Effect of nolvadex post-treatment and side effects

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Nolvadex, like Clomid, is a substance used as an anti-estrogen and (due to its anti-estrogenic effect) as Post Cycle Therapy (PCT). As PCT, it facilitates the faster restoration of the normal hormone balance after an anabolic steroid cycle. This prevents, among other things, temporary low testosterone levels that can quickly lead to the loss of muscle mass gained during the cycle. In the article about Clomid, I delve further into the necessity of PCTs for users of Anabolic Androgenic Steroids.

Nolvadex

Nolvadex is the most well-known brand name for products based on the protein Tamoxifen, just as Deca-Durabolin is the most well-known brand name for Nandrolone (with a decanoate ester). Other brand names include Caditam, Mamofen, Neotam, Oncomox, Oncotam, Tamodex, Tamoxifen, Tevafen, Tomifen, Valodex, and Xifen. Throughout the rest of the article, I will mainly use the generic name Tamoxifen and to a lesser extent the brand name Nolvadex.

Medical application of tamoxifen

In the medical world, Tamoxifen is primarily used to inhibit the growth of tumors stimulated by estrogen, while Clomid (Clomiphene citrate) is more commonly used to improve women’s fertility. However, multiple studies have shown that Tamoxifen is an equally good, and in certain conditions, even better alternative for this purpose (1-8).

The lengths of the ovulatory cycles and their luteal phases and the mid-luteal phase serum progesterone levels did not differ significantly between the two compounds. Nor did the occurrence of luteal phase defects during the tamoxifen and clomiphene treatment cycles differ. Thirty-seven of the 46 women (80.4%) responded similarly to both drugs. Thus, tamoxifen is just as effective as clomiphene in inducing ovulation in women with anovulation. I.E. Messinis, University of Ioannina

Estradiol and estrogen

Estrogen and estradiol are terms often used interchangeably. The female sex hormone estrogen can be divided into three types:

• Estrone
• Estriol
• (O)estradiol

Estradiol, or oestradiol, is the most common form. Estrone mainly occurs in women after menopause, while estriol mainly occurs during pregnancy. Although I consistently refer to estrogen in this article, it actually pertains specifically to the form of estradiol.

The mechanism of SERMs as PCT

Tamoxifen belongs to the family of SERMs, selective estrogen receptor modulators. Estrogen receptor modulator refers to the fact that these agents can influence the estrogen receptors of the cell (9). Selective refers to the fact that this influence can vary in different parts of the body from inhibiting (antagonist) or enhancing (agonist) estrogenic action. Tamoxifen works, among other ways, by inhibiting in breast tissue but acting as an agonist in bone tissue (which makes bones stronger in women).

“Hypogonadism”

Insufficient function of the gonads with hypogenitalism (insufficient development of the gonads) and impaired sexuality; more specifically, a deficiency of androgens; primary hypogonadism due to impaired or poor development of the gonads or due to disease, e.g., epidemic parotitis; secondary hypogonadism due to a deficiency of gonadotropin hormone, zinc deficiency.

(www.nederlands-woordenboek.com)

Less testosterone leads to more estrogen

During a cycle, the body’s own production of testosterone is lowered or even stopped due to the introduction of testosterone (or testosterone-based steroids) from outside (HPTA -> Hypogonadism). When a cycle is stopped, the body’s own production of testosterone is not immediately resumed to its previous level (10-13). Due to insufficient androgenic (“masculinizing”) steroids being produced, “the body compensates by producing extra estrogen”. At least, this is often described. In fact, what happens is that receptors in the cells for testosterone can no longer bind with testosterone because there is no testosterone. Instead of testosterone, estrogen then binds to these receptors, making present estrogen more active. There may indeed be excess estrogen, but this is often a result of the steroid cycle itself where testosterone is converted into estrogen by the aromatase enzyme in the hypothalamus. As long as this estrogen is extra active, there is reduced need for testosterone, and it takes longer for its production to restart.

