Androgens and the masculinization programming window: human-rodent differences.

Richard M Sharpe

doi:10.1042/bst20200200

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.

Highlights

Reproductive disorders in newborn boys and in young men are remarkably common, are inter-related, are probably increasing in incidence [1,2] and point to increasing male/couple infertility [1,3]
If androgen exposure during the masculinization programming window (MPW) is lowered experimentally in rats, a testicular dysgenesis syndrome (TDS)-like spectrum of reproductive disorders becomes manifest at birth and/or in adulthood, the severity of the disorders being linked to the degree of androgen blockade [7] or androgen suppression in the MPW [6,8]
The findings described in rats above have prompted numerous epidemiological studies in humans, examining whether exposure to any of the ‘anti-androgenic’ chemicals during pregnancy is associated with altered anogenital distance (AGD) or occurrence of hypospadias or cryptorchidism at birth in sons

Summary

Introduction

Reproductive disorders in newborn boys (cryptorchidism, hypospadias) and in young men (low sperm count, testicular germ cell cancer) are remarkably common, are inter-related, are probably increasing in incidence [1,2] and point to increasing male/couple infertility [1,3]. AGD at birth is that of a normal male [38,39] because androgen production by the fetal testis in rodents during the MPW is paracrine-regulated and does not require a functional HP-axis [37], as detailed further below.

Results

Conclusion