Gynecology

Comprehensive Gynecology 7th Ed

Endometriosis Endo teenagers investigated for obstructive
 Benign reproductive tract abnormalities that
 Progressive and aggressive disease. increase the amount of retrograde
 Presence and growth of the glands and stroma of menstruation
the lining of the uterus in an aberrant or heterotopic  extensive endometriosis  asymptomatic
location.  minimal implants  incapacitating chronic pelvic
 Has characteristics of a malignancy pain
locally infiltrative,  deep infiltrating endometriosis
invasive, esp in retroperitoneal spaces
Widely disseminating. severe episodes of pain.

 Estrogen levels stimulate the growth of ectopic  Pelvic lesions of endometriosis

endometrium positive immunostaining for smooth muscle
 contraceptive steroids of various doses as well as nerve cells
Beneficial for treatment.  The clinical variability in responses among women
 inverse relationship between the extent of pelvic with endometriosis may relate to differences in
endometriosis and the severity of pelvic pain immunologic function and variations in cytokine
production
Adenomyosis
 Growth of endometrial glands and stroma into ETIOLOGY
the uterine myometrium at least 2.5 mm from  No single theory adequately explains all the
the basalis layer of the endometrium. manifestations of the disease.
 sometimes termed internal endometriosis  Only speculation as to why develop endometriosis
semantic misnomer because most and others do not.
likely they are separate diseases Complex interplay between a dose-
response curve of the amount of retrograde
 Mild endometriosis as diagnosed by the increasing menstruation and an individual woman’s
use of laparoscopy. immunologic response (these in turn may
 cause of endometriosis is uncertain and involves depend on ethnic and genetic variability).
many mechanisms including Retrograde Menstruation
retrograde menstruation,  Most popular theory: endometriosis results from
vascular dissemination, retrograde menstruation.
metaplasia,  Pelvic endometriosis  secondary to implantation
genetic predisposition,
of endometrial cells shed during menstruation
immunologic changes
 Suggested that the shedding of endometrial-
hormonal influences
based adult stem cells and mesenchymal cells
may explain this phenomenon
 environmental factors Cells attach to the pelvic peritoneum and
dioxin
under hormonal influence grow as
other endocrine disruptors. homologous grafts.

 typical patient with endometriosis

 Reflux of menstrual blood and viable endometrial
mid-30s
cells in the pelvis of ovulating women
nulliparous
involuntarily infertile,
 Endometriosis
symptoms of secondary dysmenorrhea
Discovered most frequently in areas
pelvic pain – classic symp of endo but
adjacent to the tubal ostia or in the
majority cases are not classic
dependent areas of the pelvis.
freq found in women with outflow
 Aberrant endometrial tissue
obstruction of the genital tract.
grows under influence of ovarian hormones
Attachment of the shed endometrial cells
particularly estrogen dependent involves the expression of adjacent
 MC during the reproductive years. molecules and there receptors.
5% with endometriosis are diagnosed
following menopause.
Postmenopausal endometriosis
 Stimulated by exogenous estrogen

1|P ag e #MAHESHEBETH Gracia Fire

Gynecology
Comprehensive Gynecology 7th Ed
Metaplasia
 theory that endometriosis arises from metaplasia of
the coelomic epithelium or proliferation of
embryonic rests
 The Müllerian ducts and nearby mesenchymal
tissue form the majority of the female reproductive
tract.
 Müllerian duct  from coelomic epithelium during
fetal development.
 metaplasia hypothesis
coelomic epithelium retains the ability for
multipotential development.
decidual reaction of isolated areas of
peritoneum during pregnancy is an
example of this process.
Surface epithelium of the ovary can
differentiate into several different histologic
cell types.
 Endometriosis
prepubertal girls, women with congenital
absence of the uterus, and rarely in men.
support the coelomic metaplasia theory.
Metaplasia occurs after an “induction
phenomenon” has stimulated the
multipotential cell.
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Induction substance  combination of
menstrual debris and estrogen and
progesterone.
histogenesis of endometriosis in peritoneal
pockets of the posterior pelvis results from
a congenital anomaly involving rudimentary
duplication of the Müllerian system
peritoneal pockets
 posterior pelvis, the posterior
aspects of the broad ligament, and
cul-de-sac
ovarian endometriosis --> metaplasia of
the coelomic epithelium that invaginates
into the ovarian cortex
Lymphatic and Vascular Metastasis
 The theory of endometrium being transplanted via
lymphatic channels and the vascular system
 rare and remote sites of endometriosis, such as the
spinal column and nose.
 30% with the disease.
 Hematogenous dissemination of endometrium
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 after a cesarean delivery.
 The hypothesis is that endometrial glands and
stroma are implanted during the procedure.
 found subcutaneously at the abdominal incision.
 Rarely, discovered in an episiotomy scar.
Immunologic Changes
 Changes in the immune system, especially altered
function of immune-related cells, are directly related
to the pathogenesis of endometriosis.
 Abnormalities in cell-mediated and humoral
components of the immune system in both
peripheral blood and peritoneal fluid
 depicts various cytokines and growth factors that
implicated in the pathogenesis of endometriosis
Gracia Fire
Gynecology
Comprehensive Gynecology 7th Ed

