Content on this page:
Content:
Principles of therapy
The short-term objectives in treating endometriosis are decreasing
pain and enhancing fertility. The long-term goal is to prevent progression or
recurrence.
Medical management of infertile patients with minimal and mild
endometriosis should not be offered since it does not improve fertility. No
studies have shown the benefits of one medical therapy over another when
treating pain due to endometriosis.
Eighty to ninety percent of patients will have some improvement in
symptoms with medical therapy; however, there is a recurrence rate of 5-15% in
the first year and 40-50% in the fifth year.
Due to the chronic nature of the condition, medical therapy should
be safe and effective to use until pregnancy is desired or until menopause. Patients
with persistent symptoms after medical therapy should be referred for a laparoscopy.
The severity of symptoms does not match with the degree of endometriosis.
Pharmacological therapy
First-line Therapeutic Options
Combined Oral Contraceptives (COCs)1
Combined estrogen and progestin oral contraceptives are considered
the first-line treatment for pelvic pain secondary to endometriosis. It decreases
dysmenorrhea, non-menstrual pain, and endometriosis-related dyspareunia and is
considered a good choice for women with minimal or mild symptoms.
It induces decidualization and subsequent atrophy of endometrial
tissue by suppression of ovarian function. Low-estrogen combination pill with relatively
high progestin is given to induce amenorrhea and “pseudopregnancy”.
It may be administered cyclically with 7 days of placebo pills
between cycles or may be taken continuously. Better pain relief may be achieved
with continuous therapy since menses, withdrawal bleeding, and associated pain
are prevented. Withdrawal of pills every month that causes cyclic menstrual
bleeding may be associated with some retrograde spill of blood that contains
cytokines and other inflammatory chemicals. This administration may decrease
80% of the symptoms of patients during therapy.
It provides contraception and has a low rate of side
effects (eg weight gain, breast tenderness). No oral contraceptive combination
has been shown to be more effective than another.
1Various combinations of estrogen and progestogens are available.
Please see the latest MIMS for specific formulations.
Progestins
Progestins are used for treating chronic pain in patients with
endometriosis. It is considered the first choice for the treatment of
endometriosis due to its effective reduction in ASRM scores and pain, with lower
cost and side effects as compared to gonadotropin-releasing hormone (GnRH) analogs
and Danazol. It shows that >80% of patients have partial or complete relief.
It inhibits endometriotic tissue growth by directly causing
initial decidualization and eventual atrophy. It also inhibits pituitary
gonadotropin secretion and ovarian hormone production.
Dienogest is a progestin with selective 19-nortestosterone and
progesterone activity. It has the same effectiveness as GnRH agonist therapy in
relieving endometriosis-associated pelvic pain as shown in clinical trials and
in the treatment of deep infiltrating endometriosis. It may be an effective
option in long-term treatment of endometriosis.
Depot Medroxyprogesterone acetate may alleviate pelvic pain low
treatment cost. It may be best indicated for patients with no issues regarding
future conception and irregular uterine bleeding and has remaining
endometriosis after hysterectomy with or without bilateral
salpingo-oophorectomy. It is not an option for women who desire pregnancy in
the near future as it delays the resumption of ovulation and for long-term use
as it may have negative effects on bone mineral density (BMD).
Norethindrone acetate is approved for continuous use in treating
endometriosis. It relieves dysmenorrhea and chronic pelvic pain. It may cause
breakthrough bleeding in some patients but is likely to have a positive effect
on calcium metabolism maintaining a good BMD.
Second-line Therapeutic Options
Gonadotropin-Releasing Hormone (GnRH) Agonists
GnRH agonists are recommended for patients who failed to respond
to combined oral contraceptives or progestins or who have symptom recurrence
after initial improvement. It is very effective in alleviating
endometriosis-associated pelvic pain but is not superior to other therapeutic options.
It may induce hypoestrogenism that inactivates pelvic lesions and resolves
pelvic pain.
Monotherapy with GnRH agonist may result in symptoms secondary to
estrogen deficiency (eg hot flushes, insomnia, vaginal dryness, loss of BMD,
breakthrough bleeding in the first month of therapy, irritability, fatigue, and
skin problems). Hence, GnRH agonists may be given add-back therapy which can be
started immediately.
