Endoxifen

updated

Endoxifen is a tamoxifen metabolite studied orally in cancer patients, in healthy women for mammographic density, and as an add-on to tamoxifen in women with impaired CYP2D6 metabolism. No FDA approval was found, and an Indian approval exists for acute mania. A PubMed search on 10 October 2026 for endoxifen with gynecomastia, anabolic steroid, post-cycle, hypogonadism or male infertility terms returned 0 records, and no trial compares endoxifen with tamoxifen on clinical outcomes.

Estrogen receptor antagonist (tamoxifen metabolite)

  • No FDA approval was found: openFDA Drugs@FDA returned no record for endoxifen and DailyMed returned no label on 10 October 2026.
  • A 2023 commentary critiques the Indian government decision to approve endoxifen for acute mania in adults, and gives no approval date or product.
  • In KARISMA, 240 healthy premenopausal women took placebo or 1 or 2 mg of oral (Z)-endoxifen for 6 months, and relative mammographic density fell 19.3% at 1 mg and 26.5% at 2 mg versus placebo. The trial is industry-linked and had no tamoxifen arm.
  • In TAMENDOX (235 women on tamoxifen), adding 3 mg a day of (Z)-endoxifen brought 92.3% of CYP2D6 poor metabolizers above the 32 nmol/L target after 6 weeks; the endpoint was blood level, not recurrence.
  • A PubMed search on 10 October 2026 for endoxifen with gynecomastia, anabolic steroid, bodybuilding, post-cycle, hypogonadism or male infertility terms returned 0 records.
  • Topical endoxifen caused skin rashes and a high discontinuation rate in a 90-woman trial, and the authors wrote that it may not be suitable for topical administration.

What is endoxifen, and has anyone approved it?

Endoxifen is a tamoxifen metabolite, N-desmethyl-4-hydroxytamoxifen. No FDA approval was found on 10 October 2026, and a 2023 commentary shows an Indian approval exists for acute mania in adults.

Z-endoxifen (N-desmethyl-4-hydroxytamoxifen) is C25H27NO2 (373.5 g/mol, CAS 112093-28-4, PubChem CID 10090750, also NSC-749798). The PubChem record is the (Z) isomer. The topical phase 1 gel trial used an (E/Z) mixture, and the oral trials used (Z)-endoxifen, some as the hydrochloride salt. A vendor product that does not state isomer and salt is not shown to be the studied drug.

openFDA Drugs@FDA returned no record for endoxifen, and DailyMed returned no label, both on 10 October 2026. A 2023 commentary critiques the Indian government decision to approve endoxifen for acute mania in adults, so an Indian approval exists for that bipolar use. The commentary abstract gives no approval date or product, and the sources reviewed do not show an approval for gynecomastia or breast protection. A phase 3 trial in bipolar I mania (NCT06608641, Jina Pharmaceuticals, 8 mg enteric-coated tablet, 490 estimated, status unknown) is registered. Atossa Therapeutics sponsors the registered breast studies.

PubChem: Z-endoxifen identity, isomer and salt

Chemical identity record

National Library of Medicine. PubChem compound record CID 10090750 (Z-endoxifen).

Z-endoxifen (N-desmethyl-4-hydroxytamoxifen): PubChem CID 10090750, C25H27NO2, 373.5 g/mol, CAS 112093-28-4, also NSC-749798. The PubChem record is the (Z) isomer. The topical phase 1 gel trial used an (E/Z) mixture, and the oral trials used (Z)-endoxifen, some as the hydrochloride salt, so a vendor product that does not state isomer and salt is not shown to be the studied drug.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source
Drugs@FDA and DailyMed, 10 October 2026: no record; India: approval for acute mania per a 2023 commentary

Regulatory record

Gupta R et al. J Clin Psychopharmacol. 2023;43(1):3-5. PMID 36584243.

openFDA Drugs@FDA returned no record for endoxifen, and DailyMed returned no label, both on 10 October 2026. A 2023 commentary critiques the Indian government decision to approve endoxifen for acute mania in adults, so an Indian approval exists for that bipolar use. The commentary abstract gives no approval date or product. A phase 3 trial in bipolar I mania (NCT06608641, Jina Pharmaceuticals, 8 mg enteric-coated tablet, 490 estimated, status unknown) is registered. Atossa Therapeutics sponsors the registered breast studies.

Participants / model
Adults with acute mania (India); not a gynecomastia population
Treatment
Oral endoxifen
Follow-up
Searches run on 10 October 2026
Study design
FDA record searches, a commentary and a trial registry record
Funding
not stated in the source

The absence of a US record is a US-scoped statement. The date and product of the Indian approval are not given in the sources reviewed.

Read the original source

What did the oral endoxifen studies in people find?

Oral endoxifen was tested in 40 cancer patients, in 240 healthy women for mammographic density, and as an add-on to tamoxifen in 235 women. Density fell in the healthy-women trial, which is a proxy marker, and blood levels rose in impaired tamoxifen metabolizers.

A phase 1 dose-escalation study of oral Z-endoxifen enrolled 40 patients (34 evaluable) with treatment-refractory gynecologic, desmoid or hormone receptor-positive solid tumors. No maximum tolerated dose was reached over 8 dose levels, and 360 mg a day was used in expansion. Three patients had partial responses and 8 had stable disease of at least 6 cycles; 8 of 18 patients (44.4%) at dose levels 6 to 8 had one of those outcomes. The abstract does not give the sex breakdown, and the study is not a gynecomastia or healthy-person study (NCT01273168).

In the KARISMA Endoxifen trial, 240 healthy premenopausal women in the Stockholm screening program took placebo or 1 or 2 mg of oral (Z)-endoxifen daily for 6 months. Relative mammographic density fell 19.3% (95% CI 6.15% to 32.4%) at 1 mg and 26.5% (95% CI 14.1% to 38.9%) at 2 mg versus placebo. There was no tamoxifen arm, so the authors' comparison with tamoxifen 20 mg is to other studies. Density is a proxy for response, not breast cancer incidence. Atossa Therapeutics, the drug developer, is linked to the trial, and its chief executive is a co-author (NCT05068388).

TAMENDOX randomized 235 women with hormone receptor-positive breast cancer on tamoxifen 20 mg a day to add (Z)-endoxifen or placebo, stratified by CYP2D6 genotype or baseline endoxifen level. Adding 3 mg a day brought 92.3% of CYP2D6 poor metabolizers and all women with baseline endoxifen of 15 nmol/L or less above the 32 nmol/L target after 6 weeks, and 1.5 mg did so in 88% of intermediate metabolizers. The endpoint was blood level, not recurrence, and endoxifen was added to tamoxifen, not compared with it. This supports the pharmacokinetic logic for poor metabolizers in women, not a clinical outcome advantage (NCT03931928).

Phase 1: 40 patients with refractory tumors, no maximum tolerated dose over 8 dose levels

Clinical trial

Takebe N et al. Oncotarget. 2021;12(4):268-277. PMID 33659039.

No maximum tolerated dose was reached over 8 dose levels, and 360 mg a day was used in expansion. Three patients had partial responses and 8 had stable disease of at least 6 cycles; 8 of 18 patients (44.4%) at dose levels 6 to 8 had one of those outcomes.

