Archimetrosis: the evolution of a disease and its extant presentation : Pathogenesis and pathophysiology of archimetrosis (uterine adenomyosis and endometriosis).

PURPOSE: This article presents a novel concept of the evolution and, thus, the pathogenesis of uterine adenomyosis as well as peritoneal and peripheral endometriosis. Presently, no unifying denomination of this nosological entity exists. METHODS: An extensive search of the literature on primate evolution was performed. This included comparative functional morphology with special focus on the evolution of the birthing process that fundamentally differs between the haplorrhine primates and most of the other eutherian mammals. The data were correlated with the results of own research on the pathophysiology of human archimetrosis and with the extant presentation of the disease. RESULTS: The term Archimetrosis is suggested as a denomination of the nosological entity. Archimetrosis occurs in human females and also in subhuman primates. There are common features in the reproductive process of haplorrhine primates such as spontaneous ovulation and corpus luteum formation, spontaneous decidualization and menstruation. These have fused Müllerian ducts resulting in a uterus simplex. Following a usually singleton pregnancy, the fetus is delivered in the skull position. Some of these features are shared by other mammals, but not in that simultaneous fashion. In haplorrhine primates, with the stratum vasculare, a new myometrial layer has evolved during the time of the Cretaceous-Terrestrial Revolution (KTR) that subserves expulsion of the conceptus and externalization of menstrual debris in non-conceptive cycles. Hypercontractility of this layer has evolved as an advantage with respect to the survival of the mother and the birth of a living child during delivery and may be experienced as primary dysmenorrhea during menstruation. It may result in tissue injury by the sheer power of the contractions and possibly by the associated uterine ischemia. Moreover, the lesions at extra-uterine sites appear to be maintained by biomechanical stress. CONCLUSIONS: Since the pathogenesis of archimetrosis is connected with the evolution of the stratum vasculare, tissue injury and repair (TIAR) turns out to be the most parsimonious explanation for the development of the disease based on clinical, experimental and evolutionary evidence. Furthermore, a careful analysis of the published clinical data suggests that, in the risk population with uterine hypercontractility, the disease develops with a yet to be defined latency phase after the onset of the biomechanical injury. This opens a new avenue of prevention of the disease in potentially affected women that we consider to be primarily highly fertile.

Impact of the opioid system on the reproductive axis.

Endogenous opioids, first described more than 40 years ago, have long been recognized for their main role as important neuromodulators within the central nervous system. More recently endogenous opioids and their receptor have been identified in a variety of reproductive and nonreproductive tissues outside the central nervous system. Their role within these tissues and organs, however, is only incompletely understood. In the central nervous system, endogenous opioids inhibit pulsatile GnRH release, in part mediating the stress response within the central nervous-pituitary gonadal axis, resulting in hypothalamic amenorrhea. In the ovary, the presence of endogenous opioids primarily produced by granulosa cells has been demonstrated within the follicular fluid, likely influencing oocyte maturation. In hypothalamic amenorrhea, normal cycles can be restored by the administration of opioid antagonists, such as naltrexone. In polycystic ovarian syndrome, endogenous opioids have found to be elevated and may stimulate insulin secretion from the endocrine pancreas. This effect can be inhibited by opioid antagonists, resulting in a decrease of circulating insulin levels in response to glucose challenge. Endogenous opioids may also play a role in the pathogenesis of ovarian hyperstimulation syndrome. In summary, endogenous opioids exert a wide variety of actions within the reproductive system and are worthy of further scientific study.

A new concept of endometriosis and adenomyosis: tissue injury and repair (TIAR).

Pelvic endometriosis, deeply infiltrating endometriosis and uterine adenomyosis share a common pathophysiology and may be integrated into the physiological mechanism and new nosological concept of 'tissue injury and repair' (TIAR) and may, in this context, just represent the extreme of a basically physiological, estrogen-related mechanism that is pathologically exaggerated in an extremely estrogen-sensitive reproductive organ. The acronym TIAR describes a fundamental and apparently ubiquitous biological system that becomes operative in mesenchymal tissues following tissue injury and, upon activation, results in the local production of estradiol. Endometriosis and adenomyosis are caused by trauma. In the spontaneously developing disease, chronic uterine peristaltic activity or phases of hyperperistalsis induce, at the endometrial-myometrial interface near the fundo-cornual raphe, microtraumatisations, with activation of the TIAR mechanism. With ongoing traumatisations, such sites of inflammation might accumulate and the increasingly produced estrogens interfere in a paracrine fashion with ovarian control over uterine peristaltic activity, resulting in permanent hyperperistalsis and a self-perpetuation of the disease process. Overt autotraumatisation of the uterus with dislocation of fragments of basal endometrium into the peritoneal cavity and infiltration of basal endometrium into the depth of the myometrial wall ensues. In most cases of endometriosis/adenomyosis a causal event early in the reproductive period of life must be postulated, rapidly leading to archimetral hyperestrogenism and uterine hyperperistalsis. In late premenopausal adenomyosis such an event might not have occurred. However, as indicated by the high prevalence of the disease, it appears to be unavoidable that, with time, chronic normoperistalsis throughout the reproductive period of life accumulates to the same extent of microtraumatisation. With activation of the TIAR mechanism followed by chronic inflammation and infiltrative growth, endometriosis/adenomyosis of the younger woman and premenopausal adenomyosis share in principal the same pathophysiology.

Polycystic ovarian disease unmasked by pulsatile GnRH therapy in a subgroup of women with hypothalamic amenorrhea.

