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20 2 14 18 10 16 1 1.0mg 0.035mg 2 1

20 2 14 18 10 16 1 1 1 52 1 1 21 7 28 1 29 2

1 20 1 24 18 10 16 1 1 21 7 28 1 29 1 NET 1.0mg EE 0.035mg *NET *NET 1999 2007 *NET *NET 88 NSAIDs GnRH GnRH NSAIDs 20 2008 1 3

2 1 2 PVC PTP PET PE *NET *NET *NET 1 PTP PVC / 4075 RH 6 PVC PTP 4075 RH 6 4

PTP PVC PTP PET PE 1 2TLC 3 1 2560 RH 12 36 / 4075 RH 6 / 50 /3 4075 RH/ 3 D65 1000lx 134.7 lx hr 232.70W hr/m 2 / 8 TLC 12 1 36 1 2 8 8 5

/ 1 24 2 ~ 13 5 1 568 3 6

1 4.2.1.1-1 2 *NET *NET 1999 9 NET P 2.45 EE17β- E2 1.10 NET EE in vivo P E2 12 3 4 7 2 34.2.1.3-1 NET EE 1000 NET 20mg/kg EE 1mg/kg NET EE ALT AST 4 *NET E2P 1 MMP 7

in vitro E2 P MMP-3 MMP-7 J Clin Endocrinol Metab 87(10):4782-91,2002 5 athymic ncr/nude 10 12 E2 90 2 3 E2 P Fertil Steril 83:529-37,2005 2 EE LPSLPS EE ALT AST Alcohol Clin Exp Res 26(8):70S-74S,2002 *NET *NET *NET 14.2.2.2-1 3 14 C NET 14 C-NET 3mg/kg0.15mg/kg 1 Cmax 35.3 14 C EE 14 C-EE 0.15mg/kg+NET 3mg/kg 0.5 Cmax 4 8 12 49.7 BA NET 16 54EE 4 14 C-NET 3mg/kg 0.15mg/kg 14 C-EE 0.15mg/kg+NET 3mg/kg 1 1 21 24 7 80.0 65.4 24.2.2.3-1 8

14 C-NET 3mg/kg 0.15mg/kg 14 C-EE 0.15mg/kg+NET 3mg/kg NET EE 1 1 14 72 14 C-NET 3mg/kg 0.15mg/kg 14 C-EE 0.15mg/kg+NET 3mg/kg 30 NET 96EE 93 18 NET EE 34.2.2.4-1 4 14 C-NET 3mg/kg 0.15mg/kg 30 8 NET NET 14 C-EE 0.15mg/kg+NET 3mg/kg 30 50 EE 8 EE 5 in vitro 44.2.2.5-1 2 14 C-NET 3mg/kg EE 0.15mg/kg 120 17.0 80.1 14 C-EE 0.15mg/kg+NET 3mg/kg 120 3.2 92.5 48 70 NET EE 5 4.2.2.6-1 3 3 H-EE NET EE 2 *NET 9

1 EE 0.125 1mg/kg EE Cmax 6 J Chromatogr 793:309-15,2003 2 3α NET EE EE Drug Metab Disp 29:76-71&976-82,2001 3 EE 1mg/kg EE AUC Cmax Contraception 62:253-57,2000., Contraception 70:423-27,2004 *NET 4 1 *NET NET LC/MS/MSRIA100 30pg/mLEE LC/MS/MS RIA ELISA10 18 10pg/mL 1 5.3.1.2 IKH-01-3 *NET BE 2 2 20 45 32 *NET 1 10

1 1 150mL 1 Cmax AUCt AUC *NET 90 NET log 0.856log 1.105 log 0.925log 1.030EE log 0.898log 1.034 log 0.912 log 1.076 log 0.80log 1.25 25.3.5.2-1 IKH-01-2 1 1 21 7 1 * 三相性 * 三相性 1999 2007 * 三相性 * 三相性 1 0.500mg /0.750mg/1.000mg 0.035mg 1 1 7 7 7 21 7 1 4 16 E2 pg/ml 41.9±0.3 53.3±0.4-2 5 ±* 三相性 U/mL 36.5±0.4 23.8±0.2 * 三相性 83.6±0.3 32.6±0.2 CA125 25.8±0.4 18.6±0.3 35.3.5.1 IKH-01-4 4 CA125 U/mL 26.62±0.36 18.42±0.37-2 5 ± 4 5.3.5.2-2 IKH-01-5 13 52 CA125 U/mL 21.57±0.31 13.67±0.32 13.62±0.30-2 7 14 14 13.38±0.30 ± 5 in vitro 5.3.3.1-3 NET A 3α 3β-hydroxy EE 2 2-hydroxy 2 3-metylether EE UGT1A1 1A4 1A8 UGT Ann Rev Pharmacol Toxicol 40:581-616, 2000 6 *NET NET 7 *NET 5.3.3.1-1 5.3.3.1-2 NET NET NET NET NET NET T max 1.1±0.2 Cmax 10.8±2.6ng/mL AUC 24 46.7±14.0ng h/ml 11

