Enclomiphene
updated
Enclomiphene can raise testosterone while preserving sperm concentration in selected men with secondary hypogonadism. Regulators did not accept hormone and sperm surrogates as proof of symptom benefit, and no FDA- or EU-approved product exists.
Trans-clomiphene selective estrogen receptor modulator
- Trans isomer related to clomiphene
- Oral selective estrogen receptor modulator
- Base, citrate, and compounded preparations are not interchangeable labels
Which outcomes were measured in enclomiphene trials?
The strongest trials answer whether serum testosterone, LH, FSH, and sperm concentration change in overweight men with secondary hypogonadism. They do not establish relief of low-testosterone symptoms, conception, pregnancy, live birth, fracture prevention, or cardiovascular benefit.
The trials measured hormones and sperm concentration, not symptoms, conception, pregnancy, live birth, fractures, or cardiovascular events.
Enclomiphene phase 3 · hormones and sperm
Randomized trials
Kim et al., BJU International, 2016
Two parallel phase 3 studies found that enclomiphene citrate raised testosterone, LH, and FSH and maintained sperm concentration, while testosterone gel raised testosterone but suppressed gonadotropins and sperm.
- Participants / model
- Overweight men aged 18 to 60 with secondary hypogonadism
- Treatment
- Two enclomiphene citrate doses, testosterone gel, or placebo
- Follow-up
- 16 weeks
- Study design
- Randomized, double-blind, double-dummy multicenter phase 3 studies
The outcomes were hormones and sperm concentration, not symptoms, pregnancy, or live birth.
Read the original sourceEMA EnCyzix · surrogate and VTE concerns
Regulatory assessment
European Medicines Agency, 2018
EMA reviewed four studies in 588 men and refused authorization because testosterone increases were not linked to symptom outcomes and venous-thromboembolism risk remained.
- Participants / model
- Overweight men with hypogonadotropic hypogonadism
- Treatment
- Oral enclomifene citrate, placebo, and testosterone gel conditions
- Record date
- Application reviewed through 2018
- Study design
- CHMP marketing-authorization assessment
The EMA decision concerns an EU refusal; it does not establish U.S. status or the status of every current formulation.
Read the original sourceWhat happened versus testosterone gel?
Two 16-week randomized, double-blind, double-dummy phase 3 studies found that enclomiphene citrate and testosterone gel both raised serum testosterone. LH and FSH rose with enclomiphene and fell with testosterone gel; sperm concentrations stayed in the normal range with enclomiphene and dropped with gel.
The participants were overweight men aged 18 to 60 with secondary hypogonadism and repeated morning testosterone at or below 300 ng/dL. The trials did not enroll men with primary testicular failure or unexplained infertility.
Enclomiphene phase 3 · hormones and sperm
Randomized trials
Kim et al., BJU International, 2016
Two parallel phase 3 studies found that enclomiphene citrate raised testosterone, LH, and FSH and maintained sperm concentration, while testosterone gel raised testosterone but suppressed gonadotropins and sperm.
- Participants / model
- Overweight men aged 18 to 60 with secondary hypogonadism
- Treatment
- Two enclomiphene citrate doses, testosterone gel, or placebo
- Follow-up
- 16 weeks
- Study design
- Randomized, double-blind, double-dummy multicenter phase 3 studies
The outcomes were hormones and sperm concentration, not symptoms, pregnancy, or live birth.
Read the original sourceWhy did EMA refuse EnCyzix despite positive hormone results?
EMA reviewed four main studies involving 588 men and concluded that increased testosterone did not show improvement in bone strength, weight, impotence, or libido. With venous-thromboembolism concern, the committee judged that benefits did not outweigh risks and refused authorization in 2018.
The proposed population was overweight men with hypogonadotropic hypogonadism. EMA accepted that hormone measures changed but found no adequate symptom or clinical benefit to outweigh venous-thromboembolism concerns.
