Comprehensive Pharmacological and Clinical Monograph: Buserelin (DB06719)

Executive Summary

Buserelin is a potent synthetic analogue of gonadotropin-releasing hormone (GnRH), classified as a GnRH superagonist. Its mechanism of action is biphasic: an initial, transient stimulation of the pituitary-gonadal axis results in a surge of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and consequently, sex steroids (testosterone and estradiol). This is followed by a profound and sustained downregulation of pituitary GnRH receptors with chronic administration, leading to a state of medical castration characterized by a 95% reduction in sex hormone levels. This reversible suppression of the hypothalamic-pituitary-gonadal axis is the cornerstone of its therapeutic utility.

Buserelin is indicated for a range of hormone-dependent conditions. In oncology, it is a key component of androgen-deprivation therapy for advanced, hormone-sensitive prostate cancer and is also used for premenopausal breast cancer. In gynecology, it is effective in treating endometriosis, uterine fibroids, and endometrial hyperplasia by inducing a hypoestrogenic state. Furthermore, it plays a critical role in assisted reproductive technologies (ART) by providing precise control over the menstrual cycle for ovarian stimulation protocols.

The drug's pharmacokinetic profile dictates its formulation and administration. With negligible oral bioavailability, it is administered via subcutaneous injection, depot implant, or nasal spray. The high bioavailability of subcutaneous routes makes them suitable for long-term, consistent suppression in cancer therapy, while the lower bioavailability and short half-life of the nasal spray allow for flexible dosing and rapid cessation of effect, which is advantageous in ART.

The safety profile of Buserelin is dominated by the predictable physiological consequences of sex hormone deprivation. Common adverse effects include hot flashes, decreased libido, sexual dysfunction, and mood changes. Long-term use carries significant risks, including osteoporosis, adverse metabolic changes such as hyperglycemia, and an increased risk of cardiovascular events, including QTc prolongation. A critical initial risk is the "tumor flare" phenomenon, which necessitates co-administration of anti-androgens in prostate cancer patients.

Buserelin is widely approved and available in Europe, Canada, and other regions under brand names such as Suprefact®, Suprecur®, and Profact®. However, it is not approved for medical use in the United States, where other GnRH agonists like leuprolide and goserelin dominate the market. This regulatory divergence is likely attributable to historical market dynamics rather than significant differences in the drug's efficacy or safety profile. Overall, Buserelin remains a vital therapeutic agent in its approved markets for the management of a diverse spectrum of hormone-sensitive diseases.

1.0 Drug Identification and Physicochemical Properties

This section provides a definitive summary of the nomenclature, chemical identifiers, structural details, and physical characteristics of Buserelin, establishing a foundational reference for its identification in clinical, research, and pharmaceutical contexts.

1.1 Nomenclature and Identifiers

Buserelin is identified by a standardized set of names and codes across global pharmacopeias, regulatory bodies, and scientific databases. Consistency in identification is paramount for accurate prescribing, dispensing, and research.

• Generic Name: Buserelin [1]
• Synonyms: Common synonyms include Buserelina, Busereline, Buserelinum, and Etilamide.[1]
• DrugBank ID: The unique accession number in the DrugBank database is DB06719.[1]
• CAS Numbers: The Chemical Abstracts Service (CAS) registry assigns distinct numbers to the free base and its common salt form, a critical distinction for formulation and dosing.
• Primary (Free Base): 57982-77-1 [2]
• Acetate Salt: 68630-75-1 [2]
• Deprecated CAS: 104428-01-5, 111520-35-5 [2]
• Other Key Identifiers:
• FDA UNII: PXW8U3YXDV [3]
• European Community (EC) Number: 261-061-9 [2]
• Anatomical Therapeutic Chemical (ATC) Code: L02AE01 [3]

1.2 Chemical Structure and Formula

Buserelin is a small molecule classified as a synthetic oligopeptide.[2] It is a potent analogue of the naturally occurring gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH).[4] Structurally, it is a nonapeptide (a peptide consisting of nine amino acids) with specific modifications to enhance its potency and duration of action compared to native GnRH.[7]

• Amino Acid Sequence: The sequence is Pyr-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-Arg-Pro-NHEt.[2]
• Chemical Name: A more formal chemical name is 5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-O-(2-methyl-2-propanyl)-D-seryl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide.[2] The notationGnRH ethylamide also describes its structure relative to native GnRH.[7]
• Molecular Formula:
• Free Base: C60​H86​N16​O13​ [10]
• Acetate Salt: C62​H90​N16​O15​ [5]
• Molecular Weight:
• Free Base: 1239.42 g/mol [3]
• Acetate Salt: 1299.5 g/mol [12]

The distinction between the free base and the acetate salt is of significant clinical and pharmaceutical importance. Pharmaceutical products are often formulated using the acetate salt to enhance stability and solubility. This difference in molecular weight must be accounted for in dosage calculations to ensure the correct amount of the active Buserelin moiety is administered. Prescribers and pharmacists must be aware of which form is specified in the product monograph to prevent dosing errors.

1.3 Physicochemical Properties

The physical and chemical properties of Buserelin influence its formulation, storage, and handling.

