Transcript UTERINE LEIOMYOMATA - Saint Francis Care

UTERINE LEIOMYOMATA
Ozgul Muneyyirci-Delale
Classification of Leiomyomata
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Intracavitary
Submucosal
Intramural
Subserosal
Pedunculated
Fibroid
Tumors
ETIOLOGY
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.
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Estrogen
Progesterone
Growth hormone
Increase of 4-hydroxylation of estradiol
Increase aromatase enzyme
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
Dysregulation of a number of growth factors in the
myometous uterus (many of these factors regulate the
process of angiogenesis)
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Fibroblast growth factor
Vascular endothelial growth factor
Heparin-binding epidermal growth factor
Platelet-derived growth factor
Transforming growth factor ,
Parathyroid hormone-related protein
Prolactin
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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.
Uterine leiomyomas are monoclonal tumors
that demonstrate nonrandom cytogenetic mutation.
The most frequently reported cytogenetic
abnormalities in myomas are:
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+ (12:14) (q13-15, q23-24)
del (7) (q21)
+ (1;2) (p36, p24)
Nonhormonal Risk Factors for Uterine Leiomyoma
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Any history of hypertension (odd ratio (OR):1.7)
Hypertension requiring mediation (OR:2.1)
Hypertension at age less than 35 years (OR:2.7)
Hypertension of 5 or more years duration (OR:3.1
Pelvic inflammatory disease (3 or more episodes
OR:3.7)
Chlamydial infection (OR:3.2)
Use of intrauterine device with PID (OR:5.3)
Perineal talc use (daily vs. no use:PR=2.2)
Symptomatology
Twenty to fifty percent of uterine leiomyomas are
estimated to produce symptoms.
Menorrhagia (29 - 59%)
Pelvic pain and pressure (34%)
Pregnancy complications
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
Pregnancy Complications Due to Leiomyoma
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Abortion
Premature labor
Disturbances in labor
Postpartum hemorrhage
(questionable
Ectopic pregnancy
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Premature rupture of
membrane
Dystocia secondary low
segment myoma
Increase operative
deliveries
Inversion of uterus
Effects of the Pregnancy on the Myoma
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Degeneration of myomas
Infection (the process is usually sterile but may be
complicated by secondary infection from uterine
cavity)
Causes of Uterine Degeneration
A.
Vascular Insufficiency
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B.
Hypoestrogenic State
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C.
Rapid growth during pregnancy
Torsion of pedunculated myoma
Uterine artery embolization
Postpartum or postabortal
GnRH – agonist or antiagonist
Postmenopausal (perimenopausal)
Other Causes
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High dosage progestin therapy
Progesterone receptor modulator
Type of Degenerative Change
Persaud & Arjoon, Obstet &
Gynecol, 1970
70
60
50
40
30
20
10
0
Hya.
Myx.
Calc.
Muc. Cystic
Red
Fatty
Sarc.
445 Pregnancies Complicated by Leiomyoma
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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
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
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
Changes in Myomas During Pregnancy
Increase
31%
No Change
60.6%
Decrease
7.8%
(max 42.1%)
(max 11.4%)
Data from Rosati, et al.
Infertility (27%)
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
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
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
Other Problems Associated with Uterine Leiomyoma
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Polycythermia
Ascites
Impingement
Related complications
Sarcomatous changes
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
Surgical Treatment of Uterine Leiomyomas
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Hysterectomy
Laparotomy
Laparoscopic
Myomectomy
Vaginal
Hysteroscopic
Laparoscopic
Laparotomy
Myolysis
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
The major indications for aggressive management of
uterine myomas are as follows:
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Abnormal uterine bleeding
Rapid growth
Growth after menopause
Infertility
Recurrent pregnancy loss
Pain or pressure symptoms
Urinary tract symptoms or obstruction
Possibility of ovarian neoplasia
Iron deficiency anemia secondary to chronic blood
loss
Management of Nonpregnant Patients with Uterine Leiomyomata
Asymptomatic
Fertility
Status
Desires
pregnancy
now
Desires
pregnancy
now
Does not desire future
pregnancy
a
<10-12 weeks’ >10-12 weeks’ Symptomatica
size and
size or
(regardless
slow growth
rapid growth
of size
or growth)
Trial for conTrial for conMyomectomy
ception
ception
Observation
Myomectomy
Myomectomy
Observation
Hysterectomy
Hysterectomy
Includes infertility, recurrent abortion, pain, bleeding, and
impingment; all other causes ruled out, uncontrolled by
conservative therapy.
Complication Rate with Abdominal Myomectomy
Complication
Febrile
Hemorrhage
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%)
1 (1%)
1 (1%)
Effect of Patient Age on Conception Following
Myomectomy
Author
<35 years
>35 years
Ingersoll
77%
17%
Malone
78%
24%
Mabaknia
76%
0%
Berkeley
62%
33%
Pregnancy Rate in Infertile Women Following
Myomectomy
Number
(Myomectomy)
Infertile
Infertile
Women Who
Conceive
4541
1202
480 (40%)
Buttram and Reiter
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 Patients Who
Conceives
Did Not
(n=42)
Conceive
(n=46)
28.3+7.4
(14-55)
0 (0)
(100)
42 (63.6)
(36.4)
14 (25.9)
(74.1)
28 (82.4)
P Value
26.4+7.5
(13-45)
22
24
40
6 (17.6)
<001
<001
Factors Influencing Pregnancy Rates After
Myomectomy
(Continued)
Patient
Characteristi
c
Duration of
infert.
>3 y
<3 y
Type of infert.
Unexplained
Multifactorial
Primary
Secondary
Patients Who Patients Who
Conceives
Did Not
(n=42)
Conceive
(n=46)
6 (15)
36 (75)
34 (85)
12 (25)
32
10
14
28
12
34
15
32
(72.7)
(22.7)
(50)
(46.7)
Dessolle Fertil & Steril, 2001
(27.3)
(77.3)
(50)
(53.3)
P Value
<.001
<.001
NS
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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.
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.
Some indications for the use of GnRH agonists in
women with uterine leiomyomata are as follows:
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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 women approaching menopause in an
effort to avoid surgery
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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 personal or medical
indications for delaying surgery
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
Judicious patient observation and follow-up are indicated
primarily for uterine leiomyomas; intervention is
reserved for specific indications and symptoms.
Uterine Artery Embolization
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Following the procedure the fibroids shrunk by 39-60%.
Complications
Endometritis
Tubo-ovarian abscess
Necrobiosis
Vaginal expulsion of submucous myoma
Amenorrhea
Death
Recurrent Rate – 20% in 5 years
Operation – 10% in 1 year.
Future Investigation in Treatment of Uterine Leiomyomata
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Cryomyolysis
Laser-induced interstitial thermotherapy (LITT)
(Magnetic-resonance-guided percutaneous laser ablation)
Mifepristone (RU-486)
Pirfemidone (inhibits leiomyoma cell proliferation and collagen
production)
Interferone-alpha (inhibitor of basic fibroblast growth factorstimulated cell proliferation)
Chinese herbal medicines (Keishi-bukuryogan and Shakuyakukenzo-to)
Pharmacological agents that counteract angiogenic factors
Gene therapy
Laparoscopic occlusion of uterine vessels
Asoprisnil
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