Endometriosis: new facts, concepts beneath etiology and biomedicine

Endometriosi: nuove scoperte e prospettive biomediche

Endometriosis is an estrogen-dependent pelvic inflammatory disease characterized by implantation and growth of endometrial tissue (glands and stroma) outside the uterine cavity. It affects approximately 10-15% of women of reproductive age. The most common symptoms of the disease are pelvic pain, temporarily tamponable with analgesics, and infertility. In fact, the prevalence of endometriosis in women with pelvic pain is between 30-45% of the infertile population. However, endometriosis can also be asymptomatic or accompanied by symptoms such as menstruation with increasing pain. The etiology of endometriosis is not yet clear: these are the three classical theories that attempted to designate the definitive pathogenetic mechanism of endometriosis. They are Sampson’s implant theory, Mayer’s theory of coelomic metaplasia and the theory of induction, but none of them has succeeded in prevailing over the other. Recent studies have also considered the role of other contributing factors, such as genetic predisposition and familiarity.

An ezio-pathogenetic theory, also in vogue because it is supported by enough laboratory demonstrations, indicates that oxidative stress could be a key mechanism of the disease. Macrophages, erythrocytes, and breakdown endometrial tissue transplanting into the peritoneal cavity through retrograde menstruation can induce the production of oxidizing radicals (ROS); therefore, their peritoneal production could be involved in endometriosis. The association between endometriosis and infertility is well established in the literature. The monthly fertility rate in infertile women with endometriosis is between 2-10%, while in healthy women the rate varies between 15-20%. Markers of oxidative stress are present in the serum, in the peritoneal fluid, in the follicular ovarian fluid and even in the ovaries of women suffering from endometriosis. A measurable marker in all these fluids is the heat shock protein (Hsp70), which is a signal that there is a defense reaction going on both by inflammation and oxidative stress.

In the literature, it is well explained how ROS can influence a variety of physiological functions such as oocyte maturation, ovarian hormone synthesis, ovulation, implantation, blastocyst formation, luteolysis and luteal maintenance in pregnancy. Oxidative stress affects fertility in women with endometriosis in natural or assisted conception. The imbalance between ROS and antioxidant mechanisms leads to the state of oxidative stress in the peritoneal environment, in follicular flow and in the surrounding ovary, which can partly explain the infertility status associated with endometriosis. Still on the subject of the biological fluids discussed, as some markers have increased (Hsp70, MDA, LOOH, 8-ISOP), others have decreased. Not surprisingly, these are enzymes or antioxidant molecules involved in protecting against ROS. Several studies have shown that women with chronic endometriosis have levels of vitamin C, vitamin E and the  scavenger enzyme SOD lower than normal women. However, it is not clear yet whether these are reduced as a consequence of the oxidative stress produced by the disease; or, they are a predisposing factor behind its progression.

Recent findings have focused attention on the role of altered iron metabolism in the development of endometriosis. The presence of iron overload in the various components of the peritoneal cavity of patients with endometriosis has been extensively studied; however, it remains strongly localized in the pelvic cavity and does not influence the iron content in the body. Higher levels of iron, ferritin and hemoglobin were found in the peritoneal fluid of affected women compared to controls. The stroma of endometriotic and peritoneal lesions also revealed the presence of microscopic iron aggregates. Peritoneal iron overload may be a consequence of the increase in influx caused by the degradation of red blood cells, resulting from more abundant menstrual reflux, or bleeding lesions or a deficiency of the metabolic system of peritoneal iron. Some research groups have curiously observed that cells in endometriotic lesions grow in number after injection of erythrocytes into the mouse model. When desferrioxamine, an iron chelator, was administered to these animals, the process was suppressed, thus concluding that iron can contribute to the growth of endometriotic lesions.

That endometriosis is a pathology with inflammatory background, no expert has doubts about it. The inflammation markers that appear constantly are the cytokines. These substances are very powerful hormones that regulate the immune system, the nervous system, the maturation of the bone marrow and many other phenomena of our body. Some of them are characteristically high in chronic inflammation, such as interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF-alpha). These can be more produced if there is a dysfunction of microRNAs and parallel immune alterations. MicroRNAs are a class of small messenger RNAs that do not encode any protein, but can also influence gene activity and RNA degradation that instead encode proteins, including those of the cytokines themselves. MicroRNAs control cell development, differentiation, proliferation and survival. MicroRNAs have been studied in endometriosis: in affected women, some of them increase in presence, others are reduced. Furthermore, the microRNAs responsible for targeting inflammatory and pain-causing molecules are very low in women with endometriosis: This means that behind their deficiency would hide the indirect cause of pain that afflicts patients.

