Estrogen-associated thromboembolism.

Most of the linkage of atherosclerosis and thrombosis with estrogens is epidemiologic in origin. Although the effects of estrogens on the mechanisms of hemostasis are wide ranging, many are benign; only a few may account for thrombus formation. Platelet function tests have provided extensive but contradictory data, and interpretation is limited because it is uncertain whether a rise in one or more of these parameters is a primary or secondary effect. The most consistent effects of estrogens on coagulation proteins are elevations of fibrinogen; factors II, VII, IX, X, and XII; protein C; and plasminogen. Although these elevations have been attributed to the estrogenic component in oral contraceptives, the progestogen concentration may also influence these increases. Among other coagulation proteins studied, the following are unaffected by oral contraceptive use: factors V, VIII, and XI; prekallikrein; and high-molecular-weight kininogen. In contrast, protein S values are decreased. The plasma concentration of plasmin inhibitor is unchanged, whereas both proteinase inhibitor and macroglobulin are significantly increased by oral contraceptive use. Cl esterase inhibitor is decreased in women taking oral contraceptives and correlates with the increase in Hageman factor. Antithrombin III is one plasma inhibitor for which a decrease in quantity and activity have been associated with a thrombotic tendency in humans. Although data on estrogen-associated changes in the quantity of antithrombin III have been conflicting, the ability of plasma to inhibit factor Xa is significantly reduced in a dose-dependent manner among pre- and postmenopausal estrogen users.(ABSTRACT TRUNCATED AT 250 WORDS)     

Current issues and available options in combined hormonal contraception

Development of hormonal contraception marked a revolutionary step in social change that has improved the lives of women and families worldwide. Since the first oral contraceptive was introduced in the 1960s, hormonal contraception has undergone various stages of advancement. Today, oral contraceptive regimens are safer and more tolerable, with equal or improved efficacy, than the early formulations. Incremental decreases in the dose of estrogens have helped to alleviate some of the unwanted estrogenic side effects of combined hormonal contraceptives. Progestogens have also evolved over time, and newer generations of progestins have minimal side effects. New delivery methods have further extended the range of options available to women. Among these, the transdermal patch and vaginal ring are widely used. This review examines available combined hormonal contraceptive options and compares them, where data are available, for efficacy, safety, cycle control, adverse events profiles and associated risks, and user preference and satisfaction. We also examine particular areas of interest, including bone mineral density, venous thrombosis and use of antiepileptic drugs.     

Replacement estrogen use and body mass index

Peripheral fat is a major source of endogenous estrogens in menopausal women. To investigate whether obesity affects use of replacement estrogens in postmenopausal women, we examined the relation between body mass index and use of replacement estrogens in data from Group Health Cooperative of Puget Sound, the German Cardiovascular Prevention Study, and the Cancer and Steroid Hormone (CASH) study. In each data set, there was a major decline in replacement estrogen use with higher body mass index. All data sets showed hysterectomy to be a strong predictor of replacement estrogen use. Smoking, past use of oral contraceptives and other estrogens, and ages at menarche and menopause did not appear to influence the body mass-estrogen relation. The strong and consistent association between body mass index and use of replacement estrogens in data collected at different times and in different places by different methodologies strongly suggests a common underlying biologic mechanism.     

Environmental and dietary estrogens and human health: is there a problem?

It has been hypothesized that organochlorine pesticides and other environmental and dietary estrogens may be associated with the increased incidence of breast cancer in women and decreased sperm concentrations and reproductive problems in men. However, elevation of organochlorine compounds such as dichlorodipehenyldichloroethylene (DDE) and polychlorinated biphenyls (PCBs) in breast cancer patients is not consistently observed. Reanalysis of the data showing that male sperm counts decreased by over 40% during 1940 to 1990 indicated that inadequate statistical methods were used and that the data did not support a significant decline in sperm count. Humans are exposed to both natural and industrial chemicals which exhibit estrogenic and antiestrogenic activities. For example, bioflavonoids, which are widely distributed in foods, and several industrial compounds, including organochlorine pesticides and various phenolic chemicals, exhibit estrogenic activity. Humans are also exposed to chemicals which inhibit estrogen-induced responses such as the aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin and related chlorinated aromatics, polynuclear aromatic hydrocarbon combustion products, and indole-3-carbinol, which is found in cruciferous vegetables. Many of the weak estrogenic compounds, including bioflavonoids, are also antiestrogenic at some concentrations. A mass balance of dietary levels of industrial and natural estrogens, coupled with their estimated estrogenic potencies, indicates that the dietary contribution of estrogenic industrial compounds is 0.0000025% of the daily intake of estrogenic flavonoids in the diet.(ABSTRACT TRUNCATED AT 250 WORDS)     

Estrogen and thromboembolic disorders: should patients stop hormones prior to cosmetic surgery?

