Pregnancy and lactation-associated osteoporosis as a major type of premenopausal osteoporosis: a retrospective cohort study based on real-world data.

BACKGROUND: Pregnancy and lactation-associated osteoporosis (PLO), as well as premenopausal osteoporosis, might be a predictor of future fracture. This study aimed to describe the clinical features of PLO as a subtype of premenopausal osteoporosis and to evaluate medical interventions for it. METHODS: From an administrative claims database including 4,224,246 people in Japan, we classified women for whom the date of childbirth had been defined and who had suffered low-trauma fracture between the ages of 18-47 years as the premenopausal osteoporosis group. A fracture site for which the odds ratio for fractures occurring between 5 months before and 12 months after childbirth (around childbirth) was greater than 1 was considered the PLO site. We classified patients with a fracture at the PLO site around childbirth as the PLO group. The control group consisted of 500 women without fragility fractures. We investigated some drugs and diseases to explore fracture-causing factors, as well as medical interventions such as osteoporosis diagnosis, bone densitometry, anti-osteoporosis pharmacotherapy, and lactation inhibitors. RESULTS: In total, 231 parous women were classified into the premenopausal osteoporosis group. The most common fracture was vertebral fracture and was likely to occur around childbirth, followed by distal radius and sacral fractures, which were rare around childbirth. Considering vertebral, pelvic, and proximal femoral fractures as PLO sites, 56 women with 57 PLO fractures were classified into the PLO group. The incidence of PLO was estimated at 460 per million deliveries. Ovulation disorder and high maternal age were associated with the development of PLO. Vertebral fracture was the most common PLO fracture. It was mainly diagnosed a few months, and possibly up to 1 year, postpartum. PLO patients with vertebral fractures underwent more medical interventions than did those with other fractures, but they were still inadequate. CONCLUSIONS: PLO with vertebral fracture was one of the major types of premenopausal osteoporosis. The prevalence of PLO is considered to be higher than previously thought, indicating the presence of potentially overlooked patients. More timely interventions for PLO might lead to the improved management of latent patients with premenopausal osteoporosis and reduce future fracture risk.

Influence of Cesarean Section on Postpartum Fertility and Dysmenorrhea: A Retrospective Cohort Study in Japan.

Objective: To investigate the association between cesarean section (CS) and postpartum fertility and dysmenorrhea using data from a Japanese insurance registry. Methods: This retrospective cohort study used a data set of patients registered between 2007 and 2021 in an insurance registry comprising specific employee-based health insurance companies in Japan. Of those data sets, we included data from participants who had their first recorded childbirth between 2014 and 2018. The exclusion criteria were any prior deliveries, dysmenorrhea, or complications that would affect the next pregnancy or postpartum dysmenorrhea since 2007. The occurrence of subsequent childbirth and postpartum dysmenorrhea until 2021 was compared between the CS and vaginal delivery (VD) groups using the log-rank test and Cox proportional hazards model with stratification according to age and age matching. Results: This study included 25,984 (5,926 after age matching) and 5,926 participants in the VD and CS groups, respectively. After age matching, the rate of subsequent childbirth was 18.3% and 16.3%, and the rate of postpartum dysmenorrhea was 6.5% and 7.8% in the VD and CS groups, respectively. There were fewer subsequent childbirths in the CS group than in the VD group after age matching in the stratified Cox proportional hazards model (hazard ratio [HR] 95% confidence interval [CI]: 0.86 [0.79-0.94]). The CS group had a significantly higher risk of dysmenorrhea (HR [95% CI]: 1.18 [1.03-1.36]). Conclusions: Although confounding might be existing, our study suggests that CS might be associated with decreased postpartum fertility and increased dysmenorrhea. The medical indications for CS should be carefully determined; post-CS women should be meticulously followed up.

Amelioration of prevalence of threatened preterm labor during the COVID-19 pandemic: nationwide database analysis in Japan.

