Written by William Llewellyn
11 July 2006

Anabolic Research
By William Llewellyn

Steroid Fatigue: A Proposed Explanation

 It doesn’t seem too cavalier to operate on the assumption that estrogen is the common link here (or that its suppression is the common cause).
Even though our primary male androgen (testosterone) may offer positive benefits in regard to mental energy and fatigue resistance, these effects might actually be mediated by its conversion to the “female” sex steroid estrogen, and not the androgen itself.

I remember well the first time I took steroids. It was injecting testosterone cypionate and within a few weeks I understood what steroids were all about. It was extremely alluring. The gains were coming with every workout; I had tons of energy and felt like a million bucks. Why wasn’t everyone taking steroids, I quickly wondered.
As my experiences broadened, and the cycles started growing in number, the general feeling of well-being that accompanied my first run of testosterone almost always returned. Almost always, that is. It took a while, but eventually I saw the other side of the coin— that ever-so-occasional cycle that just seemed to suck the energy out of you. You know you’re making progress and know the drugs are working. But you’re simply dragging ass while taking them. If you haven’t been on a cycle like this, experiment long enough and there’s a decent chance you will. On this note, I felt it would be good to take a look at “steroid fatigue” this month, and propose a mechanism that may account for this unusual side effect.

A Common Link
Personally, I’ve only noticed fatigue associated with steroid use on a few occasions. When I did, it always involved one of two scenarios: I was either taking a strong aromatase inhibitor, or I was taking non-aromatizable steroids exclusively. The obvious link in both cases seems to be the suppression of estrogen levels. I was either suppressing estrogen with an aromatase inhibitor, or I was suppressing its precursor (testosterone). And indeed, adding in a little testosterone or dropping the aromatase inhibitor always seemed to fix the problem.
At least for me, the estrogen link always made the most sense. Looking around, I see a very similar trend amongst the bodybuilders I talk to. Again, this side effect is almost invariably associated with the use of strong aromatase inhibitors, such as anastrozole, letrozole, or exemestane, or non-aromatizable anabolic steroids. Not everyone taking these drugs notices such effects mind you, not even close. But they’re consistently the common factor when the subject of fatigue is raised.
It’s starting to look like we need estrogen for a whole new reason. To be sure, let’s first see if we can find some support for this link that isn’t just anecdotal.
A quick search through the medical literature yields some interesting information regarding the effects of estrogen suppression. To begin with, fatigue seems to be a very common complaint during menopause.1 This, of course, is the phase in a woman’s life when estrogen levels are declining. Supplementing with estrogen is popular during menopause and seems to help with this complaint a great deal. We even see a similar complaint with PMS (pre-menstrual syndrome), common when women are at the end of their menstrual cycles and have low estrogen levels. Again, fatigue seems to be somewhat commonly reported.2
What about the aromatase inhibitors themselves? Surely if bodybuilders are noticing this side effect clinical patients must be too. Indeed they are, as has been reported in breast cancer treatment studies with anastrozole,3 letrozole,4 exemestane,5 and fadrozole6. In those papers that quantify the prominence of this side effect, it seems to come up in about eight percent of patients taking the drug. It’s not a majority of users by any means, but it’s one of the most commonly reported side effects of drug use nonetheless.

Serotonin: A Proposed Explanation
At this point it doesn’t seem too cavalier to operate on the assumption that estrogen is the common link here (or that its suppression is the common cause). Key to making a working theory out of this, however, is going to be some type of a plausible explanation.
The answer to this is going to rest in examining the effects estrogen has in the brain. Clearly estrogen is very active here, as the body has seen fit to express both estrogen receptors and the aromatase enzyme (which makes estrogen from precursor hormones) in most regions of the brain7. In fact, the amount of aromatase found here is comparable to that in adipose and testicular tissues, so it’s not small by any means. But can this hormone actually affect wakefulness?
Although the exact role estrogen plays in the central nervous system is largely speculative, a few things are understood at this point. Among them is the fact that estrogen affects certain neurotransmitters in the brain, and among these is the all-important serotonin. I think we’re on to something.
Serotonin (5-hydroxytryptamine) is one of the primary neurotransmitters in the central nervous system. It’s involved in a number of biological functions, including appetite, libido, temperature regulation, hormone regulation, pain modulation, learning and memory and mood.8 Although its exact role here remains to be determined, serotonin is believed to be closely tied to the sleep-wake cycle,8 of particularly obvious interest to our working theory on estrogen and fatigue.
This neurotransmitter has been shown to play a role at both ends of the spectrum, in fact, it was first identified as a sleep-promoting chemical back in the 1950s and much later, (the 1970s) as a “wake” neurotransmitter. The currently accepted model calls for serotonin to be most active during waking hours, where it helps maintain a mentally alert state, but also to play a permissive role toward sleep later, when needed. Interestingly, it’s also been noted that sufferers of chronic fatigue syndrome tend to have a lower density of serotonin transporters than normal subjects,10 and that alterations in the serotonogenic system may play a role in the etiology of this disease.11
Although not entirely understood, estrogen appears to have some notable control over the activity of serotonin in the brain. This may be mitigated in one or a combination of ways. To begin with, some studies have shown substantial changes in serotonin receptor concentrations and binding when this hormone is administered.12,13,1 Greater receptor concentrations, in light of constant levels of serotonin, should result in greater signaling, as the neurotransmitter finds it easier to locate and activate cellular targets.
Other studies have shown estrogen to have a stimulatory effect on local levels of serotonin, perhaps mediated by a hindrance of serotonin reuptake.15 It’s also interesting to note some additional studies with testosterone, which demonstrated that this hormone too has a stimulatory effect on serotonin receptor proliferation. This effect, however, could not be maintained when dihydrotestosterone (which can’t convert to estrogen) was administered. This study suggests that even though our primary male androgen (testosterone) may offer positive benefits in regard to mental energy and fatigue resistance, these effects might actually be mediated by its conversion to the “female” sex steroid estrogen, and not the androgen itself.16