 primary immunologic change  Steroid interactions

alteration in the function of the peritoneal enhance the progression of disease.
macrophages Estrogen production is enhanced locally,
Prevalent in the peritoneal fluid of patients  upregulation of aromatase activity,
with endometriosis.  increased COX-2 expression,
 dysregulation of 17β-
 women who do not develop endometriosis dehydrogenase activity,
monocytic-type macrophages in their  deficiency in 17β-dehydrogenase
peritoneal fluid that have a short life span II activity and possibly an
and limited function enhancement of type II activity
favoring local estradiol production
 women who develop endometriosis
more peritoneal macrophages that are
larger
Hyperactive cells secrete multiple growth
factors and cytokines that enhance the
development of endometriosis.
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.
 Natural killer (NK) cells decreased cytotoxicity
against endometrial and hematopoietic cells
 peritoneal fluid of women with endometriosis
less influence of NK activity than in fertile
women without endometriosis.
 aromatase, and HSD 17β2 in disease-free women,
 Another attractive theory is the finding of a protein and endometrium and ectopic lesions in women
similar to haptoglobin in endometriosis with endometriosis where high local
epithelial cells called Endo 1. concentrations of estrogen and prostaglandin
This chemoattractant protein-enhanced E2 predominate.
local production of interleukin-6 (IL-6)
self-perpetuates lesion/cytokine  Enhanced aromatase activity
interactions. overexpression of the orphan nuclear
proliferative activity of endometriosis receptor steroidogenic factor-1 (SF-1) in
lesions are angiogenic factors that are lesions.
increased in lesions. local production of estrogen through
Expression of basic fibroblast factor, IL-6, aromatase activity explains why
IL-8, platelet derived growth factor (PDGF), progression of lesions may occur even with
and vascular endothelial growth factor ovarian suppression.
(VEGF) are all increased. progesterone “resistance”

