currently , gonadotropin - releasing hormone ( gnrh ) agonist is commonly used for various sex - hormone - related diseases ( uterine myoma , endometriosis , precocious puberty , dysfunctional uterine bleeding , assisted reproductive technology , etc . ) .
the main mechanism of action is the change in the secretion of gonadotropin and sex hormones . in the initial administration , they are associated with an increase in estrogen due to the increase of follicle stimulating hormone and luteinizing hormone , and with the prolonged administration , they are associated with estrogen reduction due to desensitization by down - regulation of gnrh receptor .
the main side effects of these drugs are hypoestrogenism - induced symptoms , such as facial flushing , headache , depression , anxiety , insomnia , colpoxerosis , and osteoporosis .
meanwhile , the autoimmune thyroid diseases , including graves ' disease and painless thyroiditis , are affected by various genetic and environmental factors . of environmental factors ,
the typical example that can infer from the relation between sex hormones and thyroid immune tolerance and autoimmunity is postpartum thyroid dysfunction [ 3 - 5 ] .
in addition , some case reports have shown that gnrh agonist - induced relative estrogen reduction may cause autoimmune thyroid disease by immune rebound [ 6 - 10 ] , but there have been no reports in the korean literature . here ,
we report three cases of thyroid dysfunction related to the prolonged administration of gnrh agonist .
a 30-year - old female came to the department of obstetrics and gynecology at cheil general hospital & women 's healthcare center with dysmenorrhea 3 months ago .
she received subcutaneous injections of leuprorelin acetate 3.75 mg per month , three times in all , with a diagnosis of uterine myoma and endometriosis .
she was examined for thyroid function prior to laparoscopic surgery 1 week ago and she was sent to the department of internal medicine because of thyroid dysfunction .
her blood pressure was 116/76 mm hg , pulse was 60 per minute , and body mass index ( bmi ) was 21.9 kg / m 160 cm , 56 kg .
she had no past medical history , but her mother had previously taken medication for hypothyroidism .
she had no special symptoms , such as fatigue , weight fluctuation , edema , and gastrointestinal problems .
however , she complained of recently occurred sweating and facial flushing . on physical examination , she had slightly diffuse thyroid enlargement and the electrocardiography ( ecg ) was normal .
serum free t4 ( ft4 , 6.9 pmol / l ) was decreased and thyroid stimulating hormone ( tsh , 154.4 u / ml ) was elevated .
antithyroglobulin antibody ( anti - tg ab , 100 u / ml ) and anti thyroid peroxidase antibody ( anti - tpo ab , 58 u / ml ) were both positive , whereas tsh binding inhibitory immunoglobulin ( tbii , 4% ) was negative .
thus , she started thyroid hormone replacement therapy ( levothyroxine 0.1 mg ) with a diagnosis of hypothyroidism .
one month later , her thyroid function was normalized ( ft4 , 21.9 pmol / l ; tsh , 2.91 u / ml ) and 2 months later , she underwent laparoscopic myomectomy .
after the operation , she received injections of leuprorelin acetate three more times ; thereafter , her thyroid function was maintained within the normal range .
she is currently maintaining levothyroxine 0.1 mg under serial assessment by the department of internal medicine ( table 1 ) .
a 35-year - old female came to the department of obstetrics and gynecology at cheil general hospital & women 's healthcare center with sterility 6 months ago .
in the past medical history , she had been treated with medication for hyperthyroidism and had underwent surgery for endometriosis .
she had received subcutaneous injections of leuprorelin acetate of 3.75 mg per month , three times in all , as a pretreatment for in vitro fertilization from 2 months ago .
since she had a past history of hyperthyroidism , she was refered to the department of internal medicine for further evaluation .
her blood pressure was 118/79 mm hg , pulse was 79 per minute , and bmi was 18.6 kg / m ( 159 cm/47 kg ) . she had been diagnosed with hyperthyroidism a decade ago and had taken methimazole 10 to 2.5 mg until 3 months before she came to our hospital because her thyroid function was normalized .
she complained of sweating , heat sensation intolerance , and facial flushing . on physical examination , she had slightly diffuse thyroid enlargement and the ecg was normal .
