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

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Gynecology
Comprehensive Gynecology 7th Ed
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
Metaplasia
spinal column and nose.
 theory that endometriosis arises from metaplasia of
 30% with the disease.
the coelomic epithelium or proliferation of
 Hematogenous dissemination of endometrium
embryonic rests
Best theory to explain endometriosis of the
 The Müllerian ducts and nearby mesenchymal
forearm and thigh, as well as multiple
tissue form the majority of the female reproductive
lesions in the lung.
tract.
 Müllerian duct  from coelomic epithelium during Iatrogenic Dissemination
fetal development.  Endometriosis of the anterior abdominal wall is
 metaplasia hypothesis sometimes after a cesarean delivery.
coelomic epithelium retains the ability for  The hypothesis is that endometrial glands and
multipotential development. stroma are implanted during the procedure.
decidual reaction of isolated areas of  found subcutaneously at the abdominal incision.
peritoneum during pregnancy is an  Rarely, discovered in an episiotomy scar.
example of this process.
Surface epithelium of the ovary can Immunologic Changes
differentiate into several different histologic  Changes in the immune system, especially altered
cell types. function of immune-related cells, are directly related
to the pathogenesis of endometriosis.
 Endometriosis  Abnormalities in cell-mediated and humoral
prepubertal girls, women with congenital components of the immune system in both
absence of the uterus, and rarely in men. peripheral blood and peritoneal fluid
support the coelomic metaplasia theory.  depicts various cytokines and growth factors that
Metaplasia occurs after an “induction implicated in the pathogenesis of endometriosis
phenomenon” has stimulated the
multipotential cell.

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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

 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
 Autoimmunity  exist in women with endometriosis receptor β, which increase the risk of developing
 abnormalities of the histocompatibility locus endometriosis
antigen (HLA) system have not been consistent,  Certain ethnic groups have an increased risk
 increased B and T cells, and serum immunoglobulin  Asian women (ninefold increase)
(IgG, IgA, and IgM) autoantibodies in
endometriosis. 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.

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,
 Deep lesions
 Loci on 7p and 10q  increase the susceptibility
Penetrations of greater than 5 mm,
for endometriosis
represent a more progressive form of the
 Genetic liability depends on an interaction with disease
environmental and epigenetic factors
 Bilateral ovarian endometrial cysts arise
independently from different clones.

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Gynecology
Comprehensive Gynecology 7th Ed
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
 superficial implant lesions assume a light or dark brown color, and
on peritoneal surfaces, including the ovary, described as “powder burn” areas or
from deep endometriotic ovarian cysts and “chocolate cysts.”
cul-de-sac nodules is important for therapy The older lesions
latter abnormalities may suggest different o white,
causes of the disease (e.g., metaplasia), o more intense scarring,
which require a surgical approach. o puckered or retracted from the
surrounding tissue.
 10% - 15% lesions involving the rectosigmoid.
 Amount of scarring, endometriosis of the bowel may White or mixed colored lesions
be difficult to differentiate grossly from a primary o histologic confirmation of endometriosis.
neoplasm of the large intestine. Progression from red to white lesions also
 Endometriosis may be found in a wide variety of seems to correlate with age.
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.  pattern of ovarian endometriosis  variable.
 gross appearance of the implant depends on the from 1 mm to large chocolate cysts greater
site, activity, relationship to the day of the menstrual than 8 cm in diameter
cycle, and chronicity of the area involved.  adhesions may be filmy or dense.
 The color of the lesion varies widely and may be  Larger cysts  densely adherent to the surrounding
red, brown, black, white, yellow, pink, clear, or a pelvic sidewalls or broad ligament.
red vesicle.
predominant color depends on the blood  three cardinal histologic features
supply and the amount of hemorrhage and ectopic endometrial glands,
fibrosis. ectopic endometrial stroma,
color also appears related to the size of the hemorrhage into the adjacent tissue
lesion, the degree of edema, and the
amount of inspissated material  Previous hemorrhage  discovered by identifying
 Other peritoneal lesions that grossly appear similar large macrophages filled with hemosiderin near the
to endometriosis, but on histologic examination are periphery of the lesion.