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Gynecology
Comprehensive Gynecology 7th Ed
dysregulation of the isoform B of the
progesterone receptor in most
endometriotic lesions where levels may be
undetectable.
The latter propensity may be on a genetic
basis
 Autoimmunity  exist in women with endometriosis
 abnormalities of the histocompatibility locus
antigen (HLA) system have not been consistent,
 increased B and T cells, and serum immunoglobulin
(IgG, IgA, and IgM) autoantibodies in
endometriosis.
Genetic Predisposition
 sevenfold increase incidence of endometriosis in
relatives of women with the disease
 Family history
 deletions of genes, most specifically increased
heterogenicity of chromosome 17 and
aneuploidy,
 Loci on 7p and 10q  increase the susceptibility
for endometriosis
 Genetic liability depends on an interaction with
environmental and epigenetic factors
 Bilateral ovarian endometrial cysts arise
independently from different clones.
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 Matrix metalloproteinases (MMPs) and
integrins,  important implications for endometrial
lesion attachment and for implantation defects,
which may exist in infertile women with
endometriosis.
 Reflux of MMPs into the peritoneal cavity at
menstruation may contribute to peritoneal
attachment in susceptible women.
 genetic predisposition or exposure to environmental
factors, may program fetal progenitor cells in an
epigenetic way to overexpress SP1 and estrogen
receptor β, which increase the risk of developing
endometriosis
 Certain ethnic groups have an increased risk
 Asian women (ninefold increase)
Pathology
 The majority of endometrial implants are located in
the dependent portions of the female pelvis
 ovaries  most common site
 bilateral
 common sites where endometriosis develops
Pelvic peritoneum over the uterus
anterior and posterior cul-de-sac;
uterosacral, round, and broad ligaments
 Pelvic lymph nodes found to be involved
 cervix, vagina, and vulva are other possible pelvic
locations.
 Deep lesions
Penetrations of greater than 5 mm,
represent a more progressive form of the
disease
Gracia Fire
Gynecology
Comprehensive Gynecology 7th Ed
 superficial implant lesions
on peritoneal surfaces, including the ovary,
from deep endometriotic ovarian cysts and
cul-de-sac nodules is important for therapy
latter abnormalities may suggest different
causes of the disease (e.g., metaplasia),
which require a surgical approach.
 10% - 15% lesions involving the rectosigmoid.
 Amount of scarring, endometriosis of the bowel may
be difficult to differentiate grossly from a primary
neoplasm of the large intestine.
 Endometriosis may be found in a wide variety of
sites, including the umbilicus, areas of previous
surgical incisions of the anterior abdominal wall or
perineum, the bladder, ureter, kidney, lung, arms,
legs, and even the male urinary tract
 Gross pathologic changes of endometriosis
exhibit wide variability in color, shape, size,
and associated inflammatory and fibrotic
changes.
 visual manifestations of endometriosis in the female
pelvis
protean and have many appearances.
 Clinicians closely inspect the pelvic peritoneum to
identify abnormal areas and small, nonhemorrhagic
lesions.
 biopsy confirmation  increasing awareness of
subtle lesions.
 gross appearance of the implant depends on the
site, activity, relationship to the day of the menstrual
cycle, and chronicity of the area involved.
 The color of the lesion varies widely and may be
red, brown, black, white, yellow, pink, clear, or a
red vesicle.
predominant color depends on the blood
supply and the amount of hemorrhage and
fibrosis.
color also appears related to the size of the
lesion, the degree of edema, and the
amount of inspissated material
 Other peritoneal lesions that grossly appear similar
to endometriosis, but on histologic examination are
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not, include necrotic areas of an ectopic pregnancy,
fibrotic reactions to suture, hemangiomas, adrenal
rest, Walthard rest, breast cancer, ovarian cancer,
epithelial inclusions, residual carbon from laser
surgery, peritoneal inflammation, psammoma
bodies, peritoneal reactions to oil-based
hysterosalpingogram dye, and splenosis.
 New lesions are small, bleblike implants that are
less than 1 cm in diameter.
these areas are raised above the
surrounding tissues.
Red, blood-filled lesions by histologic and
biochemical studies, to be the most active
phase of the disease
areas of endometriosis become larger and
assume a light or dark brown color, and
described as “powder burn” areas or
“chocolate cysts.”
The older lesions
o white,
o more intense scarring,
o puckered or retracted from the
surrounding tissue.
White or mixed colored lesions
o histologic confirmation of endometriosis.
Progression from red to white lesions also
seems to correlate with age.
 pattern of ovarian endometriosis  variable.
from 1 mm to large chocolate cysts greater
than 8 cm in diameter
 adhesions may be filmy or dense.
 Larger cysts  densely adherent to the surrounding
pelvic sidewalls or broad ligament.
 three cardinal histologic features
ectopic endometrial glands,
ectopic endometrial stroma,
hemorrhage into the adjacent tissue
 Previous hemorrhage  discovered by identifying
large macrophages filled with hemosiderin near the
periphery of the lesion.
Gracia Fire
Gynecology
Comprehensive Gynecology 7th Ed
 aberrant endometrial glands and stroma respond in
cyclic fashion to estrogen and progesterone.
These changes may or may not be in
synchrony with the endometrial lining of the
uterus.
The ectopic endometrial stroma will
undergo classic decidual changes similar to
pregnancy when exposed to high
physiologic or pharmacologic levels of
progesterone.
 Repetitive episodes of hemorrhage
lead to severe inflammatory changes
result in the glands and stroma undergoing
necrobiosis secondary to pressure atrophy
or lack of blood supply.
 presumptive diagnosis of endometriosis
visualizing the intense inflammatory
reaction
large macrophages filled with blood
pigment.
 pathophysiology of progression from subtle to severe disease
may be expected from the multiple mechanisms of potential
disease acceleration discussed earlier, with immune function
most likely involved.
CLINICAL DIAGNOSIS
Symptoms
 one in three women being asymptom (1/3)
 Extremely unpredictable course.
 The classic symptoms of endometriosis
cyclic pelvic pain
infertility.
 chronic pelvic pain  presents as secondary
dysmenorrhea or dyspareunia (or both).
Secondary dysmenorrhea  36 to 48
hours prior to the onset of menses.
 pelvic pain
inversely related to the amount of
endometriosis in the female pelvis.
 moderate to severe chronic pain
Large, fixed adnexal masses sometimes
have minor symptoms, whereas other
patients with only a few small foci with
deep infiltration
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 cyclic pelvic pain
related to the sequential swelling
extravasation of blood and menstrual
debris into the surrounding tissue.
 prostaglandins and cytokines.
chemical mediators of this intense sterile
inflammation and pain
 Infiltrative endometriosis,
extensive areas of the retroperitoneal space,
moderate to severe pelvic pain.
 Secondary dysmenorrhea
common component of pain
dull ache to severe pelvic pain.
unilateral or bilateral
radiate to the lower back, legs, and groin.
