Clinical pearls: Endometriosis

April 04, 2022
By Erica Evangelista

Background

Endometriosis affects over 176 million individuals worldwide. Pharmacists play a significant role both in reducing the economic costs of endometriosis & in managing consequences of co-morbidities associated with the disease, such as chronic pain. Pharmacists can also effectively consider factors regarding peri- & post-operative management.

Endometriosis is an inflammatory disease associated with pelvic pain & infertility, characterized by lesions of endometrial-like tissue outside of the uterus.1 As a result of this chronic inflammatory reaction, scar tissue may form primarily in the pelvic peritoneum, ovaries, bladder, bowel, & in the diaphragm & lungs.2,3

Clinical presentation

  • Not pathognomonic symptoms include fatigue, pelvic pain, infertility, mittelschmerz, dyspareunia & dysfunctional uterine bleeding4,5,6 painful bowel movements, constipation & low back pain.7
  • Some patients diagnosed with endometriosis are asymptomatic.6

Diagnosis

  • Challenging to diagnose: definitive diagnosis often takes 7 -12 years from symptom onset 9
  • Clinical suspicion: physical examination & history of pelvic pain, dysmenorrhea & dyspareunia
  • Confirmation of diagnosis: direct visualization via laparoscopy & biopsy if required 4,6

Epidemiology

Endometriosis affects over 1 million people in Canada & over 176 million worldwide.10,11 1 in 10 women & unmeasured numbers of transgender & gender diverse people are diagnosed.10

Risk factors 5

  • Low body mass index (BMI)
  • Tall height
  • Family history of endometriosis
  • Gynaecologic factors e.x. early age of menarche, short menstrual cycle & heavy menstrual flow

Pathogenesis

Mechanism

The underlying mechanism of endometriosis is not yet established. Plausible theories include:

  • Histogenesis: transplantation, celomic metaplasia & induction 6
  • Genetic predisposition (family history) 12,13
  • Aberrant endocrine signaling 14
  • Imbalanced cell proliferation and apoptosis 14
  • Altered immunity 14
  • Retrograde menstrual flow 14

Management & treatment options

There is currently no known cure for endometriosis, but symptom management can successfully target associated pain, infertility & pelvic masses. 4,6

In managing endometriosis, the goals of therapy include relieving pain, treating infertility & preventing recurrence.4 Management can be multifaceted & can include medications, surgery, or both. 4,6 Surgery should be reserved for patients with endometriosis-associated pain for whom medication has failed.15 It is inadvisable to initiate medication alone or in combination with surgery if the patient’s only symptom is infertility, as this does not improve pregnancy rates.16 However, laparoscopic treatment of mild disease does improve pregnancy rates.15

Figure 1: Management of Endometriosis

Created by Erica Evangelista, adapted from The Compendium of Pharmaceuticals and Specialties (CPS) Algorithm on Endometriosis4  and Society of Obstetricians and Gynaecologists of Canada (SOGC) Management of Symptoms Associated with Suspected or Confirmed Endometriosis17






Table 1 (below) examines types of medications appropriately indicated for symptoms associated with endometriosis. Note: Most of these treatments are not suitable for long-term use due to side-effects.2,18 Up to 50% of patients have a recurrence of symptoms within 5 years of medical management.

Table 1: Pharmacologic choices

Category

Class & examples

Symptom control

Mechanism of efficacy

Advantages

Disadvantages

Analgesics

NSAIDs

e.x. Ibuprofen, Naproxen

 

1st line for mild menstrual pain with or without endometriosis diagnosis

Inhibit endometrial prostaglandins to prevent abnormal uterine contractions 4

Can be used as adjunct to hormonal therapies if needed

Do not always relieve endometriosis-related pain. Typically work better in combination with other treatment 19

Long-term use not recommended due to side effect profile 20

Not appropriate in patients with renal insufficiency

Opioids 

e.x. 

Oxycodone, Hydromorphone, Codeine, Tramadol hydrochloride21

 

Pelvic pain

Effect on bowel motility may reduce pelvic pain4

 

Not recommended for endometriosis pain due to limited evidence & lack of established guidelines. 22,23 Opioid use before diagnosis significantly increases risk of prolonged opioid use after diagnosis.24

Hormonal therapies

Combined oral contraceptives

e.x.

