endometriosis

dra. butaran

ENDOMETRIOSIS o Classic symptom of endometriosis:
• Benign but a progressive and aggressive disease pelvic pain
• Presence and growth of the glands and stroma
of the lining of the uterus in an aberrant or PHYSIOLOGY
heterotopic location • Aberrant endometrial tissue grows under the
• Benign disease but has characteristics of a cyclic influence of ovarian hormones and is
malignancy particularly estrogen dependent
o Locally infiltrative o Therefore, the disease is most
o Invasive commonly found during the
o Widely disseminating reproductive years
• However, 5% of women with endometriosis are
ADENOMYOSIS diagnosed following menopause
• Growth of endometrial glands and stroma into • Postmenopausal endometriosis is usually
the uterine myometrium to a depth of at least stimulated by exogenous estrogen
2.5 mm from the basalis layer of the • Endometriosis in teenagers should be
endometrium investigated for obstructive reproductive tract
• Sometimes termed internal endometriosis abnormalities that increase the amount of
o Semantic misnomer because most likely retrograde menstruation
they are separate diseases • Although previously thought to be rare in
adolescents, in teens with pelvic pain,
INCIDENCE OF ENDOMETRIOSIS endometriosis has been found in approximately
• Overall prevalence of endometriosis in half the cases
reproductive aged women: 11%
• Endometriosis present in laparotomies ETIOLOGY
performed on reproductive-age females: 5-15% • Several theories to explain pathogenesis of
• Prevalence of active endometriosis in women endometriosis
with chronic pelvic pain: 33% • One popular theory:
• Women with infertility: 30-45% o Complex interplay between a dose-
response curve of the amount of
CAUSE OF ENDOMETRIOSIS retrograde menstruation and an
• Uncertain individual woman’s immunologic
• Involves many mechanisms: response
o Retrograde menstruation
o Vascular dissemination RETROGRADE MENSTRUATION
o Metaplasia • Most popular theory
o Genetic predisposition • Pelvic endometriosis was secondary to
o Immunologic changes implantation of endometrial cells shed during
o Hormonal influences menstruation
• Environmental factors may play a role o Shedding of endometrial-based adult
o Exposure to dioxin and other endocrine stem cells and mesenchymal cells may
disruptors explain this phenomenon
• These cells attach to the pelvic peritoneum and
TYPICAL PATIENT WITH ENDOMETRIOSIS under hormonal influence grow as homologous
• Mid-30s grafts
• Nulliparous and Involuntary infertile • Endometriosis is discovered most frequently in
• Has symptoms of secondary dysmenorrhea and areas immediately adjacent to the tubal ostia
pelvic pain or in the dependent areas of the pelvis
o S/Sx may be extremely variable • Endometriosis is frequently found in women
with outflow obstruction of the genital tract
 • Attachment of the shed endometrial cells o Peritoneal pockets à found in posterior
involves the expression of adhesion molecules pelvis, posterior aspects of the broad
and their receptors ligament, and the cul-de-sac
o Extremely rapid process • Metaplasia of the coelomic epithelium that
invaginates into the ovarian cortex à
pathogenesis for the development of ovarian
endometriosis

LYMPHATIC AND VASCULAR METASTASIS
• Theory of endometrium being transplanted via
lymphatic channels and the vascular system
helps to explain rare and remote sites of
endometriosis, such as the spinal column and
nose
• Endometriosis has been observed in the pelvic
lymph nodes of approximately 30% of women
with the disease
• Hematogenous dissemination of endometrium
is the best theory to explain endometriosis of
the forearm and thigh, as well as multiple
lesions in the lung

IATROGENIC DISSEMINATION
• Endometriosis of the anterior abdominal wall is
sometimes discovered in women after a
cesarean delivery
METAPLASIA • Endometrial glands and stroma are implanted
• Endometriosis arises from metaplasia of the during the procedure
coelomic epithelium or proliferation of • The aberrant tissue is found subcutaneously at
embryonic rests the abdominal incision
• Müllerian ducts and nearby mesenchymal tissue • Rarely, iatrogenic endometriosis may be
à Majority of the female reproductive tract discovered in an episiotomy scar
• Müllerian duct
o Derived from coelomic epithelium
during fetal development
• Metaplasia hypothesis postulates that the
coelomic epithelium retains the ability for
multipotential development
• Endometriosis has been discovered in
prepubertal girls, women with congenital
absence of the uterus, and rarely in men
• Occurs after an “induction phenomenon” has
stimulated the multipotential cell
• Induction substance à combination of
menstrual debris and the influence of estrogen
and progesterone
• It has been hypothesized that the histogenesis
of endometriosis in peritoneal pockets of the
posterior pelvis results from a congenital
anomaly involving rudimentary duplication of
the Müllerian system


