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1 대한내과학회지 : 제 85 권제 4 호 뇌하수체줄기형성부전으로발생한시상하부성뇌하수체기능저하증 1예 1 건양대학교의과대학내과학교실, 내분비대사내과, 2 가천대학교의학전문대학원내과학교실 이승주 1 윤혜진 1 조아름 1 엄유진 1 박근용 1 임동미 1 김병준 2 Hypothalamic Hypopituitarism Caused by Pituitary Stalk Dysgenesis Seong-Ju Lee 1, Hye-Jin Yoon 1, A-Reum Cho 1, Yoo-Jin Um 1, Keun-Young Park 1, Dong-Mee Lim 1, and Byung-Joon Kim 2 1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Konyang University College of Medicine, Daejeon; 2 Department of Internal Medicine, Graduate School of Medicine, Gachon University of Medicine and Science, Incheon, Korea Functional defects of the pituitary gland are a rare cause of pubertal delay. The pituitary stalk is an important structure that connects the hypothalamus and pituitary gland. A defect in fusion of the pituitary stalk and anterior pituitary gland will block the function of the anterior pituitary gland. A 28-year-old man was referred to our clinic with poorly developed secondary sexual characteristics. He had undeveloped facial, axillary, and pubic hair and was Tanner stage I. Laboratory tests gave random serum testosterone < ng/ml, luteinizing hormone (LH) < 0.1 miu/ml, follicle-stimulating hormone (FSH) miu/ml, thyroid-stimulating hormone (TSH) 6.85 µiu/ml, and ft pmol/l. Sella magnetic resonance imaging (MRI) showed no pituitary stalk enhancement. The response in the combined pituitary function test revealed multiple hormonal defects, while the TSH response to thyrotropin-releasing hormone (TRH) was exaggerated and delayed. Therefore, we concluded that pituitary stalk dysgenesis had led to hypothalamic-type panhypopituitarism. (Korean J Med 2013;85: ) Keywords: Delayed puberty; Hypothalamic hypopituitarism; Pituitary stalk dysgenesis 서론사춘기지연은사춘기의신체적변화가여아에서 13세, 남아에서 14세까지나타나지않는경우를의미한다. 사춘기 지연의원인은체질적인지연에서부터식이장애및만성질환, 터너증후군및클라인펠터증후군과같은유전적질환, 갑상선기능저하증, 뇌하수체기능저하증같은호르몬이상에의한것까지다양하다 [1,2]. Received: Revised: Accepted: Correspondence to Byung-Joon Kim, M.D. Department of Internal Medicine, Graduate School of Medicine, Gachon University of Medicine and Science, 21 Namdong-daero 774beon-gil, Namdong-gu, Incheon , Korea Tel: , Fax: , kbjoon4u@gilhospital.com Copyright c 2013 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - Seong-Ju Lee, et al. Hypothalamic hypopituitarism due to stalk dysgenesis - 뇌하수체기능저하를초래하는원인은종양, 외상, 구조적이상등여러가지가있으며그중가장많은원인은뇌하수체종양이다 [3,4]. 뇌하수체줄기형성부전은터키안장부위에서의이상소견과뇌하수체줄기의소실, 뇌하수체전엽의위축이나결손, 이소성신경뇌하수체등을특징으로한다. 뇌하수체줄기형성부전의원인은저산소증이나둔위분만으로인한주산기손상이나뇌하수체의발생에관여하는 PROP-1, PIT-1, HESX-1 유전자들의변이에의한것으로알려졌으나정확한발생기전은밝혀져있지않다 [5,6]. 