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ENDOMETRIOSIS
Ozgul Muneyyirci-Delale
Endometriosis
The presence of functional endometrial tissue
outside the uterine cavity.
Prevalence of Endometriosis
Affects 10% menstruating women Found in 25% - 50% of all infertile
women 71-87% of women with chronic pelvic
pain
Often begins in adolescence
Endometriosis in Adolescents
A 65% incidence of endometriosis was found among 43 laparoscopies in symptomatic teenagers.
DL Chatman & AB Ward, 1982
Endometriosis was encountered in 66 of 140 patients (47%) who underwent laparoscopy for chronic pelvic pain.
DP Goldstein et al., 1980
Theories on the Pathogenesis of Endometriosis
Retrograde menstruation/transplantation Coeleomic metaplasia Altered cellular immunity Metastasis Genetic basis Environmental basis Multifactorial mode of inheritance with interactions
between specific genes and the environment
Genetic Factors
Simpson and coworkers reported 6.9% of first-degree relatives of patients with endometriosis had the disease, compared with 1.0% in control group.
The proposed inheritance is characterized of polygenic-multifactorial mechanism.
Candidate Genes and Susceptibility to Endometriosis
Cytochrome P450 1A1 N-actyl transferase 2 Glutathione-S-transferase M1, T1 Galactose-1-phosphate uridyl transferase Oestrogen receptor Progesterone receptor Androgen receptor PTEN p53 Peroxisome proliferator-activated receptor y2 Pro-12-Ala
allele
Genes and Gene Products
Aromatase Endometrial bleeding factor Hepatocyle growth factor 17-B-hydroxysteroid dehydrogenase HOX A10 HOX A11 Leukaemia inhibitory factor Matrix metalloproteinases 3,7, and 11 Tissue inhibitors of metalloproteinases Progsterone-receptor isoforms Complement 3
Glutathione peroxidase Catalase Thrombospondin 1 Vascular endothelial growth factor Integrin
Immune System
The immune system is believed to be involved in the
pathogenesis of endometriosis and a lack of adequate
immune surveillance in the peritoneum is thought to be
a cause of the disorder.
The major immune alterations include:
Increased presence of circulating autoantibodies
Increased numbers and activation of peritoneal
macrophages
Decreased T-lymphocytes reactivity and natural
killing activity.
IMMUNOLOGIC ABNORMALITIES IN ENDOMETRIOSIS
SystemicIncreased immunoglobulin productionIncreased presence of helper (CD4) cells
Deficient lymphocyte-mediated cytotoxicity against
endometriumEmbryotoxic serumSerum that suppresses natural killer cell
activityDeficient cellular immunityDefective natural killer activityAbnormal autoimmune functionDecrease in suppressor cell activity
PeritonealEndometrial stromal cell proliferationIncreased cytotoxicity of peritoneal macrophagesDecreased sperm binding to zona pellucidaProliferation of lymphocytesIncreased sperm phagocytosis by
peritoneal macrophagesIncreased cytokine levelsIncreased sperm phagocytosis by
peritoneal macrophages
Environmental Factors
Rhesus monkeys exposed to whole-body proton irradiation have a higher frequency of endometriosis than controls (53% vs. 26%).
Rhesus monkeys exposed to 5-25 ppm dioxin per day for 4 years developed endometriosis that dose-dependent in staging.
Increase Risk Factors for Endometriosis
Heavy menstrual flow
Prolonged menstrual flow
Outflow obstruction
Early menarche without pregnancy
Decrease Risk Factors for Endometriosis
Exercise-induced menstrual disorders
Decrease in body-fat content
Tobacco smoking
Delay in Diagnosing Endometriosis
Times to diagnosis can be very long (mean 11.7 years in
the USA and 8.0 years in the UK) because of variability
in symptoms and signs and confusion with other
disorders.
Research Shows Risk forAutoimmune Diseases in Endo
Hypothyroidism was seven times more common.
Fibromyalgia was twice as common.
The autoimmune inflammatory diseases, systemic lupus erythematosus, Sjogren’s syndrome, rheumatoid arthritis, and multiple sclerosis occurred more frequently.
Allergies and allergic conditions such as asthma and eczema were higher: 61 percent of the endo sufferers had allergies, compared with 18 percent of the U.S. general population, and 12 percent had asthma, compared with 5 percent. If a woman had endo plus an endocrine disease (such as hypothyroidism), the figure for allergies rose to 72 percent, and to 88 percent is she had endo plus fibromyalgia or chronic fatigue syndrome.
Two-thirds reported they had family members with diagnosed or suspected endo, confirming research that suggested there is a familial tendency.
0
5
10
15
20
25
30
Non-Hodg.Lymph
OvarianCa.