Oral contraceptives and replacement estrogenic hormones have been associated with a significant risk of thromboembolism. Cosmetic surgery consists of elective procedures in otherwise healthy individuals. The prospect of thromboembolism should be diminished in these patients by avoiding those factors that may give rise to the problem. Stopping oral contraceptives and replacement estrogens three weeks before surgery to two weeks after surgery is not difficult for most patients and should be part of the custom and practice of all cosmetic surgeons.     

Factors associated with oral contraceptive use.

We studied factors associated with oral contraceptive (OC) use among 1,855 premenopausal women who were admitted to hospital with conditions unrelated to OC use. Among this group, 15 per cent reported having used OCs within the preceding year and 35 per cent reported having last used them more than a year previously. A higher estrogenic dose (more than 60 micrograms) was reported by past users; the relationship of numerous other variables to past and present OC use is reported.     

Estrogen use and stroke risk in postmenopausal women.

Among postmenopausal women (58-98 years of age) in a retirement community use of oral estrogens was not significantly associated with overall risk of stroke. Estrogen use was significantly associated with blood-pressure status. An observed association between estrogen use and nonembolic cerebral infarction in women aged 70-79 may be secondary to an interaction between hypertension and estrogen usage.     

Incidence of thyroid cancer in women in relation to reproductive and hormonal factors

Female residents of western Washington state aged 18-80 years in whom thyroid cancer was diagnosed between January 1974 and December 1979 were interviewed concerning their reproductive histories and their prior use of exogenous estrogens. Their responses were compared with those of a sample of women from the same population, individually matched to cases on telephone prefix. Use of each of several estrogen-containing preparations was associated with a small increased risk of thyroid cancer; parous women who had ever used a lactation suppressant had 1.7 times the risk of parous nonusers (95% confidence interval, 1.1-2.8); ever users of oral contraceptives had 1.6 times the risk of never users (95% confidence interval, 0.98-2.5); and ever users of postmenopausal estrogens had 1.4 times the risk of never users (95% confidence interval, 0.89-2.3). Among the low risk group of women, i.e., those who had never undergone radiation therapy and who had never had a goiter, a history of one or more pregnancies was also associated with a small increase in the risk of thyroid cancer (relative risk = 1.8, 95% confidence interval, 1.1-3.1). However, no increase in risk with increasing duration of use of oral contraceptives or menopausal estrogens or with increasing number of pregnancies was noted. While pregnancy and use of exogenous estrogens have an impact on the production of thyroid-stimulating hormone, their effect on the incidence of thyroid carcinoma, if present at all, appears to be small.     

Removal of estrogens and estrogenicity through drinking water treatment

Estrogenic compounds have been shown to be present in surface waters, leading to concerns over their possible presence in finished drinking waters. In this work, two in vitro human cell line bioassays for estrogenicity were used to evaluate the removal of estrogens through conventional drinking water treatment using a natural water. Bench-scale studies utilizing chlorine, alum coagulation, ferric chloride coagulation, and powdered activated carbon (PAC) were conducted using Ohio River water spiked with three estrogens, 17β-estradiol, 17α-ethynylestradiol, and estriol. Treatment of the estrogens with chlorine, either alone or with coagulant, resulted in approximately 98% reductions in the concentrations of the parent estrogens, accompanied by formation of by-products. The MVLN reporter gene and MCF-7 cell proliferation assays were used to characterize the estrogenic activity of the water before and after treatment. The observed estrogenic activities of the chlorinated samples showed that estrogenicity of the water was reduced commensurate with removal of the parent estrogen. Therefore, the estrogen chlorination by-products did not contribute appreciably to the estrogenic activity of the water. Coagulation alone did not result in significant removals of the estrogens. However, addition of PAC, at a typical drinking water plant dose, resulted in removals ranging from approximately 20 to 80%.     

