Endometriosis

Pharm 565
Kerry Mansell
October 2012
Learning Objectives
Be familiar with the proposed etiologies /
pathogenesis of endometriosis
Recognize the signs & symptoms of endometriosis
Describe the available therapies for the treatment
of pain-associated & infertility-associated
endometriosis
Recognize common side effects & limiting factors
associated with certain therapies
Be able to make appropriate recommendations for
endometriosis therapy
What is Endometriosis?
The presence of endometrial tissue
outside of the uterus
This results in pelvic pain, and/or sub-
fertility or infertility
Endometriosis can present anywhere, but
is commonly limited to the pelvic area
E.g. ovaries, fallopian tubes, bowel,
bladder, rectum



What is endometriosis?
If endometrial cells implant outside the uterus,
endometriosis results
The presence of ectopic endometrial tissue evokes an
estrogen-dependant chronic inflammatory process
Endometrial implants contain estrogen, progestin,
and androgen which respond to the bodys cyclic
release of hormones during the menstrual cycle
As estrogen decreases, cyst decreases
In general, estrogen stimulates the implants, whereas
androgens cause them to atrophy (progestins have
variable effects)
Withdrawal of E and P cause the endometriomas to
bleed - leading to inflammation in the adjacent
tissues
Repetitive cycles of bleeding and inflammation may
lead to adhesions and scarring on adjacent tissues
Size of the cyst does not correlate with pain large cyst can
have no pain

Endometriosis: link to pain & infertility
Endometriosis-associated pain is secondary to structural
+/or inflammatory causes
The purported mechanism for the pain:
The release of prostaglandins
Endometrial lesions may compress on nerve fibres or
adjacent structures
Chemical peritoneal irritation (leaking endometriomas)
Blood stays in the body rather than bleeding out
The purported mechanism for infertility:
Chronic inflammation can lead to scar tissue which can
block the fallopian tubes (or lead to a distorted pelvic
structure)
Endometriosis may remain stable or regress in 50% of
women; remaining 50% have progression at variable rates
May get worse as years go on
Epidemiology
Affects an estimated 5-10% of women of
reproductive age
Affects 3 in 10 women experiencing infertility
Affects 7 in 10 women experiencing chronic
pelvic pain
Most commonly occurs in women in their late
20s / early 30s who have delayed
pregnancies
Risk Factors
Asian > Caucasian > African races
Maternal inheritance relative risk is 3-10x higher if
you have a 1
st
degree maternal relative with
endometriosis
Sister or mom who has endometriosis
Having an autoimmune disease
Early menarche
Short monthly cycle (<27 days)
Heavy menses; menses lasting longer than 7 days
Decreased incidence in smokers and with OCP use
Some evidence suggests regular exercise may
decrease risk
Etiology
The cause remains unknown
There are a few theories as to the cause,
however it is most likely multi-factorial
1. Retrograde Menstruation Theory:
Endometrium shed during menstruation flows
back through the fallopian tubes and becomes
implanted on organs / tissues in the pelvic
area
However, this happens in 80-90% of all women
suggests something else might be in play

Etiology
2. Immunologic Theory
An underlying, immunologic disorder is responsible
Abnormal B-/T-cell function
Endometrial tissue is able to evade the immune
system (deficient cell-mediated immunity)
Tissue/cells are able to evade and grow
This theory is supported by the presence of
abnormal B & T cell function, and altered levels of
cytokines & ILs in endometrial lesions
Some of these changes may create an environment
which is toxic to sperm


Etiology
3. Coelomic Metaplasia Theory
The coelomic epithelium is epithelial tissue that lines the surface of
the abdominal organs
Metaplasia turns one type of cell into another type of cell,
cancerous process
It retains its ability to differentiate into multiple cell types
The trigger for metaplasia appears to be estrogen and/or
environmental factors
However, this occurs in women 20-30, and metaplasia is more of an
aging process only a theory, does not entirely describe the process
of endometriasis
4. Vascular / Lymphatic Theory:
Endometrial cells are spread to distant locations via the lymphatic
system or vascular pathways
(i.e. to the lung, brain, eyes)

Likely because of a combination of the above etiology

Symptoms / Clinical Presentation
Symptoms vary greatly from person to person; up to 1/3
may be asymptomatic
Major symptom:
Pain most commonly presents as pelvic pain, but also as:
dysmenorrhea
dyspareunia painful intercourse
painful defecation
lower back pain
May occur anytime during the cycle; may be intermittent
or continuous
Character of the pain is not that of normal menstrual
cramps