OBJECTIVE: To present the observation in six out of 120 women treated with pulsatile GnRH for ovulation induction, who developed hyperandrogenemia and polycystic ovaries during treatment. DESIGN: Clinical observation. SETTING: Department of Gynecologic Endocrinology and Reproductive Medicine, Medical University of Innsbruck, Austria. PATIENT(S): A total of 120 women initially diagnosed as suffering from primary or secondary hypothalamic amenorrhea were treated for ovulation induction with pulsatile administration of GnRH for up to 140 days. There was no indication of the presence of polycystic ovaries or hyperandrogenemia before therapy. INTERVENTION(S): Pulsatile GnRH therapy using the Zyklomat pump. MAIN OUTCOME MEASURE(S): Ovulatory menstrual cycles. RESULT(S): Initially, all patients responded to pulsatile GnRH administration with ovulation and corpus luteum formation. During continuation of treatment, 6 patients developed an increase in LH and LH/FSH ratio as well as a progressive rise in serum T levels resulting in hyperandrogenemia. This was accompanied by the development of polycystic ovaries and cessation of follicular maturation. CONCLUSION(S): We conclude from these observations that restoration of normal GnRH stimulation of the pituitary gland can result in the development of hyperandrogenemia and polycystic ovaries, suggesting a pituitary or ovarian defect underlying the pathogenesis of this disorder.

Utero-tubal sperm transport and its impairment in endometriosis and adenomyosis.

The uterus is composed of different smooth muscle layers that serve various functions. First, menstrual debris is expulsed at the time of the menses. Second, sperm is transported in the preovulatory phase to maximize fertility, and third, the human embryo is placed in an adequate setting during implantation. Endometriosis is a gynecologic disorder leading to severe pain symptoms such as severe pain during menstruation (dysmenorrhea), chronic pelvic pain, pain during sexual intercourse (dyspareunia), and abnormal uterine bleeding. Besides, endometriosis is often associated with female infertility and exhibits a massive impairment in the physiology of uterine contractility that can be documented by the in vivo examination method of hysterosalpingoscintigraphy (HSSG). In addition, endometriosis is associated in 80-90% of subjects with adenomyosis and our data clearly indicate that sperm transport is disturbed by hyperperistalsis when at least one focus of adenomyosis can be detected via magnetic resonance imaging (MRI) and turns into dysperistalsis (a complete failure in sperm transport capacity) when diffuse adenomyosis affecting all myometrial uterine muscle layers is detected. Hence, dysperistalsis is significantly associated with reduced spontaneous pregnancy rates. We therefore recommend MRI and HSSG in every sterility workup.

Adenomyosis and reproduction.

Evidence has been provided that pelvic endometriosis is significantly associated with uterine adenomyosis and that the latter constitutes the major factor of infertility in such conditions. Furthermore, it has become evident that both adenomyosis and endometriosis constitute a pathophysiological and nosological entity. Mild peritoneal endometriosis of the fertile woman and premenopausal adenomyosis of the parous and non-parous woman, as well as adenomyosis in association with endometriosis of the infertile woman, constitute a pathophysiological continuum that is characterized by the dislocation of basal endometrium. Due to the postponement of childbearing late into the period of reproduction, premenopausal adenomyosis might increasingly become a factor for infertility in addition to adenomyosis associated with endometriosis of younger women. In any event, the presence or absence of uterine adenomyosis should be examined in a sterility work-up.

Uterine peristaltic activity and the development of endometriosis.

Peristaltic activity of the nonpregnant uterus serves fundamental functions in the early process of reproduction, such as directed transport of spermatozoa into the tube ipsilateral to the dominant follicle, high fundal implantation of the embryo, and, possibly, retrograde menstruation. Hyperperistalsis of the uterus is significantly associated with the development of endometriosis and adenomyosis. In women with hyperperistalsis, fragments of basal endometrium are detached during menstruation and transported into the peritoneal cavity. Fragments of basal endometrium have, because of their equipment with estrogen and progesterone receptors and because of their ability to produce estrogen, an increased potential of implantation and proliferation, resulting in pelvic endometriosis. In addition, hyperperistalsis induces the proliferation of basal endometrium into myometrial dehiscencies. This results in endometriosis-associated adenomyosis with a prevalence of approximately 90%. Adenomyosis results in impaired directed sperm transport and thus constitutes an important cause of sterility in women with endometriosis. Our own date and that from the literature strongly suggest that the principal mechanism of endometriosis/adenomyosis is the paracrine interference of endometrial estrogen with the cyclical endocrine control of archimyometrial peristalsis exerted by the ovary, thus resulting in hyperperistalsis.

Uterine peristaltic activity during the menstrual cycle: characterization, regulation, function and dysfunction.

Unlike other smooth muscle organs, the uterine muscle was regarded to be normally functional for only a brief period, following a lengthy gestation. However, recently it has been shown that uterine peristalsis constitutes one of the fundamental functions of the non-pregnant uterus. Its morphological basis is the archimyometrium, which is the muscular component of the archimetra and which preserves a functional bipartition of the primarily unpaired uterus. Three types of uterine peristaltic contractions can be distinguished: cervico-fundal, fundo-cervical and isthmical peristaltic activity, which changes during the menstrual cycle and is controlled by the dominant ovarian structure via the secretion of sex steroids systemically and into the utero-ovarian vascular countercurrent system. Uterine peristalsis of the non-pregnant uterus is actively involved in very early reproductive processes, such as rapid and sustained directed sperm transport and high fundal implantation, as well as serving retrograde menstruation for the preservation of body iron content. Furthermore, it became apparent that hyper- and dysfunctions of this contractile activity, such as hyper- and dysperistalsis, might be causally involved in the development of pelvic endometriosis, uterine adenomyosis and infertility, as obtained from immunohistochemistry, vaginal sonography, hysterosalpingoscintigraphy and magnetic resonance imaging.