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Gynecology
Comprehensive Gynecology 7th Ed
 aberrant endometrial glands and stroma respond in
cyclic fashion to estrogen and progesterone.  cyclic pelvic pain
These changes may or may not be in related to the sequential swelling
synchrony with the endometrial lining of the extravasation of blood and menstrual
uterus. debris into the surrounding tissue.
The ectopic endometrial stroma will
undergo classic decidual changes similar to  prostaglandins and cytokines.
pregnancy when exposed to high chemical mediators of this intense sterile
physiologic or pharmacologic levels of inflammation and pain
progesterone.
 Infiltrative endometriosis,
 Repetitive episodes of hemorrhage extensive areas of the retroperitoneal space,
lead to severe inflammatory changes moderate to severe pelvic pain.
result in the glands and stroma undergoing
necrobiosis secondary to pressure atrophy  Secondary dysmenorrhea
or lack of blood supply. common component of pain
dull ache to severe pelvic pain.
 presumptive diagnosis of endometriosis unilateral or bilateral
visualizing the intense inflammatory radiate to the lower back, legs, and groin.
reaction pelvic heaviness or a perception of the
large macrophages filled with blood internal organs being swollen.
pigment. pain may last for many days, including
several days before and after the menstrual
 pathophysiology of progression from subtle to severe disease flow.
may be expected from the multiple mechanisms of potential
disease acceleration discussed earlier, with immune function  dyspareunia associated with endometriosis
most likely involved. 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.
CLINICAL DIAGNOSIS
Symptoms abnormal bleeding is not associated with
anovulation and related to abnormalities of
 one in three women being asymptom (1/3)
the endometrium.
 Extremely unpredictable course.
patients with endometriosis frequently have
 The classic symptoms of endometriosis
ovulatory dysfunction.
cyclic pelvic pain
have coincidental anovulation or luteal
infertility.
dysfunction (15%)
 chronic pelvic pain  presents as secondary
 untreated endometriosis
dysmenorrhea or dyspareunia (or both).
increased incidence of first-trimester
Secondary dysmenorrhea  36 to 48
abortion
hours prior to the onset of menses.
unproven
Less common, yet troublesome,
 pelvic pain symptoms influencing the gastrointestinal
inversely related to the amount of and urinary tracts.
endometriosis in the female pelvis.  Cyclic abdominal pain, intermittent
constipation, diarrhea, dyschezia,
 moderate to severe chronic pain urinary frequency, dysuria, and
Large, fixed adnexal masses sometimes hematuria
have minor symptoms, whereas other  Bowel obstruction and
patients with only a few small foci with hydronephrosis
deep infiltration
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Gynecology
Comprehensive Gynecology 7th Ed
 Ultrasound examination
catamenial hemothorax no specific pattern to screen but helpful in
 rare clinical manifestation differentiating solid from cystic lesions
 bloody pleural fluid occurring distinguish an endometrioma from other
during menses. adnexal abnormalities. Because the lesions
are vascular, increased Doppler flow may
Massive ascites be demonstrated in endometriosis (Fig.
 rare symptom of endometriosis, 19.12).
 important because the disease transvaginal ultrasound (TVUS) detect DIE,
process initially masquerades as with the greatest sensitivity and specificity
ovarian carcinoma. for detection of rectosigmoid lesions.
Modified techniques such as rectal water
Clinical Findings (Physical Exam)
contrast transvaginal ultrasound can
 classic pelvic finding of endometriosis increase the probability of detecting a DIE
 fixed retroverted uterus, lesion, which is now considered to be the
 with scarring and tenderness posterior to more sensitive technique for the
the uterus. diagnosis of DIE

