Leuprorelin (leuprolide)

Origin and structure

Leuprorelin is a modified form of gonadotrophin-releasing hormone (GnRH, also called LHRH or gonadorelin), the ten-amino-acid hormone that the hypothalamus releases in pulses to make the pituitary produce LH and FSH. Two changes set it apart from the natural hormone: the glycine at position 6 is replaced by D-leucine, and the final glycine amide is replaced by an ethylamide on the proline, which leaves a peptide of nine amino acids. Its sequence is pGlu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt, formula C59H84N16O12, molar mass about 1209 g/mol. The US labels describe it as more potent than the natural hormone.

The peptide itself is short-lived: after an injection into a vein its half-life is about three hours, and it does not work when swallowed. The medicines therefore come as a daily injection under the skin or as depots that release it over one, three, four or six months. Lupron Depot (US) and Lucrin PDS Depot (Netherlands) are powders that are mixed into a suspension just before the injection; the Lupron Depot powder consists of microspheres of a biodegradable polymer of lactic acid, with glycolic acid added in the monthly depot. Eligard and Fensolvi are injected under the skin as a liquid polymer that sets into a solid depot, Camcevi is a ready-to-use emulsion of the mesylate salt, and there is also a small implant placed under the skin of the abdomen.

Leuprorelin is the international non-proprietary name used in Europe, leuproreline in Dutch; leuprolide is the US name for the same molecule. The first product, the daily injection Lupron, was approved in the US in April 1985.

How it works

Natural GnRH works because it arrives in pulses. Leuprorelin binds the same receptor on the pituitary and keeps it stimulated, and the effect comes in two phases. First there is a surge: LH and FSH rise, and with them testosterone and dihydrotestosterone in men or oestrone and oestradiol in women. In the US trial of the monthly depot, testosterone rose by 50% or more in most men during the first week. With continued exposure the pituitary stops responding and the output of LH and FSH falls. Within two to four weeks testosterone drops to castrate levels (below 50 ng/dL) and oestrogen to postmenopausal levels, and the US label reports castrate testosterone maintained for more than five years in men with prostate cancer.

The suppression lifts after treatment stops. In the US trial of the monthly depot in early puberty, 87.9% of the children followed up had pubertal LH levels again six months after their last injection, and according to the Farmacotherapeutisch Kompas the suppression of female fertility after up to six months of continuous use was fully reversible.

Every licensed use relies on the shutdown. Prostate cancer depends on testosterone, endometriosis and fibroids on oestrogen, hormone-sensitive breast cancer before the menopause on oestrogen from the ovaries, and central precocious puberty on a pituitary that has switched on too early. The surge is the drawback. In men with prostate cancer it can briefly worsen symptoms, which is why the Farmacotherapeutisch Kompas advises considering an anti-androgen during the first weeks. In girls treated for early puberty it can cause bleeding or spotting in the first month, as it did in 7 of 36 girls (19.4%) without a first period in the US trial of the monthly depot.

Is leuprorelin approved?

Yes. Leuprorelin is a prescription medicine in the EU and the US, with indications that differ by product and country.

In the EU most leuprorelin products are licensed by national regulators. The exception is Camcevi (Accord), a ready-to-use six-month depot that received an EU-wide marketing authorisation on 24 May 2022 for hormone-dependent advanced prostate cancer and, with radiotherapy, for high-risk localised and locally advanced hormone-dependent prostate cancer. The EMA assessed it as a hybrid medicine, with Eligard as its reference product.

In the Netherlands leuprorelin is prescription-only, and reimbursement is subject to the conditions in Annex 2 (bijlage 2) of the Dutch health-insurance regulation. The Farmacotherapeutisch Kompas lists Lucrin PDS Depot (AbbVie: 3.75 mg, 11.25 mg and 30 mg), Eligard (Recordati: 7.5 mg, 22.5 mg and 45 mg), Camcevi (Accord: 21 mg and 42 mg) and a 5 mg implant from several manufacturers. The depots may only be prepared and injected by healthcare professionals who are familiar with the procedure.

