Why Use Both Clomid and Nolvadex Together for PCT?

This is one of the explanations that Dr. Scally has given:
I strongly disagree with Dr. Scally's reasoning behind the use of clomid. What he is describing here is "estrogen priming," the concept that estrogen makes the pituitary more sensitive to GnRH from the hyp[othalamus, so that more LH is released for a given GnRH stimulus. This is well known to occur in females leading up to ovulation. Unlike females, however, men don't have a preovulatory period or spikes in LH. The research is fairly clear that estrogen priming does not occur in males. For starters, take a look at an authoritative reference work like Grossman's Clinical Endocrinology, which states (pg. 99):That states pretty clearly that there is no priming in males, only negative feedback. The last emboldened sentence in this quote directly contradicts Dr Scally's quote at the top. If clomid were to produce estrogenic action in the pituitary, it would only serve to inhibit LH secretion.

Grossman's statement is corroborated by the most recent research on the specific effects of androgens and estrogen on the pituitary and hypothalamus of healthy men. Here, it was shown that estrogenic action at the pituitary has an inhibitory effect on LH output. In other words, estrogen decreases pituitary sensitivity to GnRH. Estrogen does not produce positive feedback as seen in estrogen priming in females. The paper stated in its conclusion that "These data confirm previous work from our group which ... showed [estrogen] has both hypothalamic and pituitary sites of negative feedback in the male." In fact, "negative feedback at the pituitary requires aromatization," as testosterone itself doesn't produce negative feedback at the pituitary.

This older paper had a very interesting finding:In other words, estrogen levels during brain development are responsible for the sex-specific differences in gonadotrophin secretion and estrogen feedback at the pituitary. The important point of this research is that males (with the exception of homosexuals) were not found to have any positive feedback from estrogen. Those results that were "strongly confirmed."

Finally, there's this research, which couldn't have been any more relevant. It directly examined the effects of nolva and clomid on the pituitary of human males. They infused the men with 100 mcg of GnRH and then measured LH output from the pituitary. The men taking nolvadex at 20mg/day had a significantly increased LH response to GnRH. In contrast, the men taking clomid had reduced LH output, a decreased sensitivity to GnRH. The researchers stated that "a role of the intrinsic estrogenic activity of Clomid which is practically absent in Tamoxifen seems the most probable explanation."

All in all, I don't understand Dr. Scally's position for using clomid during PCT. It assumes estrogen priming in males, yet both research and experts in endocrinology seem to squarely contradict the notion. Clomid appears to produce an estrogenic effect at the pituitary, yes, but the evidence shows that in males this serves to inhibit LH output in contrast to nolva. All else being equal, that would make the use of clomid inferior to nolva for purposes of PCT.

I'd really like to hear Dr. Scally's response to this.

-Conciliator

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So what you are saying is this... Clomid will make you gay... or it only works to restart htpa in fags...

And PCT works best with Nolva only...

While I certainly do appreciate the intellectual banter, and the insight you have given in order to help the cause... Out of curiosity, Governor, What experience do have in using these compounds other than what you have read in other peoples work...

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The reason I didn't mention any of my experience is because my uncontrolled personal anecdote is essentially worthless when it comes to evidence. That's true for everyone.

That said, I've tried nolva, clomid, nolva+clomid, and toremifene for PCT after different AAS cycles. For the last few years I've used nolva alone for PCT, based on 1) clear evidence that it's more effective than toremifene or raloxifene (I can elaborate if you're interested) and 2) based on inferences from the differences it has from clomid (as explained above).

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I'm sure many of you have read this article by William Llewellyn pertaining to Nolvadex vs Clomid, but for those of you who haven't here goes!...

