Endometrial assessment with Isaacs cell sampler.

The value of the Isaacs endometrial cell sampler in the cytologic assessment of the endometrium was studied in 121 unanaesthetised patients aged over 40. Satisfactory aspirates for cytological diagnosis of endometrial state were obtained in 111 patients (91%) whereas endometrial specimens for histological diagnosis were obtained in only 89 patients (79%). In only four out of 83 cases were there diagnostic discrepancies between the aspirates and the curettings. It is concluded that the technique is safe, quick, comfortable, and reliable for assessing endometrial state. It should therefore prove valuable for screening, particularly in the management of menopausal women requiring oestrogen treatment.     

The Isaacs cell sampler: an alternative to curettage.

The Isaacs cell sampler was tested in 150 women (102 of them postmenopausal) referred for curettage. The results of cytological testing of material obtained with the sampler were compared with histological findings from curettage performed immediately afterwards. Satisfactory aspirates for cytological diagnoses were obtained in 141 patients and satisfactory material for histological diagnosis in 124. In the 102 postmenopausal patients the cytological method yielded 94 satisfactory specimens, while curettage yielded only 76. All the 17 carcinomas were diagnosed cytologically. Of the 12 cases of premalignant change, nine were diagnosed cytologically; two cytologically diagnosed premalignant cases did not, however, yield satisfactory material by curettage. The Isaacs cell sampler is a simple and reliable way of diagnosing malignancies. Further investigation is needed to define the cytological criteria for diagnosing premalignant cases, but as the material is well preserved accuracy should improve with increasing experience. The method should be valuable in screening women having oestrogen substitution therapy.     

An alternative to the diagnostic dilatation and curettage--endometrial cytology.

Endometrial aspiration cytology has been shown by multicentre prospective studies to be an acceptable and valuable method of assessing the endometrium. A retrospective study was undertaken over three years'' routine use of the Isaacs cell sampler. In 86% of the cases suitable endometrium was obtained, with experience of the technique being the important factor. When compared with histological findings, all 11 cases of malignancy were confirmed, including one ovarian adenocarcinoma. Of the cytological reports of endometrial hyperplasia, 78% were confirmed by the histological findings, with the remainder showing minor degrees of cystic hyperplasia or normal endometrium. In no case was a more abnormal lesion present on histological examination than had been suggested by cytological findings. The use of progestogens in reversing hyperplasia is seen to be effective, though the long term benefit remains uncertain. It is concluded that with an experienced cytologist, Isaacs endometrial aspiration should be used routinely for the primary investigation of dysfunctional uterine bleeding and postmenopausal bleeding.     

Organisation of cervical cytology screening in Croatia: past, present and future

This presentation highlights strengths and weaknesses of cervical cytology screening in Croatia, with particular reference to the opportunistic screening, the use of conventional Papanicolaou (Pap) test and the analysis of some organizational, educational and performance issues that are associated with it. Its aim is to propose measures to improve the efficacy of cervical cytology screening in order to reduce cervical cancer mortality. Currently, in excess of 450,000 Pap tests/ year are examined at 35 laboratories scattered throughout the country. All of these laboratories use standard operating procedures including internal and external quality control. They employ a total of 68 cytologists and 91 cytotechnologists. The sensitivity of cervical screening in Croatia is 90.0%, specificity 98.6%, positive predictive value 92.3%, negative predictive value 98.1% and overall diagnostic accuracy 97.2%. The high diagnostic accuracy of cervical cytology is attributed to the long-standing tradition of education and training of cytologists (postgraduate MSc course since 1967, independent residency since 1974) and cytotechnologists (since 1968). This tradition spanning more than half a century means that today in Croatia there is a developed network of cytology laboratories staffed by highly competent cytologists and trained cytotechnologists. The high accuracy of cancer detection through Pap tests provides strong evidence in support of cervical cytology screening remaining the basic method of prevention for cervical carcinoma. However, some modifications to the current situation are needed. These relate primarily to opportunistic screening. The current screening coverage rate is 68%, although there is capacity, which would allow for all women at risk, i.e. those aged 25-64, to be screened once in three years. The screening coverage relates mainly to those women visiting gynecological out patient clinics for unrelated conditions. A properly organized and controlled national screening programme should replace this. This should be accompanied by the introduction of alternative, highly sensitive methods of sample collection and preparation, such as are available through the introduction of new technologies, e.g. liquid based cytology.     

