2. Endometriosis is defined as the presence of endometrial
tissue (glands and stroma) outside the uterus. This tissue is not
only morphologically similar to normal endometrium ,but is also
functional. It typically a disease of reproductive years. It is
estimated to occur in 7%-10% of reproductive age women
Introduction
3. Site of endometriosis PELVIC ENDOMETRIOSIS- Tubes &
ovaries Uterus-adenomyosis Peritoneum Uterovesical fold Posterior
cul de sac Pelvic side wall EXTRA PELVIC ENDOMETRIOSIS Gynecologic
sites-vulva, vagina, cervix. Non gynecologic sites- Bowel lungs and
pleural cavity skin (episiotomy or other surgical scars, lymph
glands, nerves, and brain
4.
5. Although signs and symptoms of endometriosis have been
described since the 1800s, its widespread occurrence was
acknowledged only during this century. Endometriosis is an
estrogen-dependent disease. Three theories have been proposed to
explain the histogenesis of endometriosis: 1. Ectopic
transplantation of endometrial tissue 2. Coelomic metaplasia 3. The
induction theory No single theory can account for the location of
endometriosis in all cases. Etiology
6. The transplantation theory, originally proposed by Sampson
in the mid-1920s, is based on the assumption that endometriosis is
caused by the seeding or implantation of endometrial cells by
transtubal regurgitation during menstruation Transplantation
Theory
7. The transformation (metaplasia) of coelomic epithelium into
endometrial tissue has been proposed as a mechanism for the origin
of endometriosis. This theory proposed by Meyer could explain
endometriosis in nearly all ectopic sites. This theory has not been
supported by either strong clinical or experimental data. Coelomic
Metaplasia Theory
8. The induction theory is, in principle, an extension of the
coelomic metaplasia theory. It proposes that an endogenous
(undefined) biochemical factor can induce undifferentiated
peritoneal cells to develop into endometrial tissue. This theory
has been supported by experiments in rabbits but has not been
substantiated in women and primates. Induction Theory
9. Halban suggest that endometriosis could result from
lymphatic & haematogenous dissemination of endometrial cells.
There is extensive communication of lymphatic between the uterus
,tubes,ovaries,pelvic & vaginal lymph nodes,kidneys &
umbilicus. This explain disease effecting remote sites like-
lungs,muscle,skin etc. Lymphatic & vascular metastases
theory
10. The risk or endometriosis is 7 times greater if a first-
degree relative has been affected by endometriosis . Multifactorial
inheritance has been postulated. Monozygotic twins are markedly
concordant for endometriosis. A worldwide collaborative project
(The Oxford Endometriosis Gene Study) has been organized to
identify a genetic basis for endometriosis Genetic Factors
11. Steroid Receptor Genetics An association of estrogen
receptor gene polymorphisms (two-allele and multiallele
polymorphism) with endometriosis has been reported .
12. Aneuploidy Epithelial cells of endometriotic cysts are
monoclonal , but normal endometrial glands are polyclonal. Recent
studies using comparative genomic hybridization or multicolor in
situ hybridization showed aneuploidy for chromosomes 11, 16, and 17
, increased.
13. Loss of Heterozygosity Microsatellite DNA assays reveal an
allelic imbalance (loss of heterozygosity) in p16 (Ink4), GALT,
p53, and APOA2 loci in patients with endometriosis.
14. Although retrograde menstruation appears to be a common
event in women, not all women who have retrograde menstruation
develop endometriosis. It has been hypothesized that the disease
may develop as a result of reduced immunologic clearance of viable
endometrial cells from the pelvic cavity Immunologic Factors
15. Decreased clearance of peritoneal fluid endometrial cells
due to- Reduced natural killer (NK) cell activity, or decreased
macrophage activity. Decreased cell-mediated cytotoxicity toward
autologous endometrial cells. There is no clinical evidence,
however, that the prevalence of endometriosis is increased in
immunosuppressed patients.
16. Substantial evidence suggests that endometriosis is
associated with a state of subclinical peritoneal inflammation,
marked by peritoneal fluid volume, peritoneal fluid white blood
cell concentration inflammatory cytokines, growth factors, and
angiogenesis-promoting substances Macrophages or other cells may
promote the growth of endometrial cells by secretion of growth and
angiogenic factors such as epidermal growth factor (EGF)
Inflamation
17. There is increasing evidence that local inflammation and
secretion of prostaglandins (PG) is related to differences in
endometrial aromatase activity between women with and without
endometriosis
18. Endometriosis should be suspected in women with
subfertility, dysmenorrhea, dyspareunia, or chronic pelvic pain.
