{"format":"citation-manifest/v1","page":"https://enclomiphenedirect.com/monograph","claim_count":56,"claims":[{"id":"ENC-001","text":"Enclomiphene is the trans isomer of clomiphene citrate, a non-steroidal estrogen receptor antagonist (SERM); clomiphene itself is FDA-approved for ovarian dysfunction in women.","source_url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC5009465/","grade":"review","grade_label":"Review or guideline"},{"id":"ENC-002","text":"Enclomiphene is C26H28ClNO, molecular weight 406.0, PubChem CID 1548953, CAS 15690-57-0.","source_url":"https://pubchem.ncbi.nlm.nih.gov/compound/1548953","grade":"chemical-reference","grade_label":"Chemical reference"},{"id":"ENC-003","text":"Enclomiphene carries development codes RMI 16,289 and ICI 46476, was developed by Repros Therapeutics as Androxal, and was filed in Europe as EnCyzix.","source_url":"https://pubchem.ncbi.nlm.nih.gov/compound/1548953","grade":"chemical-reference","grade_label":"Chemical reference"},{"id":"ENC-004","text":"No FDA-approved enclomiphene product exists: an openFDA Drugs@FDA search for enclomiphene as an active ingredient returns NOT_FOUND.","source_url":"https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm","grade":"regulatory","grade_label":"Regulatory record"},{"id":"ENC-005","text":"Enclomiphene Citrate appears in Category 1 (Bulk Drug Substances Under Evaluation) of FDA's 503A interim category list, updated May 14, 2026.","source_url":"https://www.fda.gov/media/94155/download","grade":"regulatory","grade_label":"Regulatory record"},{"id":"ENC-006","text":"Clomiphene citrate (Clomid, NDA 016131) is an FDA-approved drug with marketed generic versions; male use is off-label.","source_url":"https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=016131","grade":"regulatory","grade_label":"Regulatory record"},{"id":"ENC-007","text":"Category 1 status means under evaluation for the 503A bulks list, an interim posture during rulemaking; it is not an approval.","source_url":"https://www.fda.gov/media/94155/download","grade":"regulatory","grade_label":"Regulatory record"},{"id":"ENC-008","text":"FDA states that compounded drugs are not FDA-approved and that FDA does not verify their safety, effectiveness or quality before they are marketed.","source_url":"https://www.fda.gov/drugs/human-drug-compounding/compounding-and-fda-questions-and-answers","grade":"regulatory","grade_label":"Regulatory record"},{"id":"ENC-009","text":"Mechanism: in overweight men with hypogonadotropic hypogonadism, excess estrogen suppresses gonadotropin release; enclomiphene blocks that estrogen signal, enabling gonadotropin release and testicular stimulation.","source_url":"https://www.ema.europa.eu/en/documents/smop-initial/questions-and-answers-refusal-marketing-authorisation-encyzix-enclomifene_en.pdf","grade":"regulatory","grade_label":"Regulatory record"},{"id":"ENC-010","text":"In the phase II trial, morning total testosterone at week 6 was 604 +/- 160 ng/dL on enclomiphene 25 mg vs 500 +/- 278 ng/dL on transdermal testosterone (p = 0.23); all three enclomiphene doses raised testosterone into the normal range.","source_url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC4155868/","grade":"human-trial","grade_label":"Human trial"},{"id":"ENC-011","text":"In the phase II trial, enclomiphene did not significantly affect TSH, ACTH, cortisol, lipids or bone markers; IGF-1 decreased in both groups, more with enclomiphene.","source_url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC4155868/","grade":"human-trial","grade_label":"Human trial"},{"id":"ENC-012","text":"The Androxal program studied oral enclomiphene 6.25 mg, 12.5 mg and 25 mg daily.","source_url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC4155868/","grade":"human-trial","grade_label":"Human trial"},{"id":"ENC-013","text":"Enclomiphene raised LH and FSH while transdermal testosterone suppressed LH; testosterone and LH effects persisted at least one week after stopping enclomiphene.","source_url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC4155868/","grade":"human-trial","grade_label":"Human trial"},{"id":"ENC-014","text":"In