We aimed to evaluate the changes in maternal and neonatal complications such as threatened preterm labor (TPL) and preterm birth before and during the coronavirus disease 2019 (COVID-19) pandemic using large-scale real-world data in Japan. We obtained data from the Japan Medical Data Center claims database and evaluated differences in maternal and neonatal complications, such as the prevalence of TPL and preterm birth before the COVID-19 pandemic (in the year 2018 or 2019) and during the COVID-19 pandemic (in 2020). We included 5533, 6257, and 5956 deliveries in the years 2018, 2019, and 2020, respectively. TPL prevalence and preterm birth had significantly decreased in 2020 (41.3%, 2.6%, respectively) compared with those reported in 2018 (45.3%, 3.9%, respectively) and 2019 (44.5%, 3.8%, respectively). Neonatal outcomes such as low-birth-weight infants and retinopathy of prematurity were also improved during the pandemic. There were no clear trends in the prevalence of maternal complications such as hypertensive disorders of pregnancy; hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; and preeclampsia. Oral ritodrine hydrochloride usage in all participants had significantly decreased during the COVID-19 pandemic. In conclusion, our results suggest that the COVID-19 pandemic has ameliorated TPL and consequently reduced the number of preterm births.

A novel surgical treatment for labial adhesion - The combination of Z- and Y-V-plasty: A case report.

Labial adhesion is characterised by complete or partial fusion of the labia minora. It occurs rarely in postmenopausal women. Although various methods have been proposed, there is no established treatment for postmenopausal patients with labial adhesions due to its low prevalence in this age group. Severe cases require surgical intervention, and the postoperative recurrence rate is relatively high at 14-20%. In this study, a novel therapeutic method was designed to treat labial adhesions: a combination of Z- and Y-V-plasty. An 82-year-old woman was diagnosed with severe long labial adhesion during an episode of urinary tract infection. The labia could not be separated manually; hence, Z-plasty was performed on the ventral side and Y-V-plasty on the anal side under general anaesthesia. No recurrence was noted eight months postoperatively. This method is relatively easy and produced the desired therapeutic effect with decreased risk of recurrence. This is a novel approach for postmenopausal patients with severe labial adhesion.

Current Overview of Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI), or brittle bone disease, is a heterogeneous disorder characterised by bone fragility, multiple fractures, bone deformity, and short stature. OI is a heterogeneous disorder primarily caused by mutations in the genes involved in the production of type 1 collagen. Severe OI is perinatally lethal, while mild OI can sometimes not be recognised until adulthood. Severe or lethal OI can usually be diagnosed using antenatal ultrasound and confirmed by various imaging modalities and genetic testing. The combination of imaging parameters obtained by ultrasound, computed tomography (CT), and magnetic resource imaging (MRI) can not only detect OI accurately but also predict lethality before birth. Moreover, genetic testing, either noninvasive or invasive, can further confirm the diagnosis prenatally. Early and precise diagnoses provide parents with more time to decide on reproductive options. The currently available postnatal treatments for OI are not curative, and individuals with severe OI suffer multiple fractures and bone deformities throughout their lives. In utero mesenchymal stem cell transplantation has been drawing attention as a promising therapy for severe OI, and a clinical trial to assess the safety and efficacy of cell therapy is currently ongoing. In the future, early diagnosis followed by in utero stem cell transplantation should be adopted as a new therapeutic option for severe OI.

Alteration in endometrial helper T-cell subgroups in chronic endometritis.

PROBLEM: The effect of chronic endometritis (CE) on the subpopulation of CD4+ T cells, Th1, Th2, Th17, and regulatory T cells in the endometrium is unknown. METHOD OF STUDY: Lymphocytes were isolated from the endometrium of CE patients (n = 12) and non-CE patients (n = 7). The CD4+ T-cell profile was analyzed by flow cytometry and immunofluorescence. RESULTS: In the endometrium of CE patients, there were significantly more Th1 cells among CD4+ cells and fewer Th2 cells in comparison to non-CE patients. No marked difference was observed in Th17 cells or Foxp3+ Treg cells. Moreover, the proportion of Th1 cells increased and the proportion of Th2 cells decreased as the number of CD138+ cells increased. Furthermore, when the localization of CD138+ cells and CD4+ cells was examined, CD4+ cells were found to be clustered around CD138+ cells in CE patients. CONCLUSION: The CD4+ T-cell profile in the endometrium is altered in women with CE. This finding may help to clarify the pathophysiology and development of treatment methods for CE.

