Leuprorelin

Leuprorelin, also known as leuprolide, is a manufactured version of a hormone used to treat prostate cancer, breast cancer, endometriosis, uterine fibroids, and early puberty, to perform chemical castration of violent sex offenders, or as part of transgender hormone therapy.[7][8][9] It is given by injection into a muscle or under the skin.[7]

Leuprorelin
Clinical data
Trade namesLupron, Eligard, Lucrin, others
Other namesleuprolide, leuprolidine, A-43818, Abbott-43818, DC-2-269, TAP-144
AHFS/Drugs.comMonograph
MedlinePlusa685040
License data
Pregnancy
category
  • AU: D
Routes of
administration		implant, subcutaneous, intramuscular
Drug classGnRH analogue; GnRH agonist; Antigonadotropin
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life3 hours
ExcretionKidney
Identifiers
IUPAC name
  • N-[1-[[1-[[1-[[1-[[1-[[1-[[5-(diaminomethylideneamino)-1-
    [2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxo-pentan-2-
    yl]carbamoyl]-3-methyl-butyl]carbamoyl]-3-methyl-
    butyl]carbamoyl]-2-(4-hydroxyphenyl)ethyl]
    carbamoyl]-2-hydroxy-ethyl]carbamoyl]-2-(1H-indol-3-
    yl)ethyl]carbamoyl]-2-(3H-imidazol-4-yl)ethyl]-5-oxo-
    pyrrolidine-2-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.161.466
Chemical and physical data
FormulaC59H84N16O12
Molar mass1209.421 g·mol−1
3D model (JSmol)
SMILES
  • CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc2ccc(cc2)O)NC(=O)[C@H](CO)NC(=O)[C@H](Cc3c[nH]c4c3cccc4)NC(=O)[C@H](Cc5c[nH]cn5)NC(=O)[C@@H]6CCC(=O)N6
InChI
  • InChI=1S/C59H84N16O12/c1-6-63-57(86)48-14-10-22-75(48)58(87)41(13-9-21-64-59(60)61)68-51(80)42(23-32(2)3)69-52(81)43(24-33(4)5)70-53(82)44(25-34-15-17-37(77)18-16-34)71-56(85)47(30-76)74-54(83)45(26-35-28-65-39-12-8-7-11-38(35)39)72-55(84)46(27-36-29-62-31-66-36)73-50(79)40-19-20-49(78)67-40/h7-8,11-12,15-18,28-29,31-33,40-48,65,76-77H,6,9-10,13-14,19-27,30H2,1-5H3,(H,62,66)(H,63,86)(H,67,78)(H,68,80)(H,69,81)(H,70,82)(H,71,85)(H,72,84)(H,73,79)(H,74,83)(H4,60,61,64)/t40-,41-,42-,43+,44-,45-,46-,47-,48-/m0/s1 N
  • Key:GFIJNRVAKGFPGQ-LIJARHBVSA-N N
 NY (what is this?)  (verify)

Leuprorelin is in the gonadotropin-releasing hormone (GnRH) analogue family of medications.[7] It works by decreasing gonadotropin and therefore decreasing testosterone and estradiol.[7] Common side effects include hot flashes, unstable mood, trouble sleeping, headaches, and pain at the site of injection.[7] Other side effects may include high blood sugar, allergic reactions, and problems with the pituitary gland.[7] Use during pregnancy may harm the baby.[7]

Leuprorelin was patented in 1973 and approved for medical use in the United States in 1985.[7][10] It is on the World Health Organization's List of Essential Medicines.[8] It is sold under the brand name Lupron among others.[7]

Medical use

Leuprorelin may be used in the treatment of hormone-responsive cancers such as prostate cancer and breast cancer. It may also be used for estrogen-dependent conditions such as endometriosis[11] or uterine fibroids.

It may be used for precocious puberty in both males and females,[12] and to prevent premature ovulation in cycles of controlled ovarian stimulation for in vitro fertilization (IVF). 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.[13]

It may be used to reduce the risk of premature ovarian failure in women receiving cyclophosphamide for chemotherapy.[14]

Along with triptorelin and goserelin, it has been used to delay puberty in transgender youth until they are old enough to begin hormone replacement therapy.[15] Researchers have recommended puberty blockers after age 12, when the person has developed to Tanner stages 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 and without data on long-term effects of this use.[16]

They are also sometimes used as alternatives to antiandrogens like spironolactone and cyproterone acetate for suppressing testosterone production in transgender women.[17][18][19] It also is used for suppressing estrogen production in transgender men.[20]

It is considered a possible treatment for paraphilias.[21] Leuprorelin has been tested as a treatment for reducing sexual urges in pedophiles and other cases of paraphilia.[22][23]

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,[5] 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.[24] The rates of gynecomastia with leuprorelin have been found to range from 3 to 16%.[25]

Pharmacology

Mechanism of action

Leuprorelin is a gonadotropin-releasing hormone (GnRH) analogue acting as an agonist at pituitary GnRH receptors. Agonism of GnRH receptors initially results in the stimulation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion by the anterior pituitary ultimately leading to increased serum estradiol and testosterone levels via the normal physiology of the hypothalamic–pituitary–gonadal axis (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 and thus a dramatic reduction in estradiol and testosterone levels regardless of sex.[26][27]

In the treatment of prostate cancer, 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, or flutamide which function to block the downstream effects of testosterone.

