{"paper_id":"6be6693d-cbb5-4754-8a2c-b312a57f77f5","body_text":"Transient thyrotoxicosis following prolonged use of\ngonadotropin-releasing hormone agonist in women with\nendometriosis – a case report\nAkira Nakashima1, Koji Nakagawa1, Shirei Ohgi1, Takashi Horikawa1, Toshiharu Kamura2, \nHidekazu Saito1\nAbstract\nThis paper reports two cases showing transient thyrotoxicosis caused by\nprolonged use of gonadotropin-releasing hormone (GnRH) agonist. Case 1, \na 31-year-old woman, was administered GnRH-agonist (leuprorelin acetate) for\ntreatment of endometriosis. After four months she showed thyroid dysfunction.\nCase 2, a 43-year-old woman, who was previously diagnosed with chronic\nthyroiditis, was treated with GnRH-agonist (nafarelin acetate) for her\nendometriosis. Five months later, her thyroid functions worsened. After\ndiscontinuation of the GnRH-agonist, thyroid function of both cases recovered.\nIn selected patients, who are on GnRH-agonist, attention to thyroid function is\nimportant.\nKKeeyy  wwoorrddss:: GnRH-agonist, endometriosis, thyroid grand, thyroiditis.\nIntroduction\nAdministration of gonadotropin-releasing hormone (GnRH) agonists\n(i.e. leuprorelin acetate, buserelin acetate and nafarelin acetate) is\na common treatment for endometriosis and uterine fibromas. In recent\nyears, some cases that appeared as thyroid dysfunction following\nadministration of GnRH-agonist have been reported [1-6]. All these cases\nwere treated by GnRH-agonist for various causes such as\ndysmenorrhoea, abnormal genital bleeding and endometriosis. With\nprolonged administration of GnRH-agonist, the GnRH receptors on the\npituitary gland were desensitized with subsequent very low levels of\noestrogen and progesterone, as if in a post-menopausal state. It was\nsuggested that this low oestrogen level might be a trigger of thyroiditis.\nRecently, we had two cases of unexpected thyrotoxicosis, that occurred\nduring the long-term administration of GnRH-agonist in the treatment\nof severe dysmenorrhoea. In this case report, we describe these two\ncases in detail, and caution clinicians to be circumspect in their use of\nGnRH-agonist.\n1Division of Reproductive Medicine, Department of Perinatal and Maternal Care, National\nCentre for Child Health and Development, Tokyo, Japan\n2Department of Obstetrics and Gynaecology, Kurume University School of Medicine,\nFukuoka, Japan\nSSuubbmmiitttteedd::  18 December 2007\nAAcccceepptteedd::  30 March 2008\nArch Med Sci 2008; 4, 2: 200–203\nCopyright © 2008 Termedia & Banach\nCCoorrrreessppoonnddiinngg  aauutthhoorr::\nAkira Nakashima, MD\nDivision of Reproductive\nMedicine\nDepartment of Perinatal and\nMaternal Care\nNational Centre for Child Health\nand Development\n2-10-1 Okura, Setagaya\nTokyo, 157-8535, Japan\nPhone: +81 3 3416 0181\nFax: +81 3 3416 2222\nE-mail: nakashima-\na@ncchd.go.jp\nCase report\n\nArch Med Sci 2, June / 2008 201\nCase reports\nCCaassee  II\nA 31-year-old infertile woman with a regular\nmenstrual cycle presented with severe intractable\ndysmenorrhoea. Her basal gonadotropin levels,\nprolactin level and thyroid function were normal.