Endometriosis

Pharm 565Kerry MansellOctober 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 body’s 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

20’s / early 30’s who have delayed pregnancies

Risk Factors• Asian > Caucasian > African races• Maternal inheritance – relative risk is 3-10x higher if

you have a 1st 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-factorial1. 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

Etiology2. 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 & IL’s 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 women’s desired outcomes: – Relieve pain– Improve fertility

• Tx options: surgery, pharmacotherapy, or both

PAIN-ASSOCIATED ENDOMETRIOSIS

1. Medical Management• 1st line treatment: NSAID’s, OCP’s, or both

– Best treatment is OCP, or OCP + NSAID – some sort of hormonal therapy should be involved

NSAIDS • Appropriate 1st choice if mild sx’s & 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 analgesicsAcetaminophen: • Perhaps for mild symptoms• Less effective due to lack of anti-inflammatory

propertiesNarcotic 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 Sx’s & women with

no current desire to get pregnant• Good safety profile

CHC’sWhat 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•SE’s, precautions, and contraindications…..– These are considerably better tolerated than

alternative hormonal options (and cost less!)

Hormonal Therapy2. 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: 2nd line to OCP’s b/c of ’ed SE’s•AE’s: 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 1st 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 GnRHMOA:• 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 pseudomenopausal (hypoestrogenic) state

• Result: Diminishes endometrial implants & pain reliefEfficacy: 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®) IMIntranasal sprays: • nafarelin (Synarel®)• buserelin (Suprefact®)

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

Hypoestrogenic SE’s:• 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 AE’s yet maintain efficacy• HOW? Theory: there is an estrogen threshold effect– Amount of estrogen given is enough to alleviate Sx’s 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 SE’s: – Weight gain Acne– Hirsutism increase LDL’s– Hot flashes ↓ breast size

• Estrogen deficit: – vasomotor sx’s– 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• SE’s: 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

treatmentConservational 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 ptsB. Watchful waiting - for younger ptsC. 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 SE’s

Examples of how to manage certain SE’s:• 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– AE’s of therapy

• Manage expectations– Should achieve relief from endometriosis-related pain

within 2 months– With respect to fertility