Approved & therapeutic
Enclomiphene
Androxal
The trans-isomer of clomiphene citrate, an oral selective estrogen receptor modulator that acts as an antagonist at the hypothalamus and pituitary. It was developed for secondary hypogonadism in men but has never been approved: FDA accepted the New Drug Application in April 2015 and issued a Complete Response Letter in December 2015, and no successor sponsor has resubmitted. There is no FDA-approved enclomiphene product and no generic. US access is via compounding pharmacies, but that route is contested — FDA's Pharmacy Compounding Advisory Committee voted against adding enclomiphene citrate to the 503A Bulks List. Enclomiphene is also on the WADA Prohibited List and the US Department of Defense Prohibited List.
- Status
- Enclomiphene is a research compound and not approved by the FDA for human use.
- Evidence
- Human trials. Published clinical trials in people report results.
- Half-life
- Approximately 10 hours in men (commonly reported as 10 to 12 hours), with maximum serum concentration reached about 2 to 3 hours after an oral dose, from the human pharmacokinetic substudy in Wiehle et al., BJU International 2013 (a phase II study in 48 men with secondary hypogonadism). No FDA-labeled value exists: the approved racemic clomiphene citrate label gives no numeric half-life for enclomiphene, stating only that the zuclomiphene isomer has a longer half-life than enclomiphene.
- How it's taken
- Oral.
- Mechanism
- Reproductive axis (GnRH / kisspeptin / oxytocin)
- Pathways
- GnRH, Estrogen, Androgen
How Enclomiphene works
Enclomiphene blocks estrogen receptors at the hypothalamus and pituitary, removing the negative feedback that estradiol exerts on gonadotropin release. LH and FSH rise, which stimulates endogenous testicular testosterone production while leaving spermatogenesis intact, in contrast to exogenous testosterone.
What research has looked at
- In two randomised, double-blind, double-dummy, placebo- and active-controlled phase 3 studies (ZA-304 and ZA-305) in 256 overweight men aged 18 to 60 with secondary hypogonadism, enclomiphene raised mean total testosterone from about 205 ng/dL at baseline to 446 and 413 ng/dL in the two studies, both statistically superior to placebo. FDA subsequently raised concerns about bioanalytical method validation in this programme that it said could affect the interpretability of certain pivotal study data, so these hormone values should not be treated as independently confirmed.
- In the same studies sperm concentration rose about 12 to 15 percent in the enclomiphene groups, while it fell 33 to 57 percent in the topical testosterone gel groups.
- The pre-registered primary endpoint of both studies was a composite of testosterone in the normal range together with sperm concentration at or above 15 million per millilitre. The widely quoted composite success figures of 63.5 percent for enclomiphene versus 24.7 percent for testosterone gel and 5.8 percent for placebo come from a published analysis using a lowered sperm threshold of 10 million per millilitre, and are therefore not the pre-registered primary result.
- A separate pooled analysis from the morning-testosterone-normalisation phase 3 studies (NCT01532414 and NCT01739595, not ZA-304/305) reported normalisation of morning testosterone above 300 ng/dL in 75.6 and 82.1 percent of treated men across the two dose groups, versus 36.7 percent on placebo.
- No symptomatic or functional benefit was ever established. Hormone-level changes are surrogate endpoints; nothing in this programme demonstrated improvement in energy, mood, sexual function, body composition or fertility outcomes.
Evidence level: Human trials. Published clinical trials in people report results. These are areas studied or reported, not promised effects.
Reported side effects and risks
- Not FDA-approved. FDA's Complete Response Letter of 1 December 2015 stated that, based on recent scientific developments, the design of the phase 3 studies was no longer adequate to demonstrate clinical benefit, and cited concerns regarding study entry criteria, titration and bioanalytical method validation. The advisory committee scheduled for November 2015 was cancelled and never convened, so no advisory committee ever reviewed this drug. Development was discontinued.
- No FDA-approved label exists, so there is no authoritative boxed warning, contraindication list, drug-interaction section or pregnancy statement for a US enclomiphene product. The safety information below is read across from the approved racemic clomiphene citrate label, which contains enclomiphene as one of its two isomers; how completely it transfers to the isolated trans-isomer has not been established.
- Contraindications on the racemic clomiphene citrate label that are not sex-specific and should be assumed to apply: liver disease or a history of liver dysfunction; an organic intracranial lesion such as a pituitary tumour; uncontrolled thyroid or adrenal dysfunction; and known hypersensitivity to clomiphene citrate. The pituitary-lesion contraindication is directly relevant, because a pituitary lesion is itself one of the causes of secondary hypogonadism. Anyone with low testosterone and low or normal LH needs a pituitary cause excluded before any SERM is considered.
- Visual disturbances including blurring, spots, flashes and scintillating scotomata are documented for racemic clomiphene. The label states these increase in incidence with increasing total dose or duration, may be prolonged, have occurred after discontinuation, and may be irreversible. They may make driving or operating machinery hazardous, particularly in variable lighting. Any visual symptom warrants stopping the drug and prompt ophthalmological evaluation.
- Further label precautions that are not sex-specific: hypertriglyceridemia has been reported, with pretreatment triglyceride screening and periodic monitoring recommended; pancreatitis has been reported; postmarketing hepatic events include hepatitis and increased transaminases; postmarketing cardiovascular and thromboembolic reports include pulmonary embolism, thrombophlebitis, stroke and seizure.
- Adverse events reported in the phase 3 programme were most commonly headache, hot flushes and nausea, each in a small percentage of treated men.