\nShe gave no family history of thyroid disease. She\nhad been diagnosed with endometriosis at 27 years\nof age, with bilateral ovarian endometriomas, but\nhad not undergone any medical treatment. She\nfinally decided to seek medical treatment for her\nendometriosis. Treatment with GnRH-agonist\n(leuprorelin acetate, Leuplin® 1.88 mg every\n4 weeks, Takeda, Osaka) was commenced. After\nthe 3\nrd injection of leuprorelin acetate, a slight\nthyroid swelling appeared and the value of\nanti-thyroperoxidase (TPO) and anti-thyroglobulin\n(TG) antibodies was slightly elevated (anti-TPO\n2.6 U/ml, normal range <0.3 U/ml, anti-TG\n5.5 U/ml, normal range <0.3 U/ml), but the values\nfor serum FT4 (1.6 ng/dl, normal range 0.7-1.5 ng/dl),\nFT3 (2.3 pg/ml, normal range 1.7-3.7 pg/ml) and TSH\n(0.76 µIU/ml, normal rage 0.35-4.94 µIU/ml) were\nalmost normal.\nA laparoscopic endometrial cystectomy was\nperformed, and additional administration of\nleuprorelin acetate was done for her severe\nendometriosis (stage IV of revised AFS classification)\n[7]. Four weeks after the additional administration of\nGnRH-agonist, severe symptoms such as mild\ntachycardia, diaphoresis and loss of body weight\nappeared. Clinically, her thyroid was remarkably\nswollen, and serum FT4 (2.2 ng/dl) and FT3 (6.4 pg/ml)\nlevels had increased, accompanied by a very low TSH\nvalue (0.014 µIU/ml). Based on these results, she was\ndiagnosed as having thyrotoxicosis, and leuprorelin\nacetate was discontinued. The clinical symptoms\ngradually improved without further medical treatment.\nSix months later her thyroid function recovered to\na normal range (Table I).\nCCaassee IIII\nA 43-year-old woman, gravida 2, para 2, with\nregular menstrual cycles, complained of severe\ndysmenorrhoea due to endometriosis. She had also\nbeen diagnosed with chronic thyroiditis (Hashimoto’s\nthyroiditis), but her thyroid functions were normal\nwithout medication. She gave no family history of\nthyroid disease. Although she had a unilateral large\nendometrial cyst, she did not agree to laparoscopic\nsurgery. She then decided to have GnRH-agonist \n(300 µg per day of nafarelin acetate, Nasanyl®,\nAstellas, Tokyo) therapy. Five months after the\nadministration of nafarelin acetate, her thyroid gland\nwas slightly enlarged. Her FT4 (2.3 ng/ml) and FT3\n(6.8 pg/ml) levels were elevated with a significantly\nlow value of TSH (0.01 µIU/ml) and TSH binding\ninhibitor immunoglobulin (TBII, normal range <10%)\n–4.8%. The anti-microsomal antibody was very high\n(6400, normal range <100). Based on these results,\nshe was diagnosed as having painless thyroiditis.\nAdministration of nafarelin acetate was stopped\nimmediately, and potassium iodide was administered\nfor the treatment of the painless thyroiditis. One\nmonth later, her thyroid function recovered to\na normal range (Table II).\nDiscussion\nIn recent years, there have been several reports\ndescribing thyroid dysfunction, triggered by the\nadministration of GnRH-agonist [1-6]. Sonoda et al.