Endometriosis

Clinical Snapshot

Endometriosis is a chronic, estrogen-dependent inflammatory condition defined by the presence of endometrium-like tissue outside the uterine cavity — most often on the ovaries and the cul-de-sac (rectouterine pouch), though deeper disease can infiltrate the bowel, bladder, ureter, or rectovaginal septum.^[1] It is a heterogeneous disease: the extent of disease found at surgery does not reliably predict pain severity or the chance of pregnancy, and pain and infertility can occur together, separately, or not at all in a given patient.^[2] A major shift in contemporary practice — reflected in current Canadian and European guidance — is that a laparoscopic or histologic diagnosis is no longer required before starting treatment: clinical suspicion supported by history, examination, and (where available) a targeted transvaginal ultrasound is now sufficient grounds to start empiric medical therapy.^[3] This chapter covers pharmacologic management of endometriosis-associated pain and the distinct approach required when infertility, rather than or in addition to pain, is the presenting concern.

Recognize the Condition

Typical presentation

Cyclic pelvic pain that, as disease progresses, can become increasingly acyclic is the dominant symptom — dysmenorrhea, deep dyspareunia, dyschezia (painful defecation, especially perimenstrual), dysuria, and chronic pelvic pain extending beyond the menstrual window. Infertility is the other major presentation, sometimes with no pain at all. On examination, findings suggestive of endometriosis include a fixed, retroverted uterus, adnexal masses, and nodularity or tenderness in the posterior vaginal fornix/cul-de-sac — a normal examination does not exclude the diagnosis.

The 3 disease phenotypes

Superficial peritoneal endometriosis

Implants on the peritoneal surface, classically blue or black powder-burn lesions, though red, white, yellow, or brown lesions are just as often histologically confirmed as endometriosis.

Ovarian endometrioma

A cystic ovarian mass containing old blood, fluid, and menstrual debris. Along with the cul-de-sac, the ovary is the most common site of disease.

Deep infiltrating endometriosis (DIE)

Disease penetrating beneath the peritoneal surface, often involving the rectovaginal septum, bowel, bladder, or ureter. This phenotype drives the most severe pain, the greatest surgical complexity, and the bowel/bladder-obstruction red flags below.

Risk Factors

Early age of menarche.
Short menstrual cycle length and prolonged or heavy menstrual flow.
Family history of endometriosis in a first-degree relative.
Müllerian tract anomalies causing outflow-tract obstruction.
Nulliparity.
Factors associated with lower risk include parity, current hormonal contraceptive use, regular exercise, and omega-3 fatty acid intake — the overall evidence linking lifestyle/dietary factors to endometriosis risk remains limited.

Red Flags & Refer

Refer or escalate urgently for any of the following:

Acute, severe pelvic pain — especially sudden-onset, one-sided pain, with or without nausea/vomiting — suggesting ovarian torsion or a ruptured endometrioma; this needs emergency gynecologic assessment, not a scheduled follow-up.
Signs of bowel or bladder obstruction (progressive constipation, obstipation, abdominal distension, hematochezia, or urinary retention/hematuria) in a patient with known or suspected deep infiltrating endometriosis — suggests organ infiltration requiring imaging and surgical planning.
Fever, peritoneal signs, or hemodynamic instability accompanying pelvic pain — evaluate for pelvic inflammatory disease, appendicitis, or another acute surgical process rather than assuming an endometriosis flare.
A new or rapidly enlarging adnexal mass, or an ultrasound feature concerning for malignancy — refer for gynecologic oncology assessment rather than managing as a routine endometrioma.
Treatment-refractory pain that has not responded to an adequate trial of first- and second-line hormonal therapy — refer for specialist reassessment and consideration of surgical evaluation rather than repeating the same approach.
Any positive pregnancy test in a patient with acute pelvic pain — rule out ectopic pregnancy before attributing pain to endometriosis.

Assessment & Diagnosis

Differentiating endometriosis-associated pelvic pain from its common mimics

Parameter	Endometriosis	Primary dysmenorrhea	Pelvic inflammatory disease	Overlapping chronic pain syndrome (IBS / bladder pain syndrome / pelvic floor dysfunction)
Pain timing	Often begins before menses and persists after; may become acyclic/constant as disease progresses	Cyclic only — onset with or just before menses, resolves within a few days	Acute onset	Chronic, fluctuates with bowel habit or bladder filling rather than tightly with the cycle
Deep dyspareunia	Common, often positional	Uncommon	Can occur with cervical motion tenderness	Variable, may be present
Fever / abnormal discharge	Absent	Absent	Often present	Absent
Exam findings	Fixed retroverted uterus, adnexal mass, posterior cul-de-sac nodularity/tenderness	Normal pelvic exam	Cervical motion/adnexal tenderness, possible mass	Normal pelvic exam; bowel- or bladder-focused tenderness
Response to NSAIDs/hormonal suppression	Often improves, though frequently incompletely	Reliably improves	No effect — needs antibiotics	Variable, often incomplete
First-line workup	Targeted transvaginal ultrasound	Clinical diagnosis of exclusion	Clinical assessment plus NAAT for chlamydia/gonorrhea	Clinical, symptom-based criteria

These conditions frequently overlap rather than presenting as a clean either/or — a patient with confirmed endometriosis can also have an overlapping chronic pain syndrome, and treating only the endometriosis will leave residual symptoms in that case.

