Enclomiphene and Pregnenolone: Explore the Hormone-Supporting Combo

Key takeaways:

• Pregnenolone is a precursor hormone. It provides the raw material for testosterone and other steroid hormones.

• Enclomiphene stimulates the body’s own testosterone production while helping preserve fertility.

• Enclomiphene and pregnenolone are sometimes used in compounded products, but there’s no strong clinical evidence that this works better than using them individually.

When it comes to men’s health, hormone balance plays a big role in everything from reproductive function to overall well-being. Two compounds that may come up when looking into testosterone and fertility are enclomiphene and pregnenolone.

These compounds work in very different ways, with one signaling the body to make more testosterone, and the other (in theory) acting as a raw material for hormone production. This is why some compounding pharmacies may combine them.

That combination, which isn’t supported by randomized trials, may offer a complementary approach to supporting healthy testosterone levels (aka T levels) and male fertility.

Here’s what to know about each and how enclomiphene and pregnenolone might be used in combination.

Pregnenolone is a naturally occurring steroid hormone precursor in the body, meaning it’s required to make pretty much every other steroid hormone. For this reason, pregnenolone is sometimes called “the mother hormone.”

Pregnenolone is a neurosteroid — that is, one produced by the central nervous system. It’s made from cholesterol in the brain, adrenal glands, and gonads (the testes or ovaries).

Pregnenolone then acts as the starting point for making hormones like:

• Testosterone

• Estrogen

• Cortisol

• Progesterone

• Dehydroepiandrosterone (DHEA)

It can also be made artificially and used as a supplement or medicine.

Age-Related Pregnenolone Decline

Some studies suggest that certain forms of pregnenolone in the body drop with age. Since pregnenolone is a precursor for many hormones, even small changes could, theoretically, affect multiple body systems, possibly contributing to cognitive decline or lower hormone levels.

However, it’s still unclear whether lower pregnenolone actually causes these age-related changes — or if taking supplements can help.

Similarly, pregnenolone as a supplement isn’t an established therapy to raise testosterone or treat infertility. It’s a precursor molecule, so any effect on downstream hormones is indirect and variable.

One observational study found that male shift workers had lower pregnenolone and testosterone than daytime workers. But it’s unclear whether pregnenolone decline directly caused the hormone drop or if both were linked to disrupted sleep cycles. 

No robust clinical trials have tested pregnenolone supplementation in men with fertility or testosterone outcomes — such as sperm count, motility, conception, or hormone response — as the main focus.

In one small clinical trial of 94 U.S. veterans with chronic low back pain, participants took pregnenolone for four weeks, starting at 100 milligrams (mg) per day and increasing up to 500 milligrams per day — doses much higher than typical supplement amounts.

Compared to the placebo group, those taking pregnenolone reported about a 20 percent reduction in pain, versus a 6 percent reduction with the placebo. But the treatment didn’t lead to meaningful improvements in sleep, mood, memory, or physical function.

Enclomiphene citrate is an isomer of clomiphene citrate, a selective estrogen receptor modulator (SERM). This means enclomiphene citrate and clomiphene citrate have the same chemical formula but in different arrangements.

While clomiphene is FDA-approved for treating infertility in women, enclomiphene itself isn’t FDA-approved for any use.

Enclomiphene has been studied as an investigational therapy for men with low testosterone (secondary hypogonadism). It’s only available through compounding pharmacies, and any use in men is considered off-label. 

Enclomiphene vs. Testosterone Replacement Therapy

Unlike therapies that supply the body with external testosterone (known as testosterone replacement therapy or TRT), SERMs like enclomiphene and clomiphene stimulate the brain to boost the body’s own natural testosterone production.

Here’s a more detailed explanation of how enclomiphene works:

• Enclomiphene blocks estrogen receptors in one of the brain’s control centers (the hypothalamus). This signals the pituitary gland to release more luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

• These hormones then act directly on the testes, prompting them to produce testosterone and support sperm production.

• The result? An increase in total testosterone levels that helps maintain fertility. This is a key distinction from many standard testosterone therapies, which can actually suppress sperm production over time.

Clinical trials have shown that oral enclomiphene raises total testosterone and preserves or restores sperm counts in men with secondary hypogonadism. Studies show it does this while preserving sperm counts. 

However, these studies are smaller than typical phase-3 drug programs. And enclomiphene hasn’t been approved by regulators for routine use.

By targeting the body’s hormone-signaling system rather than supplying outside testosterone, enclomiphene may offer an alternative way of treating low testosterone levels while supporting reproductive health. 