t 1/2 6.3±1.0 EE 1.1±0.2 154.7±35.4pg/mL 1266±324pg h/ml 12.0±4.7 9 *NET 1 1 21 21 NET T max 2.6±3.7 Cmax 22.4±11.1ng/mL AUC 24 175.7±51.3ng h/ml t 1/2 9.7±2.2 EE 1.3±1.0 172±52pg/mL 1999±455pg h/ml 12.5±2.7 RIA 7 1 5.3.4.2-1 5.3.4.2-2 1 NET 0.5mg 0.035mg 21 FSH LH NET EE DSG 0.15mg 0.030mg 21 DSG 0.050mg 0.125mg 15 FSH LH 25.3.4.2-3 5 DSG 0.150mg 0.030mg 21 EE 0.050mg 7 DSG 0.150mg 0.050mg 15 E2 E2 E2 35.3.4.2-8 12 PG 0.150mg 0.030mg PGF 2α NET PG 45.3.4.2-13 15 r-afs in vitro E2 10-7 mol/l 10-6 mol/l TNF α IL -8 12

5 EE 5.3.4.2-17 18 E2 E2 EE NET 1 *NET *NET BE 1 NET 1.0mg EE 0.035mg 9 12 12 487 13 5 31 786 BE BE *NET *NET BE 18 11 24 1124004 EE NET ph1.2 ph4.0 50 ph1.2 ph4.0 50 ph1.2 ph4.0 50 *NET 1 NET LC/MS/MS EE ELISA LC/MS/MS EE ELISA LC/MS/MS RIA ELISA 17β-16-- 13

0.2NET ELISA NET 2 3 NET EE T max 1.5 t 1/2 7 9 NET NET ELISA ELISA NET 3α-hydroxy-5α-steroid NET BE BE BA *NET BE ph1.2 ph4.0 50 NET *NET BE BE BE BE *NET 2 NSAIDs GnRH NSAIDs 5 NSAIDs 14

*NET *NET NET EE GnRH 3 EE EE NET NET EE EE 15

3 6 1 1 5.3.5.2-1 IKH-01-2 20 20 4 Andersch Fertil Steril. 60(1):75-9,1993 Biberoglu Fertil Steril. 77(1):52-61,2002 1 18 1 3 1 1 21 7 1 * 三相性 NET1 0.500mg/0.750mg/1.000mg 0.035mg 1 1 7 7 7 21 7 1 4 16 41 2 1-1 1 37 20 * 三相性 17 Full Analysis Set FAS 3 1 36 19 NET NET * 三相性 17 Per Protocol Set PPS 16

1 0 1 2 1 3 0 1 1 2 2 3 3-1 5 5 4 4 ± 4.5±1.1 2.3±1.6 * 三相性 NET 4.5±1.0 2.0±1.7 p<0.0001 1 t -2.3±1.4 * 三相性 NET -2.5±1.5 p=0.5818 2 t * 三相性 NET 10 2 10 * 三相性 * 三相性 NET NET 20 20 17 17 n n n n 20 100 17 100 8 40.0 7 41.2 2 10.0 7 41.2 3 15.0 3 17.6 0 0 2 11.8 3 15.0 3 17.6 3 15.0 0 0 12 60.0 7 41.2 2 10.0 2 11.8 3 15.0 0 0 8 40.0 8 47.1 1 5.0 2 11.8 3 15.0 0 0 3 15.0 2 11.8 2 10.0 4 23.5 2 10.0 0 0 4 20.0 0 0 2 10.0 1 5.9 3 15.0 2 11.8 20/20 100 * 三相性 NET 14/17 82.4 10* 三相性 NET 17

