Evolutionism

Jekyll and Hyde: Two Faces of Cannabinoid Signaling in Male and Female Fertility

Departments of Pediatrics, Cell and Developmental Biology, and Pharmacology (H.W., S.K.D.), Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232; Department of Biomedical Sciences (M.M.), University of Teramo, Teramo 64100, Italy; and Mondino-Tor Vergata Neuropharmacology Center (M.M.), University of Rome Tor Vergata, 00133 Rome, Italy

Correspondence: Address all correspondence and requests for reprints to: S. K. Dey, Division of Reproductive and Developmental Biology, Departments of Pediatrics and Cell & Developmental Biology and Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232. E-mail: sk.dey@vanderbilt.edu; or M. Maccarrone, Department of Biomedical Sciences, University of Teramo, 64100 Teramo, Italy. E-mail: mmaccarrone@unite.it

	Abstract

Mammalian reproduction is a complicated process designed to diversify and strengthen the genetic complement of the offspringand to safeguard regulatory systems at various steps for propagating procreation. An emerging concept in mammalian reproduction is the role of endocannabinoids, a group of endogenously produced lipid mediators, that bind to and activate cannabinoid receptors. Although adverse effects of cannabinoids on fertility have been implicated for years, the mechanisms by which they exert these effects were not clearly understood. With the identification of cannabinoid receptors, endocannabinoid ligands, their key synthetic and hydrolytic pathways, and the generation of mouse models missing cannabinoid receptors, a wealth of information on the significance of cannabinoid/endocannabinoid signaling in spermatogenesis, fertilization, preimplantation embryo development, implantation, and postimplantation embryonic growth has been generated. This review focuses on various aspects of the endocannabinoid system in male and female fertility. It is hoped that a deeper insight would lead to potential clinical applications of the endocannabinoid signaling as a target for correcting infertility and improving reproductive health in humans.

I. Lipid Signaling in Reproduction 

II. The Endocannabinoid System

A. Introduction 

B. Metabolic routes 

C. Molecular targets and signaling pathways 

III. Endocannabinoids and Male Fertility

A. Introduction 

B. The endocannabinoid system in Sertoli cells 

C. The endocannabinoid system in sperm 

IV. Endocannabinoids and Female Fertility: Embryo Implantation

A. Introduction 

B. Endocannabinoids and preimplantation embryo development 

C. Endocannabinoids and oviductal embryo transport 

D. Biphasic endocannabinoid sensor in blastocyst implantation 

V. Endocannabinoids and Female Fertility: Immunoregulation

A. Th1/Th2 cytokines and fertility 

B. The endocannabinoid system in lymphocytes of pregnant women 

C. FAAH as a molecular integrator of fertility signals 

VI. Endocannabinoids and Clinical Implications 

VII. Conclusions and Future Direction