Clomid & Nolvadex – The Dark Side

Preface – Over the past 15 years, the use of Clomid and Nolvadex, as Selective Estrogen Receptor Modulators (SERMs) has become a staple in the Hormone Replacement Therapy (HRT) and bodybuilding communities.

The popularity of these drugs stems from the popular advice to use these drugs for everything from testosterone recovery, bloat reduction, to gyno prevention. In many communities SERMs have become akin to vitamins — vitamins that can do no wrong and provide seemingly endless benefits.

This article is not intended to examine the proper use or possible applications of Clomid or Nolvadex. Instead, we will be exploring the historical development of these drugs, the short-term side-effects and long-term consequences.

As I will illustrate, these drugs are truly dangerous to men’s health.

Synthetic estrogens, the beginning –

It was the 1930s and there was a new age of hormone-dependant pathologies on the rise. Scientists were eager to determine the structural requirements of estrogen for new drug design.Diphenylethane

In 1937 Sir Charles Dodd of the Middlesex Hospital of London found estrogenic activity in a molecule with two benzene rings linked together via a short carbon chain (e.g., diphenylethane). (1) Soon thereafter, a synthetic, non-steroidal estrogen known as diethylstilboestrol (DES) was created from this basic molecular backbone. (1) By 1941, DES was an FDA approved drug, and by the 1950s, DES gained widespread popularity as the drug of choice for menopausal symptoms, cancer treatment, and prevention of miscarriages. (2)Diethylstilboestrol

DES sparked the interest of ambitious drug manufactures who saw this synthetic molecule as a potential “molecular backbone” which could be tailored for estrogenic activity, and patented for maximum profit.

Within months, a research group from the University of Edinburgh found that the addition of a benzene ring to the original diphenylethane structure created somewhat of an anti-estrogen known as triphenylethylene. (1) Although it had very weak estrogenic activity, it was called an anti-estrogen because it competed with the body’s more powerful estradiol for the ER receptors.

Although the complex estrogenic action of triphenylethylene was not fully understood, it was considered the perfect molecular platform for future drug development because of its high oral bioavailability and extended half-Triphenylethylenelife due to its lipophilicity (fat solubility). As it was later discovered, the estrogenic action could be manipulated with structural modifications for more specific agonist/antagonist actions. (3) Despite the lack of understanding of its many physiological effects, triphenylethylene would become the molecular backbone for generations of SERMs to come.

By the early 1940s, the world’s largest chemical manufacturers, including Imperial Chemical Industries (ICI), got word of the triphenylethylene development, and seized the opportunity to expand this new class of compounds. By the 1950s, the synthesis of new triphenylethylene based molecules had begun picking up momentum, as the first FDA approved SERMs started appearing on the market.

One of the first was Triparanol, which was sold as a cholesterol lowering SERM, until it was eventually pulled from the market in the 1950s for causing cataracts in patients. (7) Later, Ethamoxytriphetol (MER-25) was discovered and found to be a reliable contraceptive and anti-cancer agent in rats, but failed in humans due to the drug’s severe toxicity and stimulation of “acute psychotic episodes”. (6)

Despite these early warning signs, development continued.

Among one of the newer SERMs to appear in the late 1950s, was a mixture of two stereoisomers — zuclomiphene and enclomiphene — both having unique estrogenic and anti-estrogen actions. This mixture was collectively called clomiphene, and later marketed as Clomid.


Then, in 1962, ICI synthesized ICI-46474, another mixture of a trans and cis isomers with mixed estrogenic and anti-estrogenic activity. (7) Ultimately, the trans isomer was found to be the predominate anti-estrogen, which was isolated and eventually named tamoxifen, and later marketed as Nolvadex.

Originally, ICI pushed these new SERMs to market as a “morning after” contraceptives, which were eventually approved by the FDA. (4) Yet again, the profit hungry and presumptuous drug manufacturer based its findings on rat studies, which would prove to be a mistake upon subsequent human research that showed the SERMs induced, rather than inhibited ovulation. (4) Needless to say, tamoxifen was withdrawn as a contraceptive.