Just as testosterone must bind to specific receptors in the cell, estrogen must also bind to the estrogen receptors of the cell to exert its influence. SERMs bind to the same receptors, so, like a game of musical chairs, the (stronger) estrogens no longer have a place to bind and thus cannot exert their influence anymore. So, they occupy the place for estrogen just as estrogen occupied the place for testosterone. This makes the body think again that there are not enough steroids and accelerates the production of both estrogen and testosterone, but in more normal proportions. In this way, the period during which one’s own testosterone is produced again after ending a cycle is shortened.

HPTA and testosterone production

A term often encountered when discussing the production of testosterone and estrogen is the HPTA, the Hypothalamus-Pituitary-Testes-Axis. It is useful to know this process to better understand the above and the rest of the article.

SERMs like Tamoxifen and Clomid stimulate the hypothalamus to release more gonadotropin-releasing hormone (GnRH) by blocking estrogen receptors. This hormone then causes the anterior pituitary gland to produce gonadotropins. Gonadotropins are the hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates the testes to produce more testosterone. FSH, in men, is responsible for the production and “maturation” of sperm cells. In women, FSH stimulates the ovaries to produce estrogen. In men, the testes produce estrogen alongside testosterone, albeit to a much lesser extent (14,15).

Negative feedback

Based on the amount of testosterone and estrogen, the hypothalamus will then produce more or less GnRH. If there is a lot of testosterone present, the hypothalamus will produce less GnRH, resulting in less LH, which in turn leads to less testosterone. This is also called the negative feedback loop. The negative influence of estrogen on the hypothalamus is 200 times stronger than that of testosterone (10). This means that excess estrogen can disrupt the HPTA for a long time.

Regulation of the secretion of GnRH, FSH, and LH occurs partially by the negative feedback of testosterone and estradiol at the level of the hypothalamo-pituitary. Estradiol has a much larger, inhibitory effect than testosterone, being 200-fold more effective in suppressing LH secretion. R.S. Tan, HPT/Axis Inc., OPAL Medical Clinic

Aromatase

Most estrogen in men is produced by the conversion of testosterone to estrogen in the hypothalamus by the enzyme aromatase. A cycle involving the introduction of a lot of testosterone from the outside also leads to the production of more estrogen due to the conversion of this extra testosterone. For this reason, aromatase inhibitors are often recommended during a testosterone-based cycle.

It’s not Tamoxifen but its metabolites that do the real work

I write in this article for simplicity that tamoxifen binds to estrogen receptors. However, tamoxifen is a so-called prodrug. These are agents that are not or less active themselves until they are converted into substances that are active in the body (usually through normal metabolism). Tamoxifen itself has little affinity for the estrogen receptor. It is converted in the liver into active metabolites (derived substances) such as (alpha -/ 3-/4-) hydroxytamoxifen (afimoxifen) and N-desmethyl-4-hydroxytamoxifen (endoxifen) (16). The majority is converted into the latter, endoxifen. This metabolite has up to 100 times more affinity with the estrogen receptor.

How your body responds and the dosage you need partly depend on how well the body can convert tamoxifen into this metabolite. This conversion is mainly determined by the activity of the enzymes cytochrome P450 2D6 and 3A4 (CYP2D6 and CYP3A4) and varies from person to person (16-19).

Cough syrup to determine the dosage?

The extent to which tamoxifen can be converted into endoxifen may possibly be predicted by… cough syrup? Yes, the latter was found in research by Erasmus MC-Daniel den Hoed (20). The researchers used the cough syrup dextromethorphan (available without a prescription in the Netherlands) as a so-called probe drug or phenotyping probe to predict the effect of the activity of the enzymes CYP2D6 and CYP3A4 on the conversion of tamoxifen into endoxifen. It was already known that dextromethorphan could be used to measure the activity of the enzymes CYP2D6 and CYP3A4 (21). The researchers used this knowledge by observing how much dextromethorphan was converted into its metabolites (dextrorphan, 3-methoxymorphinan, and 3-hydroxymorphinan) and comparing this with the conversion of tamoxifen.

