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. 2016 Sep 30;49(9):488–496. doi: 10.5483/BMBRep.2016.49.9.141

Extra-gonadal sites of estrogen biosynthesis and function

Radwa Barakat 1,2, Oliver Oakley 3, Heehyen Kim 4, Jooyoung Jin 4, CheMyong Jay Ko 1,*
PMCID: PMC5227141  PMID: 27530684

Abstract

Estrogens are the key hormones regulating the development and function of reproductive organs in all vertebrates. Recent evidence indicates that estrogens play important roles in the immune system, cancer development, and other critical biological processes related to human well-being. Obviously, the gonads (ovary and testis) are the primary sites of estrogen synthesis, but estrogens synthesized in extra- gonadal sites play an equally important role in controlling biological activities. Understanding non-gonadal sites of estrogen synthesis and function is crucial and will lead to therapeutic interventions targeting estrogen signaling in disease prevention and treatment. Developing a rationale targeting strategy remains challenging because knowledge of extra-gonadal biosynthesis of estrogens, and the mechanism by which estrogen activity is exerted, is very limited. In this review, we will summarize recent discoveries of extra-gonadal sites of estrogen biosynthesis and their local functions and discuss the significance of the most recent novel discovery of intestinal estrogen biosynthesis. [BMB Reports 2016; 49(9): 488-496]

Keywords: Estrogen, Estrogen receptor, Extra-gonadal

INTRODUCTION

Estrogens are a class of steroid hormones that regulate the development and function of male and female reproductive organs. In the ovary, estrogen synthesis begins in theca cells with androgen synthesis and ends with conversion of androgens to estrogens in granulosa cells by the enzyme aromatase. In the male gonad, estrogens are synthesized in the Leydig cells, Sertoli cells, and mature spermatocytes (1). Like other steroid hormones, estrogens enter passively into the cells and bind to the estrogen receptors, which then regulate the transcription of downstream estrogen-responsive genes. Among the number of different forms of estrogens, 17β-estradiol (estradiol) is the most common and potent form of estrogen in mammals. Estradiol is also produced in a number of extragonadal organs, including the adrenal glands, brain, adipose tissue, skin, pancreas (2-4), and other sites yet to be identified. The discoveries of extra-gonadal sites of estradiol synthesis greatly expands our knowledge of the novel roles of estrogens beyond the reproductive system.

EXTRA-GONADAL SITES OF ESTROGEN SYNTHESIS AND ITS LOCAL ROLES

The first discovery of extra-gonadal estrogen synthesis was made in 1974 by Hemsell and his colleagues when they made an unexpected observation that androgens were converted to estrogens in adipose tissue (5). Since then, a number of other extra-gonadal sites of estrogen synthesis have been discovered. Adipose tissues are considered to be the major source of circulating estrogen after the gonads in both men and women, and the contribution made by the adipose tissues to the total circulating estrogens increases with advancing age (5). The chemical structure and biological activity of the estrogens synthesized in the extra-gonadal sites are not different from those that are produced by the gonads. However, there are unique features that make the extra-gonadal estrogen synthesis differ from the gonadal synthesis. A major difference is in the biochemical pathway of estrogen synthesis. The tissues and cells of the extra-gonadal sites of estrogen synthesis are unable to synthesize C19 steroids, the precursors of estrogen synthesis, but are able to convert C19 steroids to estrogens, a critical and rate-limiting step mediated by Cyp19 aromatase. Hence, extra-gonadal estrogen synthesis is dependent on an external source of C19 precursors (4) and the level of aromatase expression. Because C19 steroids can be supplied to a local tissue via circulation and are converted to estrogens in any tissue where aromatase is expressed, the presence of aromatase expression in a local tissue confirms extra-gonadal estrogen synthesis. Table 1 lists the peripheral tissues that express aromatase and are therefore able to convert C19 precursors to estrogens. These extra-gonadally synthesized estrogens are thought to act and be metabolized locally, which limits their systemic effects (6). Another unique feature of extra-gonadal estrogen synthesis is that while the total amount of estrogen synthesized in each tissue may be small, the local tissue concentrations of estrogens could be high enough to exert biological impact locally. The functional roles of estrogens are mediated mostly by estrogen receptors that are nuclear receptor transcription factors. Therefore, a tissue that expresses one or more estrogen receptors is considered to be a target of estrogenic regulation. Table 2 lists key organs and tissues that express estrogen receptors.

