Usefulness of random-start progestin-primed ovarian stimulation for fertility preservation.

BACKGROUND: Progestin-primed ovarian stimulation (PPOS) has been used in infertility cases in recent years, and several reports have stated that it has oocyte collection results similar to those of gonadotropin-releasing hormone antagonist (GnRH-ant) protocol. For emergency fertility preservation, random-start ovarian stimulation is usually recommended. Therefore we compared the clinical outcomes of random-start PPOS with those of conventional random-start GnRH-ant protocols in fertility-preserving cases. METHODS: We retrospectively examined 86 cycles of oocyte collection, of which 56 were random-start GnRH-ant and 30 were random-start PPOS for fertility preservation at our hospital between January 2016 and April 2021. The primary outcome was the number of mature oocytes per cycle. The secondary outcome was the number of vitrified blastocysts per cycle for embryo freezing cases. RESULTS: No significant differences were noted in the number of days of stimulation, total dose of gonadotropin preparation, and the number of mature oocytes and vitrified blastocysts. The number of hospital visits for monitoring was significantly lower in the PPOS group. The start of menstruation before oocyte collection was significantly less in the PPOS group. CONCLUSIONS: Random-start PPOS and GnRH-ant were similar in oocyte collection results. PPOS can reduce the number of hospital visits, thus reducing patient stress. PPOS at the start of the luteal phase can prevent the start of menstruation during ovarian stimulation.

Severe hemoperitoneum resulting from restart of letrozole after oocyte retrieval procedure: a case report.

BACKGROUND: In the field of oncofertility, patients with breast cancer are often administered letrozole as an adjuvant drug before and after oocyte retrieval to prevent an increase in circulating estradiol. CASE PRESENTATION: We report a case of abdominal hemorrhage due to an ovarian rupture in a 29-year-old Japanese patient who restarted letrozole 2 days after an oocyte retrieval procedure in which 14 mature oocytes were retrieved. The patient had sought embryo cryopreservation as a fertility preservation option before undergoing treatment for recurrent breast cancer. A day after restarting letrozole treatment, the patient unexpectedly developed severe abdominal pain. Laparoscopic hemostasis was performed to manage the ovarian swelling and hemorrhage. CONCLUSIONS: The ovaries can be restimulated by restart letrozole after an oocyte retrieval procedure. Therefore, reproductive-medicine practitioners should understand the potential complications of letrozole administration in such cases and take steps to ensure that they are minimized.

Safety of transvaginal aspiration of cysts in pregnancies complicated with ovarian endometrioma.

OBJECTIVES: Pregnancy complicated with ovarian endometrioma is a risk factor for preterm delivery and rupture or infection during pregnancy. This study aimed to clarify the effectiveness and safety of transvaginal aspiration during pregnancy for endometrioma diagnosed in the first trimester. DESIGN: This retrospective observational study included 8 pregnant women with endometrioma who underwent transvaginal cyst aspiration at 12-14 weeks (aspiration group) between March 2011-March 2018 and 23 pregnant women with endometrioma who refused aspiration during the same period (observation group). METHODS: Characteristics of patients were compared in both groups. Safety, feasability and complications of transvaginal cyst aspiration were reported. Complications and obstetrical outcomes were reported and compared in both groups. RESULTS: The maximum cyst diameter was 8.9 ± 1.5 cm (mean ± standard deviation) in the aspiration group, which was significantly larger than that in the observation group (4.7 ± 0.2 cm). Four preterm deliveries (17.3%) occurred in the observation group and none in the aspiration group. The emergency cesarean section rate during delivery was 14.2% in the aspiration group and 43.7% in the observation group. CONCLUSIONS: The aspiration group tended to have lower rate of preterm deliveries and emergency cesarean sections, suggesting that cyst aspiration could be an effective, minimally invasive, and safe management option for endometrioma during pregnancy.

Late-onset ovarian hyperstimulation syndrome developing during ovarian stimulation in an ectopic pregnancy: a case report.