Participants / model
40 adults (34 evaluable) with treatment-refractory gynecologic, desmoid or hormone receptor-positive solid tumors
Treatment
Oral Z-endoxifen daily, 8 dose levels up to 360 mg
Follow-up
Not stated in the source
Study design
Phase 1 dose-escalation study (NCT01273168)
Funding
not stated in the source

The abstract does not give the sex breakdown, and the study is not a gynecomastia or healthy-person study.

Read the original source
KARISMA: 240 healthy women, density down 19.3% at 1 mg and 26.5% at 2 mg versus placebo

Randomized controlled trial

Hall P et al. J Natl Cancer Inst. 2026;118(10):1899-1906. PMID 42070780.

Relative mammographic density fell 19.3% (95% CI 6.15% to 32.4%) at 1 mg and 26.5% (95% CI 14.1% to 38.9%) at 2 mg versus placebo. Discontinuations for related adverse events were 4 (placebo), 5 (1 mg) and 11 (2 mg), and the 2 mg group reported more vasomotor symptoms. There was no tamoxifen arm, so the authors' comparison with tamoxifen 20 mg is to other studies.

Participants / model
240 healthy premenopausal women in the Stockholm screening program
Treatment
Oral (Z)-endoxifen 1 or 2 mg a day, or placebo
Follow-up
6 months
Study design
Randomized phase 2 trial (NCT05068388), industry-linked
Funding
not stated in the source

Density is a proxy for response, not breast cancer incidence. Atossa Therapeutics, the drug developer, is linked to the trial, and its chief executive is a co-author.

Read the original source
TAMENDOX: 235 women on tamoxifen, endoxifen lifted blood levels in poor and intermediate metabolizers

Randomized controlled trial

Mürdter TE et al. Clin Cancer Res. 2025;31(23):4903-4911. PMID 41036998.

Adding 3 mg a day of (Z)-endoxifen brought 92.3% of CYP2D6 poor metabolizers and all women with baseline endoxifen of 15 nmol/L or less above the 32 nmol/L target after 6 weeks; 1.5 mg did so in 88% of intermediate metabolizers. Grade 3 adverse events were 6 of 80 (7.5%) with endoxifen versus 8 of 155 (5.2%) with placebo. The endpoint was blood level, not recurrence, and endoxifen was added to tamoxifen, not compared with it.

Participants / model
235 women with hormone receptor-positive breast cancer on tamoxifen, stratified by CYP2D6 genotype or baseline endoxifen level
Treatment
Oral tamoxifen 20 mg a day plus (Z)-endoxifen 1.5 or 3 mg a day, or placebo
Follow-up
6 weeks
Study design
Randomized phase I/II trial (NCT03931928)
Funding
not stated in the source

This supports the pharmacokinetic logic for poor metabolizers in women, not a clinical outcome advantage.

Read the original source

Does topical endoxifen work in the studies so far?

Topical endoxifen is not a practical route so far. In a 90-woman trial density fell, but skin rashes drove a high discontinuation rate and the authors wrote it may not be suitable for topical use.

In a 90-woman randomized trial of 10 or 20 mg topical Z-endoxifen versus placebo for 6 months, density fell significantly, but the discontinuation rate was high, driven by skin rashes, and the authors wrote that endoxifen may not be suitable for topical administration.

A 32-woman phase 1 trial gave (E/Z)-endoxifen gel at 10 or 20 mg a day before mastectomy. The abstract reports no dermal or systemic toxicity versus placebo, a median breast tissue level of 0.6 ng/g against median plasma 0.2 ng/mL, and a non-significant fall in Ki-67. The abstract's wording on dermal toxicity is a summary: the trial's registry entry (NCT03317405) lists dermal toxicity counts, and their grades were not reviewed. Both trials were in women.

Topical endoxifen: 90 women, density fell but skin rashes drove discontinuation

Randomized controlled trial

Bäcklund M et al. Oncologist. 2022;27(7):e597-e600. PMID 35604960.

In a randomized trial of 10 or 20 mg topical Z-endoxifen versus placebo for 6 months, density fell significantly, but the discontinuation rate was high, driven by skin rashes, and the authors wrote that endoxifen may not be suitable for topical administration.

Participants / model
90 women
Treatment
Topical Z-endoxifen 10 or 20 mg, or placebo
Follow-up
6 months
Study design
Randomized trial
Funding
not stated in the source

Women only. A high discontinuation rate limits what the density result shows.

Read the original source
Endoxifen gel phase 1: 32 women, tissue 0.6 ng/g, plasma 0.2 ng/mL

Randomized controlled trial

Lee O et al. Biomed Pharmacother. 2024;171:116105. PMID 38171245.

The abstract reports no dermal or systemic toxicity versus placebo, a median breast tissue level of 0.6 ng/g against median plasma 0.2 ng/mL, and a non-significant fall in Ki-67.

Participants / model
32 women planning mastectomy
Treatment
(E/Z)-endoxifen gel 10 or 20 mg a day, or placebo, before mastectomy
Follow-up
Not stated in the source
Study design
Phase 1 trial (registry NCT03317405)
Funding
not stated in the source

Women only. The abstract's wording on dermal toxicity is a summary: the trial's registry entry lists dermal toxicity counts, and their grades were not reviewed.

Read the original source

Is endoxifen better than tamoxifen in CYP2D6 poor metabolizers?

Only the blood-level logic is supported, and only in women. No trial compared endoxifen with tamoxifen on clinical outcomes in poor metabolizers, and the link from low CYP2D6 activity to worse tamoxifen outcomes is itself mixed.

The poor-metabolizer argument depends on the claim that low CYP2D6 activity worsens tamoxifen outcome, and that claim is disputed. In BIG 1-98 (4,393 postmenopausal women with a phenotype call), no association was found between CYP2D6 phenotype and recurrence for tamoxifen monotherapy without prior chemotherapy (P = 0.35). In an ATAC subset (1,203 patients), CYP2D6 genotype was not significantly associated with recurrence in tamoxifen-treated patients (poor versus extensive metabolizers, distant recurrence HR 1.25, 95% CI 0.55 to 3.15).

A 2025 bias-adjusted meta-analysis of 33 studies found higher recurrence or mortality in poor metabolizers (RR 1.34, 95% simulation interval 1.10 to 1.63) and a smaller rise in intermediate metabolizers (RR 1.15, 1.00 to 1.34). A WHEL cohort analysis (1,370 patients) found a possible endoxifen threshold, with women in the upper four quintiles at lower recurrence risk (HR 0.74, 95% CI 0.55 to 1.00) than the lowest quintile. TAMENDOX shows endoxifen added to tamoxifen lifts blood levels in impaired metabolizers, but its endpoint was blood level, not recurrence.

Male data are sparse. In 230 infertile men with idiopathic oligozoospermia treated with tamoxifen citrate plus testosterone undecanoate, the CYP2D6*10 variant genotype had smaller hormone and sperm gains and a lower spontaneous pregnancy incidence than wild type. In 53 men with male breast cancer on adjuvant tamoxifen, the CYP2D6*4 poorer-metabolizer group had more recurrence (P = 0.034), a small single-center series. Neither tested endoxifen, neither studied gynecomastia, and neither involved anabolic steroid users.

