Relationship of serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate to the risk of developing postmenopausal breast cancer.

Dehydroepiandrosterone and dehydroepiandrosterone sulfate are endogenous steroids that are produced in the adrenal cortex. A number of studies have suggested that circulating levels of these hormones are related in some way to the risk of developing breast cancer. We measured serum levels of these steroids in 30 postmenopausal women who donated blood in 1974 for a community-based serum bank and who subsequently, at least 9 years later, developed breast cancer and in 59 matched controls from the same group of volunteers. Significantly elevated serum levels of dehydroepiandrosterone were found among cases prior to diagnosis compared to controls; serum levels of dehydroepiandrosterone sulfate were slightly increased among cases. In controls, current cigarette use was associated with increased serum levels of these steroids, and levels of both steroids decreased with age.

Relationship of prediagnostic serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate to the risk of developing premenopausal breast cancer.

Dehydroepiandrosterone and dehydroepiandrosterone sulfate are steroids which may be associated with the development of breast cancer. To examine the association between serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate and the risk of developing premenopausal breast cancer, we measured hormone levels in 15 women who donated blood to a community-based serum bank in 1974 and who subsequently developed premenopausal breast cancer and in 29 matched controls from the same group of volunteers. The mean serum level of dehydroepiandrosterone among cases was 10% lower than among controls. The risk of developing breast cancer for women in the highest tertile compared with the lowest tertile of serum dehydroepiandrosterone was 0.40 with a suggestion of a dose-response trend with increasing levels. No consistent association between dehydroepiandrosterone sulfate and the risk of premenopausal breast cancer was evident. In contrast to postmenopausal breast cancer, a protective effect of dehydroepiandrosterone against premenopausal breast cancer is suggested, but because of the small sample size, the results of this study need to be replicated by others.

In vitro and in vivo inhibition of glioblastoma and neuroblastoma with MDL101731, a novel ribonucleoside diphosphate reductase inhibitor.

We examined the effects of MDL101731, a novel ribonucleoside reductase inhibitor, against human glioblastomas and neuroblastoma, both in vitro and in xenograft models, to determine its activity against malignant brain tumors. MDL101731 produced a concentration-dependent inhibition of both glioblastoma cell lines (HS683 and J889H) and neuroblastoma (SK-N-MC) in nanomolar concentrations (IC50, 30-90 nM). s.c. xenografts of human glioblastoma (D54) in athymic mice increased to five times their initial volume at a median of 7.4 days in control animals, while tumor regression occurred in 12 of 12 animals treated with MDL101731 (100 mg/kg, i.p., two times/week) during 22 days of treatment (P < 0.0001). Intracerebral implants of D54 carried a median survival of 20 days in control animals, whereas animals receiving MDL101731 (100 mg/kg, i.p., two times/week, days 10-35) had a median survival of 46.5 days (P < 0.0001). Intracerebral xenografts of SK-N-MC in athymic mice resulted in a median survival of 23 days in control animals and 26 days in animals treated with carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea 20 mg/kg/week, i.v. x 2; difference not significant). There was 90% survival in animals treated with MDL101731 (200 mg/kg, i.v., two times/week, days 7-35) up to 90 days after implant. These studies indicate that MDL101731 has potent antiproliferative activity against human malignant brain tumors.

Regression of human breast tumor xenografts in response to (E)-2'-deoxy-2'-(fluoromethylene)cytidine, an inhibitor of ribonucleoside diphosphate reductase.