the randomized ZA-203 phase II trial (NCT01270841), enclomiphene raised morning testosterone, estradiol and LH similarly to topical testosterone gel, increased FSH and LH, and conserved sperm counts.","source_url":"https://europepmc.org/article/MED/25044085","grade":"human-rct","grade_label":"Human RCT"},{"id":"ENC-015","text":"In men coming off topical testosterone, enclomiphene elevated sperm counts in 7 of 7 men at 3 months and 6 of 6 at 6 months (75-334 million/mL), while testosterone gel failed to raise counts above 20 million/mL in all 5 men at 3 months.","source_url":"https://europepmc.org/article/MED/23530575","grade":"human-trial","grade_label":"Human trial"},{"id":"ENC-016","text":"In two parallel randomized double-blind double-dummy placebo-controlled phase III trials (ZA-304, ZA-305; 16 weeks; overweight men 18-60 with TT at or below 300 ng/dL and LH below 9.4 IU/L), enclomiphene raised TT, LH and FSH and restored normal testosterone.","source_url":"https://europepmc.org/article/MED/26496621","grade":"human-rct","grade_label":"Human RCT"},{"id":"ENC-017","text":"In the phase III trials, enclomiphene maintained sperm concentration in the normal range while the testosterone gel group showed a marked reduction in spermatogenesis.","source_url":"https://europepmc.org/article/MED/26496621","grade":"human-rct","grade_label":"Human RCT"},{"id":"ENC-018","text":"The filed NDA 207959 covered enclomiphene citrate 12.5 mg and 25 mg capsules for secondary hypogonadism in fertile men (over 15 million sperm/mL), younger than 60, with BMI over 25.","source_url":"https://www.federalregister.gov/documents/2015/08/20/2015-20540/bone-reproductive-and-urologic-drugs-advisory-committee-notice-of-meeting","grade":"regulatory","grade_label":"Regulatory record"},{"id":"ENC-019","text":"Both regulatory applications and the entire trial program were in men; there is no female evidence base for isolated enclomiphene.","source_url":"https://www.federalregister.gov/documents/2015/08/20/2015-20540/bone-reproductive-and-urologic-drugs-advisory-committee-notice-of-meeting","grade":"regulatory","grade_label":"Regulatory record"},{"id":"ENC-020","text":"FDA accepted the enclomiphene NDA on April 1, 2015, assigned a PDUFA goal date of November 30, 2015, and scheduled an advisory committee for November 3, 2015; on October 29, 2015 FDA cancelled that meeting citing late-arising bioanalytical method validation questions affecting interpretability of pivotal data.","source_url":"https://www.sec.gov/Archives/edgar/data/897075/000117184315005822/newsrelease.htm","grade":"regulatory","grade_label":"Regulatory record"},{"id":"ENC-021","text":"On December 1, 2015 Repros received an FDA Complete Response Letter stating that, based on recent scientific developments, the design of the enclomiphene phase 3 studies was no longer adequate to demonstrate clinical benefit, recommending additional phase III work, and noting concerns about study entry criteria, titration and bioanalytical method validation.","source_url":"https://www.sec.gov/Archives/edgar/data/897075/000114420416087730/v432873_10k.htm","grade":"regulatory","grade_label":"Regulatory record"},{"id":"ENC-022","text":"On January 25, 2018 the EMA's CHMP refused marketing authorisation for EnCyzix (enclomifene): 4 main studies in 588 patients showed testosterone rising, but did not look at whether symptoms (bone strength, weight gain, impotence, libido) would improve, and there is a risk of venous thromboembolism; benefits did not outweigh risks.","source_url":"https://www.ema.europa.eu/en/documents/smop-initial/questions-and-answers-refusal-marketing-authorisation-encyzix-enclomifene_en.pdf","grade":"regulatory","grade_label":"Regulatory record"},{"id":"ENC-023","text":"On December 12, 2017, Repros announced its acquisition by Allergan plc for a cash payment of $0.67 per share.","source_url":"https://www.sec.gov/Archives/edgar/data/897075/000114420417063250/tv481177_ex99-1.htm","grade":"regulatory","grade_label":"Regulatory record"},{"id":"ENC-024","text":"Two later randomized placebo-controlled phase III enclomiphene trials (NCT01993212, NCT01993225; 120 