The cannabinoid system and male reproductive functions. Acrosome Reaction/ drug effects; Acrosome Reaction/physiology; Animals; Cannabinoid Receptor. First evidence of an effect of cannabinoid in male reproduction comes . In this mini-review we highlighted the physiological role of ECS and its. One specific area of concern is the effect of marijuana on the male It must therefore play a role in a number of physiological processes and.
of male physiology Role cannabinoids in
This involves direct binding of ER to the ERE sites in the faah promoter and the induction of epigenetic modifications in order to confer transcriptional competence. The presence of histone demethylase LSD1, which is recruited at this site, ensures estrogens stimulation of faah transcription.
LSD1 could interact with ligand-bound ER or with other different partners and activate gene transcription. The pro-survival role of E 2 in Sertoli cells has a clear impact on spermatogenesis. In fact regulation of Sertoli cell apoptosis could be important to maintain their population size, and consequently, to sustain a normal spermatogenic output.
The final outcome is an increase AEA-induced apoptosis of Sertoli cells. This is not the only example about the cross-talks between estrogens and ECS in the testis. Recent evidences reveal that estrogens affect spermiogenesis and regulate chromatin remodeling of germ cells Indeed, in mice, genetic loss of CB 1 receptor causes a reduction in FSH and estrogen plasma levels and alteration in spermatid differentiation due to an inefficient histone displacement in the sperm.
Estrogens treatment is able to rescue histone displacement suggesting a role in preserving chromatin condensation in spermatozoa. In this mini-review we highlighted the physiological role of ECS and its interplay with sex hormones, in male reproduction. Interfering with this system by exposure to exogenous cannabinoids, may alter the physiological function of ECS in male reproduction thus affecting male fertility.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. National Center for Biotechnology Information , U. Journal List Front Endocrinol Lausanne v. Published online Dec Prepublished online Nov Author information Article notes Copyright and License information Disclaimer. This article was submitted to Experimental Endocrinology, a section of the journal Frontiers in Endocrinology.
Received Nov 4; Accepted Nov The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms. This article has been cited by other articles in PMC. Abstract Spermatogenesis is a complex process in which male germ cells undergo a mitotic phase followed by meiosis and by a morphogenetic process to form mature spermatozoa. Spermatogenesis Spermatogenesis is a complex differentiative process starting from spermatogonial stem cells SSCs , known as A-single A s. The Endocannabinoid System and Spermatogenesis ECS and germ cells Following the discovery of ECS, many studies about its expression and function in male reproductive system have been carried out Open in a separate window.
ECS and testicular somatic cells Endocannabinoid system components are expressed also in somatic cells of mammalian testis. The Endocannabinoid System and Sex Hormone As described above, the ECS is widely distributed in testicular cells and it is an important regulator of spermatogenesis and sperm functions.
Concluding Remarks In this mini-review we highlighted the physiological role of ECS and its interplay with sex hormones, in male reproduction. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments This work was supported by grants from Agenzia Spaziale Italiana. Association of marijuana use and the incidence of testicular germ cell tumors.
Cancer 6: Proliferation and differentiation of spermatogonial stem cells. Evidence from Sertoli cell-depleted rats indicates that spermatid number in adults depends on numbers of Sertoli cells produced during perinatal development.
Endocrinology 3: Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. J Cell Sci Dev Biol Signaling through extracellular signal-regulated kinase is required for spermatogonial proliferative response to stem cell factor. J Biol Chem The biology of infertility: Nat Med 14 Trends Neurosci International Union of Pharmacology.
Classification of cannabinoid receptors. Pharmacol Rev 54 2: Identification and functional characterization of brainstem cannabinoid CB 2 receptors. Molecular characterization of a phospholipase D generating anandamide and its congeners. M [ PubMed ] [ CrossRef ]. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain.
J Cell Biol 3: Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science Beltramo M, Piomelli D. Carrier-mediated transport and enzymatic hydrolysis of the endogenous cannabinoid 2-arachidonylglycerol. Neuroreport 11 6: A catalytically silent FAAH-1 variant drives anandamide transport in neurons. Nat Neurosci 15 1: Structure and function of fatty acid amide hydrolase. Annu Rev Biochem Brain monoglyceride lipase participating in endocannabinoid inactivation.
