Leuprolide Acetate (DB00007): A Comprehensive Pharmacological and Clinical Review

Abstract

Leuprolide acetate is a potent, synthetic superagonist of the gonadotropin-releasing hormone (GnRH) receptor, classified as a small molecule peptide. Its mechanism of action is paradoxical; while it initially stimulates the pituitary-gonadal axis, its continuous, non-pulsatile administration leads to profound receptor downregulation and desensitization. This results in a sustained, reversible state of medical castration, characterized by the suppression of gonadal sex hormones—testosterone in males and estrogen in females. This unique pharmacodynamic profile has established leuprolide as a cornerstone of androgen deprivation therapy (ADT) for the palliative treatment of advanced, hormone-sensitive prostate cancer. Its utility extends into gynecology, where it is a key therapeutic agent for managing endometriosis and uterine fibroids by inducing a hypoestrogenic state. Furthermore, specific pediatric formulations are indicated for the treatment of central precocious puberty, effectively halting premature sexual development. The clinical application of leuprolide has been revolutionized by the development of long-acting depot formulations, which provide sustained drug release over one to six months, enhancing patient compliance and therapeutic consistency. Its safety profile is largely defined by the expected consequences of hormone deprivation, including hot flashes, decreased bone mineral density, and metabolic and cardiovascular risks. Leuprolide is also subject to extensive and often controversial off-label use, including for ovarian suppression in breast cancer, in vitro fertilization protocols, and as a puberty blocker in gender dysphoria. Ongoing research focuses on its role in combination therapies, the development of more convenient formulations, and a deeper understanding of its long-term safety profile, ensuring its continued relevance in modern medicine.

Section 1: Drug Profile and Chemical Characteristics

1.1. Nomenclature and Identification

Leuprolide, also known internationally as leuprorelin, is a synthetic peptide therapeutic agent.[1] Its systematic chemical name is 5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide.[2] In clinical use and commercial formulations, it is most commonly available as its acetate salt, leuprolide acetate.[1]

To ensure unambiguous identification across scientific and regulatory databases, leuprolide is assigned a series of unique identifiers. The Chemical Abstracts Service (CAS) has assigned the number 53714-56-0 to the leuprolide base and 74381-53-6 to the acetate salt.[1] In pharmacological and drug databases, it is cataloged under DrugBank ID DB00007.[1] Other critical identifiers include its PubChem Compound ID (657181), ChEMBL ID (CHEMBL1201199), FDA Unique Ingredient Identifier (UNII) EFY6W0M8TG, and Anatomical Therapeutic Chemical (ATC) classification code L02AE02.[1] These identifiers provide a standardized cross-reference system essential for research, clinical practice, and regulatory oversight.

1.2. Chemical Structure and Physicochemical Properties

Leuprolide is a synthetic nonapeptide, meaning it is composed of a chain of nine amino acid residues.[2] It was designed as an analogue of the naturally occurring hypothalamic decapeptide (10-residue peptide) known as gonadotropin-releasing hormone (GnRH).[2] A pivotal modification in its structure is the substitution of glycine at position 6 of the native GnRH sequence with a D-leucyl residue.[2] This substitution of a D-amino acid for the naturally occurring L-amino acid renders the peptide significantly more resistant to degradation by peptidases. This enhanced stability is a primary contributor to its increased biological half-life and potency compared to endogenous GnRH.[2]

The molecular formula for the leuprolide base is C59​H84​N16​O12​, corresponding to a molar mass of approximately 1209.4 g/mol.[1] Physically, it presents as a white or nearly white powder that is hygroscopic, meaning it readily absorbs moisture from the atmosphere, a property that necessitates careful storage conditions.[6]

The solubility of leuprolide is a key determinant of its formulation for parenteral administration. It is soluble in water (reported as >20.6 mg/mL) and dimethyl sulfoxide (DMSO) (reported as >22 mg/mL), which allows it to be prepared as an aqueous solution for injection or as part of a suspension in depot formulations.[5] For long-term stability in its pure form, storage at -20°C under desiccated conditions is recommended.[5]

1.3. Historical Context and Development

Leuprolide acetate was first approved for medical use by the U.S. Food and Drug Administration (FDA) in 1985 under the trade name Lupron™, marketed by TAP Pharmaceutical Products, a subsidiary of Abbott Laboratories.[1] This initial approval was for a daily subcutaneous injection for the palliative treatment of prostate cancer.[2]

A transformative step in the drug's clinical lifecycle occurred with the development and subsequent approval of long-acting depot formulations. The first Lupron Depot formulation, for monthly intramuscular injection, was approved by the FDA in 1989.[1] This innovation was critical, as it shifted the treatment paradigm from a burdensome daily injection to a more convenient monthly, and later multi-monthly, administration schedule. This enhancement in patient convenience and compliance was instrumental in establishing leuprolide as a standard of care and a commercially successful therapeutic agent. Over the subsequent decades, the development of new delivery technologies and formulations by various pharmaceutical companies has continued to shape its clinical use.[1]

Table 1: Key Chemical and Physical Properties of Leuprolide

Property	Value	Source(s)
Common Names	Leuprolide, Leuprorelin	1
Drug Type	Small Molecule, Synthetic Peptide	2
DrugBank ID	DB00007	1
CAS Number	53714-56-0 (base)	2
Molecular Formula	C59​H84​N16​O12​	1
Molar Mass	1209.4 g/mol	1
Appearance	Hygroscopic, white to off-white powder	6
Solubility	Water: >20.6 mg/mL; DMSO: >22 mg/mL	5
Storage (Neat)	Desiccate at -20°C	5
ATC Code	L02AE02	6

Section 2: Mechanism of Action and Pharmacodynamics

2.1. Classification: A Synthetic GnRH Superagonist

Leuprolide is pharmacologically classified as a potent synthetic analogue of gonadotropin-releasing hormone (GnRH), which is also known as luteinizing hormone-releasing hormone (LHRH).[1] It functions as a powerful agonist at GnRH receptors located on the surface of gonadotrope cells in the anterior pituitary gland.[1] Due to structural modifications, primarily the D-leucyl substitution at position 6, leuprolide exhibits a significantly higher binding affinity for the GnRH receptor and greater resistance to enzymatic breakdown compared to the native hormone. These characteristics result in a potency that is estimated to be 50 to 100 times greater than that of endogenous GnRH, coupled with a substantially longer duration of action.[3]

2.2. The Hypothalamic-Pituitary-Gonadal (HPG) Axis: The Target Pathway

To understand the action of leuprolide, it is essential to first understand the normal physiology of the hypothalamic-pituitary-gonadal (HPG) axis. In a healthy state, the hypothalamus secretes GnRH in a rhythmic, pulsatile fashion.[1] These pulses of GnRH travel to the anterior pituitary and bind to GnRH receptors on gonadotrope cells, stimulating them to synthesize and release the two primary gonadotropin hormones: Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH).[7] These gonadotropins then enter the systemic circulation and act on the gonads. In males, LH stimulates the Leydig cells of the testes to produce testosterone, while FSH supports spermatogenesis. In females, LH and FSH orchestrate the menstrual cycle, stimulating follicular development, ovulation, and the production of the primary female sex steroids, estradiol and progesterone, by the ovaries.[1] This finely tuned hormonal cascade is the central pathway targeted by leuprolide therapy.

2.3. The Biphasic Effect: A Pharmacological Paradox

The mechanism of leuprolide is defined by a paradoxical, biphasic response. Although it is a receptor agonist, its ultimate therapeutic effect is profound hormonal suppression, a state akin to surgical castration. This is achieved through the exploitation of a key regulatory feature of the HPG axis.

2.3.1. Initial Agonist Action: The Gonadotropin and Steroid Surge

Upon initial administration, leuprolide acts as a superagonist, delivering a powerful and sustained stimulatory signal to the pituitary GnRH receptors.[3] This potent stimulation triggers a significant, transient release of stored LH and FSH from the gonadotropes.[15] This surge in gonadotropins, in turn, leads to a temporary increase in gonadal steroidogenesis, causing serum levels of testosterone in males and estradiol in females to rise, often to levels well above their normal baseline.[1] This initial stimulatory phase typically lasts for the first one to two weeks of continuous therapy.

