Adaptation of Leydig cells

Most of the initial effects of LH or hCG on steroid production are stimulatory, as can be seen from the rapid increase of the testosterone concentration in plasma. In rats this response is much faster and more pronounced than in man (Huhtaniemi et al. 1983; Saez 1989). Although studies with isolated cells from human testis have shown that a small proportion of the human cells can respond more or less similarly to those in rats, it is unknown why the magnitude of the steroido-genic response of the intact human testis in vivo is small (Simpson etal. 1987). In both species the period of stimulated steroid production after hCG administration in vivo is followed by a period of diminished output of testosterone. This transient steroidogenic desensitization is the result of four different phenomena:

1) the coupling between the LH receptors and the adenylate cyclase is diminished, probably as a result of receptor phosphorylation or direct binding of arrestin (Hunzicker-Dunn etal. 2002);

2) the number of LH receptors is also decreased owing to an increased rate of receptor internalisation;

3) at the same time the mRNA level for the LH receptors has also decreased owing to a higher turnover of this mRNA pool;

4) the activities of the steroidogenic activities in the endoplasmic reticulum are lower.

In different species these LH-induced adaptive responses do not always occur to the same extent. This drop in androgen production, which occurs in rats 24-36 h after hCG administration, is accompanied by a rise in the secretion of 17aOH-progesterone, indicating a partial block at the level of C17-20-lyase activity. In the same period the production of 17^-estradiol increases. Estrogens have therefore been implicated as a causal factor in the development of steroidogenic lesions (Saez 1989). But other mechanisms are possible (Brinkmann et al. 1982). Following a period of diminished androgen production, plasma testosterone levels rise over the next period of 3-4 days, whereas 17a-hydroxyprogesterone levels diminish. This biphasic response of steroid production depends on the stage of development of the Leydig cells. In prepubertal children and in hypogonadal adult men, one injection of hCG induces a sustained rise in testosterone without significant changes in 17a-hydroxyprogesterone and 176-estradiol plasma levels. After long-term treatment with hCG, an adult pattern of response is observed in both groups (reviewed by Forest 1989). It therefore appears that the long-term steroidogenic response of Leydig cells depends on previous exposure to gonadotropins. After exposure of rat Leydig cells to high doses of gonadotropins, the degree of stimulation of adenylyl cyclase is greatly diminished within several hours, and after 24 h the number of LH receptors is diminished (Saez 1989). These phenomena have been described as desensitization and receptor down regulation, respectively, and they have often been used to explain the decreased production of androgens that develops after initial stimulation. However, as mentioned earlier, Leydig cells are still active in the production of steroids other than androgens. Moreover, the regulation of steroidogenic activities is complex and not all changes in cellular activities are synchronized in time. For instance, in Leydig cells from mature rats isolated 10 days after injections of hCG (administered at day 0 and day 7), LH receptors were down regulated and adenylate cyclase desensitized. However, LH-dependent androgen production was increased (Calvo et al. 1984). Similarly, in the period of low receptor number and reduced cyclic AMP response, LH-dependent prostaglandin production in the rat testis is very high (Haour et al. 1979) and Leydig cells show hypertrophy (Hodgson and de Kretser 1984). High doses of hCG that cause desensitisation of steroid production stimulate proliferation of Leydig cells (Teerds etal. 1988). Thus rodent Leydig cells do not always show a diminished responsiveness after exposure to gonadotropins. Especially when LH is released in a pulsatile fashion it is difficult to predict how the cells respond. In mice Leydig cells do not show any sign of desensitisation after exposure to a chaotic pattern of LH pulses (Coquelin and Desjardins 1982), whereas in rats the response depends on the profile of LH administration (Hakola etal. 1998). The steroidogenic response also depends on the age of the animal. Foetal Leydig cells do not show the desensitisation phenomena as described for mature animals (Huhtaniemi 1996). On the other hand, in Leydig cells from aged animals the initial signal transduction after LH stimulation appears to be diminished. These cells can produce normal amounts of androgens when stimulated at the level of cAMP (Chen etal. 2002). Long-term suppression of steroid production ("steroidogenic hibernation") may reduce this age-related decline in sensitivity to steroid production (Chen and Zirkin 1999).

Leydig cells can therefore adapt their activities to changes in the environment such as exposure to hCG. Depending on the species, developmental stage, the function of interest and the time interval after exposure to the gonadotropin, this adaptive process includes inhibitory changes (desensitisation), but also stimulatory actions.

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