And remember DES, the original synthetic estrogen developed back in the 1930s? As it turned out, DES was found to increase the risk of breast cancer by 50%. Further research linked DES to millions of vaginal and testicular cancers among the children of mothers who took DES during pregnancy. (2, 5)

The light on synthetic anti-estrogens was dim, and by the late 1960s, there was little enthusiasm to continue R&D with triphenylethylene based SERMs, especially considering their inherently toxic effects (7, 10)

It wasn’t until 1971, that tamoxifen would be dug up from the dead and considered as a candidate for cancer treatment.

Treating cancer with a carcinogen –

When research is done on anti-cancer drugs (such as SERMs), the aim is to find a drug that prolongs life, with the least amount of acute side-effects. In other words, the goal isn’t so much about finding a cure, as it is finding something that can alleviate the symptoms and/or prolong life. Tamoxifen

For an estrogen dependant cancer, the idea was simple – Block the proliferative action of estrogen with an anti-estrogen and slow the cancer growth. What could be more appropriate than an already available, orally active, patentable synthetic estrogen such as tamoxifen? It was a practical shoo-in.

Therefore, in 1971, when drug researchers decided to examine all of the historical anti-cancer SERM data, they found that all of the SERMs showed anti-proliferative activity on estrogen dependant cancer, and all of them demonstrated some extent of toxicity. (10, 37-39) However, the SERM that happened to show the least amount of toxicity was tamoxifen. (clomiphene missed the mark by showing a high rate of cataract formation)

At the time, Pierre Blais, a well known drug researcher, commented on the finding (5) –

“Tamoxifen is a garbage drug that made it to the top of the scrap heap. It is a DES in the making.”

In spite of the criticism from a number of researchers, the FDA approved tamoxifen as a cancer treatment in 1977, and in 1985 ICI was awarded a US patent for tamoxifen in the treatment of breast cancer. (5) Soon, tamoxifen would become the most popularly prescribed cancer drug.

“Its FDA approved for cancer treatment. It must be safe!”

It’s wrong to assume that an “FDA approved” drug has a proven safety profile. The FDA has continually issued stronger health warnings for tamoxifen over the years. For instance, in 1994 the FDA demanded that the tamoxifen manufacturer Zeneca (an ICI sub-division), issue warning letters to health care practitioners about the increased risk of endometrial and gastro-intestinal cancers with tamoxifen use. Zeneca also reported adverse effects similar to those seen with DES, such as reproductive abnormalities in the animals whose mothers received tamoxifen. (remember, DES was the original synthetic estrogen, and also an analog to tamoxifen)

A number of cancer researchers have pointed out the health risks too, such as Elwood et al (6) –

“[Tamoxifen], therefore, is not appropriate for use in the general population because of the known increased risk of endometrial cancer”

“So why is tamoxifen the most popularly prescribed cancer drug, if it’s so toxic?”

The answer is simple. Tamoxifen is the lesser of two evils.

Tamoxifen remains the most popularly prescribed drug because it is one of the few drugs that has shown a “statistically significant” improvement of the survival rate of breast cancer patients.* (Not to mention, tremendous financial motives for its patent holder, Zeneca)

Remember, the goal in cancer treatment is to prolong life — even if it means committing to therapy that is potentially cancerous or injurious to future health (as confirmed in long-term follow ups and close examinations of tamoxifen patients).

So, perhaps the risks are worthy for the cancer patient, but are they worthy for the health conscious male?

* Most research has shown tamoxifen to improve the survival rate by 4-14%. For instance, over a 5 year period, 74% of the women survived who used tamoxifen, compared to 70% of the women on placebo. Depending on the type of cancer, this may translate into an extra 2-3 years of life for a cancer patient. (9) Continuing tamoxifen therapy for more than 5 years, results in increased tumor recurrences and serious side effects. (8)

Translating the science, for men’s health –

Fast forward 30 years, through hundreds of human and animal trials, and we find that the research is quite extensive, and contradicting. (21)

The damaging evidence from many early rat studies showed severely toxic effects, including the development of cancer in the liver, uterus, or testes upon tamoxifen administration. (30-34,41) However, this evidence was largely disregarded by further test tube studies on human cell-lines which appeared to show a lack of toxic effects. (21)

