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Leuprolide

Also known as Leuprorelin, Lupron, Lupron Depot, Eligard, Camcevi, Fensolvi, leuprolide acetate

The most widely used GnRH agonist: flare then profound suppression, given as depots lasting one to six months.

clinically proven Hormonal & sexual approved drug

At a glance

Category
Hormonal & sexual
Status
approved drug
Route
intramuscular (Lupron Depot) or subcutaneous (Eligard, Camcevi, Fensolvi, daily injection)
Half-life
the free peptide has a terminal half-life of roughly 3 hours after subcutaneous injection; depot formulations release drug over 1, 3, 4 or 6 months
Onset
flare over days 1-14; castrate testosterone typically by week 2-4
Molecular weight
approximately 1209 g/mol for the free base; supplied as the acetate or mesylate salt
Sequence
pGlu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt (native GnRH with D-leucine at position 6 and the C-terminal glycinamide replaced by an ethylamide)

Approved in the US and EU since the 1980s. Licensed for advanced prostate cancer (Lupron Depot 7.5/22.5/30/45 mg, Eligard, Camcevi), endometriosis and preoperative haematologic improvement in anaemia caused by uterine fibroids, given with iron (Lupron Depot 3.75/11.25 mg) 2, and central precocious puberty (Lupron Depot-PED, Fensolvi). A daily 1 mg/0.2 mL subcutaneous injection is also approved for palliative treatment of advanced prostate cancer. Off-label it is used for ovarian suppression in breast cancer and in gender-affirming care.

Doping status: Prohibited in males (WADA S2.2.1, GnRH agonist analogues)

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

Mechanism of action

Leuprolide is a nonapeptide GnRH agonist. Two modifications to native GnRH account for its behaviour: D-leucine at position 6 blocks the main enzymatic cleavage site, and the C-terminal ethylamide replaces the glycinamide, further slowing degradation. The molecule binds the pituitary GnRH receptor with higher affinity than the natural hormone and stays bound far longer.

The pharmacology is biphasic and the label states it plainly: a single depot injection produces initial stimulation followed by prolonged suppression of pituitary gonadotropins. In the first phase, LH and FSH surge and sex steroids temporarily rise above baseline — the label warns that an increase in symptoms may be observed during the initial days of therapy. In the second phase, continuous receptor occupancy causes receptor downregulation and gonadotroph desensitisation, so LH and FSH fall and gonadal steroid output drops to castrate levels in men and postmenopausal levels in women. The effect is reversible once the drug is cleared.

This flare-then-suppress pattern is the defining feature of the GnRH agonist class, shared with triptorelin and nafarelin. It is the direct opposite of the GnRH antagonists cetrorelix and ganirelix, which competitively block the receptor and suppress from the first injection with no flare. It also contrasts with gonadorelin, which is native GnRH and, when given in physiological pulses, sustains rather than suppresses the axis. Whether a GnRH-active drug stimulates or suppresses is determined by the pattern of receptor exposure, not by whether the molecule is labelled an agonist.

The consequence of suppression is a deliberate hypogonadal state. That is therapeutic in androgen-driven prostate cancer, oestrogen-driven endometriosis and premature activation of the axis in central precocious puberty. It is also the source of essentially every adverse effect: hot flushes, sexual dysfunction, mood change and, over months to years, loss of bone mineral density.

What the research shows

Leuprolide has been in clinical use since 1985 and is among the best-characterised hormonal agents in oncology. Testosterone suppression to castrate levels is a hard, reproducible endpoint, and multiple formulations have been separately registered on that basis. Efficacy in endometriosis and in central precocious puberty rests on controlled trials, and the bone density penalty of long-term use has been quantified in those same trials.

Research in humans

Registrational studies of the depot formulations demonstrated maintenance of testosterone below 50 ng/dL across the dosing interval in the large majority of men. In endometriosis, Lupron Depot 3.75 mg produced clinically meaningful reduction in pelvic pain and lesion burden, with a mean loss of vertebral bone mineral density of about 3.2% at six months by DEXA 2. Adding norethindrone acetate as add-back therapy reduced BMD loss at 52 weeks from -6.3% to -1.0%, which is why add-back is mandatory beyond six months and why total therapy is capped at 12 months 2. In central precocious puberty, treatment suppresses gonadotropins to prepubertal levels and improves predicted adult height.

Animal and lab research

Preclinical work in rodents and dogs established the downregulation mechanism and the reversibility of suppression, and characterised the depot release profiles. Not the basis for human dosing.

