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  • Nathan Riley, MD

Beloved Holistics Radio Episode 80 - Management of Endometriosis

"Spontaneous labour in a normal woman is an event marked by a number of processes so complicated and so perfectly attuned to each other that any interference will only detract from the optimal character. The only thing required from the bystanders is that they show respect for this awe-inspiring process by complying with the first rule of medicine--nil nocere [do no harm]." - G. J. Kloosterman



PB#114 - Published July 2010 (Reaffirmed 2018)


Five Pearls

1. Pelvic pain and infertility are characteristic. Severe dyspareunia and dyschezia are indicative of deeply infiltrative disease.

2. The etiology is unknown, but currently thought to be due to the implantation of endometrial glands and stromal cells outside the uterus within the peritoneal cavity due to retrograde menstruation

3. Histologic evaluation of a surgical specimen is the gold standard for diagnosis. Visualization of endometriotic lesions has a high false positive rate. The finding of an endometriomas on imaging studies can alone be highly predictive, though.

4. Excision of endometriosis can improve fertility rates, particularly with the excision of an endometrioma.

5. NSAIDs, COCs, GnRH analogues, and progestins are all great alternatives to surgery for managing endometriosis-related pain


Background

- up to 10% of women carry the diagnosis (but it's likely much higher, as these symptoms are non-specific, and diagnostics have poor sensitivity)

- in patients with infertility, incidence is as high as 50%

- ~85% in patients with chronic pelvic pain

- unlikely a racial predisposition

- likely a familial association (strong concordance with monozygotic twins), though exact polymorphism(s) hasn't been identified


Etiology of endometriosis is unclear

- leading theory among Western OBGYNs: the implantation of endometrial glands and stromal cells outside the uterus within the peritoneal cavity due to retrograde menstruation

- this implantation elicits a local immune response: flood of macrophages and pro-inflammatory cytokines (e.g. TNF, IL-1, IL-6, and IL-8) --> increased COX-2 activity --> prostaglandin release --> pain!

- also notable progesterone resistance (further enhancing the estrogenic effect on the misplaced endometrial tissue!)

- the endometriotic lesions have also been found to express nerve growth factor (a greater density of nerve fibers means more pain signaling to the brain)


Why do these patients experience infertility?

- again we don't know!

- the combination of inflammation and progesterone resistance may be the underlying cause, but this is all speculation (either may impact embryogenesis)

- inflammation may disrupt the path of the ovum, function of sperm, or implantation of an embryo

- in more severe cases, the tubes and adnexa are often glued together, which could explain things, but infertility is experienced even in "milder" or earlier stages of the disease

- other theories include autoimmunity (pretty nice review of this concept here)




Left: Normal pelvis; Right: Severe (stage III or IV) endometriosis

Risk factors

- early menarche (<11 yrs)

- short cycles (<27 days)

- heavy, prolonged bleeding

- smoking, alcohol use, and lower BMI

- Caucasian > black women

- people who exercise >4 hrs per week have lower risk

- higher parity and prolonged breastfeeding are associated with lower risk of endometriosis


Clinical manifestations

- dysmenorrhea, which generally appears a week or so before the onset of menstruation (odds ratio: 8.1)

- abdominopelvic pain (odds ratio: 5.2)

- deep dyspareunia, which is intensified during menses (odds ratio: 6.0)

- dyschezia (odds ratio: 6.0)


Note: stage of disease does not correlate with severity of the pain


- if endometriosis involves the bowel, it can also generate GI symptoms like diarrhea, constipation, and cramping during flare-ups

- heavy menstruation (odds ratio: 4.0)

- sacral backache during menses

- infertility

- uterosacral nodularity (palpated on rectal exam)





Endometrioma on US (source: SciELO)

Diagnosis

- at present, histologic evaluation of surgical specimens is the gold standard for diagnosis

- the terms used to describe these lesions on laparoscopic exploration are "black powder lesions" and "red or white lesions"

- you can see them anywhere in the pelvis, on the bowel, on the diaphragm, on the liver, inside the bladder, within the abdominal wall, or along the peritoneum

- high false positive rate from visual inspection alone --> need biopsy!


