T Nation

Bill Roberts: AI vs. SERM Toxicity

Bill, I recently had a conversation with someone who advocated the use of AIs during cycle rather than using SERMs–if needed–in part because, he contended, SERMs have much higher toxicity than Ais and are thus much more dangerous.

What is your opinion of this statement? Are SERMs such as Nolva (which he contended is carcinogenic) and Clomid really that toxic compared to Ais?



No. These drugs have been around a long time and have an excellent safety record.

Lets not forget breast cancer patients can be on these drugs for months, even years in some cases

Generally years.

That actually is the one area where there is substantial concern: not that Nolvadex becomes cancer-causing, but that in some cases it loses effectiveness after about 5 years of continuous use.

For this reason I don’t recommend using it continuously. Not that that is standard practice in bb’ing anyway.

However, while the reason of the person arguing with the OP was wrong, the action suggested – using an AI instead of a SERM during the cycle – is the better way to go these days.

“However, while the reason of the person arguing with the OP was wrong, the action suggested – using an AI instead of a SERM during the cycle – is the better way to go these days.”

Bill, could you please expand/explain this statement.



[quote]crowbar46 wrote:
“However, while the reason of the person arguing with the OP was wrong, the action suggested – using an AI instead of a SERM during the cycle – is the better way to go these days.”

Bill, could you please expand/explain this statement.



If you’re wondering why using an AI is better than using a SERM (assuming you mean for controlling estrogen on cycle) during your cycle, you can find the answer in the AI and SERM sticky.

Aromatase inibitors directly act to avoid the problem of excess estrogen and to keep estrogen levels normal, whereas instead using a SERM in a cycle with aromatizing steroids allows estrogen levels to go out of the normal range and acts only to largely block the effect in many but not all tissues.

It’s cleaner to not allow the problem to develop in the first place.

Thanks bill. I have another question concerning the use of Ais during PCT. Another poster summed it up well in the SERM and AI sticky:

I was going to use a serm and AI in my PCT but I was advised not to use the AI. However, it sounds like you are saying an AI should be used to help keep estrogen in check as you taper off the serm.

But isn’t the whole point of tapering off the SERM to make sure your estrogen levels slowly recover without rebound?

If you throw an AI into the mix as you’re tapering off the serm then you are effectively supressing estrogen again and defeating the point of tapering off the serm. Then you have to taper off the AI to make sure your estrogen levels slowly recover without rebound. So why introduce the AI?

Is my logic/understanding wrong? If you are tapering off the serm why isn’t that sufficient?

Could you please address this issue.



Bill, if one were to use a cycle of non-aromatizing steroids–e.g., designer steroids. Am I correct to assume that the body would respond to the shutdown of Test–and therefore no, or little, Test aromatization to estrogen–by upregulating the aromatase enzyme and/or the estrogen receptors in response?

If this is the case and one were to follow the typical PCT protocol of 4 weeks of Clomid, tapering the dosage down, would this be sufficient time for the body to readjust aromatase enzyme levels and/or estrogen receptor levels back to baseline, or would the use of an Ai–say after the first couple of weeks of PCT and running it several weeks past PCT–be advisable?



I don’t know whether the ER or aromatase enzyme are upregulated in response to low estrogen: never looked into it. It’s not something that could be assumed to occur or not occur.

Way, way back I once actually did this out of lack of having figured that particular thing out yet. I did suffer the classic effects of abnormally low estrogen but no “rebound.” That doesn’t prove anything though, other than that it at least is not necessarily the case that a noticeable rebound effect must occur.

If there were a regulation issue it most likely would be only a matter of days before the number of ER’s was back to normal, anyway.

I’d suggest that instead of being concerned with after-cycle effects from running a cycle in this particular wrong way, to NOT run it this wrong way, but keep estrogen levels in the normal range with either HCG or some dose of an aromatizing steroid.

Thanks Bill, that makes perfectly good sense. So, I assume as to my previous question (in the post above my last one) concerning the concurrent use of a SERM and AI during PCT, you would find this unnecessary?