BACKGROUND: Ovarian hyperstimulation syndrome is normally induced by ovarian stimulation drugs. Severe cases of ovarian hyperstimulation syndrome involve complications such as renal failure and thrombosis. Evidence has recently been developed for a method to prevent ovarian hyperstimulation syndrome. Most cases of ovarian hyperstimulation syndrome are of an early-onset type, which occurs shortly after injection of human chorionic gonadotropin. However, late-onset ovarian hyperstimulation syndrome, which occurs in a pregnancy cycle, also requires caution. We report our experience in treating a woman who was transported to our hospital with a severe case of ovarian hyperstimulation syndrome occurring during ovarian stimulation and who was determined to have an ectopic pregnancy. CASE PRESENTATION: Assisted reproductive technology was planned for a 29-year-old nulligravida Japanese woman diagnosed with bilateral fallopian tube obstruction and right-sided hydrosalpinx. On day 1 of controlled ovarian stimulation, the result of her human chorionic gonadotropin urine test was negative, and her serum levels of luteinizing hormone, estradiol, and progesterone were normal. On day 11 of controlled ovarian stimulation, the levels of estradiol and progesterone had risen to 9679 pg/ml and 16 ng/ml, respectively, prompting suspension of controlled ovarian stimulation. Eleven days after controlled ovarian stimulation was suspended, the patient demonstrated ascites that did not improve despite administration of cabergoline, and she was transported to our hospital 2 days after. Late-onset ovarian hyperstimulation syndrome suggested that she was pregnant, and her serum human chorionic gonadotropin level was 27,778 IU/ml. She underwent laparoscopic bilateral salpingectomy and was diagnosed with right tubal pregnancy. CONCLUSION: In an ectopic pregnancy, human chorionic gonadotropin sometimes increases later than in an intrauterine pregnancy. In our patient's case, endogenous human chorionic gonadotropin following the start of controlled ovarian stimulation may have caused late-onset ovarian hyperstimulation syndrome. The key to early detection of similar cases may be to suspect pregnancy in the event of unexpectedly high progesterone levels during ovarian stimulation.

Kagami-Ogata syndrome in a fetus presenting with polyhydramnios, malformations, and preterm delivery: a case report.

BACKGROUND: Kagami-Ogata syndrome is also known as paternal uniparental disomy 14 and related disorders and is caused by abnormal genomic imprinting in the long arm of the chromosome 14q32.2 region. Its clinical manifestations include polyhydramnios in the fetal stage, respiratory insufficiency because of a small thorax, abdominal wall abnormalities, and peculiar facial features after birth. CASE PRESENTATION: A 38-year-old Japanese primigravida woman was referred to our hospital in the 19th week of pregnancy for suspected omphalocele. She had a history of hypothyroidism but was prescribed orally administered levothyroxine (50 µg/day) prior to conception and was euthyroid. Her ultrasound scan prior to visiting our hospital revealed fetal omphalocele, heavy for date, and polyhydramnios. The mother was advised to be admitted for observation from 28 weeks of gestation for threatened premature delivery. She required amniodrainage at 29 and 32 weeks of gestation. At 35 weeks of gestation, the fetal membrane prematurely ruptured and she gave birth after an emergency Cesarean section. The infant was a male child with a birth weight of 3188 g, and was suspected to have Kagami-Ogata syndrome after birth based on thoracic hypoplasia, swallowing function abnormalities, and peculiar facial features. A definitive diagnosis was established by performing genetic testing of the infant after obtaining informed written consent from both the parents; the results of the genetic testing revealed hypermethylated intergenic-differentially methylated region and maternally expressed gene 3-differentially methylated region in the corresponding chromosome 14 region. Both the parents were genetically tested after adequate genetic counseling, which revealed a de novo microdeletion in a differentially methylated region. CONCLUSION: Kagami-Ogata syndrome should have been suspected because of the presence of polyhydramnios and omphalocele during pregnancy. Respiratory insufficiency soon after birth, because of a small thorax, is expected in this disease and a diagnosis during pregnancy may have enabled appropriate care after birth.

Molecular cytogenetic analysis of a hydatidiform mole with coexistent fetus: a case report.

BACKGROUND: A hydatidiform mole with a coexisting fetus is a rare condition that commonly occurs as either a partial mole with fetus or a twin pregnancy comprising a complete mole and normal fetus. In the former case, the fetus is triploid, and in the latter case, the fetus is diploid with different alleles from those of the mole. Because there is a difference in the persistent trophoblastic disease incidence between the two, an accurate diagnosis is required. CASE PRESENTATION: We present a case of a 34-year-old Japanese woman who was pregnant with a hydatidiform mole and two coexisting fetuses. At 17 weeks of gestation, hemorrhage-induced progressive anemia in the mother prompted the decision to terminate the pregnancy, after which no complications occurred. Molecular cytogenetic analysis revealed that one of the fetuses was a normal diploid fetus with the same allele in the fetus and placenta. The hydatidiform mole was revealed to be a mosaic of two diploids, and the other coexisting fetus was a normal diploid that shared one of the mole alleles. CONCLUSIONS: This was presumed to be a rare case of twin pregnancy by triploid embryo formation, followed by loss of an allele due to postzygotic diploidization, development of a diploid fetus, and development of another fetus from a separate embryo. Because of the existence of cases such as this one with a diploid fetus, but without a normal pregnancy coexistent with a complete hydatidiform mole, diagnosis by genetic analysis is required for prognosis.

