Endogenous Estradiol Levels Research Articles

Estradiol and Progesterone Regulate HIV Type 1 Replication in Peripheral Blood Cells

Endogenous levels of estradiol and progesterone fluctuate in the peripheral blood of premenopausal women during the reproductive cycle. We studied the effects of these sex hormones on HIV-1 replication in peripheral blood mononuclear cells (PBMCs). We compared HIV-1 replication in PBMCs infected in the presence of mid-secretory (high concentrations) and mid-proliferative (low concentrations) or in the absence of sex hormones. With PBMCs from men, we used concentrations of estradiol and progesterone that are normally present in their plasma. Our findings demonstrate that mid-proliferative phase conditions increased, and mid-secretory phase conditions decreased, HIV-1 replication. To determine if sex hormones affect specific stages of the viral life cycle we performed real-time PCR assays and found decreased levels of HIV-1 integration in the mid-secretory phase and increased levels viral transcription in the mid-proliferative phase. No significant effects on HIV-1 reverse transcription or on CCR5 expression were found. In addition, we assessed hormonal regulation of the HIV-1 LTR in the absence of the viral regulatory protein Tat. We observed that mid-proliferative hormone levels enhanced, whereas mid-secretory hormone concentrations reduced, the activity of the LTR. These findings demonstrate that in HIV-1-infected cells, estradiol and progesterone regulate HIV-1 replication most likely by directly altering HIV-1 transcriptional activation. An additional indirect mechanism of sex hormone regulation of cytokine and chemokine secretion cannot be excluded.

Nonsteroidal Anti-inflammatory Drug Use and Serum Total Estradiol in Postmenopausal Women

Laboratory and epidemiologic evidence suggest that nonsteroidal anti-inflammatory drug (NSAID) use may be inversely related to the risk of breast cancer; however, the mechanism by which NSAIDs may protect against the development of this disease is uncertain. The objective of this observational study was to assess the relationship between current NSAID use and endogenous estradiol levels, an established breast cancer risk factor. To evaluate this aim, we conducted a cross-sectional investigation among 260 postmenopausal women who were not recently exposed to exogenous hormones. Information on current NSAID use (aspirin, cyclooxygenase-2 inhibitors, and other NSAIDs combined) was collected using a questionnaire at the time of blood draw. Estradiol was quantified in serum by radioimmunoassay. General linear models were used to evaluate the association between NSAID use and serum total estradiol. The age-adjusted and body mass index-adjusted geometric mean serum estradiol concentration among NSAID users (n = 124) was significantly lower than nonusers of NSAIDs (n = 136; 17.8 versus 21.3 pmol/L; P = 0.03). Further adjustment for additional potential confounding factors did not substantially alter estimates (17.7 versus 21.2 pmol/L; P = 0.03). To our knowledge, this report is the first to examine the relationship between NSAID use and serum estradiol in postmenopausal women. These cross-sectional findings suggest that NSAID use may be associated with lower circulating estradiol levels, potentially representing one mechanism through which NSAIDs exert protective effects on breast cancer.

Insulin, Insulin-like Growth Factor-I, Endogenous Estradiol, and Risk of Colorectal Cancer in Postmenopausal Women

Obesity is a risk factor for colorectal cancer, and hyperinsulinemia, a common condition in obese patients, may underlie this relationship. Insulin, in addition to its metabolic effects, has promitotic and antiapoptotic activity that may be tumorigenic. Insulin-like growth factor (IGF)-I, a related hormone, shares sequence homology with insulin, and has even stronger mitogenic effects. However, few prospective colorectal cancer studies directly measured fasting insulin, and none evaluated free IGF-I, or endogenous estradiol, a potential cofactor in postmenopausal women. Therefore, we conducted a case-cohort investigation of colorectal cancer among nondiabetic subjects enrolled in the Women's Health Initiative Observational Study, a prospective cohort of 93,676 postmenopausal women. Fasting baseline serum specimens from all incident colorectal cancer cases (n = 438) and a random subcohort (n = 816) of Women's Health Initiative Observational Study subjects were tested for insulin, glucose, total IGF-I, free IGF-I, IGF binding protein-3, and estradiol. Comparing extreme quartiles, insulin [hazard ratio (HR)(q4-q1), 1.73; 95% confidence interval (CI), 1.16-2.57; P(trend) = 0.005], waist circumference (HR(q4-q1), 1.82; 95% CI, 1.22-2.70; P(trend) = 0.001), and free IGF-I (HR(q4-q1), 1.35; 95% CI, 0.92-1.98; P(trend) = 0.05) were each associated with colorectal cancer incidence in multivariate models. However, these associations each became nonsignificant when adjusted for one another. Endogenous estradiol levels, in contrast, were positively associated with risk of colorectal cancer (HR comparing high versus low levels, 1.53; 95% CI, 1.05-2.22), even after control for insulin, free IGF-I, and waist circumference. These data suggest the existence of at least two independent biological pathways that are related to colorectal cancer: one that involves endogenous estradiol, and a second pathway broadly associated with obesity, hyperinsulinemia, and free IGF-I.

