Leuprorelin, also known as leuprolide, is a manufactured version of a

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...

used to treat

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 su ...

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a ...

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, fall ...

uterine fibroids Uterine fibroids, also known as uterine leiomyomas or fibroids, are benign smooth muscle tumors of the uterus. Most women with fibroids have no symptoms while others may have painful or heavy periods. If large enough, they may push on the b ...

, as part of

transgender hormone therapy Transgender hormone therapy, also called hormone replacement therapy (HRT) or gender-affirming hormone therapy (GAHT), is a form of hormone therapy in which sex hormones and other hormonal medications are administered to transgender or gender no ...

, for

early puberty In medicine, precocious puberty is puberty occurring at an unusually early age. In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. In a minority of childr ...

, or to perform

chemical castration Chemical castration is castration via anaphrodisiac drugs, whether to reduce libido and sexual activity, to treat cancer, or otherwise. Unlike surgical castration, where the gonads are removed through an incision in the body,

of violent sex offenders. It is given by

injection into a muscle Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles ha ...

or under the skin. Leuprorelin is in the gonadotropin-releasing hormone (GnRH) analogue family of medications. It works by decreasing

gonadotropin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/chorionic ...

and therefore decreasing

testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristic ...

and

estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of ...

. Common side effects include

hot flashes Hot flashes (also known as hot flushes) are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and ...

, unstable mood, trouble sleeping,

headaches 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 ...

, and pain at the site of injection. Other side effects may include high blood sugar,

allergic reactions Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermati ...

, and problems with the pituitary gland. Use during

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

may harm the baby. Leuprorelin was patented in 1973 and approved for medical use in the United States in 1985. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. It is sold under the brand name Lupron among others.

Medical use

Leuprorelin may be used in the treatment of hormone-responsive

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...

s such as

and

. It may also be used for estrogen-dependent conditions such as

. It may be used for

precocious puberty In medicine, precocious puberty is puberty occurring at an unusually early age. In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. In a minority of childr ...

in both males and females, and to prevent premature ovulation in cycles of controlled ovarian stimulation for in vitro fertilization (

IVF In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's ovulatory process, removing an ovum or ova (egg or eggs) fr ...

). This use is controversial since the Lupron label advises against using the drug when one is considering pregnancy, due to a risk of birth defects. It may be used to reduce the risk of

premature ovarian failure Primary ovarian insufficiency (POI) (also called premature ovarian insufficiency, premature menopause, and premature ovarian failure) is the partial or total loss of reproductive and hormonal function of the ovaries before age 40 because of fol ...

in women receiving

cyclophosphamide Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...

for chemotherapy. Along with triptorelin and

goserelin Goserelin, sold under the brand name Zoladex among others, is a medication which is used to suppress production of the sex hormones (testosterone and estrogen), particularly in the treatment of breast and prostate cancer. It is an injectable gon ...

, it has been used to delay

puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a boy ...

transgender youth 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 ...

until they are old enough to begin

hormone replacement therapy Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. These symptoms can include hot flashes, vagina ...

. Researchers have recommended puberty blockers after age 12, when the person has developed to

Tanner stages The Tanner scale (also known as the Tanner stages or Sexual Maturity Rating (SMR)) is a scale of physical development in children, adolescents and adults. The scale defines physical measurements of development based on external primary and secon ...

2–3, and then cross-sex hormones treatment at age 16. This use of the drug is off-label, however, not having been approved by the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

and without data on long-term effects of this use. They are also sometimes used as alternatives to

antiandrogen Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking t ...

s like

spironolactone Spironolactone, sold under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood pressur ...

and

cyproterone acetate Cyproterone acetate (CPA), sold alone under the brand name Androcur or with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the treatment of androgen-dependent conditions ...

for suppressing

production in

transgender women A trans woman or a transgender woman is a woman who was assigned male at birth. Trans women have a female gender identity, may experience gender dysphoria, and may transition; this process commonly includes hormone replacement therapy and some ...

. It also is used for suppressing estrogen production in transgender men. It is considered a possible treatment for

paraphilia Paraphilia (previously known as sexual perversion and sexual deviation) is the experience of intense sexual arousal to atypical objects, situations, fantasies, behaviors, or individuals. It has also been defined as sexual interest in anything ot ...

s. Leuprorelin has been tested as a treatment for reducing sexual urges in

pedophiles Pedophilia ( alternatively spelt paedophilia) is a psychiatric disorder in which an adult or older adolescent experiences a primary or exclusive sexual attraction to prepubescent children. Although girls typically begin the process of puberty a ...

and other cases of paraphilia.