This initial hormonal surge is not merely a pharmacological curiosity; it is a critical clinical consideration that directly drives a major adverse event and shapes treatment strategies. In men with advanced prostate cancer, particularly those with bone metastases, this transient rise in testosterone can lead to a phenomenon known as "tumor flare".[8] This flare can manifest as a temporary but dangerous worsening of symptoms, including an increase in bone pain, and in some cases, can precipitate acute spinal cord compression or urinary tract obstruction.[18] To mitigate this risk in high-risk patients, clinical practice has evolved to include the co-administration of an anti-androgen medication (e.g., bicalutamide) at the beginning of leuprolide therapy to block the effects of the testosterone surge at the tumor site.[20] Similarly, in women treated for endometriosis, this initial estrogen surge can cause a temporary exacerbation of pelvic pain and other symptoms.[21] This inherent initial agonist effect also represents the primary mechanistic difference and competitive advantage of GnRH

antagonists (e.g., degarelix), which achieve hormonal suppression by directly blocking the GnRH receptor without causing an initial stimulatory surge.[13]

2.3.2. Chronic Administration: Receptor Downregulation and Desensitization

The normal functioning of the HPG axis is critically dependent on the pulsatile nature of GnRH release from the hypothalamus.[1] The continuous, high-level stimulation provided by leuprolide, especially with long-acting depot formulations, disrupts this essential rhythm. The constant presence of the agonist leads to the internalization and degradation of GnRH receptors on the pituitary cell surface, a process known as downregulation.[1] The remaining receptors become desensitized and uncoupled from their intracellular signaling pathways.

After approximately two to four weeks of continuous therapy, the pituitary gonadotropes become refractory and largely unresponsive to further stimulation by either leuprolide or endogenous GnRH.[1] This leads to a profound and sustained suppression of LH and FSH secretion.[8]

2.4. The State of Medical Castration: Therapeutic Suppression of Sex Hormones

The sustained inhibition of pituitary LH and FSH secretion effectively shuts down the primary signal for the gonads to produce sex steroids.[3] This results in a state of medical castration.

• In Males: Testicular steroidogenesis is dramatically reduced, and serum testosterone levels fall to castrate levels, which are clinically defined as a concentration of less than 50 ng/dL.[6] Achieving and maintaining this level of testosterone suppression is the primary therapeutic objective in the palliative treatment of hormone-sensitive prostate cancer.
• In Females: Ovarian steroidogenesis is suppressed, causing serum estradiol levels to fall to the low levels characteristic of a post-menopausal state.[1] This induced hypoestrogenism is the mechanism by which leuprolide alleviates symptoms and causes the regression of lesions in estrogen-dependent conditions like endometriosis and uterine fibroids.

This chemically induced hypogonadal state is the cornerstone of leuprolide's efficacy. The effect is maintained for as long as the drug is administered and is fully reversible upon cessation of therapy, as the pituitary receptors are gradually re-sensitized and the HPG axis resumes its normal function.[3]

2.5. Direct vs. Indirect Effects: Evidence for GnRH Receptors in Non-Pituitary Tissues

While the primary therapeutic mechanism of leuprolide is indirect, mediated through the suppression of the HPG axis, a growing body of evidence suggests a potential for direct action on peripheral tissues. Research has identified the expression of GnRH receptors (GnRH-R) in a wide array of non-pituitary tissues, including the cells of several hormone-sensitive cancers such as prostate, breast, ovarian, and endometrial cancers.[11]

The presence of these receptors on cancer cells themselves implies that GnRH analogues like leuprolide might exert direct anti-tumoral effects, such as inhibiting cell proliferation or inducing apoptosis, independent of their systemic hormone-lowering action.[11] This potential dual mechanism—indirect suppression of hormonal growth factors and direct action on tumor cells—is an active area of oncological research. It suggests future therapeutic possibilities, such as the development of GnRH-based targeted therapies or the use of these agents in clinical scenarios where systemic hormone suppression is no longer the primary goal, for instance, in hormone-refractory cancers. This line of investigation represents a significant evolution from the classical understanding of leuprolide's action, pointing toward a more complex and multifaceted role in cancer therapy.

Section 3: Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

3.1. Administration and Absorption

Leuprolide is a peptide-based drug, and like most peptides, it is subject to rapid degradation by proteolytic enzymes in the gastrointestinal tract. Consequently, it has very low oral bioavailability and is ineffective when administered orally.[4] This necessitates parenteral administration, which is achieved through either subcutaneous (SC) or intramuscular (IM) injection.[1] Studies have shown that the bioavailability following subcutaneous administration is comparable to that of direct intravenous (IV) administration.[3]

The clinical utility of leuprolide has been defined by the development of long-acting depot formulations. These formulations encapsulate the drug within a biodegradable polymeric matrix (e.g., polylactide-co-glycolide microspheres in Lupron Depot) or a polymer-based gel system (e.g., the ATRIGEL® system in Eligard).[4] When injected, these depots form a drug reservoir at the site of administration, from which leuprolide is released in a controlled, sustained manner over a period of one, three, four, or even six months.[25] Following injection of a depot formulation, plasma concentrations typically exhibit a biphasic profile: an initial "burst" phase where peak concentrations (Cmax) are reached within approximately 4 to 5 hours, followed by a decline to a sustained "plateau" phase where therapeutic concentrations are maintained for the duration of the dosing interval.[7]

The pharmacokinetic profile experienced by the patient is therefore almost entirely a function of the drug delivery technology rather than the intrinsic properties of the leuprolide molecule itself. The drug's native 3-hour half-life is rendered clinically irrelevant by formulations designed to last for months. Thus, the therapeutic concentrations, dosing intervals, and even brand-specific characteristics are dictated by the science of the depot formulation. This makes any clinical comparison between different brands, such as Lupron Depot and Eligard, fundamentally a comparison of their respective drug delivery systems and the resulting in-vivo release profiles.[26]

3.2. Distribution

Once absorbed into the systemic circulation, leuprolide distributes throughout the body. In healthy male subjects, the mean volume of distribution at steady state has been determined to be approximately 27 liters.[8] Leuprolide exhibits moderate binding to plasma proteins, with reported binding percentages ranging from 43% to 49%.[3] Animal studies investigating tissue distribution have shown that leuprolide concentrates to a high degree in the kidneys, liver, and the pituitary gland—its primary site of action—while lower concentrations are found in muscle tissue and the cerebral cortex.[8] Evidence also indicates that the drug is capable of crossing the blood-brain barrier.[8]

3.3. Metabolism

The metabolic pathway of leuprolide is characteristic of a peptide drug. It is primarily degraded through enzymatic proteolysis by peptidases found in plasma and various tissues.[3] This process breaks the nonapeptide down into smaller, pharmacologically inactive peptide fragments. The principal metabolite identified in human plasma is an inactive pentapeptide known as M-I, which reaches its peak concentration 2 to 6 hours after dosing.[3] Other smaller fragments, including tripeptides and a dipeptide, have also been identified.[3]

A clinically crucial aspect of leuprolide's metabolism is its independence from the cytochrome P-450 (CYP450) enzyme system.[3] The CYP450 system is responsible for the metabolism of a vast number of drugs and is the primary site of many clinically significant drug-drug interactions (DDIs). Because leuprolide's clearance does not rely on these enzymes, it has a very low potential for pharmacokinetic DDIs where it would either inhibit or induce the metabolism of a co-administered drug, or have its own metabolism affected. This metabolic profile, combined with its moderate plasma protein binding, makes it a relatively "clean" drug from a pharmacokinetic interaction standpoint. This is a significant clinical advantage, particularly in the context of oncology, where patients are often receiving multiple concurrent medications. The primary DDI concerns for leuprolide are therefore pharmacodynamic in nature (i.e., additive effects on physiological systems, such as QT interval prolongation) rather than pharmacokinetic.

