The Relationship Between Anogenital Distance and Reproductive Hormone Levels in Adult Men

Eisenberg, Michael L.; Jensen, Tina Kold; Walters, R. Chanc; Skakkebæk, Niels E.; Lipshultz, Larry I.

doi:10.1016/j.juro.2011.10.041

Cited by 121 publications

(108 citation statements)

References 21 publications

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“…Our finding that fetal deficits in androgen action can result in compromised adult Leydig cell function in rodents fits with emerging evidence from humans (14,16). There is a similar connection between reduced fetal androgens and reduced adult sperm counts/sperm production in men and rats (15,16).…”

Section: -Hsd3supporting

confidence: 87%

“…There is also evidence from human (13,14) and animal experimental (15) studies that fetal programming can influence adult testosterone levels, particularly that reduced fetal androgen exposure leads to lower adult male testosterone levels (14,15). This data fits with growing evidence that subtle deficiency in fetal androgens is a major determinant of adult male reproductive disorders, such as low sperm production (16,17), and might explain why low sperm counts are often associated with compensated Leydig cell failure in men (18).…”

supporting

confidence: 67%

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Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Kilcoyne

Smith

Atanassova

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

160

135

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Fetal growth plays a role in programming of adult cardiometabolic disorders, which in men, are associated with lowered testosterone levels. Fetal growth and fetal androgen exposure can also predetermine testosterone levels in men, although how is unknown, because the adult Leydig cells (ALCs) that produce testosterone do not differentiate until puberty. To explain this conundrum, we hypothesized that stem cells for ALCs must be present in the fetal testis and might be susceptible to programming by fetal androgen exposure during masculinization. To address this hypothesis, we used ALC ablation/regeneration to identify that, in rats, ALCs derive from stem/progenitor cells that express chicken ovalbumin upstream promoter transcription factor II. These stem cells are abundant in the fetal testis of humans and rodents, and lineage tracing in mice shows that they develop into ALCs. The stem cells also express androgen receptors (ARs). Reduction in fetal androgen action through AR KO in mice or dibutyl phthalate (DBP) -induced reduction in intratesticular testosterone in rats reduced ALC stem cell number by ∼40% at birth to adulthood and induced compensated ALC failure (low/normal testosterone and elevated luteinizing hormone). In DBP-exposed males, this failure was probably explained by reduced testicular steroidogenic acute regulatory protein expression, which is associated with increased histone methylation (H3K27me3) in the proximal promoter. Accordingly, ALCs and ALC stem cells immunoexpressed increased H3K27me3, a change that was also evident in ALC stem cells in fetal testes. These studies highlight how a key component of male reproductive development can fundamentally reprogram adult hormone production (through an epigenetic change), which might affect lifetime disease risk.adult Leydig stem/progenitor cells | compensated Leydig cell failure | GATA4 | ethane dimethane sulfonate

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Section: -Hsd3supporting

confidence: 87%

supporting

confidence: 67%

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Kilcoyne

Smith

Atanassova

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

160

135

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“…In humans, recent studies have reported shorter AGD in boys with hypospadias or cryptorchidism as compared with boys with normal genitalia (Hsieh et al 2008), and decreased AGD in adult men has been correlated to changes in semen parameters and decreased testosterone level (Eisenberg et al 2011, 2012a, 2012b, Mendiola et al 2011. The reproductive effects of prenatal BPA exposure in humans was evaluated by Miao et al (2011), who compared AGD in sons of workers who had or had not been occupationally exposed to BPA during pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Low-dose effects of bisphenol A on early sexual development in male and female rats

Christiansen¹,

Axelstad²,

Boberg³

et al. 2014

Reproduction

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Bisphenol A (BPA) is widely detected in human urine and blood. BPA has been reported to impair many endpoints for reproductive and neurological development; however, it is controversial whether BPA has effects in the microgram per kilogram dose range. The aim of the current study was to examine the influence of BPA on early sexual development in male and female rats at dose levels covering both regulatory no observed adverse effect levels (NOAELs) (5 and 50 mg/kg bw per day) as well as doses in the microgram per kilogram dose range (0.025 and 0.25 mg/kg bw per day). Time-mated Wistar rats (nZ22) were gavaged during pregnancy and lactation from gestation day 7 to pup day 22 with 0, 0.025, 0.25, 5 or 50 mg/kg bw per day BPA. From 0.250 mg/kg and above, male anogenital distance (AGD) was significantly decreased, whereas decreased female AGD was seen from 0.025 mg/kg bw per day and above. Moreover, the incidence of nipple retention in males appeared to increase dose relatedly and the increase was statistically significant at 50 mg/kg per day. No significant changes in reproductive organ weights in the 16-day-old males and females and no signs of maternal toxicity were seen. The decreased AGD at birth in both sexes indicates effects on prenatal sexual development and provides new evidence of low-dose adverse effects of BPA in rats in the microgram per kilogram dose range. The NOAEL in this study is clearly below 5 mg/kg for BPA, which is used as the basis for establishment of the current tolerable daily intake (TDI) by EFSA; thus a reconsideration of the current TDI of BPA appears warranted.

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“…Hence, AGD could be measured at any postnatal age in rats and used to retrospectively decipher the level of fetal androgen exposure during the MPW (11,21). In human males, AGD shows similar male-female differences as in rats (11,(24)(25)(26), and lower AGD has been related to the occurrence of TDS disorders evident at birth (27)(28)(29)(30)(31)(32)(33) and, in a majority of studies, to lower sperm counts (34)(35)(36)(37) and hormone levels (38,39) in adult men, similar to rats (reviewed in ref. 11).…”

Section: Introductionmentioning

confidence: 99%

Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window

Driesche¹,

Kilcoyne²,

Wagner³

et al. 2017

JCI Insight

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The Relationship Between Anogenital Distance and Reproductive Hormone Levels in Adult Men

Abstract: Anogenital distance may provide a novel metric to assess testicular function in men. Assuming that anogenital distance at birth predicts adult anogenital distance, our findings suggest a fetal origin for adult testicular function.

Cited by 121 publications

References 21 publications

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Low-dose effects of bisphenol A on early sexual development in male and female rats

Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window

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