Endogenous Estrogen Production Research Articles

Comparative assessment of estrogenic responses with relevance to the metabolic syndrome and to menopausal symptoms in wild-type and aromatase-knockout mice

Knockout of the Cyp-19 gene (aromatase) renders mice to have insufficient endogenous estrogen production and contributes to the development of symptoms related the metabolic syndrome, including excess adiposity and insulin resistance. This study comparatively assessed the estrogen responsiveness in animal models of genetical versus surgical (ovariectomy) origin of estrogen deficiency. Evaluation of physiological parameters and gene expression pattern in response to estrogens revealed differences in estrogen responsiveness between aromatase deficient and castrated or intact wild-type mice. ArKO mice had a significantly higher bodyweight than matched ovariectomized wild-type mice. The weight of the completely regressed uterus following ovariectomy was higher than the uterine weight of ArKO mice. Further, alterations in metabolic parameters like increased serum leptin levels and decreased plasma glucose levels in genetically deficient mice became apparent. Finally, expression pattern of estrogen responsive genes differed in the two experimental models of estrogen deficiency. Both, in uterine and adipose tissues the regulation of expression of some genes either was inversed of regulation or considerably differed in the magnitude of the response in the two models. Our studies demonstrate that the cause of estrogen deficiency significantly impacts on estrogen responsiveness and may be of relevance for investigations on aspects of estrogen deficiency and metabolic and/or menopausal symptoms.

The effect of selective oestrogen receptor antagonists in an in vitro model of growth plate chondrogenesis

While oestrogen is recognized to play a key role in regulating growth, particularly in relation to epiphyseal fusion, the mechanisms that mediate its effects are still unclear. We utilized an in vitro model of chondrogenesis, the RCJ3.1C5.18 cell line, to explore the effect of oestrogen on this process. We demonstrated the presence of oestrogen receptors (ER) α and β in these cells, with increased abundance of both receptor sub-types evident as the cells differentiated. ERα localized to the nucleus, suggesting it was signalling by genomic pathways, while ERβ was seen predominantly in the cytoplasm, suggesting it may be utilizing non-genomic signalling. While exogenous oestrogen had no effect on proliferation or differentiation, we found some evidence for the endogenous production of oestrogen (intracrinology), as suggested by the expression of aromatase in these cells. Selective ERα blockade with methyl piperidinopyrazole (MPP) led to a significant reduction in both proliferation and differentiation, while ERβ blockade with R,R tetrahydrochrysene (THC) led to an increase in these parameters. This is in keeping with results from mouse knockout models suggesting that unopposed ERβ signalling leads to an inhibition of skeletal growth. Our results are further evidence for the importance of differential ER signalling in regulating chondrogenesis. Future studies examining in vivo effects of these agents are required to extrapolate these findings to a mammalian model.

Serum total estrogen levels and urinary excretion of calcium and hydroxyproline in premenopausal and postmenopausal Chinese women.

Ruey-Jian Chen, MD1 Abstract The study subjects included 26 normal young women with regular menstruation cycles and 30 postmenopausal women. The blood and fasting morning urine samples of premenopausal women were taken between the 4th to 11th day of menstrual cycle. In postmenopausal women the blood and urine specimens were taken at least one year after natural menopause, two months after surgical castration, and two months after completion of radiation therapy for cervical cancer. Serum total estrogen level was measured by radioimmunoassay. The urine hydroxyproline concentration was determined by Kivirikko's method. The mean concentrations of serum total estrogens levels were 185.5 pg/ml and 71.7 pg/ml in premenopausal and postmenopausal women respectively. The mean values of urinary calcium/creatinine (Ca/Cr) molar ratio in premenopausal and postmenopausal women were 0.139 and 0.249 respectively. The mean value of hydroxyproline/creatinine (HOPr/Cr) molar ratio was 0.012 in premenopausal women and 0.028 in postmenopausal women. The parameters of bone loss, such as Ca/Cr ratio and HOPr/Cr ratio, are inversely related with the circulating total estrogen concentration. Therefore, decreased endogenous estrogen production seems to be the major pathophysiologic basis for the enhanced rate of urinary calcium and hydroxyproline excretion in Chinese postmenopausal women.