IMMUNOLOGIC CHANGES • Autoimmunity
• Changes in the immune system, especially o May well exist in women with
altered function of immune-related cells, are endometriosis
directly related to the pathogenesis of o HLA abnormalities à still inconsistent
endometriosis o Increased B and T cells, and serum
• Primary immunologic change involves an immunoglobulin (IgG, IgA, and IgM)
alteration in the function of the peritoneal autoantibodies in endometriosis
macrophages so prevalent in the peritoneal
fluid of patients with endometriosis
• Women who develop endometriosis have more
peritoneal macrophages that are larger
o Hyperactive cells secrete multiple
growth factors and cytokines that
enhance the development of
endometriosis
o Attraction of leukocytes to specific
areas is controlled by chemokines,
which are chemotactic cytokines
• Changes in the expression of integrins also may
be an important local factor
o Destroying of normally extruded
endometrial cells in endometriosis may

be deficient
o Natural killer (NK) cells have decreased
cytotoxicity against endometrial and
hematopoietic cells in women with
endometriosis
• Endo 1
o Chemoattractant protein-enhanced
local production of interleukin-6 (IL-6)
self-perpetuates lesion/cytokine
interactions
• Angiogenic factors
o Further compounding the proliferative
activity of endometriosis lesions
o Expression of basic fibroblast factor, IL-
6, IL-8, plateletderived growth factor
(PDGF), and vascular endothelial growth
factor (VEGF) are all increased
• Steroid interactions
o Enhance the progression of disease
o Estrogen production is enhanced locally GENETIC PREDISPOSITION
o There is evidence for: • Familial predisposition to endometriosis with
§ Upregulation of aromatase grouping of cases of endometriosis in mothers
activity and their daughters
§ Increased COX-2 expression • Incidence of endometriosis in first-degree
§ Dysregulation of 17β- relatives, women with severe endometriosis:
dehydrogenase activity 7%
§ Deficiency in 17β- • Women who have a family history of
dehydrogenase II activity endometriosis are likely to develop the disease
§ Enhancement of type II activity earlier in life and to have more advanced
favoring local estradiol disease than women whose first-degree
production relatives are free of the disease
 • Deletion of genes
• Increased heterogenicity of chromosome 17
and aneuploidy
• Loci on 7p and 10q à increase susceptibility for
endometriosis
• Matrix Metalloproteinases (MMPs) and
integrins
o Important implications for endometrial
lesion attachment and for implantation

defects
• Genetic predisposition or exposure to • Gross pathologic changes:
environmental factors à may program fetal o Wide variability in color, shape, size and
progenitor cells in an epigenetic way to associated inflammatory and fibrotic
overexpress SP1 and estrogen receptor B, which changes
increase the risk of having endometriosis
• Visual manifestations à protean and have

many appearances
• Closely inspect the pelvic peritoneum to identify
abnormal areas and small, nonhemorrhagic
lesions
• Biopsy confirmation of endometriosis because
of increasing awareness of subtle lesions
• GROSS APPEARANCE OF IMPLANT
o Depends on site, activity, relationship to
the day of the menstrual cycle, and
chronicity of the area involved
• COLOR OF THE LESION
o Varies widely
o May be red, brown, black, white,
yellow, pink, clear, or a red vesicle
o Predominant color depends on the
blood supply and the amount of
hemorrhage and fibrosis
PATHOLOGY o Appears related to the size of the
• Majority of endometrial implants are located in lesion, the degree of edema, and the
the dependent portions of the female pelvis amount of inspissated material
• Ovaries à most common site • Other peritoneal lesions that grossly appear
o In most women, involvement is bilateral similar to endometriosis, but on histologic
• Other common sites: examinations are not, include:
o Pelvic peritoneum over the uterus o Necrotic areas of an ectopic pregnancy
o Anterior and posterior cul-de-sac o Fibrotic reactions to suture
o Uterosacral, round and broad ligaments o Hemangiomas
• Other possible sites: o Adrenal rest
o Cervix o Walthard rest
o Vagina o Breast cancer
o Vulva o Ovarian cancer
• Deep lesions, penetrations of greater than 5 o Epithelial inclusions
mm, represent a more progressive form of the o Residual carbon from laser surgery
disease o Peritoneal inflammation
• 10-15% à involves the rectosigmoid o Psammoma bodies
o Peritoneal reactions to oil-based
hysterosalpingogram dye
o Splenosis
 • Red, blood-filled lesions à most active phase § Presents as secondary
of the disease dysmenorrhea or dyspareunia
• “Powder burn” areas or “Chocolate cysts” (or both)
o When areas of endometriosis become o Infertility
larger and assume light or dark brown • Paradox: the extent of pelvic pain is often
color inversely related to the amount of
• Older lesions à White, have more intense endometriosis in the female pelvis
scarring, and are usually puckered or retracted • Women with large, fixed adnexal masses
from the surrounding tissue sometimes have minor symptoms, whereas
• White or mixed colored lesion à provide other patients with only a few small foci with
histologic confirmation of endometriosis deep infiltration may experience moderate to
severe chronic pain
• Cyclic pelvic pain is related to the sequential
swelling and the extravasation of blood and
menstrual debris into the surrounding tissue
o Chemical mediators: Prostaglandins &
cytokines
• Infiltrative endometriosis
o Involves extensive areas of the
retroperitoneal space
o Associated with moderate to severe
pelvic pain
• SECONDARY DYSMENORRHEA
o Common component of pain that varies
from a dull ache to severe pelvic pain
o May be unilateral or bilateral
o May radiate to lower back, legs, and
groin
o Patient often complain of pelvic
heaviness or a perception of their
internal organs being swollen
o Pain may last for many days
• DYSPAREUNIA
o Pain deep in the pelvis
o Cause:
§ Immobility of the pelvic organs
during coital activity