• Appearance: Buserelin is a white to off-white or slightly yellowish powder.[3]
• Solubility: It is described as sparingly soluble in water and in dilute acids, though other sources note it as water-soluble, suggesting solubility sufficient for aqueous formulations.[1]
• Stability: The compound is hygroscopic, meaning it tends to absorb moisture from the air.[3] Despite this, it is considered stable enough for shipment under ambient temperature conditions.[10]
• Storage: For optimal stability, long-term storage is recommended under dry, dark conditions at -20°C. For short-term storage (days to weeks), 0-4°C is acceptable.[10]

Table 1: Summary of Buserelin Identification and Physicochemical Properties

Property	Buserelin (Free Base)	Buserelin Acetate	Source(s)
Generic Name	Buserelin	Buserelin Acetate	1
DrugBank ID	DB06719	N/A (Ingredient of DB06719)	1
CAS Number	57982-77-1	68630-75-1	2
Molecular Formula	C60​H86​N16​O13​	C62​H90​N16​O15​	5
Molecular Weight	1239.42 g/mol	1299.5 g/mol	10
Appearance	White to slightly yellowish powder	Amorphous, white substance	3
Solubility	Sparingly soluble in water and dilute acids	Freely soluble in water and dilute acids	3
Stability	Hygroscopic	N/A	3
ATC Code	L02AE01	L02AE01	3

2.0 Pharmacological Profile: Mechanism of Action

The therapeutic effects and adverse reaction profile of Buserelin are direct consequences of its potent and unique interaction with the gonadotropin-releasing hormone receptor (GnRHR) in the anterior pituitary gland. A thorough understanding of its biphasic mechanism is essential for its safe and effective clinical use.

2.1 Classification

Buserelin is a hormonal agent classified as a gonadotropin-releasing hormone agonist (GnRH agonist), also referred to as a luteinizing hormone-releasing hormone agonist (LHRH agonist).[7] It is a synthetic peptide designed as an analogue of the endogenous GnRH decapeptide.[2]

Crucially, Buserelin is not merely an agonist but a superagonist of the GnRHR.[7] Its structural modifications, including the substitution of a D-amino acid at position 6 and modification of the C-terminus, confer greater resistance to enzymatic degradation and higher binding affinity to the GnRHR.[8] This results in a pharmacological potency for inducing the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) that is approximately 20 to 170 times greater than that of native GnRH.[7]

2.2 Biphasic Mechanism of Action

The clinical effects of Buserelin are defined by a paradoxical, two-phase response to its administration. The initial response is stimulatory, while the long-term response is profoundly inhibitory.

2.2.1 Phase 1: Initial Stimulation (The "Flare" Effect)

Upon initial administration, Buserelin acts as a powerful GnRH receptor agonist. It binds to the GnRHRs on the gonadotroph cells of the anterior pituitary, triggering a potent and sustained release of the gonadotropins, LH and FSH, into the bloodstream.[7] This surge in gonadotropins travels to the gonads (the testes in males and the ovaries in females) and stimulates them, resulting in a transient but significant increase in the production and secretion of sex hormones.[1] In males, serum testosterone levels rise; in premenopausal females, serum estradiol levels increase.[8] This initial stimulatory phase is commonly referred to as the "flare" effect and typically occurs within the first week of initiating therapy.[15] The increase in plasma LH and FSH levels can persist for at least 7 hours after a dose, with a return to baseline requiring about 24 hours.[1]

2.2.2 Phase 2: Pituitary Desensitization and Downregulation

The key to Buserelin's therapeutic action lies in what happens after the initial flare. Endogenous GnRH is released from the hypothalamus in a pulsatile manner, a rhythm that is essential for maintaining the sensitivity of the pituitary GnRH receptors.[7] In contrast, the continuous, non-pulsatile exposure to a potent agonist like Buserelin leads to a state of constant receptor stimulation.[7]

This sustained exposure triggers a profound adaptive response in the pituitary gonadotrophs. The GnRH receptors become desensitized and are subsequently internalized from the cell surface, a process known as downregulation.[1] As a result, the pituitary gland becomes refractory and stops responding to stimulation from both Buserelin and any remaining endogenous GnRH.[7]

2.2.3 Consequence of Pituitary Downregulation

The profound desensitization of the GnRHR leads to a dramatic and sustained shutdown of LH and FSH secretion from the anterior pituitary.[1] Without the trophic support of these gonadotropins, the gonads cease their primary function of sex hormone production. This results in a state of reversible, medical castration.[17]

• In Males: Testicular production of testosterone, which accounts for approximately 95% of circulating levels, is shut down. This leads to a reduction in serum testosterone levels by about 95%, bringing them down to castrate levels.[7]
• In Females: Ovarian production of estradiol and progesterone is profoundly suppressed. Estradiol levels are reduced by approximately 95%, and progesterone levels fall to less than 1 ng/mL, reaching levels equivalent to those seen in postmenopausal women.[7] This state also leads to anovulation.[7]

This ability to induce a profound but reversible hypogonadal state is the unifying principle behind all of Buserelin's clinical applications.

