The Efficacy of Letrozole in Women with a Poor Endometrial Response to Clomiphene Citrate

장은정,지병철,Jang, Eun-Jeong,Jee, Byung-Chul The Korean Society for Reproductive Medicine 2010 Clinical and Experimental Reproductive Medicine Vol.37 No.1

목 적: 클로미펜을 이용한 배란유도 주기에서 불량한 자궁내막 발달을 보이는 불임 여성에서 레트로졸의 효용성을 알아보고자 하였다. 연구방법: 2004년 3월부터 2009년 8월까지 분당서울대학교병원에서 클로미펜을 이용한 배란유도 주기에서 자궁내막 두께가 6.5 mm 이하여서 다음 주기에 레트로졸을 사용하였던 18명의 불임 여성을 선정하였다. 환자들의 평균 연령은 $30.7{\pm}2.8$세, 불임 기간은 $33.1{\pm}26.6$개월이었다. 불임의 인자는 자궁내막증이 1명, 다낭성난소증후군이 5명, 원인불명의 불임증이 12명이었다. 레트로졸은 2.5 mg의 용량으로 월경 3~5일 사이에 시작하여 5일간 투여하였다. 결 과: 이전 클로미펜 사용시와 비교하였을 때 레트로졸 주기에서 우성난포의 개수는 더 적었으나 ($1.1{\pm}0.3$ vs. $2.2{\pm}1.5$, p=0.011) 자궁내막 두께는 유의하게 증가하였으며 ($8.4{\pm}1.7$ mm vs. $5.8{\pm}0.5$ mm, p<0.001) 자궁내막 패턴 중 type C의 빈도는 이전 클로미펜 주기에서 50%이었던 것이 레트로졸 사용시 94.4%로 유의한 증가를 보였다 (p=0.036). 레트로졸을 이용한 배란 유도 주기에서 임신율은 11.1%였다. 결 론: 얇은 자궁내막 발달을 보였던 클로미펜 주기에 비해 레트로졸 사용시 자궁내막이 좀 더 두꺼워지고 패턴이 호전되는 것으로 보아 클로미펜에 불량한 자궁내막을 보이는 여성에서 이차 선택약제로 레트로졸의 사용은 유용한 방법으로 사료된다. Objective: To examine the efficacy of letrozole in infertile women showing a poor endometrial development at previous ovulation induction cycle by using clomiphene citrate. Methods: Eighteen infertile women were selected who showed a poor endometrial development (endometrial thickness$\leq$6.5 mm) after clomiphene treatment (50~100 mg) as ovulation induction for timed coitus. The mean age of the patients was $30.7{\pm}2.8$ years old and the mean duration of infertility was $33.1{\pm}26.6$ months. The infertility factors were identified as corrected endometriosis (n=1), polycystic ovary syndrome (n=5) and unexplained (n=12). Letrozole was given orally in a dose of 2.5 mg for 5 days starting 3~5 of menstrual cycle. Results: The number of follicles was significantly lower in the letrozole cycle when compared with previous clomiphene cycle ($1.1{\pm}0.3$ vs. $2.2{\pm}1.5$, p=0.011). The endometrial thickness (mm) at the time of triggering or LH surge was significantly greater in the letrozole cycle ($8.4{\pm}1.7$ vs. $5.8{\pm}0.5$, p<0.001). The endometrial pattern 'type C' was significantly higher in the letrozole cycle (94.4% vs. 50%, p=0.036). The pregnancy was achieved in 11.1% of the letrozole cycle. Conclusion: Use of letrozole was associated with more thick and improved endometrium than previous clomiphene cycles in which thin endometrium was identified. Use of letrozole appears to be an effective strategy for second-line treatment in women with inadequate endometrial response to clomiphene.

클로미펜에 얇은 자궁내막을 보이는 환자에서 성선자극호르몬 병합 과배란유도시 클로미펜과 레트로졸의 임상적 효용성

이은주,박현종,양효인,이경은,서석교,김혜연,조시현,최영식,이병석,박기현,조동제,Lee, Eun-Joo,Park, Hyun-Jong,Yang, Hyo-In,Lee, Kyung-Eun,Seo, Seok-Kyo,Kim, Hye-Yeon,Cho, Si-Hyun,Choi, Young-Sik,Lee, Byung-Seok,Park, Ki-Hyun,Cho, Dong-Ja 대한생식의학회 2009 Clinical and Experimental Reproductive Medicine Vol.36 No.2