The role of hormone replacement therapy in the management of premature ovarian failure

Premature ovarian failure (POF) generally occurs before 40 years of age and is characterized by amenorrhea and follicle-stimulating hormone levels within the menopausal range. Variations in the endogenous estradiol levels can also occur. The potential risks and benefits of hormone replacement therapy for women with POF are discussed in this Viewpoint.

Endogenous Estrogen Levels and the Effects of Ultra-Low-Dose Transdermal Estradiol Therapy on Bone Turnover and BMD in Postmenopausal Women

In a randomized controlled trial of a 0.014 mg/d transdermal estradiol patch, serum bone turnover markers decreased to a greater degree in postmenopausal women with lower versus higher endogenous estradiol levels. This suggests that the protective effects of ultra-low-dose estrogen therapy on the postmenopausal skeletal health may depend critically on women's endogenous estrogen levels before treatment. Postmenopausal women with very low or undetectable estradiol levels have lower BMD, increased bone turnover, and increased risk of hip and vertebral fracture. We assessed whether the effects of ultra-low-dose 0.014 mg/d transdermal estradiol (Menostar; Berlex, Montvale, NJ, USA) on bone turnover and BMD are influenced by endogenous estradiol levels. We analyzed data from postmenopausal women (mean age, 66 yr) randomized to an 0.014-mg/d transdermal estradiol patch or placebo in the ultra-low-dose transdermal estrogen (ULTRA) trial. The free estradiol index (FEI), calculated as the ratio of total estradiol (by mass spectometry) to sex hormone-binding globulin (SHBG; by immunoradiometric assay) x 100, was used to estimate bioavailable estradiol at baseline. Among the 382 women who adhered to >or=80% of study medication, we examined change in serum osteocalcin and bone-specific alkaline phosphatase levels at 12 mo and total hip and lumbar spine BMD at 24 mo in each quintile of FEI. Compared with women in the highest quintile of FEI, those in the lowest quintile of FEI had a 26% greater reduction in bone-specific alkaline phosphatase and 15% greater reduction in osteocalcin in response to ultra-low estradiol treatment (p for trend across quintiles < 0.05). There was a trend toward greater improvement in total hip BMD (p = 0.06) but not spine BMD (p = 0.90) in those with lower versus higher FEI levels. The beneficial effects of ultra-low-dose 0.014-mg/d transdermal estrogen therapy on skeletal health may depend critically on women's endogenous estrogen levels before treatment.

Gender and endogenous levels of estradiol do not influence adult hippocampal neurogenesis in mice

In several species, including rat and vole, the proliferation of new neurons in the adult dentate gyrus (DG) subgranular zone (SGZ) is influenced by both gender and endogenous levels of the gonadotropic steroid hormone estradiol. However, little is known about how adult neurogenesis is regulated by these factors in the mouse. We report here that adult C57BL/6 mice do not have gender differences in hippocampal proliferation or neurogenesis. In addition, the production of new SGZ cells in female mice was not influenced by estrous cycle or after ovariectomy, suggesting that fluctuations in endogenous estradiol levels do not alter adult neurogenesis in the mouse. Both male and female mice had a greater number of BrdU-immunoreactive SGZ cells following chronic treatment with fluoxetine. This demonstrates a parallel proliferation response in both genders, and opens avenues for addressing the neurogenesis hypothesis of depression in female rodents. These findings underscore a distinct regulation of adult neurogenesis in mice vs. other rodents, and are discussed in regard to their implications for the study of adult hippocampal neurogenesis.