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.     

Liquid-based endometrial cytology: cyto-histological correlation in a population of 917 women

OBJECTIVE: Liquid-based cytology, because of its capacity to reduce the obscuring factors and to provide thin-layer specimens, represents an opportunity to reevaluate endometrial cytology. In order to assess the utility of the liquid-based method in endometrial diagnosis, we evaluated its accuracy in comparison with histology. METHODS: Nine hundred and seventeen women scheduled for hysteroscopy were enrolled in the study. After providing informed consent, all the women proceeded sequentially to hysteroscopy, endometrial cytology and then biopsy endometrial sampling. RESULTS: Cyto-histological correlations were possible in 519 cases (57%): in 361 (39%) cases the biopsy was inadequate, in 15 (2%) the cytology was inadequate, and in 22 (2%) both were inadequate. At biopsy 25 (3%) women had adenocarcinoma, 5 (1%) had adenomatous atypical hyperplasia and 21 (2%) had simple non atypical hyperplasia. At cytology two adenocarcinomas and one adenomatous atypical hyperplasia were underrated as atypical hyperplasias and as non-atypical hyperplasia; two simple non-atypical hyperplasias were reported as negative; and eight cases were false positive (non-atypical hyperplasia at cytology, negative at biopsy). In our population, the cytology provided sufficient material more often than biopsy (P < 0.04). Sensitivity was estimated at 96%, specificity at 98%, positive predictive value at 86% and negative predictive value at 99%. CONCLUSIONS: We concluded that endometrial cytology may be an efficient diagnostic method. It could be applied to selected patients solely or in association with ultrasonography. The combination of these two noninvasive procedures may improve their diagnostic accuracy and reduce unnecessary hysteroscopies, thereby producing benefits for women and society.     

绝经后妇女子宫内膜增厚的临床意义探讨

目的评估对绝经后经阴道超声诊断子宫内膜≥5mm的妇女病理活检的价值,减少因盲目性诊刮对老年妇女的伤害。方法对92例绝经子宫内膜增厚（≥5mm）妇女,分无症状与有症状两组进行临床与病理分析、比较。结果无症状组63例,正常绝经后内膜47例（75%）,良性病变16例（25%）,无恶性病变;有症状组29例,正常绝经后内膜15例（52%）,良性病变10例（34%）,恶性病变4例（14%）;22例激素替代治疗者中,有1例是内膜癌,并伴有阴道出血、流液症状。结论绝经后不伴出血等症状,内膜≥5mm,可免诊刮。激素替代治疗者,在停药、数次出血后,内膜〈5mm,同样可以免刮,但两者必须严密监测。     

Usefulness of endometrial aspiration cytology for the preoperative diagnosis of ovarian carcinoma

OBJECTIVE: To evaluate the usefulness of endometrial aspiration cytology for the preoperative diagnosis of ovarian carcinoma. STUDY DESIGN: A total of 210 patients with ovarian carcinoma were investigated by endometrial aspiration cytology. RESULTS: Fifty-five of 210 patients (26.2%) had positive endometrial aspiration cytology. The positive rates of endometrial cytology were 3.9% in stage I, 23.8% in stage II, 36.5% in stage III and 53.3% in stage IV. When classified by histologic type, the positive rates of endometrial cytology in patients with serous adenocarcinoma, mucinous adenocarcinoma, clear cell adenocarcinoma, undifferentiated carcinoma and yolk sac tumor were 38.9%, 11.8%, 21.1%, 16.7% and 16.7%, respectively. One hundred twenty-eight of 210 patients (61.0%) were positive on peritoneal cytology, and 54 of these 128 cases (42.2%) were also positive on endometrial cytology. The positive rates of endometrial cytology were especially high in patients with serous adenocarcinoma (51.2%) and those with clear cell adenocarcinoma (40.0%) among those who were positive on peritoneal cytology. Of 74 patients who were negative on peritoneal cytology, only one (1.4%) with mucinous adenocarcinoma had positive endometrial cytology. Hysterectomy was performed on 130 patients, and the positive rate of endometrial cytology was 100% in 4 patients with endometrial invasion and 15.9% in 126 cases without invasion. CONCLUSION: Endometrial aspiration cytology can detect ovarian carcinoma cells not only in patients with endometrial involvement but also in patients with positive peritoneal cytology. Endometrial aspiration cytology appears to be useful for the preoperative diagnosis of ovarian carcinoma.     

