Diagnostic accuracy of liquid‐based endometrial cytology in the evaluation of endometrial pathology in postmenopausal women

C. Remondi, F. Sesti, E. Bonanno, A. Pietropolli and E. Piccione
Diagnostic accuracy of liquid‐based endometrial cytology cytology in the evaluation of endometrial pathology in postmenopausal women Objective: The aim of this study was to compare liquid‐based endometrial cytology with hysteroscopy and endometrial biopsy regarding its diagnostic accuracy in a series of postmenopausal women with abnormal uterine bleeding (AUB) or asymptomatic women with thickened endometrium assessed by transvaginal ultrasound as a screening procedure. Methods: Inclusion criteria were: menopausal status; the presence of AUB and/or thickened endometrium assessed by ultrasound (cut‐off 4 mm); a normal Papanicolaou (Pap) smear; and no adnexal pathology at ultrasound. Exclusion criteria were: previous endometrial pathology; and previous operative hysteroscopy. Of 768 postmenopausal women referred to our general gynaecology clinics, 121 fulfilled the inclusion criteria and were recruited to the trial. Twenty‐one refused to participate. Cytological sampling was carried out by brushing the uterine cavity using the Endoflower device with no cervical dilation and the vial was processed using a ThinPrep® 2000 automated slide processor. The slides were stained using a Pap method. Results: In 98 cases with histological biopsies, endometrial cytology detected five cases of endometrial carcinoma, 10 of atypical hyperplasia and 47 of non‐atypical hyperplasia; 36 cases were negative. In two cases cytology was inadequate because of uterine cervical stenosis. Taking atypical hyperplasia or worse as a positive test and outcome, the diagnostic accuracy of the endometrial cytology was 93.5%, with a sensitivity of 92% and specificity of 95%, a positive predictive value of 73% and a negative predictive value of 99%. All the carcinomas were detected by cytology. Only 42% of women with a positive diagnosis were symptomatic. The cytological sampling was well tolerated by all patients. No complication was registered. Conclusions: Liquid‐based endometrial cytology can be considered an useful diagnostic method in the detection of endometrial pathology as a first‐line approach, particularly if associated with transvaginal ultrasound.     

Factors controlling epidermal growth factor (EGF) gene expression in the endometrium of the mare

Previous studies showed a dramatic increase in EGF gene expression in the endometrial glands of pregnant mares around day 40 after ovulation. To investigate how the steroid hormones of pregnancy might regulate this expression, in situ hybridization was used to monitor the levels of EGF mRNA in endometrial biopsies obtained from seasonally anoestrous or ovariectomised mares given exogenous progesterone and oestrogen, alone or in combination, for up to 46 days. Biopsies were also taken from mares during the non‐pregnant cycle, during normal pregnancies and pregnancies compromised by endometrial pathology (endometrosis) or because of incompatible extraspecific embryo transfers (donkey‐in‐horse pregnancies). Only a few samples showed weak EGF expression during the late luteal phase of the oestrous cycle. During normal pregnancy, the previously observed dramatic increase of expression after day 40 of gestation was confirmed. Although aged mares suffering from endometrosis and mares carrying an extraspecific donkey conceptus showed the same increase of EGF mRNA in normal glands, this was virtually absent from gland cross‐sections compromised due to inflammatory or fibrotic changes. Administration of various doses and combinations of progesterone and oestrogen for <35 days yielded negative or only weakly positive hybridization results, whereas progesterone alone for ≥40 days upregulated EGF expression strongly irrespective of additional treatment with oestrogen. This is the first experimental evidence that EGF expression in the endometrium can be induced by progesterone alone. The requirement for prolonged progesterone priming is of considerable interest in the context of the unusually late stage of gestation at which placental attachment commences in equids. Mol. Reprod. Dev. 53:255–265, 1999. © 1999 Wiley‐Liss, Inc.     

Reporting endometrial cells in Papanicolaou smears of women age 40 and older: a qualifying educational note could prevent unnecessary follow-up biopsy

OBJECTIVE: To determine the impact of adding a qualifying educational note when exfoliated endometrial cells were present in the first half of the menstrual cycle. STUDY DESIGN: We identified all Pap smears that had endometrial cells in women > or = 40 years, between July and November, 2004. When endometrial cells were seen in the first half of menstrual cycle, it was stated that, "endometrial cells correlate with the menstrual history provided." We then attempted to determine if this qualifying comment had an impact on the decision to obtain a follow-up endometrial biopsy. RESULTS: A total of 325 women were identified. Of these, 51 (15.7%) had follow-up endometrial biopsy without clinical evidence of endometrial pathology, compared to a rate of 36.9% before implementation of the note (p < 0.0001). Biopsies were performed in 21 of 195 (10.8%) when the note indicated that endometrial cells correlated with menstrual history, compared to 30 of 130 (23%) in whom a different note was appended because endometrial cells were out of phase or patients were postmenopausal (p = 0.0032). Biopsies did not reveal significant endometrial pathology in any of the 51 patients. CONCLUSION: Adding an educational note when endometrial cells are reported in the first half of the menstrual cycle in women > or = 40 years may help reduce unnecessary biopsies.     

