Estradiol cypionate is estradiol, the main human estrogen, with a cyclopentylpropionate ester attached. The ester lets it sit in an oil depot after intramuscular injection and release slowly over one to several weeks. In the US it is sold as Pfizer’s Depo-Estradiol, a 5 mg/mL injection approved for menopausal hot flashes and for low estrogen caused by hypogonadism.
It was also half of a once-a-month injectable contraceptive (Lunelle in the US, Cyclofem elsewhere), and it is one of the two injectable estradiol esters used off-label in feminizing gender-affirming hormone therapy. The single most important fact: like every systemic estrogen in the US, it carries a boxed warning for endometrial cancer, cardiovascular disease, breast cancer and dementia, based largely on trials of other estrogens.
This page summarizes what the FDA label, pharmacokinetic studies and clinical trials report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Drug class | Estrogen; ester of 17β-estradiol |
| Brand / approval | Depo-Estradiol (Pharmacia & Upjohn, a Pfizer company), ANDA 085470 |
| Route | Intramuscular only (label) |
| Strength | 5 mg/mL in cottonseed oil, 5 mL vial |
| Labeled dose | 1–5 mg every 3–4 weeks (menopause); 1.5–2 mg monthly (hypogonadism) |
| Half-life | Not stated on the label; estradiol terminal half-life ≈8 days after a 5 mg dose (Lunelle study) |
| Estradiol content | About 69% of the ester’s weight (5 mg ester ≈ 3.4 mg estradiol) |
| US status | Prescription only; not a controlled substance |
| WADA status | Not on the 2026 Prohibited List (anti-estrogens are, under S4.2) |
What it is
Chemically, estradiol cypionate is estradiol 17-cyclopentanepropionate, formula C₂₆H₃₆O₃, molecular weight 396.6 g/mol (FDA label; PubChem). Estradiol on its own weighs 272.4 g/mol (PubChem). The ester therefore makes up about 31% of the weight, so a 5 mg injection delivers about 3.4 mg of estradiol.
The ester has no hormonal activity of its own. Esterases cleave it off and release ordinary estradiol, which then acts on the two estrogen receptors in the uterus, breast, bone, brain and other tissues. Estradiol also feeds back on the pituitary and lowers LH and FSH, the hormones that drive the ovaries and testes (FDA label). It is the same cyclopentylpropionate ester used in testosterone cypionate.
The labeled formulation contains, per mL:
| Ingredient | Amount |
|---|---|
| Estradiol cypionate | 5 mg |
| Chlorobutanol anhydrous (preservative, a chloral derivative) | 5.4 mg |
| Cottonseed oil (carrier) | 913 mg |
The label warns that chlorobutanol “may be habit forming.” Crystals can form if the vial is stored cold; the label says warming and shaking should redissolve them.
How it compares with other estradiol esters
The only head-to-head kinetic comparison gave women a single 5 mg intramuscular dose of one of three esters in arachis (peanut) oil (Oriowo et al., Contraception 1980). All 29 women were taking a combined oral contraceptive to suppress their own estrogen.
| Ester | n | Time to peak estradiol | Duration of raised estrogen levels |
|---|---|---|---|
| Benzoate | 10 | ≈2 days | 4–5 days |
| Valerate | 9 | ≈2 days | 7–8 days |
| Cypionate | 10 | ≈4 days | ≈11 days |
Cypionate gave significantly lower peaks than the other two esters and the longest duration. No woman in any group still had raised levels two weeks after the injection. The authors judged valerate the most predictable of the three. See the separate pages on estradiol valerate and topical estradiol.
Pharmacokinetics
The label gives no half-life. It states only that oily estradiol ester injections are “absorbed over several weeks,” and that estradiol is then handled like the body’s own estradiol (FDA label):
- it circulates mostly bound to SHBG and albumin;
- the liver converts it reversibly to estrone, and both to estriol, the main urinary metabolite;
- it is partly metabolized by the liver enzyme CYP3A4;
- it undergoes enterohepatic recirculation via sulfate and glucuronide conjugates.
The best numeric data come from studies of the 5 mg estradiol cypionate plus 25 mg medroxyprogesterone acetate (MPA) monthly contraceptive:
| Study | Design | Estradiol peak | Time to peak | Other findings |
|---|---|---|---|---|
| Rahimy et al. 1999 | 14 surgically sterile women, 3 monthly injections | 247 pg/mL (mean) | ≈2 days | Terminal half-life ≈8 days; back to baseline by ≈14 days; day-28 trough 40–55 pg/mL; no accumulation |
| Thurman et al. 2013 | 15 surgically sterile women, 3 monthly injections | 254 pg/mL (mean) | 3.3 days | No accumulation at steady state |
| Sierra-Ramírez et al. 2011 | 30 women randomized to subcutaneous or intramuscular injection | Similar by route | Similar by route | Peak, AUC and half-lives did not differ between routes |
The ≈8-day “half-life” in these studies reflects slow release from the injection site, not how fast the body clears estradiol itself. The subcutaneous finding comes from the combined contraceptive. The Depo-Estradiol label still specifies intramuscular use only.