목 적: 클로미펜을 사용한 배란유도시 얇은 자궁내막을 보였던 환자들에서 성선자극호르몬에 클로미펜 또는 레트로졸을 병합 투여하는 과배란유도 방법의 임상적 효용성을 비교 분석하고자 하였다. 연구방법: 이전의 클로미펜을 사용한 배란유도 주기에서 8 mm 미만의 얇은 자궁내막을 보였던 불임 환자들에서 시행된 성선자극호르몬 병합 과배란유도/인공수정 51주기가 연구에 포함되었다. 월경주기 제3일째부터 5일 동안 클로미펜+성선자극호르몬 군은 일일 클로미펜 100 mg을 투여하였고 (n=26) 레트로졸+성선자극호르몬 군은 일일 레트로졸 2.5 mg 또는 5 mg을 투여하였다 (n=25). 양 군에서 월경주기 제5~7일째부터 우성난포의 크기가 18 mm 이상에 도달할 때까지 이틀에 한 번씩 성선자극호르몬은 75~150 IU를 투여하였다. 양 군에서 성선자극호르몬 총 사용량, 자궁내막의 두께, 자궁내막의 형태, hCG 투여일의 14 mm 이상 난포의 수, hCG 투여일, 임신율, 다태 임신율을 비교하였으며 통계 분석은 Mann-Whitney U test or Fisher's exact test 등을 이용하였다. 결 과: 연령, 불임기간, 이전 인공수정 횟수, 기저 혈중 LH, FSH, $E_2$ 농도, 불임의 원인 등의 임상적 특성은 양 군간 차이가 없었다. 성선자극호르몬 병합 과배란유도시 배란전 자궁내막의 두께는 이전의 클로미펜을 사용한 주기와 비교하여 유의하게 증가되었다. 성선자극호르몬 총 사용량, hCG 투여일, 자궁내막의 삼중선 비율, 임신율 및 다태 임신율은 유의한 차이가 없었다. 클로미펜+성선자극호르몬 군에 비하여 레트로졸+성선자극호르몬 군에서 14 mm 이상 난포의 개수는 유의하게 적었고 ($3.7{\pm}1.7$ vs. $2.8{\pm}1.7$, p=0.03). 배란 전 자궁내막 두께는 유의하게 두꺼웠다 ($7.7{\pm}1.5\;mm$ vs. $9.1{\pm}1.7\;mm$, p<0.05). 결 론: 배란유도를 위하여 클로미펜 사용시 얇은 자궁내막을 보였던 환자들에서 인공수정을 위한 과배란유도시클로미펜 또는 레트로졸을 성선자극호르몬과 병합하여 사용하는 방법은 클로미펜의 자궁내막에 대한 부정적인 효과를 피할 수 있는 것으로 사료된다. 적절한 자궁내막의 발달 및 적절한 난포의 성장 측면에서 성선자극호르몬에 레트로졸을 병합하는 과배란유도 방법이 클로미펜을 병합하는 방법에 비하여 더 유용할 수 있으나 추가적인 대규모 전향적 연구가 필요할 것으로 사료된다. Objective: The aim of this study was to compare the clinical efficacy of clomiphene citrate (CC) and letrozole combined with gonadotropins for controlled ovarian stimulation (COS) in patients with CC-induced thin endometrium Methods: Fifty-one intrauterine insemination cycles performed in patients who previously had a thin endometrium (<8 mm) to ovulation induction using CC were included in this study. A CC 100 mg/day (CC+gonadotropin group, n=26) or letrozole 2.5 or 5 mg/day (letrozole+gonadotropin group, n=25) was administered on day 3~7 of the menstrual cycle, combined with gonadotropins at dose 75~150 IU every other day starting on day 5~7. We compared total dose of gonadotropin used, endometrial thickness, endometrial pattern, number of follicles ${\geq}14\;mm$ on hCG day, pregnancy rate and multiple pregnancy rate between the two groups, which were statistically analyzed using Mann-Whitney U test or Fisher's exact test, where appropriate. Results: There were no significant differences in clinical characteristics such as age, duration of infertility, number of previous IUI cycles, basal serum hormone levels and cause of infertility between the two groups. In both groups, the endometrium was significantly thicker than that of previous ovulation induction cycles using CC. No significant differences were found in the total dose of gonadotropin used, day of hCG administration, the rate of triple endometrium and pregnancy rate. The number of follicles ${\geq}14\;mm$ was significantly lower ($3.7{\pm}1.7$ vs. $2.8{\pm}1.7$, p=0.03) and the endometrium on hCG day was significantly thicker ($7.7{\pm}1.5$ vs. $9.1{\pm}1.7$, p=0.001) in letrozole+gonadotropin group compared to CC+gonadotropin group. Conclusion: The clomiphene citrate and letrozole combined with gonadotropins appear to avoid the undesirable effects on the endometrium frequently seen with CC for ovulation induction. However, in terms of adequate endometrial development or optimal follicular growth, letrozole may be more beneficial than CC for gonadotropin-combined COS in patients with CC-induced thin endometrium. Further prospective randomized controlled studies in a larger scale will be necessary to confirm our findings.

