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Theoretical Frame of Puberty Suppression
Fig.: Hormonal Controls of Puberty [Credit: Wikimedia Commons]
Concept of Gender Events
According to the prevailing theory of pediatric transgender care - children first are “assigned gender at birth” (AGAB) which can be “assigned male at birth” (AMAB) or “assigned female at birth” (AFAB). This is first gender event and it is not “affirming event”since the gender is imposed on the unconscious neonate.
The gender affirmation is defined as follows:
“Gender affirmation, also referred to as gender transitioning, is a dynamic process whereby an individual affirms their gender through social (e.g., name, pronoun, and gender expression changes, gender identity disclosure) and medical (e.g., hormones, surgery) processes”
According to this reasoning, the first gender affirming event is not puberty but rather any social even in which a child says that he/she feels to be of the opposite sex and someone else in the position of authority confirms that. This can occur long before puberty onset.
First Gender Affirming Event
WPATH states clearly that that puberty suppression is a first stage of gender affirming intervention. BMJ blog explains it further as follows:
“The World Professional Association for Transgender Health (WPATH) Guidelines, on the clinical care of transgender adolescent, set out three stages of gender-affirming interventions with progressive levels of irreversibility:
· Stage 1, puberty suppression
· Stage 2, gender-affirming hormones
· Stage 3, gender-affirming surgery”
Most of transgender theorists do agree that after going through natural puberty, the vast majority of gender non-conforming children tends to accept their assigned at both gender. For instance in this informal literature compilation from 2016 - author found that:
“Despite the differences in country, culture, decade, and follow-up length and method, all the studies have come to a remarkably similar conclusion: Only very few trans- kids still want to transition by the time they are adults. Instead, they generally turn out to be regular gay or lesbian folks. The exact number varies by study, but roughly 60–90% of trans- kids turn out no longer to be trans by adulthood.”
A recent study from 2021 of the boys experiencing gender dysphoria shows virtually the same result as the earlier studies:
“Of the 139 participants, 17 (12.2%) were classified as persisters and the remaining 122 (87.8%) were classified as desisters.”
Indication for the Use of Puberty Blockers
Based upon the above research, theoretically, the puberty blockers are to be used ONLY in those cases in which the desire for sex change persists or increases after puberty started. However, theory usually do not correspond to the reality.
Clinical Information Database “UpToDate”, which is one of the most frequently used source material in modern medicine and a basis for most of Clinical Decision Supporting Modules of Electronic Health Records first states:
“Hormonal interventions to suppress puberty and/or promote development of cross-gender secondary sexual characteristics may be beneficial in TGD youth whose assertion of gender identity being different from their designated sex at birth is persistent, consistent, and intensifies with the onset of pubertal changes”
But it immediately adds:
“Suppression of endogenous puberty may be warranted for TGD youth with persistent gender dysphoria that intensifies after the onset of puberty and nonbinary gender-diverse youth who are in the process of determining their gender identity.Pubertal suppression also may be beneficial for youth who are exploring a nonbinary identity and have concerns about the irreversible changes of endogenous puberty. Youth with intense feelings of gender dysphoria are at risk for adverse psychosocial outcomes.”
Source: Olson-Kennedy, J. Management of transgender and gender-diverse children and adolescents. In: UpToDate, Waltham, MA, 2022.
Hence, it appears that current mainstream recomendations defaults to virtually universal allowance for puberty blockade - because any child of pubertal age will be likely nervous about puberty.
The clear and impartial conclusion from this reasoning is that:
Irreversible changes of endogenous natural puberty are BAD, but irreversible changes of artificial manipulation of puberty via suppressants and sex-hormones and surgery are GOOD.
Modalities of Puberty Suppression
Thanks to amazing advances in reproductive endocrinology, we know that suppression of puberty can be achieved by numerous interventions, including the use of:
From those numerous options, GnRH analogs are usually preferred. It is said by the most commonly relied on CDS, that is because of:
“their efficacy, safety profile, and clinical experience in treating children with precocious puberty”
But is it, really?
Here are the citation which the CDS article ( Olson-Kennedy, J. Management of transgender and gender-diverse children and adolescents. In: UpToDate, Waltham, MA, 2022) uses to justify this statement:
Meyer WJ 3rd. Gender identity disorder: an emerging problem for pediatricians. Pediatrics. 2012 Mar;129(3):571-3. doi: 10.1542/peds.2011-3696. Epub 2012 Feb 20. PMID: 22351880.
