Leuprolide
GnRH altered at two positions so that, given continuously, it first stimulates the pituitary and then shuts testosterone and oestrogen down. Approved in the US since 1985, it now comes as anything from a daily pen to a six-month depot.
Leuprolide (leuprorelin) switches off the reproductive hormones on purpose, for advanced prostate cancer, endometriosis, fibroids and early puberty. Its labels describe a flare first, with testosterone about 50% above baseline, then suppression that reverses when treatment stops, though slowly after long depots. Bone loss, hot flashes and, in men, metabolic and heart risks are the costs.
What is it?
Leuprolide, leuprorelin outside the US, is GnRH with two changes: D-leucine replaces the glycine at position 6, and an ethylamide replaces the tenth residue, leaving nine amino acids. The result is a GnRH superagonist. Given in pulses, GnRH switches the reproductive axis on; given continuously, as leuprolide is, the pituitary is first stimulated and then stops responding. The prescribing information describes it plainly as an inhibitor of gonadotropin secretion: after an initial stimulation, continuous administration suppresses ovarian and testicular steroid production, and the effect reverses when treatment stops.
It has been a US prescription drug since April 9, 1985, when the daily Lupron injection was approved (it is now discontinued). Lupron Depot followed on January 26, 1989 and today comes as 7.5 mg monthly, 22.5 mg three-monthly, 30 mg four-monthly and 45 mg six-monthly injections for advanced prostate cancer, and as 3.75 mg and 11.25 mg depots for endometriosis and fibroids. Lupron Depot-Ped (1993), Fensolvi (2020) and, from August 26, 2026, Vobrig, a daily prefilled pen, treat central precocious puberty; Eligard (2002) is a gel that forms a depot under the skin, and Camcevi (2021) is another depot. Generic leuprolide injections are approved too.
Prostate cancer is its largest use. The label warns that testosterone may rise about 50% above baseline when treatment starts, which can briefly worsen bone pain or urinary symptoms and, rarely, compress the spinal cord. Then it falls: with the four-month 30 mg depot, testosterone reached castrate levels at a median of 22 days and within four weeks in 96% of 49 men, and the Eligard gel took 98% of men on the monthly form below 20 ng/dL. Three months of leuprolide with flutamide before prostatectomy cut positive surgical margins from 48% to 18% in a randomised trial. It is also the comparator newer drugs are measured against: in HERO, oral relugolix kept testosterone suppressed in 97% of men against 89% on leuprolide, and in EMBARK, adding enzalutamide to leuprolide improved metastasis-free survival over leuprolide alone.
In women, suppressing oestrogen treats endometriosis and fibroids but thins bone, and the labels are built around that trade-off. In a one-year trial of 201 women with endometriosis, monthly 3.75 mg improved pain in every group by week 8; without add-back hormones, bone density fell 6.3%, while norethindrone add-back preserved it. The labels therefore limit an initial course to six injections, allow retreatment only with add-back, and cap total therapy with add-back at 12 months. Against danazol it caused more bone loss, while danazol lowered HDL cholesterol. For fibroids before surgery it controlled bleeding in 89% of women, a benchmark that daily ulipristal matched with far fewer hot flashes (about 10% against 40%). In premenopausal breast cancer it is paired with an aromatase inhibitor, and a three-monthly 22.5 mg injection suppressed the ovaries as reliably as monthly dosing.
In children with central precocious puberty it pauses puberty until the right age. A 2026 study of 132 girls found that an LH level taken 40 minutes after the first depot injection identified gonadotropin activation about as well as the standard GnRH stimulation test, with a cut-off of 5.4 IU/L giving 86% sensitivity and 90% specificity, which matters where the GnRH test is unavailable. It is also used off-label to suppress puberty in transgender and gender-diverse youth: in a 2023 chart review of 48 adolescents, clinical suppression occurred in all, with biochemical suppression in 90% on Eligard and 69% on intramuscular Lupron. The newest pediatric label (Vobrig) warns of a rise in pubertal signs, including vaginal bleeding, in the first two to four weeks, and of psychiatric events such as emotional lability, irritability and aggression.