11 55.0 7 41.2 7 35.0 5 29.4 5 25.0 1 5.9 3 15.0 3 17.6 3 15.0 2 11.8 2 10.0 1 5.9 1 2 5.3.5.1 IKH-01-4 20 20 19 1 3 ±2 1 1 21 7 1 4 107 100 51 49 1 99 50 49 99 3 1 2 96 49 47 FAS -1 5 5 CA125 IL-6-2.0±1.50-0.6±1.42 p<0.0001 2 t 4 3 4 18

3 FAS -1 ) 1 2 3 4 5 6 49 49 49 48 46 45 44 49 4.4 1.12 4.2 1.36 2.7 1.65 2.4 1.62 2.4 1.54 2.5 1.59 2.9 1.77 2.4 1.43 1 t 1) p<0.0001 47 47 47 46 45 44 43 47 4.3 1.02 3.9 1.23 3.6 1.44 3.4 1.48 3.6 1.56 3.6 1.30 3.7 1.48 3.7 1.27 1 t 1) P=0.0047 1 4 FAS 1 2 3 4 5 6 49 49 48 46 45 44 49-0.3-1.7-2.1-2.1-1.9-1.4-2.0 1.29 1.63 1.60 1.58 1.72 1.78 1.50 47 47 46 45 44 43 47-0.4-0.7-0.9-0.7-0.7-0.6-0.6 1.34 1.53 1.61 1.52 1.48 1.44 1.42 2 2 t 1) p<0.0001 1) 5 5 FAS N ± VAS 1,3 49 58.7 18.59 27.6 21.58 47 55.8 17.49 46.2 24.18 49 1.6±1.50 1.3±1.46 1,4 47 1.1±1.09 1.2±1.37 49 27.5±25.12 19.1±22.87 VAS 1,4 47 22.8±24.53 21.0±25.95 95 N 11244.07 3907.46 47 7352.81 17194.66 1661.86 9187.47 2,3 mm 3 11665.73 4610.04 44 7474.86 18206.27 1791.75 11861.27 26.62 18.42 49 CA125 2,3 20.96 33.80 14.46 23.46 U/mL 47 24.33 19.19 30.84 25.18 18.69 33.93 p<0.0001 5) p=0.1371 5) p=0.2560 5) p=0.0378 6) p=0.0009 6) 19

0.4498 49 IL-6 2,3 0.3838 0.5270) pg/ml 0.5028 47 0.4018 0.6292 1-1 2-2 35 5 44 4 52 t 62 Wilcoxon 0.3593 0.3191 0.4045 0.4474 0.3415 0.5862 p=0.4374 6) 5 p=0.6423 p=0.7763 2 Wilcoxon 49/50 98.0 49/49 100 10 6 6 10 50 49 50 49 n n n n 49 98.0 49 100.0 15 30.0 14 28.6 4 8.0 5 10.2 3 6.0 6 12.2 2 4.0 5 10.2 32 64.0 18 36.7 14 28.0 2 4.1 11 22.0 8 16.3 13 26.0 21 42.9 5 10.0 0 0.0 1 2.0 5 10.2 n 40/50 80.0 33/49 67.3 10 30 60.0 13 26.5 12 24.0 0 0 10 20.0 5 10.2 7 14.0 8 16.3 2/4.0 6 12.2 5 10.0 0 0 3 2 1 1 1 4 1 1 1 INR 1 3 1 1 1 3 5.3.5.2-2 IKH-01-5 20

20 20 13 52 22 18 3 1 5 1 1 21 7 1 13 141 128 1 1 126 FAS 3 123 PPS 22 106 14 15 7 7 FAS 1 t 1) -1 123 4.3 0.99 1 123 4.0 1.39-0.3 1.32 p=0.0265 2 123 2.7 1.90-1.6 1.86 p<0.0001 3 123 2.4 1.80-1.9 1.78 p<0.0001 4 121 2.1 1.67-2.1 1.54 p<0.0001 7 115 1.8 1.61-2.5 1.65 p<0.0001 10 107 1.5 1.64-2.7 1.63 p<0.0001 13 106 1.4 1.55-2.8 1.50 p<0.0001 14 107 1.5 1.64-2.7 1.67 p<0.0001 14 123 1.6 1.69-2.6 1.68 p<0.0001 15 105 2.6 1.60-1.6 1.47 p<0.0001 1 1 p=0.0265 2 15 p<0.0001 p<0.0001 1 t 15 2 127/128 99.2 21

