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November 2008

Estrogens and vascular thrombosis.

PIP: The incidence of thromboses among young women has increased with widespread use of oral contraceptives (OCs) due to the significant thromboembolic risk of estrogen. Estrogens intervene at the vascular, platelet, and plasma levels as a function of hormonal variations in the menstrual cycle, increasing the aggregability of the platelets and thrombocytes, accelerating the formation of clots, and decreasing the amount of antithrombin III. Estrogens are used in medicine to treat breast and prostate cancers and in gynecology to treat dysmenorrhea, during the menopause, and in contraception. Smoking, cardiovascular disease and hypertension, hypercholesterolemia, and diabetes are contraindicators to estrogen use. Thrombosis refers to blockage of a blood vessel by a clot or thrombus. Before estrogens are prescribed, a history of phlebitis, obesity, hyperlipidemia, or significant varicosities should be ruled out. A history of venous thrombosis, hyperlipoproteinemia, breast nodules, serious liver condition, allergies to progesterone, and some ocular diseases of vascular origin definitively rule out treatment with estrogens. A family history of infarct, embolism, diabetes, cancer, or vascular accidents at a young age signals a need for greater patient surveillance. All patients receiving estrogens should be carefully observed for signs of hypertension, hypercholesterolemia, hypercoagulability, or diabetes. Nurses have a role to play in carefully eliciting the patient’s history of smoking, personal and family medical problems, and previous and current laboratory results, as well as in informing the patients of the risks and possible side effects of OCs, especially for those who smoke. Nurses should educate patients receiving estrogens, especially those with histories of circulatory problems, to avoid standing in 1 position for prolonged periods, avoid heat which is a vasodilator, avoid obesity, excercise regularly, wear appropriate footgear, and follow other good health practices.

Soins Gynecol Obstet Pueric Pediatr. 1982 Sep;(16):39-41

Serum estradiol and risk of stroke in elderly men.

OBJECTIVE: To determine if levels of serum estradiol and testosterone can predict stroke in a population-based sample of elderly men. METHODS: Serum 17beta estradiol and testosterone were measured in 2,197 men aged 71 to 93 years who participated in the Honolulu-Asia Aging Study from 1991 to 1993. All were free of prevalent stroke, coronary heart disease, and cancer. Participants were followed to the end of 1998 for thromboembolic and hemorrhagic events. RESULTS: During the course of follow-up, 124 men developed a stroke (9.1/1,000 person-years). After age adjustment, men in the top quintile of serum estradiol (> or =125 pmol/L [34.1 pg/mL]) experienced a twofold excess risk of stroke vs men whose estradiol levels were lower (14.8 vs 7.3/1,000 person-years, p < 0.001). Among the lower quintiles, there were little differences in the risk of stroke. Findings were also significant and comparable for bioavailable estradiol and for thromboembolic and hemorrhagic events. After additional adjustment for hypertension, diabetes, adiposity, cholesterol concentrations, atrial fibrillation, and other characteristics, men in the top quintile of serum estradiol continued to have a higher risk of stroke vs those whose estradiol levels were lower (relative hazards = 2.2; 95% CI = 1.5 to 3.4, p < 0.001). Testosterone was not related to the risk of stroke. CONCLUSIONS: High levels of serum estradiol may be associated with an elevated risk of stroke in elderly men.

Neurology. 2007 Feb 20;68(8):563-8

Estradiol in elderly men.

The role of estrogens in male physiology has become more evident, as a consequence of the discovery of human models of estrogen deficiency such as estrogen resistance or aromatase deficiency. In males, testosterone is the major source of plasma estradiol, the main biologically active estrogen, only 20% of which is secreted by the testes. Plasma estrone, 5% of which is converted to plasma estradiol, originates from tissue aromatization of, mainly adrenal, androstenedione. The plasma concentration of estradiol in males is 2-3 ng/dl and its production rate in blood is 25-40 micrograms/24 h; both of these values are significantly higher than in postmenopausal women. Plasma levels of estradiol do not necessarily reflect tissue-level activity as peripherally formed estradiol is partially metabolized in situ; thus, not all enters the general circulation, with a fraction remaining only locally active. Of the factors influencing plasma estradiol levels, plasma testosterone is a major determinant. However, the age-associated decrease in testosterone levels is scarcely reflected in plasma estradiol levels, as a result of increasing aromatase activity with age and the age-associated increase in fat mass. Free and bioavailable estradiol levels do decrease modestly with age as does the ratio of free testosterone to free estradiol, the latter testifying to the age-associated increased aromatization of testosterone. Estradiol levels are highly significantly positively related to body fat mass and more specifically to subcutaneous abdominal fat, but not to visceral (omental) fat. Indeed, aromatase activity in omental fat is only one-tenth of the activity in gluteal fat. Estrogens in males play an important role in the regulation of the gonadotropin feedback, several brain functions, bone maturation, regulation of bone resorption and in lipid metabolism. Moreover, they affect skin metabolism and are an important factor determining sex interest in man.

