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Enclomiphene Citrate: Metabolism and Energy Expenditure

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At a glance

  • Approval status / Not FDA-approved; EMA refused EnCyzix in 2018 [3][2]
  • Energy expenditure data / The reported trial results cover testosterone, LH, FSH, sperm, BMI and glucose, not energy expenditure [1][8]
  • 6-month safety study / Mean BMI +0.2 to +0.3 kg/m2 and fasting glucose about -5 mg/dL at 26 weeks, with no placebo group [8]
  • Half-life / About 10 hours; peak 2 to 3 hours after a dose [3]
  • Main metabolite / 4-hydroxy enclomiphene, excreted mainly in feces [3]
  • Testosterone body-composition data / Fat mass down 1.6 kg, fat-free mass up 1.6 kg in a meta-analysis of testosterone therapy, not enclomiphene [4]
  • Most frequent side effects / Headache, hot flushes, nausea, muscle spasm [5]

Does enclomiphene raise metabolic rate?

No trial result shows that it does. The outcomes reported for the phase 3 comparison with AndroGel are hormones and sperm [1], and the 6-month safety study reported BMI and fasting glucose [8].

EMA's CHMP, in its negative opinion on the EnCyzix (enclomifene) application on 25 January 2018, said the studies showed higher testosterone but did not look at whether symptoms (bone strength, weight gain, impotence, libido) improved [2].

What the trials measured

ZA-301 (151 overweight men, 12 weeks) and ZA-302 (181 men) compared enclomiphene 12.5 mg or 25 mg daily with placebo; 78.8% and 81.3% of treated men reached an average 24-hour testosterone in the normal range [6][5]. In ZA-304 and ZA-305, 16-week studies against AndroGel 1.62%, LH and FSH rose with enclomiphene and fell with the gel [1].

ZA-300 was a 6-month open-label safety study of 499 men aged 18 to 65 taking 12.5 or 25 mg daily, with no placebo group. Its posted results give a mean BMI change from baseline of +0.2 kg/m2 on 12.5 mg (n=216) and +0.3 kg/m2 on 25 mg (n=283), and a mean fasting plasma glucose change of -5.4 mg/dL (n=168) and -5.0 mg/dL (n=242) at 26 weeks [8].

What testosterone itself does to body composition

Testosterone treatment shifts body composition modestly. A meta-analysis of 29 randomized trials in 1,083 middle-aged and older men (mean age 64.5) found testosterone reduced total body fat by 1.6 kg (95% CI, -2.5 to -0.6 kg), increased fat-free mass by 1.6 kg (95% CI, 0.6 to 2.6 kg), and did not change body weight [4]. Those are tissue-composition results, not measures of calorie burn.

Enclomiphene raised morning testosterone, estradiol and LH while increasing FSH and preserving sperm counts in a randomized phase 2 trial of men with secondary hypogonadism [7].

How the drug is handled and safety concerns

Oral enclomiphene peaks 2 to 3 hours after a dose, has a half-life of about 10 hours, is converted mainly to 4-hydroxy enclomiphene and is excreted mainly in feces [3]. No dose is approved [3]; the phase 3 protocols used 12.5 mg once daily, up-titrated to 25 mg at week 6 if morning testosterone stayed below 300 ng/dL [6].

The most frequent side effects were headache, hot flushes, nausea and muscle spasm [5]. FDA's 2022 list of safety concerns included cardiac and thromboembolic events, raised estradiol, raised PSA and raised hematocrit, with no long-term safety data [3]. HealthRX.com offers enclomiphene by prescription.

Frequently asked questions

Does enclomiphene speed up metabolism?
No trial result shows that it does: the reported outcomes are testosterone, LH, FSH, sperm counts, BMI and fasting glucose, not energy expenditure [1][8]. Testosterone therapy itself lowered fat mass by 1.6 kg in a meta-analysis of 29 trials [4].
How is enclomiphene metabolised?
It peaks 2 to 3 hours after an oral dose, has a half-life of about 10 hours, is converted mainly to 4-hydroxy enclomiphene and is excreted mainly in feces [3].
Is enclomiphene FDA-approved?
No. FDA stated in 2022 that no FDA-approved drugs contain enclomiphene, and EMA refused marketing authorisation for EnCyzix in January 2018 [3][2].
What side effects matter most?
Headache, hot flushes, nausea and muscle spasm were most frequent; FDA also listed cardiac and thromboembolic events, raised estradiol, raised PSA and raised hematocrit, with no long-term safety data [3][5].

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. Official web page. Official web page
  3. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  4. Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol (Oxf). 2005;63(3):280-93. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis
  5. Official web page. Official web page
  6. Official web page. Official web page
  7. 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
  8. Official web page. Official web page
Evidence overview for Enclomiphene Citrate: Metabolism and Energy Expenditure