Endocannabinoids as regulators of transient receptor potential TRP channels: Curr Med Chem Endocr Rev 27 5: Cannabinoids reduce fertility of sea urchin sperm. Biochem Cell Biol 65 2: Reduction of the fertilizing capacity of sea urchin sperm by cannabinoids derived from marihuana. Inhibition of the acrosome reaction induced by egg jelly. Mol Reprod Dev 29 1: Anandamide arachidonylethanolamide , a brain cannabinoid receptor agonist, reduces sperm fertilizing capacity in sea urchins by inhibiting the acrosome reaction.
N-acylethanolamines in human reproductive fluids. Chem Phys Lipids Endocannabinoid system in frog and rodent testis: Biol Reprod 75 A gradient of 2-arachidonoylglycerol regulates mouse epididymal sperm cell start-up. Biol Reprod 82 2: Human sperm express cannabinoid receptor CNR1, the activation of which inhibits motility, acrosome reaction and mitochondrial function.
J Clin Endocrinol Metab Characterization of the endocannabinoid system in boar spermatozoa and implications for sperm capacitation and acrosome reaction. Cannabinoid receptor 1 influences chromatin remodeling in mouse spermatids by affecting content of transition protein 2 mRNA and histone displacement.
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Int J Androl 35 5: The activity of anandamide at vanilloid VR1 receptors requires facilitated transport across the cell membrane and is limited by intracellular metabolism. The endocannabinoid system and pivotal role of the CB 2 receptor in mouse spermatogenesis. PLoS One 6 2: Characterization of the endocannabinoid system in human spermatozoa and involvement of transient receptor potential vanilloid 1 receptor in their fertilizing ability.
Fatty acid amide hydrolase deficiency limits early pregnancy events. J Clin Invest 8: Effect of capacitation on the endocannabinoid system of mouse sperm. Mol Cell Endocrinol 1—2: Differences in the endocannabinoid system of sperm from fertile and infertile men. PLoS One 7 Anandamide modulates human sperm motility: Hum Reprod 28 8: Anandamide activity and degradation are regulated by early postnatal aging and follicle-stimulating hormone in mouse Sertoli cells.
Follicle-stimulating hormone activates fatty acid amide hydrolase by protein kinase A and aromatase-dependent pathways in mouse primary Sertoli cells. Modulation of the endocannabinoid-degrading enzyme fatty acid amide hydrolase by follicle-stimulating hormone. Vitam Horm Similar expression studies were also performed using dormant and estrogen-activated blastocysts.
The results showed that normal blastocysts collected in the early morning of d 4 have higher levels of AEA binding, but this binding remarkably declines in blastocysts recovered on d 4 in late afternoon before the attachment reaction These observations suggest that down-regulation of AEA binding to the blastocyst is important for achieving implantation competence. Similarly, dormant blastocysts also show increased levels of AEA binding sites, but this binding significantly decreases by 12 h after termination of dormancy by an E 2 injection These results collectively suggest that coordinated down-regulation of blastocyst CB1 and uterine AEA levels in the receptive uterus are important for implantation.
It is interesting to note that the peripheral AEA levels remain relatively low during implantation, whereas the levels increase before and during parturition in humans Increasing evidence suggests that the bioeffectiveness of AEA depends on its concentration in the extracellular space, which is regulated by its synthesis by NAPE-PLD, its transport across the plasma membrane, and its degradation by FAAH 92 , 93 — 98 , To further address the underlying mechanism by which differential uterine AEA levels are spatiotemporally established under different pregnancy status, we examined the expression profiles of NAPE-PLD and FAAH in the mouse uterus during early pregnancy.
It is interesting to note that the implanting blastocyst exerts an inhibitory effect on uterine Nape-pld expression These observations suggest a potential role of the implanting embryo in regulating uterine AEA levels, perhaps to serve as a protective mechanism against exposure to detrimental levels of AEA.
This is further confirmed by the observation of higher FAAH expression and activity in the implanting embryo , This tight regulation of AEA synthesis and hydrolysis in the pregnant uterus further indicates that endocannabinoid ligand-receptor signaling plays an important role in implantation.