BreastCancer
Melanoma
% of Women with Endo WhoHave Cancer
% of Women with Endo WhoHave Blood Relatives withCancer*
% of General Population(U.S. & Canada) with Cancer
Frequency of Commoner Symptoms ofEndometriosis
Symptom Likely Frequency (%)Dysmenorrhea 60-80Pelvic pain 30-50Infertility 30-40Dyspareunia 25-40Menstrual irregularities 10-20Cyclical dysuria/hematuria 1-2Dyschesia (cyclic) 1-2Rectal Bleeding (cyclic) <1
0 10 20 30 40 50
Registry II (N=4,000)registry I (N=3,020)
Irregular bleeding
Low resisatanceto infection
Infertility
Premenstrual Spotting
Low-Grade Fever
Pain related to urination
Cardidiasis
Midcycle Bleeding
Mitral valve prolapse
Endo Symtoms Reported
44
3943
4441
36
2932
31
31
26
15
%
0 20 40 60 80 100
Registry II (N=4,000)registry I (N=3,020)
Dysmenorrhea
Fatigue, Exhaustion
Intestinal upset
Abdominal Bloating
Heavy or Irregular Bleeding
Dyspareunia
Nausea, Stomach Upset
Dizziness, Headaches
Endo Symtoms Reported
96
87
95
82
8579
65
84
65
6064
58
5963
64
%
Implants and Adhesions in 182 Patients with Endometriosis According to Anatomical Location
Location Implants Adhesions # of patients (%)
Anterior cul-de-sac 63 (34.6) 4 (2.2)Posterior cul-de-sac 62 (34.0) 20 (11.0)Right ovary 57 (31.3) 26 (14.3)Left ovary 81 (44.0) 45 (24.7)Right anterior broad ligament 2 (1.1) 2 (1.1)Left anterior broad ligament 0 3 (1.6)Right round ligament 1 (0.5) 2 (1.1)Left round ligament 1 (0.5) 2 (1.1)Right fallopian tube 8 (1.6) 20 (11.0)
Left fallopian tube 8 (4.4) 28 (15.4)R. posterior broad ligament 39 (21.4) 30 (16.5)Left posterior broad ligament 46 (25.3) 50 (27.5)Right uterosacral ligament 28 (15.4) 5 (2.7)Left uterosacral ligament 38 (20.9) 8 (4.4)Uterus 21 (11.5) 6 (3.3)Sigmoid 7 (3.8) 22 (12.1)Right ureter 3 (1.6) 0 Left ureter 2 (1.1) 3 (1.6)Anterior bladder flap 1 (0.5) 1 (0.5)
Small bowel 1 4 (2.2)
Anterior abdominal wall 0 3 (1.6)
Omentum 0 4 (2.2)
Detection
History Clinical exam Operative visualization Operative palpation
Clinical Manifestations
Nodularity of the utero-sacral ligaments and/or pelvic floor
Adnexal mass
Lateral displacement of cervix and uterus
APPEARANCE AND AGE
Appearance 20-25 31-35 41-45
Red lesions 27% 19% 0%“Typical” lesions 57% 61%
75%>6mm infiltration 15% 21%
42%
Konincky PR, et al.: Fertil Steril 55:763, 1991
APPEARANCE AND AGE
Appearance Age Range
Any clear papuls 17 - 31Any red lesions 16 - 43Any white lesions 17 - 43Any black lesions 17 - 52
Redwine DB: Fertil Steril 106, 1987
Management
Decision-making factors Reproductive status -
a. Desire of future pregnancyb. Childbearing complete or undesired
Severity of symptoms Extension of lesions Failure of conservative treatment Additional factors (age, economic
aspects)
Treatment of Endometriosis
Surgical extirpation or excision
Medical therapy
Combination of both
Conservative Surgery for Pelvic Pain Associated with Endometriosis
Author Therapy Symptom Outcome Relief
Puolakka CSEL 80% 17% CSEL + PN 90%
CSEL+PN 83% Req. reop.Candiani Repeat CSEL 75% 9% req. reopPolan CSEL + PN 80% 25% req.
reopLee CSEL = PN 61% 9% req. reop
Operative Laparoscopy in the Treatment of Endometriosis-Associated Pain
Author Therapy Symptom Outcome Relief
Hasson Unipolar 63% 14% (30melectrocoag.
Sulewski Unipolar 67% 14% (16.5m)electrocoag.
Daniell KTP/532 laser 100% No (30m)
Keye Argon laser ab. 92% 33% (9m)
Davis CO2 laser vap. 94% Rec. (?)
Operative Laparoscopy in the Treatment of Endometriosis-Associated Pain
Author Therapy Symptom Outcome Relief
Shirk Nd:YAG laser 45% Rec. (?)abl. 79% Rec. (?)
96% Rec. (?)
Sutton & Hill CO2 or Nd:YAG 79% 12% (12m)Perez CO2 or Nd:YAG 96% 16%
(req.reop)laser abl. & pre-sacral neur.
Author Therapy Symptom Outcome Relief
Nezhat & Co2 laser vap. 94% Rec. (?)