In estrogen and progestin add-back therapy, the concentration of
serum estrogen is low enough to cause endometriosis but high enough to prevent
hypoestrogenic symptoms. The addition of add-back therapy lessens or eliminates
GnRH agonist-induced bone mineral loss and is also useful in relieving symptoms
without affecting the efficacy of GnRH agonist. Add-back regimens (eg sex
steroid hormones or other specific bone-sparing agents) are recommended in women
who will undergo >6 months of GnRH agonist therapy.
GnRH agonists should be given with caution in young women and
adolescents since they may not have reached their maximum bone density. Daily
calcium supplementation (1,000 mg) is advised in patients using GnRH agonists with
add-back therapy.
GnRH Receptor Antagonist
Example drug: Elagolix
GnRH receptor antagonists are indicated in patients with moderate
to severe pain associated with endometriosis. It is an oral, non-peptide, small
molecule GnRH receptor antagonist that can dose-dependently suppress luteinizing hormone (LH),
follicle-stimulating hormone FSH, estradiol and progesterone secretion.
In comparison to GnRH agonists, its dose can be titrated to obtain
a nearly full or partial hormonal suppression. It causes a dose- and
duration-dependent reduction in BMD. It is therefore vital to assess the patient’s
BMD if the patient has risk factors for bone loss and limit treatment duration
to decrease bone loss. Advise the patient to take adequate amounts of calcium and
vitamin D.
Levonorgestrel Intrauterine System (LNG-IUS)
Levonorgestrel is a 19-nortestosterone-derived progestin that has
effective anti-estrogenic effects on the endometrium. It causes atrophic
endometrium and amenorrhea in up to 60% of patients without affecting ovulation.
LND-IUS provides continuous therapy for five years and has lesser
systemic side effects. It may be a good option for rectovaginal endometriosis,
and it reduces dysmenorrhea, non-menstrual pelvic pain, deep dyspareunia, and
dyschezia. It may have a 5% expulsion rate, a 1.5% risk for pelvic infection,
and an increased risk for ovarian endometrioma.
Danazol
Danazol is effective in resolving implants when treating mild or
moderate stages of the disease. It is a synthetic isoxazole derivative of
ethisterone which inhibits pituitary gonadotropin secretion, endometriotic implant
growth, and ovarian enzymes responsible for estrogen production. It has
immunologic effects like decreasing serum immunoglobulins, auto-antibodies, and
CA-125 levels, increasing serum C4, and inhibiting interleukin-1 (IL-1) and
tumor necrosis factor (TNF) production.
It causes high androgen and low estrogen levels, and amenorrhea, and
prevents new seeding of implants from the uterus into the peritoneal cavity. More
than 80% of patients experience relief or improvement of pain symptoms within two
months of treatment with beneficial effects lasting up to six months after
stopping it. Nevertheless, large endometriotic cysts and adhesions do not
respond well to Danazol.
Its use is limited by the occurrence of androgenic side effects
(eg weight gain, acne, hirsutism, breast atrophy, and rarely virilization) and
adverse effects on blood lipid levels. It should be used if other medical
therapies are unavailable and should be given in low doses or via the vaginal
route. It should not be used long term. A small study showed an increased risk
for ovarian cancer in endometriosis patients treated with Danazol.
Aromatase Inhibitors
Aromatase inhibitors work by decreasing the local estradiol
production thus lessening lesion growth. It can reduce pain from rectovaginal
endometriosis when combined with oral contraceptives, progestogens, or GnRH
analogs.
It should only be given to women refractory to medical or surgical
treatment due to severe side effects (eg hot flushes, vaginal dryness,
decreased BMD, arthralgia). Studies show a lack of evidence on long-term effects.
Supportive Therapy
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
NSAIDs cause central inhibition of prostaglandin synthesis, local
anti-nociceptive effects, and anti-inflammatory effects. They are frequently
given as initial treatment to women with pelvic pain where the diagnosis of
endometriosis is still uncertain. It may also be given to patients to provide
analgesia until primary medical management becomes effective.
Surgery
Surgery is recommended in some circumstances to confirm the
diagnosis and provide treatment to achieve pain relief or improve fertility (ie
“see and treat”). It should only be done in women with endometriosis-related
pain after medical treatment has failed.
It may improve fertility as the patient benefits from the
mechanical clearance of adhesions and obstructive lesions.