Effect of aromatase inhibitors on the lipid profile of postmenopausal breast cancer patients

The two most commonly used alternative strategies of endocrine treatment in postmenopausal women with hormone-receptor-positive breast cancers are either the interference with estrogen signaling by a selective estrogen-receptor modulator, such as tamoxifen, or the inhibition of endogenous estrogen production via an aromatase inhibitor (AI). Tamoxifen has been used effectively for over 30 years and it is generally accepted that it exerts a beneficial effect on lipid profiles. Still, its use has been questioned especially in recent years, following indication of an increased risk of endometrial cancer, thromboembolic events and tolerability concerns, along with, most importantly, the development of resistance during long-term adjuvant treatment. On the other hand, inhibition of aromatase, the enzyme that converts androgens to estrogens, with an AI has been shown to be an effective alternative to tamoxifen in multiple clinical trials with anastrozole, letrozole and exemestane. At the same time, due to the high levels of estrogen deprivation caused by Als, there is uncertainty over the long-term safety of these agents, in particular with respect to the effects on bone metabolism of postmenopausal women and the lipid profile, and thus, cardiovascular disease. Current data on Als showing favorable, neutral or unfavorable effect on different lipid parameters in various studies, do not allow the drawing of any final conclusions about their effect on lipid metabolism. However, considering disease outcome, particularly in high-risk patients, the benefits of receiving an AI are likely to outweigh the disadvantages of any changes to lipid profiles. Therefore, each patient should be carefully evaluated before the appropriate therapy is decided and blood lipid levels should be monitored during adjuvant hormonal treatment; the instigation of lipid-lowering treatment should be undertaken if required.

Sex Differences in Outcome after Mild Traumatic Brain Injury

The objective of this study was to estimate the independent association of sex with outcome after mild traumatic brain injury (mTBI). We performed an analysis of a subset of an established cohort involving 1425 mTBI patients presenting to an academic emergency department (ED). The associations between sex and three outcomes determined 3 months after the initial ED visit were examined: post-concussive symptom (PCS) score (0, 1-5, 6-16, and >16), the number of days to return of normal activities (0, 1-7, and >7), and the number of days of work missed (0, 1-7,and >7). Logistic regression analyses were used to determine the relationship between sex and each outcome after controlling for 12 relevant subject-level variables. Of the 1425 subjects, 643 (45.1%) were female and 782 (54.9%) were male. Three months after mTBI, males had significantly lower odds of being in a higher PCS score category (odds ratio [OR] 0.62, 95% confidence interval [CI]: 0.50, 0.78); this association appeared to be more prominent during child-bearing years for females. Males and females did not significantly differ with respect to the odds of poorer outcome as defined by the number of days to return of normal activities or the number of days of work missed. Female sex is associated with significantly higher odds of poor outcome after mTBI, as measured by PCS score, after control for appropriate confounders. The observed pattern of peak disability for females during the child-bearing years suggests disruption of endogenous estrogen or progesterone production. Attempts to better understand how mTBI affects production of these hormones acutely after injury and during the recovery period may shed light on the mechanism behind poorer outcome among females and putative therapeutic interventions.

Revisiting estrogen: efficacy and safety for postmenopausal bone health.

The rapid decline in endogenous estrogen production that occurs during menopause is associated with significant bone loss and increased risk for fragility fracture. While hormone therapy (HT) is an effective means to re-establish endogenous estrogen levels and reduce the risk of future fracture, its use can be accompanied by undesirable side effects such as stroke and breast cancer. In this paper, we revisit the issue of whether HT can be both safe and effective for the prevention of postmenopausal bone loss by examining standard and alternative doses and formulations of HT. The aim of this paper is to continue the dialogue regarding the benefits and controversies of HT with the goal of encouraging the dissemination of-up-to date evidence that may influence how HT is viewed and prescribed.

Uterine and fetal blood flow indexes and fetal growth assessment after chronic estrogen suppression in the second half of baboon pregnancy.