2025 meta-analysis of 33 studies: poor metabolizers RR 1.34 for recurrence or mortality

Systematic review and meta-analysis

MacLehose RF et al. Cancer Epidemiol Biomarkers Prev. 2025;34(2):224-233. PMID 39540781.

A 2025 bias-adjusted meta-analysis of 33 studies found higher recurrence or mortality in poor metabolizers (RR 1.34, 95% simulation interval 1.10 to 1.63) and a smaller rise in intermediate metabolizers (RR 1.15, 1.00 to 1.34).

Participants / model
Women with ER-positive breast cancer on tamoxifen, 33 studies
Treatment
Oral tamoxifen, genotype and phenotype comparison
Follow-up
Pooled studies
Study design
Bias-adjusted meta-analysis
Funding
not stated in the source

It concerns tamoxifen, not endoxifen. No trial compared endoxifen with tamoxifen on clinical outcomes in poor metabolizers.

Read the original source
BIG 1-98: 4,393 women, no CYP2D6 association with recurrence on tamoxifen alone

Human study

Regan MM et al. J Natl Cancer Inst. 2012;104(6):441-51. PMID 22395644.

In BIG 1-98 (4,393 postmenopausal women with a phenotype call), no association was found between CYP2D6 phenotype and recurrence for tamoxifen monotherapy without prior chemotherapy (P = 0.35).

Participants / model
4,393 postmenopausal women with a CYP2D6 phenotype call
Treatment
Oral tamoxifen monotherapy without prior chemotherapy
Follow-up
Not stated in the source
Study design
Genotype substudy of a randomized trial
Funding
not stated in the source

It concerns tamoxifen, not endoxifen.

Read the original source
ATAC subset: 1,203 patients, CYP2D6 genotype not significantly linked to recurrence

Human study

Rae JM et al. J Natl Cancer Inst. 2012;104(6):452-60. PMID 22395643.

In an ATAC subset (1,203 patients), CYP2D6 genotype was not significantly associated with recurrence in tamoxifen-treated patients (poor versus extensive metabolizers, distant recurrence HR 1.25, 95% CI 0.55 to 3.15).

Participants / model
1,203 patients in an ATAC subset
Treatment
Oral tamoxifen
Follow-up
Not stated in the source
Study design
Genotype substudy of a randomized trial
Funding
not stated in the source

It concerns tamoxifen, not endoxifen.

Read the original source
WHEL cohort: 1,370 patients, a possible endoxifen threshold for recurrence

Human study

Madlensky L et al. Clin Pharmacol Ther. 2011;89(5):718-25. PMID 21430657.

A WHEL cohort analysis (1,370 patients) found a possible endoxifen threshold, with women in the upper four quintiles at lower recurrence risk (HR 0.74, 95% CI 0.55 to 1.00) than the lowest quintile.

Participants / model
1,370 women with breast cancer on tamoxifen
Treatment
Oral tamoxifen, endoxifen level compared by quintile
Follow-up
Not stated in the source
Study design
Cohort analysis
Funding
not stated in the source

It concerns blood endoxifen level on tamoxifen, not endoxifen given as a drug.

Read the original source
230 infertile men: CYP2D6*10 variant linked to smaller gains and fewer pregnancies

Human study

Tang KF et al. J Zhejiang Univ Sci B. 2015;16(3):191-7. PMID 25743120.

In 230 infertile men with idiopathic oligozoospermia treated with tamoxifen citrate plus testosterone undecanoate, the CYP2D6*10 variant genotype had worse clinical effects: smaller hormone and sperm gains and a lower spontaneous pregnancy incidence than wild type.

Participants / model
230 infertile men with idiopathic oligozoospermia
Treatment
Oral tamoxifen citrate with testosterone undecanoate
Follow-up
Not stated in the source
Study design
Observational study
Funding
not stated in the source

It did not test endoxifen, and it did not study gynecomastia or anabolic steroid users.

Read the original source
53 men with breast cancer: CYP2D6*4 poorer-metabolizer group had more recurrence

Human study

Abreu MH et al. Breast. 2015;24(4):481-6. PMID 25963137.

In 53 men with male breast cancer on adjuvant tamoxifen, the CYP2D6*4 poorer-metabolizer group had more recurrence (P = 0.034), in a small single-center series.

Participants / model
53 men with breast cancer on adjuvant tamoxifen
Treatment
Oral tamoxifen
Follow-up
Not stated in the source
Study design
Observational, small single-center series
Funding
not stated in the source

It did not test endoxifen, and it did not study gynecomastia or anabolic steroid users.

Read the original source
TAMENDOX: 235 women on tamoxifen, endoxifen lifted blood levels in poor and intermediate metabolizers

Randomized controlled trial

Mürdter TE et al. Clin Cancer Res. 2025;31(23):4903-4911. PMID 41036998.

Adding 3 mg a day of (Z)-endoxifen brought 92.3% of CYP2D6 poor metabolizers and all women with baseline endoxifen of 15 nmol/L or less above the 32 nmol/L target after 6 weeks; 1.5 mg did so in 88% of intermediate metabolizers. Grade 3 adverse events were 6 of 80 (7.5%) with endoxifen versus 8 of 155 (5.2%) with placebo. The endpoint was blood level, not recurrence, and endoxifen was added to tamoxifen, not compared with it.

Participants / model
235 women with hormone receptor-positive breast cancer on tamoxifen, stratified by CYP2D6 genotype or baseline endoxifen level
Treatment
Oral tamoxifen 20 mg a day plus (Z)-endoxifen 1.5 or 3 mg a day, or placebo
Follow-up
6 weeks
Study design
Randomized phase I/II trial (NCT03931928)
Funding
not stated in the source

This supports the pharmacokinetic logic for poor metabolizers in women, not a clinical outcome advantage.

Read the original source

What is known about endoxifen in bipolar mania?

A systematic review found short-term improvement in manic symptoms in mostly 8 mg studies, with important methodological limits and a significant lipid rise within 3 weeks. This use is unrelated to estrogen-receptor effects in the breast.

A systematic review of endoxifen in bipolar disorder found 7 case reports, 2 clinical trials and 1 prospective study, mostly with 8 mg, with short-term improvement in manic symptoms but important methodological limits. The comparator, divalproex 1,000 mg, was judged sub-therapeutic, and a significant lipid rise appeared within 3 weeks. This is the other human use of endoxifen, and the Indian approval found concerns it.

Bipolar systematic review: 7 case reports, 2 trials, 1 prospective study, lipid rise in 3 weeks

Systematic review and meta-analysis

Joseph JT et al. Hum Psychopharmacol. 2024;39(4):e2899. PMID 38683854.

The review found 7 case reports, 2 clinical trials and 1 prospective study, mostly with 8 mg, with short-term improvement in manic symptoms but important methodological limits, a comparator (divalproex 1,000 mg) judged sub-therapeutic, and a significant lipid rise within 3 weeks.

Participants / model
Adults with bipolar I mania
Treatment
Oral endoxifen, mostly 8 mg a day
Follow-up
About 3 weeks
Study design
Systematic review
Funding
not stated in the source

This is the other human use of endoxifen and is unrelated to estrogen-receptor effects in the breast.

