• Information
  1. Definitions
  2. Regions
  3. Adenomyosis
  4. Etiology
  5. Symptoms
  6. Diagnosis
  7. Treatment

A. Definitions

1. Endometriosis
   1. Ectopic endometrial tissue
   2. That is, endometrial tissue outside of the uterine cavity
2. Adenomyosis is endometrial tissue within uterine musculature
3. Symptomatic disease usually related to peritoneal seeding

B. Regions (in decreasing order of occurrence)

1. Ovary
2. Pouch of Rathke
3. Uterosacral Ligament
4. Round Ligament
5. Fallopian Tubes
6. Uterine Serosa
7. Uncommon: cervix, vagina, appendix, urinary bladder, colon, thoracic cavity, surgical scar [6]

C. Adenomyosis

1. Adenomyoma - intramyometrial collection, circumscribed and nodular
2. May lead to intramural hematomas
3. Distinguish from endometrial adenoma

D. Etiology (Theories)

1. Transport (Sampson Theory) - most widely accepted
   1. Retrograde (mesntrual) flow through fallopian tubes
   2. Especially with small cervix or cervical obstruction
   3. Endometriomas form on ovaries and/or in pelvic cavity
2. Formation in Situ
   1. Metaplasia of coelemic epithelium
   2. Does not explain distant migrations such as nasal septum
3. Other
   1. Altered cellular immunity
   2. Tissue metastasis
   3. Genetic contributions
   4. Gene-environment interactions
4. Endometriomas show elevated estradiol production and resistance to progesterone
5. Increased risk of pelvic malignancies in women with endometriosis versus those without

E. Symptoms [3]

1. Pelvic Pain
   1. Not proportional to amount of tissue
   2. Depends on location of ectopic endometrium
   3. Often cyclical pain (hormone response) - begins before menses and abates with flow
   4. Sex steroid refractory endometrium does not cause pain (usually)
   5. Dyspareunia
2. Infertility
   1. About 35% of infertile women have endometriosis
   2. Pathogenesis is not well understood
   3. Cyclic pelvic bleeding leads to inflammation, fibrosis and adhesions
   4. These adhesions are belived to cause disordered anatomy and endocrinopathies
   5. Altered embryo implantation may occur
3. Amenorrhea
4. Menorrhagia
5. Intussusception [4]
   1. Endometriosis uncommonly causes intussusception
   2. Intussusception occurs when a segment of bowel telescopes into the lumen of a more distal bowel segment
   3. Abdominal pain, vomiting, diarrhea, and hematochezia may occur
   4. Colonic spasm may occur leading to the pain
   5. Urgent treatment with reduction of intussusception is required
6. Thoracic Endometriosis [5]
   1. Pneumothorax
   2. Hemothorax
   3. Uncomon; generally presents ~5 years after pelvic endometriosis

F. Diagnosis

1. Suspect diagnosis in women with pain or infertility
2. Tender nodular masses along thickened uterosacral ligments, posterior uterus, cul de sac
3. Ovarian disease may be accompanied by adnexal tenderness
4. Laparoscopy
   1. Procedure of choice for diagnosis and treatment
   2. May be done as outpatient
5. Serum levels of CA-125 are often elevated in endometriosis
6. Ultrasound and MRI have some utility, but are insensitive to diffuse pelvic endometriosis
7. Stages I through IV used to predict future risk of fertility reduction
8. Note that endometriosis is underdiagnosed and undertreated

