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The cyclic change of human endometrial cells are controlled by the interaction between hypothalamus, pituitary gland and ovaries, thus making the endometrium proliferate, differentiate, exfoliate and then reproduce. The menstrual cycle is divided into three phases which are called follicle, ovulatory and luteal phase by the morphological change of the ovarium. The endometrial cycle is also classified to proliferative, secretory and menstrual phase. Estradiol (E2) stimulates the proliferation of endometrial cells by the indirect positive mechanism activated by the binding of E2 to E2 receptor. Growth factors (IGF- I, EGF, TGF- alpha etc.) induced by the transcription of the gene promote the proliferation of endometrial cells. Progesterone (P) has antagonistic effects on E2 actions and transform proliferative phase to secretory phase in endometrium. It is suggested that the possible mechanism of carcinogenesis of normal endometrium is the progression of endometrial hyperplasia due to the prolonged and unphysiological exposure to E2. The additional role of oncogenes (fos, fms, myc, myb, erb-B, neu) and growth factors on the mechanism of carcinogenesis of hyperplasia to cancer is very interested.

To examine the possible role of androgens in hyperplasia of the endometrium, the concentrations of testosterone (T), androstenedione (A), dehydroepiandrosterone sulfate (DHEA-S), sex hormone-binding globulin (SHBG), estradiol (E2), follicle stimulating hormone (FSH) and luteinizing hormone (LH), were measured in peripheral venous serum obtained from 42 premenopausal women with adenomatous hyperplasia of the endometrium (group A) and from 18 women without hyperplasia (group B). In patients with hyperplasia of the endometrium, significantly higher peripheral venous concentrations were found for all androgens (P less than 0.05) and estradiol (P less than 0.001) than in control patients. In contrast, there was no statistically significant difference in the mean serum values of SHBG as well as in gonadotropins among the population of compared groups. We conclude that apart from the increased estrogenic activity in patients with adenomatous hyperplasia of the endometrium, androgens may play a significant role.

The study of local blood flow in the uterus in 100 cases of uterine fibromyoma established increased blood levels of estradiol and progesteron. Blood estradiol level in the local flow of the uterus was relatively high in postmenopausal women, particularly, in those suffering uterine myoma. "Foreign" estradiol-dependent tissue substrates such as myoma and hyperplastic lesions of the endometrium were found to be responsible for potentiating local transfer and thus raising local concentration of ovarian hormones. Regulation of subovarian transfer and accumulation of hormones was shown to be to a large extent independent of levels of basic sex steroids in the general blood flow of the female body. Chronic local hyperestradiolemia in the uterus is the key factor for hyperplastic lesions development in the endometrium.

Status of the endometrium was assessed in 357 patients with hormone-producing tumors of the ovaries of major histological types such as theca cell (161 cases), granulosa cell (123) and mixed theca-granulosa cell tumors (22) as well as androblastoma (23) and Brenner's tumor (28 patients). Hyperplastic lesions of the endometrium, cancer included, were established in 250 (74.8%) patients with feminizing hormone-producing tumors whereas androblastoma patients showed either atrophic or normal endometrium (78.3% cases) and failed to reveal atypical hyperplasia or cancer of that site.

Apparent signs of hormonal activity were observed in 65.3% of patients with hormone-producing ovarian tumors of different histology. Feminization was evident in 69.1% of cases of granulosa-stromal cell tumors: it was most often seen in patients with mixed theca-granulosa cell tumors (86.2%) but was least frequent in those with Brenner's tumor (22.2%). The occurrence of proliferative lesions of the uterus such as hyperplasia of the endometrium, cervical canal polyps and uterine myoma (81.8%) was higher in patients with granulosa-stromal cell tumors, too, the highest rate being observed for cases of mixed theca-granulosa cell tumors (93.1%) whereas the lowest--for patients with Brenner's tumor (27.8%). Various clinical signs of masculinization were most often seen in cases of androblastoma (79.2%) whereas the proliferative disorders in that group were rare (12.5%). As a result, the authors placed mixed theca-granulosa cell, theca cell, granulosa cell tumors and Brenner's tumor in the order of decreasing feminizing activity. In the granulosa-stromal cell tumor subgroup, masculinization was most often observed in granulosa cell tumor patients (12.1%).