Leuprorelin sold as a research chemical is none of these products. It has no marketing authorisation, is not made under a medicines licence, and may not be used in people. The approvals below describe the licensed products only.

• Netherlands: all four products are registered for high-risk localised and locally advanced testosterone-sensitive prostate cancer, with or without radiotherapy, and for metastatic prostate cancer. Lucrin is also registered for moderate to severe endometriosis, for fibroids before surgery to remove them or the uterus, as adjuvant treatment of oestrogen-receptor-positive breast cancer in premenopausal women, and for idiopathic precocious puberty in girls under 9 and boys under 10. The Kompas also describes its use to quiet the pituitary before ovarian stimulation in IVF, but IVF is not among the Dutch indications.
• US: the daily injection Lupron was approved on 9 April 1985 for advanced prostate cancer; the brand has been discontinued, but generic daily injections remain. The monthly Lupron Depot 7.5 mg followed on 26 January 1989, later joined by 3-, 4- and 6-month depots. A 3.75 mg monthly depot, approved on 22 October 1990, and an 11.25 mg three-month depot are labelled for endometriosis, alone or with norethindrone acetate (norethisterone acetate) as add-back, and, with iron, for anaemia caused by fibroids before surgery. Lupron Depot-Ped for central precocious puberty was approved on 16 April 1993 and now comes as 1-, 3- and 6-month depots for children aged 1 and over. Eligard, injected under the skin, was approved on 23 January 2002, Fensolvi for early puberty from age 2 on 1 May 2020, and Camcevi (42 mg every six months) on 25 May 2021, with a 21 mg three-month version (Camcevi ETM) on 25 August 2025. No US leuprolide product is approved for breast cancer or IVF.

What the research shows

The evidence comes from four decades of registration trials, most of them open and without a comparison group, and from a handful of randomised trials in which leuprorelin was tested against another treatment. The main results:

• Prostate cancer, against oestrogen (NEJM 1984): 199 men with metastatic prostate cancer were randomised to a daily injection of leuprolide or diethylstilbestrol (DES) tablets. The tumour responded or stayed stable in 86% and 85%. Leuprolide caused less painful breast enlargement, nausea and oedema, and fewer blood clots, though that difference was not statistically significant, but more hot flushes. One-year survival was 87% against 78%, also not a significant difference.
• Depot registration trials (US labels): open trials of 49 to 151 men per formulation, most without a comparison group. On the monthly 7.5 mg depot, 94% of 54 evaluable men reached castrate testosterone within 30 days. On the six-month 45 mg depot, testosterone stayed at castrate levels from week 4 to week 48 in an estimated 93.4% of 148 men. The subcutaneous Eligard depots brought 94 to 99% of men below 50 ng/dL by day 28, and Camcevi 98.5% of 137 men by week 4.
• Endometriosis: in two controlled trials, the monthly 3.75 mg depot for six months (166 women) relieved pain and shrank endometriosis lesions about as well as danazol 800 mg a day. In a one-year randomised trial of 201 women (Obstet Gynecol 1998), leuprorelin alone reduced spinal bone density by 6.3%, while adding 5 mg of norethisterone acetate a day (add-back therapy) preserved bone density and still relieved pelvic pain.
• Fibroids with anaemia (US label): women received iron with either the monthly 3.75 mg depot (104 women) or iron alone (98 women). After 12 weeks, 75% against 49% reached a haemoglobin of at least 12 g/dL and a haematocrit of at least 36%. Uterus and fibroids shrank, but in 46 women followed up the uterus regained its pretreatment size after a mean of 8.3 months.
• Breast cancer, TABLE (J Clin Oncol 2007): 599 pre- or perimenopausal women with oestrogen-receptor-positive, node-positive early breast cancer received either a three-monthly leuprorelin depot or CMF chemotherapy. After a median of 5.8 years, recurrence-free survival was similar (hazard ratio 1.19, 95% CI 0.94 to 1.51), and an exploratory analysis of overall survival favoured leuprorelin. Hot flushes and sweating were more common at first with leuprorelin, nausea, vomiting and hair loss with chemotherapy.
• Central precocious puberty (US labels, no untreated control groups): in a randomised trial of two three-month depots in 84 children aged 1 to 11, peak LH stayed suppressed from month 2 to month 6 in 95% on 30 mg and in about four in five on 11.25 mg. In the monthly-depot trial, 55 children were treated for about four years; 96% were suppressed after one month, and the 33 followed to final or near-final height reached a mean height standard deviation score of -0.2. The six-month subcutaneous Fensolvi suppressed LH in 87% of 62 children at month 6.
• Puberty suppression in transgender adolescents (off-label): a retrospective study of 30 transgender adolescents treated with leuprolide or a histrelin implant found that LH, FSH and testosterone were suppressed about as much as in children treated for precocious puberty, although oestradiol stayed higher in those assigned female at birth. A 2024 systematic review of 50 studies on puberty suppression for gender dysphoria rated only one as high quality: puberty was reliably suppressed and bone density fell during treatment, but no conclusions could be drawn about effects on gender dysphoria, mental health or cognitive development.

