Oral contraceptive use and hormone replacement therapy are associated with microalbuminuria

BACKGROUND: Controversy exists regarding the adverse and beneficial effects of oral contraceptive use and hormone replacement therapy. Microalbuminuria is associated with increased risk of renal and cardiovascular disease. OBJECTIVE: To examine the association between oral contraceptive use or hormone replacement therapy and microalbuminuria. METHODS: We performed a case-control study of the baseline data and historical pharmacy data of 4301 female subjects of the Prevention of Renal and Vascular End Stage Disease study cohort, aged 28 to 75 years, excluding women who were pregnant or had type 1 diabetes mellitus. The main outcome measure was microalbuminuria, defined as a urinary albumin excretion of 30 to 300 mg per 24 hours (recorded as the mean of two 24-hour urine collections). RESULTS: After adjusting for age, hypertension, diabetes, obesity, hyperlipidemia, and smoking, the odds ratio (OR) for having microalbuminuria was 1.90 (95% confidence interval [CI], 1.23-2.93) for premenopausal oral contraceptive users and 2.05 (95% CI, 1.12-3.77) for postmenopausal hormone replacement therapy users. The point estimate increased in a dose-dependent fashion, albeit insignificantly, according to the estrogen content of the oral contraceptives (<30 microg ethinyl estradiol: OR, 1.11; 95% CI, 0.14-8.56; 30 to <50 microg: OR, 1.83; 95% CI, 1.17-2.87; and 50 microg: OR, 2.72; 95% CI, 0.81-9.08). The OR was greater in oral contraceptives with a second-generation (OR, 2.04; 95% CI, 1.28-3.25) vs a third-generation progestin (OR, 1.39; 95% CI, 0.63-3.06). The OR increased with the duration of hormone replacement therapy (< or =5 years, OR, 1.28; 95% CI, 0.37-4.50; >5 years, OR, 2.56; 95% CI, 1.32-4.97). CONCLUSION: Regular and long-term oral contraceptive use and hormone replacement therapy are associated with an increased risk for microalbuminuria and cardiovascular disease.     

Sex hormones and thrombosis

There is compelling evidence that use of oral formulations of female hormone replacement and of the combined oral contraceptive induces a prothrombotic state. This translates to an increased thrombotic risk. Within the individual, the absolute risk is determined by the interaction between that induced by hormone use and heritable and acquired risk factors for thrombosis. Knowledge of the accumulating epidemiologic and clinical trial-derived data on this topic is essential for the delivery of evidence-based counseling in the clinical environment and is the subject of this review.     

Plasma fibrinogen in women: relationships with oral contraception, the menopause and hormone replacement therapy

Summary. Plasma fibrinogen was measured in 4837 women aged 25-64 years as part of the Scottish Heart Health Study and Scottish MONICA population surveys. The relationships of oral contraceptive use, the menopause and hormone replacement therapy were examined.
Univariate analyses found that women with a history of oral contraceptive use, premenopausal women and those on hormone replacement therapy all had significantly lower fibrinogen levels than women who had never used oral contraceptives, postmenopausal women and non-hormone replacement users respectively. These differences persisted after age standardization.
On multivariate analysis, menopausal status and hormone replacement therapy had independent effects on fibrinogen levels. Together with the common risk factors, 9.9% of the total variation in plasma fibrinogen levels was explained. However, less than 1% of this was from the combined menopausal and hormonal factors.
These results confirm a postmenopausal rise in fibrinogen level which may be relevant to an increased risk of coronary heart disease. In addition, a protective effect with hormone replacement therapy is noted, although this was probably due to selection bias.     

Female hormones and thrombosis

Exogenous hormones are used by more than a hundred million women worldwide as oral contraceptives or for postmenopausal hormone replacement. Oral contraceptives increase the risk of venous thrombosis, of myocardial infarction, and of stroke. The risk is highest during the first year of use. The venous thrombotic risk of oral contraceptives is high among women with coagulation abnormalities and with so-called third-generation contraceptives (containing desogestrel or gestodene). The risk of myocardial infarction does not appear to depend on coagulation abnormalities or the type of oral contraceptive. Hormone replacement therapy increases the risk of venous thrombosis. This risk is also highest in the first year of use and among women with coagulation abnormalities. The risk becomes very high in women with a previous venous thrombosis. Randomized trials have not confirmed a beneficial effect of postmenopausal hormones on the occurrence of myocardial infarction.     