We investigated the effects of energy restriction on the pituitary-ovarian axis and on a hormone responsive gene, the mouse mammary tumor virus (MMTV). Female C3H/SHN F1-hybrid mice, known to display a high incidence of mammary tumors, ate an energy-restricted diet (48 kcal/wk) or a control diet (95 kcal/wk) beginning at the time of weaning. By 67 wk of age, 12 of 32 mice in the control group, but none of the 33 mice in the energy-restricted group, had developed mammary tumors. Six tumor-free mice from each group were studied in detail at 67 wk of age. All six tumor-free control mice, but none of the six energy-restricted mice, showed uterine endometrial hyperplasia at autopsy. Mice subjected to energy restriction did not display an estrous cycle. The average levels of MMTV mRNA in mammary glands and uteri were strongly reduced by energy restriction. MMTV mRNA levels in mammary glands from control mice were two orders of magnitude lower than those in mammary tumors. Energy restriction lowered the percentage of pituitary mammatropes and suppressed proliferation of mammatropes with advancing age. Energy restriction thus appeared to inhibit endometrial hyperplasia and to decrease MMTV production at the mRNA level in the mammary glands and in the uterus. These effects may be a consequence of hormonal changes originating at the pituitary-ovarian axis.

Of eight mongrel bitches, the antimesometrial side of the nonpregnant left horn of the uterus at the pregnant or nonpregnant luteal phase was scratched with a Kirschner's wire. Cystic endometrial hyperplasia (CEH) was induced in seven of the eight bitches (87.5%). No difference in the incidence of CEH in the left horn was seen between the pregnant and the nonpregnant groups. Histological examinations showed CEH with a dilatation of the basal glands, resembling "Swiss cheese endometrium".

Ovarian and endometrial changes in most patients with uterine myoma had a histophysiologic nature. Clinical symptoms of "rapid growth" of myoma were largely determined by degenerative changes in the tumor and the surrounding myometrium. Uterine bleedings in patients with myoma may be related to hyperplastic lesions of the ovaries and endometrium, vascular myometrial and hemodynamic endometrial disorders.

Endometrial cancer is currently the commonest pelvic malignancy affecting American women, most of whom share the same pathophysiologic basis, that is, unopposed estrogenic stimulation. The initial result of hyperestrogenism is the development of endometrial hyperplasia, which is reversible in most cases by appropriate hormonal therapy. Persistent stimulation eventually leads to atypical hyperplasia with nuclear atypia and invasive carcinoma. Because there is no cost-effective screening method for the detection of endometrial hyperplasia and carcinoma, it is essential to survey the high-risk population with appropriate diagnostic techniques. After diagnosis, therapy should be individualized based on pathologic findings (cell type and histologic grade) and extent of disease (International Federation of Gynaecologists and Obstetricians stage, depth of myometrial invasion, and pelvic and para-aortic lymph node status). Recent studies suggest that sex hormone receptors and nuclear DNA ploidy patterns provide useful prognostic information independent of histologic grade.

Costs, risks, and benefits of estrogen-progestin therapy in the menopause were compared with those for estrogen alone, using techniques of cost-effectiveness analysis. With the progestin added, reduced costs of endometrial monitoring and treatment of endometrial lesions more than offset the increased cost of the drug regimen with a net saving of $230-$430 per patient, depending on the duration of treatment. An estimated gain in life expectancy with estrogen-progestin compared to estrogen alone may be partly offset by a perceived reduction in the quality of life owing to the prolongation of menstruation in women receiving progestin. Overall, based on currently available evidence, estrogen-progestin therapy appears to be cost-effective, except in women who consider the adverse effects of continued menstruation to offset the relief of menopausal symptoms. These conclusions must be viewed as tentative, pending further clarification of the roles of estrogens and progestins in cardiovascular disease and breast cancer.

Twenty-five symptomatic postmenopausal women with an intact uterus were assigned in random double-blind fashion to receive 0.625 mg of conjugated estrogens on either a cyclic (3 weeks on, 1 week off) or continuous (daily) basis. The incidence of endometrial hyperplasia as demonstrated by screening biopsies at 6 and 12 months of therapy was 4.5 per 100 woman-months in the cyclic group and 3.7 per 100 woman-months in the continuous group (a difference not statistically significant). Thus, in this study, cyclic therapy was found to offer no advantage over continuous therapy. In our opinion, the rate of hyperplasia development in both groups unacceptably high, and efforts must be directed at reducing its incidence primarily.