Other Signs / Symptoms
Symptoms:
GI (urinary disturbances, constipation),
abdominal bloating
Premenstrual spotting, heavy, irregular bleed
Fatigue
Signs:
Pelvic mass
Adnexal tenderness (tenderness in the pelvic
area)
Subfertility (a women presents with
subfertility, pelvic pain, dysmenorrhea she
should be investigated into endometriosis)
***Endometriosis should be suspected in women
complaining of subfertilty, dysmenorrhea,
dyspareunia, chronic pelvic pain***


Diagnosis
Diagnosis is often delayed or missed for many years
The diagnosis should be based on a thorough history,
physical exam, and imaging assessments
The physical exam / ultrasound / MRI are suggestive
markers but not definitive
The gold standard is visualization at laparoscopy and
histological study
Can determine extent of dx
CONS: $$$ and invasive
Does not affect treatment, or treatment rate just
purely for diagnostic purpose
Diagnostic laparascopy is not required before
treatment can be started

Treatment
There is no cure, so treatment is aimed at
managing the condition
The goals of treatment will vary depending on
the womens desired outcomes:
Relieve pain
Improve fertility

Tx options: surgery, pharmacotherapy, or both


PAIN-ASSOCIATED ENDOMETRIOSIS

1. Medical Management
1st line treatment: NSAIDs, OCPs, or both
Best treatment is OCP, or OCP + NSAID some sort of hormonal
therapy should be involved
NSAIDS
Appropriate 1
st
choice if mild sxs & if do not desire
contraception
MOA: There is increased expression of cyclooxygenase in
endometriosis lesions; NSAIDs treat the pain by
interfering with PG synthesis
Efficacy: NSAIDs produce a variable response - failure with
one does not preclude use of others
Dosing: use on a scheduled basis
can administer intermittently or continuously
Precautions: GI, renal, reactive airway disease
Use until primary medical treatment becomes effective
Help control the pain
Other analgesics
Acetaminophen:
Perhaps for mild symptoms
Less effective due to lack of anti-inflammatory
properties
Narcotic analgesics:
Codeine, hydrocodone, propoxyphene (usually
with ASA or acetaminophen)

Hormonal Therapy
1. Combined Hormonal Contraceptives (CHCs):
They work by suppressing ovulation, ing
hormone levels, & they keep the menstrual cycle
regular, shorter, and lighter
The estrogen used (ethinyl estradiol) has less
estrogenic activity than endogenous estradiol
Less amount of estrogen-therapy decrease peaking of
estrogen
Ideal for adolescents with mild Sxs & women with
no current desire to get pregnant
Good safety profile
CHCs
What you need to know
They can be used cyclically or continuously
They are as effective as any other hormonal
therapy
Studies and use typically with OCPs (unsure of
role of patch or ring) work possibly?
They are safe and can be used long-term
SEs, precautions, and contraindications..
These are considerably better tolerated than
alternative hormonal options (and cost less!)

Hormonal Therapy
2. Progestins:
MPA 30-100mg po od; levonorgestrel IUS; Depot
MPA 150mg IM q3mos
MOA: inhibit ovulation, reduce hormone levels, &
induce endometrial atrophy
Are equally efficacious to other hormonal
therapies
Place in therapy: 2
nd
line to OCPs b/c of ed SEs
AEs: breakthrough bleeding, weight gain, fluid
retention, mood




Dienogest 2mg tabs (Visanne

)
A new progestin indicated for the management of
pelvic pain associated with endometriosis
It has progestogenic effects (and is
antiandrogenic) and acts by decreasing estradiol
production
It inhibits ovulation, but it is not recommended to
be used as a contraceptive if required combine
with a barrier method
Dose: 2mg od (taken continuously)
AEs: headache & breast discomfort (~5%)
Menstrual cycle changes (particularly 1
st
3 months)
A new drug, so long-term efficacy & safety
unknown in those who take it beyond 15 months
3. GnRH agonists
Synthetic analogs of human GnRH
MOA:
Bind to GnRH receptors in the pituitary, and initially cause
an release of LH/FSH
Due to their long t , down-regulation of the hypothalamic-
pituitary-ovarian axis occurs
This prevents the release of endogenous GnRH from the
hypothalamus, blocking the release of FSH/LH, and
results in a pseudomenopausal (hypoestrogenic) state
Result: Diminishes endometrial implants & pain relief
Efficacy: comparable to other hormonal methods
(85-100% response after 6 months)
Usual course: 3-6 months (up to a year) mostly 6 months
Place in therapy: after OCPs, progestins due to AE profile
(bone loss), cost


GnRH agonists
Available products:
Injectables:
leuprolide depot (Lupron

) IM
goserelin (Zoladex

) SC
buserelin (Suprefact

) SC
Triptorelin (Trelstar

) IM
Intranasal sprays:
nafarelin (Synarel

)
buserelin (Suprefact

)

