Leuprolide (also called leuprorelin) is a synthetic version of gonadotropin-releasing hormone (GnRH), the hypothalamic signal that tells the pituitary to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). It is sold as Lupron Depot, Eligard and several generics, and is used to lower sex hormones in advanced prostate cancer, endometriosis, uterine fibroids and central precocious puberty.
The single most important fact about leuprolide is that it works in two phases. For the first one to two weeks it stimulates the reproductive axis and testosterone rises, often by about 50%. With continuous exposure the pituitary then stops responding, and testosterone falls to castrate levels within about four weeks. In other words, leuprolide is a drug that shuts down natural testosterone production. It is not a testosterone booster.
This page summarizes what the FDA labels, clinical trials and regulators report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Drug class | GnRH agonist (synthetic nonapeptide analog of GnRH) |
| Formula / weight | C₅₉H₈₄N₁₆O₁₂; 1209.4 g/mol (base). Sold as the acetate salt |
| First US approval | Lupron daily injection, April 9, 1985 (brand now discontinued); Lupron Depot, January 26, 1989 |
| Main brands | Lupron Depot, Lupron Depot-PED, Eligard; generic daily injection kits |
| Route | Intramuscular depot (Lupron Depot), subcutaneous depot (Eligard), daily subcutaneous injection |
| Labeled doses (prostate cancer) | 7.5 mg monthly, 22.5 mg every 3 months, 30 mg every 4 months, 45 mg every 6 months; or 1 mg daily subcutaneously |
| Half-life | About 3 h after an IV dose; depot forms release the drug over 1–6 months |
| Key mechanism fact | Brief testosterone flare, then suppression to castrate levels within 2–4 weeks |
| US status | Prescription-only; not listed in DEA Schedule III |
| WADA status | Prohibited at all times in males (S2.2.1, “leuprorelin”) |
What it is
Natural GnRH is a 10-amino-acid peptide. Leuprolide is a 9-amino-acid analog of it, described in the labels as having “greater potency than the natural hormone” (Lupron Depot label). Its chemical name shows the two changes from the native hormone: a D-leucine in place of the natural glycine at position 6, and an N-ethyl amide on the final proline in place of the natural C-terminal glycine-amide. PubChem lists the free base as C₅₉H₈₄N₁₆O₁₂, 1209.4 g/mol (PubChem CID 657181), and the acetate salt as C₆₁H₈₈N₁₆O₁₄, 1269.4 g/mol (PubChem CID 657180).
The native hormone is covered on the gonadorelin page. The key difference is timing. Natural GnRH arrives in pulses, and pulses keep the pituitary responsive. Leuprolide is given as a steady exposure, and steady exposure desensitizes the pituitary.
The labels describe the effect in humans (Lupron Depot label):
- Flare phase. LH and FSH rise at first, so testosterone and dihydrotestosterone (DHT) rise in men, and estrone and estradiol rise in premenopausal women.
- Suppression phase. With continued dosing LH and FSH fall. Testosterone drops to castrate levels in men, and estrogens drop to postmenopausal levels in women, within two to four weeks.
- Duration. Castrate testosterone has been maintained for more than five years in prostate cancer patients.
Leuprolide is not active by mouth, so every product is an injection.
Products
| Product | Route | Strengths and schedule | Labeled use |
|---|---|---|---|
| Leuprolide acetate injection (generic; brand Lupron discontinued) | Subcutaneous, daily | 5 mg/mL vial; 1 mg once daily | Palliative treatment of advanced prostate cancer |
| Lupron Depot | Intramuscular | 7.5 mg (4 weeks), 22.5 mg (12 weeks), 30 mg (16 weeks), 45 mg (24 weeks) | Advanced prostate cancer |
| Lupron Depot | Intramuscular | 3.75 mg (monthly), 11.25 mg (every 3 months) | Endometriosis; anemia from fibroids before surgery |
| Lupron Depot-PED | Intramuscular | 7.5, 11.25 or 15 mg monthly; 11.25 or 30 mg every 3 months; 45 mg every 6 months | Central precocious puberty |
| Eligard | Subcutaneous | 7.5 mg monthly, 22.5 mg every 3 months, 30 mg every 4 months, 45 mg every 6 months | Advanced prostate cancer |
Sources for the table: the leuprolide acetate injection label, the Lupron Depot labels for prostate cancer, 3.75 mg and 11.25 mg, the Lupron Depot-PED label and the Eligard label. DailyMed also lists other leuprolide products, including Camcevi, Fensolvi and Vabrinty (DailyMed search).