enrolled each) are marked Completed with no results posted, and no publication of either was found among the 97 PubMed-indexed enclomiphene records retrieved August 14, 2026.","source_url":"https://clinicaltrials.gov/study/NCT01993212","grade":"absence-of-evidence","grade_label":"Absence of evidence"},{"id":"ENC-025","text":"Materials presented at FDA's June 8, 2022 PCAC meeting summarize 11 prospective randomized blinded trials with 953 men on enclomiphene, 290 on placebo and 130 on testosterone gel; hemoglobin and hematocrit were higher on testosterone gel, and PSA increases on enclomiphene were clinically insignificant.","source_url":"https://www.fda.gov/media/159043/download","grade":"regulatory","grade_label":"Regulatory record"},{"id":"ENC-026","text":"Compounded enclomiphene requires a prescription through the 503A pathway; FDA review of the dispensed product's safety, effectiveness and quality does not occur.","source_url":"https://www.fda.gov/drugs/human-drug-compounding/compounding-and-fda-questions-and-answers","grade":"regulatory","grade_label":"Regulatory record"},{"id":"ENC-027","text":"Clomiphene citrate is a mixture of two geometric isomers, cis (zuclomiphene) and trans (enclomiphene), containing between 30% and 50% of the cis isomer.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2ca373c1-4dba-4126-8616-5c533d606fe5","grade":"fda-label","grade_label":"FDA label"},{"id":"ENC-028","text":"Per FDA-hosted PCAC meeting material, zuclomiphene has a half-life measured in days while enclomiphene's is measured in hours; zuclomiphene is an estrogen agonist and enclomiphene an estrogen antagonist.","source_url":"https://www.fda.gov/media/159043/download","grade":"regulatory","grade_label":"Regulatory record"},{"id":"ENC-029","text":"The Clomid label reports oral absorption with principally fecal excretion, radiolabel still present in feces 6 weeks after dosing, zuclomiphene detectable for longer than a month in volunteers, and possible stereo-specific enterohepatic recycling or sequestering of zuclomiphene.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2ca373c1-4dba-4126-8616-5c533d606fe5","grade":"fda-label","grade_label":"FDA label"},{"id":"ENC-030","text":"In men on long-term clomiphene 25 mg daily, median serum zuclomiphene was 44.0 ng/mL vs enclomiphene 2.2 ng/mL, a 20:1 ratio.","source_url":"https://europepmc.org/article/MED/27511863","grade":"human-obs","grade_label":"Human observational"},{"id":"ENC-031","text":"In the same men, testosterone rose from a median 205.0 to 488.0 ng/dL and estradiol from 17.0 to 34.0 pg/mL on clomiphene therapy (both p < 0.001).","source_url":"https://europepmc.org/article/MED/27511863","grade":"human-obs","grade_label":"Human observational"},{"id":"ENC-032","text":"After a single 50 mg clomiphene dose, zuclomiphene AUC(0-456h) was 1289 ng/mL x h vs enclomiphene AUC(0-72h) 65 ng/mL x h; tmax was about 7 h vs 3 h; the zuclomiphene terminal phase was too flat for conventional half-life estimation.","source_url":"https://europepmc.org/article/MED/19033451","grade":"human-pk","grade_label":"Human PK"},{"id":"ENC-033","text":"Across consecutive monthly clomiphene cycles, day-3 zuclomiphene rose progressively for three cycles then plateaued, while day-3 enclomiphene was uniformly undetectable: isomer-specific accumulation of zuclomiphene.","source_url":"https://europepmc.org/article/MED/10202872","grade":"human-pk","grade_label":"Human PK"},{"id":"ENC-034","text":"In 12 healthy men taking clomiphene 50 mg daily for 30 days, testosterone rose 146%, LH 177% and FSH 170%; the zuclomiphene urinary detection window ranged from 121 to more than 261 days.","source_url":"https://europepmc.org/article/MED/30295816","grade":"human-uncontrolled","grade_label":"Uncontrolled human series"},{"id":"ENC-035","text":"In male mice dosed with separated isomers, zuclomiphene produced profound adverse effects on Leydig cells, epididymis, seminal vesicles and kidneys with hormonal changes, while isolated enclomiphene had positive effects on testosterone and no effects on testicular histology (authors were Repros