EMA EnCyzix · surrogate and VTE concerns
Regulatory assessment
European Medicines Agency, 2018
EMA reviewed four studies in 588 men and refused authorization because testosterone increases were not linked to symptom outcomes and venous-thromboembolism risk remained.
- Participants / model
- Overweight men with hypogonadotropic hypogonadism
- Treatment
- Oral enclomifene citrate, placebo, and testosterone gel conditions
- Record date
- Application reviewed through 2018
- Study design
- CHMP marketing-authorization assessment
The EMA decision concerns an EU refusal; it does not establish U.S. status or the status of every current formulation.
Read the original sourceIs enclomiphene FDA approved?
No. The U.S. application received a complete response letter in 2015, and FDA Drugs@FDA and openFDA records contained no exact-name approval. A later compounding advisory discussion did not create an approved drug.
A compounded prescription is not an FDA-approved enclomiphene product and does not inherit a final federal label.
FDA application history · complete response letter
Company regulatory filing
Repros Therapeutics SEC filing, December 2015
The sponsor disclosed that FDA issued a complete response letter rather than approving the enclomiphene application.
- Participants / model
- U.S. new drug application
- Treatment
- Enclomiphene citrate application
- Follow-up
- December 2015 action
- Study design
- Sponsor disclosure filed with SEC
The SEC-filed sponsor disclosure reports that FDA issued a complete response letter in 2015.
Read the original sourceFDA records · enclomiphene status
Regulatory database record set
FDA Drugs@FDA and openFDA records
The cited U.S. approval records contain no exact-name enclomiphene or enclomifene entry.
- Participants / model
- United States drug approvals
- Treatment
- Aliases enclomiphene, enclomifene, EnCyzix, and Androxal
- Study design
- Exact-name and alias U.S. approval coverage
Does preserved sperm concentration prove pregnancy or live birth benefit?
No. The phase 3 studies support preserved sperm concentration relative to testosterone gel over 16 weeks. They did not establish time to pregnancy, pregnancy rate, live birth, offspring outcomes, or treatment of a female partner.
Enclomiphene phase 3 · hormones and sperm
Randomized trials
Kim et al., BJU International, 2016
Two parallel phase 3 studies found that enclomiphene citrate raised testosterone, LH, and FSH and maintained sperm concentration, while testosterone gel raised testosterone but suppressed gonadotropins and sperm.
- Participants / model
- Overweight men aged 18 to 60 with secondary hypogonadism
- Treatment
- Two enclomiphene citrate doses, testosterone gel, or placebo
- Follow-up
- 16 weeks
- Study design
- Randomized, double-blind, double-dummy multicenter phase 3 studies
The outcomes were hormones and sperm concentration, not symptoms, pregnancy, or live birth.
Read the original sourceHow should the clotting concern be described?
EMA identified venous thromboembolism as a material risk in its refusal. The public assessment contains event narratives, but available exposure is too limited to turn them into a stable incidence rate for current compounded products.
The trials do not provide reliable rates for clotting, mood, vision, liver, or hormone effects in current compounded-product users.
EMA EnCyzix · surrogate and VTE concerns
Regulatory assessment
European Medicines Agency, 2018
EMA reviewed four studies in 588 men and refused authorization because testosterone increases were not linked to symptom outcomes and venous-thromboembolism risk remained.
- Participants / model
- Overweight men with hypogonadotropic hypogonadism
- Treatment
- Oral enclomifene citrate, placebo, and testosterone gel conditions
- Record date
- Application reviewed through 2018
- Study design
- CHMP marketing-authorization assessment
The EMA decision concerns an EU refusal; it does not establish U.S. status or the status of every current formulation.
Read the original sourceAre enclomiphene base, enclomiphene citrate, and compounded products equivalent?
The phase 3 publication and EnCyzix application concern enclomiphene citrate. A free-base amount, citrate salt amount, capsule formulation, and compounded preparation can differ in molecular weight, content, impurities, and exposure. Trial doses cannot be copied across products by name alone.