Diagnosis of female 17α-hydroxylase deficiency after gonadectomy: a case report.

BACKGROUND: 17α-Hydroxylase deficiency is a recessively inherited autosomal disease caused by mutations in the CYP17A1 gene. It is a rare disease and accounts for approximately 1% of congenital adrenal cortex hyperplasias. Inhibition of 17α-hydroxylase causes low levels of cortisol and high levels of adrenocorticotropic hormone in the blood as well as excessive levels of mineralocorticoids that lead to hypertension and hypokalemia. Usually, the female patients are diagnosed with abnormality of the genitalia or extra genitalia, primary amenorrhea, or hypertension in puberty. We report a case of a 29-year-old woman who had undergone gonadectomy in her childhood due to complete androgen insensitivity syndrome and was diagnosed with 17α-hydroxylase deficiency in adulthood. CASE PRESENTATION: Our patient was a Japanese female diagnosed with androgen insensitivity syndrome, and both gonadectomy and episioplasty were performed at the age of 11 years at the University of Tsukuba Hospital. Thereafter, she was transferred to our hospital at the age of 21 years for vaginoplasty. At the age of 25 years, she presented with hypertension followed by complicated hypokalemia at the age of 28 years. The captopril loading test and adrenocorticotropic hormone loading test of her adrenal steroidogenesis revealed primary aldosteronism. After sufficient genetic counseling, a genetic test was performed that identified her as having CYP17A1 gene mutation. CONCLUSIONS: The differential diagnosis of disorders of sex development can be difficult at a young age without complete expression of the phenotype. However, diagnosis at a later age would change the treatment and prognosis of the disease; therefore, a genetic examination should be considered.

Retrospective study of umbilical cord ulceration related to congenital intestinal atresia: A single-center report.

AIM: Umbilical cord ulceration (UCU) is a disease in which an ulcer forms in the umbilical cord in the pregnant uterus and is accompanied by hemorrhaging from the same site. UCU occurs in fetuses with congenital upper-intestinal atresia (CUIA); however, its onset mechanism remains unclear. Here, we report our investigation of cases of UCU in our hospital. METHODS: Among the 9825 deliveries performed between 2007 and 2016 at this hospital, 20 fetuses were diagnosed with CUIA, 4 (20%) of which had UCU. There was no difference in the backgrounds of the fetuses with UCU (UCU group: 4 fetuses) and those without (non-UCU group: 16 fetuses). RESULTS: There was no intergroup difference in gestational age at delivery. Four cases in the UCU group had maternal age 35 weeks (26-39), weeks of delivery 35 weeks (35-36) and weight 2178.5 g (1600-2640); three out of four fetuses were female; and the location of gastrointestinal obstruction was in the duodenum in one case and in the jejunum in three cases. Death occurred in three of four fetuses in the UCU group versus none in the non-UCU group. CONCLUSION: We performed a retrospective statistical investigation on the risk of UCU onset in cases from this hospital; however, we could not identify any prognostic factors for its onset. We investigated a total of 27 past reported UCU cases and the 4 cases in this study. Mean gestational age at onset was 33.3 ± 2.7 for all 27 cases. Various methods for the early discovery of UCU have been reported in the past; however, there is currently no gold standard. Based on this report and a review of past papers, for CUIA, it is desirable to perform in-hospital management from gestational week 30 onward and decide proper delivery timing on a case-by-case basis.

Differences in home blood pressure and pulse rates between singleton and twin pregnancies.

Objectives To evaluate home blood pressure (HBP) measurements during pregnancy and postpartum and investigate differences between singleton and twin pregnancies. Methods This prospective study involved normotensive, pregnant women who were planning to give birth at Saitama Medical Centre, Saitama, Japan between September 2013 and March 2017. HBP and pulse rate were measured twice daily and clinical blood pressure values were determined from patient records. Results HBP values were available from 101 participants; 69 women with singleton and 32 women with twin pregnancies. Systolic BP was statistically significantly higher in twin pregnancies from 23 weeks of gestation until 8 weeks after delivery compared with singleton pregnancies. Pulse rate was also statistically significantly higher between 11 and 30 weeks gestation in women with twin pregnancies compared with those with singleton pregnancies. Conclusions BP monitoring is important in the management of twin pregnancies, especially during the later gestational weeks and postpartum period and HBP would facilitate this monitoring.