(E)-2'-Deoxy-2'-(fluoromethylene)cytidine (MDL 101,731) is a mechanism-based inhibitor of ribonucleoside diphosphate reductase (J. Stubbe, personal communication), an enzyme involved in DNA synthesis and therefore a potential target for cancer chemotherapy. In the present report, we show that MDL 101,731 inhibits the proliferation of several human breast cancer cell lines, including the estrogen-dependent cell line, MCF-7, and the estrogen-independent cell lines MDA-MB-231, MDA-MB-468, and MDA-MB-435 in vitro at nanomolar concentrations (50% inhibitory concentration, 15-26 nM). Administration of MDL 101,731 caused marked regression of tumors which formed after s.c. inoculation of all four of the cell lines in athymic (nude) mice. MDA-MB-231 tumors were found to be most sensitive to MDL 101,731 with a 90-100% cure rate at doses of MDL 101,731 between 2 and 20 mg/kg, given as once daily i.p. injections, 5 days/week for as little as 3 weeks. Almost complete cessation of MDA-MB-231 tumor growth was obtained with a dose of 0.5 mg/kg MDL 101,731 following the same dosing regimen. MDA-MB-468, MDA-MB-435, and MCF-7 tumors were not as sensitive as MDA-MB-231, but tumor regression of 50, 65, and 80%, respectively, was obtained after 5-6 weeks of treatment. The effects of MDL 101,731 on spontaneous metastasis of MDA-MB-435 cells from the mammary fat pad to the lung was also examined, and it was found that the number of lung metastases was significantly decreased if mice received MDL 101,731 while the primary tumors were growing and after primary tumors were surgically excised. Additionally, preliminary evidence raises the possibility that MDL 101,731 may induce apoptosis in MDA-MB-231 tumors. Our data suggest that the use of MDL 101,731 for the treatment of breast cancer and possibly other solid tumors should be pursued.

Plasma lipoprotein levels as predictors of cardiovascular death in women.

BACKGROUND: The association of lipoprotein levels with cardiovascular disease (CVD) is less well understood in women than in men. To better characterize any relationships, associations between CVD death and total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol and triglyceride levels in women were explored using data from female participants in the Lipid Research Clinics' Follow-up Study. METHODS: Using a sample of 1405 women aged 50 to 69 years from the Lipid Research Clinics' Follow-up Study, age-adjusted CVD death rates and summary relative risk (RR) estimates by categories of lipid and lipoprotein levels were calculated. Multivariate analysis was performed to provide RR estimates adjusted for other CVD risk factors. RESULTS: Average follow-up was 14 years. High-density lipoprotein and triglyceride levels were strong predictors of CVD death in age-adjusted and multivariate analyses. Low-density lipoprotein and total cholesterol levels were poorer predictors of CVD mortality. After adjustment for other CVD risk factors, HDL levels less than 1.30 mmol/L (50 mg/dL) were strongly associated with cardiovascular mortality (RR = 1.74; 95% confidence interval [CI], 1.10 to 2.75). Triglyceride levels were associated with increased CVD mortality at levels of 2.25 to 4.49 mmol/L (200 to 399 mg/dL) (RR = 1.65; 95% CI, 0.99 to 2.77) and 4.50 mmol/L (400 mg/dL) or greater (RR = 3.44; 95% CI, 1.65 to 7.20). At total cholesterol levels of 5.20 mmol/L (200 mg/dL) or greater and at all levels of LDL and triglycerides, women with HDL levels of less than 1.30 mmol/L (< 50 mg/dL) had CVD death rates that were higher than those of women with HDL levels of 1.30 mmol/L (50 mg/dL) or greater. CONCLUSIONS: High-density lipoprotein and triglyceride levels are independent lipid predictors of CVD death in women. Cholesterol screening guidelines should be re-evaluated to reflect the importance of HDL and triglyceride levels in determining CVD risk in women.

Decreased risk of stroke among postmenopausal hormone users. Results from a national cohort.

