Endometriosis Flashcards
What is endometriosis? Where can it present? What can it result in?
The presence of endometrial tissue outside of the uterus
It can present anywhere, but is commonly limited to the pelvic area
This can result in pain, and/or infertility (e.g. Endometrial tissue in fallopian tubes leading to blockage)
Describe the prevalence of endometriosis?
Affects ~10% of females of reproductive age
Affects up to 50% of women experiencing infertility
Affects ~70-80% of women experiencing chronic pelvic pain
Peak prevalence in those 25-35yo (Avg age at diagnosis is 27.9)
Describe the cause of endometriosis?
The exact cause remains unknown
There are a few theories, however it is most likely multi-factorial
Describe the theories for the cause of endometriosis
- Retrograde Menstruation Theory
- Immunologic Theory
- Coelomic Metaplasia Theory (Induction Theory)
- Vascular / Lymphatic Theory
Describe retrograde menstruation therapy
Endometrium shed during menstruation flows back through the fallopian tubes and becomes implanted on organs / tissues in the pelvic area
Rather than flowing out through the vagina
Describe the immunologic theory for endometriosis
An underlying, immunologic disorder is responsible
Endometrial tissue is able to evade the immune system (deficient cell-mediated immunity)
This theory is supported by the presence of abnormal B & T cell function, and altered levels of cytokines & IL’s in endometrial lesions
Some of these changes may create an environment which is toxic to sperm (contributing to infertility)
Describe the coelomic metaplasia theory for endometriosis
Coelomic Metaplasia Theory (Induction Theory)
The coelomic epithelium is epithelial tissue that lines the surface of the abdominal organs
Lesions develop when cells covering the peritoneum undergo metaplasia. I.e. normal peritoneal tissue transforms via metaplastic transition to ectopic endometrial-like tissue
Metaplasia – Once cell type to another
Describe the vascular/lymphatic theory for endometriosis
Endometrial cells are spread to distant locations via the lymphatic system or vascular pathways (i.e. to the lung, brain, eyes)
Describe the pathophysiology of 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 ↑ E
Decreased progesterone (P) receptors, hence P can’t antagonize the effects of E: “progesterone-resistance”
Overall, there is ↑ E stimulation of the endometriosis
Stimulation by E can stimulate PGE2, COX2 – i.e. can have pro-inflammatory effects
Describe the relationship between estrogen and pain in endometriosis
Repetitive cycles of bleeding and inflammation may lead to adhesions and scarring on adjacent tissues
What are some of the reasons for pain in endometriosis?
Inflammation
Immune responses to the endometrial lesions may lead to ↑ levels of pro-inflammatory cytokines
Neuropathic Pain
Endometrial lesions may compress on nerve fibres or adjacent structures
Central sensitization
Persistent pain can alter response to stimuli, leading to central sensitization (i.e. ↑ pain perception)
Bleeding from endometrial tissues
Describe the relationship between pain and severity of endometriosis
Pain is not indicative of severity
e.g. a large amount of pain is not indicative of a severe pathology
Is endometriosis in regards to the experience of pain often diagnosed as endometriosis?
Endometriosis may not be discovered until one is investigated for infertiity
Describe the hallmarks of the pathophysiology of endometriosis? What is the course of endometriosis?
Genetic predisposition
Estrogen dependence
Progesterone resistance
Inflammation
Endometriosis may remain stable, regress, or progress (approximately 1/3 each)
What are some risk factors for endometriosis?
What are the major symptoms of endometriosis? Are the sx the same for everyone? Are sx indicative of the severity of the condition?
Pain
Sub/Infertility (reason why most seek MD)
Note: Sx’s vary from person to person, are unpredictable, and up to 1/3 may be asymptomatic
Sx’s also do not always correlate with extent of the disease
Describe the clinical presentation of endometriosis
Major symptom: pain
dysmenorrhea (80-90%)
chronic pelvic pain
–> Non-cyclical abdominal and pelvic pain ≥6 months
dyspareunia (30%)
painful defecation / urination
lower back pain
*** Can still worsen at times in the cycle – Can occur at any time in the cycle **
Describe the timeline of pain in endometriosis
Pain can be intermittent or constant; often occurs with menstrual cycle, but can occur anytime in cycle
What are some other signs and symptoms of endometriosis that an individual may experience?
