UTERINE LEIOMYOMATA UTERINE LEIOMYOMATA

Ozgul Muneyyirci-DelaleOzgul Muneyyirci-Delale

Classification of LeiomyomataClassification of Leiomyomata

IntracavitaryIntracavitary SubmucosalSubmucosal IntramuralIntramural SubserosalSubserosal PedunculatedPedunculated

Fibroid Tumors

ETIOLOGYETIOLOGY

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

EstrogenEstrogen Progesterone Progesterone Growth hormoneGrowth hormone Increase of 4-hydroxylation of estradiolIncrease of 4-hydroxylation of estradiol Increase aromatase enzymeIncrease aromatase enzyme

J.C.M. Tsibris, et al, analyzed 12,000 genes J.C.M. Tsibris, et al, analyzed 12,000 genes using the Affymetrix platform. Their analysis using the Affymetrix platform. Their analysis revealed 67 overexpressed and 78 revealed 67 overexpressed and 78 underexpressed genes and they speculate underexpressed genes and they speculate that leiomyoma might be characterized by that leiomyoma might be characterized by the loss of a contractile phenotype.the loss of a contractile phenotype.

Fertility & SterilityFertility & Sterility

80(2):279-28, 200380(2):279-28, 2003

Dysregulation of a number of growth factors in Dysregulation of a number of growth factors in the myometous uterus (many of these factors the myometous uterus (many of these factors regulate the process of angiogenesis)regulate the process of angiogenesis)

Fibroblast growth factorFibroblast growth factor Vascular endothelial growth factorVascular endothelial growth factor Heparin-binding epidermal growth Heparin-binding epidermal growth

factorfactor Platelet-derived growth factorPlatelet-derived growth factor Transforming growth factor Transforming growth factor ,, Parathyroid hormone-related proteinParathyroid hormone-related protein ProlactinProlactin

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

Uterine leiomyomas are monoclonal Uterine leiomyomas are monoclonal tumors that demonstrate nonrandom tumors that demonstrate nonrandom cytogenetic mutation. The most frequently cytogenetic mutation. The most frequently reported cytogenetic abnormalities in reported cytogenetic abnormalities in myomas are: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)

Nonhormonal Risk Factors for Uterine Nonhormonal Risk Factors for Uterine LeiomyomaLeiomyoma

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:3.1Hypertension of 5 or more years duration (OR:3.1 Pelvic inflammatory disease (3 or more episodes Pelvic inflammatory disease (3 or more episodes

OR:3.7)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)

SymptomatologySymptomatology

Twenty to fifty percent of uterine Twenty to fifty percent of uterine leiomyomas are estimated to produce leiomyomas are estimated to produce symptoms.symptoms.

Menorrhagia (29 - 59%)Menorrhagia (29 - 59%)

Pelvic pain and pressure (34%)Pelvic pain and pressure (34%)

Pregnancy complicationsPregnancy complications

Incidence of Myoma During PregnancyIncidence of Myoma During Pregnancy

0-30 – 7.2%0-30 – 7.2%

17.3% had clinical pathological state17.3% had clinical pathological state

7.28 % requiring surgical intervention7.28 % requiring surgical intervention

HL Gainey and JE HL Gainey and JE KeelerKeeler

Am J Obstet Am J Obstet Gynecol, 1949Gynecol, 1949

Pregnancy Complications Due to LeiomyomaPregnancy Complications Due to Leiomyoma

AbortionAbortion Premature laborPremature labor Disturbances in laborDisturbances in labor

Postpartum hemorrhagePostpartum hemorrhage

(questionable(questionable Ectopic pregnancyEctopic pregnancy

Premature rupture of Premature rupture of membranemembrane

Dystocia secondary low Dystocia secondary low segment myomasegment myoma

Increase operative Increase operative deliveriesdeliveries

Inversion of uterusInversion of uterus

Effects of the Pregnancy on the MyomaEffects of the Pregnancy on the Myoma

Degeneration of myomasDegeneration of myomas

Infection (the process is usually sterile but Infection (the process is usually sterile but may be complicated by secondary infection may be complicated by secondary infection from uterine cavity)from uterine cavity)