이러한뇌하수체줄기형성부전증으로인한뇌하수체기능저하및사춘기지연은국내에서도 3예가보고되어있다 [7]. 하지만본증례는사춘기이전부터성장장애가있어여러차례의뇌하수체기능검사를시행하여이를비교할수있는증례이며환자의 2차성징의발현과생식을위한치료를시행하였기에이에대한경험을보고하고자한다. 증례환자 : 28세남자주소 : 성기능장애와이차성징이없는것에대한불안감현병력 : 20년전저신장 (108 cm) 으로종합병원방문하여호르몬검사를하였고, 성장호르몬과갑상선호르몬결핍을진단받고성장호르몬및갑상선호르몬치료를하였으나 18년전자의로약물치료를중단하였다. 13년전키가자라지않아개인한의원을방문하여약물치료를시작하였다. 10년 전저신장 (142 cm) 으로병사용진단서발부를위하여다른종합병원에서뇌하수체호르몬검사를시행하여이상이있다는이야기들었으나 (Table 1) 복용중이던한의원약물치료만 3년간더유지하였다. 환자이차성징이나타나지않고한달전부터성기능장애에대한불안감이있어본원정신과외래내원후내분비내과적검사를위해내분비내과로의뢰되었다. 과거력 : 출생시특별한문제는없었으며두경부외상을입은과거력은없었다. 가족력및사회력 : 특이사항없었다. 진찰소견 : 입원시혈압 120/80 mmhg, 맥박수 54회 /min, 호흡수 20회 /min, 체온 36.5 였으며신장 cm, 몸무게 57.2 kg, 체질량지수 21 kg/m 2 였다. 환자난청이나시야결손, 후각기능이상등은관찰되지않았다. 갑상선비대및여성형유방은관찰되지않았고음모및생식기발달정도에따른성성숙척도인태너 1단계에해당하였다 (I/V). 고환은양쪽모두음낭내에서만져졌으며고환측정계 2번의크기였다. 혈액검사소견 : 말초혈액검사에서백혈구 6,200/uL, 혈색소 12.1 g/dl, 혈소판 220,000/uL였다. 혈청생화학검사에서혈액요소질소 9.4 mg/dl, 크레아티닌 0.8 mg/dl, 나트륨 138 mmol/l, 칼륨 3.88 mmol/l, 염소 105 mmol/l이었다. 내분비검사소견 : 기저치의호르몬검사에서총테스토스테론 ng/ml ( ), 유리테스토스테론 0.16 ng/ml (8.8-27), 유리티록신 6.69 pmol/l ( ), 갑상선자극호르몬 6.85 uiu/ml ( ), 인슐린유사성장인자 23 ng/ml (69-303), 부신피질자극호르몬 pg/ml (5-60), 코르티솔 0.74 ug/dl ( ) 이었다. 복합뇌하수체자극검사에서갑 Table 1. Results of the combined pituitary stimulation test, 10 years ago Glucose (mg/dl) GH (µg/l) ACTH (pg/ml) 11.2 < 10 < 10 < Cortisol (µg/dl) TSH (IU/L) Prolactin (µg/l) LH (IU/L) FSH (IU/L) T3 (ng/ml) 143 Testosterone (ng/ml) < 20 GH, Growth hormone; ACTH, Adrenocorticotropic hormone; TSH, Thyroid-stimulating hormone; LH, Luteinizing hormone; FSH, Follicle-stimulating hormone; IGF-1, Insulin like growth factor

- 대한내과학회지 : 제 85 권제 4 호통권제 638 호 2013 - Table 2. Results of the combined pituitary stimulation test Glucose (mg/dl) 90 35 80 85 85 GH (µg/l) 0.03 0.02 0.01 < 0.01 0.02 ACTH (pg/ml) 11.93 20.85 13.

537 0.869 0.958 1.04 1.05 T3 (ng/ml) 112.92 FT4 (pmol/l) 8.89 Testosterone (ng/ml) < 0.

3 - 대한내과학회지 : 제 85 권제 4 호통권제 638 호 Table 2. Results of the combined pituitary stimulation test Glucose (mg/dl) GH (µg/l) < ACTH (pg/ml) Cortisol (µg/dl) TSH (IU/L) Prolactin (µg/l) LH (IU/L) < FSH (IU/L) T3 (ng/ml) FT4 (pmol/l) 8.89 Testosterone (ng/ml) < GH, Growth hormone; ACTH, Adrenocorticotropic hormone; TSH, Thyroid-stimulating hormone; LH, Luteinizing hormone; FSH, Follicle-stimulating hormone. A B Figure 1. A radiograph of both hands shows opened epiphyses (arrow) in the wrist and hand. The measured bone age was 17 years. 상선자극호르몬, 프로락틴을제외하고여포자극호르몬, 황체형성호르몬, 성장호르몬, 코르티솔등은기저치에서증가하지않았다 (Table 2). 