Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI study.

PURPOSE: In a series of publications, we had developed the concept that uterine adenomyosis and pelvic endometriosis as well as endometriotic lesions at distant sites of the body share a common pathophysiology with endometriosis constituting a secondary phenomenon. Uterine auto-traumatization and the initiation of the mechanism of tissue injury and repair (TIAR) were considered the primary events in the disease process. The present MRI study was undertaken (1) to corroborate this concept by re-visiting, in view of discrepant results in the literature, the association of adenomyosis with endometriosis and (2) to extend our views concerning the mechanisms of uterine auto-traumatization. PATIENTS AND METHODS: MRI was performed in 143 women attending our center, in whom, on the basis of transvaginal sonography (TVS) and historical data, such as documented endometriosis and dysmenorrhea of various degrees of severity, the presence of uterine adenomyosis was suspected. In addition to the measurement of the diameter of junctional zone (JZ) of the anterior and posterior walls in the mid-sagittal plane, the diagnosis of adenomyosis was based on visualization, in that all planes were analyzed with scrutiny. By this method of "visualization" all transient enlargement of the JZ, such as peristaltic waves of the archimyometrium and sporadic neometral contractions that might mimic adenomyotic lesions could be excluded. At the same time, this method allowed to lower the limit of detection in terms of thickness of the JZ for assured diagnosis of adenomyosis. Furthermore, the localizations of the individual lesions, their shapes and patterns were described. RESULTS: With the method of 'visualization', the diagnosis of uterine adenomyosis could be verified in 127 of the 143 patients studied. The prevalence of endometriosis in adenomyosis was 80.6% and the prevalence of adenomyosis in endometriosis was 91.1%. As concluded from their localization within the uterine wall, the adenomyotic lesions predominantly developed in the median region of the upper two-thirds of the uterine wall. Cystic cornual angle adenomyosis was a distinct phenomenon that was only observed in patients suffering from extreme primary dysmenorrhea. Aside from this, the majority of the patients complained of primary dysmenorrhea (80%). On the basis of these findings and the fact that particularly extreme primary dysmenorrhea is associated with high intrauterine pressure, menstrual 'archimetral compression by neometral contraction' has to be considered as an important cause of uterine auto-traumatization in addition to uterine peristalsis and hyperperistalsis. Both mechanical functions of the non-pregnant uterus exert their strongest power in the upper region of the uterus, which is compatible with the predominant localization of the adenomyotic lesions. CONCLUSIONS: The data confirm our previous results of a high association of adenomyosis with endometriosis and vice versa. Our view of the mechanism of uterine auto-traumatization by mechanical functions of the non-pregnant uterus has to be extended, in that 'archimetral compression by neometral contractions' could be realized as the predominant cause of mechanical strain to the non-pregnant uterus. The data of this study confirm our concept of the etiology and pathophysiology of adenomyosis and endometriosis in that the process of chronic proliferation and inflammation is induced at the level of the archimetra by chronic uterine auto-traumatization. Furthermore, with respect to the diagnosis of uterine adenomyosis (and consequently endometriosis) this study shows a high degree of accordance between the findings in real-time TVS and MRI.

The pathophysiology of endometriosis and adenomyosis: tissue injury and repair.

INTRODUCTION: This 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. METHODS: In 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 CONCLUSIONS: Circumstantial 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.

Duration of dysmenorrhoea and extent of adenomyosis visualised by magnetic resonance imaging.

OBJECTIVE: Enlargement of the junctional zone (JZ) on T2-weighted resonance imaging of the uterus has recently been established as the major criterion for adenomyosis in patients with endometriosis. This study was conducted to analyse the extent of adenomyosis using magnetic resonance imaging (MRI) and relate it to the duration of dysmenorrhoea. STUDY DESIGN: This was a prospective study of 70 patients presenting with the complaint of severe dysmenorrhoea. Forty patients (57%) reported dysmenorrhoea as their major complaint and 30 patients (43%) suffered additionally from infertility. Group I (n=40) consisted of patients with dysmenorrhoea of between 1 and 10 years' duration, group II (n=30) consisted of patients with dysmenorrhoea of longer than 11 years' duration. All patients underwent laparoscopy to detect the presence and degree of endometriosis, and all patients underwent T2-weighted resonance imaging of the uterus to detect the extent of adenomyosis by measurement of the "junctional zone". RESULTS: In group I, adenomyosis could be detected via MRI in 21 patients (52.5%), while 19 patients (47.5%) showed no signs of adenomyosis. By contrast, in group II a distinct enlargement of the JZ, as the major radiological criterion of adenomyosis, could be observed in 26 patients (87%), while only 4 patients (13%) revealed no signs of adenomyosis (p=0.04). The mean thickness of the JZ was significantly enlarged in group II (11.07 mm) compared with group I (6.38 mm; p<0.0001). The prevalence of adenomyosis in endometriosis after dysmenorrhoea of more than 11 years' duration was 87%. CONCLUSIONS: In deep infiltrating endometriosis, a correlation between a specific localisation and dysmenorrhoea can often not be found. Recently, endometriosis and adenomyosis have been believed to result from a common uterine disease, the dislocation of the basal endometrium. Our data clearly show that dysmenorrhoea of long duration in patients who have had endometriosis for over a threshold value of 11 years is significantly related to adenomyosis of the uterus. Hence, evaluation of adenomyosis using MRI should become a standard procedure in cases of dysmenorrhoea and endometriosis. Severe dysmenorrhoea of long duration should always focus clinical interest on adenomyosis of the uterus.