Ethinylestradiol administered by oral and sublingual routes: a comparative study in ovariectomized women

Eight ovariectomized women with an intact uterus received 12.5 micrograms ethinylestradiol for 14 days, in a cross over fashion. Ethinylestradiol was administered as a paper disc for sublingual application or as a tablet for oral administration. The parameters studied were FSH secretion, plasma protein synthesis, endometrial morphology, cervical mucus properties and the karyopyknotic index. Both types of treatment resulted in estrogenic effects with a more pronounced effect on sperm penetration and the Spinnbarkeit test after paper disc treatment than after conventional tablet treatment. The post-treatment FSH concentration 20 h after ethinylestradiol administration was significantly lower than the pretreatment value only in the case of the paper disc treatment. There was no evidence of any difference in effects on protein synthesis. The results indicate that the availability of ethinylestradiol for peripheral tissues may be increased by sublingual administration compared to oral tablet administration, whereas the effects on liver protein synthesis may remain unchanged.     

Acceptability of an oral contraceptive that reduces the frequency of menstruation: the tri-cycle pill regimen.

The frequency of menstruation was reduced to once every three months in 196 women by the continuous administration of the oral contraceptive pill, Minilyn, for 84 days (tri-cycle regimen). No pregnancies occurred. One hundred and sixty-one women (82%) welcomed the reduction in the number of periods with the associated freedom from menstrual and premenstrual symptoms, and many found the tri-cycle regimen easier to follow. Weight gain of more than 2 kg, irregular cycle control, especially in the first three months, breast tenderness, and headaches were the main side effects. Menstrual loss was unchanged or reduced in all but seven women. The doctors and nurses on the clinic staff were less enthusiastic about this regimen than the volunteers themselves.     

Increased risk of recurrence of pregnancies complicated by fetal neural tube defects in mothers receiving poor diets,and possible benefit of dietary counselling.

One hundred and seventy-four women who had previously had a child with a neural-tube defect were assessed retrospectively on the quality of their diets during the first trimester of that pregnancy, between pregnancies, and during the first trimester of other pregnancies. They were then studied prospectively during the first trimester of 186 following pregnancies and the outcome of these was recorded. One hundred and three women (with 109 pregnancies) were given dietary counselling before the pregnancy, the remaining 71 (with 77 pregnancies) not being counselled. Seventy-eight (72%) of the counselled women improved their diet compared with only nine (12%) of the uncounselled women. The difference was significant (p < 0.001). There were three recurrences of neural-tube defects in the counselled women (3%) and five recurrences in the uncounselled (7%). Although this difference was not significant, the relative risk in the counselled group was reduced to less than half of that in the uncounselled group. All eight recurrences occurred in the 45 pregnancies in women taking poor diets (18%), whereas there were no recurrences in the 141 other pregnancies. This difference is significant (p < 0.001). It is concluded that women receiving adequate diets have a lower incidence and recurrence of fetal neural-tube defects than women receiving poor diets and that dietary counselling may be effective in reducing the incidence of fetal neural-tube defects.     

Lessons from an audit of unplanned pregnancies.

To determine the effectiveness of contraceptive use a two year audit of pregnant women registered in one group practice was carried out. The methods of contraception used by women with unplanned pregnancies were studied and the rates of failure assessed. Of the 518 pregnancies during the study, 187 (36%) were unplanned. Unplanned pregnancies were most common in the 15-19 age group (54 out of 187), and women aged under 25 used contraceptives less reliably than women aged 25 and over. The combined pill was the most effective method of contraception in all age groups. The methods that resulted in most unplanned pregnancies were the sheath in women aged 25 and over and incorrect use of oral contraceptive or no contraception in those aged under 25. The fear of side effects was an important reason why women did not use the combined pill, being cited by 22 out of 134 women, and inappropriate medical advice was cited by a further 20 women. More discussion between doctors and patients and readily available information on the use of oral contraceptives might help to reduce the number of unplanned pregnancies.     

