The addition of dydrogesterone improves the outcomes of pregnant women with low progesterone levels when receiving vaginal progesterone alone as luteal support in HRT-FET cycles.

Purpose: Vaginal progesterone (VP) alone has been used as luteal support (LS) in HRT-FET cycles without measuring serum progesterone concentrations (SPC) because it can achieve adequate intrauterine progesterone levels. However, several reports showed that the co-administration of progestin produced better outcomes than VP alone. We tried to address this discrepancy, focusing on SPC. Methods: VP was given to 180 women undergoing HRT-FET. We measured SPC when pregnancy was diagnosed on day 14 of LS. We compared assisted reproductive technology outcomes between VP alone versus VP + dydrogesterone (D). Results: When using VP alone, average SPC in the miscarriage cases (9.6 ng/mL) were significantly lower compared with the ongoing pregnancy (OP) cases (14.7 ng/mL). The cut-off value for progesterone, 10.7 ng/mL, was a good predictor for the subsequent course of the pregnancy. Of 76 women receiving D ± VP from the start of LS and achieving a pregnancy, the numbers of OP were 44 (84.6%) in SPC ≥ 10.7 ng/mL and 20 (83.3%) in SPC ≤ 10.7 ng/mL with no significant difference. Conclusion: VP alone resulted in lower SPC in some pregnant women in HRT-FET cycles and exhibited a lower OP rate. The co-administration of D improved an OP rate of low progesterone cases to the level comparable with non-low progesterone cases.

A novel orally active gonadotropin-releasing hormone antagonist, relugolix, is a potential substitute for injectable GnRH antagonists in controlled ovarian stimulation in assisted reproductive technology.

PURPOSE: To evaluate the efficacy of an oral gonadotropin-releasing hormone antagonist (GnRH Ant), relugolix (R), for assisted reproductive technology (ART). METHODS: We enrolled women undergoing ART using a GnRH Ant for controlled ovarian stimulation. We compared R; 20 mg/day with cetrorelix acetate (C); 0.125 mg. C was administered to 88 women in 2019, and R to 93 women in 2020. Clinical outcomes associated with ART were assessed in both groups. RESULTS: The luteinizing hormone levels on the day of human chorionic gonadotropin injection in the R group (1.26 ± 0.93 IU/L) were significantly lower than those in the C group (2.85 ± 3.02 IU/L). There were no cases in which egg retrieval was canceled in both groups. The total doses of gonadotropins administered were greater in the R group compared with the C group. The number of days of GnRH Ant administration in the R group (1.71 ± 0.57 days) was significantly longer compared with the C group (1.48 ± 0.58 days). The number of oocytes collected, fertilization rates, and pregnancy rates (R; 47.1% vs C; 45.8%) did not differ between the two groups. CONCLUSION: An orally active GnRH Ant, relugolix, when used in controlled ovarian stimulation for ART, showed comparable clinical outcomes with cetrorelix.

Different anti-Mullerian hormone (AMH) levels respond to distinct ovarian stimulation methods in assisted reproductive technology (ART): Clues to better ART outcomes.

PURPOSE: We asked whether the relationship between anti-Mullerian hormone (AMH) value and the response to ovarian stimulation (OS) might be AMH value-related and differ for each regimen, aiming at getting clues as to how to choose OS protocols according to AMH levels. We further addressed how AMH value connects with ART outcome. METHODS: A total of 1112 women undergoing egg retrieval in ART were included. We adopted four OS protocols, that is, clomiphene, clomiphene + low-dose gonadotropins (Gns), GnRH (Gn-releasing hormone) + Gns (short), and GnRH antagonist. RESULTS: Anti-Mullerian hormone showed a stronger correlation with egg number compared with age over a wide age range. When patients were stratified into four groups by AMH value (<1, 1-2, 2-3, and 3≦ ng/mL), the relationship between AMH and egg number differed among differential OS regimes. The number of eggs rose as AMH and total doses of Gn increased. When analyzed for each AMH group, egg number, but not AMH, was associated with pregnancy rate. CONCLUSION: Different AMH levels exhibit characteristic responses to distinct OS regimens. To improve ART outcomes, personalized OS should be selected so as to maximize egg number, which seems to be a more precise variable than AMH for predicting pregnancy.

