Endometriosis Flashcards
What is endometriosis?
presence of endometrial tissue outside of the uterus
-can present anywhere, but is commonly limited to the pelvic area
-this can result in pain and/or infertility
When is the peak prevalence of endometriosis seen?
those 25-35 yo
What causes endometriosis?
exact cause remains unknown
-there are a few theories, however it is most likely multifactorial
theories:
-retrograde menstruation
-immunologic
-coelomic metaplasia (induction)
-vascular/lymphatic
Describe the retrograde menstruation theory.
endometrium shed during menstruation flows back through the fallopian tubes and becomes implanted on organs/tissues in the pelvic area
Describe the immunologic theory.
an underlying, immunologic disorder is responsible
endometrial tissue is able to evade the immune system
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
What is coelomic epithelium?
the coelomic epithelium is epithelial tissue that lines the surface of abdominal organs
Describe the coelomic metaplasia theory (induction theory).
lesions develop when cells covering the peritoneum undergo metaplasia
-i.e. normal peritoneal tissue transforms via metaplastic transition to ectopic endometrial-like tissue
Describe the vascular/lymphatic theory.
endometrial cells are spread to distant locations via the lymphatic system or vascular pathway
What is going on in endometriosis?
endometrial tissue deposits outside the uterus
-likely via retrograde menstruation
these implants are dependent on estrogen (E)
-they can grow & bleed similar to the uterine lining during a menstruation cycle
aromatase is present in lesions, leading to increased E
decreased progesterone (P) receptors, hence P cant antagonize the effects of E (progesterone resistance)
overall, there is increased E stimulation of the endometriosis
stimulation by E can stimulate PGE2, COX-2 (pro-inflammatory)
How does estrogen fuel endometriosis pain?
proliferation of endometriotic lesions
inflammation
Describe the factors that might contribute to the pain that might be seen in endometriosis.
inflammation:
-immune responses to the endometrial lesions may lead to increased levels of pro-inflammatory cytokines
neuropathic pain:
-endometrial lesions may compress nerve fibres or adjacent structures
central sensitization:
-persistent pain can alter response to stimuli, leading to central sensitization (increased pain perception)
bleeding from endometrial tissues
What are the hallmarks of the pathophysiology of endometriosis?
genetic predisposition
estrogen dependence
progesterone resistance
inflammation
may remain stable, regress, or progress
What are the risk factors for endometriosis?
European descent
1st degree maternal relative with endometriosis
not having children
early menarche (< 10 yo)
short monthly cycle (< 28 days)
heavy menses; > 5-6 days
What are the major symptoms of endometriosis?
pain
sub/infertility
What can be said about the variability of the symptoms of endometriosis?
symptoms vary from person to person, are unpredictable, and up to 1/3 may be asymptomatic
symptoms do not always correlate with extent of disease
Which symptoms contribute to the pain in endometriosis?
dysmenorrhea
chronic pelvic pain
-non-cyclical abdominal and pelvic pain > 6 months
dyspareunia
painful defecation/urination
lower back pain
Is the pain in endometriosis constant?
can be intermittent or constant; often occurs with menstrual cycle, but can occur anytime in cycle
What are some other signs and symptoms that might be seen in endometriosis?
symptoms:
-GI (urinary disturbances, constipation, bloating)
-premenstrual spotting, heavy/irregular bleed
-fatigue
signs:
-pelvic mass
-pelvic/adnexal tenderness
-subfertility
In which women should we suspect endometriosis?
women complaining of subfertility, dysmenorrhea, chronic pelvic pain, or dyspareunia
What are the impacts of endometriosis?
persistent pain - QoL
disrupt work/studies
physical/mental toll
How long is the average time between initial symptoms of endometriosis and the diagnosis?
average 6-12 years
-pain is shared with many diseases, leading to a delay
What is the gold standard for diagnosis of endometriosis?
laparoscopy and histological study
-can determine extent of disease, but is not required before treatment can be started
What is the cure for endometriosis?
there is no cure, so treatment is aimed at management
What are the goals of therapy for endometriosis?
the goals of treatment will vary depending on the persons desired outcomes
-relieve symptoms
-improve fertility
What are the treatment options for endometriosis?
surgery
pharmacotherapy
or both
What are the goals of therapy for pain-associated endometriosis?
suppress the menstrual cycle
create amenorrhea
stop ovulation if that process is painful
What are the 1st line pharmacotherapy options for pain-associated endometriosis?
hormonal therapies
-combined hormonal contraceptives
-progestins
Which symptoms of endometriosis can NSAIDs help with?
dysmenorrhea
How does the efficacy of hormonal therapies compare to newer therapies for pain-associated endometriosis?
similarly effective
-fewer AEs and less $$
What is the MOA of CHC in endometriosis?
suppress ovulation and the growth of implants
-they decrease hormone levels & keep the menstrual cycle regular, shorter, and lighter
How come ethinyl estradiol in CHC doesnt stimulate growth of implants?
