Enclomiphene and clomiphene: raising testosterone without shutting down fertility

Testosterone gel or injections do work, but they come with a well-known knock-on effect: when testosterone is supplied from outside, the brain stops asking the testicles to make it and, in the process, sperm production slows down. Hence the appeal of a different approach: instead of giving testosterone, nudging the body into producing more of its own. Enclomiphene and clomiphene are the two names that come up most often in that conversation. Before getting into the mechanism and what the trials say, one thing needs saying first, because it completely changes how you should read the rest.

Not authorised in Spain for raising testosterone

Neither enclomiphene nor clomiphene is authorised in Spain for raising testosterone in men. That is not a technicality: it is the central fact.

Enclomiphene has no registration at all with the AEMPS, the Spanish medicines agency: it is not marketed in Spain. Clomiphene does exist here, under the name Omifin 50 mg tablets (AEMPS registration no. 43880), but the only indication authorised in its summary of product characteristics is female infertility due to anovulation or ovulatory dysfunction, and ovarian stimulation. The product information makes no mention of use in men or of testosterone. Any use in men is therefore off-label, in other words outside the approved indication.

And this is not just a Spanish administrative gap. In Europe, the EMA refused authorisation for enclomiphene (brand name EnCyzix), with a negative opinion from its committee, the CHMP, in January 2018. In the United States, the FDA never approved enclomiphene: the company developing it as Androxal received complete response letters from the FDA and never got the green light, with the final rejection coming towards the end of 2015. Clomiphene is approved by the FDA, but, just as in Spain, only for inducing ovulation in women. On top of that, clinical development of enclomiphene was discontinued for all indications in April 2021, so this is not a drug that is about to arrive: it is one that was dropped.

What they are and how they work

Both are SERMs, selective oestrogen receptor modulators. Rather than supplying testosterone, they act on the switch that regulates it. Oestradiol (an oestrogen) tells the hypothalamus to turn the hormonal signal down; these drugs block that negative feedback in the hypothalamus. In doing so, GnRH rises, which in turn raises LH and FSH, and those two hormones stimulate the testicle to make more of its own testosterone. The important consequence is that sperm production is not switched off, precisely because the signal comes from above and the testicle keeps working.

Enclomiphene and clomiphene are not the same thing, even though they get mentioned together. Clomiphene citrate is a mixture of two isomers: enclomiphene (the trans form, which acts as an anti-oestrogen) and zuclomifene (the cis form, a weak oestrogen with a long half-life). Enclomiphene is, so to speak, the clean half of the molecule. Treating them as equivalent is not accurate: clomiphene also drags along that persistent oestrogenic component.

What the trials found

The most frequently cited experimental work on enclomiphene comes from two phase 3 trials, known as ZA-304 and ZA-305. A word of warning before the figures: they come from abstracts of a paywalled article (Kim and McCullough, BJU International, 2016), not from the verified full text, so they should be read as approximate rather than as settled numbers.

Those studies enrolled overweight men aged 18 to 60 with secondary (central) hypogonadism (testosterone at or below 300 ng/dL), randomised between enclomiphene, testosterone gel (AndroGel 1.62%) and placebo, over 16 weeks, with a total of around 256 participants. This is what was reported:

• Enclomiphene raised mean total testosterone from around 205 ng/dL at baseline to approximately 446 and 413 ng/dL in the two studies, also raising LH and FSH.
• On fertility, the difference was the key point: enclomiphene maintained or increased sperm concentration (by roughly +12 to +15%), whereas testosterone gel reduced it markedly (by approximately -33 to -57%).

That contrast is exactly the argument in favour of the approach: raising testosterone without sacrificing sperm. But here comes the honest caveat, and it is the one that explains why the drug is not on pharmacy shelves. Both the FDA and the EMA rejected enclomiphene precisely because, despite raising testosterone in blood tests, its trials were not designed to show that this translated into an improvement in symptoms. Pushing up a number on a lab report is not the same as feeling better, and the regulators did not accept that leap as proven. The EMA also flagged a safety signal for venous thromboembolism (blood clots). In other words: the number went up, the clinical benefit was not demonstrated, and there was a flagged risk. With those three things on the table, it was not approved.

Side effects

The most solid and verifiable safety data do not come from use in men, but from the Spanish product information for clomiphene (Omifin), where the indication is in women. It lists, from clinical trials, hot flushes in up to 10.4% of cases and visual disturbances in around 2%. These are useful reference figures for understanding the drug's profile, even though they come from its authorised use in women. Added to that is the venous thromboembolism risk signal the EMA highlighted when assessing enclomiphene.

What is available in Spain today

Enclomiphene was refused in Europe and its development was abandoned; clomiphene is only approved for female infertility. In Spain, neither is authorised for raising testosterone in men, and what you read from the United States about off-label prescriptions does not apply here. An elegant mechanism does not mean a drug has passed the test that matters: showing that it helps the person, not just their blood results.

The underlying need, on the other hand, does have a legal medical answer: if you recognise yourself in the symptoms of low testosterone, the way forward is to measure it properly and treat it under supervision, not a forum or a website with no guarantees. In Spain there is now male hormonal health treatment with a prior assessment, a prescription from a registered doctor when appropriate and ongoing follow-up. You can check whether you are eligible.