\nreported painless thyroiditis that appeared after the\nadministration of leuprolide acetate [1]. This patient\nshowed normal TSH, FT3 and FT4 levels but positive\nanti-TG antibodies. She was diagnosed with\nHashimoto’s thyroiditis. The clinical symptoms\n(palpitations, general fatigue and disconcertment)\nimproved without medical treatment. In another case\nreported by Fukuda et al., painless thyroiditis also\nappeared after the administration of nafarelin acetate\n* – free thyroxine, *2 – free triiodothyronine, *3 – thyroid-stimulating hormone, *4 – thyrotropin receptor antibodies, *5 – anti-thyroperoxidase\nantibody, *6 – anti-thyroglobulin antibody, *7 – gonadotropin-releasing hormone, *8 – not tested\nThe serum levels of FT4, FT3 and TSH were measured using chemiluminesent immunoassay (DPC immrise HS-free T4, HS-free T3, HS-TSH,\nDiagnostic Products Corporation EURO/DPC Ltd.). TRAb was measured by radioreceptor assay kit (CosmicIII, RSR limited, UK). TPOAb and TGAb\nwere measured by radioreceptor assay kit [CosmicII (500), CosmicII RSR limited, UK]\nTTaabbllee II..  Changes in serum levels of FT4, FT3 and TSH of case 1\nTTwwoo  mmoonntthhss  aafftteerr FFoouurr  mmoonntthhss  aafftteerr  FFiivvee  mmoonntthhss  aafftteerr NNiinnee  mmoonntthhss  aafftteerr  \nGGnnRRHHaa**77 iinniittiiaattiioonn GGnnRRHHaa  iinniittiiaattiioonn GGnnRRHHaa  iinniittiiaattiioonn GGnnRRHHaa  iinniittiiaattiioonn\nFFTT44** [[nngg//ddll]] 1.64 2.20 1.65 1.15\nFFTT33**22 [[ppgg//mmll]] 2.3 6.4 4.7 2.9\nTTSSHH**33 [[µµIIUU//mmll]] 0.76 0.014 <0.001 2.1\nTTRRAAbb**44 NT*8 NT*8 negative NT *8\nTTPPOOAAbb**55 2.6 NT *8 <0.3 NT *8\nTTGGAAbb**66 5.5 NT *8 NT*8 34.2\nTransient thyrotoxicosis during use of GnRH-agonist\n\n202 Arch Med Sci 2, June / 2008\nTTaabbllee  IIII..  Changes in serum levels of FT4, FT3 and TSH of case 2\nFFiivvee  mmoonntthhss  aafftteerr OOnnee  mmoonntthh  aafftteerr  TTwwoo  mmoonntthhss  aafftteerr\nGGnnRRHHaa**55 iinniittiiaattiioonn aaddmmiinniissttrraattiioonn  ooff  iiooddiiddee aaddmmiinniissttrraattiioonn  ooff  iiooddiiddee\nFFTT44** ((nngg//ddll)) 2.3 1.0 0.70\nFFTT33**22 ((ppgg//mmll)) 6.8 2.5 1.37\nTTSSHH**33 ((µµIIUU//mmll)) 0.01 0.018 3.68\nTTBBIIII**44 ((%%)) –4.8 NT *6 NT*6\nAAnnttii--mmiiccrroossoommaall 6400 NT *6 NT*6\naannttiibbooddyy  ((ttiimmeess))\n* – free thyroxine, *2 – free triiodothyronine, *3 – thyroid-stimulating hormone, *4 – TSH-binding inhibitory immunoglobulin, *5 – gonadotropin-\nreleasing hormone, *6 – not tested \nTBII was measured by radioreceptor assay kit (CosmicIII, RSR limited, UK). Anti-microsomal antibody was measured by particle agglutination kit\n(SERODIA®-AMC, FUJIREBIO, Japan)\nTTaabbllee IIIIII.. Reported cases of transient thyroiditis induced by administration of GnRH agonist \nRReeffeerreenncceess AAggee IInndduuccttiioonn  ffoorr  GGnnRRHH  DDrruugg AAddmmiinniissttrraattiioonn CCoommpplliiccaattiioonn\n((yyeeaarrss)) [[yyeeaarrss]] aaggoonniisstt  ttrreeaattmmeenntt ppeerriioodd  uunnttiill  oonnsseett ooff  aauuttooiimmmmuunnee\n[[mmoonntthhss]] ddiisseeaassee\nFukuda (1999) 20 endometriosis nafarelin 6 basedow\nacetate\nSonoda (1999) 34 endometriosis leuprorelin 4 chronic thyroiditis\nacetate\nKasayama (2000) 45 uterine fibroma leuprorelin 5 ITP *\nacetate\nTanaka (2000) 37 adenomyosis buserelin 6 none\nacetate\nleuprorelin \nacetate\nAmino (2003) 49 uterine fibroma buserelin 4 basedow\nacetate\n41 uterine fibroma leuprorelin 4 basedow\nacetate\n29 endometriosis buserelin 4 ITP *\nacetate\nEyal (2004) 9 precocious leuprorelin 8 none\npuberty acetate\n* – idiopathic thrombocytopenic purpura\n[2], but no abnormality of thyroid function was\nobserved. On the other hand, Eyal et al. reported that\nleuprolide acetate induced hypothyroidism in\na patient with precocious puberty and cautioned care\nwith use of GnRH-agonist for patients who have\nautoimmune thyroid disease [5, 8].