Endometriosis 2

TREATMENT
Medical Care:
Endometriosis and subfertility
Peritubal and periovarian adhesions can interfere mechanically with ovum transport and contribute to subfertility. Peritoneal endometriosis has been postulated to contribute to subfertility by interfering with tubal motility, folliculogenesis, and corpus luteum function. Results from studies on the role of prostaglandins are inconclusive.
Medical treatment of minimal or mild endometriosis has not been shown to increase pregnancy rates (Badawy, 1988). Moderate-to-severe endometriosis should be treated surgically (Marcoux, 1997).
Other options for achieving pregnancy include intrauterine insemination, superovulation, and in vitro fertilization. In a case-controlled study, pregnancy rates with intracytoplasmic sperm injection were not affected by the presence or extent of endometriosis (Bukulmez, 2001). Further, other analyses have shown improvement in in vitro fertilization pregnancy rates with pretreatment of stage 3 and 4 endometriosis with gonadotropin-releasing hormone (GnRH) agonists.
Interval treatment
Some authorities believe that endometriosis should be suppressed prophylactically by continuous combined oral contraceptives, GnRH analogs, medroxyprogesterone, or danazol in order to cause regression of asymptomatic disease and enhance subsequent fertility.
Surgical ablation of asymptomatic endometriosis has also been shown to improve fecundity rates on a 3-year follow-up (Marcoux, 1997).
Recurrent pregnancy loss: Based on results from controlled prospective studies, no evidence indicates that endometriosis is associated with recurrent pregnancy loss and no evidence indicates that medical or surgical treatment of endometriosis reduces the spontaneous abortion rate (Vercammen, 2000).
Medical therapy: Combination oral contraceptive pills (COCPs), danazol, progestational agents, and GnRH analogs form the mainstay of medical therapy. All these therapies have similar clinical efficacy in terms of reduction in pain-related symptoms and duration of relief.
COCPs act by ovarian suppression and continuous progestin administration.
Initially, a trial of continuous or cyclic COCPs should be administered for 3 months. If pain is relieved, this treatment is continued for 6-12 months. Subsequent pregnancy rates upon discontinuation of the pill are 40-50%. This applies to a population unselected for stage and fertility status of the disease.
Although few choices are available among individual formulations, note that the long-term efficacy of multiphasic preparations remains unproven.
Continuous noncyclical administration of COCPs, omitting the placebo menstrual tablets, for 3-4 months helps avoid any menstruation and associated pain.
All progestational agents act by decidualization and atrophy of the endometrium.
Medroxyprogesterone acetate has proven efficacy in pain suppression in both the oral and injectable depot preparations (Hull, 1987; Kauppila, 1993). Oral doses of 10-20 mg/d can be administered continuously. The time to resumption of ovulation is longer and variable with depot preparations. Adverse effects include weight gain, fluid retention, depression, and breakthrough bleeding.
Megestrol acetate has been used in doses of 40 mg with similarly good results (Schlaff, 1990).
GnRH analogs produce a hypogonadotrophic-hypogonadic state by down-regulation of the pituitary gland. Currently, goserelin and leuprolide acetate are the commonly used agonists.
Once again, efficacy is limited to pain suppression and fertility rates may show no improvement (Hughes, 2000).
Treatment is usually restricted to monthly injections for 6 months.
Loss of trabecular bone density caused by GnRH is restored by 2 years after cessation of therapy (Paoletti, 1996). Other prominent adverse effects include hot flashes and vaginal dryness.
Much interest has been shown in whether add-back therapy should be instituted to prevent osteoporosis and hypoestrogenic symptoms. Hormone replacement therapy preparations, progestins, tibolone maleate, and bisphosphonates have all been shown to be effective (Friedman, 1993; Taskin, 1997; Surrey, 1995; Lane, 1991). Add-back therapy has been shown to prevent loss in bone density and to relieve vasomotor symptoms without reducing the efficacy of GnRH regimens. GnRH agonists have been used for 12 months with norethindrone add-back therapy with good results (Surrey, 1999).
A clinical trial has shown that a 3-month empiric course of GnRH, based on a diagnostic algorithm without definitive laparoscopic diagnosis, is efficacious (Ling, 1999). However, long-term effects of GnRH analogs on bone density in this population remain unproven. Therefore, add-back therapy remains the standard of care while the patient is on GnRH treatment. Also, empiric treatment without a firm diagnosis could result in unnecessary treatment in patients with chronic pelvic pain, whose condition could be due to other causes. In Ling's study, 13% of subjects were shown to not have endometriosis.
GnRH therapy has also been proven to relieve the pain and bleeding associated with extrapelvic distant endometriosis (Espaulella, 1991).
Danazol acts by inhibiting the midcycle follicle-stimulating hormone (FSH) and luteinizing hormone (LH) surges and preventing steroidogenesis in the corpus luteum. It is the most extensively studied agent for endometriosis.
Danazol has been shown to be as effective as any of the newer agents, but with a higher incidence of adverse effects.
Its androgenic manifestations include oily skin, acne, weight gain, deepening of the voice, and facial hirsutism. Hypoestrogenic features due to danazol include emotional lability, hot flashes, vaginal dryness, and reversible breast atrophy.