The adult labels list the costs of androgen deprivation: metabolic changes including hyperglycaemia, diabetes and fatty liver, reports of heart attack, sudden cardiac death and stroke in men, QT prolongation, convulsions and severe skin reactions; the women's labels add bone loss, possible harm to a pregnancy, and hypersensitivity including anaphylaxis. Recovery can be slow. After 48 weeks of three-monthly injections, only 3.2% of men had testosterone back above 280 ng/dL 90 days after stopping, against 54% of men stopping oral relugolix, and a case report describes interstitial pneumonitis beginning three months after a first depot dose.
The depot itself is the technology. The one-month Lupron Depot is leuprolide in poly(lactic-co-glycolic acid) microspheres; a 2018 reverse-engineering study found about 23% of the dose released in an initial burst and the rest at a steady rate, and noted that no generic of it had been approved despite the patent's expiry. Leuprolide is not a wellness peptide and has no place outside a prescriber's care; in sport, WADA's Prohibited List names leuprorelin among the releasing factors prohibited for males.
Mechanism of Action
Leuprolide binds the same pituitary receptor as GnRH but, delivered continuously from a depot, turns its message from 'release LH and FSH' into silence. Everything it is used for follows from that switch, and so do its side effects.
First, a flare
At the start gonadotropins and sex steroids rise: testosterone about 50% above baseline in men, and in children signs of puberty, including vaginal bleeding, can increase during the first two to four weeks (labels).
Then shutdown
Continuous exposure suppresses testicular and ovarian steroid production; testosterone reached castrate levels by about three weeks with depot dosing, and oestrogen falls enough to thin bone within a year.
Delivered by depot
Free leuprolide has a terminal half-life of about 3 hours after an intravenous dose (label), so every long-term form is a depot: microspheres releasing it over 1 to 6 months, an in-situ gel, or a daily pen.
Reversible, slowly
The label calls suppression reversible, but after 48 weeks of three-monthly depots only 3.2% of men had recovered testosterone above 280 ng/dL 90 days later.
Published Research
PubMed returns about 4,200 records for leuprolide or leuprorelin. Our evidence set holds 49 papers; 30 name it in their titles and have an abstract, and 17 are carded below: 14 studies in people, 2 reviews and 1 laboratory study. Leuprolide is an approved drug in wide use, so its evidence runs from registration-era trials to large practice cohorts; the cards pick one or two per use.
Depot doses in advanced prostate cancer, 43 men
In a randomised phase II trial of 3.75 to 30 mg depot every four weeks under the skin, 5% had complete and 53% partial remission and 30% stable disease, with no difference by dose. Androgens fell rapidly to castration levels at every dose, bone pain improved in 63% and urinary symptoms in 79%. Side effects were mild: gynecomastia 16%, nausea or vomiting 13%.
The 30 mg four-month depot, 49 men
Intramuscular 30 mg every 16 weeks brought mean testosterone to castrate levels by week 3; the median time was 22 days and 96% were castrate within four weeks. One man had a transient escape, and a delay of up to three weeks in the next injection did not break suppression. There was no progression in 90% at week 16 and 80% at week 32.
Eligard: leuprolide in an in-situ gel
A review of the polymer-and-solvent formulation that forms a depot after injection under the skin. In trials 98% of men on the one-month and 94% on the three-month form reached testosterone of 20 ng/dL or less, and breakthroughs above 50 ng/dL after castration were rare (0 of 117 and 1 of 111).
Eligard and deeper testosterone suppression
A literature review of the Atrigel formulation: all patients in its studies reached 50 ng/dL or less and up to 98% reached 20 ng/dL, the level of surgical castration, with a side-effect profile like other agonists. The 7.5 mg and 22.5 mg forms last one and three months, and the kit tolerates two weeks at room temperature before mixing.
HERO: testosterone recovery after relugolix vs leuprolide
In the HERO trial (934 men), oral relugolix kept testosterone suppressed in 97% against 89% on leuprolide. Among 184 men stopping after 48 weeks, testosterone recovered above 280 ng/dL within 90 days in 54% after relugolix and 3.2% after leuprolide, with median recovery times of 86 and 112 days.