§ Direct pressure on areas of
• THREE CARDINAL HISTOLOGIC FEATURES OF
endometriosis in the
ENDOMETRIOSIS
uterosacral ligaments or the
o Ectopic endometrial glands
cul-de-sac
o Ectopic endometrial stroma
o Sometimes described as areas of point
o Hemorrhage into the adjacent tissue
tenderness

o Acute pain, experienced during deep
CLINICAL DIAGNOSIS
penetrations, may continue for several
SYMPTOMS
hours following intercourse
• 1 in 3 women à asymptomatic
• ABNORMAL BLEEDING
• Conversely, 1 in 3 women à primary symptom
o 15-20%
is chronic pelvic pain
o Most frequent complaints:
• Extremely unpredictable course premenstrual spotting and menorrhagia
• Classic symptoms: o Not associated with anovulation
o Cyclic pelvic pain o May be related to abnormalities of the
endometrium
 • Patients with endometriosis frequently have with its associated scarring and adhesion
ovulatory dysfunction formation
• 15% à coincidental anovulation or luteal • Infertility à Biopsy implants confirms the
dysfunction diagnosis of endometriosis
• SYMPTOMS INFLUENCING THE GIT & GUT
o Less common IMAGING
o Includes: • Useful adjunct to the clinical presentation & PE,
§ Cyclic abdominal pain especially with deep infiltratinf endometriosis
§ Intermittent constipation (DIE)
§ Diarrhea • ULTRASOUND
§ Dyschezia o Helpful in differentiating solid from
§ Urinary frequency cystic lesions
§ Dysuria o May help distinguish an endometrioma
§ Hematuria from other adnexal abnormalities
§ Bowel obstruction o Increased Doppler flow à
§ Hydronephrosis endometriosis
§ Catamenial hemothorax o TVUS à fair sensitivity (49-91%) and
• Bloody pleural fluid high specificity (93-100%) to detect DIE
occurring during § Greatest sensitivity and
menses specificity in detection of
• Rare rectosigmoid lesions
§ Massive ascites • MRI
• Rare o Provides the best diagnostic tool for
• Important because the endometriosis
disease process o Not always practical
masquerades as ovarian o Sensitivity and Specificity: 91-95%
carcinoma o Characteristic hyperintensity on T1-
weighted images and a hypointensity
PHYSICAL EXAM on T2-weighted images
• Classical pelvic finding: fixed retroverted
uterus, with scarring and tenderness posterior DIAGNOSTIC LAPAROSCOPY
to the uterus • Important to describe systematically the extent
• Advanced cases have extensive scarring and of the pathology
narrowing of the posterior vaginal fornix • Although a benign disease, endometriosis
• Ovaries may be enlarged and tender and are exhibits characteristics of both malignancy and
often fixed to the broad ligament or lateral sterile inflammation
pelvic sidewall • Differential diagnosis include:
• Adnexal enlargement is rarely symmetric o Chronic pelvic inflammatory disease
• Speculum examination: small areas of o Ovarian malignancy
endometriosis on the cervix or upper vagina o Degeneration of myomas
• Digital exam on vagina and cervix: Lateral o Hemorrhage or torsion of ovarian cysts
displacement or deviation of the cervix is o Adenomyosis
visualized or palpated o Primary dysmenorrhea
o 15% in moderate to severe o Functional bowel disease
endometriosis • Occasionally, a large endometrioma of the
• Carrying out a pelvic examination during the ovary may rupture into the peritoneal cavity à
first or second day of menstrual flow may aid acute surgical abdomen à brings into the Ddx:
in the diagnosis as it is the time of maximum o Ectopic pregnancy
swelling and tenderness in the areas of o Appendicitis
endometriosis o Diverticulitis
• DIAGNOSTIC CONFIRMATION: direct o Bleeding corpus luteum cyst
laparoscopic visualization of endometriosis