Physiology of upward transport in the human female genital tract.

The uterus and fallopian tubes represent a functionally united peristaltic pump under the endocrine control of ipsilateral ovary. We have examined this function by using hysterosalpingoscintigraphy (HSS), recording of intrauterine pressure, electrohysterography, and Doppler sonography of the fallopian tubes. An uptake of labeled particles into the uterus was observed during the follicular and luteal phases of the cycle after application into the vagina. Transport into the oviducts, however, could only be demonstrated during the follicular phase. Furthermore, the predominant transport was into the tube ipsilateral to the ovary containing the dominant follicle. The pregnancy rate following spontaneous intercourse or insemination was higher in those women in whom ipsilateral transport could be demonstrated. The amount of material transported to the ipsilateral tube was increased after oxytocin administration, as demonstrated by radionuclide imaging and by Doppler sonography following instillation of ultrasound contrast medium. An increase in the basal tone and amplitude of contractions was observed after oxytocin administration. These results support the idea that the uterus and fallopian tubes act as a peristaltic pump, which increases transport of sperm into the oviduct ipsilateral to the ovary bearing the dominant follicle. Oxytocin appears to play a critical role in this peristaltic pump. A failure of the peristaltic mechanism is possibly responsible for infertility. We propose the term tubal transport disorder (TTD) as a nosological entity. Results from HSS could be a useful adjunct for choosing treatment modalities in patients with patent fallopian tubes suffering from infertility. These patients may be better served with in vitro fertilization (IVF).

Induction of ovulation by the chronic administration of naltrexone in hypothalamic amenorrhea.

Ovulatory menstrual cycles were induced by the administration of the specific opiate antagonist naltrexone at a dose of 50 mg/day for 28 days in 3 women suffering from secondary hypothalamic amenorrhea. The occurrence of ovulation was based on demonstration of follicular growth and corpus luteum formation by ultrasonography and a LH midcycle surge and rise of progesterone. After discontinuation of treatment, the women became amenorrheic again and serum gonadotropins as well as estradiol declined to the low levels found before naltrexone administration. Naltrexone or other specific opiate antagonists may be useful agents for the induction of ovulation in patients with hypothalamic amenorrhea.

Pregnancies following chronic intermittent (pulsatile) administration of Gn-RH by means of a portable pump ("Zyklomat")--a new approach to the treatment of infertility in hypothalamic amenorrhea.

In previous studies it could be demonstrated that in severe hypothalamic amenorrhea, which is associated with absent or deficient hypothalamic secretion of Gn-RH, ovarian function could be restored by chronic intermittent (pulsatile) administration of Gn-RH. In order to apply chronic intermittent administration of Gn-RH as a new mode of treatment of infertility in hypothalamic amenorrhea on an outpatient basis a portable device ("Zyklomat") was constructed consisting of a peristaltic pump, a computerized timing device and a Gn-RH containing bag, which delivers 50 microliters of a Gn-RH containing solution once every 90 minutes via an i.v. catheter into the circulation. It is the purpose of this communication to present this new method of treatment and the successful induction of the first two pregnancies with this method in two patients with severe hypothalamic amenorrhea.

Clinical, endocrinological, and cytological characterization of two 46, XX males.

In two 46,XX males, 20 and 21 yr of age, gonadotropins, testosterone, and estradiol were measured in serum and compared to those in a control group of four men. In addition, in one subject, androgen metabolism was measured in biopsied skin and cultured skin fibroblasts. In both XX men, a pulsatile pattern of gonadotropin, testosterone, and estradiol release into serum was observed. The levels of the gonadotropins and estradiol were higher and the levels of testosterone were lower in XX men than in normal men. hCG stimulation resulted in a significant increase in testosterone secretion, and LRH administration caused a more prolonged rise in gonadotropin levels in the XX men. The administration of estradiol caused a positive feedback response in the XX men and resulted in a suppression of gonadotropin secretion in the controls. Finally, the formations of C-19 metabolites from testosterone and estrone from androstenedione were found to be in the same range in skin and skin fibroblasts from the XX men as in those from normal men. It can be concluded that 46,XX men have altered hypothalamic-pituitary and gonadal function compared to normal men.

Bone mass reduction after estrogen deprivation by long-acting gonadotropin-releasing hormone agonists and its relation to pretreatment serum concentrations of 1,25-dihydroxyvitamin D3.