pelvic heaviness or a perception of the
internal organs being swollen.
pain may last for many days, including
several days before and after the menstrual
flow.
 dyspareunia associated with endometriosis
pain deep in the pelvis.
cause of this symptom seems to be
immobility of the pelvic organs during coital
activity or direct pressure on areas of
endometriosis in the uterosacral ligaments
or the cul-de-sac.
areas of point tenderness.
acute pain, experienced during deep
penetration, may continue for several hours
following intercourse.
 Abnormal bleeding (15-20%)
most frequent complaints are premenstrual
spotting and menorrhagia.
abnormal bleeding is not associated with
anovulation and related to abnormalities of
the endometrium.
patients with endometriosis frequently have
ovulatory dysfunction.
have coincidental anovulation or luteal
dysfunction (15%)
 untreated endometriosis
increased incidence of first-trimester
abortion
unproven
Less common, yet troublesome,
symptoms influencing the gastrointestinal
and urinary tracts.
 Cyclic abdominal pain, intermittent
constipation, diarrhea, dyschezia,
urinary frequency, dysuria, and
hematuria
 Bowel obstruction and
hydronephrosis
Gracia Fire
Gynecology
Comprehensive Gynecology 7th Ed
catamenial hemothorax
 rare clinical manifestation
 bloody pleural fluid occurring
during menses.
Massive ascites
 rare symptom of endometriosis,
 important because the disease
process initially masquerades as
ovarian carcinoma.
Clinical Findings (Physical Exam)
 classic pelvic finding of endometriosis
 fixed retroverted uterus,
 with scarring and tenderness posterior to
the uterus.
 characteristic nodularity of the uterosacral
ligaments and culde-sac may be palpated on
rectovaginal examination
 Advanced cases
 extensive scarring
 narrowing of the posterior vaginal fornix.
 ovaries
enlarged
tender
often fixed to the broad ligament or lateral
pelvic sidewall.
 adnexal enlargement
rarely symmetric, as one may expect in
some benign pelvic conditions.
 Speculum examination
small areas of endometriosis on the cervix
or upper vagina.
 Lateral displacement or deviation of the cervix is
visualized or palpated by digital exam of the vagina
and cervix in approximately 15% of women with
moderate or severe endometriosis.
 pelvic examination  first or second day of
menstrual flow may aid in the diagnosis as it is the
time of maximum swelling and tenderness in the
areas of endometriosis.
 diagnosis can be confirmed in most cases by direct
laparoscopic visualization with its associated
scarring and adhesion formation.
 endometriosis was discovered for the first time
during an infertility investigation, although routine
laparoscopy is no longer being carried out in the
infertility investigation.
 Biopsy of selected implants confirms the diagnosis
Imaging
 adjunct to the clinical presentation
 physical exam for evaluation of endometriosis,
especially with deep infiltrating endometriosis (DIE).
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 Ultrasound examination
no specific pattern to screen but helpful in
differentiating solid from cystic lesions
distinguish an endometrioma from other
adnexal abnormalities. Because the lesions
are vascular, increased Doppler flow may
be demonstrated in endometriosis (Fig.
19.12).
transvaginal ultrasound (TVUS) detect DIE,
with the greatest sensitivity and specificity
for detection of rectosigmoid lesions.
Modified techniques such as rectal water
contrast transvaginal ultrasound can
increase the probability of detecting a DIE
lesion, which is now considered to be the
more sensitive technique for the
diagnosis of DIE
 Magnetic resonance imaging (MRI)
best overall diagnostic tool for
endometriosis
not always a practical modality for its
diagnosis.
hyperintensity - T1-weighted images
hypointensity - T2-weighted images
Diagnostic Laparoscopy
 important to describe systematically the extent of
the pathology.
 point-scoring system in 1996 (American Society
for Reproductive Medicine)
record the extent of the disease in fertility
patients
provide characterization of disease extent
for fertility and not for pain assessment.
 scoring system by Adamson
focuses on the fertility potential of patients
with endometriosis
Endometriosis Fertility Index (EFI),
shown in prospective evaluation to
correlate with pregnancy rates
 endometriosis exhibits characteristics of both
malignancy and sterile inflammation kahit benign
siya.
common considerations in the differential
diagnosis include chronic pelvic
inflammatory disease, ovarian malignancy,
degeneration of myomas, hemorrhage or
torsion of ovarian cysts, adenomyosis,
primary dysmenorrhea, and functional
bowel disease.
 large endometrioma of the ovary may rupture into
the peritoneal cavity.
This results in an acute surgical abdomen
and brings into the differential diagnosis
conditions such as ectopic pregnancy,
appendicitis, diverticulitis, and a bleeding
corpus luteum cyst
Gracia Fire
Gynecology
Comprehensive Gynecology 7th Ed
MONITORING THE COURSE OF DISEASE: ARE
THERE MARKERS?
 Serial pelvic examinations
poor indicator of progression of disease.
 cancer antigen-125 (CA-125) have been used as
a marker for endometriosis.
CA-125 levels are elevated
increases incrementally with advanced
stages.
assays for serum levels of CA-125 have a
low specificity because they also increase
with other pelvic conditions such as
leiomyomas, acute pelvic inflammatory
disease, and the first trimester of
pregnancy.
CA-125 levels have a low sensitivity for the
diagnosis of early or minimal endometriosis
 Glycodelin
previously known as placental protein 14,
elevated in endometriosis
produced in endometriotic lesions.
Levels also fall with removal of the disease.
not proved to be useful clinically.
 The most predictive markers appear to be Il-1,
chemoattractant protein-1 and interferon gamma,
with Il-1 being the most useful marker
 generally thought that endometriosis improves
during pregnancy, this is not always the case, and
an increase in lesions has been documented,
although primarily in the first trimester.
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 Ovarian endometriomas,
have a different pathogenetic origin, from
surface implants of endometriosis on the
ovary may persist during pregnancy.
ovarian endometriosis rupture during
pregnancy may occur.
 Endometriosis may be associated with ovarian
cancer
risk of developing ovarian cancer
Loss of heterozygosity
Mutations in suppressor –ei. p53
caution in the long-term follow-up of
women who have extensive disease and
ovarian endometriomas, particularly with
large masses and those that increase in
size
 cervical endometriosis  particular condition that
can produce abnormalities in cervical cytology.
 Endometriosis is dependent on ovarian hormones
stimulate growth.
With natural menopause  gradual relief of
symptoms.
Following surgical menopause, areas of
endometriosis rapidly disappear.
5% of symptomatic cases present after
menopause.
majority of cases  late 50s or early 60s
are related to the use of exogenous
estrogen.
TREATMENT
 two primary short-term goals in treating
endometriosis
relief of pain
promotion of fertility.
 primary long term goal
attempting to prevent progression or
recurrence of the disease process.
 Cochrane review of evidence-based therapies lists
a variety of agents that may be helpful but does not
specify a clearly preferred agent
because there have been few prospective
