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Enclomiphene Citrate Cardiovascular Impact: Long-Term Evidence Review

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At a glance

  • Approval status / Not approved by FDA or EMA; no FDA-approved drug contains enclomiphene [1][3]
  • Class and action / Oral selective estrogen receptor modulator; raises LH and FSH [1]
  • Phase 3 comparison / 16 weeks against testosterone gel in ZA-304 and ZA-305 [4]
  • FDA-listed concerns / Cardiac and thromboembolic events, including PE and DVT in a safety study; raised estradiol, PSA and hematocrit [1]
  • EMA refusal / Venous thromboembolism risk and slightly higher cardiac and thromboembolic events than testosterone [3][1]
  • Clomid label / Covers the clomiphene mixture, not enclomiphene alone [5]

What did FDA flag?

In its June 2022 advisory-committee review, FDA listed cardiac and thromboembolic events, including pulmonary embolism and deep vein thrombosis in a safety study, raised estradiol, raised PSA and raised hematocrit [1]. The review drew on published trials, adverse event reports and EMA's review [1].

What did EMA conclude?

EMA's CHMP adopted a negative opinion on 25 January 2018 recommending refusal of marketing authorisation for EnCyzix (enclomifene) for hypogonadotropic hypogonadism in overweight men with a BMI of at least 25 [3]. EMA's reasons included a risk of venous thromboembolism and studies that showed higher testosterone but did not look at whether symptoms improved [3]. EMA also noted a slightly higher rate of cardiac and thromboembolic events than with testosterone [1]. The refusal was based on 4 main studies in 588 patients [3].

How did enclomiphene compare with testosterone in the trials?

Two parallel randomized, double-blind, double-dummy, placebo-controlled phase 3 studies, ZA-304 and ZA-305, compared enclomiphene with AndroGel 1.62% for 16 weeks in overweight men aged 18 to 60 with secondary hypogonadism and morning testosterone of 300 ng/dL or lower [4]. Total testosterone rose in all treatment groups [4]. LH and FSH rose with enclomiphene and fell with testosterone gel [4]. Sperm concentration stayed in the normal range on enclomiphene, while spermatogenesis fell markedly on testosterone gel [4].

What about estradiol and hematocrit?

In a phase 2 trial, enclomiphene raised morning testosterone, estradiol and LH to levels similar to 1% topical testosterone gel [6]. Long-term efficacy and safety data for enclomiphene are lacking [2].

Does the Clomid label apply to enclomiphene?

No. Clomid is clomiphene citrate, a mixture of enclomiphene and zuclomiphene, and its approved use is ovulatory dysfunction in women desiring pregnancy [5][1]. The label has no male indication and says there are no adequate or well-controlled studies demonstrating effectiveness in male infertility [5]. Its postmarketing adverse reaction list includes cardiovascular terms such as arrhythmia, chest pain, edema, hypertension, palpitation, phlebitis, pulmonary embolism, shortness of breath, tachycardia and thrombophlebitis; the label says these are voluntary reports, so frequency and causation cannot always be reliably established [5].

Frequently asked questions

Is enclomiphene approved for low testosterone?
No. FDA says no FDA-approved drugs contain enclomiphene as an active ingredient, and EMA refused marketing authorisation for EnCyzix in 2018 [1][3]. Clomiphene citrate is FDA-approved only for ovulatory dysfunction in women [5].
Did any trial compare enclomiphene with testosterone?
Two 16-week phase 3 trials compared enclomiphene with AndroGel 1.62% [4]. Total testosterone rose in all groups; LH and FSH rose with enclomiphene and fell with testosterone gel; sperm concentration stayed normal on enclomiphene while spermatogenesis fell markedly on gel [4].
Does the Clomid label apply to enclomiphene?
No. Clomid is the clomiphene mixture, which contains enclomiphene and zuclomiphene, and its approved use is ovulation induction in women [5][1]. Its postmarketing list includes cardiovascular reactions such as arrhythmia, hypertension, pulmonary embolism and thrombophlebitis, reported voluntarily [5].
Does enclomiphene raise estradiol?
In a phase 2 trial, enclomiphene raised morning testosterone, estradiol and LH to levels similar to topical testosterone gel [6]. FDA's 2022 review lists raised estradiol, raised PSA and raised hematocrit among its safety concerns [1].

References

  1. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  2. 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
  3. Official web page. Official web page
  4. 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
  5. U.S. National Library of Medicine, DailyMed. Clomid (clomiphene citrate) tablets, Cosette prescribing information. Clomid (clomiphene citrate) tablets, Cosette label
  6. Wiehle RD, Fontenot GK, Wike J, Hsu K, Nydell J, Lipshultz L, et al. Enclomiphene citrate stimulates testosterone production while preventing oligospermia: a randomized phase II clinical trial comparing topical testosterone. Fertil Steril. 2014;102(3):720-7. Enclomiphene citrate stimulates testosterone production while preventing oligospermia: a randomized phase II clinical trial comparing topical testosterone
Evidence overview for Enclomiphene Citrate Cardiovascular Impact: Long-Term Evidence Review