Enclomiphene

Enclomiphene citrate is the trans (E) geometric isomer of clomiphene citrate, a nonsteroidal selective estrogen receptor modulator. No FDA-approved enclomiphene product exists. Compounded oral preparations are made pursuant to patient-specific prescriptions.

No FDA-labeled indication or dose exists. Prescribers use compounded enclomiphene in men with secondary (hypogonadotropic) hypogonadism, particularly when preserving spermatogenesis and fertility is a goal, as an alternative to exogenous testosterone. It requires an intact hypothalamic-pituitary-testicular axis and is not appropriate for primary testicular failure.

Enclomiphene antagonizes estrogen receptors in the hypothalamus and pituitary, blocking estradiol's negative feedback. GnRH pulsatility and pituitary LH and FSH secretion increase; LH stimulates Leydig-cell testosterone production and FSH supports spermatogenesis. Compared with clomiphene, enclomiphene lacks the weak estrogen agonist activity attributed to zuclomiphene.

In published clinical pharmacology studies, enclomiphene is rapidly absorbed after oral dosing, with peak concentrations in about 2 to 3 hours. Its elimination half-life is about 10 hours, much shorter than that of zuclomiphene, so it does not accumulate in the same way. It is metabolized in the liver, mainly by CYP2D6 with a CYP3A4 contribution, and CYP2D6 genotype alters exposure to enclomiphene and its hydroxylated metabolites.

No FDA labeling exists. The following are carried over from clomiphene labeling and class considerations:

• Women, including pregnancy; enclomiphene is not intended for use in women.
• Hypersensitivity to enclomiphene or clomiphene.
• Liver disease or a history of hepatic dysfunction.
• Uncontrolled thyroid or adrenal dysfunction.
• An organic intracranial lesion such as a pituitary tumor.

• Venous thromboembolism: deep vein thrombosis and pulmonary embolism were reported in clinical development. Use caution in men with prior thrombosis, thrombophilia or other risk factors.
• Visual disturbances, a known clomiphene class effect, can occur; discontinue and evaluate.
• Estradiol rises with increased testicular steroidogenesis and can cause breast tenderness or gynecomastia.
• Hematocrit can rise; monitor during treatment.
• Mood changes, including irritability, have been reported.
• Long-term safety data are limited.

• CYP2D6 inhibitors (for example paroxetine, fluoxetine, bupropion, quinidine) may raise enclomiphene exposure and alter formation of its active metabolites.
• Strong CYP3A4 inducers (for example rifampin, carbamazepine, phenytoin) may lower exposure; strong CYP3A4 inhibitors may raise it.
• Exogenous testosterone and anabolic steroids suppress the gonadotropin axis that enclomiphene acts on.
• Aromatase inhibitors such as anastrozole lower estradiol and are sometimes co-prescribed; monitor testosterone and estradiol.

Reported adverse effects include headache, hot flashes, nausea, dizziness, muscle spasm, fatigue, visual disturbances, irritability or mood change, breast tenderness, acne and increased hematocrit. Venous thromboembolism has been reported rarely.

Enclomiphene is not intended for use in women. It is contraindicated in pregnancy based on clomiphene class data, in which animal studies showed fetal harm. No human lactation data exist, and it should not be used during breastfeeding.

Baseline and periodic morning total testosterone, estradiol, LH and FSH; hematocrit; lipids and liver function; PSA as appropriate for age; semen analysis when fertility is a goal; and symptoms of thrombosis, visual change or mood change.

• Clomid (clomiphene citrate tablets USP) Prescribing Information.
• Evaluation and Management of Testosterone Deficiency: AUA Guideline. American Urological Association.