These studies clearly establish the concept that whereas lower levels of AEA and CB1 are beneficial for implantation, higher levels are detrimental. Using the delayed implantation mouse model, we have provided further evidence that AEA at low concentrations confers blastocyst competency to implantation via CB1 , whereas experimentally elevated natural or synthetic cannabinoid levels interfere with implantation.
These findings are consistent with our previous observations of stimulation and inhibition of trophoblast growth at low and high AEA levels, respectively To reveal the underlying mechanism of this biphasic AEA action in blastocyst implantation, we further explored the potential signaling pathways that are coupled with CB1 under different AEA concentrations.
We found that AEA-induced stimulatory and inhibitory influences on blastocyst function and implantation are executed by different signal transduction pathways: An association of spontaneous pregnancy loss with elevated peripheral AEA levels in women , is consistent with the observations in mice see Section V. These findings in mice and humans reinforce the concept that endocannabinoid signaling is at least one of the pathways determining the fate of embryo implantation.
In this regard, there is evidence that activation of CB1 inhibits human decidualization and promotes apoptosis of decidual cells in vitro , thus adding a new role of endocannabinoids in human pregnancy. The possible physiological consequence of the different signaling pathway triggered by AEA through GPR55 , , deserves further investigation.
Taken together, these studies demonstrate that under normal physiological conditions, endocannabinoid signaling through CB1 is crucial to various female reproductive events that include development of embryos, their oviductal transport, and ultimately their homing and implantation in the receptive uterus; conversely, an aberration in endocannabinoid signaling, either silenced or enhanced, derails these processes Fig.
These observations add a new dimension to the concern that the adverse effects of maternal use of cannabinoids on offspring may be seeded very early in pregnancy. There is now evidence that defective implantation creates an adverse ripple effect during the subsequent course of pregnancy both in humans and mice 12 , 33 , Therefore, our findings in mice raise a cautionary note for women of reproductive ages regarding chronic abuse or medicinal consumption of marijuana or other endocannabinoid system-oriented drugs.
More importantly, they raise caution against the use of CB1 antagonists to treat obesity in humans. Endocannabinoid signaling in blastocyst activation and implantation. Evidence suggests that regulated levels of endocannabinoids, primarily AEA, in the receptive uterus and CB1 in activated blastocysts, are beneficial for implantation, whereas higher levels are detrimental to this process. There is evidence for the role of peripheral lymphocytes in embryo implantation and successful pregnancy in humans In fact, normal gestation is based on an early immunological adaptation that involves peripheral T lymphocytes in pregnant women 40 , , These cells produce type 1 T-helper Th1 and type 2 T-helper Th2 cytokines, which have opposite effects on trophoblast growth, as schematically depicted in Fig.
Th2 cytokines IL-3, IL-4, and IL favor blastocyst implantation and successful pregnancy by promoting trophoblast growth either directly or indirectly through the inhibition of natural killer NK cell activity and the stimulation of natural suppressor cells.
The latter cells play a role in this network, but several aspects of their contribution to the balance of Th1 and Th2 cytokines remain to be elucidated. In addition, P 4 plays a role in this network, and in fact it induces a Th2 bias by binding to the intracellular P 4 receptor in T cells , The resulting hormone-cytokine network is a key element at the fetal-maternal interface, and a defect in its integrity may result in fetal loss , — Additionally, T lymphocytes produce leukemia inhibitory factor LIF , which favors embryo implantation and survival — Clinical observations that women with unexplained recurrent abortions have reduced expression of LIF production suggest that this cytokine is indeed critical for implantation and pregnancy maintenance in humans , , Th2 cytokines IL-3, -4, and are released by T cells and favor blastocyst implantation by promoting trophoblast growth through inhibition of NK cell activity.
Also, P 4 induces the Th2 bias by binding to T lymphocytes. In this respect, lymphocyte FAAH has been shown to influence pregnancy outcome by regulating AEA level at the fetal-maternal interface 40 , which appears to interfere with the lymphocyte-dependent cytokine network.