Effect of quinestrol-chlormadinone acetate on the endometrium, cervix uteri and vaginal epithelium

The effects of a combination of 4 or 5 mg quinestrol and 10 mg chlormadinone acetate on the female genitalia were studied in 15 women on the 14th, 21st, and 28th days of the cycle. The cervicotropic effect of quinestrol was stronger (studied by cervical mucus, Fern test, and opening of the os uteri) than its endometrial effect. Hormone withdrawal bleeding occurred overwhelmingly from proliferated endometrium. The chlormadinone acetate dose of 10 mg was sufficient to provoke an endometrial secretion in only 4 cases. Cervical, vaginal, and endometrial findings were functionally consistent.     

Ovulation Inhibitors

One hundred and eighty-five women were followed up for periods up to 15 months (a total of 964 menstrual cycles) to determine the contraceptive efficacy and side effects of 2 mg. norethindrone with 0.1 mg. mestranol, as well as other therapeutic benefits. No pregnancies occurred in those using this method alone for contraception. Side effects were minimal. This low dosage was also useful in the management of dysmenorrhea, menorrhagia and irregular menses.     

Evaluation of BCL6 and SIRT1 as Non-Invasive Diagnostic Markers of Endometriosis

(1) Background: Endometriosis is characterized by the presence of endometrial glands and stroma outside of the uterus and is often associated with severe pelvic pain and infertility. Our study explored the utilization of B-Cell Lymphoma 6 (BCL6) and Sirtuin 1 (SIRT1) as potential biomarkers in serum, plasma, urine, and cervical mucus for a non-invasive diagnostic test for endometriosis. BCL6 was chosen based on its previously reported elevated expression in endometrial biopsies, and SIRT1 is co-expressed and upregulated in the endometrium of women with endometriosis. (2) Methods: BCL6 and SIRT1 levels were measured using enzyme-linked immunoassay (ELISA) in samples from 20 women with endometriosis (ten with stages I/II and ten with stages III/IV) and ten women without endometriosis. (3) Results: Levels of SIRT1 in sera showed a statistically significant elevation in advanced stages III/IV compared to controls and stages I/II. No significant differences were found in other bodily fluids for SIRT1 or any bodily fluids tested for BCL6. (4) Conclusions: These results suggest some potential of SIRT1 expression within serum as a predictor of advanced asymptomatic stages of endometriosis. Using immunohistochemistry (IHC) staining and H-SCORE values for the elevated BCL6 (and potentially SIRT1) levels in endometrial biopsy samples seems to have higher diagnostic potential based on the previously published studies.     

Menstrual blood as a potential source of endometrial derived CD3+ T cells

Studies of T cell-mediated immunity in the human female genital tract have been problematic due to difficulties associated with the collection of mucosal samples. Consequently, most studies rely on biopsies from the lower female genital tract or remnant tissue from hysterectomies. Availability of samples from healthy women is limited, as most studies are carried out in women with underlying pathologies. Menstruation is the cyclical sloughing off of endometrial tissue, and thus it should be a source of endometrial cells without the need for a biopsy. We isolated and phenotyped T cells from menstrual and peripheral blood and from endometrial biopsy-derived tissue from healthy women to determine the types of T cells present in this compartment. Our data demonstrated that T cells isolated from menstrual blood are a heterogeneous population of cells with markers reminiscent of blood and mucosal cells as well as unique phenotypes not represented in either compartment. T cells isolated from menstrual blood expressed increased levels of HLA-DR, αEβ7 and CXCR4 and reduced levels of CD62L relative to peripheral blood. Menstrual blood CD4+ T cells were enriched for cells expressing both CCR7 and CD45RA, markers identifying naïve T cells and were functional as determined by antigen-specific intracellular cytokine production assays. These data may open new avenues of investigation for cell mediated immune studies involving the female reproductive tract without the need for biopsies.     

Use of a new steroid (Org OD 14) in the climacteric syndrome

A double-blind study was carried out in 60 women with climacteric symptoms: 30 women were given Org OD 14 (2.5 mg) and 30 were given a placebo to be taken daily for six weeks. The effects of the medication on the climacteric symptoms, the subjective sensations, the plasma FSH levels and endometrial histology were studied. In the treated group compared with the control group the relief or improvement of the following climacteric symptoms were recorded: perspiration, palpitations, irritability and backache. A favourable effect on the subjective sensations was noted in both groups, although no significant difference for the group which received Org OD 14 was found. At the end of the treatment with Org OD 14, the FSH levels were found to be greatly reduced in comparison with the basal values; this, however, was not the case with the placebo group. With regard to endometrial histology, no sign of hyperplasia was found in any of the patients. No relevant side effects or symptoms of estrogenic or androgenic stimulation were recorded. For the climacteric patient needing estrogen therapy, it can be concluded that Org OD 14 is an effective and innocuous medication in the doses used.     