Comparison of Pharmacokinetics and Safety of Two Formulations of Letrozole (2.5 mg) in Healthy Male Volunteers

노육환,배균섭,조상헌,최상민,김종률,정진아,김운집,진석준,박현정,김정철,임형석,Noh, Yook-Hwan,Bae, Kyun-Seop,Cho, Sang-Heon,Choe, Sangmin,Ghim, Jong-Lyul,Jung, Jin Ah,Kim, Un-Jib,Jin, Seok-Joon,Park, Hyun-Jung,Kim, Jung-Chul,Lim, Hyeon Korean Society for Clinical Pharmacology and Thera 2012 臨床藥理學會誌 Vol.20 No.2

배경: 레트로졸은 유방암 치료에 사용되는 경구용 비스테로이드성 aromatase 억제제이다. 방법: 이 연구는 건강한 성인 남성을 대상으로 무작위 배정, 단회 투여, 공개설계로서 두 치료군, 두 순서, 두 시기의 교차 시험법으로 진행되었다. 각 순서군에 13명씩 무작위 배정되어, 한군은 1기에 페마라$^{(R)}$정(대조약)을, 2기에 유한 레트로졸정(시험약)을, 다른 한군은 반대 순서로 두 시기 사이에 약 5주의 휴약기를 가지고 각각 2.5 mg정 1정씩 투여 받았다. 약동학 분석을 위한 혈액 검체는 공복 상태에서 투약 후 312 시간까지 얻어졌다. 레트로졸의 혈장 내 농도는 liquid chromatography-tandem mass spectrometry를 이용하여 측정하였다. 안전성 평가는 활력징후, 문진 및 신체검사, 심전도, 진단검사실 검사와 이상반응 모니터링을 통하여 이루어졌다. 결과: 총 26명의 피험자가 연구를 완료하였고, 약동학 분석에 26명의 자료가 모두 사용되었다. $C_{max}$와 $AUC_{last}$ 파라미터에 대한 시험약과 대조약의 기하평균비는 각각 0.92 (90 % 신뢰구간: 0.85 - 0.99)와 1.01 (90 % 신뢰구간: 0.97 - 1.04)였다. 보고된 중대한 이상반응은 없었으며, 임상적으로 유의한 변화도 관찰되지 않았다. 결론: 건강한 자원자에서 페마라$^{(R)}$정과 유한 레트로졸정의 약동학 특성과 안전성은 유사하였다. Background: Letrozole is an oral non-steroidal inhibitor of the aromatase enzyme, which has proven to be a useful drug against breast cancer. Methods: This single-dose, randomized $2{\times}2$ crossover study was conducted in healthy male volunteers. Participants of each sequence group (each 13 volunteers for sequence group) received, in randomized sequence, a single oral 2.5-mg dose of generic letrozole (test) or branded letrozole (reference). Each treatment period was separated by a 5-week washout period. Blood samples were collected for up to 312 hours after drug administration, and drug concentrations were determined using validated LC/MS-MS. Pharmacokinetic properties were obtained using noncompartmental analysis. Drug tolerability was assessed throughout the study, using measurements of vital signs, physical examination, clinical chemistry testing, EKG, and interviews. Results: A total of 26 subjects completed the study. The geometric mean ratios (90% CI) of $C_{max}$ and $AUC_{last}$ were 0.92 (0.85 - 0.99) and 1.01 (0.97 - 1.04), respectively. No serious AEs were reported, and there were no clinically significant differences between test and reference groups. Conclusion: The findings from this study suggest bioequivalence between two formulations of letrozole in healthy male volunteers. The safety profile of two formulations had similar characteristics.