Age-related immune-modulating properties of seminal fluid that control the severity of asthma are gender specific.

Reproductive organs play a pivotal role in asthma development and progression, especially in women. Endocrine environment changes associated with the menstrual cycle, pregnancy, and menopause can exacerbate the clinical features of asthma. Factors secreted by reproductive organs may be responsible for the gender difference and age-related changes in adult asthma. Here, we show that mammalian seminal fluid has anti-asthma effects exclusively in females. Exposure to murine seminal fluid markedly reduced eosinophilic airway inflammation in 2-month-old female mice upon ovalbumin inhalation. The anti-asthma effect with seminal fluid from 10-month-old males was double that with fluid from 2-month-old males, suggesting that it depended on male sexual maturation. We further found that seminal fluid from middle-aged human volunteers had beneficial effects in asthmatic female mice; these effects were associated with transcriptional repression of osteopontin and IL-17A, which are poor prognostic factors for asthma. In 2-month-old male mice, however, human seminal fluid failed to decrease asthmatic features and even enhanced osteopontin and IL-17A transcription. Our data demonstrate that age-related seminal fluid exerts opposing effects in asthmatic male and female mice. These findings may help the development of novel approaches to control the prevalence and age-related progression of asthma in women.

Identifying a possible factor for the increased newborn size in singleton pregnancies after assisted reproductive technology using cryopreserved embryos, in comparison with fresh embryos.

PURPOSE: To determine whether the cycle regimens that are used for endometrial preparation are associated with the birthweight (BW) after assisted reproductive technology (ART) using frozen-thawed embryo transfer (FET). METHODS: The BW of singletons who were born by ART using FET was compared retrospectively, according to whether a FET was conducted in a hormone replacement therapy cycle (HRT, n = 403) or an ovulatory cycle (OVL, n = 117). The BW after timed intercourse (NAT, n = 162) also was investigated. RESULTS: There were no significant differences in the age of the mothers, percentage of primiparas, gestational periods, Body Mass Index, and sex ratio between the HRT and OVL cycles. The average BW from HRT was significantly greater than that of OVL. The BW from HRT was also greater, compared with NAT, while statistical significance was not achieved between OVL and NAT. The putative factors affecting the BW, such as ovarian stimulation protocols, endometrial thickness, and the stage and quality of embryos, could not explain the difference in the BW between the HRT and OVL cycles. CONCLUSION: An increased BW from ART using FET seems to be ascribable to conditions of the endometrium, but not cryopreservation procedures per se, which might provide a mechanistic framework for understanding heavier neonates who are born by FET.

Does the presence of coexisting diseases modulate the effectiveness of a low-dose estrogen/progestin, ethinylestradiol/drospirenone combination tablet in dysmenorrhea? Reanalysis of two randomized studies in Japanese women.

BACKGROUND: The purpose of this study was to investigate the effectiveness of a combination of ethinylestradiol (EE) and 0.02 mg/drospirenone (DRSP) 3 mg in Japanese women with dysmenorrhea and in particular to determine whether or not the presence of specific coexisting organic diseases (eg, endometriosis, uterine fibroids, uterine adenomyosis) has an impact on treatment. METHODS AND RESULTS: Four hundred and ten patients with dysmenorrhea aged 20 years or older (315 without coexisting organic disease, 28 with endometriosis, 37 with uterine fibroids, and 46 with uterine adenomyosis [some patients had multiple coexisting organic diseases]) were enrolled and treated with EE/DRSP in either a 16-week comparator study or a 52-week long-term safety study. Evaluations included changes in total dysmenorrhea score, visual analog scale for dysmenorrhea, severity of symptoms, hormone levels, endometrial thickness, and safety outcomes. In both studies, the total dysmenorrhea score was significantly (P<0.001) decreased from baseline during treatment with EE/DRSP. Time-dependent changes in visual analog score for dysmenorrhea and alleviation of symptoms, such as lower abdominal pain, low back pain (lumbago), headache, and nausea/vomiting, were similar in all patient groups with and without any specific coexisting organic diseases. These improvements with EE/DRSP were observed for both short-term (16 weeks) and long-term (52 weeks) use. These effects were associated with suppressed increases in serum estradiol and progesterone levels and decreased endometrial thickness. The safety profile of EE/DRSP was similar in all patients, irrespective of the presence of coexisting organic diseases. CONCLUSION: EE/DRSP may be prescribed for patients with dysmenorrhea irrespective of the presence of any specific coexisting organic diseases.

