1. UTERINE LEIOMYOMATA Ozgul Muneyyirci-Delale

2. Classification of Leiomyomata Intracavitary Intracavitary Submucosal Submucosal Intramural Intramural Subserosal Subserosal Pedunculated Pedunculated

3. Fibroid Tumors

4. ETIOLOGY

5. Townsend and co-workers have demonstrated that each of the cells comprising a leiomyoma is of identical glucose-6-phosphate dehydrogenase electrophoretic type. Their data strongly suggest that leiomyomata are unicellular in origin.

6. Estrogen Estrogen Progesterone Progesterone Growth hormone Growth hormone Increase of 4-hydroxylation of estradiol Increase of 4-hydroxylation of estradiol Increase aromatase enzyme Increase aromatase enzyme

7. J.C.M. Tsibris, et al, analyzed 12,000 genes using the Affymetrix platform. Their analysis revealed 67 overexpressed and 78 underexpressed genes and they speculate that leiomyoma might be characterized by the loss of a contractile phenotype. Fertility & Sterility 80(2):279-28, 2003

8. Dysregulation of a number of growth factors in the myometous uterus (many of these factors regulate the process of angiogenesis) Fibroblast growth factor Fibroblast growth factor Vascular endothelial growth factor Vascular endothelial growth factor Heparin-binding epidermal growth factor Heparin-binding epidermal growth factor Platelet-derived growth factor Platelet-derived growth factor Transforming growth factor , Transforming growth factor , Parathyroid hormone-related protein Parathyroid hormone-related protein Prolactin Prolactin

9. Forty percent of the myomas evaluated by Bronsen F, et al demonstrated an abnormal karyotype and had a significantly lower DNA content than chromosomally normal myomas. Forty percent of the myomas evaluated by Bronsen F, et al demonstrated an abnormal karyotype and had a significantly lower DNA content than chromosomally normal myomas.

10. Uterine leiomyomas are monoclonal tumors that demonstrate nonrandom cytogenetic mutation. The most frequently reported cytogenetic abnormalities in myomas are: + (12:14) (q13-15, q23-24) + (12:14) (q13-15, q23-24) del (7) (q21) del (7) (q21) + (1;2) (p36, p24) + (1;2) (p36, p24)

11. Nonhormonal Risk Factors for Uterine Leiomyoma Any history of hypertension (odd ratio (OR):1.7) Any history of hypertension (odd ratio (OR):1.7) Hypertension requiring mediation (OR:2.1) Hypertension requiring mediation (OR:2.1) Hypertension at age less than 35 years (OR:2.7) Hypertension at age less than 35 years (OR:2.7) Hypertension of 5 or more years duration (OR:3.1 Hypertension of 5 or more years duration (OR:3.1 Pelvic inflammatory disease (3 or more episodes OR:3.7) Pelvic inflammatory disease (3 or more episodes OR:3.7) Chlamydial infection (OR:3.2) Chlamydial infection (OR:3.2) Use of intrauterine device with PID (OR:5.3) Use of intrauterine device with PID (OR:5.3) Perineal talc use (daily vs. no use:PR=2.2) Perineal talc use (daily vs. no use:PR=2.2)

12. Symptomatology Twenty to fifty percent of uterine leiomyomas are estimated to produce symptoms. Menorrhagia (29 - 59%)

13. Pelvic pain and pressure (34%)

14. Pregnancy complications

15. Incidence of Myoma During Pregnancy 0-30 – 7.2% 17.3% had clinical pathological state 7.28 % requiring surgical intervention HL Gainey and JE Keeler Am J Obstet Gynecol, 1949

16. Pregnancy Complications Due to Leiomyoma Abortion Abortion Premature labor Premature labor Disturbances in labor Disturbances in labor Postpartum hemorrhage (questionable (questionable Ectopic pregnancy Ectopic pregnancy Premature rupture of membrane Premature rupture of membrane Dystocia secondary low segment myoma Dystocia secondary low segment myoma Increase operative deliveries Increase operative deliveries Inversion of uterus Inversion of uterus

