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

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Impact of different medications used for the treatment of endometriosis on trabecular vertebral bone mass

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(M Y Dawood 1993 )

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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.