Endometriosis Part II: Treatment

How do we treat endometriosis? 

• Approach 

  • Should be based on severity of symptoms and make sure that other causes of pelvic pain are excluded 

  • Usually, medications are tried first because of the risks, recovery, and costs of surgery

  • Discussion of desire for fertility in the future can also help guide your management 

  • Review with patients that this is a chronic disease - it is not curable, but can be treated. Also, discuss that the road through treatment can be long, and that one mode of therapy that is effective for some, may not be effective for others 

• Medical 

  • NSAIDS 

    • Can be used to treat primary dysmenorrhea, and is first line for that 

    • However, no high-quality data reporting its efficacy in endometriosis; however it is low-cost and readily available; usually combined with combined hormonal therapy 

  • Estrogen-progestin contraceptives 

    • First line treatment for endometriosis because can be used long-term, well tolerated, and are relatively easy to use 

    • No formulation has demonstrated superiority

    • Both cyclic and continuous dose appear to be effective at reducing pain, but two systemic reviews reported that continuous COC regimens were more effective at reducing pain than cyclic (meaning you take the active pills in one pack → move on to the next pack, skip the placebos) 

    • This is because COCs suppress ovarian function while they are being taken and can reduce endometriosis disease activity and pain 

    • Obviously, there are risks and benefits of taking COCs, and there are many people that cannot take COCs because of the estrogen component (check out our past episode!)

  • Progestins 

    • If people can’t take estrogen, then they can use progestin only therapy 

    • Most commonly = norethindrone acetate 5 mg by mouth daily, but can be increased by 2.5 until l15 mg daily is the max

    • Depo Provera - 150 mg IM injection q12 weeks 

    • Progestins inhibit endometrial tissue growth. It also doesn’t carry the risk of VTE with COCs, and avoids risk of bone loss and menopausal symptoms associated with GnRH agonists

    • However, side effects include increased breakthrough bleeding, weight gain (Depo Provera), mood changes 

    • Alternatives: Etonogestrel implant - observational trial of 41 women showed it decreased intensity of endometriosis-related pain

    • LNG-IUD - limited evidence, but postop IUD can reduce recurrence of dysmenorrhea in women with surgically confirmed endo 

  • Gonadotropin-releasing hormone agonists 

    • I.e., leuprolide; others are things like buserelin, goserelin, etc 

    • Meta-analysis shows they are more effective than placebo, and just as effective as other medical therapies 

    • Common doses: Leuprolide 3.75 IM qmonth or 11.25 mg q3 month 

    • However, remember that it is a GnRH AGONIST 

      • Initially, can worsen symptoms for a little bit due to initial surge of LH and FSH before eventually suppressing the HPO axis (warn patients about 7-14 days of worsening symptoms) 

    • To counteract the hypoestrogenic effects (ie. menopausal symptoms, vasomotor symptoms), usually will do add-back therapy with 5 mg oral norethindrone 

  • GNRH Antagonist 

    • Also suppress HPO axis, but does so immediately, without initial LH and FSH surge like agonists 

    • Also induces a hypoestrogenic state and can cause vasomotor symptoms, as well as leads to decrease in bone density  

    • Easier to dose because they are oral rather than IM 

    • Ex: elagolix (Orilissa), dosed 150 daily up to 200 mg twice daily 

  • Danazol

    • Can be effective in reducing pain, but not common because it can cause androgenic side effects  

  • Aromatase inhibitors 

    • Usually reserved for severe, refractory endometriosis-related pain 

    • Often used in combination with progestins 

    • Off-label use of AI 

    • Limited data overall, but does seem to decrease pain compared to placebo 

    • Similarly, can cause hypoestrogenic side effects 

  • Neuropathic pain treatments 

    • Can be used if there is still pain from endometriosis (see other below)  

• Other 

  • Often, long-lasting pain from endometriosis can become chronic pain 

  • See our chronic pain episode → basically can lead to a cycle of lowered threshold of stimulus to cause pain, central sensitization 

  • May also need other therapy such as pelvic floor PT

  • May need neuropathic pain treatments (ie. gabapentin) to decrease sensitization. Remember to remind your patients that gabapentin does not take pain away immediately, and needs to be used consistently for several weeks 

• A note on opioids 

  • Patients with endometriosis and pelvic pain may receive opioids for pain relief when presenting for treatment urgently 

  • Opioids should be used sparingly or avoided for endometriosis and CPP because they only treat symptoms and do not address the issue 

  • Can lead to dependence and overuse 

• Surgical 

  • There are many, many surgeries out there for endometriosis, from simple ablation, to adhesiolysis, to nerve transections, to hysterectomies. We will cover a few 