head-to-head comparisons and because
the disease is heterogeneous with vast
differences in the spectrum of clinical
symptoms and extent of disease from one
woman to another.
Thus, treatment plan must be
individualized.
 Choice of therapy, for whose primary symptom is
pelvic pain, depends on multiple variables,
including the patient’s age, her future reproductive
plans, the location and extent of her disease, the
severity of her symptoms, and associated pelvic
pathology.
Gracia Fire
Gynecology
Comprehensive Gynecology 7th Ed
 laparoscopy
gold standard for making a diagnosis
this is not always possible, particularly in a
younger population.
 Imaging techniques
only be helpful if a mass is identified,
suggestion of performing an endometrial
biopsy
too invasive for younger nulliparous
If gynecologic conditions such as chronic
pelvic inflammatory disease or neoplasia
have been ruled out,
 empiric medical therapy for 3
months
 Various suppressive treatments
 Treatment of endometriosis
Medical
Surgical
combination of both.
 sex steroids, alone or in combination, to suppress
the growth of endometriosis.
Optimal regression secondary to medical
treatment is observed in small
endometriomas that are less than 1 to 2 cm
in diameter.
larger areas of endometriosis may be
minimal with medical therapy.
poor therapeutic result governed by the
reduction of blood supply to the mass
caused by surrounding scar tissue.
suppressive therapies, such as the use of
dienogest  decrease in nerve fiber
density in endometriosis lesions
 Surgical therapy is divided into
conservative and definitive operations.
 Conservative surgery
 resection or destruction of endometrial
implants, lysis of adhesions
 attempts to restore normal pelvic
anatomy.
 Definitive surgery
 removal of both ovaries, the uterus,
and all visible ectopic foci of
endometriosis.
 analogous to cytoreductive surgery in
ovarian carcinoma
MEDICAL THERAPY
 suppression of lesions and associated symptoms,
particularly pain.
 best achieved by menstrual suppression, ideally
without inducing hypoestrogenism.
 once suppressive therapy is stopped, symptoms
tend to recur at variable rates.
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 suppresses symptomatology and prevents
progression but not provide a long-lasting cure of
the disease.
 medical therapy should be
individualized,
weighing in potential adverse effects,
side effects,
cost of therapy
expected patient compliance.
 clinical effectiveness  measured by relief of
symptoms and recurrence rates of current medical
therapies, are largely similar.
 chance of recurrence is directly related to the extent
of initial disease.
 (FDA) has approved only
danazol
gonadotropin releasing hormone
(GnRH) agonists
 Other therapies
traditional oral contraceptives (OCs),
novel progestogens such as gestinone and
dienogest, an oral GnRH antagonist,
levonorgestrel-releasing intrauterine
system (IUS),
aromatase inhibitor letrozole,
certain selective progesterone receptor
modulators.
Danazol
 clinicians rarely prescribe danazol (because of lack
of familiarity, side effect profile, and availability of
other agents)
most frequently select GnRH agonists,
progestogens, or oral contraceptives.
 for women with benign cystic mastitis, menorrhagia,
and hereditary angioneurotic edema.
 attenuated androgen that is active when given
orally.
 synthetic steroid that is the isoxazole derivative of
ethisterone (17-α-ethinyltestosterone).
 oral androgens such as methyl testosterone were
also used, as they induce endometrial atrophy.
 Has hypoestrogenic and hyperandrogenic effect on
steroid-sensitive end organs.
mildly androgenic and anabolic leading to
its side-effect profile.
 induces atrophic changes in the endometrium of the
uterus and similar changes in endometrial implants.
 modulate immunologic function
Gracia Fire
Gynecology
Comprehensive Gynecology 7th Ed
 doses of 400 to 800 mg of danazol have been
prescribed,
many clinicians reduce the total daily
dosage of the drug to 200, and even
100 mg daily.
 Danazol begun during menses (days 1 to 5).
relief of the symptoms is directly related
to the incidence of amenorrhea
***lower dosages of danazol are not as effective.
 Side effects
deepening of the voice did not resolve after
discontinuation.
Mild elevation in serum liver enzyme
who take danazol for longer than 6 months
should have serum liver enzyme
determinations.
androgenic effect on lipids occurs, with
reduction in high density lipoprotein (HDL)
cholesterol and triglycerides and an
increase in low-density lipoprotein (LDL)
cholesterol.
 6 to 9 months - standard length of treatment
objective improvement discovered at a
second-look laparoscopy.
uncorrected fertility rate
symptoms will recur in 15% to 30% of
women within 2 years following therapy.
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GONADOTROPIN-RELEASING HORMONE
AGONISTS
 Representative agonists
leuprolide acetate (Lupron, injectable),
nafarelin acetate (Synarel, intranasal),
goserelin acetate (Zoladex, subcutaneous
implant).
 leuprolide acetate
 3.75 mg IM once per month or
 11.25-mg depot injection q 3 months.
 Nafarelin acetate
nasal spray
one spray (200 μg) in one nostril in the
morning
one spray (200 μg) in the other nostril in
the evening
maximum of 800 μg daily.
 Goserelin acetate
 3.6 mg every 28 days in a biodegradable
subcutaneous implant
 dose-response curve of the GnRH agonists
establishing the optimal dose to produce sufficient
down-regulation and desensitization of the pituitary
to produce extremely low levels of circulating
estrogen and amenorrhea.
 Chronic use  produces a “medical
oophorectomy.”
 reduction occurs in serum estrone, E2,
testosterone, and androstenedione to levels similar
to the hormonal levels in oophorectomized women.
 no significant changes in total serum cholesterol,
HDL, or LDL levels during therapeutic periods as
long as 6 months.
 Endometrial samples obtained after several months
of chronic agonist therapy demonstrated either
atrophic or an early proliferative endometrium.
 three most common symptoms
hot flushes
vaginal dryness
insomnia.
 decrease in bone mineral content
demonstrated in the trabecular bone of the
lumbar spine by quantitative computer
tomography.
not seen in the compact bone of the distal
radius.
decrease in measured bone mass of 2% to
7% during a 6-month course of agonist
therapy.
decrease in bone density associated with 6
months of therapy completely recovers
between 12 and 24 months.
Gracia Fire
Gynecology
Comprehensive Gynecology 7th Ed
 The clinical response to agonist therapy depends
when is initiated in regard to the menstrual cycle.
 If agonist therapy is begun during the follicular
phase,
agonist phase results in an initial rapid rise
in follicle-stimulating hormone (FSH) and
E2 for approximately 3 weeks.
FSH levels fall to basal levels
 third to fourth week of therapy.
E2 levels rapidly decline after 21 days
LH does not occur,
progesterone do not become elevated.
 Amenorrhea induced within 6 to 8 weeks.
beginning agonist therapy during the luteal
phase or if artificially manipulated by the
concurrent administration of oral
progestogen, serum E2 levels are
suppressed within 2 weeks.
 Amenorrhea is induced in 4 to 5 weeks.
ensure that the patient is not pregnant
when beginning GnRH agonist therapy
during the luteal phase
 GnRH agonist therapy improves symptoms of
endometriosis.