방사선검사소견 : 생식기초음파에서음낭에고환이정상적으로있었으며크기는오른쪽 2 cc, 왼쪽 2.5 cc 측정되었다 ( 정상성인 20 cc). 손목단순촬영에서골연령은 17세였다 (Fig. 1). 치료및경과 : 뇌하수체잔여기능평가를위한복합뇌하수체자극검사및구조적인이상을확인하기위해뇌하수체자기공명영상촬영을시행하였다. 자기공명영상에서정상 Figure 2. On sella MRI (A) sagittal T1-weighted images show a small high signal change suggesting ectopic neurohypophysis located at the break in the pituitary stalk. The white arrows indicate no visible pituitary stalk. (B) T1-weighted enhanced images ordered temporally show no enhancing pituitary stalk. The yellow arrows indicate the ectopic neurohypophysis. 뇌하수체줄기는관찰되지않았으며 T1 영상에서이소성신경뇌하수체가관찰되었다 (Fig. 2). 복합뇌하수체자극검사에서갑상선자극호르몬분비호르몬에갑상선자극호르몬은정상보다높아지고늦어진최대치를보이고있었다. 성선자극호르몬분비호르몬 (GnRH, Gonatotropin releasing hormone) 을 0.1 mg을하루에 1번, 5일간연속적으로투여후 6일째에성선자극호르몬분비호르몬을 0.1 mg 사용후 30분, 60분, 90분, 120분에황체형성호르몬및난포자극호르몬을측정하였다 (Table 3). 그결과초기수치와비교하면난포자극호르몬과황체형성호르몬이증가하였다. 저자등은복합뇌하수체자극검사및뇌하수체자기공명영상, 장기성선자극호르몬분비호르몬자극검사결과에따라뇌하수체줄기형성

4 - 이승주외 6 인. 뇌하수체줄기형성부전에기인된시상하부성기능저하증 - Table 3. Results of the GnRH stimulation test after long-term GnRH stimulation LH (IU/L) < FSH (IU/L) Testosterone (ng/ml) < Free Testosterone (ng/ml) < 0.01 LH, Luteinizing hormone; FSH, Follicle-stimulating hormone. 부전과이소성신경뇌하수체를동반한뇌하수체기능저하증으로진단하였다. 호르몬보충요법으로갑상선호르몬제 ( 신지로이드 ) 100 mcg, 프레드니솔론 7.5 mg으로치료를시작하였으며사춘기발현및정자형성을위해사람융모성선자극호르몬 (hcg, Human chorionic gonadotropin) 5,000 IU을 1주에 3번근육주사로 3개월시행후사람폐경성선자극호르몬 (hmg, Human menopausal gonadotropin) 75 IU과같이 1주에 3번근육주사로병용하기로했다. 2달간투여후시행한검사에서황체형성호르몬과여포자극호르몬의수치는초기수치와비슷하였으나유리테스토스테론의수치 ng/ml로증가하였다. 치료전에는발기되지않았으나치료진행후발기가되었으며아직은초기지만음모생성을확인할수있었다. 고환크기는고환측정계 3번의크기로증가하였다. 입원시에는발기되지않아정액검사를시행하지못하였던자로발기관찰되어정액검사를시행하였으나정자는검출되지않았다. 현재치료를유지하며고환의크기변화와정자의생성여부를추적관찰후에고환의조직검사도고려중이다. 고찰뇌하수체는뇌하수체줄기를통해시상하부와연결되어있으며시상하부의자극호르몬이뇌하수체줄기를통해뇌하수체전엽을자극하고호르몬의분비를조절한다. 따라서뇌하수체줄기에문제가발생하게되면뇌하수체전엽의호르몬분비기능이저하된다 [3]. 뇌하수체전엽의기능저하에의한증상은결핍된호르몬의종류및결핍된시기에따라무증상에서부터저신장또는이차성징결핍등다양하게나타난다. 어린나이에뇌하수체기능저하가발생하면저신장과사춘기지연이발생할 수있다 [2]. 호르몬의분비이상은일차성, 이차성그리고삼차성으로나눌수있다. 일차성호르몬기능저하증은표적기관의문제로표적호르몬은감소하지만자극호르몬은상승한다. 이차성및삼차성호르몬기능저하증은표적기관에는문제가없으나표적기관을자극하는자극호르몬의부족에기인한것으로표적호르몬과자극호르몬모두감소하여있다. 본증례의경우에서갑상선자극호르몬분비호르몬의자극에의한갑상선자극호르몬의분비최대치가 30-60분사이로늦어져있고오히려 120분이후에도분비자극이지속하는현상을보여시상하부이상에의한뇌하수체기능장애즉삼차성분비장애의현상을보인다 [8]. 또한삼차성분비장애는뇌하수체유리호르몬의장기간투여로뇌하수체호르몬분비를원활하게한후자극하면뇌하수체호르몬의분비가회복된다. 본증례에서는성선자극호르몬분비호르몬을 5일간투여후검사한결과난포자극호르몬및황체형성호르몬의수치가증가하였다. 이에뇌하수체줄기의형성부전으로인한삼차성선기능저하증으로진단하였다. 뇌하수체의발생시에여러유전자가관여하는데 PROP, PIT-1, HESX1 유전자들이여기에해당한다. Fernandez-Rodrguez 등 [4] 및 Sloop 등 [9] 의연구에따르면 HESX1, LHX3, LHX4, PROP-1 등의유전자변이가이소성뇌하수체와의연관성이유의하게나타나지는않았으나한유전자가아닌다형성으로여러유전자가연관되어발생할것으로생각된다. 뇌하수체줄기형성장애및이소성신경뇌하수체가있는상태에서보이는호르몬결핍은성장호르몬단독결핍부터뇌하수체전엽호르몬의다발성결핍까지다양하지만대부분에서뇌하수체후엽의기능은보존된다. Jagtap 등 [10] 의연구에서보면뇌하수체줄기가보이지않는군이보이는군에비해다발성호르몬결핍이더많으며성장호르몬단독결핍에서다발성호르몬결핍으로의진행이잘나타난다. 본

