Two Hormones for One Receptor: Evolution, Biochemistry, Actions, and Pathophysiology of LH and hCG

Abstract

LH and chorionic gonadotropin (CG) are glycoproteins fundamental to sexual development and reproduction. Because they act on the same receptor (LHCGR), the general consensus has been that LH and human CG (hCG) are equivalent. However, separate evolution of LHβ and hCGβ subunits occurred in primates, resulting in two molecules sharing ~85% identity and regulating different physiological events. Pituitary, pulsatile LH production results in an ~90-minute half-life molecule targeting the gonads to regulate gametogenesis and androgen synthesis. Trophoblast hCG, the "pregnancy hormone," exists in several isoforms and glycosylation variants with long half-lives (hours) and angiogenic potential and acts on luteinized ovarian cells as progestational. The different molecular features of LH and hCG lead to hormone-specific LHCGR binding and intracellular signaling cascades. In ovarian cells, LH action is preferentially exerted through kinases, phosphorylated extracellular-regulated kinase 1/2 (pERK1/2) and phosphorylated AKT (also known as protein kinase B), resulting in irreplaceable proliferative/antiapoptotic signals and partial agonism on progesterone production in vitro. In contrast, hCG displays notable cAMP/protein kinase A (PKA)-mediated steroidogenic and proapoptotic potential, which is masked by estrogen action in vivo. In vitro data have been confirmed by a large data set from assisted reproduction, because the steroidogenic potential of hCG positively affects the number of retrieved oocytes, and LH affects the pregnancy rate (per oocyte number). Leydig cell in vitro exposure to hCG results in qualitatively similar cAMP/PKA and pERK1/2 activation compared with LH and testosterone. The supposed equivalence of LH and hCG has been disproved by such data, highlighting their sex-specific functions and thus deeming it an oversight caused by incomplete understanding of clinical data.

Follicle-Stimulating Hormone (FSH) Action on Spermatogenesis: A Focus on Physiological and Therapeutic Roles

“…Of note, all available results on this topic used hCG to stimulate intra-testicular testosterone production rather than the physiological hormone LH. Although LH and hCG act on the same receptor, recent studies demonstrated different signal transduction pathways at the cellular level and different clinical outcomes in vivo, at least in women undergoing assisted reproduction [2,154]. The reason for using hCG instead of LH is more related to historical and practical reasons (availability, half-life, and costs) than to scientific evidence.…”

“…Therefore, there is the need to add hCG (from the urine of pregnant women) to modern hMG preparations. Considering hCG potency and half-life, no attempts were made to obtain pituitary LH from urine in the certainty that the two gonadotropins had the same biological effect [2]. Now that recombinant gonadotropins are available, the new evidence on the differences between LH and hCG action should be considered and could open further perspectives in the potential therapeutic role of LH in stimulating testicular function.…”

“…The therapeutic approach to male HH aims at restoring the physiological functioning of the testis and can be obtained by the administration of gonadotropin-releasing hormone (GnRH), which mediates the endogenous, pituitary production of both FSH and LH. Proper serum gonadotropin levels may also be achieved by exogenous administration of these hormones, typically human chorionic gonadotropin (hCG), which, acting on the same membrane receptor for LH, the LHCGR, was assumed to be identical to LH for long time [2]. hCG administration may be supported by adding FSH activity with either urinary-derived or recombinant follitropins [3].…”

FSH for the Treatment of Male Infertility

“…To overcome the relatively short half-life of FSH, which requires daily administration, a new recombinant molecule with a prolonged action was produced in transfected CHO cells [81], corifollitropin alpha (Elonva ® ; MSD, Readington, NJ, USA). This chimeric molecule includes the sequence encoding the CTP extension of hCGβ fused to the human FSHβ subunit, which bears four O-linked glycosylation sites and provides extended half-life [82,83]. Corifollitropin alpha has slower absorption and longer elimination half-time than follitropin alpha [84] so that one single injection can replace seven daily injections of follitropin alpha [85][86][87].…”

“…Most studies using gonadotropins were based on hCG, instead of the physiological hormone LH, which was present in the old hMG preparations but is absent from the modern, highly purified urinary gonadotropins. In light of the different intracellular signaling pattern mediated by LH and hCG [83] in Leydig cells [104,105], and considering that hCG has no functions in the adult male, where androgen production is supported by LH action, hCG might not be the optimal therapy and this possibility should be verified in future studies. In any case, intratesticular testosterone plays a central role in sustaining spermatogenesis, and this can be induced through the steroidogenic action of hCG, while FSH contribution would be mainly supportive of sperm quality [106,107].…”