 characteristic nodularity of the uterosacral  Magnetic resonance imaging (MRI)

ligaments and culde-sac may be palpated on best overall diagnostic tool for
rectovaginal examination endometriosis
 Advanced cases not always a practical modality for its
 extensive scarring diagnosis.
 narrowing of the posterior vaginal fornix. hyperintensity - T1-weighted images
hypointensity - T2-weighted images
 ovaries
Diagnostic Laparoscopy
enlarged
tender  important to describe systematically the extent of
often fixed to the broad ligament or lateral the pathology.
pelvic sidewall.  point-scoring system in 1996 (American Society
for Reproductive Medicine)
 adnexal enlargement record the extent of the disease in fertility
rarely symmetric, as one may expect in patients
some benign pelvic conditions. provide characterization of disease extent
for fertility and not for pain assessment.
 Speculum examination
small areas of endometriosis on the cervix  scoring system by Adamson
or upper vagina. focuses on the fertility potential of patients
with endometriosis
 Lateral displacement or deviation of the cervix is Endometriosis Fertility Index (EFI),
visualized or palpated by digital exam of the vagina shown in prospective evaluation to
and cervix in approximately 15% of women with correlate with pregnancy rates
moderate or severe endometriosis.
 pelvic examination  first or second day of  endometriosis exhibits characteristics of both
menstrual flow may aid in the diagnosis as it is the malignancy and sterile inflammation kahit benign
time of maximum swelling and tenderness in the siya.
areas of endometriosis. common considerations in the differential
 diagnosis can be confirmed in most cases by direct diagnosis include chronic pelvic
laparoscopic visualization with its associated inflammatory disease, ovarian malignancy,
scarring and adhesion formation. degeneration of myomas, hemorrhage or
 endometriosis was discovered for the first time torsion of ovarian cysts, adenomyosis,
during an infertility investigation, although routine primary dysmenorrhea, and functional
laparoscopy is no longer being carried out in the bowel disease.
infertility investigation.
 Biopsy of selected implants confirms the diagnosis  large endometrioma of the ovary may rupture into
the peritoneal cavity.
Imaging This results in an acute surgical abdomen
 adjunct to the clinical presentation and brings into the differential diagnosis
 physical exam for evaluation of endometriosis, conditions such as ectopic pregnancy,
especially with deep infiltrating endometriosis (DIE). appendicitis, diverticulitis, and a bleeding
corpus luteum cyst
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Gynecology
Comprehensive Gynecology 7th Ed
 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.
MONITORING THE COURSE OF DISEASE: ARE
majority of cases  late 50s or early 60s
THERE MARKERS?
are related to the use of exogenous
 Serial pelvic examinations estrogen.
poor indicator of progression of disease. TREATMENT
 two primary short-term goals in treating
 cancer antigen-125 (CA-125) have been used as endometriosis
a marker for endometriosis. relief of pain
CA-125 levels are elevated promotion of fertility.
increases incrementally with advanced
stages.
 primary long term goal
assays for serum levels of CA-125 have a
attempting to prevent progression or
low specificity because they also increase
recurrence of the disease process.
with other pelvic conditions such as
leiomyomas, acute pelvic inflammatory
 Cochrane review of evidence-based therapies lists
disease, and the first trimester of
a variety of agents that may be helpful but does not
pregnancy.
specify a clearly preferred agent
CA-125 levels have a low sensitivity for the
because there have been few prospective
diagnosis of early or minimal endometriosis
head-to-head comparisons and because
the disease is heterogeneous with vast
 Glycodelin
differences in the spectrum of clinical
previously known as placental protein 14,
symptoms and extent of disease from one
elevated in endometriosis
woman to another.
produced in endometriotic lesions.
Thus, treatment plan must be
Levels also fall with removal of the disease.
individualized.
not proved to be useful clinically.
 Choice of therapy, for whose primary symptom is
 The most predictive markers appear to be Il-1,
pelvic pain, depends on multiple variables,
chemoattractant protein-1 and interferon gamma,
including the patient’s age, her future reproductive
with Il-1 being the most useful marker
plans, the location and extent of her disease, the
severity of her symptoms, and associated pelvic
 generally thought that endometriosis improves pathology.
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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Gynecology
Comprehensive Gynecology 7th Ed
 laparoscopy  suppresses symptomatology and prevents
gold standard for making a diagnosis progression but not provide a long-lasting cure of
this is not always possible, particularly in a the disease.
younger population.  medical therapy should be
individualized,
 Imaging techniques weighing in potential adverse effects,
only be helpful if a mass is identified, side effects,
suggestion of performing an endometrial cost of therapy
biopsy expected patient compliance.
too invasive for younger nulliparous
If gynecologic conditions such as chronic  clinical effectiveness  measured by relief of
pelvic inflammatory disease or neoplasia symptoms and recurrence rates of current medical
have been ruled out, therapies, are largely similar.
 empiric medical therapy for 3  chance of recurrence is directly related to the extent
months of initial disease.
 Various suppressive treatments  (FDA) has approved only
danazol
 Treatment of endometriosis gonadotropin releasing hormone
Medical (GnRH) agonists
Surgical
combination of both.  Other therapies
traditional oral contraceptives (OCs),
 sex steroids, alone or in combination, to suppress novel progestogens such as gestinone and
the growth of endometriosis. dienogest, an oral GnRH antagonist,
Optimal regression secondary to medical levonorgestrel-releasing intrauterine
treatment is observed in small system (IUS),
endometriomas that are less than 1 to 2 cm aromatase inhibitor letrozole,
in diameter. certain selective progesterone receptor
larger areas of endometriosis may be modulators.
minimal with medical therapy.
poor therapeutic result governed by the Danazol
reduction of blood supply to the mass  clinicians rarely prescribe danazol (because of lack
caused by surrounding scar tissue. of familiarity, side effect profile, and availability of
suppressive therapies, such as the use of other agents)
dienogest  decrease in nerve fiber most frequently select GnRH agonists,
density in endometriosis lesions progestogens, or oral contraceptives.

