Sex hormone-binding globulin stimulates chorionic gonadotrophin secretion from human cytotrophoblasts in culture

Abstract

The effects of sex hormone-binding globulin (SHBG) on the secretion of human chorionic gonadotrophin (HCG) and cAMP by cultured human cytotrophoblasts were investigated. Cytotrophoblasts obtained from normal term placentae were cultured in serum-free medium with or without the addition of human SHBG. The presence of SHBG in the medium increased the release of HCG and the accumulation of cAMP. Ligand-free SHBG was able to raise both HCG and cAMP concentrations and the maximal response was observed with 1 nM of the steroid-binding globulin. Addition of either oestradiol or 5alpha-dihydro-testosterone (DHT) to cultures previously incubated with SHBG in a final molar ratio of 1:10 resulted in a further increase of HCG and cAMP concentrations. This effect was blocked when cultured placental cells were exposed to SHBG that was previously saturated with DHT or when incubated in the presence of steroids only. The results of the present study provide evidence for the in-vitro regulation of HCG secretion by SHBG and further support the concept that this steroid-binding protein may act as a mediator of steroid action at the cellular level. Finally, the increase in cAMP suggests that SHBG receptor located in the surface of syncytiotrophoblast membranes is coupled to adenylate cyclase as part of the G-protein receptor family. Our results may provide new insights into the biological implications of extracellular steroid-binding proteins as well as new perspectives on the endocrinology of pregnancy.

Sex hormone-binding globulin is synthesized in target cells

“…DHT, testosterone, and 2-methoxyestradiol, are not agonists, but instead antagonize the effects of 3 -diol. On the contrary, DHT is an agonist for SHBG-R SHBG in both the LNCaP prostate cancer cell line (Nakhla et al 1990) and in cultured human placenta (Queipo et al 1998). Not surprisingly, the degree to which agonists induce cAMP through R SHBG appears to vary with cell type.…”

“…For instance, the fractional increase in cAMP in cultures of human (Nakhla et al 1994) and canine prostate (Nakhla et al 1995) far exceeds that seen in LNCaP cells. It should not be lost sight of that, in both LNCaP cells (Nakhla et al 1990) and placenta (Queipo et al 1998), SHBG in the absence of steroid causes a modest increase in cAMP. Although the relationship between steroidal structure and affinity for SHBG has been examined in some detail (Cunningham et al 1979(Cunningham et al , 1981, those studies shed no light on whether a given steroid might be an agonist or antagonist in the SHBG-R SHBG system.…”

Protective Effect of Sex Hormone-Binding Globulin against Metabolic Syndrome:In VitroEvidence Showing Anti-Inflammatory and Lipolytic Effects on Adipocytes and Macrophages

“…In addition, a single nucleotide polymorphism related to an elevated plasma SHBG concentration reportedly correlates with a reduced risk of diabetes [ 13 ]. The hormone-like effect of SHBG has also been demonstrated in experiments using prostatic cells [ 14 , 15 ], MCF-7 breast cancer cells [ 16 ], cytotrophoblasts [ 17 ], proximal tubule epithelial cells [ 18 , 19 ], and hepatocytes [ 12 ]. The results of these previous studies led us to speculate that the serum SHBG level is not only simply a consequence of altered metabolic conditions but also exerts favorable effects protecting against the development of metabolic disorders.…”

Androgen Physiology, Pharmacology, and Abuse

“…[71][72][73][74][75] These mechanisms include the megalin receptor, which is a multivalent low-density lipoprotein endocytic receptor located on cell surface membranes that can mediate receptor-mediated cellular uptake of SHBG loaded with testosterone by endocytosis 76,77 and may influence tissue androgen action. According to the free hormone hypothesis, 68-70 the free (nonprotein bound) fraction of testosterone is the most biologically active, with the loosely protein-bound testosterone constituting a less accessible but mobilizable fraction, with the largest moiety tightly bound to SHBG constituting only an inactive reservoir.…”