Jain J, Dutton C, Nicosia A, Wajszczuk C, Bode FR, Mishell DR Jr. Pharmacokinetics, ovulation suppression and return to ovulation following a lower dose subcutaneous formulation of Depo-Provera. Contraception. 2004 Jul;70(1):11-8. doi: 10.1016/j.contraception.2004.01.011. PMID: 15208047.
Mieszczak J, Eugster EA. Treatment of precocious puberty in McCune-Albright syndrome. Pediatr Endocrinol Rev. 2007 Aug;4 Suppl 4(0 4):419-22. PMID: 17982389; PMCID: PMC4118734.
Richman RA, Underwood LE, French FS, Van Wyk JJ. Adverse effects of large doses of medroxyprogesterone (MPA) in idiopathic isosexual precocity. J Pediatr. 1971 Dec;79(6):963-71. doi: 10.1016/s0022-3476(71)80191-9. PMID: 4332067.
de Vries AL, Cohen-Kettenis PT. Clinical management of gender dysphoria in children and adolescents: the Dutch approach. J Homosex. 2012;59(3):301-20. doi: 10.1080/00918369.2012.653300. PMID: 22455322.
de Vries AL, Steensma TD, Doreleijers TA, Cohen-Kettenis PT. Puberty suppression in adolescents with gender identity disorder: a prospective follow-up study. J Sex Med. 2011 Aug;8(8):2276-83. doi: 10.1111/j.1743-6109.2010.01943.x. Epub 2010 Jul 14. PMID: 20646177.
Hewitt JK, Paul C, Kasiannan P, Grover SR, Newman LK, Warne GL. Hormone treatment of gender identity disorder in a cohort of children and adolescents. Med J Aust. 2012 May 21;196(9):578-81. doi: 10.5694/mja12.10222. PMID: 22621149.
This list of papers does not strike as especially persuasive evidence and the careful study of the listed publication confirms that skepticism. Those are either reviews or the small cohort short term studies.
Let’s compare the presented above short list of reference assuring the “safety” of puberty suppression with the with the following list of selected references dealing with side effects of lupron - the most commonly used GnRH analog. At which point no further discussion would appear to be necessary in the view of the obvious conclusions:
List of Selected References dealing with Side Effects of Lupron:
1. Abbasi D, Faiek S, Shetty S, Khan E. Shock from twisting peaks: A rare case of recurrent torsades de pointes secondary to leuprolide-induced prolonged QT. Cureus. 2020;12(7):e9041. doi:10.7759/cureus.9041 [PubMed 32782861]
2. ACOG Committee Opinion No. 760: Dysmenorrhea and Endometriosis in the Adolescent. Obstet Gynecol. 2018 Dec;132(6):e249-e258. doi:10.1097/AOG.0000000000002978 [PubMed 30461694]
3. Adjuvant Breast Cancer Trials Collaborative Group. Ovarian ablation or suppression in premenopausal early breast cancer: results from the international adjuvant breast cancer ovarian ablation or suppression randomized trial. J Natl Cancer Inst. 2007;99(7):516-525. doi:10.1093/jnci/djk109 [PubMed 17405996]
4. Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr. 2001;139(2):317-319. doi:10.1067/mpd.2001.116281 [PubMed 11487763]
5. Akaboshi S, Takeshita K. A case of atypical absence seizures induced by leuprolide acetate. Pediatr Neurol. 2000;23(3):266-268. doi:10.1016/s0887-8994(00)00181-8 [PubMed 11033292]
6. Alade SL, Brown RE, Paquet A Jr. Polysorbate 80 and E-ferol toxicity. Pediatrics. 1986;77(4):593-597. [PubMed 3960626]
7. Bhatia N, Santos M, Jones LW, et al. Cardiovascular effects of androgen deprivation therapy for the treatment of prostate cancer: ABCDE steps to reduce cardiovascular disease in patients with prostate cancer. Circulation. 2016;133(5):537-541. doi:10.1161/CIRCULATIONAHA.115.012519 [PubMed 26831435]
8. Basch E, Loblaw DA, Oliver TK, et al. Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline. J Clin Oncol. 201420;32(30):3436-3448. doi:10.1200/JCO.2013.54.8404[PubMed 25199761]
