Enclomiphene: How It Works, Usage and Side Effects

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Enclomiphene, also known as enclomiphene citrate, is a selective estrogen receptor modulator (SERM) – a class of drugs that act on estrogen receptors.

It offers a targeted approach to increasing testosterone levels in men with secondary hypogonadism.

Instead of supplying exogenous bioidentical testosterone like in traditional methods, enclomiphene supports the body and stimulates natural testosterone production.

Unlike testosterone therapy, it does not suppress fertility which makes it a suitable choice for young men interested in boosting testosterone without having to add HCG or HMG to maintain their reproductive potential. Many men can also add gonadotropins to TRT treatment when fertility is desired with good results.

Despite all these beneficial effects, enclomiphene is not fully approved for widespread therapeutic use. However, off-label interest has brought this medication into the spotlight of men’s health discussions.

In this article, we explain all you need to know about enclomiohene, including its mechanism of action, usage, dosage, side effects and more.

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What is enclomiphene citrate?

Enclomiphene citrate, popularly sold under the brand name Androxal®, is a medication prescribed off-label for male infertility and secondary hypogonadism.

Off-label means that it’s used for a purpose for which it’s not approved.

This estrogen receptor antagonist has been clinically tested for treating hypogonadism, testosterone deficiency and type 2 diabetes.

Mechanism of action: How does enclomiphene work?

Enclomiphene is an estrogen antagonist, meaning it produces an anti-estrogenic effect by blocking estrogen receptors in the brain.

It directly impacts the hypothalamic-pituitary-gonadal axis (HPG axis) by preventing the negative feedback induced by estrogen.

Normally, when estrogen levels are sufficient, estrogen signals the HPG axis to stop making gonadotropin-releasing hormone (GnRH) which prevents the production of hormones supporting estrogen synthesis.

So, when enclomiphene competes with estrogen and binds to estrogen receptors in the hypothalamus in its place, it tricks the brain into thinking that estrogen levels are below normal.

Hypothalamus responds to this by releasing more GnRH, which signals the pituitary gland to produce more luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

LH gets to work and stimulates Leydig cells (that are found in the testes) to synthesize testosterone. Similarly, FSH promotes sperm production, helping men improve fertility.

What is enclomiphene used for?

Doctors may prescribe enclomiphene for testosterone restoration or other medical conditions if they think you are the right candidate for this therapy.

Here is what enclomiphene is commonly prescribed for:

Secondary hypogonadism

Secondary hypogonadism is a medical condition that causes low testosterone because the brain fails to send proper signals to the testes to synthesize testosterone. Men suffering from this issue usually have low LH and FSH levels.

It leads to symptoms like decreased libido, low sperm count, hot flashes, fatigue, mood changes and more.

A 2024 study conducted on 66 hypogonadal men concludes that “enclomiphene provides improvement in testosterone levels with a lower rate of documented adverse events. These findings support enclomiphene as a comparable treatment option for hypogonadal men while minimizing the risk of adverse effects.”

It indicates enclomiphene’s potential ability to treat male hypogonadism without testosterone supplementation.

Blood glucose regulation

By restoring testosterone levels, enclomiphene may help increase insulin sensitivity and regulate blood glucose levels in hypogonadal and diabetic men.

Male infertility

Studies show that male infertility due to low testosterone can be improved with enclomiphene.

Enclomiphene prevents or treats infertility by boosting testosterone formation that eventually leads to improved sperm count, mobility and concentration.

Ovarian dysfunction

Enclomiphene citrate is a part of the clomiphene citrate medication that’s approved for treating female infertility caused by ovarian dysfunction.

Hormone replacement conditions like PCOS

Female reproductive health conditions like polycystic ovary syndrome, which happen because of hormonal imbalance, may also be treated with enclomiphene.

More studies should be done to evaluate enclomiphene’s effectiveness.

Enclomiphene for bodybuilding

Testosterone – a hormone well-known for its role in sexual function – is essential for improving muscle mass, muscle strength, bone density and body fat distribution.

Some bodybuilders take medications that stimulate natural testosterone production to elevate their testosterone levels (sometimes beyond normal) and build muscles in less time.