The recommended dose is 600-800 mg/d. However, smaller doses have been used with success (Telimaa, 1987; Dmowski, 1982).
Because of the possibility of virilizing changes in a female fetus, additional barrier contraception must be used while on danazol therapy.
Surgical Care: Surgical care can be broadly classified as conservative when reproductive potential is retained, semiconservative when reproductive ability is eliminated but ovarian function is retained, and radical when the uterus and ovaries are removed. Age, desire for future childbearing, and deterioration of quality of life are the main considerations when deciding on the extent of surgery.
Conservative surgery
With conservative surgery, the aim is to destroy visible endometriotic implants and lyse peritubal and periovarian adhesions that are a source of pain and may interfere with ovum transport. The laparoscopic approach is the method of choice for treating endometriosis conservatively (Cook, 1991; Saidi, 1996). Ablation can be performed with laser or electrodiathermy. Overall, the recurrence rate is 19% and is similar for all techniques (Revelli, 1995). Ovarian endometriomas can be treated by drainage or cystectomy. Laparoscopic cystectomy was found to yield better pain relief and pregnancy rates than drainage (Beretta, 1998). Medical therapy with GnRH agonists reduces the size of the cyst but does not influence pain relief (Donnez, 1990).
Presacral neurectomy is used to relieve severe dysmenorrhea. The nerve bundles are transected at the level of the third sacral vertebra, and the distal ends are ligated. Vascular injury to the middle sacral artery and vein is a potential complication, and some authors advocate prophylactic ligation. Also, constipation is a long-term adverse effect (94%) of this procedure and should be considered while deciding whether to perform this procedure.
Nodularity of the uterosacral ligaments may contribute to dyspareunia and low back pain. The transmission of neural pathways is via the Lee-Frankenhäuser plexus. Laparoscopic uterine nerve ablation (LUNA) is performed to interrupt the pain fibers. Potential complications of this procedure include uterine prolapse and pelvic denervation. A systematic review of trials of LUNA found no advantage in terms of pain relief when compared to placebo (Wilson, 2000). However, when combined with laparoscopic ablation, LUNA significantly reduced pain attributed to endometriosis (Sutton, 1997). In patients with subfertility, tissue ablation significantly increased the cumulative pregnancy rate (Marcoux, 1997).
For patients with mild disease, postoperative adjunctive hormonal treatment has been shown effective in reducing pain but has no impact on fertility. GnRH analogs, danazol, and medroxyprogesterone have all been found to be useful for this indication (Prentice, Deary, and Bland, 2000; Prentice et al, 2000; Selak, 2001; Moore, 2000). However, for severe endometriosis, the efficacy of preoperative or postoperative hormonal treatment has not yet been established.
Semiconservative surgery
The indication for this type of surgery is mainly in women who have completed their childbearing, are too young to undergo premature menopause, and are debilitated by the symptoms. Such surgery involves hysterectomy and cytoreduction of pelvic endometriosis. Ovarian endometriosis can be removed surgically because one tenth of functioning ovarian tissue is all that is needed for hormone production. Patients who undergo hysterectomy with ovarian conservation have a 6-fold higher rate of recurrence compared to women who undergo oophorectomy (Namnoum, 1995).
Medical therapy in women who have completed childbearing is equally efficacious for symptom suppression (Vercellini, 1997; Waller, 1993; Society of Obstetricians and Gynaecologists of Canada, 1999).
Radical surgery
This involves total hysterectomy with bilateral oophorectomy and cytoreduction of visible endometriosis. Adhesiolysis is performed to restore mobility and normal intrapelvic organ relationships.
Ureteric obstruction may warrant surgical release or excision of a damaged segment. Bowel obstruction may require a resection anastomosis or a wedge resection if the obstruction is confined to the anterior rectosigmoid.
Endometriosis may recur in 15% of women after extirpative surgery, irrespective of whether ERT is given postoperatively (Redwine, 1994). ERT can be instituted safely immediately after surgery, especially in younger women who face the prospect of accelerated bone loss and vasomotor symptoms (Redwine, 1994; Hickman, 1998). No trials have reported the use of estrogen plus progestin therapy compared to estrogen therapy alone postoperatively. However, theoretically, the addition of a continuous progestin could decrease the regrowth of endometriosis.
Comparison of medical and surgical therapy: In women who wish to preserve their reproductive potential, the rates of recurrent pain symptoms are 44% with surgical management and 53% with medical management (Sutton, 1997; Waller, 1993).
MEDICATION
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Oral contraceptives -- COCPs act by ovarian suppression and continuous progestin administration. Initially, a trial of continuous or cyclic COCPs should be given for 3 mo. If pain is relieved, this treatment is continued for 6-12 mo. Subsequent pregnancy rates are 40-50% upon discontinuation of the contraceptive pill. Although individual formulations offer few variations, note that the long-term efficacy of multiphasic preparations remains unproven. In addition, continuous noncyclical administration of COCPs, omitting the placebo menstrual tablets, for 3-4 months helps avoid any menstruation and associated pain.