Available forms

Leuprorelin is available in the following forms, among others:[28][29][30][31][32]

  • Short-acting daily intramuscular injection (Lupron)[1]
  • Long-acting depot intramuscular injection (Lupron Depot)[5][33][34][35]
  • Long-acting depot subcutaneous injection (Eligard)[2]
  • Long-acting subcutaneous injection (Fensolvi)[3]
  • Long-acting subcutaneous implant (Viadur)[4]
  • Long-acting leuprolide mesylate (Camcevi) for the treatment of advanced prostate cancer.[36]
  • Leuprolide acetate and norethindrone acetate combination pack (Lupaneta Pack)[37][38]

Chemistry

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

History

Leuprorelin was discovered and first patented in 1973 and was introduced for medical use in 1985.[39][40] It was initially marketed only for daily injection, but a depot injection formulation was introduced in 1989.[40]

Approvals
  • Lupron injection was approved by the FDA for treatment of advanced prostate cancer on April 9, 1985.[41][1][39][40]
  • Lupron depot for monthly intramuscular injection was approved by the FDA for palliative treatment of advanced prostate cancer on January 26, 1989.[5]
  • Viadur was approved by the FDA for palliative treatment of advanced prostate cancer on March 6, 2000.[4]
  • Eligard was approved by the FDA for palliative treatment of advanced prostate cancer on January 24, 2002.[2]
  • Fensolvi was approved by the FDA for children with central precocious puberty on May 4, 2020.[3][42]

Society and culture

On 24 March 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (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.[43] The applicant for this medicinal product is Accord Healthcare S.L.U.[43]

Names

Leuprorelin is the generic name of the drug and its INN and BAN, while leuprorelin acetate is its BANM and JAN, leuprolide acetate is its USAN and USP, leuprorelina is its DCIT, and leuproréline is its DCF.[44][45][46][47] It is also known by its developmental code names A-43818, Abbott-43818, DC-2-269, and TAP-144.[44][45][46][47]

Leuprorelin is marketed by Bayer AG under the brand name Viadur,[4] by Tolmar under the brand names Eligard and Fensolvi,[2][3] and by TAP Pharmaceuticals (1985–2008), by Varian Darou Pajooh under the brand name Leupromer and Abbott Laboratories (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 and illegal marketing of the drug leuprorelin.[48] TAP paid a total of $875 million, which was a record high at the time.[49][50] 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.[50] The case arose under the False Claims Act with claims filed by Douglas Durand, a former TAP vice president of sales, and Joseph Gerstein, a doctor at Tufts University's HMO practice.[49] Durand, Gerstein, and Tufts shared $95 million of the settlement.[49]

There have since been various suits concerning leuprorelin use, none successful.[51][52] 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.[53] 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.[54]

"Lupron protocol"

A 2005 paper in the controversial and non-peer reviewed journal Medical Hypotheses suggested leuprorelin as a possible treatment for autism,[55] 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 testosterone and therefore leuprorelin can help cure autism by lowering the testosterone levels and thereby mercury levels.[56] However, there is no scientifically valid or reliable research to show its effectiveness in treating autism.[57] This use has been termed the "Lupron protocol"[58] 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[59][60][61] and has had his medical license revoked.[58] Medical experts have referred to Geier's claims as "junk science".[62]

Research

As of 2006, leuprorelin was under investigation for possible use in the treatment of mild to moderate Alzheimer's disease.[63]

A by mouth formulation of leuprorelin is under development for the treatment of endometriosis.[64] It was also under development for the treatment of precocious puberty, prostate cancer, and uterine fibroids, but development for these uses was discontinued.[64] The formulation has the tentative brand name Ovarest.[64] As of July 2018, it is in phase II clinical trials for endometriosis.[64]

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,[65] and one with concurrent diabetes mellitus.[66] It is also used to treat pet parrots with chronic egg laying behavior.[67]

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Further reading
  • Shajnfeld A, Krueger RB (July 2006). "Reforming (Purportedly) Non-Punitive Responses to Sexual Offending". Developments in Mental Health Law. 25: 81. SSRN 1077282.
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