 Surgical therapy is divided into  for women with benign cystic mastitis, menorrhagia,
conservative and definitive operations. and hereditary angioneurotic edema.
 attenuated androgen that is active when given
 Conservative surgery orally.
 resection or destruction of endometrial  synthetic steroid that is the isoxazole derivative of
implants, lysis of adhesions ethisterone (17-α-ethinyltestosterone).
 attempts to restore normal pelvic  oral androgens such as methyl testosterone were
anatomy. also used, as they induce endometrial atrophy.
 Has hypoestrogenic and hyperandrogenic effect on
 Definitive surgery steroid-sensitive end organs.
 removal of both ovaries, the uterus, mildly androgenic and anabolic leading to
and all visible ectopic foci of its side-effect profile.
endometriosis.
 analogous to cytoreductive surgery in  induces atrophic changes in the endometrium of the
ovarian carcinoma uterus and similar changes in endometrial implants.
 modulate immunologic function
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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Gynecology
Comprehensive Gynecology 7th Ed
GONADOTROPIN-RELEASING HORMONE
AGONISTS
 doses of 400 to 800 mg of danazol have been
 Representative agonists
prescribed,
leuprolide acetate (Lupron, injectable),
many clinicians reduce the total daily
nafarelin acetate (Synarel, intranasal),
dosage of the drug to 200, and even
goserelin acetate (Zoladex, subcutaneous
100 mg daily.
implant).
 Danazol begun during menses (days 1 to 5).
relief of the symptoms is directly related  leuprolide acetate
to the incidence of amenorrhea  3.75 mg IM once per month or
 11.25-mg depot injection q 3 months.