Leuprolide and flutamide before prostatectomy, 303 men (RCT)
Men with stage cT2b cancer were randomised to surgery alone or after three months of leuprolide depot and flutamide. Pretreatment lowered capsule penetration (47% vs 78%), positive surgical margins (18% vs 48%) and tumour at the urethral margin (6% vs 17%), without adding surgical complications. Whether this improves survival needed longer follow-up.
EMBARK: enzalutamide with or without leuprolide, by age
In 1,068 men with high-risk biochemically recurrent prostate cancer randomised to enzalutamide plus leuprolide, leuprolide with placebo, or enzalutamide alone, both enzalutamide arms improved metastasis-free survival over leuprolide alone in men under and over 70. Serious treatment-related adverse events were more common in older men but low in all groups (0.6% to 11.7%).
Eligard in routine German practice, 1,906 men
Pooled data from two open, non-interventional studies of three- and six-month Eligard over 12 months: median PSA fell from 12.0 to 0.5 ng/mL in treatment-naive and pretreated men, and adverse events were recorded in 8.8%.
Interstitial pneumonitis after leuprorelin, one man
A 94-year-old developed interstitial pneumonitis three months after a first dose of leuprorelin with bicalutamide for metastatic prostate cancer. After other causes were excluded he improved strikingly on corticosteroids. The authors judged leuprorelin, which stays in the blood for months from its depot, the most probable cause.
Endometriosis with and without add-back, 201 women (RCT)
All women received 3.75 mg depot every four weeks for a year with placebo or one of three norethindrone-based add-back regimens. Pelvic pain improved in every group by week 8. Without add-back, bone density fell 6.3% by week 52; it was preserved in all add-back groups, and norethindrone 5 mg alone or with 0.625 mg conjugated oestrogens kept pain control.
Leuprolide vs danazol in endometriosis, 270 women (RCT)
In a double-blind trial of 3.75 mg monthly against danazol 800 mg daily, most women on either had side effects, from low oestrogen with leuprolide (such as hot flushes) and from androgens with danazol (such as weight gain). Leuprolide caused more bone loss, apparently recovering after stopping; danazol lowered HDL cholesterol. Neither caused serious complications.
Fibroids: ulipristal vs leuprolide, 307 women (RCT)
Before surgery, bleeding was controlled in 89% on monthly 3.75 mg leuprolide against 90% and 98% on daily ulipristal 5 or 10 mg, which was non-inferior. Median time to amenorrhoea was 21 days on leuprolide against 5 to 7, and moderate-to-severe hot flushes affected 40% against 10% to 11%.
Breast cancer: monthly vs three-monthly leuprolide, 201 women
With an aromatase inhibitor in premenopausal hormone-receptor-positive breast cancer, ovarian ablation was reached by 100% on 7.5 mg monthly and 99% on 22.5 mg every three months; one-year disease-free survival was 95% and 97%. Musculoskeletal pain, hot flashes, fatigue and insomnia were most common. A retrospective single-centre study.
Breast cancer: two vs three or more years of leuprorelin, 222 women
Ten-year follow-up of a randomised trial of leuprorelin every three months for two years or at least three, with five years of tamoxifen: disease-free survival did not differ overall (HR 0.94), though a small higher-risk subgroup of 17 did better with longer treatment. Bone-related adverse events occurred in about 5% of each group.
A 40-minute LH test after the first depot, 132 girls
Girls with central precocious puberty were randomised to three depot regimens. LH measured 40 minutes after the first injection matched the peak of a standard GnRH test (9.4 vs 11.0 IU/L); a cut-off of 5.4 IU/L diagnosed activation with 86% sensitivity and 90% specificity, and a post-injection LH below 3.07 IU/L helped monitor suppression at six months.
Puberty suppression in transgender and gender-diverse youth, 48 patients
A retrospective review of 22.5 mg every three months as intramuscular Lupron or subcutaneous Eligard (mean age 13.7). Clinical puberty suppression occurred in every patient; biochemical suppression one hour after an injection was seen in 90% on Eligard and 69% on Lupron (p = 0.06). Some patients switched from Lupron because of shortages.
