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The prevalence of major depressive disorder is two-folder higher in women compared to men suggesting that physiological levels of testosterone in the healthy range may reduce the risk of depression . Testosterone secreted by the testis exerts negative feedback control of hypothalamic GnRH release, while estradiol formed by 5α-reductase conversion of testosterone exerts negative feedback control of anterior pituitary luteinizing hormone (LH) secretion. Testosterone and the more biological active androgen, dihydrotestosterone (DHT), formed by conversion of testosterone by 5α-reductase, act as the primary sex hormones in men regulating male sexual development during puberty and spermatogenesis and sexual function in adulthood 1–3 (Fig. 1). The benefits of testosterone replacement therapy in men with major depressive disorder and low testosterone levels in the clinically defined hypogonadal range remain uncertain and require further investigation.Between days 5 and 7, one follicle is selected to continue development while the others undergo atresia, a process influenced by anti-Müllerian hormone (AMH). Additionally, the granulosa cells of the dominant follicle release peptides that may inhibit the growth of nearby follicles through autocrine and paracrine mechanisms. The distinct hormone profiles characterizing each phase represent two stable states, with sharp transitions between them ensuring proper timing of ovulation and endometrial preparation. Insulin sensitivity in GnRH neurons is important for maintaining normal reproductive function, particularly in the face of metabolic challenges such as obesity.
Dysregulation of the hypothalamic-pituitary–gonadal (HPG) axis has been observed in patients with major depressive episodes. In 2006, a Canadian study reported that total and bioavailable testosterone were significantly lower in middle-aged depressed men (40–65 years) who had considerably higher BDI and Hamilton depression scores than men enrolled in the Rancho Bernardo Study . Preclinical research has provided further evidence that androgens may reduce the risk of depression in men due to their antidepressant and neuroprotective actions in the hippocampus, limbic system, and other brain regions regulating mood 12, 13.
Decline of testosterone production with age has led to interest in androgen replacement therapy. In androgen-deficient men with concomitant autoimmune thyroiditis, substitution therapy with testosterone leads to a decrease in thyroid autoantibody titres and an increase in thyroid's secretory capacity (SPINA-GT). In people who have undergone testosterone deprivation therapy, testosterone increases beyond the castrate level have been shown to increase the rate of spread of an existing prostate cancer.
Leptin serves as a permissive signal for puberty onset, with a threshold level necessary for normal pubertal progression. Ghrelin's action on GnRH neurons involves a decrease in the frequency of GABAergic miniature postsynaptic currents and is dependent on retrograde endocannabinoid signaling. This effect appears to be sexually dimorphic, with a more pronounced response observed in female rodents compared to males. These kisspeptin neurons act as central processors for relaying signals from the periphery to GnRH neurons and are essential for the onset of puberty and maintenance of normal reproductive function. This role of exercise in modulating activin inhibition and influencing the HPO axis presents a compelling direction for future exercise physiology research. Follistatin, which is also produced in all body tissue, inhibits activin and gives the rest of the body more control over the axis.
When testosterone levels are low, gonadotropin-releasing hormone (GnRH) is released by the hypothalamus, which in turn stimulates the pituitary gland to release FSH and LH. This important new finding indicates inhibiting androgen receptor signaling in brain regions regulating mood generates a stronger depressogenic action than inducing very low testosterone levels with ADT in men with prostate cancer. Basal secretion of LH and FSH, LH pulse frequency, and GnRH-stimulation gonadotropin secretion by the anterior pituitary are not altered in major depressive disorder indicating that anterior pituitary gonadotropin dysregulation may not contribute to low testosterone levels 36, 43, 44. Increasing testosterone levels have been found to inhibit hypothalamic GnRH release via classical negative feedback thereby reducing anterior pituitary secretion of LH and FSH and their stimulation of testosterone steroidogenesis . Because circulating levels of gonadotropins do not change when pituitary androgen receptors are knocked out in transgenic mice, gonadotrophs in the anterior pituitary do not appear to be a site for testosterone negative feedback .
