The Low-Molecular-Weight Ligands of the Gonadotropin Receptors as the New Generation of the Regulators of the Reproductive Functions and Steroidogenesis

Abstract

In clinic, the luteinizing (LH) and follicle-stimulating (FSH) hormones and human chorionic gonadotropin (hCG) are used to treat reproductive dysfunctions and in assisted reproductive technology. They are the αβ-heterodimeric complexes and specifically bind to ectodomain of G protein-coupled LH and FSH receptors. This leads to activation of many signaling cascades; some of which are responsible for steroidogenesis, folliculogenesis, and spermatogenesis, while the others, such as β-arrestin pathways, trigger the downregulation of gonadotropin receptors. A low selectivity of the intracellular signaling of gonadotropins and a large number of their isoforms are the main causes of undesirable effects of gonadotropins, limiting their clinical applications. Unlike gonadotropins, the low-molecular-weight (LMW) ligands interact with an allosteric site located in the transmembrane domain of the LH and FSH receptors and selectively activate the certain signaling pathway, preventing a number of side effects of gonadotropins. The LMW ligands are characterized by activity of the full and inverse agonists and neutral antagonists, as well as the positive and negative modulators, and they have the in vivo activity, including when administered orally. This review focuses on the advances in the development of LMW allosteric ligands of the LH and FSH receptors and the prospects for their use in reproductive medicine.Innovations in Assisted Reproduction Technology 2 folliculogenesis, and spermatogenesis in patients with the dysfunctions in the hypothalamo-pituitary-gonadal axis, (ii) the induction of ovulation in the assisted reproductive technologies, and (iii) the treatment of sex hormone-dependent tumors [1][2][3][4]. The gonadotropins with LH activity are isolated from the urine of pregnant women (the urinary forms of hCG) or produced in the specialized cellular cultures (the recombinant forms of LH and hCG), while FSH is isolated from the urine of postmenopausal women (the urinary forms of FSH) or produced by genetic engineering approaches (the recombinant forms of FSH) [1,5,6]. Despite the fact that these forms of gonadotropins are widely used in the clinic, they have the significant side effects. In the case of urinary forms of hCG and FSH, the main disadvantages are the presence of biologically active impurities in the gonadotropin preparations and a low degree of its standardization [2,7]. The placental hCG differs significantly in both the structure and functions from the LH and sulfated hCG which are secreted by the pituitary gonadotrophs and circulate in the blood of adult men and women [2,8]. Furthermore, the placental hCG is produced only during pregnancy and regulates the growth and development of the embryo [9]. The urinary FSH contains mainly highly glycosylated forms of this gonadotropin with the reduced activity, which associated with the impaired reproductive functions and infertility at the postmenopausal period [10]. At the same time, the recombinant forms of gonadotropins differ from their natural forms in the ...

From cell surface to signalling and back: the life of the mammalian FSH receptor

“…Inspite of the high sequence similarity across the TMD of the three GPHRs, and a common mechanism of receptor activation, the unliganded FSHR displays low basal activity, and mutations conferring a constitutive activity to the receptor as rare, unlike that reported for LHGCR and TSHR [147]. Lowmolecular-weight (LMW) ligands have been developed that interact with an allosteric site located in the TMD of FSHR and LHCGR and preferentially activate selective signaling pathways, preventing a number of side effects of gonadotropins [148]. A thiazolidine named compound 2 that exhibited suppression of FSH-induced stimulating effects, has been developed for pharmacological use [149] whereas a terphenyl derivative LUF5771 has been developed as an inverse agonist at LHCGR which [157 ] and timing of pubertal onset [158 ] remain to be proven convincingly.…”

Determinación de la calidad seminal, daño al DNA espermático y su relación en la fecundación y desarrollo embrionario (día 2) en pacientes con problemas reproductivos

“…Para ello, se requiere de dos tipos de hormonas, las glucoproteínicas y esteroidogénicas. Las hormonas glucoproteínicas son liberadas al torrente sanguíneo por la hipófisis anterior por medio de secreciones pulsátiles de la hormona Folículo Estimulante (FSH, Follicle Stimulating Hormone) y la hormona Luteinizante (LH, Luteinizing Hormone) (Dufau, 1998;Flück & Pandey, 2017;Shpakov, et al, 2020). La esteroidogénesis de los andrógenos involucra la síntesis de novo a partir del colesterol en los testículos proceso que se activa a la unión de la LH al a su receptor de membrana (LHR, Luteinizing Hormone Receptor) acoplado a la proteína específica reguladora de nucleótidos de guanina (proteína G) en la membrana de la célula de Leydig, ubicadas en el espacio intersticial del túbulo seminífero.…”

“…En la transducción de señales, la LHR interacciona principalmente con la proteína Gs y de forma variable con la proteína Gq/11 y Gi. Las proteínas Gq dependen de enzimas de la familia de fosfolipasa C (PLC, por sus siglas en inglés: Phospholipase C) mientras que las proteínas Gs y Gi promueven e inhiben (respectivamente) la activación de la adenilato-ciclasa (AC) y por consecuencia la cantidad de adenosina 3'5' monofosfato citosólico cíclico (cAMP, ciclic adenosine 3'5'monophosphate) (Dufau, 1998;Shpakov, et al, 2020). El cAMP participa en la fosforilación de proteínas específicas para liberar el colesterol desde sus depósitos celulares en el citosol para ser translocado hacia el espacio intermembranal de la mitocondria (Hinson, et al, 2010) y así promover la síntesis de T.…”