History

Characterize pain: timing relative to the cycle, dysmenorrhea, deep dyspareunia, dyschezia, dysuria, and chronic (noncyclic) pelvic pain.
Ask directly about a history of infertility or difficulty conceiving.
Diagnosis is often significantly delayed — nonspecific symptom presentation, normalization or dismissal of symptoms, and limited access to expert-level pelvic imaging all contribute; keep a low threshold to consider the diagnosis in anyone with pain not explained by primary dysmenorrhea.^[4]

Examination

Look specifically for a fixed, retroverted uterus, adnexal masses, and nodularity or tenderness in the posterior vaginal fornix/cul-de-sac.

Investigations

Pelvic transvaginal ultrasound is the first-line investigation. A targeted, endometriosis-specific ultrasound protocol can identify both endometriomas and deep infiltrating disease; a standard, non-targeted pelvic ultrasound reliably identifies endometriomas but is much less sensitive for deep disease. Findings are highly operator-dependent.
MRI is useful for characterizing deep infiltrating lesions, particularly when expert-level endometriosis ultrasound is not accessible.
Peritoneal (superficial) endometriosis cannot currently be identified on imaging — if peritoneal disease is the specific remaining question after imaging, diagnostic laparoscopy ± biopsy may be considered, though this is no longer a prerequisite for starting treatment.^[2]
No blood test reliably diagnoses endometriosis. Serum CA-125 is often elevated but is neither sensitive nor specific — it is also elevated in pelvic inflammatory disease, epithelial ovarian cancer, and pregnancy — and should not be ordered as part of routine diagnostic workup.

Treatment Targets

Relieve pelvic pain, dysmenorrhea, and dyspareunia.
Suppress disease activity to reduce the risk of symptom progression and recurrence.
Preserve or restore fertility potential in patients who desire pregnancy — this requires a fundamentally different approach than pain management.
Minimize treatment-related adverse effects, particularly the bone mineral density loss associated with prolonged hypoestrogenic therapy.
Avoid unnecessary surgery while still identifying patients who genuinely need it.
Address the overlapping chronic pain syndromes that commonly accompany endometriosis, not just the disease itself.

Choose Initial Treatment

Direct treatment rule

Empiric treatment

Start empiric medical therapy based on clinical suspicion and a supportive history, examination, and imaging pattern — a laparoscopic or histologic diagnosis is not required before starting treatment.^[3]^[1]

First-line pharmacotherapy

1st line, pain add a scheduled (not as-needed) NSAID — ibuprofen or naproxen — started at the onset of menstrual symptoms and continued regularly through the expected pain window.

1st line, hormonal suppression start a continuous (extended-cycle, no hormone-free interval) combined hormonal contraceptive OR a progestin-only option (oral norethindrone acetate, oral medroxyprogesterone acetate, dienogest, depot medroxyprogesterone acetate injection, the etonogestrel implant, or the levonorgestrel intrauterine system) — the choice between these is individualized on contraindications, cost, need for reliable contraception, and desire for amenorrhea, not a fixed hierarchy between CHC and progestins.

2nd line — use once CHC and at least 1 progestin option have both had an adequate trial (generally more than 3 months) without adequate relief, or are contraindicated/not tolerated: a GnRH agonist with mandatory add-back hormone therapy, or a GnRH antagonist (elagolix, or the relugolix combination product, which already contains built-in add-back therapy).

Special situation — fertility is desired do not start CHC, a progestin, or a GnRH agonist/antagonist — all of these suppress ovulation. Manage pain with NSAIDs alone while pursuing a fertility-focused pathway (surgical excision of endometriosis, ovulation induction, intrauterine insemination, or IVF, as appropriate) instead.

Avoid as routine therapy danazol and opioid analgesics — danazol's androgenic and lipid adverse-effect profile has left it well behind better-tolerated options, and opioids carry substantial dependence and adverse-effect risk without addressing the underlying disease process; reserve either only for genuinely refractory situations under specialist direction.

Non-Pharmacologic Treatment

Pelvic floor physiotherapy — particularly valuable when pelvic floor muscle dysfunction contributes to dyspareunia, dyschezia, or urinary symptoms, and as part of an interdisciplinary chronic pain approach.
Regular exercise is associated with lower endometriosis risk and is a reasonable general adjunct, though it is not a substitute for disease-directed therapy.
For any patient on long-term progestin, GnRH agonist, or GnRH antagonist therapy, counsel on bone health: adequate calcium intake (about 1200 mg/day total, preferably through diet) and vitamin D supplementation (400-1000 units/day).
Refer patients to a dedicated endometriosis patient-support organization (e.g., the Endometriosis Network Canada) for education and community support — the chronic, often years-long nature of this disease benefits from peer and community resources beyond a single clinic visit.
Provide analgesia and symptom management while a patient awaits surgery or the full effect of a newly started medical therapy, rather than leaving pain untreated in the interim.
Do not use preoperative hormonal therapy specifically to shrink implants before surgery in the expectation that this will prolong the postoperative pain-free interval, reduce recurrence, or increase pregnancy rates — it does none of these, even though it may reduce implant size.

