Carcinoma of the endometrium--changing trends in aetiology and management.
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Climacteric↗
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Endometrial phospholipase A2 enzymes and their regulation by steroid hormones.
The presence of two phospholipase A2 (PLA2) enzymes, designated PLA2(i) and PLA2(ii), has been demonstrated in human endometrium. These enzymes differ with respect to pH and calcium requirements, location within the tissue and regulation by steroid hormones. Phospholipase A2(i) is calcium dependent, optimally active at pH 7.5-9.0 and present mainly in the glandular component of the endometrium. Changes in activity occur during the menstrual cycle which are indicative of regulation by ovarian steroids. Conversely, PLA2(ii) is calcium independent, optimally active at pH 7.0 and located predominantly in the stromal layer. Wide variation in PLA2(ii) activity was found between individual subjects and there was no relationship with the stage of the menstrual cycle. Activity was, however, much higher in pathological endometrium and in endometrium from subjects with severe dysmenorrhoea. Triton X-100 activated PLA2(i) but not PLA2(ii). In cultured explants of endometrium, both enzymes were inhibited by progesterone whereas oestradiol and dexamethasone had no effect. However, progesterone priming followed by treatment with oestradiol caused a 2-fold stimulation of PLA2(i) but not PLA2(ii). Phospholipase A2 is favoured as the rate-limiting step in the generation of arachidonic acid for prostaglandin synthesis. However, our studies so far do not support a direct relationship between PLA2 and endometrial concentrations of prostaglandins, which implies that other important regulatory steps are involved. Other enzymes which are potentially capable of mobilizing arachidonic acid should also be investigated.
Calcium↗
Dating of the endometrium by microhysteroscopy.
In 173 consecutive cases of hysteroscopy, the microhysteroscope was brought into contact with the anterior part of the fundus uteri. The vascular pattern of the endometrium was then visualized and photographed. As the vascularization of the endometrium changes during the menstrual cycle, a dating of the endometrium was made based on the blood vessel pattern. An endometrial biopsy was taken in each case. Hysteroscopically we were able to define five different phases in the menstrual cycle: early proliferative, late proliferative, early secretory, late secretory, and premenstrual-menstrual phase. Histopathological examination confirmed the hysteroscopical diagnosis of the phases in 72, 69.7, 81.3, 53.8 and 70%, respectively.
Biopsy↗
[Effects of low doses of lynestrenol on endometrium and nidation (author's transl)].
In 10 women taking 0.5 mg lynestrenol for oral contraception endometrium biopsies were carried out in several consecutive cycles between the 21st and 25th day of each cycle. In addition pregnandiol excretion in the urine was measured in one of the last three treatment cycles always on the 10th and 21st day of cycle. During treatment of a characteristic, monomorphic microscopical endometrium picture was observed with hardly distinct endometrium glands and only slight decidualike transformation of cellular elements of the stroma. From these histological pictures it is concluded that oral application of 0,5 mg lynestrenol produces endometrium changes characterized by insufficient transformation so that nidation of a blastocyte becomes impossible.
Biopsy↗
[Clinic-pathological study of 485 cases of postmenopausal bleeding].
Four hundred and eighty-five patients with postmenopausal bleeding (PMB) who underwent a curettage were studied retrospectively to evaluate the relationship of clinical cause and pathological findings. The results showed that nonorganic causes were the most common, benign causes were much commoner than malignant causes. Bleeding from the uterus was the most common in all PMB. Pathological examination revealed atrophic endometrium in 41.5%, proliferative and secretory endometrium only a few. Endometrial and cervical carcinoma were the most common among the malignant causes. PMB with an enlarged uterus, and women with advanced age have a statistically significant correlation with more serious pathology. It is suggested that the postmenopausal endometrium changes are regulated by ovarian and ectopic sex hormones, and endometritis or vascular diseases of the endometrium may be involved in the mechanism of bleeding.
Adult↗
[Ultrasonographic changes in the endometrium during ovulatory cycles--correlation to serum estradiol and progesterone concentrations].
