82,84,85 The SP of boars and humans contains immune-regulatory molecules, including high concentrations of the potent immune-deviating TGF-β (particularly TGF-β1, but also TGFβ2- RAD001 and 3 isoforms), a member of the multifunctional cytokine TGF family.86,87 TGFβ1 concentrations are higher than in other body fluids, as blood plasma or breast milk, and similar to colostrum levels,88 reaching 120–150 ng/mL in boar semen87 or even higher levels in human bulk ejaculates (∼150–200 ng/mL) most of it being the latent (inactive) form and solely 1–2 ng/mL being the short-lived active form.65,89 The origin of the human TGF-β1

latent form is yet discussed, while TGF-β3 is apparently synthetized by the prostate as levels are highest in semen from men with agenesia of the seminal vesicles and lowest in samples there the seminal vesicle secretion dominates (Rodriguez-Martinez H, Kvist U, Ernerudh J, unpublished data). The latent forms can be converted to its active form under acidic conditions (as in the vagina) or by SP acid enzymes upon ejaculation and be then more firmly

attached to the sperm post-acrosomal membrane.87,90 TGF-β seems to induce the differentiation and expansion of the bank of regulatory T (Treg) cells, a 5–10% sub-population of suppressor CD4+ T cells, to reach a state of adaptative functional p53 inhibitor immune maternal 2-hydroxyphytanoyl-CoA lyase tolerance to male antigens.84,91,92 Males differ in their SP contents of TGF-β, without straight relation to fertility.86,89 However, a female could express different levels of endogenous cytokines depending on the exposure to SP from different males, which might thus relate to the often-observed differences in embryo survival among sires (e.g. innate fertility), a real long-lasting effect of the SP on the female.12,93 Whether such mechanism is valid also for humans remains to be fully elucidated, but clinical

evidence exists that fertility after ART is enhanced by accompanying unprotected intercourse or vaginal exposure to homologous SP.12 Interesting is the circumstantial evidence that the latent form of TGF-β2 (as for TGF-β1) could also have a preferential production by the epithelium of the prostate.94 Whether both are activated by PSA in relation to differences among men (or women) is yet to be tested. SP proteomes have been assessed in relation to reproductive outcomes (either fertility levels or (in)fertility), in several species of mammals, particularly domestic animals but also human. SP proteins have been identified as associated with high, respectively, low fertility in bulls,95 isolated as osteopontin (OPN) and lipocalin-type prostaglandin D synthase.96,97 The latter has been always present in the sperm-rich spurts of ejaculates in species (including humans) with fractionated ejaculation.