Histrelin

A synthetic nonapeptide GnRH agonist delivered as a 12-month subcutaneous hydrogel implant — FDA-approved as Supprelin LA for central precocious puberty (2007) and formerly as Vantas for advanced prostate cancer (2004, discontinued 2021) — that suppresses gonadotropins through pituitary desensitization.

Also referenced as: Histrelin acetate, Supprelin LA, Vantas, Supprelin, ORF 17070, RWJ 17070, Histrelin implant

Also appears in: Other

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What is Histrelin?

Histrelin is a synthetic nonapeptide agonist of the gonadotropin-releasing hormone (GnRH) receptor, supplied as the acetate salt. Its sequence — pGlu-His-Trp-Ser-Tyr-D-His(imBzl)-Leu-Arg-Pro-NHEt, molecular formula C66H86N18O12, molecular weight 1323.5 as the free base and 1443.70 as the diacetate — is native GnRH with a benzyl-protected D-histidine at position 6 and the C-terminal Gly-NH2 replaced by an ethylamide on proline 9. Those two edits make the molecule far more potent and longer-lived than the native decapeptide, and they place it in the same family as leuprolide, triptorelin, and goserelin.

What sets histrelin apart is not the peptide but the package. Both approved products load 50 mg of histrelin acetate into a nonbiodegradable, diffusion-controlled hydrogel reservoir roughly 3.5 cm long and 3 mm across, inserted under the skin of the inner upper arm, where it releases drug continuously for 12 months. Supprelin LA (NDA 022058, approved May 3, 2007) treats central precocious puberty in children. Vantas (NDA 021732, approved October 12, 2004) was the palliative prostate-cancer product; its manufacturer, Endo, discontinued it in 2021, Drugs@FDA now lists it as discontinued, and FDA’s drug-shortage database carries a discontinuation entry for the histrelin acetate implant. An earlier daily subcutaneous injection, Supprelin (NDA 019836, approved December 24, 1991), was also discontinued.

Histrelin appears in the clinic rather than on the research-peptide market: the once-a-year implant is the format that makes it worth discussing, and that format cannot be reproduced from a vial.

How it works

• Continuous GnRH-receptor occupancy shuts the axis down after first switching it on. The pituitary releases LH and FSH only in response to pulsatile GnRH; constant exposure first stimulates gonadotropes and then desensitizes and downregulates the receptor. In rhesus monkeys with hypothalamic lesions, hourly GnRH pulses restored gonadotropin secretion while continuous infusion failed to sustain it and, when started in pulse-replaced animals, suppressed it (Belchetz et al., Science, 1978;202(4368):631–633). GnRH agonists exploit exactly this paradox (Conn and Crowley, New England Journal of Medicine, 1991;324(2):93–103).
• The flare is measurable, then gone within weeks. In the Vantas pivotal study, mean serum testosterone was 388.3 ng/dL at baseline and 382.8 ng/dL at the end of week 1, fell to 92.2 ng/dL by week 2 and 15 ng/dL by week 4, and sat at 14.3 ng/dL at week 52; peak serum histrelin (1.10 ± 0.375 ng/mL) arrived at a median of 12 hours after insertion. Labeling for both products warns that sex steroids transiently rise during the first week and that suppression generally arrives within four weeks.
• A zero-order reservoir replaces the depot injection. The implant is a hydrogel of 2-hydroxyethyl and 2-hydroxypropyl methacrylates that delivers approximately 65 mcg/day of histrelin acetate in Supprelin LA and approximately 50 mcg/day in Vantas (assayed residual-content release in the prostate program averaged 56.7 ± 7.71 mcg/day over 52 weeks). Serum histrelin remained measurable for the full year, with a median maximum of 0.43 ng/mL in children (Supprelin LA label). Because the reservoir does not degrade, drug delivery stops only when the implant is removed — which is also why retained implants keep working (see Key considerations).
• In children the readout is a prepubertal LH response. In the Phase 3 CPP trial, peak stimulated LH fell from 28.2 ± 19.97 to 0.8 ± 0.39 mIU/mL in treatment-naive children within one month, estradiol fell from 24.5 ± 22.27 to 5.9 ± 2.37 pg/mL, and suppression held for the 12-month study (Eugster et al., Journal of Clinical Endocrinology & Metabolism, 2007;92(5):1697–1704).