However, endometriosis may be asymptomatic. Clinical
Presentation
19. In adult women, dysmenorrhea may be especially suggestive
of endometriosis if it begins after years of pain-free menses.
Dysmenorrhea often starts before the onset of menstrual bleeding
and continues throughout the menstrual period. In adolescents, the
pain may be present after menarche without an interval of pain-free
menses. The distribution of pain is variable but most often is
bilateral. Pain
20. A common observation is that some women with extensive
endometriosis have little or no pain, whereas others with only
minimal endometriosis complain of severe pain. Very severe pain,
however, is associated with deeply infiltrating endometriosis.
Local symptoms can arise from rectal, ureteral, and bladder
involvement. Lower back pain can occur. Dyspareunia may be
associated with deep infiltrating subperitoneal endometriosis
21. An association between endometriosis and subfertility is
generally accepted. Although numerous mechanisms have been
proposed- ovulatory dysfunction, luteal insufficiency, luteinized
unruptured follicle syndrome, recurrent abortion, altered immunity,
and intraperitoneal inflammation. The association between fertility
and minimal or mild endometriosis remains controversial.
Subfertility
22. Endometriosis has been associated with- Anovulation,
abnormal follicular development with impaired follicle growth,
reduced circulating E 2 levels during the preovulatory phase,
disturbed luteinizing hormone (LH) surge patterns, premenstrual
spotting, the luteinized unruptured follicle syndrome, and
galactorrhea and hyperprolactinemia. Endocrinologic
Abnormalities
23. Extrapelvic endometriosis, although often asymptomatic,
should be suspected when symptoms of pain or a palpable mass occur
outside the pelvis in a cyclic pattern. Intestinal Tract
(especially colon and rectum) is the most common site of
extrapelvic disease and may cause abdominal and back pain.
abdominal distention, cyclic rectal bleeding, constipation, and
obstruction. Extrapelvic Endometriosis
24. Ureteral -involvement can lead to obstruction and result in
cyclic pain, dysuria, and hematuria. Pulmonary endometriosis can
manifest as pneumothorax, hemothorax, or hemoptysis during menses.
Umbilical endometriosis should be suspected when a patient has a
palpable mass and cyclic pain in the umbilical area Scar
Endometriosis may present with cyclical pain &swelling.
25. Recommended that pelvic examination be performed at the
time of menses when tenderness is easier to detect. The vulva,
vagina, and cervix should be inspected for any signs of
endometriosis, although the occurrence of endometriosis in these
areas is rare (e.g., episiotomy scar). The uterus is often in fixed
retroversion, and the mobility of the ovaries and fallopian tubes
is reduced. CLINICAL EXAMINATIONS
26. Other possible signs of endometriosis include uterosacral
or cul-de-sac nodularity, cervical displacement due to uterosacral
scarring , painful swelling of the rectovaginal septum, and
unilateral ovarian (cystic) enlargement.
27. The classic chocolate cyst of the ovary is the result of a
blood-filled cavity within an endometrioma. Ultrasonography and
magnetic resonance imaging can be helpfulin diagnosing
endometriomas. However, neither can diagnose small peritoneal
implants or adhesions. Although transvaginal ultrasonography is
highly accurate in diagnosing ovarian endometriomas, hemorrhagic
cysts account for a significant false positive rate IMAGING
STUDY
28. Ultrasound pictures of endometriotic cyst which shows fine
stippling inside ovary (ground glass appearance)
29. Serum CA-125 levels are often elevated in patients with
endometriosis and correlate with both the degree of disease and the
response to treatment. Serum CA-125 determinations may be able to
differentiate endometriotic from nonendometriotic benign adnexal
cysts, especially when combined with transvaginal ultrasonography
The CA-125 Assay
30. During diagnostic laparoscopy, the pelvic and abdominal
cavity should be systematically investigated for the presence of
endometriosis. This examination should include a complete
inspection and palpation in a clockwise or counterclockwise fashion
with a blunt probe of the bowel, bladder, uterus, tubes, ovaries,
cul-de-sac, and broad ligament. Laparoscopic Findings- GOLD
STANDARD
31. Characteristic findings include typical (powder-burn,
gunshot) lesions on the serosal surfaces of the peritoneum. These
are black, dark brown, or bluish nodules or small cysts containing
old hemorrhage surrounded by a variable degree of fibrosis.
