We assessed the magnitude of the genetic component in the variation of circulating levels of insulin-like growth factors I and II (IGF-I and IGF-II), and their binding proteins IGFBP-1 and IGFBP-3 by measuring their serum concentrations in 32 monozygotic and 47 dizygotic adult twin pairs of the same sex. The intrapair correlation for the IGF-I levels was r = 0.41 (P < 0.009) for monozygotic twins and r = 0.12 (P < 0.22) for dizygotic twins. For the IGF-II concentration the intrapair correlations were r = 0.66 (P < 0.0001) for the monozygotic and r = 0.34 (P < 0.01) for the dizygotic twins. No significant intrapair correlation was found for IGFBP-1 levels in either group. The correlations for IGFBP-3 concentration were r = 0.65 (P < 0.0001) and r = 0.23 (P < 0.06) for monozygotic and dizygotic twins, respectively. Women had higher IGF-II levels than men (635+/-175 vs. 522+/-144 microg/liter; P < 0.0001) and IGFBP-3 levels were also higher in women compared with men (5441+/-1018 vs. 4496+/-1084 microg/liter; P < 0.001). The proportion of variance attributable to genetic effects was 38% for the IGF-I concentration, 66% for the IGF-II concentration, and 60% for the IGFBP-3 concentration. No significant heritability was found for the IGFBP-1 concentrations. Our results show that, in adults, there is a substantial genetic contribution responsible for interindividual variation of the circulating levels of IGF-I, IGF-II, and IGFBP-3, but not for the IGFBP-1 levels.

Glycodelin is a glycoprotein that belongs to the lipocalin superfamily. Depending on glycosylation, glycodelin appears in various isoforms. In the uterus, glycodelin-A is the major progesterone-regulated glycoprotein secreted into uterine luminal cavity by secretory/decidualized endometrial glands. The other tissues expressing glycodelin include fallopian tubes, ovary, breast, seminal vesicle, bone marrow, and eccrine glands. Glycodelin-A potently and dose-dependently inhibits human sperm-egg binding, whereas differently glycosylated glycodelin-S from seminal plasma has no such effect. Absence of contraceptive glycodelin-A in the uterus during periovulatory midcycle is consistent with an open “fertile window.” Glycodelin induced by local or systemic administration of progestogens may potentially reduce the fertilizing capacity of sperm in any phase of the menstrual cycle. Glycodelin also has immunosuppressive activity. Its high concentration at the fetomaternal interface may contribute to protection of the embryonic semiallograft. Besides being an epithelial differentiation marker, glycodelin appears to play a role in glandular morphogenesis, as transfection of glycodelin cDNA into a glycodelin-negative breast cancer cells resulted in formation of gland-like structures, restricted proliferation, and induction of other epithelial markers. These various properties, as well as the chemistry, biology, and clinical aspects of glycodelin, continue to be areas of active investigation reviewed in this communication.

Glycodelin, also known as placental protein 14 (PP14) or progesterone-associated endometrial protein (PAEP), is a human glycoprotein with potent immunosuppressive and contraceptive activities. In this paper we report the first characterization of glycodelin-derived oligosaccharides. Using strategies based upon fast atom bombardment and electrospray mass spectrometry we have established that glycodelin is glycosylated at Asn-28 and Asn-63. The Asn-28 site carries high mannose, hybrid and complex-type structures, whereas the second site is exclusively occupied by complex-type glycans. The major non-reducing epitopes in the complex-type glycans are: Galβ1-4GlcNAc (lacNAc), GalNAcβ1-4GlcNAc (lacdiNAc), NeuAcα2-6Galβ1-4GlcNAc (sialylated lacNAc), NeuAcα2-6GalNAcβ1-4GlcNAc (sialylated lacdiNAc), Galβ1-4(Fucα1-3)GlcNAc (Lewis), and GalNAcβ1-4(Fucα1-3)GlcNAc (lacdiNAc analogue of Lewis). It is possible that the oligosaccharides bearing sialylated lacNAc or lacdiNAc antennae may manifest immunosuppressive effects by specifically blocking adhesive and activation-related events mediated by CD22, the human B cell associated receptor. Oligosaccharides with fucosylated lacdiNAc antennae have previously been shown to potently block selectin-mediated adhesions and may perform the same function in glycodelin. The potent inhibitory effect of glycodelin on initial human sperm-zona pellucida binding is consistent with our previous suggestion that this cell adhesion event requires a selectin-like adhesion process. This result also raises the possibility that a convergence between immune and gamete recognition processes may have occurred in the types of carbohydrate ligands recognized in the human.