Although estrogen regulates important aspects of maternal cardiovascular physiology, the role of estrogen on uteroplacental and fetal blood flow is incompletely understood. This study tested the hypothesis that chronically suppressing endogenous estrogen production during the second half of baboon pregnancy alters uterine and fetal blood flow dynamics assessed by ultrasonography. Pregnant baboons were untreated or treated daily with the aromatase inhibitor letrozole or letrozole plus estradiol on days 100-160 of gestation (term = 184 days). Blood flow dynamics were determined by Doppler ultrasonography on day 60 and longitudinally between days 110 and 160 of gestation. Letrozole decreased maternal serum estradiol and estrone concentrations by 95% (P < 0.001). Fetal growth biometrical parameters increased (P < 0.001) between days 110 and 160 of gestation and were similar in untreated and letrozole-treated animals. Uterine, umbilical, and fetal middle cerebral artery pulsatility index and resistance index declined (P < 0.01) by 30-50% and uterine artery volume flow increased sixfold (P < 0.001) between days 60 and 160, but values were similar in untreated, letrozole-treated, and letrozole plus estradiol-treated baboons. Thus uterine and fetal artery blood flow indexes, uterine artery volume flow, and fetal growth were maintained at normal levels despite chronic estrogen suppression in the second half of baboon pregnancy. This suggests that elevated levels of endogenous estrogen are not required to maintain low impedance blood flow within the uteroplacental vascular bed during the second half of nonhuman primate pregnancy.

In Asian-American Women, Westernization Influences Estrogen Metabolism, but Not Total Endogenous Estrogen Production.

Abstract Background: Historically, breast cancer incidence rates were 4-7 times higher in the United States than in China and Japan. When Asian women migrate to the U.S., their risk rises over several generations and approaches that in U.S. Whites. Endogenous estrogen has been postulated to explain these international differences. Methods: In a population-based case-control study in Chinese, Japanese, and Filipino women living in San Francisco-Oakland, CA; Los Angeles, CA; or Oahu, HI, we documented a six-fold gradient in breast cancer risk with Westernization. Using 12-h, overnight urines from 263 premenopausal mid-luteal and 168 postmenopausal control subjects, we investigated associations of estrogens and estrogen metabolites (EM) with Westernization, particularly birthplace in the East or West. Fifteen EM were measured concurrently by liquid chromatography-tandem mass spectrometry with high accuracy, precision, and sensitivity. Log-transformed EM measures, adjusted for age and ethnicity, were compared by robust linear regression. Results: Total urinary EM (pmol/mg creatinine) was not associated with birthplace in premenopausal or postmenopausal women. When the three estrogen hydroxylation pathways were expressed as percent of total EM, the relative difference by birthplace, West compared to East, was 15% lower for 2-pathway EM (p=0.009), 7% lower for 4-pathway EM (p=0.37), and 10% higher for 16-pathway EM (p=0.008). Similar results were observed for individual EM in each pathway, premenopausal and postmenopausal women, and the three ethnicities. In both menopausal groups, 2-pathway EM concentration decreased steadily with increasing risk across six categories of Westernization. Conclusions: Our results do not indicate that total estrogen production explains the increased breast cancer risk in Western societies. However, estrogen metabolism patterns, especially reduced 2-hydroxylation, may contribute to the elevated risk; and underlying mechanisms merit further exploration. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3063.

Postmenopausal Hypertension

Hypertension in women is often undiagnosed or inadequately treated, especially after menopause when cardiovascular risk increases. In premenopausal women, endogenous estrogens maintain vasodilation and thus contribute to blood pressure control. Aging and the loss of endogenous estrogen production after menopause are accompanied by increases in blood pressure, contributing to the high prevalence of hypertension in older women. Currently, ≈75% of postmenopausal women in the United States are hypertensive. The high prevalence of obesity, the lack of regular physical exercise, and dietary salt are important factors contributing to and aggravating postmenopausal hypertension. In view of the ongoing population aging throughout the world, diagnosis and treatment of hypertension in postmenopausal women are important to reduce the excess burden of associated cardiovascular disease and to improve outcomes of potentially fatal complications such as stroke and myocardial infarction. This article discusses current knowledge about the mechanisms and therapeutic issues related to postmenopausal hypertension. More than 25% of the female adult world population is hypertensive.1 Elevations in blood pressure in women are related to cardiovascular risk (Figure, panel A),2,3 with the prevalence of hypertension being particularly high among women aged ≥60 years.1 In the United States, ≈75% of postmenopausal women are hypertensive.4 Hypertension is often accompanied by other cardiovascular risk factors, eg, obesity, dyslipidemia, and diabetes mellitus.5 It is noteworthy that the prevalence of hypertension-related cardiovascular complications is greater in postmenopausal women than in age-matched men.6 Indeed, these complications represent the leading cause of death in women.6 Figure. A, Cumulative incidence of cardiovascular events in women without hypertension, according to blood pressure category at the baseline examination. Vertical bars indicate 95% CIs. According to earlier classifications from the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, optimal blood …

