Clinical relevance of animal models for the study of androgen actions

A comprehensive set of data is available to indicate that the cynomolgus monkey model is highly representative for preclinical studies on the endocrine regulation of spermatogenesis. Unlike the rhesus monkey, bonnet monkey or Japanese macaque, this nonhuman primate species does not show annual variations of testicular activity. A series of experimental studies is available and has been reviewed above. The findings obtained clearly prove that the data collected in the cynomolgus monkey on the LH/testosterone and FSH regulation of spermatogenesis are fully representative for what would be seen in man. This relationship holds even true for quantitative aspects of spermatogenesis. Hence, at present, the cynomolgus monkey is recommended as preclinical model for the study of the relationship between testosterone and other reproductive hormones and human spermatogenesis.

The rat model provides an interesting feature regarding the effects of selective testosterone replacement. In the gonadotropin-suppressed rat testosterone paradoxically stimulates the levels of FSH. Studies showed that testosterone maintains and restores the levels of immunoactive and bioactive FSH by direct action on pituitary FSH expression and also release. This is in sharp contrast to gonadotropin-suppressed nonhuman primates and men, in whom testosterone does not alter FSH secretion at all. Hence the rat model has only limited suitability for studying the relative roles of LH/testosterone and FSH for spermatogenesis.

Targeted disruption of FSH or the FSH receptor was initially thought not to interfere with spermatogenesis in mice (Kumar et al. 1997). Whether this really indicates that FSH is dispensable for mouse spermatogenesis remains to be seen. This view is derived from the fact that FSH receptor is only expressed in Sertoli cells and, hence, such specific expression pattern would imply a physiological role. More recently, it has become clear that FSH action is also important for spermatogenesis in the mouse (Huhtaniemi 2000; Sairam and Krishnamurthy 2001, and discussion above).

Another interesting exception to the endocrine control of primate spermato-genesis is provided by the seasonal control of reproduction in the Djungarian hamster. This species is a short-day breed undergoing testicular involution when the LD light regimen is shifted from 16:8 to 8:16. In this species administration of LH to animals with regressed testes is unable to restore spermatogenesis, whereas FSH reinitiates the entire process including the production of fertile sperm (Lerchl et al. 1993; Niklowitz et al. 1997). It is not entirely clear whether this separation of LH and FSH sensitivity of the involuted testis is confined to this hamster species or applies more generally to seasonally breeding mammals. In the prairie dog (Cynomys ludovicanus) also FSH but not LH/testosterone induced germ cell activation when administered during the seasonal involution phase (Foreman 1998). Interestingly, in the seasonal bonnet monkey, merely blocking the nocturnal peak of testosterone secretion is sufficient to inhibit spermatogenesis, implying a surprising dependence of adult spermatogenesis on diurnal testosterone in a primate. In general, however, usingseasonal experimental species as models for the endocrine control of human spermatogenesis does not seem advisable in view of the fact that a highly relevant non-seasonal primate model (cynomolgus monkey) is available.

An alternative route of stimulating testosterone production from Leydig cells has apparently developed in the common marmoset (Callithrix jacchus). In the intact and normal marmoset, LH receptor exon 10, although genomically present, is not expressed (Zhang etal. 1997). For the human LH receptor, this exon is necessary for the expression of receptor protein (Zhang etal. 1998). Interestingly, a clinical case lacking LH receptor exon 10 has been described (Gromoll etal. 2000). This boy had developed a male phenotype but presented with retarded pubertal development, small testes and delayed bone maturation, all indicative of androgen deficiency. Given the similarity to marmoset LH receptor status, this patient was successfully treated with hCG, indicating that exon 10 is involved in differential LH/hCG recognition. More recently it was found that marmoset pituitary expresses hCG (Gromoll et al. 2003) raising the possibility that marmoset Leydig cells are driven by hCG rather than LH. It would be interesting to know the dependence of marmoset spermatogenesis on intratesticular testosterone. In any case, it is obvious that the control of Leydig cell function and testosterone production by LH is entirely different in humans and marmosets. Equally interesting, lack of LH receptor exon 10 expression was also found in Cebidae and other Callithrichidae, raising the question whether this particular LH receptor type II could be predominant in neotropical primate species.

5.10 Key messages

• Testosterone is able to qualitatively initiate, maintain and re-initiate spermatogenesis and formation of spermatozoa.

• FSH is able to qualitatively initiate, maintain and re-initiate spermatogenesis and formation of spermatozoa.

• Under physiological circumstances, only the combination of testosterone and FSH yields quantitatively normal germ cell numbers.

• Adult primate spermatogenesis is probably more dependant on FSH than on testosterone.

• Testosterone acts indirectly via somatic testicular cells on spermatogenesis. Whether ABP or non-genomic actions mediate direct testosterone effects on germ cells is unclear.

• The testicular effects of testosterone are mediated via DHT and estradiol. Whether estradiol is essential for spermatogenesis is still unclear.

• Testosterone and FSH cooperate during regulation of spermatogenesis but act via different mechanisms.

• Macaques currently represent the most appropriate preclinical model for the study of the role of testosterone in spermatogenesis.

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