Forty women with breast cancer were given dextromethorphan after receiving tamoxifen. Subsequently, blood samples were taken to observe how both substances were converted into their metabolites in the body. They found a strong correlation between the conversion of dextromethorphan and that of tamoxifen (see graph in the image to the right). In this way, the cough syrup dextromethorphan can demonstrate how much tamoxifen is converted into active metabolites, and this can help better estimate the dosage someone should receive. Poor conversion requires a higher dosage, while very good conversion requires a lower dosage. An excessively high dosage can cause unnecessary side effects, while a too low dosage can result in the desired effect not being achieved.

In conclusion, this dextromethorphan phenotyping probe was a good predictor for endoxifen exposure during tamoxifen treatment because it incorporated the impact of CYP2D6 as well as CYP3A activity. This test could aid in future studies on the association of tamoxifen and CYP2D6 genotype and phenotype and, ultimately, in the additional personalization and optimization of tamoxifen treatment for breast cancer. A.M. de Graan, Erasmus MC-Daniel den Hoed

The study was conducted among women. It seemed to me that this also applies to men because it is independent of hormone production and mainly concerns metabolism. Just to be sure, I sent this question by email to one of the researchers who (within an hour) replied that he did not have “evidence that the outcomes would be different for men than for women”.[/stextbox]

Excess estrogen becomes less active, but does not disappear with tamoxifen?

Agents like tamoxifen and clomiphene work very quickly to increase one’s own testosterone production by lowering the activity and production of estrogen. This is because they do not need to work to lower estrogen itself, but only occupy the spot for estrogen. This would mean that the already present estrogen in large quantities remains in the body after the use of SERMs such as tamoxifen or clomiphene has been discontinued.

Other products such as Arimidex or Proviron can lower estrogen production itself. These are the so-called “aromatase inhibitors” or “anti-estrogens”. Aromatase is the name of the enzyme that converts testosterone (and its derivatives) into estrogen. Aromatase inhibitors thus reduce the production of new estrogen. They are not used to increase testosterone production inhibited by estrogen but to counteract potential side effects of too much estrogen, the most well-known of which are gynecomastia (“bitch tits”), water retention, and increased fat storage.

In short, tamoxifen and clomiphene quickly combat the symptoms of excess estrogen, while anti-estrogens such as Arimidex and Proviron tackle the cause itself but take more time to do so.

Action 2: Anti-Estrogen by Influencing Aryl Hydrocarbon Receptor

This could have been the end of the story regarding anti-estrogens, but then there wouldn’t have been a question mark behind the title of the previous paragraph. It might be a bit more complex, actually. For instance, Ergogenics.org pointed out a study from American soil two years ago (2010). The researchers found it odd that Tamoxifen had effects that should be independent of its influence on estrogen receptors (ER). They discovered that Tamoxifen (or its metabolite, TAM) affected the aryl hydrocarbon receptor. This receptor is normally activated by the presence of toxins, poisonous substances. In response to these toxins, the aryl hydrocarbon receptor signals cells to produce the enzymes CYP1A1 and CYP1B1, which have a detoxifying effect. These enzymes convert estrogen into less active metabolites.

In this study, we demonstrate that 4-hydroxy-TAM (4OHT), an active metabolite of TAM, directly binds to and modulates the transcriptional activity of the aryl hydrocarbon receptor… Cumulatively, these findings provide evidence that it is necessary to reevaluate the relative roles of ER and AHR in manifesting the pharmacological actions and therapeutic efficacy of TAM and other SERMs… Further, studies show that agonist-activated AHR induces proteosome-dependent degradation of ER protein. Together, these data suggest that AHR activation may be antiestrogenic and could thus have antitumorigenic activity in the breast. C.D. DuSell, Duke University

The researchers also point out that Tamoxifen and other SERMs work in more ways than just blocking the estrogen receptor. They not only block the action of estrogen but also contribute to the conversion of estrogen into less active substances.

