhea, and chronic abdominal pain. 17ß estradiol (E2) stimulates the growth of endometriotic lesions. Although estetrol (E4), produced by human fetal liver, is also a natural estrogen, it may have the opposite effects on endometriotic cells. We investigated different effects of E4 and E2 on the invasion and migration of immortalized human endometrial stromal cells (HESCs) and evaluated whether E4 affects the expression of Wiskott-Aldrich syndrome protein (WASP) family member 1 (WASF-1). We measured the invasion of HESCs by a Matrigel chamber assay. Cell migration was measured by wound healing assay and cell tracking analysis. The expression of WASF-1 was confirmed by independent real-time PCR analysis. Transfection of cells with siRNAs was carried out to knock down the expression of WASF-1 in HESCs. E4 significantly inhibited E2-induced invasion and migration of HESCs. WASF-1 was found to be a potential mediator based on metastasis PCR array. WASF-1 was upregulated by E2 and downregulated by E4. Knockdown of WASF-1 inhibited migration. Our results suggest that E4 may inhibit E2-induced growth of endometriotic lesions. Downregulation of WASF-1 is involved in the inhibitory effects of E4 on migration. The use of E4 combined with progestins as combined oral contraceptives may cause endometriotic lesions to regress in women with endometriosis.

Effects of 10-Hydroxy-2-decenoic Acid and 10-Hydroxydecanoic Acid in Royal Jelly on Bone Metabolism in Ovariectomized Rats: A Pilot Study.

Although previous studies have demonstrated that royal jelly (RJ) may have estrogenic properties and prevent postmenopausal bone loss, the underlying mechanisms are not fully understood. This animal study aimed to investigate the effects of specific fatty acids of RJ, 10-hydroxy-2-decenoic acid (10H2DA) and 10-hydroxydecanoic acid (10HDAA), in ovariectomized rats. Ten-week-old female Wistar rats were divided into the Baseline, Sham, Ovx, Ovx + 10H2DA, and Ovx + 10HDAA groups. Rats in the Baseline group were sacrificed immediately, whereas those in the other groups were subjected to either a sham operation or bilateral ovariectomy. The animals in the Ovx + 10H2DA and Ovx + 10HDAA groups were fed diets containing 10H2DA and 10HDAA, respectively. Twelve weeks after surgery, the rats were sacrificed, and indices of bone mass and bone mechanics were analyzed. Femoral bone mineral density was significantly lower in the Ovx group than in the Sham group (p < 0.01). Administration of 10H2DA or 10HDAA did not ameliorate bone loss after ovariectomy. In addition, administration of these fatty acids diminished femur bone stiffness in ovariectomized rats (p < 0.01 and p < 0.05, respectively). These findings suggest that the favorable effects of RJ may not be exerted solely by 10H2DA or 10HDAA. However, these effects may be exhibited in combination with other RJ constituents.

Inhibition of MLCK­mediated migration and invasion in human endometriosis stromal cells by NF­κB inhibitor DHMEQ.

Endometriosis is initiated by the movement of endometrial cells in the uterus to the fallopian tubes, the ovaries and the peritoneal cavity after the shedding of the uterus lining. To cause endometriosis, it is often necessary for these endometrial cells to migrate, invade and grow at the secondary site. In the present study, immortalized human endometriosis stromal cells (HESC) were employed to look for the inhibitors of migration and invasion. Using a chemical library of bioactive metabolites, it was found that an NF­κB inhibitor, DHMEQ, inhibited the migration and invasion of HESC. Both whole­genome array and metastasis PCR array analyses suggested the involvement of myosin light chain kinase (MLCK) in the mechanism of inhibition. DHMEQ was confirmed to inhibit the expression of MLCK and small inhibitory RNA knockdown of MLCK reduced cellular migration and invasion. The addition of DHMEQ to the knockdown cells did not further inhibit migration and invasion. DHMEQ is particularly effective in suppressing disease models by intraperitoneal (IP) administration and this therapy is being developed for the treatment of inflammation and cancer. DHMEQ IP therapy may also be useful for the treatment of endometriosis.

Increased urinary albumin leakage is related to injuries of glomerular glycocalyx and podocytes, and associated with tubular dysfunction in preeclampsia.