Ethinyl estradiol (EE) /norethindrone (Brevicon ®)

 EE/desogestrel (Marvelon ®)

 EE/drospirenone (Yasmin ®)

 EE/levonorgestrel (Min-Ovral ®, Seasonale ®, Alesse ®)

 

1st line for endometriosis pain & dysmenorrhea ideally administered continuously 15

 

 

Decidualization & atrophy of endometrial implants 6

Reduction of retrograde menstrual flow

Ovulation suppression

Prostaglandin generation reduction

 

 

Initial proliferative response can exacerbate  symptoms in months prior to improvement 6 

Must use lowest effective estrogen dose to limit estrogen dependency of lesions

Not appropriate in patients with liver disease & breast cancer

Progestin-Only Contraceptives

 

e.x.

Dienogest (Visanne ®)

Norethindrone acetate (Norlutate ®)

Medroxyprogesterone acetate (Provera ®, Depo-Provera ®

Levonorgestrel intrauterine system (Mirena ®)

1st line for endometriosis pain

 

 

Decidualization & atrophy of endometrial tissue 6

Significant pain relief

 

Use if patient has contraindication to estrogen use

Potential BMD loss

Not effective in improving infertility. Particularly, Depo-Provera has slow return to fertility upon discontinuation

Androgen Agonists

e.x.

Danazol (Cyclomen ®)

2nd line for dysmenorrhea

Treats moderate to severe disease

Hypoestrogenic vaginal changes, vasomotor symptoms, & endometrial atrophy 6

 

Highly effective for dysmenorrhea but less effective for chronic pelvic pain 25

Teratogenic

Many side effects from androgenic properties (hair loss, weight gain, acne, hirsutism) 26

Gonadotropin-Releasing Hormone Agonists +/- add-back hormone therapy

 

e.x.

Buserelin acetate (Suprefact ®)

Goserelin acetate (Zoladex ®)

Leuprolide acetate  (Lupron Depot ®)

 Nafarelin acetate (Synarel ®)

Triptorelin pamoate (Trelstar ®)

 

 

2nd line for endometriosis associated pain 15

Reserved for patients with persistent symptoms after use of 1st-line therapy 20

Hypoestrogenic state to induce atrophy & regression of endometriotic implants 27

No significant differences in pain relief with 3 month vs. 6 month treatment duration 28

 

* GnRH agonist + add-back therapy is as effective as GnRH agonist monotherapy for relieving pelvic symptoms 29

If patient undergoes IVF, using GnRH agonist with HT add-back 3-6 months before IVF is associated with improved pregnancy rate 15

Gonadotropic flare & pain prior to long-term receptor down-regulation 14

Use add-back hormonal therapy when appropriate to mitigate BMD loss & flare up. Women should be encouraged to have adequate calcium intake & vitamin D supplementation while on therapy 4

Recurrence of symptoms over 5 yrs after completion of therapy ranges from 37% in mild disease to 74% in severe 30

Gonadotropin-Releasing Hormone Antagonists

 

e.x.

Elagolix (Orilissa ®)

Dysmenorrhea

Reduces dysmenorrhea, nonmenstrual pain and dyspareunia 4

Quick onset & avoids gonadotropin flare upon initiation

Hypoestrogenic side effects (hot flashes, increased lipid level & BMD loss)

Neuromodulators 16,32

TCA

Amitriptyline

 

SNRI

Duloxetine

Venlafaxine

 

Anti-convulsants

Gabapentin

Pregabalin

 

Muscle relaxants

Cyclobenzaprine

Pelvic pain

 

Treatment should come from an interdisciplinary approach according to the type of pain they experience 31

 

Muscle relaxants can help reduce overall muscle tone & spasms contributing to pelvic pain

Alters pain processing due to central sensitization 31,32

For TCAs and SNRIs, may benefit patients with concurrent mental health issues

Association between endometriosis-associated pain & psychiatric conditions such as depression are highly prevalent. 24,33

Affordable & well tolerated 34

Could prevent unnecessary long-term hormone therapy & surgery that may compromise fertility 34

Lack of studies involving neuromodulators in endometriosis 31

 

Complimentary therapies

    • Pelvic floor physiotherapy 6
    • CBT 6
    • Electrotherapy * 20
    • Acupuncture 20
    • Exercise 6
    • Dietary products & vitamins B1. B6 and D * 20,35,36
    • Aromatase P450 inhibitors * 4,6,14,20
    • Selective progesterone receptor modulators * 4,6,14,20

