GnRH Agonist Analogues
Several GnRH agonists have been approved for use in en-dometriosis [see Table 3). These agents are analogues of the native decapeptide GnRH, with substitutions in amino acids 6 and 10. The introduction of D-amino acids at position 6 of native GnRH produces GnRH analogues that are resistant to degradation by endopeptidases and have long half-lives, high affinity for the GnRH receptor, and long receptor occupancy.
Paradoxically, initial treatment with a GnRH agonist analogue stimulates the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Prolonged treatment, however, suppresses gonadotropin secretion through the cellular processes of downregulation and desensitization. The suppression of secretion is greater for LH than for FSH. The suppression of pituitary gonadotropin secretion results in suppression of ovarian follicle growth and a 95% decrease in estrogen production. In women treated with many GnRH analogues, the circulating estradiol concentration is suppressed to about 15 pg/ml, which is in the range observed in menopausal women. In essence, this therapy constitutes a reversible medical oophorectomy.
Numerous clinical trials have demonstrated that approximately 85% of women with endometriosis and pelvic pain who are treated with GnRH agonist analogues experience relief of their pain. In one placebo-controlled trial, treatment with a GnRH agonist resulted in better relief of pelvic pain than the administration of placebo (85% and 30%, respectively).39
Table 3 GnRH Agonists Approved for the Treatment of Endometriosis*
|
GnRH Agonist |
Dose |
|
Leuprolide acetate depot |
3.75 mg I.M. every 4 wk |
|
Goserelin acetate |
3.6 mg subcutaneous implant every 4 wk |
|
Nafarelin acetate |
200 |g twice daily as a nasal spray |
*Note: In the United States, GnRH agonist therapy is approved for 6 mo as single-agent therapy and for 1 yr when used in combination with a steroid add-back.
GnRH Agonist Analogues plus Steroid Add-Back
GnRH agonist treatment is associated with hypoestrogenic side effects such as vasomotor symptoms (hot flashes), decreased libido, dry vagina, and decreased bone density. Recent trials have demonstrated that use of a steroid (either high-dose progestin or very low dose estrogen) in so-called add-back therapy can minimize these side effects. GnRH agonist treatment combined with low-dose steroid add-back causes atrophy of en-dometriosis lesions and improves pelvic pain while minimizing hypoestrogenic vasomotor symptoms and bone loss. In one clinical trial, women with endometriosis and chronic pelvic pain were randomized to four different hormone treatment groups: GnRH agonist alone, GnRH agonist plus progestin only (norethindrone, 5 mg daily), GnRH agonist plus low-dose estro-gen-progestin (conjugated equine estrogen, 0.625 mg daily, plus norethindrone acetate, 5 mg daily), or GnRH agonist plus high-dose estrogen plus progestin (conjugated equine estrogen, 1.25 mg daily, plus norethindrone acetate, 5 mg daily). All women were treated with the GnRH agonist leuprolide acetate, given in a depot injection of 3.75 mg I.M. every 4 weeks for 1 year. The rate of treatment discontinuance because of continuing pain was significantly higher in the group that received the combination of GnRH agonist and high-dose estrogen than in any of the other treatment groups.40 The high-dose estrogen probably stimulated continuing function of the endometriosis implants. Consequently, treatment with a combination of GnRH agonist and high-dose estrogen is not recommended for most women with endometriosis and pelvic pain. The women in the three other groups experienced similar decreases in their pelvic pain, suggesting that all three regimens are effective. Bone density de-creased significantly in the women who received the GnRH agonist alone. Bone density was preserved in the groups that were treated with a combination of a GnRH agonist and steroid add-back therapy, and vasomotor symptoms were significantly reduced. This study and others suggest that an optimal treatment of pelvic pain from endometriosis may involve the use of GnRH agonists to suppress ovarian estrogen production, followed by add-back therapy with low doses of estrogen-progestin or progestin alone [see Table 4].