***lower dosages of danazol are not as effective.  Nafarelin acetate

nasal spray
 Side effects
one spray (200 μg) in one nostril in the
deepening of the voice did not resolve after morning
discontinuation. one spray (200 μg) in the other nostril in
Mild elevation in serum liver enzyme the evening
who take danazol for longer than 6 months maximum of 800 μg daily.
should have serum liver enzyme
determinations.
 Goserelin acetate
androgenic effect on lipids occurs, with
 3.6 mg every 28 days in a biodegradable
reduction in high density lipoprotein (HDL)
subcutaneous implant
cholesterol and triglycerides and an
increase in low-density lipoprotein (LDL)
cholesterol.  dose-response curve of the GnRH agonists
establishing the optimal dose to produce sufficient
 6 to 9 months - standard length of treatment down-regulation and desensitization of the pituitary
objective improvement discovered at a to produce extremely low levels of circulating
second-look laparoscopy. estrogen and amenorrhea.
uncorrected fertility rate  Chronic use  produces a “medical
symptoms will recur in 15% to 30% of oophorectomy.”
women within 2 years following therapy.  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.

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Gynecology
Comprehensive Gynecology 7th Ed
 The clinical response to agonist therapy depends bisphosphonates not recommended in
when is initiated in regard to the menstrual cycle. younger women who may wish to become
 If agonist therapy is begun during the follicular pregnant.
phase,  Add-back regimens not only reduce or eliminate
agonist phase results in an initial rapid rise adverse clinical and metabolic side effects
in follicle-stimulating hormone (FSH) and associated with hypoestrogenism but also
E2 for approximately 3 weeks. facilitate safe and effective prolongation of
FSH levels fall to basal levels GnRH agonist therapy for up to 12 months.
 third to fourth week of therapy.  Additional agents that have been used for add back
therapy are
E2 levels rapidly decline after 21 days tibolone
LH does not occur, raloxifene
progesterone do not become elevated.
 GnRH antagonists have no “flare” effect.
 Amenorrhea induced within 6 to 8 weeks.  women not wishing to conceive, who predominantly
beginning agonist therapy during the luteal have pain and no indication for surgery (which may
phase or if artificially manipulated by the include failed medical therapy), stopping and
concurrent administration of oral starting various treatments and interchanging them
progestogen, serum E2 levels are is a reasonable approach to control symptoms.
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. ORAL CONTRACEPTIVES
 very large doses of norethynodrel with mestranol
 greatest therapeutic effects are seen when areas of daily
endometriosis are less than 1 cm in diameter. produce amenorrhea
 Ovarian function usually returns to normal in 6 to 12 “pseudopregnancy.”
weeks after 6 months of GnRH agonist therapy.
 Large ovarian endometriomas and severe adhesive  low-estrogen monophasic combination pills,
disease have not responded to hormonal therapy. specifically the ones with a relatively high
 many clinicians “add back” hormone replacement progestin potency, are equally effective
therapy with dosages similar to those used in when used in a continuous fashion.
menopausal therapy in combination with chronic most economical regimen for the treatment
GnRH agonist regimens. with mild or moderate symptoms of
add-back medication will reduce or endometriosis has been continuous daily
eliminate the vasomotor symptoms and oral contraceptives for 6 to 12 months.
vaginal atrophy
diminish or overcome the demineralization  Continuous dose regimens are aimed at more
of bone. complete suppression, with an advantage over
add-back therapy not interfere with the cyclic use
effectiveness of agonists to relieve the  only concern is with breakthrough bleeding, which
pelvic pain from endometriosis. can be dealt with in a variety of ways as with
no diminished therapeutic efficacy when contraceptive therapy
add-back therapy is initiated  potential risk of using oral contraceptives or
simultaneously with the GnRH agonist. progestogens
risk of rupture if a large endometrioma is
