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.

A Systematic Review of Anogenital Distance and Gynecological Disorders: Endometriosis and Polycystic Ovary Syndrome

“…Accordingly, the testosterone level was positively associated with AGD in adult women in the included studies conducted by Wu et al, though this was not confirmed by the included study conducted by Peters et al and the Spanish study group (21,24,26). AGD may be affected not only by intrauterine androgen exposure but also by postnatal hormones, i.e., prenatal androgen exposure may initially dictate the AGD, but postnatal androgen exposure may be required for AGD to grow to the preplanned size (46).…”

Maternal Exposure to Airborne Polychlorinated Biphenyls (PCBs) and Risk of Adverse Birth Outcomes

“…We observed an increased risk of cryptorchidism for exposed pregnancies, which could be due to the hypothesized estrogenic and anti-androgenic activity of LC-PCBs during the 'male programming window' in the rst trimester [59].…”

Men born small for gestational age or with low birth weight do not improve their rate of reproduction over time: a Swedish population-based study

“…Phthalates (33) and bisphenols (34) have been intensively investigated as potential causes of TDS, which has led to their banning by the European Union. However, much of the experimental evidence is on the basis of rodent studies and has been strongly questioned (35), and human studies have had divergent results (36,37). We cannot link the men in the cohorts we studied to any particular environmental exposure, but surely exposure to EDCs was present, to varying degrees, for the entire period of the study.…”