Understanding the role of thyroid hormone in Sertoli cell development: a mechanistic hypothesis

Abstract

More than a decade of research has shown that Sertoli cell proliferation is regulated by thyroid hormone. Neonatal hypothyroidism lengthens the period of Sertoli cell proliferation, leading to increases in Sertoli cell number, testis weight, and daily sperm production (DSP) when euthyroidism is re-established. In contrast, the neonatal Sertoli cell proliferative period is shortened under hyperthyroid conditions, but the mechanism by which thyroid hormone is able to negatively regulate Sertoli cell proliferation has been unclear. Recent progress in the understanding of the cell cycle has provided the opportunity to dissect the molecular targets responsible for thyroid-hormone-mediated effects on Sertoli cell proliferation. In this review, we discuss recent results indicating a critical role for the cyclin-dependent kinase inhibitors (CDKI) p27(Kip1) and p21(Cip1) in establishing Sertoli cell number, testis weight, and DSP, and the ability of thyroid hormone to modulate these CDKIs. Based on these recent results, we propose a working hypothesis for the way in which thyroid hormone regulates the withdrawal of the cell cycle by controlling CDKI degradation. Finally, although Sertoli cells have been shown to have two biologically active thyroid hormone receptor (TR) isoforms, TRalpha1 and TRbeta1, experiments with transgenic mice lacking TRalpha or TRbeta illustrate that only one TR mediates thyroid hormone effects in neonatal Sertoli cells. Although significant gaps in our knowledge still remain, advances have been made toward appreciation of the molecular sequence of events that occur when thyroid hormone stimulates Sertoli cell maturation.

Mono-butyl phthalate-induced mouse testis injury is associated with oxidative stress and down-regulated expression of <i>Sox9</i> and <i>Dazl </i>

“…Sertoli cell number in the testis establishes the upper limit of sperm production because Sertoli cells support a relatively fixed number of germ cells. Thus, Sertoli cell alterations lead to a progressive degeneration of spermatogenic cells which ultimately slough off into the tubular lumen (Holsberger and Cooke, 2005). Sertoli cell number is the ultimate determinant of sperm-producing capacity, and therefore of sperm count in man, in adulthood (Hess and Renato de Franca, 2008).…”

Type 2 iodothyronine deiodinase is highly expressed in germ cells of adult rat testis

“…Furthermore, as recently reported in the rdw rats with congenital hypothyroidism, thyroid hormone seems to be important for the maintenance of testicular structure after full maturation (Sakai et al 2004). Although thyroid hormones are the best described modulators of the developing testis, their role in the adult organ is still undefined (Holsberger & Cooke 2005). A critical development in this field was the finding that TRs are also present, at a low but significant level, in rat and human adult testis (Buzzard et al 2000, Jannini et al 2000, indicating that T 3 may have a direct effect on the adult organ.…”

“…Thyroid hormones play an important role in rat testicular development, especially on differentiation of Sertoli cells and spermatogenesis in the pre-pubertal stage (Holsberger & Cooke 2005). Experimentally induced neonatal hypothyroidism has been shown to lengthen the proliferative period of Sertoli cells, resulting in a significant increase in adult testis size and sperm production (Hess et al 1993).…”

Cell‐specific ablation in the testis: what have we learned?

“…This suggests that germ cells play little role in the architecture of the developing testis. Indeed W/W v mice, which lack germ cells, have been used to demonstrate that germ cells play no role in the increase in Sertoli cell numbers observed in cases of hypothyroidism (Saxena et al ., 2002), strongly suggesting that hypothyroidism acts through a direct effect on Sertoli cells [reviewed in (Holsberger & Cooke, 2005)]. This apparent lack of impact on testicular architecture is also observed if germ cells are ablated in adulthood (Fig.…”