Fibroadenoma and the use of exogenous hormones. A case-control study

The association between fibroadenoma and the use of exogenous hormones in women aged 18-74 years was examined in a case-control study conducted in Connecticut during 1979-1981. The study population included 251 women with biopsy-confirmed fibroadenoma and 1,081 control women drawn from inpatient and outpatient general surgical services of five Connecticut hospitals. Among women under age 45 years, oral contraceptive use was negatively associated with the occurrence of fibroadenoma (age-adjusted odds ratio (OR) = 0.57, 95% confidence interval (CI) = 0.42-0.79). The odds ratio for women over age 45 years who had ever used oral contraceptives was 1.65 (95% CI = 0.58-4.68). Women over age 45 years who had ever used replacement estrogens had an elevated odds ratio for fibroadenoma (OR = 2.83, 95% CI = 1.21-6.60). The data suggest either that the effects of exogenous hormones may differ by age, or that the changing composition of exogenous hormones has brought about different associations depending upon the cohort of women.     

Benign breast tumor and estrogenic hormones: a population-based retrospective study.

Histories of the usage of oral contraceptives and other estrogens were obtained from 320 women 20-49 years of age who had pathologically confirmed diagnoses of benign breast disease made at Washington County Hospital in Hagerstown, Maryland, during the period 1968 through 1972. Similar histories were obtained from 320 controls matched for race, sex, age, residence in county, and willingness to participate in a health survey. No association could be found between oral contraceptive usage and benign breast tumor. The use of other estrogens, notably diethylstilbestrol, was significantly related to the presence of benign breast disease.     

Maternal and prepubertal diet, mammary development and breast cancer risk

At present, we do not know what causes sporadic breast cancer. Environmental factors,particularly diet, appear to explain at least 70% of newly diagnosed breast cancers, but it is not clear what these factors are. We propose that the lack of progress in this area is due to a lack of considering the effect of timing of environmental and dietary exposures on the breast. The evidence provided above suggests that an in utero exposure to an estrogenic environment-including that caused by diet [high (n-6) PUFA or genistein]-increases breast cancer risk. This increase may be mediated by an increased presence of TEB in the mammary epithelial tree and increased ER-alpha levels, reduced ER-beta levels or both. Prepubertal estrogenic exposure, in contrast, reduces later risk of developing breast cancer. The protective effect of estrogens may be mediated by early epithelial differentiation, reduced presence of ER-alpha and increased levels of ER-beta in the mammary gland. The challenge we are now facing is to determine whether the data obtained mainly through the use of animal models is relevant to women and if so, how we might be able to modulate pregnancy and childhood estrogenic exposure by appropriate dietary modifications to reduce breast cancer risk in women.     

The additional risk of endometrial cancer associated with unopposed estrogen use in women with other risk factors.

We analyzed data from a population-based case-control study of endometrial cancer. Our goal was to identify a subgroup of women in whom the additional cancer risk associated with unopposed estrogen use was sufficiently small so as to not be a deterrent to taking a hormone preparation of this type. Researchers interviewed women with endometrial cancer (N = 553) and controls (N = 752) regarding hormone use. The additional risk of endometrial cancer associated with unopposed estrogen use did not vary substantially in the presence or absence of hypertension, parity, oral contraceptive use, or smoking. The results suggest that, although heavier women may experience a greater risk of endometrial cancer associated with unopposed estrogen use (8.2 per 1,000 per year) than lighter women (4.2 per 1,000 per year), long-term users in the latter group nonetheless face a substantial absolute increase in risk. We conclude that subdividing women on the basis of the presence or absence of other known risk factors for endometrial cancer fails to delineate a subgroup that is exempt from the increased risk of this cancer associated with use of unopposed estrogens. 83.6% of estrogen users reported taking conjugated estrogens.     

Breast cancer risk after estrogen replacement therapy: results from the Toronto Breast Cancer Study.

The authors examined noncontraceptive estrogen use in relation to breast cancer risk in women under age 70 in a case-control study conducted in Toronto, Canada. Cases were 607 women with incident primary breast cancer, identified at the time of hospitalization for treatment. They were compared to 1,214 controls matched to the cases on neighborhood and decade of age. Information was obtained through personal interviews conducted in the subjects' homes. Most estrogen users had taken conjugated estrogens, and only 7% had also taken progestogens. Compared with never use, the estimated relative risk for ever use of unopposed conjugated estrogens was 0.9 (95% confidence interval (Cl) 0.6-1.2) after allowance for multiple confounding factors. Relative risk estimates for most duration categories were close to 1.0; the estimate for the longest duration category, greater than or equal to 15 years of use, was elevated (1.5, 95% Cl 0.6-3.8), but there was not a significant trend with increasing duration. The estimate for current use or use that ended less than 12 months before interview and had lasted for at least 5 years was 0.9 (95% Cl 0.4-1.9). The results provide evidence against an increase in risk among women who used unopposed conjugated estrogens for less than 15 years and for recent users; for women with durations of at least 15 years, an increase could not be ruled out.     