Growth is arrested, diminished, or
eliminated.
 greatest therapeutic effects are seen when areas of
endometriosis are less than 1 cm in diameter.
 Ovarian function usually returns to normal in 6 to 12
weeks after 6 months of GnRH agonist therapy.
 Large ovarian endometriomas and severe adhesive
disease have not responded to hormonal therapy.
 many clinicians “add back” hormone replacement
therapy with dosages similar to those used in
menopausal therapy in combination with chronic
GnRH agonist regimens.
add-back medication will reduce or
eliminate the vasomotor symptoms and
vaginal atrophy
diminish or overcome the demineralization
of bone.
add-back therapy not interfere with the
effectiveness of agonists to relieve the
pelvic pain from endometriosis.
no diminished therapeutic efficacy when
add-back therapy is initiated
simultaneously with the GnRH agonist.
 therapeutic window in a circulating level of
approximately 30 pg/mL of E2
 E2 is enough to protect the body from substantial
bone loss and is not high enough to interfere with
the inhibition of growth of endometriosis
 clinicians additionally give bisphosphonates and
calcium with the low-dose progestins and estrogen,
11 | P a g e #MAHESHEBETH
bisphosphonates not recommended in
younger women who may wish to become
pregnant.
 Add-back regimens not only reduce or eliminate
adverse clinical and metabolic side effects
associated with hypoestrogenism but also
facilitate safe and effective prolongation of
GnRH agonist therapy for up to 12 months.
 Additional agents that have been used for add back
therapy are
tibolone
raloxifene
 GnRH antagonists have no “flare” effect.
 women not wishing to conceive, who predominantly
have pain and no indication for surgery (which may
include failed medical therapy), stopping and
starting various treatments and interchanging them
is a reasonable approach to control symptoms.
ORAL CONTRACEPTIVES
 very large doses of norethynodrel with mestranol
daily
produce amenorrhea
“pseudopregnancy.”
 low-estrogen monophasic combination pills,
specifically the ones with a relatively high
progestin potency, are equally effective
when used in a continuous fashion.
most economical regimen for the treatment
with mild or moderate symptoms of
endometriosis has been continuous daily
oral contraceptives for 6 to 12 months.
 Continuous dose regimens are aimed at more
complete suppression, with an advantage over
cyclic use
 only concern is with breakthrough bleeding, which
can be dealt with in a variety of ways as with
contraceptive therapy
 potential risk of using oral contraceptives or
progestogens
risk of rupture if a large endometrioma is
present.
Rupture of large endometriomas may result
in an acute surgical abdomen during the
first 6 weeks of oral contraceptive therapy.
 prolonged therapy
endometrial glands atrophy
stroma undergoes a marked decidual
reaction.
Gracia Fire
Gynecology
Comprehensive Gynecology 7th Ed
 smaller endometriomas (∼3 cm) can undergo
necrobiosis and resorption.
 most common side effects of inducing
amenorrhea with oral contraceptives
weight gain
breast tenderness.
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
 for pain relief
 concomitant therapy may improve the bleeding
control of patients on oral contraceptives.
 direct therapeutic value in endometriosis.
 cyclooxygenase-2 (COX-2) inhibitors are now
infrequently used because of cardiovascular
concerns in older individuals,
 this therapy for endometriosis has a rationale in that
lesions of endometriosis have been found to
express high levels of COX-2
 beneficial for pain relief
 potentially for the treatment of endometriosis,
particularly when other suppressive therapy cannot
be used.
Other Hormonal Treatments
 who cannot tolerate the high dosage of estrogen in
an oral contraceptive or have contraindication to
estrogen therapy
treatment with progestogens only has been
successful.
 Medroxyprogesterone acetate (Provera)
20 to 30 mg orally per day or
depo-medroxyprogesterone acetate
(DepoProvera)
 150 mg IM q 3 months
 maximum of 200 mg q month will
produce a prolonged amenorrhea.
most appropriate for the older woman who
has completed childbearing.
time of resumption of ovulation following
discontinuation of injectable
medroxyprogesterone is prolonged and
extremely variable.
Some women will not ovulate for more than
a year after their last injection.
 Thus, this form of therapy should not be
prescribed for a young woman who is
contemplating pregnancy in the near
future.
Oral medroxyprogesterone in a dosage of
30 mg/day is an alternative mode of
therapy, as is norethindrone acetate (10 to
40 mg) daily. This more androgenic
progestogen, although quite effective, has
a similar symptom profile to that for
continuous medroxyprogesterone.
12 | P a g e #MAHESHEBETH
 Gestrinone
progestogen
once a-week oral contraceptive.
2.5 to 7.5 mg/ week.
agonist–antagonist of progesterone receptors
agonist of androgen receptors
binds weakly to estrogen receptors.
tendency for prolonged pain relief was
observed
 Dienogest
selective progestogen
causes anovulation
antiproliferative effect on endometrial cells
inhibit cytokine secretion.
2 mg/day orally effective as GnRH agonists
 levonorgestrel IUS
for pain relief in women with endometriosis
compared to expectant management.
for women who have rectocervical and cul-de-
sac disease
 Aromatase inhibitors
anastrozole 1 mg
letrozole 2.5 and 5 mg
beneficial in estrogen tend to cause proliferation of
the disease and also endometriosis lesions have
been found to contain the aromatase enzyme
given alone to premenopausal women it will cause
stimulation of gonadotropins and been used to
induce ovulation;
postmenopausal women and premenopausal
women in combination with a progestogen or oral
contraception pills there is good promise that it will
be beneficial
OTHER POSSIBLE MEDICAL THERAPIES
 several other less well-proved therapies.
peroxisome proliferator-activated
receptor (PPAR) ligands,
 inhibit macrophage action
targeting haptoglobin
 because of structural similarity to
Endo-1
targeting MMPs
tumor necrosis factor α and VEGF
 ERβ agonists
increasing VEGF and angiogenetic factors
are mediated through ERβ
modulate immune function.
***selective estrogen receptor modulators, specifically
tamoxifen and raloxifene, have not been shown to be
beneficial
 anti-inflammatory immunomodulator, pentoxifylline,
has also shown promise.
 medicinal herbs
antiproliferative and anti-inflammatory and
pain-relieving properties
no rigorous clinical trial data are available
at present.
Gracia Fire
Gynecology
Comprehensive Gynecology 7th Ed
ROUTE OF ADMINISTRATION
 Delivering various progestogens or danazol locally
(intrauterine as with the levonorgestrel IUS or
vaginally) may also enhance effectiveness.
 benefit of using suppositories and local agents,
particularly in those women with cul-de-sac disease
SURGICAL THERAPY
 adjunct or alternative to medical therapy
 Prevent or delay further disease progression.
 main roles of surgical therapy in endometriosis
provide symptomatic relief (pain)
improve fertility outcomes.
 includes conservative and definitive approaches
address three main categories of
lesions:
 superficial endometriosis
 endometriomas
 deep infiltrating endometriosis
(DIE).
 Conservative surgery
 preservation of reproductive organs
 restoration of normal pelvic anatomy while
removing all macroscopic endometriotic
lesions or endometriomas and performing