A case of ureteral obstruction occurring in a postmenopausal woman treated with long-standing unopposed estrogen is reported.

To facilitate our understanding of estrogen participating in the genesis of human endometrial hyperplasia and carcinoma and the influence of the surrounding mesenchyme in their development, we assayed estrogen receptors in the epithelium and stroma of various human endometrial tissues by immunocytochemistry. The receptors were localized in fresh frozen sections using the ER-ICA kits (Abbott Laboratories, North Chicago, Illinois). The receptor content was highest in the proliferative endometrium and decreased gradually throughout the postovulatory phase of the menstrual cycle in both the epithelium and the stroma and this occurred more rapidly in the stroma. Estrogen receptor content was high in both the epithelium and the stroma of hyperplasia and was thus similar to that of the proliferative endometrium, the receptor content was low in the epithelium of endometrial intraepithelial neoplasia (hyperplasia with cytologic atypia) closely resembling that of carcinoma. In carcinomas there was a heterogenous distribution of estrogen receptors both in the epithelium and the stroma, but in general, the receptor content was low as compared with normal proliferative or hyperplastic endometrium; however, in selected cases the content of estrogen receptor in the stroma was high, despite the lack of receptors in the epithelium.

Our present knowledge of the role of sex steroids in the development as well as the prevention of endometrial cancer is reviewed. Factors which increase the exposure of the uterus to unopposed estrogens, either exogenous or endogenous, are associated with increased risk of endometrial adenocarcinoma. However, there is increasing evidence that progestogens can reverse endometrial hyperplasia and protect against the development of endometrial cancer. The mechanisms to explain the antiestrogenic effects of progestogens include changes in enzyme activity and steroid receptors in endometrial tissue. Postmenopausal women treated with combined estrogen and progestogen have the lowest incidence of endometrial carcinoma. Oral contraceptives containing both estrogen and progestogen in each tablet are protective against adenocarcinoma of the endometrium, while the sequential oral contraceptive pills afforded less protection. The risks and benefits of these hormone therapies are discussed in relation to the etiology and prevention of endometrial cancer.

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.

Serum placental lactogen (HPL) and urinary chorionic gonadotrophin (HCG) were measured in 14 patients with the endometrial Arias-Stella phenomenon and in 35 comparable patients without this reaction in order to explore a possible causative relationship between the hormonal levels and the endometrial changes. The concentrations of HPL and HCG were similar in both groups of patients, indicating a lack of correlation between the levels of these two hormones and endometrial changes.

There is an increased risk of cancer (mainly breast cancer) in patients with Cowden disease. Little is known of the etiopathogenic mechanisms of this condition, but immunologic abnormalities may be evoked. A young patient with Cowden disease was submitted for gynecologic examination and immunologic investigations. Although no neoplastic disorder had appeared, laboratory investigations disclosed abnormalities of the humoral and cellular immune compartments in the peripheral blood. This rare observation of gynecologic involvement in a very young girl with family antecedents of Cowden disease prompted a review of the gynecologic features and etiopathogenic bases of Cowden disease. The possible role of neoplasia such as breast cancer in this syndrome makes early diagnosis a criterion for good prognosis.

The authors noted an unusual finding in the fallopian tubes of a 31-year-old woman who had received external and internal whole pelvis radiotherapy for squamous cell carcinoma of the cervix. Aggregates of macrophages containing pigment, identified in a subepithelial location, were reminiscent of melanosis coli, which is caused by abuse of anthracene-containing laxatives. Electron microscopic examination of the pigment revealed cytoplasmic material with the appearance of lipofuscin, identical to the pigment described in cases of colonic melanosis. After a careful study of possible etiologic agents, it was concluded that the pigment most likely resulted from cellular damage caused by radiotherapy. The authors are not aware of any other reported case of this entity, which will be called pigmentosis tubae.

The paper discusses the incidence and peculiarities of proliferative changes in cervical and uterine mucosa of women with a record of using polyethylene intrauterine contraceptives (Lipps' loop) under 12 years. Intrauterine contraception is not conducive to a rise in the frequency of either precancer or cancer of the uterine cervix; nor is it responsible for endometrial malignancies.