The initial "flare" effect is not merely an incidental side effect but a direct and predictable consequence of Buserelin's superagonist mechanism. This understanding has fundamentally shaped clinical practice. In the context of hormone-sensitive prostate cancer, the transient surge in testosterone can temporarily accelerate tumor growth, potentially leading to a worsening of clinical symptoms such as bone pain, or causing acute complications like ureteral obstruction or spinal cord compression in patients with metastatic disease.[8] The recognition of this causal link between the drug's mechanism and a potentially dangerous clinical event led to the development of a critical mitigation strategy. The standard of care now involves the co-administration of an anti-androgen drug (e.g., flutamide, bicalutamide) starting before or concurrently with the initiation of Buserelin therapy.[8] The anti-androgen acts by blocking the androgen receptor at the tumor site, effectively shielding the cancer cells from the testosterone surge. This proactive management transforms a potentially hazardous initial effect into a manageable and temporary phase of treatment, showcasing a key principle where deep pharmacological understanding directly informs and improves clinical safety protocols.

3.0 Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The disposition of Buserelin within the body—its absorption, distribution, metabolism, and excretion (ADME)—is a critical determinant of its clinical utility. The pharmacokinetic profile explains the need for parenteral or intranasal administration and has driven the development of various formulations tailored to specific therapeutic goals.

3.1 Absorption and Bioavailability

As a peptide, Buserelin is susceptible to enzymatic degradation, which heavily influences its route of administration.

• Oral Administration: Buserelin is pharmacologically ineffective when taken orally. It undergoes extensive first-pass metabolism by proteolytic enzymes (peptidases) in the gastrointestinal tract, resulting in negligible absorption of the active drug.[7]
• Intranasal Administration: When administered as a nasal spray, Buserelin is absorbed through the nasal mucosa. However, bioavailability via this route is low and somewhat variable, reported to be in the range of 2.5% to 3.3%.[7] Despite this low efficiency, this route can achieve sufficient plasma concentrations to be therapeutically effective with appropriate dosing.[1]
• Subcutaneous (SC) Injection: Administration via subcutaneous injection provides significantly higher and more reliable absorption. The bioavailability of Buserelin following an SC injection is approximately 70%.[1]

3.2 Distribution

Once absorbed into the systemic circulation, Buserelin distributes throughout the body.

• Plasma Protein Binding: Buserelin exhibits low affinity for plasma proteins, with a binding percentage of approximately 15%.[3] This means a large fraction of the drug in circulation is unbound and pharmacologically active.
• Tissue Accumulation: The drug circulates predominantly in its intact, active form.[1] It shows preferential accumulation in the organs of metabolism and excretion—the liver and kidneys—as well as in its primary biological target organ, the anterior pituitary lobe.[1]

3.3 Metabolism

Buserelin is metabolized by enzymatic cleavage of its peptide bonds.

• Metabolic Pathways: The metabolism of Buserelin is mediated by peptidases, specifically identified as pyroglutamyl peptidase and chymotrypsin-like endopeptidases.[1]
• Sites of Metabolism: This metabolic inactivation occurs primarily in the liver and kidneys, as well as in the gastrointestinal tract.[1] Additionally, Buserelin is inactivated at its site of action by membrane-bound enzymes located in the pituitary gland.[1]

3.4 Excretion

The parent drug and its inactive metabolites are cleared from the body through multiple routes.

• Elimination Routes: Buserelin and its metabolites are eliminated from the body via both the renal (urine) and biliary (bile) routes.[1] A significant portion, approximately 50%, of an administered dose is excreted in the urine as the unchanged, intact drug.[1]
• Elimination Half-Life: The elimination half-life of Buserelin is relatively short and is largely independent of the route of administration:
• Intravenous (IV): Approximately 50 to 80 minutes.[1]
• Subcutaneous (SC): Approximately 72 to 80 minutes.[1]
• Intranasal: Slightly longer, at approximately 1 to 2 hours.[1]

The marked difference in bioavailability between the subcutaneous (70%) and intranasal (approx. 3%) routes is a pivotal factor that has guided the formulation and clinical application of Buserelin. This pharmacokinetic reality necessitates distinct strategies for different therapeutic goals. The short half-life of around 80 minutes means the drug is cleared rapidly from the body. For the low-bioavailability nasal spray, this combination requires frequent, multi-dose daily administration (e.g., three or more times per day) to maintain a steady-state plasma concentration above the therapeutic threshold needed for pituitary suppression.[7] While demanding, this regimen offers the clinical advantage of flexible control and rapid reversal of effect upon discontinuation, making it highly suitable for assisted reproduction protocols where pituitary suppression must be precisely timed and then ceased to allow for controlled ovulation induction.[16]

Conversely, for chronic conditions like advanced prostate cancer, a frequent daily dosing schedule would present significant challenges to patient adherence. To overcome the short half-life and ensure continuous, reliable hormonal suppression, formulations with high bioavailability were developed. Daily subcutaneous injections and, more conveniently, long-acting depot implants provide sustained release of the drug over weeks or months, ensuring consistent pituitary downregulation with far less frequent administration.[7] Thus, the drug's pharmacokinetic profile is the fundamental driver behind the development of different formulations, each tailored to meet the unique demands of distinct clinical scenarios.

Table 2: Comparative Pharmacokinetic Parameters of Buserelin by Route of Administration

Parameter	Oral	Intranasal	Subcutaneous	Source(s)
Bioavailability (%)	Negligible	2.5% - 3.3%	~70%	1
Elimination Half-Life	N/A	~60 - 120 minutes	~72 - 80 minutes	1
Plasma Protein Binding (%)	N/A	~15%	~15%	7
Key Clinical Considerations	Ineffective route.	Low bioavailability requires frequent daily dosing. Useful for flexible control (e.g., ART).	High, reliable bioavailability. Route of choice for injections and long-acting depot implants for sustained suppression (e.g., prostate cancer).	7

4.0 Clinical Applications and Therapeutic Efficacy

The ability of Buserelin to induce a profound and reversible state of medical castration makes it a versatile therapeutic agent for a wide range of hormone-dependent diseases. Its applications span the fields of oncology, gynecology, and reproductive medicine.

