hCG or Enclomiphene: What's the Difference

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

What hCG is and what enclomiphene is

hCG is a glycoprotein hormone 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. Because of this, hCG binds to the same receptor as LH — the LH/CG receptor on the Leydig cells in the testicles.

Medicinal hCG preparations are obtained either by purification from the urine of pregnant women or by recombinant methods. They are used in reproductive medicine: to induce ovulation in women, and to treat 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 from 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 a means of 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 lingers 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.

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

Different points of impact on the hormonal axis

Testosterone production in men is regulated by the hypothalamus–pituitary–testicular axis. The hypothalamus releases gonadotropin-releasing hormone (GnRH) in pulses, the pituitary responds by secreting LH and follicle-stimulating hormone (FSH), and the testicles, under the action of LH, synthesize testosterone. Testosterone and the estradiol formed from it, through a negative feedback mechanism, inhibit the upper links of the axis.

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 is working. At the same time, the rise in testosterone and estradiol under hCG suppresses the body'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 deficit of sex hormones, the hypothalamus increases the secretion of GnRH, and the pituitary — of LH and FSH. The testicles receive a stronger natural signal and produce more testosterone.

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

Spermatogenesis and testicular size

Two things are needed for sperm formation: a very high level of testosterone inside the testicles (many times higher than in the blood) and FSH, which acts on the Sertoli cells. This is exactly where the difference between the two substances becomes most noticeable.

hCG maintains intratesticular testosterone. A study by Coviello et al. (2005) showed that even small doses of hCG preserved intratesticular testosterone in healthy men whose 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 a full restoration of spermatogenesis.

Enclomiphene raises both LH and FSH, that is, it launches both branches of spermatogenesis regulation by a natural route. In a phase II randomized study (Wiehle et al., 2014) enclomiphene raised testosterone in men with secondary hypogonadism without lowering sperm count, whereas transdermal testosterone lowered it. Similar results were obtained by Kim et al. (2016) in obese men.

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

• hCG— directly supports testosterone production in the testicles, but the body's own LH and FSH decline.
• 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 an injection the hormone concentration rises over hours, and its half-life is measured in a day or 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 violating storage conditions reduces its activity.

Enclomiphene is an oral drug that is well absorbed. Its half-life is considerably shorter than that of zuclomiphene and is measured in hours, so the substance does not accumulate in the body the way clomiphene does. 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 a treatment for 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 (prohibited for men), and clomiphene and other antiestrogenic agents to section S4, ‘Hormone and Metabolic Modulators’. The ban applies at all times — both in competition and out of competition.

Risks and side effects

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

Enclomiphene, as a SERM, has a different spectrum of risks. Studies have reported headache, hot flashes, and nausea. For clomiphene, visual disturbances are known (blurring, ‘floaters’, flashes of light), which are grounds to stop taking it immediately and consult an ophthalmologist. Whether this problem applies to pure enclomiphene to the full extent 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 counterfeit hCG without active hormone and ‘enclomiphene’ of unknown composition. No laboratory indicators, without medical supervision, allow a safe assessment of what exactly has entered the body.

Editorial conclusions

hCG and enclomiphene lead to a similar result — a rise in testosterone — but by different routes. hCG replaces the pituitary signal and acts directly on the testicles, while suppressing the body's own gonadotropins. Enclomiphene makes the pituitary itself work harder by blocking estrogen feedback.

It follows 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 availability. The answer is given by 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 unsupervised use carries risks that cannot be assessed without laboratory monitoring.

We also recommend reading our materials on who 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).