The Effect of Aromatase Inhibitors on Bone Metabolism

Aromatase inhibitors increase the disease-free survival in patients with receptor-positive breast cancer. Aromatase is a cytochrome P450 enzyme complex catalysing the conversion of androgens to oestrogens. These properties cause a significant increase in bone loss. In this MiniReview, we present data from the aromatase inhibitor studies and the studies designed to investigate aromatase inhibitor effect on bone metabolism. At the cellular level, oestrogen has profound effects on both osteoblasts and osteoclasts. Oestrogen decreases the osteoblastic production of resorptive cytokines and simultaneously increases the production of antireceptive cytokines, which leads to increased osteoclastic apoptosis and increased osteoblastic activity. Aromatase inhibitors inhibit the endogenous production of oestrogen by 50-90%. Studies designed to look at the effect of aromatase inhibitors on bone mineral density have shown a significant decrease in bone mineral density of the femoral neck in the aromatase inhibitor groups compared to placebo groups. Placebo-controlled studies lack statistical power to detect changes in fracture incidence; however, aromatase inhibitors increase the incidence of fractures in comparison with tamoxifen. We conclude that treatment with aromatase inhibitors leads to an increased bone loss and thus an increase in the risk of fractures in women with breast cancer.

Estrogen and hearing from a clinical point of view; characteristics of auditory function in women with Turner syndrome

Turner syndrome is a chromosomal aberration affecting 1:2000 newborn girls, in which all or part of one X chromosome is absent. This leads to ovarial dysgenesis and little or no endogenous estrogen production. These women have, among many other syndromal features, a high occurrence of ear and hearing problems, and neurocognitive dysfunctions, including reduced visual-spatial abilities; it is assumed that estrogen deficiency is at least partially responsible for these problems. In this, study 30 Turner women aged 40–67, with mild to moderate hearing loss, performed a battery of hearing tests aimed at localizing the lesion causing the sensorineural hearing impairment and assessing central auditory function, primarily sound localization. The results of TEOAE, ABR and speech recognition scores in noise were all indicative of cochlear dysfunction as the cause of the sensorineural impairment. Phase audiometry, a test for sound localization, showed mild disturbances in the Turner women compared to the reference group, suggesting that auditory-spatial dysfunction is another facet of the recognized neurocognitive phenotype in Turner women.

Abstract B126: Does adult soy intake influence total estrogen levels and estrogen metabolism patterns?

Abstract B126 Background Soy foods are a dietary staple in Asian countries and may play a role in this region’s historically low rates of breast cancer incidence. Isoflavones found in soy have structural similarities to estrogens and could exert protective effects by interacting with estrogen receptors, binding proteins, or metabolic enzymes. In a sample of Asian-American women we test whether soy is associated with urinary concentrations of estrogens and estrogen metabolites (EM). Methods This analysis was conducted among controls from a population-based case-control study of breast cancer among women of Chinese, Japanese and Filipino ancestry, aged 20-55 years, and living in San Francisco-Oakland (CA), Los Angeles (CA) and Oahu (HI). Of 966 controls, we included the 571 (59%) women who donated a 12-hour urine and had not been pregnant or lactating or used exogenous hormones in the last 6 months. At urine collection, 168 women were postmenopausal, 233 were pre-menopausal in mid-luteal phase, and 170 were in other categories. Fifteen EM were measured simultaneously with a highly sensitive and reproducible liquid chromatography-tandem mass spectrometry method. Participants had been queried about their usual adult frequency of intake of tofu and other selected soy foods. Robust regression was used to model the associations of soy intake (in tertiles) with EM measures. Models were adjusted for age, ethnicity, body mass index (BMI), and birthplace (Asia/West). Results No statistically significant associations were seen between soy intake and urinary concentrations of estrone, estradiol, estriol, or total EM in postmenopausal women or premenopausal women. In postmenopausal but not premenopausal women, we found significant trends across tertiles of soy intake for EM grouped by metabolic pathways. The 2- and 4-hydroxylated EM and the methylated catechols, each expressed as a percent of total EM, increased with soy intake, while relative levels of EM in the 16-hydroxylation pathway decreased. Models adjusted for age and ethnicity were similar. Factor analysis was used to confirm EM groupings. Among postmenopausal women, factor analysis identified four independent EM patterns, termed ‘catechols’, ‘methylated catechols’, ‘16-hydroxylation pathway EM’, and ‘parent estrogens’ based on the predominant EM. Factors for premenopausal women were similar. Discussion Our findings do not support the hypothesis that soy intake influences endogenous production of estrogens but they do suggest that soy intake can modify estrogen metabolism in postmenopausal women. Increased ratios of 2-hydroxyestrone to 16α-hydroxyestrone have been associated with lower breast cancer risk in some epidemiologic studies. Methylation of catechol estrogens results in deactivation of these metabolites and prevents conversion into genotoxic quinones. Thus, the trends by soy intake represent variations in EM metabolism that could reduce breast cancer risk. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B126.

