How Enclomiphene Works to Support Male Hormone Health

Normal testosterone levels are important for several reasons. For example, when you have low testosterone, you may experience lower libido, energy levels, and mood. If you’re diagnosed with low testosterone (male hypogonadism), know that plenty of treatments are available that may help.

One such popular intervention is testosterone replacement therapy (TRT), which works by increasing the amount of testosterone in your system by taking synthetic testosterone — but it’s not for everyone. TRT is associated with several adverse effects and risks, including low sperm count, which may not be ideal if you’re hoping to have kids in the future.

One alternative option to TRT is oral enclomiphene citrate, a medication that can increase testosterone without affecting spermatogenesis. Unlike TRT, which replaces your body’s natural testosterone with a synthetic version of the hormone, enclomiphene supports your natural testosterone production. It’s not testosterone replacement — it’s testosterone restoration.

Below, find out how enclomiphene works, how it compares to TRT, and side effects you should know about.

Belonging to a class of drugs known as selective estrogen receptor modulators (SERMs), enclomiphene is one of two isomers found in clomiphene citrate (Clomid^®), a medication approved by the United States Food and Drug Administration (FDA) to treat female infertility.

In men with hypogonadism, a condition characterized by low testosterone caused by insufficient signaling from the pituitary gland, clomiphene and enclomiphene can help restore natural testosterone production. 

Enclomiphene is not FDA-approved and is considered an investigational or off-label drug. It can only be obtained through compounding pharmacies with a prescription or by joining a clinical trial. Any use is considered off-label because it hasn’t gone through full FDA approval. Enclomiphene is a compounded drug product. The FDA does not approve or verify compounded drugs for safety, effectiveness, or quality.

Before we can explain how SERMs can support healthy testosterone levels, it may be helpful to know how your body makes testosterone.

The brain (specifically the hypothalamus) releases a hormone, called gonadotropin-releasing hormone (GnRH), in pulses. This release signals the pituitary gland to release two hormones: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates Leydig cells in the testes to make testosterone, and FSH stimulates the Sertoli cells to produce sperm.

Typically, a negative feedback loop keeps testosterone levels in balance: High testosterone tells the brain and pituitary to reduce GnRH and LH, thus lowering testosterone production. This works, unless testosterone levels drop too low.

Like clomiphene, enclomiphene disrupts this negative feedback loop. As an estrogen antagonist, enclomiphene blocks estrogen from binding to its receptors, which helps the brain release more gonadotropins, specifically LH and FSH. This encourages the testes to make more testosterone and sperm.

Increasing your testosterone levels isn’t just about getting to an acceptable total testosterone number on a blood test. Men with low testosterone may struggle with symptoms indicative of testosterone deficiency, like erectile dysfunction (ED), low libido, fatigue, weakness, loss of muscle mass, increased body fat, mood changes, and smaller testicular volume.

Erectile dysfunction is not always caused by low testosterone, but the two conditions often overlap. Because of this, ED treatments are sometimes considered in conjunction with low T therapy, which is why ED medications are often discussed alongside testosterone support. Hims offers a 2-in-1 combination therapy for ED and low testosterone for this very reason. The medication contains enclomiphene and tadalafil (Cialis^®) to support testosterone production and sexual performance at the same time.

Like clomiphene and TRT, enclomiphene may help reduce symptoms of low testosterone, leading to a higher libido, a leaner body mass, increased energy, and an improved mood.

Enclomiphene has been found to maintain fertility while increasing testosterone and alleviating symptoms of low T. This sets the medication apart from exogenous testosterone, a side effect of which is suppressed fertility.

How Well Can Enclomiphene Raise Testosterone Levels?