Aging Male. 2002 Jun;5(2):98-102

Low serum testosterone and high serum estradiol associate with lower extremity peripheral arterial disease in elderly men. The MrOS Study in Sweden.

OBJECTIVES: This study sought to determine whether serum levels of testosterone and estradiol associate with lower extremity peripheral arterial disease (PAD) in a large population-based cohort of elderly men. BACKGROUND: Few studies have explored the relationship between serum sex steroids and lower extremity PAD in men. METHODS: The Swedish arm of the MrOS (Osteoporotic Fractures in Men) study (n = 3,014; average age 75.4 years) assessed ankle-brachial index (ABI) and defined lower extremity PAD as ABI <0.90. Radioimmunoassay measured serum levels of total testosterone, estradiol, and sex hormone-binding globulin, and we calculated free testosterone and free estradiol levels from the mass action equations. RESULTS: A linear regression model including age, current smoking, previous smoking, diabetes, hypertension, body mass index, free testosterone, and free estradiol showed that free testosterone independently and positively associates with ABI (p < 0.001), whereas free estradiol independently and negatively associates with ABI (p < 0.001). Logistic regression analyses showed that free testosterone in the lowest quartile (vs. quartiles 2 to 4; odds ratio [OR] 1.65, 95% confidence interval [CI] 1.22 to 2.23, p = 0.001) and free estradiol in the highest quartile (vs. quartiles 1 to 3; OR 1.45, 95% CI 1.09 to 1.94, p = 0.012) independently associate with lower extremity PAD. CONCLUSIONS: This cross-sectional study shows for the first time that low serum testosterone and high serum estradiol levels associate with lower extremity PAD in elderly men. Future prospective and interventional studies are needed to establish possible causal relationships between sex steroids and the development of lower extremity PAD in men.

J Am Coll Cardiol. 2007 Sep 11;50(11):1070-6

Endogenous sex hormones and C-reactive protein in healthy postmenopausal women.

Background. Oral oestrogen replacement therapy increases levels of C-reactive protein (CRP). CRP is an established strong predictor of cardiovascular events. It is unknown whether endogenous oestrogen levels are associated with CRP. We therefore studied the relationship between endogenous sex hormones and CRP in healthy postmenopausal women emphasizing the role of body composition as peripheral fat is both a main source of oestrogen production after menopause and an endocrine tissue with inflammatory activities. Subjects and methods. The study population comprised 889 women participating in the PROSPECT study, an ongoing population-based cohort study. Information on risk factors was collected by questionnaires and clinical examination. Endogenous sex hormone levels and CRP were measured with double antibody radio immuno assay (RIA) from fasting plasma samples. In this cross-sectional study, associations between risk factors and lnCRP were studied using linear regression models. Results. Increases in oestrone and free oestradiol levels and the free androgen index were related to an increase in lnCRP of 1.19, 1.23 and 1.21 mg dL(-1) respectively. Body mass index (BMI), waist circumference and physical activity were strongly related to CRP levels, independent of age and other cardiovascular risk factors. Levels of all sex steroids but dehydroepiandrostenedione decreased with age. In age-adjusted analyses, an increase in waist circumference or BMI by one quartile was associated with a 1.28-fold and 1.26-fold increase in CRP. The relationship between endogenous hormones and CRP was modestly attenuated but remained highly significant after adjustment for body composition, physical activity and other traditional cardiovascular risk factors. Conclusions. Our findings show that in postmenopausal women high levels of endogenous oestrogenic and androgenic sex steroids coincide with high CRP levels. This was only explained in part by markers of body composition or intra-abdominal fat.

J Intern Med. 2008 Mar 12

A potential paradox in prostate adenocarcinoma progression: oestrogen as the initiating driver.