P18 Toremifene as a reference drug in the treatment of breast cancer

To report a case of a pelvic desmoid tumor that was treated with the antiestrogen toremifene after a failed attempt at surgical excision.Case report.University reproductive endocrine practice.A reproductive-aged woman with a recurrent desmoid tumor.After surgical excision of a desmoid tumor that presented during childbirth, subsequent recurrence resulted in the use of toremifene for tumor stabilization.Magnetic resonance imaging was used to monitor desmoid tumor size.One year after postsurgical recurrence of the desmoid tumor, the patient began treatment with the antiestrogen toremifene. Tumor stabilization and regression with symptomatic relief was observed. Nine years of antiestrogen use revealed no progression in tumor size or patient symptoms. After the patient demonstrated perimenopausal symptoms, toremifene administration was discontinued without a return of symptoms or tumor growth after 3 years.Our case demonstrates that toremifene is a safe and effective therapy that can be used for the stabilization and regression of desmoid tumors. An antiestrogen should be considered as adjuvant therapy after surgery and as a first-line treatment with disease recurrence. Discontinuation of antiestrogen therapy was shown to be done safely after the patient started to show signs of decreased endogenous estrogen production.

A CYP19 (aromatase) polymorphism is associated with increased premenopausal breast cancer risk

Due to the established association between estrogen levels and breast cancer risk, polymorphic variation in genes regulating estrogen levels is thought to be related to breast cancer risk. Aromatase, the protein product of the CYP19 gene, is involved in the production of endogenous estrogens via androgen conversion. We examined whether polymorphic variation in CYP19 associated with increased breast cancer risk in a population based case-control study. We examined two single nucleotide polymorphisms (SNP), rs1008805 (A/G) and rs730154 (C/T), which have been shown to tag SNPs within two different haplotype blocks in CYP19. Among premenopausal women, the presence of at least one G allele at rs1008805 was significantly associated with an increase in the risk of breast cancer (OR = 1.72 [95% CI, 1.20-2.49]), especially with estrogen and progesterone receptor negative breast cancer (OR = 3.89 [1.74-8.70] and OR = 2.52 [1.26-5.05], respectively). No association was observed among postmenopausal women (OR = 1.06 [0.82-1.36]). There was no significant association between rs730154 and breast cancer, regardless of menopausal status. Our results suggest that premenopausal women carrying the G allele at CYP19 rs1008805 have increased risk of breast cancer. The finding supports the potential role of variation in estrogen biosynthesis genes in premenopausal breast cancer risk.

Aromatase Expression Predicts Survival in Women with Early-Stage Non–Small Cell Lung Cancer

Estrogen signaling is critical in the progression of tumors that bear estrogen receptors. In most patients with breast cancer, inhibitors that block interactions of estrogen with its receptors or suppress the production of endogenous estrogens are important interventions in the clinic. Recent evidence now suggests that estrogen also contributes to the pathogenesis of non-small cell lung cancer (NSCLC). We used a human lung cancer xenograph model system to analyze the effect of aromatase or estradiol on tumor growth. We further examined the level of protein expression of aromatase in 422 patients with NSCLC using a high-density tissue microarray. Results were confirmed and validated on an independent patient cohort (n = 337). Lower levels of aromatase predicted a greater chance of survival in women 65 years and older. Within this population, the prognostic value of aromatase was greatest in earlier stage lung cancer (stage I/II). In addition, for women with no history of smoking, lower aromatase levels were a strong predictor of survival. Our findings implicate aromatase as an early-stage predictor of survival in some women with NSCLC. We predict that women whose lung cancers have higher levels of aromatase might be good candidates for targeted treatment with aromatase inhibitors.

