3. Umbruch 4.4..2005 - Online Pot

68 M. Maccarrone
it appears to accelerate trophoblast differentiation [3]. On the other hand, only
CB 1 mRNA is present in the mouse uterus [3]. In the context of CB receptor
modulation a recent study has shown a role for progesterone receptor in
∆ 9 -THC modulation of female sexual receptivity [7], further demonstrating
that dysregulation of cannabinoid signalling disrupts uterine receptivity for
embryo implantation [8]. Also, sea urchin (Strongylocentrotus purpuratus)
sperm has been shown to have a CB receptor, and binding of AEA to this receptor
reduces sperm-fertilizing capacity, by inhibiting the egg jelly-stimulated
acrosome reaction [9, 10]. This observation has been recently extended to
humans [11], and the implications for male fertility will be discussed later in
this review. The biological activity of AEA via CB 1 and CB 2 receptors depends
on its concentration in the extracellular space, which is controlled by its synthesis
through a specific phospholipase D (PLD), by its cellular uptake through
a specific AEA membrane transporter (AMT) and by its intracellular degradation
by the enzyme fatty acid amide hydrolase (FAAH) [12]. Among these proteins,
which together with AEA and congeners form the endocannabinoid system,
FAAH has emerged as a pivotal check-point in several human diseases
(for comprehensive reviews see [13–17]). Evidence in favour of its critical role
in mammalian fertility will be discussed in the following sections.
Endocannabinoid degradation during pregnancy
FAAH activity has been demonstrated in mouse uterus [18], and the level of
its mRNA has been shown to change during the peri-implantation period, in
both mouse uterus and embryos [19]. FAAH localizes in the endometrial
epithelium [20], where its activity and expression decrease during early pregnancy,
due to a lower expression of the same gene rather than to FAAH
isozymes with different kinetic properties [20].
Despite the growing evidence that AEA adversely affects uterine receptivity
and embryo implantation (reviewed in [3, 4]) and that AEA degradation by
FAAH may have physiological significance in these processes [18–20], the
regulation of FAAH during early pregnancy is still obscure. Recently, we
observed down-regulation of FAAH expression in pseudopregnant mice, and a
fall of FAAH activity and expression from day 0 to day 5.5 of gestation [20].
We also reported that this fall was smaller in ovariectomized animals and larger
in the same animals treated with estrogen, compared to controls [20]. These
findings suggest that sex hormones might regulate FAAH activity by modulating
gene expression at the translational level. The results of the treatment of
virgin females with progesterone or estrogen, showing a similar down-regulation
of FAAH compared to controls, strengthened this hypothesis. Therefore,
it can be concluded that in mouse uterus sex hormones down-regulate FAAH
activity by reducing gene expression at the level of protein synthesis.
Interestingly, an AEA synthase activity was also measured in mouse uterus,
and was found to respond to sex hormones in the same way as FAAH [20].