Caveats. The clinical trials answer the questions regulators asked — hormone suppression, symptom reduction, safety — not questions about optimal treatment duration, intermittent versus continuous therapy in prostate cancer, or long-term skeletal and cardiovascular outcomes, where evidence is more mixed. Individual GnRH agonists have rarely been compared head to head. The evidence says nothing about use outside licensed indications.

What it is used for

  • Advanced prostate cancer, as androgen deprivation therapy 1
  • Endometriosis: pain relief and reduction of lesions, with or without norethindrone acetate add-back therapy 2
  • Preoperative treatment of anaemia caused by uterine fibroids, together with iron therapy 2
  • Central precocious puberty in children
  • Ovarian suppression in premenopausal hormone-receptor-positive breast cancer (off-label in the US)
  • Pituitary downregulation in long-protocol IVF, and as an ovulation trigger in antagonist protocols
  • Suppression of endogenous sex steroids in gender-affirming care

Dosing

Dose
Almost all leuprolide is given as a depot lasting one to six months, and each depot strength carries its own interval. One product is instead a 1 mg daily injection. The two are set out separately in the notes below, because reading a depot figure as a daily one is a thirty- to two-hundred-fold error.
Frequency
Depot: 7.5 mg every 4 weeks, 22.5 mg every 12 weeks, 30 mg every 16 weeks, 45 mg every 24 weeks in prostate cancer; 3.75 mg every 4 weeks or 11.25 mg every 12 weeks in gynaecological use. Daily injection: 1 mg once a day. A strength is chosen and repeated at its own interval — the figures are alternatives, not a sequence
Route
Intramuscular for Lupron Depot; subcutaneous for Eligard, Camcevi, Fensolvi and the daily 1 mg injection
Duration
Prostate cancer: often indefinite. Endometriosis: 6 months, extendable to a maximum of 12 months total only with norethindrone acetate add-back. Fibroids: up to 3 months. Precocious puberty: until the appropriate age for puberty
  • Advanced prostate cancer, depot, clinician-administered: 7.5 mg every 4 weeks, 22.5 mg every 12 weeks, 30 mg every 16 weeks or 45 mg every 24 weeks 1. Each figure is one injection covering the whole interval, not a daily amount.
  • Endometriosis and uterine fibroids, depot, clinician-administered: 3.75 mg every 4 weeks or 11.25 mg every 12 weeks. Endometriosis courses run up to 6 months, or up to 12 months in total with add-back; fibroid courses up to 3 months 2.
  • Prostate cancer, daily subcutaneous injection: 1 mg once a day, from a 14 mg/2.8 mL multi-dose vial delivering 1 mg per 0.2 mL. This is the only leuprolide product taken daily, and its milligram figure is roughly a thirtieth of the monthly depot that treats the same disease.
  • Depot formulations are clinician-administered. The daily 1 mg subcutaneous product is patient-administered but is a prescription medicine with a fixed dose — there is no protocol to individualise.
  • Do not retreat for endometriosis without norethindrone acetate add-back, and assess bone mineral density before retreatment 2.
  • In prostate cancer with vertebral metastases or bladder outlet obstruction, an antiandrogen is usually started before or with the first injection to cover the flare, or a GnRH antagonist is used instead.
  • Testosterone should be measured to confirm castrate levels rather than assumed.
  • Lupron Depot and Eligard are not interchangeable formulations: they use different delivery systems, different routes and different reconstitution procedures.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Protocols

Lupron Depot (advanced prostate cancer)

approved product information

Source: LUPRON DEPOT 7.5 / 22.5 / 30 / 45 mg prescribing information, DailyMed

7.5 mg strengthone intramuscular injection every 4 weeks
22.5 mg strengthone intramuscular injection every 12 weeks
30 mg strengthone intramuscular injection every 16 weeks
45 mg strengthone intramuscular injection every 24 weeks

One strength is chosen and repeated at its own interval; the rows are alternatives, not steps in a course. As with every GnRH agonist there is an initial testosterone surge, which is why an antiandrogen is usually started before or with the first injection in men with vertebral metastases or bladder outlet obstruction. Lupron Depot and Eligard use different delivery systems and different routes, and their schedules are not interchangeable.

Lupron Depot (endometriosis)

approved product information

Source: LUPRON DEPOT 3.75 mg prescribing information, DailyMed

Initial course, up to 6 months3.75 mg intramuscularly every 4 weeks, or 11.25 mg every 12 weeks
Retreatment, one further course of up to 6 monthsthe same dose plus norethindrone acetate 5 mg daily as add-back

Six months is the limit per course because of cumulative bone loss, and total exposure is capped at 12 months. Bone mineral density should be assessed before retreatment, and retreatment without add-back is not recommended.