Drug Name
Ethinyl estradiol and norgestimate (Ortho-Cyclen, Ortho-Prefest, Ortho Tri-Cycle -- Reduces the secretion of LH and FSH from the pituitary by decreasing amount of GnRH.
Adult Dose
Schedule 1 (Sunday starter)Begin dose on first Sunday after onset of menstruation; start that Sunday if menstrual period starts on Sunday21-tab package: 1 tab qd for 21 d followed by 7 d off medication; new course begins on day 8 after taking last tab28-tab package: 1 tab qd without interruptionSchedule 2 (day 1 starter)Start dose on d 1 of menstrual cycle21-tab package: 1 tab qd for 21 d followed by 7 d off medication; begin new course on day 8 after taking last tabContinue dosing cycle if one period missed; pregnancy test required if 2 periods missed
Pediatric Dose
Not recommended
Contraindications
Documented hypersensitivity; endometrial and hepatic cancer; thromboembolic disorders; undiagnosed vaginal bleeding; smokers >35 y; cardiovascular disease
Interactions
Phenobarbital, phenytoin, paramethadione, carbamazepine, troglitazone, rifampicin, and griseofulvin induce enzymes that decrease levels of contraceptive steroids; PO anticoagulants may increase thromboembolic potential
Pregnancy
X - Contraindicated in pregnancy
Precautions
Caution in patients diagnosed with hepatic impairment, migraine, seizure disorders, cerebrovascular disorders, breast cancer, or thromboembolic disease
Drug Category: Progestational agents -- All act by decidualization and atrophy of the endometrium.
Drug Name
Medroxyprogesterone (Amen, Cycrin, Provera) -- Progestins stop endometrial cell proliferation, allowing organized sloughing of cells after withdrawal. Typically does not stop acute bleeding episode but produces normal bleeding episode following withdrawal.
Adult Dose
10-20 mg PO qd continuously
Pediatric Dose
Not recommended
Contraindications
Documented hypersensitivity; cerebral apoplexy; undiagnosed vaginal bleeding; thrombophlebitis; liver dysfunction
Interactions
May decrease effects of aminoglutethimide
Pregnancy
X - Contraindicated in pregnancy
Precautions
Caution in asthma, depression, renal or cardiac dysfunction, or thromboembolic disorders; adverse effects include weight gain, fluid retention, depression, and breakthrough bleeding

Drug Name
Megestrol (Megace) -- Results similar to medroxyprogesterone.
Adult Dose
40 mg PO qd
Pediatric Dose
Not recommended
Contraindications
Documented hypersensitivity
Interactions
Elevated dofetilide plasma concentrations may occur (with increased risk of ventricular arrhythmias, including torsades de pointes) if coadministered; may alter thyroid and liver function test results
Pregnancy
X - Contraindicated in pregnancy
Precautions
Caution in patients with a history of thrombophlebitis; elderly women may experience vaginal bleeding/discharge, which is an adverse effect
Drug Category: Gonadotropin-releasing hormone analogs -- Produce a hypogonadotrophic-hypogonadic state by down-regulation of the pituitary gland. Currently, goserelin and leuprolide acetate are the commonly used agonists.
Drug Name
Goserelin (Zoladex) -- Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels.
Adult Dose
3.6 mg SC q28d or 10.8 mg SC q12wk for 6 mo
Pediatric Dose
Not recommended
Contraindications
Documented hypersensitivity; undiagnosed vaginal bleeding; spinal cord compression
Interactions
None reported
Pregnancy
X - Contraindicated in pregnancy
Precautions
Urinary tract obstruction, tumor flare, and bone pain may occur; monitor patients for weakness and paresthesias

Drug Name
Leuprolide (Lupron) -- Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels.
Adult Dose
3.5-7.5 mg/mo IM; not to exceed 6 mo without adding low-dose estrogen and progestin therapy
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; undiagnosed vaginal bleeding; spinal cord compression
Interactions
None reported
Pregnancy
X - Contraindicated in pregnancy
Precautions
Urinary tract obstruction, tumor flare, and bone pain may occur; monitor patients for weakness and paresthesias
Drug Category: Antigonadotropic agents -- Act by inhibiting the midcycle FSH and LH surge and preventing steroidogenesis in the corpus luteum. Most extensively studied agents for endometriosis. Danazol has been shown to be as effective as any of the newer agents, but with a higher incidence of adverse effects.
Drug Name
Danazol (Danocrine) -- Synthetic steroid analog with strong antigonadotropic activity (inhibits LH and FSH) and weak androgenic action.
Adult Dose
600-800 mg/d PO
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; seizure disorders; hepatic, renal, or hepatic insufficiency; breastfeeding; conditions influenced by edema; undiagnosed genital bleeding; porphyria
Interactions
Decreases insulin requirements and increases effects of anticoagulants; may increase carbamazepine levels
Pregnancy
X - Contraindicated in pregnancy
Precautions
Caution in renal, hepatic, or cardiac insufficiency and seizure disorders
FOLLOW-UP
Prognosis:
Endometriosis was found to resolve spontaneously in one third of women who were not actively treated (Harrison, 2000).