Read the original source
Drugs@FDA and DailyMed, 10 October 2026: no record; India: approval for acute mania per a 2023 commentary

Regulatory record

Gupta R et al. J Clin Psychopharmacol. 2023;43(1):3-5. PMID 36584243.

openFDA Drugs@FDA returned no record for endoxifen, and DailyMed returned no label, both on 10 October 2026. A 2023 commentary critiques the Indian government decision to approve endoxifen for acute mania in adults, so an Indian approval exists for that bipolar use. The commentary abstract gives no approval date or product. A phase 3 trial in bipolar I mania (NCT06608641, Jina Pharmaceuticals, 8 mg enteric-coated tablet, 490 estimated, status unknown) is registered. Atossa Therapeutics sponsors the registered breast studies.

Participants / model
Adults with acute mania (India); not a gynecomastia population
Treatment
Oral endoxifen
Follow-up
Searches run on 10 October 2026
Study design
FDA record searches, a commentary and a trial registry record
Funding
not stated in the source

The absence of a US record is a US-scoped statement. The date and product of the Indian approval are not given in the sources reviewed.

Read the original source

Does endoxifen prevent or treat gynecomastia, or support post-cycle recovery?

No study found tests it. A PubMed search on 10 October 2026 for endoxifen with gynecomastia, anabolic steroid, bodybuilding, post-cycle, hypogonadism or male infertility terms returned 0 records, in any population.

Sellers market endoxifen to prevent and treat gynecomastia, to support post-cycle therapy, to protect the breast during anabolic steroid use, and as better than tamoxifen for CYP2D6 poor metabolizers.

A PubMed search on 10 October 2026 for endoxifen with gynecomastia, gynaecomastia, anabolic steroid, bodybuilding, post-cycle, hypogonadism or male infertility terms returned 0 records. A ClinicalTrials.gov search for endoxifen returned 42 records: 30 female-only, 11 open to all sexes and 1 male-only (NCT01821066, a palbociclib and tamoxifen interaction study in healthy male volunteers, where endoxifen is not the tested drug). None studies endoxifen for gynecomastia, anabolic steroid users or post-cycle recovery, and a search for endoxifen gynecomastia returned no records.

The CYP2D6 part of the claim is a plausible pharmacokinetic rationale in women, covered in the section above. A person with normal CYP2D6 activity has no demonstrated reason to prefer endoxifen over tamoxifen in these sources, and no trial shows endoxifen beating tamoxifen on any clinical endpoint.

PubMed, 10 October 2026: 0 records; ClinicalTrials.gov: 42 endoxifen records, none for gynecomastia

PubMed search record

PubMed search run on 10 October 2026: endoxifen AND (gynecomastia OR gynaecomastia OR "anabolic steroid" OR bodybuilding OR "post-cycle" OR "post cycle" OR hypogonadism OR "male infertility") (0 records). ClinicalTrials.gov searches run on 10 October 2026: endoxifen (42 records); endoxifen gynecomastia (no records).

The PubMed search returned 0 records. A ClinicalTrials.gov search for endoxifen returned 42 records: 30 female-only, 11 open to all sexes and 1 male-only (NCT01821066, a palbociclib and tamoxifen interaction study in healthy male volunteers, where endoxifen is not the tested drug). None studies endoxifen for gynecomastia, anabolic steroid users or post-cycle recovery, and a search for endoxifen gynecomastia returned no records. No evidence was found that endoxifen prevents or treats gynecomastia or supports post-cycle recovery, in any population.

Participants / model
Records reviewed, not a population
Treatment
Not applicable
Follow-up
Searches run on 10 October 2026
Study design
Literature and registry search
Funding
not stated in the source

A search result shows what PubMed and the registry returned on that date. It is not proof that no unindexed study exists.

Read the original source
230 infertile men: CYP2D6*10 variant linked to smaller gains and fewer pregnancies

Human study

Tang KF et al. J Zhejiang Univ Sci B. 2015;16(3):191-7. PMID 25743120.

In 230 infertile men with idiopathic oligozoospermia treated with tamoxifen citrate plus testosterone undecanoate, the CYP2D6*10 variant genotype had worse clinical effects: smaller hormone and sperm gains and a lower spontaneous pregnancy incidence than wild type.

Participants / model
230 infertile men with idiopathic oligozoospermia
Treatment
Oral tamoxifen citrate with testosterone undecanoate
Follow-up
Not stated in the source
Study design
Observational study
Funding
not stated in the source

It did not test endoxifen, and it did not study gynecomastia or anabolic steroid users.

Read the original source
53 men with breast cancer: CYP2D6*4 poorer-metabolizer group had more recurrence

Human study

Abreu MH et al. Breast. 2015;24(4):481-6. PMID 25963137.

In 53 men with male breast cancer on adjuvant tamoxifen, the CYP2D6*4 poorer-metabolizer group had more recurrence (P = 0.034), in a small single-center series.

Participants / model
53 men with breast cancer on adjuvant tamoxifen
Treatment
Oral tamoxifen
Follow-up
Not stated in the source
Study design
Observational, small single-center series
Funding
not stated in the source

It did not test endoxifen, and it did not study gynecomastia or anabolic steroid users.

Read the original source

How does endoxifen work, and what happens to it in the body?

Endoxifen is a tamoxifen metabolite and a more potent antiestrogen than tamoxifen, formed by CYP2D6. Pharmacokinetic data exist only in cancer patients, and no half-life or peak time appears in the sources reviewed.

The CPIC guideline states that tamoxifen is biotransformed by CYP2D6 to 4-hydroxytamoxifen and endoxifen, both more potent antiestrogens than tamoxifen, and that patients with certain CYP2D6 polymorphisms or on strong CYP2D6 inhibitors have lower endoxifen and, in some studies, a higher recurrence risk. A 2021 review calls endoxifen a more potent antiestrogen than N-desmethyltamoxifen or tamoxifen and notes it may act through other pathways as well. This is the pharmacology behind the bypasses-CYP2D6 idea, derived in women with breast cancer.

A population pharmacokinetic analysis of 1,256 plasma samples from 80 patients with advanced solid tumors on oral Z-endoxifen (20 to 360 mg a day) fit a 2-compartment model with linear elimination. Apparent total clearance was 4.89 L/h, apparent central volume 323 L and apparent peripheral volume 39.7 L. Weight, race (on clearance) and aspartate aminotransferase (on absorption rate) were significant covariates. These doses are far above the 1 to 3 mg used in the breast density and tamoxifen-supplement trials, and no half-life or Tmax is given in the sources reviewed.

CPIC guideline: CYP2D6 converts tamoxifen to 4-hydroxytamoxifen and endoxifen

Human study

Goetz MP et al. Clin Pharmacol Ther. 2018;103(5):770-777. PMID 29385237.

The guideline states that tamoxifen is biotransformed by CYP2D6 to 4-hydroxytamoxifen and endoxifen, both more potent antiestrogens than tamoxifen, and that patients with certain CYP2D6 polymorphisms or on strong CYP2D6 inhibitors have lower endoxifen and, in some studies, a higher recurrence risk.

Participants / model
Women with breast cancer treated with tamoxifen (guideline scope)
Treatment
Oral tamoxifen metabolism, not endoxifen dosing
Follow-up
Not applicable
Study design
Clinical practice guideline
Funding
not stated in the source

This is the pharmacology behind the bypasses-CYP2D6 idea, derived in women with breast cancer.