Reducing endogenous estrogens during the neonatal and juvenile periods affects reproductive tract development and sperm production in postpuberal boars

Increased Sertoli cell proliferation during the neonatal period, transient negative effects on epididymal sperm maturation, larger postpuberal testis size reflective of increased Sertoli cell numbers, and increased testicular sperm production characterized boars subjected to continuous inhibition of endogenous estrogen production. The objective in the present experiment was to extend these previous observations to evaluate the effects of a shorter period of reduced estrogen production during the neonatal and juvenile periods on Sertoli cell proliferation, postpuberal testis size, sperm production and epididymal function. Experiments were designed to detect cumulative effects on accessory sex glands as well. Four pairs of littermate boars were assigned to the experiment with one member of each pair randomly selected to receive weekly oral treatment with the aromatase inhibitor, Letrozole, beginning at 1 week of age; the littermates received weekly oral treatment with the corn oil vehicle. Treatment stopped at 12 weeks of age and effects were examined at 10 months. Treated animals had approximately 25% larger testes ( P < 0.05) correlated with increased Sertoli cell numbers ( P < 0.05) and larger epididymides. Sperm quality was approximately equivalent in treated and control littermates. Accessory sex glands tended to be smaller in the treated boars. Sertoli cell proliferation during the neonatal and juvenile interval appears to be influenced by endogenous estrogen levels in the boar. A relatively short postnatal interval of Letrozole treatment effectively increased postpuberal testis size. Increased sperm production capacity in response to decreased endogenous estrogens has intriguing possibilities for animal agricultural production.

Surgical versus natural menopause

Women who undergo both natural and surgical menopause experience the loss of cyclic ovarian production of estrogen, but hormonal and demographic differences distinguish these two groups of women. Our objective was to review published evidence on whether the premature cessation of endogenous estrogen production in women who underwent a surgical menopause has deleterious consequences for cognitive aging and to determine whether consequences differ for women if they undergo natural menopause. Studies of estrogen-containing hormone therapy are relevant to this issue. We reviewed evidence-based research, including the systematic identification of randomized clinical trials of hormone therapy with cognitive outcomes that included an objective measure of episodic memory. As inferred from very small, short-term, randomized, controlled trials of high-dose estrogen treatment, surgical menopause may be accompanied by cognitive impairment that primarily affects verbal episodic memory. Observational evidence suggests that the natural menopausal transition is not accompanied by substantial changes in cognitive abilities. For initiation of hormone therapy during perimenopause or early postmenopause when the ovaries are intact, limited clinical trial data provide no consistent evidence of short-term benefit or harm. There is stronger clinical trial evidence that initiation of hormone therapy in late postmenopause does not benefit episodic memory or other cognitive skills. Further research is needed on the long-term cognitive consequences of surgical menopause and long-term cognitive consequences of hormone therapy initiated near the time of surgical or natural menopause. A potential short-term cognitive benefit might be weighed when a premenopausal woman considers initiation of estrogen therapy at the time of, or soon after, hysterectomy and oophorectomy for benign conditions, although data are still quite limited and estrogen is not approved for this indication. Older postmenopausal women should not initiate hormone therapy to improve or maintain cognitive skills.