One in 10 men in the developed world will present with prostate cancer (CaP), and in an ageing population developing strategies for its chemoprevention or treatment is of significance. For decades, androgen ablation has remained the frontline treatment for CaP that is no longer organ-confined and thus deemed surgically inoperable. Orchidectomy or drug-induced reduction of serum testosterone levels with the consequent removal of growth-promoting effects in the prostate is the driving rationale for this regimen. However, resistance often develops within a few months to years and androgen-insensitive tumours develop. In recent years, there has been an increasing focus on chemoprevention with agents such as finasteride being employed to reduce the risk of developing CaP. Significantly, such chemoprevention strategies are also based on 5alpha-reductase inhibition thus reducing intraprostatic dihydrotestosterone levels. Although there may be an overall reduction in CaP incidence in cohorts using such chemoprevention, in a subset of users who do develop this pathology there results a more aggressive, higher-grade disease. There have also been suggestions regarding the protective role of androgens against high-grade CaP. This leads to the intriguing notion that 17beta-oestradiol (E2) may be an initiating driver of CaP; in fact, in old studies in which CaP was induced in rodents, E2 often accelerated the effect of the carcinogen. Might certain chemoprevention strategies or androgen ablation result in a systemic feedback loop in hormone synthesis or metabolism? If so, elevated serum E2 levels could result in its increased conversion to genotoxic catechol oestrogens in target tissues such as the prostate. Paradoxically, if E2 were to be an initiating factor in CaP, anti-oestrogens might be an overlooked treatment or chemoprevention strategy.

Eur J Cancer. 2008 May;44(7):928-36

Catechol quinones of estrogens in the initiation of breast, prostate, and other human cancers: keynote lecture.

Estrogens can be converted to electrophilic metabolites, particularly the catechol estrogen-3,4-quinones, estrone (estradiol)-3,4-quinone [E(1)(E(2))-3,4-Q], which react with DNA to form depurinating adducts. These adducts are released from DNA to generate apurinic sites. Error-prone repair of this damage leads to the mutations that initiate breast, prostate, and other types of cancer. The reaction of E(1)(E(2))-3,4-Q with DNA forms the depurinating adducts 4-hydroxyE(1)(E(2))-1-N3adenine [4-OHE(1)(E(2))-1-N3Ade] and 4-OHE(1)(E(2))-1-N7guanine(Gua). These two adducts constitute >99% of the total DNA adducts formed. The E(1)(E(2))-2,3-Q forms small amounts of the depurinating 2-OHE(1)(E(2))-6-N3Ade adducts. Reaction of the quinones with DNA occurs more abundantly when estrogen metabolism is unbalanced. Such an imbalance is the result of overexpression of estrogen-activating enzymes and/or deficient expression of deactivating (protective) enzymes. Excessive formation of E(1)(E(2))-3,4-Q is the result of this imbalance. Oxidation of catechols to semiquinones and quinones is a mechanism of tumor initiation not only for endogenous estrogens, but also for synthetic estrogens such as hexestrol and diethylstilbestrol, a human carcinogen. This mechanism is also involved in the initiation of leukemia by benzene, rat olfactory tumors by naphthalene, and neurodegenerative diseases such as Parkinson’s disease by dopamine. In fact, dopamine quinone reacts with DNA similarly to the E(1)(E(2))-3,4-Q, forming analogous depurinating N3Ade and N7Gua adducts. The depurinating adducts that migrate from cells and can be found in body fluids can also serve as biomarkers of cancer risk. In fact, a higher level of estrogen-DNA adducts has been found in the urine of men with prostate cancer and in women with breast cancer compared to healthy controls. This unifying mechanism of the origin of cancer and other diseases suggests preventive strategies based on the level of depurinating DNA adducts that generate the first critical step in the initiation of diseases.

Ann N Y Acad Sci. 2006 Nov;1089:286-301

The role of estrogens and estrogen receptors in normal prostate growth and disease.

Estrogens have significant direct and indirect effects on prostate gland development and homeostasis and have been long suspected in playing a role in the etiology of prostatic diseases. Direct effects are mediated through prostatic estrogen receptors alpha (ERalpha) and beta (ERbeta) with expression levels changing over time and with disease progression. The present review examines the evidence for a role of estrogens and specific estrogen receptors in prostate growth, differentiation and disease states including prostatitis, benign prostatic hyperplasia (BPH) and cancer and discusses potential therapeutic strategies for growth regulation via these pathways.

Steroids. 2008 Mar;73(3):233-44

Important functions of estrogens in men—breakthrough in contemporary medicine.