Read the original source
2021 review: endoxifen is a more potent antiestrogen and may act through other pathways

Human study

Jayaraman S et al. Endocrinology. 2021;162(12). PMID 34480554.

A 2021 review calls endoxifen a more potent antiestrogen than N-desmethyltamoxifen or tamoxifen and notes it may act through other pathways as well.

Participants / model
Not a clinical population
Treatment
Not drug-specific
Follow-up
Not applicable
Study design
Narrative review
Funding
not stated in the source

A review of pharmacology. It does not report a trial result.

Read the original source
Population PK: 80 patients, 1,256 samples, clearance 4.89 L/h

Human study

Koubek EJ et al. J Clin Pharmacol. 2022;62(9):1121-1131. PMID 35358345.

A 2-compartment model with linear elimination fit 1,256 plasma samples from 80 patients on oral Z-endoxifen (20 to 360 mg a day). Apparent total clearance was 4.89 L/h, apparent central volume 323 L and apparent peripheral volume 39.7 L. Weight, race (on clearance) and aspartate aminotransferase (on absorption rate) were significant covariates.

Participants / model
80 patients with advanced solid tumors
Treatment
Oral Z-endoxifen hydrochloride daily, 20 to 360 mg a day
Follow-up
28-day cycles
Study design
Population pharmacokinetic analysis
Funding
not stated in the source

These doses are far above the 1 to 3 mg used in the breast density and tamoxifen-supplement trials.

Read the original source

What risks and side effects were reported?

Reported adverse effects are from women and cancer patients. In KARISMA, there were 11 discontinuations for related adverse events at 2 mg and vasomotor symptoms were more common, topical use caused rashes, and no safety data exist in men or in anabolic steroid users.

In KARISMA, discontinuations for related adverse events were 4 (placebo), 5 (1 mg) and 11 (2 mg), and the 2 mg group reported more vasomotor symptoms. In TAMENDOX, grade 3 adverse events were 6 of 80 (7.5%) with endoxifen versus 8 of 155 (5.2%) with placebo. In the 40-patient phase 1 study in refractory tumors, no maximum tolerated dose was reached over 8 dose levels, a result in cancer patients, not healthy people.

Topical endoxifen caused skin rashes that drove a high discontinuation rate in a 90-woman trial. The systematic review in bipolar mania reported a significant lipid rise within 3 weeks.

No safety data exist in men for the breast-related uses, because no study of endoxifen in gynecomastia, anabolic steroid users or post-cycle recovery was found. A vendor product that does not state isomer and salt is not shown to be the studied drug.

KARISMA: 240 healthy women, density down 19.3% at 1 mg and 26.5% at 2 mg versus placebo

Randomized controlled trial

Hall P et al. J Natl Cancer Inst. 2026;118(10):1899-1906. PMID 42070780.

Relative mammographic density fell 19.3% (95% CI 6.15% to 32.4%) at 1 mg and 26.5% (95% CI 14.1% to 38.9%) at 2 mg versus placebo. Discontinuations for related adverse events were 4 (placebo), 5 (1 mg) and 11 (2 mg), and the 2 mg group reported more vasomotor symptoms. There was no tamoxifen arm, so the authors' comparison with tamoxifen 20 mg is to other studies.

Participants / model
240 healthy premenopausal women in the Stockholm screening program
Treatment
Oral (Z)-endoxifen 1 or 2 mg a day, or placebo
Follow-up
6 months
Study design
Randomized phase 2 trial (NCT05068388), industry-linked
Funding
not stated in the source

Density is a proxy for response, not breast cancer incidence. Atossa Therapeutics, the drug developer, is linked to the trial, and its chief executive is a co-author.

Read the original source
TAMENDOX: 235 women on tamoxifen, endoxifen lifted blood levels in poor and intermediate metabolizers

Randomized controlled trial

Mürdter TE et al. Clin Cancer Res. 2025;31(23):4903-4911. PMID 41036998.

Adding 3 mg a day of (Z)-endoxifen brought 92.3% of CYP2D6 poor metabolizers and all women with baseline endoxifen of 15 nmol/L or less above the 32 nmol/L target after 6 weeks; 1.5 mg did so in 88% of intermediate metabolizers. Grade 3 adverse events were 6 of 80 (7.5%) with endoxifen versus 8 of 155 (5.2%) with placebo. The endpoint was blood level, not recurrence, and endoxifen was added to tamoxifen, not compared with it.

Participants / model
235 women with hormone receptor-positive breast cancer on tamoxifen, stratified by CYP2D6 genotype or baseline endoxifen level
Treatment
Oral tamoxifen 20 mg a day plus (Z)-endoxifen 1.5 or 3 mg a day, or placebo
Follow-up
6 weeks
Study design
Randomized phase I/II trial (NCT03931928)
Funding
not stated in the source

This supports the pharmacokinetic logic for poor metabolizers in women, not a clinical outcome advantage.

Read the original source
Phase 1: 40 patients with refractory tumors, no maximum tolerated dose over 8 dose levels

Clinical trial

Takebe N et al. Oncotarget. 2021;12(4):268-277. PMID 33659039.

No maximum tolerated dose was reached over 8 dose levels, and 360 mg a day was used in expansion. Three patients had partial responses and 8 had stable disease of at least 6 cycles; 8 of 18 patients (44.4%) at dose levels 6 to 8 had one of those outcomes.

Participants / model
40 adults (34 evaluable) with treatment-refractory gynecologic, desmoid or hormone receptor-positive solid tumors
Treatment
Oral Z-endoxifen daily, 8 dose levels up to 360 mg
Follow-up
Not stated in the source
Study design
Phase 1 dose-escalation study (NCT01273168)
Funding
not stated in the source

The abstract does not give the sex breakdown, and the study is not a gynecomastia or healthy-person study.

Read the original source
Topical endoxifen: 90 women, density fell but skin rashes drove discontinuation

Randomized controlled trial

Bäcklund M et al. Oncologist. 2022;27(7):e597-e600. PMID 35604960.

In a randomized trial of 10 or 20 mg topical Z-endoxifen versus placebo for 6 months, density fell significantly, but the discontinuation rate was high, driven by skin rashes, and the authors wrote that endoxifen may not be suitable for topical administration.

Participants / model
90 women
Treatment
Topical Z-endoxifen 10 or 20 mg, or placebo
Follow-up
6 months
Study design
Randomized trial
Funding
not stated in the source

Women only. A high discontinuation rate limits what the density result shows.

Read the original source
Bipolar systematic review: 7 case reports, 2 trials, 1 prospective study, lipid rise in 3 weeks

Systematic review and meta-analysis

Joseph JT et al. Hum Psychopharmacol. 2024;39(4):e2899. PMID 38683854.

The review found 7 case reports, 2 clinical trials and 1 prospective study, mostly with 8 mg, with short-term improvement in manic symptoms but important methodological limits, a comparator (divalproex 1,000 mg) judged sub-therapeutic, and a significant lipid rise within 3 weeks.

Participants / model
Adults with bipolar I mania
Treatment
Oral endoxifen, mostly 8 mg a day
Follow-up
About 3 weeks
Study design
Systematic review
Funding
not stated in the source

This is the other human use of endoxifen and is unrelated to estrogen-receptor effects in the breast.