Research status

Prostate cancer (approved 2004; product discontinued 2021). The registrational program was a pair of open-label Phase 3 studies started in 2000. In the pivotal study (NCT01697384), 138 men with advanced prostate cancer received a single implant; of 134 with week-4 values, 100% reached chemical castration (≤50 ng/dL), suppression was maintained in more than 99% through week 52, PSA fell an average of 90% from baseline by week 16, and no testosterone or LH surge followed reimplantation at week 52 (Schlegel et al., Journal of Urology, 2006;175(4):1353–1358). A second study (NCT01394263) randomized 59 men against goserelin as an active control; no results are posted. The dose-finding work compared one, two, or four implants in 42 men and found no advantage beyond one (Schlegel et al., Urology, 2001;58(4):578–582). In Europe, Vantas was authorized in Denmark on November 17, 2005; during mutual recognition, five concerned member states (Germany, Spain, Ireland, Italy, and the United Kingdom) objected that efficacy had not been shown against existing treatments, and an Article 29 referral ended with a positive CHMP opinion on May 24, 2007 and a European Commission decision on July 30, 2007. There is no centrally authorized histrelin product. No trial has ever compared histrelin’s survival outcomes with another androgen-deprivation agent.

Central precocious puberty (approved 2007). Supprelin LA was approved on two single-arm, open-label studies: 11 previously treated girls, and the nine-center Phase 3 trial of 36 children (33 girls, 3 boys; 20 treatment-naive) summarized above (Eugster et al., 2007; NCT00779103, start September 2004, results posted). Thirty-one children received a second implant, with peak LH falling further between months 12 and 24 and predicted adult height rising by 5.1 cm; minor implant-site reactions occurred in 61% and minor difficulties with explantation in 32.2% (Rahhal et al., International Journal of Pediatric Endocrinology, 2009;2009:812517). The final report followed the same cohort for up to six years of treatment plus one year off: suppression was maintained throughout, bone-age-to-chronological-age ratio fell from 1.417 to 1.18 at 48 months in naive children, predicted adult height in girls rose from 151.9 cm to 166.5 cm at month 60 (n = 6), and hypothalamic-pituitary-gonadal recovery was observed after removal (Silverman et al., Journal of Clinical Endocrinology & Metabolism, 2015;100(6):2354–2363). An earlier Israeli pilot had reported the implant concept in CPP (Hirsch et al., Pediatrics, 2005;116(6):e798–e802). None of these studies was randomized or controlled against an injectable GnRH agonist; a 2022 U.S. consensus review concluded that the five approved pediatric GnRH agonists show similar first-year efficacy and safety and that none is superior (Popovic et al., Frontiers in Pediatrics, 2022;10:968485).

Extended retention beyond the labeled 12 months. Equivalent suppression at 12 and 24 months was reported when a single implant was left in place for two years in 33 children (Lewis et al., Journal of Pediatrics, 2013;163(4):1214–1216). A two-center retrospective series of 49 youths — 42 treated for gender dysphoria, 7 for CPP — with implants retained at least 17 months found an average single-implant use of 37.5 ± 13.6 months, with biochemical or clinical escape in 8 of 50 implants at an average of 30.4 months (Pine-Twaddell et al., Transgender Health, 2023;8(3):264–272). Single cases document continuous suppression for seven years from one implant (Villalta and Quintos, Journal of the Endocrine Society, 2022;6(2):bvab189). The label still specifies removal at 12 months; extended use is off-label and rests on retrospective data.

Procedural safety. A single-surgeon series of 377 pediatric patients and 866 procedures (352 insertions, 329 replacements, 185 removals) reported complications in 1% of cases and a shift toward clinic-based rather than operating-room placement (Swendiman et al., Journal of Pediatric Surgery, 2019;54(7):1457–1461).

Registered studies. ClinicalTrials.gov lists 15 studies naming histrelin as an intervention. Beyond the sponsor’s three Phase 3 trials and a 142-patient non-interventional Vantas registry, histrelin appears mainly as one permitted androgen-deprivation backbone in large cooperative-group prostate radiotherapy trials (for example NCT03678025, NCT04513717, NCT05050084), and in small terminated pediatric studies (a QTc study in transgender females, n = 3; a pubertal-suppression biomarker study, n = 4; a bone-health study, n = 78). No new indication for histrelin is in active development, and no generic implant has been approved.