방향화효소억제제의 생식호르몬 분비와 배란유도에 대한 효과

김숙현,김정아,박준철,배진곤,신소진,권상훈,조치흠,윤성도,차순도,김종인,이정호,Kim, Sook-Hyun,Kim, Jeong-Ah,Park, Joon-Cheol,Bae, Jin-Gon,Shin, So-Jin,Kwon, Sang-Hoon,Cho, Chi-Heum,Yoon, Sung-Do,Cha, Soon-Do,Kim, Jong-In,Rhee, Jeong-Ho 대한생식의학회 2008 Clinical and Experimental Reproductive Medicine Vol.35 No.2

목 적: 방향화효소억제제가 생식호르몬 분비 양상에 미치는 영향과 무배란 여성에서의 배란유도 효과를 평가하기 위함. 연구방법: 정상 월경주기를 가진 여성 30명을 대상으로 letrozole을 투여하지 않은 주기 (대조군)와 투여한 주기 (연구군)에서 생식호르몬 혈중치를 측정하였다. 각 월경주기 3, 11, 21일에 LH, FSH, $E_2$, testosterone, DHEA-S의 혈중치를 측정하였고 각 주기 21일에는 progesterone 측정이 추가되었다. 불임의 원인이 무배란으로 진단된 환자 60명에게 크로미펜과 letrozole을 투여한 후 (각 치료 군, 30명) 배란율, 임신율, LH 분비폭발 시점, 성장 난포 수, 자궁내막 두께, 자궁경관 점액의 양과 견사성, LH 분비폭발 시점의 난포 직경 등을 측정하여 두 군 간의 임상 효과를 비교하였다. 결 과: Letrozole은 LH, FSH, $E_2$, DHEA-S 분비에는 영향을 미치지 않았으나 letrozole 투여 주기 11일째의 testosterone과 21일째의 progesterone 혈중치는 대조군에 비해 유의한 상승을 보였다 ($0.40{\pm}0.16$ vs $0.28{\pm}0.11\;ng/ml$, p=0.002, $18.18{\pm}13.07$ vs $8.38{\pm}7.64\;ng/ml$, p=0.001). Letrozole과 크로미펜 군 간의 배란유도 효과에 대한비교에서 배란율, 임신율, 성장 난포 수, 배란 전 난포 직경에서는 두 군 간에 유의한 차이가 없었으나 크로미펜 군과 비교할 때 letrozole 군에서 조기에 LH 분비폭발이 발생했고 ($12.12{\pm}2.46$일 vs $14.52{\pm}3.18$, p=0.006), LH 분비폭발 시점에서의 자궁내막 두께가 두꺼웠으며 ($10.48{\pm}1.23$ vs $8.52{\pm}0.93\;mm$, p=0.000), 자궁경관 점액 양이 많았고 견사성이 높았다 ($2.04{\pm}0.61$ vs $1.57{\pm}0.59$, p=0.012, $6.00{\pm}1.12$ vs $4.95{\pm}1.61\;cm$, p=0.003). 결 론: Letrozole은 정상 월경주기를 가진 여성에서 난포 성장을 촉진하고 자궁내막을 호전시키며 무배란 여성에서는 크로미펜에 필적하는 배란유도 효과가 있으며 더욱 생리적인 배란유도가 이루어질 것으로 사료된다. Objective: To investigate the effects of aromatase inhibitor on reproductive hormone profiles and evaluate it's ovulation inducing capability in anovulatory infertile women. Methods: We quantified the blood levels of reproductive hormones from 30 healthy normal cycling women in natural cycle (control) and letrozole medicated cycle (study). LH, FSH, estradiol, testosterone, DHEA-S were quantified on third, 11th, 21th day in both cycles, and on 21th day, progesterone was added. Sixth anovulatory infertile women received either letrozole or clomiphene citrate for ovulation induction (n=30 in each groups). We compared the clinical parameters such as ovulation rate, pregnancy rate, the day of LH surge, number of follicles and endometrial thickness, cervical mucus amount, spinnbarkeit, mean diameter of follicles on the day of LH surge. Results: Letrozole had no effect on the LH, FSH, estradiol, DHEA-S secretion but there were significant increase in testosterone level on day 11 and progesterone level on day 21 in letrozole medicated cycle compared than control cycle ($0.40{\pm}0.16$ vs $0.28{\pm}0.11\;ng/ml$, p=0.002, $18.18{\pm}13.07$ vs $8.38{\pm}7.64\;ng/ml$, p=0.001, respectively). In comparison between letrozole and clomiphene groups, there were no significant difference in ovulation rate, pregnancy rate, number of mature follicle, mean diameter of follicles, but showed earlier LH surge, thicker endometrium, more cervical mucus, and higher spinnbarkeit in letrozole group ($12.12{\pm}2.46$ vs $14.52{\pm}3.18$ days, p=0.006, $10.48{\pm}1.23$ vs $8.52{\pm}0.93\;mm$, p=0.000, $2.04{\pm}0.61$ vs $1.57{\pm}0.59$, p=0.012, $6.00{\pm}1.12$ vs $4.95{\pm}1.61\;cm$, p=0.003, respectively). Conclusion: Letrozole may augment folliculogenesis and improve the endometrial condition for implantation in normal cycling women. Ovulation efficacy of letrozole in anovulatory women was comparable to clomiphene citrate and letrozole may be more physiological in ovulation induction.