Associations between the levels of soluble (pro)renin receptor in maternal and umbilical cord blood and hypertensive disorder of pregnancy.

INTRODUCTION: The prorenin (PR) receptor [(P)RR] contributes to the regulation of the tissue renin-angiotensin system (RAS) and Wnt signaling, which is involved in embryogenesis and the pathological progression of malignant tumors and diabetes mellitus. Placental (P)RR is significantly upregulated in placental tissues from preeclamptic women. However, because it cannot be examined during pregnancy, the chronological relationship between the acceleration of tissue RAS and the disease state of hypertensive disorder of pregnancy (HDP) has not been reported. In this study, we examined whether chronological changes in placental tissue RAS can be assessed by measuring soluble (P)RR [s(P)RR]. METHODS: We obtained maternal and umbilical cord blood samples from 517 pregnant women (441 singleton and 76 twin pregnancies). The concentrations of s(P)RR and prorenin (PR) were measured using enzyme-linked immunosorbent assays. RESULTS: Multivariate analysis showed that maternal serum s(P)RR levels were significantly higher in patients with HDP or fetal growth restriction (FGR) and were positively correlated with serum PR levels. Furthermore, the maternal s(P)RR level was significantly higher in HDP with severe hypertension and after the onset of HDP. However, maternal s(P)RR levels were not affected by the severity of proteinuria. Serum s(P)RR levels in umbilical cord blood of singleton pregnancies were significantly correlated with gestational week at delivery and PR level. DISCUSSION: Maternal serum s(P)RR concentrations may reflect acceleration of tissue RAS in the placenta and blood pressure severity; however, the umbilical serum s(P)RR concentration was not affected by maternal HDP.

Provisional criteria for the diagnosis of hypertension in pregnancy using home blood pressure measurements.

Most guidelines for the management of hypertension define it as a home blood pressure (HBP) value >135/85 mm Hg. However, there is no reference HBP value to diagnose hypertension in pregnant women. Therefore, in this study, we analyzed HBP measurements of pregnant women to determine whether it is appropriate to use the criteria for non-pregnant subjects for pregnant women. The participants of this study were 100 singleton pregnant women who visited our hospital between September 2013 and September 2016. We lent sphygmomanometers to the patients so they could measure their BP at home twice daily, and we measured their clinical BP when they visited the hospital. Six patients developed hypertensive disorders in pregnancy, whereas there were 63 women without hypertension or other complications that may affect BP. In the normotensive pregnant women, HBP values significantly correlated with the clinical BP values. HBP values equivalent to a clinical BP of 140/90 mm Hg, determined using the standard major axis method, were 120.8/83.5 mm Hg, 126.0/85.2 mm Hg and 136.3/89.3 mm Hg in the first, second and third trimesters, respectively. In normotensive pregnant women, HBP levels that indicate a risk of hypertensive disorder in pregnancy may be lower than 135/85 mm Hg before 28 weeks of gestation.

Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation.

Eukaryotic cells have signalling pathways from the endoplasmic reticulum (ER) to cytosol and nuclei, to avoid excess accumulation of unfolded proteins in the ER. We previously identified a new type of ER stress transducer, OASIS, a bZIP (basic leucine zipper) transcription factor, which is a member of the CREB/ATF family and has a transmembrane domain. OASIS is processed by regulated intramembrane proteolysis (RIP) in response to ER stress, and is highly expressed in osteoblasts. OASIS(-/-) mice exhibited severe osteopenia, involving a decrease in type I collagen in the bone matrix and a decline in the activity of osteoblasts, which showed abnormally expanded rough ER, containing of a large amount of bone matrix proteins. Here we identify the gene for type 1 collagen, Col1a1, as a target of OASIS, and demonstrate that OASIS activates the transcription of Col1a1 through an unfolded protein response element (UPRE)-like sequence in the osteoblast-specific Col1a1 promoter region. Moreover, expression of OASIS in osteoblasts is induced by BMP2 (bone morphogenetic protein 2), the signalling of which is required for bone formation. Additionally, RIP of OASIS is accelerated by BMP2 signalling, which causes mild ER stress. Our studies show that OASIS is critical for bone formation through the transcription of Col1a1 and the secretion of bone matrix proteins, and they reveal a new mechanism by which ER stress-induced signalling mediates bone formation.

Regulation of endoplasmic reticulum stress response by a BBF2H7-mediated Sec23a pathway is essential for chondrogenesis.