Estradiol (E2) is traditionally recognised as the female sex hormone. Since discovery of estrogens in the early forties of XX century it has been believed, that these hormones caused impairment of the gonadal function in men or didn’t exert any influence. New studies are contradictory, but indicate also a possible involvement of estrogens in the pathogenesis of some systemic diseases of men. The main source of E2 in men is adipose tissue and the brain. E2 is also produced in adrenals, liver, mammary glands, hair and in male gonads. Daily production and blood level of E2 in men are higher than those in postmenopausal women. In 1988 we were the first to demonstrate that E2 is an important hormonal signal for initiation of spermatogenesis. The traditional view about unimportant or inhibitory role of E2 in male physiology was finally refuted thanks to discovery of the estrogen receptors in males. In the middle 90ties transgenic mice with the lack of estrogen receptor (ER knockout) or enzyme aromatase, that enable the conversion of testosterone into E2, were produced. Observations of men with inherited mutations of these genes, considerably extended our knowledge about stimulatory role of E2 in men in the formation of bone stroma, inhibition of their linear growth, lipids metabolism and sexual maturation, the effects that were attributed to testosterone action until today. New data indicate role of estrogens and ER in the function of the cardio-vascular system. Their link with development of arteriosclerosis seems, however, to be bipolar. In single reported cases of men with the inactivating mutations of ERalpha or aromatase genes, a precocious arteriosclerosis is noted. From the other site, men homozygous for the most common variant of ERalpha gene (ESR1c.454-397cc) have a significantly increased risk of myocardial infraction. Estrogens are the risk factors in prostatic cancer and their local tissue increase in autoimmune diseases is connected with aggravation of the proliferative complications of these disorders.

Przegl Lek. 2005;62(9):908-15

Estrogens and bone health in men.

It has generally been held that estrogen and testosterone are the major sex steroids regulating bone metabolism in women and men, respectively. However, the description of several “experiments of nature” led to a reconsideration of this notion. Thus, a male carrying homozygous mutations in the ER-alpha gene and two males with homozygous mutations in the aromatase gene had osteopenia, unfused epiphyses, and elevated indices of bone turnover. Though these findings indicated that estrogen plays a role in regulating the male skeleton, they left unresolved the issue of whether estrogen acted on the male skeleton mainly to enhance bone mass acquisition during growth and maturation, or whether it also acted to retard bone loss in aging individuals. To address this issue, several cross-sectional observational studies have related bone mineral density (BMD) to sex steroids in elderly men, and found that estrogen correlated better than testosterone with BMD. In addition, recent longitudinal studies from our group indicate that bioavailable estrogen correlated better than testosterone both with the gain in BMD in young men and with loss of BMD in elderly men. These observational studies do not, however, prove causality, which requires direct interventional studies. Thus, we eliminated endogenous testosterone and estrogen production in 59 elderly men (mean age 68 years), studied them first under conditions of physiologic testosterone and estrogen replacement, and then assessed the impact on bone turnover of withdrawing both testosterone and estrogen, withdrawing only testosterone, only estrogen, or continuing both. We found that estrogen played the major role in regulating bone resorption in these men, and that both estrogen and testosterone were important in maintaining bone formation. Collectively then, these findings indicate that estrogen plays a dominant role in regulating the male skeleton.

Calcif Tissue Int. 2001 Oct;69(4):189-92

Estradiol, testosterone, and the risk for hip fractures in elderly men from the Framingham Study.

BACKGROUND: Low serum estradiol has been more strongly associated with low bone mineral density in elderly men than has testosterone, but its association with incident hip fracture is unknown. We examined whether low estradiol increases the risk for future hip fracture among men and explored whether testosterone levels influence this risk. METHODS: We examined 793 men (mean age = 71 years) evaluated between 1981 and 1983, who had estradiol measures and no history of hip fracture, and followed until the end of 1999. Total estradiol and testosterone were measured between 1981 and 1983. Hip fractures were identified and confirmed through medical records review through the end of 1999. We created 3 groups of men based on estradiol levels and performed a Cox-proportional hazards model to examine the risk for incident hip fracture, adjusted for age, body mass index, height, and smoking status. We performed similar analyses based on testosterone levels, and then based on both estradiol and testosterone levels together. RESULTS: There were 39 men who sustained an atraumatic hip fracture over follow-up. Incidence rates for hip fracture (per 1000 person-years) were 11.0, 3.4, and 3.9 for the low (2.0-18.1 pg/mL [7-67 pmol/L]), middle (18.2-34.2 pg/mL [67-125 pmol/L]), and high (> or =34.3 pg/mL [> or =126 pmol/L]) estradiol groups, respectively. With adjustment for age, body mass index, height, and smoking status, the adjusted hazard ratios for men in the low and middle estradiol groups, relative to the high group, were 3.1 (95% confidence interval [CI], 1.4-6.9) and 0.9 (95% CI, 0.4-2.0), respectively. In similar adjusted analyses evaluating men by their testosterone levels, we found no significant increased risk for hip fracture. However, in analyses in which we grouped men by both estradiol and testosterone levels, we found that men with both low estradiol and low testosterone levels had the greatest risk for hip fracture (adjusted hazard ratio: 6.5, 95% CI, 2.9-14.3). CONCLUSION: Men with low estradiol levels are at an increased risk for future hip fracture. Men with both low estradiol and low testosterone levels seem to be at greatest risk for hip fracture.

Am J Med. 2006 May;119(5):426-33