Table 4 Steroid Hormone Regimens for Pelvic Pain from Endometriosis
|
Regimen |
Comments |
|
Transdermal estradiol patch, 25 | g daily, plus medroxypro-gesterone acetate, 2.5 mg daily27 |
Does not completely prevent bone loss; achieves estradiol concentration in the range of 30 pg/ml |
|
Norethindrone acetate, 5 mg daily26 |
A high dose of progestin; may be associated with symptoms such as bloating and mood changes |
|
Conjugated equine estrogen, 0.625 mg daily, plus norethin-drone, 5 mg daily26 |
Preserves bone density and markedly reduces vasomotor symptoms |
Endometriosis lesions grow when serum estradiol concentration is in the premenopausal range (30 to 300 pg/ml), and they regress when estradiol levels are in the menopausal range (< 20 pg/ml). An important clinical question is, What concentration of estradiol will minimize the growth of endometriosis implants but not cause severe hypoestrogenic side effects? Treatments that achieve estradiol levels in the range of 20 to 30 pg/ml are associated with amenorrhea and regression of endometriosis lesions. In addition, these treatments are associated with fewer side effects than treatments that target estradiol levels to less than 20 pg/ml.41
Danazol
The first hormonal treatment of endometriosis was the intramuscular administration of testosterone. High-dose parenteral testosterone therapy was demonstrated to cause regression in en-dometriosis lesions. Unfortunately, many women became virilized by this treatment. Androgen treatment of endometriosis was resurrected after the development of synthetic oral androgens, such as danazol, which had attenuated androgen properties.42
Randomized clinical trials that have directly compared dana-zol and the GnRH agonists have demonstrated that both treatments improve pelvic pain in approximately 85% of treated women.43 The side effects of these two treatments are very different. The main side effects of the GnRH agonists are those associated with hypoestrogenism (see above). The main side effects of danazol are weight gain (on average, approximately 4 kg at doses of 800 mg/day), muscle cramps, decrease in breast size, oily skin, and hirsutism.44 In the United States, these side effects have limited the use of danazol for the treatment of en-dometriosis.45 Many of the side effects of danazol are dose dependent. Doses of 50, 100, and 200 mg daily can be effective in relieving pelvic pain caused by endometriosis and are associated with less severe side effects than daily doses of 400 or 800 mg. Doses of danazol of less than 400 mg/day do not reliably suppress ovulation. Danazol crosses the placenta and is a known teratogen, so patients who are taking low doses of danazol must use a reliable method of contraception.
Progestins
High-dose synthetic progestins have been demonstrated to be effective in the treatment of pelvic pain in women with en-dometriosis [see Table 5]. These agents have multiple mechanisms of action: (1) suppression of LH and FSH secretion, which suppresses estradiol production; (2) direct antiestrogenic effects on endometriosis lesions; and (3) induction of pseudodecidual-ization. A problem with progestin treatment is that many women gain weight or experience symptoms typical of the premenstrual period, such as mood changes and bloating.
Surgical treatment
Surgical treatment of endometriosis is termed either conservative or definitive. In conservative surgery, all the pelvic or-gans are preserved; in definitive surgery, both ovaries are removed.
Table 5 Progestins Effective for Single-Agent Treatment of Endometriosis
|
Progestin |
Dose |
|
Norethindrone acetate |
5 mg p.o. daily |
|
Medroxyprogesterone acetate |
50 mg p.o. daily; 150 mg I.M. every 90 days |
|
Norgestrel |
0.075 mg p.o. daily |
Conservative Surgery
Conservative endometriosis surgery is best accomplished by laparoscopy because postoperative recovery is very rapid, with discharge usually occurring within 1 day. Most surgeons utilize sharp excision to remove endometriosis lesions, electrosurgery to ablate endometriosis lesions, or a combination of the two methods. In one clinical trial, women with pelvic pain caused by endometriosis were randomized to undergo diagnostic laparos-copy and aspiration of peritoneal fluid or to undergo conservative surgery with laparoscopy and resection or ablation of en-dometriosis lesions. Six months after surgery, 63% of the women treated with surgical resection of endometriosis lesions reported relief of pain, whereas 23% of those treated with diagnostic lap-aroscopy without surgical resection reported pain relief.46
Conservative surgery typically fails to provide permanent relief of endometriosis, however. Within 2 years after surgical treatment, pain recurs in most women with endometriosis.47 Also, surgical treatment may result in pelvic adhesions, which can become a primary cause of continuing pelvic pain.
Definitive Surgery
Definitive surgery for endometriosis involves removal of both ovaries. Typically, the uterus is removed as well; indeed, in the United States, endometriosis is second only to uterine fibroids as a reason for performing hysterectomy. Many large cohort studies report that about 90% of women with endometri-osis and pelvic pain experience long-term relief of their pain through bilateral oophorectomy.48,49
After bilateral oophorectomy for endometriosis, patients are typically started on low-dose estrogen replacement. Low-dose estrogen therapy prevents vasomotor symptoms and osteoporosis; pelvic pain usually does not recur.