Daily changes in the thickness and texture of the endometrium were assessed by ultrasonography in 15 natural ovulatory cycles. The endometrium in the follicular phase became thicker every day until ovulation [5.8 +/- 1.8 mm (mean +/- SD) on day -8, 10.7 +/- 2.9 mm on day 0, day 0: ovulation], but the thickness did not change during the luteal phase. There was a significant correlation between the thickness of the endometrium and the serum estradiol concentration in the follicular phase (r = 0.64, n = 89, p less than 0.01), but the change in the thickness of the endometrium varied with the individual. The texture of the endometrium changed in the menstrual cycle. The hyperechoic area of the endometrium spread from the basal layer to the lumen during the early-mid luteal phase. The ratio of the thickness of the hyperechoic area to the total thickness of the endometrium (hyperechoic endometrial area ratio, HEA ratio) increased from 34.3 +/- 11.0% on day 0 to 100% on day 9. There was a significant correlation between the HEA ratio and the serum progesterone concentration in the period from day -2 to day 9 (r = 0.68, n = 91, p less than 0.01).
Adult↗
[Morphology of the tubal drainage angle of the human uterus and of the pars intramuralis of the tuba uterina].
The morphology of the pars intramuralis of the fallopian tube has been histological examined in 500 uteri which were exstirpated in the Department of Gynaecology and Obstetrics of the University of Kiel in the years of 1972 to 1973. It was found that the interstitial pars of the endometrium changes regularly during the menstrual cycle. In the same way the endometrium in the interstitial part of the tubal canal suffers from an atrophy if patients were treated with gestagens. The adenomatous hyperplasie or the polypes of the endometrium which are often found near the utero-tubal junction are to be considered as the matrix of the carcinoma of the endometrium; continuous changes between the adenomatous hyperplasie and the carcinoma of the endometrium can be observed. The frequency of precancers near the utero-tubal junction underlines the demand for an accurate curettage in this region of the cavum uteri. The histological examination of the region of the utero-tubal junction after the extirpation of the uterus is absolutely necessary and has to be generally to be asked for.
Endometrium↗
Cytopathological changes in human cervix and endometrium following prolonged retention of copper-bearing intrauterine contraceptive devices.
Since 1971, cytological evaluation of cervical smears and endometrial aspirates was carried out in 604 women wearing CuT200 intrauterine contraceptive devices (IUDs) for periods ranging from 6 mo to 15 yr. No cases of cervical neoplasia or endometrial carcinoma were encountered, even after continuous use of the device for 15 years. Dysplastic cervical smears were, however, found in 45 postinsertional smears, and endometrial hyperplasia was detected in seven aspirates; in no cases was the dysplasia or hyperplasia higher than of moderate degree. Thirty-nine of the 45 women with postinsertional dysplastic smears were followed for 3-4 yr; in no case did the lesion progress to a higher grade or to frank malignancy. However, persistence and recurrence of dysplasia were seen in 10 women, necessitating removal of the IUDs. The incidence of cervical dysplasia and endometrial hyperplasia was found to be much higher when the IUDs had been changed than when the original devices were worn continuously. The rate of removal of IUDs because of persistent or recurring dysplasia was also much higher in the former group. Since no pregnancies were reported in any of the women wearing the original device for as long as 15 yr, we do not advocate the practice of changing the device at the end of 3 yr for maintaining contraceptive efficacy as recommended by the manufacturers; instead, we recommend the uninterrupted retention of the original device for periods not longer than 5 yr in view of occurrence of endometrial hyperplasia in two 6-yr wearers.
Adult↗
A possible mechanism of action of danazol and an ethinylestradiol/norgestrel combination used as postcoital contraceptive agents.
Twenty-seven women requesting postcoital contraception were randomly allocated to take an ethinylestradiol/dl-norgestrel combination or danazol. Urine specimens were assayed for luteinising hormone (LH) and pregnanediol-3-glucuronide (P3G) levels from the day of the postcoital treatment to the next period. In addition, the urine samples of these recruits and 12 additional women were assayed for the Beta-subunit of human chorionic gonadotropin (B-hCG). A consistent pattern of alteration in urinary steroids was lacking, indicating a heterogeneous effect on ovarian function. There was no evidence of early pregnancy in successfully treated cases. We suggest that the main mechanism of action of these drugs is at the endometrial level.