  • Surgery offers the benefit of definitive diagnosis, but risks include damage to organs (especially if there is heavy burden of endometriosis as well as adhesions) like bladder and bowel

  • Most people will achieve initially pain relief after surgery - women who underwent operative laparoscopy were 3x more likely to report improvement in pain at 12 months than controls who had diagnostic laparoscopy (one study showed 73 vs 21%) 

  • However, nearly 20% of patient will undergo repeat surgery within 2 years because of recurrent symptoms, and risk of symptom recurrence is as high as 40% at 10 year follow up 

  • Risk factors for persistent or recurrent pain: incomplete excision, ovarian cyst drainage instead of cyst excision, and ovarian conservation

  • Endometriosis tends to get better with Menopause, and so longer latency to menopause gives more time for symptoms to recur 

  • Postoperative medical therapy: ASRM advises posteropative medical suppressive therapy for most women treated surgically 

    •  6-24 months of suppression can reduce symptom recurrence and thus potentially avoid need for multiple surgeries 

    • Best evidence comes from 2 systemic reviews: one using LNG-IUD, and another for postoperative use of COCs for prevention of relapse 

• Surgical techniques

  • Laparoscopy generally favored over laparotomy because less invasive and improves visualization, with better recovery and shorter hospital stay, elss pain 

  • Conservative 

    • Excision or ablation of endometriosis lesions with intent of preserving the uterus and as much ovarian tissue as possible 

    • First line option for most people who want surgery for endometriosis because it preserves fertility and hormone production

    • Remember: even in young patients who don’t want fertility, hormone production is necessary for bone and cardiac health!  

    • Less invasive and morbid than definitive surgery, and there is documented short term efficacy 

    • 2014 systematic review: decreased pain and increased live birth rate after conservative surgery 

    1. Disadvantages: 

       1. Rate of recurrent symptoms is higher compared to definitive surgery 

       2. Rate of reoperation increases with time, whereas it is relatively stable with definitive surgery 

  1. Hysterectomy without oophorectomy 

     1. For patients who have debilitating symptoms and whom have completed childbearing 

     2. Failed both medical therapy and at least one conservative treatment procedure 

     3. Also reasonable if other indications for a hyst (ie symptomatic fibroids, prolapse, etc) 

     4. Effective treatment for pain symptoms from endometriosis, with reoperative rates that are relatively low (19% in one study, compared to 58% in people undergoing conservative therapy) 

     5. Disadvantages 

        1. Longer, more morbid surgery with higher rates of complication 

  2. Hysterectomy with oophorectomy

     1. Those who would benefit are those with extensive adnexal disease and those for whom the risks of reoperation outweigh the risks of premature menopause 

     2. Likely increases the efficacy of definitive surgery but is accompanied by quality of life issues and potential adverse outcomes due to early menopause 

     3. Reason to do it: endometriosis is an estrogen-dependent disease, and tends to get better with menopause 

     4. Early menopause (<44 years) is associated with increase risks of overall mortality, cardiovascular disease, neurologic disease, osteoporosis 

Endometriosis Part I: Evaluation and Diagnosis

Be sure to check out our previous episode on chronic pelvic pain with Dr. Eva Reina to round out your CPP diagnosis skills!

What is endometriosis? 

• Gynecologic condition where endometrial glands and stroma occur outside of the uterine cavity that can respond to hormonal shifts of the menstrual cycle.

  • Most within pelvis, but can occur elsewhere: bowel, diaphragm, and even in the pleural cavity 

  • Benign, but can cause dysmenorrhea, dyspareunia, chronic pain, and infertility 

• Incidence

  • Occurs in 6-10% of reproductive age women, but is present in 38% of women with infertility and 71-87% of women with chronic pelvic pain! 

  • No data to suggest that endometriosis is increasing, but it is likely more recognized and being diagnosed more often now.

  • There is a familial association - first degree relatives of someone with endometriosis are at higher risk for also developing it, but the inheritance is likely polygenic-multifactorial 

• Risk factors

  • Nulliparity, prolonged exposure to endogenous estrogen (ie. early menarche, late menopause)

  • Shorter menstrual cycles, heavy periods, obstruction of menstrual outflow

  • Increased height, lower BMI, and high consumption of trans unsaturated fats

    • This does not mean that you’re going to get endometriosis if you’re tall or have a low BMI! And you’re not going to treat it by stopping eating trans fats.

    • Association doesn’t equate to causation.