Action 3: Increasing LH Responsiveness to GnRH

“Nolvadex as a testosterone booster independent of testosterone deficiency?” The action of SERMs is often explained by their influence on the pituitary gland by occupying estrogen receptors. This surplus of estrogen is caused by a testosterone deficiency, so logically, SERMs only increase testosterone when there’s already a deficiency (which led to more estrogen). It’s commonly said that there’s no point in using SERMs before your own testosterone production is reduced. Research from the University of Ghent shows that a distinction must be made between Clomid and Nolvadex (23). There is a difference in how LH responds to GnRH (responsiveness). Higher responsiveness means GnRH leads to more LH (and thus more testosterone), while low responsiveness results in relatively less LH produced in response to GnRH. Nolvadex seemed to increase LH responsiveness to GnRH, while Clomid decreased it. Nolvadex, therefore, not only affects the hypothalamus but also has a direct effect on the testes (23)

However, whereas Clomid produced a decrease in the LH response to LH-releasing hormone (LHRH), no such effect was seen after the administration of tamoxifen. In fact, prolonged treatment (6 weeks) with tamoxifen significantly increased the LH response to LHRL* A.Vermeulen, Universiteit van Gent

*LHRH = Luteinizing-hormone-releasing hormone, another name for GnRH. The fact that Nolvadex increases the responsiveness of LH to GnRH suggests that this leads to an increase in testosterone independent of a prior deficiency. In a study conducted at the Queen Elizabeth Hospital in Birmingham in 1976, researchers looked at the effects of 10mg of tamoxifen per day (24). According to the explanation of the HPTA and its influence by SERMs like tamoxifen and clomiphene, you would expect GnRH to rise, causing LH and FSH to increase, and subsequently, testosterone to rise. However, the researchers saw no change in the levels of LH and FSH while testosterone significantly increased. They suspected that tamoxifen directly influences the gonad(s). This means that tamoxifen (and possibly clomiphene in larger amounts) works as a testosterone booster, independent of an existing testosterone deficiency.

On this short term, with only 10 mg daily, a significant increase in testosterone was observed, however, the authors note that no change in basal LH, FSH or gonadotrophin response to GnRH was produced during the short trial. The authors speculate that tamoxifen might stimulate the gonad directly, or alter its sensitivity to gonadotrophin, or that it has some effect on prolactin secretion K.J. Willis, Queen Elizabeth Hospital, Birmingham

This is also confirmed by reactions on various forums from people who used Nolvadex without having cycled first, also talking about a doubling of testosterone and more.

Clomid or Nolvadex?

In practice, sometimes Clomid is used as an anti-estrogen while Nolvadex is more often used as PCT. This is odd because they both have the same action and can be used for both purposes. A significant difference, however, is the effectiveness of both products. Nolvadex has a much stronger effect than Clomid. For instance, 20mg of Tamoxifen per day for 10 days had a comparable effect to 150 mg of Clomiphene citrate (23).

The administration of tamoxifen, 20 mg/day for 10 days, to normal males produced a moderate increase in luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol levels, comparable to the effect of 150 mg of clomiphene citrate (Clomid). A.Vermeulen, Universiteit van Gent

Difference in side effects between Nolvadex and Clomid It’s generally believed that Clomid is more likely to cause side effects than Nolvadex, if only because of the higher dosage needed to achieve the same effect. Depression and acne are common reasons people switch from Clomid to Nolvadex. That doesn’t mean Nolvadex is free of dangers. While Tamoxifen is used to prevent certain types of breast cancer, long-term use increases the risk of endometrial cancer (cancer of the uterine lining)(25,26). This was shown in research from Great Britain in 2005 when women who had been treated for breast cancer and later got endometrial cancer were compared with women who had “only” gotten breast cancer (25). By long-term, in this case, they mean longer than 5 years (25,27) “There is an increasing risk of endometrial cancer associated with longer tamoxifen treatment, extending well beyond 5 years. – A. Swerdlow, Institute of Cancer Research While it’s mostly men who use tamoxifen for non-medical reasons, it also happens among women, mainly to get leaner. Men should be more concerned about the “lighter” side effects.

