HPTA Handbook

Sanjac's Work via YellowJacket

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

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
IGF-I and IGF-II
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

Good Article on Understanding HPTA Inhibition and Recovery from AS
The Causes of Inhibition

Elevated hormone levels, in general, will cause inhibition of natural testosterone production. Many bodybuilders have come to believe that elevated estrogen levels alone are the sole cause of inhibition, and believe that by blocking estrogen, they can block inhibition.

This is not true. For example, consider the results seen in the second 2-on / 4-off cycle case study reported on Meso-Rx where Jim used 50 mg/day of trenbolone acetate, which does not aromatize, 50 mg/day of Dianabol, which does aromatize, with 250 mg/day of Cytadren as an aromatase inhibitor and 50 mg/day Clomid as an estrogen receptor blocker. His estrogen levels remained in the normal range, though elevated from baseline, since apparently the Cytadren was not sufficient to block aromatization completely. The Clomid should easily have been able to overcome normal estrogen levels, and so if the estrogen-only theory of inhibition were correct, Jim should have been suffering no inhibition. But the fact is, his testosterone levels dropped to only 1/10 his baseline value. Estrogen alone was not the cause of his inhibition. It could not have been the cause of any of it, given the normal levels and the Clomid use.

So much for the estrogen-only theory of inhibition that has been claimed by other writers. That isn’t to say, though, that estrogen is not also inhibitory: it is.

What then besides estrogen can cause inhibition? DHT, which does not aromatize, has been extensively shown to cause inhibition of testosterone production. Androgen alone, then, is sufficient to cause inhibition. In Jim’s case, androgen use was moderately heavy, and androgen alone would seem the cause of the inhibition.

Progesterone is another hormone that can cause inhibition, when used long-term. Paradoxically, in the short term it can be stimulatory. Other relevant factors include beta agonists, opiates, melatonin, prolactin, and probably other compounds. With the exception of beta agonists (e.g. ephedrine and Clenbuterol) and opiates (natural endorphins on the one hand being inhibitory, and Nubain blocking such inhibition) manipulation of these would not seem useful in bodybuilding.

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The Hypothalamic/Pituitary/Testicular Axis (HPTA)

To understand inhibition of testosterone production, we need to know first how it is produced and how production is controlled. The broad general picture is that the hypothalamus receives a variety of inputs, for example, levels of various hormones, and decides whether or not more sex hormones should be produced. If the inputs are high, for example, high estrogen or high androgen or both, then it decides that little or no sex hormones should now be produced, but if all inputs are low, then it may decide that more sex hormones should be produced. It seems that the hypothalamus doesn’t respond only to current hormone levels, but also to the past history of hormone levels.

The hypothalamus itself cannot produce any sex hormones – instead it produces LHRH, or luteinizing hormone (LH) releasing hormone, also called GnRH (gonadotropin releasing hormone.) This then stimulates the pituitary gland.

The pituitary uses the amount of LHRH as one of its signals in deciding how much LH it should produce. Proper response depends on having sufficient receptors for LHRH. These receptors must be activated for LH to be produced. The pituitary also uses sex hormone levels, both current and the past history, in deciding how much LH to produce. Some aspects of the pituitary’s behavior are peculiar. For example, too much LHRH results in the pituitary downregulating LHRH receptors, with the result that very high LHRH production, which one would think should result in high testosterone production, actually lowers testosterone production. Another oddity is that while high estrogen levels inhibit the pituitary, still some estrogen is required to maintain a high number of LHRH receptors. So both very low and high levels of estrogen can inhibit LH production.

LH produced by the pituitary then stimulates the testicles to produce testosterone. Here, the amount of LH is the main factor, and high levels of sex hormones do not seem to cause inhibition at this level.

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Inhibition From AAS Cycles

Because high androgen levels sustained around the clock will cause inhibition, traditional cycles simply cannot avoid inhibition of LH production while on cycle. There are three ways to avoid it:

Avoid having high androgen levels around the clock. This can be done, for example, by using oral AAS only in the morning, with the last dose being approximately at noontime. Even 100 mg/day Dianabol can be used in this fashion with little inhibition. The problem with this approach is that gains are not very good compared to what is seen when high androgen levels are sustained around the clock.
Use an amount and kind of AAS that is low enough to avoid much inhibition. Primobolan at 200-400 mg/week may achieve this effect. Again, gains will be compromised compared to a more substantial cycle. Testosterone esters and Deca are substantially inhibitory even at 100 mg/week so using a low dose of these drugs will simply result in both inhibition and poor gains.
In principle, one could use an antiandrogen, but this would totally defeat the purpose of the cycle.
Where AAS doses are sufficient for good gains, an interesting pattern is seen. For the first two weeks of the cycle, only the hypothalamus is inhibited, and it produces much less LHRH as a result of the high levels of sex hormones it senses. The pituitary is not inhibited at all: in fact, it is actually sensitized, and will respond to LHRH (if any is provided) even moreso than normally. After two weeks however, the pituitary also becomes inhibited, and even if LHRH is provided, the pituitary will produce little or no LH. This then is a deeper type of inhibition. After this point, there seems to be no definite further "switching point" where inhibition again becomes deeper and harder to reverse. As a general rule, I would say that there seems to be little difference between using AAS for 3 weeks vs. 8 weeks: recovery is about the same either way. Between 8 and 12 weeks, it becomes more and more likely that recovery will be difficult and slow, though even at 12 weeks it is common for recovery to not be too problematic, taking only a few weeks. Cycles past 12 weeks seem much more likely to cause substantial problems with recovery. In the hundreds of consultations I have done for people with recovery problems, very few (I can recall two) were for very short cycles such as 6 weeks, while most were for usages of 12 weeks straight or more.

I do not know what changes take place in the hypothalamus and pituitary over a long period of time that result in this problem, but it certainly is true that long-term inhibition makes recovery more difficult on average. I suspect the problem may have to do with change in the "clock" that regulates the pulse rate of LHRH secretion, but I am not sure that that is so.

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Drugs of Use With Regard to Inhibition

Arimidex: This accomplishes the same purposes as Cytadren but without the possible side effects mentioned above. It is however far more expensive. A typical dose is 1 mg./day. The timing of the dosage does not matter, since the drug has a long half-life.

Clomid: After a cycle is over, Clomid at 50 mg/day is usually very effective in restoring natural testosterone production. It acts by blocking estrogen receptors at the hypothalamus and pituitary. If androgen levels are not elevated, this is enough to cause production of at least normal amounts of LH, or often more LH than normal. During the cycle Clomid cannot prevent inhibition, though some think using it during the cycle will allow a faster recovery afterwards. That is not proven though. If nothing else, though, it is useful as an antigyno/antibloating agent during the cycle.

Nolvadex: This works in the same manner as Clomid, but not nearly so well with regard to reversing inhibition. It is better to use this only as an anti-gyno/antibloating agent, if at all. If Clomid is used, there is no need for Nolvadex.

HCG: This does nothing with regard to inhibition of the hypothalamus and pituitary. Rather it acts like LH, and causes the testicles to produce testosterone just as if LH were present. It is useful then for avoiding testicular atrophy during the cycle. The best dosing method is to use small amounts frequently: 500 IU per day is sufficient, and 1000 IU may optionally be used. The amount may be given as a single daily dose or divided into two doses. Administration may be intramuscular or subcutaneous. More is not better: too much HCG can result in downregulation of the LH receptors in the testes, and is therefore counterproductive. Overdosing of HCG can also result in gynecomastia.