4.1 Hormone-Responsive Cancers

Buserelin is a cornerstone therapy for cancers whose growth is driven by sex hormones.

• Prostate Cancer: Buserelin is approved for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland (Stage D).[7] By suppressing testosterone production to castrate levels, it serves as a primary modality of androgen-deprivation therapy (ADT), slowing tumor progression and alleviating symptoms.[8] Its utility continues to be explored in modern oncology, with ongoing Phase 3 clinical trials investigating its use in combination with advanced radiotherapy techniques.[23]
• Premenopausal Breast Cancer: The drug is also approved for the treatment of hormone-responsive breast cancer in premenopausal women.[7] By suppressing ovarian estrogen production, Buserelin effectively removes the primary hormonal stimulus for estrogen receptor-positive (ER+) tumors in this patient population.

4.2 Gynecological and Uterine Diseases

Many benign but debilitating gynecological conditions are estrogen-dependent, making them amenable to treatment with Buserelin.

• Endometriosis: Buserelin is a primary medical therapy for endometriosis, a condition characterized by the growth of endometrial-like tissue outside the uterus.[1] The drug induces a hypoestrogenic state, which leads to the atrophy of endometriotic implants, resulting in significant relief from pain and a reduction in disease activity.[16] The nasal spray formulation is specifically noted for this indication.[7] Due to the long-term effects of estrogen deprivation on bone health, treatment is typically limited to a duration of six to nine months.[16]
• Uterine Fibroids (Leiomyomas): These benign tumors of the uterine muscle are also estrogen-sensitive. Buserelin is used to suppress estrogen production, which can lead to a reduction in fibroid size, thereby alleviating symptoms such as heavy menstrual bleeding and pelvic pain.[7] It is frequently employed as a pre-surgical adjunct to shrink fibroids, which can make subsequent surgical procedures like myomectomy less invasive and reduce operative blood loss.[16]
• Endometrial Hyperplasia: Buserelin is an approved treatment for this condition, which involves the abnormal thickening of the uterine lining, often driven by unopposed estrogen stimulation.[7]

4.3 Assisted Reproductive Technologies (ART)

In the context of female infertility, Buserelin is used not for long-term suppression but for short-term, precise control of the reproductive axis.

• In Vitro Fertilization (IVF) Protocols: Buserelin is widely used for pituitary suppression (or downregulation) as a preparatory step before controlled ovarian hyperstimulation with exogenous gonadotropins.[7] By temporarily shutting down the patient's endogenous production of LH and FSH, it prevents a premature LH surge that could trigger ovulation before the ovarian follicles are mature and ready for oocyte retrieval. This allows clinicians to gain complete control over follicular development and to precisely time the final maturation and retrieval of eggs, thereby optimizing the chances of a successful IVF cycle.[16] A completed Phase 4 clinical trial has further investigated its role in ovarian stimulation protocols.[25]

4.4 Off-Label and Investigational Uses

The potent hormonal effects of Buserelin have led to its use in several off-label and investigational settings.

• Precocious Puberty: Buserelin is used off-label to treat central precocious puberty by halting the premature activation of the pituitary-gonadal axis, thereby delaying the development of secondary sexual characteristics until a more appropriate age.[3]
• Transgender Hormone Therapy: It is utilized as a puberty blocker in transgender adolescents to pause endogenous pubertal development, providing time to explore gender identity. It is also a component of hormone therapy in transgender adults to suppress the production of endogenous sex hormones (testosterone or estrogen) before or during the administration of gender-affirming hormones.[3]
• Hormonal Contraception: Buserelin has been investigated as a potential female hormonal contraceptive. When administered as a nasal spray, it has been shown to induce anovulation in 96% of cycles, demonstrating its potential to prevent pregnancy, although this is not an approved indication.[7]

The remarkably diverse clinical applications of Buserelin—from treating metastatic cancer in men to facilitating pregnancy in women—are all underpinned by a single, unifying pharmacological principle: the potent, reversible suppression of the hypothalamic-pituitary-gonadal axis. Conditions like prostate cancer, breast cancer, endometriosis, and uterine fibroids are pathologically distinct, yet they share a common vulnerability—their dependence on gonadal sex hormones for growth and proliferation.[7] Buserelin's therapeutic effect is not specific to any one disease but is rather mechanism-specific; by inducing a profound hypogonadal state, it removes the critical fuel source for these conditions. Its application in ART represents a more nuanced manipulation of this same mechanism. Here, the goal is not long-term suppression but rather to create a temporary, controlled "blank slate" by silencing the patient's unpredictable natural cycle. This allows clinicians to then construct a new, artificial cycle using exogenous gonadotropins with precise timing and control, maximizing the efficiency of the IVF process.[16] This demonstrates how a single, well-understood molecular interaction can be strategically leveraged to achieve diametrically opposed clinical outcomes—either halting hormone-driven processes or precisely controlling them to enable reproduction.