serum t3 ( 120.6 ng / dl ) , ft4 ( 21.8 pmol / l ) , and tsh ( 0.51 u / ml ) were all whinin the normal range , but anti - tg ab ( 13 u / ml ) , anti - tpo ab ( > 100 u / ml ) , and tbii ( 22% ) were all positive .
one month later , she complained of palpitation and fatigue , while t3 ( 259.5 ng / dl ) and ft4 ( 60.6
pmol / l ) were elevated , tsh ( < 0.01 u / ml ) was suppressed , and anti - tg ab ( 17 u / ml ) , anti - tpo ab ( > 100 u / ml ) , and tbii was elevated to 27% .
two months later , t3 ( 304.0 ng / dl ) , ft4 ( 57.0 pmol / l ) , tsh ( < 0.01 u / ml ) , and tbii was elevated to 37% and medication was changed to propylthiouracil 200 mg .
three months later , she is currently maintaining propylthiouracil 100 mg under serial assessment by the department of internal medicine ( table 2 ) .
a 24-year - old female came to the department of obstetrics and gynecology at cheil general hospital & women 's healthcare center with right lower abdominal pain 2 months ago and she underwent laparoscopic ovarian cystectomy .
subsequently , she had received subcutaneous injections of leuprorelin acetate of 3.75 mg per month , twice in all .
it was accidentally found by another hospital that she had thyroid dysfunction and thyroid enlargement verified by a sonogram 2 days ago .
her blood pressure was 111/67 mm hg , pulse was 80 per minute , and bmi was 18.4 kg / m ( 165 cm/50 kg ) . nothing was noteworthy in her medical histoy or family history .
she complained of weight loss of 4 kg over 1 year , cold sensation intolerance , and facial flushing . on physical examination , she had diffuse thyroid enlargement and the ecg was normal .
pmol / l ) were elevated and tsh ( < 0.01 u / ml ) was suppressed .
anti - tg ab ( 17 u / ml ) and anti - tpo ab ( > 100 u / ml ) were all positive and tbii was 4% .
one month later , tsh ( 0.01 u / ml ) still had been suppressed , but both t3 ( 112.3 ng / dl ) and ft4 ( 14.3
pmol / l ) were normalized ; thereafter , leuprorelin acetate was injected subcutaneously four more times .
two months later , ft4 ( 9.1 pmol / l ) was decreased and tsh ( 9.81 u / ml ) was elevated without symptoms of hypothyroidism , and observation was continued .
four months later , both ft4 ( 11.5 pmol / l ) and tsh ( 2.33 u / ml ) were normalized and she is currently under serial assessment ( table 3 ) .
a 30-year - old female came to the department of obstetrics and gynecology at cheil general hospital & women 's healthcare center with dysmenorrhea 3 months ago .
she received subcutaneous injections of leuprorelin acetate 3.75 mg per month , three times in all , with a diagnosis of uterine myoma and endometriosis .
she was examined for thyroid function prior to laparoscopic surgery 1 week ago and she was sent to the department of internal medicine because of thyroid dysfunction .
her blood pressure was 116/76 mm hg , pulse was 60 per minute , and body mass index ( bmi ) was 21.9 kg / m 160 cm , 56 kg .
she had no past medical history , but her mother had previously taken medication for hypothyroidism .
she had no special symptoms , such as fatigue , weight fluctuation , edema , and gastrointestinal problems .
however , she complained of recently occurred sweating and facial flushing . on physical examination , she had slightly diffuse thyroid enlargement and the electrocardiography ( ecg ) was normal .
serum free t4 ( ft4 , 6.9 pmol / l ) was decreased and thyroid stimulating hormone ( tsh , 154.4 u / ml ) was elevated .
antithyroglobulin antibody ( anti - tg ab , 100 u / ml ) and anti thyroid peroxidase antibody ( anti - tpo ab , 58 u / ml ) were both positive , whereas tsh binding inhibitory immunoglobulin ( tbii , 4% ) was negative .
thus , she started thyroid hormone replacement therapy ( levothyroxine 0.1 mg ) with a diagnosis of hypothyroidism .
one month later , her thyroid function was normalized ( ft4 , 21.9 pmol / l ; tsh , 2.91 u / ml ) and 2 months later , she underwent laparoscopic myomectomy .
after the operation , she received injections of leuprorelin acetate three more times ; thereafter , her thyroid function was maintained within the normal range .