Compared with other GnRH medicines

Leuprorelin belongs to the GnRH agonists, with triptorelin, goserelin, nafarelin and buserelin, and they all work through the same surge and shutdown. Leuprorelin and triptorelin have been compared head to head in a randomised trial in men with prostate cancer, which our triptorelin article describes. The GnRH antagonists, degarelix by injection and relugolix by mouth, block the receptor instead, so testosterone falls without a surge. Leuprolide was the comparator in two large trials of these antagonists:

• HERO (NEJM 2020): 930 men with advanced prostate cancer received oral relugolix (622) or leuprolide every three months (308) for 48 weeks. Testosterone stayed at castrate levels throughout in 96.7% on relugolix against 88.8% on leuprolide, and on day 4 it was castrate in 56.0% on relugolix and in none on leuprolide. Major cardiovascular events occurred in 2.9% against 6.2% (hazard ratio 0.46, 95% CI 0.24 to 0.88). Ninety days after stopping, mean testosterone was 288.4 ng/dL after relugolix and 58.6 ng/dL after leuprolide, in a subgroup of 184 men.
• PRONOUNCE (Circulation 2021): 545 men with prostate cancer and known atherosclerotic cardiovascular disease were randomised to degarelix or leuprolide for 12 months. The trial was stopped early because enrolment was slow and there were fewer events than expected. Major cardiovascular events occurred in 5.5% on degarelix and 4.1% on leuprolide (hazard ratio 1.28, 95% CI 0.59 to 2.79), no significant difference. The authors concluded that the relative cardiovascular safety of GnRH agonists and antagonists remains unresolved.

Side effects and warnings

Most side effects follow from the lowered sex hormones. In the main US trials of the four Lupron Depot strengths for prostate cancer, 47 to 59% of men had hot flushes, and on the three-month depot 20.2% had testicular shrinkage. Among 166 women with endometriosis on the monthly 3.75 mg depot, 84% had hot flushes (57% on danazol, 29% on placebo), 32% headache, 28% vaginitis, 22% depression or mood swings and 11% lower libido. In children treated for early puberty the most common reactions were injection-site pain, headache and mood changes.

Bone loss limits treatment in women: on leuprorelin alone, spinal bone density fell by 3.2% after six months and 6.3% after a year, which is why courses for endometriosis and fibroids are capped and add-back therapy is used for longer treatment. According to the Kompas, the loss recovered after a six-month course. In men, long-term medical castration also thins the bones, and the Kompas lists osteoporosis with long-term use (six to twelve months).