Causes of Uterine DegenerationCauses of Uterine Degeneration

A.A. Vascular InsufficiencyVascular Insufficiency– Rapid growth during pregnancyRapid growth during pregnancy– Torsion of pedunculated myomaTorsion of pedunculated myoma– Uterine artery embolizationUterine artery embolization

B.B. Hypoestrogenic StateHypoestrogenic State– Postpartum or postabortalPostpartum or postabortal– GnRH – agonist or antiagonistGnRH – agonist or antiagonist– Postmenopausal (perimenopausal)Postmenopausal (perimenopausal)

C.C. Other CausesOther Causes– High dosage progestin therapyHigh dosage progestin therapy– Progesterone receptor modulatorProgesterone receptor modulator

Type of Degenerative ChangeType of Degenerative Change Persaud & Arjoon, Obstet & Persaud & Arjoon, Obstet & Gynecol, 1970Gynecol, 1970

0

10

20

30

40

50

60

70

Hya. Myx. Calc. Muc. Cystic Red Fatty Sarc.

445 Pregnancies Complicated by Leiomyoma445 Pregnancies Complicated by Leiomyoma

Degeneration of MyomaDegeneration of Myoma

Only one of four myomas evidences degeneration. Only one of four myomas evidences degeneration. Degeneration was variable in successive pregnancies. Of the Degeneration was variable in successive pregnancies. Of the cases that degenerated in the first pregnancy, 6 percent did cases that degenerated in the first pregnancy, 6 percent did not degenerate subsequently, whereas 10 percent that did not degenerate subsequently, whereas 10 percent that did not evidence degeneration in the first pregnancy did not evidence degeneration in the first pregnancy did degenerate in later ones.degenerate in later ones.

Antepartum CourseAntepartum Course

28 percent had pain of varying degrees. In the 28 percent had pain of varying degrees. In the successive pregnancies, 15 percent had pain the the first successive pregnancies, 15 percent had pain the the first pregnancies and none subsequently, whereas 7.5 percent pregnancies and none subsequently, whereas 7.5 percent had no pain in the first pregnancies, but did have pain in had no pain in the first pregnancies, but did have pain in following ones.following ones.

According to DJ Grandin, 1949According to DJ Grandin, 1949

The Significance of Leiomyoma Uteri in The Significance of Leiomyoma Uteri in PregnancyPregnancy

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

FA DuckeringFA Duckering

Am J Obstet GynecolAm J Obstet Gynecol

Changes in Myomas During PregnancyChanges in Myomas During Pregnancy

Increase

31%

(max 42.1%)

No Change

60.6%

Decrease

7.8%

(max 11.4%)

Data from Rosati, et al.

Infertility (27%)Infertility (27%)

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

Fertility & Sterility, 1981Fertility & Sterility, 1981

Outcome and Resource Use Outcome and Resource Use Associated with MyomectomyAssociated with Myomectomy

Conversion to more invasive procedure occurred in 5.4% Conversion to more invasive procedure occurred in 5.4% of the patients. Conversion to open myomectomies of the patients. Conversion to open myomectomies occurred in 13.3% of laparoscopies and 7.4% of occurred in 13.3% of laparoscopies and 7.4% of hysteroscopies. Hysterectomy conversion occurred in hysteroscopies. Hysterectomy conversion occurred in 3.7%, 2.8% and 1.5% of the open, laparoscopic and 3.7%, 2.8% and 1.5% of the open, laparoscopic and hysteroscopic procedures respectively. The rate of hysteroscopic procedures respectively. The rate of additional surgeries was 8.3% in 6 months. 10.6% in additional surgeries was 8.3% in 6 months. 10.6% in 1 year, and 16.5% in 2 years.1 year, and 16.5% in 2 years.