scientists).","source_url":"https://europepmc.org/article/MED/26220499","grade":"animal","grade_label":"Animal"},{"id":"ENC-036","text":"Enclomiphene has a serum half-life of about 7 hours.","source_url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC4155868/","grade":"human-pk","grade_label":"Human PK"},{"id":"ENC-037","text":"CYP2D6 is primarily responsible for metabolizing enclomiphene in vitro: quinidine completely inhibited its metabolism in human liver microsomes, and microsomes from a CYP2D6 poor metabolizer showed no metabolism.","source_url":"https://europepmc.org/article/MED/18445989","grade":"in-vitro","grade_label":"In vitro"},{"id":"ENC-038","text":"Class warnings: the clomiphene label warns of visual symptoms (blurring, spots, flashes) requiring discontinuation and ophthalmologic evaluation; the current AndroGel label carries a venous thromboembolism warning; the EMA cited VTE risk for enclomiphene itself.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2ca373c1-4dba-4126-8616-5c533d606fe5","grade":"fda-label","grade_label":"FDA label"},{"id":"ENC-039","text":"The clomiphene label contraindicates use in liver disease or history of liver dysfunction, uncontrolled thyroid or adrenal dysfunction, organic intracranial lesions such as pituitary tumor, and pregnancy.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2ca373c1-4dba-4126-8616-5c533d606fe5","grade":"fda-label","grade_label":"FDA label"},{"id":"ENC-040","text":"In 400 men on clomiphene (mean 25.5 months, up to 84), 88% of those treated over 3 years achieved eugonadal testosterone, 77% reported symptom improvement, 8% reported side effects (mood changes 5, blurred vision 3, breast tenderness 2), estradiol rose significantly, and no significant adverse event occurred.","source_url":"https://europepmc.org/article/MED/31216250","grade":"human-obs","grade_label":"Human observational"},{"id":"ENC-041","text":"In 46 men on long-term clomiphene, testosterone rose from 228 ng/dL to 612 (1 year), 562 (2 years) and 582 ng/dL (3 years, p < 0.001); femoral neck and lumbar spine bone density improved; ADAM scores fell from 7 to 3; no adverse events were reported.","source_url":"https://europepmc.org/article/MED/22458540","grade":"human-obs","grade_label":"Human observational"},{"id":"ENC-042","text":"In 86 young hypogonadal men (mean age 29), clomiphene 25 mg every other day titrated to 50 mg targeted testosterone of 550 +/- 50 ng/dL; 64% originally presented for infertility.","source_url":"https://europepmc.org/article/MED/22044663","grade":"human-obs","grade_label":"Human observational"},{"id":"ENC-043","text":"In 76 men, 62% met a robust responder definition (testosterone rise of at least 200 ng/dL) on clomiphene; testicular volume of 14 mL or more and LH of 6 IU/mL or less predicted response.","source_url":"https://europepmc.org/article/MED/24902614","grade":"human-obs","grade_label":"Human observational"},{"id":"ENC-044","text":"In 178 men with secondary hypogonadism and erectile dysfunction on clomiphene for 4 months, LH and free testosterone rose significantly in all patients and sexual function improved in 75%, with weaker responses in older men and those with diabetes, hypertension, coronary disease or polypharmacy.","source_url":"https://europepmc.org/article/MED/12904801","grade":"human-obs","grade_label":"Human observational"},{"id":"ENC-045","text":"A systematic review and meta-analysis (19 studies, 1642 patients) found clomiphene raised total and free testosterone, LH, FSH, SHBG and estradiol with symptom improvement; side effects affected under 10% of study populations and no serious adverse events were reported.","source_url":"https://europepmc.org/article/MED/34933414","grade":"meta-analysis","grade_label":"Meta-analysis"},{"id":"ENC-046","text":"Meta-analysis of randomized trials: SERM therapy raised total testosterone 273.76 ng/dL (95% CI 191.87-355.66) vs placebo, LH 4.66 IU/L and FSH 4.59 IU/L, with no significant total testosterone difference vs testosterone gel.","source_url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12510335/","grade":"meta-analysis","grade_label":"Meta-analysis"},{"id":"ENC-047","text":"In obese men with