It’s unnecessary, but using an AI at what is known for the individual to be a suitable dose for maintaining low-normal estrogen is okay, if they have reason to think that their typical estrogen levels aren’t best for the physique, e.g. from tending to having substantial fat on the legs without an AI but not with the AI.

Bill, I’ve been having a conversation with someone who is absolutely convinced that SERMS are highly toxic and likely to increase the risk of cancer, but I just don’t buy this. Here are some studies he quoted, can you give me your thoughts on these. Also, he contends that patients are often maintained on SERMS for years at a time despite their carcinogenic properties because the cancer for which they are being treated would kill them anyway:

Here are the studies he cited:

Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma
An increased incidence of uterine malignancies has been reported in association with NOLVADEX treatment. The underlying mechanism is unknown, but may be related to the estrogen-like effect of NOLVADEX. Most uterine malignancies seen in association with NOLVADEX are classified as adenocarcinoma of the endometrium. However, rare uterine sarcomas, including malignant mixed mullerian tumors (MMMT), have also been reported. Uterine sarcoma is generally associated with a higher FIGO stage (III/IV) at diagnosis, poorer prognosis, and shorter survival. Uterine sarcoma has been reported to occur more frequently among long-term users ( â?¥ 2 years) of NOLVADEX than non-users. Some of the uterine malignancies (endometrial carcinoma or uterine sarcoma) have been fatal.

In the NSABP P-1 trial, among participants randomized to NOLVADEX there was a statistically significant increase in the incidence of endometrial cancer (33 cases of invasive endometrial cancer, compared to 14 cases among participants randomized to placebo (RR=2.48, 95% CI: 1.27-4.92). The 33 cases in participants receiving NOLVADEX were FIGO Stage I, including 20 IA, 12 IB, and 1 IC endometrial adenocarcinomas. In participants randomized to placebo, 13 were FIGO Stage I (8 IA and 5 IB) and 1 was FIGO Stage IV. Five women on NOLVADEX and 1 on placebo received postoperative radiation therapy in addition to surgery. This increase was primarily observed among women at least 50 years of age at the time of randomization (26 cases of invasive endometrial cancer, compared to 6 cases among participants randomized to placebo (RR=4.50, 95% CI: 1.78-13.16). Among women â?¤ 49 years of age at the time of randomization there were 7 cases of invasive endometrial cancer, compared to 8 cases among participants randomized to placebo (RR=0.94, 95% CI: 0.28-2.89). If age at the time of diagnosis is considered, there were 4 cases of endometrial cancer among participants â?¤ 49 randomized to NOLVADEX compared to 2 among participants randomized to placebo (RR=2.21, 95% CI: 0.4-12.0). For women â?¥ 50 at the time of diagnosis, there were 29 cases among participants randomized to NOLVADEX compared to 12 among women on placebo (RR=2.5, 95% CI: 1.3-4.9). The risk ratios were similar in the two groups, although fewer events occurred in younger women. Most (29 of 33 cases in the NOLVADEX group) endometrial cancers were diagnosed in symptomatic women, although 5 of 33 cases in the NOLVADEX group occurred in asymptomatic women. Among women receiving NOLVADEX the events appeared between 1 and 61 months (average=32 months) from the start of treatment.