"Nolvadex vs Clomid"

by William Llewellyn

I have received a lot of heat lately about my preference for Nolvadex over Clomid, which I hold for all purposes of use (in the bodybuilding world anyway); as an anti-estrogen, an HDL (good) cholesterol-supporting drug, and as a testosterone-stimulating compound. Most people use Nolvadex to combat gynecomastia over Clomid anyway, so that is an easy sell. And for cholesterol, well, most bodybuilders unfortunately pay little attention to this important issue, so by way of disinterest, another easy opinion to discuss. But when it comes to using Nolvadex for increasing endogenous testosterone release, bodybuilders just do not want to hear it. They only seem to want Clomid. I can only guess that this is based on a long rooted misunderstanding of the actions of the two drugs. In this article I would therefore like to discuss the specifics for these two agents, and explain clearly the usefulness of Nolvadex for the specific purpose of increasing testosterone production.

Clomid and Nolvadex

I am not sure how Clomid and Nolvadex became so separated in the minds of bodybuilders. They certainly should not be. Clomid and Nolvadex are both anti-estrogens belonging to the same group of triphenylethylene compounds. They are structurally related and specifically classified as selective estrogen receptor modulators (SERMs) with mixed agonistic and antagonistic properties. This means that in certain tissues they can block the effects of estrogen, by altering the binding capacity of the receptor, while in others they can act as actual estrogens, activating the receptor. In men, both of these drugs act as anti-estrogens in their capacity to oppose the negative feedback of estrogens on the hypothalamus and stimulate the heightened release of GnRH (Gonadotropin Releasing Hormone). lh - leutenizing hormone - output by the pituitary will be increased as a result, which in turn can increase the level of testosterone by the testes. Both drugs do this, but for some reason bodybuilders persist in thinking that Clomid is the only drug good at stimulating testosterone. What you will find with a little investigation however is that not only is Nolvadex useful for the same purpose, it should actually be the preferred agent of the two.

Pituitary Sensitivity to GnRH

Studies conducted in the late 1970's at the University of Ghent in Belgium make clear the advantages of using Nolvadex instead of Clomid for increasing testosterone levels (1). Here, researchers looked the effects of Nolvadex and Clomid on the endocrine profiles of normal men, as well as those suffering from low sperm counts (oligospermia). For our purposes, the results of these drugs on hormonally normal men are obviously the most relevant. What was found, just in the early parts of the study, was quite enlightening. Nolvadex, used for 10 days at a dosage of 20mg daily, increased serum testosterone levels to 142% of baseline, which was on par with the effect of 150mg of Clomid daily for the same duration (the testosterone increase was slightly, but not significantly, better for Clomid). We must remember though that this is the effect of three 50mg tablets of Clomid. With the price of both a 50mg Clomid and 20mg Nolvadex typically very similar, we are already seeing a cost vs. results discrepancy forming that strongly favors the Nolvadex side.

But something more interesting is happening. Researchers were also conducting GnRH stimulation tests before and after various points of treatment with Nolvadex and Clomid, and the two drugs had markedly different results. These tests involved infusing patients with 100mcg of GnRH and measuring the output of pituitary lh - leutenizing hormone - in response. The focus of this test is to see how sensitive the pituitary is to Gonadotropin Releasing Hormone. The more sensitive the pituitary, the more lh - leutenizing hormone - will be released. The tests showed that after ten days of treatment with Nolvadex, pituitary sensitivity to GnRH increased slightly compared to pre-treated values. This is contrast to 10 days of treatment with 150mg Clomid, which was shown to consistently DECREASE pituitary sensitivity to GnRH (more lh - leutenizing hormone - was released before treatment). As the study with Nolvadex progresses to 6 weeks, pituitary sensitivity to GnRH was significantly higher than pre-treated or 10-day levels. At this point the same 20mg dosage was also raising testosterone and lh - leutenizing hormone - levels to an average of 183% and 172% of base values, respectively, which again is measurably higher than what was noted 10 days into therapy. Within 10 days of treatment Clomid is already exerting an effect that is causing the pituitary to become slightly desensitized to GnRH, while prolonged use of Nolvadex serves only to increase pituitary sensitivity to this hormone. That is not to say Clomid won't increase testosterone if taken for the same 6 week time period. Quite the opposite is true. But we are, however, noticing an advantage in Nolvadex.

