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 mutationEstrogen,Progesterone

IGF-I, II, EGF, bFGF HBGF, TGF-

Fibroidgrowth

Fibroid

ECMCell 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

60

50

40

30

20

10

0

Rat

e p

er o

ocyt

e re

trie

val (

%)

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 DGroup 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 Patient group

35

30

25

20

15

10

5

0

Pre

gnan

cy o

r im

pla

nta

tion

rat

e (%

)

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

controls SS

SS

IM

IM

SM

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 alYear Author No. Pregnancy Live birth patients

% mo1983 Berkeley et al. 1/6 16.7 16.7 59 (17 to 127 )*

1984 Garcia and 8/13 61.5 46.2+ At least 10 Tureck

1986 Rosenfeld 15/23 65.2 56.5 At least 121987 Reyniak and 7/10 70.0 NS NS (8 to 26)s

Corenthal1988 Stark 14/24 58.3 NS 20 (12 to 36)1990 Smith and NS

Uhlir1991 Verkauf and 2/3 66.7 42 42 (4 to 112)

Bernhisel (unpublished data)

Total 47/79 59.5

+ 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 ofAuthor preop removed uterus incisions Age infertility

Berkeley et al (1983) NS+ + + NS + NSGarcia and Tureck (984) - NS NS NS NS NSRosenfeld (1986) - - - NS - +Reyniak and - NS NS NS NS NS Corenthal (1987)Stark (1988) NS NS NS NS + +Smith and Uhlir (1990) NS NS - NS - NSVerkauf 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 thecomplication 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. 11 7 (67) Term : 5 Pts (1987)Brooks et al. 15 5 (33) Term (1990)Loffer (1991) 12 7 (58) Term

Corson & 10 (77) Term : 8 Pts Brooks (1991) 13

YDSH (1999) 27 16 (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 beanalogous 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) 1,000 14 ? Survey of multiple centersRavina (2000) 184 12 7 9 women 5 first-trimester losses 7 births: 3 preterm, 4 termNicholson (1999) 24 1 1 Regrowth of fibroid during

pregnancy, term cesarean sectionPron (1999) 77 1 ? Regrowth of fibroid during pregnancyHutchins (1999) 305 2 1 1 term delivery; 1 case of IVF twins,

ongoing first trimesterBradley (1998) 8 1 ? First-trimester viability confirmedRavina (1997) 80 3 1 1 abortion at 6 months in AIDS patient 1 35-week operative delivery of twins 18-week abortionRavina (1995) 16 1 1 Premature delivery, AIDS patient Total 1,730 32 9

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 arteryCondition mectomy embolization

Multiple symptomatic subserosal, intramural, + + and submucosal myomasRapidly enlarging myoma + 0Infertility + 0Desire to retain fertility + ?Does not desire future fertility but wishes ? + to retain uterusPoor surgical risk 0 +Hemodynamic instability because of hemorrhage 0 +Diffuse multiple uterine leiomyomas 0 +

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

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