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Enclomiphene Citrate and Cognitive Function: What the Evidence Actually Shows

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At a glance

  • Approval / Not approved by FDA or EMA [1][3]
  • Drug class / Oral selective estrogen receptor modulator [1]
  • Outcomes reported / Total testosterone, LH, FSH, sperm counts [4][2]
  • Regulators' view / Testosterone rose; symptom benefit not shown [1][3]
  • Common side effects / Headache, hot flushes, nausea, muscle spasm [5]
  • Stopping reasons / Blurred vision, muscle spasm, headache, aggression [5]
  • Doses studied / 12.5 mg daily, up-titrated to 25 mg in phase 3 [4]

Does enclomiphene improve cognitive function?

Enclomiphene is an oral selective estrogen receptor modulator: it blocks estrogen receptors in the pituitary, so the pituitary releases more LH and FSH and the testes make more testosterone [1]. In ZA-301 and ZA-302, most men reached the normal range for average 24-hour testosterone [4][5]. Their results are hormone levels and sperm, not memory, attention or mood scores.

Regulators say the symptom question is open. FDA's May 2018 guidance on secondary hypogonadism, as described by FDA in 2022, says it is unclear whether raising testosterone in this population gives clinical benefit, and that trials should show meaningful improvement in at least one symptom or sign [1]. EMA's 2018 refusal of EnCyzix said the studies showed higher testosterone but did not examine whether symptoms improved [3].

What the trials measured instead

ZA-301 (NCT01532414) gave 151 men aged 18 to 60 with morning testosterone under 300 ng/dL either 12.5 mg, 25 mg or placebo for 12 weeks; pooled across doses, 78.8% (95% CI 70.3 to 85.3, n=113) reached an average 24-hour testosterone of 300 to 1040 ng/dL [4]. ZA-302 used the same design in 181 men; 81.3% (95% CI 73.9 to 87.0, n=134) reached that range [5].

Kim et al. reported ZA-304 and ZA-305 in BJU International in 2016: two randomized, double-blind, placebo-controlled trials comparing two enclomiphene doses with AndroGel 1.62% for 16 weeks. Testosterone rose in every treatment group, LH and FSH rose with enclomiphene and fell with the gel, and sperm concentration stayed normal on enclomiphene while spermatogenesis fell on the gel [2]. These trials reported hormone and sperm-count results, but did not report cognitive or mood test results [2].

Side effects and mood-related events

The most frequent side effects were headache, hot flushes, nausea and muscle spasm, and reasons for stopping included blurred vision, muscle spasm, headache and aggression [5]. In ZA-302, headache was reported by 7 of 112 men on 12.5 mg versus 1 of 47 on placebo, and nausea by 4 of 112 versus 3 of 47 [5].

The Clomid label covers clomiphene, the mixture of enclomiphene and zuclomiphene, not enclomiphene alone [1]. Its postmarketing list includes anxiety, irritability, mood changes and psychosis, reported voluntarily with no reliable frequency [6].

Frequently asked questions

Does enclomiphene improve memory or thinking?
The phase 3 results reported so far list testosterone, LH, FSH and sperm counts rather than memory or thinking scores, so a cognitive benefit is unproven [4][5][2].
What did the phase 3 trials show?
In ZA-301, 78.8% of the pooled enclomiphene group reached an average 24-hour testosterone of 300 to 1040 ng/dL (95% CI 70.3 to 85.3, n=113); in ZA-302 the figure was 81.3% (95% CI 73.9 to 87.0, n=134) [4][5].
Did men report mood effects on enclomiphene?
Aggression was listed among the reasons men stopped enclomiphene, alongside blurred vision, muscle spasm and headache [5].
Is enclomiphene FDA-approved?
No. No FDA-approved drug contains enclomiphene, FDA's 2015 complete response letter said the phase 3 design was not adequate to demonstrate clinical benefit [1], and EMA recommended refusing authorisation in 2018 [3]. FDA lists enclomiphene citrate as a bulk drug substance under evaluation, an enforcement-discretion position rather than an approval [7].

References

  1. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  2. Kim ED, McCullough A, Kaminetsky J. Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement. BJU Int. 2016;117(4):677-85. Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement
  3. Official web page. Official web page
  4. Official web page. Official web page
  5. Official web page. Official web page
  6. U.S. National Library of Medicine, DailyMed. Clomid (clomiphene citrate) tablets, Cosette prescribing information. Clomid (clomiphene citrate) tablets, Cosette label
  7. U.S. Food and Drug Administration. U.S. Food and Drug Administration
Evidence overview for Enclomiphene Citrate and Cognitive Function: What the Evidence Actually Shows