The label’s clinical data fit the same timescale. In menopausal women, a single 5 mg dose produced an estrogenic effect on vaginal smears lasting about 3–4 weeks. Hot flashes eased within 1–5 days and stayed relieved for 1–8 weeks, about 5 weeks on average (FDA label).
Approved medical use
The Depo-Estradiol label covers two indications (FDA label):
| Indication | Labeled dose |
|---|---|
| Moderate to severe vasomotor symptoms (hot flashes) of menopause | 1–5 mg IM every 3–4 weeks, lowest dose that controls symptoms |
| Hypoestrogenism due to hypogonadism (women) | 1.5–2 mg IM monthly |
The label adds several conditions:
- A woman with a uterus should also take a progestin to reduce the risk of endometrial cancer. A woman without a uterus does not need one.
- Treatment should use the lowest effective dose for the shortest time. Attempts to taper or stop should be made every 3–6 months.
- Dosing should be guided by clinical response rather than by serum estradiol or FSH levels.
Drugs@FDA lists Depo-Estradiol under ANDA 085470, with one 5 mg/mL product still marketed (Drugs@FDA). It is the only finished estradiol cypionate product in the US; estradiol valerate, by contrast, is also available as generics (Misakian et al., JCEM 2025).
What the research shows
Menopausal symptoms
There are no modern randomized trials of estradiol cypionate for hot flashes. The evidence specific to this product is the label’s older comparative data, which found its effects qualitatively the same as other estradiol esters, with relief lasting about 5 weeks per 5 mg dose. Most of what is known about the risks and benefits of menopausal estrogen comes from trials of other products, mainly oral conjugated estrogens (see Side effects).
Monthly injectable contraception
Combined with 25 mg MPA, 5 mg estradiol cypionate was tested as a once-a-month contraceptive in large trials. The estrogen’s main job is to produce regular, predictable bleeding.
| Trial | Design and size | Pregnancy rate, first year | Notes |
|---|---|---|---|
| WHO Task Force, HRP112 (Contraception 1989) | Randomized, 12 countries, 2320 women per arm vs a norethisterone/valerate injectable | Not reported in this bleeding-pattern paper | About 70% of users had a regular bleeding pattern similar to untreated cycles |
| Lunelle Study Group (Kaunitz et al., Contraception 1999) | Open-label, nonrandomized; 782 injection users vs 321 pill users; 60 weeks | 0 pregnancies in 8008 cycles | 2.5% stopped because of irregular bleeding; 55.5% completed the trial |
| Sang et al. (Contraception 1995) | Phase III in Chinese women; 990 on Cyclofem | 0% | 19.1% discontinued for any reason at one year |
The FDA approved Lunelle (NDA 020874) on October 5, 2000 (Drugs@FDA). It was recalled in 2002 (Cockey, AWHONN Lifelines 2002) and is now listed as discontinued.
Gender-affirming hormone therapy (off-label)
Injectable estradiol esters are widely used in feminizing hormone therapy, and the Endocrine Society guideline lists them as options (Hembree et al., JCEM 2017). This use is not on the Depo-Estradiol label. A 2024 scoping review summarized the guideline starting doses as 2–10 mg weekly or 5–30 mg every 2 weeks of cypionate or valerate. It concluded that these doses are probably too high and suggested starting at 5 mg weekly or less (Rothman et al., Endocr Pract 2024).
The largest dataset is a retrospective study of 562 adults at six US centers (Misakian et al., JCEM 2025):
| Finding | Result |
|---|---|
| Ester used | 92% valerate, 8% cypionate (45 patients) |
| Weekly injectors in the guideline range of 100–200 pg/mL | 27.5% (131 patients) |
| Median weekly dose in that group | 4.0 mg (IQR 3.0–5.0 mg) |
| Patients above 200 pg/mL | The majority |
| Cypionate vs valerate, IM vs SC | No significant differences in estradiol levels |
Because only 45 patients used cypionate, the study had limited power to detect differences between esters. A companion analysis of 357 weekly injectors found that injectable estradiol alone suppressed testosterone below 50 ng/dL in 82.6% of patients, similar to estradiol plus an antiandrogen (Misakian et al., Endocr Pract 2025).