OBJECTIVE: The pathogenesis of preeclampsia (PE) is known to be endothelial cell damage; however, the existence of dysfunction in glomerular endothelial glycocalyx, podocytes and tubules remains unclear. The glomerular endothelial glycocalyx, basement membrane, podocytes, and tubules are permeability barriers against albumin excretion. This study aimed to assess the relationship between urinary albumin leakage and injuries of the glomerular endothelial glycocalyx, podocytes, and tubules in patients with PE. METHODS: A total of 81 women with uncomplicated pregnancies (control, n = 22), PE (PE, n = 36), or gestational hypertension (GH) (GH, n = 23) were enrolled. We assessed urinary albumin and serum hyaluronan for glycocalyx injuries, podocalyxin for podocytes injuries, and urinary N-acetyl-ß-d-glucosaminidase (NAG) and liver-type fatty acid-binding protein (l-FABP) for renal tubular dysfunctions. RESULTS: The serum hyaluronan and the urinary podocalyxin levels were higher in the PE and GH groups. The urinary NAG and l-FABP levels were higher in the PE group. Urinary NAG and l-FABP levels positively correlated with urinary albumin excretion. CONCLUSIONS: Our findings suggest that increased urinary albumin leakage is related to injuries of the glycocalyx and podocytes, and associated with tubular dysfunction in pregnant women with PE. The clinical trial described in this paper was registered at the UMIN Clinical Trials Registry under registration number UMIN000047875. URL of registration: https://centre6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000054437.

Impact of Menopause and the Menstrual Cycle on Oxidative Stress in Japanese Women.

Although estrogen possesses both pro- and anti-oxidant properties, its overall role in oxidative stress among women remains unclear, particularly since the influence of exogenously administered estrogen during previous studies differed by dose, administration route, and estrogen type. The aim of this study was to elucidate the effects of endogenous estrogen on oxidative stress in women. Thus, we performed a non-interventional observational study of healthy postmenopausal (n = 71) and premenopausal (n = 72) female volunteers. Serum levels of derivatives of reactive oxygen metabolites (d-ROMs, which are collectively a marker of oxidative stress), as well as the biological antioxidant potential (BAP, an indicator of antioxidant capacity), were compared between (1) pre- versus post-menopausal women, and (2) premenopausal women in early follicular versus mid-luteal phases of their menstrual cycles. We found that serum d-ROMs and BAP values in postmenopausal women were significantly higher than those in premenopausal women. Moreover, the d-ROM levels were significantly correlated with serum copper concentrations. However, neither d-ROMs nor BAP values were significantly affected by the menstrual cycle phase, although changes in d-ROMs between the follicular and luteal phases were significantly correlated with copper concentration shifts. These data indicate that postmenopausal hypoestrogenism is associated with elevated oxidative stress, although regular fluctuations of estrogen levels during the menstrual cycle do not influence oxidative stress.

Ameliorating Effect of the Edible Mushroom Hericium erinaceus on Depressive-Like Behavior in Ovariectomized Rats.

Estrogen deficiency during menopause causes a variety of neurological symptoms, including depression. The edible Lion's Mane mushroom, Hericium erinaceus (Bull.: Fr.) Pers. (HE), is a medicinal mushroom that has the potential for a neuroprotective effect and ameliorating neurological diseases, such as depression, anxiety, and neurodegenerative diseases. HE contains phytoestrogens, including daidzein and genistein. However, the ameliorating effect of HE on menopausal symptoms is not well understood. Here we investigated the impact of methanol extract of the HE fruiting body on depressive-like behavior in postmenopausal model rats. The activation of estrogen receptor alpha (ERα) causes body weight loss and uterine weight gain. Body weight gain and uterine weight loss by estrogen deficiency in ovariectomized (OVX) rats were reversed with 17ß-estradiol (E2) but not with HE. Thus, the phytoestrogens in HE may hardly activate ERα. Estrogen receptor beta (ERß) is expressed in the brain, and activation of ERß ameliorates menopausal depressive symptoms. Notably, depressive-like behavior in OVX rats evaluated in forced swim test was reduced by administration of not only E2 but also HE for 92 d. Long-term activation of ERα increases the risk of breast and uterine cancers. HE, therefore, may be effective in treating menopausal depression without the risk of carcinogenesis caused by ERα activation.

Amount of proteinuria as associated with severity classification of pregnant women with preeclampsia.

