Hypothalamic Pituitary Testicular Axis: Structure

The Hypothalamic-Pituitary-Testicular Axis refers to the release of hormones by three glands and the effects of those hormones on the body. These three glands release multiple hormones and cause multiple widespread and localized effects on the body. The Hypothalamus produces and releases a Gonadotropin-Releasing Hormone (GnRH). GnRH is a peptide hormone that is synthesized and released by the neurons in the Hypothalamus. The Pituitary gland produces luteinizing hormone (LH), and follicle-stimulating hormone (FSH). The Gonads produce Estrogen (Females), and Testosterone (Males). This axis is functional in all animals and controls development, reproduction, and aging.

The Hypothalamus, located in the brain, produces and secretes GnRH. GnRH then travels to the Anterior Pituitary Gland through the Hypophyseal Portal System. It then binds with receptors on the secretory cells, or Gonadotrophs, of the Adenohypophysis and the cells then begin to produce and release LH and FSH into the blood stream. When LH and FSH are released into the blood stream, they travel to the testes. LH causes the interstitial cells, or Leydig cells, in the testes to produce Testosterone, and FSH plays a major role in Spermatogenesis and also helps in stimulating Testosterone production.

The Hypothalamus is constructed of epithelial tissue and has many neuron cell bodies which allow the Hypothalamus to help control which hormones are released from the Pituitary gland. Most of, if not all of, the capillaries are fenestrated to allow easy passage of proteins and other molecules into and out of the blood. There are three regions of the Hypothalamus; Anterior, Tuberal, and Posterior. There are also medial and lateral areas of these three regions. The Hypothalamus is also composed of many different nuclei, each region of the Hypothalamus houses one or more of these nuclei. In accordance with the Hypothalamic-Pituitary-Testicular Axis is the Tuberal Medial Region of the Hypothalamus which houses the Arcuate nucleus, or AR, which stimulates the release of GnHR from the neuroendocrine cells in the Hypothalamus.

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When GnRH is released, it enters what is known as the hypophyseal portal system. The hypophyseal portal system is the vascular connection between the Hypothalamus and the Anterior Pituitary. It is composed of a primary and secondary capillary plexus, and the hypophyseal portal veins which flow through the Anterior Pituitary gland. First, GnRH enters the blood and flows through the Superior Hypophyseal Artery into the primary capillary plexus. The Primary capillary plexus is located in the Infundibulum, or connecting stalk between the Pituitary gland and the Hypothalamus. After flowing through the primary capillary plexus, the blood then reaches the hypophyseal veins and then the secondary hypophyseal plexus. Through these three sections of the hypophyseal portal system, GnRH is released into the Anterior Pituitary Gland.

The Anterior Pituitary Gland, also known as the Adenohypophysis, is located just below the Hypothalamus. The Hypothalamus and Anterior Pituitary have no neural connections, but there is a vascular connection. The Anterior Pituitary gland is made up of glandular tissue. Glandular tissue is made up of epithelial cells that carry out secretions. These secretory cells, or Gonadotrophs, are stimulated by GnRH. In turn, these cells produce LH when high concentrations of GnRH are released and FSH when lower concentrations of GnRH are released. LH and FSH are then released back into the secondary capillary plexus of the hypophyseal portal system and then travel into the blood stream and down to the testes.

Luteinizing Hormone (LH), or Lutropin, is a glycoprotein that stimulates the interstitial cells, known as Leydig Cells, in the testes to produce Testosterone. Testosterone is an androgen that promotes activity within the Endocrine System. It also stimulates intratesticular activity and spermatogenesis. Follicle-Stimulating Hormone (FSH) is also a glycoprotein. FSH stimulates the production of sperm cells in the testes through a process called spermatogenesis.

The process of spermatogenesis takes place in the testes, in a cell known as a Sertoli Cell. The Sertoli cell has FSH receptors throughout and is usually referred to as a “nurse”, or “mother” cell. Spermatogenesis takes place in the Sertoli cell within the seminiferous tubules of the testes and is the process by which sperm are created in the testes. Spermatogenesis is further enabled by an Androgen-Binding Protein, or ABP, a product produced and also released from Sertoli cell. ABP is a glycoprotein that binds with Testosterone and allows it to become more concentrated within the seminiferous tubules to enable spermatogenesis.

