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Copyright The Korean Academy A Successful Live Birth Through in vitro Fertilization Program AfterConservative Treatment of FIGO Grade I Endometrial Cancer Infertile women with chronic anovulation are prone to be exposed to unopposed estrogen stimulation and have the high risk of being suffering from endometrial hyperplasia or even endometrial carcinoma. A few reports have suggested that Department of Obstetrics and Gynecology, Keimyung nulliparous young women (under 40 yr of age) with endometrial carcinoma could University, School of Medicine, Daegu, Korea be treated conservatively to preserve fertility and succeed the live birth. We reporton a 36-yr-old woman who received conservative treatment of endometrial carci- noma (stage I, grade 1) by curettage and progestin. After megestrol medication of total 71,680 mg during 24 weeks, we found the regression of endometrial lesion bycurettage and hysteroscopic examination. Then we decided to perform in vitro ferti- lization program. Two embryos were transferred and heterotypic pregnancy was Jeong-Ho Rhee, M.D.
Department of Obstetrics and Gynecology, Keimyung diagnosed 27 days after embryo transfer. After right salpingectomy, she received University, School of Medicine, 194 Dongsan-dong, routine obstetrical care and delivered by cesarean section at 38 weeks in gestational periods. Two years after delivery, she is healthy without any evidence of recurrent Tel : +82.53-250-7871, Fax : +82.53-250-7599E-mail : rl670416@dsmc.or.kr disease. The fertility preserving treatment is an option in endometrial cancer patientsif carefully selected, and assisted reproductive technologies would be helpful.
*The abstract was presented in 7th World congress oncontroversies in Obstetrics, Gynecology and infertility Key Words : Endometrial Neoplasms; Fertilization in Vitro; Progestins INTRODUCTION
prognosis because the tumors are detected at an early stageand likely to be highly differentiated and hormonally depen- Endometrial carcinoma is the most common malignant dent. In such a setting, high dose progestins followed by tumor of the female genital tract in western country. Many curettage may be the alternative treatment in patients who patients with endometrial carcinoma are in their 50’s and only 5% of them are under age 40 (1). Endometrial adeno- We report a case of successful live birth through the in vitro carcinoma in child bearing age is relatively uncommon, fertilization (IVF) program after conservative treatment of except in those with obesity, chronic anovulation, irregular endometrial cancer (stage I, grade I).
menstruation, infertility and is associated with so-called poly-cystic ovary syndrome or estrogen producing tumor. Pro-longed unopposed estrogen exposure in infertile women with CASE REPORT
chronic anovulation may induce endometrial hyperplasiaprogressing to carcinoma. Failure of ovulation, characteristi- A 36-yr-old woman visited in our infertility clinic, com- cally expressed with amenorrhea or oligomenorrhea, occurred plaining of primary infertility for 1 yr. Her menstrual cycle in 21% of infertile patients, ovulatory dysfunction cause sub- was irregular, about 60-120 days, body mass index was 27.5 fertility in 15-20% of couples (2). The risk of endometrial (body weight: 73 kg, height: 163 cm). She had a history of carcinoma was increased 4.8-folds in infertile patients and explo-laparotomy due to endometriosis. Neither she nor any 10.3-folds in infertile women with chronic anovulation (3).
other members of her family had diabetes or hypertension.
So it is essential to evaluate the endometrial disease thoroughly Abdomino-pelvic examination showed the unremarkable during infertility work up in these patients (4, 5).
findings and transvaginal ultrasonogram showed small uter- Most patients with endometrial carcinoma undergo hys- ine myoma, 24-21 mm, normal contour of endometrium, terectomy, however, in a young woman who wishes to bear 10 mm, and well defined normal both ovaries. Full infertility a child, trial treatment with progestins has been attempted, work up was performed, results of semen analysis was nor- and successful pregnancies after the conservative treatment mal, hormonal study (LH, FSH, Estradiol, Prolactin, TSH, have been reported. Endometrial cancer in younger patients Testosterone, DHEA-S) showed normal findings except high (age under the 40 yr) is generally associated with a better FSH level of 9.66 mIU/mL. The office endometrial aspira- tion biopsy showed secretory phase and finding of luteal phase defect. Hysterosalpingogram revealed one point filling defect After counseling, the patient wished to retain her ability in the uterine cavity and mild dilatation of ampullary por- to conceive, so high dose progestin therapy was recommend- tion of Fallopian tubes, but good intraperitoneal spillage (Fig.