9. Bellón T. Mechanisms of severe cutaneous adverse reactions: Recent advances. Drug Saf. 2019;42(8):973-992. doi:10.1007/s40264-019-00825-2 [PubMed 31020549]
10. Bernad DM, Dal Pra A, Baule C, Frey BN, Faria S. New-onset psychosis following androgen deprivation therapy for prostate cancer. Can J Urol. 2013;20(4):6868-68670. [PubMed 23930615]
11. Blumenthal KG, Peter JG, Trubiano JA, Phillips EJ. Antibiotic allergy. Lancet. 2019;393(10167):183-198. doi:10.1016/S0140-6736(18)32218-9[PubMed 30558872]
12. Boccardo F, Rubagotti A, Amoroso D, et al. Endocrinological and clinical evaluation of two depot formulations of leuprolide acetate in pre- and perimenopausal breast cancer patients. Cancer Chemother Pharmacol. 1999;43(6):461-466. doi:10.1007/s002800050924 [PubMed 10321505]
13. Burris K, Ding CY, Lim GF. Leuprolide acetate-induced generalized papular eruption. J Drugs Dermatol. 2014;13(6):755-757. [PubMed 24918569]
14. Burstein HJ, Lacchetti C, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline update on ovarian suppression. J Clin Oncol. 2016;34(14):1689-1701. doi:10.1200/JCO.2015.65.9573 [PubMed 26884586]
15. Burstein HJ, Lacchetti C, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: ASCO clinical practice guideline focused update. J Clin Oncol. 2019;37(5):423-438. doi:10.1200/JCO.18.01160 [PubMed 30452337]
16. Caballero ML, Krantz MS, Quirce S, Phillips EJ, Stone CA Jr. Hidden dangers: Recognizing excipients as potential causes of drug and vaccine hypersensitivity reactions. J Allergy Clin Immunol Pract. 2021;9(8):2968-2982. doi:10.1016/j.jaip.2021.03.002 [PubMed 33737254]
17. Camcevi (leuprolide mesylate) [prescribing information]. Taipei City 115, Taiwan: Foresee Pharmaceuticals Co., Ltd; May 2021.
18. Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics. 2009;123(4):752-762. doi:10.1542/peds.2008-1783 [PubMed 19332438]
19. Centers for Disease Control (CDC). Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982;31(22):290-291. http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm [PubMed 6810084]
20. Centers for Disease Control (CDC). Unusual syndrome with fatalities among premature infants: association with a new intravenous vitamin E product. MMWR Morb Mortal Wkly Rep. 1984;33(14):198-199. http://www.cdc.gov/mmwr/preview/mmwrhtml/00000319.htm. [PubMed 6423951]
21. Chavez B, Reilly T. Manic and psychotic symptoms following subcutaneous leuprolide in a male patient with no prior psychiatric history. J Clin Psychiatry. 2010;71(12):1696-1698. doi:10.4088/JCP.10l06190yel [PubMed 21190641]
22. Cook T, Sheridan WP. Development of GnRH antagonists for prostate cancer: new approaches to treatment. Oncologist. 2000;5(2):162-168. doi:10.1634/theoncologist.5-2-162 [PubMed 10794807]
23. Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989;321(7):419-424. doi:10.1056/NEJM198908173210702. Erratum in: N Engl J Med 1989;321(20):1420. [PubMed 2503724]
24. Dangle P, Palit V, Sundaram SK, Weston P. Noninfective cutaneous granuloma with leuprorelin acetate--reality or myth. Urology. 2007;69(4):779.e5-e6. doi:10.1016/j.urology.2007.02.013 [PubMed 17445679]
25. Dawood MY, Ramos J, Khan-Dawood FS. Depot leuprolide acetate versus danazol for treatment of pelvic endometriosis: changes in vertebral bone mass and serum estradiol and calcitonin. Fertil Steril. 1995;63(6):1177-1183. doi:10.1016/s0015-0282(16)57593-1 [PubMed 7750585]
26. Dittrich R, Binder H, Cupisti S, Hoffmann I, Beckmann MW, Mueller A. Endocrine treatment of male-to-female transsexuals using gonadotropin-releasing hormone agonist. Exp Clin Endocrinol Diabetes. 2005;113(10):586-592. doi: 10.1055/s-2005-865900. [PubMed 16320157]