Surgical excision of ovarian masses
Endometriomas require surgical excision if they are causing pain or are enlarging. Large ovarian cysts may be the result of ovarian cancer. Surgical removal of the cyst allows a definitive diagnosis of the cause of the cyst to be made. A randomized clinical trial demonstrated that surgical removal of endometri-omas resulted in better long-term results than simple aspiration and fenestration of the cyst.
Treatment of Infertility
Early-stage endometriosis and infertility
Women with minimal or mild (stage I or II) endometriosis and infertility have a baseline fecundity of approximately 0.03 (3% per cycle, compared with 20% to 36% in normal couples). Numerous randomized studies have demonstrated that a step-wise approach to treatment can increase pregnancy rates in women with early-stage endometriosis [see Table 6).
Table 6 Stepwise Treatment of Infertility in Early-Stage Endometriosis
|
Step |
Description |
Recommendation |
|
1 |
Identify and treat all reversible causes of infertility |
Proper timing of coitus in relation to ovulation |
|
Optimal coital frequency |
||
|
Cessation of cigarette smoking |
||
|
Optimal body mass index |
||
|
Reduce consumption of alcohol and caffeine |
||
|
2 |
Laparosocopic surgery to resect endometrio-sis and remove adhesions |
Attempt to restore pelvic anatomy to normal |
|
3 |
Ovarian stimulation with clomiphene plus intrauterine insemination |
Insemination timed to the day before and day of ovulation |
|
4 |
Ovarian stimulation with gonadotropin injections plus intrauterine insemination |
Insemination timed to the day before and day of ovula-tion; because of increased risk of twin, triplet, and quadruplet pregnancy, some clinicians prefer to skip step 4 and move directly to step 5 |
|
5 |
In vitro fertilization and embryo transfer |
— |
Treatment of Infertility from Other Causes
The first step in the management of early-stage endometrio-sis and infertility is to identify and treat all reversible causes of infertility in the couple. Many couples have multiple causes of their infertility (e.g., endometriosis in the female partner and a low sperm count in the male partner).
Laparoscopic Surgery
If other causes of infertility have been addressed but the woman is still unable to conceive, the next step is to consider a laparoscopic surgical procedure to ablate or excise endometriosis implants and adhesions and to attempt to restore the pelvis to normal. In one randomized, prospective trial, diagnostic laparos-copy alone was compared with diagnostic laparoscopy combined with surgical resection or ablation of endometriosis in 341 women with early-stage endometriosis. During 36 weeks of post operative follow-up, fecundity was 0.024 in the diagnosis-only group and 0.047 in the surgically treated group; cumulative pregnancy rates during follow-up were 18% and 31%, respectively.51
Intrauterine Insemination
Women who fail to become pregnant after laparoscopic surgery can be treated with intrauterine insemination (IUI) in combination with either clomiphene or gonadotropin injections. Clomiphene is far less expensive than gonadotropins; therefore it is generally used first. These methods are designed to cause multifollicle development and multiple ovulation. In addition, IUI places a large number of motile sperm high in the reproductive tract. Thus, the spermatazoa do not have to travel through the vagina, cervix, and lower portion of the uterus. Both of these methods have been demonstrated to improve pregnancy rates in women with early-stage endometriosis. In one randomized study in 40 women with early-stage endometriosis, fecundity was 0.045 (4.5% per cycle pregnancy rate) in the group that received no treatment and 0.15 in the group treated with three cycles of gonadotropin injections in combination with IUI.52 Similar findings have been reported by other groups.53-56
Table 7 Stepwise Treatment of Infertility in Advanced Endometriosis
|
Step |
Description |
Recommendation |
|
1 |
Identify and treat all reversible causes of infertility |
Proper timing of coitus in relation to ovulation Optimal coital frequency Cessation of cigarette smoking Optimal body mass index Reduce consumption of alcohol and caffeine |
|
2 |
Surgery to resect endometriosis and remove adhesions |
Attempt to restore pelvic anatomy to normal |
|
3 |
Ovarian stimulation with clomiphene plus intrauterine insemination |
Insemination timed to the day before and day of ovula-tion; limited to patients with patent fallopian tubes and no dense ovarian adhesions |
|
4 |
Ovarian stimulation with gonadotropin injections plus intrauterine insemination |
Insemination timed to the day before and day of ovula-tion; limited to patients with patent fallopian tubes and no dense ovarian adhesions; because of increased risk of twin, triplet, or quadruplet pregnancy, some clinicians prefer to skip step 4 and move directly to step 5 |
|
5 |
In vitro fertilization and embryo transfer |
— |
Many authorities believe that the per-cycle pregnancy rate drops significantly after three or four cycles of clomiphene or gonadotropin injections in combination with IUI. Consequently, after three cycles of such treatment, the clinician should review with the couple the advantages of proceeding to the next step, which is in vitro fertilization (IVF) with embryo transfer.57
In Vitro Fertilization
There are no prospective, large-scale, randomized trials that demonstrate the efficacy of IVF in the treatment of infertility caused by endometriosis. However, the use of IVF in women with endometriosis and infertility routinely results in treatment-cycle pregnancy rates of approximately 0.30, a 10-fold increase over the baseline fecundity seen in such women.58-60 It should be noted, however, that the outcome of IVF is highly influenced by the woman's age: women younger than 37 years have much better success with IVF than do women older than 37 years.