Side effects

Common side effects of leuprorelin injection include redness/burning/stinging/pain/bruising at the injection site, hot flashes (flushing), increased sweating, night sweats, tiredness, headache, upset stomach, nausea, diarrhea, impotence, testicular shrinkage, constipation, stomach pain, breast swelling or tenderness, acne, joint/muscle aches or pain, trouble sleeping (insomnia), reduced sexual interest, vaginal discomfort/dryness/itching/discharge, vaginal bleeding, swelling of the ankles/feet, increased urination at night, dizziness, breakthrough bleeding in a female child during the first two months of leuprorelin treatment, weakness, chills, clammy skin, skin redness, itching, or scaling, testicle pain, impotence, depression, or memory problems. The rates of

gynecomastia Gynecomastia (also spelled gynaecomastia) is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse ...

with leuprorelin have been found to range from 3 to 16%. A cohort of women that were prescribed leuprorelin to delay precocious puberty as children has developed osteoporosis and brittle teeth at an unexpected rate; However, the FDA has not established that these conditions were caused by leuprorelin.

Pharmacology

Mechanism of action

Leuprorelin is a

gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and release ...

(GnRH) analogue acting as 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 ...

pituitary In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The hyp ...

GnRH receptors. Agonism of GnRH receptors initially results in the stimulation of

luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnR ...

(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, and ...

(FSH) secretion by 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 ...

ultimately leading to increased serum

and

levels via the normal physiology of the

hypothalamic–pituitary–gonadal axis The hypothalamic–pituitary–gonadal axis (HPG axis, also known as the hypothalamic–pituitary–ovarian/testicular axis) refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single en ...

(HPG axis); however, because propagation of the HPG axis is incumbent upon pulsatile hypothalamic GnRH secretion, pituitary GnRH receptors become desensitised after several weeks of continuous leuprorelin therapy. This protracted downregulation of GnRH receptor activity is the targeted objective of leuprorelin therapy and ultimately results in decreased LH and FSH secretion, leading to

hypogonadism Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estroge ...

and thus a dramatic reduction in estradiol and testosterone levels regardless of sex. In the treatment of

, the initial increase in testosterone levels associated with the initiation of leuprorelin therapy is counterproductive to treatment goals. This effect is avoided with concurrent utilisation of 5α-reductase inhibitors, such as

finasteride Finasteride, sold under the brand names Proscar and Propecia among others, is a medication used to treat hair loss and benign prostatic hyperplasia (BPH) in men. It can also be used to treat excessive hair growth in women and as a part of ho ...

, or

flutamide Flutamide, sold under the brand name Eulexin among others, is a nonsteroidal antiandrogen (NSAA) which is used primarily to treat prostate cancer. It is also used in the treatment of androgen-dependent conditions like acne, excessive hair grow ...

which function to block the downstream effects of testosterone.

Available forms

Leuprorelin is available in the following forms, among others: * Short-acting daily intramuscular injection (Lupron) * Long-acting depot intramuscular injection (Lupron Depot) * Long-acting depot subcutaneous injection (Eligard) * Long-acting subcutaneous injection (Fensolvi) * Long-acting subcutaneous implant (Viadur) * Long-acting leuprolide mesylate (Camcevi) for the treatment of advanced prostate cancer. * Leuprolide acetate and norethindrone acetate combination pack (Lupaneta Pack)

Chemistry

The

peptide sequence Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

is Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt (Pyr = L- pyroglutamyl).

History

Leuprorelin was discovered and first

patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A p ...

ed in 1973 and was introduced for medical use in 1985. It was initially marketed only for daily injection, but a

depot injection A depot injection is a term for an injection formulation of a medication which releases slowly over time to permit less frequent administration of a medication. They are designed to increase medication adherence and consistency, especially in ...

formulation was introduced in 1989.

Approvals

* Lupron injection was approved by the FDA for treatment of advanced

on April 9, 1985. * Lupron

depot Depot ( or ) may refer to: Places * Depot, Poland, a village * Depot Island, Kemp Land, Antarctica * Depot Island, Victoria Land, Antarctica * Depot Island Formation, Greenland Brands and enterprises * Maxwell Street Depot, a restaurant in ...

for monthly intramuscular injection was approved by the FDA for

palliative Palliative care (derived from the Latin root , or 'to cloak') is an interdisciplinary medical caregiving approach aimed at optimizing quality of life and mitigating suffering among people with serious, complex, and often terminal illnesses. Wit ...

treatment of advanced prostate cancer on January 26, 1989. * Viadur was approved by the FDA for palliative treatment of advanced prostate cancer on March 6, 2000. * Eligard was approved by the FDA for palliative treatment of advanced prostate cancer on January 24, 2002. * Fensolvi was approved by the FDA for children with central precocious puberty on May 4, 2020.

Society and culture

Legal status

On 24 March 2022, the

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee A committee or commission is a body of one or more persons subordina ...

(CHMP) of the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...

(EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Camcevi, intended for the treatment of the cancer of the prostate in adult men when the cancer is "hormone-dependent", which means that it responds to treatments that reduce the levels of the hormone testosterone. The applicant for this medicinal product is Accord Healthcare S.L.U. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

Names

Leuprorelin is the generic name of the drug and its and , while leuprorelin acetate is its and , leuprolide acetate is its and , leuprorelina is its , and leuproréline is its . It is also known by its developmental code names A-43818, Abbott-43818, DC-2-269, and TAP-144. Leuprorelin is marketed by

Bayer AG Bayer AG (, commonly pronounced ; ) is a German multinational pharmaceutical and biotechnology company and one of the largest pharmaceutical companies in the world. Headquartered in Leverkusen, Bayer's areas of business include pharmaceutica ...

under the brand name Viadur, by Tolmar under the brand names Eligard and Fensolvi, and by TAP Pharmaceuticals (1985–2008), by Varian Darou Pajooh under the brand name Leupromer and

Abbott Laboratories Abbott Laboratories is an American multinational medical devices and health care company with headquarters in Abbott Park, Illinois, United States. The company was founded by Chicago physician Wallace Calvin Abbott in 1888 to formulate known dr ...

(2008–present) under the brand name Lupron.

Controversy

In October 2001, the US Department of Justice, states attorneys general, and TAP Pharmaceutical Products, a subsidiary of Abbott Laboratories, settled criminal and civil charges against TAP related to federal and state

medicare fraud In the United States, Medicare fraud is the claiming of Medicare health care reimbursement to which the claimant is not entitled. There are many different types of Medicare fraud, all of which have the same goal: to collect money from the Medicare ...

and illegal marketing of the drug leuprorelin. TAP paid a total of $875 million, which was a record high at the time. The $875 million settlement broke down to $290 million for violating the Prescription Drug Marketing Act, $559.5 million to settle federal fraud charges for overcharging Medicare, and $25.5 million reimbursement to 50 states and Washington, D.C., for filing false claims with the states' Medicaid programs. The case arose under the

False Claims Act The False Claims Act (FCA), also called the "Lincoln Law", is an American federal law that imposes liability on persons and companies (typically federal contractors) who defraud governmental programs. It is the federal government's primary litig ...

with claims filed by Douglas Durand, a former TAP vice president of sales, and Joseph Gerstein, a doctor at

Tufts University Tufts University is a private research university on the border of Medford and Somerville, Massachusetts. It was founded in 1852 as Tufts College by Christian universalists who sought to provide a nonsectarian institution of higher learnin ...

's HMO practice. Durand, Gerstein, and Tufts shared $95 million of the settlement. There have since been various suits concerning leuprorelin use, none successful. They either concern the oversubscription of the drug or undue warning about the side effects. Between 2010 and 2013, the FDA updated the Lupron drug label to include new safety information on the risk of thromboembolism, loss of bone density and convulsions. The FDA then asserted that the benefits of leuprorelin outweigh its risks when used according to its approved labeling. Since 2017, the FDA has been evaluating leuprorelin's connection to pain and discomfort in musculoskeletal and connective tissue.

"Lupron protocol"

A 2005 paper in the controversial and non-

peer review Peer review is the evaluation of work by one or more people with similar competencies as the producers of the work ( peers). It functions as a form of self-regulation by qualified members of a profession within the relevant field. Peer revie ...

ed journal '' Medical Hypotheses'' suggested leuprorelin as a possible treatment for

autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...

, the hypothetical method of action being the now defunct hypothesis that autism is caused by mercury, with the additional unfounded assumption that mercury binds irreversibly to

and therefore leuprorelin can help cure autism by lowering the testosterone levels and thereby mercury levels. However, there is no scientifically valid or reliable research to show its effectiveness in treating autism. This use has been termed the "Lupron protocol" and Mark Geier, the proponent of the hypothesis, has frequently been barred from testifying in vaccine-autism related cases on the grounds of not being sufficiently expert in that particular issue and has had his medical license revoked. Medical experts have referred to Geier's claims as "junk science".

Research

, leuprorelin was under investigation for possible use in the treatment of mild to moderate

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...

. A

by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are in ...

formulation Formulation is a term used in various senses in various applications, both the material and the abstract or formal. Its fundamental meaning is the putting together of components in appropriate relationships or structures, according to a formul ...

of leuprorelin is under development for the treatment of

. It was also under development for the treatment of

, and

, but development for these uses was discontinued. The formulation has the tentative brand name Ovarest. As of July 2018, it is in phase II

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s for endometriosis.

Veterinary use

Leuprorelin is frequently used in ferrets for the treatment of adrenal disease. Its use has been reported in a ferret with concurrent primary hyperaldosteronism, and one with concurrent diabetes mellitus. It is also used to treat pet parrots with chronic egg laying behavior.

References

External links

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