27. Eligard (leuprolide acetate) [prescribing information]. Fort Collins, CO: Tomar Therapeutics, Inc; April 2019.
28. Eligard (leuprolide acetate) [product monograph]. Oakville, Ontario, Canada: Innomar Strategies Inc; December 2021.
29. Fabiano AJ, George S. Pituitary Apoplexy After Initial Leuprolide Injection. World Neurosurg. 2016;95:616.e7-616.e9. doi:10.1016/j.wneu.2016.08.091 [PubMed 27586180]
30. Fensolvi (leuprolide acetate) [prescribing information]. Fort Collins, CO: Tolmar Pharmaceuticals Inc; March 2022.
31. Francis PA, Pagani O, Fleming GF, et al; SOFT and TEXT Investigators and the International Breast Cancer Study Group. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379(2):122-137. doi:10.1056/NEJMoa1803164 [PubMed 29863451]
32. Fujisaki A, Kondo Y, Goto K, Morita T. Life-threatening anaphylaxis to leuprorelin acetate depot: case report and review of the literature. Int J Urol. 2012;19(1):81-84. doi:10.1111/j.1442-2042.2011.02886.x [PubMed 22050405]
33. Gatti J, Brinker A, Avigan M. Spontaneous reports of seizure in association with leuprolide (lupron depot), goserelin (zoladex implant), and naferelin (synarel nasal spray). Obstet Gynecol. 2013;121(5):1107. doi:10.1097/AOG.0b013e31828c9cb3 [PubMed 23635751]
34. Gava G, Cerpolini S, Martelli V, Battista G, Seracchioli R, Meriggiola MC. Cyproterone acetate vs leuprolide acetate in combination with transdermal oestradiol in transwomen: a comparison of safety and effectiveness. Clin Endocrinol (Oxf). 2016;85(2):239-46. doi:10.1111/cen.13050 [PubMed 26932202]
35. Gnanaraj J, Saif MW. Hypersensitivity vasculitis associated with leuprolide (Lupron). Cutan Ocul Toxicol. 2010;29(3):224-227. doi:10.3109/15569527.2010.487505 [PubMed 20470239]
36. Guay DR. Drug treatment of paraphilic and nonparaphilic sexual disorders. Clin Ther. 2009;31(1):1-31. doi:10.1016/j.clinthera.2009.01.009[PubMed 19243704]
37. Heger S, Partsch CJ, Sippell WG. Long-term outcome after depot gonadotropin-releasing hormone agonist treatment of central precocious puberty: Final height, body proportions, body composition, bone mineral density, and reproductive function. J Clin Endocrinol Metab. 1999;84(12):4583-4590.
38. Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine treatment of gender-dysphoric/gender-incongruent persons: an Endocrine Society clinical practice guideline. Endocr Pract. 2017;23(12):1437. doi:10.4158/1934-2403-23.12.1437 [PubMed 29320642]
39. Houk CP, Kunselman AR, Lee PA. The diagnostic value of a brief GnRH analogue stimulation test in girls with central precocious puberty: a single 30-minute post-stimulation LH sample is adequate. J Pediatr Endocrinol Metab. 2008;21(12):1113-1118. doi:10.1515/jpem.2008.21.12.1113 [PubMed 19189683]
40. Hu JR, Duncan MS, Morgans AK, et al. Cardiovascular effects of androgen deprivation therapy in prostate cancer: Contemporary meta-analyses. Arterioscler Thromb Vasc Biol. 2020;40(3):e55-e64. doi:10.1161/ATVBAHA.119.313046 [PubMed 31969015]
41. "Inactive" ingredients in pharmaceutical products: update (subject review). American Academy of Pediatrics Committee on Drugs. Pediatrics. 1997;99(2):268-278. doi:10.1542/peds.99.2.268 [PubMed 9024461]
42. Isaksson M, Jansson L. Contact allergy to Tween 80 in an inhalation suspension. Contact Dermatitis. 2002;47(5):312-323. doi:10.1034/j.1600-0536.2002.4705104.x [PubMed 12534540]
43. Jaggi S, Slone H, Strauss R, Zaeeter W, Pallie V. SUN-421 leuprolide injection induced pituitary apoplexy. J Endocrine Society. 2019;3(suppl 1);SUN-421. https://doi.org/10.1210/js.2019-SUN-421
44. Kappy MS, Stuart T, Perelman A. Efficacy of leuprolide therapy in children with central precocious puberty. Am J Dis Child. 1988;142(10):1061-1064. doi:10.1001/archpedi.1988.02150100055025 [PubMed 3140654]
