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.[1][2] It is given by injection into a muscle or under the skin.[1]

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
Drug classGnRH analogue; GnRH agonist; Antigonadotropin
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life3 hours
ExcretionKidney
Identifiers
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)
 NY (what is this?)  (verify)

Common side effects include hot flashes, unstable mood, trouble sleeping, headaches, and pain at the site of injection.[1] Other side effects may include high blood sugar, allergic reactions, and problems with the pituitary gland.[1] Use during pregnancy may harm the baby.[1] Leuprorelin is in the gonadotropin-releasing hormone (GnRH) analogue family of medications.[1] It works by decreasing gonadotropin and therefore decreasing testosterone and estradiol.[1]

Leuprorelin was patented in 1973 and approved for medical use in the United States in 1985.[1][3] It is on the World Health Organization's List of Essential Medicines.[2] It is sold under the brand name Lupron among others.[1]

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[4] or uterine fibroids.

It may be used for precocious puberty in both males and females,[5] 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.[6]

It may be used to reduce the risk of premature ovarian failure in women receiving cyclophosphamide for chemotherapy.[7]

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.[8] 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.[9]

They are also sometimes used as alternatives to antiandrogens like spironolactone and cyproterone acetate for suppressing testosterone production in transgender women.

It is considered a possible treatment for paraphilias.[10] Leuprorelin has been tested as a treatment for reducing sexual urges in pedophiles and other cases of paraphilia.[11][12]

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[13], 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.[14] The rates of gynecomastia with leuprorelin have been found to range from 3 to 16%.[15]

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.[16][17]

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:[18][19][20][21][22]

  • Short-acting daily intramuscular injection (Lupron): 5 mg/mL (2.8 mL) used as 1 mg every day.
  • Long-acting depot intramuscular injection (Lupron Depot): 7.5 mg once a month, 22.5 mg every 3 months, or 30 mg every 4 months.
  • Long-acting depot subcutaneous injection (Eligard): 7.5 mg once a month, 22.5 mg every 3 months, 30 mg every 4 months, or 45 mg every 6 months.
  • Long-acting subcutaneous injection (Fensolvi): 45 mg every 6 months.
  • Long-acting subcutaneous implant (Viadur): 65 mg pellet once every 12 months.

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.[23][24] It was initially marketed only for daily injection, but a depot injection formulation was introduced in 1989.[24]

Approvals
  • Lupron injection was first approved by the FDA for treatment of advanced prostate cancer on April 9, 1985. [23][24]
  • Lupron depot for monthly intramuscular injection was first approved by the FDA for palliative treatment of advanced prostate cancer on January 26, 1989, and subsequently in 22.5 mg/vial and 30 mg/vial for intramuscular depot injection every 3 and 4 months, respectively. 3.75 mg/vial and 11.25 mg/vial dosage forms were subsequently approved for subcutaneous depot injection every month and every three months, respectively for treatment of endometriosis or fibroids. 7.5 mg/vial, 11.25 mg/vial, and 15 mg/vial dosage forms were subsequently approved for subcutaneous depot injection for treatment of children with central precocious puberty.
  • Viadur (72 mg yearly subcutaneous implant) was first approved by the FDA for palliative treatment of advanced prostate cancer on March 6, 2000. Bayer will fulfill orders until current supplies are depleted, expected by the end of April 2008
  • Eligard (7.5 mg for monthly subcutaneous depot injection) was first approved by the FDA for palliative treatment of advanced prostate cancer on January 24, 2002, and subsequently in 22.5 mg, 30 mg, and 45 mg doses for subcutaneous depot injection every 3, 4, and 6 months, respectively.
  • Fensolvi (45 mg, subcutaneous injection every 6 months) was first approved by the FDA for pediatric patients with central precocious puberty on May 4, 2020.[25]
  • Leupromer 7.5 (7.5 mg, one month depot for subcutaneous injection) is the second in situ-forming injectable drug in the world. It is used for palliative treatment of advanced prostate cancer, endometriosis, and uterine fibroids. It was approved by The Ministry of Health and Medical Education Of Iran.