Comparison of Pharmacokinetics and Safety of Two Formulations of Letrozole (2.5 mg) in Healthy Male Volunteers

Yook-Hwan Noh,Kyun-Seop Bae,Sang-Heon Cho,Jong-Lyul Ghim,Jin Ah Jung,Un-Jib Kim,Hyun-Jung Park,Jung-Chul Kim,Hyeong-Seok Lim,Sangmin Choe 대한임상약리학회 2012 Translational and Clinical Pharmacology Vol.20 No.2

Background: Letrozole is an oral non-steroidal inhibitor of the aromatase enzyme, which has proven to be a useful drug against breast cancer. Methods: This single-dose, randomized 2 × 2 crossover study was conducted in healthy male volunteers. Participants of each sequence group (each 13 volunteers for sequence group) received, in randomized sequence, a single oral 2.5-mg dose of generic letrozole (test) or branded letrozole (reference). Each treatment period was separated by a 5-week washout period. Blood samples were collected for up to 312 hours after drug administration, and drug concentrations were determined using validated LC/MS-MS. Pharmacokinetic properties were obtained using noncompartmental analysis. Drug tolerability was assessed throughout the study, using measurements of vital signs, physical examination, clinical chemistry testing, EKG, and interviews. Results: A total of 26 subjects completed the study. The geometric mean ratios (90% CI) of Cmax and AUClast were 0.92 (0.85 – 0.99) and 1.01 (0.97 – 1.04), respectively. No serious AEs were reported, and there were no clinically significant differences between test and reference groups. Conclusion: The findings from this study suggest bioequivalence between two formulations of letrozole in healthy male volunteers. The safety profile of two formulations had similar characteristics. Background: Letrozole is an oral non-steroidal inhibitor of the aromatase enzyme, which has proven to be a useful drug against breast cancer. Methods: This single-dose, randomized 2 × 2 crossover study was conducted in healthy male volunteers. Participants of each sequence group (each 13 volunteers for sequence group) received, in randomized sequence, a single oral 2.5-mg dose of generic letrozole (test) or branded letrozole (reference). Each treatment period was separated by a 5-week washout period. Blood samples were collected for up to 312 hours after drug administration, and drug concentrations were determined using validated LC/MS-MS. Pharmacokinetic properties were obtained using noncompartmental analysis. Drug tolerability was assessed throughout the study, using measurements of vital signs, physical examination, clinical chemistry testing, EKG, and interviews. Results: A total of 26 subjects completed the study. The geometric mean ratios (90% CI) of Cmax and AUClast were 0.92 (0.85 – 0.99) and 1.01 (0.97 – 1.04), respectively. No serious AEs were reported, and there were no clinically significant differences between test and reference groups. Conclusion: The findings from this study suggest bioequivalence between two formulations of letrozole in healthy male volunteers. The safety profile of two formulations had similar characteristics.

최신임상강좌 : 다양한 약제를 통한 배란유도의 최신 지견

김상돈 ( Sang Don Kim ),지병철 ( Byung Chul Jee ) 대한산부인과학회 2009 Obstetrics & Gynecology Science Vol.52 No.7

Ovulation induction is to make ovulation occur in a woman with ovulatory problems by giving her medical or surgical treatment. The method of ovulation induction varies depends on the cause and classification. In group I of WHO classification, gonadotropins should be used, and in group Ⅴ or Ⅵ which shows hyperprolactinemia, dopamine agonist such as bromocriptine can be used to lower the serum level of prolactin. Group Ⅲ is not an indication of ovulation induction and ovum donation should be recommended. In group Ⅱ which is clinically most common, the first choice of treatment is clomiphene. If the initial treatment doesn`t work, glucocorticoids, insulin sensitizers such as metformin, or gonadotropins can be added to induce ovulation. Aromatase inhibitor or gonadotropin alone can be an alternative treatment. In patients with polycystic ovary syndrome, ovarian electrocautery, diathermy or laser vaporization can be helpful. In patients with prolactinoma, transsphenoidal pituitary adenomectomy is available.