 therapeutic window in a circulating level of present.
approximately 30 pg/mL of E2 Rupture of large endometriomas may result
 E2 is enough to protect the body from substantial in an acute surgical abdomen during the
bone loss and is not high enough to interfere with first 6 weeks of oral contraceptive therapy.
the inhibition of growth of endometriosis  prolonged therapy
 clinicians additionally give bisphosphonates and endometrial glands atrophy
calcium with the low-dose progestins and estrogen, stroma undergoes a marked decidual
reaction.
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Gynecology
Comprehensive Gynecology 7th Ed
 Gestrinone
 smaller endometriomas (∼3 cm) can undergo progestogen
necrobiosis and resorption. once a-week oral contraceptive.
 most common side effects of inducing 2.5 to 7.5 mg/ week.
amenorrhea with oral contraceptives agonist–antagonist of progesterone receptors
weight gain agonist of androgen receptors
breast tenderness. binds weakly to estrogen receptors.
tendency for prolonged pain relief was
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS observed
 for pain relief
 concomitant therapy may improve the bleeding  Dienogest
control of patients on oral contraceptives. selective progestogen
 direct therapeutic value in endometriosis. causes anovulation
 cyclooxygenase-2 (COX-2) inhibitors are now antiproliferative effect on endometrial cells
infrequently used because of cardiovascular inhibit cytokine secretion.
concerns in older individuals, 2 mg/day orally effective as GnRH agonists
 this therapy for endometriosis has a rationale in that
lesions of endometriosis have been found to  levonorgestrel IUS
express high levels of COX-2 for pain relief in women with endometriosis
 beneficial for pain relief compared to expectant management.
 potentially for the treatment of endometriosis, for women who have rectocervical and cul-de-
particularly when other suppressive therapy cannot sac disease
be used.
 Aromatase inhibitors
Other Hormonal Treatments anastrozole 1 mg
 who cannot tolerate the high dosage of estrogen in letrozole 2.5 and 5 mg
an oral contraceptive or have contraindication to beneficial in estrogen tend to cause proliferation of
estrogen therapy the disease and also endometriosis lesions have
treatment with progestogens only has been been found to contain the aromatase enzyme
successful. given alone to premenopausal women it will cause
stimulation of gonadotropins and been used to
induce ovulation;
 Medroxyprogesterone acetate (Provera)
postmenopausal women and premenopausal
20 to 30 mg orally per day or women in combination with a progestogen or oral
depo-medroxyprogesterone acetate contraception pills there is good promise that it will
(DepoProvera) be beneficial
 150 mg IM q 3 months
 maximum of 200 mg q month will OTHER POSSIBLE MEDICAL THERAPIES
produce a prolonged amenorrhea.  several other less well-proved therapies.
most appropriate for the older woman who peroxisome proliferator-activated
has completed childbearing. receptor (PPAR) ligands,
time of resumption of ovulation following  inhibit macrophage action
discontinuation of injectable
medroxyprogesterone is prolonged and targeting haptoglobin
extremely variable.  because of structural similarity to
Some women will not ovulate for more than Endo-1
a year after their last injection. targeting MMPs
 Thus, this form of therapy should not be tumor necrosis factor α and VEGF
prescribed for a young woman who is  ERβ agonists
contemplating pregnancy in the near increasing VEGF and angiogenetic factors
future. are mediated through ERβ
Oral medroxyprogesterone in a dosage of modulate immune function.
30 mg/day is an alternative mode of ***selective estrogen receptor modulators, specifically
therapy, as is norethindrone acetate (10 to tamoxifen and raloxifene, have not been shown to be
40 mg) daily. This more androgenic beneficial
progestogen, although quite effective, has  anti-inflammatory immunomodulator, pentoxifylline,
a similar symptom profile to that for has also shown promise.
continuous medroxyprogesterone.  medicinal herbs
antiproliferative and anti-inflammatory and
pain-relieving properties
no rigorous clinical trial data are available
at present.