Schedules are reproduced as their source states them. Units, IU and milligrams explains why the figures are not interchangeable between products.

Reconstitution

Vial sizes
3.75 mg, 7.5 mg, 11.25 mg, 22.5 mg, 30 mg, 45 mg, 1 mg/0.2 mL daily injection (14 mg/2.8 mL multi-dose vial)
Solvent
Formulation-specific and supplied with the kit. Lupron Depot uses a prefilled dual-chamber syringe with its own diluent; Eligard is mixed between two coupled syringes containing the polymer delivery vehicle. Bacteriostatic water is not used for any of these
Storage
Depot kits at controlled room temperature; Eligard is refrigerated and must be brought to room temperature before mixing. Reconstituted depot suspensions are injected immediately. The daily injection multi-dose vial is refrigerated before first use and kept at room temperature thereafter, discarded after 28 days.

Worked example

Lupron Depot is supplied as a prefilled dual-chamber syringe: the plunger is depressed to mix the microspheres with the diluent, the syringe is shaken to a milky suspension and injected in full. Each syringe is one complete dose, so no concentration calculation is required.

Eligard in particular must be injected within 30 minutes of mixing, because the polymer viscosity rises rapidly. These are not compounds that can sensibly be handled outside a pharmacy or clinic.

This is not reconstituted from a powder — it is supplied as a ready-made solution, or as a kit that mixes to a single fixed dose. The vial-and-solvent arithmetic used elsewhere on this site does not apply.

Safety

Side effects

  • Hot flushes and sweats, reported in about 47-59% of men on the prostate cancer depots 1 and in 84% of women treated for endometriosis 2
  • Initial symptom flare during the first weeks as serum testosterone rises roughly 50% above baseline, with worsening bone pain, neuropathy or haematuria, and a risk of spinal cord compression that can lead to paralysis 1
  • Loss of bone mineral density: lumbar spine BMD fell about 3.2% at 6 months on leuprolide alone in endometriosis trials, against about 0.3% with norethindrone acetate add-back 2; cumulative loss also occurs with long-term androgen deprivation in men
  • Headache, reported in about 32% in the endometriosis trials 2
  • Depression and emotional lability, about 22% in the endometriosis trials 2; post-marketing reports include rare suicidal ideation and attempts 1
  • Vaginitis, about 28%, along with vaginal dryness and amenorrhoea in women 2
  • Erectile dysfunction, loss of libido, testicular atrophy and gynaecomastia in men
  • Injection site pain, erythema and induration; sterile abscess reported rarely
  • Weight change and general pain
  • Hyperglycaemia, new-onset diabetes and hyperlipidaemia; non-alcoholic fatty liver disease including cirrhosis has been reported post-marketing 1
  • Increased risk of myocardial infarction, sudden cardiac death and stroke reported in association with androgen deprivation 1
  • QT/QTc prolongation with androgen deprivation therapy 1
  • Convulsions, reported post-marketing in patients with and without predisposing factors 1
  • Severe cutaneous adverse reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, which the label instructs should prompt discontinuation 1
  • Rare pituitary apoplexy, usually within two weeks of the first dose 1

Do not use if

  • Hypersensitivity to GnRH, GnRH agonists or any component of the formulation 1
  • Pregnancy — leuprolide may cause fetal harm and pregnancy is a listed contraindication 12 — and breastfeeding
  • Undiagnosed abnormal uterine bleeding 2
  • Caution in men with vertebral metastases or urinary obstruction because of flare-related risk of spinal cord compression and ureteral obstruction 1
  • Caution with existing osteoporosis or strong risk factors, including chronic alcohol or tobacco use, anticonvulsants or corticosteroids
  • Caution with congenital long QT syndrome, electrolyte abnormalities or other QT-prolonging drugs
  • Caution in patients with a history of seizures, cerebrovascular disease or CNS lesions

Interactions

No cytochrome P450-mediated interactions of clinical significance are established, and leuprolide is a peptide cleared largely by peptidases. Relevant interactions are pharmacodynamic: additive QT prolongation with class IA and III antiarrhythmics and other QT-prolonging drugs; worsened glycaemic control requiring adjustment of diabetes therapy; additive bone loss with corticosteroids, anticonvulsants and heavy alcohol use. Norethindrone acetate add-back is a deliberate interaction used to protect bone 2. Concurrent GnRH antagonists negate the effect. Exogenous sex steroids and hormonal contraception confound both effect and monitoring. The label notes that diagnostic tests of pituitary gonadotropic and gonadal function are unreliable during treatment and for up to three months after stopping 1.

Sources