Chorionic Gonadotropin↗
Mechanism of action of intrauterine devices: biochemical changes.
The mechanism of action of intrauterine devices varies from one type of device to another, although the principle of action is the same, namely, to interfere with the physiology of reproduction at the endometrial level. The biochemical changes of the endometrial tissue and the composition of the uterine fluid have been reviewed in relation to the use of inert, copper-medicated and steroid-releasing IUDs. All IUDs, whether inert or medicated, provoke a significant increase in the number of neutrophils, mononuclear cells and plasma cells, the presence of which is unrelated to the tissue infiltration of inflammatory cells occurring pre-menstrually of the normal menstrual cycle. The increase of leucocytes in IUD-users is compatible with a foreign body reaction which may be related to the antifertility effect. The addition of copper to an inert IUD has been shown to significantly alter the metabolism of the endometrial cells, e.g. the enzymatic activity and the DOVA-synthesis. The steroid-medicated IUDs represent a new approach to intrauterine contraception where the morphology of the endometrium is considerably altered, showing massive decidual changes, atrophic glands and sometimes atrophy of the whole functional layer. In addition, there is an important foreign body reaction, similar to that of the inert IUDs. The enzymatic activity, as well as the proliferative activity was significantly altered in the endometrium of these IUD-users. Changes in the endometrial fibrinolytic activity in IUD-users have been demonstrated to be related to the presence of irregular bleeding. Micro-traumata of the endometrium and the increased fibrinolytic activity may also interfere with the protective processes present in the physiologically normal endometrium. Further studies on the factors influencing the fertilizing ability of the spermatozoa in the female genital tract, as well as on the conditions of the human endometrium required for the implantation of a blastocyst, may yield important information for the improvement of intrauterine contraception.
Endometrium↗
Marked deciliation and insufficient secretory modification of endometrial surface during treatment with a new progestogen-estrogen combination.
Endometrial modifications induced by SHB 209 AE, a new progestogen-estrogen combination, was investigated using scanning and transmission electron microscopy, in order to demonstrate specific variations of the endometrial surface and if these contribute to the contraceptive effects of the preparation. Endometrial biopsies were performed in 27 volunteers who had taken SHB 209 AE during the preceding 3 months. Endometrial biopsies of 15 normomenstruating volunteers were used as controls. Each fragment was subdivided for scanning and transmission electron microscopy examination. The ciliated cells were always significantly fewer in the various phases of the treatment cycle than in the control endometria although, as in the controls, their number and ratio with nonciliated cells was greater mid-way through the cycle. Ciliogenesis was always notably delayed compared to the normal endometria during the different treatment cycle phases. Secretory modifications appeared prematurely but remained incomplete through the treatment cycle. These modifications caused total and characteristic alterations of the mucosal architecture and cellular maturation that comprised the implantation phase.
Adolescent↗
Vascular changes in the human endometrium following the administration of the progesterone antagonist RU 486.
Eleven healthy women were assigned to one of two groups. They received 50 mg RU 486 orally per day either on cycle days 7 to 10 (preovulatory group n = 5) or on cycle days 20 to 23 (postovulatory group, n = 6). An endometrial biopsy was taken on the fourth day of the RU-treatment in the preovulatory group and on the second (n = 2) or fourth (n = 4) treatment day in the postovulatory group. Biopsies from 34 untreated women representing matched samples from early and mid preovulatory phase (n = 10) and mid and late postovulatory phase (n = 24) were used as control. The ultrastructure of the endometrial capillaries was investigated by morphometric methods. The administration of RU 486 during the preovulatory phase did not modify the vascular structure. However, when given in the postovulatory phase, necrosis occurred in the capillary endothelial cells with and without regressive changes of the adjacent stroma. The area and diameter of the capillary lumen and the area of the adventitia was smaller than in the control material (p less than 0.01). The result of the study suggests that RU 486, when administered in the postovulatory phase, directly affects the capillary vessels of the endometrium.