OBJECTIVE: To assess the impact of postmenopausal hormone use on the risk of stroke incidence and stroke mortality. DESIGN: Longitudinal study consisting of three data collection waves. The average follow up for cohort members was 11.9 years (maximum, 16.3 years). Cox proportional hazards regression models were used to estimate the relative risk of stroke for postmenopausal hormone ever-users compared with never-users. PARTICIPANTS: A national sample of 1910 (of 2371 eligible) white postmenopausal women who were 55 to 74 years old when examined in 1971 through 1975 as part of the first National Health and Nutrition Examination Survey and who did not report a history of stroke at that time. MAIN OUTCOME MEASURE: The main outcome measure was incident stroke (fatal and nonfatal). Events were determined from discharge diagnosis information coded from hospital and nursing home records and cause of death information coded from death certificates collected during the follow-up period (1971 through 1987). RESULTS: There were 250 incident cases of stroke identified, including 64 deaths with stroke listed as the underlying cause. The age-adjusted incidence rate of stroke among postmenopausal hormone ever-users was 82 per 10,000 woman-years of follow-up compared with 124 per 10,000 among never-users. Postmenopausal hormone use remained a protective factor against stroke incidence (relative risk, 0.69; 95% confidence interval, 0.47 to 1.00) and stroke mortality (relative risk, 0.37; 95% confidence interval, 0.14 to 0.92) after adjusting for the baseline risk factors of age, systolic blood pressure, diabetes, body mass index, smoking, history of hypertension and heart attack, and socioeconomic status. CONCLUSIONS: The results suggest that postmenopausal hormone use is associated with a decrease in risk of stroke incidence and mortality in white postmenopausal women.

Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality.

BACKGROUND: Non-high-density lipoprotein cholesterol (non-HDL-C) contains all known and potential atherogenic lipid particles. Therefore, non-HDL-C level may be as good a potential predictor of risk for cardiovascular disease (CVD) as low-density lipoprotein cholesterol (LDL-C). OBJECTIVES: To determine whether non-HDL-C level could be useful in predicting CVD mortality and to compare the predictive value of non-HDL-C and LDL-C levels. METHODS: Data are from the Lipid Research Clinics Program Follow-up Study, a mortality study with baseline data gathered from 1972 through 1976, and mortality ascertained through 1995. A total of 2406 men and 2056 women aged 40 to 64 years at entry were observed for an average of 19 years, with CVD death as the main outcome measure. RESULTS: A total of 234 CVD deaths in men and 113 CVD deaths in women occurred during follow-up. Levels of HDL-C and non-HDL-C at baseline were significant and strong predictors of CVD death in both sexes. In contrast, LDL-C level was a somewhat weaker predictor of CVD death in both. Differences of 0.78 mmol/L (30 mg/dL) in non-HDL-C and LDL-C levels corresponded to increases in CVD risk of 19% and 15%, respectively, in men. In women, differences of 0.78 mmol/L (30 mg/dL) in non-HDL-C and LDL-C levels corresponded to increases in CVD risk of 11% and 8%, respectively. CONCLUSIONS: Non-HDL-C level is a somewhat better predictor of CVD mortality than LDL-C level. Screening for non-HDL-C level may be useful for CVD risk assessment.

Effect of postmenopausal hormone therapy on glucose and insulin concentrations. PEPI Investigators. Postmenopausal Estrogen/Progestin Interventions.

OBJECTIVE: To characterize the long-term impact of four hormone therapy regimens on insulin and glucose concentrations measured during a standard oral glucose tolerance test. RESEARCH DESIGN AND METHODS: The Postmenopausal Estrogen/Progestin Intervention Study was a 3-year placebo-controlled randomized trial to assess effects of four hormone regimens on cardiovascular risk factors. This efficacy analysis describes glucose and insulin concentrations from 788 adherent women at baseline and at 1 and 3 years' postrandomization. RESULTS: When compared with women taking placebo, those taking conjugated equine estrogen (CEE) at 0.625 mg/day with or without a progestational agent had mean fasting insulin levels that were 16.1% lower, mean fasting glucose levels 2.2 mg/dl lower, and mean 2-h glucose levels 6.4 mg/dl higher (each nominal P < 0.05). No significant differences were apparent between women taking CEE only versus the three progestin regimens: medroxyprogesterone acetate (MPA) at 2.5 mg daily (continuous MPA), MPA at 10 mg on days 1-12 (cyclical MPA), and micronized progesterone (MP) (cyclical) at 200 mg on days 1-12. The impact of hormone therapy on insulin and glucose depended on baseline levels of fasting insulin and 1-h glucose (P < 0.05). However, the treatment effects on carbohydrate metabolism appeared to be consistent across participant subgroups formed by lifestyle, clinical, and demographic characteristics. CONCLUSIONS: Oral hormone therapy involving 0.625 mg/day of CEE may modestly decrease fasting levels of insulin and glucose. Postchallenge glucose concentrations are increased, however, which may indicate delayed glucose clearance.

