The Never Ending Cycle

We've long speculated that certain steroids and prohormones (like 4-AD or the new 4-AD-EC) might be okay to use for extended periods of time with little or no side effects. Although we've seen evidence of this in the real world, we decided to ask Cy Willson to delve into the pharmacology behind this type of usage and report back to us on its feasibility. This article will sum up his findings and provide guidelines to those who want to give long term usage a shot.

Anabolic steroids. You gotta love 'em. After all, what other substances allow you to achieve so much in such a short time frame? Steroids improve the two aspects of living often referred to as the "spice of life": more muscle and less fat. And on top of that, you'll feel pretty damned good about the world when on them, at least in most cases. (Okay, maybe that's just my version of the "spice of life," but I digress.)

The results you get when "on" are so remarkable that you may be tempted to stay on for extended periods. Not a good idea. But there may be a way to do this while minimizing or even avoiding most side effects. The same may also be true for legal steroids like prohormones or prosteroids.

What I'm going to do is let you in on a way to continually stay on a few select androgens while causing a minimal amount of inhibition when it comes to your endogenous Testosterone production. I'm going to explain what the two main determinants are that essentially cause inhibition of endogenous Testosterone production, explain how to minimize this, and list which drugs or supplements are best to use.

Essentially, the fate of Testosterone production depends on both the AR and ER.

The AR (Androgen Receptor)

The first determinant of how well any given androgen will inhibit endogenous Testosterone production is the degree to which it binds to the androgen receptor. Hence, the stronger or more avidly it binds to the AR, the more it will inhibit Testosterone production. How do I know? Glad you asked! Get ready for my usual flood of studies.

First, in one study using normal men, they found that "blocking" the androgen receptor (using a nonsteroidal androgen receptor antagonist called flutamide) and hence preventing androgens from binding to the AR, caused an increase in LH (luteinizing hormone). As you might know, LH signals the testicles to produce Testosterone. (1)

In short, no binding of androgens, no decrease in Testosterone.

In another study, dihydrotestosterone (DHT), which binds to the AR even better than Testosterone, was given to twelve normal men for a period of ten days. What did they find? Testosterone, both free and unbound, as well as LH, were significantly reduced. (2)

Binding of androgens? A decrease in Testosterone.

In yet another study, researchers gave normal men either Testosterone by itself or Testosterone along with testolactone (Teslac), an aromatase inhibitor which prevents Testosterone from converting to estrogen, and evaluated the effects on LH. In the group that only received Testosterone, they found a 50% reduction of LH and a 50% increase of estradiol. However, in those receiving both Testosterone and testolactone there was no increase in estradiol, but there was still a significant reduction of LH. This means there's definitely another way in which androgens inhibit endogenous Testosterone production, aside from conversion to estrogen. The degree to which they bind to the AR is surely that other mechanism. (3)

DHT was also found to suppress LH even greater than Testosterone alone. (4) This idea is also supported in other ways. Take a look at trenbolone acetate (TA), which is far more androgenic. TA binds to the AR much more avidly than Testosterone and as such it's nearly three times as antigonadotropic. (5) Nandrolone also binds well and is extremely effective at binding to the AR, although the fact that it promotes progesterone may contribute to its potent effects in terms of reducing LH and Testosterone. (6,7)

In short, it's pretty conclusive that the tighter a steroid binds to the androgen receptor, the more it ends up inhibiting your own production of Testosterone.

The ER (Estrogen Receptor)

Okay, now this portion shouldn't be much of a surprise to most of you. When an androgen is converted (aromatized) to an estrogen, that estrogen will then bind to estrogen receptors in the hypothalamus and pituitary and thus cause suppression of LH secretion. After all, this is the mechanism through which anti-estrogens such as clomiphene exert their "Testosterone-boosting" effects. By simply acting as estrogen antagonists at the ER, they increase LH levels and in turn increase Testosterone production. This is the same reason why anastrozole (Arimidex) is effective at increasing LH and Testosterone, since it inhibits estrogen formation all together. (8,9)

So, with this in mind, using an anti-estrogen along with an androgen that aromatizes should at the very least reduce the severity of LH and consequently, Testosterone secretion. A study that supports this notion consisted of 47 healthy young men either receiving KTCZ (a drug that inhibits Testosterone formation) alone, KTCZ along with estradiol, KTCZ and Testosterone, or KTCZ, anastrozole (Arimidex) and Testosterone. Of course, there was also a placebo group.