Table 1. Extra-gonadal sites of estrogen synthesis.

Sites Evidence of 17β-estradiol synthesis References

Cyp19 mRNA Cyp19 protein 17β-estradiol

Brain Astrocyte (rat, mouse, human), Hippocampus and hypothalamus (rat, mouse, monkey, human) Astrocyte (mouse), GnRH (rat), Dentate gyrus/ pyramidal cell (rat, mouse, human, monkey), Interneurons (human), Granular cell (human, monkey), Purkinje cell (human, mouse), Ependymal andsubependymal cell (human). Astrocyte (rat, monkey). (7-16)
Fat Stromal cell (human), Adipocyte (human) Stromal cell (human), Adipocyte, mesenchymal cell (human) (13-16)
Bone Osteoblast (human) Osteoblast (human) Osteoblast (human) (17-19)
Liver HepG2 hepatoma andhepatocellular carcinoma (human), Hepatocyte (porcine). HepG2 hepatoma and hepatocellular carcinoma (human) HepG2 hepatoma and hepatocellular carcinoma (human) (20-22)
Adrenal gland Adrenocortical cell (human, porcine, rat) Adrenocortical cell (human) Adrenocortical cell (rat) (22-24)
Intestine Parietal cell (rat) Parietal cell (rat) Parietal cell (rat) (25)
Skin Fibroblast (human). Keratinocyte (human). Fibroblast (chicken, human), Keratinocyte (human) Fibroblast (chicken) (26-28)
Blood vessel Smooth muscle cell (human, rat, bovine) Smooth muscle cell (human, rat, bovine) (29-31)
Spleen T cell (mouse) T cell (mouse) (32)

Table 2. Extra-gonadal sites of estrogen receptor expression.

Sites Receptor subtypes References

ERα ERβ Other receptors

Brain Cholinergic neuron (rat), GABAergic neuron (rat), Pro-opiomelanocortin neuron (mouse). GnRH neurons (mouse), Subiculum neuron (monkey), Ammon GPER1 (glial cell, rat), GPER1 (GABAergic neuron, rat). (33-37)
Fat Adipocyte (human) Adipocyte (human) GPER (adipocyte, mouse) (38-40)
Bone Osteoblast (mouse), Osteocyte (mouse). Osteoblast (human), Osteocyte (human), Osteoclast (rat, human). (41-46)
Liver Hepatocyte (rat) (25)
Blood vessel Smooth muscle cell (human), Vascular endothelial cell (human) Endothelial cell (human) GPR30 (endothelial cell, rat) (47-50)
Intestine Epithelial cell (rat), Parietal cell (rat), Myenteric neuron (rat) Epithelial cell (rat), Parietal cell (rat) GPER (colonic epithelia, human) (51, 52)
Skin Keratinocyte (human), Mast cell (human) Sebocyte (human) Keratinocyte (human), Mast cell (human) (53-55)
Adrenal gland Adrenal cortex (rat) Adrenal cortex (rat) GPER1 (rat) (56)
Muscle Satellite cell (rat) Satellite cell (rat) (57)
Kidney Mesangial cells (human, mouse) Mesangial cells (human, mouse) (58)
Pancreas β-cell (mouse) β-cell (mouse) (59, 60)

Adipose tissues

Adipose tissues, where estradiol stimulates the production of high density lipoprotein cholesterol (HDL) and triglycerides while decreasing LDL production and and fat deposition (61,62), are the most extensively studied sites of extra-gonadal estrogen synthesis. Both male and female aromatase-deficient (Cyp19KO) mice exhibit obesity and dyslipidemia (61,62), proving that estradiol plays a beneficial role in the lipogenesis. However, an adverse effect of adipose tissue-driven estradiol is also indicated in the pathogenesis of breast cancer. For instance, in a breast with a tumor, adipose tissues proximal to the tumor exhibit higher aromatase activity than those distal to the tumor (63).