Surgical management

Conservative (uterine-sparing) surgery

Laparoscopic excision or ablation of endometriotic implants, aiming to preserve the uterus and, where possible, the ovaries. Excision is generally preferred over ablation, particularly for deep disease, since ablation cannot ensure a lesion has been treated in its entirety.^[1] Indicated when patients cannot tolerate or decline medical therapy, for acute complications (torsion, rupture), for deep disease, alongside management of other concurrent gynecologic pathology, or when pain and infertility coexist. Even after effective excision, recurrence is common — postoperative suppressive hormonal therapy meaningfully reduces this risk and should be discussed with every patient preoperatively.^[5]

Presacral neurectomy

Resection of the presacral nerve plexus, used in select cases alongside conservative surgery specifically for severe midline dysmenorrhea. Benefit depends on complete resection of the plexus, and significant complications limit how often it is used.

Hysterectomy

An option for pelvic pain in patients not wishing to carry a future pregnancy; should be performed together with excision of any extrauterine disease. Associated with low rates of recurrence and reoperation.

Hysterectomy with bilateral salpingo-oophorectomy

Definitive therapy for treatment-resistant pelvic pain or adnexal masses in patients with extensive extrauterine disease. Requires counselling about the consequences of iatrogenic premature ovarian failure, and about the need for combined estrogen-plus-progestogen menopausal hormone therapy afterward (see Special Populations).

Pharmacologic Treatment Options

Drug / intervention	Role	Dose / use	Important adverse effects	Teaching points
Ibuprofen Preferred	1st-line analgesic for pain	400 mg PO Q4-6H, scheduled (not PRN); maximum 2400 mg/day	Dyspepsia, nausea; less commonly rash, dizziness, headache	Start at the onset of menstrual symptoms and continue regularly. Naproxen (250 mg PO Q6-8H or 500 mg PO Q12H) is an equally acceptable NSAID alternative — no evidence one outperforms the other.
Combined hormonal contraceptive (continuous) Preferred	1st-line hormonal suppression	1 tablet PO daily, continuous — no hormone-free interval	Breakthrough bleeding/spotting (most common, especially early), nausea, breast tenderness, mood changes; rare but serious VTE, stroke, MI	Confirm no CHC contraindication first. Counsel on ACHES warning symptoms (Abdominal pain, Chest pain, severe Headache, Eye problems, Severe leg pain) needing urgent care. The vaginal ring and transdermal patch are equally valid continuous-use routes.
Norethindrone acetate Preferred	1st-line progestin-only option	5 mg PO daily, titrate by 2.5 mg/day every 2 weeks to a maximum of 15 mg/day	Breakthrough bleeding, weight gain, mood changes	Ovulation resumes promptly after stopping. CYP3A4 substrate — review interacting drugs. Oral medroxyprogesterone acetate, dienogest, DMPA injection, the etonogestrel implant, and the levonorgestrel IUS are other progestin-only options — see Drug Tables.
Levonorgestrel intrauterine system (52 mg) Preferred	1st-line hormonal suppression, long-acting option	Insert; the 52 mg system may remain in place for its full approved duration while used for this indication	Irregular spotting for the first 3-6 months, then amenorrhea in many patients; simple ovarian cyst formation	Do not confuse with the Drug Database's Levonorgestrel monograph, which covers the oral emergency-contraception formulation (1.5 mg), not this intrauterine system.
Leuprolide acetate Special situation	2nd line — GnRH agonist, once CHC and a progestin have failed or are contraindicated	3.75 mg depot: 3.75 mg IM monthly, up to 6 months 11.25 mg depot: 11.25 mg IM every 3 months, up to 6 months	Hypoestrogenic: hot flashes, vaginal dryness, insomnia, decreased libido; reduced bone mineral density with use beyond 6 months	Mandatory add-back hormone therapy for any course beyond a brief initial trial. Goserelin, triptorelin, and nafarelin are alternative GnRH agonists — see Drug Tables.
Elagolix Special situation	2nd line — GnRH antagonist	150 mg dose: 150 mg PO once daily, up to 24 months 200 mg dose: 200 mg PO twice daily, up to 6 months (reserved for more severe pain, e.g. with dyspareunia)	Headache, nausea, hot flashes, mood/depressive symptoms, dose-dependent reduced bone mineral density	Contraindicated in severe hepatic impairment, known osteoporosis, and pregnancy. Does not reliably prevent pregnancy on its own — use a backup method.
Relugolix / estradiol / norethindrone acetate Special situation	2nd line — GnRH antagonist with built-in add-back therapy	1 tablet (relugolix 40 mg / estradiol 1 mg / norethindrone acetate 0.5 mg) PO daily, for up to 24 months	Hot flashes, night sweats, headache, decreased libido	No separate add-back prescription needed. Contraindicated with a personal history of VTE, ischemic heart/cerebrovascular disease, or migraine with aura.
Danazol Avoid	Avoid as routine therapy	600-800 mg PO daily in divided doses, without interruption, for 3-6 months	Androgenic effects (hirsutism, acne, voice deepening — may be irreversible), adverse lipid changes, weight gain	Reserve only for genuinely refractory situations under specialist direction; avoid in dyslipidemia or liver disease.

