Case report Transient thyrotoxicosis following prolonged use of gonadotropin-releasing hormone agonist in women with endometriosis – a case report

This paper reports two cases showing transient thyrotoxicosis caused by prolonged use of gonadotropin-releasing hormone (GnRH) agonist. Case 1, a 31-year-old woman, was administered GnRH-agonist (leuprorelin acetate) for treatment of endometriosis. After four months she showed thyroid dysfunction. Case 2, a 43-year-old woman, who was previously diagnosed with chronic thyroiditis, was treated with GnRH-agonist (nafarelin acetate) for her endometriosis. Five months later, her thyroid functions worsened. After discontinuation of the GnRH-agonist, thyroid function of both cases recovered. In selected patients, who are on GnRH-agonist, attention to thyroid function is important. KKeeyy wwoorrddss:: GnRH-agonist, endometriosis, thyroid grand, thyroiditis.

Administration of gonadotropin-releasing hormone (GnRH) agonists (i.e. leuprorelin acetate, buserelin acetate and nafarelin acetate) is a common treatment for endometriosis and uterine fibromas. In recent years, some cases that appeared as thyroid dysfunction following administration of GnRH-agonist have been reported [1-6]. All these cases were treated by GnRH-agonist for various causes such as dysmenorrhoea, abnormal genital bleeding and endometriosis. With prolonged administration of GnRH-agonist, the GnRH receptors on the pituitary gland were desensitized with subsequent very low levels of oestrogen and progesterone, as if in a post-menopausal state. It was suggested that this low oestrogen level might be a trigger of thyroiditis. Recently, we had two cases of unexpected thyrotoxicosis, that occurred during the long-term administration of GnRH-agonist in the treatment of severe dysmenorrhoea. In this case report, we describe these two cases in detail, and caution clinicians to be circumspect in their use of GnRH-agonist. 1Division of Reproductive Medicine, Department of Perinatal and Maternal Care, National Centre for Child Health and Development, Tokyo, Japan 2Department of Obstetrics and Gynaecology, Kurume University School of Medicine, Fukuoka, Japan SSuubbmmiitttteedd:: 18 December 2007 AAcccceepptteedd:: 30 March 2008 Arch Med Sci 2008; 4, 2: 200–203 Copyright © 2008 Termedia & Banach CCoorrrreessppoonnddiinngg aauutthhoorr:: Akira Nakashima, MD Division of Reproductive Medicine Department of Perinatal and Maternal Care National Centre for Child Health and Development 2-10-1 Okura, Setagaya Tokyo, 157-8535, Japan Phone: +81 3 3416 0181 Fax: +81 3 3416 2222 E-mail: nakashima- [email protected] Case report Arch Med Sci 2, June / 2008 201 Case reports CCaassee II A 31-year-old infertile woman with a regular menstrual cycle presented with severe intractable dysmenorrhoea. Her basal gonadotropin levels, prolactin level and thyroid function were normal. She gave no family history of thyroid disease. She had been diagnosed with endometriosis at 27 years of age, with bilateral ovarian endometriomas, but had not undergone any medical treatment. She finally decided to seek medical treatment for her endometriosis. Treatment with GnRH-agonist (leuprorelin acetate, Leuplin® 1.88 mg every 4 weeks, Takeda, Osaka) was commenced. After the 3 rd injection of leuprorelin acetate, a slight thyroid swelling appeared and the value of anti-thyroperoxidase (TPO) and anti-thyroglobulin (TG) antibodies was slightly elevated (anti-TPO 2.6 U/ml, normal range <0.3 U/ml, anti-TG 5.5 U/ml, normal range <0.3 U/ml), but the values for serum FT4 (1.6 ng/dl, normal range 0.7-1.5 ng/dl), FT3 (2.3 pg/ml, normal range 1.7-3.7 pg/ml) and TSH (0.76 