EE has less estrogenic activity than endogenous estradiol and the progestin helps prevent a rise in estradiol
For which endometriosis patients is CHC an ideal option?
no current desire to get pregnant
How should CHCs be used in endometriosis?
cyclically or continuously
-some evidence favours continuous use
What is the evidence for CHCs in endometriosis?
trials show clinically significant decrease in endo-related pain
-evidence primarily with OCPs (but patch or ring are options)
What are some common adverse effects of CHCs?
breast tenderness
headache
nausea
weight gain
mood changes
safe and can be used long-term
considerably better tolerated than alt hormonal options and less $$
What is the efficacy of progestins in endometriosis-associated pain?
similar efficacy to other hormonal options
What are some common adverse effects of progestins?
breakthrough bleeding
weight gain/fluid retention
mood changes
headache
Depot: delay return in ovulation, decreased BMD (long use)
dienogest: may be detrimental to BMD, associated with less anti-androgenic effects, require non-hormonal contraception
IUS: risk of expulsion, long-term effect on BMD unknown
How long should CHC/progestins be trialed before moving onto another option for pain control in endometriosis?
a minimum of a 3 month trial
What is the MOA of NSAIDs in endometriosis?
interfere with PG synthesis (which is overexpressed in endometrial lesions)
What is the evidence for NSAIDs in endometriosis?
lack of high-quality evidence assessing their efficacy
no evidence favouring one over another
When are NSAIDs an appropriate choice in endometriosis?
symptoms are mild & women do not want to take a hormonal treatment option
in conjunction with hormonal treatment options
How are NSAIDs dosed in endometriosis?
on a scheduled basis
-can administer intermittently or continuously
What is the MOA of GnRH agonists?
bind to GnRH receptors in the pituitary, and initially cause an increased release of LH and FSH
due to their long t1/2, down-regulation of the HPO axis occurs
-this prevents the release of endogenous GnRH from the hypothalamus, blocking the release of LH/FSH, and results in a hypoestrogenic state, endometrial atrophy, and amenorrhea
What is seen with the first injection of a GnRH agonist depot?
temporary increase in estrogen levels
-temporary worsening of symptoms for ~ 1 month
What are examples of GnRH agonists?
buserelin
goserelin
leuprolide
nafarelin
triptorelin
What are side effects of GnRH agonists?
hypoestrogenic AEs
-bone loss (reversible on d/c)
-vasomotor symptoms
-headache/migraine
-mood swings
the AEs are analogous to menopause due to E depletion
What can be used to combat the adverse effects of GnRH agonists?
add back therapy
What should be ruled out before starting a GnRH agonist?
pregnancy
What kind of birth control should be used while on a GnRH agonist?
non-hormonal
What is add-back treatment?
low dose estrogen +/or progestin to counter bone loss and vasomotor symptoms
-not CHC
What is the benefit of add-back treatment in endometriosis?
decrease AE of GnRH agonists yet maintain efficacy
-how? theory: there is an estrogen threshold effect
What is the MOA of elagolix?
oral GnRH receptor antagonist
-competitively binds to GnRH in the pituitary and suppresses gonadotropins & causes rapid, reversible, dose-dependent hypoestrogenic state
How is elagolix dosed?
start at lower doses as there is dose-dependent decrease in BMD; adjust based on symptoms
-partial estradiol suppression: 150 mg daily
-nearly full estradiol suppression: 200 mg BID
How should elagolix be administered?
can be taken with or without food
begin at time of menstruation
use effective method of contraception not containing estrogen
What are the adverse effects of elagolix?
hot flashes
headache
insomnia
nausea
amenorrhea
mood swings
night sweats
dose-dependent increases in TC, LDL, TG, and decrease in BMD
What are drug interactions of elagolix?
CYP
-CYP inducer
-3A4 substrate
What needs to be ruled out before starting elagolix?
pregnancy
What is the max dose and duration of use for elagolix?
200 mg BID x 6 months
-due to BMD concerns/not studied beyond 1 year
What are examples of aromatase inhibitors?
anastrozole
letrozole
exemestane
What is the MOA of aromatase inhibitors?
inhibiting aromatase, lowering overall estrogen
-aromatase is a key enzyme in the conversion of adrenal androgens to estrogens
What is the efficacy evidence for aromatase inhibitors?
not a lot of evidence available
-some signals they decrease pain alone or in combo with CHCs, progestins, and GnRH agonists
What are the adverse effects of aromatase inhibitors?
headache
nausea
diarrhea
hot flash
vaginal dryness
long-term may impact BMD
less than GnRH agonists
What can be considered to combat adverse effects of aromatase inhibitors?
add-back therapy
What is the MOA of danazol?
induces a pseudomenopausal state by increasing androgen levels & decreasing estrogen levels (it suppresses the production of LH & FSH)
-estradiol suppression will cause anovulation, amenorrhea, and atrophy of the endometrial tissue
-a synthetic androgen derived from 17-ethinyl testosterone
Describe the efficacy of danazol.
80-90% achieve symptomatic improvement
-however, use is no longer supported due to androgenic AE
When is surgical management considered for endometriosis?
infertile and desire pregnancy
not responding to pharmacologic therapies
What is the typical surgical option for endometriosis?
laparoscopy
What are the benefits of laparoscopy?
fertility:
-can help improve fertility in women with minimal/mild endometriosis
-effect on deeply infiltrating endometriosis is unclear
pain:
-recurrence of pain in up to 50% 5yrs post-surgery
-some will require repeat surgery
What should be considered post-op for endometriosis?
long-term hormonal suppression to reduce risk of recurrent pain
What is the most definitive surgical option for endometriosis?
hysterectomy
Upon discontinuing medical therapy, how long should a women wait to conceive?
1 month after d/c medical therapy
What generally occurs to endometriosis with pregnancy?
endometriosis generally enters remission
-can recur after birth
What are the multiple proposed explanations for why endometriosis causes infertility?
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
increased uterine peristaltic activity, which may prevent embryo implantation
irregularities in menstrual cycle
What are the management options for infertility-associated endometriosis?
watchful waiting
NSAIDs for pain relief
conservational surgery (minimal endometriosis)
ovarian stimulation or in vitro fertilization
What is the difference in tolerability between GnRH agonists and elagolix?
elagolix does not cause the initial worsening of symptoms
-better tolerated than GnRH agonists
What is the MOA of progestins in endometriosis?
prevent the rise in estradiol, without the estrogen related stimulation of endometriotic growth, & induce a hypoestrogenic environment