5.0 Dosing Regimens and Administration

The clinical administration of Buserelin is tailored to the specific indication, leveraging different formulations and dosing schedules to achieve the desired therapeutic outcome, whether it be sustained hormonal suppression or short-term pituitary control.

5.1 Available Formulations

Buserelin is available in several formulations to accommodate different clinical needs and administration frequencies.

• Nasal Spray: A solution for intranasal administration, typically requiring multiple doses per day. It is marketed under brand names such as Suprecur®.[7]
• Subcutaneous (SC) Injection: An aqueous solution for injection, allowing for rapid absorption and typically administered one or more times daily. It is marketed under the brand name Suprefact®.[7]
• Depot Implant: A long-acting, biodegradable implant that is injected subcutaneously and provides sustained release of Buserelin over several weeks or months, greatly reducing the frequency of administration. This formulation is marketed as Suprefact® Depot.[7]

5.2 Dosing by Indication

Dosage regimens for Buserelin are highly specific to the condition being treated.

• Prostate Cancer: The treatment for advanced prostate cancer often involves a two-phase approach: a higher-dose induction phase followed by a long-term maintenance phase.
• Induction Phase: The standard induction regimen consists of 500 mcg of Buserelin administered via subcutaneous injection every 8 hours for the first 7 days of therapy.[19]
• Maintenance Phase: After the initial 7-day induction, patients are transitioned to a maintenance regimen. Several options are available:
• Daily SC Injection: 200 mcg administered subcutaneously once daily.[19]
• Nasal Spray: 400 mcg total dose administered three times daily (TID), with 200 mcg (one spray) delivered into each nostril at each dosing time.[19] Other sources describe a regimen of one spray into each nostril six times per day, spaced around meals.[20] Clinical studies have used total daily intranasal doses ranging from 600 mcg to 1200 mcg.[13]
• Depot Implant: For long-term, convenient maintenance, a 6.3 mg implant is administered subcutaneously every 2 months, or a 9.45 mg implant is administered subcutaneously every 3 months.[13]
• Endometriosis:
• Nasal Spray: The typical dosage for endometriosis is similar to that used for prostate cancer maintenance.[7] One large multicenter study evaluated a regimen of 300 mcg administered intranasally three times per day (total daily dose of 900 mcg) for a duration of 6 months.[31] Another common recommendation is two sprays into each nostril three times a day.[27]
• Assisted Reproductive Technologies (IVF):
• SC Injection: Dosing for pituitary downregulation in IVF protocols is individualized. A common approach is a total daily dose of 500 mcg administered as a single subcutaneous injection, starting in either the early follicular phase (day 1 or 2) or the mid-luteal phase (day 21) of the menstrual cycle.[28] General guidelines suggest a daily dose range of 200–500 mcg.[21] In some cases, doses may be increased up to 500 mcg twice daily to achieve adequate pituitary suppression.[21] A randomized study demonstrated that a single daily injection of 600 mcg was as effective as 300 mcg administered twice daily, suggesting that a once-daily regimen is a viable and simpler option.[32]

The distinct, two-stage dosing strategy for prostate cancer—a high-dose subcutaneous induction followed by a more convenient maintenance regimen—is a direct clinical application designed to optimize the drug's pharmacological profile. The primary therapeutic goal is to lower serum testosterone to castrate levels as rapidly and reliably as possible. The initial 7-day period of frequent, high-dose subcutaneous injections (500 mcg every 8 hours) leverages the most bioavailable route to ensure rapid saturation and subsequent desensitization of the pituitary GnRH receptors.[8] This aggressive induction phase ensures that the initial testosterone flare is traversed quickly and that profound suppression is achieved in a timely manner. Once this suppressed state is established, the therapeutic goal shifts to long-term maintenance. The pituitary now only requires a continuous, lower level of the drug to keep the GnRH receptors downregulated. This allows for a transition to more convenient, lower-burden maintenance options, such as a lower once-daily subcutaneous dose (200 mcg), the non-invasive nasal spray, or the highly convenient long-acting depot implants.[13] This two-step approach represents a sophisticated therapeutic strategy that balances the immediate need for a rapid onset of action with the long-term requirements of patient convenience and adherence in a chronic disease setting.

Table 3: Recommended Dosing Regimens for Buserelin by Indication

Indication	Formulation	Phase	Recommended Dosage and Frequency	Source(s)
Prostate Cancer	SC Injection	Induction	500 mcg every 8 hours for 7 days	19
	SC Injection	Maintenance	200 mcg once daily	19
	Nasal Spray	Maintenance	400 mcg (200 mcg/nostril) every 8 hours (TID)	19
	Depot Implant	Maintenance	6.3 mg every 2 months OR 9.45 mg every 3 months	13
Endometriosis	Nasal Spray	Treatment	300 mcg three times daily (900 mcg/day)	31
ART / IVF	SC Injection	Downregulation	200 - 500 mcg once daily (individualized)	21

6.0 Comprehensive Safety and Tolerability Profile

The safety profile of Buserelin is well-characterized and is intrinsically linked to its mechanism of action. The majority of adverse effects are the direct, predictable consequences of inducing a profound hypogonadal state. However, several serious risks require careful patient selection and diligent monitoring.

6.1 Common and Serious Adverse Drug Reactions

Adverse reactions can be categorized by their cause: those stemming from the initial hormonal flare, those resulting from long-term hormone deprivation, and those related to administration or hypersensitivity.