Scarring of perotoneum causes adhesions Endometriosis can appear as
subtle lesions ,including red implants (petechial, vesicular,
polypoid, hemorrhagic, red flamelike), serous or clear vesicles,
white plaques or scarring, yellow-brown discoloration of the
peritoneum, and subovarian adhesions. Laparoscopic view of
peritoneal lesion
32.
33.
34. 36 Upon closer view, these five small areas of
endometriosis have a reddish-brown to bluish appearance.
35. EXTENSIVE PELVIC ENDOMETRIOSIS
36. DENSE ADHESIONS
37. The diagnosis of ovarian endometriosis is facilitated by
careful inspection of all sides of both ovaries, which may be
difficult when adhesions are present in more advanced stages of
disease. With superficial ovarian endometriosis, lesions can be
both typical and subtle. Larger ovarian endometriotic cysts
(endometrioma) are usually located on the anterior surface of the
ovary and are associated with retraction, pigmentation, and
adhesions to the posterior peritoneum. These ovarian endometriotic
cysts often contain a thick, viscous dark brown fluid (chocolate
fluid) composed of hemosiderin derived from previous intraovarian
hemorrhage. Ovarian endomeriosis
38.
39. 41 This is a section through an enlarnged 12 cm ovary to
demonstrate a cystic cavity filled with old blood typical for
endometriosis with formation of an endometriotic, or "chocolate",
cyst.
40. Histologic confirmation is essential in the diagnosis of
endometriosis. Microscopically, endometriotic implants consist of
endometrial glands and stroma with or without hemosiderin-laden
macrophages Histologic Confirmation
41.
42. Stage I (Minimal) 1-5 Stage II (Mild) 6-15 Stage III
(Moderate) 16-40 Stage IV (Severe) >40 American society for
reproductive medicine revised classification of endometriosis
43.
44.
45. In most cases, preservation of reproductive function is
desirable. The least invasive and least expensive approach that is
effective should be used. GOAL- is to excise or coagulate all
visible endometriotic lesions and associated adhesions -and to
restore normal anatomy. Laparoscopy can be used in most women, and
this technique decreases cost, morbidity, and the possibility of
recurrence of adhesions postoperatively. Laparotomy should be
reserved for patients with advanced-stage disease who cannot
undergo a laparoscopic procedure and for those in whom fertility
conservation is not necessary. SURGICAL TREATMENT
46. Endometriosis lesions can be removed during laparoscopy by
surgical excision with scissors, bipolar coagulation, or laser
methods (CO 2 laser, potassium-titany-phosphate laser, or argon
laser). Peritoneal Endometriosis
47.
48. LAPAROSCOPIC EXCISION
49. Superficial ovarian lesions can be vaporized. Small ovarian
endometrioma (3 cm in diameter) ovarian endometrioma should be
aspirated, followed by incision and removal of the cyst wall from
the ovarian cortex. To prevent recurrence, the cyst wall of the
endometrioma must be removed, and normal ovarian tissue must be
preserved. OVARIAN ENDOMETRIOSIS
50. The removal of endometriosis-related adhesions
(adhesiolysis) should be performed carefully . Routine use of
pharmacologic or liquid agents to prevent postoperative adhesions
after fertility surgery cannot be recommended based on evidence
from randomized controlled trials. Adhesiolysis
51. Deep Rectovaginal and Rectosigmoidal Endometriosis The
surgical excision of deep rectovaginal and rectosigmoidal
endometriosis is difficult and can be associated with major
complications. Postoperative bowel perforations with peritonitis
have been reported in 2% to 3% of cases . LUNA(Laparoscopic
uterosacral nerve ablation) Extrapelvic endometrios-surgical
excision may be difficult. Scar endometriosis may need excision.
