hCG or Enclomiphene: what is the difference

Human chorionic gonadotropin (hCG) and enclomiphene are often mentioned side by side when it comes to supporting one's own testosterone production. However, these are fundamentally different substances: one acts directly on the testes, the other on the brain. The editorial team explains exactly where the boundary between them runs and why this difference has practical significance for health.

What hCG is and what enclomiphene is

hCG is a glycoprotein hormone that is normally produced by the placenta during pregnancy. In structure it is very similar to the pituitary luteinizing hormone (LH): both have an identical alpha subunit and a similar beta subunit. Thanks to this, hCG binds to the same receptor as LH — the LH/hCG receptor on the Leydig cells in the testes.

Medical hCG preparations are obtained either by purification from the urine of pregnant women or by a recombinant method. They are used in reproductive medicine: for ovulation induction in women, for the treatment of hypogonadotropic hypogonadism and cryptorchidism in men and boys. hCG is administered by injection, because the protein molecule is destroyed in the digestive tract.

Enclomiphene is not a hormone but a synthetic small molecule of the class of selective estrogen receptor modulators (SERMs). It is one of the two geometric isomers of clomiphene — the trans isomer. Clomiphene, known since the 1960s as an agent for stimulating ovulation, is a mixture of enclomiphene and zuclomiphene.

The idea of isolating enclomiphene into a separate drug arose because it is precisely this isomer that is responsible for the antiestrogenic action in the hypothalamus, whereas zuclomiphene has weak estrogenic activity and stays in the body for a very long time. Enclomiphene is taken orally, which in itself already makes it an entirely different tool than injectable hCG.

Thus, at the level of definitions we have a protein hormone analogous to LH and a synthetic blocker of estrogen receptors. Everything that follows is a consequence of this fundamental difference.

Different points of influence on the hormonal axis

Testosterone production in men is regulated by the "hypothalamus — pituitary — testes" axis. The hypothalamus releases gonadotropin-releasing hormone (GnRH) in pulses, the pituitary in response secretes LH and follicle-stimulating hormone (FSH), and the testes under the action of LH synthesize testosterone. Testosterone and the estradiol formed from it inhibit the upper links of the axis by the mechanism of negative feedback.

hCG "bypasses" the hypothalamus and pituitary: it itself performs the role of LH and directly stimulates the Leydig cells. Therefore the effect of hCG does not depend on whether the pituitary works. At the same time the increase in testosterone and estradiol on hCG suppresses one's own LH and FSH even more strongly — the pituitary "falls silent."

Enclomiphene works at the upper level of the axis. It blocks estrogen receptors in the hypothalamus and pituitary, and the brain "does not see" the estradiol circulating in the blood. Perceiving this as a deficiency of sex hormones, the hypothalamus increases the secretion of GnRH, and the pituitary — of LH and FSH. The testes receive more natural signal and produce more testosterone.

Hence the key condition: enclomiphene is effective only when the pituitary and testes are able to respond to the stimulus. In primary (testicular) hypogonadism or with organic damage to the pituitary it will not help, whereas hCG gives its effect in secondary hypogonadism.

Spermatogenesis and testicular size

Two things are needed for the formation of spermatozoa: a very high level of testosterone inside the testes (many times higher than in the blood) and FSH, which acts on the Sertoli cells. It is precisely here that the difference between the two substances becomes most noticeable.

hCG maintains intratesticular testosterone. A study by Coviello and co-authors (2005) showed that even small doses of hCG preserved intratesticular testosterone in healthy men in whom gonadotropins were suppressed by exogenous testosterone. However, hCG does not replace FSH, so in some patients with a profound gonadotropin deficiency doctors add FSH preparations for full restoration of spermatogenesis.

Enclomiphene raises both LH and FSH, that is, it triggers both branches of spermatogenesis regulation by a natural route. In a randomized phase II study (Wiehle et al., 2014) enclomiphene increased testosterone in men with secondary hypogonadism without decreasing sperm count, whereas transdermal testosterone decreased it. Similar results were obtained by Kim and co-authors (2016) in men with obesity.

As for testicular size: hCG, by stimulating the Leydig cells, prevents the atrophy caused by a lack of LH. Enclomiphene in itself does not cause atrophy, because it does not suppress but, on the contrary, stimulates the gonadotropins. But these observations concern people with preserved axis function, not states after prolonged suppression.