OBJECTIVE: This study aimed to verify whether the severity classification of preeclamptic women differed by the presence or absence of proteinuria exceeding 2.0 g/24 h. METHODS: In this retrospective cohort study, data were collected from women with singleton pregnancies who presented with preeclampsia and proteinuria at Aichi Medical University Hospital between April 1, 2008 and September 30, 2021. Participants were divided into two groups (high proteinuria and low proteinuria) based on whether or not their proteinuria exceeded 2.0 g/24 h. Between the two groups, severity of maternal was assessed using the American College of Obstetricians and Gynecologists (ACOG) severity classification (Severe Features) and perinatal and neonatal outcomes were compared. RESULTS: Relative to preeclamptic women with lower proteinuria group, those with higher proteinuria group delivered and were diagnosed with preeclampsia at an earlier gestational week. The latter group also exhibited higher rates of pleural effusion or ascites, preterm birth, and early preterm birth, in addition to lower birth weight and birth weight SD. Rates of admission to the NICU were also higher for neonates born to preeclamptic women in the higher proteinuria group. The percentage of women classified as 'severe' was higher in the higher proteinuria group relative to that in the lower proteinuria group. The percentage of those with severe hypertension and new-onset headache was higher in the higher proteinuria group compared to the lower proteinuria group. The optimal proteinuria cutoff value that distinguished between severe and non-severe maternal cases was determined to be 2.2 g/24 h. CONCLUSIONS: Severity classifications were more common among preeclamptic women with proteinuria exceeding 2.0 g/24 h, particularly with regard to the percentage of those with severe hypertension and new-onset headache.

Effects of maternal magnesium sulfate treatment on newborns.

BACKGROUND: Antenatal magnesium sulfate (MgSO4 ) has been used with mothers, but the influence of MgSO4 on the fetus is unclear. The purpose of this study is to determine whether longer antenatal MgSO4 exposure correlates with adverse effects in newborns. METHODS: The clinical data of 77 infants born to mothers treated with MgSO4 were collected. The infants were divided into two groups according to (1) the serum Mg concentration, (2) cumulative Mg dose, and (3) duration of antenatal maternal Mg treatment, respectively. RESULTS: The serum Mg level of the infants correlated with that of the mothers but not with the duration of Mg treatment or the cumulative dose of Mg. There were no significant differences in the infants' clinical variables according to either the duration of Mg treatment or the cumulative dose of Mg. By contrast, enteral feeding tolerance began at a significantly later age and the heart rate on admission was significantly lower in infants with a serum Mg level ≥4.0 mmol/L than in those with a serum Mg level <4.0 mmol/L. CONCLUSIONS: Modest effects on the clinical variables of infants with higher serum Mg levels were determined, whereas neither the duration of Mg treatment nor the cumulative Mg dose correlated with the clinical variables of the infants. Thus, in newborns with only moderately elevated serum Mg levels, serious adverse effects are unlikely.

Hypoalbuminemia is related to endothelial dysfunction resulting from oxidative stress in parturients with preeclampsia.

Serum albumin levels are inversely related with oxidative stress, but positively related with endothelial function, in pregnant women. However, it is unclear whether hypoalbuminemia in pregnant women with preeclampsia (PE) increases the production of oxygen-derived free radicals and impacts endothelial function. The present study aimed to assess the relationship between serum albumin, oxidative stress, and endothelial dysfunction in pregnant women with PE. A total of 75 women with control pregnancy (Control group, n = 30), PE (PE group, n = 24), or gestational hypertension (GH) (GH group, n = 21) were enrolled. We assessed serum albumin levels, diacron-reactive oxygen metabolites (d-ROMs) as an oxygen-derived free radical marker, and flow-mediated dilation (FMD) as a readout for vascular endothelial function during the gestational period and at one month after delivery. During the gestational period, FMD was lower, but d-ROM levels were higher, in the PE and GH groups compared with the Control group. Serum albumin levels were lower in the PE group compared with the Control and GH groups. d-ROM levels were inversely correlated with serum albumin levels (r = -0.54, p < 0.05) and FMD (r = -0.56, p < 0.05) in the PE group, and negatively correlated with FMD, but not serum albumin levels, in the GH group. Serum levels of d-ROMs and albumin, as well as FMD, were similar between groups after delivery. Our findings suggest that reduced serum albumin levels enhance the production of oxygen-derived free radicals, resulting in impaired maternal vascular endothelial function in parturients with PE.

Roles of glomerular endothelial hyaluronan in the development of proteinuria.