ICMR Task Force Study on hormonal contraception. Biological activity of ethinyl estradiol present in the breast milk

A study was conducted to compare the biological activity of the estrogenic component of the endogenous steroids in breast milk samples collected during various phases of lactation with those milk samples collected from women who were on estrogen therapy. The estrogenic biological activity in the milk sample was assessed by the immature mouse uterine weight gain assay. Milk samples collected during postpartum period from six different study groups, viz., control colostrum of 1-3 days and 4-6 days, transitional milk (10-20 days) and mature milk (1-3 months) were compared with colostrum and mature milk of women treated with Lynoral (ethinyl estradiol 0.1 mg) three times a day for three days. Estrogenic activity was observed only in animals injected with milk extracts of colostrum samples from both control and Lynoral-treated women; however, they were not significantly different from each other. Therefore it is not the exogenous estrogens, but the endogenous estrogen present in large quantities in the colostrum that is responsible for the biological activity.     

Identification of estrogenic compounds in wastewater effluent

In order to identify the dominant contributors to estrogenic activity in environmental waters, a comprehensive fractionation method using silica gel column chromatography, combined with recombinant yeast assay for detecting estrogenic activity and with gas chromatography-mass spectrometry for quantifying endocrine disruptors and natural estrogens, was developed. The method was applied to the municipal sewage treatment plant (STP) secondary effluent discharged to the Tamagawa River in Tokyo, Japan, where endocrine disruption was observed in wild carp. The instrumental analysis demonstrated that averaged concentrations of nonylphenol, bisphenol A, estrone (E1), and 17beta-estradiol (E2) were 564 +/- 127, 27 +/- 19, 33 +/- 11, and 4.6 +/- 3.0 ng/L, respectively. Based on the concentration and relative potency of these compounds, the natural estrogens E1 and E2 represented more than 98% of the total estrogen equivalent concentration (EEQ) in the STP effluent, while the contribution of phenolic compounds to total EEQ was less than 2%. Estrogenic activities associated with the dissolved phase of the effluent samples were detected by a recombinant yeast assay. By using silica gel column chromatography, the dissolved phase was separated into several fractions that were subjected to the bioassay. The polar fractions exhibited estrogenic activity. The greatest estrogenic activity was found in a polar fraction containing E1 and E2 and represented 66 to 88% of the total estrogenic activities estimated from the bioassay data. These results lead to the conclusion that E1 and E2 were the dominant environmental estrogens in the STP effluent, but a significant contribution to estrogenic activities stems from unidentified components in the effluents.     

LETHAL DOSE AND REPRODUCTIVE PARAMETERS OF p-NONYLPHENOL IN RATS

Male reproductive abnormalities may be due to an increased level of maternal estrogens affecting the developing fetus. Man is exposed to environmental estrogens in multiple ways: diet, drinking water, air, and skin. para-Nonylphenol (p-NP), an alkylphenol, has estrogenic properties. This study was performed to evaluate the potency and workable concentrations before reproductive tests could be performed. The oral LD₅₀ (median lethal dose) value for rats was 1475 mg/kg. For both males in the reproductive test the litter size after long-term treatment at 50 mg/kg p-NP was smaller than that in the breeding records. Five females did not conceive at all.     

The environmental compartments of environmental hormones

Compounds with estrogenic activity are ubiquitous in nature. Phytoestrogens and steroidal estrogens are found naturally in the food, in particular legumes and milk products. Naturally occurring steroidal estrogens and synthetic estrogens such as ethinylestradiol are constantly excreted into the environment as the result of the release of animal and human waste. As the result of this constant exposure, testosterone, estrogens, and ethinylestradiol are readily detectable in every stream examined in Israel. The concentrations observed of the estrogenic compounds are physiological, i.e., at these concentrations fish reproductive function can be affected. Estrogenic compounds do not usually reach the groundwater but testosterone percolates through the soil and is frequently found in the groundwater. In the dry season, there are no natural or synthetic steroids in the streams of the Jordan River watershed. However, at the beginning of the rainy season, both estrogen and testosterone reach the surface waters in the runoff from fields with manure, whereas ethinylestradiol reaches the streams in overflows from oxygenation ponds used to treat sewage prior to irrigation.