Subramanian S, et alSubramanian S, et al

Obstet Gynecol, 2001, Obstet Gynecol, 2001, 98(4):583-57698(4):583-576

Fertility Among Women with Uterine Fertility Among Women with Uterine LeiomyomaLeiomyoma

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

VE Eqwuatu, J Fertility, 1989VE Eqwuatu, J Fertility, 1989

Other Problems Associated with Uterine Other Problems Associated with Uterine LeiomyomaLeiomyoma

PolycythermiaPolycythermia AscitesAscites ImpingementImpingement Related complicationsRelated complications Sarcomatous changesSarcomatous changes

Management of Uterine Leiomyomata: What Do Management of Uterine Leiomyomata: What Do We Really Know?We Really Know?

Systematically review the literature on the surgical and Systematically review the literature on the surgical and non surgical management of uterine leiomyomata.non surgical management of uterine leiomyomata.

Despite the clinical and public health importance of Despite the clinical and public health importance of uterine leiomyomata, the available literature has uterine leiomyomata, the available literature has significant limitations that prevent patients, clinicians, significant limitations that prevent patients, clinicians, and policymakers from reaching conclusions about the and policymakers from reaching conclusions about the relative risks, benefits, and costs of currently used relative risks, benefits, and costs of currently used treatments for leiomyomata. Rectifying these treatments for leiomyomata. Rectifying these limitations should be a major research priority.limitations should be a major research priority.

Myers ER et al, Obstet Gynecol 2002Myers ER et al, Obstet Gynecol 2002

Surgical Treatment of Uterine LeiomyomasSurgical Treatment of Uterine Leiomyomas

HysterectomyHysterectomy

LaparotomyLaparotomy

LaparoscopicLaparoscopic MyomectomyMyomectomy

VaginalVaginal

HysteroscopicHysteroscopic

LaparoscopicLaparoscopic

LaparotomyLaparotomy MyolysisMyolysis

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

Kung R. et al, 2000Kung R. et al, 2000

The major indications for aggressive The major indications for aggressive management of uterine myomas are as follows:management of uterine myomas are as follows:

Abnormal uterine bleedingAbnormal uterine bleeding Rapid growthRapid growth Growth after menopauseGrowth after menopause InfertilityInfertility Recurrent pregnancy lossRecurrent pregnancy loss Pain or pressure symptomsPain or pressure symptoms Urinary tract symptoms or obstructionUrinary tract symptoms or obstruction Possibility of ovarian neoplasiaPossibility of ovarian neoplasia Iron deficiency anemia secondary to chronic Iron deficiency anemia secondary to chronic

blood lossblood loss

Management of Nonpregnant Patients with Uterine Management of Nonpregnant Patients with Uterine LeiomyomataLeiomyomata

Asymptomatic

Fertility Status

<10-12 weeks’ size and slow growth

>10-12 weeks’ size or rapid growth

Symptomatica (regardless of size or growth)

Desires pregnancy now

Trial for con- ception

Trial for con- ception

Myomectomy

Desires pregnancy now

Observation Myomectomy Myomectomy

Does not de- sire future pregnancy

Observation Hysterectomy Hysterectomy

aIncludes infertility, recurrent abortion, pain, bleeding, and impingment; all other causes ruled out, uncontrolled by conservative therapy.

