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Study Question: Does ambient temperature exposure affect outcomes including clinical pregnancy and live birth in women undergoing IVF?, Summary Answer: Both extreme cold and hot ambient temperatures were significantly associated with adverse pregnancy outcomes of IVF cycles., What Is Known Already: Heat exposure has been linked to adverse pregnancy outcomes worldwide. However, the effect of ambient temperature on infertile women undergoing IVF treatment is unclear., Study Design, Size, Duration: A retrospective cohort study was conducted from a database of 3452 infertile women who underwent their first fresh or frozen embryo transfer in the Shanghai First Maternity and Infant Hospital from April 2016 to December 2020., Participants/materials, Setting, Methods: Daily mean ambient temperature exposure for each patient was obtained based on their residential address. Temperature-stratified multiple logistic regression analysis was performed to investigate associations between temperature exposure and pregnancy outcomes after controlling for confounders. Vulnerable sub-groups were identified using forest plots., Main Results and the Role of Chance: The clinical pregnancy rate and live birth rate were 45.7% and 37.1%, respectively. Regarding clinical pregnancy, a higher temperature during cold weather was significantly associated with a higher pregnancy rate in the period about 11 weeks before ovarian stimulation (adjusted odds ratio (aOR) = 1.102, 95% CI: 1.012-1.201). Regarding live birth, an increased temperature during cold weather was significantly related to a higher live birth rate in the period after confirmation of clinical pregnancy or biochemical pregnancy, with the aORs of 6.299 (95% CI: 3.949-10.047) or 10.486 (95% CI: 5.609-19.620), respectively. However, a higher temperature during hot weather was negatively associated with the live birth rate in the periods after confirmation of clinical pregnancy or biochemical pregnancy, with the aORs at 0.186 (95% CI: 0.121-0.285) or 0.302 (95% CI: 0.224-0.406), respectively. Moreover, the decline in live birth rates during cold and hot weather was accompanied by increased rates of early miscarriage (P < 0.05). Stratified analyses identified susceptibility characteristics among the participants., Limitations, Reasons for Caution: Climate monitoring data were used to represent individual temperature exposure levels according to the patient's residential address in the study. We were not able to obtain information of personal outdoor activity and use of indoor air conditioners in this retrospective study, which may affect actual temperature exposure., Wider Implications of the Findings: This study highlights that the ambient temperature exposure should be taken into account during IVF treatment and afterwards. There is a need to be alert to extremes in cold and hot ambient temperatures, especially during the period of follicle development and pregnancy. With this knowledge, clinicians can scientifically determine the timing of IVF treatment and reinforce patients' awareness of self-protection to minimize adverse pregnancy outcomes associated with extreme temperatures., Study Funding/competing Interest(s): This work was supported by a grant from the Clinical Research Plan of Shanghai Hospital Development Center [SHDC2020CR4080], a grant from the Science and Technology Commission of Shanghai Municipality [19411960500], and two grants from the National Natural Science Foundation of China [81871213, 81671468]. B.W.M. is supported by a NHMRC Investigator grant (GNT1176437). B.W.M. reports consultancy for ObsEva, and research grants from Merck KGaA, Ferring and Guerbet. The other authors have no conflict of interest to declare., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Context: Up-regulation of aromatase expression in endometrial cells disseminated into the peritoneal cavity may enhance their survival via local estrogen synthesis, which may lead to endometriosis. The factors that mediate induction of aromatase in the endometrium are not well defined, but increased expression of steroidogenic factor (SF)-1 may play a role., Objective: The objective of the study was to determine whether androstenedione (A4), the predominant sex steroid in peritoneal fluid, regulates endometrial aromatase expression., Design: This was a cell/tissue culture study., Setting: The study was conducted at an academic center., Methods: Quantitative real-time PCR, HPLC, and chromatin immunoprecipitation were used in this study., Results: Treatment of cultured human endometrial explants and stromal cells with A4 (10 nm) significantly up-regulated expression of aromatase mRNA transcripts containing exon IIa at their 5'-ends. In endometrial stromal cells and the human endometrial surface epithelial (HES) cell line, induction of aromatase mRNA by A4 was associated with increased expression of SF-1. In HES cells, tritiated A4 was metabolized to estradiol, testosterone (T), dihydrotestosterone, and androstanediol. Both estradiol and T, but not nonaromatizable androgens, up-regulated aromatase and SF-1 mRNA in HES cells. Chromatin immunoprecipitation revealed that A4 enhanced recruitment of SF-1 to its response element (-136 bp) upstream of CYP19 exon IIa. This, together with the findings that both estrogen receptor antagonist, ICI 182,780, and aromatase inhibitor, fadrozole, suppressed A4 and T induction of aromatase and SF-1 mRNA, indicates that the inductive effects of A4 and T are mediated by their conversion to estrogens., Conclusions: Exposure of endometrial cells to A4 may enhance CYP19 gene expression through its aromatization to estrogens.