Volumetric BMD and Vascular Calcification in Middle-Aged Women: The Study of Women's Health Across the Nation

The association of spine vBMD with AC and CAC was studied in a biracial cohort of 490 middle-aged women in the Study of Women's Health Across the Nation. Lower vBMD was related to high AC, but not to CAC, independent of age and shared risk factors between osteoporosis and cardiovascular disease. This analysis studied the association of spine volumetric BMD (vBMD) with aortic (AC) and coronary artery (CAC) calcification in middle-aged women and evaluated whether such associations were independent of age and shared risk factors between osteoporosis and cardiovascular disease (CVD) or explained by endogenous estradiol levels. Vascular calcification and trabecular vBMD of the spine were measured using electron-beam CT in 490 women free from clinical CVD in the Study of Women's Health Across the Nation. Women were 45-58 years of age, 61% were white, and 64% were perimenopausal. Calcification scores were categorized into three levels (no AC, N = 146; moderate AC, scores = 1-74, N = 221; high AC, N = 123; no CAC, N = 256; moderate CAC, score = 1-7.54, N = 111; high CAC, N = 123). The highest categories were set at the 75th percentiles. Multinomial logistic regression was used to assess the association between vBMD (per SD) and the AC and CAC levels, with no calcification as the reference group. AC and CAC were detected in 70% and 48% of the population, respectively. Mean vBMD was 161.6 +/- 37.2 (SD) mg/ml. vBMD was associated with high AC in unadjusted, age-adjusted, and risk factor-adjusted analysis. Per 1 SD decrease in vBMD, the adjusted odds of high AC compared with no AC was significantly increased by 68% (95% CI, 1.06-2.68). Estradiol did not influence this association. vBMD was related to high CAC in unadjusted (OR = 1.35; 95% CI, 1.08-1.70) but not adjusted models. No associations of vBMD with moderate AC or CAC were observed. Lower vBMD was related to high AC, but not to CAC, in a biracial cohort of healthy middle-aged women independent of age and shared risk factors between osteoporosis and CVD. Further research should study possible pathophysiological links between the two conditions and the potential for common preventive and therapeutic interventions.

The relationship between factors affecting endogenous oestradiol levels in postmenopausal women and breast cancer

Breast cancer accounts for 1 in 4 of all female cancers worldwide; approaching 13,000 women dying per year in the UK alone. Seventy five per cent of all diagnosed breast cancers are oestrogen receptor (ER) positive. Ovarian synthesis of oestrogens ceases at menopause and as breast cancer is more prevalent in postmenopausal women the non-ovarian sources of oestrogen are important in disease progression. There is now considerable evidence that associates increased breast cancer risk with prolonged exposure to oestrogens hence greater attention is now being given to determining whether the measurement of plasma oestrogen may assist in identifying chemoprevention target groups. Studies suggest that in most postmenopausal patients the intra-tumoural concentrations of oestrogens are up to 20-fold higher than those present in the plasma however, while the extent of biosynthesis of oestrogens within breast tissue is a major determinant of local exposure, plasma levels are a useful indicator of overall metabolism in peripheral tissues. As such it is important to understand factors that influence these measurements. This review summarises the impact of lifestyle such as body mass index, together with the role of genetic polymorphisms placed within the context of designing future epidemiological studies and breast cancer risk algorithms.

Risk factors for breast cancer in older women: the relative contribution of bone mineral density and other established risk factors

To determine the contribution of bone mineral density (BMD) to breast cancer risk relative to other established breast cancer risk factors in postmenopausal women with osteoporosis. Data for this analysis comprised those collected from women randomized to placebo in the MORE and CORE trials (N = 2,576). Risk factors measured at baseline included age, family history of breast cancer, estradiol level, body mass index, prior hormone therapy, BMD and vertebral fracture status. Cox proportional hazards regression models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). Over a total of 13,698 woman-years of follow-up, 65 incident breast cancers occurred. In univariate analyses, older age and family history of breast cancer were the strongest predictors of breast cancer risk, associated with a 2.4- and 2.6-fold increase in breast cancer incidence. A higher estradiol level was associated with a 1.9-fold increase in breast cancer incidence. The association between femoral neck BMD and breast cancer incidence was only significant after adjustment for age (P = 0.03). The final multivariable model included age, family history, estradiol, BMD, and the BMD-estradiol interaction since the effect of BMD on breast cancer varied by estradiol level (interaction P-value, 0.04); in those with a lower estradiol level, a higher BMD was associated with a 2.6-fold increased in breast cancer. Overall, BMD is a relatively weak predictor of breast cancer risk in these postmenopausal women with osteoporosis, after taking into consideration age, family history and endogenous estradiol level.

