Leuprolide

Leuprolide replaces glycine at position 6 with D-leucine and the C-terminal glycinamide with an ethylamide, giving roughly 15-fold greater potency than native GnRH and much greater metabolic stability. Continuous depot exposure produces the characteristic biphasic response: a testosterone or oestradiol surge over the first 1 to 2 weeks, then progressive receptor downregulation reaching castrate levels by weeks 3 to 4. It is used in advanced prostate cancer, endometriosis, uterine fibroids, central precocious puberty, in IVF as a long-protocol downregulator, and as gender-affirming puberty suppression. Depot microsphere and gel formulations range from monthly to six-monthly.

Targets: GnRH receptor (GnRHR), Pituitary gonadotrophs, LH, FSH, Testosterone, Oestradiol

• · 7.5 mg monthly, 22.5 mg every 3 months, 30 mg every 4 months or 45 mg every 6 months for Lupron Depot. Eligard uses a subcutaneous gel depot at the same intervals.
• · 1 mg daily from the older multi-dose vial. Largely superseded by depots but still used where rapid reversibility matters.
• · Reduced to 0.5 mg once downregulation is confirmed. Antagonist protocols using cetrorelix or ganirelix have largely displaced this.

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• very commonHot flushes— Affects the large majority of patients on depot therapy.
• very commonLibido loss and erectile dysfunction
• very commonTestosterone flare— First 1 to 2 weeks; requires antiandrogen cover in high-risk metastatic disease.
• commonFatigue
• commonInjection-site reaction— More prominent with the Eligard gel depot.
• commonBone mineral density loss— Cumulative and clinically significant with long-term use; fracture risk rises materially.
• commonMetabolic syndrome, insulin resistance and weight gain— Well documented with long-term androgen deprivation.
• commonDepression and cognitive complaints
• uncommonQT prolongation— Androgen deprivation lengthens the QT interval.
• rarePituitary apoplexy— After a first dose in undiagnosed pituitary adenoma.

• Pregnancy - can cause fetal harm.
• Undiagnosed abnormal vaginal bleeding.
• Known hypersensitivity to GnRH analogues or to benzyl alcohol in some formulations.
• Metastatic prostate cancer with impending cord compression, without antiandrogen flare cover.

• conflictgonadorelin — Desensitises the receptor gonadorelin needs.
• synergyAntiandrogens such as bicalutamide — Standard combined androgen blockade and flare protection.
• cautionQT-prolonging drugs — Additive QT effect on top of androgen deprivation.
• redundantdegarelix — Same endpoint by the opposite mechanism, without a flare.

• · Serum testosterone at 4 weeks and periodically - target under 50 ng/dL, ideally under 20.
• · PSA every 3 to 6 months in prostate cancer.
• · Bone density by DEXA at baseline and every 1 to 2 years, with calcium and vitamin D.
• · HbA1c, lipids and blood pressure, since long-term androgen deprivation drives metabolic disease.

Prescription drug worldwide, available as multiple branded depots and now generically.

• Lupron Depot (leuprolide acetate) prescribing information (label)
• Eligard (leuprolide acetate) prescribing information (label)
• Nguyen et al. 2015, adverse effects of androgen deprivation therapy, European Urology systematic review (review)

Leuprolide is the reference compound for continuous GnRH receptor agonism, and its clinical behaviour is entirely a story about the delivery vehicle rather than about the molecule. The peptide itself has a terminal half-life of roughly 3 hours; everything that makes leuprolide leuprolide comes from the microsphere or gel depot that maintains occupancy for one to six months. That sustained occupancy produces the classic biphasic response. Phase one, over the first one to two weeks, is receptor activation and release of stored gonadotropins - testosterone rises about 50 percent above baseline, and in a man with metastatic disease this is the dangerous window. Phase two is homologous desensitisation: uncoupling of the receptor from Gq/11, loss of receptor number, and reduced transcription of the gonadotropin subunit genes, producing castrate testosterone in 87 to 95 percent of men within 30 days depending on formulation. The same mechanism does entirely different clinical jobs depending on who receives it. In endometriosis and fibroids it produces a reversible medical menopause. In central precocious puberty it holds the axis in a prepubertal state for years and preserves adult height. In gender-affirming care it suspends endogenous puberty reversibly. In IVF long protocols it downregulates the axis so the cycle can be controlled from outside - though antagonist protocols have largely displaced that use because they achieve the same control in days rather than weeks and without a flare. The unifying point is that the depot is the drug. Anyone reasoning about leuprolide from its three-hour half-life will get every clinical prediction wrong.

The flare is the sharp end. A man with spinal metastases who receives a first depot without antiandrogen cover can develop cord compression during the testosterone surge, and that is a permanent injury caused by a treatment. Beyond that, the failures are slow. Bone loss accumulates silently until a fracture; metabolic syndrome and insulin resistance develop over years; depression and cognitive complaints are common, frequently dismissed, and genuinely attributable. Incomplete suppression happens in a minority and is missed unless someone actually measures testosterone rather than assuming the injection worked. Recovery after stopping is slower than people expect - 3 to 12 months, and sometimes incomplete after years of continuous use, particularly in older men. And the depot formulations are unforgiving procedurally: they must be mixed with the supplied vehicle and injected within about 30 minutes, they cannot be reconstituted with bacteriostatic water, and a botched reconstitution wastes a month of therapy.