Increased tissue levels of omega-3 polyunsaturated fatty acids prevents pathological preterm birth.

Omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) have anti-inflammatory effects. Preterm birth is an important problem in modern obstetrics and one of the main causes is an inflammation. We here showed that abundance of omega-3 fatty acids reduced the incidence of preterm birth induced by LPS with fat-1 mice, capable of converting omega-6 to omega-3 fatty acids. We also indicated that the gene expression of IL-6 and IL-1ß in uteruses and the number of cervical infiltrating macrophages were reduced in fat-1 mice. The analyses of lipid metabolomics showed the high level of 18-hydroxyeicosapentaenoate in fat-1 mice, which was derived from EPA and was metabolized to anti-inflammatory product named resolvin E3 (RvE3). We finally showed that the administration of RvE3 to LPS-exposed pregnant wild type mice lowered the incidence of preterm birth. Our data suggest that RvE3 could be a potential new therapeutic for the prevention of preterm birth.

Omega-3 polyunsaturated Fatty acids suppress the cystic lesion formation of peritoneal endometriosis in transgenic mouse models.

Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) play a role in controlling pathological inflammatory reactions. Endometriosis is characterized by the presence of endometrial tissue on the peritoneum and an exaggerated inflammatory environment around ectopic tissues. Here peritoneal endometriosis was reproduced using a mouse model in which murine endometrial fragments were inoculated into the peritoneal cavity of mice. Fat-1 mice, in which omega-6 can be converted to omega-3 PUFAs, or wild type mice, in which it cannot, were used for the endometriosis model to address the actions of omega-3 PUFAs on the development of endometriotic lesions. The number and weight of cystic endometriotic lesions in fat-1 mice two weeks after inoculation were significantly less than half to those of controls. Mediator lipidomics revealed that cystic endometriotic lesions and peritoneal fluids were abundant in 12/15-hydroxyeicosapentaenoic acid (12/15-HEPE), derived from eicosapentaenoic acid (EPA), and their amount in fat-1 mice was significantly larger than that in controls. 12/15-Lipoxygenase (12/15-LOX)-knockout (KO) and control mice with or without EPA administration were assessed for the endometriosis model. EPA administration decreased the number of lesions in controls but not in 12/15-LOX-KO mice. The peritoneal fluids in EPA-fed 12/15-LOX-KO mice contained reduced levels of EPA metabolites such as 12/15-HEPE and EPA-derived resolvin E3 even after EPA administration. cDNA microarrays of endometriotic lesions revealed that Interleukin-6 (IL-6) expression in fat-1 mice was significantly lower than that in controls. These results suggest that both endogenous and exogenous EPA-derived PUFAs protect against the development of endometriosis through their anti-inflammatory effects and, in particular, the 12/15-LOX-pathway products of EPA may be key mediators to suppress endometriosis.

Characterization of transplacental transfer of paroxetine in perfused human placenta: development of a pharmacokinetic model to evaluate tapered dosing.

The aim of this study was to determine whether a tapered dosage regimen of paroxetine in pregnant women might be useful to avoid withdrawal syndromes in neonates after delivery. We characterized the transplacental transfer of paroxetine in perfused human placenta, fitting a pharmacokinetic model to the results and applying the model and parameters to evaluate a tapered dosage regimen. Paroxetine was perfused from the maternal or fetal side of an isolated human placental preparation with various perfusion protocols, and paroxetine concentrations in the effluent and placental tissue were determined. The transplacental pharmacokinetic parameters of paroxetine were estimated by simultaneous fitting of a five-compartment transplacental pharmacokinetic model to the set of paroxetine concentration profiles. The developed model and parameters were used to simulate the maternal and fetal concentrations of paroxetine, and the results were compared with reported data. Paroxetine showed a larger distribution volume in placental tissue and a smaller transplacental transfer as compared with antipyrine, a passive diffusion marker. A five-compartment model could well describe the transplacental transfer of paroxetine and could well simulate the maternal and umbilical venous concentrations of paroxetine at delivery. Transplacental transfer kinetic parameters of paroxetine were estimated by fitting a pharmacokinetic model to perfusion study data. The model and parameters appeared to be suitable for simulation of paroxetine kinetics in fetus. The model was also applicable to design a dosage regimen to avoid an abrupt decrease of paroxetine concentration in fetal plasma.