Please see Infertility disease management chart for
further information.
The following are indications of surgical management:
- Symptoms are severe, incapacitating, or acute (eg acute adnexal torsion or rupture of ovarian cyst)
- Symptoms have failed to resolve or have worsened under medical management
- With advanced disease or invasive disease that affected the bowel, ureters, bladder, or pelvic nerves
- Anatomic distortion of the pelvic organs, endometriotic cysts, or obstruction of the bowel or urinary tract
- Patient declines or has contraindications to medical treatment
- Endometriosis-related infertility, pain, or pelvic mass
- Treatment for postmenopausal endometriosis
It may be performed by laparoscopy or laparotomy, although laparoscopy
is preferred over laparotomy for the treatment of endometriosis-related
infertility. After surgery, the median time for pain recurrence is 20 months.
Surgical
management may be classified as “conservative” or “definitive” surgery.
Conservative Surgery
Conservative surgery preserves the uterus and as much ovarian
tissue as possible. It is performed in women of reproductive age, those who
wish to get pregnant, or those who wish to avoid menopausal induction at an
early age.
It includes removal of macroscopic endometrial tissue, lysis of
adhesions, and repair of normal anatomy. A high recurrence rate (80-100%) is
noted after six months of drainage of endometriomas.
The excision of endometriomas provides better pain relief,
decreased recurrence rate, a histopathological diagnosis, and improves the chances
of pregnancy. Women with >3 cm ovarian endometriomas and with pelvic pain
should be advised to undergo excision of endometrioma.
Surgical ablation or resection of endometriosis plus laparoscopic
adhesiolysis should be offered to patients with minimal or mild endometriosis
who will undergo laparoscopy to improve the chances of pregnancy. Operative
laparoscopy in patients with severe endometriosis increases spontaneous
pregnancy rates.
Laser Uterosacral Nerve Ablation (LUNA)
LUNA reduces the pain of minimal to moderate endometriosis. It works
by disrupting the efferent nerve to reduce uterine pain. It is not performed as
an additional procedure to conservative surgery for pain reduction as
randomized controlled trials (RCTs) showed no additional benefit.
Presacral Neurectomy
Although rarely indicated, presacral neurectomy may be helpful in
decreasing midline pain (eg dysmenorrhea, dyspareunia) but not in other pelvic
areas. It may be considered as an adjunct to surgical management of
endometriosis-related pelvic pain.
Tubal Flushing
Studies have shown that flushing of fallopian tubes using
oil-soluble media may increase the chances of
pregnancy.
Definitive Surgery
Cystectomy
In women with ovarian endometrioma, cystectomy rather than
drainage and coagulation or carbon dioxide (CO2) laser vaporization should
be performed.
Hysterectomy
Hysterectomy with or without removal of the fallopian tubes and ovaries
may be done on patients with endometriosis. Case series studies have shown that
80-90% of women who failed with medical or surgical management experienced pain
relief after hysterectomy with bilateral salpingo-oophorectomy; however,
recurrence of pain was noted within one to two years in 10% of women.
It may be an option for patients with intractable pain despite
conservative treatment, severe disease, and if childbearing is no longer
desired.
In
young women who underwent total abdominal hysterectomy with bilateral
salpingo-oophorectomy (TAHBSO), hormonal replacement therapy (HRT) is
recommended. Combined hormone therapy (estrogen and progestin) or Tibolone may
be given.
Combined Medical and Surgical Therapy
Combination therapy wherein medical therapy is given before and/or
after surgery is also an option for endometriosis.
Hormonal suppression may be given prior to surgery in hopes of
decreasing the size of endometriotic implants thereby reducing the extent of the
surgery required. In cases where complete removal of implants is not possible
or advisable, post-op medical therapy may be used to treat residual disease and
delay its recurrence.
A randomized controlled trial study showed a reduction in
recurrence with post-op use of combined oral contraceptives. LNG-IUS implanted
after surgery showed a major decrease in recurrence (10%) of moderate to severe
dysmenorrhea after one year. Progestin, Danazol, or GnRH analogs may be used in
conjunction with laparotomy or laparoscopic conservative or definitive surgical
treatment.
It is not recommended to prescribe preoperative or adjunctive
hormonal therapy after surgery for the treatment of pain as it does not improve
the surgery’s outcome for pain.