Increasing diagnostic accuracy with a cell block preparation from thin-layer endometrial cytology: a feasibility study

OBJECTIVE: To investigate (1) the feasibility of preparing cell blocks by inverted filter sedimentation (IFS-CB) from endometrial samplings processed by the ThinPrep (TP) technique (Cytyc Corp., Boxborough, Massachusetts, U.S.A.), and (2) the possibility of increasing the diagnostic accuracy of TP endometrial cytology by examining the tissue architecture as an adjunctive method of detecting endometrial lesions. STUDY DESIGN: Three hundred one endometrial samplings were obtained, using the Endogyn endometrial device (Biogyn S. n.c., Italy), from perimenopausal and postmenopausal women. The endometrial samplings were collected in a vial with liquid fixative for the TP processing. One TP slide was prepared from each case. If adequate material remained in the vial after the TP slide preparation, it was processed for IFS-CB preparation. RESULTS: IFS-CB preparation was processed in 263 cases (87%) with adequate material. Diagnoses on IFS-CB preparations obtained by endometrial sampling matched those of the hysterectomy specimens. The addition of IFS-CB histology to the cytologic diagnosis by TP increased the diagnostic accuracy of endometrial cytology to 96.3% and 100% for benign/atrophic endometrium and adenocarcinoma, respectively (p = 0.39 and 0.46). In hyperplasia without atypia and hyperplasia with atypia, the diagnostic accuracy increased significantly, to 96% and 95.3%, respectively (p = 0.037 and < 0.001). CONCLUSION: This study illustrates the merit of linking TP cytology with direct endometrial sampling, including small tissue fragments and material adequate for IFS-CB preparation. TP cytology provides an accurate cytologic diagnosis and the possibility of IFS-CB preparation, which could be a valuable diagnostic adjunct to TP cytology.     

O-9Uncommon subtypes of borderline nuclear changes: cytological features and predictive value

Introduction:  To establish the significance of cytological features which could predict clinically significant endometrial pathology, and therefore guide reporting practice in cervical samples.
Methods:  A retrospective review of SurePath liquid-based cytology (LBC) cervical samples between 2002 and 2006, obtained at screening and colposcopy. These smears contained normal endometrial cells present at inappropriate times of the menstrual cycle, endometrial cells with atypia (borderline change) and with features suspicious / diagnostic of endometrial carcinoma (glandular neoplasia). False negative and false positive cases detected on subsequent histology were also included. The control group comprised negative samples and a few abnormal smears. All smears were randomly assigned and blinded to menopausal status, age, use of oral contraceptive pill and hormone replacement therapy and presence of intrauterine device. Each smear was reviewed for 16 cytologic criteria and a cytological diagnosis was given for each.
Results:  A total of 219 smears were available for review; 137 were negative, out of which 85 contained normal endometrial cells, 41 contained endometrial cells with atypia, 10 contained endometrial cells with features suggestive of adenocarcinoma and 31 contained endometrial cells with features diagnostic of adenocarcinoma. The feature most associated with benign endometrial cells is top hat with central cell condensation. In contrast, the features associated with malignant endometrial cells are smooth nuclear membrane, pale chromatin, small nucleoli and scalloped borders.
Discussion:  The criteria identified in this study do not definitively define a neoplastic process, but appear to be helpful in individual cases. This study emphasises that endometrial changes should be always interpreted with the relevant clinical information, which would otherwise lead to overdiagnosis in premenopausal women.     