Common dosage forms

• Supprelin LA 50 mg subcutaneous implant (prescription) — a single sterile hydrogel implant, about 3.5 cm × 3 mm, in a glass vial of sodium chloride solution, packaged with an insertion kit. Releases approximately 65 mcg/day for 12 months; removed at 12 months, at which point a new implant may be placed. Insertion and removal are minor surgical procedures performed by a clinician, under local anesthesia, conscious sedation, or general anesthesia at the provider’s discretion. Remains the only marketed histrelin product in the United States.
• Vantas 50 mg subcutaneous implant (discontinued) — the same reservoir design releasing approximately 50 mcg/day, labeled for 12 months in advanced prostate cancer. Discontinued in 2021; the product is no longer available in the United States, although its label continues to be revised (most recently in a supplement approved May 6, 2026).
• Supprelin daily injection (discontinued) — the original 1991 product, histrelin acetate solution for once-daily subcutaneous injection at 0.2, 0.5, and 1 mg base/mL. Long off the market and superseded by the implant.
• No oral, nasal, or depot-injection formats. The Vantas label states that histrelin acetate is not active when given orally, and unlike leuprolide or triptorelin it was never developed as a microsphere depot.
• Research-market presence is marginal. Histrelin acetate is uncommon in research-compound catalogs; where it is listed, it is as a lyophilized peptide powder, which bears no relationship to the controlled-release hydrogel that defines the clinical product.

This section describes formats only and is not dosing guidance.

Key considerations

• Approved, single-manufacturer, and one of its two products is gone. Supprelin LA (NDA 022058) has been FDA-approved since 2007 with no generic; Vantas (NDA 021732) was approved in 2004 and discontinued by Endo in 2021 — a supply decision, not a safety withdrawal, as the Vantas label is still being updated and no safety action is on record. Because Vantas carried the same peptide at a lower daily release, it had been used off-label for pubertal suppression in transgender youth (Olson-Kennedy et al., Transgender Health, 2021;6(1):36–42); its loss narrowed access to the implant format rather than to histrelin as a molecule. The only labeled indication that remains is CPP in children, and the FDA Approved status reflects that an approved drug product containing the molecule exists.
• The evidence is deep in duration and shallow in design. Every efficacy study behind both approvals was open-label and single-arm, sized at 36 children and 138 men. The six-year CPP follow-up is unusually long for a pediatric endocrine therapy, but it never compared histrelin against injectable agonists, and the predicted-adult-height data at later time points rest on single-digit numbers of children. No survival or disease-progression comparison exists in prostate cancer.
• Implant-specific safety signals dominate the pediatric label. Implant-site reactions were reported in 51.1% (24 of 47) of children in the approval studies, with keloid scar, scar, and suture complications in 6.4% each. Breakage during removal is a labeled warning, and retained fragments are pharmacologically active: a case series published online in 2025 documented continued pubertal suppression for five to six years from fragments or forgotten implants, resolving only after surgical extraction (Marpuri et al., Hormone Research in Paediatrics, 2026;99(5):642–646). The label also warns of the first-week agonist flare, pseudotumor cerebri (idiopathic intracranial hypertension, added to pediatric GnRH-agonist labeling in 2022), convulsions, severe cutaneous adverse reactions, and psychiatric events (emotional lability). Post-marketing reports of depression, including rare reports of suicidal ideation and attempt, appear in the current Supprelin LA label (revised September 2025); the discontinued Vantas label likewise added suicidal ideation and attempt to its post-marketing section in a supplement approved May 6, 2026. In neither label is suicidality a boxed or stand-alone warning.
• In men, the signals are the androgen-deprivation class effects. Hot flashes occurred in 65.5% of Vantas patients, local insertion-site reactions in 13.8%, and an implant extruded through the incision in 8 of 171 patients in the first year; eight implants could not be recovered at all, two of them with testosterone rising above castrate level. The label carries the standard GnRH-agonist warnings on tumor flare with spinal cord compression or ureteral obstruction, hyperglycemia and diabetes, cardiovascular disease, and QT prolongation.
• Naming traps. “Supprelin” (1991 daily injection) and “Supprelin LA” (2007 implant) are different products with the same peptide. Vantas and Supprelin LA are both 50 mg histrelin implants but release different daily amounts and were never interchangeable on the label. “GnRH analog” covers both agonists like histrelin and antagonists like cetrorelix and degarelix, which suppress the axis by the opposite mechanism and without a flare. Development codes ORF 17070 and RWJ 17070 refer to the same molecule.