In Closing
Admittedly, a great deal of exploration still needs to take place concerning the connections between hormones, neurotransmitters, and mental alertness. However, we have enough data to foster some heavy speculation at this time and it strongly suggests a couple of things. First, it suggests that estrogen suppression is responsible for “steroid fatigue.” I think the anecdotal reports alone make this explanation difficult to dismiss. Secondly, it seems to suggest that an interference with serotonin signaling (secondary to suppressed estrogen) is the underlying mechanism for this fatigue. With this understanding, we should be a little better prepared to deal with the problem next time it presents itself.
Altering one’s drug intake so that estrogen suppression isn’t as marked, seems to be the key “workaround” in virtually all such cases. Those insisting on dramatic estrogen suppression, however, may either have to suck it up or get creative. Perhaps this means targeting serotonin instead of estrogen. Selective serotonin reuptake inhibitors, which increase serotonin levels, seem to be very helpful in treating chronic fatigue syndrome. Maybe they could be of use with steroid fatigue also. There are many stimulants that might be worth experimenting with as well.
Steroid fatigue is a side effect only recently being talked about with any frequency, so it may ultimately take some time for the most effective treatment options to be presented. Until then, we’ll have to settle for a better understand of the problem.

References:
1. Menopause, HRT and menopausal symptoms. Kenemans P. J Epidemol Biostat, 1999;4(3):141-6; discussion 146-53.
2. Premenstrual Syndrome. Dickerson LM et al. Am Fam Physician 2003 Apr 15;67(8):1743-52
3. Phase II trial of anastrozole in women with asymptomatic mullerian cancer. Gynecol Oncol, 2003 Dec;91(3):596-602.
4. Letrozole. A review of its use in postmenopausal women with advanced breast cancer. Drugs, 1998 Dec;56(6):1125-40. Review.
5. Exemestane: a review of its clinical efficacy and safety. Breast, 2001 Jun;10(3):198-208.
6. A study of fadrozole, a new aromatase inhibitor, in postmenopausal women with advanced metastatic breast cancer. J Clin Oncol, 1992 Jan;10(1):111-6.
7. Neurosteroid biosynthesis in the human brain and its clinical implications. Birgit Stoffel-Wagner. Ann N.Y. Acad Sci, 1007: 64-78 (2003)
8. Effect of estrogen-serotonin interactions on mood and cognition. Zenab Amin et al. Behav Cogn Neurosci Reviews, 4(1) 2005:43-58
9. Serotonin and the sleep/wake cycle: special emphasis on miscodialysis studies. Chiara M Portas et al. Progress in Neurology, 60(200) 13-35.
10. Reduction of serotonin transporters of patients with chronic fatigue syndrome. Neuroreport, 2004 Dec 3;15(17):2571-4
11. Association between serotonin transporter gene polymorphism and chronic fatigue syndrome. Narita M et al. Biochem Biophys Res Commun, 2003 Nov 14;311(2)264-6
12. Serotonin receptor modulation by estrogen in discrete brain nuclei. Biegon A. et al. Neuroendocrinol, 1982 Oct;35(4):287-91
13. Effects of oral estrogen, raloxifene and arzolifene on gene expression in serotonin neurons of macaques. Bethea C: et al. Psychpneuroendocrinol, 2002 May;27(4):431-5.
14. Changes in 5-HT1A receptor binding and G-protein activation in the rat brain after estrogen treatment: comparison with tamoxifen and raloxifene. Maryvonne Le Saux et al. Rev Psychiatr Neurosci, 2005;30(2)
15. Intracellular signaling involved in estrogen regulation of serotonin reuptake. Koldzic-Zivanovic N. et al. Mol Cell Endocrinol, 2004 Oct 29;236(1-2):33-42
16. Testosterone as well as estrogen increases serotonin1A receptor mRNA and binding site densities in the male rat brain. Sumner BE, Fink G. Brain Res Mol Brain Res, 1998 Aug 31;59(2);205-14