The labels stress that depot strengths are not interchangeable. Because each formulation releases the drug differently, doses are “not additive,” and a fraction of a long-acting depot does not equal a shorter one.
Pharmacokinetics
Leuprolide itself is cleared quickly. In healthy men given a 1 mg IV bolus, mean clearance was 7.6 L/h and the terminal half-life was about 3 hours (leuprolide acetate injection label). Subcutaneous bioavailability is comparable to IV. Volume of distribution is 27 L, and 43–49% is bound to plasma proteins.
Depot products get around the short half-life by packing the peptide into slowly dissolving polymer microspheres. Each shows an initial burst, then a low, steady level for the rest of the dosing interval (Lupron Depot label):
| Lupron Depot dose | Early peak | Level at end of interval |
|---|---|---|
| 7.5 mg (1-month) | 20 ng/mL at 4 h | 0.36 ng/mL at 4 weeks |
| 22.5 mg (3-month) | 48.9 ng/mL at 4 h | 0.67 ng/mL at 12 weeks |
| 30 mg (4-month) | 59.3 ng/mL at 4 h | 0.30 ng/mL at 16 weeks |
| 45 mg (6-month) | 6.7 ng/mL at 2 h | 0.07 ng/mL at 24 weeks |
The label notes that the assays used for the shorter depots could not separate intact leuprolide from an inactive metabolite. In animals, leuprolide is broken down into smaller inactive peptide fragments. Less than 5% of a 3.75 mg depot dose was recovered in urine as parent drug or its main metabolite.
Approved medical use
| Indication | Labeled regimen | Notes |
|---|---|---|
| Advanced prostate cancer | Lupron Depot or Eligard on the schedules above; or 1 mg/day subcutaneously | Treatment usually continues after the cancer becomes castration-resistant |
| Endometriosis | Lupron Depot 3.75 mg monthly for up to 6 injections, or 11.25 mg every 3 months for up to 2 | May be combined with norethindrone acetate 5 mg/day (“add-back”); total therapy with add-back not to exceed 12 months |
| Anemia from uterine fibroids, before surgery | Lupron Depot 3.75 mg monthly for up to 3 months, with iron | Add-back therapy is not indicated for this use |
| Central precocious puberty | Lupron Depot-PED; monthly starting dose by weight (7.5 mg up to 25 kg, 11.25 mg over 25 to 37.5 kg, 15 mg over 37.5 kg), or 3- or 6-month forms | Response checked with LH or sex steroid levels; height and bone age every 6–12 months |
Sources: Lupron Depot labels for prostate cancer, 3.75 mg and 11.25 mg; Lupron Depot-PED label; Eligard label; leuprolide acetate injection label.
For the antiandrogen used alongside GnRH agonists in prostate cancer, see bicalutamide.
What the research shows
Prostate cancer: leuprolide vs estrogen therapy
Before GnRH agonists, medical castration relied on the estrogen diethylstilbestrol (DES). In a randomized trial, 199 men with metastatic prostate cancer received either leuprolide 1 mg/day subcutaneously (n = 98) or DES 3 mg/day by mouth (n = 101) (Leuprolide Study Group, NEJM 1984):
| Outcome | Leuprolide | DES |
|---|---|---|
| Objective response (complete, partial or stable) | 86% | 85% |
| Survival at 1 year | 87% | 78% (P = 0.17) |
| Testosterone and DHT suppression | Comparable | Comparable |
| Painful gynecomastia, nausea/vomiting, edema | Less frequent | More frequent |
| Hot flashes | More frequent | Less frequent |
The authors concluded leuprolide was therapeutically equivalent to DES with fewer side effects.