ed. Oral megestrol acetate was prescribed 600 mg daily for 8 1A). On laparoscopic examination, peritubal adhesion was weeks. On follow-up hysteroscopic examination, she still detected and adhesiolysis was performed. On hysteroscopic got a small protruding mass on fundal area. We performed examination, there was a polypoid mass on fundal area and hysteroscopic biopsy and endometrial curettage. The patho- hysteroscopic biopsy and curettage was done. The patholog- logic evaluation of endometrium revealed complex hyper- ic evaluation of endometrial tissue revealed well differenti- plasia without cellular atypia (Fig. 2B). She continued to ated endometrial adenocarcinoma (Grade 1, Fig. 2A) with receive megestrol acetate but complained intolerable weight positive estrogen and progesterone receptors. After curettage, gain from 73 to 88 kg. We decided to reduce the dose to we confirmed that there was no detectable endometrial mass 400 mg, daily for 4 weeks, then 320 mg, daily for 12 weeks.
or myometrial invasion or cervical involvement by MRI imag- After megestrol medication of total 71,680 mg during 24 ing (Fig. 1B). Final diagnosis was primary infertility accom- weeks, we found smooth atrophic endometrium by hystero- panying endometrial carcinoma, FIGO grade I without myo- scopic examination, and this was confirmed as atrophic endo- Fig. 1. (A) Hysterosalpingogram shows a small filling defect in theuterine cavity. (B and C) MRI reveals no residual tumor in the en-dometrium nor myometrial involvement after curettage. IVF Program After Conservative Treatment of Endometrial Cancer Fig. 2. (A) A well-differentiated endometrioid adenocarcinoma. Light micrograph shows anaplastic proliferation of the endometrial glandsassociated with foci of squamoid differentiation (H&E stain, ×200). (B) After progestin therapy for 8 weeks, the endometrium shows com-plex hyperplasia without nuclear atypia in the dilated endometrial glands (H&E stain, ×200).
metrium through the histological examination of tissue ob- sured by transvaginal ultrasonography was 4 mm and endo- tained by curettage. Then we decided to perform IVF pro- metrial biopsy revealed no evidence of recurrent disease. Two gram in order to optimize the patient’s potential for fertility years after delivery, she was healthy without any evidence of and achieve a viable pregnancy without further delay.
After pituitary down-regulation by the GnRHa (Busere- lin acetate, Superfact�, Hoechst), follicle-stimulating hor-mone preparation (Follimon�, LGIC, Korea) was adminis- DISCUSSION
trated, 375 IU daily for 12 days. The follicular growth wasmonitored from gonadotropin day 5 by 3 days interval and Endometrial carcinoma is the most common malignant human chorionic gonadotropin (IVF-C�, LGIC, Korea) 10,000 tumor of the female genital tract in western country. But in IU was administrated when the at least 3 or more follicles Korea, endometrial carcinoma is the third frequent malig- reached 18 mm in diameter. And 35 hr later, oocytes aspira- nant tumor of the female genital tract (10.4% of the female tion was performed under the guidance of transvaginal ultra- genital tract) and only 13.5% of them are under age 40 yr, sonography. Two mature oocytes were retrieved and insemi- but its incidence has been increasing steadily.
nated with her husband’s prepared spermatozoa. Fifty seven The standard therapy for endometrial carcinoma is staging hours after oocyte retrieval, the two high grade 4-cell embryos laparotomy with total abdominal hysterectomy and bilater- were transferred. Measurement of -hCG revealed 3,449 al salpingo-oophorectomy, followed by adjuvant radiation mIU/mL on 19 days after embryo transfer, and on 23 days for patients judged to be at high risk for local recurrence.