MARKERS • If other gynecologic conditions such as chronic
• Serial pelvic examinations are a poor indicator pelvic inflammatory disease or neoplasia have
of progression of disease been ruled out, empiric medical therapy for 3
• CA-125 months is a reasonable option
o Marker for endometriosis
o Elevated in most patients
o Increases incrementally in advanced
stages
o Low specificity because it is also
increased in:
§ Leiomyomas
§ Acute PID
§ First trimester of pregnancy
o Low sensitivity for the diagnosis of early
or minimal endometriosis
• GLYCODELIN
o Placental protein 14
o Elevated in endometriosis
o Produced in endometriotic lesions
o Has not proved to be useful clinically
• Il-1, chemoattractant protein-1 & interferon
gamma
o Most predictive markers
o Il-1 à most useful
• Proteomic analyses
• Endometriosis may be associated with ovarian
cancer
o Risk of developing ovarian cancer may
increase fourfold in women with
endometriosis
o Loss of heterozygosity and mutations in
suppressor genes (p53)
• Endometriosis is dependent on ovarian
hormones to stimulate growth

TREATMENT
• Two primary short-term goals in treating
endometriosis are: • Treatment of endometriosis can be medical,
o Relief of pain surgical, or a combination of both
o Promotion of fertility • Surgical therapy is divided into conservative and
• Primary long-term goal in the management of definitive operations
endometriosis is attempting to prevent • Conservative surgery
progression or recurrence of the disease o Involves the resection or destruction of
process endometrial implants, lysis of
• Treatment plan must be individualized adhesions, and attempts to restore
• Choice of therapy, for women whose primary normal pelvic anatomy
symptom is pelvic pain, depends on multiple • Definitive surgery
variables, including: o Involves the removal of both ovaries,
o Patient’s age the uterus, and all visible ectopic foci of
o Her future reproductive plans endometriosis
o Location and extent of her disease o Analogous to cytoreductive surgery in
o Severity of her symptoms ovarian carcinoma
o Associated pelvic pathology
MEDICAL THERAPY • Usual dose of leuprolide acetate is 3.75 mg
• Aimed at suppression of lesions and associated intramuscularly once per month or an 11.25-mg
symptoms, particularly pain depot injection every 3 months
o Best achieved by menstrual • Nafarelin acetate nasal spray is given in a dose
suppression, without inducing of one spray (200 μ g) in one nostril in the
hypoestrogenism morning and one spray (200 μ g) in the other
• Choice of medical therapy should be nostril in the evening up to a maximum of 800 μ
individualized g daily
• Recurrence rate following medical therapy is 5% • Goserelin acetate is given in a dosage of 3.6 mg
to 15% in the first year and increases to 40% to every 28 days in a biodegradable subcutaneous
50% in 5 years implant
• Usually suppresses symptomatology and • Chronic use of GnRH agonists à medical
prevents progression of endometriosis, but it oophorectomy
does not provide a long-lasting cure of the • Side effects associated with GnRH agonist
disease therapy are primarily those associated with
• FDA approved only danazol and gonadotropin- decreased estrogen, similar to menopause
releasing hormone (GnRH) agonists • The three most common symptoms:
o Hot flushes
DANAZOL o Vaginal dryness
• Rarely prescribed o Insomnia
• Prescribed for women with benign cystic • The clinical response to agonist therapy
mastitis, menorrhagia, and hereditary depends on when the therapy is initiated in
angioneurotic edema regard to the menstrual cycle
• Attenuated androgen that is active when given • If agonist therapy is begun during the follicular
orally phase, an agonist phase results in an initial
• Synthetic steroid that is the isoxazole derivative rapid rise in follicle-stimulating hormone (FSH)
of ethisterone (17-α -ethinyltestosterone) and E2 for approximately 3 weeks
• Produces a hypoestrogenic and o FSH levels fall to basal levels by the
hyperandrogenic effect on steroid-sensitive end third to fourth week of therapy
organs o Amenorrhea is induced within 6 to 8
• Mildly androgenic and anabolic leading to its weeks
side-effect profile • Beginning agonist therapy during the luteal
• Induces atrophic changes in the endometrium phase or if artificially manipulated by the