Recurrence of endometrioma after laparoscopic excision and its prevention by medical management.

Laparoscopic excision is considered as the 'gold standard' treatment of ovarian endometrioma. However, a frustrating aspect is that disease can recur. While laparoscopic excision is known to improve fertility, recurrence can cause significant ovarian damage and adverse affects on fertility. It is therefore crucial to prevent recurrence in order to conserve 'improved' fertility. Recurrence rates for endometrioma are reported from 11 to 32% within 1-5 years after excision. The recurrence rate is higher in patients with advanced endometriosis at surgery and in younger patients. Previous medical treatment for endometriosis prior laparoscopy is a risk factor for recurrence. Pregnancy soon after surgery has a protective effect for recurrence. The accumulating evidence suggests that the administration of oral contraceptives (OC), levonorgestrel-releasing intrauterine system (LNG-IUS) and a combination of gonadotropin releasing hormone (GnRH) analogue and OC may also have therapeutic benefits. Collectively, we propose that women should be well informed about the risks of endometrioma recurrence. We recommend that women who wish pregnancy should try conception as soon as possible. Further, we strongly advise hormonal therapy for patients, who do not want to conceive immediately, and until pregnancy is desired.

A novel interaction between hScrib and PP1γ downregulates ERK signaling and suppresses oncogene-induced cell transformation.

Previous studies have shown that the cell polarity regulator hScrib interacts with, and consequently controls, the ERK signaling pathway. This interaction occurs through two well-conserved Kinase Interacting Motifs, which allow hScrib to bind ERK1 directly, resulting in a reduction in the levels of phospho-ERK. This suggests that hScrib might recruit a phosphatase to regulate this signaling pathway. Using a proteomic approach we now show that Protein Phosphatase 1γ (PP1γ) is a major interacting partner of hScrib. This interaction is direct and occurs through a conserved PP1γ interaction motif on the hScrib protein, and this interaction appears to be required for hScrib's ability to downregulate ERK phosphorylation. In addition, hScrib also controls the pattern of PP1γ localization, where loss of hScrib enhances the nuclear translocation of PP1γ. Furthermore, we also show that the ability of hScrib to interact with PP1γ is important for the ability of hScrib to suppress oncogene-induced transformation of primary rodent cells. Taken together, these results demonstrate that hScrib acts as a scaffold to integrate the control of the PP1γ and ERK signaling pathways and explains how disruption of hScrib localisation can contribute towards the development of human malignancy.

Retreatment with nedaplatin in patients with recurrent gynecological cancer after the development of hypersensitivity reaction to carboplatin.

AIM: Platinum is a milestone drug against gynecologic malignancies. The purpose of this retrospective study was to investigate the feasibility of replacing carboplatin with nedaplatin in patients who had developed a hypersensitivity reaction to carboplatin. MATERIAL AND METHODS: Fifteen patients with recurrent gynecologic cancer (12 ovarian, 1 fallopian tube, 1 endometrial and 1 cervical cancer) who had experienced a hypersensitivity reaction to carboplatin and a possible clinical indication for continuing treatment with platinum were treated with nedaplatin (80 mg/m(2) )-containing regimen. RESULTS: The total number of nedaplatin cycles given was 137 (range 1-29). Four (27%) patients developed hypersensitivity reactions on the second, second, fourth, and ninth administration, respectively. The severities of all the hypersensitivity reactions were grade 3 or less. The other 11 patients (73%) had no nedaplatin-associated hypersensitivity reactions. The incidence of hypersensitivity reactions in the paclitaxel and nedaplatin group (three of four, 75%) was more frequent than the docetaxel and nedaplatin group (none of seven, P=0.024). The objective response rate in eleven patients with measurable disease was 36% (complete response at 9% and partial response at 27%), and the disease control rate was 73% (stable disease at 36%). CONCLUSION: Nedaplatin-associated hypersensitivity reactions are not rare in patients who developed allergic reactions to carboplatin. Retreatment of carboplatin-allergic patients with nedaplatin cannot be recommended without careful consideration of the potential risks and benefits.

