Sexual Dimorphism in the Closure of the Hippocampal Postnatal Critical Period of Synaptic Plasticity after Intrauterine Growth Restriction: Link to Oligodendrocyte and Glial Dysregulation.

Intrauterine growth restriction (IUGR) resulting from hypertensive disease of pregnancy (HDP) leads to sexually dimorphic hippocampal-dependent cognitive and memory impairment in humans. In our translationally relevant mouse model of IUGR incited by HDP, we have previously shown that the synaptic development in the dorsal hippocampus including GABAergic development, NPTX2+ excitatory synaptic formation, axonal myelination, and perineural net (PNN) formation were perturbed by IUGR at adolescent equivalence in humans (P40). The persistence of these disturbances through early adulthood and the potential upstream mechanisms are currently unknown. Thus, we hypothesized that NPTX2+ expression, PNN formation, axonal myelination, all events closing synaptic development in the hippocampus, will be persistently perturbed, particularly affecting IUGR female mice through P60 given the fact that they had worse short-term recognition memory in this model. We additionally hypothesized that such sexual dimorphism is linked to persistent glial dysregulation. We induced IUGR by a micro-osmotic pump infusion of a potent vasoconstrictor U-46619, a thromboxane A2-analog, in the last week of the C57BL/6 mouse gestation to precipitate HDP. Sham-operated mice were used as controls. At P60, we assessed hippocampal and hemispheric volumes, NPTX2 expression, PNN formation, as well as myelin basic protein (MBP), Olig2, APC/CC1, and M-NF expression. We also evaluated P60 astrocytic (GFAP) reactivity and microglial (Iba1 and TMEM119) activation using immunofluorescent-immunohistochemistry and Imaris morphological analysis plus cytokine profiling using Meso Scale Discovery platform. IUGR offspring continued to have smaller hippocampal volumes at P60 not related to changes in hemisphere volume. NPTX2+ puncta counts and volumes were decreased in IUGR hippocampal CA subregions of female mice compared to sex-matched shams. Intriguingly, NPTX2+ counts and volumes were concurrently increased in the dentate gyrus (DG) subregion. PNN volumes were smaller in CA1 and CA3 of IUGR female mice along with PNN intensity in CA3 but they had larger volumes in the CA3 of IUGR male mice. The myelinated axon (MBP+) areas, volumes, and lengths were all decreased in the CA1 of IUGR female mice compared to sex-matched shams, which correlated with a decrease in Olig2 nuclear expression. No decrease in the number of APC/CC1+ mature oligodendrocytes was identified. We noted an increase in M-NF expression in the mossy fibers connecting DG to CA3 only in IUGR female mice. Reactive astrocytes denoted by GFAP areas, volumes, lengths, and numbers of branching were increased in IUGR female CA1 but not in IUGR male CA3 compared to sex-matched shams. Lastly, activated microglia were only detected in IUGR female CA1 and CA3 subregions. We detected no difference in the cytokine profile between sham and IUGR adult mice of either sex. Collectively, our data support a sexually dimorphic impaired closure of postnatal critical period of synaptic plasticity in the hippocampus of young adult IUGR mice with greater effects on females. A potential mechanism supporting such dimorphism may include oligodendrocyte dysfunction in IUGR females limiting myelination, allowing axonal overgrowth followed by a reactive glial-mediated synaptic pruning.

Determining the Optimal Time Interval between Vaginal Dinoprostone Administration and Diagnostic Office Hysteroscopy in Nulliparous Women: A Randomized, Double-blind Trial.

STUDY OBJECTIVE: To determine the optimal timing of vaginal dinoprostone administration before office hysteroscopy (OH) in nulliparous women. DESIGN: Randomized, double-blind trial. SETTING: Tertiary referral hospital. PATIENTS: A total of 180 nulliparous women undergoing diagnostic OH. INTERVENTIONS: We randomly allocated the women to long-interval or short-interval dinoprostone groups: three mg dinoprostone was administered vaginally 12 hours before OH in the long-interval group and 3 hours before OH in the short-interval group. MEASUREMENTS AND MAIN RESULTS: The primary outcome was pain during OH measured using a 100-mm visual analog scale (0 = no pain; 100 = worst pain imaginable). The secondary outcomes were ease of hysteroscope passage, patient satisfaction score, and drug-related adverse effects. The patients in the long-interval dinoprostone group had lower pain scores during OH (p <.001). Contrarily, pain scores 30 minutes after the procedure were similar in both groups (p = .1). The patient satisfaction score was higher and clinicians found hysteroscope passage through the cervical canal easier and quicker in the long-interval dinoprostone group than in the short-interval group (p <.001, p = .003, and p <.001, respectively). Side effects were comparable in both study groups. CONCLUSION: Vaginal dinoprostone administered 12 hours before OH was more effective than that administered 3 hours before OH in reducing pain during OH in nulliparous women, with easier hysteroscope insertion, shorter procedure duration, and higher patient satisfaction score.

