Gerhard Leyendecker

The pathophysiology of endometriosis and adenomyosis: tissue injury and repair

IntroductionThis study presents a unifying concept of the pathophysiology of endometriosis and adenomyosis. In particular, a physiological model is proposed that provides a comprehensive explanation of the local production of estrogen at the level of ectopic endometrial lesions and the endometrium of women affected with the disease.MethodsIn women suffering from endometriosis and adenomyosis and in normal controls, a critical analysis of uterine morphology and function was performed using immunohistochemistry, MRI, hysterosalpingoscintigraphy, videohysterosonography, molecular biology as well as clinical aspects. The relevant molecular biologic aspects were compared to those of tissue injury and repair (TIAR) mechanisms reported in literature.Results and conclusionsCircumstantial evidence suggests that 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, microtraumatizations with the activation of the mechanism of ‘tissue injury and repair’ (TIAR). This results in the local production of estrogen. With ongoing peristaltic activity, such sites might increase and the increasingly produced estrogens interfere in a paracrine fashion with the ovarian control over uterine peristaltic activity, resulting in permanent hyperperistalsis and a self-perpetuation of the disease process. Overt auto-traumatization 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 leading rapidly to 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 leads to the same extent of microtraumatization. With the activation of the TIAR mechanism followed by infiltrative growth and chronic inflammation, endometriosis/adenomyosis of the younger woman and premenopausal adenomyosis share in principle the same pathophysiology. In conclusion, endometriosis and adenomyosis result from the physiological mechanism of ‘tissue injury and repair’ (TIAR) involving local estrogen production in an estrogen-sensitive environment normally controlled by the ovary.

Uterine peristaltic activity and the development of endometriosis.

Abstract: 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.

Utero-Tubal Sperm Transport and Its Impairment in Endometriosis and Adenomyosis

Abstract:  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.

Hypophysäre Gonadotropine und ovarielle Steroide im Serum während des normalen menstruellen Cyclus und bei Corpus-luteum-Insuffizienz

SummaryLH, FSH, estradiol-17β, progesterone, 20α-dihydroprogesterone, 17α-hydroxyprogesterone, Δ4-androstenedione and testosterone are determined by radioimmunoassay in serum daily during 11 menstrual cycles. Three of them had to be considered as cycles with corpus luteum insufficiency on the basis of basal body temperature, length of the luteal phase and the pattern of progesterone concentration in serum. One woman conceived during the investigated cycle.The present concepts of the regulation of ovulation are discussed on the basis of the chronological relationship of changing endocrine parameters in serum during the cycles. The analysis of the hormone concentrations in serum during the cycles with corpus luteum insufficiency supports the view that corpus luteum insufficiency could be caused by an insufficient stimulation of the growing follicle, but other etiological factors have also to be considered.ZusammenfassungLH, FSH, Östradiol-17β, Progesteron, 20α-Dihydroprogesteron, 17α-Hydroxyprogesteron, Δ4-Androstendion und Testosteron wurden während 11 menstrueller Cyclen täglich im Serum radioimmunologisch bestimmt. Von den 11 untersuchten Cyclen stellten sich 8 nach Beurteilung von Basaltemperatur, Dauer der Sekretionsphase und Progesteronkonzentration im Serum als wahrscheinlich normal heraus, während 3 Cyclen die Zeichen einer Corpus-luteum-Insuffizienz unterschiedlicher Ausprägung boten. Während eines der 8 normalen Cyclen kam es zur Konzeption. Heute existierende Anschauungen über die Regulation der Ovulation werden auf der Basis der in dieser Untersuchungsreihe beobachteten chronologischen Beziehungen cyclischer Hormonschwankungen im Serum diskutiert. Die Analyse der Hormonkonzentrationen im Serum während der Cyclen mit Corpus-luteum-Insuffizienz stützt die Auffassung, daß dieser Funktionsstörung eine ungenügende Stimulation des heranreifenden Follikels zugrunde liegt. Andere kausale Faktoren müssen jedoch ebenfalls in Betracht gezogen werden.LH, FSH, estradiol-17beta, progesterone, 20alpha-dihydroprogesterone, 17alpha-hydroxyprogesterone, delta4-androstenedione and testosterone are determined by radioimmunoassay in serum daily during 11 menstrual cycles. Three of them had to be considered as cycles with corpus luteum insufficiency on the basis of basal body temperature, length of the luteal phase and the pattern of progesterone concentration in serum. One woman conceived during the investigated cycle. The present concepts of the regulation of ovulation are discussed on the basis of the chronological relationshp of changing endocrine parameters in serum during the cycles. The analysis of the hormone concentrations in serum during the cycles with corpus luteum insufficiency supports the view that corpus luteum insufficiency could be caused by an insufficient stimulation of the growing follicle, but other ethiological factors have also to be considered.

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

Abstract 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.