• Hormone Deprivation Symptoms: These are the most frequently reported side effects and are analogous to symptoms of menopause in women or andropause in men.[7]
• Vasomotor: Hot flashes and increased sweating are very common in both sexes.[1]
• Reproductive/Sexual (Male): Decreased libido and impotence or erectile dysfunction are expected pharmacological effects.[1]
• Reproductive/Sexual (Female): Decreased libido, vaginal dryness, vaginal atrophy, and dyspareunia (painful intercourse) are common.[7]
• Psychiatric and Neurological: Mood changes, emotional lability, and an increased risk of depression, which may be severe, have been reported.[15] Headache and dizziness are also common.[1]
• General: Fatigue and asthenia (weakness) are frequently experienced.[18]
• Administration Site Reactions: Local reactions are common with parenteral and nasal formulations.
• Injection Site: Pain, redness, swelling, irritation, or hardening of the skin can occur at the injection site.[1]
• Nasal Spray: Nasal irritation, dryness, and in some cases, nosebleeds may occur.[1]
• Serious Adverse Events:
• Cardiovascular: Androgen deprivation therapy with GnRH agonists is associated with an increased risk of serious cardiovascular events. These include QTc interval prolongation, which can lead to life-threatening arrhythmias like Torsades de Pointes, as well as an increased risk of myocardial infarction, stroke, and sudden cardiac death.[1] Severe hypertension or hypertensive crises have also been reported.[15]
• Musculoskeletal: Long-term induction of a hypogonadal state leads to accelerated bone mineral density loss, increasing the risk of osteopenia and osteoporosis, and consequently, fragility fractures.[7]
• Metabolic: Buserelin can impair glucose tolerance, leading to hyperglycemia and an increased risk of developing new-onset diabetes or worsening of pre-existing diabetes.[15] Hyperlipidemia has also been reported.[15]
• Endocrine: Pituitary apoplexy, a rare but serious condition involving hemorrhage or infarction of the pituitary gland, has been reported following the administration of GnRH agonists, typically occurring within the first two weeks of the first dose and usually in patients with a pre-existing pituitary adenoma.[15]
• Hypersensitivity: Although rare, serious allergic reactions, including anaphylaxis, can occur.[7]

6.2 The "Tumor Flare" Phenomenon

As detailed in Section 2.2, the initial agonistic action of Buserelin causes a transient surge in testosterone or estradiol levels. In patients with hormone-sensitive cancers, this can lead to a temporary exacerbation of the disease, known as "tumor flare" or "disease flare".[1]

• In Prostate Cancer: This flare can manifest as a temporary increase in bone pain in patients with skeletal metastases. More critically, it can precipitate acute urinary retention due to tumor swelling around the bladder outlet or, in severe cases, lead to spinal cord compression in patients with vertebral metastases, potentially causing neurological deficits.[8]
• Management: To mitigate this risk, the standard of care is to initiate therapy with an anti-androgen agent several days before or concurrently with the first dose of Buserelin and continue it for the first few weeks of treatment.[8]

6.3 Key Warnings and Precautions

Given the significant physiological changes induced by Buserelin, several warnings and precautions must be observed.

• Cardiovascular Disease: The drug should be used with caution in patients with a history of cardiovascular disease, multiple cardiovascular risk factors (hypertension, hyperlipidemia, smoking), or a personal or family history of congenital long QT syndrome.[8] Baseline and periodic ECGs and electrolyte monitoring should be considered.
• Diabetes Mellitus: Patients with diabetes require close monitoring of their blood glucose levels, as Buserelin can adversely affect glycemic control.[24]
• Osteoporosis: Caution is warranted in patients with pre-existing osteoporosis or significant risk factors for bone loss (e.g., chronic corticosteroid use, family history). Bone mineral density should be monitored during long-term therapy.[8]
• Depression: Patients with a history of depression should be monitored for worsening of their condition, as GnRH agonist treatment is associated with an increased risk of depression, which can be severe.[15]
• Pregnancy and Breastfeeding: Buserelin is strictly contraindicated in pregnancy as it may cause fetal harm. Women of childbearing potential must use an effective non-hormonal method of contraception during therapy. The drug is also contraindicated during breastfeeding.[8]

6.4 Contraindications

Buserelin is absolutely contraindicated in the following situations:

• Known hypersensitivity to Buserelin, other GnRH analogues, or any component of the formulation.[7]
• Pregnancy and breastfeeding.[7]
• Undiagnosed abnormal vaginal bleeding, as it may mask a serious underlying pathology.[7]
• Prostate cancer that has been demonstrated to be non-hormone-dependent, as the therapy would offer no benefit.[7]
• Patients who have undergone a surgical orchiectomy (removal of the testes), as their testosterone levels are already at castrate levels and cannot be further lowered by Buserelin.[7]

