Buserelin, sold under the brand name Suprefact among others, is a medication which is used primarily in the treatment of

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...

and

endometriosis Endometriosis is a disease of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, f ...

. It is also used for other indications such as the treatment of premenopausal breast cancer, uterine fibroids, and early puberty, in assisted reproduction for female infertility, and as a part of transgender hormone therapy. In addition, buserelin is used in veterinary medicine. The medication is typically used as a nasal spray three times per day, but is also available for use as a solution or

implant Implant can refer to: Medicine *Implant (medicine), or specifically: ** Brain implant ** Breast implant **Buttock implant **Cochlear implant **Contraceptive implant **Dental implant ** Fetal tissue implant **Implantable cardioverter-defibrillator ...

for injection into fat. Side effects of buserelin are related to sex hormone

deprivation Deprivation or deprive may refer to: * Poverty, pronounced deprivation in well-being ** Objective deprivation or poverty threshold, the minimum level of income deemed adequate in a particular country ** Relative deprivation, the lack of resources ...

and include

symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...

s of low testosterone levels and low estrogen levels such as hot flashes, sexual dysfunction,

vaginal atrophy Atrophic vaginitis is inflammation of the vagina as a result of tissue thinning due to not enough estrogen. Symptoms may include pain with sex, vaginal itchiness or dryness, and an urge to urinate or burning with urination. It generally does no ...

, and

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...

. Buserelin is a gonadotropin-releasing hormone agonist (GnRH agonist) and works by preventing the production of sex hormones by the

gonad A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sper ...

s. It can lower sex hormone levels by about 95% in both sexes. Buserelin is a peptide and an analogue of . Buserelin was first patented in 1974 and approved for medical use in 1985. It is not available in the United States, but is marketed widely elsewhere in the world, including in the United Kingdom, Canada, and many other countries. The medication is one of only two medically used GnRH analogues that are available as nasal sprays, the other being

nafarelin Nafarelin, sold under the brand name Synarel among others, is a gonadotropin-releasing hormone agonist (GnRH agonist) medication which is used in the treatment of endometriosis and early puberty.https://www.accessdata.fda.gov/drugsatfda_docs/labe ...

. Buserelin is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

Medical uses

Buserelin is approved for the treatment of hormone-responsive cancers including

and premenopausal breast cancer, sex hormone-dependent

uterine disease The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the hollow organ, organ in the female reproductive system, reproductive system of most female mammals, including humans that accommodates the embryonic development, embryonic an ...

s including endometrial hyperplasia,

, and uterine fibroids, and in assisted reproduction for female infertility. It is also used off-label for the treatment of precocious puberty, as a puberty blocker in

transgender children Transgender youth are children or adolescents who do not identify with the sex they were assigned at birth. Because transgender youth are usually dependent on their parents for care, shelter, financial support, and other needs, transgender yo ...

, and as a component of transgender hormone therapy. In ovulation induction, buserelin is used for pituitary suppression as an

adjunct Adjunct may refer to: * Adjunct (grammar), words used as modifiers * Adjunct professor, a rank of university professor * Adjuncts, sources of sugar used in brewing * Adjunct therapy used to complement another main therapeutic agent, either to impr ...

to gonadotropin administration. It has also been assessed as a nasal spray for use as a

hormonal contraceptive Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The origin ...

in women, with a 96% anovulation rate.

Dosages

For prostate cancer, the dosage of buserelin by

subcutaneous injection Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, ...

is 500 μg three times per day (once every 8 hours, 1,500 μg/day total) for one week and then 200 μg once daily thereafter. If buserelin is used as a nasal spray, the dosage for prostate cancer is 800 μg sprayed into the nostrils three times per day (once every 8 hours, 2,400 μg/day total) for one week followed by 400 μg sprayed into the nostrils three times per day (once every 8 hours, 1,200 μg/day total) thereafter. For endometriosis, buserelin is used specifically as a nasal spray and the dosage is the same as that used for prostate cancer. These dosages of buserelin for both subcutaneous injection and nasal spray have been found to decrease testosterone levels to near-

castrate Castration is any action, surgical, chemical, or otherwise, by which an individual loses use of the testicles: the male gonad. Surgical castration is bilateral orchiectomy (excision of both testicles), while chemical castration uses pharmaceut ...

levels in men with prostate cancer, although suppression was more complete with subcutaneous injection presumably due to suboptimal

absorption Absorption may refer to: Chemistry and biology * Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which ...

with intranasal administration.

