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After research indicated GnRH neurons do not express androgen receptors, kisspeptin and its G protein-coupled receptor KISS1R were discovered as important regulators of GnRH neurons . When hypogonadotropic hypogonadal men were treated with testosterone replacement therapy, their Beck depression score decreased by 90% and was similar to normal male controls . The cross-sectional Health in Men Study (HIMS) in Australia reported that the risk of depression increased threefold in men with free testosterone level below 60 pg/ml compared to men with a free testosterone level above 100 pg/ml . It is assumed that they carry out the receptor-mediated transport of leptin through the BBB and, possibly, through other tissue barriers 29, 30. Along with the adipose tissue, the ob gene expression is detected in other tissues, including the pituitary and testes . A prolonged increase in the plasma leptin level leads to leptin resistance, resulting in the impaired metabolism and eating behavior 23, 24. Fasting reduces the plasma leptin level, while food intake, on the contrary, leads to its elevation. The role of adipokines in the dysregulation of the male reproductive system and the impaired steroidogenic activity in the testes in obesity and DM2 are also discussed. The introduction of recombinant human visfatin into chicken did not stimulate, but, on the contrary, suppressed the basal and IGF-1-stimulated expression of the Star and Hsd3b1 genes, which led to a decrease in estrogens production by follicular cells . The data on the involvement of visfatin in regulation of the reproductive system are mainly related to the female HPG axis, folliculogenesis and steroidogenesis in the ovaries . These data suggest that, as in the case of leptin and insulin, the transport of visfatin into the brain can be receptor-mediated, and decreases in the conditions of visfatin resistance. In the earlier studies, it was shown that adiponectin, acting on the testes, suppressed both the basal and hCG-stimulated T production, although the expression of the steroidogenesis enzymes, such as cytochrome P450scc and dehydrogenases 3β-HSD and 17β-HSD3, did not change 17, 148. With regard to the adiponectin signaling in spermatozoa, it is shown that, in addition to adiponectin, both types of adiponectin receptors are expressed in them. In rats, during the neonatal period, when LH level is low, the content of adiponectin in the testes is also very low. The main regulators of the Adiponectin gene expression in the testes are gonadotropins with LH activity. The effects of leptin on the male HPG axis can be carried out at the level of hypothalamic neurons, pituitary gonadotrophs and testicular cells. This latter finding suggests that men with an androgen receptor having higher sensitivity and transcription activity due to shorter CAG repeats is more strongly impacted by higher testosterone levels and will be more responsive to testosterone replacement therapy. However, a study using a logistic regression analysis with stratification for AR CAG repeat length found that the risk for depression was significantly lower in men with a highly sensitive androgen receptor due to short CAG repeats if their testosterone levels were high . A genetically informed precision medicine approach using genes regulating testosterone levels and androgen receptor sensitivity will likely be essential in gaining critical insight into the role of testosterone in depression. The regulatory effects of adiponectin circulating in the blood and adiponectin synthesized in the pituitary and testes on the activity of the male HPG axis and the testosterone production. It is also not possible to exclude the possibility of reducing leptin transport through the BTB, although such data have not yet been obtained. Leptin also regulates steroidogenesis in the ovaries and adrenal glands, and the mechanisms of its regulatory effect are believed to be similar to those in Leydig cells 37, 94. Further, the level of intracellular cAMP is reduced due to its hydrolysis by cAMP-specific phosphodiesterases (cAMP-PDE), which leads to the attenuation of signal transduction generated by gonadotropins and inhibits their stimulating effect on steroidogenesis. Based on high rate of leptin transport through the BTB and high permeability of this barrier to other proteins, it was concluded that the mechanisms of leptin transport through the BBB and BTB differ significantly. In 1999, Banks and coauthors showed that leptin circulating in the blood was transported through the BTB, and the permeability was higher than in the case of the BBB . This assumption is supported by the data obtained in mice with tissue-specific knockout of the ob gene, either in the adipose tissue or in the pituitary. The stimulating effect of melanotan-II on LH production in mice lacking the kisspeptin receptor GPR54 was reduced significantly . Testosterone levels follow a circadian rhythm that peaks early each day, regardless of sexual activity. 2020 guidelines from the American College of Physicians support the discussion of testosterone treatment in adult men with age-related low levels of testosterone who have sexual dysfunction. Common side effects from testosterone medication include acne, swelling, and breast enlargement in males. It is unclear if the use of testosterone for low levels due to aging is beneficial or harmful. Adult testosterone effects are more clearly demonstrable in males than in females, but are likely important to both sexes. In general, androgens such as testosterone promote protein synthesis and thus growth of tissues with androgen receptors.
