**9. Hypothesis**

The identification of genetic sequences homologous to shigella bacteria (Kodati V et al, 2007) in the ectopic endometriotic tissue in this study unravels an understanding of the etiopathogenesis of endometriosis, which has not yet been reported. An important element in the initiation of inflammatory responses is the activation of macrophages, resulting in the

Fig. 8. Right side of the figure shows the saggittal section of the pelvis showing the route of shigella invasion from the colon to the Pouch of Douglas. Note the close proximity of the colon and Cul-de-sac/ posterior surface of uterus. Left side of the figure is the microscopic appearance of the mucous cells of the colon showing migration of the non-motile bacteria from cell to cell upto the lamina propria.

production of pro-inflammatory cytokines such as interleukins-12 (IL-12). Toll-Like Receptors (TLRs) which are expressed on macrophages, recognize microbial molecules and transmit signals that initiate transcription of cytokine genes. TLR4 recognizes the gram-negative bacterial product lipopolysaccharide (LPS). TLRs use several signaling pathways to initiate gene transcription. With the environmental toxins theory of endometriosis being now disproved, and with inconsistent results from genetic polymorphism studies amongst different ethnic groups, it could be postulated that the "infection theory" caused by Shigella or a similar bacteria may be the trigger that sets into action the immunological changes in the pelvic peritoneum resulting in the phenotype of endometriosis. While this can explain the pelvic and abdominal endometriosis, the occurrence of distant metastasis is yet unclear. Further work in this area should enhance the understanding of TLR signaling and the regulatory mechanisms controlling the inflammatory response by bacteria like shigella and their role in endometriosis.

#### **9.1 Probable mechanism of Shigellosis to endometriosis**

Commonly, shigella bacteria are known to invade the mucosa of the colon through the fecooral route causing Shigellosis. The non-motile bacteria travel from cell to cell of the colonic epithelium through the cytoplasm by a unique mechanism called F-actin polymerization. Thereby the bacteria reach the lamina propria of the colonic mucosa (Fig. 8). It is hypothesized that by the same mechanism the bacteria can enter the blood stream and/or travel across the colon wall to reach the outer peritoneal surface of the colon which is in close proximity to the posterior uterine surface, the site which incidentally happens to be the commonest site of early endometriosis (Cul-de-sac or Pouch of Douglas) as shown in Fig. 8. We propose that the peritoneal reaction to this bacterial invasion may be similar to any antigenic response by the host immune system resulting in the activation of macrophages and production of cytokines characteristic of acute inflammatory response. The endometrial cells that are shed during the retrograde menstruation into the cul-de-sac adhere to the inflamed peritoneal and ovarian surfaces and come under the influence of circulating ovarian hormones. The thus implanted endometrial cells in the peritoneum progress to endometriosis through angiogenesis. Our postulated bacterial hypothesis proposes that shigella or shigella-like organisms may be the trigger for the immunological changes in the pelvic peritoneum which initiate the etiopathogenesis of endometriosis. The inflammatory hypothesis is further reinforced by our subsequent research on TNF-alpha -C850T polymorphism, which showed significant association with endometriosis. (Lakshmi KV et al 2009) The bacterial hypothesis is supported by our recent research work on TLR-4 (A896G) polymorphism. Toll- Like Receptor 4 is specific for recognition of the molecular pattern of gram-negative bacteria. TLR-4 is present on the surface of endometrial cells. TLR-4 A896G is a functional polymorphism resulting in hypo-responsiveness of the receptor, causing peritoneal inflammation in the female pelvis. The molecular micro-environment of the culde-sac becomes favourable for initiation of endometriosis.( Latha M et al 2011)

#### **10. Conclusion**

150 Endometriosis - Basic Concepts and Current Research Trends

The identification of genetic sequences homologous to shigella bacteria (Kodati V et al, 2007) in the ectopic endometriotic tissue in this study unravels an understanding of the etiopathogenesis of endometriosis, which has not yet been reported. An important element in the initiation of inflammatory responses is the activation of macrophages, resulting in the