Vascular endothelial cells are covered with glycocalyx comprising heparan sulfate, hyaluronan, chondroitin sulfate, and associated proteins. Glomerular endothelial glycocalyx is involved in protecting against induction of proteinuria and structural damage, but the specific components in glycocalyx that represent therapeutic targets remain unclear. Anti-vascular endothelial growth factor (VEGF) therapy is associated with an increased risk of glomerular endothelial injury. This study investigated whether hyaluronan could provide a therapeutic target to protect against proteinuria. We conducted ex vivo and in vivo experiments to explore the effects of degrading glomerular hyaluronan by administering hyaluronidase and of supplementation with hyaluronan. We investigated hyaluronan expression using biotin-labeled hyaluronan-binding protein (HABP) in human kidney specimens or serum hyaluronan in endothelial injuries under inhibition of VEGF signaling. We directly demonstrated hyaluronan in glomerular endothelial layers using HABP staining. Ex vivo and in vivo experiments showed the development of proteinuria after digestion of hyaluronan in glomerular capillaries. Supplementation with hyaluronan after hyaluronidase treatment suppressed proteinuria. Mice in the in vivo study developed albuminuria after intraperitoneal injection of hyaluronidase with decreased glomerular hyaluronan and increased serum hyaluronan. In human kidneys with endothelial cell dysfunction and proteinuria due to inhibition of VEGF, glomerular expression of hyaluronan was reduced even in normal-appearing glomeruli. Serum hyaluronan levels were elevated in patients with pre-eclampsia with VEGF signaling inhibition. Our data suggest that hyaluronan itself plays crucial roles in preventing proteinuria and preserving the integrity of endothelial cells. Hyaluronan could provide a therapeutic target for preventing glomerular endothelial glycocalyx damage, including VEGF signaling inhibition.

Effects of androgenic properties of progestin combined with ethinyl estradiol on vascular endothelial reactivity, plasma lipids and free radical production in women with endometriosis.

AIM: Endothelial reactivity is inhibited and oxidative stress is enhanced in women with endometriosis. Testosterone may adversely affect lipids and endothelium. We investigated the effects of androgenic properties of progestins combined with ethinyl estradiol (EE) on endothelial function, lipids and free radical production in such women. METHODS: Women with endometriosis were treated with 20 µg EE + 3 mg drospirenone (DRSP) or 35 µg EE + 1 mg norethisterone (NET) for 3 months. Plasma concentrations of sex hormone-binding globulin (SHBG), lipids, copper (Cu), derivatives of reactive oxygen metabolites (d-ROMs), biological antioxidant potential (BAP), nitrite/nitrate, endothelin-1 and asymmetrical dimethylarginine (ADMA) were measured before and after treatment. Flow-mediated vasodilation (FMD) of the brachial artery was measured by ultrasonography. RESULTS: DRSP group, but not NET group, significantly increased FMD and concentrations of nitrite/nitrate and small dense LDL cholesterol, while decreased endothelin-1 concentrations. In both groups, ADMA and LDL cholesterol concentrations were significantly decreased, but triglyceride, SHBG, d-ROMs, Cu and ceruloplasmin concentrations increased, and BAP concentrations did not change. DRSP group significantly increased HDL cholesterol concentrations, whereas NET group decreased its concentrations. Changes in triglyceride correlated positively either with changes in SHBG (r = 0.57, P < 0.001) or with small dense LDL cholesterol (r = 0.45, P = 0.005). Changes in Cu correlated positively with changes in d-ROMs (r = 0.87, P < 0.001). CONCLUSION: Androgenic properties of progestin may counteract EE's favorable effects on endothelial function and HDL cholesterol, while eliminating its adverse effects on increased triglyceride-induced small dense LDL cholesterol in women with endometriosis.

Patient-reported outcomes after surgery among patients with gynecological diseases in Japan.

PURPOSE: This study aimed to investigate quality of life (QOL) and psychological distress based on patient-reported outcomes (PROs) after surgery among patients with gynecological diseases in Japan. METHODS: We recruited 100 women from patients who underwent gynecological surgery followed by regimens standard for each disease. Subjects completed a questionnaire relating to life interferences, the Hospital Anxiety and Depression Scale (HADS) and the EuroQol 5 Dimension (EQ-5D) questionnaire. We compared differences in PROs between patients with benign tumors (n = 30) and malignant tumors (n = 70), and subsequently examined correlations between PROs after surgery and related variables. RESULTS: Although the EQ-5D score was significantly higher in patients with benign tumors compared to those with malignant tumors, this association disappeared after controlling for confounders such as adjuvant therapies. Multiple regression analysis revealed that the number of months after surgery was positively correlated with the EQ-5D score, while the number of chemotherapy series was positively correlated with the number of life interferences. Moreover, the total number of drugs used in chemotherapy was positively correlated with the HADS-depression score and negatively correlated with the EQ-5D score. CONCLUSIONS: The QOLs among gynecological cancer survivors may be associated with the chemotherapy and the term after surgery.