In the first weeks the testosterone surge can worsen prostate cancer, with bone pain, nerve symptoms, blood in the urine, urinary blockage and, in men with spinal metastases, spinal cord compression that can lead to paralysis. The labels also warn of raised blood sugar and diabetes, raised lipids, fatty liver, a higher risk of heart attack, sudden cardiac death and stroke in men, a longer QT interval on the ECG, convulsions, depression that can be severe, severe skin reactions such as Stevens-Johnson syndrome and DRESS, and, rarely, bleeding into an undiagnosed pituitary adenoma (pituitary apoplexy), mostly within two weeks of the first dose and sometimes within the first hour.

In children the labels warn of mood and behaviour changes such as crying, irritability and aggression, and of idiopathic intracranial hypertension (raised pressure in the skull, with headache and visual problems), which the Kompas also lists for adults. The Dutch information mentions a slipped growth plate at the top of the thigh bone after treatment has stopped, while peak bone mass in late adolescence appears unaffected. Leuprorelin can harm an unborn child and is not for use in pregnancy.

Frequently asked questions

Is leuprorelin available in the Netherlands?

Yes, as a prescription medicine. Lucrin PDS Depot, Eligard, Camcevi and a leuprorelin implant are registered, all for prostate cancer, and Lucrin also for endometriosis, fibroids, premenopausal breast cancer and early puberty. Reimbursement depends on the conditions in Annex 2 of the Dutch health-insurance regulation. Leuprorelin sold as a research chemical is not a registered medicine and may not be used in people.

Are leuprorelin, leuprolide, Lupron and Lucrin the same thing?

They contain the same molecule. Leuprorelin is the international name used in Europe (leuproreline in Dutch) and leuprolide the US name. Lupron Depot is the US brand of the intramuscular depots, Lucrin the name of AbbVie's product in the Netherlands, and Eligard, Fensolvi and Camcevi are other formulations, injected under the skin. The products differ in release time, so the strengths are not interchangeable: the US label warns that they are not additive.

Is leuprorelin banned in sport?

For men, yes, at all times, in and out of competition. The WADA Prohibited List 2026 names GnRH and its agonist analogues, with leuprorelin by name, in class S2.2.1, testosterone-stimulating peptides in males. It is not prohibited for women. The Dutch translation of the list by the Dopingautoriteit carries the same class.

Why does leuprorelin first raise testosterone?

Because it is an agonist: it first stimulates the GnRH receptor, so LH and testosterone rise, by 50% or more in most men in the first week of the US monthly-depot trial. Only after the pituitary has stopped responding does testosterone fall, reaching castrate levels within two to four weeks. In prostate cancer this flare can briefly worsen symptoms, which is why the Farmacotherapeutisch Kompas advises considering an anti-androgen at the start. GnRH antagonists such as degarelix and relugolix lower testosterone without this surge.

Is leuprorelin (Lupron) a puberty blocker?

Yes, it is one of the GnRH agonists used as puberty blockers. Its licensed use is central precocious puberty, puberty that the brain starts too early: in the Netherlands Lucrin is registered for girls under 9 and boys under 10, and in the US Lupron Depot-Ped is approved from age 1 and Fensolvi from age 2. Off-label, leuprolide has also been used to pause puberty in transgender adolescents. A 2024 systematic review found the evidence for puberty suppression in gender dysphoria too weak to draw conclusions about gender dysphoria or mental health, and found that bone density fell during treatment.

Does leuprorelin cause bone loss?

Yes, because it lowers oestrogen and testosterone. In the US endometriosis trials, spinal bone density fell by 3.2% after six months and 6.3% after a year on leuprorelin alone, while daily norethisterone acetate as add-back therapy largely prevented the loss. That is why courses for endometriosis and fibroids are limited, in the Netherlands to at most six months. Men on long-term treatment for prostate cancer also lose bone, and the Kompas lists osteoporosis with long-term use (six to twelve months).

Storage and handling

Store according to product-label instructions and batch handling notes. Lyophilized research peptides are commonly kept dry, protected from light, and handled with clean laboratory technique.

References

Checked against these sources on 28 October 2026.

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