Estrogen deficiency results in bone mass reduction of largely varying extent in postmenopausal females, indicating that additional mechanisms influence the response of bone. They are by no ways identified in either the animal experiment or under clinical conditions. In search for factors, conditioning the response of bone to estrogen deficiency, we have conducted a study in females under treatment with the GnRH agonist decapeptyl (D-Trp6-LHRH). This drug blocks ovarian function and was administered for treatment of endometriosis or uterine leiomyoma. We determined spinal (dual photon absorptiometry) and forearm (single photon absorptiometry) bone mineral density before and 3 and 6 months after the onset of therapy and measured biochemical parameters of bone metabolism. Our results showed an increase in bone turnover after initiation of estrogen deficiency, as indicated by the elevation of alkaline phosphatase and osteocalcin. This resulted in a secondary decrease in serum intact PTH and 1,25-dihydroxy-vitamin D3. Furthermore, we found a positive correlation between pretreatment values of serum 1,25-dihydroxyvitamin D3 as well as its decrease and the reduction in bone mass during GnRH agonist treatment. This demonstrates that the patients' metabolic conditions predict their response to estrogen deficiency.

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.

[Computed tomography and the clinical picture of carcinoma of the uterine cervix]. / Computertomographie und Klinik beim Karzinom des Collum uteri.

The clinical and computer tomographic findings in 142 patients with carcinoma of the body of the uterus have been compared. The CT findings at the first examination were then compared with the clinical results. The likelihood of a recurrence was related to infiltration of the parametrium. There was strong positive correlation between the CT findings during treatment and the probability of recurrences. The wealth of information provided by computed tomography makes any other form of investigation during tumour staging and during follow-up unnecessary.

From physiology to clinics--20 years of experience with pulsatile GnRH.

The physiological and the pathophysiological basis of unvariant pulsatile administration of gonadotrophin-releasing hormone (GnRH) as well as the clinical results are reviewed. Pulsatile administration of GnRH not only proved to be a very effective treatment mode but also became an important tool for research in the central control of pituitary and ovarian function under normal and disease conditions.

The uterine peristaltic pump. Normal and impeded sperm transport within the female genital tract.

Rapid as well as sustained sperm transport from the cervical canal to the isthmical part of the fallopian tube is provided by cervico-fundal uterine peristaltic contractions that can be visualized by vaginal sonography. The peristaltic contractions increase in frequency and presumably also in intensity as the proliferative phase progresses. As shown by placement of labeled albumin macrospheres of sperm size at the external cervical os and serial hysterosalpingoscintigraphy (HSSG) sperm reach, following their vaginal deposition, the uterine cavity within minutes. In the early follicular phase a large proportion of the macrospheres remains at the site of application, while a smaller proportion enters the uterine cavity with even a smaller one reaching the isthmical part of the tubes. In the mid-follicular phase of the cycle with increased frequency and intensity of the uterine contractions the proportion of macrospheres entering the uterine cavity as well as the tubes has significantly increased. In the late follicular phase with maximum frequency and intensity of uterine peristalsis the proportion of macrospheres entering the tube increases further at the expense of those at the site of application as well as within the uterine cavity. The transport of the macrospheres into the tube is preferentially directed into the tube ipsilateral to the dominant follicle, which becomes apparent in the mid-follicular phase as soon as a dominant follicle can be identified by ultrasound. Since the macrosphere are inert particles the directed sperm transport into the tube ipsilateral to the dominant follicle is not functionally related to a mechanism such as chemotaxis but is rather provided by uterine contraction of which the direction may be controlled by a specific myometrial architecture in combination with an asymmetric distribution of myometrial oestradiol receptors. Women with infertility and mostly mild endometriosis display on VSUP a uterine hyperperistalsis with nearly double the frequency of contractions during the early and mid- as well as midluteal phase in comparison to the fertile and healthy controls. During midcycle these women display a considerable uterine dysperistalsis in that the normally long and regular cervico-fundal contractions during this phase of the cycle have become more or less undirected and convulsive in character. Hyperperistalsis results in the transport of inert particles from the cervix into the tubes within minutes already during the early follicular phase, and may therefore constitute the mechanical cause for the development of endometriosis in that it transports detached endometrial cells and tissue fragments via the tubes into the peritoneal cavity. Moreover, dysperistalsis may contribute to the infertility in these patients since it results in a break down of sperm transport within the female genital tract.

Pulsatile administration of Gn-RH in hypothalamic amenorrhea.

The physiological and pathophysiological basis of hypothalamic amenorrhoea are reviewed as well as the clinical results of chronic intermittent (pulsatile) administration of Gn-RH in the treatment of infertility. Hypothalamic amenorrhoea is considered to be the result of a deficient hypothalamic secretion of Gn-RH. By pulsatile administration of Gn-RH, which is a pre-requisite of normal pituitary gonadotrophic function, deficient endogenous Gn-RH is replaced. If an adequate dose of Gn-RH is provided, which takes into account the degree of impairment of hypothalamic function in the individual case, follicular maturation, ovulation and corpus luteum formation are achieved in nearly every treatment cycle. Although dependent also on factors other than the treated dysfunction, a high conception rate is achieved.