Black powder lesions on the pelvis sidewall

- endometrioma: on US, endometriomas appear unilocular w/ diffuse salt and pepper speckling due to repeated hemorrhage inside the cyst; can also be seen on CT/MRI

- imaging studies have a high predictive accuracy alone

- cystoscopy with biopsy may be appropriate if bladder endometriosis is suspected

- CA-125 isn't useful (poor specificity)


Note: be sure that you're not missing other potential contributors to her pain, including IBS, interstitial cystitis, urinary tract infections, and PID!


Surgery improves fertility rates

- number needed to treat is 12 for mild disease (data from 2x RCTs)

- no RCT has been done for severe disease

- surgery for advanced disease is challenging and often results in worse fecundity, but excision of endometriomas (esp if >4 cm) is definitely effective (you must remove the whole thing, not simply drain it otherwise it will recur! Pregnancy rate is 65% with full excision versus 23% with drainage)

- if fertility remains an issue after 1x operation to excise endometriosis, going straight to IVF is recommended, as reoperation risks further decreasing ovarian reserve and worse IVF outcomes in the future


A word of caution: excision of an endometrioma may also result in decreased ovarian reserve as a result of damage to the ovary


COCs and NSAIDs are your starting point in managing endometriosis-related pain when fertility preservation is desired


NSAIDs and COCs

- initial treatment: NSAIDs (inhibit COX --> decrease prostaglandin production), COCs (ovarian suppression --> less estrogen and progesterone), or GnRH analogues (negative feedback centrally to suppress gonadotropin release)

- if cyclical COCs isn't sufficient, you can suppress the hypothalamic-pituitary-ovarian axis more completely through continuous or extended cycle formulations


GnRH analogues

- GnRH analogues should only be tried once NSAIDs and COCs have failed

- GnRH analogues last for 3 months, and they come with menopause-like side effects: hot flushes, vaginal dryness, osteopenia, and myalgias

- you can use it up for 4x doses (12 months) if progestin add-back therapy is initiated (can go even longer than 1 year if your patient desires: risks versus benefits!)

- this can be started immediately rather than waiting until the 1 year mark

- add-back therapy will mitigate the bone loss without any major downsides or effects on pain control (your patient should also start taking 1000 mg calcium daily)

- norethindrone acetate has been approved for this purpose (5 mg daily)

- medroxyprogesterone acetate 2.5 mg daily + transdermal estradiol 25 mcg/day is another option


Note: GnRH analogues are the only effective means of managing symptoms related to extra-pelvic endometriosis. An exception might a blocked ureter, which will likely require surgical excision.


DMPA

- depot IM medroxyprogesterone acetate (DMPA) has been demonstrated to be equivalent to GnRH analogues


Recall: the time to restoration of ovarian function with DMPA is longer than other hormonal contraceptives. It's also associated with decreased bone mineral density.


Progestin IUDs

- levonorgestrel intrauterine systems (e.g. progestin-releasing IUDs like Mirena) are also effective, but they come with the side effect of intermenstrual bleeding, breast tenderness, or weight gain


Androgen therapy

- androgenic drugs like Danozol are also highly effective (works through negative feedback at the hypothalamus and pituitary to inhibit release of gonadotropins), but they come with terrible side effects: hirsutism, acne, and myalgias

- for any of these options, symptoms will return when discontinued


Surgery doesn't work all that well for endometriosis-related pain

- surgery (i.e. going in an remove visible lesions) may work to some degree for severe disease

- one study found that 36% of patients required reoperation within 3 years on average

- at reoperation for recurrence of pain, many patients had no visible lesions

- the younger that patient, the more likely they'll undergo reoperation (obviously, because the underlying cause hasn't been addressed)

- total hysterectomy with bilateral salpingo-oophorectomy (BSO) is considered the definitive therapy for endometriosis-related pain

- 62% of women in whom ovaries are left in place experience recurrence of symptoms and 30% chance of reoperation (compared to 10% and 4% if the bilateral adnexa are removed); the issue with this study was that it wasn't clarified if endometriotic lesions were removed intraoperatively

- another study showed that the risk of recurrence was less after hysterectomy even if the ovaries are preserved, but the researchers ALSO removed visible endometriotic lesions if noted intraoperatively


Are neurectomies helpful?

- ablation of nerves or nerve bundles to inhibit or diminish the pain signal to the brain

- uterosacral nerve ablations haven't been found to be effective

- presacral neurectomies might be helpful for midline pain alone

- these procedures carry the risk of neurogenic bowel or bladder (No thanks, I'll pass...)


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