Bone

Aromatase expression in human bone has been demonstrated in osteoblasts, chondrocytes, and fibroblasts (Table 1), where they convert circulating androgens into estrogens (64). In the bone of prepubertal children, the locally synthesized estradiol stimulates epiphyseal maturation during the growth phase (65). However, in both males and females, the massive pubertal increase of estradiol leads to increased apoptosis of chondrocytes in the epiphyseal plate, causing chondrocyte depletion and hence, ossification and growth slow-down (66). In adults, estradiol increases bone formation and mineralization and reduces bone resorption, thus reducing the risk of osteoporosis (64). Therefore, it is not surprising that the incidence of osteoporosis increases in postmenopausal women as their ovaries lose estradiol synthetic capacity.

Skin

Aromatase expression in the skin occurs mainly in hair follicles and sebaceous glands (67). Glucocorticoids, cAMP analogs, growth factors, and cytokines modulate aromatase expression in these cells and therefore, local estrogene synthesis (68). Estradiol enhances collagen synthesis, increases skin thickness, and stimulates blood flow in the skin. Therefore, in situ estrogen synthesis in the skin is vital for maintaining healthy skin (69). Estradiol also prolongs the anagen phase of the hair cycle and therefore enhances hair growth by increasing the synthesis of essential growth factors stimulating the proliferation of hair follicle cells (70).

Liver

In the liver, estradiol regulates protein synthesis, including lipoprotein and proteins responsible for blood clotting (factors II, VII, IX, X, plasminogen) (71). Estrogen signaling is also essential in regulating glucose homeostasis, thus improving glucose tolerance and insulin sensitivity (72). Recent research has explored the possibility that postmenopausal women with nonalcoholic fatty liver disease and with long durations of estrogen deficiency could have a higher risk of having severe fibrosis than premenopausal women (73). Estrogen receptor beta (ERβ) is implicated in mediating the protective role that estradiol plays under pathogenic condition in the liver as it shows potent anti-proliferative and anti-inflammatory properties. As such, chronic disease is linked to elevated ERβ expression in the liver (74). ERβ is also known to mediate the anti-tumor action of estrogens in intrahepatic cholangiocarcinoma (75).

Brain

High levels of estrogen receptors are expressed during brain development. During this period, sex hormones determine apoptosis, neuronal migration, neurogenesis, axonal guidance, and synaptogenesis. Estradiol induces sexual differentiation in the developing brain. Aromatase mRNA expression in the hypothalamus of males peaks before and after birth, inducing sexual differentiation of the brain (76). In the brains of both males and females, estradiol provides a neuroprotective effect. Estradiol’s prevention of neurodegeneration in brain tissues is proven in both the Cyp19KO mouse model and the aromatase inhibitor-treated mouse (8). Inhibition or null mutation of aromatase, a key enzyme for estradiol synthesis, results in accelerated neurodegeneration (8). Estradiol effects in the brain also include regulating mood, pain sensitivity, motor control, and cognitive behavior (13-16). Estradiol regulates neuronal metabolism by modulating the expression of metabolic enzymes such as GLUT (glucose-transporter), glycolytic enzyme hexokinase, pyruvate dehydrogenase (PDH), aconitase, and ATP synthase (77).

Adrenal gland

Estrogens stimulate adrenal cortex growth during development by promoting cell proliferation and enhancing steroidogenic activity by increasing StAR and SF-1 expression in the adrenal gland (30). In the fetal adrenal gland, estradiol and ACTH form as a positive regulatory loop in which estradiol increases ACTH secretion from adrenal cortex while ACTH increase estradiol in the ovary (78).

Pancreas

Estradiol increases insulin gene expression and insulin content in β-cells (59,79), increases β-cell proliferation during pancreatic development and recovery from injury (80), and prevents apoptosis of β-cells upon inflammatory insult (59) via ERα- and ERβ-mediated pathways.