The prevalence of hyperlipidemia in women and its association with use of oral contraceptives, sex hormone replacement therapy and nonlipid coronary artery disease risk factors. Canadian Heart Health Surveys Research Group.

OBJECTIVE: To report the prevalence of lipid and nonlipid coronary artery disease risk factors in women classified by use of oral contraceptives or sex hormone replacement therapy. DESIGN, SETTING AND PARTICIPANTS: A population-based cross-sectional survey in nine Canadian provinces (not including Nova Scotia) between 1988 and 1992 invited 13,506 women aged 18 to 74 years to participate. During a clinic visit after a home interview, a blood sample was obtained following a fast of 8 h or more from 8637 women. OUTCOME MEASURES: Fasting plasma total cholesterol, triglycerides, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, blood pressure, smoking status, self-reported diabetes, and self-reported use of oral contraceptive or sex hormone replacement therapy pills. MAIN RESULTS: The prevalence of oral contraceptive use was 41% for women 18 to 24 years old and 20% for women 25 to 34 years old. The prevalence of sex hormone replacement therapy was 4% for women 35 to 44 years old, 20% for women 45 to 64 years old and 11% for women 65 to 74 years old. Users of sex hormone replacement therapy aged 35 to 44 years had slightly higher mean LDL cholesterol than nonusers (3.04 versus 2.89 mmol/L). Users and nonusers aged 45 to 54 years had similar LDL cholesterol levels, and users aged 55 to 64 and 65 to 74 years had lower LDL cholesterol and higher HDL cholesterol levels, respectively, than nonusers. Triglyceride levels were higher in oral contraceptive users and in younger women on sex hormone replacement therapy than in nonusers. In the general population of Canada the use of oral contraceptives in women less than age 35 years had only a marginal effect on the prevalence of lipid and nonlipid risk factors. Women aged 18 to 24 years using oral contraceptives had a higher mean LDL cholesterol level of 2.73 versus 2.35 mmol/L for nonusers. The prevalence of lipid and nonlipid risk factors in women using sex hormone replacement therapy increased slightly for those aged 35 to 54 years and decreased in women aged 55 to 74 years. A lower percentage of women using sex hormone replacement therapy, aged 55 to 74 years, had high risk LDL cholesterol levels (21% versus 36% for nonusers). A larger percentage of women using sex hormone replacement therapy had low risk HDL cholesterol levels (54% versus 29% for nonusers). The nonlipid risk factor profile for women aged 35 to 54 years on sex hormone replacement therapy was less favourable than for nonusers: obesity was more common (36% versus 28%, respectively), hypertension was higher (22% versus 12%, respectively), and the proportion of women with one or more nonlipid risk factors was higher. The nonlipid risk factor profile for women 55 to 74 years of age who were using sex hormone replacement therapy was more favourable than for nonusers: obesity was lower (31% versus 47%, respectively), smoking was lower (7% versus 16%, respectively), sedentary behaviour was lower (28% versus 37%, respectively), and fewer women had two or more of these risk factors (31% versus 52%, respectively). CONCLUSION: The findings suggest that women at higher risk for coronary artery disease tend to have a lower prevalence of use of sex hormone replacement therapy.     

Age-related changes in fibrin networks and platelets of individuals over 75: a scanning electron microscopy study showing “thrombotic preparedness”

During aging, changes in vasculature, haemostasis and endothelium, including alterations of platelets, coagulation and fibrinolytic factors, occur. Research has also reported that healthy, aged individuals have heightened coagulation enzyme activity, accompanied by signs of enhanced formation of fibrin and secondary hyperfibrinolysis. It is now believed that the impaired fibrinolytic potential in old age results in a condition that has previously been described as a systemic state of ‘‘thrombotic preparedness’’. This state is far out of proportion to the physiological needs of the person. In the current research we investigate whether this apparent changed thrombotic profile in healthy aged individuals (over the age of 75), is evident in their platelet and fibrin network ultrastructure, when compared to healthy individuals under 25 years. The main differences among young and older individuals were found in the fibrin network ultrastructure. It is concluded that with age, major fibers seem to become thinner and more sparsely arranged and that minor, thin fibers dominate it the coagulum, forming a fine netlike structure. At irregular intervals in the coagulum, thicker, fibrin fiber lattices are present; this is not found in healthy individuals. This might be due to the previously suggested enhanced fibrin formation and heightened coagulation enzyme activity. Here we therefore provide ultrastructural evidence for the thrombotic preparedness previously suggested after studying biochemistry of fibrinolysis and coagulation factors in the elderly.     