To test the hypothesis that increased androgenic activity is involved in breast cancer, the urinary testosterone was assayed in 19 clinically cured breast cancer patients and in 22 patients developing metastases from breast cancer during the same period of observation (5 to 15 years after mastectomy). The levels in the clinically cured patients were near normal whereas those in patients with metastases were significantly above normal.

Development and (or) growth of myoma uteri in pre- and post-menopause is accompanied by hyperestrogenia which is shown by histological investigation of the endometrium and the ovaries. A comparative clinical and morphological study of 853 patients with myoma uteri, 996 patients with glandular, atypical hyperplasia and endometrial carcinoma was carried out. Benign tumors of the ovaries were revealed in 9.5% of patients with myoma, 12.7% of patients with atypical endometrial hyperplasia and 19.8% of patients with endometrial cancer. A significant increase of the occurrence of endometrial cancer in postmenopausal patients with myoma, in comparison with patients in the reproductive period was determined, 13.4% and 1.1% respectively, P = 0.01. In postmenopause "growth" of the tumor was more often and significantly simulated by malignant disease of the uterus and adnexa. In postmenopausal patients with myoma and uterine bleeding, endometrial carcinoma was 5.5 times more often revealed in comparison with the analogous group of patients in the reproductive period. The "relative risk" of the development of endometrial cancer, sarcoma uteri and ovarian tumors was calculated. The "relative risk" was shown to increase in the postmenopausal period. In the processes of observation of patients with myoma in postmenopause, cytological investigation of endometrial aspirates, ultrasound and mammographic screening should be carried out.

The various forms of endometrial hyperplasia are classified and a description given of their pathology and of their inter-relationships. The nosological status of endometrial adenocarcinoma in situ and the histological differentiation between hyperplasia with severe cellular atypia and endometrial adenocarcinoma are discussed. The aetiology and pathogenesis of the various endometrial hyperplasias are considered and grounds are given for the belief that glandular hyperplasia with cellular atypia is a form of intraendometrial neoplasia. A new terminology, based on the biological nature of the various endometrial abnormalities, is proposed and a plea is made for the introduction of the term 'intraendometrial neoplasia' to encompass all forms of endometrial glandular hyperplasia with cellular atypia and intraendometrial adenocarcinoma.

This investigation pursued the question of how many patients with precancerous endometrial hyperplasia were not recommended for screening programs solely because of the lack of risk factors. The median age of precancerous hyperplasia patients in Erlangen is 54, 8 years before the median age for endometrial carcinoma. Just under 10% (8.5%) of precancerous endometria occur before the age of 45. Only 18.3% of all precancerous patients do not suffer from overweight. Because age and adiposity were missing from the list of risk factors, one quarter (23.9%) of the women studied in Erlangen had not been included in a screening program. One-fifth (19.1%) of the precancerous stages in the risk patients would not be determined cytologically because nuclear criteria were either missing or deeply situated. Consequently, a minimum failure rate of 38.5% for precancerous patients must be reckoned with when using a cytological screening routine with risk patients. In the period under study, it is surprising to note that six times as many endometrial carcinoma as precancerous endometrial were treated. There is no universally suitable treatment for all precancerous patients. Certainly, an individualized, conservative form of treatment would seem to offer more hope of success than surgical therapy, which would always be aggressive.

Different methods of pregnancy termination such as curettage, prostaglandins and vacuum aspiration have been compared with respect to the subsequent reproductive function in 560 patients. The first year of the 5 year follow-up was characterized by inflammation changes. A high rate of ovarian dysfunction was found in the first post-abortion menstrual cycles. The post-abortion period is considered a high risk condition.

Mammary and endometrial status was examined in 162 female patients with benign ovarian tumors and tumor-like formations. Abnormal changes were found in the brests of 69.1% of the patients, and in the endometrium of 33%. A study of the secretory endometrium in patients with benign ovarian tumors and endometrioid cysts by means of the measurement of estradiol and progesterone receptors, demonstrated definite intracellular changes concerning the transmission of an adequate hormonal signal in endometrial cells, in which with respect to mammary hyperplasia.

Under observation were 1780 females operated upon for ovarian tumors and cysts. Special attention is given to the frequent occurrence in them of hormone-dependent hyperplastic and blastomatous processes in the uterus. These processes in the uterus were observed in 41.7% of all operated patients and in 86.2% of patients, in whom the uterus was studied morphologically.