In what other conditions should endometriosis be suspected?
Endometriosis should be suspected in women complaining of subfertilty, dysmenorrhea, dyspareunia, or chronic pelvic pain
Describe the impact of endometriosis
Functional impairments across domains: Psychological, Social, Occupational, and Academic
Persistent pain and decreased QOL
Disruption in work and studies
Physical and mental toll
Describe the diagnosis of endometriosis
Average 6-12yrs between initial sx’s and diagnosis
–> Pain is shared with many diseases, leading to a delay
The diagnosis is based on a thorough history, physical exam, and imaging assessments
The gold standard is visualization at laparoscopy and histological study**
–> Can determine extent of dx, but is not required before treatment can be started
** Histological examination of endometrial lesions**
Describe the staging of endometriosis. Issue with staging?
Limited clinical usefulness - Does not correlate with sx severity
Is there a cure for endometriosis?
There is no cure, so treatment is aimed at management
Describe the goals of therapy for endometriosis
The goals of treatment will vary depending on the person’s desired outcomes:
Relieve symptoms
Improve fertility
What are the tx options for endometriosis? What is treatment based on?
Tx options: surgery, pharmacotherapy, or both
Treat based on symptoms, preference, and priorities
Describe the management of sx associated with suspected or confirmed endometriosis?
Diagnosis made and then patient decides if sx control or fertility
Describe the first line pharamcotherapy options for endometriosis. Benefit?
1st line:
Hormonal therapies
Combined hormonal contraceptives (CHC)
Progestins
Oral, IM, SC implants, IUD
Similarly effective to later treatment options but with fewer AEs and less $
NSAIDs: can help for dysmenorrhea
Describe the goals of hormonal therapy
1) Supress the menstrual cycle
2) Create amenorhhea
3) Stop ovulation if that process is painful
Describe the role of combined hormonal contraceptives?
Suppress ovulation and the growth of implants
They decrease hormone levels, & they keep the menstrual cycle regular, shorter, and lighter
With oral combined hormonal contraceptives, does the estrogen component stimulate endometrial tissue growth?
The estrogen used (ethinyl estradiol) has less estrogenic activity than endogenous estradiol, and the progestin helps prevent a rise in estradiol
Does not cause endometrial lesions to grow
Describe who oral combined hormonal contraceptive is useful for
Ideal for people with no current desire to get pregnant
Describe the dosing of CHC’s in endometriosis
They can be used cyclically or continuously
Some evidence favours continuous use
Describe the evidence for the use of CHC’s in endometriosis? Safety?
Trials show clinically significant ↓ in endo-related pain
Evidence primarily with OCPs (but patch or vaginal ring are options as well)
They are safe and can be used long-term
What are some of the side effects of CHC?
SE’s (i.e. breast tenderness, h/a, nausea, weight gain, mood changes), precautions (i.e DVT risk), and contraindications
Describe the tolerability of CHC compared to other hormonal therapies in endometriosis
CHCs are considerably better tolerated than alternative hormonal options (and less $)
What are some of the initial potential adverse effects of COC? Management of the side effects?
Common in first 3 months of starting pill:
Breakthrough bleeding (BTB) (Spotting – Not a full on period)
–> Check adherence
–> If lasts >6 months look for other causes (STIs) – check at how they are taking the pill, if forgetting, different times
–> Change to pill with ↑ estrogen/progestin (depending when BTB occurs in cycle)
Breast tenderness
–> If lasts longer than first 3 months, look for other causes
Change to pill with ↓ estrogen
Nausea
Take at HS or with food
Change to pill with ↓ estrogen
Weight gain (controversial)
Some notice ↑ appetite in first month, but overall little or minimal weight gain
Remember weight fluctuates with age and water retention
Headache or migraine
Can be hormone-related
Can either ↓ or ↑ with use
Mood changes – Depression
–> Observational study
Acne
Can worsen initially…but…
Usually improves with long-term use
Several OC have official indications for acne…but all combined OC can be beneficial
–> Lowers amount of endogenous androgens produced or (bio)available (androgens stimulate sebum production → acne)
If a continued problem, change to pill with ↓ androgenic activity
Or use topical therapy
What are some of the potential risks of COC?