Circulating Estradiol Is an Independent Predictor of Progression of Carotid Artery Intima-Media Thickness in Middle-Aged Men

Estrogen treatment of men with prostate cancer is associated with increased cardiovascular morbidity and mortality; however, the role of endogenous estrogen levels for atherosclerotic disease in men is unknown. The objective of the study was to determine whether endogenous serum estradiol (E2) levels predict the progression of carotid artery intima-media thickness in men. This was a population-based, prospective cohort study (the Atherosclerosis and Insulin Resistance study) conducted in Göteborg, Sweden, among 313 Caucasian men without cardiovascular or other clinically overt diseases. Carotid artery intima-media thickness, an index of preclinical atherosclerosis, was measured by ultrasound at baseline (58 yr of age) and after 3 yr of follow-up. Serum sex hormone levels and cardiovascular risk factors (body mass index, waist to hip ratio, systolic blood pressure, serum triglycerides, plasma c-peptide, and smoking status) were assessed at study entry. There was no intervention. Association between baseline total and free E2 levels and progression of carotid intima-media thickness over 3 yr with adjustments for cardiovascular risk factors was measured. In univariate analyses, both total and free E2 levels at baseline were positively associated with the annual change in intima-media thickness. In linear regression models including E2 and cardiovascular risk factors, low-density lipoprotein and high-density lipoprotein cholesterol and E2 were identified as independent predictors of progression of carotid artery intima-media thickness (total E2 beta = 0.187, P = 0.001; and free E2 beta = 0.183, P = 0.003). Circulating E2 is a predictor of progression of carotid artery intima-media thickness in middle-aged men. Further studies are needed to investigate the role of endogenous E2 for incident cardiovascular disease events.

Endogenous sex hormones, cognitive decline, and future dementia in old men

To estimate the association of endogenous levels of bioavailable testosterone and estradiol with risk for cognitive decline and dementia in old men. Within the population-based, prospective Honolulu-Asia Aging Study, 2,974 men, aged 71 to 93 years, without dementia were reexamined 3 times over an average of 6 years for development of dementia and cognitive decline. Cognitive decline was measured with the Cognitive Abilities Screening Instrument. Incident dementia was diagnosed according to standard criteria. A total of 134 men experienced development of Alzheimer's disease (AD; including 40 cases with contributing cerebrovascular disease) and 44 experienced development of vascular dementia. Adjusting for age and other covariates, testosterone was not associated with risk for dementia (using Cox regression analyses) or cognitive decline (using random coefficient analyses). However, higher levels of estradiol were associated with risk for AD (hazard ratio per standard deviation increase, 1.25; 95% confidence interval, 1.05-1.47) and AD with cerebrovascular disease (hazard ratio, 1.19; 95% confidence interval, 1.02-1.38). Also, compared with the lowest tertile of estradiol, men in the middle and highest tertile of estradiol had 0.24 and 0.28 points lower Cognitive Abilities Screening Instrument scores, respectively, for each year increase in age. In old men, endogenous testosterone levels are not associated with risk for cognitive decline and AD, whereas higher estrogen levels increase risk for cognitive decline and AD.

