**Disclosure**

*Innovations in Assisted Reproduction Technology*

detected when gonadotropins are used.

absorbed by intestinal cells.

including their late stages [79, 81, 82].

binding sites.

i.The LMW allosteric agonists of the gonadotropins receptors do not compete with the gonadotropins for the binding sites and, thus, do not suppress the effects of LH, hCG, and FSH, and in some cases they enhance them, acting as PAM or ago-PAM. The inhibition of the stimulating effect of gonadotropins by the LMW allosteric inverse agonists and NAMs is due to their allosteric effects, but not the result of the competition for receptor

ii.The LMW ligands of the LH and FSH receptors are characterized by the selectivity for intracellular signaling cascades, functioning as the bias ligands, which allows predicting and determining the functional response of cells to their action and prevents a number of undesirable side effects that are

iii.Since the LMW agonists are selective, they, unlike gonadotropins, have a little effect on the β-arrestin signaling pathways responsible for downregulation of the receptors. As a result, under conditions of treatment with the LMW allosteric agonists, the sensitivity of the tissues to endogenous gonadotropins is preserved, which makes it possible to use the long-term courses of

LMW agonists as well as to use them with the gonadotropins.

iv.The LMW allosteric ligands of the LH and FSH receptors can be active not only with their parenteral routes of administration but also with their oral delivery, since they are stable in the gastrointestinal tract and are well

v.The LMW agonists have chaperone-like properties in relation to the LH and FSH receptors, preventing their intracellular degradation and increasing their translocation to the plasma membrane. In this regard, the LMW agonists can be used to enhance the response of the reproductive system to the gonadotropins in the case of the mutant LH and FSH receptors that are not capable of translocation as well as in the conditions of the metabolic, inflammatory, and autoimmune disorders inducing the impaired posttranslational processing of these receptors. It should be noted that the mutations and polymorphisms in the gonadotropin receptors lead to a decrease in the sensitivity of the testes and ovaries to gonadotropins [78, 79]. In the assisted reproductive technologies, they reduce the response of the ovaries to the gonadotropin stimulation, which leads to the impaired folliculogenesis, the reduced output of high-quality oocytes, and the deterioration of the development and implantation of the embryo [78, 80]. Since both gonadotropins, LH and FSH, play an important role in the development and maturation of the follicles and oocytes, the polymorphisms in the LH and FSH receptors can be the main causes of an impairment of folliculogenesis and oogenesis,

Despite the advantages listed above, the LMW allosteric ligands of the LH and FSH receptors have not yet found use in the clinic. The main reason is insufficient knowledge of the pharmacokinetics and the distribution of these compounds in the body, as well as the problems with the development of their dosage forms, especially since most of these compounds are highly hydrophobic and dissolve in DMSO. The attempts to reduce the hydrophobicity of LMW ligands by modifying their structure lead to the partial or complete loss of their specific activity, due to their reduced ability of penetration into the transmembrane channel of

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Conflicts of interest are absent.