Human exposure to medicinal, dietary, and environmental estrogens

Estrogens are a broad class of compounds which exert many physiological effects. In addition to gonadal and peripheral endogenous estrogen production, humans can be exposed to exogenous estrogenic compounds (xenoestrogens) from medicinal, dietary and environmental sources. These compounds can exert effects similar to that of 17β-estradiol (E2) through estrogen receptor (ER)-mediated mechanisms, or via ER-independent pathways. Although estrogens are used for a number of medical purposes such as birth control and for hormone replacement therapy (HRT) in the treatment of post-menopausal symptoms, studies have found adverse health effects from their use. Increased risk of stroke and invasive breast cancer are associated with medicinal estrogen use. As an alternative to HRT, diets rich in phytoestrogens are used by many women. Even though phytoestrogen consumption is associated with reduced risk of hormone-dependent cancers and antioxidant properties, concerns about adverse effects, such as endocrine disruption, cannot be dismissed. Widespread use of chemicals with estrogenic properties in agriculture and industry has resulted in endocrine disruption in wildlife populations although the impact on human health is still in debate. In general, the ranking order of estrogen equivalent factors compared to E2 is medicinal estrogens > phytoestrogens > environmental estrogens. Serum concentrations of estrogens vary among populations depending on choice of diet, use of medicinal estrogens, and environmental exposure. Thus, determination of total exposure levels (i.e. E2 equivalent concentration) is complex and can vary greatly within a larger population.

Ontogeny of androgen and estrogen receptor expression in porcine testis: Effect of reducing testicular estrogen synthesis

Reducing endogenous estrogen leads to increased proliferation of porcine Sertoli cells during the first 2 months of life. The resulting increase in porcine Sertoli cell numbers is maintained through puberty. The reduced estrogen appears to be the direct hormonal mediator because essentially no changes are observed in other hormones. However, the mechanism for this effect on Sertoli cell proliferation is unknown. The objective of these studies was to evaluate estrogen receptors α and β (ESR1 and ESR2) in conjunction with androgen receptor (AR) on Sertoli cells and other testicular cell types, as an initial step toward understanding how reduced estrogen leads to increased Sertoli cell numbers. Testis sections from treated animals (aromatase inhibition to decrease endogenous estrogen beginning at 1 week of age) and from littermate controls treated with vehicle were subjected to immunocytochemical labeling for ESR1, ESR2, and AR. Three observers scored Sertoli cells, interstitial cells, peritubular myoid cells, and germ cells for intensity of labeling (0: absent; 1+: weak; 2+: moderate; or 3+: strong labeling). AR in Sertoli cells was readily detected at 1 week of age, was very faint in 2-month vehicle controls, and labeling appeared to increase in 3-month vehicle controls. AR in Sertoli cells, interstitial cells, and apparently germ cells was increased in treated animals at 2 months of age compared with the vehicle controls. This increase was confirmed in western blots. ESR1 and ESR 2 were clearly present in Sertoli cells from 1-week-old animals; ESR in Sertoli cells generally decreased with age with the decrease more apparent for ESR2. ESR1 in Sertoli cells and peritubular myoid cells exhibited some treatment-related effects but reduction of endogenous estrogen did not appear to affect ESR2 in the boar testis. The observed alterations in AR and ESR1 may mediate the increases in Sertoli cell proliferation following inhibition of endogenous estrogen production or may reflect the altered function of the Sertoli cells and peritubular myoid cells.

Exposure assessment of prepubertal children to steroid endocrine disrupters: 1. Analytical strategy for estrogens measurement in plasma at ultra-trace level

Global concern has been raised in recent years over adverse effects that may result from exposure to chemicals that may interfere with the endocrine system. A specific question is related to low-dose effects and long-term exposure consequences, especially for critical populations (foetus, new born, prepubertal children). In this context, we decided to focus our attention on steroid hormones as they are the most potent endocrine disrupters. Our general goal is to investigate whether the steroid intake through food may represent a risk for prepubertal children, from an endocrine disruption point of view, especially with regard to the corresponding endogenous production level in this target population. As a starting point, it was estimated that a (re)-evaluation of the endogenous production of natural estrogens for this population was necessary, on the basis of a very sensitive and specific confirmatory measurement technique (gas chromatography–tandem mass spectrometry or gas chromatography–high resolution mass spectrometry). Thus, a new ultra-sensitive approach for steroid trace measurement in biological samples was developed, which was mainly based on a specific derivatisation (pentafluorobenzyl derivative) and negative chemical ionisation (NCI). Preliminary results obtained by applying this method on plasma samples from healthy prepubertal children demonstrated that estradiol endogenous level in prepubertal children is unsurprisingly very low. Estrone was determined in almost all samples at concentration in the 2–70ngL−1 range while 17α and 17β estradiol were quantified in only few samples at concentrations ranging from 2 to 6ngL−1. Exogenous contributions of estrogens will therefore constitute a relatively higher proportion of sex hormone activity in the immature child.