A descriptive investigation of the ultrastructure of fibrin networks in thrombo-embolic ischemic stroke

Stroke is one of the leading causes of death worldwide. Formation of a fibrin clot is controlled by a group of tightly regulated plasma proteases and cofactors and a change in the fibrin fiber formation causes an alteration in clot morphology. This plays an important role during thrombotic events. In the current study we investigated the ultrastructure of fibrin networks from fifteen ischemic stroke patients by using scanning electron microscopy. Clot morphology was investigated with and without the addition of human thrombin to the platelet rich plasma. Previously it was shown that, when studying the ultrastructure of fibrin networks, the addition of thrombin is necessary to form an expansive, fully coagulated layer of fibers. Results from the addition of thrombin to the plasma showed thick, matted fibrin fibers and a net covering some of the major fibers in stroke patients. Typical control morphology with major thick fibers and minor thin fibers could be seen in some areas in the stroke patients. In stroke patients, without the addition of thrombin, a matted fibrin network still formed, indicating that the factors responsible for the abnormal fibrin morphology are present in the circulating plasma and is the cause of the observed matted, layered morphology. This is not present in healthy individuals. From the results obtained we suggest that this changed morphology might be useful in a screening regime to identify the possibility of a stroke or even to follow the progress of stroke patients after treatment.     

Deep venous thrombosis: epidemiology,acquired risk factors

Deep vein thrombosis is a frequent disease with an annual incidence reaching 5 per thousand among subjects over 75 years. Major acquired risk factors for venous thrombosis include surgery, neoplasm, reduced mobility or paresis, and a previous episode of deep vein thrombosis. Among women, hormonal status (pregnancy, oral contraceptive, hormone replacement therapy) is responsible for the majority of all venous thrombotic events. The impact of other factors is controversial: obesity, tobacco use and varicose veins. Venous thrombosis is a multifactorial disease and analysis of the interactions between acquired and inherited risk factors is an extremely interesting field of investigation.     

Thrombophilia related issues in women and children

Women experience increased thrombotic risk at pregnancy and puerperium as well as during hormonal therapy with oral contraceptives or hormone replacement therapy. Physiological and anatomical changes in pregnancy contribute to the hypercoagulable situation. Women with thrombophilia have an increased risk for venous and arterial thromboembolism as well as for gestational vascular complications including fetal loss, pre-eclampsia, placental abruption, and fetal growth restriction. Children are at increased thrombotic risk, particularly at the neonatal period, and may express thrombosis often in association with thrombophilia. This article will focuses on the clinical association, pathogenesis, and treatment of thrombophilia-related issues in women and children.     

Risk of venous thromboembolic disease associated with hormonal contraceptives and hormone replacement therapy: a clinical review

Venous thromboembolic events (VTEs) represent a serious complication related to hormonal contraception and hormone replacement therapy (HRT). Evidence on hormonal contraceptive- and HRT-related VTEs is derived almost exclusively from observational studies and points to a 2- to 6-fold increased relative risk of VTEs with either therapy. Oral contraceptive pills that contain third-generation progestins (desogestrel or gestodene) seem to be associated with greater VTE risk than those that contain levonorgestrel. Oral contraceptive pill use and HRT are associated with exponentially higher VTE relative risks when used by women who carry an inherited hypercoagulable state. The indication of a lower or a lack of VTE risk associated with the use of progestin-only contraceptives and with transdermal HRT suggests that these therapies may be safer than combination oral contraceptive pills and oral HRT for women in whom oral estrogen therapy is considered contraindicated. Data that support such safety advantages are limited and should be interpreted with caution.     