Read the original source
PubChem: Z-endoxifen identity, isomer and salt

Chemical identity record

National Library of Medicine. PubChem compound record CID 10090750 (Z-endoxifen).

Z-endoxifen (N-desmethyl-4-hydroxytamoxifen): PubChem CID 10090750, C25H27NO2, 373.5 g/mol, CAS 112093-28-4, also NSC-749798. The PubChem record is the (Z) isomer. The topical phase 1 gel trial used an (E/Z) mixture, and the oral trials used (Z)-endoxifen, some as the hydrochloride salt, so a vendor product that does not state isomer and salt is not shown to be the studied drug.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source

Why does endoxifen sit in C tier?

C fits a compound with more human data than most in its class but no approval for the uses sellers describe. Nothing tests it in men, in gynecomastia or in anabolic steroid users.

Endoxifen has oral phase 1 data in cancer patients (40 patients, no maximum tolerated dose), a 240-woman randomized phase 2 trial in healthy women that lowered mammographic density, and a 235-woman randomized trial showing a 1.5 to 3 mg supplement lifts blood levels in impaired tamoxifen metabolizers. The density result is a proxy marker from an industry-linked trial.

No FDA approval was found, and the Indian approval found is for bipolar mania. The supplier claims for gynecomastia, steroid-cycle breast protection and post-cycle recovery are not supported, because no studies were found. The CYP2D6 rationale holds for blood levels in women, but the link from low endoxifen to worse outcomes is mixed, and no trial shows endoxifen beating tamoxifen on a clinical endpoint.

Phase 1: 40 patients with refractory tumors, no maximum tolerated dose over 8 dose levels

Clinical trial

Takebe N et al. Oncotarget. 2021;12(4):268-277. PMID 33659039.

No maximum tolerated dose was reached over 8 dose levels, and 360 mg a day was used in expansion. Three patients had partial responses and 8 had stable disease of at least 6 cycles; 8 of 18 patients (44.4%) at dose levels 6 to 8 had one of those outcomes.

Participants / model
40 adults (34 evaluable) with treatment-refractory gynecologic, desmoid or hormone receptor-positive solid tumors
Treatment
Oral Z-endoxifen daily, 8 dose levels up to 360 mg
Follow-up
Not stated in the source
Study design
Phase 1 dose-escalation study (NCT01273168)
Funding
not stated in the source

The abstract does not give the sex breakdown, and the study is not a gynecomastia or healthy-person study.

Read the original source
KARISMA: 240 healthy women, density down 19.3% at 1 mg and 26.5% at 2 mg versus placebo

Randomized controlled trial

Hall P et al. J Natl Cancer Inst. 2026;118(10):1899-1906. PMID 42070780.

Relative mammographic density fell 19.3% (95% CI 6.15% to 32.4%) at 1 mg and 26.5% (95% CI 14.1% to 38.9%) at 2 mg versus placebo. Discontinuations for related adverse events were 4 (placebo), 5 (1 mg) and 11 (2 mg), and the 2 mg group reported more vasomotor symptoms. There was no tamoxifen arm, so the authors' comparison with tamoxifen 20 mg is to other studies.

Participants / model
240 healthy premenopausal women in the Stockholm screening program
Treatment
Oral (Z)-endoxifen 1 or 2 mg a day, or placebo
Follow-up
6 months
Study design
Randomized phase 2 trial (NCT05068388), industry-linked
Funding
not stated in the source

Density is a proxy for response, not breast cancer incidence. Atossa Therapeutics, the drug developer, is linked to the trial, and its chief executive is a co-author.

Read the original source
TAMENDOX: 235 women on tamoxifen, endoxifen lifted blood levels in poor and intermediate metabolizers

Randomized controlled trial

Mürdter TE et al. Clin Cancer Res. 2025;31(23):4903-4911. PMID 41036998.

Adding 3 mg a day of (Z)-endoxifen brought 92.3% of CYP2D6 poor metabolizers and all women with baseline endoxifen of 15 nmol/L or less above the 32 nmol/L target after 6 weeks; 1.5 mg did so in 88% of intermediate metabolizers. Grade 3 adverse events were 6 of 80 (7.5%) with endoxifen versus 8 of 155 (5.2%) with placebo. The endpoint was blood level, not recurrence, and endoxifen was added to tamoxifen, not compared with it.

Participants / model
235 women with hormone receptor-positive breast cancer on tamoxifen, stratified by CYP2D6 genotype or baseline endoxifen level
Treatment
Oral tamoxifen 20 mg a day plus (Z)-endoxifen 1.5 or 3 mg a day, or placebo
Follow-up
6 weeks
Study design
Randomized phase I/II trial (NCT03931928)
Funding
not stated in the source

This supports the pharmacokinetic logic for poor metabolizers in women, not a clinical outcome advantage.

Read the original source
Drugs@FDA and DailyMed, 10 October 2026: no record; India: approval for acute mania per a 2023 commentary

Regulatory record

Gupta R et al. J Clin Psychopharmacol. 2023;43(1):3-5. PMID 36584243.

openFDA Drugs@FDA returned no record for endoxifen, and DailyMed returned no label, both on 10 October 2026. A 2023 commentary critiques the Indian government decision to approve endoxifen for acute mania in adults, so an Indian approval exists for that bipolar use. The commentary abstract gives no approval date or product. A phase 3 trial in bipolar I mania (NCT06608641, Jina Pharmaceuticals, 8 mg enteric-coated tablet, 490 estimated, status unknown) is registered. Atossa Therapeutics sponsors the registered breast studies.

Participants / model
Adults with acute mania (India); not a gynecomastia population
Treatment
Oral endoxifen
Follow-up
Searches run on 10 October 2026
Study design
FDA record searches, a commentary and a trial registry record
Funding
not stated in the source

The absence of a US record is a US-scoped statement. The date and product of the Indian approval are not given in the sources reviewed.

Read the original source
PubMed, 10 October 2026: 0 records; ClinicalTrials.gov: 42 endoxifen records, none for gynecomastia

PubMed search record

PubMed search run on 10 October 2026: endoxifen AND (gynecomastia OR gynaecomastia OR "anabolic steroid" OR bodybuilding OR "post-cycle" OR "post cycle" OR hypogonadism OR "male infertility") (0 records). ClinicalTrials.gov searches run on 10 October 2026: endoxifen (42 records); endoxifen gynecomastia (no records).

The PubMed search returned 0 records. A ClinicalTrials.gov search for endoxifen returned 42 records: 30 female-only, 11 open to all sexes and 1 male-only (NCT01821066, a palbociclib and tamoxifen interaction study in healthy male volunteers, where endoxifen is not the tested drug). None studies endoxifen for gynecomastia, anabolic steroid users or post-cycle recovery, and a search for endoxifen gynecomastia returned no records. No evidence was found that endoxifen prevents or treats gynecomastia or supports post-cycle recovery, in any population.

Participants / model
Records reviewed, not a population
Treatment
Not applicable
Follow-up
Searches run on 10 October 2026
Study design
Literature and registry search
Funding
not stated in the source

A search result shows what PubMed and the registry returned on that date. It is not proof that no unindexed study exists.

Read the original source

Studies and sources

PubChem: Z-endoxifen identity, isomer and salt

Chemical identity record

National Library of Medicine. PubChem compound record CID 10090750 (Z-endoxifen).

