Dr David Redwine – endometriosis orginis

Let’s talk about endometriosis origins – retrograde menstruation vs Mulleriosis. What is Mulleriosis and why it is the only theory that explains all types of endometriosis?

Dr David Redwine: If reflux menstruation were the origin of endometriosis, it should be easy to find microscopic evidence of refluxed endometrial cells attached to the pelvic lining. In my career, I have come across less than 15 purported photomicrographs of such ‘attachment’. Also, it should be easy to find microscopic evidence of subsequent proliferation of those attached cells and invasion of the pelvic lining by those proliferating and invading cells. I am aware of no such photomicrogrpahic evidence of proliferation and invasion. 

Moreover, given the millions of patients with endometriosis and the billions upon billions of refluxed cells that must have been shed since that theory began almost a century ago, that should be more than enough time and shedding of cells for robust microscopic evidence to have been observed and tabulated. Our textbooks should be filled with easily-obtainable photomicrographs of the steps of attachment, proliferation, and invasion. Since there is no robust photomicrographic evidence of those important steps, cartoons are used as ‘evidence’ in support of this theory. If scientists can visualize the spikes on covid why can’t something millions of times larger be seen? Support for Sampson’s theory is based on faith that reflux menstruation really is the origin of endometriosis despite this fatal lack of photomicrographic evidence.

Adherents of Sampson are following a faith-based religion or cult; they are not following science. This is not just idle chatter because therapies such as hysterectomy, removal of the ovaries, prolonged ovarian suppression by hormonal medical therapies, are based wholly or in part on the theory of reflux menstruation. The number of patients that have received ineffective treatment based in some way on this theory is huge. This and the continuing lack of easily-obtainable evidence makes Sampson’s theory of reflux menstruation the most dangerous theory in the history of medicine. Ever. When one considers that reflux menstruation can’t explain cerebral endometriosis, endometriosis in the thigh, in males, under fingernails, etc, support for the theory on any level is worrisome. Proponents of Sampson’s theory will eventually die, taking the theory with them, fulfilling the prophecy of Max Planck. Unfortunately, the published literature cannot be effectively purged of papers that use or support this theory.

Where does endometriosis come from if not from reflux menstruation? To answer that question, it first is necessary to know that endometriosis has been reported in elderly males with advanced prostate cancer who had been given estrogen for bone pain.  In some patients, blood in the urine prompted a urological workup and endometriosis has been found in the male bladder and prostate. There have been probably less than 20 cases, but any single theory must explain even ‘outliers’. The fact that endometriosis occurs in males immediately suggests an embryonic origin because between 6 – 8 weeks of embryonic life, we all contain precursors of both the male and female systems. The tubes, uterus and upper vagina are formed from fusion of the Mullerian ducts, named after their discoverer, Johann Müller. In genetic males, the Mullerian system is supposed to wither away before birth, but biology being imperfect, it doesn’t always. It’s in this group that persistent islands of endometriosis may remain behind waiting to be stimulated by estrogen in the distant future. In genetic females, the male system is supposed to wither away, but doesn’t always and females can develop benign cysts along the walls of the vagina as a result.

Another incontrovertible fact is that all endometriosis is derived from mesoderm, the middle of the three embryonic layers. If you think of the embryonic layers like ravioli, the upper layer is the ectoderm which forms skin, brain and spinal cord; the lower layer is the endoderm which forms the mucosal lining of the bowel and urinary tract; the middle of the ravioli is the mesoderm which forms everything else including endometriosis.

So for these reasons an embryonic origin immediately emerges as the most likely origin of endometriosis. Interestingly, an embryonic origin was first proposed in 1882 and by 1899 Opitz had commented on the mesoderm being the origin of endometriosis. The only thing missing was plausible genetic proof. But the wait is over. Genome-wide association studies (GWAS) have thrown up several single nucleotide polymorphisms (SNP) whose downstream genetic effects include the building blocks of endometriosis: genes for cell proliferation, angiogenesis, estrogen response, and embryonic development. Future studies will find more genes. We no longer need Sampson’s theory, because a genetically-based embryonic origin explains 100% of all we know about the disease. The many different manifestations of endometriosis are the result of dozens or hundreds of genes interacting with one another in an infinite assortment of possibilities.

But looking just at endometriosis is missing its important relationship with other gyn and pelvic problems, including fibroids, adenomyosis, peritoneal pockets, renal agenesis, and more. To understand endometriosis, we need to stand back and look at the bigger picture of problems related to abnormal differentiation and migration of organs derived from the Mullerian ducts. It’s this stepping back and looking at a bigger picture that is encouraged by the term ‘Mulleriosis’. Mulleriosis invites one to consider that other known and unknown problems are associated with abnormal development of the Mullerian ducts. So Mulleriosis is basically an embryonic origin on steroids.

While we are stepping back and looking at a bigger picture, let’s step further back and consider that 7,000,000 years ago, macaque monkeys split from the human clade. Macaques develop spontaneous endometriosis. Other primates that develop endometriosis include baboons, which split from humans 8,000,000 years ago, cynomolgus monkeys 10,000,000 years ago, and rhesus monkeys 25,000,000 years ago. The first mammals emerged about 340,000,000 years ago. So the gene ensemble associated with endometriosis is ancient and may extend beyond early mammalian development. Was there some marine animal that had receptive reproductive tissue all over its surface that gave it a genetic advantage and that’s where the Mulleriotic genetic ensemble originated? Sequencing the genome of these primates, then doing tissue genomics on specimens excised according to corresponding anatomic areas will develop a comprehensive picture of the origin of the disease.

All past, current and future embryonic origin theories will converge at the intersection of genetics and embryology and then become one.