The Estrogen Clomid

The above discrepancies are likely explained by differences in the estrogenic nature of the two compounds. The researchers' clearly support this theory when commenting in their paper, "The difference in response might be attributable to the weak intrinsic estrogenic effect of Clomid, which in this study manifested itself by an increase in transcortin and testosterone/estradiol-binding globulin [sex hormone binding globulin ] levels; this increase was not observed after Tamoxifen treatment". In reviewing other theories later in the paper, such as interference by increased androgen or estrogen levels, they persist in noting that increases in these hormones were similar with both drug treatments, and state that," ?a role of the intrinsic estrogenic activity of Clomid which is practically absent in Tamoxifen seems the most probable explanation".

Although these two are related anti-estrogens, they appear to act very differently at different sites of action. Nolvadex seems to be strongly anti-estrogenic at both the hypothalamus and pituitary, which is in contrast to Clomid, which although a strong anti-estrogen at the hypothalamus, seems to exhibit weak estrogenic activity at the pituitary. To find further support for this we can look at an in-vitro animal study published in the American Journal of Physiology in February 1981 (2). This paper looks at the effects of Clomid and Nolvadex on the GnRH stimulated release of lh - leutenizing hormone - from cultured rat pituitary cells. In this paper, it was noted that incubating cells with Clomid had a direct estrogenic effect on cultured pituitary cell sensitivity, exerting a weaker but still significant effect compared to estradiol. Nolvadex on the other hand did not have any significant effect on lh - leutenizing hormone - response. Furthermore it mildly blocked the effects of estrogen when both were incubated in the same culture.

Conclusion

To summarize the above research succinctly, Nolvadex is the more purely anti-estrogenic of the two drugs, at least where the hpta - hypothalamic-pituitary-testicular axis - (Hypothalamic-Pituitary-Testicular Axis) is concerned. This fact enables Nolvadex to offer the male bodybuilder certain advantages over Clomid. This is especially true at times when we are looking to restore a balanced hpta - hypothalamic-pituitary-testicular axis - , and would not want to desensitize the pituitary to GnRH. This could perhaps slow recovery to some extent, as the pituitary would require higher amounts of hypothalamic GnRH in the presence of Clomid in order to get the same level of lh - leutenizing hormone - stimulation.

Nolvadex also seems preferred from long-term use, for those who find anti-estrogens effective enough at raising testosterone levels to warrant using as anabolics. Here Nolvadex would seem to provide a better and more stable increase in testosterone levels, and likely will offer a similar or greater effect than Clomid for considerably less money. The potential rise in sex hormone binding globulin levels with Clomid, supported by other research (3), is also cause for concern, as this might work to allow for comparably less free active testosterone compared to Nolvadex as well. Ultimately both drugs are effective anti-estrogens for the prevention of gynecomastia and elevation of endogenous testosterone.

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Based on research like this, I wouldn't go any higher than 20mg/day of Nolva. It's common for people to run 40mg/day for the first week or two, but I think that doses that high probably only increase the incidence and severity of side effects with little to no additional recovery benefit. I personally run either 10 or 20mg per day, starting after the last injection (if not used on cycle), and continued for 6-8 weeks AFTER the injected compound would be expected to have cleared from the body. So in the case of test cyp, for example, I'd start the nolva after the last shot. I'd run it for the two weeks or so you'd expect it to take for test to drop below suppressive levels, and then, as part of the true recovery phase, I'd run it for an additional 8 weeks. So my doses are lower than typical and I run it for longer than typical.
Right, I use nolva only. I think you could also include an AI, which might further improve recovery of the HPTA, but I personally don't think it does much good to drive estrogen even lower than it already is during PCT (i.e. from "low" to "into the ground"). You want some estrogen for its beneficial effects, particularly on your libido and on your lipid profile (that's likely been compromised by the AAS cycle). Estrogen levels will be higher without an AI, but the SERM should block most of what's there at the HPTA.
I think hCG is more important for recovery than a SERM is. I take hCG throughout every cycle to prevent testicular atrophy and dysfunction from occurring in the first place. That's the primary impediment to recovery, so if you can prevent it with use of hCG while on cycle, you've taken your largest step towards recovery. I usually run hCG throughout a cycle at 250-350 IU per shot with 2 shots per week. I run it after the last shot until the esterfied steroid would be expected to have cleared. So again, in the case of test cyp, I'd run the hCG for an additional 2 weeks after the last shot, since you're essentially still on cycle and suppressed during that time.