P1-188: Endogenous sex hormones and cognitive decline in elderly men

Decline in cognitive function is an early symptom of dementia. Studies conducted in elderly women and men suggested that higher levels of endogenous estradiol and testosterone are associated with better cognitive function. However, recent studies in women demonstrated adverse effects of estrogen on cognition. To determine whether low levels of endogenous sex hormones are associated with increased risk of cognitive decline in very old men. The Frail Old Men Study is a population based prospective cohort study among 403 independently living elderly men in The Netherlands to determine risk factors of health and aging in the oldest old. Participants were aged 73–94 years at baseline in 1996 and were re–examined in 2000. At baseline, serum concentrations of total and free testosterone, total and free estradiol, estrone, and relevant covariates were determined. As a measure of global cognitive functioning, participants underwent the Mini Mental State Examination (MMSE) at baseline and follow–up after 4 years. Cognitive decline was defined as a decline of 4 or more points on the MMSE at follow–up. Follow–up was complete in 244 men. Of these, the mean (SD) baseline age was 77.4 (3.2), and the mean (range) baseline MMSE was 27.5 (20–30). At follow–up, 44 men (18%) had a decline of 4 or more points on the MMSE. Using multiple logistic regression analyses, levels of total and free testosterone were not associated with cognitive decline (OR per SD increase 1.1; 95%CI 0.8–1.5 and 1.0; 95%CI 0.7–1.4, respectively). Higher levels of total and free estradiol were related to increased risk of cognitive decline (OR per SD increase 1.5; 95%CI 1.0–2.1 and 1.4; 95%CI 1.0–2.0, respectively). For estrone the OR per SD increase was 1.4 (95%CI 1.0–2.0). These associations were independent of age, education, ApoE4, BMI, waist–to–hip ratio, blood pressure, diabetes, smoking, and serum cholesterol levels. The results do not support the hypotheses that high levels of endogenous sex hormones in elderly men are associated with lower risk of cognitive decline. Further longitudinal investigations are needed to more fully understand the role of hormonal effects on cognitive decline and dementia in older men.

Polymorphisms in O 6-methylguanine DNA methyltransferase and breast cancer risk

Endogenous and exogenous estrogens influence breast cancer risk by interacting with estrogen receptor (ER). The O-methylguanine DNA methyltransferase (MGMT) gene has a dual role in repairing alkylation damage and in inhibiting ER-mediated cell proliferation. We assessed the two MGMT polymorphisms, Leu84Phe and Ile143Val, with breast cancer risk. We also evaluated the potential interactions between the two polymorphisms and estrogen-related risk factors and cigarette smoking on breast cancer risk. We conducted a nested case-control study within the Nurses' Health Study (1311 cases, 1760 controls). Compared with the 84Leu/Leu genotype, the Phe/Phe genotype had a multivariate odds ratio (OR) of 1.68 (95% confidence interval (CI), 0.98-2.88). This positive association was magnified among postmenopausal women with body mass index>25 (OR, 3.01; 95% CI, 1.30-6.94), those in the highest tertile of pre-diagnostic plasma endogenous estradiol levels (Phe carriers versus non-carriers, OR, 2.42; 95% CI, 1.49-3.94), non-current postmenopausal hormone users (OR, 2.60; 95% CI, 1.19-5.64), and possibly estrogen receptor-positive cases (OR, 1.82; 95% CI, 0.99-3.35). We did not observe a main effect of the Ile143Val polymorphism or its interactions with these factors. No interaction was observed between either of the polymorphisms and cigarette smoking on breast cancer risk. These data suggest that the Leu84Phe polymorphism affect the capacity of MGMT to inhibit estrogen receptor-mediated cell proliferation and is associated with breast cancer risk.

Hormone dependency of breast tumours developing in the Guernsey Cohort Study

The aim of this study was to determine whether endogenous estradiol levels in postmenopausal women helped determine the estrogen receptor status of subsequent breast cancers. Within the Guernsey Cohort study of 6127 women, 140 have been diagnosed with breast cancer of whom 59 had estradiol assays performed and ER status available. Estradiol levels in serum and urine were measured by radioimmunoassay and ER status of tumours by immunohistochemistry. Of the individuals in the highest tertile of serum estradiol 35% had ER+ve tumours compared with 27% in the lowest tertile. In terms of 16hydroxyestrone excretion the proportions ER+ve tumours were 22% in the lowest tertile and 38% in the highest tertile. This suggests that endogenous estrogen levels do impact on the phenotype of subsequent breast cancer.