3.4. Elimination

The terminal elimination half-life of leuprolide, when administered as an IV bolus, is approximately 3 hours.[2] This relatively short half-life highlights the critical importance of the D-leucyl substitution in its structure, which significantly extends its duration of action compared to native GnRH (which has a half-life of only 3 to 4 minutes), and underscores the necessity of depot formulations for achieving sustained therapeutic effects in chronic conditions.[2]

Systemic clearance of leuprolide in healthy males is in the range of 7.6 to 8.3 L/h.[3] The drug and its inactive peptide metabolites are eliminated from the body primarily through renal excretion. Studies have shown that following a single subcutaneous injection, a very small fraction of the dose (less than 5%) is excreted in the urine as the intact parent drug.[6]

Section 4: FDA-Approved Indications and Clinical Efficacy

Leuprolide acetate has a range of well-established, FDA-approved indications that span oncology, gynecology, and pediatric endocrinology. The approval for these uses is often highly specific to the brand, dosage strength, and formulation, reflecting the distinct clinical trials and development pathways for each product.

4.1. Advanced Prostate Cancer

The palliative treatment of advanced, hormone-sensitive prostate cancer is the cornerstone indication for leuprolide and its most common application.[1] The therapeutic goal is to induce and maintain a state of medical castration by suppressing serum testosterone to levels below 50 ng/dL.[8] This androgen deprivation therapy (ADT) slows the proliferation of hormone-dependent tumor cells, leading to disease stabilization and relief of symptoms such as metastatic bone pain.[19]

Clinical efficacy is robust and well-documented. Across numerous trials, various depot formulations of leuprolide have consistently demonstrated the ability to achieve and maintain castrate levels of testosterone in over 90% of patients, typically within two to four weeks of initiating therapy.[14] Therapeutic response is routinely monitored by measuring serum testosterone and prostate-specific antigen (PSA) levels.[3] A wide array of long-acting formulations are approved for this indication, including Lupron Depot (IM), Eligard (SC), and Camcevi (SC), offering dosing schedules of one, three, four, and six months to accommodate patient and provider preference.[18]

4.2. Endometriosis

In gynecology, leuprolide is indicated for the management of endometriosis, a condition characterized by the growth of endometrial-like tissue outside the uterus.[1] The primary goals of therapy are to provide pain relief from symptoms like dysmenorrhea (painful periods) and dyspareunia (painful intercourse) and to achieve a reduction in the size and activity of endometriotic lesions.[4]

The mechanism of action relies on inducing a profound hypoestrogenic state, mimicking menopause, which leads to the atrophy of the ectopic endometrial tissue.[24] While effective, this induced hypoestrogenism raises concerns about adverse effects on bone mineral density (BMD). Consequently, when used as a monotherapy, the duration of treatment is limited by the FDA to a maximum of six months.[21] To mitigate bone loss and ameliorate vasomotor symptoms like hot flashes, leuprolide can be administered with "add-back" therapy, typically a daily low dose of norethindrone acetate. This combination allows for a single retreatment course of an additional six months, for a total maximum treatment duration of 12 months.[32] The formulations approved for this indication are Lupron Depot 3.75 mg (monthly) and 11.25 mg (3-monthly).[4]

4.3. Uterine Leiomyomata (Fibroids)

Leuprolide is also FDA-approved for use in women with uterine leiomyomata, commonly known as fibroids.[1] Specifically, it is indicated for use concomitantly with iron therapy for the preoperative hematologic improvement of patients who have developed anemia as a result of heavy menstrual bleeding (menorrhagia) caused by the fibroids.[4]

Similar to its use in endometriosis, the therapeutic goal is to induce a hypoestrogenic state. This leads to a reduction in both uterine and fibroid volume, which in turn decreases excessive bleeding and allows for the correction of anemia before a planned surgical procedure, such as a hysterectomy or myomectomy.[4] Treatment for this indication is typically short-term, limited to a single course of up to three months with Lupron Depot 3.75 mg or a single injection of the 11.25 mg formulation.[4]

4.4. Central Precocious Puberty (CPP)

In pediatric endocrinology, leuprolide is a primary treatment for central precocious puberty (CPP), a condition defined by the premature onset of secondary sexual characteristics (before age 8 in girls and age 9 in boys) due to early activation of the HPG axis.[1] The goal of therapy is to suppress this premature pubertal surge, thereby halting or reversing the progression of pubertal signs, slowing the rate of bone age advancement, and ultimately preserving the potential for achieving a normal adult height, which can be compromised by premature growth plate fusion.[2]

Clinical studies utilizing specific pediatric formulations have demonstrated high efficacy in suppressing pubertal development, as measured by Tanner staging, and in reducing gonadotropin levels to prepubertal ranges (e.g., peak stimulated LH < 4.0 mIU/mL).[41] Treatment is carefully monitored and is typically discontinued at an age deemed appropriate for the onset of normal puberty, allowing the HPG axis to reactivate.[31] Formulations specifically approved for this pediatric population include Lupron Depot-PED and Fensolvi, which are available in 1-, 3-, and 6-month depot injections, with dosing often tailored to the child's body weight.[31]

Table 2: FDA-Approved Indications for Major Leuprolide Formulations

Brand Name	Formulation / Strength	FDA-Approved Indication(s)	Patient Population	Source(s)
Lupron Depot	7.5 mg (1-mo), 22.5 mg (3-mo), 30 mg (4-mo), 45 mg (6-mo)	Palliative treatment of advanced prostate cancer	Adult Males	18
Lupron Depot	3.75 mg (1-mo), 11.25 mg (3-mo)	Management of endometriosis; Preoperative treatment of anemia due to uterine fibroids	Adult Females	4
Eligard	7.5 mg (1-mo), 22.5 mg (3-mo), 30 mg (4-mo), 45 mg (6-mo)	Palliative treatment of advanced prostate cancer	Adult Males	17
Camcevi	42 mg (6-mo)	Treatment of advanced prostate cancer	Adult Males	1
Lupron Depot-PED	7.5, 11.25, 15 mg (1-mo); 11.25, 30 mg (3-mo); 45 mg (6-mo)	Central precocious puberty (CPP)	Pediatric (≥2 years)	41
Fensolvi	45 mg (6-mo)	Central precocious puberty (CPP)	Pediatric (≥2 years)	31

The specificity of these approvals is a critical point for clinicians and pharmacists. For instance, prescribing Lupron Depot 7.5 mg for endometriosis would constitute an off-label use, as the 7.5 mg strength is approved for prostate cancer, whereas the 3.75 mg strength is the approved dose for endometriosis.[4] This table clarifies these regulatory distinctions, which are vital for ensuring safe and appropriate medication use.

Section 5: Off-Label and Investigational Applications

Beyond its FDA-approved indications, leuprolide is widely used off-label for a variety of conditions. These applications range from evidence-based practices that have become standards of care to more controversial uses that are the subject of ongoing debate. This spectrum of off-label use makes leuprolide a compelling case study in the complexities of modern clinical practice and pharmaceutical ethics.

5.1. Breast Cancer

One of the most significant off-label applications of leuprolide is for ovarian function suppression (OFS) in premenopausal women diagnosed with hormone receptor-positive (HR+) breast cancer.[1] In this setting, leuprolide is typically used in combination with other endocrine therapies, such as tamoxifen or, more commonly, an aromatase inhibitor (e.g., letrozole, anastrozole).[47]

The rationale for this use is straightforward: by inducing a medical menopause, leuprolide eliminates the ovaries as the primary source of estrogen, which acts as a fuel for the growth of HR+ breast cancer cells. This hypoestrogenic state is essential for the efficacy of aromatase inhibitors, which work by blocking the peripheral conversion of androgens to estrogens but cannot overcome the high levels of estrogen produced by functioning ovaries.[47]

This application, while historically off-label, is now firmly supported by data from major clinical trials (e.g., SOFT/TEXT trials) and is recommended as a standard-of-care option in guidelines from major oncology organizations, including the American Society of Clinical Oncology (ASCO) and the St. Gallen International Breast Cancer Conference.[46] The National Cancer Institute (NCI) appears to have formally recognized this use as hormone therapy for coding purposes as of 2017.[48] Clinical studies have shown that leuprolide is equally effective as the other commonly used GnRH agonist, goserelin, for achieving OFS.[46] This evolution from off-label use to an evidence-based standard of care demonstrates how clinical practice can advance ahead of formal regulatory label changes.