she is currently maintaining levothyroxine 0.1 mg under serial assessment by the department of internal medicine ( table 1 ) .
a 35-year - old female came to the department of obstetrics and gynecology at cheil general hospital & women 's healthcare center with sterility 6 months ago . in the past medical history , she had been treated with medication for hyperthyroidism and had underwent surgery for endometriosis .
she had received subcutaneous injections of leuprorelin acetate of 3.75 mg per month , three times in all , as a pretreatment for in vitro fertilization from 2 months ago .
since she had a past history of hyperthyroidism , she was refered to the department of internal medicine for further evaluation .
her blood pressure was 118/79 mm hg , pulse was 79 per minute , and bmi was 18.6 kg / m ( 159 cm/47 kg ) . she had been diagnosed with hyperthyroidism a decade ago and had taken methimazole 10 to 2.5 mg until 3 months before she came to our hospital because her thyroid function was normalized .
she complained of sweating , heat sensation intolerance , and facial flushing . on physical examination , she had slightly diffuse thyroid enlargement and the ecg was normal .
serum t3 ( 120.6 ng / dl ) , ft4 ( 21.8 pmol / l ) , and tsh ( 0.51 u / ml ) were all whinin the normal range , but anti - tg ab ( 13 u / ml ) , anti - tpo ab ( > 100 u / ml ) , and tbii ( 22% ) were all positive .
one month later , she complained of palpitation and fatigue , while t3 ( 259.5 ng / dl ) and ft4 ( 60.6
pmol / l ) were elevated , tsh ( < 0.01 u / ml ) was suppressed , and anti - tg ab ( 17 u / ml ) , anti - tpo ab ( > 100 u / ml ) , and tbii was elevated to 27% .
two months later , t3 ( 304.0 ng / dl ) , ft4 ( 57.0 pmol / l ) , tsh ( < 0.01 u / ml ) , and tbii was elevated to 37% and medication was changed to propylthiouracil 200 mg .
three months later , she is currently maintaining propylthiouracil 100 mg under serial assessment by the department of internal medicine ( table 2 ) .
a 24-year - old female came to the department of obstetrics and gynecology at cheil general hospital & women 's healthcare center with right lower abdominal pain 2 months ago and she underwent laparoscopic ovarian cystectomy .
subsequently , she had received subcutaneous injections of leuprorelin acetate of 3.75 mg per month , twice in all .
it was accidentally found by another hospital that she had thyroid dysfunction and thyroid enlargement verified by a sonogram 2 days ago .
her blood pressure was 111/67 mm hg , pulse was 80 per minute , and bmi was 18.4 kg / m ( 165 cm/50 kg ) .
she complained of weight loss of 4 kg over 1 year , cold sensation intolerance , and facial flushing . on physical examination , she had diffuse thyroid enlargement and the ecg was normal . both serum t3 ( 211.6 ng / dl ) and ft4 ( 38.6
pmol / l ) were elevated and tsh ( < 0.01 u / ml ) was suppressed .
anti - tg ab ( 17 u / ml ) and anti - tpo ab ( > 100 u / ml ) were all positive and tbii was 4% .
one month later , tsh ( 0.01 u / ml ) still had been suppressed , but both t3 ( 112.3 ng / dl ) and ft4 ( 14.3
pmol / l ) were normalized ; thereafter , leuprorelin acetate was injected subcutaneously four more times .
pmol / l ) was decreased and tsh ( 9.81 u / ml ) was elevated without symptoms of hypothyroidism , and observation was continued .
four months later , both ft4 ( 11.5 pmol / l ) and tsh ( 2.33 u / ml ) were normalized and she is currently under serial assessment ( table 3 ) .
one of them , gnrh agonist has a strong affinity to the gnrh receptor with a long half - life ; therefore , it has almost the same effect as when gonadotropin has been continuously exposed to gnrh .
after the initial flare effect , hormones administered repeatedly reveal the paradoxical antagonistic effect by down - regulation and desensitization , resulting in a hypogonadotrophic hypogonadism state .
accordingly , this agonist has been used for various sex - hormone - related diseases , but it also has side effects inducing pseudomenopause state with long - term use .
many environmental factors have been reported to induce autoimmune thyroid disease , and the fluctuation of sex hormones is one of the important factors of thyroid autoimmunity .