Opioid analgesics are not a first-line or routine therapy for endometriosis-associated pain — reserve short-term, cautious use for when NSAIDs are contraindicated or ineffective, following standard opioid-prescribing principles for chronic non-cancer pain.

Special Populations

Pregnancy: symptoms often improve during pregnancy, as the natural suppression of ovulation and menses reduces disease activity; however, patients with significant anatomic disease (large endometriomas, deep infiltrating disease involving the cul-de-sac) or an overlapping chronic pain syndrome may continue to have symptoms. No endometriosis-specific hormonal suppressive therapy is given during pregnancy — every agent above is either contraceptive or ovulation-suppressing and is not appropriate once a patient is pregnant. Manage breakthrough pain with acetaminophen first; avoid NSAIDs from around 20 weeks gestation onward given the risk of fetal renal impairment and premature closure of the ductus arteriosus with later use.

Breastfeeding

Symptoms frequently remain in remission during breastfeeding provided nursing is frequent and intense enough to suppress ovarian estrogen release; treatment is often not required under these conditions. Prolonged breastfeeding is itself associated with a lower long-term risk of endometriosis. If suppressive therapy is needed while breastfeeding, a progestin-only option is generally preferred over an estrogen-containing one.

Adolescents

Consider endometriosis in an adolescent with dysmenorrhea or pelvic pain that does not respond to NSAIDs and cyclic hormonal therapy. Continuous CHC or a progestin-only option remains first-line. GnRH agonists and antagonists are used more cautiously in this population, given ongoing bone mass accrual through adolescence, and are generally reserved for severe, refractory disease under specialist direction with mandatory add-back therapy.

Patients desiring pregnancy (fertility considerations)

Endometriosis carries a genuine dual burden of pain and infertility, and the two are managed very differently. Ovarian-suppressing hormonal therapy is not used to manage endometriosis-associated infertility — it prevents pregnancy — and is appropriate in this population only if severe pain coexists and fertility is not the immediate goal. For patients actively trying to conceive: conservative surgical excision of minimal-to-mild disease improves spontaneous fecundity; letrozole-based ovulation induction with intrauterine insemination is an option for minimal-to-mild disease with patent tubes; and IVF is generally used when the surgically-assessed Endometriosis Fertility Index is low, other treatments have failed, or male-factor infertility coexists. Fecundity declines and pregnancy-loss risk rises after age 35, supporting a more expedited fertility-focused treatment plan in this group rather than working through the full pain-management ladder first.

Post-hysterectomy and bilateral salpingo-oophorectomy

Menopausal hormone therapy after hysterectomy with bilateral salpingo-oophorectomy for endometriosis should include both estrogen and progestogen, not estrogen alone, even without a uterus — unopposed estrogen can reactivate residual endometriotic tissue. The same combined-therapy principle applies to a patient remaining on an unopposed GnRH agonist.

Renal/hepatic impairment

Danazol is avoided in significant liver disease. Elagolix is contraindicated in severe hepatic impairment. Standard renal precautions apply to NSAID use.

Monitoring & Follow-Up

Reassess pain response after an adequate trial of any new therapy — generally at least 3 months — before judging it a failure and switching. For a patient on long-term progestin, GnRH agonist, or GnRH antagonist therapy, consider bone mineral density (DXA) screening, particularly when additional bone-loss risk factors are present, and reinforce calcium/vitamin D counselling at each visit. Monitor for hypoestrogenic symptoms (hot flashes, mood changes, vaginal dryness) with GnRH agonist/antagonist therapy and adjust or add add-back therapy accordingly. Monitor lipids periodically in a patient on danazol. Confirm ongoing contraceptive needs at every visit for a patient not desiring pregnancy — a GnRH agonist or antagonist does not reliably prevent pregnancy on its own and needs a backup method if the patient is sexually active with pregnancy potential. For a patient who underwent surgery, confirm postoperative suppressive therapy has actually been started (unless fertility is being actively pursued) and reassess periodically for symptom recurrence.

Treatment Failure / Next Step

Confirm adherence and correct use — continuous dosing with no unintended hormone-free interval, correct DMPA injection timing, or a confirmed in-place LNG-IUS/implant — and confirm a genuinely adequate trial (generally more than 3 months) has elapsed before calling a therapy a failure.
Reassess for an alternative or coexisting diagnosis — primary dysmenorrhea, adenomyosis, pelvic inflammatory disease, an ovarian cyst, or an overlapping chronic pain syndrome (IBS, bladder pain syndrome, pelvic floor dysfunction) — rather than assuming the same disease has simply progressed.
If only one first-line class has been tried (for example, CHC alone), switch to the other first-line class (a progestin option) before escalating further.
If both CHC and at least one progestin option have failed an adequate trial, or are contraindicated, escalate to a GnRH agonist with mandatory add-back hormone therapy, or a GnRH antagonist.
If pain remains refractory despite adequate hormonal escalation, hormonal therapy cannot be tolerated or is declined, or the patient desires pregnancy, refer for surgical evaluation (diagnostic/therapeutic laparoscopy with excision).
After surgery, start or resume suppressive hormonal therapy — unless fertility is being actively pursued — to reduce the risk of symptom and disease recurrence.
For pain that persists despite optimized medical and surgical therapy, refer for a multidisciplinary chronic pelvic pain program (pelvic floor physiotherapy, pain specialist, psychological support) — an overlapping chronic pain syndrome is common in this situation and needs its own dedicated treatment approach.