Cytodiagnosis of endometrial malignant mixed mesodermal tumor

The accuracy of endometrial aspiration smears obtained with the Isaacs cell sampler in the diagnosis of malignant mixed mesodermal tumors (MMMT) was compared to the results obtained with routine cervical and vaginal smears in five cases of MMMT found in a series of 220 endometrial aspirations. Cervical and vaginal smears previously taken on these patients were positive for adenocarcinoma or MMMT in two cases and suspicious for adenocarcinoma in the remaining three cases. Endometrial aspirates were positive for MMMT in three cases and positive for adenocarcinoma or MMMT in two cases. The endometrial aspiration smears contained a variety of cells: malignant glandular, squamous, spindly stromal, undifferentiated, osteoid and tumor giant cells; chondrocytes and free psammoma bodies were also observed. These cases indicated that endometrial aspiration can accurately detect the heterologous cellular elements found in MMMT and is an effective technique in its diagnosis.     

O-10THE ACCURACY OF CERVICAL CYTOLOGY: A COMPARISON BETWEEN THE THINPREP IMAGING SYSTEM AND CONVENTIONAL METHODS

Douglass Hanly Moir is a large Australian laboratory which has recently introduced the ThinPrep Imaging System (TPI) for reading ThinPrep slides, which is still performed using a split-sample technique. The Imager is a computerized system which identifies 22 fields for the cytologist to review using automated light microscopy. We compared the accuracy of TPI and conventional cytology (CC) during normal laboratory operation. The ThinPrep sample was prepared after taking a conventional Pap smear. TPI and CC reading was done without knowledge of the result of the other reading. The final cytology report issued to the referring doctor reflected the more severe of these two results. Histology results for all cases in which TPI and CC cytology results showed more than minimal disagreement were sought from the NSW Pap Test Register. Of 55 164 split sample pairs, 3.1% of CC of slides and 1.8% of TPI slides were unsatisfactory. There were 1758 women for whom there was more than minimal discrepancy between TPI and CC cytology results. TPI gave the more severe result in 1193 of the 1758 cases. In cases where only one of each pair of discrepant cytology results was CIN1 or higher grade, TPI detected 133 cases of high-grade histology among 380 biopsies (35%), whereas CC detected 62 cases among 210 biopsies (29.5%). A repeat analysis based on reading of histology by one pathologist blinded to initial Pap smear result showed a similar result. Reading times were measured over 5 months for both TPI and CC for twenty cytologists who read both types of smears. On average, they read 13.3 TPI slides per hour and 6.1 CC slides per hour. This study provides evidence that cervical cytology read using the TPI detects more histological high-grade disease than does CC. Further evidence shows that reading times are significantly reduced for cytologists using the TPI.     

Significance of cytologically normal endometrial cells in cervical smears from postmenopausal women

OBJECTIVE: To determine the significance of cytologically normal endometrial cells in cervicovaginal (CV) smears from postmenopausal women over age 55 years. STUDY DESIGN: From January 1995 to January 1998, 220 women had CV smears demonstrating cytologically normal endometrial cells. The menopausal status, hormone replacement therapy (HRT) and information related to subsequent CV smears and endometrial sampling within 12 months of the initial diagnosis was recorded. RESULTS: Eighty-one of the 220 cases (36.8%) had histologic sampling of the endometrium. Thirty-four of 81 (42%) showed no endometrial pathology. Endometrial pathology was identified in 28 of 81 (34%), of which 19 were endometrial polyps (23.4%), 4 were endometrial hyperplasia (4.9%), 4 were endometrial carcinoma (4.9%) and 1 was a leiomyoma (1.2%). Nineteen (23.4%) were insufficient for diagnosis. Ninety-one of 220 women were on HRT, and 129 were not. In the group without HRT, endometrial disease was identified in 22/51 (43%) cases as compared to 6/30 (20%) in the group with HRT (P < .001). Endometrial carcinoma was identified in three (5.8%) cases and one (3.3%) case without and with HRT, respectively. CONCLUSION: Although the finding of normal endometrial cells in Pap smears from postmenopausal women was without any clinical significance in the majority of women in this study, in a small number it was associated with endometrial hyperplasia and carcinoma. Women who were not on HRT had a higher incidence of endometrial pathology.     

