Fluoxymesterone: Clinical Uses and Molecular Interactions

Fluoxymesterone is a synthetic androgen used to treat low testosterone, delayed puberty, and breast cancer. It may cause serious health problems, liver damage, and dependence. It is used only for men with low testosterone levels caused by certain medical conditions, including disorders of the testicles, pituitary gland, (a small gland in the brain) or hypothalamus (a part of the brain) that cause hypogonadism. Fluoxymesterone is also used to stimulate puberty in men with delayed puberty. It may also be used alone or along with other medications in certain women with breast cancer that has spread to other parts of the body and can not be removed with surgery. Fluoxymesterone is in a class of medications called androgenic hormones. It works by supplying testosterone to replace the testosterone that is normally produced naturally in the body. Testosterone is a hormone produced by the body that contributes to the growth, development, and functioning of the male sexual organs and typical male characteristics. When used to treat breast cancer, testosterone works by blocking the release of estrogen to stop or slow the growth of breast cancer.

Fluoxymesterone-induced gynaecomastia

Gynaecomastia is a benign condition characterised by enlargement of the male breast, which is attributable to proliferation of the glandular tissue and local fat deposition. It can be physically uncomfortable, psychologically distressing and may have a negative impact on self-confidence and body image. Pseudogynecomastia, however, is common in obese men, and consists of lipomastia alone, without glandular proliferation. Although the mechanism is not fully clear, some mechanisms include oestrogen-like activities, stimulation of testicular production of oestrogens, inhibition of testosterone synthesis or blockade of androgen action. Anabolic steroids, in particular when used during the pubertal stage, may cause significant irreversible gynaecomastia. We report a case of persistent pubertal gynaecomastia from fluoxymesterone (anabolic steroid) use in the treatment of childhood aplastic anaemia. This is a case of a 28-year-old Filipino man who presented with persistent pubertal gynaecomastia. At the age of 9 during his prepubertal age, he was diagnosed to have aplastic anaemia based on bone marrow biopsy and aspirate result after presenting with several months of recurrent gum bleeding, purpura and febrile episodes. He was then seen by a haematologist–oncologist who started him on prednisone (20 mg/day), human antithymocyte globulin and fluoxymesterone (25 mg/day).[1]

The patient was on continued follow-up and treatment for aplastic anaemia for 2 years until remission was achieved. At this time, prednisone was tapered and discontinued but fluoxymesterone was continued for another 6 years, tapered and finally stopped at the age of 16 years, when the patient was considered cured of the disease. His breasts continued to enlarge and reached female-like maturity without galactorrhoea. This caused him social embarrassment especially when with his male peers. Breast mammography showed normal glandular breast and normal breast tissue on biopsy. Abdominal ultrasound revealed normal liver, pancreas, kidneys and prostate. Based on the clinical history, temporal relationship between drug initiation and appearance of gynaecomastia and the absence of pathological causes, the patient was diagnosed to have drug-induced (fluoxymesterone) gynaecomastia. Fluoxymesterone is a drug belonging to a group of fluorine-substituted derivatives of methyltestosterone and has been shown to have more potent anabolic and androgenic properties than testosterone and methyltestosterone. This potent anabolic androgenic steroid has been clinically used to treat male hypogonadism.8 In combination with the antithymocyte globulin, it was a promising treatment for cases of aplastic anaemia during the 1980s. Certain studies showed beneficial additive effect while others did not, hence its usage was controversial.

Evaluation of the androgen receptor in patients treated with adjuvant tamoxifen ± fluoxymesterone

Estrogen receptor α (ER) is expressed in the majority of breast cancers in women and the vast majority of ER-positive breast cancers also express the androgen receptor (AR), e.g., 74.8% in review by Vera-Badillo, 85.9% in the Nurses’ Health Study, but the AR is not routinely determined in clinical practice. NCCTG 89-30-52 was a randomized trial that evaluated the addition of the AR-agonist fluoxymesterone (Flu) to tamoxifen (Tam) in women with resected early-stage breast cancer. This trial attempted to corroborate, and was powered by, the findings of superiority for the combination of Tam + Flu over Tam alone seen in a previous randomized trial in metastatic disease. Tissue microarrays (TMAs) were prepared from primary tumor blocks from patients entered on a prospective randomized adjuvant trial of tamoxifen (Tam) alone or combined with fluoxymesterone (Flu), an AR-agonist, (NCCTG 89-30-52). TMAs were stained for ER and AR and expression examined in decile increments (0–100%) of positive invasive tumor nuclei. The primary endpoint was relapse-free survival (RFS). The proportion of the ER-enriched tumors that also had AR-enriched expression levels was 56.3% in the Tam arm and 51.8% in the Tam + Flu arm. Within the AR-enriched patients, the cumulative incidence of RFS events showed an advantage for Tam + Flu over Tam alone that reached significance (Gray’s test p = 0.0472).[2]

Fluoxymesterone Inhibits Glucocorticoid Inactivation

Anabolic androgenic steroids (AAS) are testosterone derivatives used either clinically, in elite sports, or for body shaping with the goal to increase muscle size and strength. Clinically developed compounds and nonclinically tested designer steroids often marketed as food supplements are widely used. Despite the considerable evidence for various adverse effects of AAS use, the underlying molecular mechanisms are insufficiently understood. Whereas oxymetholone, oxymesterone, danazol, and testosterone showed medium inhibitory potential, fluoxymesterone was a potent inhibitor of human 11β-HSD2 (half-maximal inhibitory concentration [IC50] of 60–100nM in cell lysates; IC50 of 160nM in intact SW-620, and 530nM in MCF-7 cells). Measurements with rat kidney microsomes and lysates of cells expressing recombinant mouse 11β-HSD2 revealed much weaker inhibition by the AAS tested, indicating that the adverse effects of AAS-dependent 11β-HSD2 inhibition cannot be investigated in rats and mice. Furthermore, we provide evidence that fluoxymesterone is metabolized to 11-oxofluoxymesterone by human 11β-HSD2.[3]

References

[1]Lo TE, Andal ZC, Lantion-Ang FL. Fluoxymesterone-induced gynaecomastia in a patient with childhood aplastic anaemia. BMJ Case Rep. 2015 May 6;2015:bcr2014207474. doi: 10.1136/bcr-2014-207474. PMID: 25948845; PMCID: PMC4434366.

[2]Ingle JN, Suman VJ, Solanki MH, Passow MR, Campbell JD, Wang L, Goetz MP. Evaluation of the androgen receptor in patients with ERα-positive early breast cancer treated with adjuvant tamoxifen ± fluoxymesterone. Breast Cancer Res. 2025 Mar 19;27(1):40. doi: 10.1186/s13058-025-01992-0. PMID: 40108635; PMCID: PMC11924783.

[3]Fürstenberger C, Vuorinen A, Da Cunha T, Kratschmar DV, Saugy M, Schuster D, Odermatt A. The anabolic androgenic steroid fluoxymesterone inhibits 11β-hydroxysteroid dehydrogenase 2-dependent glucocorticoid inactivation. Toxicol Sci. 2012 Apr;126(2):353-61. doi: 10.1093/toxsci/kfs022. Epub 2012 Jan 23. PMID: 22273746.

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