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Enclomiphene Citrate and Sleep Architecture: What the Evidence Shows

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At a glance

  • Sleep studies / None in a PubMed search for enclomiphene with sleep or polysomnography
  • Approval / Not approved by FDA or EMA [1][3]
  • Class / Oral selective estrogen receptor modulator (SERM) [1]
  • Action / Blocks pituitary estrogen receptors, raising LH, FSH and testosterone [1]
  • Studied doses / 6.25, 12.5 and 25 mg once daily in a 6-week phase 2 trial [4]
  • Phase 3 outcomes / Testosterone, LH, FSH and sperm counts [2]
  • Common adverse events / Headache, hot flushes, nausea and muscle spasm [5]
  • Clomiphene label / Insomnia reported in fewer than 1% of patients; the label covers the mixture, not enclomiphene alone [1][6]

Does Enclomiphene Change Sleep Architecture?

Sleep architecture is the pattern of sleep stages recorded during polysomnography: non-REM stages, slow-wave sleep and REM. The enclomiphene trials measured hormones and sperm counts, not sleep. The 2016 BJU International report covered two parallel randomized, double-blind, double-dummy, placebo-controlled phase 3 studies in overweight men aged 18 to 60 with secondary hypogonadism, comparing enclomiphene with testosterone gel over 16 weeks [2]. Testosterone rose in all treatment groups; LH and FSH rose with enclomiphene and fell with testosterone gel [2].

What Did the Trials Report?

A phase 2 study tested 6.25, 12.5 and 25 mg once daily for 6 weeks; testosterone and LH rose with enclomiphene [4]. Reported common side effects were headache, hot flushes, nausea and muscle spasm; 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 and 1 of 47 on placebo; nausea by 4 of 112 and 3 of 47 [5].

The Clomid label for clomiphene citrate lists insomnia among adverse events reported in fewer than 1% of patients in clinical trials [6]. That label covers the clomiphene mixture, not enclomiphene alone [1][6].

What Is Known About Testosterone and Sleep?

Hormones and sleep can be related, but these findings do not show whether enclomiphene changes sleep stages. In 149 healthy men aged 16 to 83, mean deep slow-wave sleep fell from 18.9% in early adulthood to 3.4% in midlife, in parallel with a major decline in growth hormone secretion [7]. A 2011 review describes androgen receptors in the suprachiasmatic nucleus and androgen effects on light responses in males [8].

Frequently asked questions

Can enclomiphene cause insomnia?
Reported common adverse events were headache, hot flushes, nausea and muscle spasm [5]. The Clomid label for clomiphene citrate lists insomnia in fewer than 1% of patients, but that label covers the mixture, not enclomiphene alone [1][6].
Is enclomiphene FDA-approved?
No. FDA has not approved any drug containing enclomiphene, and the EMA committee recommended refusing marketing authorisation in 2018 [1][3].
What doses were studied?
A phase 2 trial tested 6.25, 12.5 and 25 mg once daily for 6 weeks [4]. Phase 3 protocols used 12.5 mg daily, with up-titration to 25 mg at week 6 if morning testosterone stayed below 300 ng/dL [10].

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. Wiehle R, Cunningham GR, Pitteloud N, Wike J, Hsu K, Fontenot GK, et al. Testosterone Restoration by Enclomiphene Citrate in Men with Secondary Hypogonadism: Pharmacodynamics and Pharmacokinetics. BJU Int. 2013;112(8):1188-200. Testosterone Restoration by Enclomiphene Citrate in Men with Secondary Hypogonadism: Pharmacodynamics and Pharmacokinetics
  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. Van Cauter E, Leproult R, Plat L. Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men. JAMA. 2000;284(7):861-8. Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men
  8. Mong JA, Baker FC, Mahoney MM, Paul KN, Schwartz MD, Semba K, et al. Sleep, rhythms, and the endocrine brain: influence of sex and gonadal hormones. J Neurosci. 2011;31(45):16107-16. Sleep, rhythms, and the endocrine brain: influence of sex and gonadal hormones
  9. Foster J, Choo L, Patel A, Kirby M, Hackett G. British Society of Sexual Medicine: Position Statement for the Potential Use of Enclomiphene in the Treatment of Male Hypogonadism. World J Mens Health. 2026;44(3):480-483. British Society of Sexual Medicine: Position Statement for the Potential Use of Enclomiphene in the Treatment of Male Hypogonadism
  10. Official web page. Official web page
Evidence overview for Enclomiphene Citrate and Sleep Architecture: What the Evidence Shows