Furthermore, gonadotropin secretion was upregulated and the testosterone/ luteinizing hormone ratio was decreased indicating declining Leydig cell function despite these men being young. The slower genomic actions resulting from classical, canonical androgen receptor signaling involve dissociation of cytosolic AR from heat shock proteins, translocation of AR with chaperones to the nucleus, and then binding of AR and co-regulators to androgen response elements on target genes to activate or repress their expression. Synthesis of testosterone and dihydrotestosterone (DHT) by the testis is stimulated by LH activating G protein-coupled LH receptors in Leydig cells. It is also important how the treatment of men with GnRH analogous, gonadotropins with LH-like activity and androgens will affect the systemic and autonomic regulation of the GPH axis by adipokines. In the case of autonomous regulation, the adipokines synthesized in the pituitary and testes function as the autocrine and paracrine factors and to a large extent determine functional activity of the components of the HPG axis. Claims like these can only legitimately be made for drugs, not dietary supplements." . That means supplements should not make claims, such as "reduces pain" or "treats heart disease". The US Food and Drug Administration (FDA) clearly states that, "Unlike drugs, supplements are not intended to treat, diagnose, prevent, or cure diseases. Approximately 50% of American adults consume dietary supplements to promote overall health and fill dietary gaps 4,5. These may be used in addition to TRT for males with diagnosed symptomatic hypogonadism, or as a stand-alone regimen. 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. During puberty, when plasma LH concentration and the proliferation of Leydig cells are increased, the expression of adiponectin also increased rapidly, reaching a maximum in rats at 2 months of age . As noted above, the expression of the Adiponectin gene was found in the testes, which demonstrates the intratesticular production of adiponectin, and the main source of this adipokine is Leydig cells . As in the hypothalamic GnRH- and KNDy-neurons, regulatory effects of adiponectin on gonadotrophs are mediated by its ability to activate AMPK . This is largely due to adiponectin-induced decrease in the expression of GnRH receptors in gonadotrophs . A long-term treatment of the primary culture of gonadotrophs with adiponectin results in a decrease in the AdipoR1 expression, but has a little effect on the expression of AdipoR2, indicating the development of receptor-specific resistance of gonadotrophs to adiponectin . However, taking into account the high density of the truncated isoform Ob-Ra of leptin receptor on the surface of endothelial cells forming the BTB, there is reason to believe that, like the BBB, leptin transport through the BTB is also a receptor-dependent . At the same time, in the in vivo conditions, leptin increases LH level, but does not affect the secretion of FSH . The sensitivity of gonadotrophs to leptin is indicated by the fact that this adipokine at relatively low concentrations, 10−9 and 10−11 M, stimulates the LH and FSH secretion in the hemi-anterior pituitaries of adult male rats. The gene Ob-R encoding leptin receptor is expressed in a large number of gonadotrophs, and this suggests that these cells are the main target for leptin 8, 37, 67, 68, 74. It is shown that leptin influences the production of gonadotropins, changing the GnRH receptor activity and, thereby, controlling the sensitivity of gonadotrophs to hypothalamic regulation . It is important to note that between the systemic and autonomous adipokine-mediated regulation of the male HPG axis there are the complex integrative relationships and interactions that are realized at different levels of this axis. A prolonged i.c.v. administration of resistin into rats and mice results in a decrease in the expression of both types of adiponectin receptors, AdipoR1 and AdipoR2, and also reduces the functional activity of APPL-1 protein, thereby weakening the APPL-1-mediated adiponectin signaling. The treatment of Leydig cells with adiponectin did not affect the expression of LH receptor, and this indicates the preservation of the sensitivity of these cells to gonadotropins . The mechanisms of adiponectin action on Leydig cells include the stimulation of PI3K and Akt kinase, which results in the changed expression of Akt-dependent genes, as well as the regulation of ERK1/2, whose activity decreases at low concentrations of adiponectin and increases at its high concentrations . Studying the male rats, it was shown that during puberty with an increase in plasma LH level the expression of AdipoR2 in the testes also increases, which positively correlates with an increase in the adiponectin expression. Androgens may modulate the physiology of vaginal tissue and contribute to female genital sexual arousal. Men who watch a sexually explicit movie have an average increase of 35% in testosterone, peaking at 60–90 minutes after the end of the film, but no increase is seen in men who watch sexually neutral films. This reaction engages penile reflexes (such as erection and ejaculation) that aid in sperm competition when more than one male is present in mating encounters, allowing for more production of successful sperm and a higher chance of reproduction. Studies conducted in rats have indicated that their degree of sexual arousal is sensitive to reductions in testosterone. Sexual arousal and masturbation in women produce small increases in testosterone concentrations. In the recent years, the evidence has been obtained that leptin plays a very important role in the control of male reproductive functions and puberty, which is based on leptin-mediated regulation of the HPG axis 8, 37. The leptin-induced activation of the kisspeptin/neurokinin B/dynorphin (KNDy)-neurons leads to the secretion of kisspeptin that triggers the GnRH secretion by the GnRH-expressing neurons, the main target of kisspeptin 34, 35. The regulatory effects of leptin are realized due to its specific interaction with leptin receptors (Ob-R) that are generated by alternative splicing and include at least six isoforms . This suppression results in changes to the pulsatile release of GnRH from the hypothalamus, reverting the LH secretion pattern to pre-pubertal levels.. Adiponectin inhibits both the basal and GnRH-stimulated LH secretion, and its effect is detected even after a short exposure with gonadotrophs 14, 144.} These findings suggest that hypogonadal levels of testosterone can dysregulate mood and induce depressive symptoms. Increasing synaptic levels of serotonin with selective serotonin reuptake in inhibitors contributes to antidepressant responses in depression . Other research has found that testosterone promotes an antidepressant response by activating androgen receptor signaling via the MAPK-ERK2 cascade in the hippocampus 12, 117.