Fig. 8. Right side of the figure shows the saggittal section of the pelvis showing the route of shigella invasion from the colon to the Pouch of Douglas. Note the close proximity of the colon and Cul-de-sac/ posterior surface of uterus. Left side of the figure is the microscopic appearance of the mucous cells of the colon showing migration of the non-motile bacteria

production of pro-inflammatory cytokines such as interleukins-12 (IL-12). Toll-Like Receptors (TLRs) which are expressed on macrophages, recognize microbial molecules and transmit signals that initiate transcription of cytokine genes. TLR4 recognizes the gram-negative bacterial product lipopolysaccharide (LPS). TLRs use several signaling pathways to initiate gene transcription. With the environmental toxins theory of endometriosis being now disproved, and with inconsistent results from genetic polymorphism studies amongst different ethnic groups, it could be postulated that the "infection theory" caused by Shigella or a similar bacteria may be the trigger that sets into action the immunological changes in the pelvic peritoneum resulting in the phenotype of endometriosis. While this can explain the pelvic and abdominal endometriosis, the occurrence of distant metastasis is yet unclear. Further work in this area should enhance the understanding of TLR signaling and the regulatory mechanisms controlling the inflammatory response by bacteria like shigella and their role in endometriosis.

Commonly, shigella bacteria are known to invade the mucosa of the colon through the fecooral route causing Shigellosis. The non-motile bacteria travel from cell to cell of the colonic epithelium through the cytoplasm by a unique mechanism called F-actin polymerization.

**9. Hypothesis** 

from cell to cell upto the lamina propria.

**9.1 Probable mechanism of Shigellosis to endometriosis** 

Endometriosis remains a difficult clinical problem today and warrants more extensive research to understand the disease pathology. The future is to confirm early diagnosis by non-invasive test using a panel of potential genetic and molecular bio- markers. A long term goal is to be able to identify genetic determinants that contribute to the expression of the different phenotypes seen in endometriosis.

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immunoreactive monocyte-lineage cells in experimentally-induced adenomyosis


**9** 

Nick Pullen

*UK* 

**Progesterone Resistance and Targeting** 

**Approach to Endometriosis** 

*Pfizer Global Research & Development,* 

**the Progesterone Receptors: A Therapeutic** 

Endometriosis is characterised by the benign growth of endometrial glands and stroma on the surface of peritoneal tissues and other organs. It is generally regarded as an aberrant estrogen-dependent growth condition, which presents with symptoms of chronic pelvic pain, bleeding and infertility. Steroidal progestogens are already widely used in the treatment of the condition, dienogest (Visanne) the most recent of which has gained EU approval for clinical use (McCormack, 2010). Progestogens appear to work by both directly inhibiting the functional effects of estrogen on endometrial cell proliferation, and also suppressing ovarian function, to induce anovulatory amenorrhoea. The efficacy of this class of agents in patients with endometriosis, however, is relatively modest and the tolerability (breakthrough bleeding and bloating) as well as concerns on the long term safety (risk of breast cancer and thromboembolism, effect on bone mineral density) has also limited their broader utility. Progesterone receptor antagonists (PRAs) have emerged in recent years as an alternative approach to treating the disease. This class of agents has contrasting effects on reproductive function compared with progestogens. This review will focus on what we know about the PRA mechanism of action from pre-clinical in vitro and in vivo evidence and how clinical data have shaped confidence in this class of agents as a new approach to

The steroid hormone, progesterone, is a key modulator of normal reproductive function, including ovulation, uterine and mammary gland development and the neurobehavioral expression associated with sexual responsiveness (Clarke & Sutherland, 1990; Lydon et al., 1995). Progesterone is absolutely essential for the maintenance of pregnancy, maintaining uterine quiescence by suppressing expression of genes that mediate increased myometrial

1 Zhu Y, Bond J & Thomas P (2003) Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. *Proc. Natl Acad. Sci.*

treating endometriosis symptoms and disease progression1.

**2. Progesterone receptor structure & function** 

**1. Introduction** 

USA 100(5):2237-2242.