Cytologic diagnosis of laryngeal and hypopharyngeal squamous cell carcinoma in sputum

A prospective study of the value of sputum cytology in the diagnosis of squamous cell carcinoma of the larynx and hypopharynx is reported. Sputum cytology established the diagnosis in 63.5% of the patients with laryngeal lesions and in 77.4% of the patients with hypopharyngeal lesions. In laryngeal cancer, a positive diagnosis by sputum cytology was related to clinical T factors (according to the TNM classification): while only 29.4% of T1 lesions were positively detected by sputum cytology, 63.3% of T2 lesions, 69.7% of T3 lesions and 79.2% of T4 lesions were so detected. In hypopharyngeal cancer, there was no discernible relationship between sputum cytodiagnosis and clinical T factors. Generally, there was only a small number of cancer cells present in the sputum in these cases. Some of the squamous cancer cells were not very conspicuous and would require careful screening of the sputum specimens to be detected.     

Endocyte endometrial smears in the cytodiagnosis of endometrial carcinoma

The cytologic diagnosis of endometrial cancer using material obtained with the Endocyte endometrial sampler was assessed for 874 patients. The samples obtained were smeared directly on slides for fixation and staining; the smears were more difficult to assess than cervicovaginal smears, however, due to the presence of blood, the small size and density of the cells and the flattened three-dimensional architecture of the tissue fragments obtained. Only 8.2% of the samples were classified as inadequate; repeat sampling in some of those cases produced diagnostic material. All 12 cases of carcinoma (including one case in a woman less than 40 years of age) were diagnosed by cytology as malignant; however, the original cytologic sample in one of those cases was inadequate. For the diagnosis of benign versus malignant, cytology had a sensitivity of 92%, a specificity of 100% and predictive value of 100%. Cytology also diagnosed as suspicious the smears from 5 of 13 cases of endometrial hyperplasia and 2 of the 9 cases of endometrial polyps. The cytologic findings for benign and malignant samples are described and illustrated in detail. Relative to other endometrial sampling devices, the Endocyte is inexpensive and was easily used by the gynecologist and well tolerated by the patients, with no complications and minimal discomfort.     

Comparative study of cytology and punch biopsy in cervical intraepithelial neoplasia during pregnancy. A preliminary report

To elucidate the accuracy of cytology in diagnosing cervical intraepithelial neoplasia (CIN) during pregnancy, cytologic screenings for uterine cervical cancer in pregnant women were reviewed for a five-year period. Of the 967 pregnant women screened, abnormal cytologic findings were recorded for 15 (1.6%). Only nine of these were subsequently examined by colposcopy and punch biopsy, which demonstrated CIN in all cases, for an incidence of documented CIN during pregnancy of 0.93%. Including two referral cases also examined by colposcopy and biopsy, cytology and histology agreed on the degree of CIN in four cases and disagreed by one degree in four cases, by two degrees in two cases and by three degrees (mild dysplasia versus carcinoma in situ) in one case. Review of the specimens from these cases did not readily explain the poor concordance between cytology and punch biopsy; some findings suggest that overestimation of the punch biopsy sample may be the explanation.     