OTHERS
52. In patients with severe endometriosis, it has been
recommended that surgical treatment be preceded by a 3- month
course of medical treatment to reduce vascularization and nodular
size. However, a recent randomized study comparing 3 months of
preoperative treatment with GnRH and no treatment in 75 women with
moderate to severe endometriosis failed to show a significant
difference in ease of surgery between the two groups . Preoperative
Hormonal Treatment
53. Postoperative medical therapy may be required in patients
with incomplete surgical resection and persistent pain. Treatment
should last at least 3 to 6 months, and pain relief may be of short
duration, presumably because endometriosis recurs Postoperative
medical therapy
54. Although hormonal therapy of infertility associated with
endometriosis is not of proven value, medical therapy for
dysmenorrhea, dyspareunia, and pelvic pain associated with
endometriosis is very successful (although relief may be
short-term). Medical Treatment
55. Implants of endometriosis react to steroid hormones in a
manner somewhat, but not exactly,similar to normally stimulated
endometrium. Because estrogen is known to stimulate the growth of
endometriosis, hormonal therapy has been designed to suppress
estrogen synthesis, thereby inducing atrophy of ectopic endometrial
implants or interrupting the cycle of stimulation and bleeding.
Manipulation of the endogenous hormonal milieu is the basis for the
medical management of endometriosis. Basis For The Medical
Management
56. The treatment of endometriosis with continuous low-dose
monophasic combination contraceptives ( for 6 to 12months) was
originally used to induce pseudopregnancy caused by the resultant
amenorrhea and decidualization of endometrial tissue. In addition,
the subsequent amenorrhea induced by oral contraceptives could
potentially reduce the amount of retrograde menstruation (one of
the many risk factors proposed in the etiology of endometriosis).
Oral Contraceptives
57. Pathologically, oral contraceptive use is associated with
decidualization of endometrial tissue, necrobiosis, and possibly
absorption of the endometrial tissue . Unfortunately, there is no
convincing evidence that medical therapy with oral contraceptives
offers definitive therapy. Instead, the endometrial implants
survive the induced atrophy and, in most patients, reactivate after
termination of treatment. Any low-dose combination oral
contraceptive containing 30 to 35 mg of ethinyl estradiol used
continuously can be effective in the management of
endometriosis
58. Progestins may exert an anti endometriotic effect by
causing initial decidualization of endometrial tissue followed by
atrophy. They can be considered as the first choice for the
treatment of endometriosis because they are as effective as danazol
or GnRH analogues and have a lower cost and a lower incidence of
side effects than these agents. Progestins
59. Medroxyprogesterone acetate (150 mg) given intramuscularly
every 3 months is effective for the treatment of pain associated
with endometriosis. Megestrol acetate has been administered in a
dose of 40 mg/d with good results . Other treatment strategies have
included dydrogesterone (20 to 30 mg/d, either continuously or on
days 5 to 25) and lynestrenol (10 mg/d).
60. Local progesterone treatment with a levonorgestrel-
releasing intrauterine system for 12 months has resulted in a
significant reduction in dysmenorrhea, pelvic pain, and
dyspareunia.
61. Progesterone antagonists and progesterone receptor
modulators may suppress endometriosis based on their
antiproliferative effects on the endometrium, without the risk for
hypo-estrogenism or bone loss that occurs with GnRH treatment
Progesterone Antagonists
62. Mifepristone Mifepristone (RU-486) is a potent
antiprogestagen with a direct inhibitory effect on human
endometrial cells and, in high doses, an antiglucocorticoid action
. The recommended dose for endometriosis is 25 to 100 mg/d.
mifepristone, 50 to 100 mg/d, reduced pelvic pain and induced 55%
regression of the lesions without significant side effects .
63. Gestrinone Gestrinone is a 19-nortestosterone derivative
with androgenic, antiprogestagenic, antiestrogenic, and
antigonadotropic properties. It acts centrally and peripherally to
free testosterone and sex hormonebinding globulin levels
(androgenic effect), serum estradiol values to early follicular
phase levels(antiestrogenic effect), mean LH levels, and obliterate
the LH and follicle-stimulating hormone (FSH) surge
(antigonadotropic effect). Gestrinone causes cellular inactivation
and degeneration of endometriotic implants but not their
disappearance . The standard dose has been 2.5 mg twice a week 6-9
months.
