Masculinization depends on the fetal testis. Exposure of the human fetus during pregnancy to paracetamol and/or to other mild analgesics is associated with an increased risk of cryptorchidism. We aimed to determine whether mild analgesics disrupted the morphology and endocrine function of the human testis. We used an in vitro system based on the culture of human fetal testes exposed or not to paracetamol, its metabolite N-(4-hydroxyphenyl)-arachidonoylethanolamide (AM404), aspirin, indomethacin, and ketoconazole at 10(-4) to 10(-7) M. The study was conducted at the University of Rennes I. Human fetal testes were from pregnant women after induced abortion, between 7 and 12 weeks of gestation (GW). Testosterone (RIA), anti-Müllerian hormone (ELISA), insulin-like factor 3 (RIA), and prostaglandin (PG) D2 and PGE2 (ELISA) were assayed in the medium. Testicular cells were counted using histology and image analysis. The possible nuclear receptor-mediated activities of the analgesics were investigated using reporter cell lines expressing estrogen, androgen, and peroxisome proliferator-activated γ receptors. Indomethacin and aspirin stimulated testosterone production, particularly by the younger testes (8-9 GW vs 10-12 GW). Paracetamol, AM404, and ketoconazole decreased insulin-like factor 3 levels. Aspirin stimulated whereas ketoconazole inhibited AMH production. PGE2 levels were inhibited by paracetamol and aspirin in the 7 to 12 GW testes and by indomethacin but only in 7 to 9.86 GW testes. The inhibitory trends seen for PGD2 were not statistically significant. Analgesics at concentrations relevant to human exposure cause endocrine disturbances in the fetal testis. We suggest that the fetal human testis displays slight critical age windows for sensitivity to direct exposure to aspirin, indomethacin, and paracetamol. The analgesic-induced inhibition of INSL3 may be the mechanism by which analgesics increase the risk of cryptorchidism. Greater caution is required concerning consumption of analgesics during pregnancy.

In the context of the COVID-19 pandemic, specific recommendations are required for the management of patients with gynecologic cancer. The FRANCOGYN group of the National College of French Gynecologists and Obstetricians (CNGOF) convened to develop recommendations based on the consensus conference model. If a patient with a gynecologic cancer presents with COVID-19, surgical management should be postponed for at least 15 days. For cervical cancer, radiotherapy and concomitant radiochemotherapy could replace surgery as first-line treatment and the value of lymph node staging should be reviewed on a case-by-case basis. For advanced ovarian cancers, neoadjuvant chemotherapy should be preferred over primary cytoreduction surgery. It is legitimate not to perform hyperthermic intraperitoneal chemotherapy during the COVID-19 pandemic. For patients who are scheduled to undergo interval surgery, chemotherapy can be continued and surgery performed after 6 cycles. For patients with early stage endometrial cancer of low and intermediate preoperative ESMO risk, hysterectomy with bilateral adnexectomy combined with a sentinel lymph node procedure is recommended. Surgery can be postponed for 1-2 months in low-risk endometrial cancers (FIGO Ia stage on MRI and grade 1-2 endometrioid cancer on endometrial biopsy). For patients of high ESMO risk, the MSKCC algorithm (combining PET-CT and sentinel lymph node biopsy) should be applied to avoid pelvic and lumbar-aortic lymphadenectomy. During the COVID-19 pandemic, management of a patient with cancer should be adapted to limit the risks associated with the virus without incurring loss of chance.

Few studies have been undertaken to assess the possible effects of bisphenol A (BPA) on the reproductive hormone balance in animals or humans with often contradictory results. We investigated possible direct endocrine disruption by BPA of the fetal testes of 2 rat strains (14.5–17.5 days post-coitum) and humans (8–12 gestational weeks) and under different culture conditions. BPA concentrations of 10^-8M and 10^-5M for 72h reduced testosterone production by the Sprague-Dawley fetal rat testes, while only 10^-5M suppressed it in the Wistar strain. The suppressive effects at 10^-5M were seen as early as 24h and 48h in both strains. BPA at 10^-7-10^-5M for 72h suppressed the levels of fetal rat Leydig cell insulin-like factor 3 (INSL3). BPA exposure at 10^-8M, 10^-7M, and 10^-5M for 72h inhibited testosterone production in fetal human testes. For the lowest doses, the effects observed occurred only when no gonadotrophin was added to the culture media and were associated with a poorly preserved testicular morphology. We concluded that (i) BPA can display anti-androgenic effects both in rat and human fetal testes; (ii) it is essential to ascertain that the divergent effects of endocrine disruptors between species in vitro do not result from the culture conditions used, and/or the rodent strain selected; (iii) the optimization of each in vitro assay for a given species should be a major objective rather than the search of an hypothetical trans-species consensual model-system, as the organization of the testis is intrinsically different between mammalian species; (iv) due to the uncertainty existing on the internal exposure of the human fetal testis to BPA, and the insufficient number of epidemiological studies on the endocrine disruptive effects of BPA, caution should be taken in the extrapolation of our present results to the human reproductive health after fetal exposure to BPA.