Androgens and the masculinization programming window: human–rodent differences

Abstract

Human male reproductive disorders are common and may have a fetal origin — the testicular dysgenesis syndrome (TDS) hypothesis. In rats, experimentally induced TDS disorders result from disruption of fetal androgen production/action specifically in the masculinization programming window (MPW). MPW androgen action also programs longer anogenital distance (AGD) in male versus female rats; shorter male AGD is correlated with risk and severity of induced TDS disorders. AGD thus provides a lifelong, calibrated readout of MPW androgen exposure and predicts likelihood of reproductive dysfunction. Pregnant rat exposure to environmental chemicals, notably certain phthalates (e.g. diethyl hexl phthalate, DEHP; dibutyl phthalate, DBP), pesticides or paracetamol, can reduce fetal testis testosterone and AGD and induce TDS disorders, provided exposure includes the MPW. In humans, AGD is longer in males than females and the presumptive MPW is 8–14 weeks’ gestation. Some, but not all, epidemiological studies of maternal DEHP (or pesticides) exposure reported shorter AGD in sons, but this occurred at DEHP exposure levels several thousand-fold lower than are effective in rats. In fetal human testis culture/xenografts, DEHP/DBP do not reduce testosterone production, whereas therapeutic paracetamol exposure does. In humans, androgen production in the MPW is controlled differently (human chorionic gonadotrophin-driven) than in rats (paracrine controlled), and other organs (placenta, liver, adrenals) contribute to MPW androgens, essential for normal masculinization, via the ‘backdoor pathway’. Consequently, early placental dysfunction, which is affected by maternal lifestyle and diet, and maternal painkiller use, may be more important than environmental chemical exposures in the origin of TDS in humans.