Endogenous and Synthetic Regulators of the Peripheral Components of the Hypothalamo-Hypophyseal-Gonadal and -Thyroid Axes

Abstract

Activity in the peripheral components of the hypothalamo-hypophyseal-gonadal and -thyroid axes is regulated by hypophyseal hormones – gonadotropins and thyrotropic hormones (thyroid-stimulating hormone, TSH), which are secreted by specialized cells in the adenohypophysis. Luteinizing hormone (LH) and its homolog chorionic gonadotropin (CG) realize their steroidal effects by binding to LH/CG receptors on the surfaces of Leydig cells in the testes and theca cells and granulosa cells in mature follicles in the ovaries. Follicle-stimulating hormone (FSH) binds FSH receptors on Sertoli cells in the testes and granulosa cells in primordial and maturing follicles in the ovaries, controlling the processes of folliculogenesis, spermatogenesis, and steroidogenesis. TSH, via activation of TSH receptors, stimulates the synthesis of thyroid hormones by thyrocytes in the thyroid gland. Gonadotropins (LH, CG, and FSH) and TSH, which bind with high affinity to the extracellular domains of specific G protein-coupled receptors, directly activate various signal cascades operating via different types of G-proteins and β-arrestins. Recombinant gonadotropins and gonadotropins extracted from natural sources and used for the treatment of reproductive dysfunction and as assisted reproduction technologies have a number of drawbacks, which has led to the development of peptide and low molecular weight regulators of LH/CG and FSH receptors which interact with allosteric sites on the transmembrane or cytoplasmic domains of the receptors. Wide perspectives in the regulation of reproductive functions and the control of fertility are opened up by the use of adipokines, peptides of the insulin and relaxin families, and the antidiabetic drug metformin, which not only regulate and modify the responses of the gonads to gonadotropins, but also themselves influence steroidogenesis and gamete maturation. In the case of TSH receptors, the most acute problem is that of reversing increases in their activity in autoimmune and oncological diseases of the thyroid gland and in endocrine ophthalmopathy. The greatest potential in this direction lies in the ongoing development of low molecular weight inverse agonists and neutral antagonists, which interact with an allosteric site located in the transmembrane domain of the TSH receptor. The present review addresses contemporary advances in the development and study of endogenous and synthetic regulators and modulators of gonadotrophic and TSH receptors, along with their influences on the peripheral components of the hypothalamo-hypophyseal-gonadal and -thyroid axes.