What did they find? When administering estrogen or Testosterone without the aromatase inhibitor, LH was decreased significantly. However, when Testosterone was given along with anastrozole, no effect was seen on LH. In other words, there was no suppression. (10) Awesome right? Well, yes, but the only problem is that they were using ten milligrams per day and that's just a bit excessive. I think one milligram would be sufficient for our intended purposes.

The take home message is that if estrogen binds to the estrogen receptor, it ends up causing a decrease in your own production of Testosterone.

Putting It All Together

Now that I've provided this info you're probably wondering how it will apply to you. Well, with the two mechanisms above in mind, we can conclude that an androgen that doesn't bind very avidly to the AR and doesn't aromatize to estrogen would be the best in terms of preventing an excessive reduction of endogenous Testosterone production.

So, with this reasoning, if you were to use something like methandrostenolone (D-bol), along with anastrozole or an estrogen antagonist of some sort, you could prevent most of the suppression of LH and endogenous Testosterone. (D-bol alone, however, causes around a 50% reduction of LH and a 69% reduction of Testosterone in normal men).

Stanozolol (Winstrol) would be a good candidate for a long-term drug but one study showed it to decrease Testosterone by 55%. True, it isn't as much of a reduction as D-bol, but I think the fact that it works by binding to androgen receptors is the reason for the reduction.

Fluoxymesterone (Halotestin/Stenox) is probably the closest thing to an illegal steroid that we could use long-term, aside from D-bol used in combo with an anti-estrogen. The drug was shown to have no effect on LH in normal men. (11,12,13)

As far as legal steroids, we need to take a long hard look at 4-AD. This is probably the best option aside from D-bol along with anastrozole (Arimidex) or an estrogen antagonist (clomiphene). First, 4-AD doesn't bind well to the AR so it must work via some non-AR mediated mechanism. Secondly, it doesn't aromatize so this makes it a perfect candidate for long term usage.

Essentially, that's why I've written this article. With a few select androgens, you can stay on for a longer period of time without having to worry about suppression of your endogenous Testosterone production. This will also help to alleviate some of the "crash" most guys experience after coming off of a cycle. Of course, when you include the fact that the two androgens I did mention are 17 alpha-alkylated, this limits the amount of time you should be using them because of liver toxicity issues. The only other option that leaves us with would be low dosages of Testosterone (<200 mg per week) taken concurrently with anastrozole or 4-AD. Even so, the overall winner in each case is 4-AD.

If you look at 4-AD, it isn't 17-AA, doesn't aromatize, and doesn't bind well to the AR. Now, there's still one problem you need to consider and this is inherent of most androgens: a potentially negative effect on blood lipids. Well, considering that 4-AD actually increases endogenous Testosterone production to a high normal range, this will actually decrease LDL and increase HDL. In other words, it may actually be good for your blood lipids. (14-17)

But then again, we still have to remember that this is an androgen so I suppose we should still be somewhat cautious here. Even so, negatives effects seen with changes in blood lipids don't occur immediately and take years to develop. With that being said, I'm going to take a middle of the road approach and recommend 100 to 200 mg of 4-AD per day for 12 to 16 weeks without taking a break. After 16 weeks, you'll only need to take two weeks off and then you may repeat for another 12 to 16 weeks and so on. The best version of 4-AD in terms of bioavailability and duration of action would be 4-AD-EC.

