NOT FOR HUMAN CONSUMPTION

Enclomiphene is the trans (E) isomer of clomiphene citrate and acts as a selective estrogen-receptor modulator (SERM). In men, it blocks estradiol’s negative feedback at the hypothalamus/pituitary, raising GnRH → LH/FSH, which in turn stimulates endogenous testosterone production by Leydig cells while maintaining spermatogenesis (via FSH/Sertoli). Unlike exogenous testosterone, enclomiphene does not suppress the HPG axis and is commonly used off-label for men with functional/secondary hypogonadism who desire fertility preservation. (Not FDA/EMA-approved as a branded drug.)

Additional Benefits of Enclomiphene Now Under Investigation

2. Molecular Mechanism of Action

2.1 Receptor pharmacodynamics

• SERM activity (ERα/ERβ): Antagonist at hypothalamus/pituitary → ↑ GnRH → ↑ LH/FSH.

• Testis: LH → Leydig → testosterone; FSH → Sertoli → spermatogenesis.

• Enclomiphene vs zuclomiphene: Enclomiphene has shorter half-life, less estrogenic persistence, and a cleaner antiestrogenic profile centrally.

2.2 Down-stream biology

3. Pharmacokinetics

• Route: Oral tablet (usually compounded).

• Onset: T rises within weeks; sperm parameters respond over 2–3+ months.

• Half-life: Shorter than zuclomiphene (days vs weeks), reducing long tail accumulation typical of clomiphene mixes.

• Dosing used clinically (off-label): 6.25–25 mg daily (common: 12.5–25 mg QD), or 25 mg QOD, titrated to mid-normal TT/FT and symptom control.

4. Clinical Evidence (high-level)

• Secondary hypogonadism (men): RCTs and open-label studies show TT/FT increases comparable to low-dose TRT, with LH/FSH maintained and sperm counts preserved or improved.

• Symptoms/QoL: Improvements in sexual function and vitality correlate with biochemical response.

• Metabolic labs: Neutral to mildly favorable effects on lipids/insulin sensitivity; far lower rates of erythrocytosisthan TRT.

• Female fertility: Clomiphene citrate remains standard; enclomiphene monotherapy is investigational.

Evidence quality note: Solid male endocrine data for biochemical efficacy; fewer large, long-term outcome trials than for TRT. Regulatory approval attempts in the US previously received complete response letters; enclomiphene remains unapproved as a branded product.

5. Emerging Clinical Interests

6. Safety and Tolerability

• Common: Headache, hot flashes, mood lability/irritability, GI upset, transient visual disturbances (rare; caution with night driving).

• Endocrine: Possible E2 increase → breast tenderness/gynecomastia in sensitive men; consider dose adjustment or low-dose AI if symptomatic.

• Hematologic: Erythrocytosis uncommon vs TRT, but check CBC.

• Thromboembolic risk: SERMs carry a theoretical VTE risk (low in men but screen for history/family risk).

• Hepatic: Rare transaminase elevations—obtain baseline and periodic LFTs.

• Psych: Anxiety/irritability in a minority—monitor.

• Ocular: Very rare optic events have been described with clomiphene-class SERMs—stop if visual symptomsoccur.

• Contraindications: Active liver disease, prior VTE, uncontrolled polycythemia, hypersensitivity to SERM class.

• Pregnancy: Contraindicated (SERM class).

• Anti-doping: SERMs are prohibited by WADA (S4).

Comparative safety/efficacy matrix

7. Regulatory Landscape

• Not FDA/EMA-approved as a branded product for male hypogonadism (prior NDA efforts were not approved).

• Male hypogonadism treatment guidelines typically endorse TRT for confirmed organic deficiency; SERMs (clomiphene/enclomiphene) are discussed off-label for secondary hypogonadism with fertility intent.

8. Practical Use (clinic playbook)

• Who’s a good candidate? Men with secondary/functional hypogonadism (low morning TT/FT with low/normal LH/FSH), desiring fertility preservation, without major SERM contraindications.

• Baseline work-up: TT/FT (2 mornings), LH/FSH, E2, SHBG, prolactin, TSH, CBC, LFTs, semen analysis if fertility relevant; assess OSA, meds (opioids), obesity.

• Dosing: Start 12.5 mg QD (range 6.25–25 mg). Recheck labs at 4–6 weeks; titrate to mid-normal TT/FT and symptom relief.

• Follow-up (q8–12 wks early, then q3–6 mo): TT/FT, E2, LH/FSH, CBC, LFTs, BP/weight, symptoms; semen parameters every 3–6 months if fertility is an endpoint.

• Adjuncts: If E2 climbs with symptoms, consider dose reduction, EOD dosing, or low-dose AI; if T response is blunted, consider add-on hCG.

• Stop/hold if: Visual symptoms, VTE signs, persistent mood instability, significant LFT rise, or absent biochemical/clinical response after adequate trial.

Selected References

• Journal of Clinical Endocrinology & Metabolism — SERM therapy for male secondary hypogonadism; enclomiphene vs clomiphene pharmacology.

• Fertility and Sterility; Andrology — Effects on spermatogenesis, semen parameters, and fertility outcomes.

• Endocrine Reviews; Clinical Endocrinology — Algorithms for diagnosing functional hypogonadism and fertility-preserving strategies.

• Urology; BJU International — Comparative data: enclomiphene vs TRT on TT/FT, LH/FSH, hematologic and metabolic outcomes.

• Drug Testing & Analysis; WADA Code — SERM prohibition in sport.