Background: “Jamie” consulted with me when she was 34 years of age, after 3 years of failed treatment and a diagnosis of “unexplained infertility.” A laparoscopy had revealed her to have mild (Stage 1) endometriosis, which was ablated at the time of surgery. She had undergone 3 IUI procedures, using clomiphene citrate in the first two procedures and Letrozole in the last one. In all cases she developed between 5-8 follicles and triggered with 10,000 units of hCG. Ovulation occurred uniformly throughout, but she failed to conceive. She then moved on to In Vitro Fertilization (still with her previous clinic), and over the course of 18 months, she underwent 3 failed IVF attempts. In each case she was stimulated with a modest, long pituitary down-regulation protocol involving the use of birth control pills, overlapped with an agonist (Lupron). Between 12 and 16 oocytes were recovered at egg retrieval, and following ICSI, she consistently produced between 2 and 5 blastocysts. Embryo transfers involving 2-3 blastocysts failed to achieve a pregnancy.
Our Treatment Approach: We performed immunologic testing on this patient and found her to have activated Natural Killer cells (NKa) by the K562 target cell test, as well as antiphospholipid antibodies (APA). We made a diagnosis of autoimmune implantation dysfunction and scheduled the patient for a frozen embryo transfer (FET) with her residual cryobanked blastocysts. We prepared her with twice-weekly injections of Delestrogen (6 mg) combined with 0.75 mg dexamethasone daily, and 30 mg Lovenox daily starting at the onset of her cycle.
Approximately 10 days prior to the anticipated FET she received an Intralipid (IL) infusion. At ET, we transferred 3 thawed blastocysts. Eight days later, her first beta hCG was 45, and 2 days afterward it had risen to 160. She thereupon received a second and final intralipid infusion. A subsequent ultrasound examination 3 weeks later revealed a healthy set of twins. She was weaned off the dexamethasone at 10 weeks gestation. The patient went on to give birth to healthy twins.
Commentary: This patient’s infertility was really not “unexplainable” it was simply undiagnosed. Clearly there was not an underlying egg/embryo issue at all. The reason she failed to conceive on her own (in spite of spontaneous and regular ovulation) and following IUI was almost certainly due to the fact that all women with endometriosis (regardless of severity) have an underlying toxic peritoneal factor that compromises fertilization as the eggs pass from the ovary (ies) to the sperm waiting in the fallopian tube(s).This reduces fertilization potential and therefore compromises fecundity. This toxic peritoneal factor is present in 100% of women with this condition and explains why the chance of having a baby is reduced 4-6 fold in women with even the mildest of endometriosis. Since the visual endometriotic deposits represent just a small percentage of those that are in the process of developing, neither surgery to remove such lesions nor fertility drugs with or without IUI will likely significantly improve the baby rate per cycle (fecundity).
Furthermore, there was the issue of an immunologic implantation dysfunction (IID) as evidenced by NK cell activation and antiphospholipid antibodies. IID occurs in about 30% of women who have endometriosis, and when it is associated with NK cell activation, the chance of a successful pregnancy is very low. When we administered intralipid, heparin (Lovenox) and steroids (dexamethasone), down-regulated the activated uterine NK cells, and counteracted the influence of antiphospholipid antibodies, the patient readily conceived following FET.
The lesson, in this case, is that all women with endometriosis have diminished fecundity because of the consistent presence of a toxic pelvic environment that cannot be resolved through surgery or medical manipulation. Only IVF, by transferring the embryo directly to the uterus, can bypass this problem.
I do not mean to imply that all women with endometriosis will require IVF. In fact, for younger women who have associated ovulation dysfunction (which is not uncommon in women with endometriosis), fertility drugs can be tried. However, this will only deal with the ovulation dysfunction, but will not address the toxic peritoneal factor. Simply stated, women with mild to moderate endometriosis that conceive following the use of fertility drugs (with or without IUI), usually achieve this in spite of, rather than due to, such treatment. Ultimately, only IVF (which consistently bypasses the toxic pelvic environment), will address this problem.
Since 1/3 of women with endometriosis will have an IID which will prevent implantation, even IVF will fail unless this problem is dealt with through down-regulation of NK cell activity and treatment of often associated anti-phospholipid antibodies (as was done in this case).
In summary, normally ovulating women with endometriosis-associated infertility who are under the age of 35 years, should consider timed intercourse (using home ovulation testing).If this fails to result in a pregnancy, IVF will in all likelihood be required. For women who do not ovulate normally, fertility drugs can be used to correct this problem, but when such treatment is implemented, it must be done with the full understanding that ovulation induction will not reverse the toxic peritoneal effect. Ultimately, IVF might still be needed.