Jan Friberg
Endometriosis affect between 6-10% of all reproductive age women. Patients with pelvic pain and infertility has a much higher prevalence that may be as high as 35 – 50 %. The normal fertility rate for couples attempting to have a baby is approximately 25 – 30 % for the first 3 months whereas patients with endometriosis only achieve a pregnancy rate of approximately 2- 10 % under the same circumstances. If they have tried to have a baby for more than a year that figure goes down to less than 4 %. Even minimal endometriosis may be marked with reduced fertility raising the need for diagnosis and early treatment. In some women symptoms direct the attention to the diagnosis of endometriosis but in the majority of women the symptoms are very limited and it is not uncommon to have a delay of 5 – 6 years from the start of symptoms until the final diagnosis is made. In the past laparoscopy used to be the main stay for the diagnosis but over the years new laboratory studies as well as careful use of sonograms have indicated that even indirect observations can result in an adequate diagnosis.
Endometriosis is a hormone dependent inflammatory disease. The endometriotic Implants create a pronounced inflammatory response with production of multiple inflammatory proteins which result in an altered autoimmune response. This reaction creates a more proinflammatory environment and further promotes the development of an increased amount of endometriosis. The inflammatory response is not only active in the pelvic peritoneal cavity, but it is also affecting the entire body with effects such as fatigue, altered bowl and bladder function, dysfunction of liver and adipose tissue and even the central nervous system with the development of symptoms such as anxiety and depression.
During normal implantation of the embryo the progesterone levels after the ovulation are high and the estrogen levels relatively low. This is represented as an anti-inflammatory response. In endometriosis however, we have a more proinflammatory response with relatively low progesterone and high estrogen levels. The inflammatory response fails to activate the enzymes necessary for implantation. The proinflammatory substances present in endometriosis results in oxidative stress through the production of reactive oxygen spices. This promotes fibrosis, reduces blood supply with a loss of stroma in the ovarian cortex and the subsequent reaction is follicular death with a lower follicular density. The ovarian granulosa cells from endometriosis patients are also affected. With each cell division chromosomes tend to break and become shorter and the lost portion of the chromosome is normally repaired by the enzyme telomerase. In endometriosis telomerase activity is inhibited and this results in a shortening of the chromosomes. Low telomesase activity predisposes women to poor function of their oocytes and put the endometriosis patients on the path to premature ovarian failure.
The clinical treatment of endometriosis has been based on symptoms rather than an anti-inflammatory response. The main emphasis has been on empiric use of anti-inflammatory drugs, hormonal contraceptives, progestragens, anti-progesterones, gonadotrophin releasing hormones agonists and antagonists, as well as aromatase inhibitors. Surgical fulguration and excision with laparoscopy have been a common approach and even hysterectomy has been used when the medical therapy has failed. All these therapies are relatively good for the treatment of pain but are mostly inadequate to restore fertility.
Endometrial receptibility and pregnancy rates are not affected in endometriosis patients who receive donated embryos but a large number of progesterone dependent genes are underexpressed and are the cause for progesterone resistance. Lower implantation success has been seen in non-endometriosis patients receiving donor oocytes from patients with endometriosis whereas normal pregnancy rates are obtained when healthy oocytes are given to women without the disease. All oocyte donations were performed after down regulation of patients own hormones with gonadotropin releasing hormone (GnRH) agonist and this regimen appears to have influenced pregnancy rates in a positive way.
Ovarian suppression using gonaldotropin releasing hormone (GnRH) agonists or antagonists reduces angiogenesis due to the inhibition of vascular endothelial growth factor secretion. It also inhibits cell proliferation and induces cell death in the endometrium.
It was thought for a long time that the low estrogen and progesterone levels obtained in GnRH agonist and antagonist treatments were beneficial for endometriosis treatment particularly in patients with more advanced disease. Recently it has been shown that add back therapy with estrogen and progesterone to reduce antiestrogenic menopause-like symptoms created during GnRH therapies were also effective in treating as well as preventing recurrence of endometriosis. At randomized trials using suppression of the ovaries with GnRH agonists and antagonists for 3 – 6 months with inhibition of ovulation and then starting a stimulation for the fertility treatment, improved pregnancy rate compared to non-treated patients. A subsequent trial with add back contraceptive pills indicated an equally beneficial effect on pregnancy rate and take-home baby rate when used continuously for 6-9 week followed by aggressive ovulation stimulation. Not all studies have been able to confirm that lengthy suppression of ovulation creates a high pregnancy rate in severe endometriosis. However, after several failed IVF’s in patients with endometriosis this approach may be worth trying. Furthermore, two new oral antagonists Elagolix, (Corilissa® or Oriahnn®) and Relugolix (Myfembree®) have come onto the market and will make an important impact since injections are avoided.
The suggested treatment of infertile endometriosis patients therefore includes 3 -6 months continuous suppression of ovulation with GnRH agonists or antagonist and estrogen/progesterone (contraceptives) and then adding on immunomodulating approach just prior to starting the stimulation for ovulation. It is not known if a longer suppression time has any benefits. Natural conception could be possible but because of the improved success of invitro-fertilization (IVF) that is the recommended approach. If success is not achieved with ovulation stimulation/IVF an even more aggressive anti-inflammatory treatment is recommended with the use of intravenous infusions of exosomes.
Exosome rational
During stem cell therapy it was thought that the cells migrated to the inflamed site and supported the healing process. Instead, it has been discovered that infused stem cells mostly locate to the lungs, liver, and adrenals where they secrete small particles, so called exosomes, which are 30-150 nm in diameter. They contain messenger RNA, micro RNA, growth factors, enzymes, receptors, transcription factors, matrix proteins, immunomodulating and anti-inflammatory substances. These exosomes circulate and reach the inflammatory focus and are taken up by local stem cell that then cascade the response. The beneficial factors in the exosome results is reduced inflammatory response. The exosomes are commercially available and are obtained from non-embryonic mesenchymal placental stem cells. Exosomes do not contain any DNA and does therefore not create any host versus graft reaction. The preliminary use of these protocols has given exciting results.
To further enhance the pregnancy rate in patients with endometriosis the immune-modulating drug Naltrexone has found it way into the treatment of endometriosis. This is the same drug that is used for treatment of opioid overdoses but only a fraction of the dose used for opioid overdose patients is likely to go to endometriosis patients. The starting dose is 1.5 mg for 10 – 14 days and then the dose is increase to 3 mg in the treatment cycle. This low dose Natrexone tablet need to be compounded in a specialty pharmacy. I stop the treatment with the first positive pregnancy test but if no pregnancy occurs the dose is kept at 3 mg for the next cycles. In endometriosis patients ovarian stimulation is often necessary to induce an effective progesterone level in the luteal phase. IVF is not always necessary and I have had multiple pregnancies after only clomid has been used.