Raloxifene
Evista
Raloxifene (Evista) is a second-generation selective estrogen receptor modulator (SERM): it acts as an estrogen antagonist in breast tissue and, in men, blocks estrogen negative feedback on the pituitary while acting as an estrogen agonist on bone and lipids. It is FDA-approved only for prevention/treatment of postmenopausal osteoporosis and reduction of invasive breast cancer risk in postmenopausal women. The main danger is thrombosis: across large randomized trials it roughly doubles-to-triples the risk of venous thromboembolism (DVT/PE), and in the RUTH trial it significantly increased the risk of fatal stroke. It is a proven human teratogen (pregnancy contraindicated). Any use in men (e.g., for anabolic-steroid-associated gynecomastia or hormonal "recovery") is entirely off-label: the only human data in men are three small trials showing it raises LH/FSH, testosterone, and estradiol and modestly increases bone density, with no controlled trials for gynecomastia treatment or HPTA restoration. This monograph is risk-forward and is not medical advice; SERM use should be supervised by a physician with baseline and interval bloodwork.
Mechanism of action
Pharmacokinetics
Approximately 28-33 hours at steady state (single-dose elimination half-life averaged ~32.5 hours in review data); enterohepatic recycling prolongs residence.
Dosed once daily; bone-turnover and lipid effects are sustained with continuous daily dosing and reverse after discontinuation. This washout information is for monitoring/perioperative planning (e.g., stopping before prolonged immobilization), not for evading drug testing.
Oral.
Rapidly absorbed (~60% of a dose) but undergoes extensive presystemic (first-pass) glucuronidation, so absolute bioavailability is only ~2%. Metabolized almost exclusively by UGT glucuronidation (no meaningful cytochrome P450 involvement) to glucuronide conjugates; eliminated predominantly in feces via biliary excretion with <0.2% excreted unchanged in urine. Concomitant cholestyramine markedly reduces absorption.
For monitoring and washout planning, not drug-test evasion.
Physiological & performance effects
- Reduces bone resorption and increases bone mineral density; reduces incidence of vertebral (clinical and radiographic) fractures in postmenopausal women with osteoporosis
- Reduces the incidence of invasive, predominantly estrogen-receptor-positive, breast cancer in postmenopausal women
- Lowers total and LDL cholesterol (estrogen-agonist hepatic effect)
- Does not significantly stimulate the endometrium and did not increase endometrial cancer risk in trials
- In men: raises serum LH, FSH, total and free testosterone, and estradiol by blocking estrogen negative feedback (small RCTs)
- In men on androgen-deprivation therapy: modestly increases hip (and trends toward spine) bone mineral density (small RCT)
- No proven benefit on coronary heart disease events despite favorable lipid changes
Adverse effects by system
Significantly increases venous thromboembolism (DVT and pulmonary embolism). In the RUTH trial it also significantly increased fatal stroke (HR 1.49, 95% CI 1.00-2.24), though total stroke incidence was not increased, and it had no effect on coronary heart disease events (HR 0.95). Hot flashes and leg cramps are common. This is the dominant, potentially life-threatening risk category.
Extensively metabolized by hepatic glucuronidation. Raloxifene is not a recognized cause of clinically significant drug-induced liver injury and did not produce a hepatotoxicity signal in the large RCTs; however, its safety and clearance in hepatic impairment have not been adequately studied, and elevated plasma levels are expected, so use is cautioned/generally avoided in hepatic dysfunction.
Unlike suppressive agents, raloxifene raises gonadotropins in men: in healthy men it increased LH (~29%), FSH (~21%), total/free testosterone (~16-20%), and estradiol (~21%) over 3 months. In postmenopausal women it does not meaningfully change gonadotropins. It does not directly suppress the hypothalamic-pituitary-gonadal axis.