Possible Side Effects of Nolvadex in Men

Nolvadex has various possible side effects (28,29). Many of these side effects can be strongly dependent on the duration of use and the levels of endoxifen (28)

• Fluid retention
• Insomnia
• Mood swings
• Headache
• Leg cramps
• Hair loss
• Sweating
• Dizziness
• Sensitive stomach
• Acne (due to the increase in testosterone)
• Reduced blood flow to heart and vessels
• Formation of blood clots
• Lowering IGF-1
• With long-term use: Reduced libido

However, these side effects occur relatively rarely (2%-5% of men). Women have a few other side effects, such as the mentioned increased risk of endometrial cancer, irregular menstruation, and hot flashes, “vaginal dryness,” and weight gain.

Use in Practice

As an anti-estrogen during a cycle. Dosage: To limit estrogen side effects during a cycle, you can use tamoxifen to quickly counter these effects. For this, 20-30grams per day should suffice. Although tamoxifen may also break down/convert estrogen into other substances, an anti-estrogen like Arimidex would be more effective for this purpose. It may therefore be advisable (I say “may” because I generally do not recommend the use of anabolic steroids) to use tamoxifen in such a case together with a product like Arimidex. You then stop using Arimidex as soon as you are rid of the symptoms, to not unnecessarily break down too much estrogen (estrogen also has muscle-building qualities). As Post Cycle Therapy. When to start: When you start with a PCT like tamoxifen depends on the type of anabolic steroids you have used and how long they are active. Since the same considerations are important as with Clomid, I will repeat the explanation I gave in that article: Regarding the classic explanation of the action of SERMs (i.e., blocking the estrogen receptor), the right time to start with tamoxifen/clomiphene depends on the ester of the used anabolics and the used amount. The ester is a chemical compound with the molecule of the anabolic-androgenic steroid (AAS) that determines the half-life. The half-life is the time in which the AAS loses half of its effectiveness because the amount in the blood has decreased by half. Below is a table that indicates for some AAS when you could start with tamoxifen/clomiphene. For testosterone, various esters are indicated, for nandrolone only one (decanoate, Deca-Durabolin). The longer the ester, the longer it takes for the steroids to disappear from your blood, or at least have decreased in amount enough that tamoxifen/clomiphene can be meaningful. As you can see, in the case of Deca Durabolin (which has a decanoate ester, so still long in the blood) and Sustanon (which partly consists of testosterone with medium-long and long esters) it only makes sense to use tamoxifen/clomiphene after 3 weeks. In these three weeks, the level of androgenic hormones (nandrolone in the case of Deca-Durabolin and testosterone in the case of Sustanon) is still high according to this table. If you start too early, tamoxifen will not help increase testosterone according to the traditional explanation. If you used a cycle of various AAS, then you set the start of tamoxifen based on the longest-lasting AAS in the cycle. If you start too late, you will have a low level of androgenic hormones in the meantime, and you will lose muscle mass (more quickly). The table I have seen on various sites and often referred to. A major problem with this table, however, is that it does not take into account the taken amounts of AAS (bold for the quick guys who want to get started with the table immediately and skip the explanation). Because tamoxifen, according to the traditional explanation, only works when the amount of androgenic hormones in the blood, such as testosterone, comes close to and below the natural level, the right start time depends on the used amount in combination with the half-life. Men produce on average 7mg of testosterone per day (women 1-2mg) and their blood normally contains somewhere between 10 and 30 nmol/l (nanomoles per liter. mol is a defined unit for an amount of substance) of testosterone. For example, consider the difference between using 50mg of testosterone suspension per day and 200mg. Testosterone suspension is testosterone without an ester and has a short half-life of about a day (depending on metabolism and other used substances). The table states that you can start with Clomid/Nolvadex after 4-8 hours. In the case of 50mg per day, of the first injection, 25mg is left after 1 day (“in depot” not necessarily in blood), after 2 days 12.5 mg, after 3 days 6.25mg, etc. With 200mg per day, this is 100mg after 1 day, 50mg after 2 days, 25mg after 3 days, 12.5mg after 4 days, and only after 5 days 6.25mg, etc. It thus takes two days longer to reach the same amount. With longer half-lives, this difference in time is even greater. Without going into too much detail on the units of measurement and conversions and the final amount in your blood, you don’t need to be a genius to understand that this can make a big difference in the amount of testosterone in your blood and the time you have to wait to start with tamoxifen/clomiphene. So, you really don’t have anything to do with the table except that it provides a bit of insight into the differences. I’m talking here about the testosterone-increasing property of tamoxifen by blocking the estrogen receptors. However, you’ve been able to read that tamoxifen also increases testosterone by increasing the responsiveness of LH to GnRH. This mechanism is independent of the used anabolics. The question is to what extent which process contributes to increasing testosterone. Based on reported user experiences, you can assume that you should take into account ingested, still present active steroids and wait until these have disappeared from the blood to benefit from the full advantages of tamoxifen use.

