Management of Myoma In Infertile Patients 연세대학교 의과대학 영동세브란스 병원 산부인과 이 병 석

Leiomyoma, Fibroid of Uterus Most common benign tumor of the reproductive tract 20-40% of women during the reproductive years More than 70% of hysterectomies Myoma account for 2% to 3% of infertility Exact pathophysiologic mechanism is not known

Biology of Myoma The effect of gonadal steroid hormones Genetic abnomalities Growth factor abnormalities Increased amount of extracellular matrix

Myometrial smooth cell somatic mutation Estrogen, Progesterone IGF-I, II, EGF, bFGF HBGF, TGF-  Fibroid growth Fibroid ECM Cell proliferation

Uterine Myoma Infertility ? Buttram et al ( Fertil & Steril, 1981), Verkauf et al ( Fertil & Steril, 1992) :40-45% of Infertile couples conceive after myomectomy Buttram et al ( Fertil & Steril, 1981) :Recurrent pregnancy loss rates are reduced from 40% to 20% after myomectomy

Uterine myoma and ART Stovall et al (1998): Reduce the efficacy of ART Ashkenazi et al (1995): Implantation rate and pregnancy rate are impaired only when the deformation of the uterine cavity is present Ramzy et al (1998): Myoma without encroaching on the cavity and <7cm in diameter do not affect the implantation rate or miscarriage rates in IVF or ICSI

Pregnancy Delivery Rate per oocyte retrieval (%) Pregnancy and delivery rates of cases (white bars) and controls (filled bars). (Stovall et al, 1998)

Pregnancy outcome of Assisted Reproduction Total pregnancies Clinical Implantation per Abortions Deliveries Pregnancies embryo (% total cases) Group I (39 cycles) 18 (45.0%) 15 (38.5%) 16/128 (12.5%) 3 (20.0%) 9 (23.1%) Group II (367 cycles)154 (42.0%)123 (33.5%)165/1192 (13.8%)19 (15.5%) 95 (25.9%) Total (406 cycles)172 (42.4%)138 (34.0%)181/1320 (13.7%)22 (15.9%)105 (25.9%) (Ramzy et al, 1998) Group I: not encroaching on the cavity and <7cm in D Group II: controls

Hypothetic Mechanism Causing Infertility Submucosal Myoma Disarray of the straight and radial arteries endometrial vascular support may be compromised Inflammation and Ulceration biochemical alteration in the uterine fluid Intramural Myoma Distortion and elongation of endometrial cavity impede sperm transport Impairment of the neuromuscular mechanism that control the uterotubal junction The cornua can be obstructed

Intraligamentary Myoma Distort the normal course of the F-tube and alter the anatomic relationship between the distal portion of the tube and the ovary prevent the extruded ovum from entering the oviduct Cervical Myoma The position of the cervix can be displaced thus potentially interfering with sperm pick-up from the seminal pool in the posterior fornix following coitus

Patient group Pregnancy or implantation rate (%) Pregnancy and implantation rates in the groups of patients without fibroids (controls) and with subserosal fibroids (SS), intramural fibroids (IM), and submucosal (SM). *P<0.05 for IM versus controls or SS. **P<0.005 for IM versus control. controls SS IM SM Pregnancy rate Implantation rate * **

Surgical Treatment Abdominal, Laparoscopic, Hysteroscopic Myomectomy Uterine Artery Embolization Myolysis Laser, Bipolar needle, Diathermy, Cryomyolysis Myoma interstitial thermo-therapy Medical treatment GnRH analogue, Antiprogestins(RU486) Current Current Therapy of Uterine Myoma

Abdominal Myomectomy Traditionally is performed when infertility enhancement or uterine preservation is desired Adequate exposure and removal of larege myomas with favorable reconstruction of the uterine wall general report up to 50% postop preg rate 10-45% recurrence rate

Pregnancy in Patients Attempting Conception After Myomectomy Myoma alone Length offollow-up with exposure in al Year Author No. Pregnancy Live birth patients % mo 1983Berkeley et al. 1/ (17 to 127 ) * 1984Garcia and 8/ At least 10 Tureck 1986Rosenfeld15/ At least Reyniak and 7/ NSNS (8 to 26) s Corenthal 1988Stark14/ NS20 (12 to 36) 1990Smith andNS Uhlir 1991Verkauf and 2/ (4 to 112) Bernhisel (unpublished data) Total47/ One termination of pregnancy; one spontaneous abortion followed by subsequent conception in late second trimester doing well * Values are averages or medians with ranges in parentheses. S NS, not stated.