µIU/ml, normal rage 0.35-4.94 µIU/ml) were almost normal. A laparoscopic endometrial cystectomy was performed, and additional administration of leuprorelin acetate was done for her severe endometriosis (stage IV of revised AFS classification) [7]. Four weeks after the additional administration of GnRH-agonist, severe symptoms such as mild tachycardia, diaphoresis and loss of body weight appeared. Clinically, her thyroid was remarkably swollen, and serum FT4 (2.2 ng/dl) and FT3 (6.4 pg/ml) levels had increased, accompanied by a very low TSH value (0.014 µIU/ml). Based on these results, she was diagnosed as having thyrotoxicosis, and leuprorelin acetate was discontinued. The clinical symptoms gradually improved without further medical treatment. Six months later her thyroid function recovered to a normal range (Table I). CCaassee IIII A 43-year-old woman, gravida 2, para 2, with regular menstrual cycles, complained of severe dysmenorrhoea due to endometriosis. She had also been diagnosed with chronic thyroiditis (Hashimoto’s thyroiditis), but her thyroid functions were normal without medication. She gave no family history of thyroid disease. Although she had a unilateral large endometrial cyst, she did not agree to laparoscopic surgery. She then decided to have GnRH-agonist (300 µg per day of nafarelin acetate, Nasanyl®, Astellas, Tokyo) therapy. Five months after the administration of nafarelin acetate, her thyroid gland was slightly enlarged. Her FT4 (2.3 ng/ml) and FT3 (6.8 pg/ml) levels were elevated with a significantly low value of TSH (0.01 µIU/ml) and TSH binding inhibitor immunoglobulin (TBII, normal range <10%) –4.8%. The anti-microsomal antibody was very high (6400, normal range <100). Based on these results, she was diagnosed as having painless thyroiditis. Administration of nafarelin acetate was stopped immediately, and potassium iodide was administered for the treatment of the painless thyroiditis. One month later, her thyroid function recovered to a normal range (Table II).

In recent years, there have been several reports describing thyroid dysfunction, triggered by the administration of GnRH-agonist [1-6]. Sonoda et al. reported painless thyroiditis that appeared after the administration of leuprolide acetate [1]. This patient showed normal TSH, FT3 and FT4 levels but positive anti-TG antibodies. She was diagnosed with Hashimoto’s thyroiditis. The clinical symptoms (palpitations, general fatigue and disconcertment) improved without medical treatment. In another case reported by Fukuda et al., painless thyroiditis also appeared after the administration of nafarelin acetate * – free thyroxine, *2 – free triiodothyronine, *3 – thyroid-stimulating hormone, *4 – thyrotropin receptor antibodies, *5 – anti-thyroperoxidase antibody, *6 – anti-thyroglobulin antibody, *7 – gonadotropin-releasing hormone, *8 – not tested The serum levels of FT4, FT3 and TSH were measured using chemiluminesent immunoassay (DPC immrise HS-free T4, HS-free T3, HS-TSH, Diagnostic Products Corporation EURO/DPC Ltd.). TRAb was measured by radioreceptor assay kit (CosmicIII, RSR limited, UK). TPOAb and TGAb were measured by radioreceptor assay kit [CosmicII (500), CosmicII RSR limited, UK] TTaabbllee II.. Changes in serum levels of FT4, FT3 and TSH of case 1 TTwwoo mmoonntthhss aafftteerr FFoouurr mmoonntthhss aafftteerr FFiivvee mmoonntthhss aafftteerr NNiinnee mmoonntthhss aafftteerr GGnnRRHHaa**77 iinniittiiaattiioonn GGnnRRHHaa iinniittiiaattiioonn GGnnRRHHaa iinniittiiaattiioonn GGnnRRHHaa iinniittiiaattiioonn FFTT44** [[nngg//ddll]] 1.64 2.20 1.65 1.15 FFTT33**22 [[ppgg//mmll]] 2.3 6.4 4.7 2.9 TTSSHH**33 [[µµIIUU//mmll]] 0.76 0.014 <0.001 2.1 TTRRAAbb**44 NT*8 NT*8 negative NT *8 TTPPOOAAbb**55 2.6 NT *8 <0.3 NT *8 TTGGAAbb**66 5.5 NT *8 NT*8 34.2 Transient thyrotoxicosis during use of GnRH-agonist 202 Arch Med Sci 2, June / 2008 TTaabbllee IIII.. Changes in serum levels of FT4, FT3 and TSH of case 2 FFiivvee mmoonntthhss aafftteerr OOnnee mmoonntthh aafftteerr TTwwoo mmoonntthhss aafftteerr GGnnRRHHaa**55 iinniittiiaattiioonn aaddmmiinniissttrraattiioonn ooff iiooddiiddee aaddmmiinniissttrraattiioonn ooff iiooddiiddee FFTT44** ((nngg//ddll)) 2.3 1.0 0.70 FFTT33**22 ((ppgg//mmll)) 6.8 2.5 1.37 TTSSHH**33 ((µµIIUU//mmll)) 0.01 0.018 3.68 TTBBIIII**44 ((%%)) –4.8 NT *6 NT*6 AAnnttii--mmiiccrroossoommaall 6400 NT *6 NT*6 aannttiibbooddyy ((ttiimmeess)) * – free thyroxine, *2 – free triiodothyronine, *3 – thyroid-stimulating hormone, *4 – TSH-binding inhibitory immunoglobulin, *5 – gonadotropin- releasing hormone, *6 – not tested TBII was measured by radioreceptor assay kit (CosmicIII, RSR limited, UK). Anti-microsomal antibody was measured by particle agglutination kit (SERODIA®-AMC, FUJIREBIO, Japan) TTaabbllee IIIIII.. Reported cases of transient thyroiditis induced by administration of GnRH agonist RReeffeerreenncceess AAggee IInndduuccttiioonn ffoorr GGnnRRHH DDrruugg AAddmmiinniissttrraattiioonn CCoommpplliiccaattiioonn ((yyeeaarrss)) [[yyeeaarrss]] aaggoonniisstt ttrreeaattmmeenntt ppeerriioodd uunnttiill oonnsseett ooff aauuttooiimmmmuunnee [[mmoonntthhss]] ddiisseeaassee Fukuda (1999) 20 endometriosis nafarelin 6 basedow acetate Sonoda (1999) 34 endometriosis leuprorelin 4 chronic thyroiditis acetate Kasayama (2000) 45 uterine fibroma leuprorelin 5 ITP * acetate Tanaka (2000) 37 adenomyosis buserelin 6 none acetate leuprorelin acetate Amino (2003) 49 uterine fibroma buserelin 4 basedow acetate 41 uterine fibroma leuprorelin 4 basedow acetate 29 endometriosis buserelin 4 ITP * acetate Eyal (2004) 9 precocious leuprorelin 8 none puberty acetate * – idiopathic thrombocytopenic purpura [2], but no abnormality of thyroid function was observed. On the other hand, Eyal et al. reported that leuprolide acetate induced hypothyroidism in a patient with precocious puberty and cautioned care with use of GnRH-agonist for patients who have autoimmune thyroid disease [5, 8]. Painless thyroiditis was defined as inflammation of the thyroid gland characterized by passing hyperthyroidism, followed by hypothyroidism and recovery. Our assumption is that this prolonged low oestrogen state might be a trigger for exacerbation of autoimmune thyroiditis, similar to what is sometimes seen as transient postpartum or postmenopausal thyroiditis. To our knowledge, so far 8 cases of transient thyrotoxicosis following administration of GnRH-agonist have been reported (Table III) [1-6]. Surprisingly, 7 of these 8 patients were Japanese women. The reason for this ethnic preponderance is uncertain; however, it possibly points to a higher prevalence of autoimmune thyroid disease (Hashimoto’s thyroiditis) in Japanese women. GnRH-agonist, an effective agent in the treatment of endometriosis, includes various side effects. For safe use, GnRH-agonist was used in tandem with other drugs, such as parathyroid hormone [9], and the cancer risks of these fertility drugs were studied [10]. A possibility of an induced transient hyperthyroid Akira Nakashima, Koji Nakagawa, Shirei Ohgi, Takashi Horikawa, Toshiharu Kamura, Hidekazu Saito Arch Med Sci 2, June / 2008 203 state followed by a hypothyroid state should be carefully looked for in patients on GnRH-agonist with associated hypo-oestrogenic state, caused by its prolonged use.

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