Adult↗
The effect of levonorgestrel administered in large doses at different stages of the cycle on ovarian function and endometrial morphology.
In a pharmacokinetic study, levonorgestrel (L-NOG) 0.75 mg was administered orally to 10 swedish women in the early follicular phase of the menstrual cycle. L-NOG levels were measured after L-NOG administration. A peak level of 16 nmol/l was reached after 2 hours, T 1/2 was estimated to be 14.5 hours (8.5-18.5) in the 24-48-hour interval after dosing. Seventy-two women (in Stockholm, Bombay and Shanghai) were assigned to 4 treatment groups and studied during a control cycle, a treatment cycle and a posttreatment cycle when 0.75 mg L-NOG was administered orally for 4 days in the follicular phase, periovulatory period or luteal phase. Peripheral blood was drawn 3 times weekly during the entire study for the assay of estradiol and progesterone. In 22 women in Stockholm, an endometrial biopsy was obtained on cycle day 20-22 in all 3 cycles studied. When L-NOG was administered on periovulatory days 9, 11, 13, and 15, 3 women showed follicular activity only, 7 exhibited follicular activity followed by insufficient luteal function and 7 women ovulated normally. When L-NOG was administered on periovulatory days 11, 12, 16 and 19, 7 women ovulated during treatment, 6 women exhibited follicular activity followed by insufficient luteal function and 5 exhibited follicular activity only. When L-NOG was administered in the follicular or luteal phase, no effect on ovarian function was seen. No significant prolongation of the cycle lengths was seen when L-NOG was taken during the follicular phase. Only minor effects in the endometrium were observed during treatment.
Adult↗
Endometrial morphology after 6 months of continuous treatment with a new gonadotropin-releasing hormone superagonist for contraception.
Light and electron microscopic studies were performed on endometrial curettage specimens from 27 women after 6 months of contraceptive treatment with continuous intranasal gonadotropin hormone-releasing hormone (GnRH) superagonist. The GnRH superagonist nafarelin acetate (D-Nal[2]6-GnRH) was used in single daily doses of 125 or 250 micrograms. Ovulation was inhibited during all but one of the 159 treatment months. No pregnancies occurred. In 6 women with fairly regular bleedings, the endometrium displayed weak to normal proliferation. Twenty women developed oligomenorrhea or amenorrhea, 16 of them had inactive endometrium, 1 had weakly proliferative endometrium, and 3 endometrial biopsies were too sparse for adequate evaluation. One woman reported repeated episodes of heavy uterine bleedings. The endometrial biopsy from this woman showed weak proliferation. No signs of endometrial hyperplasia were observed. Generally, the electron microscopy showed signs of low metabolic activity and weak protein synthesis. Thus, long-term continuous treatment with nafarelin acetate for inhibition of ovulation does not appear to have untoward effects on the endometrium.
Administration, Intranasal↗
Risk factors for adenomatous endometrial hyperplasia: a case-control study.
A population-based case-control study of histologically confirmed endometrial neoplasia was conducted in Toronto, Canada, between 1977 and 1978. Pathologic slide review resulted in classification of patients to diagnostic categories of endometrial carcinoma, endometrial carcinoma in situ, and endometrial hyperplasia. This report concerns the subset of patients classified as having adenomatous endometrial hyperplasia. Two age-matched neighborhood controls were selected for each case, and analyses included only those case-control sets in which the case and at least one control were concordant on menopausal status. Among postmenopausal women (87 cases and 151 controls), noncontraceptive estrogen use was a statistically significant risk factor (adjusted odds ratio (OR) = 6.7), as was heavy body weight relative to height (Quetelet index) (adjusted OR = 3.2). Long-term (5+ years) estrogen use conferred an estimated relative risk of more than 20, but use of oral contraceptives did not alter risk significantly. Among premenopausal women (62 cases and 97 controls), a high Quetelet index appeared to be a significant protective factor, even when adjusted for oral contraceptive use (adjusted OR = 0.2). While oral contraceptive use was not associated with a change in risk, long duration of use was highly, but statistically not significantly, protective against hyperplasia. The data for pre- and postmenopausal women indicate that both endogenous and exogenous estrogen exposure are important factors in the etiology of adenomatous endometrial hyperplasia.