The safety profile of Buserelin therapy requires a fundamental shift in clinical management, moving beyond simply observing for unexpected toxicities to proactively managing the well-documented and predictable physiological consequences of profound, long-term hypogonadism. The primary mechanism of the drug is to induce a state that mimics andropause or menopause.[7] The known long-term health risks of these natural life stages—including bone density loss, adverse changes in lipid profiles and insulin sensitivity, increased cardiovascular risk, and mood disturbances—are precisely mirrored in the adverse effect profile of chronic Buserelin use.[8] Consequently, managing a patient on long-term Buserelin is not just about treating their primary disease, such as prostate cancer, but also about managing the complex iatrogenic state of hypogonadism that the treatment creates. This implies that a comprehensive care plan should extend beyond the monitoring of disease-specific markers (like PSA). It should incorporate baseline and periodic monitoring of bone health (e.g., DEXA scans), metabolic parameters (e.g., lipid panels, HbA1c), cardiovascular status (e.g., blood pressure, ECGs to assess the QTc interval), and mental health (e.g., screening for depression). This broader scope of care often necessitates a multidisciplinary approach, potentially involving collaboration between the primary prescribing specialist (such as an oncologist or gynecologist) and other specialists like cardiologists, endocrinologists, and mental health professionals to ensure the holistic, long-term well-being of the patient.

7.0 Clinically Significant Drug Interactions

The potential for drug-drug interactions with Buserelin is an important clinical consideration, particularly given the comorbidities often present in the patient populations receiving this therapy. Interactions can be pharmacodynamic, affecting the physiological response, or pharmacokinetic, altering drug metabolism.

7.1 Pharmacodynamic Interactions

These interactions involve the combined physiological effects of Buserelin and other drugs.

• QTc-Prolonging Agents: Buserelin itself carries a risk of prolonging the QTc interval on an electrocardiogram.[1] When co-administered with other medications known to have this effect, the risk becomes additive, significantly increasing the potential for life-threatening ventricular arrhythmias such as Torsades de Pointes. Extreme caution and careful monitoring are required when Buserelin is used concurrently with drugs such as:
• Class IA and Class III antiarrhythmics (e.g., quinidine, procainamide, amiodarone, sotalol) [15]
• Certain antipsychotics, antidepressants (e.g., venlafaxine, amitriptyline), and opioids (e.g., methadone) [15]
• Certain antibiotics (e.g., moxifloxacin, clarithromycin) and antifungals (e.g., fluconazole) [15]
• Other agents like ondansetron, chloroquine, and sunitinib [15]
• Antidiabetic Agents: Buserelin therapy can impair glucose tolerance and lead to hyperglycemia.[15] This can directly counteract the therapeutic goal of antidiabetic medications. It is explicitly stated that the effect of antidiabetic agents may be attenuated during treatment with Buserelin.[15] Therefore, patients with diabetes mellitus who are initiated on Buserelin therapy require more frequent monitoring of their blood glucose levels. Adjustments to their diet, exercise regimen, or the dosage of their antidiabetic medications may be necessary to maintain adequate glycemic control.[24]

The interaction with antidiabetic agents is of particular clinical relevance. The typical demographic for prostate cancer treatment is older males, a population with a high prevalence of comorbidities such as type 2 diabetes and cardiovascular disease.[24] Androgen deprivation therapy with Buserelin is known to independently worsen metabolic health by reducing insulin sensitivity and increasing the risk of diabetes.[13] This is compounded by a direct drug-drug interaction that may render antidiabetic medications less effective.[15] This creates a "double-hit" scenario: the Buserelin therapy itself can exacerbate the underlying metabolic dysfunction, while simultaneously blunting the effectiveness of the medications used to manage it. This synergistic risk underscores that management cannot be passive; it requires a proactive approach. Simply advising a patient to monitor their blood sugar more often may be insufficient. A comprehensive management plan could involve a consultation with an endocrinologist to preemptively adjust the diabetes treatment regimen upon initiation of Buserelin, thereby mitigating the risk of poor glycemic control and its associated long-term complications.

7.2 Pharmacokinetic and Enzyme-Mediated Interactions

These interactions involve the effect of Buserelin on the metabolism of other drugs.

• Aromatase System: According to DrugBank's BioInteractor tool, Buserelin is classified as an aromatase inducer.[39] Aromatase (CYP19A1) is the enzyme responsible for converting androgens to estrogens. This classification suggests potential interactions with drugs that are inhibitors, substrates, or other inducers of this enzyme.
• Interaction with Aromatase Inhibitors: Drugs like letrozole and anastrozole are aromatase inhibitors used to block estrogen production, primarily in postmenopausal breast cancer. As an aromatase inducer, Buserelin could theoretically increase the expression of the aromatase enzyme, potentially opposing the therapeutic effect of these inhibitors. This interaction warrants careful consideration in clinical scenarios where both drug classes might be contemplated, such as in certain breast cancer treatment strategies.
• Interaction with Aromatase Substrates: Buserelin may increase the rate of metabolism of drugs that are substrates for the aromatase enzyme. This could potentially reduce the plasma concentrations and efficacy of these co-administered drugs. Examples of aromatase substrates include testosterone and methadone.[39]

8.0 Regulatory Status and Commercial Landscape

The global availability and market presence of Buserelin are characterized by a notable regulatory divergence between the United States and other major markets, which has shaped its position within the therapeutic class of GnRH agonists.

8.1 Regulatory Approval Status

Buserelin's approval history dates back several decades, but its market entry has not been uniform worldwide.