In an updated review of long-term data (median length of total follow-up is 6.9 years, including blinded follow-up) on 8,306 women with an intact uterus at randomization in the NSABP P-1 risk reduction trial, the incidence of both adenocarcinomas and rare uterine sarcomas was increased in women taking NOLVADEX. During blinded follow-up, there were 36 cases of FIGO Stage I endometrial adenocarcinoma (22 were FIGO Stage IA, 13 IB, and 1 IC) in women receiving NOLVADEX and 15 cases in women receiving placebo [14 were FIGO Stage I (9 IA and 5 IB), and 1 case was FIGO Stage IV]. Of the patients receiving NOLVADEX who developed endometrial cancer, one with Stage IA and 4 with Stage IB cancers received radiation therapy. In the placebo group, one patient with FIGO Stage 1B cancer received radiation therapy and the patient with FIGO Stage IVB cancer received chemotherapy and hormonal therapy. During total follow-up, endometrial adenocarcinoma was reported in 53 women randomized to NOLVADEX (30 cases of FIGO Stage IA, 20 were Stage IB, 1 was Stage IC, and 2 were Stage IIIC), and 17 women randomized to placebo (9 cases were FIGO Stage IA, 6 were Stage IB, 1 was Stage IIIC, and 1 was Stage IVB) (incidence per 1,000 women-years of 2.20 and 0.71, respectively). Some patients received post-operative radiation therapy in addition to surgery. Uterine sarcomas were reported in 4 women randomized to NOLVADEX (1 was FIGO IA, 1 was FIGO IB, 1 was FIGO IIA, and 1 was FIGO IIIC) and one patient randomized to placebo (FIGO 1A); incidence per 1,000 women-years of 0.17 and 0.04, respectively. Of the patients randomized to NOLVADEX, the FIGO IA and IB cases were a MMMT and sarcoma, respectively; the FIGO II was a MMMT; and the FIGO III was a sarcoma; and the one patient randomized to placebo had a MMMT. A similar increased incidence in endometrial adenocarcinoma and uterine sarcoma was observed among women receiving NOLVADEX in five other NSABP clinical trials.

A conventional carcinogenesis study in rats at doses of 5, 20, and 35 mg/kg/day (about one, three and seven-fold the daily maximum recommended human dose on a mg/m²basis) administered by oral gavage for up to 2 years) revealed a significant increase in hepatocellular carcinoma at all doses. The incidence of these tumors was significantly greater among rats administered 20 or 35 mg/kg/day (69%) compared to those administered 5 mg/kg/day (14%). In a separate study, rats were administered tamoxifen at 45 mg/kg/day (about nine-fold the daily maximum recommended human dose on a mg/m² basis); hepatocellular neoplasia was exhibited at 3 to 6 months.

Granulosa cell ovarian tumors and interstitial cell testicular tumors were observed in two separate mouse studies. The mice were administered the trans and racemic forms of tamoxifen for 13 to 15 months at doses of 5, 20 and 50 mg/kg/day (about one-half, two and five-fold the daily recommended human dose on a mg/m² basis).

No genotoxic potential was found in a conventional battery of in vivo and in vitro tests with pro- and eukaryotic test systems with drug metabolizing systems. However, increased levels of DNA adducts were observed by 32P post-labeling in DNA from rat liver and cultured human lymphocytes. Tamoxifen also has been found to increase levels of micronucleus formation in vitro in human lymphoblastoid cell line (MCL-5). Based on these findings, tamoxifen is genotoxic in rodent and human MCL-5 cells.


  1. Tamoxifen is known to be estrogenic in the uterus. For this reason it is inferior for women to raloxifene, as tamoxifen can promote estrogenic uterine cancer while raloxifene cannot, or not directly anyway.

(The reason for the qualification is that in pre-menopausal women, raloxifene can increase estrogen production, confounding the issue with regard to the uterus and endometrium.)

So unless your friend has a uterus, the study is not relevant.

  1. Tamoxifen has been around for decades in actual human use and is not considered to be a danger for causing cancer, other than the above which is due estrogenic activity and is not relevant to men.

But if your friend wants to be afraid of it, that’s his prerogative.

He also does not know much about their use, as they are also used in women who don’t have breast cancer but are thought to be at risk for it, and raloxifene is used for osteoporosis prevention or treatment.

I’d suggest giving up the idea of changing this person’s mind, if you have that idea. It is ordinarily a fruitless task. I recall that in my teens and maybe early (very early) 20s I felt it was important to try to change the minds of the stubborn when they are wrong, but it didn’t take long to learn how fruitless and pointless that was. When people cling to error, that is their problem, not yours or mine… this really is the best way to look at it, I’d suggest. The most it’s worth is a single statement of actual relevant facts, but when this is vehemently rejected, then I’d just not bother pursuing it further, really.

