Abstract
Simple SummaryThe reproductive hormones luteinizing hormone (LH) and human chorionic gonadotropin (hCG) are both agonists for the luteinizing hormone receptor (LHCGR) and essential for male reproduction during development and adulthood. LHCGR is expressed and stimulates testosterone production from the testicular Leydig cells. In this study, we demonstrate the presence of soluble LHCGR in blood, urine, and seminal fluid in both healthy boys and men, and patients with aberrations in sex-chromosomes. We show how circulating levels of sLHCGR are associated with pubertal development, testicular function, and semen quality and demonstrate that LHCGR is released from fetal human non-gonadal tissue. sLHCGR is released into serum by testis and other organs, which suggests possible extra-gonadal effects of LH or hCG in boys and men.Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) are agonists for the luteinizing hormone receptor (LHCGR) which regulates male reproductive function. LHCGR may be released into body fluids. We wish to determine whether soluble LHCGR is a marker for gonadal function. Cross-sectional, longitudinal, and intervention studies on 195 healthy boys and men and 396 men with infertility, anorchia, or Klinefelter Syndrome (KS) were used to correlate LHCGR measured in serum, seminal fluid, urine, and hepatic/renal artery and vein with gonadal function. LHCGR was determined in fluids from in vitro and in vivo models of human testicular tissue and cell lines, xenograft mouse models, and human fetal kidney and adrenal glands. Western blot showed LHCGR fragments in serum and gonadal tissue of similar size using three different antibodies. The LHCGR-ELISA had no species cross-reactivity or unspecific reaction in mouse serum even after human xenografting. Instead, sLHCGR was released into the media after the culture of a human fetal kidney and adrenal glands. Serum sLHCGR decreased markedly during puberty in healthy boys (p = 0.0001). In healthy men, serum sLHCGR was inversely associated with the Inhibin B/FSH ratio (β −0.004, p = 0.027). In infertile men, seminal fluid sLHCGR was inversely associated with serum FSH (β 0.006, p = 0.009), sperm concentration (β −3.5, p = 0.003) and total sperm count (β −3.2, p = 0.007). The injection of hCG lowered sLHCGR in serum and urine of healthy men (p < 0.01). In conclusion, sLHCGR is released into body-fluids and linked with pubertal development and gonadal function. Circulating sLHCGR in anorchid men suggests that sLHCGR in serum may originate from and possibly exert actions in non-gonadal tissues. (ClinicalTrials: NTC01411527, NCT01304927, NCT03418896).
Highlights
Luteinizing hormone (LH) and human chorionic gonadotropin are both agonists for the luteinizing hormone receptor (LHCGR) and essential for male reproduction during development and adulthood [1]
Female serum concentrations of Soluble LHCGR (sLHCGR) have been linked with implantation rate in fertility treatment, preeclampsia, preterm birth, and pregnancy carrying a Down’s syndrome child [15,16], but have so far not been validated by other groups. sLHCGR has to our knowledge never been described in body fluids from healthy men, boys during pubertal development, or men with sex-chromosome aberrations
By western blot (WB) the OASG04237 antibody, targeting the intracellular part, we measured LHCGR in human testis tissue and in two serum samples; one serum sample from a man with high sLHCGR measured by ELISA and one serum sample from a man with low sLHCGR
Summary
Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) are both agonists for the luteinizing hormone receptor (LHCGR) and essential for male reproduction during development and adulthood [1]. Several isoforms of LHCGR exist and it has been suggested that one isoform is secreted because it lacks the transmembrane anchor [10]. Another possibility is that the release of LHCGR into body fluids is dependent on enzymatic cleavage at the cell membrane by proteins such as ADAMs, MMPs, and others known to cleave transmembrane proteins. Soluble LHCGR (sLHCGR) has been measured by an ELISA platform in both serum and follicular fluid from women [15,16]. The putative function of sLHCGR in the circulation of men may be to transport or modify the activity of LH or hCG by high-affinity binding and thereby be a marker of gonadal function
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