- Limited human data: trials ran 16 weeks in 256 men, which is too short and too small to detect uncommon or long-term harms. Effects on bone, cardiovascular risk, lipids and mood over years are uncharacterised, and FDA specifically declined to accept this evidence base as adequate.
- Compounded product is not subject to FDA bioequivalence, potency or stability verification, so content and purity vary between pharmacies and there is no standardised package insert. FDA's Pharmacy Compounding Advisory Committee voted against including enclomiphene citrate on the 503A Bulks List.
- Prohibited in sport under Section S4 of the WADA Prohibited List and listed on the US Department of Defense Prohibited List as an unapproved drug. It is illegal to sell as a dietary supplement ingredient, and products marketed as research chemicals or testosterone boosters are unlawful and unverified.
Sources
- PubMed research on Enclomiphene · NIH · National Library of Medicine
- DrugBank record for Enclomiphene · DrugBank
- Active clinical trials for Enclomiphene · U.S. National Library of Medicine
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Enclomiphene FAQ
What is Enclomiphene?
The trans-isomer of clomiphene citrate, an oral selective estrogen receptor modulator that acts as an antagonist at the hypothalamus and pituitary. It was developed for secondary hypogonadism in men but has never been approved: FDA accepted the New Drug Application in April 2015 and issued a Complete Response Letter in December 2015, and no successor sponsor has resubmitted. There is no FDA-approved enclomiphene product and no generic. US access is via compounding pharmacies, but that route is contested — FDA's Pharmacy Compounding Advisory Committee voted against adding enclomiphene citrate to the 503A Bulks List. Enclomiphene is also on the WADA Prohibited List and the US Department of Defense Prohibited List.
How does Enclomiphene work?
Enclomiphene blocks estrogen receptors at the hypothalamus and pituitary, removing the negative feedback that estradiol exerts on gonadotropin release. LH and FSH rise, which stimulates endogenous testicular testosterone production while leaving spermatogenesis intact, in contrast to exogenous testosterone.
Is Enclomiphene FDA approved?
No. Enclomiphene is a research compound and not approved by the FDA for human use. Evidence level: human trials. Published clinical trials in people report results.
What is the half-life of Enclomiphene?
Reported half-life: Approximately 10 hours in men (commonly reported as 10 to 12 hours), with maximum serum concentration reached about 2 to 3 hours after an oral dose, from the human pharmacokinetic substudy in Wiehle et al., BJU International 2013 (a phase II study in 48 men with secondary hypogonadism). No FDA-labeled value exists: the approved racemic clomiphene citrate label gives no numeric half-life for enclomiphene, stating only that the zuclomiphene isomer has a longer half-life than enclomiphene.
How is Enclomiphene taken?
Oral.
What side effects have been reported with Enclomiphene?
Reported in the sources: Not FDA-approved. FDA's Complete Response Letter of 1 December 2015 stated that, based on recent scientific developments, the design of the phase 3 studies was no longer adequate to demonstrate clinical benefit, and cited concerns regarding study entry criteria, titration and bioanalytical method validation. The advisory committee scheduled for November 2015 was cancelled and never convened, so no advisory committee ever reviewed this drug. Development was discontinued; No FDA-approved label exists, so there is no authoritative boxed warning, contraindication list, drug-interaction section or pregnancy statement for a US enclomiphene product. The safety information below is read across from the approved racemic clomiphene citrate label, which contains enclomiphene as one of its two isomers; how completely it transfers to the isolated trans-isomer has not been established; Contraindications on the racemic clomiphene citrate label that are not sex-specific and should be assumed to apply: liver disease or a history of liver dysfunction; an organic intracranial lesion such as a pituitary tumour; uncontrolled thyroid or adrenal dysfunction; and known hypersensitivity to clomiphene citrate. The pituitary-lesion contraindication is directly relevant, because a pituitary lesion is itself one of the causes of secondary hypogonadism. Anyone with low testosterone and low or normal LH needs a pituitary cause excluded before any SERM is considered; Visual disturbances including blurring, spots, flashes and scintillating scotomata are documented for racemic clomiphene. The label states these increase in incidence with increasing total dose or duration, may be prolonged, have occurred after discontinuation, and may be irreversible. They may make driving or operating machinery hazardous, particularly in variable lighting. Any visual symptom warrants stopping the drug and prompt ophthalmological evaluation; Further label precautions that are not sex-specific: hypertriglyceridemia has been reported, with pretreatment triglyceride screening and periodic monitoring recommended; pancreatitis has been reported; postmarketing hepatic events include hepatitis and increased transaminases; postmarketing cardiovascular and thromboembolic reports include pulmonary embolism, thrombophlebitis, stroke and seizure; Adverse events reported in the phase 3 programme were most commonly headache, hot flushes and nausea, each in a small percentage of treated men; Limited human data: trials ran 16 weeks in 256 men, which is too short and too small to detect uncommon or long-term harms. Effects on bone, cardiovascular risk, lipids and mood over years are uncharacterised, and FDA specifically declined to accept this evidence base as adequate; Compounded product is not subject to FDA bioequivalence, potency or stability verification, so content and purity vary between pharmacies and there is no standardised package insert. FDA's Pharmacy Compounding Advisory Committee voted against including enclomiphene citrate on the 503A Bulks List; Prohibited in sport under Section S4 of the WADA Prohibited List and listed on the US Department of Defense Prohibited List as an unapproved drug. It is illegal to sell as a dietary supplement ingredient, and products marketed as research chemicals or testosterone boosters are unlawful and unverified.
Educational summary compiled from the sources listed above. Not medical advice. Peptide Vault does not sell, source or recommend any compound. Talk to a qualified clinician before starting or changing anything.