Gylli Mola, Monica Kam Draskau, Anne Jørgensen, Frédéric Chalmel, Cecilie Melau, Bertrand Evrard, Karen Mandrup, Hanne Hegaard, Trine Koch Hueg, Hanne Frederiksen, Christa E Flueck, Anna‐Maria Andersson, Anders Juul, Kristian Almstrup, Margit Bistrup Fischer, Terje Svingen, Casper P. Hagen
Exposure to endocrine-disrupting chemicals (EDCs) during fetal life is associated with reproductive disorders in humans. While research has largely focused on environmental EDCs and developmental exposure, some pharmaceuticals, including commonly used antifungal agents, also possess endocrine-disrupting properties. We investigate whether prenatal exposure to over-the-counter antifungal drugs is associated with altered fetal and postnatal steroidogenesis and reproductive development. We combined epidemiological, experimental, and translational approaches using data from a prospective mother-child cohort (n = 589), ex vivo human fetal adrenal cultures, and in vivo rat models. Maternal antifungal use during pregnancy was assessed prospectively, and associations with fetal growth, anogenital distance (AGD), penile measurements, and circulating steroid hormone levels during infancy were evaluated. Experimental studies examined the effects of selected antifungal agents on steroidogenesis in cultured human fetal adrenals and gestationally exposed Sprague-Dawley rats. Early-pregnancy antifungal exposure is associated with reduced circulating steroid hormone levels and indicators of diminished androgen action, including decreased penile width at infancy. In contrast, exposure during mid-to-late pregnancy is associated with elevated steroid hormone levels and longer AGD in both female fetuses and male infants. Consistent with these observations, the antifungal agent clotrimazole reduces progesterone levels in human fetal adrenal cultures and in gestationally exposed rats, whereas miconazole increases AGD in rats. These translational findings suggest that commonly used antifungal agents alter fetal adrenal steroidogenesis and influence reproductive development, with effects persisting into postnatal life. Given their widespread use and over-the-counter availability, the safety of topical azole use during pregnancy may warrant re-evaluation. Prenatal exposure to some chemicals can affect reproductive development before birth. While most research has focused on environmental chemicals, certain medicines may also influence hormone production. We investigated whether antifungal medications used during pregnancy affect fetal hormone levels and reproductive development. We combined data from a mother-child cohort with laboratory studies using human fetal tissue and animal models. We examined associations between antifungal exposure, hormone levels, anogenital distance (AGD), and genital development in infants. Early-pregnancy exposure was associated with lower steroid hormone levels and reduced androgen-related development in boys, while later exposure was associated with higher hormone levels and longer AGD. Experimental studies supported these findings. These results suggest that commonly used antifungal medications may influence fetal development and warrant further safety evaluation during pregnancy. Mola, Draskau, et al. investigate whether prenatal exposure to commonly used antifungal medications affects fetal hormone production and reproductive development. Antifungal exposure is associated with altered steroid hormone levels and changes in reproductive development in both humans and experimental models.