45. Kaya A, Cayir A, Turan MI, Ozkan B. An examination of the effects of leuprolide acetate used in the treatment of central precocious puberty on bone mineral density and 25-hydroxy vitamin D. West Indian Med J. 2015;64(2):104-107. doi:10.7727/wimj.2014.346 [PubMed 26360682]
46. Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24(27):4448-4456. doi:10.1200/JCO.2006.06.2497 [PubMed 16983113]
47. Kirkgoz T, Karakoc-Aydiner E, Bugrul F, et al. Management of systemic hypersensitivity reactions to gonadotropin-releasing hormone analogues during treatment of central precocious puberty. Horm Res Paediatr. 2020;93(1):66-72. doi:10.1159/000505329 [PubMed 31972562]
48. Kluger N, Hahtola S, Lempinen T, Jeskanen L. Cutaneous granulomas caused by subcutaneous injections of leuprorelin acetate. Presse Med. 2017;46(10):966-968. doi:10.1016/j.lpm.2017.08.004 [PubMed 28919272]
49. Krueger RB, Kaplan MS. Depot-leuprolide acetate for treatment of paraphilias: a report of twelve cases. Arch Sex Behav. 2001;30(4):409-422. doi:10.1023/a:1010213432606 [PubMed 11446201]
50. Lam C, Tjon J, Hamilton J, Ahmet AH. Recurrent anaphylaxis associated with gonadotropin-releasing hormone analogs: case report and review of the literature. Pharmacotherapy. 2006;26(12):1811-1815. doi:10.1592/phco.26.12.1811 [PubMed 17125443]
51. Laufer MR. Current approaches to optimizing the treatment of endometriosis in adolescents. Gynecol Obstet Invest. 2008;66(Suppl 1):19-27. doi:10.1159/000148027 [PubMed 18936548]
52. Lee PA, Page JG. Effects of leuprolide in the treatment of central precocious puberty. J Pediatr. 1989;114(2):321-324. doi:10.1016/s0022-3476(89)80806-6 [PubMed 2492599]
53. Letterie GS, Stevenson D, Shah A. Recurrent anaphylaxis to a depot form of GnRH analogue. Obstet Gynecol. 1991;78(5 pt 2):943-946.[PubMed 1923237]
54. Leuprolide acetate injection [prescribing information]. Princeton, NJ: Sandoz Inc; January 2019.
55. Levine GN, D'Amico AV, Berger P, et al; American Heart Association Council on Clinical Cardiology and Council on Epidemiology and Prevention, the American Cancer Society, and the American Urological Association. Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. Circulation. 2010;121(6):833-840. doi:10.1161/CIRCULATIONAHA.109.192695[PubMed 20124128]
56. Loren AW, Mangu PB, Beck LN, et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31(19):2500-2510. Accessed September 29, 2014. http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.49.2678. [PubMed 23715580]
57. Lucente P, Iorizzo M, Pazzaglia M. Contact sensitivity to Tween 80 in a child. Contact Dermatitis. 2000;43(3):172. [PubMed 10985636]
58. Lüchinger AB, Mijatovic V, Rustemeyer T, Hompes PG. Anaphylactic reaction to different gonadotropin-releasing hormone agonists for the treatment of endometriosis. Am J Med Sci. 2011;341(3):240-242. doi:10.1097/MAJ.0b013e31820094da [PubMed 21233692]
59. Lupron (leuprolide acetate) [prescribing information]. North Chicago, IL: AbbVie Inc; March 2019.
60. Lupron Depot 1-month 7.5 mg, 3-month 22.5 mg, 4-month 30 mg, 6-month 45 mg (leuprolide acetate) [prescribing information]. North Chicago, IL: AbbVie Inc; April 2022.
61. Lupron Depot 1-month 7.5 mg, 3-month 22.5 mg, 4-month 30 mg, 6-month 45 mg (leuprolide acetate) [prescribing information]. North Chicago, IL: AbbVie Inc; March 2019.
62. Lupron Depot 3.75 mg (leuprolide acetate) [prescribing information]. North Chicago, IL: AbbVie Inc; February 2021.
63. Lupron Depot 3-month 11.25 mg (leuprolide acetate) [prescribing information]. North Chicago, IL: AbbVie Inc; March 2020.
64. Lupron Depot-PED (leuprolide acetate) [prescribing information]. North Chicago, IL: AbbVie Inc; April 2022.
65. Lupron and Lupron Depot (leuprolide acetate) [product monograph]. St Laurent, Quebec, Canada: AbbVie Corp; November 2021.