5.2. Infertility Treatment (IVF Protocols)

Leuprolide plays a crucial role in many controlled ovarian stimulation protocols for in vitro fertilization (IVF).[1] Its primary purpose in this context is to prevent a premature surge of endogenous luteinizing hormone (LH), which could trigger ovulation before the developing follicles are ready for retrieval.[1]

By administering leuprolide to downregulate the pituitary gland, fertility specialists gain complete control over the patient's cycle. This allows for the administration of high doses of gonadotropins (FSH/HMG) to stimulate the synchronized growth and maturation of multiple oocytes.[24] Once the follicles reach the optimal size, leuprolide is discontinued, and a "trigger shot" of human chorionic gonadotropin (hCG), which mimics the natural LH surge, is administered to induce final oocyte maturation, precisely timing the retrieval procedure.[50] This application is a widely accepted and routine off-label use in reproductive medicine.[15] It stands as an interesting clinical scenario where a drug is used ubiquitously despite a contraindication on its label, which warns against use in women who are or may become pregnant due to a theoretical risk of fetal harm based on animal studies.[1] This highlights a notable disconnect between regulatory warnings and established clinical utility.

5.3. Gender Dysphoria

The use of leuprolide in the management of gender dysphoria is one of its most controversial off-label applications. It is used in two distinct populations:

1. Transgender Adolescents: Leuprolide is used as a "puberty blocker" to suppress the onset of endogenous puberty.[1] The rationale is to pause the development of irreversible secondary sex characteristics that are incongruent with the adolescent's gender identity. This provides the individual with more time to explore their identity and make future decisions regarding gender-affirming hormone therapy, while alleviating the psychological distress associated with unwanted pubertal changes.[1]
2. Transgender Adults: It is used as part of a gender-affirming hormone regimen to suppress the production of endogenous testosterone in transgender women or estrogen in transgender men, thereby facilitating the desired physical changes induced by cross-sex hormone administration.[1]

While this use is supported by clinical practice guidelines from professional organizations such as the World Professional Association for Transgender Health (WPATH) and the Endocrine Society [54], it is not approved by the FDA for this indication and is the subject of intense medical, ethical, and legal debate.[55] Critics and regulatory bodies have raised significant concerns about the lack of long-term safety data for this use, particularly in adolescents. The primary areas of concern include the potential for irreversible effects on fertility, the impact on bone mineral density accrual during a critical developmental period, and unknown effects on neurocognitive development.[55] This has led to legislative action in some jurisdictions to restrict or ban this use in minors and has positioned leuprolide at the center of a major societal debate about the appropriate standards of care for transgender youth.

5.4. Other Investigational Uses

Leuprolide has been explored for several other conditions, leveraging its potent hormone-suppressing effects:

• Paraphilias and Hypersexuality: By inducing a state of chemical castration, leuprolide has been tested as a treatment to reduce libido and sexual urges in individuals with paraphilias, including pedophilia, and in the management of violent sex offenders.[1]
• Hormone-Dependent Gynecologic Cancers: Beyond breast cancer, leuprolide has been studied in other hormone-sensitive gynecologic malignancies. A notable retrospective study in patients with recurrent ovarian granulosa cell tumors found that leuprolide-containing regimens provided a 6-month clinical benefit rate of 66% and a progression-free survival comparable to that of traditional chemotherapy, with significantly less toxicity.[45]
• Alzheimer's Disease: The presence of GnRH receptors in brain regions like the hippocampus and cortex has prompted investigational use of leuprolide in neurodegenerative conditions such as Alzheimer's disease, exploring the complex interplay between sex hormones, GnRH signaling, and cognitive function.[11]

Section 6: Comprehensive Safety Profile and Tolerability

The safety profile of leuprolide is extensively characterized and is dominated by the predictable physiological consequences of inducing a hypogonadal state. While generally considered safe for its approved indications, it carries several significant warnings and precautions that require careful patient counseling and monitoring.

6.1. Common Adverse Events

The most frequently reported adverse events are direct results of the suppression of testosterone in men or estrogen in women.[19]

• General and Vasomotor: The most common side effect across all populations is hot flashes or sweats, which can be significant.[1] Other general effects include headaches, fatigue, and injection site reactions such as pain, erythema (redness), bruising, or swelling.[1]
• Psychiatric and Mood: Mood swings, emotional lability, and depression are commonly reported in both men and women.[1]
• Adverse Events in Men: The hypoandrogenic state predictably leads to decreased libido, erectile dysfunction (impotence), testicular atrophy (shrinkage), and gynecomastia (breast tenderness or enlargement).[1] Loss of muscle mass can also occur.[8]
• Adverse Events in Women: The hypoestrogenic state leads to symptoms similar to menopause, including amenorrhea (cessation of menstruation), vaginal dryness, vaginitis, and decreased libido.[8]

6.2. Serious Warnings and Precautions (FDA Mandated)

The FDA label for leuprolide includes several important warnings regarding potentially serious risks.

6.2.1. Tumor Flare Phenomenon in Prostate Cancer

As a consequence of its initial agonist action, leuprolide causes a transient surge in testosterone during the first few weeks of therapy. In men with advanced prostate cancer, this can lead to a "tumor flare," manifesting as a temporary worsening of symptoms. This may include an increase in bone pain, new or worsened neuropathy, hematuria, or obstruction of the bladder outlet or ureters.[8] In rare but critical cases, this flare can cause acute spinal cord compression in patients with vertebral metastases, potentially leading to paralysis.[8] Due to this risk, close monitoring of high-risk patients is mandatory during the initial phase of treatment.

6.2.2. Cardiovascular and Metabolic Risks

Long-term androgen deprivation therapy with GnRH agonists in men has been associated with significant metabolic and cardiovascular risks.

• Cardiovascular Disease: Post-marketing reports and observational studies have indicated an increased risk of serious cardiovascular events, including myocardial infarction, sudden cardiac death, and stroke.[14] Patients, particularly those with pre-existing cardiovascular risk factors, should be monitored for signs and symptoms of cardiovascular disease.
• Hyperglycemia and Diabetes: An increased risk of developing new-onset type 2 diabetes and worsening glycemic control in patients with pre-existing diabetes has been reported.[1] Periodic monitoring of blood glucose and/or glycosylated hemoglobin (HbA1c) is recommended.

6.2.3. Effects on Bone Mineral Density (BMD)

The chronic suppression of sex hormones accelerates bone turnover, leading to a progressive decrease in bone mineral density (BMD).[8] This increases the long-term risk of osteoporosis and fragility fractures. This effect is a primary dose-limiting toxicity in women treated for endometriosis, necessitating the 6-month monotherapy limit and the use of add-back therapy for longer treatment durations.[21] It is also a significant concern for men undergoing long-term ADT for prostate cancer, who may require monitoring and management of bone health.