G. Treatment [1,4]

1. Goals are individualized and generally fall in to one of three categories:
   1. Patients with infertility ± pain
   2. Those with pelvic pain who wish to preserve fertility potential
   3. Those with pain who have completed childbirth
   4. Oral contraceptives (OCP) should generally be tried first if fertility is not an issue
   5. Continuous active OCP is better than cyclical OCPs for dysmenorrhea
   6. Drugs which control endometriosis typically reduce pain associated with the disease
2. Overview of Agents [1]
   1. Androgens
   2. GnRH Agonists
   3. Progestagens
   4. Oral contraceptives
3. Infertility Treatment
   1. Synthetic progestins (such as Norethyndryl) may improve fertility
   2. Conservative surgery will often improve fertility and decrease symptoms
   3. Operative laparoscopic cauterization may be effective (increased fertility by ~20%)
   4. Synthetic Androgens (such as Danazol®) are less effective at improving fertility
   5. Overall, no role for drug therapy in treatment of endometriosis-associated infertility [1,2]
   6. Surgery and/or assisted fertilization are preferred for treatment of infertility
4. Danazol
   1. Androgenic steroid
   2. Blocks mid-cycle surge of LH and increases serum testosterone levels
   3. Effective in decreasing pain symptoms, even up to 6 months after stopping drug
   4. No benefit over observation alone on fertility
   5. Initiate dose at 400mg po qd which is reasonably well tolerated
   6. Higher doses 600-800mg qd may be more active, but with increased androgenic effects
   7. Doses are escaled if no improvement in 6 weeks
5. Progesterones
   1. Most commly, medroxyprogesterone 10-30mg po qd is used for up to 6 months
   2. In Europe, up to 100mg po qd is used with improved efficacy and similar side effects
   3. Causes decidualization and then atrophy of endometrial tissue
   4. Side effects: uterine bleeding, nausea, breast tenderness, fluid retention, depression
   5. Pain relief is usually achieved with high doses of progestins
   6. No improvement in fertility
   7. Breakthrough bleeding treated with estrogens for 1-2 weeks
   8. Overall better tolerated, decreased cost, similar efficacy to danazol
6. Gestrinone
   1. Ethylnorgestrienone, an antiprogestional steroid
   2. Reduces estrogen and progesterone receptors
   3. Reduces serum estradiol 50% and serum sex hormone-binding globulin
   4. Given 5-10mg orally per week
   5. Androgenic and antiandrogenic side effects
   6. Uncommon severe side effects such as hirsutism, deepening voice, clitoral enlargement
7. GnRH Analogues
   1. Synthetic decapeptides which produce a "medical" oophorectomy
   2. These agents inhibit pituitary production of LH, FSH, leading to "pseudomenopause"
   3. First generation agents are agonists at the GnRH receptor level in the pituitary
   4. Normal GnRH is produced in a pulsatile fashion, required for pituitary stimulation
   5. These long acting agonists effectively stimulate GnRH receptor constantly, which actually inhibits signalling and blocks FSH and LH production
   6. Leuprolide acetate (Lupron®) and Goserelin (Zoladex®) given subcutaneously
   7. Nafarelin (Synarel®) is intranasal
   8. Regression of implants and pain relief similar to that of danazol; no effect on infertility
   9. Significant bone loss during therapy may be reversed with parathyroid hormone
   10. All patients should be on high dose calcium orally with vitamin D (800U/d)
   11. Novel GnRH antagonists are in clinical development for endometriosis indication
8. Surgery
   1. Medical therapy is good for reducing pain and anatomical extent of disease
   2. Recurrence rates with medical therapy typically ~20% at 6 months; ~50% in 1 year
   3. Surgery is definitive and most common treatment for endometriosis
   4. Laparoscopic surgery may be possible in many patients
   5. Surgery generally improves pregnancy rates
   6. Surgical treatments directed specifically at pain have been developed
   7. Uterosacral nerve resection and presacral neurectomy are most commonly used
   8. Surgery may be combined with postoperative medical therapy
9. In vitro fertilization may be considered for pregnancy

References

1. Gludice LC and Kao LC. 2004. Lancet. 364(9447):1789
2. Olive DL and Pritts EA. 2001. NEJM. 345(4):266
3. Adamson GD. 1999. JAMA. 282(24):2347 (Case Discussion)
4. Huirne JAF and Lambalk CB. 2001. Lancet. 358(9295):1793
5. Joseph J and Sahn SA. 1996. Am J Med. 100(2):164
6. Muto M, O'Neill MJ, Oliva E. 2005. NEJM. 352(24):2535 (Case Record)