Peripheral Estrogen Synthesis Research Articles

Aromatase is required for female abdominal aortic aneurysm protection

The protective effects of female gender on the development of abdominal aortic aneurysms (AAAs) have been attributed to anti-inflammatory effects of estrogen. Estrogen synthesis is dependent on the enzyme aromatase, which is located both centrally in the ovaries and peripherally in adipose tissue, bone, and vascular smooth muscle cells. It is hypothesized that deletion of aromatase in both ovarian and peripheral tissues would diminish the protective effect of female gender and would be associated with increased aortic diameter in female mice. Male and female 8- to 10-week-old mice with aromatase (wild type: WT) and without aromatase (ArKO) underwent elastase aortic perfusion with aortic harvest 14 days following. For the contribution of central and peripheral estrogen conversion to be evaluated, female WT mice were compared with female WT and ArKO mice that had undergone ovariectomy (ovx) at 6 weeks followed by elastase perfusion at 8 to 10 weeks. At aortic harvest, maximal aortic dilation was measured and samples were collected for immunohistochemistry and protein analysis. Serum was collected for serum estradiol concentrations. Groups were compared with analysis of variance. Human and mouse AAA cross sections were analyzed with confocal immunohistochemistry for aromatase, smooth muscle markers, and macrophage markers. Female WT mice had significant reduction in aortic dilation compared with male WT mice (F WT, 51.5% ± 15.1% vs M WT, 78.7% ± 14.9%; P < .005). The protective effects of female gender were completely eliminated with deletion of aromatase (F ArKO, 82.6% ± 13.8%; P < .05 vs F WT). Ovariectomy increased aortic dilation in WT mice (F WT ovx, 70.6% ± 11.7%; P < .05 vs F WT). Aromatase deletion with ovariectomy further increased aortic dilation compared with WT ovx mice (F ArKO ovx, 87.3% ± 14.7%, P < .001 vs F WT and P < .05 vs F WT ovx). Accordingly, female ArKO ovx mice had significantly higher levels of the proinflammatory cytokines monocyte chemoattractant protein 1 and interleukin-1β and were associated with increased macrophage staining and decreased elastin staining. Regarding serum hormone levels, decreasing estradiol levels correlated with increasing aortic diameter (R = -0.565; P < .01). By confocal immunohistochemistry, both human and mouse AAA smooth muscle cells (smooth muscle α-actin positive) and macrophages (CD68 positive or Mac-2 positive) expressed aromatase. The protective effect of female gender on AAAs is due to estrogen synthesis and requires the presence of both ovarian and extragonadal/peripheral aromatase. Peripheral estrogen synthesis accounts for roughly half of the protective effect of female gender. If peripheral aromatase could be targeted, high levels of local estrogen could be produced and may avoid the side effects of systemic estrogen.

Estrogen’s effects in chronic autoimmune/inflammatory diseases and progression to cancer

Endocrine–immune system interactions are the basis for predominance of autoimmune diseases in women with differences between the fertile and the postmenopausal periods. B cell-driven diseases reach the maximum incidence rate in the reproductive years, at least in women under the effects of serum estrogens and their metabolites (endocrine synthesis). On the other hand, the prevalent peripheral synthesis of estrogens, especially in advanced ages (intracrine synthesis), through the action of aromatases, modulate the immune/inflammatory response in peripheral tissues similarly in both female and male patients (final common pathway). Interestingly, tissue injury that occurs during chronic immune/inflammatory reaction induces tissue repair and homeostatic responses including cell proliferation, growth factor production and angiogenesis that might facilitate cancer progression. The successful treatment of chronic immune/inflammatory diseases obtained by using medications initially developed for use in oncology, such as antiproliferative drugs, B-cell depleting monoclonal antibodies support the inflammation–cancer link.