Complication Rate with Abdominal Complication Rate with Abdominal MyomectomyMyomectomy

ComplicationComplicationFebrileFebrileHemorrhageHemorrhageEBL > 1,000 mLEBL > 1,000 mLUnintended Unintended hysterectomyhysterectomyPost opPost op

DVTDVTWound infectionWound infectionIleusIleus

Data from LaMorte, et alData from LaMorte, et al

PatientsPatients15 (12%)15 (12%)26 (20%)26 (20%)6 (5%)6 (5%)1 (1%)1 (1%)3 (2%)3 (2%)1 (1%)1 (1%)1 (1%)1 (1%)1 (1%)1 (1%)

Effect of Patient Age on Conception Following Effect of Patient Age on Conception Following MyomectomyMyomectomy

Author

<35 years

>35 years

Ingersoll

77%

17%

Malone

78%

24%

Mabaknia

76%

0%

Berkeley

62%

33%

Pregnancy Rate in Infertile Women Following Pregnancy Rate in Infertile Women Following MyomectomyMyomectomy

Number (Myomectomy)

Infertile Infertile Women Who Conceive

4541 1202 480 (40%)

Buttram and Reiter

Factors Influencing Pregnancy After Factors Influencing Pregnancy After MyomectomyMyomectomy

Patient Patient CharacterisCharacteris

ticticMean follow-up Mean follow-up ((++SD) (range) SD) (range) (mo)(mo)

Patients agePatients age

>40 y>40 y

<40 y<40 y

>35 y>35 y

<35 y<35 y

Patients Patients Who Who

Conceives Conceives (n=42)(n=42)28.328.3++7.47.4

(14-55)(14-55)

Patients Patients Who Did Who Did

Not Not Conceive Conceive (n=46)(n=46)26.426.4++7.57.5

(13-45)(13-45)

P P ValueValue

<001<001

<001<001

0 (0) 22 0 (0) 22 (100)(100)

42 (63.6) 24 42 (63.6) 24 (36.4) (36.4)

14 (25.9) 40 14 (25.9) 40 (74.1)(74.1)

28 (82.4) 6 28 (82.4) 6 (17.6)(17.6)

Factors Influencing Pregnancy Rates After Factors Influencing Pregnancy Rates After MyomectomyMyomectomy(Continued)(Continued)

Patient Patient CharacterisCharacteris

tictic

Patients Patients Who Who

Conceives Conceives (n=42)(n=42)

Patients Patients Who Did Who Did

Not Not Conceive Conceive (n=46)(n=46)

P P ValueValue

Duration of Duration of infert.infert.

>3 y>3 y

<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.Type of infert.

UnexplainedUnexplained

MultifactorialMultifactorial

PrimaryPrimary

SecondarySecondary

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

NSNS

Dessolle Fertil & Steril, 2001Dessolle Fertil & Steril, 2001

Effects of intramural subserosal and submucosal uterine Effects of intramural subserosal and submucosal uterine fibroids on the outcome of assisted reproductive technology. fibroids on the outcome of assisted reproductive technology. (Elder-Geva et al)(Elder-Geva et al)

The pregnancy rates per transfer were 34.1%, 16.4%, 10%, The pregnancy rates per transfer were 34.1%, 16.4%, 10%, and 30.1% in the patients with subserosal fibroids, intramural and 30.1% in the patients with subserosal fibroids, intramural fibroids, submucosal fibroids and no fibroids, respectively.fibroids, submucosal fibroids and no fibroids, respectively.

Pregnancy and implantation rates were significantly lower in Pregnancy and implantation rates were significantly lower in the groups of patients with intramural and submucosal the groups of patients with intramural and submucosal fibroids, even when there was no deformation of the uterine fibroids, even when there was no deformation of the uterine cavity. Pregnancy and implantation rates were not cavity. Pregnancy and implantation rates were not influenced by the presence of subserosal fibroids. Surgical or influenced by the presence of subserosal fibroids. Surgical or medical treatment should be considered in infertile patients medical treatment should be considered in infertile patients who have intramural and/or submucosal fibroids before who have intramural and/or submucosal fibroids before resorting to ART treatment.resorting to ART treatment.