17. Effects of the Pregnancy on the Myoma Degeneration of myomas Degeneration of myomas Infection (the process is usually sterile but may be complicated by secondary infection from uterine cavity) Infection (the process is usually sterile but may be complicated by secondary infection from uterine cavity)

18. Causes of Uterine Degeneration A. Vascular Insufficiency –Rapid growth during pregnancy –Torsion of pedunculated myoma –Uterine artery embolization B. Hypoestrogenic State –Postpartum or postabortal –GnRH – agonist or antiagonist –Postmenopausal (perimenopausal) C. Other Causes –High dosage progestin therapy –Progesterone receptor modulator

19. Type of Degenerative Change Persaud & Arjoon, Obstet & Gynecol, 1970

20. 445 Pregnancies Complicated by Leiomyoma Degeneration of Myoma Degeneration of Myoma Only one of four myomas evidences degeneration. Degeneration was variable in successive pregnancies. Of the cases that degenerated in the first pregnancy, 6 percent did not degenerate subsequently, whereas 10 percent that did not evidence degeneration in the first pregnancy did degenerate in later ones. Antepartum Course Antepartum Course 28 percent had pain of varying degrees. In the successive pregnancies, 15 percent had pain the the first pregnancies and none subsequently, whereas 7.5 percent had no pain in the first pregnancies, but did have pain in following ones. According to DJ Grandin, 1949 According to DJ Grandin, 1949

21. The Significance of Leiomyoma Uteri in Pregnancy Pain occurred in 15.6 percent. In about 50 percent; however, it was of sufficient degree to require hospitalization for observation or treatment. In most cases, the acute symptoms are relieved after a few days of bed rest. Recent studies have shown that myomectomy during pregnancy carried a high fetal mortality and an increased maternal risk. FA Duckering Am J Obstet Gynecol

22. Changes in Myomas During Pregnancy

23. Infertility (27%)

24. According to VC Buttram in only 2.4% of patients who had myomectomy no cause of infertility was found. Uterine leiomyomas were the sole cause of 9.1% in among black patients. In contrast, only 1.8% of white patients had infertility after attributable to leiomyoma alone. Pelvic adhesive disease requiring surgery for infertility was significantly higher in black patients (44%) other white patients (17.5%). Fertility & Sterility, 1981

25. Outcome and Resource Use Associated with Myomectomy Conversion to more invasive procedure occurred in 5.4% of the patients. Conversion to open myomectomies occurred in 13.3% of laparoscopies and 7.4% of hysteroscopies. Hysterectomy conversion occurred in 3.7%, 2.8% and 1.5% of the open, laparoscopic and hysteroscopic procedures respectively. The rate of additional surgeries was 8.3% in 6 months. 10.6% in 1 year, and 16.5% in 2 years. Subramanian S, et al Obstet Gynecol, 2001, 98(4):583-576

26. Fertility Among Women with Uterine Leiomyoma Pelvic adhesions: 36.2 percent of the 196 women had pelvic adhesions at operation. The highest incidence (58%) of adhesions were noted in women complaining of infertility. Of special interest was the incidence of pregnancy among the 52 subjects whose presenting complaints included infertility: only 5 (9.6%) conceived, and all were of the 22 women in whom the were pelvic adhesion-free at operation. VE Eqwuatu, J Fertility, 1989

27. Other Problems Associated with Uterine Leiomyoma Polycythermia Polycythermia Ascites Ascites Impingement Impingement Related complications Related complications Sarcomatous changes Sarcomatous changes

28. Management of Uterine Leiomyomata: What Do We Really Know? Systematically review the literature on the surgical and non surgical management of uterine leiomyomata. Despite the clinical and public health importance of uterine leiomyomata, the available literature has significant limitations that prevent patients, clinicians, and policymakers from reaching conclusions about the relative risks, benefits, and costs of currently used treatments for leiomyomata. Rectifying these limitations should be a major research priority. Myers ER et al, Obstet Gynecol 2002