Fatty Acyl Esterification and Deesterification of 17β-Estradiol in Human Breast Subcutaneous Adipose Tissue

Adipose tissue has an important role in peripheral estrogen synthesis. One of the metabolic pathways of estradiol (E(2)) is its conversion to lipophilic fatty acyl esters. The aim was to study the metabolism of E(2) fatty acyl esters in adipose tissue and, specifically, the role of hormone-sensitive lipase (HSL) in steroid ester hydrolysis. Tissue samples were obtained during elective surgery in University Central Hospital in the years 2008-2011. Women undergoing reduction mammoplasty (n = 27) or surgery for breast cancer (n = 16) participated in the study. Two sc adipose tissue samples were taken from different quadrants of the breast. Radiolabeled steroids were incubated with tissue homogenate (esterase assay) or microsomal fraction (acyl transferase assay). E(2) and E(2) fatty acyl ester concentrations were determined by fluoroimmunoassay or liquid chromatography-tandem mass spectrometry. We evaluated the hydrolysis rate of E(2) fatty acyl esters as well as the esterification rate of E(2); we also related tissue concentrations of E(2) and E(2) esters to serum estrogen concentrations. Compared to esters of dehydroepiandrosterone and cholesterol, the hydrolysis of E(2) esters was much slower, whereas the esterification rate of E(2) was higher. The hydrolysis of E(2) esters in adipose tissue was reduced by 33-51% by inhibition of HSL. Estrogen concentration in sc adipose tissue was higher than in serum in both pre- and postmenopausal women. E(2) fatty acyl esters in adipose tissue surrounding the mammary gland may act as a reservoir for conversion back to biologically active E(2). This is partly dependent on HSL activity.

Variants in CYP17 and CYP19 Cytochrome P450 Genes are Associated with Onset of Alzheimer's Disease in Women with Down Syndrome

CYP17 and CYP19 are involved in the peripheral synthesis of estrogens, and polymorphisms in CYP17 and CYP19 have been associated with increased risk of estrogen-related disorders. Women with Down syndrome (DS) have early onset and high risk for Alzheimer's disease (AD). We conducted a prospective community-based cohort study to examine the relationship between SNPs in CYP17 and CYP19 and cumulative incidence of AD, hormone levels and sex hormone binding globulin in women with DS. Two hundred and thirty-five women with DS, 31 to 67 years of age and nondemented at initial examination, were assessed for cognitive and functional abilities, behavioral/psychiatric conditions, and health status at 14-20 month intervals over five assessment cycles. We genotyped these individuals for single-nucleotide polymorphisms (SNPs) in CYP17 and CYP19. Four SNPs in CYP17 were associated with a two and one half-fold increased risk of AD, independent of APOE genotype. Four SNPs in CYP19 were associated with a two-fold increased risk of AD, although three were significant only in those without an APOE ε4 allele. Further, carrying high risk alleles in both CYP17 and CYP19 was associated with an almost four-fold increased risk of AD (OR = 3.8, 95% CI, 1.6-9.5) and elevated sex hormone binding globulin in postmenopausal women. The main effect of the CYP17 and CYP19 variants was to decrease the age at onset. These findings suggest that genes contributing to estrogen bioavailability influence risk of AD in women with DS.

Sex steroid hormones in pairs of tumor and serum from breast cancer patients and pathobiological role of androstene‐3β, 17β‐diol