Risk of breast cancer in women with history of benign disease of the breast.

A consecutive series of 791 women who had attended diagnostic breast clinics during 1967-70 and been found to be free of malignant disease were later traced to determine their subsequent incidence of breast cancer. Of the 770 (97%) successfully traced, 22 had developed breast cancer. Based on data from the Welsh Cancer Registry only eight cases of breast cancer had been expected, so that the excess risk for the group was 2.7. The increased risk occurred in all age groups and in women deemed "essentially normal" as well as in those who had had a pathological abnormality. The risk was increased when epithelial hyperplasia was present. No excess mortality from breast cancer was apparent, but follow up was short. More breast symptoms were experienced and more biopsies performed than expected in this group of women. Women with a past history of benign breast disease have a slightly increased risk of breast cancer. Selective screening of these women, however, may be uneconomic and a cause of groundless anxiety.     

Urinary Estriol Estimations in Normal and Abnormal Pregnancies

Urinary estriol estimations from 24-hour urine specimens were studied in 65 women in the course of normal pregnancies and compared to 18 analyses in women in whom fetal death had occurred. There is a significant difference in the levels of estriol excretion between these two categories. Serial studies were carried out on patients whose pregnancies ended in normal delivery and in patients whose pregnancies were complicated by eclampsia and by hypertension of various degrees of severity. A definite correlation between urinary estriol excretion and the health of the fetus in utero was found. The information that these estimations provide can be of assistance to the clinician in the management of selected patients where the fetus is in danger prior to delivery.     

Decrease in serum prolactin during bromocriptine-induced pregnancy and subsequent restoration of reproductive function in some hyperprolactinemic women

Twenty-two women with hyperprolactinemia and amenorrhea were followed up for at least 18 months after 22 bromocriptine-induced full term pregnancies. Return of menstruation occurred in 9 of the 22 patients after pregnancy. Five of them conceived subsequently without any treatment. The prolactin (PRL) concentration before or during bromocriptine treatment was not significantly different between the patients who conceived spontaneously and those who did not. However, the PRL concentration after weaning was significantly lower in the patients who conceived spontaneously than in those who did not. Serum PRL levels were normal or only slightly elevated in the patients who conceived spontaneously. In 11 of the 22 patients, PRL levels were serially determined during bromocriptine-induced pregnancies. In 7 of the 11 patients, serum PRL levels fell during the second or third trimester. Spontaneous pregnancy occurred in 3 of the 7 patients who showed a decrease in PRL values during pregnancy, but in none of the 4 patients who did not. Furthermore, PRL levels after weaning correlated with PRL levels during the third trimester in these 11 women. Consequently, a decrease in PRL values during pregnancy may result in a fall in PRL levels after pregnancy, which in turn leads to the restoration of reproductive function in some subjects.     

Chromosomal abnormalities in the Kaiser-Permanente Birth Defects Study, with special reference to contraceptive use around the time of conception

Chromosomal abnormalities were studied in 33,551 abortions and births to women whose contraceptive histories had been recorded at their first antenatal visit in 1975-1977. Chromosome examinations were performed exclusively on clinical grounds. There were 45 de novo abnormalities detected (1.34/1,000); three of them were detected at amniocentesis. Trisomy 21 was observed in 27 cases (0.80/1,000), trisomy 18 in nine (0.27), other trisomies in three (0.09), and translocations or deletions in five (0.15). One case of triploidy and six cases of inherited abnormalities were detected. There were no significant racial variations. No increase in risk for chromosomal abnormalities was found among women who had used oral contraceptives prior to becoming pregnant or among women who experienced oral contraceptive breakthrough pregnancies. Two cases of trisomy 18 were observed among the 814 deliveries following oral contraceptive breakthrough conceptions (2.46/1,000), two cases of trisomy 21 occurred in 338 births following failures of rhythm contraception (5.92/1,000), and no cases of trisomy 21 or 18 among the 1,569 women using spermicides at the time of conception.     

Management of pregnancy in patients with hypertrophic cardiomyopathy.

The outcome of 54 pregnancies in 23 patients with hypertrophic cardiomyopathy was analysed. No mother or infant died in the perinatal period. Six patients developed dyspnoea requiring treatment with diuretics. Beta-adrenergic blocking drugs were given in 18 pregnancies and three of the infants in this were small for dates and in two fetal bradycardia occurred. The results comfirmed that pregnancy is safe in patients with hypertrophic cardiomyopathy. A flexible approach should be adopted towards administering beta-adrenergic blocking drugs to pregnant women with hypertrophic cardiomyopathy. Many such patients do well without these drugs and can thus avoid the potential hazards--namely, small-for-dates babies and fetal bradycardia--that are associated with them.