Smoking during Pregnancy Is a Predictor of Poor Perinatal Outcomes in Maternal Anorexia Nervosa: A Case Series and Single-Center Cross-Sectional Study in Japan.

Eating disorders are common psychiatric disorders among women of reproductive age, and the prevalence of eating disorders has been increasing over time in Japan and other countries. The aim of the present study was to assess perinatal outcomes in maternal anorexia nervosa in Japan and to explore methods to improve perinatal outcomes. This study consists of a case series describing 13 single pregnancies of 11 women with a history of anorexia nervosa, and a cross-sectional study comparing 13 cases with 240 healthy controls. In the case group, nine cases conceived while underweight, including three who had fertility treatment. Anorexia symptoms during pregnancy were quite common, and pregnant smokers presented with extremely disturbed eating behaviors. In a cross-sectional study, premature birth and the standard deviations from the mean birth weight and mean head circumference at birth were evaluated as outcome measures. The adjusted odds ratios or the adjusted differences between two means for the above outcomes were estimated by two approaches: multivariate models and matching analysis. Statistical analysis showed that maternal anorexia nervosa was associated with an increased risk of premature birth and symmetric growth restriction mediated by low pre-pregnancy body mass index and poor gestational weight gain which were adjusted as confounders. Smoking during pregnancy was a potential indicator of abnormal eating behavior and could be predictive of poor perinatal outcomes. We therefore conclude that remission of anorexia nervosa before pregnancy could improve perinatal outcomes through both normal nutrition and smoking cessation. Fertility treatment while underweight is not recommended.

Endometrial Immunity for Embryo Implantation and Pregnancy Establishment.

The uterus is an organ for raising the fetus, and its lumen is lined by the endometrium. The endometrium is an important site for the implantation and maturation of fertilized eggs. The endometrium undergoes repetitive proliferation, maturation (decidualization), and exfoliation changes every menstrual cycle. At the same time, the number and type of endometrial immunocompetent cells vary during the menstrual cycle. At the implantation stage, the immunocompetent cells occupy approximately half of the endometrial cells. Immunocompetent cells normally eliminate pathogenic microorganisms to protect the body; however, they also promote immune tolerance to accept the fetus during pregnancy. The immunocompetent cells in the uterus can perform both these functions. With the establishment of pregnancy, stimuli from the trophoblast (placenta) and fetus can also change the immune environment of the uterus, and pregnancy can be maintained only when the immune system is well adapted to the stimuli of some hormones and the fetus. Immunity for the establishment of pregnancy is not simple because multiple immunocompetent cells are involved in establishing and maintaining pregnancy. To understand the immune mechanisms associated with the establishment of pregnancy, we have to learn about each immune cell. This review, therefore, discusses the roles and distribution of the immunocompetent cells inside the uterus during menstruation and early pregnancy.

Review: Chronic endometritis and its effect on reproduction.