Estrogens play an important role in the pathobiology of breast cancer. In postmenopausal women, peripheral synthesis of estrogens from adrenal/ovarian androgens, dehydroepiandrosterone (DHEA) or androstenedione (Adione), by estrogen-metabolizing enzymes is important. Besides estrone (E1) and estradiol (E2), androgen metabolites, such as androstene-3β, 17β-diol (Aenediol) or 5α-androstane-3β, 17β-diol (Aanediol), are known to have estrogenic functions, although they have been studied much less in breast cancer. To precisely elucidate steroid metabolism in breast cancer patients and to identify the pathobiological role of estrogenic androgen metabolites, concentrations of DHEA, Adione, Aenediol, Aanediol, E1, and E2 in pairs of serum and tumor tissue from patients with primary breast cancer were measured by liquid chromatography-tandem mass spectrometry. Cell proliferation assays using Aenediol were performed for four breast cancer cell lines. Serous E2 concentration was extremely low in postmenopausal women; however, a marked increase in tumor tissue was observed in hormone receptor-positive cases. E1 concentration, in contrast, was sustained at a higher level, even in postmenopausal serum, and did not increase in tumor tissue irrespective of the hormone receptor status. Dehydroepiandrosterone was most abundant in all samples, and exhibited a similar pattern as Adione and Aenediol. 5α-Androstane-3β, 17β-diol was undetectable in most samples. Androstene-3β, 17β-diol proliferated estrogen receptor-apositive breast cancer cells in the absence of E2. The intratumoral increase of E2, but not E1, in hormone receptor-positive postmenopausal breast cancer tissue, as well as the proliferative role of Aenediol, was elucidated.

Aromatase and interleukin-10 genetic variants interactively modulate Alzheimer’s disease risk

A chronic inflammatory process with activation of microglial cells contribute to the neurodegeneration associated with Alzheimer's disease (AD). Estrogen could protect the brain from neurodegeneration by augmenting the secretion of the anti-inflammatory interleukin (IL)-10 from microglial cells. In a case-control study in 231 AD patients and 194 healthy controls, we examined whether the combined effects between the genes coding for aromatase (a critical enzyme in the peripheral synthesis of estrogens) and IL-10 might be responsible for susceptibility to AD. Subjects carrying both the aromatase (5 -UTR) GG and the IL-10 (-1082) GG genotypes had a six times lower risk of developing AD than subjects without these risk genotypes (OR = 0.17, 95% CI = 0.04-0.77, P = 0.02).

Estrogens and Autoimmune Diseases

Sex hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone (and glucocorticoids) as natural immune-suppressors . Several physiological, pathological, and therapeutic conditions may change the serum estrogen milieu and/or peripheral conversion rate, including the menstrual cycle, pregnancy, postpartum period, menopause, being elderly, chronic stress, altered circadian rhythms, inflammatory cytokines, and use of corticosteroids, oral contraceptives, and steroid hormonal replacements, inducing altered androgen/estrogen ratios and related effects. In particular, cortisol and melatonin circadian rhythms are altered, at least in rheumatoid arthritis (RA), and partially involve sex hormone circadian synthesis and levels as well. Abnormal regulation of aromatase activity (i.e., increased activity) by inflammatory cytokine production (i.e., TNF-alpha, IL-1, and IL-6) may partially explain the abnormalities of peripheral estrogen synthesis in RA (i.e., increased availability of 17-beta estradiol and possible metabolites in synovial fluids) and in systemic lupus erythematosus, as well as the altered serum sex-hormone levels and ratio (i.e., decreased androgens and DHEAS). In the synovial fluids of RA patients, the increased estrogen concentration is observed in both sexes and is more specifically characterized by the hydroxylated forms, in particular 16alpha-hydroxyestrone, which is a mitogenic and cell proliferative endogenous hormone. Local effects of sex hormones in autoimmune rheumatic diseases seems to consist mainly in modulation of cell proliferation and cytokine production (i.e., TNF-alpha, Il-1, IL-12). In this respect, it is interesting that male patients with RA seem to profit more from anti-TNFalpha strategies than do female patients.

Hormonal effects of aromatase inhibitors: focus on premenopausal effects and interaction with tamoxifen