Common Errors to Avoid

Requiring a laparoscopic or histologic diagnosis before starting treatment — current Canadian and European guidance supports empiric therapy based on history, exam, and imaging alone.
Starting a GnRH agonist for anything beyond a brief initial course without mandatory add-back hormone therapy.
Continuing a GnRH agonist or GnRH antagonist beyond its defined duration limit without a documented bone-health monitoring plan.
Prescribing any ovarian-suppressing hormonal therapy — CHC, a progestin, or a GnRH agonist/antagonist — to a patient who is actively trying to conceive.
Assuming a new, unusually severe, or different pain pattern is simply worsening endometriosis without first ruling out ovarian torsion, a ruptured endometrioma, or another acute surgical process.
Using an NSAID only as-needed rather than on a scheduled basis through the expected pain window, which reduces its effectiveness.
Overlooking an overlapping chronic pain syndrome (IBS, bladder pain syndrome, pelvic floor dysfunction) in a patient with persistent pain despite adequate disease-directed therapy.
Not counselling that pain often recurs after stopping any suppressive therapy — including after surgery — and that postoperative hormonal suppression reduces, but does not eliminate, that risk.
Forgetting that DMPA specifically delays the return of ovulation after discontinuation — important counselling for a patient who may want to conceive in the near future.
Linking the Drug Database's Levonorgestrel monograph (the oral emergency-contraception formulation) as if it were the levonorgestrel intrauterine system — they are different products with different dosing entirely.

Clinical Decision Algorithm

Initial assessment and empiric treatment

Clinical suspicion of endometriosis — cyclic or chronic pelvic pain, dysmenorrhea, dyspareunia, dyschezia, dysuria, and/or infertility

Rule out an acute surgical abdomen and pregnancy; obtain history, pelvic exam, and a transvaginal ultrasound (targeted endometriosis protocol) ± MRI if deep infiltrating disease is suspected

Red flags present

Manage as an acute gynecologic emergency (suspected torsion/ruptured endometrioma) or refer urgently for suspected bowel/bladder obstruction from deep disease — do not manage on the routine pathway

No red flags

Start empiric medical therapy based on clinical suspicion — a laparoscopic or histologic diagnosis is not required first^[3]

Fertility not an immediate priority

Scheduled NSAID + continuous CHC or a progestin-only option (oral, DMPA, implant, or LNG-IUS) — individualize on contraindications, cost, and desire for amenorrhea

Fertility desired

Avoid all ovarian-suppressing hormonal therapy — NSAIDs for pain only; refer for a fertility-focused evaluation (surgical excision, ovulation induction, IUI, or IVF as appropriate)

Escalation for persistent or refractory pain

Inadequate pain relief after an adequate trial (generally more than 3 months) of first-line hormonal therapy

Confirm adherence/correct use and reconsider the diagnosis — rule out an overlapping chronic pain syndrome (IBS, bladder pain syndrome, pelvic floor dysfunction) or an alternative gynecologic diagnosis

Only 1 first-line class tried (e.g. CHC only)

Switch to the other first-line class (a progestin option) before escalating further

Both CHC and a progestin have failed adequate trials, or are contraindicated

Escalate to a GnRH agonist with mandatory add-back hormone therapy, or a GnRH antagonist — elagolix^[6]

Confirm the duration limit and a bone-health monitoring plan: elagolix 150 mg up to 24 months, 200 mg up to 6 months; the relugolix/estradiol/norethindrone acetate combination up to 24 months^[7]

Still refractory, hormonal therapy not tolerated/declined, or fertility desired: refer for surgical evaluation (diagnostic/therapeutic laparoscopy with excision) ± a multidisciplinary chronic pelvic pain program

Drug Tables

How to use this table: Doses are adult doses and require patient-specific confirmation (renal/hepatic function, weight, allergy history). Pediatric dosing is weight-based per the current product monograph unless stated. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.