This misleading test tube data gave the green flag to perform large scale human studies with tamoxifen in the 80s and 90s. Even more misleading, the majority of the human research described tamoxifen as having a “low incidence of troublesome side effects” and that the “side effects where usually trivial”. (22)

As science would uncover, the lack of human toxicity reported in original tamoxifen research was a result of insufficient study duration, inability to detect low level DNA damage with insensitive methodologies, and/or misdiagnosis of collateral cancers as metastases from the breast cancer itself. (15, 21, 28-34)

A word on clomiphene (Clomid) –

Clomiphene (Clomid) consists of two stereoisomers which possess radically different pharmacodynamics. Zuclomiphene has predominantly estrogenic effects and slow clearance while the enclomiphene isomer has predominately anti-estrogenic effects and quick clearance. (9) This creates a divergent effects between estrogen blockage and estrogen stimulation and an acute imbalance once Clomid administration is discontinued. Bodybuilders will often complain of “estrogenic rebound” after stopping Clomid, which could be attributed to the lingering estrogenic isomer zuclomiphene as the anti-estrogenic enclomiphene has long cleared the system. (Recently, enclomiphene has been isolated by the pharmaceutical company Repros, for use in Androxal™.)

For all intents and purposes, tamoxifen is a superior SERM, simply for the fact that tamoxifen provides a purely anti-estrogenic isomer, whereas Clomid provides a mix of anti and pro estrogenic effects.

In regards to the health consequences about to be listed, it can be safely assumed that Clomid will share similar detrimental effects as tamoxifen, since it shares the same triphenylethylene backbone and carcinogenic tendencies. (44,45,57,58)

Liver cancer –

Originally, tamoxifen was accepted as being non-toxic to the human liver upon finding that tamoxifen did not cause noticeable liver damage (DNA adducts) during short-term test tube studies with human liver cells. (35,36)

However, it became apparent that test tube research was largely flawed due to the low rate of metabolism in such a superficial environment. (21) It was soon discovered that the hepatotoxic effects from tamoxifen stem from the metabolism and buildup of the a-hydroxytamoxifen and N-desmethyltamoxifen metabolites, which would only appear in an in vivo environment. (15) Surely enough, the results from the original rat studies showing dramatic carcinogenic effects on the liver, (30-34, 41) soon correlated with human data when researchers found the same type of liver DNA adducts in tamoxifen patients. (15, 28-34)

More recent human research has reported tamoxifen treated women to have 3x the risk of developing fatty liver disease, which occurs as soon as 3 months into therapy at only 20mg/day. (24-26) In some cases, the disease lasts up to 3 years, despite cessation of tamoxifen therapy. Five and ten year follow-ups with patients on long term tamoxifen therapy show cases of deadly hepatocellular carcinoma. (27-29)

In 2002, a bizarre study examined the use of tamoxifen for hepatocellular carcinoma treatment in humans. It was assumed that since tamoxifen could inhibit proliferation of breast cancer, it could offer the same benefit for liver cancer. The devastating results could not have been more indicative of tamoxifen’s hepatotoxic nature, as the tamoxifen treatment significantly increased the rate of death, compared to the group not receiving tamoxifen. (14)

Finally, in a case study reviewing tamoxifen induced liver disease; D.F Moffat et al made a profound statement –

“Hepatocellular carcinoma in tamoxifen treated patients may be under-reported since there may be reluctance to biopsy liver tumours which are assumed to be secondary carcinoma of the breast.”

In other words, it appears that liver carcinomas from a large number of breast cancer patients on tamoxifen therapy have been misdiagnosed as an infection from the breast cancer itself. (28)

Although tamoxifen induced liver cancer may take years to manifest in a healthy male, its damaging effects could easily be exaggerated by other popular hepatotoxic drugs, such as 17aa oral steroids. (15)

Prostate cancer –

In 1996, the International Agency for Research on Cancer (IARC) concluded that tamoxifen clearly promotes uterine cancer in humans – at a standard 20mg/day dose. (16,23,42) This is due to tamoxifen acting as an estrogen agonist in the uterus, presumably from the 4-hydroxytamoxifen metabolite, which triggers abnormal growth of the uterus and the formation of cancer causing DNA adducts. (33, 40)