Z-endoxifen (N-desmethyl-4-hydroxytamoxifen): PubChem CID 10090750, C25H27NO2, 373.5 g/mol, CAS 112093-28-4, also NSC-749798. The PubChem record is the (Z) isomer. The topical phase 1 gel trial used an (E/Z) mixture, and the oral trials used (Z)-endoxifen, some as the hydrochloride salt, so a vendor product that does not state isomer and salt is not shown to be the studied drug.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source
Drugs@FDA and DailyMed, 10 October 2026: no record; India: approval for acute mania per a 2023 commentary

Regulatory record

Gupta R et al. J Clin Psychopharmacol. 2023;43(1):3-5. PMID 36584243.

openFDA Drugs@FDA returned no record for endoxifen, and DailyMed returned no label, both on 10 October 2026. A 2023 commentary critiques the Indian government decision to approve endoxifen for acute mania in adults, so an Indian approval exists for that bipolar use. The commentary abstract gives no approval date or product. A phase 3 trial in bipolar I mania (NCT06608641, Jina Pharmaceuticals, 8 mg enteric-coated tablet, 490 estimated, status unknown) is registered. Atossa Therapeutics sponsors the registered breast studies.

Participants / model
Adults with acute mania (India); not a gynecomastia population
Treatment
Oral endoxifen
Follow-up
Searches run on 10 October 2026
Study design
FDA record searches, a commentary and a trial registry record
Funding
not stated in the source

The absence of a US record is a US-scoped statement. The date and product of the Indian approval are not given in the sources reviewed.

Read the original source
CPIC guideline: CYP2D6 converts tamoxifen to 4-hydroxytamoxifen and endoxifen

Human study

Goetz MP et al. Clin Pharmacol Ther. 2018;103(5):770-777. PMID 29385237.

The guideline states that tamoxifen is biotransformed by CYP2D6 to 4-hydroxytamoxifen and endoxifen, both more potent antiestrogens than tamoxifen, and that patients with certain CYP2D6 polymorphisms or on strong CYP2D6 inhibitors have lower endoxifen and, in some studies, a higher recurrence risk.

Participants / model
Women with breast cancer treated with tamoxifen (guideline scope)
Treatment
Oral tamoxifen metabolism, not endoxifen dosing
Follow-up
Not applicable
Study design
Clinical practice guideline
Funding
not stated in the source

This is the pharmacology behind the bypasses-CYP2D6 idea, derived in women with breast cancer.

Read the original source
2021 review: endoxifen is a more potent antiestrogen and may act through other pathways

Human study

Jayaraman S et al. Endocrinology. 2021;162(12). PMID 34480554.

A 2021 review calls endoxifen a more potent antiestrogen than N-desmethyltamoxifen or tamoxifen and notes it may act through other pathways as well.

Participants / model
Not a clinical population
Treatment
Not drug-specific
Follow-up
Not applicable
Study design
Narrative review
Funding
not stated in the source

A review of pharmacology. It does not report a trial result.

Read the original source
Phase 1: 40 patients with refractory tumors, no maximum tolerated dose over 8 dose levels

Clinical trial

Takebe N et al. Oncotarget. 2021;12(4):268-277. PMID 33659039.

No maximum tolerated dose was reached over 8 dose levels, and 360 mg a day was used in expansion. Three patients had partial responses and 8 had stable disease of at least 6 cycles; 8 of 18 patients (44.4%) at dose levels 6 to 8 had one of those outcomes.

Participants / model
40 adults (34 evaluable) with treatment-refractory gynecologic, desmoid or hormone receptor-positive solid tumors
Treatment
Oral Z-endoxifen daily, 8 dose levels up to 360 mg
Follow-up
Not stated in the source
Study design
Phase 1 dose-escalation study (NCT01273168)
Funding
not stated in the source

The abstract does not give the sex breakdown, and the study is not a gynecomastia or healthy-person study.

Read the original source
Population PK: 80 patients, 1,256 samples, clearance 4.89 L/h

Human study

Koubek EJ et al. J Clin Pharmacol. 2022;62(9):1121-1131. PMID 35358345.

A 2-compartment model with linear elimination fit 1,256 plasma samples from 80 patients on oral Z-endoxifen (20 to 360 mg a day). Apparent total clearance was 4.89 L/h, apparent central volume 323 L and apparent peripheral volume 39.7 L. Weight, race (on clearance) and aspartate aminotransferase (on absorption rate) were significant covariates.

Participants / model
80 patients with advanced solid tumors
Treatment
Oral Z-endoxifen hydrochloride daily, 20 to 360 mg a day
Follow-up
28-day cycles
Study design
Population pharmacokinetic analysis
Funding
not stated in the source

These doses are far above the 1 to 3 mg used in the breast density and tamoxifen-supplement trials.

Read the original source
TAMENDOX: 235 women on tamoxifen, endoxifen lifted blood levels in poor and intermediate metabolizers

Randomized controlled trial

Mürdter TE et al. Clin Cancer Res. 2025;31(23):4903-4911. PMID 41036998.

Adding 3 mg a day of (Z)-endoxifen brought 92.3% of CYP2D6 poor metabolizers and all women with baseline endoxifen of 15 nmol/L or less above the 32 nmol/L target after 6 weeks; 1.5 mg did so in 88% of intermediate metabolizers. Grade 3 adverse events were 6 of 80 (7.5%) with endoxifen versus 8 of 155 (5.2%) with placebo. The endpoint was blood level, not recurrence, and endoxifen was added to tamoxifen, not compared with it.

Participants / model
235 women with hormone receptor-positive breast cancer on tamoxifen, stratified by CYP2D6 genotype or baseline endoxifen level
Treatment
Oral tamoxifen 20 mg a day plus (Z)-endoxifen 1.5 or 3 mg a day, or placebo
Follow-up
6 weeks
Study design
Randomized phase I/II trial (NCT03931928)
Funding
not stated in the source

This supports the pharmacokinetic logic for poor metabolizers in women, not a clinical outcome advantage.

Read the original source
KARISMA: 240 healthy women, density down 19.3% at 1 mg and 26.5% at 2 mg versus placebo

Randomized controlled trial

Hall P et al. J Natl Cancer Inst. 2026;118(10):1899-1906. PMID 42070780.

Relative mammographic density fell 19.3% (95% CI 6.15% to 32.4%) at 1 mg and 26.5% (95% CI 14.1% to 38.9%) at 2 mg versus placebo. Discontinuations for related adverse events were 4 (placebo), 5 (1 mg) and 11 (2 mg), and the 2 mg group reported more vasomotor symptoms. There was no tamoxifen arm, so the authors' comparison with tamoxifen 20 mg is to other studies.

Participants / model
240 healthy premenopausal women in the Stockholm screening program
Treatment
Oral (Z)-endoxifen 1 or 2 mg a day, or placebo
Follow-up
6 months
Study design
Randomized phase 2 trial (NCT05068388), industry-linked
Funding
not stated in the source

Density is a proxy for response, not breast cancer incidence. Atossa Therapeutics, the drug developer, is linked to the trial, and its chief executive is a co-author.