Proven human teratogen: contraindicated in pregnancy and in women who may become pregnant; contraindicated in lactation. Antiestrogenic on breast; neutral on endometrium (no endometrial hyperplasia/cancer signal). In men it raises testosterone, estradiol, and PSA (~17% PSA rise in one small trial), the prostate implication of which is not established.
No well-established causal psychiatric adverse effect; insomnia and depression have been reported in labeling but are not clearly drug-attributable. Vasomotor symptoms (hot flashes) can secondarily disturb sleep. Human data specific to psychiatric effects are limited.
Minimal renal elimination (<0.2% unchanged in urine); no formal dosing adjustment is established, and it has not been adequately studied in significant renal impairment, so caution is warranted with reduced renal function.
Induces a prothrombotic/hypercoagulable state (the mechanism of the VTE and fatal-stroke risk). Modest reductions in fibrinogen have been reported. No clinically important effect on red cells, white cells, or platelet counts is characteristic.
Vasomotor flushing/sweating and leg/muscle cramps are the most common tolerability complaints. Peripheral edema is reported. Serious dermatologic reactions are rare and not a characteristic feature.
HPTA suppression & recovery
Suppression: Does not suppress the HPTA; in men it does the opposite, transiently raising LH, FSH, testosterone, and estradiol by blocking estrogen negative feedback (small RCTs). There are no controlled trials evaluating raloxifene for restoring HPTA function after anabolic-steroid use.
Any use for hormonal 'recovery' in men is off-label and unsupported by adequate human data. This monograph does not endorse or describe recovery protocols. HPTA assessment and any restoration strategy must be individualized and directed by an endocrinologist with appropriate laboratory monitoring; single-agent framing only, and this content never substitutes for that specialist evaluation.
Monitoring
Cadence: Baseline before initiation, an early check within the first few months, then at least every 6-12 months during continued use, and promptly whenever new symptoms arise; any thrombotic warning sign warrants immediate evaluation rather than waiting for scheduled labs.
- Leg pain, tenderness, warmth, or swelling (possible DVT): seek care urgently
- Sudden shortness of breath, chest pain, or coughing blood (possible pulmonary embolism): emergency
- Sudden weakness/numbness on one side, facial droop, trouble speaking, or vision loss (possible stroke): emergency
- Sudden vision changes or eye pain (possible retinal vein thrombosis)
- New or worsening severe leg cramps or persistent hot flashes affecting function
Contraindications
- Active or past history of venous thromboembolic events (deep vein thrombosis, pulmonary embolism, retinal vein thrombosis)
- Pregnancy and women of childbearing potential who may become pregnant (proven teratogen)
- Breastfeeding/lactation
- Prolonged immobilization (e.g., surgery, prolonged bed rest, long travel): discontinue at least 72 hours before and during immobilization due to thrombosis risk
- History of stroke or major stroke risk factors (RUTH showed increased fatal stroke)
- Hepatic impairment (inadequately studied; higher exposures expected): use cautioned/avoided
- Concurrent systemic estrogen therapy (not recommended)
- Concurrent cholestyramine (markedly reduces raloxifene absorption)
Interaction profile
- MajorWith an anabolic steroid: Blood / clotting
- MajorWith another SERM: Blood / clotting
- ModerateWith an aromatase inhibitor: Hormonal
- ContraindicatedWith DNP: Additive cardiovascular strain
Check a specific combination in the interaction checker.
Reducing harm & when to stop
- Do not use if you have any personal or family history of blood clots, DVT, PE, or stroke. This is the single most important safety filter given the trial-proven thrombotic and fatal-stroke risk.
- Stop the drug and seek emergency care immediately for leg swelling/pain, chest pain, shortness of breath, coughing blood, one-sided weakness, facial droop, speech difficulty, or sudden vision loss.
- Discontinue at least 72 hours before and during any prolonged immobilization (surgery, long bed rest, or long-haul travel) to reduce clot risk; discuss timing with your clinician.
