A Detailed Look at Enclomiphene Citrate

Updated February 19, 2024

As men age, their testosterone levels typically decline, but over the last several decades this decline seems to be happening to younger men at rates that researchers describe as alarming. A landmark study found that, irrespective of lifestyle factors like smoking and obesity, men have been consistently experiencing a decrease in testosterone levels leading many younger men to have lower testosterone compared to their fathers or grandfathers at the same age.

Men with low testosterone may experience lack of motivation, lack of energy, low libido, poor life outlook, fat accumulation, increased risk for chronic conditions, and countless other undesirable symptoms, fueling the question of how to safely and effectively increase testosterone in men. Many synthetic and bioidentical forms of testosterone have been developed in the form of topical gels, injectables, and oral capsules. However, some of these medications can cause side effects like testicular shrinkage, breast growth, cardiovascular issues, and infertility.

One alternative is  the oral medication enclomiphene citrate — often referred to more simply as enclomiphene. Unlike testosterone replacement therapy (TRT), which shuts down your body’s testosterone production, enclomiphene encourages your body to produce its own natural testosterone without compromising fertility.

How enclomiphene works

Enclomiphene citrate belongs to a class of medications known as selective estrogen receptor modulators (SERMs), which impact the way estrogen works in the body.

Before we break down how enclomiphene works, it’s helpful to understand how your body produces testosterone naturally. Every day,  your brain sends a signal to your testes to produce testosterone and sperm thanks to a nudge from two key hormones: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). A small amount of your testosterone is converted to estradiol, which is a form of estrogen. Your brain continually monitors your testosterone and estrogen levels and adjusts your body’s production accordingly. When there is too little of either, your body will make more. Enclomiphene dampens the feedback effects of estrogen on the brain and testicles. Thinking that your body isn’t producing enough, it amps up testosterone production.

This diagram illustrates how enclomiphene can boost the body’s testosterone levels naturally. 

This process is different from taking TRT, which supplies your body with a synthetic version of the hormone, basically telling your body that it doesn’t need to produce any more on its own.

The testes of men on TRT begin to shrink because they no longer need to produce as much testosterone. The testicles also minimize their sperm production, leading researchers to consider TRT a potential form of male birth control.

The benefits of enclomiphene

In studies comparing enclomiphene to TRT,  enclomiphene consistently raised total testosterone into the normal range (253 to 604 ng/dL) and increased FSH and LH above the normal range. Sperm count also increased. Meanwhile, those in the TRT group saw increases in testosterone but decreases in LH, FSH, and sperm count

In a recent analysis of 1,250 men taking prescription enclomiphene as part of the Maximus Testosterone Protocol, patients taking enclomiphene saw an average increase in total testosterone of 81.8% and an average increase in free testosterone of 89.7%. There were also increases in LH levels at an average of 87.1%. In a follow-up analysis that excluded participants suspected of having primary hypogonadism (low testosterone typically caused by testicular failure) or prior use of TRT, there was an increase in free testosterone of 96.5% as well as a 87.7% increase in total testosterone.

The positive findings weren’t just about testosterone levels though. Participants also saw improvements in overall quality of life, including mood and athletic ability. All improvements were considered statistically significant and included improvements in mood in 67% of subjects, increased energy in 55%, improved sports ability in 50%, increased libido in 48%, better work performance in 46%, and an increase in happiness in 42%.

The study also found enclomiphene to be safe for long-term use, with most subjects staying on the protocol for three years or more without experiencing adverse effects.

Who Might Benefit from Enclomiphene Citrate?

Enclomiphene can be helpful for men who want to increase their testosterone levels without compromising fertility. Whether you have low levels or you're experiencing low testosterone symptoms with so-called “normal” levels, you can benefit from enclomiphene with the right dose as determined by your doctor. After all, many benchmark figures that are used to define normal testosterone levels (300 ng/dL or higher) are not always representative of the optimal ranges in younger, healthy men. Such figures are typically established in older participants as explained in the analysis of 1,250 men cited above.

When it comes to dosage, the analysis also found that there was a dose-dependent response up to 12.5mg, with the two standard dosages of 6.25 mg and 12.5 mg, resulting in 67% & 150% relative increases in free testosterone respectively. The dosage can be increased up to 25 mg with your doctor’s approval after assessing your results on the protocol.

Is enclomiphene safe?

Research has found enclomiphene to be well-tolerated with few adverse effects. Some of the most common side effects noted in clinical trials included headache, hot flushes, nausea, and abdominal discomfort. Most of the side effects were considered mild or moderate in intensity and similar to the side effects people might experience when taking topical TRT, except for one notable difference with enclomiphene: no loss of infertility or risk of infertility.

In the analysis of the Maximus Testosterone Protocol, only non-specific and minor side effects were reported, with no serious adverse events recorded. Side effects included weight gain, changes in libido, allergic reactions, and acne, and lead to discontinuation of treatment in 75 participants in the study.

Enclomiphene has a relatively short half-life of around 10 hours, with the maximum serum drug concentration reached within two to three hours of taking the drug. Despite this short half-life, men taking the drug have maintained increased testosterone, FSH, and LH levels for at least seven days after discontinuing the drug, indicating a longer duration of effectiveness. This can be useful for men who occasionally miss a dose or are considering stopping the medication for a period of time.

Is enclomiphene the same as Clomid®?

Clomiphene citrate, or better known under its brand name Clomid, is another SERM like enclomiphene. It is approved by the FDA as a fertility drug for women and commonly used off label to boost testosterone in men.

