Testicular production of male sex hormones (androgens) starts in the fetal period and continues until the end of life. Androgens are quintessential for the structural and functional differentiation and maturation of all aspects of the male phenotype. Testosterone (T) is the most important androgen; some of its actions require its conversion to 5α-dihydrotestosterone (DHT) mainly in peripheral androgen target organs. In addition, some actions of T, such as on the bone, brain, and sexual desire, require its conversion to the active estrogen, estradiol (E2). Normal testicular androgen production is critically dependent on regulatory input from the hypothalamic–pituitary level through the action of luteinizing hormone (LH) and fine-tuning by a plethora of other hormones and intratesticular paracrine signals. Androgen actions in the testis and other organs are mediated by the androgen receptor (AR), a ligand-activated nuclear transcription factor. The pivotal regulatory unit in androgen production is the hypothalamic–pituitary–testicular (HPT) axis, where feed-forward and feedback actions between the hypothalamus, pituitary, and testes maintain the physiological androgen homeostasis. Disturbances of this balance, leading to hypogonadism, may occur at any level of the HPT axis and in AR function. The pathophysiological basis of androgen disorders is localized somewhere in the cascade of androgen regulation → production → action, either intrinsic to the HPT function or as a consequence of primarily nonendocrine conditions or external influences. Typical causes for hypogonadism are mutations of genes functional at the HPT axis (organic hypogonadism), consequences of nonendocrine systemic illness, or the influence of exogenous/lifestyle factors (functional hypogonadism). We will first review the normal processes of testicular androgen production, action, and regulation by the HPT axis. We then review the pathophysiological basis of the various diseases and disorders that can disturb androgen synthesis or action.
The HPT axis forms the backbone of endocrine regulation of the testis. This regulatory circuit contains hierarchical cascades of feed-forward and feedback regulatory events (Fig. 1-1). According to the classical concept, specific hypothalamic nuclei synthesize the decapeptide gonadotropin-releasing hormone (GnRH).1 The axon terminals of GnRH neurons in median eminence release the peptide into the hypophyseal portal circulation, where it is transported to the anterior pituitary gland to stimulate in gonadotropin cells the synthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).1 LH and FSH reach the testes through the peripheral circulation and exert their stimulatory effects on Leydig and Sertoli cells, respectively.
The hypothalamic–pituitary–testicular (HPT) axis. The main hormones functioning in the HPT axis are depicted, including the effects of kisspeptin on GnRH secretion, GnRH on LH and FSH secretion, and their effects on testicular function, followed by negative feedback effects of testicular sex steroids and inhibin. GnRH, gonadotropin-releasing hormone; KiSS1R, kisspeptin receptor; LH, luteinizing hormone; FSH, follicle-stimulating hormone; R, receptor.
The negative feedback effects ...