• United States (FDA): Buserelin is not approved for medical use by the U.S. Food and Drug Administration.[7] While the substance is cataloged in the FDA's Global Substance Registration System (GSRS), indicating awareness of the chemical entity, there are no approval documents for a Buserelin-containing drug product for the U.S. market within the provided materials.[2] This stands in contrast to other GnRH agonists like Goserelin (Zoladex) and Leuprolide (Lupron), which have long-standing FDA approval and are widely used in the U.S..[40]
• Europe (EMA) and Other Regions: Buserelin has a long history of use outside the U.S. It was first patented in 1974 and received its initial medical approval in 1985.[7] It was subsequently approved by the European Medicines Agency (EMA) in 1995.[43] The drug is widely marketed across Europe, including the United Kingdom, as well as in Canada and many other countries.[7] It is also approved for veterinary use in the European Union.[44]
• Market Authorization: In the regions where it is approved, Buserelin is available as both a branded product and as a generic medication, indicating that its primary patents have expired.[7]

8.2 Brand Names and Manufacturers

Buserelin is marketed globally under various trade names by several pharmaceutical companies.

• Prominent Brand Names: The most common brand names include Suprefact®, Suprecur®, Profact®, Receptal® (for veterinary use), Bigonist®, Etilamide®, and CinnaFact®.[3]
• Key Manufacturers:
• Sanofi-Aventis: A major marketer of the branded products Suprefact and Suprecur.[3]
• CinnaGen: A manufacturer of a generic version of Buserelin, marketed under the brand name CinnaFact.[46]
• Active Pharmaceutical Ingredient (API) Suppliers: The global market for the Buserelin API is robust, with numerous suppliers located in countries such as China, India, Spain, and Japan, catering to the needs of generic manufacturers.[48]

The regulatory split for Buserelin—widespread approval and use outside the United States versus its complete absence from the U.S. market—is a significant feature of its commercial profile. This situation is likely not a reflection of any inherent deficiency in Buserelin's efficacy or safety, given its long-standing approval by other stringent regulatory authorities like the EMA and Health Canada. Instead, it is more probably the result of historical market dynamics and strategic business decisions. Buserelin was developed and approved in the mid-1980s, a timeframe that coincided with the U.S. approval and market launch of other GnRH agonists, notably Leuprolide (Lupron) in 1985 and later Goserelin (Zoladex).[7] These drugs, which belong to the same therapeutic class and possess a very similar mechanism of action, quickly became entrenched as the standard of care in the lucrative U.S. market.[9]

For a new drug to successfully enter a competitive therapeutic class, particularly in the high-cost U.S. market, it typically needs to demonstrate a clear and significant advantage over existing therapies—whether in efficacy, safety, patient convenience, or cost. Buserelin, being functionally very similar to its established competitors, may not have presented a sufficiently compelling value proposition to justify the substantial investment required for U.S.-based clinical trials and the complex FDA submission process. While its availability as a nasal spray is a point of differentiation (a feature shared only by nafarelin), this may not have been perceived as a significant enough advantage over the convenient once-monthly or three-monthly depot injections offered by its competitors to drive a U.S. market entry strategy.[7] Therefore, the absence of Buserelin in the U.S. pharmacopeia is best understood as a consequence of the competitive landscape and strategic corporate decision-making during its development era.

9.0 Expert Analysis and Concluding Remarks

Buserelin is a well-established and potent GnRH superagonist with a clearly defined, albeit complex, biphasic mechanism of action. Its capacity to induce a profound and reversible state of medical castration by downregulating pituitary GnRH receptors forms the robust pharmacological basis for its efficacy across a diverse range of hormone-dependent pathologies. Its clinical utility is firmly established in the management of advanced prostate cancer, premenopausal breast cancer, endometriosis, and uterine fibroids, where the suppression of gonadal steroids is the primary therapeutic goal. Furthermore, its role in providing precise, short-term control of the pituitary-gonadal axis has made it an invaluable tool in the field of assisted reproductive technology.

The pharmacokinetic profile of Buserelin, characterized by poor oral absorption and a short elimination half-life, has necessitated the development of parenteral and intranasal formulations. The distinct bioavailability of these routes has logically led to a tailored application strategy: high-bioavailability subcutaneous injections and depot implants are ideal for the long-term, consistent suppression required in oncology, whereas the flexible, rapidly reversible nature of the nasal spray is well-suited to the dynamic requirements of IVF protocols.

The safety profile of the drug is significant but is largely a direct and predictable extension of its intended pharmacological effect. The adverse events are predominantly those associated with a profound hypogonadal state. While common symptoms like hot flashes and decreased libido are manageable, the long-term risks to bone, metabolic, and cardiovascular health require proactive, multidisciplinary clinical management that extends beyond the treatment of the primary disease. The initial "tumor flare" phenomenon remains a critical consideration that must be managed with concurrent anti-androgen therapy in prostate cancer patients to ensure safety at the start of treatment.

In the global therapeutic landscape, Buserelin holds a unique position. It is a vital and widely used medication in Europe, Canada, and many other parts of the world. However, its absence from the U.S. market, likely a result of historical competitive dynamics, means that clinical experience with the drug is geographically partitioned. For most of its indications, particularly in oncology, Buserelin is functionally interchangeable with other GnRH agonists like leuprolide and goserelin. Its key differentiator remains its availability as a nasal spray, a formulation that offers a non-invasive alternative for patients who may be averse to injections, particularly in the context of fertility treatments. In conclusion, Buserelin is a potent and effective therapeutic agent whose clinical role, safety considerations, and market position are all direct and logical consequences of its fundamental pharmacology.

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