This may also enhance their athletic performance and give them an edge over others – which is why enclomiphene’s use for aesthetic and performance purposes may be banned in some competitive sports.

This is mostly done without any medical supervision, which can jeopardize their health.

Enclomiphene may also be used during post-cycle therapy (PCT) by men recovering from anabolic steroid use.

Long-term usage of anabolic steroids disturbs the HPG axis and shuts down natural testosterone production in athletes.

To reactivate the hypothalamus and pituitary, bodybuilders take enclomiphene citrate and restore their natural testosterone levels.

How long does enclomiphene take to work?

Enclomiphene therapy affects each individual differently.

For some, it may show results in just a few weeks while for others results may become noticeable after months.

According to some studies, enclomiphene citrate may increase total serum testosterone in men after 2 weeks.

Enclomiphene dosage

What enclomiphene dosage you need is determined based on your:

• Health condition
• Testosterone levels
• Treatment goals
• Response to the medication

Enclomiphene citrate is an oral medication typically available in two doses: 12.5 mg and 25 mg.

Most healthcare professionals start with a 12.5 mg dose per day and then eventually increase it to 25 mg every other day.

Remember to always follow your healthcare provider’s instructions carefully. Do not exceed or reduce the prescribed dosage without a consultation.

How to take enclomiphene?

Take enclomiphene orally with or without food according to your doctor’s instructions.

It is best to take it consistently around the same time daily so your body can maintain a regular response to the medication. Consistency is crucial for results.

Enclomiphene therapy requires regular monitoring for optimal health. Your doctor may ask you to get your testosterone, LH, FSH and estradiol levels checked regularly.

These blood tests will help them see how this medication is affecting your hormonal balance and if there is any need for dosage adjustment.

Note that if you have missed a dose, take the medication as soon as you remember it. Skip it if your next scheduled dose is approaching and resume your regular dosing routine.

What are the benefits of enclomiphene for men’s health?

Enclomiphene is beneficial for low testosterone in men and those dealing with infertility.

The best thing about enclomiphene therapy is that it boosts natural testosterone levels without suppressing LH, FSH and sperm count.

Unlike traditional therapies, you restore your endogenous testosterone, not replace it with man-made testosterone.

Although it is not studied much, available data indicate enclomiphene may have fewer side effects than traditional testosterone-increasing treatments.

What are the side effects of enclomiphene?

All medications come with possible side effects and enclomiphene is no exception. However, its side effects may be milder than testosterone replacement therapy (TRT) and clomiphene.

Studies show enclomiphene may cause the following side effects in men:

• Dizziness
• Erectile dysfunction
• Fatigue
• Mood changes and mood swings
• Gynecomastia

More research needs to be done on this medication to understand its long-term effects.

Enclomiphene therapy vs TRT

Both enclomiphene and testosterone therapy are used to raise testosterone levels. Since they are used for the same purpose, it can be difficult for a man to choose which one is best.

Before you decide which treatment to choose, here is what you should know about them.

TRT is an approved treatment that doctors prescribe for both primary hypogonadism and secondary hypogonadism. However, its downside is, it decreases endogenous testosterone production, leading to infertility.

With enclomiphene, you increase natural testosterone levels with no infertility issues. You also experience fewer adverse side effects.

So far, TRT has been studied by researchers much more than enclomiphene; hence it has more online data available.

TRT is available in various forms such as topical testosterone, skin patches, creams, gels, and injections, providing you with multiple options to choose from. In contrast, enclomiphene is currently available in only oral form.

TRT vs enclomiphene estrogen conversion risk

TRT

• Direct conversion: Exogenous testosterone, particularly at higher doses or when administered as larger single doses, can increase the activity of aromatase, an enzyme converting testosterone directly into estradiol.
• Dose-dependent effect: Higher peak levels of testosterone can result in spikes in estradiol, which may cause symptoms like water retention, mood changes, gynecomastia, and libido issues if not managed properly.
• Management: Frequent injections (smaller doses administered more often), or using topical gels/creams, can minimise peaks in testosterone, reducing excessive estradiol conversion. Aromatase inhibitors (like low-dose anastrozole) are sometimes required.