Correlates of bone mineral density in the postmenopausal estrogen/progestin interventions trial.

We assessed the cross-sectional relationship of age, menopausal years, body mass, previous estrogen use, and ethnic background to bone mineral status in a sample of 875 healthy postmenopausal women at the time they were recruited from the community to participate in a multicenter clinical trial. The women were 1-10 years postmenopause, 45-64 years of age, and had not received estrogen replacement therapy within 3 months of enrollment. Of the participants, 89% were white, 69% had a spontaneous menopause, and 53% had a history of previous estrogen replacement therapy. Bone mineral density (BMD) of the lumbar spine (L2-4) and proximal femur was measured by dual-energy x-ray absorptiometry. Results were consistent with a significant negative linear regression of BMD on age or years from menopause. Body mass index (BMI) correlated significantly with BMD at all sites (L 2-4 r = 0.28; femoral neck r = 0.34, p < 0.0001). BMD adjusted for age and BMI were higher at both sites in women who had taken estrogen versus those who had not (L2-4 0.976 +/- 0.009 versus 0.932 +/- 0.01; femoral neck 0.740 +/- 0.006 versus 0.708 +/- 0.008, p < 0.05). Adjusted BMD also increased with duration of ERT. Parity was negatively associated with L2-4 BMD (p = 0.03) but did not correlate significantly with BMD at the femoral neck. Black women had the highest L2-4 BMD, and Hispanic women had the highest femoral neck BMD, even when results were adjusted for age and BMI. When data were corrected for differences in bone size, these interethnic differences were no longer significant. We conclude that increased body mass is positively correlated with BMD, and this may confer a degree of skeletal protection to heavier postmenopausal women. Exposure for 5 years to exogenous estrogen is associated with significantly increased age- and BMI-adjusted BMD.

Prediagnostic serum levels of carotenoids and vitamin E as related to subsequent cancer in Washington County, Maryland.

In 1974 and 1975, serum specimens were collected from 25,802 volunteers in Washington County, Maryland. The serum was kept frozen at -73 degrees C until the time of assay. Prediagnostic samples from 436 cancer cases and 765 matched control subjects have been assayed. Nine sites have been studied: colon, rectum, pancreas, lung, melanoma, basal cell of skin, breast, prostate, and bladder. Serum beta-carotene levels showed a strong protective association with lung cancer, suggestive protective associations with melanoma and bladder cancer, and a suggestive but nonprotective association with rectal cancer. Serum vitamin E levels had a protective association with lung cancer; none of the other sites showed impressive associations. Low levels of serum lycopene were strongly associated with pancreatic cancer and less strongly associated with cancer of the bladder and rectum.

Serological precursors of cancer: malignant melanoma, basal and squamous cell skin cancer, and prediagnostic levels of retinol, beta- carotene, lycopene, alpha-tocopherol, and selenium.

To determine the association between prediagnostic serum levels of retinol, beta-carotene, lycopene, alpha-tocopherol, and selenium and the subsequent risk of malignant melanoma, and basal and squamous cell skin cancer, a nested case-control study among residents of Washington County, MD, was performed. Cases with melanoma (n = 30), basal cell (n = 32), and squamous cell (n = 37) skin cancer who were admitted to hospital for treatment or biopsy of metastatic lesions were each matched by age, sex, and race with two controls. There were no significant associations between serum micronutrient levels and the risk of subsequent skin cancer.

Clomiphene analogs with activity in vitro and in vivo against human breast cancer cells.

