**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.

**Keywords:** sex steroid hormone, steroidogenesis, low-molecular-weight agonist, luteinizing hormone, follicle-stimulating hormone, receptor of luteinizing hormone

### **1. Introduction**

The most important areas of clinical applications of the gonadotropins, such as the luteinizing (LH) and follicle-stimulating (FSH) hormones and human chorionic gonadotropin (hCG), are (i) the stimulation of the steroidogenesis,

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 [1–4]. 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 posttranslational modifications, primarily in the number, structure, and charge of N-glycans, which significantly changes their specific biological activity and pharmacological profile. All this not only significantly limits the use of natural and recombinant forms of gonadotropins in the treatment of androgen deficiency, hypogonadotropic hypogonadism, and amenorrhea but also reduces their effectiveness in the controlled induction of ovulation and in other assisted reproductive technologies.

Thus, one of the urgent tasks of reproductive medicine is to minimize the side effects of gonadotropins and to increase their effectiveness and specificity. An alternative approach is the development of a new generation of the selective regulators of the LH and FSH receptors, the most suitable among which are the low-molecular-weight (LMW) allosteric ligands of these receptors.