Available forms

Buserelin is available in the form of a 1 mg/mL solution for use as a nasal spray or

once every 8 hours (three times per day) and as 6.3 mg and 9.45 mg

s for subcutaneous injection once every two and three months, respectively.

Contraindications

Contraindications of buserelin include the following: * Hypersensitivity to buserelin or any of the other components of the medication (case reports of anaphylaxis exist) * Prostate cancer that is not hormone-dependent (as there will be no benefit from testosterone suppression) * Individuals who have undergone gonadectomy (as hormone levels will not be affected) * Pregnancy and breastfeeding (unknown whether buserelin might be teratogenic) * Undiagnosed abnormal vaginal bleeding

Side effects

During the initial phase of the therapy, before GnRH receptors have been significantly downregulated, testosterone levels are increased. This can lead to transient tumor activation with bone pain (in patients with cancer metastases) and urinary retention. Side effects that occur later during the treatment are mainly due to low sex hormone levels and include reduced libido,

erectile dysfunction Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of male ...

, hot flashes,

vaginal dryness Vaginal lubrication is a naturally produced fluid that lubricates a vagina. Vaginal lubrication is always present, but production increases significantly near ovulation and during sexual arousal in anticipation of sexual intercourse. Vaginal d ...

menorrhagia Heavy menstrual bleeding (HMB), previously known as menorrhagia or hypermenorrhea, is a menstrual period with excessively heavy flow. It is a type of abnormal uterine bleeding Abnormal uterine bleeding (AUB), also known as (AVB) or as atypical ...

, depression, asthenia, emotional lability,

headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...

, dizziness, and application site reactions.

Overdose

Buserelin appears to be safe in the event of an overdose.

Pharmacology

Pharmacodynamics

Buserelin is a GnRH agonist, or an

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

of the GnRH receptor. It is a

superagonist In the field of pharmacology, a superagonist is a type of agonist that is capable of producing a maximal response greater than the endogenous agonist for the target receptor, and thus has an efficacy of more than 100%. For example, goserelin is a ...

of the GnRH receptor with potency for induction of luteinizing hormone (LH) and

follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, an ...

(FSH)

secretion 440px Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical ...

of about 20 to 170 times that of GnRH itself. By activating the GnRH receptor in the pituitary gland, buserelin induces the secretion of LH and FSH from the

gonadotroph Gonadotropic cells (called also Gonadotropes or Gonadotrophs or Delta Cells or Delta basophils) are endocrine cells in the anterior pituitary that produce the gonadotropins, such as the follicle-stimulating hormone (FSH) and luteinizing hormone (LH ...

s of the

anterior pituitary A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the p ...

, which travel to the

s through the bloodstream and activate gonadal sex hormone production as well as stimulate

spermatogenesis Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubule ...

in men and induce ovulation in women. With chronic administration of buserelin however, the GnRH receptor becomes desensitized and completely stops responding both to buserelin and to

endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, es ...

GnRH. This is because GnRH is normally released from the hypothalamus in pulses, which keeps the GnRH receptor sensitive, whereas chronic buserelin administration results in more constant exposure and desensitization of the receptor. The profound desensitization of the GnRH receptor results in a loss of LH and FSH secretion from the anterior pituitary and a consequent shutdown of gonadal sex hormone production, markedly diminished or abolished spermatogenesis in men, and anovulation in women. In men, approximately 95% of circulating testosterone is produced by the testes, with the remaining 5% being derived from the adrenal glands. In accordance, GnRH analogues like buserelin can reduce testosterone levels by about 95% in men. Sex hormone levels, including those of estradiol and

progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...

, are similarly profoundly suppressed in premenopausal women. The suppression of estradiol levels is 95% and progesterone levels are less than 1 ng/mL (normal range during the luteal phase approximately 10–20 ng/mL); the resulting levels are equivalent to those in postmenopausal women. Buserelin has been found to suppress testosterone levels in men with prostate cancer from 426 ng/dL to 28 ng/dL (by 93.4%) with 200 μg by subcutaneous injection once per day and from 521 ng/dL to 53 ng/dL (by 89.8%) with 400 μg by nasal spray once every 8 hours (1,200 μg/day total). The difference in suppression may have been due to poor compliance. A few small studies have also assessed the suppression of testosterone levels with buserelin nasal spray twice a day instead of three times a day. One such study found that testosterone levels in men with prostate cancer were suppressed during treatment with buserelin from 332 ng/dL to 215 ng/dL (28.9% lower than controls) with 200 μg by nasal spray twice a day (400 μg/day total), from 840 ng/dL to 182 ng/dL (71.4% lower than controls) with 500 μg by nasal spray twice a day (1,000 μg/day total), and from 598 ng/dL to 126 ng/dL (80.4% lower than controls) with 50 μg by subcutaneous injection once a day.