Impact of Additional Factors Potentially Affecting Conception Rates Distorted Weight/no. uterine No. of of myomata No. of cavity fibroids or size of uterine Duration of Author preop removed uterus incisions Age infertility Berkeley et al (1983)NS + ++NS+NS Garcia and Tureck (984)-NSNSNSNSNS Rosenfeld (1986)---NS-+ Reyniak and-NSNSNSNSNS Corenthal (1987) Stark (1988)NSNSNSNS++ Smith and Uhlir (1990)NSNS-NS-NS Verkauf and Bernhisel (unpublished data) + NS, not stated

Laparoscopic Myomectomy Difficult procedure that requires advanced surgical skill The quality of uterine repair is important thing during the procedure The number, size and location of the tumors limit the use There is no available data No definitive criteria have been established

Contraindication Daniel et al (J Gynecol Surg, 1991) > 4 large myomas (>4cm in diameter) > 10cm in diameter Durai et al (Contracept Fertil Sex, 1996) > 4 myomas > 7 cm size Careful patient selection can decrease the complication and conversion to laparotomy

Myomectomy Laparotomy Laparoscopy Outcomes were different depending on Surgen’s skill, available equipment and charicteristics of myoma there is no adequate randomized controlled trial 66.2% (Rosenfeld et al, 1986) 66.7% (Verukaf, et al, 1992) 65.35% (Ribeiro et al, 1999) 33.3% (Dubisson et al, 1996) Preg rate

Submucosal Myoma The incidence has been reported as 7.8% -29% in myomas Infertility directly related to uterine factors may be 10-15% of the etiologic factors

Treatment of Submucosal Myoma Nd:YAG laser Resectoscopy Hysteroscopic Scissors

Intramural Extension Type 0 Type I Type II (Wamsteker et al, 1993) Endoresection may be effective for type 0, I. Resection of type II should be considered in selected cases because of requirement of repeat procedures and high chance of failure rates

PREGNANCY AFTER RESECTOSCOPIC MYOMECTOMY Pregnancy Authors No. Pts No. Pts (%) Outcome Hallez et al (67) Term : 5 Pts (1987) Brooks et al (33) Term (1990) Loffer (1991) 12 7 (58) Term Corson & 10 (77) Term : 8 Pts Brooks (1991) 13 YDSH (1999) (65) Term : 14 Pts

Uterine Artery Embolization (UAE) Stancato-Pasik et al,(1997) 12 patients with postpartum hemorrhage 11:normal menses 3: pregnant term delivery Postpartum embolization therapy may not be analogous to embolization for uterine myoma (endometrial vascular supply may be compromised even before embolization)

UAE for myoma has a direct effect on endometrial maturation, histology or perfusion ? Blood flow is always lower in myoma than myometrium: Uterine myoma could decrease blood supply to the developing placenta and cause implantation failure (Rock JA, 1983) Ovarian function may be compromised after UAE : reduce fertility It is estimated that 1-2% of women may experience ovarian failure after UAE

Pregnancy outcome after uterine artery embolization (UAE) Investigator, date No. of UAE No. of No. of (reference) subjects Pregnancies deliveries Comments Forman (1999) 1, ? Survey of multiple centers Ravina (2000) women 5 first-trimester losses 7 births: 3 preterm, 4 term Nicholson (1999) Regrowth of fibroid during pregnancy, term cesarean section Pron (1999) 77 1 ? Regrowth of fibroid during pregnancy Hutchins (1999) term delivery; 1 case of IVF twins, ongoing first trimester Bradley (1998) 8 1 ? First-trimester viability confirmed Ravina (1997) abortion at 6 months in AIDS patient 1 35-week operative delivery of twins 18-week abortion Ravina (1995) Premature delivery, AIDS patient Total 1, A no study describes the number of women attempting pregnancy or evaluates the cycle fecundity rate for those trying to conceive after UAE. Hurst. Uterine artery embolization for myomas. Fertil Steril 2000.

Indications for ablative therapy for uterine leiomyomata : abdominal myomectomy versus uterine attire embolization. Myo- Uterine artery Condition mectomy embolization Multiple symptomatic subserosal, intramural,++ and submucosal myomas Rapidly enlarging myoma+0 Infertility+0 Desire to retain fertility+? Does not desire future fertility but wishes?+ to retain uterus Poor surgical risk0+ Hemodynamic instability because of hemorrhage0+ Diffuse multiple uterine leiomyomas0+ Hurst. Uterine artery embolization for moymas. Fertil Steril 2000.

Myolysis and Pregnancy Chapman (1993), Phillips (1995) Favour of pregnancy after myolysis Donnez (2000) contraindication in women desire pregnancy rupture during pregnancy adhesion due to inflammation

Myometrial smooth cell Myoma Growth Gene Therapy Growth Factor Modulation

Target Specific Clinical Symptoms Basic FGF abnormalities: abnormal myoma related bleeding TGF-beta abnormalities: excessive uterine size

Conclusion Myomas represent an isolated potential contributory cause of infertility In the absence of other factors to explain infertility in patients with myoma, myomectomy either performed endoscopically or abdominally, should be considered In selecting the surgical approach, the operative morbidity and application of meticulous surgical technique must be considered Treatment of myomas in infertility must be individualized carefully