A matured sperm cell starts out as what is called a spermatogonium, which is referred to as a stem cell in the production of sperm. Next, the spermatogonium divides into two daughter cells, one is type A the other is type B. Type A is another spermatogonium, or stem cell, while type B moves onto the first stage of Meiosis and grows into a Primary spermatocyte. From the Primary spermatocyte, the cell enters stage two of Meiosis and divides into two Secondary spermatocytes. The two spermatocytes then each divide into what are now known as Early Spermatids, from this stage they develop, through Spermiogenesis, into late spermatids and eventually, with major influence from Testosterone, the late spermatids become spermatozoa. Once the process of spermatogenesis is complete, the spermatozoa are moved into the Epididymis and are able to fertilize a female egg.

Inhibin and Activin are also released from the Sertoli cell. Inhibin and Activin are protein complexes that have opposite effects of each other. Activin, which is also released from the Pituitary gland, induces FSH synthesis and GnRH release. Activin also induces spermatogenesis. For example, when sperm count in the testes is low, Activin induces spermatogenesis to raise the sperm count. Inhibin reduces FSH synthesis and the release of GnRH. Inhibin also regulates spermatogenesis. If the sperm count in the testes is high, Inhibin will slow down the rate of spermatogenesis by communicating with the Hypothalamus and the Pituitary gland.

Leydig Cells, when stimulated by LH, produce Testosterone. When LH stimulates the Leydig Cell, it causes increased activity of cholesterol desmolase. Cholesterol desmolase is an enzyme that helps to convert cholesterol into pregnenolone, which leads to the production of Testosterone. Testosterone is then released into the blood stream and transported around the body for multiple uses. The hormone is used for many functions in the body and is usually converted into other hormones in different organs and target cells. For Example, when Testosterone reaches the prostate, it must be converted to Dihydrotestosterone, so it can bind to the nucleus of the cells present in the prostate.

Testosterone plays a very important role in the Hypothalamic-Pituitary-Testicular Axis. Although it is not produced until late in the series of events that have to occur for it to be produced, it regulates the release of the hormones that are need for it to be produced in the Leydig Cell. Testosterone does this by communicating with the Hypothalamus. When Testosterone levels are high, the Hypothalamus is stimulated to decrease its production of GnRH. In a sense, Testosterone levels can be considered a regulatory factor of the Hypothalamic-Pituitary-Testicular Axis.

Testosterone also controls many other important factors in the body. Before a male reaches puberty, Testosterone is almost non-existent in the body, besides the fetal stages of development, and in the first few months of life. In the womb, Testosterone serves a small effect on the development of the seminal vesicles in the testes and also development of the prostate. It is not truly known what Testosterone effects in the first few months outside of the womb. Puberty in males is activated and carried out through the use of Testosterone, and its levels of concentration in the blood stream. Once a Male starts puberty, there will always be a constant concentration of Testosterone within the blood plasma. Testosterone stimulates target organ growth into adult size and function of ducts, glands, and the penis. If Testosterone becomes non-existent within the body, a man may become sterile and/or unable to reproduce through sexual intercourse. Testosterone also stimulates the growth of bones, muscles, facial, pubic and body hair. Testosterone will also constantly affect certain regions of the brain into adult life. It also stimulates growth in other non-reproductive organs such as the Larynx, and also the skin. Testosterone also has, what are sometimes referred to as, Somatic Effects. First, Testosterone causes the epiphyseal plates and skeletal bones to stop growing. Second, Testosterone increases the basal metabolic rate within the body, and also influences behavior. In males, it serves as a basis for sex drive, or libido. Although Testosterone is also produced in the adrenal glands, without production in the testes, the male reproductive system would not be functional and the body may never reach its full potential size through puberty because the adrenal glands are not able to produce enough Testosterone to help regulate all of the changes, and everyday functions of the male body.

