471 Journal of Andrology, Vol. 23, No. 4, July/August 2002 Copyright  American Society of Andrology Andrology Lab Corner A Review of the Effect of Platelet-Activating Factor on Male Reproduction and Sperm Function ADAM S. LEVINE,* HILTON I. KORT,² ANDREW A. TOLEDO,² AND WILLIAM E. ROUDEBUSH² From *Tampa IVF, Tampa, Florida; and ²Reproductive Biology Associates, Atlanta, Georgia. Ten to 15% of reproductive age couples in the United States are not able to achieve a successful pregnancy and are considered infertile. Infertility affects men and women equally. Male fertility requires the production of an ade- quate number of morphologically normal spermatozoa with sufficient motility and the ability to undergo hyper- activation, capacitation, and the acrosome reaction in or- der to penetrate the oocyte’s cumulus oophorus and bind to the zona pellucida for fertilization. Defects in any of these necessary events will lead to infertility. A number of endogenous factors are implicated in the regulation of spermatozoan fertility potential, including platelet-acti- vating factor (PAF; Figure 1). Benveniste et al (1972) first identified PAF 30 years ago when they found that it was a potent mediator of rabbit platelet aggregation in immunoglobulin E–stimu- lated basophils. Since then, numerous investigators have demonstrated that PAF is a unique signaling phospholipid that has pleiotropic biologic properties in addition to platelet activation (Hanahan, 1986; Braquet et al, 1987). PAF exists endogenously as a mixture of molecular spe- cies with structural variants of the alkyl moiety. The C- 16 species is predominant in human sperm (Sanwick et al, 1992). Arrata et al (1978) used 31 P nuclear resonance spectroscopy to suggest a role for phosphate esters in male infertility. Levine et al (1987) subsequently used 31 P nuclear resonance spectroscopy to demonstrate that PAF concentrations were higher in fertile men than in infertile men and that PAF was absent in semen samples from vasectomized men. PAF clearly plays a significant role in reproductive physiology. It influences ovulation, fertilization, preim- plantation embryo development, implantation, and par- Correspondence to: Dr William E. Roudebush, 1150 Lake Hearn Dr NE, Suite 400, Atlanta, GA 30342 (e-mail: roudebush@rba-online.com). Received for publication February 4, 2002; accepted for publication February 4, 2002. turition (Harper, 1989). Although the exact mechanism or mechanisms for PAF action remain unclear, its impor- tance for normal reproductive function does not. Ulti- mately, PAF may serve as a biomarker for normal sperm function. PAF Synthesis and Metabolism Phospholipase A 2 is present in human spermatozoa. It is calcium-dependent and catalyzes the formation of 1-O- alkyl-2-lyso-sn-glycero-3-phosphocholine (lyso-PAF) from alkyl-acyl-glycerophosphocholine, an inert structur- al cell membrane component (Bennet et al, 1986). Lyso- PAF is biologically inactive. It can be acetylated by acetyl transferase using acetyl-coenzyme A (CoA) as an acetate donor to form 1-O-alkyl-2-O-acetyl-sn-glycero-3-phos- phorylcholine (PAF). Lyso-PAF may also be acetylated by a CoA-independent arachidonyltransacylase to form alkyl-acyl-glycerophosphocholine. Acetylhydrolase is the primary enzyme responsible for inactivating PAF by the removal of the acetate group from the sn-2 position, re- sulting in the reformation of lyso-PAF. The metabolic pathway for PAF synthesis is presented in Figure 2. Acetyltransferase and acetylhydrolase are both present in mammalian spermatozoa and seminal fluid (Gujarati et al, 1987). Consequently, both the enzymes necessary for PAF activation and deactivation are present in sperma- tozoa and seminal fluid. Letendre et al (1992) suggested that acetylhydrolase might itself act as a sperm decapa- citation factor. This is based on the observation that ca- pacitation occurs in human spermatozoa without exoge- nous mediators following sperm removal from seminal fluid. In fact, the data suggest that the elimination of ace- tylhydrolase during normal capacitation promotes PAF synthesis, which results in increased sperm motility and improved sperm–egg interactions (Roudebush et al, 1990, 1993; Hellstrom et al, 1991; Angle et al, 1993). PAF may indeed be a biomarker for capacitation. Much of the conflicting data regarding the presence and con- centration of PAF may be attributed to the use of non- capacitated spermatozoa. Further, some laboratory pro- cedures may inadvertently decrease PAF concentrations. PAF can become tightly bound to nonsiliconized borosil- icate glassware. Finally, Takamura et al (1996) demon- strated that media additives containing egg yolk or human