Others

In the blood vessel, estradiol positively impacts vascular function by preventing the oxidation of LDL cholesterol, stimulating nitric oxide synthesis and release, and inhibiting fibroblast transition to myofibroblast, preventing cardiac fibrosis (81-83) and atherosclerosis development. In the muscle, estradiol increases muscle mass and strength, alleviating disuse-induced muscle atrophy and promoting regrowth after reloading. It also stimulates muscle repair by stimulating satellite cell proliferation (84,85). Estradiol replacement on ovariectomized mice shows that estradiol can reduce stiffness in muscle as well as stimulate muscle regeneration (39). In the kidney, estradiol has a role of protecting kidney functions during progressive glomerulosclerosis in the female rat remnant kidney model (86). In the intestine, to maintain the intestinal epithelium, estrogens are necessary. Estrogens improve epithelial barriers and reduce intestinal permeability (87), preventing chronic mucosal inflammation in animals and humans (88).

Inflammation

Estrogens play an important role in the inflammatory response by regulating development, proliferation, migration, and apoptosis of immune cells (89). Lymphocytes have been shown to express estrogen receptors (ERα and ERβ), but the expression levels of both receptors vary among cell types. CD4+ T-lymphocytes express ERα whereas B-lymphocytes express ERβ (90). In contrast, CD8+ T-lymphocytes express both receptors at low but equivalent levels (90). Regardless of subcellular differences, estrogens appear to exert a suppressive effect on both B- and T-lymphopoiesis. In support, B-lymphocyte formation is selectively reduced with estradiol treatment (91), and ovariectomy results in increased B-lymphopoiesis (92,93). In addition to the inhibitory effect on lymphopoiesis, estradiol has been shown to influence T helper (Th) responses; inhibit the production of Th1 cytokines such as IL-12, TNF-α, and IFN-γ; and stimulate Th2 anti-inflammatory cytokine production such as IL-10, IL-4, and TGF-β (94). Estradiol has also been shown to modulate the main activities (maturation, differentiation, and migration) of myeloid cells, including monocytes, macrophages, and dendritic cells (95-98). Thus, estradiol has an important impact on immune cells and affects both the innate and the adaptive immune systems, which may account for its contribution in diseases associated with immune disorder.

ESTROGEN AND ESTROGEN RECEPTORS IN THE GUT

In an effort to identify extra-gonadal sites of de novo estradiol synthesis, we generated a double transgenic mouse line in which a transgenic aromatase (cyp19) promoter induces the expression of a red fluorescent protein (RFP) (un-published). In this animal, RFP signal is strongly expressed in the Peyer's patch (Pp), a secondary lymphoid organ in the intestine. Pp have an organizational structure similar to lymph nodes consisting of multiple follicles and interfollicular areas. A follicle is made of a germinal center that is filled with proliferating B-lymphocytes, follicular dendritic cells, and macrophages; the interfollicular area is populated with T-lymphocytes as well as B-lymphocytes, macrophages, and dendritic cells. As part of the gut-associated lymphoid tissue, Pp are known as inductive sites of intestinal immune responses (99). The induction process in the Pp starts with sensing antigens or microbes in the gut lumen by M-cells located in a monolayer of specialized intestinal epithelial cells known as the follicle-associated epithelium. M-cells transport antigens to antigen-presenting cells, specifically dendritic cells (DCs), within the underlying sub-epithelial dome through transcytosis. Dendritic cells then further present antigens to T-and B-lymphocytes, triggering priming and proliferation of lymphocytes to complete the immune response. A well-known effect of the Pp’s induction function is generating antigen-specific intestinal IgA responses, which is critical for maintaining host-microbiota interaction, generating immune tolerance, and preventing infection (100-102). Interestingly, estrogens plays a significant role in the gastrointestinal tract. In this section, we will describe some of the lesser known roles for estrogen in the gastrointestinal system.

Napoleon Bonaparte was not aware of the true importance of his words when he said “An army marches on its stomach.” Technically, an army marches on its intestines. The gastrointestinal tract (GIT) is a unique environment colonized by a remarkable variety of bacteria as well as other organisms including fungi and viruses. This superorganism, the microbiome, is not a simple spectator in biological processes but is an active component of the biochemical and metabolic health of the host (103). The microbiome is capable of digesting large molecules into simpler ones that can be efficiently reabsorbed by the host. The importance of a healthy microbiome has been well published (104-108), and multiple pathologies have been correlated with poor diversity of the microbiome, including irritable bowel (IBS) (109), osteoporosis (110,111), and gluten intolerance (112). Therefore, controlling the microbiome is paramount to maintaining an optimally functioning GIT. The mucosal epithelium is perfectly adapted to monitor both microbial and nutrient composition. The release of antimicrobial peptides (113) or anti-inflammatory molecules maintains the optimal microbial ecology depending on the current GIT contents.