therefore , gnrh gonist - induced alteration in serum levels of gonadotropin and sex hormones may trigger thyroid autoimmunity .
the increase of estrogen inhibits the immune reaction of autoimmune disease , which can be explained by the spontaneous remission of autoimmune disease during pregnancy . on the other hand ,
the reduction of estrogen induces immune rebound , as in the aggravation of autoimmune disease during postpartum period .
it is assumed that the gnrh agonist - derived relative estrogen reduction induced immune rebound and aggravated the preexisting subclinical or mild autoimmune thyroid disease . in relation to the use of leuprolide acetate ,
published a report on transient thyrotoxicosis and hypothyroidism , amino et al .   published a report on graves ' disease and painless thyroiditis , and van bon et al
reported a case of transient thyrotoxicosis after using goserelin acetate in a hypothyroid patient , but nothing has been reported in the korean literature .
furthermore , gnrh agonist - induced aggravation of autoimmune disease is not limited to thyroid disease and there is a case report that leuprolide acetate - associated lupus nephritis was also aggravated . in the above three cases
, we found hypothyroidism , hyperthyroidism , and both transient thyrotoxicosis and hypothyroidism respectively in sequence , and this indicates that there may be various kinds of thyroid dysfunction after gnrh agonist administration , like postpartum thyroid dysfunction .
considering that there was a change in thyroid function at 1 to 3 months after subcutaneous injections of leuprorelin acetate in the above cases , we assume that the main mechanism of disease was caused by the hypoestrogenic state , rather than by the initial gonadotropin surge .
the findings resembled previous cases in which thyroid dysfunction began after 3 to 4 months [ 6 - 9 ] .
moreover , since most patients who had been treated with gnrh agonist complained of symptoms derived from hypoestrogenism , like sweating and facial flushing , this most likely rules out the possibility of thyroid dysfunction . in these cases , most patients also complained of sweating and facial flushing rather than typical symptoms of thyroid dysfunction .
under these circumstances , we think that thyroid function test and autoantibody test are needed in addition to medical examination by interview and physical examination .
the gnrh agonist itself has no influence on thyroid hormone or tsh for healthy women or endometriosis patients , but it has been reported that preexisting diseases appear to be aggravated in patients with subclinical or mild autoimmune disease . given that the present cases were positive for anti - tg ab and anti - tpo ab , it is assumed that the treatment of prolonged gnrh agonist in the presence of subclinical autoimmune thyroid disease generated hypothyroidism , transient thyrotoxicosis and the aggravation of hyperthyroidism .
the above cases verified a possible association between the alteration of gonadotropin and sex hormones and thyroid dysfunction , and in the future , we suggest that clinicians pay attention to the thyroid state when starting the treatment of gnrh agonist for patients at risk of autoimmune thyroid disease .
likewise , it is very important to check the past history or family history of autoimmune diseases for all patients who will receive gnrh agonist treatment .
however , the above cases are not sufficient to establish a cause - and - effect relationship and further study of the association between the gnrh agonist and autoimmune thyroid disease is needed . in summary ,
gnrh agonist is currently used in the treatment of various sex - hormone - related diseases and the mechanism is associated with estrogen reduction from desensitization by down - regulation of gnrh receptor caused by the prolonged administration .
however , the gnrh agonist - derived relative estrogen reduction may induce immune rebound , resulting in autoimmune thyroid disease .
a few cases have been reported , but none have been reported in the korean literature .
therefore , in the present case report , we describe three cases of thyroid dysfunction after the use of gnrh agonist . in the above cases , the administration of gnrh agonist showed the possibility of thyroid dysfunction , and
therefore attention should be paid to the thyroid in patients vulnerable to autoimmune thyroid disease when beginning the treatement of gnrh agonist .
 gonadotropin - releasing hormone ( gnrh ) agonist has been used in the treatment of a wide variety of sex - hormone - related diseases , as the administration of gnrh agonist can alter the secretion of gonadotropin and sex hormones . 
 recently , we found that the long - acting gnrh agonist aggravated hyperthyroidism and induced painless thyroiditis . 
 this is the first report to demonstrate the association of thyroid dysfunction with gnrh agonist injection in korea . here , 
 we report three cases and emphasize the clinical importance of this aggravating factor in autoimmune thyroid disease . 