Analgesics

Evidence specifically for NSAID efficacy in endometriosis-associated pain remains limited in quality, though NSAIDs remain a reasonable, low-risk, low-cost first step and are frequently combined with hormonal suppression rather than used alone.^[8]

NSAIDs

First analgesic step. Start at symptom onset and take on a scheduled, not PRN, basis through the expected pain window.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Ibuprofen	Adults: 400 mg PO Q4-6H, scheduled; maximum 2400 mg/day	Dyspepsia, nausea/vomiting; less commonly nonspecific rash, pruritus, dizziness, headache	Increased GI bleeding risk with SSRIs, other NSAIDs, or anticoagulants	Contraindicated with ASA/NSAID hypersensitivity, active inflammatory bowel disease, active GI bleeding, significant renal impairment, or a clotting disorder.
Naproxen	Adults: 250 mg PO Q6-8H, or 500 mg PO Q12H; maximum 1250 mg/day	Dyspepsia, nausea/vomiting; less commonly nonspecific rash, pruritus, dizziness, headache	Increased GI bleeding risk with SSRIs, other NSAIDs, or anticoagulants	Same contraindications as ibuprofen. No evidence one NSAID outperforms another for this indication.
Acetaminophen	Adults: Per product labeling, scheduled dosing	Hepatotoxicity at supratherapeutic doses	Increased hepatotoxicity risk with chronic heavy alcohol use	A reasonable adjunct to an NSAID for additional analgesia; does not address the underlying inflammatory process.

Opioid analgesics are not first-line or routine therapy for endometriosis-associated pain given their adverse-effect and opioid-use-disorder risk; reserve short-term, cautious use for when NSAIDs are contraindicated or ineffective, following standard chronic non-cancer pain opioid-prescribing principles. Evidence for cannabis or cannabinoid-based products specifically in endometriosis pain remains insufficient to recommend their use.

Hormonal Suppression

Combined hormonal contraceptives

Continuous (extended-cycle) use is preferred over cyclic use, given a lower risk of dysmenorrhea recurrence; additional risk from continuous use, beyond the usual CHC risks, has not been demonstrated.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Ethinyl estradiol / norethindrone acetate (representative monophasic COC)	Continuous (preferred): 1 tablet PO daily, no hormone-free interval Cyclic (alternative): 1 tablet PO daily x 21 days, then a 7-day hormone-free interval	Breakthrough bleeding/spotting (most common, especially early on continuous use), nausea/vomiting, bloating, breast tenderness, mood changes; rare but serious VTE, stroke, MI, retinal artery thrombosis	Efficacy reduced by strong CYP3A4 inducers (rifampin, certain anticonvulsants, St. John's wort)	Confirm no contraindication (personal VTE/thrombogenic mutation history, migraine with aura, uncontrolled hypertension, complicated valvular/structural heart disease, active breast cancer, smoker over 35, severe cirrhosis/liver tumor). Counsel on ACHES warning symptoms — Abdominal pain, Chest pain, severe Headache, Eye problems, Severe leg pain — needing urgent care.
Ethinyl estradiol / etonogestrel vaginal ring	Adults: 1 ring inserted vaginally, continuous use, replaced per the product-specific interval without a ring-free week	Similar to oral CHC; also vaginal irritation/discharge	Efficacy reduced by strong CYP3A4 inducers	Alternative continuous-use route for a patient who prefers not to take a daily oral tablet.

Progestin-only options

Drug	Dosage	Adverse effects	Drug interactions	Comments
Medroxyprogesterone acetate	Oral: 20-40 mg PO daily Injectable (DMPA): 150 mg IM every 12 weeks	Breakthrough bleeding, weight gain, mood changes (e.g. depression, irritability); decreased bone mineral density and delayed return of fertility with long-term DMPA use	None major	Ovulation resumes promptly after stopping oral MPA, but is significantly delayed after DMPA — counsel a patient who may want to conceive soon.
Norethindrone acetate	Adults: 5 mg PO daily initially, increase by 2.5 mg/day every 2 weeks as needed to a maximum of 15 mg/day	Breakthrough bleeding, weight gain, mood changes	CYP3A4 substrate — levels increased by azole antifungals, macrolide antibiotics, protease inhibitors, and grapefruit juice; decreased by antiepileptics, rifampin, and dexamethasone	Ovulation resumes promptly after stopping.
Dienogest	Adults: 2 mg PO daily	Headache, breast discomfort, weight gain, mood changes, nausea	CYP3A4 substrate — same interaction pattern as norethindrone acetate	Ovulation resumes promptly after stopping.
Etonogestrel subdermal implant	Adults: Insert 1 subdermal implant (68 mg); replace per the product-specific interval (approximately every 3 years)	Breast tenderness, mood changes, weight gain, acne, headache, menstrual irregularity/amenorrhea	Efficacy reduced by strong CYP3A4 inducers	Requires insertion and removal by a trained provider; remove if it cannot be palpated.
Levonorgestrel intrauterine system (52 mg)	Adults: Insert within the labeled insertion window; the 52 mg system may remain in place for its full approved duration (currently up to 8 years) — confirm the specific product's current approved duration before counselling	Spotting for the first 3-6 months after insertion, then amenorrhea in many patients; simple ovarian cyst formation; rare uterine perforation or pelvic infection at insertion	None significant — minimal systemic absorption	No monograph is currently linked in the Drug Database for the intrauterine system specifically — the Drug Database's Levonorgestrel monograph covers only the oral emergency-contraception formulation (1.5 mg) and must not be used for LNG-IUS dosing or counselling.