Clomid contains two compounds, one being enclomiphene, which constitutes 62% of the drug. As mentioned above, enclomiphene boosts testosterone by blocking estrogen. The other compound is zuclomiphene, representing 38% of the drug. It actually functions as an estrogen agonist, which means it boosts estrogen in the body. It has a much longer half-life of around 30 days and is associated with a number of distinct side effects thought to be the result of the drug’s estrogen-boosting effects. These include mood swings and breast tenderness. The presence of zuclomiphene is what makes Clomid, or clomiphene, an entirely different drug compared to enclomiphene.

Comparing enclomiphene to TRT

Testosterone replacement therapy, or TRT is the default treatment for men with low testosterone. As the name suggests, TRT replaces deficient levels of testosterone with synthetic testosterone from an external source.

Some of the primary reasons men take TRT are to support libido and sexual activity, maintain muscle and decrease fat, maintain bone strength and function, and enhance energy and cognition. Impacts on motivation, muscle and strength are reasons athletes have used synthetic testosterone for performance enhancement. Side effects of TRT that have garnered most concern are prostate cancer progression and heart issues.

Another problem with TRT is that many men struggle to go off the medication because of withdrawal. Stopping TRT can cause weight gain, low energy, low sex drive, irritability, and severe depression to surface.

In comparison, stopping enclomiphene doesn’t cause these symptoms.

In a 16-week study comparing enclomiphene to topical testosterone in overweight men with low-normal testosterone (≤300 ng/dL), enclomiphene citrate consistently increased LH, FSH and testosterone. It also kept sperm concentrations in the normal range, while the topical treatment reduced sperm counts.

Is hair loss a problem when taking enclomiphene or TRT

One concern with TRT is its potential to worsen hair loss. Some of the testosterone you produce each day converts to dihydrotestosterone (DHT), another male sex hormone that may contribute to male pattern baldness. When DHT levels are too high (which typically happens when testosterone is too high), the hormone may reduce your hair follicles and shorten the hair growth cycle, leading to hair loss.

However, enclomiphene affects DHT differently than TRT. While research shows that topical TRT, for example, may disproportionately increase in DHT relative to testosterone, enclomiphene has been shown to cause a modest decrease in DHT. Thus, enclomiphene should have minimal effect on hair loss compared to TRT.

Comparing enclomiphene to some other treatment options

How does enclomiphene compare with other treatment options to increase men’s testosterone?

HCG

Human chorionic gonadotropin, or hCG, is sometimes used to treat low testosterone because it is very similar to a chemical released by the brain to stimulate your testes to produce testosterone.

The main disadvantage of hCG treatment is the need for frequent (often twice weekly) injections, which can be uncomfortable and cause pain, bruising, and swelling at the injection site. Another potential issue is that many studies on hCG are conducted on women, so scientific data on hCG to increase testosterone (and its adverse effects) is relatively scarce.

Aromatase inhibitors

Aromatase inhibitors (AIs) block the action of the enzyme aromatase that converts testosterone to estradiol. AIs can both increase testosterone levels and decrease estrogenic activity. Some men on TRT take AIs because of undesirable effects such as breast growth. AIs are not FDA-approved for use in the treatment of low testosterone.

What happens if you stop taking enclomiphene?

When you stop taking enclomiphene, your body's testosterone production may decrease back towards its baseline level prior to treatment. The speed and extent of this decline can vary greatly among individuals, depending on factors such as their natural baseline testosterone level, age, overall health, and lifestyle factors.

Is enclomiphene well-studied?

As an active compound of the well-known, FDA-approved drug Clomid, enclomiphene has been the subject of numerous clinical trials and scientific studies. These studies have shown enclomiphene's efficacy in stimulating the body's natural production of testosterone, and its relative safety profile.

Enclomiphene was first developed by Repros Therapeutics under the brand name Androxal. It underwent a phase 3 clinical trial, with results showing that it was superior to topical testosterone gel in terms of increasing testosterone without lowering sperm count. When the drug was submitted to the FDA for consideration, the company presented the clinical trial results along with a robust collection of data on safety and efficacy from more than 20 prior studies.

Is enclomiphene FDA-approved?

Though enclomiphene was submitted to the FDA for approval with promising findings, its approval process was paused in 2015 when the FDA stated the drug did not sufficiently demonstrate clinical benefit in its phase III analysis. Not much later, Repros Therapeutics was bought out by the company Allergan, and enclomiphene was shelved.

However, as a component of the FDA-approved medication Clomid, enclomiphene has been nominated for use in compounding under Section 503A of the Federal Food, Drug, and Cosmetic Act. This designation permits its legal preparation by compounding pharmacies when prescribed by a physician. Compounded drugs, like the enclomiphene + pregnenolone formulation used in the Maximus Testosterone Protocol, are not approved by the FDA.

In June 2022, the Pharmacy Compounding Advisory Committee voted on whether to exclude enclomiphene from the 503A Bulks List, but as of 2024, the list has not been updated and enclomiphene is still available for compounding.

How do I know if enclomiphene is right for me?

The best way to access enclomiphene is through a prescription from a licensed physician who specializes in men’s health. Although enclomiphene is known to have few adverse effects, it’s important to speak to a doctor and share your full medical history before taking it. This is to ensure that you do not have any contraindications that may make you a poor candidate for the medication.

At Maximus, we have licensed physicians who specialize in men’s health who will be able to customize a health plan to fit your needs. Along with a prescription for enclomiphene, you’ll receive blood tests to establish your baseline levels and monitor your progress along the way, as well as health coaching.

Keep in mind that although you may be able to find products marketed as enclomiphene online, there is no guarantee that the drug is real or contains a dosage that is right for you.

The Maximus Testosterone Protocol uses enclomiphene to increase men’s total and free testosterone levels, with men reporting many benefits such as enhanced sexual function and muscle mass. Interested in trying it out? Talk to your doctor, schedule a telemedicine visit with Maximus, and get a prescription.