6.2.4. Effect on QT/QTc Interval

Androgen deprivation therapy, including leuprolide, has been shown to prolong the QT interval on an electrocardiogram (ECG).[18] QT prolongation is a risk factor for a potentially fatal ventricular arrhythmia known as Torsades de Pointes. Therefore, the benefits and risks of leuprolide should be carefully considered in patients with congenital long QT syndrome, congestive heart failure, electrolyte abnormalities, or those taking other medications known to prolong the QT interval.[51]

6.2.5. Psychiatric Events and Convulsions

• Psychiatric Effects: In addition to common mood swings, post-marketing reports have noted cases of clinical depression, and rare instances of suicidal ideation and attempt.[8]
• Convulsions: Seizures have been observed in patients receiving leuprolide, including in individuals with no prior history of seizures or other predisposing factors.[18]
• Pituitary Apoplexy: Rare cases of pituitary apoplexy, a clinical syndrome caused by sudden hemorrhage or infarction of the pituitary gland, have been reported following the initial administration of GnRH agonists, typically within two weeks of the first dose.[18]

6.3. Contraindications and High-Risk Populations

Leuprolide is contraindicated in several specific populations:

• Hypersensitivity: Patients with a known history of hypersensitivity to leuprolide, other GnRH agonists, or any of the excipients in the formulation (such as benzyl alcohol, which can cause local reactions) should not receive the drug.[2]
• Pregnancy: Leuprolide is designated as Pregnancy Category X. It may cause fetal harm and has been associated with an increased risk of spontaneous abortion in animal studies. It must not be used in women who are or may become pregnant. Women of childbearing potential must be counseled to use an effective method of non-hormonal contraception during therapy.[1]
• Lactation: It is not known whether leuprolide is excreted in human milk. Due to the potential for adverse effects in the nursing infant, breastfeeding is generally not recommended during treatment.[2]
• Undiagnosed Abnormal Uterine Bleeding: Use is contraindicated in women with undiagnosed abnormal uterine bleeding, as it may mask an underlying pathology.[32]

6.4. Drug-Drug Interactions

As discussed in Section 3, the potential for pharmacokinetic interactions with leuprolide is low.[3] The primary concern for drug-drug interactions is pharmacodynamic, specifically the additive risk of QT prolongation. Co-administration of leuprolide with other drugs that prolong the QT interval can significantly increase the risk of cardiac arrhythmias. A comprehensive list of such drugs is extensive, but key classes to monitor closely include:

• Class IA Antiarrhythmics (e.g., quinidine, procainamide)
• Class III Antiarrhythmics (e.g., amiodarone, sotalol, dofetilide)
• Certain Antipsychotics (e.g., ziprasidone, haloperidol, thioridazine)
• Certain Antibiotics (e.g., moxifloxacin, clarithromycin, azithromycin)
• Certain Antidepressants (e.g., citalopram, escitalopram)
• Other GnRH Agonists (e.g., goserelin, triptorelin)

Clinicians must carefully review a patient's complete medication list before initiating leuprolide therapy.[7]

Table 3: Summary of Common and Serious Adverse Events with Leuprolide

System Organ Class	Common Adverse Events (>10%)	Serious / Clinically Significant Adverse Events
Cardiovascular	Hot flashes/sweats, Edema	Increased risk of MI, stroke, sudden cardiac death; QT interval prolongation
Endocrine/Metabolic	Weight gain/loss	Hyperglycemia, increased risk of diabetes; Pituitary apoplexy (rare)
Musculoskeletal	General pain, Arthralgia	Decreased bone mineral density, osteoporosis, increased fracture risk; Myalgia
Neurological/Psychiatric	Headache, Dizziness, Insomnia, Mood swings/lability	Tumor flare with potential for spinal cord compression; Depression, suicidal ideation (rare); Convulsions
Reproductive (Male)	Decreased libido, Erectile dysfunction, Testicular atrophy	Impairment of fertility (reversible)
Reproductive (Female)	Vaginitis, Vaginal dryness, Amenorrhea, Decreased libido	Impairment of fertility (reversible); Spontaneous abortion if used during pregnancy
General/Dermatologic	Injection site reactions (pain, erythema, swelling), Fatigue, Asthenia	Anaphylaxis/Hypersensitivity reactions; Serious skin reactions (rare)

Section 7: Commercial Formulations and Comparative Analysis

The commercial landscape for leuprolide is characterized by a variety of branded products, each utilizing different drug delivery technologies to provide sustained release. This diversity offers clinicians flexibility in dosing schedules and administration routes but also necessitates a clear understanding of the differences between formulations to ensure appropriate use.

7.1. Overview of Marketed Formulations

Leuprolide is available under several well-known brand names, including Lupron®, Eligard®, Camcevi®, and Fensolvi®, as well as in a combination product, Lupaneta Pack®.[1] The key innovation that has driven its market presence is the development of long-acting depot technologies.

• Formulation Types:
• Intramuscular (IM) Depot Suspension: This is the technology used by the Lupron Depot® family of products. It consists of biodegradable polylactide-co-glycolide (PLG) microspheres containing leuprolide acetate. These are supplied as a lyophilized powder that must be reconstituted with a diluent before being injected into a muscle.[4]
• Subcutaneous (SC) Depot Suspension/Gel: This technology is used by Eligard®. It employs the ATRIGEL® Delivery System, which consists of a biodegradable polymer dissolved in a biocompatible solvent. The drug and the polymer system are supplied in two separate syringes that are mixed immediately prior to injection. Once injected subcutaneously, the solvent diffuses away, causing the polymer to precipitate and form a solid, biodegradable implant that releases the drug over time.[17]
• Subcutaneous (SC) Depot Emulsion: Camcevi® is a newer formulation that is provided as a sterile, ready-to-use emulsion in a pre-filled syringe, eliminating the need for on-site reconstitution and simplifying the administration process.[1]
• Subcutaneous (SC) Implant: Viadur® was a surgically placed osmotic implant that delivered leuprolide for up to one year, but it has been discontinued.[1]
• Combination Pack: Lupaneta Pack® is a convenience kit that co-packages a Lupron Depot injection with a 30-day supply of norethindrone acetate tablets, streamlining the provision of add-back therapy for endometriosis.[1]
• Dosing Schedules: These depot technologies have enabled dosing intervals that range from one month to six months, a significant improvement over the original daily injection.[18]

7.2. Brand Comparison: Lupron® vs. Eligard®

Lupron Depot and Eligard are two of the most widely prescribed leuprolide formulations for advanced prostate cancer. While they share the same active ingredient and therapeutic goal, their differing technologies and administration routes are key points of comparison for clinicians.

7.2.1. Core Similarity

Both Lupron Depot and Eligard contain leuprolide acetate and are considered to have comparable clinical efficacy in achieving and maintaining testosterone suppression to castrate levels in men with prostate cancer.[25] Clinical trials for both brands have shown that over 94% of participants reach the target testosterone level (< 50 ng/dL) within the first month of therapy.[29] Consequently, they share the same fundamental side effect profile and long-term risks associated with androgen deprivation.[29]

7.2.2. Key Differences: Delivery Technology and Administration Route

The primary distinction lies in their formulation and how they are administered:

• Lupron Depot: Is administered via intramuscular (IM) injection, typically into the gluteal, deltoid, or anterior thigh muscle. It requires reconstitution of a powder with a diluent prior to injection.[25]
• Eligard: Is administered via subcutaneous (SC) injection, typically into the abdomen, upper buttocks, or another area with adequate subcutaneous tissue. It requires mixing the contents of two syringes to form the ATRIGEL® liquid, which then solidifies into an implant-like depot under the skin.[17]

The subcutaneous route of Eligard may be considered an advantage for patients with low muscle mass or for those on anticoagulant therapy, for whom IM injections pose a higher risk of hematoma.[64]

7.2.3. Pharmacokinetic and Clinical Trial Comparisons

Direct head-to-head comparative trials are limited. However, some studies suggest subtle pharmacokinetic differences that may arise from the different delivery systems. One crossover study noted that the IM formulation (Lupron) produced a higher initial peak concentration (Cmax), while the SC formulation (Eligard) resulted in a longer duration of quantifiable drug concentration and sustained LH suppression.[27] Another retrospective study in transgender youth found that while both were effective at suppressing clinical puberty, the rate of biochemical suppression was numerically higher with Eligard (90%) compared to Lupron (69%), although this difference did not reach statistical significance (p=0.06).[65] A Phase 4 crossover study (NCT00220194) was initiated to directly compare the maintenance of testosterone suppression when switching between the brands, but detailed results are not available in the provided materials.[66]