Correlation between pre-operative diagnosis and final pathological diagnosis of endometrial malignancies; impact on primary surgical treatment.

OBJECTIVES: to compare the accuracy of preoperative and postoperative endometrial sampling obtained by dilatation and curettage (D&C), Pipelle and hysteroscopy to diagnose endometrial malignancies and to evaluate the adequacy of surgical treatment for these patients. STUDY DESIGN: This retrospective record-based study was conducted at Gynecology Oncology Unit, Ain Shams University Maternity Hospital, Cairo, Egypt. Records of patients with an initial preoperative or a final postoperative pathological diagnosis of endometrial hyperplasia or endometrial malignancies were retrieved over a six year period from January 2013 until March 2019. The preoperative biopsy methods, results, postoperative pathology diagnosis and treatment received were recorded and analyzed. RESULTS: Records of 395 patients were retrieved. Rates of agreement between initial and postoperative pathology for endometrial hyperplasia (with and without atypia) were 10% by D&C, 7.8% by Pipelle and zero % by hysteroscopy; for endometrioid adenocarcinoma grade 1, they were 40.7% by D&C, 40.6% by Pipelle and 20% by hysteroscopy; for endometrioid adenocarcinoma grades 2 and 3, they were 83.7% and 84.6% by D&C, 97% and 60% by Pipelle, and 100% by hysteroscopy, respectively. For type II endometrial cancer and endometrial stromal sarcoma, agreement rates were 100% by all biopsy methods. Out of 13 cases diagnosed with atrophic endometrium preoperatively, 11 cases were diagnosed as endometrial stromal sarcoma. Comparing accuracy of the three biopsy methods, D&C had highest sensitivity of 61.9%; hysteroscopy showed 100% specificity, while Pipelle was the least accurate method. Finally, 61.4% of the patients received adequate surgical treatment. CONCLUSION: There were excellent concordance rates between initial biopsy and postoperative pathology in diagnosis of high grade endometrioid and other endometrial malignancies compared to endometrial hyperplasia and low grade endometrioid adenocarcinoma. Patients diagnosed initially with atrophic endometrium or hyperplasia warranted more surveillance before their surgical treatment. It is crucial to develop protocols for increasing accuracy of endometrial sampling such as performing molecular studies for preoperative pathology.

Effect of vitamin D on experimental model of polycystic ovary syndrome in female rats.

AIMS: Vitamin D plays an important role in the regulation of ovulatory dysfunction. We aimed to study the effect of vitamin D on letrozole-induced PCOS in female rats. MATERIAL & METHODS: 40 non-pregnant Wistar rats were divided into four groups: group I control (received 1 ml of 1% aqueous solution of (CMC)/d orally), group II letrozole-induced PCOS group (received letrozole 200 µg/d orally), group III vitamin D-treated group (received vitamin D 1000 IU/kg/d), group IV letrozole and vitamin D treated group (received letrozole and vitamin D as group II and group III for 90 days. BMI, ovarian weight, serum vitamin D, biochemical metabolic and oxidative stress markers were evaluated, ovarian tissues glutathione, malondialdehyde levels and caspase-3 activity were measured. Histopathological examination of the ovary and coronary artery were done. KEY FINDINGS: Letrozole-induced typical PCOS with significant decrease in vitamin D and coronary vasculopathy. Group II shows insignificant change in all parameters but there is significant increase in vitamin D and decrease in triglyceride and glutathione. In group VI all parameters were significantly improved but coronary vasculopathy was partly improved. Vitamin D was significantly negatively correlated with all parameters but significantly positively correlated with estradiol, insulin sensitivity, and HDL and insignificantly correlated with glutathione. Both Insulin resistance and testosterone were significantly positively correlated with all parameters but significantly negatively correlated with estradiol, insulin sensitivity, HDL and glutathione. SIGNIFICANCE: These results holding the promise of beneficial impact of vitamin D administration to PCOS and its associated cardiovascular disorders.

Vaginal CO2 laser therapy versus sham for genitourinary syndrome of menopause management: a systematic review and meta-analysis of randomized controlled trials.