Many tissues have a specific signal transduction system for endoplasmic reticulum (ER) dysfunction; however, the mechanisms underlying the ER stress response in cartilage remain unclear. BBF2H7 (BBF2 human homologue on chromosome 7), an ER-resident basic leucine zipper transcription factor, is activated in response to ER stress and is highly expressed in chondrocytes. In this study, we generated Bbf2h7(-/-) mice to assess the in vivo function of BBF2H7. The mice showed severe chondrodysplasia and died by suffocation shortly after birth because of an immature chest cavity. The cartilage showed a lack of typical columnar structure in the proliferating zone and a decrease in the size of the hypertrophic zone, resulting in a significant reduction of extracellular matrix proteins. Interestingly, proliferating chondrocytes showed abnormally expanded ER, containing aggregated type II collagen (Col2) and cartilage oligomeric matrix protein (COMP). We identified Sec23a, which encodes a coat protein complex II component responsible for protein transport from the ER to the Golgi, as a target of BBF2H7, which directly bound to a CRE-like sequence in the promoter region of Sec23a to activate its transcription. When Sec23a was introduced to Bbf2h7(-/-) chondrocytes, the impaired transport and secretion of cartilage matrix proteins was totally restored, indicating that by activating protein secretion the BBF2H7-Sec23a pathway has a crucial role in chondrogenesis. Our findings provide a new link by which ER stress is converted to signalling for the activation of ER-to-Golgi trafficking.

Discovery of selective PDE4B inhibitors.

In this study the first PDE4B selective inhibitor is described. Optimization of lead 2-arylpyrimidine derivatives afforded a series of potent PDE4B inhibitors with >100-fold selectivity over the PDE4D isozyme. With a good pharmacokinetic profile, a selected compound exhibited potent anti-inflammatory effects in vivo and showed less emesis compared with Cilomilast.

The development of a bioengineered organ germ method.

To bioengineer ectodermal organs such as teeth and whisker follicles, we developed a three-dimensional organ-germ culture method. The bioengineered tooth germ generated a structurally correct tooth, after both in vitro organ culture as well as transplantation under a tooth cavity in vivo, showing penetration of blood vessels and nerve fibers. Our method provides a substantial advance in the development of bioengineered organ replacement strategies and regenerative therapies.

Influence of alpha-tumor necrosis factor and beta-interleukin-1 on production of angiogenetic factors and thymidine phosphorylase activity in immortalized human decidual fibroblasts in vitro.

AIM: The aim of the present study was to investigate regulatory mechanisms of angiogenesis in the decidua using immortalized human decidual fibroblasts. METHODS: A sample of decidual fibroblasts was taken from a woman in early pregnancy. A cell line, DE-1, was established by infecting the decidual fibroblasts with the simian virus 40 large T antigen. Using this cell line, the ability to produce vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), beta-transforming growth factor (TGF-beta), and thymidine phosphorylase (TP) activity was investigated using immunohistochemistry, and the influences of beta-interleukin-1 (IL-1beta) and alpha-tumor necrosis factor (TNF-alpha) on these angiogenetic factors was investigated using enzyme-linked immunosorbent assays. Furthermore, the effects of TNF-alpha on proliferative capacity and apoptosis induction in DE-1 were studied. RESULTS: It was demonstrated that DE-1 produced all of these angiogenetic factors. The production of VEGF, bFGF and TGF-beta respectively was enhanced by both IL-1beta and TNF-alpha. TP activity was increased by TNF-alpha, but no increase was observed as a result of IL-1beta. It was shown that TNF-alpha suppressed the proliferation of DE-1 cells and significantly increased the percentage of apoptotic cells. CONCLUSION: It is suggested that IL-1beta and TNF-alpha stimulate decidual fibroblasts to up-regulate angiogenesis in the human decidua.

Thermal properties of dental materials--cavity liner and pulp capping agent.

We studied the thermal properties of cavity liners that included calcium phosphate as inorganic filler, in contrast to the conventional pulp capping agents. Therefore, thermal diffusivity, specific heat capacity, and thermal conductivity were measured. In addition, thermal conductivity results were compared with those of restorative materials and human dentin to examine thermal insulation effects. The thermal conductivity of cavity liners ranged from 0.23 to 0.28 W m(-1) K(-1), and that of pulp capping agents ranged from 0.44 to 0.48 W m(-1) K(-1). Test results indicated that the thermal conductivity of cavity liner was lower than those of human dentin, pulp capping agent, cast alloy, and composite resin for restoration, hence suggesting that cavity liner has a good thermal insulation effect.