lysis of adhesions.
 Definitive surgery
 removing the uterus and cervix along with
any visible lesions
 while preserving or removing either one or
both of the ovaries.
 invasive surgical approaches such as laparoscopy
and robotic surgery have largely replaced the need
for laparotomy
o due to advantages such as improved
visualization, shorter recovery period,
decreased blood loss, and decreased
risks of complications.
 Restoring normal pelvic anatomy, preventing
adhesions, and limiting tissue damage is essential
for successful endometriosis surgery.
 start dissections going from normal anatomy toward
abnormal anatomy.
 Energy should be used judiciously and cautiously
esp with difficult dissections with distorted anatomy
and when adjacent to vital structures such as major
blood vessels, the ureter, bladder, or bowel.
SURGICAL MANAGEMENT FOR PAIN
 chronic pelvic pain due to endometriosis who have
failed conservative medical therapy, surgery can be
an effective treatment,
esp moderate or severe endometriosis
which pelvic adhesive disease is present
along with the involvement of
nonreproductive organs.
13 | P a g e #MAHESHEBETH
 removal of the ovaries may decrease the risk of
disease recurrence,
balanced with the risks associated with
removing the ovaries
individualized based on the patient’s age,
clinical presentation, and goals.
 postsurgical hormonal suppression with progestins
or oral contraceptives may be considered in order
to decrease risks of recurrence, especially if there
is any residual or unresectable disease at the time
of surgery.
 Other surgical treatments
presacral neurectomy
 short-term improvement in
symptoms, but complications can
include bowel and bladder
dysfunction.
photodynamic therapy
 undergoing preliminary trials
 intravenous injection of a special dye
that is concentrated in areas of
endometriosis.
 laser light produces a photochemical
reaction to destroy the areas
SURGICAL MANAGEMENT FOR FERTILITY
 Medical therapy may sometimes be required for
symptomatic control while waiting for fertility
treatment; however, this is generally not
recommended.
 improved fertility outcomes with prolonged GnRH
agonist use when administered prior to assisted
reproductive treatment.
Surgical management in these women can
be considered
 stage I/II endometriosis, excision or ablation of
endometriosis
increase live birth and ongoing pregnancy
rates
thus, recommended when visible lesions are
present.
Although lack of trials, for stage III/IV,
surgical treatment has also been suggested
to increase pregnancy rates
 Endometriomas
 has potential risks such as infection
 interfering with response to infertility
treatments and oocyte retrieval,
 risks of complications in pregnancy, and
malignancy.
 decrease ovarian reserve.
 surgical removal is not generally
recommended prior to IVF.
 surgery does not necessarily increase fertility
outcome while it can further compromise
ovarian reserve, increase the risk of
premature ovarian failure, and induce early
menopause.
Gracia Fire
Gynecology
Comprehensive Gynecology 7th Ed
 surgical treatment can be beneficial for
certain cases such as in symptomatic  pregnancy rates improve with implant ablation
patients (i.e., pelvic pain) or in those with  if a laparoscopy is being performed in a woman
difficult access to follicles. wishing to conceive,
 Surgical excision of greater than 3 cm were visible lesions should be ablated
previously thought to improve pregnancy Apart from the mechanical factors
rates, but studies show no difference (endometriomas, adhesions, fibrosis)
compared to expectant management. affecting pregnancy rates, in endometriosis,
preferable over ablation or drainage, macrophage and cytokine abnormalities are
increase clinical pregnancy rates. thought to play a significant role in inhibiting
fertility
 In patients failing to conceive spontaneously  These factors affect oocyte quality,
after the initial surgery, fertilization, and embryo quality as
assisted reproductive therapy is well as endometrial receptivity.
recommended, as this more effective  Thus, in addition to ablating lesions
than repeat surgery. when present, several strategies have
repeat surgery can be considered been devised to enhance fecundity.
after failed assisted reproductive
treatments, but further studies are  Controlled ovarian stimulation along with
needed to determine optimal intrauterine insemination, an approach to enhance
management of such patients. fecundity in women with unexplained infertility, has
been found to be beneficial in women with
THERAPY FOR SUBFERTILITY
endometriosis.
 subfertility that occurs with endometriosis can be
 IVF-ET is undertaken (because of mechanical
the result of multiple mechanisms
factors or with other failed approaches)
 Medical therapy cannot be first-line treatment for
 prior suppressive therapy (before initiation of an IVF
endometriosis
cycle) has been shown to be benefit.
because suppression of ovulation
 three RCTs found that prior suppression of
interferes with the ability to conceive.
endometriosis with a GnRH agonist for 3 to 6
Occasionally as an adjunct, more
months prior to IVF-ET improves outcomes with an
prolonged (than usual) GnRH agonist
odds ratio of 9.19
therapy may be used before IVF.
surgical options are considered.  surgical therapy in the management of
endometriosis is very much dependent on the
clinical presentation of the patient and her desire for
 symptomatic women with ovarian endometriomas,
future fertility. Although there can be a beneficial
laparoscopic surgical excision should be
effect for fertility, a detrimental effect can also be
undertaken.
seen.
 extensive pelvic disease where in vitro fertilization/
 Advanced stages of disease, particularly those
embryo transfer (IVF-ET) is a necessary approach,
involving extrapelvic locations are often best
 when pelvic pain is not a significant issue, the
managed in a multidisciplinary fashion.
removal of endometriomas is of no benefit and may
be harmful
 women with endometriosis may have a lower
ovarian reserve, as reflected by lower levels of anti-
Müllerian hormone; surgery only decreases levels
further
 The size of an endometrioma also comes into play
in cases of IVF-ET;
if all visible normal ovarian tissue is
replaced by endometriomas (typically
endometriomas around 4 cm or greater),
surgical excision may be necessary.
small lesions (∼2 cm), follicle aspiration
can be accomplished avoiding the
endometriomas.
In general, the presence of
endometriomas tends to decrease the
number of oocytes aspirated but may not
impair oocyte or embryo quality.
surgery does not improve IVF rates
therefore surgery should only be selected
on an individual basis.
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Gynecology
Comprehensive Gynecology 7th Ed
ENDOMETRIOSIS AT OTHER SITES
GASTROINTESTINAL TRACT ENDOMETRIOSIS
 gastrointestinal tract involvement with histologically
proven endometriosis varies from 3% to 37%.
 Most large series approx. 5%.
 extrapelvic endometriosis
Implants that involve the gastrointestinal
tract most common site
most challenging to manage.
 cyclic GI symptoms
 generally occur
 suspicion of GI endometriosis should be
high with this type of presentation.
 Physical exam
help with diagnosis of deep infiltrating
endometriosis invading the rectosigmoid
such as by palpation of a pelvic mass or
“rectal shelf” on rectovaginal examination.