Enclomiphene phase 3 · hormones and sperm
Randomized trials
Kim et al., BJU International, 2016
Two parallel phase 3 studies found that enclomiphene citrate raised testosterone, LH, and FSH and maintained sperm concentration, while testosterone gel raised testosterone but suppressed gonadotropins and sperm.
- Participants / model
- Overweight men aged 18 to 60 with secondary hypogonadism
- Treatment
- Two enclomiphene citrate doses, testosterone gel, or placebo
- Follow-up
- 16 weeks
- Study design
- Randomized, double-blind, double-dummy multicenter phase 3 studies
The outcomes were hormones and sperm concentration, not symptoms, pregnancy, or live birth.
Read the original sourceEMA EnCyzix · surrogate and VTE concerns
Regulatory assessment
European Medicines Agency, 2018
EMA reviewed four studies in 588 men and refused authorization because testosterone increases were not linked to symptom outcomes and venous-thromboembolism risk remained.
- Participants / model
- Overweight men with hypogonadotropic hypogonadism
- Treatment
- Oral enclomifene citrate, placebo, and testosterone gel conditions
- Record date
- Application reviewed through 2018
- Study design
- CHMP marketing-authorization assessment
The EMA decision concerns an EU refusal; it does not establish U.S. status or the status of every current formulation.
Read the original sourceStudies and sources
Enclomiphene phase 3 · hormones and sperm
Randomized trials
Kim et al., BJU International, 2016
Two parallel phase 3 studies found that enclomiphene citrate raised testosterone, LH, and FSH and maintained sperm concentration, while testosterone gel raised testosterone but suppressed gonadotropins and sperm.
- Participants / model
- Overweight men aged 18 to 60 with secondary hypogonadism
- Treatment
- Two enclomiphene citrate doses, testosterone gel, or placebo
- Follow-up
- 16 weeks
- Study design
- Randomized, double-blind, double-dummy multicenter phase 3 studies
The outcomes were hormones and sperm concentration, not symptoms, pregnancy, or live birth.
Read the original sourceEMA EnCyzix · surrogate and VTE concerns
Regulatory assessment
European Medicines Agency, 2018
EMA reviewed four studies in 588 men and refused authorization because testosterone increases were not linked to symptom outcomes and venous-thromboembolism risk remained.
- Participants / model
- Overweight men with hypogonadotropic hypogonadism
- Treatment
- Oral enclomifene citrate, placebo, and testosterone gel conditions
- Record date
- Application reviewed through 2018
- Study design
- CHMP marketing-authorization assessment
The EMA decision concerns an EU refusal; it does not establish U.S. status or the status of every current formulation.
Read the original sourceFDA application history · complete response letter
Company regulatory filing
Repros Therapeutics SEC filing, December 2015
The sponsor disclosed that FDA issued a complete response letter rather than approving the enclomiphene application.
- Participants / model
- U.S. new drug application
- Treatment
- Enclomiphene citrate application
- Follow-up
- December 2015 action
- Study design
- Sponsor disclosure filed with SEC
The SEC-filed sponsor disclosure reports that FDA issued a complete response letter in 2015.
Read the original sourceFDA records · enclomiphene status
Regulatory database record set
FDA Drugs@FDA and openFDA records
The cited U.S. approval records contain no exact-name enclomiphene or enclomifene entry.
- Participants / model
- United States drug approvals
- Treatment
- Aliases enclomiphene, enclomifene, EnCyzix, and Androxal
- Study design
- Exact-name and alias U.S. approval coverage
Why is Enclomiphene in B tier?
The B tier reflects randomized phase 3 results for testosterone and sperm concentration. The trials did not establish improved libido, erectile function, bone health, conception, pregnancy, live birth, or a favorable benefit-risk decision.
read Enclomiphene in the reptides guide, chapter 50: 11 pages, free to read.