→ Learn more: Enclomiphene and Fertility: Understanding the Connection

Enclomiphene acts at the brain and pituitary gland levels, signaling the testes to produce more testosterone and sperm. Pregnenolone, on the other hand, is the basic material in the body needed to produce testosterone and other steroid hormones like estrogen, progesterone, and cortisol.

Though the idea of combining enclomiphene and pregnenolone sounds plausible in theory, there’s no solid evidence that the combination actually improves hormone outcomes.

Taking pregnenolone as a supplement hasn’t been proven to increase testosterone levels in men. Enclomiphene is the component with demonstrated (although limited) evidence for increasing testosterone while preserving fertility.

If a healthcare provider prescribes enclomiphene and pregnenolone together to help increase testosterone levels and support healthy hormone balance, know that results won’t happen overnight.

The time it takes to see changes can vary depending on things like your baseline hormone status and dosing. But testosterone generally rises within several weeks.

Since both enclomiphene and pregnenolone influence hormone production indirectly, regular bloodwork is typically recommended to track testosterone, estrogen, progesterone, and cortisol levels.

Generally, you can expect a gradual adjustment period, routine lab testing, and a personalized approach to dosing. The goal isn’t a quick fix but rather a carefully managed strategy for optimizing hormone balance.

Any treatment that affects hormones comes with potential risks, and combining enclomiphene with pregnenolone is no exception.

Since these compounds influence hormone signaling and production in different ways, adverse effects can vary depending on the individual and their baseline hormone status.

Potential side effects of using pregnenolone may include:

• Fatigue

• Stomach aches or constipation (gastrointestinal upset)

• Skin rash

• Mood changes

As for side effects of enclomiphene, some of the more common ones include: 

• Hot flashes

• Headaches

• Nausea

Some people may experience temporary visual disturbances, like blurred vision, but this is rare.

Also, know that both medications could interact with other hormone therapies, medications, or supplements. For this reason, it’s critical that dosing is personalized and hormone markers are checked regularly to ensure levels remain in a healthy range.

Who Should Avoid Enclomiphene and Pregnenolone?

Enclomiphene and pregnenolone should only be used under the guidance of a qualified healthcare professional who can assess risks, monitor lab results, and adjust dosing for your individual needs.

Your provider will determine if enclomiphene, pregnenolone, or a combination of the two is appropriate for you.

While these treatments can be helpful in certain cases, they aren’t suitable for everyone. For example, this combination may not be recommended for:

• Men with a history of prostate or breast cancer because hormone shifts could worsen these conditions

• Those with severe cardiovascular disease or uncontrolled high blood pressure (hypertension)

• Anyone currently using other hormone replacement therapies (testosterone, estrogen, or progesterone) without medical oversight

→ Read: What Is Hormone Replacement Therapy (HRT) for Men?

Here are some answers to commonly asked questions about this combo of medications.

Does pregnenolone increase testosterone?

Pregnenolone isn’t considered a treatment for low testosterone levels. It’s a hormone precursor that provides the raw material to make testosterone, but it doesn’t directly increase testosterone on its own. Pregnenolone supplementation may support testosterone production indirectly, but evidence that pregnenolone alone raises testosterone levels is lacking.

Is enclomiphene FDA-approved?

No. Enclomiphene isn’t currently FDA-approved for any indication. The treatment is considered investigational and may be prescribed under medical supervision through compounding pharmacies.

Can you take enclomiphene and pregnenolone together?

Some healthcare providers may consider enclomiphene together with pregnenolone after reviewing your health needs and medical history. But there’s no strong clinical evidence that the combination works better than enclomiphene alone.

Enclomiphene and pregnenolone act on different parts of steroid physiology.  Enclomiphene helps the body make more natural testosterone without affecting sperm production, while pregnenolone is the raw material the body uses to produce testosterone.

Here’s what to remember if you’re considering combining these treatments:

• Pregnenolone is a precursor hormone that provides the raw material for testosterone and other steroid hormones.

• Enclomiphene stimulates the body’s own production of testosterone while helping preserve fertility.

• Combining the two makes sense in theory and is sometimes used in compounded products, but there’s no strong clinical evidence that it actually works better. 

If you’re curious whether enclomiphene and pregnenolone are right for you, talk with a licensed healthcare provider who can evaluate your hormone levels and guide you through safe, personalized options.

→ Read next: How to Increase Testosterone Naturally