Reverse engineering the one-month Lupron Depot
Laboratory analysis of the PLGA microspheres matched the package insert's composition. In vitro, about 23% of the leuprolide was released in an initial burst and the rest in a zero-order manner, and residual moisture and solvent were extremely low. The authors noted that no US generic of this depot had been approved despite the patent's expiry.
Dosing Data
Leuprolide is dosed by label and given by a clinician. Depot strengths are not interchangeable: a three-month dose is not three monthly doses, because each form has its own release profile.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Side Effects & Contraindications
Reported Side Effects
From the labels and the studies above.
Contraindications & Cautions
From the labels; a clinician decides.
Legal Status
Leuprolide is an approved prescription medicine in many formulations. The sport row below comes from the dataset.
Frequently Asked Questions
?Why does leuprolide first raise testosterone?
Because it starts by stimulating the GnRH receptor before it exhausts it. The prostate cancer label warns of testosterone about 50% above baseline at the start, and the pediatric label of increased pubertal signs, including vaginal bleeding, in the first two to four weeks. Suppression follows: castrate testosterone within about three to four weeks with depots.
?How long do its effects last after the last injection?
The label calls them reversible, but depots keep releasing drug. After 48 weeks of three-monthly injections in the HERO trial, only 3.2% of men had testosterone back above 280 ng/dL 90 days after stopping, against 54% of men stopping oral relugolix.
?Does leuprolide weaken bones?
It can. In a year of endometriosis treatment without add-back hormones, bone density fell 6.3%; norethindrone add-back preserved it. That is why the endometriosis labels limit an initial course to six months and total therapy with add-back to 12 months.
?Is leuprolide used as a puberty blocker?
It is approved for central precocious puberty (Lupron Depot-Ped, Fensolvi and Vobrig) and is also used off-label to suppress puberty in transgender and gender-diverse youth. A 2023 chart review of 48 such adolescents found clinical suppression in all, with biochemical suppression in 90% on Eligard and 69% on Lupron.
?How does it compare with relugolix and degarelix?
Both are antagonists: they block the receptor, so testosterone falls without a flare. In HERO, oral relugolix kept testosterone suppressed in 97% of men against 89% on leuprolide and let it recover faster after stopping; degarelix is an injectable antagonist.
?Is leuprolide banned in sport?
For men, yes: WADA's Prohibited List names leuprorelin under S2.2.1, and the Legal table below gives the 2026 and 2027 entries. GnRH analogues are also on WADA's Monitoring Program for female athletes under 18.
References
- [fda-pi] Lupron Depot (leuprolide acetate for depot suspension) 7.5 mg, 22.5 mg, 30 mg, 45 mg Prescribing Information. AbbVie (DailyMed version of 2026-06-18, read 2026-09-28).
- [fda-pi] Lupron Depot 3.75 mg and 11.25 mg (endometriosis, fibroids) Prescribing Information. AbbVie (DailyMed versions of 2025-09, read 2026-09-28).
- [fda-pi] Vobrig (leuprolide acetate) injection Prescribing Information. Sun Pharmaceutical Industries; NDA 213225, approved August 26, 2026 (read 2026-09-28).
- [fda-pi] US FDA, Drugs@FDA: leuprolide acetate applications including Lupron NDA 019010 (1985), Lupron Depot NDA 019732 (1989), Lupron Depot-Ped NDA 020263 (1993), Eligard NDA 021343 (2002), Fensolvi NDA 213150 (2020), Camcevi NDA 211488 (2021) and Vobrig NDA 213225 (2026) (read 2026-09-28).
- [Human] Rizzo M, et al. "Leuprorelin acetate depot in advanced prostatic cancer: a phase II multicentre trial." J Int Med Res, 1990;18 Suppl 1:114-25. PMID: 2108883.
- [Human] Sharifi R, et al. "Leuprolide acetate (30-mg depot every four months) in the treatment of advanced prostate cancer." Urology, 1998;51(2):271-6. PMID: 9495710.