How reliably the depots suppress testosterone
The label trials measured how often testosterone reached and stayed in the castrate range, 50 ng/dL or less (Lupron Depot label):
| Formulation | Patients | Result |
|---|---|---|
| 7.5 mg monthly | 56, open-label | Castrate within 30 days in 94% (51/54); all 54 within 66 days |
| 22.5 mg every 3 months | 92 evaluated | Castrate within 30 days in 95% (87/92) |
| 30 mg every 4 months | 49, open-label | Castrate within 30 days in 94%; all within 43 days |
| 45 mg every 6 months | 151, open-label, 48 weeks | Castrate from week 4 through week 48 in 93.4% (95% CI 89.2–97.6%) |
In the 6-month study, mean testosterone rose from 435 ng/dL to 608 ng/dL in the first week (the flare), then fell to 16 ng/dL by week 4.
Effects on muscle and fat
Because leuprolide removes testosterone, it produces the reverse of what anabolic steroids do. In 40 men with non-metastatic prostate cancer given the 22.5 mg 3-month depot for 48 weeks (32 evaluable), testosterone fell by 96.3% (Smith et al., JCEM 2002):
| Measure at 48 weeks | Change |
|---|---|
| Body weight | +2.4% |
| Percent body fat | +9.4% (relative change) |
| Percent lean body mass | −2.7% |
| Subcutaneous abdominal fat area | +11.1% |
| Intra-abdominal fat area | No significant change |
| Paraspinal muscle area | −3.2% |
The same pattern appears in young, healthy men. In a small study, six men aged about 23 received two Lupron injections three weeks apart (Mauras et al., JCEM 1998). After 10 weeks, testosterone had fallen from 535 to 31 ng/dL. Fat-free mass fell from 56.5 to 54.4 kg, body fat rose from 19.2% to 22.2%, whole-body protein synthesis fell by 13% and leg strength decreased.
Leuprolide as a research tool in testosterone trials
Because it reliably switches off the body’s own testosterone, leuprolide is used in dose-response studies so that researchers control exactly how much testosterone each participant has. In the 5α-Reductase Trial, 139 healthy men aged 18–50 received monthly Lupron Depot 7.5 mg plus testosterone enanthate at 50, 125, 300 or 600 mg/week for 20 weeks, with or without dutasteride (Bhasin et al., JAMA 2012). In the placebo groups, fat-free mass changed by 0.8 kg (95% CI −0.1 to 1.7) at 50 mg/week and by 8.1 kg (95% CI 6.7–9.5) at 600 mg/week. Those effects come from the testosterone dose. Leuprolide’s role was to remove natural production as a variable.
Endometriosis and fibroids
In the label trials, Lupron Depot 3.75 mg monthly stopped menstruation in 74% of women after one month and 98% after two (Lupron Depot 3.75 mg label). Normal cycles returned in 95% by the third month after stopping.
In women with fibroids, three controlled trials found mean uterine volume fell by 41% and fibroid volume by 37%. After stopping, uterine size returned to pretreatment levels in a mean of 8.3 months.
Central precocious puberty
In the pivotal Lupron Depot-PED trial, 55 children (49 girls, 6 boys, mean age 7) were treated with the monthly depot for a mean of 4 years (Lupron Depot-PED label). Peak stimulated LH fell below 1.75 mIU/mL in 96% by month 1. Six months after treatment ended, mean peak stimulated LH had recovered to 20.6 mIU/mL.
Side effects and risks
Leuprolide has no boxed warning. Most of its side effects are the expected results of very low testosterone or estrogen.