Sequential effects of the proteasome inhibitor bortezomib and chemotherapeutic agents in uterine cervical cancer cell lines.

Although the prognosis of uterine cervical cancer has improved due to the advances of treatment modalities, survival of recurrent or metastatic cervical cancer remains poor. Cisplatin is an effective radiosensitizer, but its single agent activity in recurrent cervical cancer is disappointing. Inactivation of tumor suppressors through ubiquitin-mediated degradation by human papillomavirus is known to be a critical step in the carcinogenesis of uterine cervix. Bortezomib, a selective inhibitor of the proteasome, has been shown to inhibit the growth of several solid tumors. To determine the role of bortezomib in cervical cancer as a chemotherapeutic agent, we studied its biological properties. Bortezomib efficiently inhibited the proteasomal activities in cervical cancer cells, and an increased expression of tumor suppressors such as p53, hDlg and hScrib became evident. In addition, sequential or concomitant treatment of bortezomib and cisplatin stimulated the expression of p53, hScrib and p21 and the stimulation was markedly influenced by the order of drugs in HeLa cells. We further confirmed that the concomitant use of bortezomib and cisplatin has synergistic inhibitory effects on the growth of xenograft tumors derived from HeLa cells. Our data establish the possibility that the concomitant use of bortezomib and cisplatin could be an alternative choice in cases resistant to conventional chemotherapy, and sequential effects must be considered for advanced and therapy-resistant cervical cancer patients.

Spontaneous cessation and recurrence of massive uterine bleeding can occur in uterine artery pseudoaneurysm after laparoscopically assisted myomectomy.

A uterine artery pseudoaneurysm (UAP) is a rare but life-threatening complication that can occur after gynecologic surgery. Herein, we present a case of a 38-year-old woman who presented with massive uterine bleeding one month after a laparoscopically assisted myomectomy. Although the bleeding ceased spontaneously, a massive hemorrhage reoccurred three weeks thereafter, and a ruptured perfusion sac at the right uterine artery was identified by computed tomography angiography and ultrasonography. The patient was treated with transfemoral catheter embolization of the right uterine artery, and complete resolution of the UAP was successfully obtained. Our case suggests that a UAP may be a cause of unexplained repetitive metrorrhagia after myomectomy.

Müllerian cyst of the uterus treated with laparoscopy and diagnosed using immunohistology.

Among uterine cystic tumors, uterine cyst arising from secondary Müllerian epithelium is exceedingly rare. A 45-year-old woman presented with pelvic cystic mass, which was initially diagnosed as a paraovarian cyst by ultrasound and magnetic resonance imaging. At laparoscopy, the cyst proved to be a pedunculated uterine cyst, which was easily resected. Histologically, the cyst wall was lined by fallopian epithelium and positively stained for WT-1, estrogen receptor, and progesterone receptor. The final diagnosis was Müllerian cyst of the uterus. Preoperative diagnosis of uterine Müllerian cyst is usually impossible. Laparoscopy is useful as a minimally invasive treatment to diagnose and resect the cyst at the same time. Specific immunostaining is useful to make a definite diagnosis of Müllerian cyst of the uterus.

The prevalence of cervical regulatory T cells in HPV-related cervical intraepithelial neoplasia (CIN) correlates inversely with spontaneous regression of CIN.

