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Enclomiphene Citrate in Special Populations: Transplant, HIV, Chronic Disease, and Beyond

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At a glance

  • Approval / Not approved by FDA or EMA [2][3]
  • Groups studied / Overweight men aged 18 to 60; a six-month safety study allowed up to 65 [1][10]
  • Transplant, HIV, kidney or liver disease / No approved enclomiphene label addresses these groups [2]
  • Liver disease / Contraindicated on the clomiphene label, which covers the mixture, not enclomiphene alone [4]
  • Regulator-flagged risks / Clot and cardiac events, raised estradiol, PSA and hematocrit, no long-term safety data [2]
  • Doses studied / 6.25, 12.5 and 25 mg once daily [5]

Who has actually been studied

Enclomiphene is an oral selective estrogen receptor modulator. It blocks estrogen feedback at the pituitary, so the pituitary releases more LH and FSH and the testes make more testosterone. It would not be expected to work when the testes themselves have failed [2].

ZA-304 and ZA-305 compared enclomiphene with AndroGel 1.62% for 16 weeks in overweight men aged 18 to 60 [1]. ZA-301 and ZA-302 were placebo-controlled trials of 151 and 181 men [6][7]. A separate open-label six-month safety study enrolled 499 men aged 18 to 65 [10].

Transplant, HIV, kidney and liver disease

Enclomiphene has no approved label, so there is no labelled dosing or caution for transplant recipients, people living with HIV, or people with chronic kidney disease or liver disease [2][3].

The safety concerns FDA documented include clot risk. FDA's 2022 review listed cardiac and thromboembolic events, including pulmonary embolism and deep vein thrombosis in a safety study [2], and EMA noted a slightly higher rate of these events than with testosterone [2]. There are no long-term safety data [2].

The clomiphene citrate label, covering the two-isomer mixture and not enclomiphene alone, lists liver disease or a history of liver dysfunction as a contraindication [4]. Enclomiphene has no label of its own.

Men over 60

ZA-304 and ZA-305 enrolled men aged 18 to 60 [1]. The six-month safety study allowed men up to age 65 [10]. The phase 3 program measured hormones and sperm counts, not symptoms, at any age [2]. The British Society of Sexual Medicine's 2026 position statement describes the evidence as small and short-term and advises use only by experienced clinicians in specialist or research settings [8].

Safety signals regulators flagged

Headache, hot flushes, nausea and muscle spasm were the most frequent side effects, and blurred vision, muscle spasm, headache and aggression were among the reasons men stopped [7]. In ZA-302, headache occurred in 7 of 112 men on 12.5 mg against 1 of 47 on placebo [7]. FDA also listed raised estradiol, raised PSA and raised hematocrit [2].

Frequently asked questions

Is enclomiphene approved for anyone?
No. FDA's 2022 advisory committee materials state that no FDA-approved drug contains enclomiphene as its active ingredient [2], and EMA's committee recommended refusing marketing authorisation in 2018 [3].
How is enclomiphene obtained if it is not approved?
No enclomiphene product is FDA-approved [2]. FDA lists enclomiphene citrate as under evaluation and describes conditional enforcement discretion for compounding; that policy is not an approval [9].
Does enclomiphene work in men over 60?
The comparison trials enrolled men aged 18 to 60 [1], and a six-month safety study allowed men up to 65 [10]. The phase 3 program measured hormones and sperm counts, not symptoms [2].
Can men with liver disease take enclomiphene?
The clomiphene citrate label contraindicates liver disease or a history of liver dysfunction, but that label covers the two-isomer mixture, not enclomiphene alone [4].

References

  1. 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
  2. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  3. Official web page. Official web page
  4. U.S. National Library of Medicine, DailyMed. Clomid (clomiphene citrate) tablets, Cosette prescribing information. Clomid (clomiphene citrate) tablets, Cosette label
  5. 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
  6. Official web page. Official web page
  7. Official web page. Official web page
  8. 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
  9. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  10. ClinicalTrials.gov. NCT01534208: open-label 6-month enclomiphene safety study (ZA-300). ClinicalTrials.gov NCT01534208
Evidence overview for Enclomiphene Citrate in Special Populations: Transplant, HIV, Chronic Disease, and Beyond