\nPainless thyroiditis was defined as inflammation\nof the thyroid gland characterized by passing\nhyperthyroidism, followed by hypothyroidism and\nrecovery. Our assumption is that this prolonged low\noestrogen state might be a trigger for exacerbation\nof autoimmune thyroiditis, similar to what is\nsometimes seen as transient postpartum or\npostmenopausal thyroiditis.\nTo our knowledge, so far 8 cases of transient\nthyrotoxicosis following administration of\nGnRH-agonist have been reported (Table III) [1-6].\nSurprisingly, 7 of these 8 patients were Japanese\nwomen. The reason for this ethnic preponderance is\nuncertain; however, it possibly points to a higher\nprevalence of autoimmune thyroid disease\n(Hashimoto’s thyroiditis) in Japanese women.\nGnRH-agonist, an effective agent in the treatment\nof endometriosis, includes various side effects. For\nsafe use, GnRH-agonist was used in tandem with\nother drugs, such as parathyroid hormone [9], and\nthe cancer risks of these fertility drugs were studied\n[10]. A possibility of an induced transient hyperthyroid\nAkira Nakashima, Koji Nakagawa, Shirei Ohgi, Takashi Horikawa, Toshiharu Kamura, Hidekazu Saito\n\nArch Med Sci 2, June / 2008 203\nstate followed by a hypothyroid state should be\ncarefully looked for in patients on GnRH-agonist with\nassociated hypo-oestrogenic state, caused by its\nprolonged use.\nReferences\n1. Sonoda M, Nagata Y, Inoue Y, et al. A case of transient\nhyperthyroidism during pseudomenopausal therapy. Acta\nObstet Gynecol Jpn 1999; 51: 857-60.\n2. Fukuda S, Kubota J, Ito M, Tamai H, Matsuduka F, Mori H.\nA case of painless thyroiditis occurred after administration\nof Nafarelin [Japanese]. Hormone Rinsho 1999; 47: 90-2.\n3. Amino N, Hidaka Y, Takano T, Tatsumi KI, Izumi Y, \nNakata Y. Possible induction of Graves” disease and\npainless thyroiditis by gonadotropin-releasing hormone\nanologues. Thyroid 2003; 13: 815-8.\n4. Kasayama S, Miyake S, Samejima Y. Transient thyrotoxicosis\nand hypothyroidism following administration of GnRH\nagonist leuprolide acetate. Endocrine J 2000; 47: 783-5.\n5. Eyal O, Rose SR. Autoimmune thyroiditis during leuprorelin\nacetate treatment. J Pediatr 2004; 144: 394-6.\n6. Tanaka T, Umesaki N, Ogita S. Altered sensitivity to\nanti-endometriosis medicines in an adenomyosis patient\nwith thyroid dysfunction. Gynecol Endocrinol 2000;\n14: 388-91.\n7. American Society for Reproductive Medicine. Revised\nAmerican Society for Reproductive Medicine classification\nof endometriosis: 1996. Fertil Steril 1997; 67: 817-21.\n8. Eyal O. The role of leuprolide acetate therapy in triggering\nauto-immune thyroiditis. Reply. J Pediatr 2005; 146: 294-5.\n9. Finkelstein JS, Klibanski A, Arnold AL, Toth TL, Hornstein MD,\nNeer RM. Prevention of eatrogen deficiency-related bone\nloss with human parathyroid hormone (1-34). JAMA 1998;\n280: 1067-73.\n10. Hannibal CG, Jensen A, Sharif H, Kjaer SK. Risk of thyroid\ncancer after exposure to fertility drugs: result from a large\nDanish cohort study. Hum Reprod 2008; 23: 451-6.\nTransient thyrotoxicosis during use of GnRH-agonist","source_license":"CC0","license_restricted":false}