- Never use in pregnancy or if pregnancy is possible. It is a proven teratogen.
- Use in men (for steroid-associated gynecomastia or hormonal recovery) is off-label and not supported by controlled trials; involve a physician/endocrinologist, get baseline and interval bloodwork (including LH, FSH, testosterone, estradiol, PSA, lipids, LFTs), and do not self-direct dosing.
- Avoid combining with systemic estrogens; separate from cholestyramine which blocks absorption.
- This is a single-agent monograph and reference information only; it is not a protocol, not dosing advice, and not a substitute for individualized medical care.
- Seek care for any new or worsening symptom rather than waiting for a scheduled lab; when in doubt about a possible clot or stroke, treat it as an emergency.
Citations (11)
Every clinical claim above is tied to a primary source. Overall evidence grade B — graded to the best available evidence for its core claims.
- 01
Raloxifene is a SERM, antiestrogenic on breast/endometrium and estrogen-agonist on bone, lipids, and coagulation; approved for postmenopausal osteoporosis and breast-cancer risk reduction.
- 02
In the RUTH RCT (n=10,101, median 5.6 y), raloxifene had no significant effect on coronary events (HR 0.95, 0.84-1.07), increased fatal stroke (HR 1.49, 1.00-2.24) and venous thromboembolism (HR 1.44, 1.06-1.95), reduced invasive breast cancer (HR 0.56) and vertebral fracture (HR 0.65).
RCTEffects of raloxifene on cardiovascular events and breast cancer in postmenopausal women (RUTH).DOI 10.1056/NEJMoa062462 ↗
- 03
In the MORE RCT, raloxifene reduced invasive breast cancer by 76% (RR 0.24) and increased venous thromboembolic disease (RR 3.1, 1.5-6.2) without increasing endometrial cancer.
- 04
Meta-analysis of 9 RCTs (24,523 postmenopausal women) found raloxifene increased odds of DVT or PE (OR 1.62, 1.25-2.09), DVT (OR 1.54) and PE (OR 1.91).
Meta-analysisEffect of raloxifene therapy on venous thromboembolism in postmenopausal women. A meta-analysis.PMID 18278183 ↗
- 05
CORE RCT extension confirmed sustained invasive breast-cancer risk reduction (8-yr HR 0.34) and persistent increased thromboembolism risk with raloxifene.
- 06
Pharmacokinetics: ~60% absorbed but ~2% absolute bioavailability due to extensive first-pass glucuronidation; large volume of distribution; elimination half-life ~32.5 hours; recommended dose 60 mg/day; hot flashes and leg cramps most common, VTE a serious adverse effect.
ReviewRaloxifene hydrochloride.PMID 11006795 ↗
- 07
In healthy elderly men, raloxifene 120 mg/day for 3 months increased LH (+29%), FSH (+21%), total testosterone (+20%), free testosterone (+16%), estradiol (+21%), and PSA (+17%).
RCTEffects of raloxifene on gonadotrophins, sex hormones, bone turnover and lipids in healthy elderly men.DOI 10.1530/eje.0.1500539 ↗
- 08
In healthy middle-aged eugonadal men, raloxifene increased serum testosterone and estradiol and decreased bone-turnover markers, with antiresorptive effect only in men with low baseline estradiol.
- 09
In men receiving GnRH-agonist androgen-deprivation therapy, raloxifene 60 mg/day significantly increased total hip bone mineral density and trended toward increased spine BMD over 12 months (n=48).
- 10
Long-term MORE/CORE data show continued raloxifene is required to preserve BMD and that breast-cancer benefit increases with duration up to 8 years.
- 11
Raloxifene has estrogenic effects on bone and lipids and antiestrogenic effects on breast/endometrium; VTE risk is increased and endometrium is not stimulated.
Meta-analysisDOI 10.2147/cia.s3344 ↗
Last reviewed 2026-07-06 · Verified against PubMed · Educational, not medical advice