Comparing techniques: the use of recalcified plasma in comparison with citrated plasma alone and in combination with thrombin in ultrastructural studies

Fibrin plays a vital role in the coagulation process and fibrin fiber morphology can be studied using ultrastructural techniques. When studying the ultrastructure of fibrin networks, thrombin may be added to the plasma, ensuing fibrin network formation. The question that arises is whether there are differences in morphology when thrombin is added to plasma, versus morphology observed when plasma from citrated or recalcified citrated whole blood, is studied. The current study therefore aimed to compare ultrastructure of platelets and fibrin networks from these three techniques. Results indicated comparable platelet ultrastructure between smears formed from the plasma of citrated blood and that of the citrated recalcified blood. This method might give us further information regarding the 'natural state' fibrin assembly and association with platelets, when studying haemostasis. However, when studying the ultrastructure of fibrin networks, the addition of thrombin is necessary to form an expansive, fully coagulated layer of fibrin fibers.     

Comparing techniques: the use of recalcified plasma in comparison with citrated plasma alone and in combination with thrombin in ultrastructural studies

Abstract

Fibrin plays a vital role in the coagulation process and fibrin fiber morphology can be studied using ultrastructural techniques. When studying the ultrastructure of fibrin networks, thrombin may be added to the plasma, ensuing fibrin network formation. The question that arises is whether there are differences in morphology when thrombin is added to plasma, versus morphology observed when plasma from citrated or recalcified citrated whole blood, is studied. The current study therefore aimed to compare ultrastructure of platelets and fibrin networks from these three techniques. Results indicated comparable platelet ultrastructure between smears formed from the plasma of citrated blood and that of the citrated recalcified blood. This method might give us further information regarding the ‘natural state’ fibrin assembly and association with platelets, when studying haemostasis. However, when studying the ultrastructure of fibrin networks, the addition of thrombin is necessary to form an expansive, fully coagulated layer of fibrin fibers.     

Thromboembolism in women

Venous thromboembolism (VTE) occurs in one of every 1,000 individuals per year. The incidence is much lower in young persons. In persons younger than age 45, the incidence is one of every 10,000 individuals per year. VTE is a multifactorial disease due to the interaction of various risk factors that can be genetic (e.g., inherited thrombophilia), acquired (e.g., age, neoplastic or autoimmune diseases, antiphospholipid antibodies), or transient (e.g., surgical interventions, fractures, trauma, prolonged immobilization). VTE is found equally in the two sexes. There are other transient risk factors for VTE that are typical for females, and these render women more exposed than men to the risk of the disease during their lifetime. Such risk factors are encountered frequently in a woman's life; they are oral contraceptive (OC) use, hormone replacement therapy, and pregnancy/puerperium. Moreover, various obstetric complications have attributed at least in part to an impaired placental circulation, suggesting a thrombosis theory as their common basis. In this review, the relationship between VTE and risk factors specifically of women is discussed, also in relation to coagulation abnormalities causing inherited thrombophilia.     

Oral contraceptives and inherited thrombophilia: a gene-environment interaction with a risk of venous thrombosis?

There are indications in the literature that asymptomatic women with an inherited thrombophilic defect who use oral contraceptive have an increased risk of venous thrombosis. There are no consistent data regarding the thrombotic risk in users of oral contraceptives with an inherited thrombophilic defect and personal history of venous thrombosis. Selective genetic screening on the basis of clinical judgment, and family and personal history, instead of universal screening, may be useful before oral contraceptives are prescribed. Nonetheless, the actual risks and benefits of such practice remain to be examined.     

Hormones and pregnancy: thromboembolic risks for women

During their lifetimes, women face several unique situations with an increased risk of venous thromboembolism (VTE). Doctors in a variety of specialties must advise women on the risks of oral contraceptives (OC), hormone replacement or pregnancy. Modern 'low dose' OC are associated with a three to sixfold increased relative risk of VTE. Hormone replacement and selective oestrogen receptor modulators confer a similar two to fourfold increase in thrombotic risk. However, because the baseline incidence of thrombosis is higher in older postmenopausal women, the absolute risk is higher than in younger OC users. The risk of venous thrombosis is six to 10-fold higher during pregnancy than in non-pregnant women of similar age. Thrombophilic disorders increase the thrombotic risk of OC, hormone replacement and pregnancy, especially in women with homozygous or combined defects. This review focuses on recent data estimating the thrombotic risk of hormonal therapies and pregnancy in women with and without other thrombotic risk factors.     