We have recently demonstrated that a human amniotic fluid-derived glycoprotein, glycodelin-A (GdA; previously known as PP14 or PAEP), potently inhibits gamete binding in an established sperm-egg binding system and expresses immunosuppressive activities directed against a variety of different immune cell types. GdA has high mannose-, hybrid-, and complex-type biantennary oligosaccharides including structures with fucosylated or sialylated N,N′-diacetyllactosediamine (GalNAcβ1-4GlcNAc) sequences, which are rare in other human glycoproteins. We now report the characterization of glycodelin-S (GdS). This is a human seminal plasma glycoprotein that is immunologically indistinguishable from GdA, but unlike the latter, does not inhibit human sperm-zona pellucida binding under hemizona assay conditions. Analysis of the N-glycans of GdS by mass spectrometry revealed that all glycoforms of GdS are different from those of GdA. GdS glycans are unusually fucose-rich, and the major complex-type structures are biantennary glycans with Lewis^x (Galβ1-4(Fucα1-3)GlcNAc) and Lewis^y (Fucα1-2Galβ1-4(Fucα1-3)GlcNAc) antennae. It is probable that these highly fucosylated epitopes contribute to the immunosuppressive activity of human seminal plasma and to the low immunogenicity of sperm. This study provides the first evidence for gender-specific glycosylation that may serve to regulate key processes involved in human reproduction.

Glycodelin is an example of a glycoprotein whose complex-type glycans mediate biological actions in human reproduction and immune reactions. Being attached to an identical protein backbone, glycodelin oligosaccharides vary significantly from one reproductive tissue to another and have an effect on its own secretion and role in cell communication. For instance, uterine glycodelin-A inhibits sperm–oocyte interaction by binding on the sperm head. This is a glycosylation-dependent phenomenon, in which fucosyltransferase-5 plays a key role. Glycodelin-S from seminal plasma binds evenly around the sperm head and maintains an uncapacitated state in the spermatozoa, until the isoform is detached during sperm passage through the cervix. Glycodelin-F from follicular fluid and Fallopian tube binds to the acrosomal region of the sperm head, thereby inhibiting both the sperm–oocyte binding and premature progesterone-induced acrosome reaction. The cumulus cells surrounding the oocyte can capture glycodelin-A and -F from the surrounding environment and convert these isoforms to a cumulus cell isoform, glycodelin-C. It differs by glycosylation from the other isoforms, and it too attaches on the sperm head, with the highest density in the equatorial region. Glycodelin-C is capable of detaching the sperm-bound inhibitory isoforms so that the sperm–oocyte binding is enhanced. Glycodelin-A also has immunosuppressive actions directed to cellular, humoral and innate immunity. Although these actions depend mainly on the protein backbone, glycosylation also plays a part. Glycosylated glycodelin may be involved in the protection of spermatozoa against maternal immune reactions, and glycodelin also has apoptogenic activity. Some glycosylation patterns of glycodelin may mask its apoptogenic domain. This review updates the recent research and clinical associations of glycodelin, highlighting the role of glycosylation.

The mechanisms underlying the protection of the human embryo/fetus from the meternla immune response are poorly understood. Substantial evidence indicates that carbohydrate recognition plays a promary role in the sequestration of leukocytes during inflammatory processes, lumphocyte homing, and initial gamete binding. Our previous studies suggest a possible convergence inthe types of carbohydrate sequences recognized furing initial human gamete binding and immune/inflammatory cell inter-actions. Our more recent findings indicate that oligasacch-arrides participating in suchprocesses are also associated with soluble glycoconjugates found in the humanplacenta, amniotic fluid, and decidua. We theorize that such glycocon-jugates amy abrogaste the maternal immune/inflammatory response tby blocking the primary adhesice interactions requieed for the expression of such activities. Foreign embryonic cells amay also be protected by surface expression of oligosaccharide sequences that suppress immune effector cell action n a manner not dependent upon classicla major histocompatibility (MHC) recognition. Gklycoconjugates expressing selectin ligands amy also manifest a potent contraceptive effect that amy also be beneficial for both the mother anf the developing embryo/9 fetus. This hypothesis provides a preliminary frame work for undestanding how temporally and sapatially restricted immunosupressive effects could be expressed in utero that protect the human embryo/fetus during this period of human development.