Appetite

Researchers have noted a correlation between estradiol levels and appetite. Food intake is significantly decreased during the preovulatory period when estradiol levels are increasing (114). These actions are attributed to estradiol inhibiting appetite indirectly through cannabinoid receptors (115). Further, blocking estrogen receptors with ICI182,270 ablates any action of estradiol on appetite (115). What is more interesting is that appetite is influenced by the microbiome present in the GIT. Bacterial peptides signal hunger or satiation (113,116); in essence, the bacteria control our desire to eat. Locally synthesized estrogen produced in response to microbiome composition in turn may influence immune responses, bringing us back to control of microbiome composition.

Immune function. Estrogenic compounds in the gut lumen suppress immune function through targeted apoptosis and inhibition of cell proliferation in the germinal centers of ileal Pp (117). The Pp are important in generating protective immune responses to pathogens through both innate and cell medicated responses (117) and are also key in tolerizing the host to food antigens. The mucosal surfaces of the gut must maintain homeostasis, allowing sufficient function of Pp to prevent immune responses to food antigens yet not responding prolifically to commensal bacteria in the gut. Abnormal Pp function through estrogenic compounds is responsible for initializing autoimmune responses and impaired innate responses. Again, we see the constituents of the gut signaling control of the microbiome composition. This leads into the next topic of estrogens and cancer.

Cancer

The small intestine is the main absorptive area of the gastrointestinal tract. To maximize absorption, the epithelial layer is covered with invaginations or crypts of Lieberkühn and exists as a sheet of single cells. These cells are prone to injury and are therefore replaced every 3-5 days (118). To facilitate this replacement, the base of the crypts is populated with stem cells that differentiate into the mature epithelium as they migrate towards the crest of the crypt. ERα and ERβ are both expressed in the crypt cells. However, they are distributed such that ERα is predominantly expressed in the cells at the base of crypts and ERβ is expressed in the cells towards the crest. ERα signaling stimulates proliferation (119) and ERβ signaling opposes this action (120,121), and the net signaling from the two receptors controls proliferation. To further support the role of estrogen receptors in tumor development, ERβ-deficient mice demonstrate a hyper-proliferation of the colonic epithelium with progression to colon carcinoma (87,122). More than 30 years ago, it was established that there is an associative risk between reduced estrogen levels and colorectal cancer in menopausal women (123) and that hormone (estrogen) replacement therapy reduces the incidence of colorectal cancer (124). Recent literature on estrogen and colorectal cancer confirms an anti-tumorigenic role for estrogen signaling in the gut due to preferential ERβ signaling (125).

However, estrogen in the gut is not always good. A recent review by Kwa et al. (103) associated the “estrobolome” (126), bacteria with the capacity to metabolize estrogens, with level of risk for breast cancer. A phylogenetic diverse microbiome favors metabolism of conjugated estrogens. Once metabolized, the free estrogens are more easily reabsorbed increasing systemic estrogen levels. Increased circulating estrogens levels increases relative risk for hormone dependent malignancies such as breast cancer. As described above, our recent unpublished work has demonstrated that not only are Pp able to respond to estrogens, but they are also a significant site of estradiol synthesis. Thus, Pp are able to monitor the bacterial diversity of the gut lumen and secrete estradiol. This estradiol then regulates immune responses locally and ultimately alters the diversity of the microbiome.

CONCLUSION

In conclusion, although estradiol is best recognized as sex hormone that regulates the development and function of reproductive hormone across the entire mammalian species, ever-growing evidence demonstrates its multi-faceted nature in exerting its role in non-reproductive organs and systems under normal as well as pathological conditions. It will be exciting to see what other functions estradiol may play in local tissues and from where the hormone is supplied to those sites.

Acknowledgments

This work was supported by the USDA National Institute of Food and Agriculture, Hatch project (1009826).

