Foetal Exposure to Phthalates and Endocrine Effects on the Leydig Cell

Abstract

This review examines the association between early life exposure to phthalates in human males and Leydig cell endocrine function. A systematic search was performed in PubMed and EMBASE, identifying 17 studies for analysis. Association scores weighted for number of phthalates and subjects were calculated for luteinizing hormone (LH), testosterone, testosterone/LH ratio and insulin-like factor 3 (INSL3). The scores ranges from full consistency of positive (score = 1), through inconsistent (score = 0), to negative/inverse (score = -1) associations. LH and early life phthalate exposure showed a statistically significant weighted phthalate association score of 0.18. Testosterone showed largely null results, whereas testosterone/LH ratio showed a negative association, both not statistically significant. A rise in LH, and decrease of testosterone/LH ratio, indicates that early life phthalate exposure results in a demand for a larger LH stimulus to produce the same amount of testosterone, and perhaps a decreased function of the Leydig cells, that manifests with the onset of high testosterone production in puberty and adulthood. A statistically non-significant decrease in INSL3 with a weighted phthalate association score of -0.29 supports this finding. An early life phthalate exposure-induced decline in Leydig cell function could possibly impact the spermatogenesis and adult male fertility.

Keywords: Leydig cells; early life exposure; luteinizing hormone; phthalates; testosterone.

FIGURE 1

Hypothalamic–pituitary–gonadal hormone axis. GnRH from the hypothalamus stimulates the anterior pituitary gland to a pulsative secretion of LH and FSH. FSH stimulates the Sertoli cell to produce inhibin, Androgen binding protein, growth‐factors, aromatase and anti‐Müllerian hormone (AMH) (during foetal time). LH stimulates the Leydig cell to produce testosterone and INSL3. The Leydig and Sertoli cells interact through testosterone, growth factors and aromatase. The system is regulated by negative feedback of testosterone on the GnRH and LH secretion and inhibin on the FSH secretion. Adapted from figures in [3, 4].

FIGURE 2

Association between phthalate exposure and hormones. Study association score and 95% CI of the statistical analysis in unadjusted analysis of LH, testosterone, testosterone/LH ratio and INSL3. The association between phthalate exposure and LH is statistically significant (i.e., error lines do not cross zero).

FIGURE 3

Association between phthalate exposure and LH. Study association score and 95% CI of unadjusted statistical analysis as well as analyses adjusted for both total number of tested parent phthalates and number of subjects (combined) or each of the weight factors (phthalates or subjects). All of the depicted associations are statistically significant (i.e., error lines do not cross zero).