Conclusions

A role for the endogenous cannabinoid system in several aspects of human (patho)physiology has been proposed through the activation of cannabinoid and vanilloid receptors, and/or via nonreceptor-mediated actions. In the case of AEA, the role of FAAH in controlling its cellular activity seems more critical than that of NAT, NAPE-PLD, or EMT. Here, the activity of FSH, the biological relevance of Sertoli cells, and the main features of the ECS have been briefly described, to put in a better perspective the relevance of FAAH regulation by FSH for male reproduction. In particular, it is suggested that FAAH controls hormone level of AEA, by acting as a molecular integrator of fertility signals. In this context, since low FAAH levels in peripheral lymphocytes (Maccarrone ei a/., 2000), and hence high levels of AEA in blood of pregnant women (Habayeb ei a/., 2008), correlate with pregnancy failure, it can be suggested that FAAH is a critical "sensor" of reproductive abnormalities also on the female side of human gestation. Therefore, it can be proposed that substances able to enhance FAAH activity might become useful therapeutic tools for the treatment of human infertility. As yet, FSH is the only hormone known to upregulate FAAH. Two other natural compounds, like an as-yet elusive lipid substance released from mouse blastocysts (Maccarrone ei a/., 2004), and the Cannabis component cannabidiol (Massi ei a/., 2008), are known to behave as FAAH activators, whereas synthetic compounds with this activity are not available. This calls for attention to "the other side of the medal,'' because in the last few years most investigators have put efforts on the synthesis of inhibitors, rather than activators, of FAAH as novel therapeutic agents for the treatment of pain, neurodegenerative disorders, cancer, and anxiety (Di Marzo, 2008). If not as therapeutics per se, FAAH activators could be used together with other drugs to lower the doses or to shorten the treatment necessary in two to observe an effect, and hence minimize the possible side effects of substances used to treat infertility. On a final note, it should be recalled that any future development of selective FAAH modulators as therapeutics must take into account that:

(i) FAAH regulates the levels of several endogenous endocannabinoid (-like) compounds, whose functions are not yet understood. This leaves open the question of the biological consequences of their reduced/ increased degradation upon treatment with FAAH activators/inhibitors.

(ii) Other enzymes have been recently identified that catalyze the synthesis (Simon and Cravatt, 2008) and hydrolysis of AEA (Wei ei a/., 2006), and the synthesis and hydrolysis of 2-AG (Ligresti ei a/., 2005). It remains to be elucidated how these pathways may contribute to the overall endocannabinoid tone.

(iii) Therapeutic benefits derived from curbing a hyperactive ECS could be obtained by developing not only FAAH activators, but also inhibitors of endocannabinoid biosynthesis, or selective CBR antagonists.

In conclusion, we have reviewed the evidence that FAAH is a distinct target of FSH within the ECS. Of particular interest seems the fact that FSH activates FAAH, both through phosphorylation of accessory proteins and through binding of estrogen to an ERE site in the faah promoter. This is noteworthy, because only a few compounds are known to activate FAAH; it can be anticipated that these substances, like the widely studied FAAH inhibitors, might become useful therapeutics for the treatment of human diseases caused by a high endocannabinoid tone.

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