References

  • 1.Hess RA, Bunick D, Lee KH. A role for oestrogens in the male reproductive system. Nature. (1997);390:509–512. doi: 10.1038/37352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Simpson E, Rubin G, Clyne C. Local estrogen biosynthesis in males and females. Endocr Relat Cancer. (1999);6:131–137. doi: 10.1677/erc.0.0060131. [DOI] [PubMed] [Google Scholar]
  • 3.Simpson ER. Sources of estrogen and their importance. J Steroid Biochem Mol Biol. (2003);86:225–230. doi: 10.1016/S0960-0760(03)00360-1. [DOI] [PubMed] [Google Scholar]
  • 4.Nelson LR, Bulun SE. Estrogen production and action. J Am Acad Dermatol. (2001);45:S116–S124. doi: 10.1067/mjd.2001.117432. [DOI] [PubMed] [Google Scholar]
  • 5.Hemsell DL, Grodin JM, Brenner PF, Siiteri PK, MacDonald PC. Plasma precursors of estrogen. II. Correlation of the extent of conversion of plasma androstenedione to estrone with age. J Clin Endocrinol Metab. (1974);38:476–479. doi: 10.1210/jcem-38-3-476. [DOI] [PubMed] [Google Scholar]
  • 6.Labrie F, Bélanger A, Luu-The V, et al. DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: its role during aging. Steroids. (1998);63:322–328. doi: 10.1016/S0039-128X(98)00007-5. [DOI] [PubMed] [Google Scholar]
  • 7.Ishunina TA, van Beurden D, van der Meulen G, et al. Diminished aromatase immunoreactivity in the hypothalamus, but not in the basal forebrain nuclei in Alzheimer's disease. Neurobiol Aging. (2005);26:173–194. doi: 10.1016/j.neurobiolaging.2004.03.010. [DOI] [PubMed] [Google Scholar]
  • 8.Azcoitia I, Sierra A, Veiga S, Garcia-Segura LM. Aromatase expression by reactive astroglia is neuroprotective. Ann N Y Acad Sci. (2003);1007:298–305. doi: 10.1196/annals.1286.028. [DOI] [PubMed] [Google Scholar]
  • 9.Balthazart J, Foidart A, Surlemont C, Harada N. Distribution of aromatase-immunoreactive cells in the mouse forebrain. Cell Tissue Res. (1991);263:71–79. doi: 10.1007/BF00318401. [DOI] [PubMed] [Google Scholar]
  • 10.Yague JG, Muñoz A, de Monasterio-Schrader P, Defelipe J, Garcia-Segura LM, Azcoitia I. Aromatase expression in the human temporal cortex. Neuroscience. (2006);138:389–401. doi: 10.1016/j.neuroscience.2005.11.054. [DOI] [PubMed] [Google Scholar]
  • 11.Wehrenberg U, Prange-Kiel J, Rune GM. Steroidogenic factor-1 expression in marmoset and rat hippocampus: co-localization with StAR and aromatase. J Neurochem. (2001);76:1879–1886. doi: 10.1046/j.1471-4159.2001.00207.x. [DOI] [PubMed] [Google Scholar]
  • 12.Yague JG, Wang AC, Janssen WG, et al. Aromatase distribution in the monkey temporal neocortex and hippocampus. Brain Res. (2008);1209:115–127. doi: 10.1016/j.brainres.2008.02.061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Cleland WH, Mendelson CR, Simpson ER. Aromatase activity of membrane fractions of human adipose tissue stromal cells and adipocytes. Endocrinology. (1983);113:2155–2160. doi: 10.1210/endo-113-6-2155. [DOI] [PubMed] [Google Scholar]
  • 14.Bulun SE, Price TM, Aitken J, Mahendroo MS, Simpson ER. A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. J Clin Endocrinol Metab. (1993);77:1622–1628. doi: 10.1210/jcem.77.6.8117355. [DOI] [PubMed] [Google Scholar]
  • 15.Simpson ER, Zhao Y, Agarwal VR, et al. Aromatase expression in health and disease. Recent Prog Horm Res. (1997);52:185–213. [PubMed] [Google Scholar]
  • 16.Roselli CE, Resko JA. Cytochrome P450 aromatase (CYP19) in the non-human primate brain: distribution, regulation, and functional significance. J Steroid Biochem Mol Biol. (2001);79:247–253. doi: 10.1016/S0960-0760(01)00141-8. [DOI] [PubMed] [Google Scholar]