 severity and extent of involvement of the bowel by  Sigmoidoscopy

ectopic endometrium varies from the incidental demonstrates absence of a mucosal lesion
finding of a spot on the serosa of the bowel to in addition to fixation and immobility of the
obstruction of the rectosigmoid. anterior rectal wall.
 endometriosis of the gastrointestinal tract involves
 sigmoid colon  endometriosis of the rectovaginal septum is a
 anterior wall of the rectum disease process more closely related to foci of
 appendix  the next common type of adenomyosis than endometriosis
gastrointestinal (GI) tract
 Endometriosis involving the GI tract
 Endometriosis of the small bowel unresponsive to medical therapy
rare, often requires surgical excision.
approximately 200 cases of endometriosis Surgery should generally performed with a
of the ileum multidisciplinary team.
rectosigmoid lesions will also have Complete excision of these lesions
endometriosis of the ovaries sometimes necessitates bowel resection.
rectocervical lesions  bowel resection
symptomatic when lesions are greater than
 implants do not produce clinical symptoms. 2 cm,
 Classic symptoms of endometriosis of the large greater than 30% of the circumference is
bowel involved
dysmenorrhea (cyclic pelvic cramping and when there is invasion into the inner
lower abdominal pain) muscularis layer,
dyschezia (rectal pain with defecation), When surgery is indicated, while still
especially during the menstrual period. unclear which is better?
 bowel resection can be done via
 Other associated symptoms include either segmental or discoid
deep dyspareunia, resection.
change in bowel function,  considered in surgical planning
diarrhea or constipation (or both), include size, number and depth of
occasionally hematochezia. lesions, extent of bowel
circumference involvement,
 large bowel experience episodic rectal bleeding due distance to anal verge, and
to endometriosis extending into the submucosa. presence of lymph node
 dysfunction of the enteric nervous system involvement.
suggested to be the primary cause of the
abnormalities of bowel function in women with
endometriosis.
 difficult to differentiate the symptoms associated
with endometriosis from the overlapping
constellation of symptoms associated with
inflammatory disease of the colon or malignancy.
 gastrointestinal malignancy
intermittent rather than cyclic intestinal
bleeding.

 acyclic bowel symptoms can occur with GI

endometriosis,

15 | P a g e #MAHESHEBETH Gracia Fire

Gynecology
Comprehensive Gynecology 7th Ed
URINARY TRACT ENDOMETRIOSIS  Surgical therapy
 Endometriosis in the female pelvis produces  preferred treatment for ureteral obstruction
dysfunction in adjacent pelvic organs. secondary to endometriosis
 10% with endometriosis have involvement of the  Operations are rare and should be
urinary tract, which most commonly involves individualized.
endometriotic implants and associated  most common surgical approaches
retroperitoneal fibrosis located in the peritoneum removal of the uterus and both
overlying the ureter or the bladder. ovaries
 incidental finding of aberrant endometrial glands Relief of urinary obstruction
and stroma is discovered on the bladder  by ureterolysis or
peritoneum and anterior cul-de-sac.  by ureteroneocystostomy.
 ureteral obstruction
most serious consequence of urinary tract Ureteral resection is often needed if
involvement hydronephrosis is present.
1% of women with moderate or severe ureterolysis is performed
pelvic endometriosis.  Peristalsis in the involved
distal one third of the course of the ureter. segment of the ureter should
be observed,
 pathogenesis of endometriosis of the bladder is  along with adequate resection
controversial. of the endometriosis and
50% of women with endometriosis of the surrounding inflammation in
urinary tract have a history of previous the retroperitoneal space.
pelvic surgery.
 lesions may develop from implanted endometrium  Ureteroneocystostomy
during cesarean delivery or may be an extension  advantage of bypassing the
from adenomyosis of the anterior uterine wall. urinary obstruction
 Patients with endometriosis involving the urinary  easier to resect the area of
tract have nonspecific clinical presentations. endometriosis and
 Hematuria and flank pain  less than 25% of associated retroperitoneal
women. fibrosis.
 clinical challenge is to diagnose minimal ureteral
obstruction at an early stage, before loss of renal
function. EXTRA PELVIC ENDOMETRIOSIS
 Endometriosis of the bladder  Endometriosis can also involve the diaphragm
most often in the region of the trigone  incidental finding at laparoscopy
anterior wall of the bladder  asymptomatic.
 if symptomatic,
 Bladder endometriosis produces the most common presentation of
midline, lower abdominal, and suprapubic diaphragmatic endometriosis is right-
pain, sided catamenial pneumothorax.
dysuria
cyclic hematuria.  Other signs and symptoms
dyspnea,
 Treatment of endometriosis of the peritoneum over chest pain,
the bladder shoulder pain,
medical or surgical means. hemoptysis,
presence of pulmonary nodules.
 Ureteral obstruction
Intrinsic  from active endometriosis,  Medical suppressive therapy is the first approach,
Extrinsic  from long-standing fibrotic although surgery, including pleurodesis, may be
reactions to retroperitoneal inflammation. considered.
 should be referred to thoracic surgery
 Extrinsic endometriosis
 three to five times more common than the
intrinsic form.

 few reports of endometriosis of the ureter

responding to danazol or GnRH agonists.
 long-term follow-up with serial ultrasound imaging
or intravenous pyelograms must be undertaken to
ensure that the disease process does not recur.
16 | P a g e #MAHESHEBETH Gracia Fire