The formation of the HPTA and the role of positive and negative feedback mechanisms

All components of the hypothalamic-pituitary-testicular axis (HPTA) are established during fetal life, and its first activation occurs during the neonatal period, when circulating testosterone (mini puberty) reaches adult male levels for several months and produces androgenic imprinting in non-reproductive tissues. After a surge in the neonatal period, HPTA becomes stationary during the 10 years of childhood. Studies have shown that at least four gene activity mechanisms limit the activity of the hypothalamic-pituitary-testicular axis (HPTA) during these 10 years.

The HPTA axis is not reactivated until puberty.

Hypothalamic gonadotropin-releasing hormone (GnRH) neurons are functional at birth, but after the perinatal androgen surge, they are strongly inhibited directly in infancy and cannot function. Until puberty begins, waking up dormant hypothalamic GnRH neurons and releasing GnRH. GnRH secreted by the hypothalamus drives the pituitary gland to secrete gonadotropin, which ultimately leads to testicular growth and maturation, thus completing spermatogenesis and hormone production to produce circulating testosterone concentrations in adult males. This leads to testicular growth, which is the earliest and most prominent external manifestation of male puberty. After the completion of puberty, HPTA is formalized and comes into play.

Positive feedback of HPTA

After birth, testosterone output of the testicle is mainly regulated by the pulsating mode of pituitary LH secretion. This is driven by the intermittent secretion of GnRH from hypothalamic neurons into the pituitary venous blood flow, providing a direct short-circuiting pathway for pituitary gonadotropin. The pituitary gonadotropin secretes LH at high amplitude pulses at intervals of approximately 60 to 90 minutes. LH stimulates Leydig cytokine production by increasing the availability of substrate (cholesterol) and activating rate-limiting steroid-producing enzymes and cholesterol transporters.

This pattern maintains the sensitivity of testicular interstitial cells to LH, thus maintaining the testosterone secretion pattern in mature males.

Negative feedback of HPTA

Testosterone inhibits pituitary gonadotropin secretion by inhibiting hypothalamic GnRH, which is a key element in testicular negative feedback loop. This negative feedback involves the effect of testosterone through androgen receptors and estradiol in the hypothalamus. This eventually leads to a decrease in the frequency of the GnRH pulse in the hypothalamus and a decrease in the amplitude of the LH pulse due to the decreased secretion of GnRH and the gonadotropin response to GnRH stimulation. In contrast, the small proportion of estradiol in the blood directly secreted by the testes means that circulating estradiol is under minimal physiological regulation and is unlikely to have a significant impact on the negative feedback regulation of male physiological gonadotropin.