The Hypothalamic-Pituitary-Testicular Axis is a complex system, and therefore can be damaged by many pathological effects on the many pieces if the system. Liver and Kidney disease can bring on Hypogonadism, which disallows the sex glands to produce hormones. Another pathological effect is Sarcoidosis. Sarcoidosis can be caused by granulomas in the Anterior Pituitary gland. These granulomas cause extensive pressure to be exerted upon the secretory cells of the pituitary sometimes causing hypo secretion of hormones, and disallowing the secretions to be regulated. Hypopituitarism also affects the HPT axis. Hypopituitarism is a disorder which disallows the Pituitary gland to produce some or all of its hormones. Hypogonadism is a deficiency in the production of hormones by the sex glands, such as the testes or ovaries. Alcoholism can also affect the hypothalamus by inhibiting the hypothalamus’ control of the secretion of its hormones to the Pituitary gland. A major pathology of the Hypothalamus is a Hypothalamic Hammartoma. A Hypothalamic Hammartoma is a tumor caused by a mass of Neurons and Glia bunched together within the Hypothalamus. Glia is a myelin producing cells that protect Neurons in the brain. These Hammartomas can cause Precocious Puberty, which is when puberty begins at a very young age. Though, there are no direct threats to the child. Puberty is carried out normally. The early start is the only unusual factor of precocious puberty. Another condition known to affect the HPT Axis is Neurofibromatosis. Neurofibromatosis is a condition that is hereditary, and is known to cause tumors in the Hypothalamus. The tumors are usually known as Gliomas. Gliomas are formed by the abnormal growth of glial cells. These tumors can be especially aggressive in adults, more so than children.

The Pituitary gland is also susceptible to many pathological effects. The most common effects on the pituitary gland are Pituitary tumors. These tumors can be one of three different types of Pituitary tumors. There Hypersecretion tumors, Hyposecretion tumors, and Large Pituitary tumors. Hypersecretion tumors cause the Pituitary gland to secrete too much of any specific hormone that it produces. This can cause increased Testosterone production. Because Testosterone helps regulate its own production, these hyper secretion tumors make it hard for the body to regulate the production of Testosterone. Hyposecretion tumors inhibit hormone production in the Pituitary. When the Pituitary gland cannot secrete enough hormones, Spermatogenesis cannot take place, as well as Testosterone production. Head trauma, such as a hard blow that may cause a concussion can also cause Pituitary tumors.

Lastly, the testes are the most effected organ with in the HPT Axis. Testicular Trauma is one threat. Testicular Trauma is brought on by the testes being struck, kicked, hit, or crushed. Testicular trauma can be severe enough to permanently damage the testis, or testes, and can even cause it to have to be removed, which can significantly decrease the amount of Testosterone being produced. Testicular Torsion is another threat that can affect the testes. Testicular Torsion is brought on when the spermatic cord becomes twisted. This twisting of the spermatic cord can cut off blood supply to the testes. The loss of blood flow can cause the testes to develop cell damage. The testes can be damaged to the point that they must be removed. Due to the cut off of blood flow, LH and FSH cannot reach the testes, therefore testosterone cannot be produced, and spermatogenesis cannot be carried out. Testicular Cancer is a major pathological threat to the testes. If testicular cancer is caught in the early stages, the testes can resume normal function. If it is caught late, one or both testes may have to be removed. If the testes are removed, normal testosterone production is unavailable, because the adrenal glands cannot produce enough Testosterone to carry out the normal functions that require the use of the steroid hormone. Epididymitis, is the inflammation of the Epididymis. This disorder is most commonly brought on by Chlamydia, a Sexually Transmitted Disease. The Epididymis houses mature sperm and serves as a pathway for sperm to be released during ejaculation. In severe cases, this pathway may be blocked and sperm cannot leave the testis causing infertility, especially in males with Epididymitis in both testes. Hemochromatosis is a disorder where the body is unable to break down iron. The influx of iron in the blood can lead to testicular atrophy, or shrinking of the testes. Testicular atrophy can lead to loss of function in the testes, once again disallowing spermatogenesis, and Testosterone production.

In Conclusion, The Hypothalamic-Pituitary-Testicular Axis is a complex endocrine system within the body. Composed of only three organs, that together cannot weigh more than a pound makes it especially interesting. To think that these three organs can work together and cause such major changes in the body is incredible. Doing the research associated with this paper has definitely opened up a new interest for me.