1.1.2.1 Hypothalamus

The hypothalamus is connected to a variety of areas in the central nervous system and has many functions. The most notable function of the hypothalamus is its central neuroendocrine function, and its main role in the HPG axis is to transport hormones to the anterior pituitary for stimulation of peptide hormone release and gonadal regulation. Gonadotropin-releasing hormone is the most important hypothalamic hormone for reproduction. It is a 10-amino acid neuropeptide hormone produced by hypothalamic neurosecretory cells. It is released in a pulsatile manner into the hypophyseal portal circulation, where it is delivered directly to the anterior pituitary gland and stimulates LH and FSH production and secretion [1]. When GnRH pulses do not occur at the appropriate amplitude or frequency, possible complications include hypogonadism and decreased plasma gonadotropins.

1.1.2.2 Anterior Pituitary

The anterior pituitary is the target site of GnRH released from the hypothalamus, and stimulation of the anterior pituitary by GnRH results in production and release of adenohypophyseal hormones. Release of LH and FSH from the anterior pituitary is essential for regulation of testicular function. Both LH and FSH are released in a pulsatile manner, and negative feedback from estrogen and testosterone affect the secretion of these hormones by the anterior pituitary. In the testis, LH acts on Leydig cells to stimulate the production of testosterone, whereas FSH acts on Sertoli cells within the seminiferous tubules to initiate spermatogenesis during puberty and maintain spermatogenesis throughout adulthood.

1.1.2.3 Testis

The human testis is essential in steroidogenesis and the production of spermatozoa. Once LH acts on the Leydig cells and testosterone is produced, the active testosterone metabolites dihydrotestosterone and estradiol are formed to act on target organs. After FSH acts on Sertoli cells, various proteins and growth factors are produced, leading to seminiferous tubule growth during development and sperm production at puberty. The testis also produces other regulatory proteins such as inhibin and activin. Inhibin is produced by the Sertoli cells in response to FSH stimulation, acting as a negative feedback inhibitor at the anterior pituitary, whereas activin has a stimulatory effect on FSH production [2]. Testosterone and estrogen are also capable of regulating hormone production via feedback suppression on the hypothalamus and anterior pituitary.

1.2.1.1 Testicular Parenchyma

The human testis is an external, ovoid organ that hangs from the inguinal canal by the spermatic cord and is located within the scrotum. Each testis has a volume of 15–30 ml and measures 3.5–5.5 cm in length by 2.0–3.0 cm in width [3]. Each testis contains two compartments: an interstitial compartment made up of Leydig cells that are responsible for testosterone production and secretion, and a seminiferous tubule compartment that is made up of Sertoli cells and germ cells, where spermatogenesis occurs. Approximately 80 percent of testicular volume is dedicated to spermatogenesis. Figure 1.3 represents a lateral cross-section view of the human testis.

Figure 1.3 Lateral cross-section view of a human testis.

Courtesy of the National Cancer Institute

1.2.1.2 Testicular Vascular Supply and Innervation

Arterial blood supply to the testis originates from three sources: the testicular artery, which arises from the abdominal aorta; the cremasteric artery, which arises from the inferior epigastric artery; and the deferential artery, which arises from the superior or inferior vesical arteries. The pampiniform plexus is an intricate venous network responsible for venous return from the testes to the testicular vein and temperature regulation of the testis. It is this countercurrent heat exchange that is necessary for maintaining a testicular temperature lower than normal body temperature that is ideal for sperm maturation. The testis is innervated by the intermesenteric nerves and renal plexus [2].

1.2.1.3 Interstitium

The main component of the testis interstitium is Leydig cells, which are responsible for testicular androgen production. Cholesterol is the precursor to testosterone synthesis within the Leydig cells and undergoes several enzymatic reactions once inside the cells to be converted into testosterone. Regulation of androgen synthesis is controlled by numerous factors. The feed-forward mechanism of testosterone synthesis involves hypothalamic GnRH stimulation of the anterior pituitary, which leads to LH release and activation of testosterone production in Leydig cells. The other important regulatory mechanism of testosterone synthesis is via negative feedback of peptide and steroid hormones produced by the testis. Testosterone and estradiol act at the hypothalamus and the anterior pituitary to inhibit GnRH and gonadotropin secretion [3].

1.2.1.4 Seminiferous Tubules

The seminiferous tubule compartment of the testis is composed of Sertoli cells and germ cells, where spermatogenesis occurs. Sertoli cells have many functions, most of which are associated with germ cell development and movement. The following are some of the most important functions of Sertoli cells: (1) provide structural support; (2) create tight junctions that form an immunological blood–testis barrier; (3) contribute to germ cell migration and spermiation; and (4) nourish germ cells via secretory products [4].

Germ cells are located within the seminiferous tubules of the testis and give rise to spermatozoa for male reproduction. Germ cell lines are established by week four of embryogenesis, and somatic cells surrounding the germ cells lead to germ cell differentiation into the male or female pathway. In males, these somatic cells that lead to germ cell differentiation are the Sertoli and Leydig cells. Once directed down the male path, the gonocytes migrate to the basal membrane and become spermatogonia around six months after birth, remaining dormant until puberty [5].

Surrounding the seminiferous tubules are multiple layers of tissue, called peritubular tissue, which contains peritubular myoid cells that are thought to have various functions within the testis. Peritubular myoid cells are believed to create a smooth muscle layer surrounding the tubules that exerts a contractile force to traffic spermatozoa throughout the testis. In addition, myoid cells within the peritubular tissue are also responsible for maintaining spermatogonial stem cells. Studies have shown that peritubular myoid cells secrete GDNF (glial cell derived neurotrophic factor) during spermatogenesis, leading to signaling of a co-receptor RET, which leads to upregulation in Src family kinase (SFK) signaling and eventually self-renewal of spermatogonial stem cells via activation of genes encoding transcription factors [6]. Knockout studies of the GDNF pathway have demonstrated loss of spermatogonia and infertility, and overexpression studies of GDNF have revealed buildup of spermatogonial stem cells with no differentiation, leading to the conclusion that GDNF signaling is crucial for maintaining spermatogonial stem cells [6].

The blood–testis barrier is the barrier between the seminiferous tubules and the blood vessels within the testis. This barrier is actually composed of the Sertoli cells of the seminiferous tubules, which is why it is also referred to as the Sertoli cell barrier. The blood–testis barrier is composed of four separate cell junctions – tight junctions, ectoplasmic specializations, desmosomes, and gap junctions – which are all present between Sertoli cells and create two separate compartments within the blood–testis barrier: the basal and adluminal compartments [7]. This allows germ cells to be isolated from blood vessels and the lymphatic systems within the adluminal compartment, creating a microenvironment necessary for the completion of meiosis without a normal immune response from the male’s immune system acting against the newly created sperm [7].