AIM: Chronic endometritis (CE) is a disease of continuous and subtle inflammation characterized by the infiltration of plasma cells in the endometrial stromal area. Although the clinical significance of CE has been thought in clinical practice for a long time because it is either asymptomatic or presents with subtle symptoms, recent studies have shown the potential adverse effects of CE on fertility. In the present review, we focus on the concept, diagnosis, etiology, pathophysiology, diagnosis, impact on reproduction and treatment for it to understand CE. METHODS: The published articles were reviewed. RESULTS: The prevalence of CE has been found to be 2.8-56.8% in infertile women, 14-67.5% in women with recurrent implantation failure (RIF), and 9.3-67.6% in women with recurrent pregnancy loss. Microorganisms are thought to be a main cause of CE, since antibiotic treatment has been reported to be an effective therapy for CE. Common bacteria are frequently detected in the uterine cavity of CE patients by microbial culture. In CE endometrium, the prevalence of immune cells and decidualization has been reported to be modified, and these modifications are thought to adversely affect fertility. The gold standard for the diagnosis of CE is the histological detection of plasma cells in the stromal area of the endometrium in endometrial specimens, although universally accepted criteria for the diagnosis of CE have not been determined. The treatment currently thought to be most effective for the recovery of fertility in CE is administration of oral antibiotics. Patients whose CE has been cured have been reported to have a higher ongoing pregnancy rate, clinical pregnancy rate, and implantation rate compared with patients with persistent CE. CONCLUSION: CE greatly affects implantation and impairs fertility. Antibiotic administration is an effective therapeutic option. Pregnancy rate in in vitro fertilization is improved when CE is cured by antibiotic.

Protective effect of a mechanistic target of rapamycin inhibitor on an in vivo model ofcisplatin-induced ovarian gonadotoxicity.

This study aimed to evaluate the protective effect of everolimus, a mechanistic target of rapamycin (mTOR) inhibitor, on cisplatin chemotherapy-induced ovarian toxicity. Eighty sexually mature, virgin, female, 7-week-old C57BL/6J mice were divided into four groups: control, cisplatin (Cis), everolimus (mTORi), and everolimus plus cisplatin (mTORi+Cis). Mice in the Cis and mTORi+Cis groups were intraperitoneally injected with 2 mg/kg of cisplatin for 15 d. Mice in the mTORi and mTORi+Cis groups were orally administered 2.5 mg/kg of everolimus for 29 d, from one week before the first cisplatin injection to one week after the last cisplatin injection. Histological examinations were performed 24 h after the last everolimus administration. The primordial, primary, and antral follicles were significantly depleted in the Cis group compared with that in the control group, confirming the gonadotoxicity of cisplatin. The number of primordial, secondary, and antral follicles was significantly higher in the mTORi+Cis group than in the Cis group, thereby displaying the effect of mTORi-treatment on ovarian protection. Primordial, secondary, and antral follicle counts were similar in the mTORi+Cis and the control groups. The results of this study indicate a protective effect of an mTOR inhibitor against cisplatin chemotherapy-induced gonadotoxicity in the ovarian reserve in an in vivo mouse model.

Subchondral Insufficiency Fracture of the Femoral Head in a Pregnant Woman with Pre-existing Anorexia Nervosa.

Subchondral insufficiency fracture (SIF) is a fragility fracture secondary to osteoporosis that leads to collapse of the femoral head with no evidence of osteonecrosis. SIF of the femoral head has been reported in adults of varying ages and both sexes, but it has never been reported to occur in pregnant women. Herein, we describe a 40-year-old primiparous patient with pre-existing anorexia nervosa who developed SIF of the femoral head in the third trimester. At 29 weeks of gestation, the patient complained of sudden pain on walking in both hips. Despite the bed rest, her hip pain increased; consequently, cesarean section was performed at 36 weeks. After delivery, plain radiographs showed that the left femoral head was collapsed. Dual-energy X-ray absorptiometry indicated that the patient was osteoporotic. The magnetic resonance imaging (MRI) of her hips showed the findings that were compatible with SIF. Her left hip pain worsened during follow-up, and a radiograph showed progressive collapse of the left femoral head. The patient then underwent left bipolar hip arthroplasty 18 months after delivery, and she was diagnosed with SIF histopathologically. This is the first report of SIF in a pregnant woman that may reflect pregnancy-associated osteoporosis. SIF in pregnancy might be overlooked or misdiagnosed because the MRI findings have several overlaps with those of other hip disorders. Precise diagnosis of SIF in pregnancy may contribute to a better outcome by avoiding early arthroplasty in young women and appropriate evaluation of the osteopenic status of the patient.