Enclomiphene

• Indirect mechanism: Enclomiphene raises endogenous testosterone by increasing LH and FSH through its action as a selective estrogen receptor modulator (SERM). Because testosterone is produced naturally in response to gonadotropins, the aromatisation into estradiol is usually closer to physiological norms.
• Moderate estradiol increase: Typically results in milder, more physiologically balanced estradiol levels, reducing the risk of excess estrogenic side effects.
• Less aromatase inhibitor use: Often does not require an aromatase inhibitor, as estradiol tends to remain within a balanced range unless excessively high doses of enclomiphene are used or the individual has a strong predisposition to aromatisation.

Comparative summary

Estrogen Conversion Risk Summary:

• TRT poses a higher risk of estradiol conversion, especially at higher or less frequent dosing regimens.
• Enclomiphene tends to produce a more balanced hormonal environment, with less pronounced estradiol elevations and fewer estrogen-related side effects.

Thus, enclomiphene often represents a lower estrogen conversion risk compared to direct TRT, making it attractive for men who wish to avoid high estrogenic side effects or those prone to elevated aromatisation.

Enclomiphene vs. clomiphene citrate

Clomiphene citrate (brand name Clomid) is used for female infertility as it helps with ovulation induction. It contains two isomers: 62% enclomiphene and 38% zuclomiphene.

The main difference between clomiphene and enclomiphene is due to zuclomiphene (an estrogen receptor agonist).

Enclomiphene and zuclomiphene have totally different mechanisms of action. While the former shows anti-estrogenic effects, the latter has estrogenic effects due to which it can lead to prolonged estrogen stimulation and potential negative feedback on the HPG axis.

Both clomiphene and enclomiphene citrate can be used (off-label) to increase your body’s own testosterone synthesis.

However, studies show enclomiphene may raise testosterone faster and more consistently with fewer adverse effects than clomiphene citrate.

Who is the right candidate for enclomiphene treatment?

Enclomiphene citrate may be the right treatment for you if you have secondary hypogonadism due to obesity, type 2 diabetes, metabolic syndrome or other factors.

It may be prescribed for men who are ineligible for TRT.

FAQs about enclomiphene treatment

Is enclomiphene FDA-approved?

As of now, enclomiphene – a selective estrogen receptor modulator – is not FDA-approved and is available via compounding pharmacies or research clinics.

When to take enclomiphene?

Choose a time that suits your schedule or what your doctor has advised. Experts often suggest taking oral enclomiphene citrate early in the morning as it is the time when testosterone levels are naturally higher in the body.

Is enclomiphene a steroid?

Enclomiphene is a non-steroidal medication having anti-estrogenic effects.

What happens when you stop taking enclomiphene?

Your testosterone levels return to what they were before starting the treatment. Low testosterone symptoms also come back.

How long can you take enclomiphene?

Enclomiphene is safe to be taken for years under medical supervision. However, so far, no data is available about its long-term safety and efficacy. Talk to your doctor to determine what the right approach is for you to treat secondary hypogonadism.

Dealing with testosterone deficiency? Book a free consultation with BMH professionals to find effective ways to treat testosterone deficiency and bring your testosterone levels within the normal range.

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References

Kassab, J., Saffati, G., Lipshultz, L. and Khera, M., 2024. (094) Safety and Efficacy of Enclomiphene Compared to Clomiphene for Hypogonadal Men. The Journal of Sexual Medicine, 21(Supplement_1), pp.qdae001-090.

Thomas, J., Arbelaez, M.C.S., Narasimman, M., Weber, A.R., Blachman-Braun, R., White, J.T., Ledesma, B., Ghomeshi, A., Jara-Palacios, M.A., Ramasamy, R. and White, J., 2023. Efficacy of clomiphene citrate versus enclomiphene citrate for male infertility treatment: a retrospective study. Cureus, 15(7).

Rodriguez, K.M., Pastuszak, A.W. and Lipshultz, L.I., 2016. Enclomiphene citrate for the treatment of secondary male hypogonadism. Expert opinion on pharmacotherapy, 17(11), pp.1561-1567.

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