7.2.4. Tolerability and Patient-Reported Outcomes

Both formulations are generally well-tolerated, with the primary side effects being related to hormone deprivation. Some data and patient-reported reviews suggest that injection site reactions, particularly pain, may be slightly more frequent or intense with the subcutaneous administration of Eligard compared to the intramuscular injection of Lupron Depot.[29] On the patient review website Drugs.com, Lupron Depot holds a slightly higher average satisfaction rating (5.8 out of 10 from 237 ratings) compared to Eligard (4.5 out of 10 from 41 ratings), though such data must be interpreted with caution.[59] The choice between the two often comes down to physician experience, institutional contracts, insurance coverage, and patient factors such as preference for injection site or presence of contraindications to IM injections.[46]

Table 4: Comparative Profile of Lupron Depot® vs. Eligard® for Prostate Cancer

Feature	Lupron Depot®	Eligard®
Active Ingredient	Leuprolide Acetate	Leuprolide Acetate
Delivery Technology	Biodegradable PLG Microspheres	ATRIGEL® Polymer System
Administration Route	Intramuscular (IM)	Subcutaneous (SC)
Preparation	Reconstitution of powder and diluent	Mixing of two pre-filled syringes
Dosing Schedules	1, 3, 4, 6 months	1, 3, 4, 6 months
FDA-Approved Indications	Prostate Cancer, Endometriosis, Uterine Fibroids, CPP	Advanced Prostate Cancer Only
Reported Tolerability	Generally well-tolerated	Generally well-tolerated; some reports of higher injection site pain

7.3. Other Formulations

• Camcevi®: This is a newer branded product available as a 6-month (42 mg) subcutaneous injection. Its main differentiating feature is that it is supplied as a ready-to-use, pre-filled syringe, which eliminates the need for reconstitution or mixing, thereby simplifying the administration process and reducing the potential for preparation errors.[31] A 3-month formulation is currently under FDA review.[63]
• Fensolvi®: This is a branded 6-month (45 mg) subcutaneous depot formulation that is specifically FDA-approved for the treatment of pediatric central precocious puberty.[31]

Section 8: Regulatory History and Future Directions

The evolution of leuprolide from a novel chemical entity to a mature, multi-billion-dollar market therapeutic is reflected in its long and complex regulatory history, ongoing post-marketing surveillance, and the current focus of research and development.

8.1. Key FDA Approvals and Label Expansions

The regulatory journey of leuprolide in the United States has been marked by a series of key approvals that expanded its therapeutic reach:

• 1985: The initial FDA approval was granted for the daily injection formulation of Lupron® for the palliative treatment of advanced prostate cancer.[2]
• 1989: A pivotal milestone was the approval of Lupron Depot® 7.5 mg, the first long-acting monthly formulation for prostate cancer, which revolutionized its clinical use.[1]
• 1990s: The label was expanded significantly during this decade. Lupron Depot® was approved for the management of endometriosis and for preoperative use in uterine fibroids. Concurrently, Lupron Depot-PED® was approved for central precocious puberty, opening a new pediatric market.[10]
• 2000s: The market saw the entry of a major competitor with the approval of the Eligard® family of products (1, 3, 4, and 6-month subcutaneous formulations) for advanced prostate cancer, introducing a new delivery technology.[64]
• 2021-2022: The approval and subsequent launch of Camcevi®, a 6-month ready-to-use subcutaneous formulation, marked the latest innovation focused on administration convenience.[1]
• International Approvals: Leuprolide is also approved in many other jurisdictions, including a 2022 approval for Camcevi® by the European Medicines Agency (EMA).[1]

8.2. Post-Marketing Surveillance and Legal Controversies

As a widely used drug for several decades, leuprolide has been subject to extensive post-marketing surveillance and has not been without controversy.

• FDA Safety Communications: The FDA has actively monitored the safety of GnRH agonists. In 2010, the agency issued a safety communication to inform healthcare professionals and the public of an ongoing review into a possible small increased risk of diabetes and certain cardiovascular events (myocardial infarction, sudden cardiac death, stroke) in men receiving these drugs for prostate cancer.[61] While the agency noted limitations in the available data, it advised clinicians to be aware of these potential risks and to monitor patients accordingly.
• Legal and Marketing Issues: In 2001, TAP Pharmaceutical Products, the original marketer of Lupron®, settled significant criminal and civil charges with the U.S. Department of Justice. The charges were related to federal and state Medicare fraud and the illegal marketing of the drug, including allegations of incentivizing physicians to bill for free samples.[1] Separately, there has been considerable patient advocacy and litigation concerning claims of severe, long-term, and debilitating side effects associated with leuprolide, particularly arising from its off-label uses.[55]

8.3. The Evolving Market: Generic Competition and New Formulations

The leuprolide market is mature and dynamic. The expiration of key patents has led to the introduction of generic leuprolide acetate injections, increasing price competition.[44] In response, the focus of branded drug development has shifted. Rather than pursuing novel mechanisms, innovation is now centered on creating new patent-protected formulations that offer enhanced convenience. The development of Camcevi® as a pre-filled, ready-to-use emulsion is a prime example of this strategy, aiming to capture market share by simplifying the administration process for healthcare providers.[63] The global market for leuprorelin drugs is projected to continue growing, fueled by the rising global prevalence of prostate cancer and endometriosis, as well as its expanding use in other areas of hormone therapy.[44]

8.4. Ongoing Research and Future Therapeutic Potential

The future of leuprolide is not one of obsolescence but of evolution, primarily as a foundational element in more complex treatment regimens and through the development of improved delivery systems.

• Combination Therapies in Oncology: A major thrust of current research is positioning leuprolide as the backbone of androgen deprivation therapy in combination with newer, more targeted agents. The Phase 3 EMBARK trial represents a landmark in this area. It demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) when the androgen receptor inhibitor enzalutamide (XTANDI®) was added to leuprolide in men with high-risk, non-metastatic, hormone-sensitive prostate cancer.[71] This result solidifies leuprolide's role not as a standalone therapy, but as the essential platform upon which more advanced treatments are built, securing its relevance for years to come.
• New Formulations and Delivery Systems: The development pipeline continues to produce new leuprolide formulations. A New Drug Application (NDA) for a 3-month formulation of leuprolide mesylate (Camcevi® 21 mg) is currently under review by the FDA, with a target action date of August 29, 2025.[63] This reflects the market trend towards providing a complete franchise of dosing options with enhanced convenience. Research also continues into novel excipients and delivery technologies to potentially improve the drug's release profile and tolerability.[62]
• Comparative Efficacy and Safety Trials: As new classes of drugs emerge, leuprolide is often used as the active comparator. For example, ongoing and recent trials have compared leuprolide to the oral GnRH antagonist relugolix, with a particular focus on differences in cardiovascular safety profiles, an area of known concern for GnRH agonists.[74]

The commercial dynamics of the leuprolide market are now driven less by fundamental efficacy—which is well-established—and more by factors like administration convenience, cost, and intellectual property strategies surrounding novel drug delivery systems. The development of products like Camcevi, which offers no new efficacy but a significant improvement in ease of use, exemplifies this market shift.[63]

Section 9: Expert Synthesis and Concluding Remarks

Leuprolide acetate stands as a paradigm of modern pharmaceutical development, a synthetic peptide that has been a transformative therapeutic agent for nearly four decades. Its clinical success is rooted in a sophisticated and paradoxical mechanism of action: the use of a powerful GnRH receptor superagonist to achieve profound, reversible suppression of the very hormonal axis it initially stimulates. This ability to induce a state of medical castration has made it an indispensable tool in medicine.

The cornerstone of its utility remains the palliative treatment of advanced, hormone-sensitive prostate cancer, where it has long been the standard of care for androgen deprivation therapy. Its applications in gynecology for managing the debilitating symptoms of endometriosis and uterine fibroids, and in pediatric endocrinology for halting the progression of central precocious puberty, further underscore its versatility and impact. The single most important technological innovation in its history was the development of long-acting depot formulations. This advance liberated patients and providers from the burden of daily injections, cementing leuprolide's place in clinical practice and enabling its widespread, long-term use.

