Clomiphene and enclomiphene: mechanisms and side effects

When enclomiphene is said to be “clomiphene without excess,” they mean a specific pharmacology: the different behavior of the two isomers at estrogen receptors and over time. The editors consider in detail how exactly these substances change hormonal regulation in men, what explains their side effects and which of the differences have clinical confirmation.

Target: estrogen feedback

Testosterone production in men is regulated by a cascade: the hypothalamus secretes pulses of gonadotropin-releasing hormone (GnRH), the pituitary gland in response secretes luteinizing (LH) and follicle-stimulating (FSH) hormones, and the testicles synthesize testosterone under the influence of LH, and under the influence of FSH together with intratesticular testosterone support spermatogenesis.

The brain receives the "enough" signal largely from estradiol, which is formed from testosterone under the action of aromatase. Estradiol through estrogen receptors in the hypothalamus and pituitary gland reduces the frequency and amplitude of GnRH impulses and LH secretion. Studies with blockade of aromatase and estrogen receptors in men have shown that it is the estrogen link that is an important part of this inhibition.

Clomiphene and enclomiphene occupy estrogen receptors in the hypothalamus without fully activating them. The brain "perceives" this as a lack of estrogen and increases the secretion of GnRH, LH and FSH. The testicles receive a stronger signal and produce more testosterone - their own, not injected from the outside.

Hence the key difference from testosterone replacement therapy: exogenous testosterone suppresses LH and FSH and thus spermatogenesis, whereas SERMs stimulate it. That is why these drugs are being studied for men who need to preserve fertility.

Two isomers — two pharmacological behaviors

Enclomiphene (trans-isomer) behaves mainly as an estrogen receptor antagonist in preclinical models. Stimulation of gonadotropins is mainly associated with this isomer. Zuclomiphene (cis-isomer) shows more pronounced properties of a partial agonist — that is, it is able to act in certain tissues like a weak estrogen.

In a study on male mice (Fontenot et al., 2016), long-term administration of zuclomiphene was accompanied by changes in reproductive tissues, while enclomiphene had no such pronounced effects. These data are often cited as an argument in favor of pure enclomiphene, but it is worth remembering that this is an animal model and extrapolation to humans requires caution.

In humans, the partial estrogenic agonism of zuclomiphene can theoretically "mitigate" the antiestrogenic effect of enclomiphene in the hypothalamus and affect other tissues — the liver (synthesis of sex hormone-binding globulin), bones, and the central nervous system. Quantitatively, these effects in men have not been studied enough.

Pharmacokinetics: why accumulation matters

Pharmacokinetic studies of clomiphene (Mikkelson et al., 1986) showed that after a single dose, the drug is eliminated slowly, and the cis-isomer is detected in the blood much longer than the trans-isomer. With regular intake, this leads to the fact that the ratio of isomers in the blood is gradually shifted in favor of zuclomiphene.

Practical consequence: with long-term use of clomiphene, the body actually receives an increasing proportion of the isomer with estrogen-like properties. After discontinuation of zuclomiphene, it remains in the blood for some time, so both its effects and the possibility of detection during doping control last longer.

Enclomiphene, on the contrary, has a relatively short half-life, so its concentration stabilizes quickly and decreases just as quickly after withdrawal. This makes the effect more manageable, but also dependent on the regularity of intake.

It should be noted that both isomers are metabolized in the liver by cytochrome P450 enzymes, so their level can theoretically be influenced by genetic features and other drugs.

Hormonal and reproductive effects

Studies of enclomiphene in men with secondary hypogonadism (Wiehle et al., 2014; Kim et al., 2016) showed increases in LH, FSH, and total testosterone to the normal range in most participants. At the same time, sperm counts were maintained on average, while it decreased in the transdermal testosterone groups, and significantly in some men.

For clomiphene, similar effects on testosterone and gonadotropins have been described in many clinical series. An important feature of clomiphene is considered to be a more noticeable increase in estradiol: more testosterone means more substrate for aromatase, and the estrogenic component of zuclomiphene may contribute to estrogenic effects in tissues.

• Both drugs increase testosterone indirectly, through the pituitary gland, so the effect is limited to the testicular reserve.
• Estradiol level increases with both; its clinical value is assessed by the doctor taking into account the symptoms.
• Improvement in symptoms of hypogonadism (energy, libido) was less consistent across studies than changes in laboratory parameters.
• Effects on body composition and strength in healthy eugonadal men have not been proven.

It is worth mentioning sex hormone-binding globulin (SHBG). Estrogenic effects increase its synthesis in the liver, which can reduce the proportion of free testosterone. Therefore, to assess the effect of therapy, doctors often look not only at total, but also at free testosterone.

Side effects: what is known from research

The instructions for clomiphene list side effects recorded mainly in women: hot flushes, abdominal discomfort, nausea, headache, visual symptoms, ovarian enlargement. In men, in clinical series, mood swings, irritability, headache, soreness of the mammary glands, less often - visual disturbances were reported, which are grounds for immediate withdrawal of the drug.

In controlled studies of enclomiphene, headache, nausea, flushing, nasopharyngitis, and muscle spasms were most often reported; the rate of serious events was low. However, these studies lasted months, not years, so no conclusions can be drawn about long-term safety.

The hypothesis that enclomiphene is better tolerated than clomiphene is logical, but not confirmed by direct comparison in men. The editors consider the wording to be correct: "less estrogen-like effects can be expected, but the evidence is still insufficient."

Theoretical risks characteristic of the SERM class remain common to both drugs: thromboembolic events (rare), increased hematocrit during increased testosterone, influence on the lipid profile. Therefore, the doctor usually monitors the complete blood count, lipids and hormones.

Editorial conclusions

Clomiphene and enclomiphene increase own testosterone by one mechanism — blockade of estrogen feedback in the hypothalamus. The difference is that clomiphene also contains zuclomiphene — a long-lived isomer with estrogen-like properties that accumulates with regular use.

Enclomiphene in randomized trials increased testosterone while preserving spermatogenesis and had mostly mild side effects. However, direct comparisons with clomiphene and long-term data are lacking.

Both drugs require medical control, and their effect on sports results in healthy people has not been proven.

We also recommend our materials "Clomiphene or Enclomiphene: what's the difference", "Tamoxifen vs Clomiphene: comparison of the mechanism of action and side effects" and the article on SHBG and free testosterone.

References

1. Mikkelson TJ, Kroboth PD, Cameron WJ, et al. Single-dose pharmacokinetics of clomiphene citrate in normal volunteers. Fertil Steril. 1986;46(3):392–396.
2. Fontenot GK, Wiehle RD, Podolski JS. Differential effects of isomers of clomiphene citrate on reproductive tissues in male mice. BJU Int. 2016;117(2):338–345.
3. Wiehle RD, Fontenot GK, Wike J, et al. Enclomiphene citrate stimulates testosterone production while preventing oligospermia: a randomized phase II clinical trial comparing topical testosterone. Fertil Steril. 2014;102(3):720–727.
4. Kim ED, McCullough A, Kaminetsky J. Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement. BJU Int. 2016;117(4):677–685.
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7. U.S. Food and Drug Administration. Prescribing information: Clomid (clomiphene citrate) tablets.