Comparison of hormone levels in nipple aspirate fluid of pre- and postmenopausal women: effect of oral contraceptives and hormone replacement

The effects of ovarian suppression by oral contraceptives as well as hormone replacement therapy were studied on hormone levels and on products of hormone action in nipple aspirate fluid (NAF) from breasts of pre- and postmenopausal women. Multiple samples per subject revealed high consistency (intraclass correlation coefficients) for all products measured. Compared with premenopausal women, NAF progesterone was much lower in postmenopausal women, but NAF androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate concentrations were not different. With oral contraceptive use, estradiol, estrone sulfate, and progesterone levels were similarly lower in serum and NAF. In postmenopausal women, NAF estradiol and estrone sulfate were not significantly less than those in premenopausal women, nor were epidermal growth factor or cathepsin D levels, but IL-6 was elevated. Despite corresponding changes in hormones in serum and NAF over time, correlations based on simultaneous sampling were not significant. It is concluded that: 1) potential precursors of estradiol remain at comparable levels in the breast after menopause; 2) local synthesis is important for maintenance of estradiol levels in NAF of postmenopausal women but less important for progesterone; and 3) changes in the serum parameters are accurately reflected in NAF, but only after a matter of days. These findings provide additional validation for the physiological relevance of NAF hormone levels as potential breast cancer risk markers.     

Quantification of the adverse effect of ethinylestradiol containing oral contraceptive pills when used in conjunction with growth hormone replacement in routine practice

Objective Oestrogen antagonizes the action of growth hormone (GH). For women with combined GH and oestrogen deficiency, transdermal oestradiol is more favourable in this regard compared to oral oestradiol. Oral contraceptive pills containing ethinylestradiol (EE) are commonly used in young women with GHD and there is little information on the impact of this form of oestrogen. Design A case note review of women with growth hormone deficiency (GHD) attending a tertiary endocrine clinic comparing the dose of GH and serum insulin‐like growth factor 1 concentrations and the type of exogenous oestrogen. Methods All women with GHD between the ages of 18 and 47 attending University College London Hospitals (UCLH) were included and grouped according to type of oestrogen replacement. Weight, GH dose and serum IGF‐I concentrations were recorded at 121 visits in 88 women. Results The daily dose of GH was significantly higher and the GH responsivity was significantly lower in the EE group compared to those taking no oestrogen and transdermal oestrogen. The additional cost of GH for women using EE compared to transdermal oestradiol was £6016 per patient per year. Effectiveness of GH improved in all women changing from EE to another form of oestrogen. Conclusion Use of oral contraceptive pills containing EE should be avoided in women receiving treatment with GH. Alternative options include oral or transdermal hormone replacement therapy (HRT) preparations for those that require oestrogen replacement or a progesterone‐based regimen for contraceptive purposes.     

Drugs employed during pregnancy and contraceptive methods in rheumatic disease. New evidence

Voluntary birth control, the ability to identify the best moment for becoming pregnant depending on disease activity, and the need to avoid conception during the administration of teratogenic drugs are the main reasons for the use of contraceptive methods among women with rheumatic diseases. This article reviews the risks that antirheumatic drugs represent during conception, pregnancy and lactation and the contraceptive methods that are currently available to patients. Hormonal therapy has developed considerably and can further our understanding of safety aspects, especially for systemic lupus erythematosus patients. Recently the methods of administration have evolved, and now include transdermal and intravaginal routes, a progesterone-releasing intrauterine device, and an extended-cycle oral contraceptive. Rheumatologists work increasingly in conjunction with patients to assist in choices regarding contraceptive methods and pregnancy planning. Each decision should be individualized according to the personal preference and the stage of reproductive life.     

Hormone replacement therapy in ischemic heart disease prevention in women. Arguments against

Hormone replacement therapy is one of the most difficult issues women and their doctors face. Epidemiological studies have consistently found that women using hormone replacement therapy are at a substantially lower risk of developing coronary heart disease. Observational data are supported by findings demonstrating that hormone replacement therapy improves several risk factors o coronary heart disease, specially the favourable changes in lipid profile. However, no study has clearly established hormones help prevent heart disease. In women without heart disease, the benefits of hormone replacement therapy are unclear. However, recent clinical trials have sown that the use of hormone replacement therapy does not provide cardiovascular benefits in women with established heart disease.