Treatment of Infertility
Causes of Infertility in Endometriosis
There is no single cause of infertility in endometriosis but rather several factors that decrease the chances for conception. In advanced endometriosis (Stage III-IV), endometriomas (chocolate cysts) or pelvic adhesions interfere mechanically with ovulation and egg/embryo transport. In early endometriosis (Stage I-II), the mechanism of infertility is less clear and more complex. Studies from our Institute for the Study and Treatment of Endometriosis (Endometriosis Institute) and from other centers have shown that in endometriosis, the intraperitoneal environment, through a variety of mechanisms, prevents conception. It has been demonstrated that the peritoneal fluid from women with endometriosis contains different biochemical substances with anti-fertility effects. These substances produced by the endometriotic cells or cells of the immune system include several prostaglandins with smooth muscle contracting properties, various cytokines, abnormal autoantibodies, and reactive oxygen radicals. They can prevent ovulation by inducing early LUF (luteinized unruptured follicle) Syndrome; others prevent egg capture by the fimbria of the fallopian tube, interfere with tubal function and its ability to transport gametes and embryos, interfere with hormone production by the corpus luteum, and have embryo-toxic or anti-implantation effects. The anti-fertility effect of the peritoneal environment is, however, variable and depends on the amount of the peritoneal fluid produced and the concentration of these biochemical factors. Consequently, infertility in women with endometriosis is relative, which means that some women are able to conceive.
Chances for Pregnancy - Without Treatment
There is no question that chances for pregnancy in endometriosis are significantly decreased. Women with Stage I or II endometriosis have an approximately 2% chance for conceiving in any given menstrual cycle (cycle fecundity rate). That chance is less than 1% for women with Stage III or IV disease. By comparison, age-dependent cycle fecundity rates in healthy fertile women range between 15 and 25%.
Chances for Pregnancy - After Treatment
After laparoscopic resection of endometriosis, cycle fecundity rate in Stage I-II disease increases to about 4-5% but only to 1-2% in Stage III-IV. Medical treatment of Stage I-II endometriosis increases cycle fecundity rate to about 4-5% but is less effective in the advanced disease. These percentages are significantly below the expected fecundity rate of fertile women and indicate that not all biochemical and/or anatomical changes associated with endometriosis and contributing to infertility are corrected by the treatment of this disease.
Chances for Pregnancy - With Fertility Drugs
Several studies have shown that in untreated Stage I-II endometriosis, fertility drugs combined with intrauterine insemination during the so-called controlled ovarian hyperstimulation/artificial insemination (COH/AIH) cycle, increase cycle fecundity rates to about 11%. There is no improvement in endometriosis during the COH/AIH cycles but ovulation and sperm transport problems are corrected which may explain the increase in fecundity rates above those reported after resection or suppression of the disease.
Chances for Pregnancy - With IVF/ET
When fertility drugs are combined with in vitro fertilization/embryo transfer (IVF/ET) procedures, cycle fecunity is even higher than with COH/AIH - in excess of 35%. It appears that in endometriosis during the IVF/ET cycle, replacement of the adverse intraperitoneal environment with controlled 'in vitro' conditions of the laboratory corrects the majority of anti-fertility effects of the disease.
A recent report from our Endometriosis Institute compared cycle fecundity rates using COH/AIH vs. IVF/ET in women with untreated endometriosis. The study consisted of 313 women with endometriosis and infertility - 202 of whom underwent 648 cycles of COH/AIH and 111 of whom underwent 139 cycles of IVF/ET. Also included was a subgroup of 56 women who failed COH/AIH and underwent 68 IVF/ET cycles.
Figure 1 demonstrates cycle-specific and cumulative fecundity rates in these groups. Cycle one to six fecundity in the COH/AIH group was 15%, 12%, 8%, 7%, 7%, and 0%, respectively, with the six-cycle cumulative fecundity of 41%. There was a plateau effect after five cycles and there were no pregnancies during the sixth cycle. Cycle one to three fecundity in the IVF/ET group was 47%, 27%, and 33%, respectively, with the three-cycle cumulative fecundity of 73%. There was no evidence of a plateau. First cycle fecundity with IVF/ET (47%) was significantly greater (p<0.05) than the cumulative fecundity after six COH/AIH cycles (41%). In patients who underwent IVF/ET after failed COH/AIH, cycle one to three fecundity was 39%, 27%, and 14%, respectively, with the three-cycle cumulative fecundity of 62%. There was no significant difference between this group and the primary IVF/ET group but the cycle and cumulative fecundity rates were higher than in the COH/AIH group.
When pregnancies with cryopreserved embryos were considered and when couples with a significant male-factor were excluded, both cycle and cumulative fecundity rates were higher. For IVF/ET including cryopreserved embryos, cycle one to three fecundity was 50%, 30%, and 33%, respectively, with the three-cycle cumulative fecundity of 77% (Figure 2). For the IVF/ET group without male-factor, the numbers were 46%, 31%, 50%, and 81%, respectively.
Cycle and cumulative fecundity rates in the COH and IVF groups analyzed according to the stage of endometriosis are demonstrated in Figure 3 and according to the age of the wife in Figure 4. First cycle fecundity in Stage IV endometriosis was 10% with COH/AIH and there were no conceptions during subsequent cycles (Figure 3).
With IVF/ET, Stage IV fecundity during three cycles of observation was comparable to that of Stages II and III. Cycle and cumulative fecundity in women over 38 were below other age groups with COH/AIH (Figure 4). With IVF/ET, there were no significant differences.
Not analyzed in our studies but of considerable significance is the effect of ovarian stimulation on the progression of endometriosis. Ovarian stimulation for either COH/AIH or IVF/ET increases two-to-tenfold peripheral blood concentrations of estrogens produced by the ovarian follicles. It is well known that estrogens stimulate progression of endometriosis in a direct proportion to their concentration and length of exposure. Therefore, IVF/ET, with fewer cycles of ovarian stimulation required to achieve pregnancy, carries a lower risk of endometriosis recurrence than COH/AIH. There is no question that IVF/ET is a more complex and costly procedure than COH/AIH. The cost of one IVF/ET cycle is approximately equivalent to the cost of six COH/AIH cycles but the probability of pregnancy is higher with one IVF/ET cycle than with six COH/AIH cycles, as demonstrated by our studies.
We conclude from our studies that one cycle of IVF/ET offers a better probability of conception than six COH/AIH cycles in women with endometriosis regardless of age and stage of the disease. In women over 38 or with Stage III/IV endometriosis, in those with a significant adhesive or tubal disease, or in couples with a significant male-factor, IVF/ET should be the first line of treatment in the management of infertility. If an adverse effect of prolonged ovarian stimulation on the progression of endometriosis is considered and if there is an intent to limit the number of the stimulation cycles, this recommendation may be extended to all women with endometriosis and infertility. If COH-AIH is performed, the number of attempts should be limited to not more than three to four.