• GnRH receptor (GnRHR) on pituitary gonadotrophs — Roughly fifteenfold the potency of native GnRH; a specific Kd was not resolved here.

  Initial gonadotropin release, then receptor uncoupling and downregulation under continuous depot exposure. Castrate testosterone in the great majority of men within 30 days.

• LH and FSH

  Surge for 1 to 2 weeks, then profound and sustained suppression for the life of the depot.

• Gonadal steroidogenesis (indirect)

  Testosterone to castrate levels in men, oestradiol to postmenopausal levels in women. Every therapeutic effect and every adverse effect of long-term therapy flows from this single change.

• Leuprolide depot registration programme in advanced prostate cancer 3

  Suppression of testosterone to castrate levels. The label reports 87 to 95 percent of patients achieving castrate suppression within 30 days across the 7.5, 22.5, 30 and 45 mg formulations, with suppression maintained through each dosing interval.

Testosterone or oestradiol rises within 3 to 7 days of the first depot and stays up for one to two weeks. Suppression then develops, reaching castrate levels in most patients by weeks 3 to 4. Hot flushes typically begin as the hormone falls rather than during the flare. Libido and erectile function decline over the same weeks. Bone density loss is measurable within a year. Metabolic changes accumulate over one to several years. On stopping, testosterone recovery takes 3 to 12 months, and men over 70 or those treated for several years may not fully recover at all.

Bicalutamide or another antiandrogen started before the first depot is standard flare protection and is genuinely non-negotiable in metastatic disease with cord compression or obstruction risk. Combined androgen blockade continues that pairing longer term in some protocols. Add-back hormone therapy - low-dose oestrogen with a progestogen, or tibolone - is standard when leuprolide is used for endometriosis or fibroids beyond six months, and it substantially reduces both the bone loss and the vasomotor symptoms without abolishing the therapeutic effect. Bone protection with calcium, vitamin D and often a bisphosphonate or denosumab belongs in every long-term androgen deprivation plan. The interactions to avoid are other QT-prolonging drugs, since androgen deprivation lengthens QT on its own, and any GnRH stimulant such as gonadorelin, which is inert against a desensitised receptor. Degarelix is an alternative rather than an addition.

Against degarelix, leuprolide is slower to castrate - three to four weeks against three days - and passes through a testosterone flare that degarelix does not have, which is the deciding factor in men with high disease burden. Against triptorelin and goserelin, the differences are largely formulation and injection experience: goserelin is an implant through a wide-bore needle, leuprolide is a microsphere suspension or a gel depot, and castration rates are broadly comparable across all three. Against gonadorelin, leuprolide is the same receptor and the opposite outcome, which is the single most instructive pairing in this entire class. In IVF, leuprolide long-protocol downregulation has been largely displaced by cetrorelix and ganirelix antagonist cycles, which are shorter, flare-free and give lower OHSS rates - although a leuprolide trigger in an antagonist cycle remains a standard low-OHSS option.

$200–$900/month. US pricing for depot leuprolide has ranged from roughly 300 dollars a month for generics to well over 1000 dollars a month for branded products, before any payer negotiation, and the per-administration figure has to be divided by the 1, 3, 4 or 6 month interval. This is a specialist-administered oncology drug and there is no meaningful self-supply route. Figures are indicative and were not verified in this session.

• ?The three-letter sequence given here is reconstructed from the D-Leu6 and ethylamide substitutions described in the Core record rather than re-verified against a primary structural source in this session.
• ?The label does not state whether accumulation occurs with repeated depot dosing; accumulates is set to false on the basis of the short peptide half-life relative to the dosing interval, which is an inference.
• ?Participant numbers, durations and years for the registration studies are not given in the label section retrieved, so those fields are null.
• ?The 46 percent protein binding figure is the midpoint of the label's stated 43 to 49 percent range.
• ?Blood-brain barrier penetration is marked as no on physicochemical grounds; the pituitary sits outside the barrier, so it is not required for the drug to work.
• ?Cost figures are indicative and were not verified in this session.

• LUPRON DEPOT (leuprolide acetate for depot suspension) - FDA prescribing information DailyMed / FDA

  Source of the 27 L volume of distribution, 7.6 L/h clearance, 43 to 49 percent protein binding, 3-hour half-life, and the castration rates by formulation.

• ELIGARD (leuprolide acetate) injectable emulsion - FDA prescribing information DailyMed / FDA

  The subcutaneous gel depot alternative, with a different injection-site profile and refrigerated storage requirements.

• The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, Jensen JK, Olesen TK, Schröder FH, BJU International, 2008 · PMID 19035858

  The head-to-head against degarelix, with leuprolide as the comparator arm. The most useful single document for understanding what the flare actually costs in practice.