Placental hypoplasia and maternal organic vascular disorder in pregnant women with gestational hypertension and preeclampsia.

Objective: This study aimed to investigate the etiology and pathology of preeclampsia (PE), a two-stage disorder involving uteroplacental dysfunction resulting from abnormal implantation and placentation, and gestational hypertension (GH), for which maternal organic vascular disorder is often an underlying factor.Methods: We assessed concentrations of oxygen free radicals (d-ROMs), maternal angiogenic factor (PlGF), and antiangiogenic factor (sFlt-1), placental hypoxic changes, oxidative DNA damage, and maternal organic vascular disorders in 23 women with PE (PE group), 13 with GH (GH group), and 16 with uncomplicated pregnancies (normal group). Intima-media thickness (IMT) of the carotid artery was assessed as a proxy for maternal organ vascular disorder. Immunohistochemical analysis was performed to measure the proportion of placental trophoblast cell nuclei staining positive for hypoxia-inducible factor-1α (HIF-1α), which reflects hypoxic changes, and 8-hydroxy-2'-deoxyguanosine (8-OHdG), which reflects oxidative DNA damage.Results: Maternal serum d-ROM concentrations were significantly increased in both GH and PE groups relative to the normal group. Maternal serum d-ROM concentrations were significantly increased in both GH and PE groups relative to the normal group. Maternal serum sFlt-1 concentrations, ratio of sFlt-1/PlGF, and proportions of HIF-1α-positive nuclei and 8-OHdG-positive nuclei were significantly higher in the PE group compared to GH and normal groups. IMT was significantly greater in GH and PE groups compared to the normal group, and was higher in the GH group compared to the PE group.Conclusions: Our findings suggest that placental hypoxic changes and oxidative DNA damage are severe in patients with PE and accompanied by an increase in antiangiogenic factors. Moreover, maternal organ vascular disorder was more severe in patients with GH compared to those with PE, as assessed by IMT.Key message: PE is a two-stage disorder that involves uteroplacental dysfunction, and organic vascular disorder underlies GH.

Mitigation of Memory Impairment in Ovariectomized Rats Using Garlic Powder Treated with Subcritical Water.

Women with estrogen deficiency are at the risk of suffering from neurological symptoms such as memory impairment. In the present study, we investigated the effect of garlic, Allium sativum L. (Asparagales: Amaryllidaceae), treated with subcritical water on memory impairment in ovariectomized (OVX) rats. OVX rats were administered garlic powder for 84 d. Hippocampus-dependent spatial memory was assessed using the Morris water maze test. Escape latency of the OVX rats increased compared with that of sham-operated rats. The prolonged escape latency of the OVX rats decreased to the level of that of sham-operated rats upon the administration of garlic powder (0.5% in feed). The weights of the body, uterus, and brain were not affected by the garlic powder administration. These results suggest that garlic powder treated with subcritical water mitigates memory impairment in OVX rats.

Effect of anthocyanin-rich bilberry extract on bone metabolism in ovariectomized rats.

Menopause is associated with increased oxidative stress, which serves a role, in part, in the pathogenesis of postmenopausal bone loss. Fruits and vegetables are rich in antioxidative nutrients and phytochemicals. Berries are a natural source of anthocyanins, and their intake may improve bone health. The aim of the present study was to determine the effect of an anthocyanin-rich bilberry extract (VME) on bone metabolism in an ovariectomized (Ovx) rat. Female Sprague-Dawley rats (12 weeks old) were randomly divided into the following four groups: Baseline, Sham, Ovx and Ovx+VME (n=8-12 rats per group). Rats in the Baseline group were sacrificed immediately, while those in the other groups were subjected to either sham operation (Sham) or bilateral Ovx (Ovx and Ovx+VME). Rats in the Ovx+VME group were administered VME daily at a dose of 500 mg/kg body weight. At 8 weeks after surgery, bone mass and bone histomorphometry were evaluated. The femur bone mineral density (BMD) in the Ovx group was significantly lower than that in the Sham group (P<0.01). Supplementation of VME in the Ovx rats did not result in an increase in BMD. Histomorphometric analyses revealed that Ovx resulted in decreased measures of bone volume and trabecular number and increased measures of osteoid volume, mineralizing surface and bone formation rates (all P<0.01), whereas VME had no significant effects on these parameters. The present findings indicate that VME did not alter bone metabolism in Ovx rats, suggesting that consumption of VME may not be helpful in preventing postmenopausal bone loss.