Estradiol and cognition during androgen deprivation in men with prostate carcinoma

Salminen et al.1 present evidence that LHRH analogs, by lowering endogenous estradiol levels, impair certain cognitive processes in prostate cancer (PCa) patients. Others have shown that estradiol cognitively protects spatial memory in older men.2 Currently, estrogens are used as secondary, rather than primary, hormonal therapies for PCa patients. We propose that estradiol is likely to be more protective of cognition if it is used before patients start on an LHRH agonist. Salminen et al. do not cite data that has shown no cognitive benefits of estradiol treatment in PCa patients.3 To reconcile those differences, we suggest that estradiol's cognitive benefits are likely to be greatest in patients who have not already experienced cognitive decline—either from LHRH agonists or aging. We base this suggestion on data from menopausal women, which reveal a critical window of time at menopause when estrogenic compounds are protective of cognition.4 After cognitive decline has set in, exogenous estrogens may actually play a negative role. Extending these results to men, we should expect that estradiol will be most beneficial to PCa patients if used earlier rather than later. Estradiol lowers patients' risk of osteoporosis and incidences of hot flashes, while costing less than LHRH agonists. So, then, why not use estradiol as primary hormonal therapy for PCa? The risk of thromboembolism is real, but it can be greatly reduced if estradiol is applied transdermally. Supposedly, gynecomastia can be reduced with prophylactic radiotherapy; however, its effectiveness has not been proven in prospective studies, nor does it significantly reduce the incidence of breast complaints from patients on estradiol. Again, extrapolating from postmenopausal women, physicians should be aware that estrogens may increase urinary incontinence in patients already experiencing incontinence secondary to a prostatectomy and radiotherapy for localized PCa.5

Oral Contraceptive Use and Breast Cancer Risk: Modification by NAD(P)H:Quinone Oxoreductase (NQO1) Genetic Polymorphisms

Abstract Despite intensive study, the relationship between oral contraception (OC) and breast cancer remains unclear. OCs contain a potent synthetic estrogen (ethinyl estradiol) but lower endogenous estradiol levels, and ethinyl estradiol is a weak progenitor of semiquinones, catechol estrogens capable of damaging DNA. NAD(P)H:quinone oxoreductase (NQO1) stabilizes semiquinones, thus potentially preventing genetic damage from catechol estrogens, and the NQO1 C609T polymorphism seems functionally relevant. Using data from the Shanghai Breast Cancer Study, a population-based case-control study, we investigated the relationships between OC use (20% ever using), breast cancer, and NQO1 (C/C 31% and C/T + T/T 69%) among 1,039 cases and 1,121 controls. Breast cancer was not significantly associated with NQO1 genotype. There was a significant protective association between OC after age 30 years and premenopausal breast cancer [odds ratio (OR) 0.51, 95% confidence interval (95% CI) 0.29-0.89] primarily with the NQO1 T allele (C/C OR 0.76, 95% CI 0.31-1.82; C/T + T/T OR 0.38, 95% CI 0.18-0.80; P for interaction = 0.19). The association between premenopausal breast cancer and OCs significantly differed with NQO1 genotype when using OCs for &amp;gt;18 months (C/C OR 2.34, 95% CI 0.92-5.99; C/T + T/T OR 0.69, 95% CI 0.38-1.25; P for interaction = 0.02). Among women with the C/C genotype, postmenopausal breast cancer was significantly associated with ever-using OCs (C/C OR 2.01, 95% CI 1.08-3.74; C/T + T/T OR 0.72, 95% CI 0.49-1.05; P for interaction &amp;lt; 0.01). This crossover was stronger with OC use prior to age 30 years (C/C OR 3.00, 95% CI 1.43-6.25; C/T or T/T OR 0.49, 95% CI 0.29-0.81; P for interaction &amp;lt; 0.01). Our results require confirmation but suggest that the OC and breast cancer association depends on the ability to invoke protection from catechol estrogens.

Low levels of endogenous estradiol protect bone mineral density in young postmenopausal women