Choice is guided by desired administration route
Rule out pregnancy before use

Hypoestrogenic SEs:
bone loss osteoporosis
beyond 6 months use bone
loss MIGHT be irreversible
vasomotor symptoms
hot flashes, night sweats,
vaginal dryness, insomnia
usually quite bothersome
Headache
Decreased libido
Mood swings
Add-back Treatments
To counter bone loss and vasomotor symptoms, a low dose
estrogen with low dose progestin should be added to GnRH
therapy from beginning of therapy
E.g. Estrace 1mg plus pulsed dose Micronor
E.g. NE 2.5mg od + etidronate (for bone loss)
These regimens AEs yet maintain efficacy
HOW? Theory: there is an estrogen threshold effect
Amount of estrogen given is enough to alleviate Sxs and prevent
bone loss but not enough to stimulate endometrial growth and
support endometriosis

4. Danazol
A synthetic androgen derived from 17-ethinyl testosterone
Induces a pseudomenopausal state by androgen levels &
estrogen levels (it suppresses the production of LH &
FSH)
Estradiol suppression will cause anovulation, amenorrhea,
and atrophy of the endometrial tissue
Efficacy: 80-90% achieve symptomatic improvement
However, use is limited due to its SE profile

Dose: 600-800mg/d (divided BID) for 3-9 months
Danazol
Limitations:
SE occurs in 85% of women
Androgenic SEs:
Weight gain Acne
Hirsutism increase LDLs
Hot flashes breast size
Estrogen deficit:
vasomotor sxs
urogenital ageing
emotional
Teratogenic

Aromatase Inhibitors
Anastrozole, letrozole, exemestane
Aromatase is a key enzyme in the synthesis of estrogens,
and is expressed in endometriotic implants
Efficacy: Studies have shown in pain and lesion size when
used alone and in combination with other hormonal tx
Studies are small and further research needed; use is
reserved at present
SEs: h/a, nausea, diarrhea (mild)
less hot flashes than GnRH agonists
Long-term use: decreased bone density (may be
appros. to use add-back therapy)
Surgical Management
Can be used for pain relief if unresponsive to medical
treatment
Conservational Treatment:
Goal: restore normal anatomy and relieve pain
through laparascopy
Efficacy: 60-80% obtain pain relief & improved QOL
However, 20-40% may show no improvement
Recurrence of pain observed in 40-50% after 5 yrs
One study reported that women will have, on average, 3
surgical procedures
Tx with hormonal therapy should be considered after
conservative surgery (in those not wishing to get
pregnant) as not all lesions can be removed

Surgical Management
Definitive Treatment
What is it? Removal of uterus
TAH-BSO (total abdominal hysterectomy - bilateral
salpingo-oophorectomy) + removal of all visible
endometriosis
This may be followed by Short-term ERT
(e.g. 0.625mg CEE)
Why? To control vasomotor symptoms and delay
osteoporosis
Hypoestrogenic state after the procedure
This does not seem to stimulate residual endometriomas
(studies limited to a few years duration)
Definitive Surgical Management
PROS:
90% effective for controlling pain; has the best odds of
preventing disease recurrence
CONS:
Invasive surgery: risks involved
Unacceptable option for those considering pregnancy
Not 100% effective!
Performed when endometriosis is:
Unresponsive to other treatment regimens, causing
incapacitating pain, threatening other organs

INFERTILITY- ASSOCIATED ENDOMETRIOSIS
Multiple proposed explanations:
Changes in characteristics of peritoneal fluid
Extensive scarring from endometrial lesions distorts
pelvic anatomy causing mechanical obstruction
Autoimmune mechanisms
Increased concentrations of inflammatory cells;
hostile environment to sperm/embryo
Hyperprolactinemia
Increased uterine peristaltic activity, which may
prevent embryo implantation
INFERTILITY- ASSOCIATED ENDOMETRIOSIS
Management options:
A. NSAIDs for pain relief for younger pts
B. Watchful waiting - for younger pts
C. Conservational surgery
Laparascopic tx of mild endometriosis improves
pregnancy rates, however effectiveness on deeply
infilitrating endometriosis is controversial
D. Ovarian stimulation or In Vitro fertilization

Pharmacologic therapy is not effective as stand-
alone therapy or after surgery
Role of the pharmacist
Be aware that rate of recurrence is high with both
medical and conservative surgery therapy
Educate: how the medications work, expected SEs

Examples of how to manage certain SEs:
Vaginal dryness: Astroglide, Replens
Hot flashes: cold packs applied to neck
Bone loss: calcium / vit D
Role of the pharmacist
Monitoring of therapy
Efficacy of therapy
AEs of therapy
Manage expectations
Should achieve relief from endometriosis-related pain
within 2 months
With respect to fertility