• Etiology 

  • Endometriosis occurs when ectopic endometrial tissue implants, grows, and elicits inflammatory response 

  • Inflammatory response: COX-2 activity, overproduction of prostaglandins, and then chronic inflammation → triggers pain and causes infertility

    • Also why those with endometriosis will usually have flares that coincide with their menstrual cycle.

  • Nerve growth factor is also highly expressed in endometriotic lesions → increase density off nerve fibers → can explain increased sensitivity and pain 

    • Can also be explained by central sensitization (lowering threshold of pain) 

    • Go back go our CPP episode to remember what all these things are! 

  • Sampson’s Theory of Retrograde Menstruation - most popular/common theory where endometrial cells flow backwards through the fallopian tubes into the peritoneal cavity during menses

    • But, up to 90% of women HAVE retrograde menstruation, and not everyone has endometriosis 

    • Likely, there is a multifactorial cause of endometriosis, where ectopic endmoetrial tissue interacts with alterned immunity, imbalance of cell proliferation/apoptosis, aberrant signalling, and genetic factors 

    • There are certain genes that are statistically associated with endometriosis 

  • Chronic inflammation and endometriotic lesions can distort the pelvic anatomy through adhesions, endometriomas, and other substances lilke cytokines and prostaglandins that are “hostile” to normal ovarian function, fertilization, and implantation 

How do we evaluate for endometriosis? 

• History and physical

  • Usually patient will present during reproductive years with pelvic pain (ie. dysmenorrhea or dyspareunia), infertility, or ovarian mass 

  • However, there are many people with endometriosis who are asymptomatic! 

  • Diagnosis is more likely to be made in people with symptoms 

    • Remember the “PPUBS” framework 

      • Pain - can you describe your pain? 

      • Periods - menstrual history; is the pain surrounding menstruation or line up with other parts of their menstrual cycle? 

      • Urinary symptoms - there can be endometriotic lesions on the bladder → frequency, urgency, pain with voiding 

      • Bowel - symptoms include diarrhea, constipation, dyschezia, and bowel cramping 

      • Sexual dysfunction - peritoneal or deeply infiltrating endometriosis can present with dyspareunia 

  • Physical exam: can be variable depending on location and size of implants

    • You may feel nodules in the posterior fornix, uterosacral ligaments,, adnexal masses, and immobility or lateral displacement of the cervix or uterus 

    • However, exam can be completely normal 

• Rule out other causes for pelvic pain 

  • Labs - no pathognomonic lab for endometriosis 

    • CA125 can be elevated, but it’s not routinely ordered because other diseases can also elevate CA-125 levels 

    • It’s not specific and not helpful for endometriosis

  • Imaging 

    • Ultrasound is usually all you need - can see things like endometriomas, nodules, etc. 

    • Sometimes, can consider MRI

    • Imaging can help to rule out other causes of pelvic pain (ie. fibroids)  

• Definitive diagnosis vs. presumptive diagnosis 

  • Presumptive diagnosis

    • Endometriosis is a pathologic diagnosis - meaning you need histology of a lesion biopsied during surgery 

    • Sometimes, if surgery is not desired or not yet possible, presumptive diagnosis can be made based on combination of signs, symptoms, and imaging findings 

    • Clinical diagnosis is enough to start therapy that is low risk and easily tolerated

    • If patients improve, can actually hold off on surgery 

  • Definitive diagnosis 

    • Surgery - usually indicated for persistent pelvic pain that does not respond to medical therapy, evaluation of severe symptoms that limit function, andd treatment of anatomic abnormalities 

    • Usually laparoscopy - can get definitive diagnosis and treatment 

      • Peritoneal lesions can appear like reddish or bluish irregularly shaped islands, “powder burn” lesions, white opacifications, translucent blebs

      • Allen-Masters syndrome = scarred or puckered peritoneal surface 

      • Dense fibrous disease 

      • Endometriomas 

  • Pathologic Categorizations 

    • Superficial peritoneal lesions 

    • Ovarian lesion (endometrioma) 

    • Deeply infiltrating - solid endometriosis situated more than 5 mm deep to the peritoneum 

  • Surgical Staging - this is to report operative findings. They do NOT correlate with presence or severity of symptoms. However, there are studies that have shown inverse correlation with advanced stages and prognosis for fertility treatment 

    • Stage I - minimal disease; ie. isolated implants, no significant adhesions 

    • Stage II - mild endometriosis with superficial implants that are < 5 cm in aggregate and are scattered on peritoneum and ovaries. NO significant adhesions 

    • Stage III - Moderate disease with multiple implants, both superficial and deeply invasive, peritubal and periovarian adhesions may be evidence  

    • Stage IV - severe disease; multiple superficial and deep implants, including large ovarian endometriomas. Filmy and dense adhesions are usually present