Some indications for the use of GnRH agonists Some indications for the use of GnRH agonists in women with uterine leiomyomata are as in women with uterine leiomyomata are as followsfollows::

Preservation of fertility in women with large Preservation of fertility in women with large leiomyomas before attempting conception, or leiomyomas before attempting conception, or preoperative treatment before myomectomypreoperative treatment before myomectomy

Treatment of anemia to allow recovery of Treatment of anemia to allow recovery of normal hemoglobin levels before surgical normal hemoglobin levels before surgical management, minimizing the need for management, minimizing the need for transfusion or allowing autologous blood transfusion or allowing autologous blood donationdonation

Treatment of women approaching menopause Treatment of women approaching menopause in an effort to avoid surgeryin an effort to avoid surgery

Preoperative treatment of large leiomyomas Preoperative treatment of large leiomyomas to make vaginal hysterectomy, hysteroscopic to make vaginal hysterectomy, hysteroscopic resection or ablation, or laparoscopic resection or ablation, or laparoscopic destruction more feasibledestruction more feasible

Treatment of women with medical Treatment of women with medical contraindications to surgerycontraindications to surgery

Treatment of women with personal or Treatment of women with personal or medical indications for delaying surgerymedical indications for delaying surgery

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

Reiter RC et al, 1992Reiter RC et al, 1992

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

Uterine Artery EmbolizationUterine Artery Embolization

Following the procedure the fibroids shrunk by 39-Following the procedure the fibroids shrunk by 39-60%.60%.

ComplicationsComplications

EndometritisEndometritis

Tubo-ovarian abscessTubo-ovarian abscess

NecrobiosisNecrobiosis

Vaginal expulsion of submucous myomaVaginal expulsion of submucous myoma

Amenorrhea Amenorrhea

DeathDeath Recurrent Rate – 20% in 5 yearsRecurrent Rate – 20% in 5 years Operation – 10% in 1 year.Operation – 10% in 1 year.

Future Investigation in Treatment of Uterine Future Investigation in Treatment of Uterine LeiomyomataLeiomyomata

CryomyolysisCryomyolysis Laser-induced interstitial thermotherapy (LITT)Laser-induced interstitial thermotherapy (LITT)

(Magnetic-resonance-guided percutaneous laser (Magnetic-resonance-guided percutaneous laser ablation)ablation)

Mifepristone (RU-486)Mifepristone (RU-486) Pirfemidone (inhibits leiomyoma cell proliferation and Pirfemidone (inhibits leiomyoma cell proliferation and

collagen production)collagen production) Interferone-alpha (inhibitor of basic fibroblast growth Interferone-alpha (inhibitor of basic fibroblast growth

factor-stimulated cell proliferation)factor-stimulated cell proliferation) Chinese herbal medicines (Keishi-bukuryogan and Chinese herbal medicines (Keishi-bukuryogan and

Shakuyaku-kenzo-to)Shakuyaku-kenzo-to) Pharmacological agents that counteract angiogenic Pharmacological agents that counteract angiogenic

factorsfactors Gene therapyGene therapy Laparoscopic occlusion of uterine vesselsLaparoscopic occlusion of uterine vessels AsoprisnilAsoprisnil

Low-Dose Mifepristone for Uterine Low-Dose Mifepristone for Uterine LeiomyomataLeiomyomata(5 mg and 10 mg)(5 mg and 10 mg)

Mean uterine volume shrank by 48% in the 5 mg group Mean uterine volume shrank by 48% in the 5 mg group and 49% in the 10 mg group. Amenorrhea occurred in and 49% in the 10 mg group. Amenorrhea occurred in 60-65% of both groups. The incidence of hot flushes 60-65% of both groups. The incidence of hot flushes increased significantly over baseline in the 10 mg increased significantly over baseline in the 10 mg group but not in the 5 mg group. Simple hyperplasia group but not in the 5 mg group. Simple hyperplasia occurred in 28% of all groups; with no difference occurred in 28% of all groups; with no difference between groups.between groups.

Eisinger SH et al, Obstet Gynecol Eisinger SH et al, Obstet Gynecol 20032003