• hCG— directly supports testosterone production in the testes, but one's own LH and FSH decrease.
• Enclomiphene— stimulates both gonadotropins, but depends on the pituitary's ability to respond.
• In common— neither substance is a "universal" remedy for infertility; the cause of the disorder is determined by an andrologist.

Pharmacokinetics, form and status

hCG is administered subcutaneously or intramuscularly. After the injection the hormone concentration rises over hours, and its half-life is measured in a day and more, so in clinical regimens injections are usually prescribed several times a week. The protein is sensitive to temperature: the diluted solution is stored in the refrigerator, and a violation of storage conditions reduces activity.

Enclomiphene is an oral drug that is well absorbed. Its half-life is significantly shorter than that of zuclomiphene and is measured in hours, so the substance does not accumulate in the body the way it happens with clomiphene. It is precisely the absence of prolonged accumulation of the estrogenic isomer that is considered the main advantage of enclomiphene over ordinary clomiphene.

The regulatory status differs fundamentally. hCG is registered in many countries as a medicinal product with clear indications. Enclomiphene underwent clinical trials as an agent for the treatment of secondary hypogonadism, but the European Medicines Agency (EMA) in 2018 refused registration of the drug Encyzix, and in the USA it did not receive FDA approval. That is, enclomiphene is not a registered medicinal product in most jurisdictions.

For athletes both substances are banned. In the WADA Prohibited List hCG and LH belong to section S2 (banned for men), and clomiphene and other antiestrogenic agents — to section S4 "Hormones and Metabolic Modulators." The ban is in effect at all times — both in-competition and out-of-competition.

Risks and side effects

Since hCG raises testosterone, and with it estradiol, among its adverse effects are tenderness or enlargement of the mammary glands, fluid retention, acne. In reproductive medicine in women hCG can cause ovarian hyperstimulation syndrome — a serious complication that requires medical care. Like any protein drug, hCG sometimes causes injection-site reactions or allergy.

Enclomiphene, as a SERM, has a different spectrum of risks. In studies, headache, hot flashes and nausea have been reported. For clomiphene, visual disturbances are known (blurring, "floaters," flashes of light), which are a reason to stop use immediately and see an ophthalmologist. Whether this problem extends to pure enclomiphene in full is not reliably known, so caution is appropriate.

A separate issue is thromboembolic risk. Estrogen receptor modulators as a class (tamoxifen, raloxifene) are associated with an increased risk of venous thrombosis. There is little long-term data on enclomiphene in men, so drawing conclusions about its safety with prolonged use is premature.

Finally, an important risk for both substances is product quality outside the pharmacy. On the unofficial market there are counterfeits of hCG without active hormone and "enclomiphene" of unknown composition. No laboratory indicators without medical supervision make it possible to safely assess what exactly has entered the body.

Editorial conclusions

hCG and enclomiphene lead to a similar result — an increase in testosterone — but by different routes. hCG replaces the pituitary signal and acts directly on the testes, while suppressing one's own gonadotropins. Enclomiphene makes the pituitary itself work more intensively by blocking the estrogen feedback.

It follows from this that the choice between them is never a question of "which is stronger." It is determined by the level of damage to the axis, the person's reproductive plans and regulatory possibilities. The answer is given by an examination: LH, FSH, total testosterone, estradiol, prolactin, semen analysis.

For athletes both substances are banned by WADA regardless of the purpose of use, and their self-administration carries risks that cannot be assessed without laboratory control.

We also recommend reading our materials on for whom and in which clinical situations hCG or enclomiphene is more appropriate, on the differences between clomiphene and enclomiphene, and on the tests for assessing the hormonal axis.

References

1. Coviello AD, Matsumoto AM, Bremner WJ, et al. Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression. J Clin Endocrinol Metab. 2005;90(5):2595–2602.
2. 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.
3. 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.
4. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715–1744.
5. Rahnema CD, Lipshultz LI, Crosnoe LE, et al. Anabolic steroid-induced hypogonadism: diagnosis and treatment. Fertil Steril. 2014;101(5):1271–1279.
6. European Medicines Agency. Refusal of the marketing authorisation for Encyzix (enclomiphene). London: EMA; 2018.
7. World Anti-Doping Agency. The World Anti-Doping Code: International Standard. Prohibited List. Montreal: WADA (чинна редакція).