Interestingly, defective FAAH in maternal lymphocytes is also associated with failure to achieve an ongoing pregnancy after in vitro fertilization and embryo transfer Therefore, it seems that FAAH, but not AMT or cannabinoid receptors, is important in lymphocyte-mediated regulation of the hormone-cytokine network at the fetal-maternal interface in natural and medically-assisted gestation.
In addition, analysis of the lymphocyte-endocannabinoid system during human ovulatory cycles has shown the highest FAAH activity and the lowest AEA concentrations on d 21 of the cycle Table 3 , a period that temporally coincides with the putative window of uterine receptivity for implantation ; binding to CB1 and activities of AMT and NAPE-PLD were similar in T cells at all stages of the ovulatory cycle Table 3. P 4 also modulates the effects of THC on sexual receptivity It appears that this effect of P 4 occurs through increased level of the transcription factor Ikaros, which in turn increases FAAH gene expression by binding to a specific sequence in the promoter region Profertility Th2 cytokines potentiate the activation of FAAH by P 4 , whereas antifertility Th1 cytokines have the opposite effect Leptin, too, enhances FAAH gene transcription through a signal transducer and activator of transcription 3-mediated up-regulation of the FAAH promoter Leptin alone or synergistically with P 4 reduces AEA levels in T cells, without affecting the other players in the endocannabinoid system Overall, the up-regulation of lymphocyte FAAH by profertility signals strengthen the speculation that this enzyme affects human fertility by modulating the AEA levels.
Also, uterine FAAH is regulated by sex hormones , but the implications and molecular details of this regulation are still elusive. Additionally, the FAAH activator does not resemble platelet-activating factor, leukotriene B 4 , or PGs known to be present in blastocysts ; its molecular identity is under investigation. This would suggest that regulated AEA levels are critical to successful implantation and pregnancy establishment.
On a final note, it is also possible that interplay between endocannabinoids and eicosanoids prostanoids, leukotrienes, or lipoxins contributes to immunoregulation of fertility, but this speculation awaits experimental support. Implications of the endocannabinoid system working via cannabinoid and vanilloid receptors in many central and peripheral aspects of human pathophysiology have been proposed.
We describe here the endocannabinoid signaling pathways that impact both male and female fertility with the hope of designing and developing endocannabinoid-oriented drugs for the treatment of infertility. In this respect, the biphasic roles of endocannabinoid signaling in fertilization, preimplantation embryo development, oviductal embryo transport, and implantation have major clinical implications 69 , , , , , , , — , , , — , , , , , The incidence of spontaneous abortion, the most common adverse outcome of pregnancy, associated with considerable sufferings and medical costs , , is increased by cigarette smoking and the use of illicit drugs , This correlation of down-regulation of FAAH in women who are prone to miscarriage appears specific, because other members of the endocannabinoid system are not affected , , This suggests that high FAAH activity with low AEA levels are among the factors that are important for successful pregnancy and raises concerns about marijuana use by pregnant women.
We suggest that FAAH is an important player in coordinating hormone-cytokine-endocannabinoid networks critical to reproduction. Regulating endocannabinoid levels via metabolic pathways could be an advantage over the use of CB receptor agonists and antagonists to eliminate their psychotropic effects , — However, the development and use of selective FAAH activators as therapeutics for fertility regulation may significantly reduce or eliminate AEA signaling via CB receptors and increase the incidence of reproductive disturbances , Furthermore, FAAH regulates the levels of several other endogenous endocannabinoid-like compounds whose functions are not yet known, leaving open the question of the biological consequences of their enhanced degradation upon treatment with FAAH activators.
Other enzymes that catalyze the hydrolysis of N -palmitoylethanolamine and hydrolysis and synthesis of 2-AG have recently been identified. It remains to be seen how these pathways contribute to the overall endocannabinoid tone relevant to reproductive functions. Mammalian reproduction is a complex process, involving spermatogenesis, oogenesis, fertilization, preimplantation embryo development, timely passage of embryos through the oviduct, and their implantation in the uterus, eventually establishing a functional placenta for successful pregnancy.
Each step in this process requires spatiotemporally regulated various networks of endocrine, paracrine, juxtacrine, and autocrine modulators. Emerging evidence now points toward important roles of the endocannabinoid system in mammalian reproduction. With respect to male reproductive functions, endocannabinoids show biphasic roles in regulating Sertoli cell apoptosis via differential receptor signaling mechanisms.