Aberrant up-regulation of aromatase in eutopic endometrium and implants from women with endometriosis has been reported. Aromatase induction may be mediated by increased cyclooxygenase-2 (COX-2). Recently, we demonstrated that progesterone receptor (PR)-A and PR-B serve an antiinflammatory role in the uterus by antagonizing nuclear factor kappaB activation and COX-2 expression. PR-C, which antagonizes PR-B, is up-regulated by inflammation. Although estrogen receptor alpha (ERalpha) is implicated in endometriosis, an antiinflammatory role of ERbeta has been suggested. We examined stage-specific expression of aromatase, COX-2, ER, and PR isoform expression in eutopic endometrium, implants, peritoneum, and endometrioma samples from endometriosis patients. Endometrial and peritoneal biopsies were obtained from unaffected women and those with fibroids. Aromatase expression in eutopic endometrium from endometriosis patients was significantly increased compared with controls. Aromatase expression in endometriosis implants was markedly increased compared with eutopic endometrium. Aromatase mRNA levels were increased significantly in red implants relative to black implants and endometrioma cyst capsule. Moreover, COX-2 expression was increased in implants and in eutopic endometrium of women with endometriosis as compared with control endometrium. As observed for aromatase mRNA, the highest levels of COX-2 mRNA were found in red implants. The ratio of ERbeta/ERalpha mRNA was significantly elevated in endometriomas compared with endometriosis implants and eutopic endometrium. Expression of PR-C mRNA relative to PR-A and PR-B mRNA was significantly increased in endometriomas compared with eutopic and control endometrium. PR-A protein was barely detectable in endometriomas. Thus, whereas PR-C may enhance disease progression, up-regulation of ERbeta may play an antiinflammatory and opposing role.

Background: The presence of hydrosalpinges is associated with lower implantation and pregnancy rates in women undergoing IVF-embryo transfer, while salpingectomy improves these parameters. Although the mechanism by which hydrosalpinges affects fertility is not entirely understood, an adverse effect on endometrial receptivity has been postulated. In this study, we hypothesized that the adverse effects of hydrosalpinges on fertility may be in part mediated by inappropriate endometrial expression of leukaemia inhibitory factor (LIF), a cytokine implicated in implantation., Methods: In order to test our hypothesis, we prospectively examined the expression of LIF during the window of implantation in the endometrium of infertile women (n = 10) with hydrosalpinges prior to and following salpingectomy and of fertile controls (n = 10) by Western blotting and immunohistochemistry., Results: LIF expression was significantly lower in infertile women with hydrosalpinges compared with fertile controls (P < 0.05). Salpingectomy resulted in an increase in LIF expression in eight out of 10 women with hydrosalpinges. LIF levels were increased by 231 +/-49% (mean +/- SEM) following salpingectomy. Immunohistochemical analysis confirmed the Western blot findings. The increased LIF immunoreactivity was predominantly localized to luminal and glandular epithelial cells., Conclusions: Our findings suggest that observed benefit from salpingectomy in infertile women with hydrosalpinges may be in part mediated by the up-regulation of endometrial LIF expression.

Background: We aimed to assess whether salpingectomy in women with communicating hydrosalpinges influenced endometrial receptivity., Methods: The inclusion criteria were: women with communicating hydrosalpinges, absence of other confounding infertility factors and aged <40 years. Patients were scheduled for laparoscopy during the putative window of implantation (cycle days 19-21). In patients in whom salpingectomy was decided upon due to the severity of tubal disease (n = 10), an intra-operative endometrial biopsy was performed. Post-treatment endometrial sampling was done between day 19-21 of the fourth consecutive cycle. Pre-treatment and post-treatment samples were assessed by both conventional histologic criteria and alpha(v)beta3 integrin immunostaining, where histological score (HSCORE) was used for quantification., Results: Despite normal histological maturation assessed by conventional criteria, 8/10 hydrosalpinx cases yielded an epithelial HSCORE of <0.7, which was below the accepted threshold. Following salpingectomy, luminal endometrial epithelium demonstrated a significantly increased alpha(v)beta3 integrin expression (Wilcoxon's signed rank test, P = 0.017). Although the mean HSCORE for glandular epithelia improved, it failed to reach statistical significance. Ultrasound visible hydrosalpinges (n = 5) and non-visible cases (n = 5) were also compared. However, neither the pre-treatment integrin expression, nor the postoperative improvement were significantly different between these groups., Conclusions: We conclude that the surgical treatment of communicating hydrosalpinges may improve endometrial receptivity as assessed by alpha(v)beta3 integrin expression. Women with hydrosalpinges may undergo endometrial evaluation by the molecular markers of implantation, such as alpha(v)beta3 integrin. This evaluation may be decisive in determining the optimal management of cases, and may also be used to assess the efficacy of the treatment. The expression of the implantation markers should be correlated with implantation and clinical pregnancy rates in IVF-embryo transfer programs.