66. Magon N. Gonadotropin releasing hormone agonists: Expanding vistas. Indian J Endocrinol Metab. 2011;15(4):261-267. doi:10.4103/2230-8210.85575 [PubMed 22028996]
67. Margel D, Peer A, Ber Y, et al. Cardiovascular morbidity in a randomized trial comparing GnRH agonist and GnRH antagonist among patients with advanced prostate cancer and preexisting cardiovascular disease. J Urol. 2019;202(6):1199-1208. doi:10.1097/JU.0000000000000384 [PubMed 31188734]
68. McNeil BD, Pundir P, Meeker S, et al. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature. 2015;519(7542):237-241. doi:10.1038/nature14022 [PubMed 25517090]
69. Melloni C, Roe MT. Androgen deprivation therapy and cardiovascular disease. Urol Oncol. 2020;38(2):45-52. doi:10.1016/j.urolonc.2019.02.010 [PubMed 30879969]
70. Metzger ML, Meacham LR, Patterson B, et al.. Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J Clin Oncol. 2013;31(9):1239-1247. doi:10.1200/JCO.2012.43.5511 [PubMed 23382474]
71. Mitchell BG, Adams AL, Thandi PK. Psychotic exacerbation following subcutaneous leuprolide in a male patient with previous history of schizophrenia. Prim Care Companion CNS Disord. 2017;19(2). doi:10.4088/PCC.16l02038 [PubMed 28387484]
72. National Institute for Health and Care Excellence (NICE). Drug allergy: Diagnosis and management. Clinical guideline; 2014. https://www.nice.org.uk/guidance/cg183/resources/drug-allergy-diagnosis-and-management-pdf-35109811022821
73. Ökdemir D, Hatipoğlu N, Akar HH, et al. A patient developing anaphylaxis and sensitivity to two different GnRH analogues and a review of literature. J Pediatr Endocrinol Metab. 2015;28(7-8):923-925. doi:10.1515/jpem-2014-0402 [PubMed 25719301]
74. Okwuosa TM, Morgans A, Rhee JW, et al; American Heart Association Cardio-Oncology Subcommittee of the Council on Clinical Cardiology and the Council on Genomic and Precision Medicine; Council on Arteriosclerosis, Thrombosis and Vascular Biology; and Council on Cardiovascular Radiology and Intervention. Impact of hormonal therapies for treatment of hormone-dependent cancers (breast and prostate) on the cardiovascular system: Effects and modifications: A scientific statement from the American Heart Association. Circ Genom Precis Med. 2021;14(3):e000082. doi:10.1161/HCG.0000000000000082 [PubMed 33896190]
75. Omar AA, Nyaga G, Mungai LNW. Pseudotumor cerebri in patient on leuprolide acetate for central precocious puberty. Int J Pediatr Endocrinol. 2020;2020(1):22. doi:10.1186/s13633-020-00092-4 [PubMed 33292495]
76. Oshima M, Murao K, Ishigami T, Kubo Y. Drug eruption induced by gonadotropin-releasing hormone analogs accompanying radiation-recall phenomenon. J Dermatol. 2012;39(12):1080-1081. doi:10.1111/j.1346-8138.2012.01576.x [PubMed 22568476]
77. Palomba S, Affinito P, Tommaselli GA, Nappi C. A clinical trial of the effects of tibolone administered with gonadotropin-releasing hormone analogues for the treatment of uterine leiomyomata. Fertil Steril. 1998;70(1):111-118. doi:10.1016/s0015-0282(98)00128-9 [PubMed 9660431]
78. Pong YH, Lu YC, Tsai VF, Huang PL, Hsieh JT, Chang HC. Acute manic and psychotic symptoms following subcutaneous leuprolide acetate in a male patient without prior psychiatric history: A case report and literature review. 2014;25(1):22-24. https://doi.org/10.1016/j.urols.2013.05.010
79. Reilly DR, Delva NJ, Hudson RW. Protocols for the use of cyproterone, medroxyprogesterone, and leuprolide in the treatment of paraphilia. Can J Psychiatry. 2000;45(6):559-563. doi:10.1177/070674370004500608 [PubMed 10986575]
80. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350(10):1013-1022. doi:10.1056/NEJMra032426 [PubMed 14999113]
