An Internal Cannabinoid-Signaling System Regulates Human Sperm, Fertilization Potential, Study Finds

SAN FRANCISCO -- A cellular signaling system that responds to THC, the active substance in marijuana, as well as to anandamide, a cannabinoid-like molecule normally produced in the body, may regulate sperm functions required for fertilization in humans, a study headed by scientists from the University at Buffalo has found.

In addition, the findings suggest that men and women who abuse marijuana could jeopardize fertility by overloading this natural cannabinoid signaling system that regulates sperm structure, vigor and fertility.

Herbert Schuel, Ph.D., UB professor of anatomy and cell biology and lead author on the study, presented results of the research here today (Dec. 12, 2000) at the annual meeting of the American Society for Cell Biology.

Collaborating on the research were Lani Burkman, Ph.D., and Jack Lippes, M.D., of UB, and colleagues from the University of Connecticut, Eastern Virginia Medical School and University of California at Irvine.

The study presents the first evidence that anandamide exists in human seminal plasma, mid-cycle oviductal fluid and follicular fluid, and can regulate directly the human sperm's ability to fertilize an egg.

"These findings suggest that defects in the cannabinoid receptor-signaling system could account for certain types of infertility," Schuel said. "A better understanding of these mechanisms might lead to the development of novel drugs useful in reproductive medicine. For heavy marijuana users, the study results raise the possibility they are jeopardizing fertility by overloading this signaling system."

A receptor for cannabinoids was found in the human brain in the late 1980s. This finding suggested that the body must produce its own chemical version of THC to activate these receptors, and a substance called anandamide was found to be that chemical. Schuel and collaborators were the first to report cannabinoid receptors in sperm, using sea urchins as a model, and that anandamide also activated those receptors.

The regulatory mechanisms that prepare sperm to fertilize eggs within human reproductive tracts remain, for the most part, a scientific mystery. Human sperm are bathed in male reproductive-tract secretions when they are ejaculated into the female's vagina, and are not immediately capable of fertilizing eggs. However, once removed from the seminal plasma and exposed for several hours to secretions within the female reproductive tract, sperm become "capacitated" and can fertilize eggs.

Capacitated sperm exhibit a characteristic pattern of vigorous swimming called hyperactivated motility. When they bind to a specific protein in the egg's surface coat, sperm can be stimulated to secrete digestive enzymes that enable them to penetrate the egg coat during fertilization, a secretory process called the acrosome reaction.

"We know that sperm capacitation and fertilizing potential are tightly regulated within the female reproductive tract," Schuel said. "We also know that the cannabinoid receptor found in the human brain is expressed in the human testis, and that anandamide is produced in the testis and uterus of mammals. Within the uterus, anandamide regulates early development of the fertilized egg, and determines where the embryo will implant to initiate pregnancy. Cannabinoids also affect this process," he noted.

Now, Schuel and collaborators have the first evidence that anandamide can directly regulate human sperm's ability to fertilize an egg. Using a synthetic equivalent of natural anandamide called AM-356 and THC, the substance responsible for the "high" produced by marijuana smoke, the researchers showed that both chemicals regulate in vitro capacitation and fertilizing potential of human sperm in three ways:

• AM-356 produces opposite effects on hyperactivated sperm swimming, depending on the amount. Too much (a concentration of 2.5 nano Moles) inhibits hyperactivated motility, while at a 10-fold lower concentration, it stimulates hyperactivated swimming. Because anandamide is present in human-reproductive fluids and human sperm contain cannabinoid receptors, it is possible that localized differences in anandamide concentration may regulate sperm swimming patterns within the female-reproductive tract.

• Both AM-356 and THC inhibit structural changes over the acrosome. The structural integrity of the acrosome during capacitation is known to be a critical factor in sperm's ability to fertilize eggs.

• AM-356 significantly inhibits sperm binding to the zona, or egg coat. This observation provides the first evidence that anandamide (which AM-356 mimics) can regulate directly sperm fertilizing potential in humans.

"Defects in endocannabinoid signaling may be responsible for certain currently unexplained types of infertility," Schuel said. "Conversely, endocannabinoid signaling in human-reproductive tracts may provide potential targets for the future development of new drugs for use in reproductive medicine.

"In addition, the increased load of cannabinoids in people who abuse marijuana could flood natural endocannabinoid-signal systems in reproductive organs and adversely impact fertility," he said. "This possibility may explain observations made over the past 30-40 years that marijuana smoke drastically reduces sperm production in males."

Alexandros Makriyannis, Ph.D., and Robert Picone of the University of Connecticut; Mary C. Mahony, Ph.D., of Eastern Virginia Medical School, and Andrea Giuffrida, Ph.D., and Daniele Piomelli, Ph.D., of the University of California at Irvine, collaborated on this research.