    * Not well established & require further research

     

    Special populations: Pregnancy & lactation

    Women with endometriosis who are pregnant or breastfeeding may experience a temporary relief of endometriosis-associated symptoms.4 For patients desiring to conceive, excision is a preferable surgery option to ablation because spontaneous pregnancy rates are higher 9 - 12 months after surgery. 4

     

    Pharmacists’ roles 

    Information online often provides patients with misinformation on endometriosis.38 Pharmacists play a pivotal role in directing patients to evidence-based resources to better understand their diagnosis. Patients suffering from endometriosis-associated chronic pain may also experience mental health issues; there is a highly prevalent association between endometriosis & psychiatric conditions such as depression, anxiety & self-directed violence.24,33,39 Pharmacists can collaborate with the interdisciplinary team to manage chronic pain & find appropriate therapies for patients with multiple co-morbidities.

    Perioperative management

    Surgical management can be approached either conservatively or definitively. In conservative surgery, the goal of therapy is to restore normal anatomy & help relieve pain through procedures such as direct ablation or laparoscopic excision.9 This method is preferred in women of reproductive age. Ablation removes only the surface level of endometriosis via heat & is not an effective technique for treating endometriosis, as the endometrial-like cells can still grow & cause pain. Despite ablation resulting in poor outcomes, higher re-operation rates & increased pain, it remains the most common surgical approach for endometriosis.40 On the other hand, definitive surgery may involve removal of all visible lesions of endometriosis. Definitive procedures include bilateral oophorectomy, hysterectomy, and/or salpingectomy, depending on the affected organ.9 Definitive surgery is reserved for patients in significant pain for whom conservative treatment failed & who do not intend to conceive in the future. Laparoscopic excision remains the most preferred surgical approach, regardless of severity of disease, as it provides greater visualization of lesions, quicker recovery & more rapid return to normal activity.9,26

    Upon admission, pharmacists gather & document accurate medication history of the patient. This provides pharmacists with the opportunity to identify & resolve drug therapy problems, for instance holding herbal dietary supplements 1-2 weeks prior to surgery due to increased bleeding risk with anesthetic agents.41 For women & transgender & gender diverse individuals on oral contraceptives or hormone replacement therapy, these agents should be discontinued 4-6 weeks prior to surgery, as they can further increase risk of venous thromboembolism.42,43 For this reason, deep venous thrombosis prophylaxis such as low-molecular-weight heparin or unfractionated heparin should be initiated in moderate to high-risk patients. 44 At baseline, 4 to 5 non-CHC (combined hormonal contraceptive) users are at risk of experiencing a VTE per 10,000 per year, whereas that of CHC users rises to 8-9 per 10,000 per year. 45

    To minimize the risk of perioperative infection complications, the team may initiate appropriate empiric prophylaxis therapy of an antibiotic. For example, the first-line choice of antibiotic for hysterectomy is a first-generation cephalosporin.46,47 If patients are allergic to cephalosporin, alternatives include clindamycin, erythromycin, or metronidazole. 46 

    Postoperative management

    Surgeries carry a risk of postoperative nausea and vomiting (PONV). 48 Pharmacists play a role in preventing & treating PONV through initiating antiemetic agents such as 5HT3 antagonists, antidopaminergics, corticosteroids, NK-1 receptor antagonists, & prokinetic agents. Pharmacists should help advocate for prevention of PONV, as preventing is more effective than treating PONV. 49 Ondansetron, dexamethasone, & haloperidol are equally effective in preventing PONV. 49 

    Although gynecologic surgeries do provide adequate pain control, patients are still at risk of experiencing postoperative chronic pain. In the outpatient setting, pharmacists contribute to pain management by collaborating within primary care practice such as family, ambulatory, and pain clinics. In the inpatient setting, hospital pharmacists are likely to collaborate with surgeons or anaesthesiologists to ensure adequate pain control.

    Long-term health consequences 

    The available data over recent years suggests that women with endometriosis may be at higher risk of developing chronic diseases such as cancer, autoimmune diseases, asthma or allergic manifestations & cardiovascular diseases, but further studies are required to confirm the associative relationship. 50-53


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