81. Rugo HS, Rumble RB, Macrae E, et al. Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology Guideline. J Clin Oncol. 2016;34(25):3069-3103. doi:10.1200/JCO.2016.67.1487 [PubMed 27217461]
82. Sadler Gallagher J, Feldman HA, Stokes NA, et al. The effects of gonadotropin-releasing hormone agonist combined with add-back therapy on quality of life for adolescents with endometriosis: A randomized controlled trial. J Pediatr Adolesc Gynecol. 2017;30(2):215-222. doi:10.1016/j.jpag.2016.02.008 [PubMed 26927501]
83. Sasagawa Y, Tachibana O, Nakagawa A, Koya D, Iizuka H. Pituitary apoplexy following gonadotropin-releasing hormone agonist administration with gonadotropin-secreting pituitary adenoma. J Clin Neurosci. 2015;22(3):601-603. doi:10.1016/j.jocn.2014.08.015[PubMed 25455737]
84. Sathasivam A, Garibaldi L, Shapiro S, Godbold J, Rapaport R. Leuprolide stimulation testing for the evaluation of early female sexual maturation. Clin Endocrinol (Oxf). 2010;73(3):375-381. doi:10.1111/j.1365-2265.2010.03796.x [PubMed 20184599]
85. Sathasivam A, Rosenberg HK, Shapiro S, Wang H, Rapaport R. Pelvic ultrasonography in the evaluation of central precocious puberty: comparison with leuprolide stimulation test. J Pediatr. 2011;159(3):490-495. doi:10.1016/j.jpeds.2011.02.032 [PubMed 21489559]
86. Schmid P, Untch M, Kossé V, et al. Leuprorelin acetate every-3-months depot versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant treatment in premenopausal patients with node-positive breast cancer: the TABLE study. J Clin Oncol. 2007;25(18):2509-2515. doi:10.1200/JCO.2006.08.8534 [PubMed 17577027]
87. Schmid P, Untch M, Wallwiener D, et al; TABLE-study (Takeda Adjuvant Breast cancer study with Leuprorelin Acetate). Cyclophosphamide, methotrexate and fluorouracil (CMF) versus hormonal ablation with leuprorelin acetate as adjuvant treatment of node-positive, premenopausal breast cancer patients: preliminary results of the TABLE-study (Takeda Adjuvant Breast cancer study with Leuprorelin Acetate). Anticancer Res. 2002;22(4):2325-2332. [PubMed 12174922]
88. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med. 2005;352(2):154-164. doi:10.1056/NEJMoa041943 [PubMed 15647578]
89. Shalin SC, Brantley J, Diwan AH. Follicular mucinosis and mycosis-fungoides-like drug eruption due to leuprolide acetate: a case report and review. J Cutan Pathol. 2012;39(11):1022-1025. doi:10.1111/j.1600-0560.2012.01980.x [PubMed 22882386]
90. Shelley WB, Talanin N, Shelley ED. Polysorbate 80 hypersensitivity. Lancet. 1995;345(8960):1312-1313. doi:10.1016/s0140-6736(95)90963-x[PubMed 7746084]
91. Shiota M, Tokuda N, Kanou T, Yamasaki H. Injection-site granulomas resulting from the administration of both leuprorelin acetate and goserelin acetate for the treatment of prostatic cancer. J Nippon Med Sch. 2007;74(4):306-308. doi:10.1272/jnms.74.306 [PubMed 17878701]
92. Smith MR. Treatment-related osteoporosis in men with prostate cancer. Clin Cancer Res. 2006;12(20 Pt 2):6315s-6319s. doi:10.1158/1078-0432.CCR-06-0846 [PubMed 17062721]
93. Smith MR, Klotz L, Persson BE, Olesen TK, Wilde AA. Cardiovascular safety of degarelix: results from a 12-month, comparative, randomized, open label, parallel group phase III trial in patients with prostate cancer. J Urol. 2010;184(6):2313-2319. doi:10.1016/j.juro.2010.08.012[PubMed 20952020]
94. Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab. 2006;91(4):1305-1308. doi:10.1210/jc.2005-2507 [PubMed 16434464]
95. Spry NA, Galvão DA, Davies R, et al. Long-term effects of intermittent androgen suppression on testosterone recovery and bone mineral density: results of a 33-month observational study. BJU Int. 2009;104(6):806-812. doi:10.1111/j.1464-410X.2009.08458.x [PubMed 19281463]