Dosage

Opinions differ about the dosage, although you often see that less is used. Like with Clomid, the thought is that by using Nolvadex, there’s less estrogen (active) so less Nolvadex is needed to occupy the estrogen receptors. There are probably as many different examples of course schemes as there are users. I hardly find practical scientific research on this. This is probably because medical science is less concerned with restoring testosterone production after an anabolic cycle than with fighting breast cancer and promoting fertility (“crazy doctors and their priorities”). It’s thus a matter of trial and error: Try, evaluate the result, and possibly adjust next time, but with the advantage that you can at least use the experiences of others as a starting point. In many cases, you don’t wait based on the half-life of ingested steroids but start with tamoxifen on the first day you stop the cycle. This will not cause any change in the hypothalamus in principle, but can possibly provide more testosterone by increasing responsiveness to GnRH and activation of the aryl hydrocarbon receptor. Examples of such a PCT course are:

• Day 1: 60mg
• Week 1&2: 40-50 mg per day
• Week 3&4: 20-25 mg per day

or:

• Week 1: 40mg per day
• Week 2: 40mg per day
• Week 3: 20mg per day
• Week 4: 20mg per day

Generally, 4 weeks seems to suffice. In the case of very strong anabolics or long-term use, a week or two extra may be needed at 20mg per day. One injection or spread throughout the day? Due to the long half-life of Nolvadex (5-7 days), the daily dosage does not need to be divided over various moments. So, you can do this with a daily injection to keep as much active substance as possible after it has passed the liver.

Nolvadex and Clomid Lower IGF-1

Insulin-like Growth Factor, or IGF-1, is a metabolite (derived substance) of Human Growth Hormone (HGH). It promotes the growth of organs and works muscle strengthening and fat burning. Moreover, it can cause hyperplasia, the formation (division) of new cells (while normal muscle growth comes from hypertrophy, the growth of cells). High IGF-1 levels can thus have advantages for bodybuilders (stronger, bigger muscles), but also disadvantages. The fact that many of the current bodybuilders have a protruding belly while they have hardly any body fat (thick belly with a six-pack) is often attributed to the organs in the belly grown by growth hormone. You want to keep natural IGF-1 levels as high as possible because you benefit from the advantages such as an increase in muscle strength, -recovery, and -growth, but don’t have the disadvantage of large amounts of administered growth factors. However, tamoxifen and clomiphene can affect the production of IGF-1 (33-36) The dosages mentioned above in the example of a PCT course scheme are enough to lower your IGF-1 level by 30% (33-35)! This reduction in IGF-1 apparently, however, does not result in all gains in muscle mass being undone when using Nolvadex or Clomid. Otherwise, no one would use them as PCT or anti-estrogen during a cycle. The lower IGF-1 levels apparently do not outweigh the increased testosterone level when used as PCT or side effects by aromatase that are countered by using them as anti-estrogen. It can, however, seem as if you suddenly lose mass when used as an anti-estrogen because by lowering estrogen, you also retain less fluid. Moreover, estrogen itself, as said, also has muscle-building properties. You then choose to prevent a lot of nasty side effects by giving up something in extra muscle growth.

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Additional sources:

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  • W. de Ronde en F. de Jong. Aromatase inhibitors in men: effects and therapeutic options. Reproductive Biology and Endocrinology 2011, 9:93