But with all these new insights, are not there valid options for this disorder so disabling and debilitating at the same time?

So far the symptomatic treatment has been the most followed, ie pain control. Classic NSAIDs such as diclofenac, ketorolac, ketoprofen and the like are used to relieve pelvic pain that often becomes continuous and dull, without going away altogether. Given that inflammation and oxidative stress are two basic components of the disorder, there have already been attempts to intervene in this sense on an experimental level. Articles of the scientific literature are published that have tested the effect of vitamin E, melatonin, vitamin D, omega-3 fatty acids, polyphenols derived from tea or wine, spices such as turmeric; all these have shown a significant effect. A revolutionary treatment could come from the use of an antioxidant amino acid, acetylcysteine. It is present on the market and is prescribed in the case of colds, nasal congestion and bronchial catarrh, because it has mucolytic action. It is also available in formulations as a health supplement. However, it is also a direct antioxidant, has good bio-availability and is practically free of unpleasant side effects. Five clinical trials have been conducted on subjects with endometriosis, all with significant effect (Porpora G et al 2013, Onalan G et al., 2014; Agostinis C et al., 2015; Ray K et al., 2015; Giorgi S et al. 2016).

Table interventions were also taken into consideration. Surely a diet based on fruits, vegetables and vegetable fibers has been recommended, as rich in antioxidant vitamins (A, C, E). Also the consumption of vegetable proteins (all legumes), eggs and nuts (walnuts, almonds, pistachios) is recommended instead of the proteins of animal meat. Likewise, it has been recommended for women affected by the problem of avoiding the consumption of bakery products (bread) and dairy products (cheese), by virtue of the properties of bread gluten and beta-casein of milk to exert inflammatory effects on the intestine. . A single Italian research group has recently investigated the role of gluten of endometriosis pathogenesis, reporting a single case of a female patient with simultaneous celiac disease and endometriosis (Caserta D et al., 2014), from which prospects were not yet well evaluated for women with endometriosis to adopt a gluten-free diet (Marziali M, Capozzolo T. 2015). Furthermore, the role of intestinal bacterial flora (microbiota), as a possible agent or hidden cause, is under investigation. There are only hypothetical evaluation studies and possible direct or indirect causal link, due to the influence on the metabolism of estrogen hormones by intestinal bacteria. There are no publications concerning the effects in vitro, in vivo or human subjects with probiotic preparation. 

  • edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Murphy AA et al. Semin Reprod Endocrinol. 1998; 16(4):263-73.

Lousse JC et al. Front Biosci (Elite Ed). 2012 Jan 1; 4:23-40.

Agarwal A et al. Reproductive Biology and Endocrinology. 2005; 3:p28.

Carvalho LF et al. Archives Gynecol Obstet 2012; 286(4):1033–40.

Polak G et al. Mediators of Inflammation 2013; 2013:4.

Lousse JC et al. Frontiers in Bioscience (Elite Edition) 2012; 4:23–40..

Van Langendonckt A et al. Fertility and Sterility 2002; 77(5):861–870.

Defrere S et al. Molecular Human Reproduction 2008;14(7):377–385.

Lambrinoudaki IV et al. Fertility and Sterility 2009; 91(1):46–50.

Turgut A et al. Eur Rev Medand Pharmacol Sci 2013; 17(11):1472–78.

Agostinis C et al. Mediators Inflamm. 2015; 2015:918089.

Turkyilmaz E et al. Eur J Obstet Gynecol Reprod Biol. 2016; 199:164-68.

Singh AK et al. Reproductive Toxicology 2013;42:116–124.

Harlev A et al. Expert Opin Ther Targets. 2015; 19(11):1447–1464.

Porpora MG et al. Evid Based Complem Altern Med. 2013; 2013:240702.

Onalan G et al. Arch Gynecol Obstet. 2014 Jan; 289(1):193-200.

Ray K, Fahrmann J et al. Pain. 2015 Mar;156(3):528-39.

Informazioni su Dott. Gianfrancesco Cormaci 1070 Articoli
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry specialty in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica, salute e benessere sui siti web salutesicilia.com e medicomunicare.it