Read the original source
Topical endoxifen: 90 women, density fell but skin rashes drove discontinuation

Randomized controlled trial

Bäcklund M et al. Oncologist. 2022;27(7):e597-e600. PMID 35604960.

In a randomized trial of 10 or 20 mg topical Z-endoxifen versus placebo for 6 months, density fell significantly, but the discontinuation rate was high, driven by skin rashes, and the authors wrote that endoxifen may not be suitable for topical administration.

Participants / model
90 women
Treatment
Topical Z-endoxifen 10 or 20 mg, or placebo
Follow-up
6 months
Study design
Randomized trial
Funding
not stated in the source

Women only. A high discontinuation rate limits what the density result shows.

Read the original source
Endoxifen gel phase 1: 32 women, tissue 0.6 ng/g, plasma 0.2 ng/mL

Randomized controlled trial

Lee O et al. Biomed Pharmacother. 2024;171:116105. PMID 38171245.

The abstract reports no dermal or systemic toxicity versus placebo, a median breast tissue level of 0.6 ng/g against median plasma 0.2 ng/mL, and a non-significant fall in Ki-67.

Participants / model
32 women planning mastectomy
Treatment
(E/Z)-endoxifen gel 10 or 20 mg a day, or placebo, before mastectomy
Follow-up
Not stated in the source
Study design
Phase 1 trial (registry NCT03317405)
Funding
not stated in the source

Women only. The abstract's wording on dermal toxicity is a summary: the trial's registry entry lists dermal toxicity counts, and their grades were not reviewed.

Read the original source
2025 meta-analysis of 33 studies: poor metabolizers RR 1.34 for recurrence or mortality

Systematic review and meta-analysis

MacLehose RF et al. Cancer Epidemiol Biomarkers Prev. 2025;34(2):224-233. PMID 39540781.

A 2025 bias-adjusted meta-analysis of 33 studies found higher recurrence or mortality in poor metabolizers (RR 1.34, 95% simulation interval 1.10 to 1.63) and a smaller rise in intermediate metabolizers (RR 1.15, 1.00 to 1.34).

Participants / model
Women with ER-positive breast cancer on tamoxifen, 33 studies
Treatment
Oral tamoxifen, genotype and phenotype comparison
Follow-up
Pooled studies
Study design
Bias-adjusted meta-analysis
Funding
not stated in the source

It concerns tamoxifen, not endoxifen. No trial compared endoxifen with tamoxifen on clinical outcomes in poor metabolizers.

Read the original source
BIG 1-98: 4,393 women, no CYP2D6 association with recurrence on tamoxifen alone

Human study

Regan MM et al. J Natl Cancer Inst. 2012;104(6):441-51. PMID 22395644.

In BIG 1-98 (4,393 postmenopausal women with a phenotype call), no association was found between CYP2D6 phenotype and recurrence for tamoxifen monotherapy without prior chemotherapy (P = 0.35).

Participants / model
4,393 postmenopausal women with a CYP2D6 phenotype call
Treatment
Oral tamoxifen monotherapy without prior chemotherapy
Follow-up
Not stated in the source
Study design
Genotype substudy of a randomized trial
Funding
not stated in the source

It concerns tamoxifen, not endoxifen.

Read the original source
ATAC subset: 1,203 patients, CYP2D6 genotype not significantly linked to recurrence

Human study

Rae JM et al. J Natl Cancer Inst. 2012;104(6):452-60. PMID 22395643.

In an ATAC subset (1,203 patients), CYP2D6 genotype was not significantly associated with recurrence in tamoxifen-treated patients (poor versus extensive metabolizers, distant recurrence HR 1.25, 95% CI 0.55 to 3.15).

Participants / model
1,203 patients in an ATAC subset
Treatment
Oral tamoxifen
Follow-up
Not stated in the source
Study design
Genotype substudy of a randomized trial
Funding
not stated in the source

It concerns tamoxifen, not endoxifen.

Read the original source
WHEL cohort: 1,370 patients, a possible endoxifen threshold for recurrence

Human study

Madlensky L et al. Clin Pharmacol Ther. 2011;89(5):718-25. PMID 21430657.

A WHEL cohort analysis (1,370 patients) found a possible endoxifen threshold, with women in the upper four quintiles at lower recurrence risk (HR 0.74, 95% CI 0.55 to 1.00) than the lowest quintile.

Participants / model
1,370 women with breast cancer on tamoxifen
Treatment
Oral tamoxifen, endoxifen level compared by quintile
Follow-up
Not stated in the source
Study design
Cohort analysis
Funding
not stated in the source

It concerns blood endoxifen level on tamoxifen, not endoxifen given as a drug.

Read the original source
230 infertile men: CYP2D6*10 variant linked to smaller gains and fewer pregnancies

Human study

Tang KF et al. J Zhejiang Univ Sci B. 2015;16(3):191-7. PMID 25743120.

In 230 infertile men with idiopathic oligozoospermia treated with tamoxifen citrate plus testosterone undecanoate, the CYP2D6*10 variant genotype had worse clinical effects: smaller hormone and sperm gains and a lower spontaneous pregnancy incidence than wild type.

Participants / model
230 infertile men with idiopathic oligozoospermia
Treatment
Oral tamoxifen citrate with testosterone undecanoate
Follow-up
Not stated in the source
Study design
Observational study
Funding
not stated in the source

It did not test endoxifen, and it did not study gynecomastia or anabolic steroid users.

Read the original source
53 men with breast cancer: CYP2D6*4 poorer-metabolizer group had more recurrence

Human study

Abreu MH et al. Breast. 2015;24(4):481-6. PMID 25963137.

In 53 men with male breast cancer on adjuvant tamoxifen, the CYP2D6*4 poorer-metabolizer group had more recurrence (P = 0.034), in a small single-center series.

Participants / model
53 men with breast cancer on adjuvant tamoxifen
Treatment
Oral tamoxifen
Follow-up
Not stated in the source
Study design
Observational, small single-center series
Funding
not stated in the source

It did not test endoxifen, and it did not study gynecomastia or anabolic steroid users.

Read the original source
Bipolar systematic review: 7 case reports, 2 trials, 1 prospective study, lipid rise in 3 weeks

Systematic review and meta-analysis

Joseph JT et al. Hum Psychopharmacol. 2024;39(4):e2899. PMID 38683854.

The review found 7 case reports, 2 clinical trials and 1 prospective study, mostly with 8 mg, with short-term improvement in manic symptoms but important methodological limits, a comparator (divalproex 1,000 mg) judged sub-therapeutic, and a significant lipid rise within 3 weeks.

Participants / model
Adults with bipolar I mania
Treatment
Oral endoxifen, mostly 8 mg a day
Follow-up
About 3 weeks
Study design
Systematic review
Funding
not stated in the source

This is the other human use of endoxifen and is unrelated to estrogen-receptor effects in the breast.

Read the original source

Why is Endoxifen in C tier?

C fits a compound with more human data than most in its class but no approval for the uses sellers describe. It has oral phase 1 data in cancer patients, a 240-woman randomized trial that lowered mammographic density (a proxy marker, from an industry-linked trial), and a 235-woman randomized trial that raised blood levels in impaired tamoxifen metabolizers. Nothing tests it in men, in gynecomastia or in anabolic steroid users, and no trial shows endoxifen beating tamoxifen on a clinical outcome.