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I will be back later to discuss some of the points raised in the thread. As is typical for PCT discussion, there is not much data upon which to make informed decisions. Almost anyone can draw a conclusion for their own PCT by selectively picking and interpreting the literature. Unfortunately, when the direct clinical research is unavailable this is the only recourse. However, when it comes to PCT there is one thing that all AAS users can do. This is the one thing I hammer home - always obtain lab tests to ensure HPTA function. As I said initially, I will be back shortly to address other points.

A quick area for discussion. Do we really want to include studies on homosexuality as support for a theory? I mean, really! Do you think these studies have validity? If anything, ask yourself if there is a bright defining line between homo/hetero as discussed in the paper OR is there a spectrum (gray areas)? Without even reading the paper (Does anyone have the original paper?), I believe there is NO clear bright line, but a spectrum which diminishes the argument that estrogen priming is only seen in females. [Note: I do not argue for the use of clomiphene due to an E2 priming effect.]

Dorner G, Docke F, Gotz F, Rohde W, Stahl F, Tonjes R. Sexual differentiation of gonadotrophin secretion, sexual orientation and gender role behavior. J Steroid Biochem 1987;27(4-6):1081-7.

The positive estrogen feedback was found to be a relatively sex-specific reaction of the hypothalamo-hypophyseal system in rats as well as in human beings. It is dependent--most of all--on the estrogen convertible androgen level during sexual brain differentiation, but also on an estrogen priming effect in adulthood. The lower the estrogen convertible androgen or primary estrogen level during brain differentiation, the higher is the evocability of a positive estrogen action on LH secretion in later life.

In clinical studies, we were able to induce a positive estrogen feedback on LH secretion in most intact homosexual men in clear-cut contrast to intact hetero- or bisexual men. These findings were strongly confirmed by Gladue and associates. In addition, the evocability of a positive estrogen feedback was also demonstrable in most homosexual male-to-female transsexuals in significant contrast to hetero- or bisexual male-to-female transsexuals. These findings suggest that homosexual males possess, at least in part, a predominantly female-differentiated brain, which may be caused by a low estrogen convertible androgen level during brain organization.

Recently, the following relations were found between sex hormone levels during brain differentiation and sex-specific responses in adulthood: (1) estrogens--which are mostly converted, however, from androgens--are responsible for the sex-specific organization of gonadotrophin secretion and hence the evocability of a positive estrogen feedback in later life; (2) estrogens and androgens, occurring during brain differentiation, predetermine synergistically sexual orientation and (3) androgens--without conversion to estrogens--are responsible for the sex-specific organization of gender role behaviour in later life.

Furthermore, the organization periods for sex-specific gonadotrophin secretion, sexual orientation and gender role behaviour are not identical but overlapping. Thus, combinations as well as dissociations between deviations of the neuroendocrine organization of sex-specific gonadotrophin secretion, sexual orientation and gender role behaviour are conceivable. Most recently, female-type sexual orientation could be converted to male-type sexual orientation in adult rats by administration of the dopamine agonist and serotonin antagonist lisuride.

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This is all perfectly sensible and, before going the TRT route, I followed this routine for years. If Clomid was available, I would use it also, but the only real difference I noted was a hard-to-define sense of unease and sudden warm flashes. I really agree with the low-dose long-term Nolvadex protocol, and I think Doc Scally does, too, though he may think Clomid is a good insurance policy for recovery, as well. HCG? Just as Conciliator says, but even after running it on-cycle, I would boost its kick to, say, 500 iu/day for those 2 weeks after the last inject but before beginning the SERM PCT protocol.