Advanced endometriosis and infertility
In women with moderate or severe endometriosis and infertility, a stepwise approach to treatment is warranted [see Table 7].
Treatment of Infertility from Other Causes
The first step is to identify and correct all other reversible causes of infertility (see above).
Surgical Treatment
The second step is to perform surgical resection for ovarian endometriosis, peritoneal endometriosis, and pelvic adhesions to restore pelvic anatomy and function. There are no randomized, prospective studies that demonstrate the efficacy of surgery in the treatment of advanced endometriosis. However, most authorities believe that surgery improves fertility in these women. One retrospective analysis reviewed the outcome in 130 infertile women with endometriosis who were treated with expectant management, conservative surgery, or expectant management followed by surgery. Although no significant difference was noted between expectant management and surgery in women with mild or moderate endometriosis, women with severe endometriosis appeared to benefit from surgery. Of the 32 women with advanced endometriosis who were observed over 231 months of cumulative follow-up, none became pregnant. Of the 34 women with advanced endometriosis who underwent conservative surgery, 10 became pregnant during 702 cumulative months of follow-up.61 Similar results have been reported in a meta-analysis of the impact of surgery on fertility in women with endometriosis.62 These studies suggest that expectant management is not warranted in the treatment of infertility associated with advanced endometriosis and that surgical treatment may improve fecundity.
Pregnancy rates are highest in the 6 to 18 months after the surgical procedure. Additional surgical procedures have not been shown to be effective in increasing fecundity63; therefore, if pregnancy does not occur after the first surgery, the clinician should usually move on to intrauterine insemination. Physicians should carefully weigh the limited benefits of second and third operative procedures to enhance fertility against the potential risks of major surgery.
Intrauterine Insemination
Clomiphene or gonadotropin injections in combination with IUI are used empirically in patients with advanced endometriosis and infertility. Most of the clinical trials that have tested these modalities have focused on women with early-stage en-dometriosis (see above). However, many authorities believe that the benefits of these measures probably extend to women with advanced disease. In patients with severe pelvic adhesions, clinicians may choose to move directly from surgery to in vitro fertilization. Clomiphene or gonadotropins in combination with IUI should not be recommended for women with tubal blockage or dense ovarian adhesions.
In Vitro Fertilization
There are no large, randomized, controlled clinical trials that definitively demonstrate that IVF increases pregnancy rates in women with advanced endometriosis. In one small study involving 21 women with endometriosis and infertility, none of the six women randomized to undergo expectant management became pregnant, whereas five of the 15 women who were treated with IVF became pregnant.64 Because of the small sample size, however, this study did not have sufficient statistical power to detect true differences between the two groups. One analysis of various infertility treatments demonstrated that for infertile women with advanced endometriosis, rapid progression through the steps to IVF is the most cost-effective treatment approach.65 In the United States, the median projected cost per IVF cycle in 2001 was $9,226.66 The cost of having a child with IVF is within the range of the cost of adopting a child. Furthermore, over the past decade, IVF success rates have increased.67
IVF is less successful in women with advanced endometrio-sis who have previously undergone bilateral ovarian surgery; after unilateral oophorectomy and a contralateral ovarian cys-tectomy, ovarian stimulation is often ineffective, and the pregnancy rate is low. Reduced pregnancy rates for women with advanced endometriosis (compared with women who have early-stage endometriosis or tubal factor infertility) may be the result of a premature depletion of the ovarian follicle pool,68 abnormal folliculogenesis,69 or reduced fertilization potential of oocytes.70