In a study that compared Androxal^™, a brand-name form of enclomiphene that was studied but never approved by the FDA, to a placebo and testosterone gel, enclomiphene was found to increase testosterone in a dose-dependent manner over the course of 14 days:

• 12.5 milligrams (mg) per day: 412 ± 194 nanograms per deciliter (ng/dL) 

• 25 mg per day: 520 ± 160 ng/dL

• 50 mg per day: ± 589 ± 172 ng/dL

Increases were seen in both free and total testosterone without proportionally increasing dihydrotestosterone (DHT), another male sex hormone.

Despite the available data on enclomiphene, Androxal^™ has not been approved by the FDA, and the development of enclomiphene was discontinued for all uses in 2021.

In another small study that compared enclomiphene to a transdermal testosterone therapy, enclomiphene consistently increased total testosterone into the normal range and raised LH and FSH levels above the normal range. At the start of the study, 44 hypogonadal men had testosterone levels less than 350 ng/dL. After six weeks of continuous use, the average concentration of total testosterone at day 42 was 604 ng/dL for men taking the highest dose of enclomiphene citrate (25 mg daily) and 500 ng/dL in men treated with transdermal testosterone.

Both enclomiphene and transdermal testosterone increased total testosterone levels in as little as two weeks, but they had opposite effects on FSH and LH levels. In addition, enclomiphene’s effects on LH and total testosterone persisted for at least one week after stopping treatment.

While more research on safety and efficacy is needed, some evidence suggests that enclomiphene has fewer side effects. However, it may still cause unwanted reactions in some individuals.

Side effects of enclomiphene may include:

• Headaches

• Hot flashes

• Nausea

• Muscle spasms

• Blurred vision

• Aggression

• Increase in estradiol

Though rare, clinical trials have found that enclomiphene users also had a higher risk of blood clots, cardiac disorders, increased red blood cells, eye disorders, and psychiatric disorders than placebo users.

Are There Side Effects Associated With Stopping Enclomiphene?

As shown in the study of 44 hypogonadal men mentioned above, enclomiphene users continue to see elevated hormone levels for a week after stopping treatment. This is especially true for those taking higher dosages (men taking 25 mg doses had higher T one week later than those taking 12.5 mg doses). However, men taking either dosage of enclomiphene continued to have higher testosterone levels a week after stopping treatment than men who’d been taking transdermal testosterone.

The study authors point out that this persistence of testosterone levels (or “legacy” effect) after stopping treatment isn’t due to the medication’s short half-life of around seven hours. Instead, they suggest it may be due to enclomiphene’s action as an estrogen receptor blocker, which indirectly affects one or more components of the hypothalamic-pituitary-gonadal axis. This feature could be helpful for men who miss a dose or two. More research is needed to confirm this hypothesis.

Over time, testosterone levels are likely to return to baseline, after which users may experience a return of hypogonadal symptoms.

Research supports that enclomiphene is as effective as clomiphene for increasing testosterone levels, but has a lower rate of documented adverse events.

Clomiphene citrate, sold under the brand name Clomid, is a mixture of two isomers: enclomiphene and zuclomiphene, with enclomiphene generally comprising the larger proportion. The differences between clomiphene and enclomiphene mainly come down to zuclomiphene, which has an entirely different mechanism of action than enclomiphene.

About those differences: enclomiphene is an estrogen antagonist, while zuclomiphene is an estrogen agonist. This means that enclomiphene blocks estrogen receptors and increases GnRH secretion, leading to higher LH and FSH levels.As an estrogen agonist, zuclomiphene, on the other hand,  has more estrogen-like activity, which may counteract some of the beneficial effects of enclomiphene and contribute to side effects. This is likely why clomiphene is associated with more side effects, like gynecomastia (breast growth) and mood swings.

Zuclomiphene also has a longer half-life, measured in days instead of hours, like enclomiphene. This means that zuclomiphene can accumulate in the body, leading to more estrogen sticking around for longer, which opens a higher risk of associated side effects. Some research has shown that long-term clomiphene use significantly alters enclomiphene and zuclomiphene concentrations in the body, leaving behind too much zuclomiphene. This has led researchers to support the need for the development of a “pure” antiestrogenic medication.

