Interactions of the Hypothalamus, Pituitary, and Testes (HPTA)
by Sanjac

During a cycle of AAS, natural production of testosterone decreases, often times to zero. In many cases, the diminished natural testosterone production causes a cessation of sperm production (spermatogenesis), and the male becomes sterile. After the cycle, the body's ability to make testosterone may take months to start again. Aside from the undesirable sterility and loss of strength, other hormone levels get out of whack because of the low testosterone , and cause other problems such as increased body fat and depression. The body produces many hormones, and the levels of most hormones are interrelated. This article will examine the factors involved in regulating the production of certain hormones in the body, particularly by the Hypothalamic-Pituitary-Testicular Axis. As always, the author does not condone the use of steroids by persons not under the care and guidance of a qualified physician.

Endogenous Testosterone
Where is testosterone made in the body? Well, about 95% is produced in the testicles, in special cells called "interstitial cells" or Leydig cells. These cells surround cells in the seminiferous tubules, called Sertoli cells, whose function is to produce sperm. Spermatogenesis in the Sertoli cells requires testosterone, and when endogenous testosterone diminishes, then sperm production stops (and you end up with raisins). Bear in mind that Leydig cells and Sertoli cells are in close proximity to each other. Therefore, the testosterone concentration is high, relative to the concentration in the bloodstream. Sertoli cells require high testosterone concentration for the sperm cells to begin the maturation process. So, even though you might have "a lot" of exogenous testosterone when on-cycle, the concentration is not high enough at the Sertoli cells to promote spermatogenesis because the Leydig cells have shut down. This, combined with a lack of Follicle Stimulating Hormone (FSH), renders many men sterile during a cycle.

The "Axis"
Hang on a minute, the Leydig cells shut down? Why? How?

Well, the short answer is, "hormones". Hormones are the body's way of sending signals, or information from one part of the body to another. In a computer, electrons (electricity) act as the signal; in the body (which doesn't have wires!), the signals must be sent with chemicals, and that is the role of hormones. The term "HPT Axis" refers to the interaction of the hypothalamus, pituitary, and testes (there are other axes as well). For the Leydig cells, Luteinizing hormone (LH) is released from the pituitary and it signals the Leydig cells to produce testosterone. Similarly, the pituitary releases FSH, and it tells the Sertoli cells to make sperm (as well as androgen-binding-protein). The pituitary is a gland that produces and stores a number of hormones, under the control of the hypothalamus. The hypothalamus might be considered to be the General (as in military), and the pituitary would be a Colonel under the General's command. The hypothalamus decides how the body's organs should operate, and the pituitary gives the actual "orders" to the target organs. Some of the "signaling" hormones made or stored in the pituitary are:

Growth Hormone
Thyroid Stimulating Hormone (TSH)
Vasopressin (or Antidiuretic hormone)
Luteininzing Hormone (LH)
Follicle Stimulating Hormone (FSH)
Adrenocorticotropic Hormone (ACTH)

The hypothalamus and the pituitary are very close together, and are located at the base of the brain. Just as the pituitary uses hormones to signal the target organ (testes, thyroid, etc) to do something, the hypothalamus uses other hormones to signal the pituitary to do its job. Some of these "Hypothalamic Releasing Factors" are (along with the pituitary hormones affected):

Hypothalamic Hormone: Regulates:
Gonadotropin Releasing Hormone LH, FSH
Growth Hormone Releasing Hormone GH
Thyrotropin Releasing Hormone TSH
Corticotropin Releasing Hormone ACTH

But how does the hypothalamus know when its commands have been carried out? By what's called a "feedback loop". Just as a General relies on reports from the field, the hypothalamus must monitor the results of its commands. The hypothalamus has sensors (receptors) to determine the levels of the chemicals (hormones) produced by the target organs. For our purposes, we will examine only one feedback loop, the one involving the testes.

The hypothalamus has both androgen receptors and estrogen receptors. When the level of either hormone gets too high, the receptors become more highly activated, and the hypothalamus stops sending Gonadotropin Releasing Hormone to the pituitary. The pituitary, in turn, stops sending LH and FSH to the testes. Thus, the signal is, "stop producing testosterone (and sperm)". We know that androgens (and NOT just estrogen) stop the action of the testes because exogenous DHT by itself (which cannot convert to estrogen) is very effective at shutting down the testes. A schematic of the HPTA (and other glands) is shown below. Note that the other glands are involved in feedback mechanism also.

What does the estrogen/androgen feedback loop mean to bodybuilders? It means that, when using exogenous androgens, the hypothalamus is very effectively signaled (by binding to the AR's on the hypothalamus) that there is plenty of androgen, and that the testes should be shut down. As long as the level of exogenous androgen is high enough, no reasonable amount of Clomid (or other estrogen-blocker) will be able to keep the testes functioning. So, the only reason to take Clomid during a cycle is if you are susceptible to gyno, or want to try to reduce the bloating associated with elevated estrogens. Both of these actions take place at sites other than at the hypothalamus.

How does hCG work and what does it do? This hormone (produced by pregnant females) acts very much like LH, and it even closely resembles LH (and FSH) in chemical structure. So, administration of hCG sends a signal to the testes to start production of testosterone (thus, hCG can help prevent testicular atrophy during a long cycle). However, remember that the testosterone produced can signal the hypothalamus to stop sending the signals to turn on the testes. So, hCG can be somewhat inhibiting to the natural process of hormone release. That is why many believe that hCG should not be used at the end of a cycle, when the desire is to stimulate natural production of hormones.

It has become standard practice to use Clomid at the end of a cycle; because it is felt that blockage of the estrogen receptors on the hypothalamus will cause it to start signalling for the production of testosterone by releasing Gonadotropin-releasing hormone. While this sounds very good in theory and works in many cases, it does not always work, particularly in older men. For some, the use of clomid does not help "jump-start" the gonads at the end of a cycle, and some believe that only time will allow the hypothalamus to begin action again. Doctors still rely on the combination of clomid and hCG (yes, even after a cycle), and there appear to be indications that this combination therapy is a little more successful than clomid by itself. To be absolutely sure, a man who uses exogenous steroids should have blood work done after being off-cycle for a while, in order to ensure that the hormone levels have come into normal ranges.

Finally, many men who use steroids get high blood pressure very early in a cycle. While many have attributed this to erythropoiesis (production of too many red blood cells and thickening of the blood), I believe that the increase in BP is due to a direct action of androgens on the hypothalamus, altering the release of Vasopressin. Doctors who prescribe hormone-replacement therapy often monitor the hematocrit (% of red blood cells), and recommend that the patient donate blood if the hematocrit exceeds 50. I am not certain, however, that this helps the elevated blood pressure that much.