after embryo transfer, intrauterine single gestational sac with Several lines of evidence have suggested that two different yolk sac and right tubal pregnancy were identified by trans- pathogenic types of endometrial cancers exist according to vaginal ultrasonogram. Right salpingectomy was performed hyperestrogenic state or not. The type of endometrial cancer under the epidural anesthesia, on 27 days after embryo trans- associated with hyperestrogenism typically develops via a fer, we could detect the fetal pole with heart beat in the int- characteristic sequence from hyperplastic lesion of the endo- rauterine gestational sac after that procedure. Then she received metrium to premalignant lesion, finally invasive cancer and routine obstetrical care and delivered by Cesarean section at has tendency to be diagnosed in early stage, as low grade, 38 weeks in gestational periods. The baby was female, 2,590 g, with estrogen and progesterone receptors (6). In such a set- and the Apgar score was 8 at 1 min, 9 at 5 min. Placenta was ting, conservative treatment with progestin may be the alter- grossly and microscopically normal, there was no evidence of native treatment modality in patient who wishes to preserve residual tumor in the uterus and adnexa or abdominal organ.
Twelve weeks after delivery, endometrial thickness mea- In a case of series, three of eight patients with grade 1 ade- nocarcinoma, limited to the endometrium, were successfully rafallopian transfer and Pinto et al. reported successful preg- treated with progesterone followed by dilatation and curet- nancy through the in vitro fertilization after controlled overi- tage (8). A review of the pathology records at Johns Hopkins an hyperstimulation and recently Lowe et al. reported suc- Medical Center between 1990 and 1996 yield 12 patients cessful pregnancy through the oocyte donation program (7, younger than 40 yr of age who had well-differentiated ade- nocarcinoma of the endometrium were treated with progestin This is another report of conservative treatment of endome- alone for 3 to 18 months. Nine of 12 patients had regression trial carcinoma followed by successful pregnancy through of lesion and remained free of disease at a mean follow up the IVF program. We believe that hysteroscopic examina- duration of 40 months (9). Kim et al. also reported that pro- tion during the infertility work up would be helpful not only gestin treatment for well-differentiated adenocarcinoma in in the evaluation of abnormal findings of hysterosalpingog- young women was successful in 13 out of 20 cases (10).
raphy but also of endometrial pathology in patients with But no consensus exists about specific conservative treat- highly suspicion of endometrial disease due to prolonged ment for well-differentiated endometrial cancer, that is, the dose and duration of progestins treatment have not yet been We prescribed initially megestrol acetate, 600 mg daily established. The reported daily doses of progestins were vari- that was the highest dose of progestins ever reported, and able, from 40 mg to 400 mg of megestrol acetate or 200 mg observed the regression of the endometrial carcinoma through to 600 mg of medroxyprogesterone acetate, and the durations the complex hyperplasia without cellular atypia to atrophic of medication were from 3 months to 18 months (9-13).
endometrim. And we agree with Kimmig et al. in that pro- The conservative therapy has apparent risks and some inves- gestin treatment should be followed immediately by down- tigators have strongly opposed to use conservative treatment regulatory therapy with GnRHa in order to prevent reinduc- because the treatment with progestins may not always achieve tion of the menstrual cycles and unnecessary prolonged expo- remission (14). The risk of disease progression occurring dur- sure to estrogens, and assisted reproductive technologies would ing or after progestin therapy would be approximately 5% be helpful in women who wish to conceive.