Furthermore, we describe here a stage-dependent effect of AEA on sperm function in that it prevents premature capacitation via a CB1 to ensure normal transit of sperm through the uterus to oviduct.
It is tempting to suggest that such an inhibitory brake may become less stringent when sperm reaches the oviduct, the site of fertilization. Activation of CB1 by AEA extracellular signaling leads to inhibition of sperm motility, capacitation, and ZP-induced but not spontaneous acrosome reaction.
Upon fertilization, one-cell embryos initiate cell division and undergo preimplantation development. As described above, endocannabinoid signaling through CB1 is crucial to various female reproductive events that include development of embryos, their oviductal transport, and ultimately their homing and implantation in the receptive uterus; conversely, an aberration in endocannabinoid signaling, either silenced or enhanced, derails these processes.
Furthermore, decreased activity and expression of FAAH in maternal T lymphocytes and resulting increased AEA levels are associated with spontaneous abortion in women. These findings add a new dimension to the concern that the adverse effects of maternal use of cannabinoids on offspring may be seeded very early in pregnancy, thus raising a cautionary note for women of reproductive ages regarding chronic abuse or medicinal consumption of marijuana or other endocannabinoid system-oriented drugs.
We have observed that either silencing or amplifying CB signaling leads to asynchronous preimplantation embryo development , However, the underlying molecular mechanisms remain unknown. Recently, global gene expression profiles during preimplantation mouse development analyzed by microarray techniques have generated a comprehensive data set covering nearly all mouse genes during early embryogenesis , — Furthermore, it is crucial to gather in-depth information on how the endocannabinoid signaling is differentially regulated in peripheral and central systems.
It is especially an important concern for developing endocannabinoid system-oriented drugs for selectively targeting central or peripheral tissues to avoid adverse effects in unrelated tissue types.
Therefore, more efforts should be directed to explore in detail the tissue- and cell-specific effects of endocannabinoid signaling using conditional transgenic mouse models. In fact, there is a recent study showing functional dissociation of FAAH between central and peripheral tissues using brain tissue-selective mutant mice On the other hand, efforts should also be directed to elucidate the common link that encompasses the central and peripheral endocannabinoid signaling.
For example, increasing evidence suggests that AEA-CB1 signaling exerts a regulatory role on hypothalamic neuronal activity for the pulsatile release of GnRH GnRH — , a central hormone that controls reproductive performances in both males and females.
Although a wealth of knowledge on the roles of lipid mediators including endocannabinoids, LPA and PGs, and protein signaling molecules, such as growth factors, cytokines, homeotic genes, and transcription factors in embryo-uterine interactions during implantation, has been generated 5 , 6 , 8 , 23 , 36 , , their hierarchical blueprint in directing uterine and embryonic functions during pregnancy remains to be deciphered.
We need to understand whether these pathways function independently or in parallel, or converge to a common signaling pathway to establish a network of lipid-protein signaling cross-talk between the embryo and uterus that is necessary for implantation.
In this respect, another area of attention in endocannabinoid research has evolved from the finding that the COX and lipoxygenase enzymes can use AEA and 2-AG as substrates to generate novel PGs and hydroxy-endocannabinoids — , suggesting a close link between endocannabinoids and eicosanoids The potential function and signaling pathways of these metabolic products in reproductive events remain to be determined. The authors thank Prof.
We also thank G. Bonelli for excellent production of the artwork and Susanne Tranguch for her critical reading of the manuscript. We apologize for unintended omission of any relevant references. Close mobile search navigation Article navigation. Lipid Signaling in Reproduction. Endocannabinoids and Male Fertility. Endocannabinoids and Clinical Implications.
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ing that cannabinoids control male reproductive functions both directly and . the acrosome reaction, and the most important physiological regu- lator appears to. system in a variety of physiological and behavioral functions. Chronic administration of THC to male mice caused a regression in Leydig cell tissues . One possibility is that the endocannabinoid system plays a role in. In the last few years, a number of studies have suggested a physiological role for AEA as a TRPV1 agonist, leading to the concept that AEA.