Androgen agonist

Drug	Dosage	Adverse effects	Drug interactions	Comments
Danazol	Adults: 600-800 mg PO daily in divided doses (BID-QID), without interruption, for 3-6 months	Androgenic effects — hirsutism, acne, voice deepening (may be irreversible); decreased breast size, weight gain, adverse lipid changes (increased LDL, decreased HDL); menopausal-type symptoms (hot flashes, vaginal dryness)	May potentiate warfarin; caution with other hepatotoxic drugs	Avoid in dyslipidemia or liver disease. Effective nonhormonal contraception is required during treatment given teratogenic risk. Poor tolerability has left it well behind CHC/progestins/GnRH therapies for routine use.

Gonadotropin-releasing hormone (GnRH) agonists

GnRH agonists initially stimulate, then suppress, pituitary FSH/LH secretion, producing a markedly hypoestrogenic state that induces regression of endometriotic implants.^[3] A temporary symptom flare in the first 1-2 weeks of therapy is common, from the initial FSH/LH stimulation — this can be minimized by starting during the luteal phase or with concurrent aromatase-inhibitor or GnRH-antagonist pretreatment. Symptoms commonly recur within 9-12 months of stopping. Any course extending beyond a brief initial trial requires add-back hormone therapy (below) given the bone mineral density loss associated with prolonged hypoestrogenism.

GnRH agonists

Drug	Dosage	Adverse effects	Drug interactions	Comments
Leuprolide acetate	3.75 mg depot: 3.75 mg IM monthly, up to 6 months 11.25 mg depot: 11.25 mg IM every 3 months, up to 6 months	Hypoestrogenic symptoms: hot flashes, vaginal dryness, insomnia, decreased libido, emotional lability; reduced bone mineral density with courses beyond 6 months without add-back (reversible on stopping)	None major	Mandatory add-back hormone therapy for extended use.
Goserelin	3.6 mg depot: 3.6 mg SC monthly, up to 6 months 10.8 mg depot (long-acting): 10.8 mg SC every 12 weeks, up to 6 months	Hypoestrogenic symptoms as above; reduced bone mineral density with courses beyond 6 months without add-back	None major	Mandatory add-back hormone therapy for extended use.
Triptorelin	Adults: 3.75 mg IM every 28 days, up to 6 months	Hypoestrogenic symptoms as above; reduced bone mineral density with courses beyond 6 months without add-back	None major	Mandatory add-back hormone therapy for extended use.
Nafarelin	Adults: 1 spray (200 mcg) into 1 nostril each morning and 1 spray (200 mcg) into the other nostril each evening — total 400 mcg/day, up to 6 months	Hypoestrogenic symptoms as above; nasal irritation; reduced bone mineral density with courses beyond 6 months without add-back	None major	Review alternating-nostril technique with the patient at counselling. Mandatory add-back hormone therapy for extended use.

Add-back hormone therapy (mandatory with extended GnRH agonist use)

No single standard regimen exists — any regimen containing an estradiol dose approximately equivalent to 1 mg estradiol-17-beta plus a progestin is considered adequate. Add-back therapy is as effective as GnRH agonist monotherapy for pain relief without meaningfully increasing recurrence risk, and improves — though does not fully abolish — hypoestrogenic adverse effects and bone loss. Avoid in a patient with thromboembolic risk factors.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Norethindrone acetate (add-back)	Add-back: 5 mg PO daily	Breakthrough bleeding, weight gain, mood changes	CYP3A4 substrate — see interactions above	Effective alone or combined with an estrogen for maintaining lumbar spine bone mineral density.
Medroxyprogesterone acetate (add-back)	Add-back: 2.5-5 mg PO daily	Breakthrough bleeding, weight gain, mood changes	None major	Typically combined with an estrogen component.

Gonadotropin-releasing hormone (GnRH) antagonists

Unlike agonists, GnRH antagonists produce dose-dependent hypoestrogenism immediately, without an initial flare, and are as effective as GnRH agonists for pain relief.^[6]^[7]

GnRH antagonists

Drug	Dosage	Adverse effects	Drug interactions	Comments
Elagolix	150 mg dose: 150 mg PO once daily, for up to 24 months 200 mg dose: 200 mg PO twice daily, for up to 6 months — reserved for more severe pain, e.g. with dyspareunia, given a higher rate of adverse effects	Headache, nausea, hot flashes, altered mood/depressive symptoms, increased serum lipids, dose-dependent reduced bone mineral density (higher rate at the higher dose)	Hepatic (CYP3A4/OATP1B1-related) — review concurrent hepatotoxic drugs and strong OATP1B1 inhibitors per product labeling	Contraindicated in severe hepatic impairment, known osteoporosis, and pregnancy. Does not reliably prevent pregnancy on its own — use a backup method.
Relugolix / estradiol / norethindrone acetate	Adults: 1 tablet (relugolix 40 mg / estradiol 1 mg / norethindrone acetate 0.5 mg) PO once daily, for up to 24 months	Hot flashes, night sweats, headache, nasopharyngitis, decreased libido, alopecia	Efficacy of the estrogen component reduced by strong CYP3A4 inducers	Contraindicated with a history of MI/ischemic heart disease, cerebrovascular disease, complicated valvular heart disease, current/past VTE, known thrombogenic mutation, severe cirrhosis, liver tumor, breast cancer, migraine with aura, pregnancy/breastfeeding, smoking over age 35, or uncontrolled hypertension. Contains built-in add-back therapy — no separate add-back prescription is needed.