96. Swayzer DV, Gerriets V. Leuprolide. 2021 Jul 25. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. [PubMed 31869126]
97. Tanaka T, Niimi H, Matsuo N, et al. Results of long-term follow-up after treatment of central precocious puberty with leuprorelin acetate: evaluation of effectiveness of treatment and recovery of gonadal function. The TAP-144-SR Japanese Study Group on Central Precocious Puberty. J Clin Endocrinol Metab. 2005;90(3):1371-1376. doi:10.1210/jc.2004-1863 [PubMed 15598675]
98. Tang J, Weiter JJ. Branch retinal artery occlusion after injection of a long-acting risperidone preparation. Ann Intern Med. 2007;147(4):283-284. doi:10.7326/0003-4819-147-4-200708210-00021 [PubMed 17709768]
99. Tan MG, Worley B, Kim WB, Ten Hove M, Beecker J. Drug-induced intracranial hypertension: A systematic review and critical assessment of drug-induced causes. Am J Clin Dermatol. 2020;21(2):163-172. doi:10.1007/s40257-019-00485-z [PubMed 31741184]
100. Tanios G, Mungo NA, Kapila A, Bajaj K. Pituitary apoplexy: a rare complication of leuprolide therapy in prostate cancer treatment. BMJ Case Rep. 2017;2017:bcr2016218514. doi:10.1136/bcr-2016-218514 [PubMed 28710301]
101. Thibaut F, De La Barra F, Gordon H, Cosyns P, Bradford JM; WFSBP Task Force on Sexual Disorders. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of paraphilias. World J Biol Psychiatry. 2010;11(4):604-655. doi:10.3109/15622971003671628 [PubMed 20459370]
102. Thompson IM. Flare associated with LHRH-agonist therapy. Rev Urol. 2001;3 suppl 3(suppl 3):S10-S104. [PubMed 16986003]
103. Thompson IM, Zeidman EJ, Rodriguez FR. Sudden death due to disease flare with luteinizing hormone-releasing hormone agonist therapy for carcinoma of the prostate. J Urol. 1990;144(6):1479-1480. doi:10.1016/s0022-5347(17)39774-4 [PubMed 2122011]
104. Tisdale JE, Chung MK, Campbell KB, et al; American Heart Association Clinical Pharmacology Committee of the Council on Clinical Cardiology and Council on Cardiovascular and Stroke Nursing. Drug-induced arrhythmias: A scientific statement from the American Heart Association. Circulation. 2020;142(15):e214-e233. doi:10.1161/CIR.0000000000000905 [PubMed 32929996]
105. Tisdale JE, Jaynes HA, Kingery JR, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes. 2013;6(4):479-487. doi:10.1161/CIRCOUTCOMES.113.000152. Erratum in: Circ Cardiovasc Qual Outcomes. 2013;6(6):e57. [PubMed 23716032]
106. Tung YC, Lee JS, Tsai WY, Hsiao PH. The effects of gonadotropin releasing hormone analogue therapy on girls with gonadotropin-dependent precocious puberty. J Formos Med Assoc. 2007;106(10):826-831. doi:10.1016/S0929-6646(08)60047-9 [PubMed 17964961]
107. US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. Updated September 2016. Accessed October 5, 2016. http://www.cdc.gov/niosh/topics/antineoplastic/pdf/hazardous-drugs-list_2016-161.pdf.
108. Warrington R, Silviu-Dan F, Wong T. Drug allergy. Allergy Asthma Clin Immunol. 2018;14(Suppl 2):60. doi:10.1186/s13223-018-0289-y[PubMed 30275849]
109. Waxman J, Man A, Hendry WF, et al. Importance of early tumour exacerbation in patients treated with long acting analogues of gonadotrophin releasing hormone for advanced prostatic cancer. Br Med J (Clin Res Ed). 1985;291(6506):1387-1388. doi:10.1136/bmj.291.6506.1387 [PubMed 2933122]
110. Yasukawa K, Sawamura D, Sugawara H, Kato N. Leuprorelin acetate granulomas: case reports and review of the literature. Br J Dermatol. 2005;152(5):1045-1047. doi:10.1111/j.1365-2133.2005.06341.x [PubMed 15888168]
111. Zeulide Depot (leuprolide acetate) [product monograph]. Mississauga, Ontario, Canada: Verity Pharmaceuticals Inc; August 2021.