64. Pharmacologic properties of danazol include suppression of
GnRHor gonadotropin secretion, direct inhibition of
steroidogenesis, increased metabolic clearance of estradiol and
progesterone . The multiple effects of danazol produce a high-
androgen, low-estrogen environment that does not support the growth
of endometriosis, and the amenorrhea that is produced prevents new
seeding of implants from the uterus into the peritoneal cavity
Danazol
65. start treatment with 400 mg daily (200 mg twice a day) and
increase the dose, if necessary, to achieve amenorrhea and relieve
symptoms . local danazol treatment using a vaginal danazol ring
(1,500 mg) has been shown to be effective for pain relief in deeply
infiltrative endometriosis without the classic danazol sideeffects,
or detectable serum danazol levels, while allowing ovulation and
conception
66. GnRH agonists bind to pituitary GnRH receptors and
stimulate LH and FSH synthesis and release. However, the agonists
have a much longer biologic half-life (3 to 8 hours) than
endogenous GnRH (3.5 minutes), resulting in the continuous exposure
of GnRH receptors to GnRH agonist activity. This causes a loss of
pituitary receptors and downregulation of GnRH activity, resulting
in low FSH and LH levels. Consequently, ovarian steroid production
is suppressed, providing a medically induced and reversible state
of pseudomenopause. A direct effect of GnRH agonists on ectopic
endometrium is also possible because expression of the GnRH
receptor gene has been documented in ectopic endometrium and
because direct inhibition of endometriosis cells has been
demonstrated in vitro. Gonadotropin-releasing Hormone Agonists
67. These agents include leuprolide(leuporide 3.75 mg im
monthly), buserelin, nafarelin, histrelin, goserelin, deslorelin,
and triptorelin. These drugs are inactive orally and must be
administered intramuscularly, subcutaneously, or by intranasal
absorption. The best therapeutic effect is often associated with an
estradiol dose of 20 to 40 pg/mL (75 to 150 pmol/L). These
so-called depot formulations are attractive because of the reduced
frequency of administration and because nasal administration can be
complicated by variations in absorption rates and problems with
patient compliance
68. Aromatase Inhibitors-anastrozole, 1 mg/d, Selective
Estrogen Receptor Modulators-Raloxifen OTHER
69. Modulation of Cytokines- 1recombinant human TNF-abinding
protein effectively inhibits the development of endometriosis and
endometriosis-related adhesions 2.immune-enhancing modulators
loxoribine and levamisole Nonhormonal Medical Therapy
71. Based on published studies, medroxyprogesterone acetate,
danazol, gestrinone,and GnRH agonists have similar efficacy in
resolution of the laparoscopically documented disease and in pain
alleviation . Disadvantages of medical therapy over surgical
therapy include the high cost of hormone preparations, the high
prevalence of side effects, and the higher recurrence rate of
endometriosis Efficacy of Medical Treatment
72. Conception is either impossible or contraindicated during
medical treatment of endometriosis. There is no evidence that
medical treatment of minimal to mild endometriosis leads to better
chances of pregnancy than expectant management
73. Recurrence Endometriosis tends to recur unless definitive
surgery is performed. The recurrence rate is about 5% to 20% per
year, reaching a cumulative rate of 40% after 5 years. The rate of
recurrence increases with the stage of disease, the duration of
follow-up, and the occurrence of previous surgery . The likelihood
of recurrence appears to be lower when endometriosis is located
only on the right side of the pelvis than when the left side is
involved
74. The treatment of endometriosis-related infertility is
dependent on the age of the woman, the duration of infertility, the
stage of endometriosis, the involvement of ovaries, tubes, or both
in the endometriosis process, previous therapy, associated pain
symptoms, and the priorities of the patient, taking into account
her attitude toward the disease, the cost of treatment, her
financial means, and the expected results. Assisted reproduction,
including controlled ovarian hyperstimulation with intrauterine
insemination, IVF, and GIFT, may be options for infertility
treatment in addition to surgical reconstruction and
expectantmanagement. IVF is the method of choice when distortion of
the tuboovarian anatomy contraindicates the use of superovulation
with intrauterine insemination or GIFT. Assisted Reproduction and
Endometriosis
75. Conclusion Endometriosis is a chronic, costly disease
requiring long-term, multidisciplinary treatment Profound personal
and economic impact underscores urgent need for continued research
and improvement in diagnostic and treatment modalities Timely
intervention and appropriate, multifactorial treatments may restore
quality of life, preserve or improve fertility, and lead to
long-term effective management in absence of permanent cure