Nezhat & presac. neure. 92%Redwine Laparoscopic Not spec. 23% reop.
exc. 19% (rec.?m)
Medical Treatment
Pseudopregnancy (estrogen and progestin)
ProgestinMedroxyprogesterone acetateLynestrenolNorethynodielMegestrol acetateCyroterone acetateDydrogesteroneDienogestNorethindrone acetate
Danazol GnRH agonist
NafarelinGoserelinLeuprolideBuserelinHistrelinDeslorelin
Tryptorelin Gestrinone Antiprogesterones
Bon
e c
ha
nge
(%
)
-20
-15
-10
-5
0
5
10
Ora
l con
tra
ce
ptive
Pro
ge
stin
s
Dan
azol
Intr
an
asa
l
LH
RH
Sub
cu
tan
eou
s
LH
RH
D
ep
ot
gose
relin
D
ep
ot
leu
pro
lide
Impact of different medications used for the treatment of endometriosis on trabecular vertebral bone mass
1 1.64
-7.4 -7.7 -8.2 -13
(M Y Dawood 1993 )
0 4 8 12 16 20 24
Va
so
mo
tor
Sco
re
0200400600800
10001200
Week0 4 8 12 16 20 24
Va
gin
al S
co
re
0
10
20
30
40
50
60
Vasomotor Symptoms
Vaginal Symptoms
Week
GnRHa only
GnRHa + NEt
GnRHa only
GnRHa + NEt
P<0.01 vs Week 0
P<0.01 vs Week 0
Impact of a progestin (norethindrone)-only 'add-back regimen
(Surrey and Judd 1992)
(Surrey and Judd 1992)
Effect of Norethindrone Acetate in theTreatment of Symptomatic Endometriosis
Dysmenorrhea was relieved in 48/52 (92.5%)
Noncyclic pelvic pain relief 25/28 (89.2)
Overall pain relief 49/52 (94.2%)
Long-Term Treatment of SymptomaticEndometriosis with Norethindrone Acetate
Long-term Norethindrone acetate (LTNA)Other medications (OM)
LTNA patients were treated with Norethindrone acetate for at least 2 years (maximal treatment 15 years)
OM patients matched with LTNA patients with year of diagnosis and duration of follow-up
The duration of treatment for the LTNA group
was 4.39+6.09 years. The duration of treatment for the OM group varied based on treatment type.
Patients on Depot and Danazol remained on
medication for a maximal of 6 months.
Summary of Demographic Findings Before Treatment
Parameter
LTNA N+40 (%)
OM N=42 (%)
P value
Demographics Duration of Follow-up (years) Age at diagnosis
5.7+3 28.8+5.2
5.7+3 33.1+5.5
0.12 0.000
Before Treatment Oligomenorrhea Abnormal bleeding Pelvic pain Hirsutism Acne
0 10 (25.0%) 25 (62.5%) 15 (37.5%) 12 (30.0%)
4 (9.5%) 14 (33.3%) 11 (26.2%) 21 (50.0%) 23 (45.2%)
0.12 0.4 0.002 0.18 1.116
Stage of Endometriosis at Diagnosis
Stage not available Minimal Mild Moderate Severe
3 (7.5%) 0 3 (7.5%) 2 (5.0%) 32 (80%)
12 (28.6%) 5 (11.9%) 9 (21.4%) 2 (4.8%) 14 (33.3%)
0.001
Dysmenorrhea Before Treatment
Mild Moderate Severe
5 (12,5% 9 (22.5%) 26 (65.0%)
10 (25.5%) 9 (22.5%) 21 (52.5%)
0.33
Summary of Treatment Effects
Signs and Symptoms LTNA N=40 (%)
OM N=42 (%)
P value
Amenorrhea Pelvic pain Dysmenorrhea Hirsutism Acne Depression Melasma
39 (97.5%) 1 (2.5%) 1 (2.5%) 6 (15.0%) 9 (22.5%) 1 (2.5%) 3 (7.5%)
5 (11.9%) 35 (83.3%) 37 (88.1%) 18 (42.9%) 17 (40.5%) 0 4 (9.5%)
0.000 0/000 0.000 0.006 0.08 0.49 0.53
Summary of Treatment Effects(Continued)
Signs and Symptoms
LTNA N=40 (%)
OM N=42 (%)
P value
Weight Change Increase Decrease No Change
32 (80%) 2 (5.0%) 6 (15.0%)
33 (78.6%) 4 (9.5%) 5 (11.9%)
0.696
Bleeding Severity None Mild Moderate to Severe
8 (20.0%) 18 (45.0%) 14 (35.0%)
32 (76.2%) 7 (16.7) 3 (7.1%)
0.000
Only 2 (5.4% patients) had severe bleeding in the LTNA group
Weight Change by Treatment Group
Weight Kg+SD LTNA N=40
OM N=42
Before treatment At end of follow-up
66.5+14.7 73.5+11.0
66.7+12.9 73.1+11.0
Repeated measures ANCOVA (controlling for height): Treatment main effect p=0.077 Time main effect p=0.192 Treatment and time interaction p=0.278
Conclusion
LTNA seems to be a cost-effective alternative, with relatively mild side effects, for continuous treatment of symptomatic endometriosis.