Abstract
Low-molecular-weight agonists of luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptor (LHCGR), which interact with LHCGR transmembrane allosteric site and, in comparison with gonadotropins, more selectively activate intracellular effectors, are currently being developed. Meanwhile, their effects on testicular steroidogenesis have not been studied. The purpose of this work is to perform a comparative study of the effects of 5-amino-N-tert-butyl-4-(3-(1-methylpyrazole-4-carboxamido)phenyl)-2-(methylthio)thieno[2,3-d] pyrimidine-6-carboxamide (TP4/2), a LHCGR allosteric agonist developed by us, and hCG on adenylyl cyclase activity in rat testicular membranes, testosterone levels, testicular steroidogenesis and spermatogenesis in young (four-month-old), aging (18-month-old) and diabetic male Wistar rats. Type 1 diabetes was caused by a single streptozotocin (50 mg/kg) injection. TP4/2 (20 mg/kg/day) and hCG (20 IU/rat/day) were administered for 5 days. TP4/2 was less effective in adenylyl cyclase stimulation and ability to activate steroidogenesis when administered once into rats. On the 3rd–5th day, TP4/2 and hCG steroidogenic effects in young adult, aging and diabetic rats were comparable. Unlike hCG, TP4/2 did not inhibit LHCGR gene expression and did not hyperstimulate the testicular steroidogenesis system, moderately increasing steroidogenic proteins gene expression and testosterone production. In aging and diabetic testes, TP4/2 improved spermatogenesis. Thus, during five-day administration, TP4/2 steadily stimulates testicular steroidogenesis, and can be used to prevent androgen deficiency in aging and diabetes.
Highlights
One of the pharmacological approaches for correcting androgen deficiency and impaired spermatogenesis in male patients with hypogonadotrophic hypogonadism and infertility is the use of gonadotropins, such as luteinizing hormone (LH) and its structural and functional homologue, human chorionic gonadotropin [1,2,3,4]
We studied young adult and aging (18-month-old) male rats and the animals with 30-day streptozotocin-induced type 1 diabetes mellitus (T1DM) that were treated with saline (s.c.), dimethyl sulfoxide (DMSO) (i.p.), TP4/2 (20 mg/kg/day, i.p.) or human chorionic gonadotropin (hCG) (20 IU/rat/day, s.c.) for five days
We have shown that TP4/2, a LH/hCG receptor (LHCGR) allosteric agonist developed by us, stimulates T production in male Wistar rats during a five-day administration
Summary
One of the pharmacological approaches for correcting androgen deficiency and impaired spermatogenesis in male patients with hypogonadotrophic hypogonadism and infertility is the use of gonadotropins, such as luteinizing hormone (LH) and its structural and functional homologue, human chorionic gonadotropin (hCG) [1,2,3,4]. The main mechanism of gonadotropin stimulation of steroidogenesis in Leydig cells is the Gs-mediated activation of the enzyme adenylyl cyclase (AC), which causes an increase in intracellular cyclic adenosine monophosphate (cAMP) level. An increase in the cAMP level leads to the activation of protein kinase A, which stimulates the activity and expression of a wide range of steroidogenic proteins, and activates the type 8 cAMP-specific phosphodiesterase, hydrolyzing cAMP and thereby regulating the testicular steroidogenesis [6,7,9,10]. The clinical use of gonadotropin preparations leads to a number of undesirable effects due to their heterogeneity (especially in the case of urinary hCG), low selectivity for intracellular effectors systems and their ability to induce resistance of target cells to endogenous LH [6,7,13,14,15]. The gonadotropin-induced activation of cAMP-independent signaling pathways is involved in the regulation of growth, differentiation, and cytoskeletal reorganization, as well as LHCHR desensitization in the target cells [6,7]
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