Common effects
| Lupron Depot trial (prostate cancer) | Most frequent reactions |
|---|---|
| 7.5 mg monthly (n = 56) | Hot flashes/sweats 57.1%, general pain 23.2%, GI disorders 14.3%, edema 14.3% |
| 22.5 mg every 3 months (n = 94) | Hot flashes/sweats 58.5%, general pain 26.6%, testicular atrophy 20.2%, injection site reaction 13.8% |
| 45 mg every 6 months (n = 151) | Hot flush 58.9%, upper respiratory infection 21.2%, injection site pain 19.2%, fatigue 13.2% |
Source: Lupron Depot label. Decreased libido, erectile dysfunction and breast enlargement are also listed. In women with endometriosis, the most common reactions (over 10%) were hot flashes, headache, vaginitis, depression or emotional lability, weight change, nausea, decreased libido and dizziness (Lupron Depot 3.75 mg label).
Tumor flare
The early testosterone rise (about 50% above baseline) can briefly worsen prostate cancer. The label lists bone pain, nerve symptoms, blood in the urine and urinary blockage. In men with spinal metastases, spinal cord compression can lead to paralysis.
Bone loss
Removing sex hormones thins bone. In a 48-week randomized trial of 47 men with advanced or recurrent prostate cancer and no bone metastases, those on leuprolide alone lost 3.3% of lumbar spine bone mineral density (BMD) and 8.5% of trabecular spine BMD (Smith et al., NEJM 2001). Men who also received pamidronate (a bone-protecting drug) had no significant loss.
In women, the Lupron Depot 3.75 mg label reports lumbar spine BMD changes from a controlled trial (label):
| Time point | Leuprolide alone | Leuprolide + norethindrone acetate |
|---|---|---|
| Week 24 | −3.2% (95% CI −3.8 to −2.6) | −0.3% (95% CI −0.8 to 0.3) |
| Week 52 | −6.3% (95% CI −7.1 to −5.4) | −1.0% (95% CI −1.9 to −0.1) |
| 12 months after stopping | −2.2% (95% CI −3.3 to −1.1) | −0.7% (95% CI −2.1 to 0.6) |
The label warns that some bone loss may not be reversible. This is why treatment in women is time-limited.
Diabetes and heart disease
The label warns of hyperglycemia, diabetes, high lipids and fatty liver disease, and of reported increases in heart attack, sudden cardiac death and stroke in men. In a Medicare cohort of 73,196 men with localized prostate cancer, GnRH agonist use was linked to more diabetes (adjusted HR 1.44), coronary heart disease (HR 1.16), heart attack (HR 1.11) and sudden cardiac death (HR 1.16) (Keating et al., JCO 2006). This was an observational study, so it shows association rather than proof of cause. The label also notes that androgen deprivation may prolong the QT interval, a measure of the heart’s electrical recovery.
Other warnings
- Convulsions, reported with and without a prior seizure history.
- Severe skin reactions, including Stevens-Johnson syndrome and DRESS.
- Mood changes, including depression and rare reports of suicidal thoughts.
- Pituitary apoplexy (sudden bleeding or infarction of the pituitary), rare; a pituitary adenoma was diagnosed in most cases, and most occurred within 2 weeks of the first dose.
- Pregnancy. Leuprolide may cause fetal harm and is contraindicated in pregnancy for the gynecologic products. In rabbits, a single depot dose caused major fetal malformations.
Sources: Lupron Depot label; Lupron Depot 3.75 mg label.
Who should not use it
- Anyone with hypersensitivity to GnRH, GnRH agonists or the product’s excipients (all products).
- Pregnant women, and women with undiagnosed abnormal uterine bleeding (Lupron Depot 3.75 mg).
Fertility and recovery after stopping
Leuprolide suppresses the whole pituitary-gonadal axis, and the label states it may impair fertility in both sexes. In rats, the reproductive organ atrophy it caused reversed after treatment stopped. The label says normal function “is usually restored within three months” of stopping. Tests of pituitary and gonadal function can be affected for up to three months after the last dose.
Recovery in older men after long treatment can be much slower. In a retrospective study of 307 men who stopped androgen deprivation therapy for prostate cancer (mean duration 17 months), testosterone 24 months after stopping was as follows (Nascimento et al., J Sex Med 2019):
- 8% were still in the castrate range;
- 76% had returned to over 300 ng/dL;
- 51% had returned to their own baseline.