Contraceptive failure
Especially if missed pills with <20mcg estrogen (less s/e; however, need good adherence)
Venous thromboembolism (VTE)
Risk is 2-3x higher than in non-users
Risk ↑ with age, smoking, ↑ estrogen dose
Controversy whether drospirenone increases risk
MI and stroke (arterial thrombosis)
↑ risk associated with estrogen >50mcg day, age >35 years, smoking, HTN and other CVD risks
What are some of the early signs of the risks associated with COC?
A – Abdominal pain (severe)
Gallbladder, pancreatitis, thrombosis
C – Chest pain (severe) or shortness of breath
Pulmonary embolus or myocardial infarction
H – Headaches (severe)
Stroke, hypertension, migraine
E – Eye problems (blurring, flashing, vision loss)
Stroke, hypertension, vascular insufficiency
S – Severe leg pain (calf or thigh)
DVT
What are some drug interactions that alter the levels of COC? How can they be managed?
CPY450 3A4 inducers
Anticonvulsants (carbamezapine, phenytoin)
Anti-infectives (rifampin)
Herbals (St John’s wort)
Management:
Use product with higher estrogen levels (>30ug EE)
Use extended dosing (skip HFIs)
Use alternative to interacting drug or other method of birth control
What drugs metabolism is altered by combined OC? Management?
Metabolism altered by oral contraceptives
Lamotrigine (significantly ↓ levels – induction of lamotrigine glucuronidation)
Management
Use alternative to interacting drug or other method of birth control
What are some of the contraindications of COC?
Thromboembolic disease
Current or past VTE
Hypertension (>160/100mmHg)
Ischemic heart disease / Stroke
Known or suspected breast cancer
Migraine with aura
Severe / active liver disease
Post-partum
–> Wait least 3-6 weeks post-partum b/c increased risk of VTE
Smokers (>15 cigs/day)
Over 35 years old
What are the two types of the progestin-only pills?
Norethindrone 35mcg daily (no HFI)
Drospirenone 4mg OD x 24 days then 4 placebo pills
Describe the MOA of norethindrine?
Alters cervical mucus and endometrium (main moa)
Describe the MOA of drosperinone?
Primarily suppresses ovulation
Describe the indication of progestin-only contraceptives?
Estrogen contraindicated
History/risk of blood clots (VTE)
Smoker >35 years old
Obese
Migraine
Breastfeeding – won’t decrease milk supply
What are the adverse effects of progestin only pills?
Irregular bleeding (more so in first months)
Headache
Bloating, wgt gain (water)
Acne
Breast tenderness
Potential to ↑ K+ (monitor if risk for hyperkalemia) –> Drosperinone, monitor it
What are some contraindications of the progestin only pills?
Liver disease
Breast cancer
Drug interactions similar to combined OC
What are some of the progestins hormonal therapy? How do they work?
They help prevent the rise in estradiol, without estrogen related stimulation of endometriotic growth, & induce a hypoestrogenic environment
Can help with dysmenorrhea symptoms
Describe the efficacy of progestins compared to other contraceptives in endometriosis?
Similar efficacy to other hormonal therapies
What are some adverse effects of progestin contraceptives in endometriosis?
AE’s - breakthrough bleeding, weight gain/fluid retention, mood changes, h/a
Depot: may delay the return in ovulation, and decraesed BMD with prolonged use
Dienogest: may be detrimental to BMD (especially adolescants, adults can be reversed), associated with less anti-androgenic effects, requires non-hormonal contraception
IUS: risk of expulsion; long-term effect on BMD unknown
Counselling point regarding contraception in endometriosis
A minimum of a 3 month trial should be tried prior to moving on to subsequent treatment options for pain control
Describe the MOA of NSAID’s in endometriosis
MOA: interfere with PG synthesis (which is overexpressed in endometrial lesions)
Describe the evidence for NSAIDs in endometriosis and there role in therapy for endometriosis
Is a lack of high-quality evidence assessing their efficacy, and no evidence favouring one over another1
Appropriate 1st choice if sx’s are mild & women do not want to take a hormonal treatment option
Appropriate to use in conjunction with hormonal tx options
Describe the dosing of NSAIDs in endometriosis
Dosing: use on a scheduled basis
–> can administer intermittently or continuously
Counsel differently if continuous or intermittently
What are some precautions associated with NSAIDs?