Contrary to popular thought, these implications are quite scary for a male when we realize the male equivalent to the uterus is the prostate – which differentiates from the same embryonic cell line, shares the same oncogene, Bcl-2, and high concentration of estrogen receptors. In fact, there is no reason to assume that tamoxifen would not initiate the same cancerous growth in the prostate. (60-62) It is no wonder that tamoxifen failed as a treatment for prostate carcinoma. (43)

Note: This same risk would be applicable to Clomid, which has also been linked to uterine cancer and ovarian hyper-stimulation. (18, 19, 57, 59)

Libido reduction & erectile dysfunction –

Erectile dysfunction, low libido, and general impotence are typical complaints from men recently discontinuing steroids or HRT therapy, which is often combated by Clomid or Nolvadex, paradoxically so.

Regardless of any positive effects on fertility or testosterone levels, Clomid and Nolvadex use is highly correlated with erectile dysfunction, libido suppression, and even emotional disorders. (10,47)

Research with male breast cancer patients has also reported decreased libido, and thrombosis associated with tamoxifen use. (47) The thrombotic effect (blood vessel clogging) could explain the mechanism by which SERMs may inhibit erectile function, by reducing circulation to erectile tissue. (47, 52)

Increased susceptibility to gyno –

Tamoxifen is often used to combat gyno during cycle when “flare ups” occur. While tamoxifen may provide immediate inhibition of proliferation, and serve as valuable tool, it can actually increase future susceptibility to gyno.

This is caused by tamoxifen’s ability to up-regulate the progesterone receptor. (54-56) This can dramatically increase the chances of developing gyno in future cycles when utilizing progestin based anabolics such as Nandrolone (Deca) or Trenbolone (or any pro-hormone acting upon the progesterone receptor).

It is interesting to speculate. Is tamoxifen use directly related to the increased gyno occurrences seen with modern day steroid users?

Ocular toxicity –

Another possible side effect associated with SERMs is visual cloudiness, loss of vision and even cataract formation. Although this tends to be a more common side effect from high dosed SERM therapy, standard 20mg/day tamoxifen regimes have been reported to cause these symptoms of ocular toxicity. (17, 46)

Newer SERMs –

As the medical community became more aware of the side-effects associated with tamoxifen treatment, newer and safer SERMs, such as toremifene and raloxifene hit the developmental fast track. Toremifene appears to be less liver toxic, but it is a closely related analog of tamoxifen, so it also carries many of the related genotoxic effects. (48,49) Raloxifene

Raloxifene is a newer SERM based on a benzothiophene structure, which appears to make it less toxic in the liver, uterus or prostate. (50-52) Unfortunately, Raloxifene has been associated with a higher incidence of thromboembolism (52), and also has very low oral absorption, making it an expensive alternative at a typical dose (120mg/day). (53) Still, Raloxifene could presumably be equally effective as Clomid or Nolvadex at restoring HPTA function, while imparting fewer side effects. (53)

Newer SERMs are already being evaluated such as bazedoxifene, arzoxifene, and lasofoxifene, in hopes of reducing risk even further. (This further underscores the evidence of toxicity with the tamoxifen generation of SERMs)

What to do now?

Firstly, it should become a priority to create awareness about the possible side effects of SERMs. Once educated, users will be able to start reducing their use of these drugs, and begin adopting healthier, more responsible alternatives.

Carefully planned cycles, and the proper use of aromatase inhibitors (AIs) should prevail over haphazard combinations of excessive doses of aromatizing AASs — which require high doses of SERMs to reduce possible side-effects. Whereas avoiding SERMs in HRT will involve the natural clearance and management of endogenous estrogens.

It is important to maintain testicular function during a cycle for a quick and efficient recovery of natural testosterone production for PCT – negating the need for high dose 2-3 month SERM based PCT’s. (For more information on the proper use of hCG during cycle, visit here)

Thus, abolishing the bad habit of SERMing calls for community wide enlightenment with careful, comprehensive sharing and planning of worthy alternatives.

discuss this article in the forum

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