The effect of danazol on gonadotropin secretion during the follicular phase of the menstrual cycle

The effects of danazol on pulsatile luteinizing hormone (LH) release, basal LH and follicle-stimulating hormone serum levels, gonadotropin release induced by estradiol (E2) and gonadotropin-releasing hormone were examined in five eugonadal women. Danazol administration resulted in a significant suppression of follicle-stimulating hormone serum levels. LH concentrations and LH pulse frequency appeared to be reduced, but these changes did not reach statistical significance. The pituitary response to exogenous gonadotropin-releasing hormone was not altered. The stimulatory effect of E2 on LH secretion was completely abolished in one subject, severely diminished in three subjects, and unchanged in one subject. In addition, the time course of this response was altered. Serum prolactin concentrations were lowered, whereas basal E2 and progesterone levels did not seem to be affected.

Clinical and Endocrinological Characterization of Two Subjects with Reifenstein Syndrome Associated with Qualitative Abnormalities of the Androgen Receptor

The androgen receptor in fibroblasts cultured from a biopsy of scrotal skin from 1 subject with Reifenstein syndrome has been found to be normal in amount and to bind dihydrotestosterone with normal affinity but to be qualitatively abnormal as evident by thermolability and instability upon ultracentrifugation. The family study of this subject and endocrine studies document androgen resistance in the index patient and his affected uncle. These findings provide evidence for X-linkage of this disorder, and suggest that the mutations that give rise to this phenotype are probably allelic to the mutations of the androgen receptor that cause testicular feminization.

Decrease of vascular angiotensin sensitivity by l-dopa during human pregnancy

In 27 pregnant subjects (21 treated women and six control subjects), the effect of L-dopa (500 to 1,000 mg orally) on vascular sensitivity to angiotensin II amide (Hypertensin, Ciba) was examined in 16 of these women, 1,000 mg of L-dopa resulted in a significant decrease in vascular responsiveness to angiotensin, i.e., an increase in angiotensin pressor dose from 16.9 +/- 5.0 to 19.6 +/- 4.5 ng . kg-1 . min-1 (mean +/- SD). In women with an initially low angiotensin pressor dose, the changes were more pronounced. In six control subjects, in whom two angiotensin infusion tests were performed consecutively without additional administration of L-dopa, an increase in vasopressor response to angiotensin was demonstrated. Possible causes for the L-dopa-induced decrease in angiotensin sensitivity are discussed: an inhibition of sympathetic nervous activity, a directly lowered total peripheral resistance, a natriuresis and diuresis, and an altered dopaminergic activity in the hypothalamus. It is hypothesized that long-term treatment with L-dopa or bromocriptine might not only decrease angiotensin sensitivity but also elevated pregnancy-induced hypertension.

Clinical significance of measurements of carcinoembryonic antigen in serum of patients with carcinoma of the uterine cervix

SummarySerum levels of carcinoembryonic antigen (CEA) were determined radioimmunologically before initiation of therapy in the serum of 88 patients suffering from carcinoma of the uterine cervix. The overall incidence of elevated CEA levels (above 12 ng/ml) was 43%. There was a positive correlation between the incidence of elevated CEA levels and the clinical stage of disease. CEA levels before treatment had no prognostic value as far as median survival time was concerned. In contrast, CEA levels measured immediately after therapy in patients with initially elevated levels turned out to be of prognostic significance. When the posttreatment concentrations of CEA were within the normal range, the median survival time was longer than 990 days (duration of follow-up). When the CEA levels remained elevated, however, the median survival time was only 291 days. Thus, CEA measurements appear to be an additional tool in the follow-up of.

Inhibition of the renin‐aldosterone axis and of prolactm secretion during pregnancy by l‐dopa

Summary. Recently, interactions between dopaminergic mechanisms and aldosterone secretion were described in non‐pregnant subjects. The present study examined the effect of 1000 mg of l‐dopa by mouth on plasma renin activity (PRA), and the concentrations of plasma aldosterone (PA) and prolactin (PRL) during normal pregnancy. Under basal conditions, there was a clear decrease of PRA, PA and PRL 60 min after oral intake of L‐dopa in seven subjects; a further decrease was observed during the following 45 min, resulting in a total decrease of 41 (PRA), 44 (PA) and 56 (PRL) % of the respective arithmetic mean of the basal values. However, the response of PA to isopressor angiotensin II infusions was comparable before and shortly after treatment with l‐dopa in 16 pregnant subjects. The decreased activity of the renin‐aldosterone axis after administration of l‐dopa may be attributed to an accumulation of dopamine and cate‐cholamines in the brain, resulting in a diminution of sympathetic outflow from the central nervous system. The simultaneous and comparable changes of both PRA and PA after L‐dopa treatment, as well as the reversibility of aldosterone suppression by infusion of angiotensin II, suggest that the inhibition of aldosterone secretion by L‐dopa is mediated by a decrease of renin release.