5 - The Korean Journal of Medicine: Vol. 85, No. 4, 증례에서는초기장애시의호르몬검사수치가부족하고사춘기이전이어서초기결핍이갑상선호르몬과성장호르몬뿐이었는지는확실하지않지만 10년전뇌하수체기능검사의결과부터는전체호르몬의결핍이보인다. 본환자의 10년전및현재시행한복합뇌하수체자극검사결과를보았을때갑상선자극호르몬의반응양상은비슷하며모두삼차성기능저하증의양상을보이고있다. 뇌하수체기능저하증은여러가지원인에의해서발생하고임상양상은특별한증세가없는경우부터부신피질호르몬저하증, 갑상선기능저하증, 사춘기지연에이르기까지다양하다. 환자가사춘기지연은있으면서다른증상이없는경우나저신장만동반된경우에도뇌하수체기능저하증의동반을염두에두어야하며환자의상황에따라치료방법이고려되어야한다. 요약본증례는 9세경저신장으로성장호르몬및갑상선호르몬이상을진단받고불규칙하게치료받았던과거력이있는 28세남자환자가성기능장애에대한불안으로내원하여뇌하수체줄기단절에의한시상하부성뇌하수체호르몬이상을진단받고사춘기발현과생식기능의유지를위한치료를시행하게된 1예를경험하였기에문헌고찰과함께보고하는바이다. 중심단어 : 시상하부성뇌하수체기능저하증 ; 뇌하수체줄기형성부전 ; 사춘기지연 REFERENCES 1. Kim DH. Growth retardation. J Korean Soc Endocrinol 1996;11: Min HG. Clinical Endocrinology. 2nd ed. Seoul: Korea Medical Book Press, Schneider HJ, Aimaretti G, Kreitschmann-Andermahr I, Stalla GK, Ghigo E. Hypopituitarism. Lancet 2007;369: Fernandez-Rodriguez E, Quinteiro C, Barreiro J, et al. Pituitary stalk dysgenesis-induced hypopituitarism in adult patients: prevalence, evolution of hormone dysfunction and genetic analysis. Neuroendocrinology 2011;93: Lee JK, Zhu YS, Cordero JJ, et al. Long-term growth hormone therapy in adulthood results in significant linear growth in siblings with a PROP-1 gene mutation. J Clin Endocrinol Metab 2004;89: Pellegrini-Bouiller I, Bélicar P, Barlier A, et al. A new mutation of the gene encoding the transcription factor Pit-1 is responsible for combined pituitary hormone deficiency. J Clin Endocrinol Metab 1996;81: Baek IW, Kim JH, Lee GJ, et al. A case of ectopic neurohypophysis presenting with hypogonadism. Endocrinol Metab 2011;26: Cho BY. Clinical Thyroidology. 3rd ed. Seoul: Korea Medical Book Press, Sloop KW, Walvoord EC, Showalter AD, Pescovitz OH, Rhodes SJ. Molecular analysis of LHX3 and PROP-1 in pituitary hormone deficiency patients with posterior pituitary ectopia. J Clin Endocrinol Metab 2000;85: Jagtap VS, Acharya SV, Sarathi V, et al. Ectopic posterior pituitary and stalk abnormality predicts severity and coexisting hormone deficiencies in patients with congenital growth hormone deficiency. Pituitary 2012;15:

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<3231B1C732C8A32DB8F1C2F75B315DC3D6C1BE2E687770> 대한내분비학회지 : 제 21 권제 2 호 2006 증례 뇌하수체거대종양에동반된부신피질자극호르몬유리호르몬결핍증 1 예 가톨릭대학교의과대학내과학교실 남유정 김진수 조근종 길욱현 우성용 김성래 유순집 강성구 손호영 A Case of Pituitary Macroadenoma Accompanied with CRH Deficiency Yoo Jung Nahm, Jin