Six hundred triphenylethylenes were assayed for antiproliferative activity against MCF-7, LY2, and MDA-MB-231 breast cancer cells using sulforhodamine B dye to measure proliferation. Here we report on just 63 of the compounds, mostly clomiphene analogs, with substitutions on the alpha' or beta ring, at the vinyl position or in the side chain, of which 23 were active, as defined by antiproliferation IC50 values < or =1 microM. Activity profiles showed that 23 and 11 analogs were active toward MCF-7 and LY2, respectively, but none were active against MDA-MB-231. The IC50 values of tamoxifen were 2.0 microM against MCF-7 and 7.5 microM against LY2 and MDA-MB-231. Estradiol reversed antiproliferative activities of several E isomers but not their Z isomer counterparts. Clomiphene side chain analogs 46 [(E)-1-butanamine, 4-[4-(2-chloro-1,2-diphenylethenyl) phenoxy]-N,N-diethyl-dihydrogen citrate (MDL 103,323)] and 57 [(E)-N-[p-(2-chloro-1,2-diphenylvinyl) phenyl]-N,N-diethylethylenediamine dihydrogen citrate (MDL 101,986)] were 4- to 5-fold more effective than tamoxifen. Methylene additions up to (-CH2-)12 in the clomiphene side chain showed that analog 46 [(-CH2-)4 side chain] had maximal antiproliferative activity, binding affinity, and inhibition of transcription of an estrogen response element luciferase construct in transfected MCF-7 cells. Intraperitoneal administration of 46 or 57 inhibited progression of MCF-7 breast tumor xenografts in nude mice with ED50 values of <0.02 mg/mouse/day. Both analogs may hold promise for treating ER positive breast cancer and are of interest for further development.

Comorbidity measurement in elderly female breast cancer patients with administrative and medical records data.

The inter-rater reliability, cross-source (Medicare claims versus medical record) agreement, and ability to predict all-cause mortality of three aggregate comorbidity indices were evaluated in a group of 404 elderly, incident breast cancer cases identified from the Virginia Cancer Registry and linked to Medicare administrative data files. Comorbidity was based on both medical records and Medicare claims data using indices from Charlson et al (1987), Satariano and Ragland (1994), and Kaplan and Feinstein (1974). Inter-rater agreement was good for all indices (kappas > or = 0.80). Agreement between comorbidity indices measured by claims and medical records was considerably poorer (kappas between 0.30 and 0.40). However, claims-based and medical records-based comorbidity indices were similarly associated with mortality. For the Charlson index, the index best predicting survival, the adjusted relative risk for an increase from a lower to higher comorbidity category was 1.48 (95% confidence interval 1.23, 1.78) based on medical records compared to 1.53 (95% confidence interval 1.23, 1.93) based on Medicare claims. The claims-based Charlson index score still appeared to be associated with survival (relative risk = 1.30; 95% confidence interval = 1.00, 1.70) after controlling for the medical records-based score. This suggests that both comorbidity data sources add valuable prognostic information and, conversely, that the use of either source alone will result in some misclassification of comorbidity.

The epidemiology of cardiovascular disease in postmenopausal women.

This manuscript has described the principal modifiable risk factors for the major killer of postmenopausal women. Clearly women who smoke should be convinced to quit, and those who have hypertension and hypercholesterolemia should be encouraged initially to adopt hygienic interventions (that is weight reduction and moderate exercise) to lower their blood pressures and cholesterol levels. Further, given the magnitude of the risk reduction in CVD seen in estrogen users, estrogen use ought to be considered as a preventive therapy for postmenopausal women, but particularly for those who are at high risk of cardiovascular disease.

Does comorbid disease interact with cancer? An epidemiologic analysis of mortality in a cohort of elderly breast cancer patients.

BACKGROUND: Although widely believed that co-occurring chronic diseases in elderly persons do not act independently in causing death, there has been little empirical research assessing prognostic interrelationships between comorbidities. METHODS: Nonconcurrent prospective follow-up of 3,549 Virginia-resident elderly women diagnosed with a first breast cancer and 2,114 elderly women with no breast cancer history admitted to Virginia hospitals with principal diagnoses of genital prolapse during 1986-1988 was conducted through linkage of cancer registry and Medicare administrative records. Aggregate comorbidity was measured from Medicare claims via the Charlson comorbidity index (CCI). Mortality rates and relative risks were estimated for the breast cancer and non-breast-cancer groups stratified by the presence and level of comorbidity. Proportional hazards models were used to estimate Rothman's synergy index (S) measure of additive interaction. RESULTS: Over full follow-up, the excess mortality rate for women with breast cancer and other comorbidity was 17% greater than expected under the null hypothesis that risks were additive and independent (S = 1.17, p = .12). Stratified analyses revealed a pattern of S estimates across cancer stage subgroups that was biologically sensible, but this pattern was not supported by strong statistical evidence. CONCLUSIONS: This study provides the first empirical estimates of statistical interaction between breast cancer and other chronic comorbidity. S index values tended to be small, but these small effects would translate into substantial numbers of deaths attributable to interaction between cancer and comorbidity. Interactions between breast cancer and comorbid disease should be explored further in large studies that can estimate these effects with increased precision.