  • 17.Enjuanes A, Garcia-Giralt N, Supervia A, et al. Regulation of CYP19 gene expression in primary human osteoblasts: effects of vitamin D and other treatments. Eur J Endocrinol. (2003);148:519–526. doi: 10.1530/eje.0.1480519. [DOI] [PubMed] [Google Scholar]
  • 18.Watanabe M, Simpson ER, Pathirage N, Nakajin S, Clyne CD. Aromatase expression in the human fetal osteoblastic cell line SV-HFO. J Mol Endocrinol. (2004);32:533–545. doi: 10.1677/jme.0.0320533. [DOI] [PubMed] [Google Scholar]
  • 19.Janssen JM, Bland R, Hewison M, et al. Estradiol formation by human osteoblasts via multiple pathways: relation with osteoblast function. J Cell Biochem. (1999);75:528–537. doi: 10.1002/(sici)1097-4644(19991201)75:3<528::aid-jcb16>3.3.co;2-v. [DOI] [PubMed] [Google Scholar]
  • 20.Castagnetta LA, Agostara B, Montalto G, et al. Local estrogen formation by nontumoral, cirrhotic, and malignant human liver tissues and cells. Cancer Res. (2003);63:5041–5045. [PubMed] [Google Scholar]
  • 21.Hata S, Miki Y, Saito R, Ishida K, Watanabe M, Sasano H. Aromatase in human liver and its diseases. Cancer Med. (2013);2:305–315. doi: 10.1002/cam4.85. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Robic A, Feve K, Louveau I, Riquet J. Prunier A Exploration of steroidogenesis-related genes in testes, ovaries, adrenals, liver and adipose tissue in pigs. Anim Sci J. (2016);87:1041–1047. doi: 10.1111/asj.12532. [DOI] [PubMed] [Google Scholar]
  • 23.Nicol MR, Papacleovoulou G, Evans DB, et al. Estrogen biosynthesis in human H295 adrenocortical carcinoma cells. Mol Cell Endocrinol. (2009);300:115–120. doi: 10.1016/j.mce.2008.10.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Zhou Y, Kang J, Chen D, Han N, Ma H. Ample Evidence: Dehydroepiandrosterone (DHEA) Conversion into Activated Steroid Hormones Occurs in Adrenal and Ovary in Female Rat. PLoS One. (2015);10:e0124511. doi: 10.1371/journal.pone.0124511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Ueyama T, Shirasawa N, Numazawa M, et al. Gastric parietal cells: potent endocrine role in secreting estrogen as a possible regulator of gastro-hepatic axis. Endocrinology. (2002);143:3162–3170. doi: 10.1210/endo.143.8.8974. [DOI] [PubMed] [Google Scholar]
  • 26.Leshin M, Baron J, George FW, Wilson JD. Increased estrogen formation and aromatase activity in fibroblasts cultured from the skin of chickens with the Henny feathering trait. J Biol Chem. (1981);256:4341–4344. [PubMed] [Google Scholar]
  • 27.Pomari E, Dalla Valle L, Pertile P, Colombo L, Thornton MJ. Intracrine sex steroid synthesis and signaling in human epidermal keratinocytes and dermal fibroblasts. FASEB J. (2015);29:508–524. doi: 10.1096/fj.14-251363. [DOI] [PubMed] [Google Scholar]
  • 28.Berkovitz GD, Brown TR, Fujimoto M. Aromatase activity in human skin fibroblasts grown in cell culture. Steroids. (1087);50:281–295. doi: 10.1016/0039-128X(83)90078-8. [DOI] [PubMed] [Google Scholar]
  • 29.Harada N, Sasano H, Murakami H, Ohkuma T, Nagura H, Takagi Y. Localized expression of aromatase in human vascular tissues. Circ Res. (1999);84:1285–1291. doi: 10.1161/01.RES.84.11.1285. [DOI] [PubMed] [Google Scholar]
  • 30.Bayard F, Clamens S, Meggetto F, Blaes N, Delsol G, Faye JC. Estrogen synthesis, estrogen metabolism, and functional estrogen receptors in rat arterial smooth muscle cells in culture. Endocrinology. (1995);136:1523–1529. doi: 10.1210/endo.136.4.7895662. [DOI] [PubMed] [Google Scholar]