29. Surgical Treatment of Uterine Leiomyomas Hysterectomy HysterectomyLaparotomyLaparoscopic Myomectomy MyomectomyVaginalHysteroscopicLaparoscopicLaparotomy Myolysis Myolysis

30. Disseminated leiomyomatosis and diffuse endometriosis may occur following laparoscopic supracervical hysterectomy. Presumably small, even microscopic, fragments of smooth muscle or endometrium dispersed during morcellation can proliferate and ultimately result in pelvic pain and masses. Kung R. et al, 2000

33. The major indications for aggressive management of uterine myomas are as follows: Abnormal uterine bleeding Abnormal uterine bleeding Rapid growth Rapid growth Growth after menopause Growth after menopause Infertility Infertility Recurrent pregnancy loss Recurrent pregnancy loss Pain or pressure symptoms Pain or pressure symptoms Urinary tract symptoms or obstruction Urinary tract symptoms or obstruction Possibility of ovarian neoplasia Possibility of ovarian neoplasia Iron deficiency anemia secondary to chronic blood loss Iron deficiency anemia secondary to chronic blood loss

34. Management of Nonpregnant Patients with Uterine Leiomyomata

35. Complication Rate with Abdominal Myomectomy ComplicationFebrileHemorrhage EBL > 1,000 mL Unintended hysterectomy Post op DVT Wound infection Ileus Data from LaMorte, et al Patients 15 (12%) 26 (20%) 6 (5%) 1 (1%) 3 (2%) 1 (1%)

36. Effect of Patient Age on Conception Following Myomectomy

37. Pregnancy Rate in Infertile Women Following Myomectomy

38. Factors Influencing Pregnancy After Myomectomy Patient Characteristi c Mean follow-up (+SD) (range) (mo) Patients age >40 y <40 y >35 y <35 y Patients Who Conceives (n=42) 28.3+7.4 (14-55) Patients Who Did Not Conceive (n=46) 26.4+7.5 (13-45) P Value <001 <001 0 (0) 22 (100) 0 (0) 22 (100) 42 (63.6) 24 (36.4) 42 (63.6) 24 (36.4) 14 (25.9) 40 (74.1) 14 (25.9) 40 (74.1) 28 (82.4) 6 (17.6) 28 (82.4) 6 (17.6)

39. Factors Influencing Pregnancy Rates After Myomectomy (Continued) Patient Characteristi c Patients Who Conceives (n=42) Patients Who Did Not Conceive (n=46) P Value Duration of infert. >3 y <3 y 6 (15) 6 (15) 36 (75) 36 (75) 34 (85) 34 (85) 12 (25) 12 (25) <.001 <.001 Type of infert. UnexplainedMultifactorialPrimarySecondary 32 (72.7) 32 (72.7) 10 (22.7) 10 (22.7) 14 (50) 14 (50) 28 (46.7) 28 (46.7) 12 (27.3) 12 (27.3) 34 (77.3) 34 (77.3) 15 (50) 15 (50) 32 (53.3) 32 (53.3) <.001 <.001 NS NS Dessolle Fertil & Steril, 2001

40. Effects of intramural subserosal and submucosal uterine fibroids on the outcome of assisted reproductive technology. (Elder-Geva et al) Effects of intramural subserosal and submucosal uterine fibroids on the outcome of assisted reproductive technology. (Elder-Geva et al) The pregnancy rates per transfer were 34.1%, 16.4%, 10%, and 30.1% in the patients with subserosal fibroids, intramural fibroids, submucosal fibroids and no fibroids, respectively. The pregnancy rates per transfer were 34.1%, 16.4%, 10%, and 30.1% in the patients with subserosal fibroids, intramural fibroids, submucosal fibroids and no fibroids, respectively. Pregnancy and implantation rates were significantly lower in the groups of patients with intramural and submucosal fibroids, even when there was no deformation of the uterine cavity. Pregnancy and implantation rates were not influenced by the presence of subserosal fibroids. Surgical or medical treatment should be considered in infertile patients who have intramural and/or submucosal fibroids before resorting to ART treatment. Pregnancy and implantation rates were significantly lower in the groups of patients with intramural and submucosal fibroids, even when there was no deformation of the uterine cavity. Pregnancy and implantation rates were not influenced by the presence of subserosal fibroids. Surgical or medical treatment should be considered in infertile patients who have intramural and/or submucosal fibroids before resorting to ART treatment.

