Conferences

Seminar during the DGGG congress
Date: Tuesday, September 14, 2004, 8:00-9:30 a.m.
Moderation: W. Küpker, Bremen; K.-W. Schweppe, Westerstede

Summary of the contributions

New treatment strategies for endometriosis
Immune modulators, aromatase inhibitors, Cox 2 inhibitors and SERMS?
Prof. Dr. Thomas M. D’Hooghe, MD, PhD
Coordinator Leuven University Fertility Center, Belgium
Research Associate, Institute of Primate Research, Nairobi, Kenya
Address:
Leuven University Fertility Center, Dept Obstetrics and Gynecology, University Hospital Leuven, Herestraat, 3000 Leuven, Belgium.

Endometriosis remains an enigmatic disease in women of reproductive age. Current treatment regimes used to manage the disease are primarily designed to induce a hypoestrogenic state which leads to a reduction in disease and associated symptoms. While these regimes have been used with great success, there are still drawbacks and limitations to these types of therapies. In this review, we address the shortcomings of current drugs used to medically manage endometriosis and offer potential target areas which may be attractive alternatives to current therapies. Emphasis is placed upon the promising research using TNF inhibitors in this context. Further, we discuss the rationale and current status for medical therapy of endometriosis with aromatase inhibitors, SERMs and COX 2 inhibitors.

Endometriosis/adenomyosis
The syndrome of dislocated endometrium (SDE)

1. Leyendecker
   Women’s Clinic at Darmstadt Hospital
   Acad. Teaching hospital of the universities of Frankfurt and Heidelberg/Mannheim

Today, there is no doubt that transtubar dissemination of desquamated endometrium is the “cause” of pelvic endometriosis. Subfertility and sterility are major side effects of endometriosis. However, the complete surgical or medical removal of endometriosis lesions does not solve the infertility problem. The question therefore arose as to whether sterility in pelvic endometriosis is a direct consequence of the lesions, which must be doubted after the above explanation, or whether endometriosis is a much more complex clinical picture with the lesions and sterility as consequences of a hitherto unidentified underlying disorder.
Retrograde menstruation is a physiological phenomenon, although there is no data on its quantity. Endometriosis, on the other hand, only affects a small, albeit considerable, proportion of women of reproductive age.
Apart from “physiological retrograde menstruation”, however, there is a scientifically established retrograde transport function of the uterus that is of fundamental importance in the early process of reproduction. This is the cervico-fundal uterine peristalsis for directed sperm transport and high-fundal implantation of the embryo. Our research approach to clarifying the pathophysiology of endometriosis was therefore based on the question of whether there is a relationship between the development of endometriosis and a disruption of this physiological transport function of the uterus.
Archimetra and Neometra
Investigations into the morphological and functional basis of this transport function led to the concept of Archimetra. The archimetra is a phylogentically, ontogenetically and functionally independent organ within the uterus. It comprises the subendometrial musculature, the stratum subvasculare or archimyometrium with its circular fiber orientation, and the endometrium with all its three layers, the basalis, spongiosa and functionalis. The characteristic feature of the archimetra is its paramesonephric origin and the control of its function by the ovary. The archimetra is phylogentically very old and becomes ontogentically recognizable as a primordial uterus in the second trimester after fusion of the Müllerian ducts.
In contrast, the outer muscle layers of the uterus, the vascular and supravascular stratum, are not of paramesonephric origin but develop from the mesenchyme of the uterine serosa in the third trimester or even postpartum. In phylogenesis, these muscle layers only develop after the appearance of viviparity. In reference to the term Archimetra and in view of its ontogenetically and phylogenetically late development, we have chosen the term Neometra for this outer part of the uterus. The neometra is under the control of the conceptus, at least in primates.
The main functions of the archimetra are the preparation of the endometrium for implantation (proliferation and secretory transformation), the directed transport of sperm and the prevention of infection based on the immunological competence of the endometrium (macrophages; MUC-1; leukocytes). The neometra has the function of providing the expulsion forces sub partu.
The archimetra as the site of development of endometriosis
Studies on the function and structure of the archimetra in women with endometriosis have led to the view that the archimetra and in particular the basal endometrium play a central role in the development of endometriosis. The following phenomena support this concept.
Hyper- and dysperistalsis of the archimyometrium
In infertile women with endometriosis, there is increased peristaltic activity throughout the cycle, which is on average 100% higher than normal in the early and middle proliferation phase. As a result, these women already have a significantly increased retrograde transport capacity of the uterus during the menstrual phase. At the same time, the internal uterine pressure is increased.
Desquamation of basal endometrium
During menstruation, the functionalis is shed and the functionalis regenerates from the basalis or the area of the spongiosa close to the basalis. In 80% of women with endometriosis, we were able to detect fragments of basalis in the menstrual blood, whereas this was only the case in 10% of women without endometriosis. Due to the considerably increased retrograde transport capacity of the uterus in these women, transtubar fragments of basalis enter the peritoneal cavity in increased numbers, where they implant due to their genuine proliferative potency and possibly grow infiltratively and form endometriosis foci.
The parallel development of adenomyosis
Using transvaginal sonography (TVS) and magnetic resonance imaging (MRI), we were able to demonstrate that endometriosis in infertile women is associated with adenomyosis with a prevalence of 90%. Adenomyosis leads to destruction of the structure of the archimyometrium, which is responsible for sperm transport, and is therefore at least partially responsible for sterility in women with endometriosis.
The cause of the functional and morphological changes of the archimetra in women with endometriosis is a paracrine hyperestrogenism of the basalis. Throughout the cycle, the basalis expresses P450 aromatase, which forms estrogens from androgenic precursors. As the basal layer in women with endometriosis is twice as thick as in healthy women, more oestrogen is produced locally at the level of the archimetra, which has a paracrine effect. With identical peripheral oestradiol levels in the blood of women with and without endometriosis, those in the menstrual blood of women with endometriosis are significantly increased. This may be due solely to the thickening of the basalis but also to increased cellular production.
As an interim result in the study of endometriosis, the following conclusion can therefore be drawn
Endometriosis is based on a paracrine interference of increased basal estrogens at the level of the archimetra with the ovarian control of uterine peristalsis. This results in hyperperistalsis with the dislocation of basal cell fragments – transtubar retrograde with the consequence of peritoneal endometriosis and subbasal infiltrative with the development of adenomyosis.