Precautions: GI, renal, reactive airway disease
What are some other analgesics (besides NSAIDs) that can be used in endometriosis?
Acetaminophen:
–> Perhaps for milder symptoms…
Narcotic analgesics:
–> Codeine, hydrocodone, others
What are GnRH agonists in endometriosis ?
Gonadotropin-Releasing Hormone (GnRH) Agonists
Synthetic analogs of human GnRH
Describe the MOA of GnRH agonists in endometriosis?
Bind to GnRH receptors in the pituitary, and initially cause an ↑ release of LH/FSH
Due to their long t½ , 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 hypoestrogenic state, endometrial atrophy, and amenorrhea
Describe the role of GnRH in the menstrual cycle
Feedback Loop
GNRH initial increase sin LH and FSH - Increases estrogen and then progesterone
What is an example of a GnRH agonist?
Lupron Depot - Leuprolide acetate
Describe the duration of use of lupron depot for endometriosis? Why? Other counselling point/concern?
Sx may temporaily worsen after first dose and then improve in one month
Limited to 6 months of use – Adverse effect profile
Product monographs say treatment up to 6 months – treatment duration is determined by the prescriber
Describe lupron therapy in regards to endometriosis and the menstrual cycle
Describe the avilable GnRH agonits in Canada
Describe the overall side effects that may occur from GnRH agonist therapy
bone loss
vasomotor symptoms
(hot flashes, night sweats, vaginal dryness, insomnia, decreased libido)
Other common side effects:
Headache/migraine
mood swings
What are the side effects of GnRH agonists analagous with?
Sx’s are analogous to menopause due to near-depletion of E. To combat, add-back therapy can be used
Prior to GnRH agonist therapy, what is required prior to administration?
Rule out pregnancy before use; use non-hormonal birth control while taking
What is add back treatment regarding GnRH agonist therapy in endometriosis?
To counter bone loss and vasomotor symptoms, a low dose estrogen +/or progestin should be added
E.g. Estrace 1mg + MPA 2.5mg od
E.g. CES 0.625mg + norethindrone acetate 5mg od
E.g. Norethindrone acetate 5mg od
Note: not combined oral contraceptives
Describe how add back therapy in GnRH agonist therapy maintains efficacy of the GnRH agonist?
E.g. Estrace 1mg + MPA 2.5mg od
E.g. CES 0.625mg + norethindrone acetate 5mg od
E.g. Norethindrone acetate 5mg od
Add back estrogen with or without progestin
These regimens decrease AE’s yet maintain efficacy
HOW? Theory: there is an estrogen threshold effect
Why are COHC not used for GnRH therapy?
Combined oral contraceptives (COCs) are not the preferred add-back therapy because they have limited bone protection effects.
Sex hormone-based add-back therapy is the preferred method for these treatments because it can effectively protect bone mass
When add back therapy is used with GnRH agonists, what is the duration of use?
When add back tx used – Can be used for up to 12 months
Describe the efficacy of leuprolide acetate
Norethindrorne is a progestin – Estrogenic and androgenic properties
Why is add back therapy used alongside GnRH agonists? Efficacy of add back tx?
Add back therapy prevents bone loss with GnRH agonists
Describe the female sex Hypothalmus-Pituatry-Gonad (ovarian) Axis
What is an example of a GnRH antagonist?
Elagolix (Orilissa)
2018: first FDA oral medication approved for moderate –severe endometrial pain in over a decade
Describe the MOA of GnRH antagonists and its role in endometriosis therapy
An oral GnRH receptor antagonist –> it competitively binds to GnRH in the pituitary and suppresses gonadotropins & causes rapid, reversible, dose-dependent hypoestrogenic state
Describe the dosing of elagolix
Partial estradiol suppression: 150mg daily
Nearly full estradiol suppression: 200mg BID (reserved for severe refractory cases)
Start at lower dose as there is a dose-dependent decrease in BMD; adjust based on symptoms
Is there a difference between GnRH antagonists and agonists in the treatment of endometriosis?