Side effects and risks
Boxed warning
The label’s boxed warning covers three points (FDA label):
- Estrogens increase the risk of endometrial cancer. Persistent or recurring abnormal vaginal bleeding needs investigation.
- Estrogens with or without progestins should not be used to prevent cardiovascular disease.
- Estrogen plus progestin raised the risks of heart attack, stroke, invasive breast cancer, blood clots and, in women 65 and older, probable dementia.
These numbers come from the Women’s Health Initiative (WHI), which tested oral conjugated estrogens 0.625 mg plus MPA 2.5 mg daily, not estradiol cypionate. The label states that, without comparable data, the risks of other estrogens “should be assumed to be similar.” Selected results from the WHI estrogen-plus-progestin arm (16,608 women aged 50–79, 5.2 years):
| Event | Relative risk (95% CI) | Per 10,000 woman-years, placebo vs hormone |
|---|---|---|
| Coronary heart disease events | 1.29 (1.02–1.63) | 30 vs 37 |
| Stroke | 1.41 (1.07–1.85) | 21 vs 29 |
| Pulmonary embolism | 2.13 (1.39–3.25) | 8 vs 16 |
| Deep vein thrombosis | 2.07 (1.49–2.87) | 13 vs 26 |
| Invasive breast cancer | 1.26 (1.00–1.59) | 30 vs 38 |
| Hip fracture | 0.66 (0.45–0.98) | 15 vs 10 |
| Colorectal cancer | 0.63 (0.43–0.92) | 16 vs 10 |
In the WHI memory substudy, probable dementia occurred in 45 vs 22 per 10,000 woman-years (relative risk 2.05, 95% CI 1.21–3.48) in women 65 and older.
Cancer
- Endometrial cancer: in women with a uterus, unopposed estrogen raised the risk 2- to 12-fold, and 15- to 24-fold with use for 5–10 years or more. The excess risk persisted for at least 8–15 years after stopping. Adding a progestin lowers the rate of endometrial hyperplasia.
- Breast cancer: in the WHI, estrogen plus progestin raised invasive breast cancer risk (41 vs 33 per 10,000 woman-years), while conjugated estrogens alone did not (RR 0.80). Observational studies found a smaller but still raised risk with estrogen alone after several years of use.
- Ovarian cancer: the WHI estrogen-plus-progestin result was not statistically significant (RR 1.58, 95% CI 0.77–3.24).
Blood clots and cardiovascular risk
The label advises stopping estrogen at once if a heart attack, stroke or blood clot occurs or is suspected. If feasible, it should be stopped 4–6 weeks before surgery linked to clot risk, or during prolonged immobilization.
In men, the label notes that large estrogen doses (5 mg conjugated estrogens per day, as once used for prostate cancer) increased nonfatal heart attacks, pulmonary embolism and thrombophlebitis in a large prospective trial.
Other risks on the label
- Gallbladder disease requiring surgery, increased 2- to 4-fold in postmenopausal women.
- Pancreatitis in people with pre-existing high triglycerides.
- Raised blood pressure (rare, idiosyncratic) and fluid retention.
- Higher thyroid-binding globulin, so people on thyroid hormone may need a higher dose.
- Retinal vascular thrombosis; worsening of hereditary angioedema, asthma, epilepsy, migraine, lupus and porphyria.
- Common effects: headache, breast pain, irregular bleeding or spotting, abdominal cramps and bloating, nausea.
Drug interactions
Because estradiol is partly metabolized by CYP3A4 (FDA label):
- Inducers such as St. John’s wort, phenobarbital, carbamazepine and rifampin may lower estrogen levels and weaken its effect.
- Inhibitors such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may raise estrogen levels and side effects.
Who should not use it
The label lists these contraindications:
- undiagnosed abnormal genital bleeding;
- known or suspected breast cancer or other estrogen-dependent cancer;
- active or past deep vein thrombosis or pulmonary embolism;
- stroke or heart attack, active or within about the past year;
- liver dysfunction or disease;
- known or suspected pregnancy;
- hypersensitivity to any ingredient.
Monitoring
| What | Source and timing |
|---|---|
| Need for continued treatment | Reassess every 3–6 months (label) |
| Breast exam and mammogram | Yearly exam; mammography by age and risk (label) |
| Blood pressure | At regular intervals (label) |
| Endometrial sampling | For persistent or recurring abnormal bleeding (label) |
| Estradiol and testosterone in gender-affirming therapy | Guideline ranges of 100–200 pg/mL estradiol and testosterone under 50 ng/dL; levels should be read against the day since the last injection (Misakian et al., JCEM 2025) |
Regulatory status
- US: prescription-only estrogen. Estradiol cypionate is not among the anabolic steroids named in Schedule III (21 CFR 1308.13).