Adult↗
The effect of RU486 administered during the proliferative and secretory phase of the cycle on the bleeding pattern, hormonal parameters and the endometrium.
Seventeen healthy women aged 24-45 years with regular menstrual periods, proven fertility and not using steroidal contraceptives or IUD were recruited for the study. The volunteers were followed during one control, one treatment and one follow-up cycle. Daily morning urine samples were obtained during the control and the treatment cycle. The samples were analysed with regard to pregnanediol glucuronide (P2-G), oestrone glucuronide (E1-G), oestradiol (E2), progesterone (P4), LH and creatinine. During the entire 3-month study the subjects kept a record of uterine bleeding and side effects. The subjects received 50 mg RU486 daily either on cycle days 7-10 (n = 7) or on cycle days 20-23 (n = 10). An endometrial biopsy was taken on cycle day 10 in the first group and on cycle days 21-28 in the second group of patients. Treatment during the proliferative phase caused significant prolongation of the cycle length due to a delay of the oestrogen and LH surge. However, once the oestrogen concentration started to increase, the remaining part of the cycle was normal. The length of the follow-up cycle was similar to that of the control cycle. The morphology of the endometrium did not differ from control samples taken from untreated women at the same time of the cycle. All ovulating women (n = 9) treated in the mid-luteal phase started to bleed on the 3rd to 4th day of the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Serum levels of pregnancy-associated endometrial alpha 2-globulin (alpha 2-PEG) during normal menstrual and combined oral contraceptive cycles and relationship to immunohistological localization.
Serum levels of pregnancy-associated endometrial alpha 2-globulin (alpha 2-PEG), the major secretory protein of the endometrium during the late luteal phase of the menstrual cycle and early pregnancy, were measured serially during normal menstrual cycles and in women taking various combined oral contraceptives. Pill users were also sampled on an individual basis. Endometrium from women taking the combined oral contraceptive was examined immunohistochemically using a monoclonal antibody to alpha 2-PEG. Levels of alpha 2-PEG in the menstrual cycle sera showed consistent changes following the luteinizing hormone peak, with a greater than three-fold increase between basal levels at mid-cycle and those in the late luteal phase. Serum levels of alpha 2-PEG in the pill users remained at basal levels throughout the cycle, regardless of the progestagen in the formulation. This finding was noted in serial and individual samples from both monophasic and triphasic preparations. However, there was evidence of induction of alpha 2-PEG production at the local endometrial level when immunohistochemical staining was employed at various stages of the pill cycle. This suggests that serum levels of alpha 2-PEG may not necessarily reflect local endometrial production of the protein. These observations are discussed with reference to the proposed value of serum measurement of this protein in assessing relative progestagenic activity upon the endometrium.
Adult↗
Dysfunctional uterine bleeding.
Dysfunctional uterine bleeding is defined as abnormal uterine bleeding in the absence of organic disease. It is the result of anovulation or the abnormal local production of prostaglandins, and in each case the primary fault is inappropriate hormone formation. There are two approaches to diagnosis. The traditional one is primarily concerned with the exclusion of cancer of the endometrium; this concern results in the frequent resort to uterine curettage. The second approach is to limit curettage to patients whose symptoms are not ameliorated by medical therapy. The aim of medical treatment is either to produce secretory change in the endometrium or to decrease the formation of uterine prostaglandins. Intermittent progesterone treatment is used to cause secretory changes in the endometrium. Decreased production of the prostaglandins is achieved indirectly by causing atrophy of the endometrium or directly through the use of prostaglandin synthetase inhibitors. Surgery in the form of dilatation and curettage has no long-term therapeutic effect; hysterectomy is definitive therapy.
Adult↗