Hormone replacement therapy and breast cancer: a qualitative review.

OBJECTIVE: To assess whether recent epidemiologic evidence supports an association between use of estrogen replacement therapy or hormone replacement therapy and risk of breast cancer. DATA SOURCES: The keywords "estrogen," "estrogen replacement therapy," or "hormone replacement therapy," and "breast cancer" or "breast neoplasm," were used to search for articles published from 1975-2000 in MEDLINE and Dialogweb. Only articles published in peer-reviewed journals and containing original data were included in this review. METHODS: Unadjusted or age-adjusted risk estimates for breast cancer among ever users of estrogen therapy compared with never users were abstracted from published articles or calculated using the data provided in the published reports. TABULATION, INTEGRATION, AND RESULTS: We found little consistency among studies that estimated the risk of breast cancer in hormone users compared with nonusers and in studies assessing the risk by duration of use. However, there was consistently a lower risk of death from breast cancer in hormone users compared with nonusers. CONCLUSION: The evidence did not support the hypotheses that estrogen use increases the risk of breast cancer and that combined hormone therapy increases the risk more than estrogen only. Additional observational studies are unlikely to alter this conclusion. Although a small increase in breast cancer risk with hormone therapy or an increased risk with long duration of use (15 years or more) cannot be ruled out, the likelihood of this must be small, given the large number of studies conducted to date.

Decreased vascular endothelial growth factor expression associated with tumor regression induced by (E)-2'-deoxy-2'-(fluoromethylene)cytidine (MDL 101,731).

The effect of the antitumor drug MDL 101,731 [(E)-2'-deoxy-2'-(fluoromethylene)cytidine] on tumor growth and on steady-state vascular endothelial growth factor (VEGF) mRNA levels in MDA-MB-231, PC-3, MCF-7, and HT-29 human tumor xenografts grown in nude mice was examined, using quantitative in situ hybridization. MDL 101,731 caused regression of MDA-MB-231 and PC-3 tumor xenografts, but only inhibition of growth (without regression) of MCF-7 xenografts. The drug caused inhibition of growth of HT-29 xenografts at low doses, and regression at high doses. When treatment with MDL 101,731 led to tumor regression, VEGF mRNA levels were decreased. When treatment led only to inhibition of growth, there was no significant change in VEGF mRNA. Further examination of the tumor xenografts revealed that elevated VEGF mRNA was associated with hypoxic zones surrounding areas of necrosis in the tumors, and that the drop in VEGF mRNA observed in tumors from mice treated with MDL 101,731 correlated with a loss of zones of necrosis. In contrast, treatment with cisplatin led to either an increase (PC-3) or no change (MDA-MB-231) in VEGF mRNA levels, and no loss of necrotic zones. Quantitative analysis of changes in VEGF mRNA levels was supported by immunohistochemical analysis of VEGF protein in the same tumor specimens. In vitro, MDL 101,731 was a potent inhibitor of VEGF secretion in cells exposed to hypoxia, whereas there was no effect of cisplatin on VEGF secretion by three of the four cell lines tested. These findings suggest that inhibition of VEGF expression by MDL 101,731 may distinguish this compound from other classes of cytotoxic agents, such as cisplatin.

Response of human colon and prostate tumor xenografts to (E)-2'-deoxy-2'-(fluoromethylene) cytidine, an inhibitor of ribonucleotide reductase.