Suppressive regulatory T cells and latent transforming growth factor-ß-expressing macrophages are altered in the peritoneal fluid of patients with endometriosis.

BACKGROUND: Endometriosis is a known cause of infertility. Differences in immune tolerance caused by regulatory T cells (Tregs) and transforming growth factor-ß (TGF-ß) are thought to be involved in the pathology of endometriosis. Evidence has indicated that Tregs can be separated into three functionally and phenotypically distinct subpopulations and that activated TGF-ß is released from latency-associated peptide (LAP) on the surfaces of specific cells. The aim of this study was to examine differences in Treg subpopulations and LAP in the peripheral blood (PB) and peritoneal fluid (PF) of patients with and without endometriosis. METHODS: PB and PF were collected from 28 women with laparoscopically and histopathologically diagnosed endometriosis and 20 disease-free women who were subjected to laparoscopic surgery. Three subpopulations of CD4+ T lymphocytes (CD45RA+FoxP3low resting Tregs, CD45RA-FoxP3high effector Tregs, and CD45RA-FoxP3low non-Tregs) and CD11b+ mononuclear cells expressing LAP were analyzed by flow cytometry using specific monoclonal antibodies. RESULTS: Proportions of suppressive Tregs (resting and effector Tregs) were significantly higher in the PF samples of patients with endometriosis than in those of control women (P = 0.02 and P < 0.01, respectively) but did not differ between the PB samples of patients and controls. The percentage of CD11b+LAP+ macrophages was significantly lower in PF samples of patients with endometriosis than in those of controls (P < 0.01) but was not altered in the PB samples. CONCLUSION: Proportions of suppressive Tregs and LAP+ macrophages are altered locally in the PF of endometriosis patients.

Effects of ß-estradiol on cold-sensitive receptor channel TRPM8 in ovariectomized rats.

Transient receptor potential cation channel subfamily M member 8 (TRPM8) is associated with sensitivity to cold sensation in mammals. A previous study demonstrated that TRPM8 was overexpressed in the skin of ovariectomized (OVX) rats due to the loss of estrogen. In the present study, we investigated whether estrogen replacement restricts overexpression of the TRPM8 channel in the skin of OVX rats. We divided 15 Sprague Dawley rats into three groups: a non-operated group (NON-OPE), an ovariectomy group (OVX), and a group subjected to estrogen replacement during 4 weeks beginning 7 days after ovariectomy (OVX + E2). Five weeks later, TRPM8 channel mRNA and protein in lumbar skin were quantified by real-time RT-PCR, protein ELISA, and immunohistochemistry. The OVX + E2 group exhibited a trend for decreased expression of the TRPM8 channel in the lumbar skin in comparison with the OVX group, whereas ELISA data and immunohistochemistry data and immunohistochemistry graphs relating to TRPM8 protein did not show any obvious differences between the OVX group and the OVX + E2 group. Estrogen replacement may restrict the overexpression of TRPM8 in the dermis of OVX rats.

Bilateral femoral neck fractures resulting from pregnancy-associated osteoporosis showed bone marrow edema on magnetic resonance imaging.

Femoral neck fractures resulting from pregnancy-associated osteoporosis is a rare condition. Herein, we report an undoubted case of pregnancy-associated osteoporosis in a 38-year-old primiparous patient with pre-existing anorexia nervosa who suffered bilateral femoral neck fractures in the third trimester and early post-partum period. Magnetic resonance imaging revealed femoral neck fractures as well as diffuse marrow edema involving both femoral heads, which are considered under ordinary circumstances as characteristic imaging findings of transient osteoporosis of the hip. Based on our experience, we propose that pregnancy-associated osteoporosis might be present in femoral neck fractures attributed to transient osteoporosis of the hip in pregnancy. Conversely, bone status should be carefully and accurately estimated in cases of potential transient osteoporosis of the hip in pregnancy to reduce future fracture risk.