42. Some indications for the use of GnRH agonists in women with uterine leiomyomata are as follows : Preservation of fertility in women with large leiomyomas before attempting conception, or preoperative treatment before myomectomy Preservation of fertility in women with large leiomyomas before attempting conception, or preoperative treatment before myomectomy Treatment of anemia to allow recovery of normal hemoglobin levels before surgical management, minimizing the need for transfusion or allowing autologous blood donation Treatment of anemia to allow recovery of normal hemoglobin levels before surgical management, minimizing the need for transfusion or allowing autologous blood donation Treatment of women approaching menopause in an effort to avoid surgery Treatment of women approaching menopause in an effort to avoid surgery

43. Preoperative treatment of large leiomyomas to make vaginal hysterectomy, hysteroscopic resection or ablation, or laparoscopic destruction more feasible Preoperative treatment of large leiomyomas to make vaginal hysterectomy, hysteroscopic resection or ablation, or laparoscopic destruction more feasible Treatment of women with medical contraindications to surgery Treatment of women with medical contraindications to surgery Treatment of women with personal or medical indications for delaying surgery Treatment of women with personal or medical indications for delaying surgery

44. The prevalence of leiomyosarcomas discovered incidentally (1:2,000) and mortality rate for hysterectomy for benign disease (1.0-1.6 per 1,000 for premenopausal). Reiter RC et al, 1992

45. Judicious patient observation and follow-up are indicated primarily for uterine leiomyomas; intervention is reserved for specific indications and symptoms.

46. Uterine Artery Embolization Following the procedure the fibroids shrunk by 39-60%. Following the procedure the fibroids shrunk by 39-60%. Complications ComplicationsEndometritis Tubo-ovarian abscess Necrobiosis Vaginal expulsion of submucous myoma AmenorrheaDeath Recurrent Rate – 20% in 5 years Recurrent Rate – 20% in 5 years Operation – 10% in 1 year. Operation – 10% in 1 year.

47. Future Investigation in Treatment of Uterine Leiomyomata Cryomyolysis Cryomyolysis Laser-induced interstitial thermotherapy (LITT) Laser-induced interstitial thermotherapy (LITT) (Magnetic-resonance-guided percutaneous laser ablation) Mifepristone (RU-486) Mifepristone (RU-486) Pirfemidone (inhibits leiomyoma cell proliferation and collagen production) Pirfemidone (inhibits leiomyoma cell proliferation and collagen production) Interferone-alpha (inhibitor of basic fibroblast growth factor- stimulated cell proliferation) Interferone-alpha (inhibitor of basic fibroblast growth factor- stimulated cell proliferation) Chinese herbal medicines (Keishi-bukuryogan and Shakuyaku- kenzo-to) Chinese herbal medicines (Keishi-bukuryogan and Shakuyaku- kenzo-to) Pharmacological agents that counteract angiogenic factors Pharmacological agents that counteract angiogenic factors Gene therapy Gene therapy Laparoscopic occlusion of uterine vessels Laparoscopic occlusion of uterine vessels Asoprisnil Asoprisnil

48. Low-Dose Mifepristone for Uterine Leiomyomata (5 mg and 10 mg) Mean uterine volume shrank by 48% in the 5 mg group and 49% in the 10 mg group. Amenorrhea occurred in 60-65% of both groups. The incidence of hot flushes increased significantly over baseline in the 10 mg group but not in the 5 mg group. Simple hyperplasia occurred in 28% of all groups; with no difference between groups. Eisinger SH et al, Obstet Gynecol 2003