of the uterus and similar changes in concurrent administration of oral progestogen,
endometrial implants serum E2 levels are suppressed within 2 weeks
• May also modulate immunologic function o Amenorrhea is induced in 4 to 5 weeks
• Usually begun during menses (days 1 to 5) • It is important to ensure that the patient is not
• Side effects: pregnant when beginning GnRH agonist therapy
o Deepening of voice during the luteal phase
o Mild elevation in serum liver enzyme
o Androgenic effect on lipids ORAL CONTRACEPTIVES
o Reduction in HDL and triglycerides • It has been accepted that the most economical
o Increase in LDL regimen for the treatment of women with mild
• Standard length of treatment: 6 to 9 months or moderate symptoms of endometriosis has
• Symptoms will recur in 15% to 30% of women been continuous daily oral contraceptives for 6
within 2 years following therapy to 12 months
• One potential risk of using oral contraceptives
GONADOTROPIN-RELEASING HORMONE AGONISTS or progestogens is that there is some risk of
• Representative agonists are leuprolide acetate rupture if a large endometrioma is present
(Lupron, injectable), nafarelin acetate (Synarel, o May result in an acute surgical
intranasal), and goserelin acetate (Zoladex, abdomen during the first 6 weeks of
subcutaneous implant) oral contraceptive therapy
 • Most common side effects of inducing combination with a progestogen or oral
amenorrhea with oral contraceptives include contraception pills, there is good
weight gain and breast tenderness promise that it will be beneficial for the
treatment of endometriosis
NSAIDs
• For pain relief SURGICAL THERAPY
• Concomitant therapy may improve bleeding • The main roles of surgical therapy in the
control of patients on oral contraceptives management of endometriosis are to provide
• Potentially for the treatment of endometriosis, symptomatic relief (pain) and to improve
particularly when other suppressive therapy fertility outcomes
cannot be used • Includes conservative and definitive approaches
that address three main categories of lesions:
OTHER HORMONAL TREATMENTS o Superficial endometriosis
• Medroxyprogesterone acetate (Provera) in a o Endometriomas
dosage of 20 to 30 mg orally per day or depo- o Deep infiltrating endometriosis (DIE)
medroxyprogesterone acetate (Depo-Provera)
in a dosage of 150 mg intramuscularly every 3 SURGICAL MANAGEMENT FOR PAIN
months to a maximum of 200 mg every month • In women suffering from chronic pelvic pain
will produce a prolonged amenorrhea due to endometriosis who have failed
o Most appropriate for the older woman conservative medical therapy
who has completed childbearing • Especially in cases of moderate or severe
o Should not be prescribed for a young endometriosis in which pelvic adhesive disease
woman who is contemplating is present along with the involvement of
pregnancy in the near future nonreproductive organs
• GESTRINONE • Definitive surgical treatment, involving
o Progestogen originally developed as a hysterectomy, is effective for symptomatic
once-a-week oral contraceptive relief with reoperation free rates of 86% (with
o Acts as an agonist–antagonist of ovarian preservation) and 91% (without ovarian
progesterone receptors and an agonist preservation) at 5 years
of androgen receptors and also binds • PRESACRAL NEURECTOMY
weakly to estrogen receptors o Select patients with midline pain
o Tendency for prolonged pain relief o For short-improvement of symptoms
• DIENOGEST o Complications: bowel and bladder
o Selective progestogen that causes dysfunction
anovulation • PHOTODYNAMIC THERAPY
o Has an antiproliferative effect on o Involves intravenous injection of a
endometrial cells special dye that is concentrated in areas
o May inhibit cytokine secretion of endometriosis
• LEVONORGESTREL IUS o A laser light produces a photochemical
o Beneficial for pain relief in women with reaction to destroy the areas
endometriosis compared to expectant
management
o For women who have rectocervical and
cul-de-sac disease
• AROMATASE INHIBITORS
o Anastrozole 1 mg, and Letrozole 2.5 and
5 mg
o When given alone to premenopausal
women it will cause stimulation of
gonadotropins and has been used to
induce ovulation
o But in postmenopausal women and in
the premenopausal women in