If you decide to go with D-bol and anastrozole, try 50 to 75 mg per day along with 1 mg of anastrozole. Remember though, it's a 17-AA androgen so there's the risk for liver toxicity with prolonged usage. With fluoxymesterone, you can try 15 to 40 mg per day, but once again it's 17-AA so the same reasoning applies. Again, the 4-AD-EC route is the best in terms of safety. The fact that it's legal makes it a nice choice, too.

Armed with all this info, I wish you luck on your "never ending" cycle!

Highlights for Long-Term Usage:

• D-bol in combo with anastrozole might be the safest, although liver problems are a risk.

• Halotestin is also an option, but it possesses the same potential for liver damage as the D-bol.

• 4-AD, or 4-AD-EC, definitely seems to be the safest for long-term usage (possibly up to 16 weeks at a time).

References Cited

1) Urban RJ, et al. "Acute androgen receptor blockade increases luteinizing hormone secretory activity in men." J Clin Endocrinol Metab 1988 Dec;67(6):1149-55

2) Kuhn JM, et al. "Effects of 10 days administration of percutaneous dihydrotestosterone on the pituitary-testicular axis in normal men." J Clin Endocrinol Metab 1984 Feb;58(2):231-5

3) Marynick SP, et al. "Evidence that testosterone can suppress pituitary gonadotropin secretion independently of peripheral aromatization." J Clin Endocrinol Metab 1979 Sep;49(3):396-8

4) Santen RJ. "Is aromatization of testosterone to estradiol required for inhibition of luteinizing hormone secretion in men?" J Clin Invest Dec;56(6):1555-63

5) Neumann F. "Pharmacological and endocrinological studies on anabolic agents." Environ Qual Saf Suppl 1976;(5):253-64

6) Knuth UA, et al. "Clinical trial of 19-nortestosterone-hexoxyphenylpropionate (Anadur) for male fertility regulation." Fertil Steril 1985 Dec;44(6):814-21

7) Tafurt CA, et al. "Effects of progestin-estrogen combination and progestational contraceptives on pituitary gonadotropins, gonadal steroids and sex hormone-binding globulin." Fertil Steril 1980 Mar;33(3):261-6

8) Hayes FJ, et al. "Aromatase inhibition in the human male reveals a hypothalamic site of estrogen feedback." J Clin Endocrinol Metab 2000 Sep;85(9):3024-6

9) Mauras N, et al. "Estrogen suppression in males: metabolic effects." J Clin Endocrinol Metab. 2001 Apr;86(4):1836-8

10) Schnorr JA, et al. "Aromatization mediates testosterone's short-term feedback restraint of 24-hour endogenously driven and acute exogenous gonadotropin-releasing hormone-stimulated luteinizing hormone and follicle stimulating hormone secretion in young men." J Clin Endocrinol Metab 2001 Jun;86(6):2600-6

11) Holma P, Adlercreutz H. "Effect of an anabolic steroid (metandienon) on plasma LH-FSH, and testosterone and on the response to intravenous administration of LRH." Acta Endocrinol (Copenh) 1976 Dec;83(4):856-64

12) Small M, et al. "Alteration of hormone levels in normal males given the anabolic steroid stanozolol." Clin Endocrinol (Oxf) 1984 Jul;21(1):49-55

13) Jones TM, et al. "The effects of fluoxymesterone administration on testicular function." J Clin Endocrinol Metab 1977 Jan;44(1):121-9

14) Zhao S, et al. "Plasma levels of lipids, lipoproteins and apolipoproteins affected by endogenous testosterone." Hunan Yi Ke Da Xue Xue Bao 1998;23(3):299-301

15) Shapiro J, et al. "Testosterone and other anabolic steroids as cardiovascular drugs." Am J Ther 1999 May;6(3):167-74

16) Zmuda JM, et al. "Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. A 13-year follow-up of former Multiple Risk Factor Intervention Trial participants." Am J Epidemiol 1997 Oct 15;146(8):609-17

17) Barret-Connor EL. "Testosterone and risk factors for cardiovascular disease in men." Diabete Metab 1995 Jun;21(3):156-61