Third generation aromatase inhibitors have excellent specificity. Some reports indicate that letrozole may have a minor effect on cortisol synthesis but these were not confirmed: valid comparisons with other aromatase inhibitors requires randomised study. The putative use of a third generation inhibitor as a single agent in premenopausal women has been investigated using YM511. It was hypothesised that in this situation site-specific suppression of estrogens in breast carcinomas, without systemic effects, may lead to a down-regulation of tumour proliferation. Plasma levels of androstenedione and testosterone were significantly increased by 2 weeks treatment with YM511. Mean plasma estrone levels were suppressed, but some plasma estradiol levels were abnormally high and others abnormally low. These differential effects of YM511 on circulating estrogens supported the concept that peripheral synthesis of estrogens might be suppressed while ovarian production remained high. However, YM511 did not demonstrate anti-proliferative effects in hormone sensitive breast carcinomas. Consideration of the pharmacology of the estrogen receptor during tamoxifen therapy indicates that tamoxifen effectively saturates the receptor (>99.94% occupancy) in postmenopausal women. The addition of an aromatase inhibitor in this situation would be very unlikely to affect the biological activity of the estrogen receptor. This provides a possible explanation why the clinical efficacy of tamoxifen combined with an aromatase inhibitor appears to be equivalent to that of tamoxifen alone.

Breast cancer and the role of cytokines in regulating estrogen synthesis: an emerging hypothesis.

I. Introduction II. Peripheral Estrogen Synthesis and Blood and Tissue Estrogens in Breast Cancer A. Peripheral estrogen synthesis B. Aromatase C. Estrone sulfatase D. E2DH E. Origins of breast tumor estrogens III. Influence of Breast Tumor Location on Enzyme Activities in Adjacent Tissues IV. Proposed Model for the Regulation of Estrogen Synthesis in Breast Tumors V. Evidence in Support of Proposed Model of Cytokine Regulation of Estrogen Synthesis A. Identification of factors that stimulate estrogen synthesis B. Potentiation of cytokine stimulation of estrogen synthesis VI. The Role of Soluble Cytokine Receptors in Cytokine Action A. Mechanism of cytokine action B. Regulation of gp80 and gp130 C. Regulation of IL-6 sR shedding VII. Origin of Estrogen-Stimulating Factors in Breast Tumors A. The role of cells of the immune system B. Macrophages and lymphocytes in breast tumors VIII. Regulation of Lymphocyte Cytokine Production A. Th1 and Th2-helper cells B. Dehydroepiandrosterone (DHA) and glucocorticoids...

Partial deficiency in 17-ketosteroid reductase presenting as gynecomastia

We report a 14 year-old male with severe, long-lasting gynecomastia. Baseline serum androstenedione levels were elevated compared to testosterone levels (330 ng/dl vs 28ng/dl). In order to evaluate testosterone biosynthesis by this patient in more detail, androstenedione, testosterone, dehydroepiandrosterone (DHEA) and estradiol responses to a single dose of hCG were measured. The responses observed were different from those reported in normal males in two respects: 1) there was no immediate rise in testosterone two to four hours after the injection of hCG, and 2) levels of androstenedione and estradiol at 24, 36 and 48 hours after injection were much higher than expected. We postulate that a partial defect in testicular 17-ketosteroid reductase activity was responsible for the abnormal androstenedione to testosterone ratio in our patient. This, in turn, lead to an increased peripheral synthesis of estrogens and marked gynecomastia. ( Steroids45, xx (1985)

Steroid abnormalities in endometrial and breast carcinoma: A unifying hypothesis

Studies were carried out to further identify the nonendocrine tissues in which peripheral estrogen synthesis takes place. To test the hypothesis that adipose tissue is an important site the conversion of androstenedione (A) to estrone (E1), [ρ] A-E1, was measured in four obese women before and after enforced weight reduction (mean weight loss, 89 lbs). Unexpectedly the [ρ] A-E1 value increased in each subject following weight loss. These results suggest that the relationship between obesity and liver abnormalities may be more important than obesity alone in determining [ρ] A-E1. A variety of human tissues were also assayed for their ability to form E1 from A and progesterone from pregnenolone. Normal breast and other tissues had low or undetectable activities and only 1 of 4 breast tumors had significant aromatase activity. Both normal and tumorous colon and rectum had relatively high progesterone forming activity whereas other tissues were inactive. These results are discussed in relation to previously reported abnormalities in steroid production and metabolism observed in breast and endometrial cancer patients.