Enclomiphene vs. Sermorelin: Different Hormones, Different Evidence

The Short Answer

Enclomiphene and sermorelin are not two versions of the same treatment. Enclomiphene is an oral selective estrogen receptor modulator (SERM) that has been studied for raising testosterone in men with secondary hypogonadism, while sermorelin is an injected copy of the first 29 amino acids of growth hormone-releasing hormone (GHRH) that prompts the pituitary to release growth hormone. Neither is currently available in the US as an FDA-approved product, so what clinics prescribe are compounded versions, which FDA states are not FDA-approved.

The practical question is which hormone problem you actually have. Low testosterone is diagnosed with repeat morning blood tests and treated with testosterone or, in some men, with drugs that stimulate the body's own production. Sermorelin does not raise testosterone in the studies summarized below; it acts on the growth hormone axis. A clinician should match the drug to a confirmed lab problem, not to a general goal like energy or body composition.

How Enclomiphene Works

Enclomiphene blocks estrogen's feedback signal to the brain. The brain responds by releasing more luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which tell the testes to make more testosterone and sperm. Because it works through the testes, it only makes sense when the testes can respond, which is why trials enrolled men with secondary hypogonadism: low testosterone with LH that is low or not appropriately raised.

• •Phase II (Wiehle et al., 2014, Fertility and Sterility): in men with secondary hypogonadism, oral enclomiphene raised morning testosterone and LH to levels similar to 1% testosterone gel, and sperm counts were conserved.
• •Phase III (Kim, McCullough and Kaminetsky, 2016, BJU International): two parallel randomized, double-blind trials in overweight men aged 18 to 60 with morning total testosterone at or below 300 ng/dL on two occasions compared two doses of enclomiphene with AndroGel 1.62% for 16 weeks.
• •In the phase III trials, total testosterone rose in all treatment groups. LH and FSH rose with enclomiphene and fell with the testosterone gel.
• •Enclomiphene kept sperm concentration in the normal range over 16 weeks, while the testosterone gel group had a marked reduction in sperm production.

These were short trials, and they measured lab values and sperm counts. The abstracts do not report long-term outcomes such as heart, bone or prostate events, so long-term safety data for enclomiphene are limited.

How Sermorelin Works

Sermorelin binds GHRH receptors in the pituitary and triggers the body's own growth hormone release, which in turn can raise IGF-1. It has a short half-life of about 10 to 20 minutes and is given as a subcutaneous injection. It is a different approach from injecting growth hormone itself.

• •Vittone et al.: 11 men aged 64 to 76 used sermorelin nightly for 6 weeks. Growth hormone release roughly doubled over 12 hours, but IGF-1, weight, lean mass and fat mass did not change significantly. Some strength tests improved.
• •Khorram et al.: a randomized, placebo-controlled study of 10 women and 9 men aged 55 to 71 using nightly injections for 16 weeks. IGF-1 rose and stayed elevated until week 12, and men gained 1.26 kg of lean mass with no change in weight, fat mass or testosterone.
• •Corpas et al.: in older men, higher doses raised growth hormone and IGF-1 in a dose-dependent way; testosterone changes were not significant.
• •Sigalos et al.: a retrospective review of 14 hypogonadal men already on testosterone found IGF-1 rose when sermorelin was combined with two other peptides (GHRP-2 and GHRP-6). There was no sermorelin-only comparison and body composition was not measured.

The 2020 review that summarizes these studies lists nausea, facial flushing and injection site redness as rare side effects, and states that research on sermorelin in men with hypogonadism is limited. Its authors call for large long-term studies and say that without them, the role and potential long-term risks of these drugs are not well understood.

FDA Status: Why Both Are Compounded Today

• •Sermorelin: FDA approved Geref (sermorelin acetate) in 1990 for testing pituitary growth hormone secretion and in 1997 for idiopathic growth hormone deficiency in children with growth failure. The maker, EMD Serono, discontinued Geref in 2008 and FDA withdrew approval in 2009. In 2013 FDA determined that Geref was not withdrawn for reasons of safety or effectiveness.
• •Enclomiphene: it has no FDA-approved product. When FDA's Pharmacy Compounding Advisory Committee reviewed it on June 8, 2022, FDA proposed that enclomiphene citrate not be placed on the list of bulk substances pharmacies may use for compounding under section 503A, and the committee voted 8 to 4 against placing it on the list. Several members who voted no cited a lack of clinical efficacy evidence.
• •Compounded versions of either drug: FDA states that compounded drugs are not FDA-approved and that it does not verify their safety, effectiveness or quality before they are marketed. Drugs from 503B outsourcing facilities must meet current good manufacturing practice requirements; drugs compounded under 503A are not subject to them.

Side-by-Side Comparison

• •Target hormone: enclomiphene acts on LH and FSH to raise testosterone; sermorelin acts on growth hormone and IGF-1.
• •Form: enclomiphene is taken by mouth; sermorelin is a subcutaneous injection.
• •Best-studied group: enclomiphene in men 18 to 60 with secondary hypogonadism; sermorelin in small groups of healthy older adults.
• •Effect on testosterone: enclomiphene raised total testosterone in its phase III trials; sermorelin did not significantly change testosterone in the studies summarized in the 2020 review.
• •Effect on sperm: enclomiphene kept sperm concentration in the normal range over 16 weeks; sermorelin's effect on sperm is not reported in those studies.
• •FDA status: no approved enclomiphene product; sermorelin's only approved product, Geref, was discontinued in 2008. Compounded versions of both are not FDA-approved.

Who Each One Is Usually Discussed For

Enclomiphene comes up for men with confirmed low testosterone and low or normal LH who want to protect fertility, because testosterone therapy itself reduced sperm production in the phase III comparison. It is unlikely to help when the testes themselves are the problem (primary hypogonadism), since its effect depends on the testes responding to LH. Sermorelin is usually marketed for growth hormone support with aging; the adult studies are small, short and mostly in older men, and they do not show it raising testosterone.

1. 1.Which of my lab results shows the problem this drug is meant to fix: low morning testosterone with low or normal LH, or a growth hormone or IGF-1 problem?
2. 2.Is the drug compounded, and by which pharmacy? Is that a 503A pharmacy or a 503B outsourcing facility?
3. 3.Which labs will be repeated, and when? For enclomiphene that usually means testosterone, LH, FSH and estradiol; for sermorelin, IGF-1.
4. 4.What is the full ongoing monthly cost, including the medication, supplies, labs and the membership or visit fee, not only the first month?
5. 5.If my goal is fertility, will you check a semen analysis before and during treatment?

Quick Answers

• •Is enclomiphene better than sermorelin? They are not interchangeable. Enclomiphene was studied for raising testosterone in secondary hypogonadism; sermorelin acts on growth hormone. Which one, if either, fits depends on your labs.
• •Does sermorelin raise testosterone? Not in the adult studies summarized in the 2020 review: testosterone did not change significantly in the Khorram and Corpas studies.
• •Can they be taken together? Some clinics offer combinations, but we found no published trial of enclomiphene and sermorelin used together. Ask the prescriber what evidence they are relying on.
• •Is either FDA-approved? No enclomiphene product is FDA-approved. Sermorelin's approved product, Geref, was discontinued in 2008. Compounded versions of both are not FDA-approved.
• •Does enclomiphene affect fertility like TRT? In the phase III trials, enclomiphene kept sperm concentration in the normal range over 16 weeks, while testosterone gel markedly reduced it.