IMPORTANCE: The research of new therapeutic modalities, especially with energy-based devices, has been increasing nowadays for genitourinary syndrome of menopause (GSM) management. Microablative fractional CO2 laser has been used for pelvic floor dysfunction management. OBJECTIVE: To conduct a systematic review and meta-analysis of randomized controlled trials to compare fractional CO2 laser therapy versus sham therapy for GSM management. EVIDENCE REVIEW: We searched for the available randomized clinical trials in Cochrane Library, PubMed, ISI web of science, and Scopus during March 2021. We included randomized clinical trials that compared CO2 laser to sham among postmenopausal women with GSM diagnosis. We extracted the available data from included studies and pooled them in a meta-analysis model using RevMan software. Our main outcomes were total vaginal score assessment using the Vaginal Assessment Scale, sexual function using the Female Sexual Function Index, urinary symptoms using the Urogenital Distress Inventory-6, and satisfaction. FINDINGS: Three studies met our inclusion criteria with a total number of 164 women. The CO2 laser was linked to a significant reduction in Vaginal Assessment Scale score when compared with the sham group (mean difference [MD] = -0.49, 95% CI [-0.75 to -0.22], P = 0.004). The CO2 laser was associated with a significant improvement in Female Sexual Function Index score in comparison with sham group (MD = 9.37, 95% CI [6.59-12.14], P < 0.001). In addition, a significant reduction in Urogenital Distress Inventory-6 score was reported among the CO2 laser group (MD = -6.95, 95% CI [-13.24 to -0.67], P = 0.03). More women were significantly satisfied among the CO2 laser group (risk ratio  = 1.98, 95% CI [1.36-2.89], P = 0.004). CONCLUSIONS AND RELEVANCE: CO2 laser therapy is a promising alternative for GSM management. Further randomized trials with larger sample sizes are required to confirm our findings.

Evaluating efficacy of intravenous carbetocin in reducing blood loss during abdominal myomectomy: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy of carbetocin versus placebo in decreasing intraoperative blood loss and the need for blood transfusion during abdominal myomectomy. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Tertiary university hospital from September 2019 to February 2020. PATIENT(S): A total of 138 women with symptomatic leiomyoma who were candidates for abdominal myomectomy (n = 69 in each group). INTERVENTION(S): We randomized the study participants in a 1:1 ratio to carbetocin and placebo groups. Intravenous 100 µg carbetocin or placebo was administered slowly after induction of anesthesia. MAIN OUTCOME MEASURE(S): Intraoperative blood loss, need for blood transfusion, postoperative hemoglobin, operative time, length of hospitalization, and drug side-effects. RESULT(S): The baseline characteristics were similar among all groups. Carbetocin had significantly lower intraoperative blood loss compared with placebo (mean difference 184 mL). Hemoglobin level 24 hours after surgery was significantly lower in the placebo group than in the carbetocin group (9.1 ± 0.8 vs. 10.3 ± 0.6 g/dL). Eight women in the carbetocin group needed blood transfusion compared with 17 in placebo group. Operative time, length of hospitalization, and side-effects were similar in both groups. CONCLUSION(S): A single preoperative intravenous dose of 100 µg carbetocin is a simple, practical, and effective method of decreasing intraoperative blood loss and the need for blood transfusion during abdominal myomectomy, with tolerable, few, nonsignificant side-effects. CLINICAL TRIAL REGISTRATION NUMBER: NCT04083625.

Effect of self-administered vaginal dinoprostone on pain perception during copper intrauterine device insertion in parous women: a randomized controlled trial.

OBJECTIVE(S): To assess efficacy and safety of self-administered 3 mg dinoprostone vaginally in reducing pain during copper intrauterine device (IUD) insertion in parous women. DESIGN: Randomized, double-blinded, placebo-controlled trial. SETTING: Family planning clinic in a tertiary referral hospital. PATIENT(S): Multiparous women who were attending a family planning clinic and requesting copper IUD insertion. INTERVENTIONS(S): We randomly assigned 160 participants into two groups: The dinoprostone group (n = 80) received 3 mg dinoprostone vaginally, and the placebo group (n = 80) received placebo vaginally. MAIN OUTCOME MEASURE(S): Our primary outcome was mean pain scores during IUD insertion. Our secondary outcomes were mean pain scores during tenaculum application, during uterine sounding, and 15 minutes after insertion, ease of insertion, satisfaction score, need for additional analgesics, and side-effects. RESULT(S): Both groups showed no significant difference in anticipated pain score (P=.41), pain during tenaculum placement (P=.22), and pain during sound insertion (P=.07). The dinoprostone group had significantly lower pain scores during IUD insertion (34.8 ± 10.1 vs. 57.8 ± 11.8) and 15 minutes after insertion (20.6 ± 6.4 vs. 29.6 ± 6.2), easier IUD insertion (43.6 ± 21.9 vs. 64.7 ± 18.1), and higher satisfaction (83.9 ± 11.6 vs. 63.0 ± 9.1) compared with the placebo group. Fewer patients required additional analgesics in the dinoprostone group compared with the placebo group (P=.01). Side-effects were similar between the groups. CONCLUSION(S): Self-administered 3 mg dinoprostone vaginally before copper IUD insertion in parous women reduces pain scores during IUD insertion, making insertion easier and increasing women's satisfaction, with tolerable side-effects. CLINICAL TRIAL REGISTRATION NUMBER: NCT04046302.