Some researchers have suggested that most of the beneficial effects of clomiphene are due to enclomiphene, and that zuclomiphene contributes little to the intended outcomes of the medication.

Testosterone replacement therapy is a popular treatment for men with low testosterone, but it comes with side effects and risks that shouldn’t be taken lightly.

Potential side effects of TRT include decreased sperm count, breast growth and tenderness, enlarged prostate, worsened obstructive sleep apnea, fluid retention, acne, and an increase in red blood cells.

One of the reasons why TRT is associated with decreased sperm count and infertility is that it can suppress the hypothalamic-pituitary-gonadal (HPG) axis. This leads to lower FSH and LH levels and a decreased intra-testicular testosterone concentration. TRT essentially shuts down your body’s ability to produce its own testosterone by delivering a synthetic version of the hormone into your bloodstream.

Enclomiphene, on the other hand, stimulates the HPG axis. This can lead to more FSH and LH and a higher concentration of intra-testicular testosterone. Instead of shutting down your body’s ability to produce more testosterone, it supports the process.

Is Enclomiphene as Effective as TRT for Treating Low Testosterone?

A small study that compared enclomiphene to topical testosterone found that both treatments led to significant increases in testosterone that were sustained for three months. The increases were comparable at six months, with total testosterone levels being 545 ± 268 ng/dL for those taking topical testosterone and 525 ± 256 ng/dL for those taking enclomiphene.

However, only men taking enclomiphene saw increases in their LH and FSH levels. 

Enclomiphene also elevated sperm counts in all participants at three months and at six months, while topical testosterone was not found to be as effective in raising sperm counts. Granted, this was a small study, but enclomiphene’s ability to maintain fertility in hypogonadal patients has been demonstrated in other research, in which the authors presented enclomiphene as an oral option for younger men who want to raise their testosterone levels while maintaining semen quality.

How Quickly Does Enclomiphene work?

Per the results of one small study, enclomiphene can stimulate testosterone in hypogonadal men in as little as 14 days. However, results may vary from person to person.

What Are the Available Doses of Enclomiphene?

The most common dosage studied for enclomiphene is 25 mg. The medication has also been studied in dosages of 6.25 mg and 12.5 mg.

Is Enclomiphene FDA-Approved?

No, the Food and Drug Administration has not yet approved enclomiphene. It may be available through compounding pharmacies with a prescription, but compounded medications are not FDA-approved. Clomiphene and enclomiphene may be prescribed off-label by a healthcare provider to treat men with low testosterone who want to preserve their fertility. Compounded drug products are not reviewed by the FDA for safety, effectiveness, or quality.

Enclomiphene is a promising treatment for low testosterone, especially for men who are looking for the benefits of TRT with fewer side effects. Here’s what we know about this medication:

• Enclomiphene may restore natural testosterone without compromising fertility. Enclomiphene stimulates the hypothalamic-pituitary-gonadal axis to increase testosterone and sperm count. This makes it a viable option for men with low testosterone who want to preserve fertility.

• Enclomiphene offers analternative to clomiphene and TRT. Enclomiphene, the active isomer in clomiphene, provides the benefits of more testosterone with fewer side effects. It avoids the estrogenic effects associated with zuclomiphene, an ingredient in Clomid, offering a more targeted therapy that may be better tolerated. 

• Enclomiphene works, according to research. Multiple studies show that enclomiphene can significantly raise total and free testosterone levels with sustained benefits after discontinuation.

• Enclomiphene is not FDA-approved. More large-scale studies are needed to confirm its safety and effectiveness.

Want to learn more boosting your testosterone levels? Check out this guide on how to increase testosterone naturally, learn about the top testosterone-friendly foods, and explore the connection between testosterone injections and hair loss.

If you’re interested in treatment options — including prescription medications for low testosterone or general wellness support — make an appointment to speak with a licensed healthcare provider.