- [Review] Sartor O. "Eligard: leuprolide acetate in a novel sustained-release delivery system." Urology, 2003;61(2 Suppl 1):25-31. PMID: 12667884.
- [Review] Berges R, et al. "Effect of a new leuprorelin formulation on testosterone levels in patients with advanced prostate cancer." Curr Med Res Opin, 2006;22(4):649-55. PMID: 16684425.
- [Human] Tutrone R, et al. "Testosterone Recovery for Relugolix Versus Leuprolide in Men with Advanced Prostate Cancer: Results from the Phase 3 HERO Study." Eur Urol Oncol, 2024;7(4):906-913. PMID: 38143206.
- [Human] Soloway MS, et al. "Randomized prospective study comparing radical prostatectomy alone versus radical prostatectomy preceded by androgen blockade in clinical stage B2 (T2bNxM0) prostate cancer. The Lupron Depot Neoadjuvant Prostate Cancer Study Group." J Urol, 1995;154(2 Pt 1):424-8. PMID: 7541859.
- [Human] Shore ND, et al. "Enzalutamide with or without leuprolide in patients with high-risk biochemically recurrent prostate cancer: EMBARK post hoc analysis by age." Eur J Cancer, 2026;232:116110. PMID: 41274168.
- [Human] Ohlmann CH, et al. "Efficacy and Tolerability of Leuprorelin Acetate (Eligard®) in Daily Practice in Germany: Pooled Data from 2 Prospective, Non-Interventional Studies with 3- or 6-Month Depot Formulations in Patients with Advanced Prostate Cancer." Urol Int, 2018;100(1):66-71. PMID: 29197875.
- [Human] Villalba-Cuesta PL, et al. "Interstitial pneumonitis associated with leuprorelin acetate for a prostate cancer: A case report." J Oncol Pharm Pract, 2022;28(8):1910-1913. PMID: 35234109.
- [Human] Hornstein MD, et al. "Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Lupron Add-Back Study Group." Obstet Gynecol, 1998;91(1):16-24. PMID: 9464714.
- [Human] Wheeler JM, et al. "Depot leuprolide acetate versus danazol in the treatment of women with symptomatic endometriosis: a multicenter, double-blind randomized clinical trial. II. Assessment of safety. The Lupron Endometriosis Study Group." Am J Obstet Gynecol, 1993;169(1):26-33. PMID: 8333471.
- [Human] Donnez J, et al. "Ulipristal acetate versus leuprolide acetate for uterine fibroids." N Engl J Med, 2012;366(5):421-32. PMID: 22296076.
- [Human] Kendzierski DC, et al. "Efficacy of Different Leuprolide Administration Schedules in Premenopausal Breast Cancer: A Retrospective Review." Clin Breast Cancer, 2018;18(5):e939-e942. PMID: 29747931.
- [Human] Kurebayashi J, et al. "A follow-up study of a randomized controlled study evaluating safety and efficacy of leuprorelin acetate every-3-month depot for 2 versus 3 or more years with tamoxifen for 5 years as adjuvant treatment in premenopausal patients with endocrine-responsive breast cancer." Breast Cancer, 2021;28(3):684-697. PMID: 33638810.
- [Human] Helvacioglu D, et al. "Utility of a 40-minute LH level after depot leuprolide for diagnosis and treatment monitoring in girls with CPP." J Endocrinol Invest, 2026;49(9):2375-2383. PMID: 42189483.
- [Human] Eitel KB, et al. "Leuprolide Acetate for Puberty Suppression in Transgender and Gender Diverse Youth: A Comparison of Subcutaneous Eligard Versus Intramuscular Lupron." J Adolesc Health, 2023;72(2):307-311. PMID: 36404242.
- [In Vitro] Zhou J, et al. "Reverse Engineering the 1-Month Lupron Depot®." AAPS J, 2018;20(6):105. PMID: 30280294.
Sources & Citations
Every PubMed citation on this page has been checked against its record. The Lupron Depot and Vobrig labels and Drugs@FDA were read on September 28, 2026. Grey Peptides sells nothing and links to no vendor.
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