However, why should you listen to me, I'm on TRT?:rolleyes:

Then again, I did something right to still be lifting big & gearing up at my age.:cool:

Solo

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I am really busy with some writing, but thought I would provide some food for thought. The article below is a study on infertility, but shows sex hormone levels. Whether there is an appreciable physiological difference in the population of infertile vs. normal men is speculative.

But, what is relevant is the study of SERMs on different populations. Tamoxifen has been mostly studied for infertility while clomiphene is on hypogonadism. I do not know the exact numbers, but I believe there are many more studies with clomiphene in hypogonadism than tamoxifen. So, why any would get the idea of using clomiphene is very obvious.

On a more data related point. I did use clomiphene and tamoxifen alone for HPTA restoration after AAS use. the results were disappointing, very disappointing. It is only by serendipity that I used the combination with excellent results. Does this prove the combo is better? Absolutely not, but it is what has been published. I, as much as anyone, would like to see well-controlled trials of drugs to reverse HPTA suppression after stopping AAS. It would be nice to know the time course of HPTA recovery after stopping AAS (without any PCT drugs). For that, the best are the male contraceptive studies.

Elena T, Anargyros K, Dimitrios F, Ilias K, Marios S, Dimitrios P. The effect of selective estrogen receptor modulator administration on the hypothalamic-pituitary-testicular axis in men with idiopathic oligozoospermia. Fertility and sterility 2009;91(4):1427-30.

This study evaluates, compares, and contrasts the effects of three selective estrogen receptor modulators (SERMs), namely, tamoxifen, toremifene, and raloxifene, on the hypothalamic-pituitary-testicular axis in 284 consecutive subfertile men with idiopathic oligozoospermia using three therapeutic protocols: [1] tamoxifen, 20 mg, once daily (n = 94); [2] toremifene, 60 mg, once daily (n = 99); and [3] raloxifene, 60 mg, once daily (n = 91). The antiestrogenic effects of SERMs at the hypothalamic level result in a statistically significant increase of gonadotropin levels, which is more marked for tamoxifen and toremifene compared with raloxifene.

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I hope you're not implying that this is what I'm doing. If you think there's counter-evidence that I'm intentionally ignoring, then 1) you're incorrect and 2) you're welcome to man up and post it rather than just infer it's out there.
Yes, I do. Why would it be invalid merely because homosexuals were included in the research? Regardless, all of the other references stand on their own.
Personally, I think it's more of line than a spectrum, at least with men, but I admit I'm ignorant of any research on the topic. I do think it's very telling though, that when the researcher's drew a bright line and seperated the men into homo and hetero sexual groups, there was a clear-cut contrast, not a non-significant gamut of response. The hetero-sexual men simply did not exhibit any estrogen priming.
But you do admit that what you were describing is estrogen priming, right? You said, "Clomid acts as an estrogen, rather than an antiestrogen, by sensitizing pituitary cells to the action of GnRH."

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I agree there are obvious reasons why people use clomid for PCT. I think it probably works quite well for PCT. What's not obvious is how clomid compares to nolva. As far as I know, there have been no comparative studies with T levels as an end point, which is what we ultimately care about.

At the level of the pituitary (LH release), we have the research I referenced earlier showing that nolva is superior. Beyond that, as far as I know there's isn't any research comparing them at the hypothalamus (for GnRH release, probably of primary importance) and at the level of the testes (steroidogenesis in response to LH). Of course, the comparative effects at each step of the HPTA is of little importance if we know the net effect on testosterone levels (as the study below looked at with nolva, toremifene, and raloxifene).
Did you happen to collect data on the three different groups (i.e. clomid, nolva, and clomid+nolva)? Do you have baseline test levels and final LH and/or test levels after a given treatment period? Or were your observations concerning nolva alone and clomid alone more casual than that? Either way, I really do value your experience. I'm just curious as to how systematically the three different protocols were tested and compared to each other.

This is the study I was referring to earlier in this thread when I said "For the last few years I've used nolva alone for PCT, based on 1) clear evidence that it's more effective than toremifene or raloxifene (I can elaborate if you're interested)"

Here are the results of the study that I put into an image some time ago:

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