Pharmacokinetics

Buserelin is ineffective via oral administration due to first-pass metabolism in the

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...

. Its bioavailability is 2.5 to 3.3% by intranasal administration and 70% by

. The plasma protein binding of buserelin is approximately 15%. The metabolism of buserelin occurs in the liver, kidneys, and gastrointestinal tract and is mediated by peptidases, specifically pyroglutamyl peptidase and chymotrypsin-like endopeptidase. The elimination half-life of buserelin regardless of

route of administration A route of administration in pharmacology and toxicology is the way by which a medication, drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance i ...

is about 72 to 80 minutes. Buserelin and its

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s are eliminated in urine and

bile Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver bile ...

, with approximately 50% of buserelin excreted in urine unchanged.

Chemistry

Buserelin is a GnRH analogue, or a

synthetic Synthetic things are composed of multiple parts, often with the implication that they are artificial. In particular, 'synthetic' may refer to: Science * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic o ...

analogue of GnRH. It is a nonapeptide and is also known as small>D-Ser(tBu)⁶,des-Gly-NH₂¹⁰nRH ethylamide or as D-Ser(tBu)⁶EA¹⁰-GnRH. Buserelin is marketed for medical use in both its free base (buserelin) and

acetate An acetate is a salt (chemistry), salt formed by the combination of acetic acid with a base (e.g. Alkali metal, alkaline, Alkaline earth metal, earthy, Transition metal, metallic, nonmetallic or radical Radical (chemistry), base). "Acetate" als ...

salt (buserelin acetate) forms.

History

Buserelin was first described in 1976 and was introduced for medical use in 1984. Intranasal buserelin was the first GnRH agonist demonstrated to achieve medical castration in humans. This was initially observed via a marked decrease in circulating testosterone levels in a single patient in 1980.

Society and culture

Generic names

''Buserelin'' is the generic name of the drug and its and , while ''buserelin acetate'' is its , , and , ''buséréline'' is its , and ''buserelina'' is its . While under development by Hoechst AG, buserelin was also known as ''HOE-766''.

Brand names

Buserelin is marketed by Sanofi-Aventis primarily under the brand names Suprefact, Suprefact Depot, and Suprecur. It is also available under a number of other brand names including Bigonist, Bucel, Buserecur, Fuset, Metrelef, Profact, Profact Depot, Supremon, and Zerelin. CinnaFact is a generic version of the medication that is produced by CinnaGen. Buserelin is marketed for use in veterinary medicine primarily under the brand name Receptal, but is also available under the brand names Buserol, Busol, Porceptal, and Veterelin.

Availability

Buserelin is marketed in the United Kingdom, Ireland, other European countries, Canada, New Zealand, and South Africa, as well as in Latin America, Asia, and elsewhere in the world. It is not available in the United States or

Australia Australia, officially the Commonwealth of Australia, is a Sovereign state, sovereign country comprising the mainland of the Australia (continent), Australian continent, the island of Tasmania, and numerous List of islands of Australia, sma ...

Research

The

steroidal antiandrogen A steroidal antiandrogen (SAA) is an antiandrogen with a steroidal chemical structure. They are typically antagonists of the androgen receptor (AR) and act both by blocking the effects of androgens like testosterone and dihydrotestosterone (DHT) ...

cyproterone acetate has been studied for blocking the testosterone flare at the start of buserelin therapy in men with prostate cancer. While cyproterone acetate for two weeks eliminates the biological and biochemical signs of the flare, no benefits on prostate cancer outcomes were observed. Very low doses of buserelin nasal spray have been assessed for increasing testosterone levels and fertility in men with oligoasthenozoospermia and hypogonadotropic hypogonadism.

References

External links

Buserelin - AdisInsight
{{GnRH and gonadotropin receptor modulators GnRH agonists Hormonal antineoplastic drugs Peptides Puberty blockers World Anti-Doping Agency prohibited substances