Society and culture

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.[26][27][28][29] It is also known by its developmental code names A-43818, Abbott-43818, DC-2-269, and TAP-144.[26][27][28][29]

Leuprorelin is marketed by Bayer AG under the brand name Viadur, by Tolmar under the brand names Eligard and Fensolvi,[30][31] 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. It is available as a slow-release implant or subcutaneous/intramuscular injection.

In the UK and Ireland, leuprorelin is marketed by Takeda UK as Prostap SR (one-month injection) and Prostap 3 (three-month injection).

Conspiracy to violate the Prescription Drug Marketing Act settlement

In October 2001, the U.S. Department of Justice and TAP Pharmaceutical Products Inc. reached an agreement under which TAP agreed to pay $875,000,000 to resolve criminal charges and civil liabilities related to allegedly fraudulent drug pricing and marketing conduct with regard to Lupron, in violation of the Prescription Drug Marketing Act.[32] According to the Department of Justice, the penalties were the largest criminal and civil recoveries in any U.S. health care fraud case to that date.

"Lupron protocol"

A 2005 paper in the controversial and non-peer reviewed journal Medical Hypotheses suggested leuprorelin as a possible treatment for autism,[33] 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.[34] However, there is no scientifically valid or reliable research to show its effectiveness in treating autism.[35] This use has been termed the "Lupron protocol"[36] 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[37][38][39] and has had his medical license revoked.[36] Medical experts have referred to Geier's claims as "junk science".[40]

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,[41] and one with concurrent diabetes mellitus.[42] It is also used to treat pet parrots suffering from chronic egg laying behavior.[43]

Research

As of 2006, leuprorelin was under investigation for possible use in the treatment of mild to moderate Alzheimer's disease.[44]

A by mouth formulation of leuprorelin is under development for the treatment of endometriosis.[45] It was also under development for the treatment of precocious puberty, prostate cancer, and uterine fibroids, but development for these uses was discontinued.[45] The formulation has the tentative brand name Ovarest.[45] As of July 2018, it is in phase II clinical trials for endometriosis.[45]

See also

References
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  2. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  3. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 514. ISBN 9783527607495.
  4. Crosignani PG, Luciano A, Ray A, Bergqvist A (January 2006). "Subcutaneous depot medroxyprogesterone acetate versus leuprolide acetate in the treatment of endometriosis-associated pain". Human Reproduction. 21 (1): 248–56. doi:10.1093/humrep/dei290. PMID 16176939.
  5. Badaru A, Wilson DM, Bachrach LK, et al. (May 2006). "Sequential comparisons of one-month and three-month depot leuprolide regimens in central precocious puberty". The Journal of Clinical Endocrinology and Metabolism. 91 (5): 1862–7. doi:10.1210/jc.2005-1500. PMID 16449344.
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  7. Clowse ME, Behera MA, Anders CK, Copland S, Coffman CJ, Leppert PC, Bastian LA (March 2009). "Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis". Journal of Women's Health. 18 (3): 311–9. doi:10.1089/jwh.2008.0857. PMC 2858300. PMID 19281314.
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  11. Schober JM, Byrne PM, Kuhn PJ (2006). "Leuprolide acetate is a familiar drug that may modify sex-offender behaviour: the urologist's role". BJU International. 97 (4): 684–6. doi:10.1111/j.1464-410X.2006.05975.x. PMID 16536753. S2CID 19365144.
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  43. "TREATMENT OF CHRONIC EGG LAYING". Yarmouth Veterinary Center. Retrieved 29 December 2020.
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Further reading
  • Shajnfeld, Adam; Krueger, Richard Bohn (July 2006). "Reforming (Purportedly) Non-Punitive Responses to Sexual Offending". Developments in Mental Health Law. 25: 81. SSRN 1077282.
  • "Leuprorelin". Drug Information Portal. U.S. National Library of Medicine.
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