However, the profile of leuprolide is dualistic. For its approved indications, it is a well-understood, evidence-backed therapy with a predictable, albeit significant, side effect profile largely attributable to hormone deprivation. These risks, including effects on bone mineral density and the cardiovascular system, are well-characterized and can be managed with appropriate monitoring and, in some cases, adjunctive therapies. In parallel, leuprolide is the subject of extensive off-label use that spans the spectrum from accepted standards of care, such as for ovarian suppression in breast cancer, to highly controversial applications, most notably its use as a puberty blocker in transgender adolescents, which remains at the forefront of a complex medical, social, and ethical debate.

The future of leuprolide is not one of decline but of strategic evolution. In oncology, its role is maturing from that of a standalone agent to that of the foundational backbone for increasingly effective combination therapies, as powerfully demonstrated by recent trials in prostate cancer. In the broader pharmaceutical market, its trajectory will be shaped less by novel efficacy and more by innovations in drug delivery that enhance convenience and safety, and by the ongoing societal and regulatory navigation of its most contentious off-label uses. Leuprolide acetate remains a pillar of hormonal therapy and will continue to serve as a fascinating and instructive case study in the lifecycle of a modern pharmaceutical agent.

Works cited

1. Leuprorelin - Wikipedia, accessed July 15, 2025, https://en.wikipedia.org/wiki/Leuprorelin
2. Leuprolide | C59H84N16O12 | CID 657181 - PubChem, accessed July 15, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Leuprolide
3. LUPRON® INJECTION (leuprolide acetate) - accessdata.fda.gov, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019010s033,019732s031s035s036,020517s024s028s029lbl.pdf
4. LUPRON DEPOT® 3.75 mg (leuprolide acetate for depot suspension) Rx only - accessdata.fda.gov, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019943s032,020011s039lbl.pdf
5. Leuprorelin (Leuprolide) | CAS NO.:53714-56-0 | GlpBio, accessed July 15, 2025, https://www.glpbio.com/leuprorelin-leuprolide.html
6. Leuprorelin | 53714-56-0 - ChemicalBook, accessed July 15, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB8398455.htm
7. Leuprolide: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 15, 2025, https://go.drugbank.com/drugs/DB00007
8. DRUG NAME: Leuprolide - BC Cancer, accessed July 15, 2025, http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Leuprolide_monograph.pdf
9. Leuprorelin EP Reference Standard CAS 53714-56-0 Sigma Aldrich, accessed July 15, 2025, https://www.sigmaaldrich.com/US/en/product/sial/l0376000
10. Generic Lupron Depot Availability - Drugs.com, accessed July 15, 2025, https://www.drugs.com/availability/generic-lupron-depot.html
11. Leuprolide acetate: a drug of diverse clinical applications - PubMed, accessed July 15, 2025, https://pubmed.ncbi.nlm.nih.gov/17970643/
12. pubmed.ncbi.nlm.nih.gov, accessed July 15, 2025, https://pubmed.ncbi.nlm.nih.gov/17970643/#:~:text=As%20its%20basic%20mechanism%20of,suppresses%20gonadal%20sex%20steroid%20production.
13. Conventional and new proposals of GnRH therapy for ovarian, breast, and prostatic cancers, accessed July 15, 2025, https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1143261/full
14. Leuprolide Acetate Injection - accessdata.fda.gov, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/074728s011lbl.pdf
15. Leuprolide - StatPearls - NCBI Bookshelf, accessed July 15, 2025, https://www.ncbi.nlm.nih.gov/books/NBK551662/
16. Leuprolide: Package Insert / Prescribing Information - Drugs.com, accessed July 15, 2025, https://www.drugs.com/pro/leuprolide.html
17. ELIGARD™ 7.5 mg - accessdata.fda.gov, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21343lbl.pdf
18. LUPRON DEPOT (leuprolide acetate for depot ... - accessdata.fda.gov, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/019732s045,020517s043lbl.pdf
19. Lupron Depot Patient Tips: 7 things you should know - Drugs.com, accessed July 15, 2025, https://www.drugs.com/tips/lupron-depot-patient-tips
20. Lupron Depot injection: Side effects, cost, dosage, and more - Medical News Today, accessed July 15, 2025, https://www.medicalnewstoday.com/articles/lupron-depot
21. LUPRON DEPOT (leuprolide acetate for depot suspension), accessed July 15, 2025, https://www.lupron.com/pi.html
22. Eligard (Leuprolide Acetate) - AmeriPharma® Specialty Care, accessed July 15, 2025, https://ameripharmaspecialty.com/cancer/eligard-leuprolide-acetate/
23. ELIGARD® 7.5 mg, 22.5 mg, 30 mg, 45 mg - accessdata.fda.gov, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021731s005,021488s010,021379s010,021343s015lbl.pdf
24. Lupron (Leuprolide) | The Fertility Center of Oregon, accessed July 15, 2025, https://fertilitycenteroforegon.com/lupron-leuprolide/
25. Are Lupron Depot and Eligard the same drug? - Drugs.com, accessed July 15, 2025, https://www.drugs.com/medical-answers/lupron-depot-eligard-drug-3554964/
26. Clinical Pharmacology Biopharmaceutics Review(s) - CPY Document - FDA, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/021731s000_Eligard_ClinPharmR.pdf
27. Pharmacokinetic and pharmacodynamic comparison of subcutaneous versus intramuscular leuprolide acetate formulations in male subjects - PubMed Central, accessed July 15, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5805007/
28. Six-month depot formulation of leuprorelin acetate in the treatment of prostate cancer - PMC, accessed July 15, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2697591/
29. How Are Eligard and Lupron for Prostate Cancer Different? - GoodRx, accessed July 15, 2025, https://www.goodrx.com/conditions/prostate-cancer/eligard-versus-lupron-for-prostate-cancer
30. Eligard® (leuprolide acetate for injectable solution) 7.5 mg, 22.5 mg, 30 mg, and 45 mg. - accessdata.fda.gov, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/021343Orig1s033.pdf
31. Lupron, Eligard (leuprolide) dosing, indications, interactions ..., accessed July 15, 2025, https://reference.medscape.com/drug/lupron-eligard-leuprolide-342221
32. LUPRON DEPOT 11.25 mg - This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020708s035lbl.pdf
33. LUPRON DEPOT 11.25 mg (leuprolide acetate for depot suspension) for injection, for intramuscular use - This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020708s038lblrpl.pdf
34. Clinical development of the GnRH agonist leuprolide acetate depot - PMC - PubMed Central, accessed July 15, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10201295/
35. (PDF) GnRH Agonists in the Treatment of Symptomatic Endometriosis: A Review, accessed July 15, 2025, https://www.researchgate.net/publication/365651331_GnRH_Agonists_in_the_Treatment_of_Symptomatic_Endometriosis_A_Review
36. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020011Orig1s046;019943Orig1s039lbl.pdf
37. Leuprolide and norethindrone (intramuscular route, oral route) - Mayo Clinic, accessed July 15, 2025, https://www.mayoclinic.org/drugs-supplements/leuprolide-and-norethindrone-intramuscular-route-oral-route/description/drg-20060664
38. Uterine fibroids - Diagnosis and treatment - Mayo Clinic, accessed July 15, 2025, https://www.mayoclinic.org/diseases-conditions/uterine-fibroids/diagnosis-treatment/drc-20354294