androgen deficiency, pooled enclomiphene trials (12.5-25 mg daily, 1.5-4 months) raised testosterone 7.50 nmol/L (95% CI 6.52-8.48, I2 = 4%); clomiphene trials raised it 11.56 nmol/L; no unexpected safety findings were registered.","source_url":"https://europepmc.org/article/MED/36604313","grade":"meta-analysis","grade_label":"Meta-analysis"},{"id":"ENC-048","text":"In 66 men treated sequentially with clomiphene then enclomiphene, testosterone rises were statistically similar (median 166 vs 98 ng/dL, p = 0.20); estradiol fell on enclomiphene and rose on clomiphene (-5.92 vs +17.50 pg/mL, p = 0.001); adverse events were less frequent on enclomiphene (OR 0.18, 95% CI 0.07-0.44).","source_url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11491226/","grade":"human-obs","grade_label":"Human observational"},{"id":"ENC-049","text":"In a retrospective infertility cohort (46 enclomiphene, 32 clomiphene, at least 3 months), both raised total testosterone; only enclomiphene significantly raised FSH, LH and total motile sperm count; semen volume and concentration changed on neither.","source_url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10404117/","grade":"human-obs","grade_label":"Human observational"},{"id":"ENC-050","text":"Exogenous testosterone suppresses spermatogenesis (label: androgens may lead to azoospermia); the Endocrine Society recommends against starting testosterone therapy in men planning fertility in the near term; the AndroGel label limits its indication and notes safety and efficacy in age-related hypogonadism are not established.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f4e8d29b-8707-4d47-e053-2a95a90aecee","grade":"fda-label","grade_label":"FDA label"},{"id":"ENC-051","text":"No enclomiphene trial has reported pregnancy or live-birth outcomes; fertility preservation means preserved semen parameters over trial durations up to 16 weeks.","source_url":"https://europepmc.org/article/MED/26496621","grade":"absence-of-evidence","grade_label":"Absence of evidence"},{"id":"ENC-052","text":"No randomized head-to-head trial of enclomiphene vs clomiphene has been published; the best comparisons are retrospective.","source_url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12510335/","grade":"absence-of-evidence","grade_label":"Absence of evidence"},{"id":"ENC-053","text":"Monitoring anchors: hematocrit and hemoglobin rose more on testosterone gel than enclomiphene in pooled program data; the AndroGel label directs hematocrit checks at baseline, 3 to 6 months, then annually; elevated hematocrit is among Endocrine Society reasons not to start testosterone; PSA rose when clomiphene raised endogenous testosterone in an early series.","source_url":"https://www.fda.gov/media/159043/download","grade":"fda-label","grade_label":"FDA label"},{"id":"ENC-054","text":"The 2026 BSSM position statement recognises enclomiphene as a promising oral therapy for secondary hypogonadism, particularly for fertility preservation, but advises restricting use to experienced clinicians in specialist or research settings given absent long-term efficacy and safety data and unlicensed status; several authors are affiliated with men's telehealth providers.","source_url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13302965/","grade":"review","grade_label":"Review or guideline"},{"id":"ENC-055","text":"A 2026 retrospective uncontrolled case series (15 men, compounded sublingual enclomiphene 25 mg blended with boron, vitamin C and spermidine) reported testosterone rising from 347 to 805 ng/dL at 60 days; its authors state causality, clinical efficacy, fertility preservation and HPG-axis effects cannot be determined.","source_url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13189365/","grade":"human-uncontrolled","grade_label":"Uncontrolled human series"},{"id":"ENC-056","text":"Repros registered a phase 1 drug-drug interaction study of Androxal with cytochrome P450 isoenzymes in healthy men (NCT01991327); the registry marks it completed with no results posted.","source_url":"https://clinicaltrials.gov/study/NCT01991327","grade":"registry","grade_label":"Registry record"}]}