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Gynecology
Comprehensive Gynecology 7th Ed
ROUTE OF ADMINISTRATION  removal of the ovaries may decrease the risk of
 Delivering various progestogens or danazol locally disease recurrence,
(intrauterine as with the levonorgestrel IUS or balanced with the risks associated with
vaginally) may also enhance effectiveness. removing the ovaries
 benefit of using suppositories and local agents, individualized based on the patient’s age,
particularly in those women with cul-de-sac disease clinical presentation, and goals.

SURGICAL THERAPY  postsurgical hormonal suppression with progestins

 adjunct or alternative to medical therapy or oral contraceptives may be considered in order
 Prevent or delay further disease progression. to decrease risks of recurrence, especially if there
 main roles of surgical therapy in endometriosis is any residual or unresectable disease at the time
provide symptomatic relief (pain) of surgery.
improve fertility outcomes.  Other surgical treatments
presacral neurectomy
 includes conservative and definitive approaches  short-term improvement in
address three main categories of symptoms, but complications can
lesions: include bowel and bladder
 superficial endometriosis dysfunction.
 endometriomas photodynamic therapy
 deep infiltrating endometriosis  undergoing preliminary trials
(DIE).  intravenous injection of a special dye
that is concentrated in areas of
 Conservative surgery
endometriosis.
 preservation of reproductive organs
 laser light produces a photochemical
 restoration of normal pelvic anatomy while
reaction to destroy the areas
removing all macroscopic endometriotic
lesions or endometriomas and performing SURGICAL MANAGEMENT FOR FERTILITY
lysis of adhesions.  Medical therapy may sometimes be required for
symptomatic control while waiting for fertility
 Definitive surgery treatment; however, this is generally not
 removing the uterus and cervix along with recommended.
any visible lesions  improved fertility outcomes with prolonged GnRH
 while preserving or removing either one or agonist use when administered prior to assisted
both of the ovaries. reproductive treatment.
Surgical management in these women can
 invasive surgical approaches such as laparoscopy be considered
and robotic surgery have largely replaced the need
for laparotomy  stage I/II endometriosis, excision or ablation of
o due to advantages such as improved endometriosis
visualization, shorter recovery period, increase live birth and ongoing pregnancy
decreased blood loss, and decreased rates
risks of complications. thus, recommended when visible lesions are
 Restoring normal pelvic anatomy, preventing present.
adhesions, and limiting tissue damage is essential Although lack of trials, for stage III/IV,
for successful endometriosis surgery. surgical treatment has also been suggested
 start dissections going from normal anatomy toward to increase pregnancy rates
abnormal anatomy.
 Energy should be used judiciously and cautiously  Endometriomas
esp with difficult dissections with distorted anatomy  has potential risks such as infection
and when adjacent to vital structures such as major  interfering with response to infertility
blood vessels, the ureter, bladder, or bowel. treatments and oocyte retrieval,
 risks of complications in pregnancy, and
SURGICAL MANAGEMENT FOR PAIN
malignancy.
 chronic pelvic pain due to endometriosis who have
 decrease ovarian reserve.
failed conservative medical therapy, surgery can be
 surgical removal is not generally
an effective treatment,
recommended prior to IVF.
esp moderate or severe endometriosis  surgery does not necessarily increase fertility
which pelvic adhesive disease is present
outcome while it can further compromise
along with the involvement of ovarian reserve, increase the risk of
nonreproductive organs. premature ovarian failure, and induce early
menopause.

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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  cyclic GI symptoms
 generally occur
GASTROINTESTINAL TRACT ENDOMETRIOSIS
 suspicion of GI endometriosis should be
 gastrointestinal tract involvement with histologically high with this type of presentation.
proven endometriosis varies from 3% to 37%.
 Most large series approx. 5%.  Physical exam
 extrapelvic endometriosis help with diagnosis of deep infiltrating
Implants that involve the gastrointestinal endometriosis invading the rectosigmoid
tract most common site such as by palpation of a pelvic mass or
most challenging to manage. “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,

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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.
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