(8), while Randall and Kurman did not experience the patients In conclusion, we report a case of successful live birth with progressive disease except patients with persistent lesions through the IVF program after conservative treatment of endometrial cancer (stage I, grade 1). The fertility-preserv- Before the decision of conservative treatment, it is prereq- ing treatment is an option in endometrial cancer patients if uisite to know the depth of myometrial invasion and grade carefully selected, and assisted reproductive technologies of tumor cells, that is, conservative treatment is indicated only in the case of well-differentiated, early stage disease with-out extrauterine lesions. For these purposes, MRI would behelpful for evaluation of invasion depth of tumor and detect- REFERENCES
ing extrauterine tumor and the endometrial biopsy shouldbe performed for grading of tumor. There were several reports 1. Ostor AG, Adam R, Gutteridge BH, Fortune DW. Endometrial car- about inaccuracy of endometrial biopsy, incorrect diagnoses cinoma in young women. Aust N Z J Obstet Gynecol 1982; 22: 38-42. of 28 percents were reported with office Novak curette biopsy 2. Hull MG, Glazener CM, Kelly NJ, Conway DI, Foster PA, Hinton with 18% having a higher grade tumor in hysterectomy (15), RA, Coulson C, Lambert PA, Watt EM, Desai KM. Population study although the dilatation and curettage was more accurate than of causes, treatment, and outcome of infertility. Br Med J 1985; 291: office endometrial biopsy in predicting tumor grade, the dila- tation and curettage also incorrectly graded approximately 3. Ron E, Lunenfeld B, Menczer J, Blumstein T, Katz L, Oelsner G, 25% of the patients, with higher grade tumor being missed Serr D. Cancer incidence in a cohort of infertile women. Am J Epi- in about 10% (16). For the reduction of misdiagnosis, as addi- tional diagnostic tool, hysteroscopic examination such as in 4. Meirow D, Schenker JG. The link between female infertility and can- cer: epidemiology and possible aetiologies. Hum Reprod Update After the conservative treatment of endometrial carcinoma, the pregnancy rate was somewhat disappointing, that is, only 5. Salha O, Martin-Hirsch P, Lane G, Sharma V. Endometrial carci- 3 of 24 patients delivered viable infants (10). To permit sub- noma in a young patient with polycystic ovarian syndrome: first sus- sequent pregnancy as well as to prevent the recurrence of pected at time of embryo transfer. Hum Reprod 1997; 12: 959-62. disease, it is important to induce ovulation following regres- 6. Emons G, Heyl W. Hormonal treatment of endometrial cancer. J sion of carcinoma. Given the high incidence of chronic anovu- Cancer Res Clin Oncol 2000; 126: 619-23. lation and infertility in young women with endometrial car- 7. Lowe MP, Bender D, Sood AK, Davis W, Syrop CH, Sorosky JI.
cinoma, it is likely that trial of assisted reproductive technolo- Two successful pregnancies after conservative treatment of endome- gies would have resulted in a higher pregnancy rate. Kimmig trial cancer and assisted reproduction. Fertil Steril 2002; 77: 188-9. et al. reported successful pregnancy achieved by gamete int- 8. Farhi DC, Nosanchuk J, Silverberg SG. Endometrial adenocarcinoma IVF Program After Conservative Treatment of Endometrial Cancer in women under 25 years of age. Obstet Gynecol 1986; 68: 741-5. sequent pregnancy: report of two cases. Eur J Gynaecol Oncol 2000; 9. Randall TC, Kurman RJ. Progestin treatment of atypical hyperpla- sia and well differentiated carcinoma of the endometrium in women 14. Greenblatt RB, Gambrell RD Jr, Stoddard LD. The protective role under age 40. Obstet Gynecol 1997; 90: 434-40. of progesterone in the prevention of endometrial cancer. Pathol Res 10. Kim YB, Holschneider CH, Ghosh K, Nieberg RK, Montz FJ. Pro- gestin alone as primary treatment of endometrial carcinoma in pre- 15. Daniel AG, Peters WA. Accuracy of office and operating room curet- menopausal women. Cancer 1997; 79: 320-7. tage in the grading of endometrial carcinoma. Obstet Gynecol 1988; 11. Kimmig R, Strowitzki T, Muller-Hocker J, Kurzl R, Korell M, Hepp H. Conservative treatment of endometrial cancer permitting subse- 16. Larson DM, Johnson KK, Broste SK, Krawisz BR, Kresl JJ. Com- quent triplet pregnancy. Gynecol Oncol 1995; 58: 255-7. parison of D&C and office endometrial biopsy in predicting final 12. Mitsushita J, Toki T, Kato K, Fujii S, Konishi I. Endometrial carci- histopathologic grade in endometrial cancer. Obstet Gynecol 1995; noma remaining after term pregnancy following conservative treat- ment with medroxyprogesterone acetate. Gynecol Oncol 2000; 79: 17. Pinto AB, Gopal M, Herzog TJ, Pfeifer JD, Williams DB. Success- ful in vitro fertilization pregnancy after conservative management 13. Jobo T, Imai M, Kawaguchi M, Kenmochi M, Kuramoto H. Success- of endometrial cancer. Fertil Steril 2001; 76: 826-9. ful conservative treatment of endometrial carcinoma permitting sub-

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