Similar efficacy as GNRH agonist
Describe the administration of Elagolix
Can be taken with or without food. Begin at time of menstruation; patients should use an effective method of contraception not containing estrogen
Describe the adverse effects of Elagolix
ADVERSE EFFECTS: hot flashes, headache, insomnia, nausea, amenorrhea, mood swings, night sweats
Dose-dependent increases in TC, LDL, TG, and decrease in BMD
Changes in cholesterol returned to baseline; BMD recovery started at 6 months
Describe the drug interactions of Elagolix
DRUG INTERACTIONS: CYP interactions
Describe the efficacy of Elagolix
Both reduce dysmenorhhea and non-menstrual pelvic pain – Higher dose does it more effectively
Describe the critical counselling points associated with GnRH antagonist therapy
Rule out pregnancy before beginning
Use a non-estrogen contraceptive
Estrogen will reduce efficacy – Can sue progestin only and non-hormonal
200mg BID x 6mos is max use due to BMD concerns / not studied beyond 1 year
Ensure adequate calcium and Vitamin D intake
Can cause alterations in bleeding patterns
Common side effects – hot flashes, headache, nausea, insomnia, mood changes
What are some examples of aromatase inhibitors?
Anastrozole, letrozole, exemestane
Describe the MOA of aromatase inhibitors in endometriosis
Aromatase is a key enzyme in the conversion of adrenal androgens to estrogens
By inhibiting aromatase, it will lower overall estrogen
Describe the efficacy of aromatase inhibitors in endometriosis
Efficacy: not a lot of evidence available, but some signals they decraese pain alone or in combo with CHCs, progestins, and GnRH agonists
Not routinely recommended – Use if other options have not worked
More used in breast cancer and post-menopausal women in studied
What are some side effects of aromatase inhibitors? Comparison to other therapies?
SE’s: h/a, nausea, diarrhea (mild), hot flash, vaginal dryness
- Less than GnRH agonists - Long-term use may impact BMD – may consider add-back therapy with CHC or progestin
Describe the MOA and role of Danazol in endometriosis
A synthetic androgen derived from 17-ethinyl testosterone
Induces a pseudomenopausal state by increased androgen levels & decreased estrogen levels (it suppresses the production of LH & FSH)
Estradiol suppression will cause anovulation, amenorrhea, and atrophy of the endometrial tissue
Describe the efficacy of danazol in endometriosis
Efficacy: 80-90% achieve symptomatic improvement
However, use is no longer supported due to androgenic AEs (voice changes, weight gain, hair growth, acne, negative impact on lipid profile)
Rarely used due to side effects
Describe the dose of danazol in endometriosis
Dose: 600-800mg/d (divided BID) for ~6 months (po or vaginal)
When is surgical management of endometriosis considered?
For those:
who are infertile and desire pregnancy
not responding to pharmacologic therapies
What is the main surgical management method of endometriosis pain?
Conservational Treatment: Laparoscopy
Describe the expectations after laparoscopic surgery of endometriosis
What are some other surgical interventions that may be used for tx of endometriosis? Concern?
Hysterectomy with or without oophorectomy
TAH-BSO (total abdominal hysterectomy - bilateral salpingo-oophorectomy) + removal of all visible endometriosis
It does not guarantee resolution of sx’s – up to 10% may have pain recurrence at 1 year
Ovaries removed – Menopause – Low dose hormones used
What is the Alliance for Endometriosis? Statistics?
Aim: to eliminate stigma and encourage conversations to speed up diagnosis and improve treatment options
Describe pregnancy and fertility concerns in endometriosis?
Generally recommend waiting 1 month after d/c medical therapy before trying to conceive
If pregnancy occurs, endometriosis generally enters remission with pregnancy
PLAN AHEAD HERE
Describe the proposed explanations for infertility associated endometriosis
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 some of the management options for infertility-associated endometriosis?
Describe the role of the pharmacist in the management of endometriosis