PROBLEM: Local adaptive cervical regulatory T cells (Tregs) are the most likely direct suppressors of the immune eradication of cervical intraepithelial lesion (CIN). PD-1 expression on T cells induces Tregs. No studies have quantitatively analyzed the Tregs and PD-1+ cells residing in CIN lesions. METHOD OF STUDY: Cervical lymphocytes were collected using cytobrushes from CIN patients and analyzed by FACS analysis. Comparisons were made between populations of cervical Tregs and PD-1+ CD4+ T cells in CIN regressors and non-regressors. RESULTS: A median of 11% of cervical CD4+ T cells were Tregs, while a median of 30% were PD-1+ cells. The proportions of cervical CD4+ T cells that were Tregs and/or PD-1+ cells were significantly lower in CIN regressors when compared with non-regressors. CONCLUSIONS: The prevalence of cervical tolerogenic T cells correlates inversely with spontaneous regression of CIN. Cervical Tregs may play an important role in HPV-related neoplastic immunoevasion.

Expression and regulation of transient receptor potential cation channel, subfamily M, member 2 (TRPM2) in human endometrium.

To identify estrogen-responsive genes, we previously isolated estrogen receptor (ER)-binding DNA fragments from human genomic DNA using a recombinant ER protein. Six DNA fragments, each including a perfect palindromic estrogen response element (ERE), were obtained. The nucleotide sequence of one of the six fragments (E1 fragment) showed that the ERE of the E1 fragment is located in the 3'-untranslated region (UTR) of transient receptor potential cation channel, subfamily M, member 2 (TRPM2). Here, we confirmed the estrogen-dependent enhancer activity of the ERE of the E1 fragment by chloramphenicol acetyltransferase assay. TRPM2 mRNA expression was investigated in human endometrium, cultured human endometrial stromal cells (ESCs), and cultured human endometrial epithelial cells (EECs) using RT-PCR. Quantitative RT-PCR revealed that TRPM2 mRNA expression in ESCs increased after 17ß-estradiol (E2) treatment. This study demonstrated for the first time that TRPM2 is an estrogen-responsive gene expressed in human endometrial cells.

Increased risk of placenta previa is associated with endometriosis and tubal factor infertility in assisted reproductive technology pregnancy.

Although assisted reproductive technology (ART) is suspected to increase the risk of placenta previa, a life-threatening complication of pregnancy, the reason is poorly understood. We recruited consecutive 318 pregnancies conceived by ART in our clinic and examined relation of ten variables, i.e. maternal age, gravidity, parity, male or female fetus, previous abortion, previous cesarean delivery, endometriosis, ovulatory disorder, tubal disease, and male infertility, to placenta previa, by logistic regression analysis. As a result, we found that endometriosis (odds ratio = 15.1; 95% CI = 7.6-500.0) and tubal disease (odds ratio = 4.4; 95% CI = 1.1-26.3) were significantly associated with placenta previa. It would be preferable to take the increased risk of placenta previa into account in treating ART pregnancy with endometriosis and tubal disease.

Management of patient with arrhythmogenic right ventricular cardiomyopathy during pregnancy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a cardiac disease that affects the right side of the heart and causes ventricular arrhythmias. It is considered as the most common cause of sudden cardiac death in young adults. However, risk and optimal management of ARVC during pregnancy and delivery remain unclear due to the small number of reported cases. Here we report a case of successful management of pregnancy and delivery in a patient with ARVC, who had a history of sustained ventricular tachycardia from her previous pregnancy.

Uterine arteriovenous fistula treated with repetitive transcatheter embolization: case report.

Uterine arteriovenous fistula (AVF) is a rare entity, but may lead to life-threatening hemorrhage. Although transcatheter embolization, surgical ligation, or hysterectomy would be considered for treatment of uterine AVF, there is poor knowledge as to how gynecologists can manage the uterine AVF with multiple large inflow arteries. Herein we report a uterine AVF successfully treated using multiple-step transcatheter embolization. The patient, a 58-year-old postmenopausal woman with a history of dilation and curettage, had intermittent massive uterine bleeding. Radiologic imaging revealed the presence of a large vasculature mass. The mass occupied the entire pelvis, and the source of hemorrhage was identified as an accompanying AVF. We thought that surgical intervention was contraindicated because of the potential risk of uncontrollable intraoperative bleeding. Multiple-step transcatheter embolization was performed, with complete resolution of the AVF. Thereafter, the patient had no further uterine bleeding. Multiple-step transcatheter embolization might be the most beneficial and efficient treatment option for a uterine AVF with multiple large inflow arteries.