114/128 89.16 7 1 1 1 2 1 15/128 11.7 8 PT B03-0 259 B03-06 14 () 10 B03-07 ( ) 13 () 13 B06-03 ( ) 89 () 180 B10-01 ()( ) 5 B11-01 151 B13-01 148 () 1 B16-04 () 1 ( ) 1 B16-08 () 5 B17-01 () 86 B17-05 AST ALT γ-gtp () 172 B18-07 ALT AST γ-gtp Al-P () 88 B20-08 () 89 B21-04 71 95 B21-06 () 78 10 9 9 10 128 n 128 127 99.2 114 89.1 23 18.0 15 11.7 13 10.2 33 25.8 37 28.9 20 15.6 85 66.4 76 59.4 16 12.5 16 12.5 48 37.5 79 61.7 20 15.6 n n 22

4 5.3.1.2 IKH-01-3 20 20 *NET 2 20 45 2 2 1 2 2 6 5 *NET 6 6 10 10 *NET 10 9 *NET 31 13/31 41.9 *NET 8 25.8 *NET 17/31 54.8 13 41.9 10*NET 5 16.1 5 16.1 5 16.1 8 25.8 6 19.4 9 29.0 *NET 1 1 NSAIDs NSAIDs NSAIDs GnRH NSAIDs 23

GnRH 13 2004 GnRH GnRH 24

2 1 Verbal Rating Scale VRS Andersch Am J Obstet Gynecol. 144(6):655-60,1982Biberoglu Am J Obstet Gynecol. 139(6):645-54,1981 Am J Obstet Gynecol. 175:396-401,1996 Andersch 3 Biberoglu Dysmenorrhea Nonmenstrual pain Deep dyspareunia 4 10 Andersch Dysmenorrhea and nonmenstrual pelvic pain Symptom and score Sum of the three groups Limitation of ability to work Coexistence of systemic Need for analgesics Mild : 1-3 0 : Unaffected symptoms 0 : No Moderate : 4 and 5 1 : Rarely affected 0 : Absent 1 : Rarely Severe : 6 and 7 2 : Moderately affected 1 : Present 2 : Regularly 3 : Clearly inhibited 3 : Inefficacious Symptom and score Dysmenorrhea Nonmenstrual pain Deep dyspareunia 11 Biberoglu Severity 0 : Absence of pain 1 : Some loss of work efficiency Mild 2 : In bed part of 1 day, Occasional loss of work Moderate 3 : In bed for 1 or more days, Incapacitation Severe 0 : Absence of pain 1 : Occasional pelvic discomfort Mild 2 : Noticeable discomfort for most of the cycle Moderate 3 : Pain persisting during the cycle or requiring strong analgesics Severe 0 : No discomfort 1 : Tolerated discomfort Mild 2 : Intercourse painful to the point of interruption Moderate 3 : Intercourse avoided because of pain Severe 25

12 Biberoglu Category Score Description Dysmenorrhea 0 Absent No discomfort 1 Mild Some loss of work efficiency. Use of mild analgesics 2 Moderate Occasional loss of work efficiency. Use of moderate analgesics 3 Severe Incapacitation. Use of strong analgesics VAS VRS Andersch Biberoglu Andersch Andersch Biberoglu VRS VRS Andersch 26

13 VAS 13 FAS 1 2 3 4 5 6 49 49 48 46 45 44 49-0.4-1.1-1.2-1.2-1.0-0.8-1.2 0.81 0.87 0.83 0.92 0.82 0.99 0.66 47 47 46 45 44 43 47-0.3-0.4-0.5-0.5-0.4-0.4-0.4 0.62 0.85 0.75 0.84 0.73 0.79 0.74 2 1) p=0.6393 p=0.0002 p<0.0001 p=0.0001 p=0.0004 p=0.0687 p<0.0001 1 2 3 4 5 6 49 49 48 46 45 44 49 0.1-0.6-0.8-0.8-0.8-0.6-0.8 0.96 1.26 1.12 1.17 1.36 1.28 1.30 47 47 46 45 44 43 47-0.1-0.3-0.4-0.2-0.2-0.1-0.2 1.01 1.27 1.25 1.08 1.27 1.04 1.20 2 1) p=0.4118 p=0.2251 p=0.0612 p=0.0098 p=0.0301 p=0.0499 p=0.0162 2 5 1 27

