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Enclomiphene Citrate Year-1 Outcomes: Real User Results, Reddit Reports, and Clinical Data

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At a glance

  • Controlled trials / 12 weeks placebo-controlled, 16 weeks against AndroGel 1.62% [1][2][3]
  • Testosterone in normal range at 12 weeks / 78.8% and 81.3% of treated men [1][2]
  • Sperm concentration down 50% or more / 14.2% vs 2.6% and 4.3% on placebo [1][2]
  • Most frequent side effects / headache, hot flushes, nausea, muscle spasm [2]
  • FDA status / not approved; bulk substance under evaluation [5][6]
  • Long-term safety data / none [5]

What the 12- and 16-week trials measured

In ZA-301, 151 overweight men aged 18 to 60 with morning testosterone under 300 ng/dL took 12.5 mg, 25 mg or placebo for 12 weeks; 78.8% (95% CI 70.3 to 85.3) of those on enclomiphene reached an average 24-hour testosterone of 300 to 1040 ng/dL [1]. ZA-302, the same design in 181 men, reported 81.3% (95% CI 73.9 to 87.0) [2]. Sperm concentration fell by half or more in 14.2% of treated men in both trials, against 2.6% and 4.3% on placebo [1][2]. Results for both trials are posted on ClinicalTrials.gov; no peer-reviewed paper was found.

Over 16 weeks against AndroGel 1.62%, total testosterone rose in every group, LH and FSH rose on enclomiphene and fell on the gel, and sperm concentration stayed in the normal range on enclomiphene while spermatogenesis dropped markedly on the gel [3].

The longest study: 6 months in 12 men

A small randomized, open-label phase 2b study in 12 men previously on topical testosterone reached 6 months. Total testosterone was 525 pg/dL on enclomiphene and 545 pg/dL on gel, as published in the abstract. Sperm counts rose in 7 of 7 men on enclomiphene at 3 months, while the gel did not raise counts above 20 million/mL in any of 5 men. Testosterone fell back to pre-treatment values one month after treatment stopped [4]. With 12 men, this cannot show how people fare over a year.

Do normal labs mean symptoms improved?

The phase 3 trials measured testosterone, LH, FSH and sperm counts, not symptoms or quality of life. FDA's May 2018 guidance says it is unclear whether raising testosterone in this population produces clinical benefit, and that trials should show meaningful improvement in at least one symptom or sign [5]. EMA refused marketing authorisation for EnCyzix in January 2018 because studies did not look at whether symptoms improved, and it cited a risk of venous thromboembolism [7].

Safety signals and label warnings

FDA listed these concerns in 2022: cardiac and thromboembolic events including pulmonary embolism and deep vein thrombosis in a safety study, raised estradiol, raised PSA, raised hematocrit, and no long-term safety data [5]. EMA noted a slightly higher rate of cardiac and thromboembolic events than with testosterone and wanted ocular monitoring [5].

The most frequent trial side effects were headache, hot flushes, nausea and muscle spasm; reasons for stopping included blurred vision and aggression [2]. The clomiphene citrate (Clomid) label describes the two-isomer mixture, not enclomiphene alone. It says visual symptoms such as blurring, spots or flashes are usually reversible, though prolonged cases have been reported [8].

Regulatory status

No FDA-approved drug contains enclomiphene as an active ingredient [5]. FDA lists enclomiphene citrate in Category 1, bulk drug substances under evaluation, which is an enforcement-discretion position and not an approval [6]. Its 2022 advisory committee voted 4 yes, 8 no on adding it to the allowed list [9].

Frequently asked questions

Are there 12-month enclomiphene results?
No 12-month results are available. The placebo-controlled trials lasted 12 weeks and the testosterone-gel comparisons lasted 16 weeks [1][2][3]. The longest study described here ran 6 months in 12 men [4]. The trials report hormones, sperm counts and side effects rather than energy or libido [5].
How much does testosterone rise on enclomiphene?
At 12 weeks, 78.8% of men on enclomiphene in ZA-301 reached an average 24-hour testosterone of 300 to 1040 ng/dL, and 81.3% did in ZA-302 [1][2].
Does enclomiphene lower sperm counts?
In some men it did: sperm concentration fell by half or more in 14.2% of treated men versus 2.6% and 4.3% on placebo [1][2]. In the 16-week gel comparison, sperm concentration stayed in the normal range on enclomiphene while spermatogenesis fell markedly on the gel [3].
What side effects were reported in the trials?
Headache, hot flushes, nausea and muscle spasm were most frequent, and reasons for stopping included blurred vision, muscle spasm, headache and aggression [2]. The clomiphene citrate label, which covers the two-isomer mixture rather than enclomiphene alone, reports visual symptoms [8].
Is enclomiphene FDA approved?
No. FDA's 2022 presentation states that no FDA-approved drug contains enclomiphene [5], it sits on FDA's list of bulk substances under evaluation [6], and the 2022 advisory committee voted 4 yes, 8 no on adding it as an allowed bulk substance [9].

References

  1. ClinicalTrials.gov. NCT01532414 (ZA-301): enclomiphene citrate vs placebo in men with secondary hypogonadism. ClinicalTrials.gov NCT01532414
  2. ClinicalTrials.gov. NCT01739595 (ZA-302): enclomiphene citrate vs placebo in men with secondary hypogonadism. ClinicalTrials.gov NCT01739595
  3. 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
  4. Kaminetsky J, Werner M, Fontenot G, Wiehle RD. Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel. J Sex Med. 2013;10(6):1628-35. Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel
  5. U.S. Food and Drug Administration. Pharmacy Compounding Advisory Committee, June 8, 2022: enclomiphene presentation. FDA presentation on enclomiphene
  6. U.S. Food and Drug Administration. Bulk drug substances nominated for compounding, Category 1 list. FDA bulk substances list
  7. European Medicines Agency. Questions and answers on refusal of marketing authorisation for EnCyzix (enclomifene). EMA questions and answers
  8. U.S. National Library of Medicine, DailyMed. Clomid (clomiphene citrate) tablets, Cosette prescribing information. Clomid (clomiphene citrate) tablets, Cosette label
  9. U.S. Food and Drug Administration. Pharmacy Compounding Advisory Committee, June 8, 2022: meeting materials on enclomiphene citrate. FDA advisory committee materials
Evidence overview for Enclomiphene Citrate Year-1 Outcomes: Real User Results, Reddit Reports, and Clinical Data