Daily oral or intravenous administration of the ribonucleoside diphosphate reductase inhibitor, (E)-2'-deoxy-2'-(fluoromethylene)cytidine (MDL 101,731), to nude mice caused rapid regression of colon and prostate xenografts. Studies were performed to optimize dosing schedule and route of administration. MDL 101,731 was tested against colon (HT-29) and prostate (PC-3) xenografts using twice weekly oral and intravenous administration. PC-3 tumors regressed almost completely with doses of 20 mg/kg. HT-29 xenografts regressed during intravenous administration of 100 mg/kg MDL 101,731, whereas oral administration was less effective. Based on these data it seems that MDL 101,731 is effective when administered intravenously, twice weekly and is an excellent candidate for clinical development against solid tumors.

Antitumor and chemopreventive effects of a clomiphene analog, MDL 103,323, in mammary carcinoma.

MDL 103,323, an enclomiphene analog, was tested for binding to the estrogen receptor, inhibition of human tumor xenografts and prevention of carcinogen-induced mammary tumors. MDL 103,323 had 5-6 fold greater affinity for the human estrogen receptor than did either tamoxifen or enclomiphene. Consistent with enhanced binding affinity, MDL 103,323 was more potent against MCF-7 cell proliferation and MCF-7 xenografts in nude mice were inhibited almost completely by MDL 103,323 doses > or = 0.02 mg/mouse/day (ED50 l 0.01 mg/mouse/day). N-methylnitrosourea induced rat mammary carcinomas were inhibited by > or = 50% at 0.003 mg/kg daily and by 90% at 0.1 mg/kg/day. The antitumor potency and efficacy of MDL 103,323 are striking and further evaluation of the compound for potential clinical utility is warranted.

The adverse effects of hormonal therapy.

Estrogen therapy must be cycled with progestin therapy in women with intact uteri in order to prevent uterine cancer. However, these women cannot be expected to benefit (with regard to cardiovascular disease) from any estrogen-induced changes in the lipoprotein profile, as progestins will either negate or overwhelm any estrogen effects. However, such women will definitely benefit from estrogen's effects with regard to menopausal symptoms and bone loss. These clearly beneficial effects of estrogen-progestin therapy are not outweighed by any known risks. However, in women without uteri (approximately 30 per cent of women), unopposed estrogen therapy in the menopause may protect against cardiovascular disease, as well as have beneficial effects on bone metabolism and menopausal symptoms. In this special case, the beneficial effects of unopposed estrogen therapy clearly outweigh any known risk.

PIP: This review briefly outlines the pharmacology of natural and synthetic estrogens, and synthetic progestins, and summarizes their beneficial and adverse effects for contraceptive and menopausal therapy. Currently, oral contraceptives contain 30-50 mc synthetic estrogen, and 1-5 mg nor-progestin; menopausal therapy may be either 0.625-1.25 mg natural estrogen or estrogen plus 10 mg medroxyprogesterone acetate daily if the woman has her uterus. The biologic effects of estrogens are : decrease in lipoproteins, increased blood coagulation factors, increased blood pressure, decreased glucose tolerance. Progestins increase blood lipids and increase insulin and glucose. Oral contraceptives increase the risk of cardiovascular disease, particularly in smokers and in women over 35, in proportion to dose. These studies should be recapitulated in more detail with the newer low-dose pills. Orals have far more beneficial effects, besides providing an inexpensive, effective method contraception. The death rate of users of oral contraceptives is 3.7/100,000 (1.8 in nonsmokers and 6.5 in smokers), but the risk is 5.5 times higher in nonusers exposed to pregnancy and childbirth. The risk for users of barrier methods backed up by abortion is lower, but pills are cheaper and more acceptable. If woman did not take oral contraceptives, they would not be protected from cancer of the breast, ovary, endometrium, and ovarian and breast cysts. Menopausal therapy puts woman at increased risk of endometrial cancer only if the estrogen is taken alone, not if progestin is combined with the estrogen. There are no other adverse effects except decreased glucose tolerance and possible comprise of lipoproteins if a norprogestin of menopausal estrogens effectively treat hot flashes, depression, vaginal atrophy and bones loss.