That last paragraph reminds me of some discussions I’ve had (particularly religious). Unfortunately, that idealistic nature lasted for me right up into my mid twenties and is something I only recently overcame these last couple years! It took losing a couple “acquaintances” (I’m picky whom I call my friends) for it to click.

Bill, I have sort of a two part questions for you if you wouldn’t mind. Is an AI while on cycle versus a SERM always a good idea, or are there exceptions? More specifically, what about while running Anadrol?

It seems that what actually causes the “estrogenic” side effects that people experience when using Anadrol is still controversial. One idea I’ve read recently is that androgens which have a high binding affinity for SHBG can actually knock off estrogen that was bound to SHBG and that estrogen which is now free is the cause of the side effects. Now, it’s probably obvious that I am just regurgitating what I’ve read, but if this were the case I could imagine that an AI would not be much use as the estrogen has already been formed. But, I could see that a SERM still might be useful. So there is the second part I suppose - do you think it’s possible that is the cause of the said sides when using Anadrol?

jMill2, that is a very interesting question. I think this idea of androgens that don’t aromatize yet seem to cause estrogenic side effects being linked to their afinity for SHBG is an idea advocated, for example, by Seth Roberts. You’re reasoning concerning SERM use during a cycle with such a compound is also exactly what I had reasoned.


jMill2, as you suspect, there’s no reason to run an AI when the steroids being used aren’t going to elevate estrogen to undesirably high levels.

On the SHBG theory: that is a topic that basically makes me feel like banging my head against a wall. It is hopeless to get across to people in general, although occasionally someone does get it. I have tried many times and most times it is futile, and so is frustrating. I will leave it to these statements:

  1. The theory mentioned is completely and utterly wrong, as is just about every bb’ing SHBG theory, but the explanation requires correct understanding of equilibria, binding equations, and carrier proteins.

  2. If it is desired to read some previous posts on the subject, http://www.google.com/search?hl=en&source=hp&q=site:http://tnation.tmuscle.com/free_online_forum+"Bill+Roberts"+SHBG&btnG=Google+Search&aq=o&oq=&aqi=

  3. If wondering how it can be that bb’ing theories about SHBG are wrong while there are many statements in medical literature that seem similar, it is because there is such a thing as correlative truth, true in some circumstances, that may be clinically useful but which is not the same thing as causative truth.

For example, it may be true that when you’re outside and you are shivering, it is cold. But that does not mean that your shivering is what makes it cold outside.

  1. Using a correlative truth, true in certain circumstances, to predict outcome in entirely different circumstances is an invalid method but is the absolute foundation and sole basis of these bb’ing SHBG theories. And in this case not only is the method wrong, but the predictions as well.

Crowbar - I’ve read some of Seth Roberts stuff over at AM. Honestly, I don’t consider him as reputable of a source as others do on the topic of real-worl AAS use. I’ve seen him take a clinical study, draw seemingly baseless conclusions and when asked how he came to those conclusions he basically asserted (in a condescending tone) he was qualified to do so. Not very scientific if you ask me, but what the hell do I know anyway? Sorry, just had to get that off my chest, it’s not that he hasn’t contributed anything useful, I’m sure he has (if his book was cheaper I’d probably snag it up for the hell of it), it just bugs me how he has deity status over at AM and the folks over there take everything he says as the gospel as anyone who debates with him is automatically labeled as an idiot.

Bill - The reason I am curious is that I am getting ready to run a series of 2-week cycles (you may have seen my recent thread floating around) and am contemplating running Anadrol in one of them to see how it goes. I will most likely be running Trenbolone in all of these cycles and, as I read in your Anadrol profile over at meso, it seems it would stack well with Tren.

But, am I right to assume that you would recommend a cycle consisting of Dianabol and Tren over Anadrol and Tren? You state in your Anadrol profile that it may have some progestagenic activity, in which case it seems to me a compound I would rather avoid. So long as there are comparable alternatives, I personally see no need to run progestagenic compounds.