In utero exposure to synthetic sex hormones and their multigenerational impact on neurodevelopmental disorders: Endocrine disruptors as neuroendocrine disruptors.

BACKGROUND: Synthetic sex hormones, estrogens and/or progestogens, have been widely administered without sufficient long-term studies for decades to millions of pregnant women around the world and although most were banned in the 1970s and 1980s, some progestins continue to be prescribed. Psychiatric disorders, including psychoses such as schizophrenia, bipolar disorders, or severe depression, anxiety, eating disorders, as well as ASD (autism spectrum disorders), accompanied or not by co-morbidities, have been described in children exposed in utero.

AIM: In this review, we have gathered the main works concerning the harmful effects of these synthetic sex hormones on human health and especially on neurodevelopment so that they are recognized, both for the purpose of teaching medical careers and prescribers and as a precaution for the general population and future generations.

METHODS: A review of the literature was carried out by searching the PubMed and Google Scholar databases for the period from 2000 to 2024 following the PRISMA guidelines. Studies were identified using the following keywords: diethylstilbestrol, 17-α-ethinylestradiol, progestins, psychosis and endocrine disrupting compounds, estrogens and epigenetics, multigenerational effects.

RESULTS: The epigenetic nature of such disorders was demonstrated in 2017 to be linked to hypermethylation of the ZFP57 and ADAMTS9 genes that play an important role in neurodevelopment. The ensuing (third) generation of grandchildren is also impacted both on neurodevelopmental and somatic levels, revealing in particular either cognitive disorders as attention deficit hyperactivity disorders (ADHD), psychiatric disorders (bipolarity) or autism spectrum disorders, Asperger's or not. Long-term effects on the fourth generation remain largely unknown due to their young age: however, cognitive disorders (Dyspraxia) and ASD in an adolescent, as well as the warning signs of endometriosis in another adolescent have been described.

CONCLUSIONS: The multi- and transgenerational effects of these endocrine disruptors have been observed both at the neuropsychological and somatic level and the evidence strongly supports the negative impact of these endocrine disruptors on subsequent generations.