2 1/2 1/2 2/3 2/3-1 ±49 7.0±1.83 6.4±2.28 47 7.1±2.30 7.4±2.84 2 1/2 1/2 2/3 2/3 3/4 3/4 * 三相性 NET 2.51 1.50 4 0.3 Fertil and Steril. 60(1):75-9,1993 4 1.55 0.96 1.50 GnRH 4 28

4 0.96 1 1-2.0±1.50-0.6±1.42 p<0.0001 2 t 0.96 2 2 VAS CA125 CA125 3 29

123 67/123-2.5 1.6156/123-2.8 1.76 3 4 3 3 3 4 0 Beecham 30

18 20 22020 23 15 23 1823 1823 23 American College of Obstetricians and Gynecologists. ACOG Committee Opinion. Number 310, April 2005. Endometriosis in adolescents. Obstet Gynecol. 105(4):921-7,2005 NSAID 18 20 GnRH 18 17 12 OC 31

3 2 3 CA125 2 2 4 1 32

Royal College of Obstetricians and Gynecologists, 2000ACOG Committee on Practice Bulletins-Gynecology, Clinical management guidelines for obstetrician-gynecologists.1999 Novak's Gynecology. 13th edition. p951-2,2002 Fertil Steril. 78:961-72,2002 N Engl J Med. 345:266-75,2001 *NET GnRH Fertil Steril. 60(1):75-9,1993 Fertil Steril. 77(1):52-61,2002 1999 *NET 1 NET1.0mgEE0.035mg * 三相性 NET 1 1 217281 29 33

2 13 3 4 13 13 3 4 4 4 GnRH 4 13 5 3 3 GnRH 34

2 5 3 1 CTD2.7.4 2.7.4.5-2 2 10/198 5.1 12 2 2 1 1 1 1 1 1 35

1 1 6 1 148 *NET 1 7 1 2 3 *NET 3 10 14 15 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 14 128 124 119 114 111 109 107 100 128 108 84.4 92 71.9 82 66.1 46 37.1 65 54.6 31 26.1 76 66.7 41 36.0 79 71.2 44 39.6 60 55.0 28 25.7 70 65.4 26 24.3 10 10.0 6 6.0 127 99.2 114 89.1 36

1 2 15 3 4 5 6 7 8 9 10 11 12 13 14 14 128 124 119 114 111 109 107 100 128 46 35.9 33 25.8 17 13.3 2 1.6 6 4.7 15 12.1 3 2.4 3 2.4 2 1.6 4 3.2 18 15.1 2 1.7 1 0.8 2 1.7 4 3.4 18 15.8 3 2.6 3 2.6 3 2.6 1 0.9 23 20.7 2 1.8 1 0.9 6 5.4 1 0.9 18 16.5 0 0.0 0 0.0 5 4.6 1 0.9 11 10.3 0 0.0 1 0.9 2 1.9 0 0.0 2 2.0 0 0.0 0 0.0 0 0.0 0 0.0 76 59.4 33 25.8 48 37.5 16 12.5 15 11.7 2 13 13 4 2 4 OC WHO ±-2 39 71829.7±41449.30mm 3 70845.3±48128.32mm 3 p=0.7732 1 t 37

8 144315.1±131424.28mm 3 150233.4± 139189.62mm 3 p=0.4107 1 t 29.1% 48/165 36.711/30 p=0.3970 Fisher 1.5 6.7% 11/165 16.75/30 p=0.0775 Fisher 6 3000 6 0.1 95 13 38

13 13 6 30 36 13-1 13 39

2 20 2 14 1 18 10 16 2 19 5 8 1 2 1 1 GnRH 2 40

3 4 1 *NET *NET 2 GnRH 4 41

5 18 GnRH 7 6 1 42

7 2 3 7 43

8 17 10 17 91 1 9 8 12 13 DSG 0.050mg 0.125mg EE0.05mg 7 EE0.05mg DSG0.125mg 12 18 DSG 0.150mg DSG 0.125mg 13 36 16-- 16-- -17-14 4 15 32 18 12 20 22 2/4.0 2 4.0 21 4 22 23 22 7 8 B03-0 B03-01 44

23 3 23 25 23 30 33 29 35 35 1 1 35 36 1 1 1 1 37 15 48 37.5 20 15.6 3 1 2 GCP 5.3.1.2 5.3.5.1 5.3.5.2-1 5.3.5.2-2 GCP 4 4 1 1 21 7 28 1 29 45