- Sport: estradiol is not on the WADA 2026 Prohibited List. The list does prohibit anti-estrogenic substances, including aromatase inhibitors and SERMs, under S4.2.
Key takeaways
- Estradiol on a slow-release ester. About 69% of the labeled milligrams is estradiol. The ester only sets how fast it leaves the oil depot.
- The slowest of the common esters. A 5 mg dose peaks in about 2–4 days and raises levels for about 11 days, longer and with a lower peak than valerate or benzoate.
- Narrow labeled use. The label covers menopausal hot flashes (1–5 mg every 3–4 weeks) and hypogonadism in women (1.5–2 mg monthly). Gender-affirming use is off-label.
- Class-wide boxed warning. Risks of endometrial cancer, clots, stroke, breast cancer and dementia are extrapolated from trials of other estrogens. Women with a uterus need a progestin.
- Doses in practice are often too high. In the largest US study of injectable estradiol for gender-affirming therapy, most patients had levels above 200 pg/mL.
Sources
- Pharmacia & Upjohn Company LLC (Pfizer). Depo-Estradiol (estradiol cypionate injection, USP), prescribing information, revised February 2024. DailyMed; Drugs@FDA, ANDA 085470.
- National Center for Biotechnology Information. Estradiol cypionate, PubChem CID 9403; Estradiol, PubChem CID 5757. PubChem; PubChem.
- Oriowo MA, Landgren BM, Stenström B, Diczfalusy E. A comparison of the pharmacokinetic properties of three estradiol esters. Contraception. 1980;21(4):415–424. PubMed.
- Rahimy MH, Ryan KK, Hopkins NK. Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): steady-state pharmacokinetics of MPA and E2 in surgically sterile women. Contraception. 1999;60(4):209–214. PubMed.
- Thurman A, Kimble T, Hall P, et al. Medroxyprogesterone acetate and estradiol cypionate injectable suspension (Cyclofem) monthly contraceptive injection: steady-state pharmacokinetics. Contraception. 2013;87(6):738–743. PubMed.
- Sierra-Ramírez JA, Lara-Ricalde R, Lujan M, et al. Comparative pharmacokinetics and pharmacodynamics after subcutaneous and intramuscular administration of medroxyprogesterone acetate (25 mg) and estradiol cypionate (5 mg). Contraception. 2011;84(6):565–570. PubMed.
- World Health Organization Task Force on Long-Acting Systemic Agents for Fertility Regulation. A multicentred phase III comparative study of two hormonal contraceptive preparations given once-a-month by intramuscular injection. II. The comparison of bleeding patterns. Contraception. 1989;40(5):531–551. PubMed.
- Kaunitz AM, Garceau RJ, Cromie MA. Comparative safety, efficacy, and cycle control of Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension) and Ortho-Novum 7/7/7 oral contraceptive (norethindrone/ethinyl estradiol triphasic). Lunelle Study Group. Contraception. 1999;60(4):179–187. PubMed.
- Sang GW, Shao QX, Ge RS, et al. A multicentred phase III comparative clinical trial of Mesigyna, Cyclofem and Injectable No. 1 given monthly by intramuscular injection to Chinese women. I. Contraceptive efficacy and sid effects. Contraception. 1995;51(3):167–183. PubMed.
- US Food and Drug Administration. Lunelle (medroxyprogesterone acetate and estradiol cypionate), NDA 020874. Drugs@FDA.
- Cockey CD. Injectable Lunelle contraceptive being recalled. AWHONN Lifelines. 2002;6(6):499. PubMed.
- Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine treatment of gender-dysphoric/gender-incongruent persons: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(11):3869–3903. PubMed.
- Rothman MS, Ariel D, Kelley C, et al. The use of injectable estradiol in transgender and gender diverse adults: a scoping review of dose and serum estradiol levels. Endocr Pract. 2024;30(9):870–878. PubMed.
- Misakian AL, Kelley CE, Sullivan EA, et al. Injectable estradiol use in transgender and gender-diverse individuals throughout the United States. J Clin Endocrinol Metab. 2025;110(9):e2898–e2907. PubMed.
- Misakian AL, Ariel D, Sullivan EA, et al. Injectable estradiol monotherapy effectively suppresses testosterone in gender-affirming hormone therapy. Endocr Pract. 2025;31(11):1462–1469. PubMed.
- Electronic Code of Federal Regulations. 21 CFR 1308.13, Schedule III. eCFR.
- World Anti-Doping Agency. The 2026 Prohibited List. WADA 2026 Prohibited List.