39. Off-Label Prescribing - Where Lupron is the Rule, Not the Exception - and Doctors Never Have To Say They're Sorry. - HealthCommentary, accessed July 15, 2025, https://www.healthcommentary.org/2017/02/08/off-label-prescribing-never-say-youre-sorry/
40. Gonadotropin-Releasing Hormone Analogs and Antagonists - Medical Clinical Policy Bulletins | Aetna, accessed July 15, 2025, https://www.aetna.com/cpb/medical/data/500_599/0501.html
41. Clinical Studies | LUPRON DEPOT-PED® (leuprolide acetate for depot suspension), accessed July 15, 2025, https://www.lupronpedpro.com/clinical-studies.html
42. Effectiveness of leuprolide acetate administered monthly compared to three-monthly in the treatment of central precocious puberty: evaluation at the end of treatment - Frontiers, accessed July 15, 2025, https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1390674/full
43. Leuprolide - brand name list from Drugs.com, accessed July 15, 2025, https://www.drugs.com/ingredient/leuprolide.html
44. Leuprorelin Drugs Market Companies, Trends & Data Insight - Towards Healthcare, accessed July 15, 2025, https://www.towardshealthcare.com/insights/leuprorelin-drugs-market-sizing
45. Leuprolide Acetate Depot -- [Lupron Depot (1 month) 7.5mg, Lupron Depot (3 month) 22.5mg, Lupron Depot (4-Month) 30 mg, Lupron Depot (6-Month) 45 mg]; Leuprolide Acetate Depot (3-month 22.5 mg), accessed July 15, 2025, https://www.bcbst.com/mpmanual/!SSL!/WebHelp/Leuprolide_Suspension1.htm
46. Insights Into Physician Prescribing Decisions: Why Goserelin? Why ..., accessed July 15, 2025, https://theoncologynurse.com/ofs-summit/19670:insights-into-physician-prescribing-decisions-why-goserelin-why-leuprolide
47. Efficacy of Different Leuprolide Administration Schedules in Premenopausal Breast Cancer: A Retrospective Review - IU Indianapolis ScholarWorks, accessed July 15, 2025, https://scholarworks.indianapolis.iu.edu/bitstreams/1cc91fb5-e51b-453b-97c1-c3ab21d9f10d/download
48. Leuprolide Acetate - SEER*Rx Interactive Antineoplastic Drugs Database, accessed July 15, 2025, https://seer.cancer.gov/seertools/seerrx/rx/53c44afa102c1290262dc318/
49. What does Lupron do for IVF? - Drugs.com, accessed July 15, 2025, https://www.drugs.com/medical-answers/lupron-ivf-3555856/
50. SART: ART Medications - Society for Assisted Reproductive Technology, accessed July 15, 2025, https://www.sart.org/patients/a-patients-guide-to-assisted-reproductive-technology/general-information/art-medications/
51. Leuprolide - FepBlue, accessed July 15, 2025, https://www.fepblue.org/-/media/PDFs/Medical-Policies/2024/October/Pharmacy-Policies/Remove-and-Replace/5_30_067-Leuprolide.pdf
52. Leuprolide Suspension (Lupron Depot-Ped®), accessed July 15, 2025, https://www.bcbst.com/mpmanual/!SSL!/WebHelp/Leuprolide_Suspension_Lupron_Depot-Ped.htm
53. Understanding Puberty-Pausing Medications - Advocates for Trans Equality, accessed July 15, 2025, https://transequality.org/sites/default/files/2024-07/Understanding%20Puberty-Pausing%20Medications.pdf
54. Case Number: 202301-157531 - Department of Financial Services, accessed July 15, 2025, https://dfs.ny.gov/public-appeals/case-number-202301-157531
55. HB 449 and the Dangers of Lupron, accessed July 15, 2025, https://le.utah.gov/interim/2020/pdf/00002340.pdf
56. The Truth About 'Puberty Blockers' - Congress.gov, accessed July 15, 2025, https://www.congress.gov/118/meeting/house/116284/documents/HHRG-118-JU10-20230727-SD011.pdf
57. 1 September 1, 2023 [Submitted Electronically] Division of Dockets Management U.S. Food and Drug Administration 5630 Fishers - Regulations.gov, accessed July 15, 2025, https://downloads.regulations.gov/FDA-2023-P-3767-0001/attachment_1.pdf
58. Clinical outcomes of leuprolide acetate in the treatment of recurrent ovarian granulosa cell tumors - PMC, accessed July 15, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10247505/
59. Eligard vs Lupron Depot Comparison - Drugs.com, accessed July 15, 2025, https://www.drugs.com/compare/eligard-vs-lupron-depot
60. ELIGARD for the management of advanced prostate cancer, accessed July 15, 2025, https://eligard.com/
61. FDA Drug Safety Communication: Ongoing Safety Review of GnRH Agonists and possible increased risk of diabetes and certain cardiovascular diseases, accessed July 15, 2025, https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fda-drug-safety-communication-ongoing-safety-review-gnrh-agonists-and-possible-increased-risk
62. Multi-Discipline Review - accessdata.fda.gov, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/205054Orig1s000MultidisciplineR.pdf
63. FDA accepts NDA for 3-month leuprolide mesylate formulation for ..., accessed July 15, 2025, https://www.urologytimes.com/view/fda-accepts-nda-for-3-month-leuprolide-mesylate-formulation-for-advanced-prostate-cancer
64. Description - ELIGARD® Information Center, accessed July 15, 2025, https://info.eligardhcp.com/all-topics/eligard-overview/description/
65. Leuprolide Acetate for Puberty Suppression in Transgender and Gender Diverse Youth: A Comparison of Subcutaneous Eligard Versus Intramuscular Lupron - PubMed, accessed July 15, 2025, https://pubmed.ncbi.nlm.nih.gov/36404242/
66. Cancer, Prostate Completed Phase 4 Trials for Leuprolide (DB00007) | DrugBank Online, accessed July 15, 2025, https://go.drugbank.com/indications/DBCOND0035994/clinical_trials/DB00007?phase=4&status=completed
67. A Six-Month, Open-Label, Crossover Study Of the Maintenance Of Serum Testosterone And PSA Suppression After Switching Between Lupron 22.5 Mg And Eligard 22.5 Mg Or Zoladex 10.8 Mg And Eligard 22.5 Mg In Patients With Advanced Prostate Cancer | ClinicalTrials.gov, accessed July 15, 2025, https://clinicaltrials.gov/study/NCT00220194
68. Orgovyx Competitors: Comparing Prostate Cancer Medicines - Urology Specialists of the Carolinas, accessed July 15, 2025, https://urologyspecialistsnc.com/orgovyx-competitors/
69. Leuprolide (Lupron, Eligard, Fensolvi) - AmeriPharma® Specialty Care, accessed July 15, 2025, https://ameripharmaspecialty.com/cancer/leuprolide-lupron-eligard-fensolvi/
70. Leuprolide Acetate Market Share & Opportunities 2025-2032 - Coherent Market Insights, accessed July 15, 2025, https://www.coherentmarketinsights.com/industry-reports/leuprolide-acetate-market
71. FDA Approves Leuprolide Acetate Injection for Advanced Prostate Cancer, accessed July 15, 2025, https://www.targetedonc.com/view/fda-approves-leuprolide-acetate-injection-for-advanced-prostate-cancer
72. XTANDI® Plus Leuprolide Significantly Improves Survival Outcomes ..., accessed July 15, 2025, https://www.pfizer.com/news/press-release/press-release-detail/xtandir-plus-leuprolide-significantly-improves-survival
73. XTANDI® (enzalutamide) plus Leuprolide Reduced the Risk of Metastasis by 58% in Non-Metastatic Hormone-Sensitive Prostate Cancer versus Placebo plus Leuprolide | Pfizer, accessed July 15, 2025, https://www.pfizer.com/news/press-release/press-release-detail/xtandir-enzalutamide-plus-leuprolide-reduced-risk
74. Search for leuprolide acetate - Clinical Trials register, accessed July 15, 2025, https://www.clinicaltrialsregister.eu/ctr-search/search?query=leuprolide+acetate
75. Leuprolide Completed Phase 3 Trials for Prostate Cancer Treatment | DrugBank Online, accessed July 15, 2025, https://go.drugbank.com/drugs/DB00007/clinical_trials?conditions=DBCOND0062462&phase=3&purpose=treatment&status=completed