Objective Low levels of endogenous estrogens may play a role in the protection of bone mineral density (BMD) in healthy postmenopausal women. The aim of this study was to evaluate the effect of endogenous estradiol and testosterone on bone mass in young and older healthy postmenopausal women.Methods The study involved 99 postmenopausal women aged 55–75 years. The BMDs of the lumbar spine, proximal femur and total skeleton were determined. Measurements were taken of serum calcium, bone alkaline phosphatase, Crosslaps, estradiol, estrone, sex hormone binding globulin, testosterone, bioavailable testosterone and urine calcium. Estradiol was measured using a sensitive assay with a lower detection limit at 5 pg/ml.Results A multivariate analysis showed that the BMD of the lumbar spine was significantly predicted by estradiol (p < 0.05), and testosterone (p < 0.0001). Likewise, testosterone was found to be an independent predictor of the BMD of the total femur (p < 0.001) and the total skeleton (p < 0.001). The population was divided into two groups: ⩽ 65 (Group 1) and > 65 years (Group 2) of age and also stratified according to estradiol levels: > 10 and ⩽ 10 pg/ml. Significant differences in BMD were found in women in Group 1 in whom estradiol levels higher than 10 pg/ml were associated with a higher BMD of the lumbar spine ( + 14%, p < 0.01), proximal femur ( + 6%, p < 0.05) and total skeleton ( + 7%, p < 0.05) compared with women with estradiol levels below 10 pg/ml. Bone alkaline phosphatase levels (p < 0.05) and serum Crosslaps (not significant) were lower in women in Group 1 with a level of estradiol more than 10 pg/ml.Conclusion Endogenous estradiol levels higher than 10 pg/ml and testosterone protected bone mass in healthy postmenopausal women under 65 years of age. These results were not observed in the group of older women.

Cellular homeostasis and the breast

Increasing our knowledge regarding the control of cellular homeostasis in the normal human breast is important in understanding how breast tumours arise and whether compounds used for hormone replacement therapy are able to promote tumour formation In our studies on tissue from pre-menopausal, non-pregnant, non-lactating women, oestradiol is the main ovarian steroid mitogen for the breast epithelium whereas progesterone has little or no effect. Oestradiol appears to influence proliferative activity indirectly via oestrogen-receptor positive cells which control the activity of adjacent division competent cells by means of paracrine or juxtacrine growth factors. After the menopause, however, a mitogenic effect of progesterone becomes apparent which may be due to the reduction in endogenous oestradiol levels or, possibly, to tissue specific alterations in steroid sensitivity. Whatever the mechanism, the proliferative effects of progesterone on the post-menopausal breast have implications for the use of HRT.

Effects of the selective estrogen receptor modulator LY117018 on growth hormone secretion: in vitro studies

Sex steroids play an important role in modulating pulsatile growth hormone (GH) release, acting at both hypothalamic and pituitary level in both humans and experimental animals. Selective estrogen receptor modulators (SERMs) act as either estrogen receptor agonists or antagonists in a tissue-selective manner. In postmenopausal women, serum GH levels correlate positively with endogenous estradiol levels and insulin-like grwoth factor-I (IGF-I) is positively related to bone mineral density (BMD) at the spine and hip. The aim of the present study was to evaluate, for the first time, the direct effect of LY117018, an analog of raloxifene, on GH secretion from both human and rodent pituitary cells in vitro. Our results demonstrated that pharmacological concentrations of the raloxifene analog LY117018 can stimulate GH secretion through a direct action on the pituitary. LY117018 also showed an estrogen-like activity, inducing the proliferation of rat pituitary GH-secreting adenomatous cells (GH1).

Menometrorrhagia in the perimenopause is associated with increased serum estradiol

Objective: The purpose of this study was to evaluate the possible association between menometrorrhagia and the level of endogenous estrogen in perimenopausal women. Methods: A prospective controlled study in which 28 perimenopausal women >40 years presenting with menometrorrhagia were compared with 28 age-matched (±2 years) women with normal cyclical menstrual periods concerning levels of estradiol and follicle-stimulating hormone (FSH). Neither of the two groups had received sexual hormone treatment at least in 2 weeks preceding the hormonal assessment. Results: The serum level estradiol in the patients was significantly higher than in the controls (0.55 nmol/l versus 0.24 nmol/l), whereas FSH was not significantly different between the two groups (21.2 IU/l versus 11.8 IU/l). Twenty of the 28 patients had performed at histologic examination of the endometrium, and 10 of these (50%) had signs of endometrial hyperplasia. No relationship was found between the endometrial histology and the estradiol level. Conclusions: An association between a high endogenous estradiol level and menometrorrhagia in the perimenopause was demonstrated. This may have implications for the choice of treatment in this group of women. It is proposed that this type of bleeding disturbances should be controlled by progestins only, and not with combined estrogen–progestin treatment. Suppression of the associated hyperestrogenism could be achieved by use of oral contraceptives or GnRH agonists.