Editor's preface

BACKGROUND: The decisions that postmenopausal women make about whether to start hormone replacement therapy may depend on the potential risks and benefits of such therapy as well as their risk for osteoporosis-related fractures. This study examined the decisions made by women at risk for osteoporosis-related fractures who were educated about hormone replacement therapy and who were given information about their bone mineral density. METHODS: The study employed a prospective cohort design. Thirty-seven post--menopausal women with risk factors for osteoporosis-related fractures were recruited from an orthopedic clinic at a teaching hospital in Hamilton, Ont. The women were given an education kit (consisting of an audio tape and a work-book) to clarify the benefits and risks of hormone replacement therapy. Two to 4 weeks later, densitometry of the hip and the lumbar spine was performed. A summary of the risks, the densitometry findings and decisions about hormone replacement therapy were given to the women''s family physicians for follow-up. Outcome measures included decisions about hormone replacement therapy, as well as use of such therapy and other medications at 12 months. RESULTS: After the education component alone, 10 (27%) of the women requested hormone replacement therapy. After densitometry testing, 4 more requested hormone replacement therapy (for a total of 14 women [38%]). At 12 months, 2 (5%) of the women had been lost to follow-up. Of the remaining 35, 6 (17%) were receiving hormone replacement therapy, 7 (20%) were using bisphosphonates, and 24 (68%) were taking calcium supplements. INTERPRETATION: These preliminary findings suggest that the combination of education about hormone therapy and feedback about bone density is associated with an increase in the use of hormone replacement therapy and other preventive medications by women at risk for osteoporosis-related fractures. However, the observed increase was small and so the clinical significance must be confirmed and clarified.     

Endometrial hyperplasia with berrylike squamous metaplasia and pilomatrixomalike shadow cells. Report of an intriguing cytohistologic case

BACKGROUND: The usefulness of endometrial cytology as a diagnostic method in asymptomatic women, especially in postmenopause, in the interpretation of composite pictures characterized by borderline features between atypical hyperplasia and well-differentiated adenocarcinoma, especially if associated metaplastic features are present, is somewhat controversial. CASE: An asymptomatic, 50-year-old, postmenopausal woman underwent a Pap smear and endometrial cytology for routine screening, disclosing three-dimensional, sometimes pseudopapillary groupings of hyperplastic endometrial glandular cells with focal atypia in direct continuity with large, squamoid cells of the keratinizing type and shadow cells. Histologic examination of endometrial tissue was advised, and two subsequent endometrial biopsies and hysteroscopic ablation were performed. The borderline character of the lesion (complex atypical hyperplasia vs. well-differentiated adenocarcinoma) with concomitant squamous metaplasia and pilomatrixomalike shadow cells prevented diagnostic agreement between several pathologists. CONCLUSION: Diagnostic cytology with direct endometrial sampling represents a valuable diagnostic screening tool for the differential diagnosis between normal and pathologic endometrium, a mucosal picture that deserves a subsequent (histologic) diagnostic procedure. In a few cases, as in the one presented above, even histologic examination, especially of so-called borderline lesions, reveals squamous or other types of metaplasia that can lead to interobserver discrepancies.     

Hormonal modulation of interleukin-6, tumor necrosis factor and associated receptor secretion in postmenopausal women

Hormone replacement therapy (HRT) reduces the risk for osteoporosis but transiently increases cardiovascular risk for some postmenopausal women. This study investigated the hypothesis that these risks are associated with HRT-induced changes in mononuclear cell secretion of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and associated soluble receptors. Compared to the untreated condition (n=8), estrogen therapy (n=7) and estrogen+progestin therapy (n=7) both caused 2-fold elevations in TNF-alpha secretion. IL-6 secretion was increased (48%, P=0.04) only by estrogen+progestin therapy. Although soluble receptor secretion was not different among groups, soluble TNF receptor type I and IL-6 receptor secretion were inversely related to plasma follicle stimulating hormone (P<0.05). Both therapies reduced plasma osteocalcin (a marker for osteoporosis) by approximately 50% (P<0.002). Plasma C-reactive protein (CRP, a marker for cardiovascular risk) was 3-fold higher in women receiving only estrogen, compared to untreated women (P=0.01), and twice as high as those receiving estrogen+ progestin (P=0.045). Simple linear relationships were not observed between cytokine secretion and these markers, but a significant HRT/TNF-alpha interaction with osteocalcin (P=0.022) and an HRT/IL-6 interaction with CRP (P =0.016) indicated more complex relationships between hormone replacement, cytokine activity, and health risks associated with menopause.