Age over 65 and treatment longer than 6 months were linked to slower recovery. That study covered androgen deprivation in general, not leuprolide alone.
Legal status and use outside medicine
In the US, leuprolide is a prescription drug. It is not one of the anabolic steroids listed in DEA Schedule III (21 CFR 1308.13).
The WADA 2026 Prohibited List bans “leuprorelin” at all times in male athletes, under S2.2.1 (testosterone-stimulating peptides in males), together with gonadorelin, other GnRH agonists, hCG, LH and kisspeptin analogs (WADA 2026 Prohibited List).
Key takeaways
- A testosterone shut-off, not a booster. After a brief flare, continuous leuprolide drives testosterone to castrate levels within about 2–4 weeks.
- Approved for hormone-dependent disease. Labeled uses are advanced prostate cancer, endometriosis, anemia from fibroids before surgery, and central precocious puberty.
- Depots set the schedule. The peptide’s own half-life is about 3 hours, but depot forms release it over 1–6 months, and strengths are not interchangeable.
- Expect the effects of low sex hormones. Hot flashes affected about half or more of men in the prostate cancer label trials, and fat gain, lean mass loss and bone loss are documented.
- Metabolic and cardiac risks are labeled. The labels warn about diabetes, lipid changes and cardiovascular events in men on GnRH agonists.
- Recovery is not guaranteed to be quick. Function usually returns within months, but some older men on long treatment stay low for years.
Sources
- AbbVie. Lupron Depot (leuprolide acetate for depot suspension) 7.5 mg, 22.5 mg, 30 mg, 45 mg, prescribing information. DailyMed.
- AbbVie. Lupron Depot 3.75 mg (leuprolide acetate for depot suspension), prescribing information. DailyMed.
- AbbVie. Lupron Depot 11.25 mg (leuprolide acetate for depot suspension), prescribing information. DailyMed.
- AbbVie. Lupron Depot-PED (leuprolide acetate for depot suspension), prescribing information. DailyMed.
- Tolmar. Eligard (leuprolide acetate) for injectable suspension, prescribing information. DailyMed.
- Endo USA. Leuprolide acetate injection, prescribing information. DailyMed.
- National Library of Medicine. DailyMed search results for leuprolide. DailyMed.
- US Food and Drug Administration. Drugs@FDA: Lupron, NDA 019010 (approved April 9, 1985) and Lupron Depot, NDA 019732 (approved January 26, 1989). FDA, NDA 019010; FDA, NDA 019732.
- National Center for Biotechnology Information. Leuprolide, PubChem CID 657181; leuprolide acetate, PubChem CID 657180. PubChem; PubChem.
- Leuprolide Study Group. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Engl J Med. 1984;311(20):1281–1286. PubMed.
- Smith MR, Finkelstein JS, McGovern FJ, et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab. 2002;87(2):599–603. PubMed.
- Mauras N, Hayes V, Welch S, et al. Testosterone deficiency in young men: marked alterations in whole body protein kinetics, strength, and adiposity. J Clin Endocrinol Metab. 1998;83(6):1886–1892. PubMed.
- Bhasin S, Travison TG, Storer TW, et al. Effect of testosterone supplementation with and without a dual 5α-reductase inhibitor on fat-free mass in men with suppressed testosterone production: a randomized controlled trial. JAMA. 2012;307(9):931–939. PubMed.
- Smith MR, McGovern FJ, Zietman AL, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med. 2001;345(13):948–955. PubMed.
- Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24(27):4448–4456. PubMed.
- Nascimento B, Miranda EP, Jenkins LC, et al. Testosterone recovery profiles after cessation of androgen deprivation therapy for prostate cancer. J Sex Med. 2019;16(6):872–879. PubMed.
- World Anti-Doping Agency. 2026 Prohibited List. WADA 2026 Prohibited List.
- US Code of Federal Regulations. 21 CFR 1308.13, Schedule III. 21 CFR 1308.13.