A prospective, randomized, double-blind, multicentre (n = 6) study was conducted to compare the influence of either a 150 or 250 IU daily fixed-dose regimen of recombinant follicle stimulating hormone (FSH, Puregon) on the number of oocytes retrieved and the total dose used in down-regulated women between 30 and 39 years of age undergoing ovarian stimulation. In all, 138 women were treated with recombinant FSH, 67 with 150 IU and 71 with 250 IU. The number of oocytes retrieved in the low-dose group was 9.1 compared to 10.6 in the high-dose group (not significant). In the 30-33 years of age class receiving the 250 IU dose, a surplus of 4.2 oocytes (14.8 versus 10.6) was found, whereas in the 37-39 age class nearly one oocyte more was retrieved in the 150 IU group (8.1 versus 7.4). The total dose used to reach the criterion for human chorionic gonadotrophin (HCG) administration was 1727 IU for the women treated with 150 IU daily and 2701 IU for the 250 IU treated women (P < 0. 001). No significant relationships were found between serum FSH concentrations as obtained in the early follicular phase and the number of oocytes collected, or the total dose. It is concluded that in women between 30 and 39 years of age, the decline in number of oocytes retrieved with increasing age cannot be overcome by augmenting the daily dose of recombinant FSH from 150 to 250 IU.

Twelve consecutive patients with total corporal synechiae due to tuberculosis were reviewed in terms of intrauterine adhesion re-formation rate following hysteroscopic surgery. All patients presented with secondary amenorrhoea and infertility. The diagnosis was based on a 'glove finger appearance' at hysterosalpingography and classical laparoscopic and tubal biopsy findings. Intrauterine synechiae re-formation was assessed by postoperative hysterosalpingograms performed 3-4 months after the procedure. The 12 patients underwent 15 attempts for hysteroscopic lysis of total corporal synechiae. Three perforations occurred and all were managed with laparoscopic extracorporal suturing. Ultimately, adequate uterine cavity was obtained in all cases. Total intracorporal synechiae recurred in all patients at control postoperative hysterosalpingograms. We conclude that total corporal synechiae caused by tuberculosis, unlike other causes, carry a poor prognosis following hysteroscopic lysis. Surrogacy may be the only option for fertility in such couples.

Just before the time of ovulation, the number of neutrophils increases markedly in the thecal layer of the leading follicle. A preovulatory rise in chemotactic activity for neutrophils in human follicular fluid has also been detected. We hypothesized that interleukin-8 (IL-8), a neutrophil chemoattractant/activating factor and a potent angiogenic agent, may be an important modulator of leukocyte chemotaxis in ovulatory function. In this regard we investigated the expression and modulation of IL-8 in human follicular fluid samples from patients undergoing in vitro fertilization-embryo transfer therapy and in ovarian stromal and granulosa-lutein cell cultures. The concentration of IL-8 in pre-hCG follicular fluid samples (n = 4) was 16 +/- 12 (mean +/- SEM) pg/ml, and that in post-hCG samples (n = 101) was 262 +/- 45 pg/ml (P = 0.001). In post-hCG samples, the concentration of IL-8 in an individual follicle correlated with the size of that follicle (r = 0.61; P = 0.02). We also observed a correlation between serum IL-8 levels (22 +/- 3 pg/ml) and follicular fluid levels (303 +/- 143 pg/ml), with a 14-fold gradient (r = 0.71; P = 0.01) in 11 patients tested for both. IL-8 messenger RNA (mRNA) and the protein were expressed constitutively in ovarian stromal cell cultures, and the level was increased by IL-1 alpha and tumor necrosis factor-alpha in a time- and concentration-dependent manner. hCG and LH induced higher levels of IL-8 mRNA expression and protein production. Granulosalutein cells also expressed IL-8 mRNA and protein, and the levels were increased by IL-1 alpha and tumor necrosis factor-alpha. Importantly, progesterone suppressed both basal and IL-1 alpha-stimulated IL-8 expression in stromal and granulosa-lutein cell types. In summary, we found that IL-8 levels are elevated in periovulatory follicular fluid, and both granulosa-lutein and ovarian stromal cells express the mRNA and produce the protein. The modulation of IL-8 in these cell cultures by steroid and trophic hormones suggests that IL-8 may play an important role in the physiology of ovulation, such as timely follicular rupture and neovascularization of the corpus luteum.