Aromatase inhibitors (adjunctive, for refractory pain)

Used together with a CHC, progestin, or GnRH agonist/antagonist — the concurrent hormonal agent blunts the ovarian-cyst formation that aromatase-inhibitor monotherapy would otherwise cause in a premenopausal patient via reflex gonadotropin stimulation. Evidence for this specific combination remains limited to small studies; it is not a standardized first-choice regimen. A separate, well-defined letrozole dosing regimen exists for ovulation induction in endometriosis-associated infertility — see below.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Letrozole (adjunctive)	Adults: Per specialist-directed protocol	Fatigue, dizziness, hot flashes, edema, nausea	None major	Reserve for specialist-directed refractory cases.
Anastrozole (adjunctive)	Adults: Per specialist-directed protocol	Fatigue, dizziness, hot flashes, adverse lipid changes	None major	Reserve for specialist-directed refractory cases.

Selective progesterone receptor modulators

Mifepristone has shown benefit for dysmenorrhea and dyspareunia in trials, but it is not available in Canada as a standalone product for this indication — only as a fixed combination with misoprostol for medical termination of pregnancy, an entirely different use. Ulipristal acetate 5 mg (previously marketed for uterine fibroids) was voluntarily withdrawn from the Canadian market due to the risk of serious drug-induced liver injury, including cases requiring liver transplantation.^[9] This withdrawal does not affect the ulipristal acetate 30 mg product used for emergency contraception, which remains available but is not indicated for endometriosis.

Endometriosis-Associated Infertility

Drug therapy directed at endometriosis itself does not improve fecundity, and ovarian-suppressing hormonal therapy is never used to manage infertility since it prevents pregnancy. The agents below are used specifically within a fertility-focused pathway.^[3]

Ovulation induction and assisted conception

Drug	Dosage	Adverse effects	Drug interactions	Comments
Letrozole (ovulation induction)	Adults: 2.5 mg PO daily on cycle days 3-7; may increase to 7.5 mg PO daily on cycle days 3-7 in a subsequent cycle if ovulation does not occur	Fatigue, dizziness, hot flashes, edema, nausea	None major	Off-label use — not a Health Canada-approved indication for ovulation induction, but comparable ovulation and pregnancy rates to the now-discontinued clomiphene, without increased birth defects.
Chorionic gonadotropin (hCG trigger)	Adults: 5,000-10,000 units IM at midcycle	Injection-site reaction, mild abdominal discomfort; rare ovarian hyperstimulation	None major	Specialist-directed; timed to follicular maturity on ultrasound, with or without intrauterine insemination.

A 3-6 month course of a GnRH agonist (see the GnRH agonist table above) before IVF or intracytoplasmic sperm injection — used as pituitary down-regulation, sometimes called superovulation or controlled ovarian hyperstimulation, together with intrauterine insemination for minimal-to-mild disease — improves the odds of clinical pregnancy; live birth rates diminish with successive treatment cycles, and outcomes should be reviewed with a fertility specialist rather than repeated indefinitely.

References

ESHRE guideline: endometriosis — Human Reproduction Open, European Society of Human Reproduction and Embryology (Becker CM, Bokor A, Heikinheimo O, et al.). Hum Reprod Open 2022;2022(2):hoac009
Guideline No. 449: Diagnosis and Impact of Endometriosis – A Canadian Guideline — Journal of Obstetrics and Gynaecology Canada, Society of Obstetricians and Gynaecologists of Canada (Singh SS, Allaire C, Al-Nourhji O, et al.). J Obstet Gynaecol Can 2024;46(5):102450
Guideline No. 468: Clinical Management of Endometriosis — Journal of Obstetrics and Gynaecology Canada, Society of Obstetricians and Gynaecologists of Canada (Yong PJ, Allaire C, Bedaiwy M, Bougie O, Kives S, Maheux-Lacroix S, Murji A, Singh SS). J Obstet Gynaecol Can 2026;48(6):103382
Diagnosis and management of endometriosis — CMAJ (Allaire C, Bedaiwy MA, Yong PJ). CMAJ 2023;195(10):E363-E371
Endometriosis recurrence following post-operative hormonal suppression: a systematic review and meta-analysis — Human Reproduction Update (Zakhari A, Delpero E, McKeown S, et al.). Hum Reprod Update 2021;27(1):96-107
Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist — New England Journal of Medicine (Taylor HS, Giudice LC, Lessey BA, et al.). N Engl J Med 2017;377(1):28-40
Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind studies (SPIRIT 1 and 2) — The Lancet (Giudice LC, As-Sanie S, Arjona Ferreira JC, et al.). Lancet 2022;399(10343):2267-2279
Nonsteroidal anti-inflammatory drugs for pain in women with endometriosis — Cochrane Database of Systematic Reviews (Brown J, Crawford TJ, Allen C, et al.). Cochrane Database Syst Rev 2017;1:CD004753
Fibristal (ulipristal acetate tablets, 5 mg) – voluntary withdrawal in Canada due to risk of drug-induced liver injury — Health Canada, Recalls and Safety Alerts. Health Canada Recall Notice, September 30, 2020

Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.