  • 31.Bayard F, Clamens S, Delsol G, Blaes N, Maret A, Faye JC. Oestrogen synthesis, oestrogen metabolism and functional oestrogen receptors in bovine aortic endothelial cells. Ciba Found Symp. (1995);191:122–132. doi: 10.1002/9780470514757.ch7. [DOI] [PubMed] [Google Scholar]
  • 32.Samy TS, Knöferl MW, Zheng R, Schwacha MG, Bland KI, Chaudry IH. Divergent immune responses in male and female mice after trauma-hemorrhage: dimorphic alterations in T lymphocyte steroidogenic enzyme activities. Endocrinology. (2001);142:3519–3529. doi: 10.1210/endo.142.8.8322. [DOI] [PubMed] [Google Scholar]
  • 33.Abrahám IM, Han SK, Todman MG, Korach KS, Herbison AE. Estrogen receptor beta mediates rapid estrogen actions on gonadotropin-releasing hormone neurons in vivo. J Neurosci. (2003);23:5771–5777. doi: 10.1523/JNEUROSCI.23-13-05771.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Higaki S, Takumi K, Itoh M, et al. Response of ERbeta and aromatase expression in the monkey hippocampal formation to ovariectomy and menopause. Neurosci Res. (2012);72:148–154. doi: 10.1016/j.neures.2011.10.007. [DOI] [PubMed] [Google Scholar]
  • 35.Shughrue PJ, Scrimo PJ, Merchenthaler I. Estrogen binding and estrogen receptor characterization (ERalpha and ERbeta) in the cholinergic neurons of the rat basal forebrain. Neuroscience. (2000);96:41–49. doi: 10.1016/S0306-4522(99)00520-5. [DOI] [PubMed] [Google Scholar]
  • 36.Almey A, Milner TA, Brake WG. Estrogen receptor alpha and G-protein coupled estrogen receptor 1 are localized to GABAergic neurons in the dorsal striatum. Neurosci Lett. (2016);622:118–123. doi: 10.1016/j.neulet.2016.04.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Xu Y, Nedungadi TP, Zhu L, et al. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab. (2011);14:453–465. doi: 10.1016/j.cmet.2011.08.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Cooke PS, Naaz A. Role of estrogens in adipocyte development and function. Exp Biol Med (Maywood) (2004);229:1127–1135. doi: 10.1177/153537020422901107. [DOI] [PubMed] [Google Scholar]
  • 39.Davis KE, Carstens EJ, Irani BG, Gent LM, Hahner LM, Clegg DJ. Sexually dimorphic role of G protein- coupled estrogen receptor (GPER) in modulating energy homeostasis. Horm Behav. (2014);66:196–207. doi: 10.1016/j.yhbeh.2014.02.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Dieudonné MN, Leneveu MC, Giudicelli Y, Pecquery R. Evidence for functional estrogen receptors alpha and beta in human adipose cells: regional specificities and regulation by estrogens. Am J Physiol Cell Physiol. (2004);286:C655–C661. doi: 10.1152/ajpcell.00321.2003. [DOI] [PubMed] [Google Scholar]
  • 41.Sjögren K, Lagerquist M, Moverare-Skrtic S, et al. Elevated aromatase expression in osteoblasts leads to increased bone mass without systemic adverse effects. J Bone Miner Res. (2009);24:1263–1270. doi: 10.1359/jbmr.090208. [DOI] [PubMed] [Google Scholar]
  • 42.Martin-Millan M, Almeida M, Ambrogini E, et al. The estrogen receptor-alpha in osteoclasts mediates the protective effects of estrogens on cancellous but not cortical bone. Mol Endocrinol. (2010);24:323–334. doi: 10.1210/me.2009-0354. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Määttä JA, Büki KG, Gu G, et al. Inactivation of estrogen receptor alpha in bone-forming cells induces bone loss in female mice. FASEB J. (2013);27:478–488. doi: 10.1096/fj.12-213587. [DOI] [PubMed] [Google Scholar]
  • 44.Crusodé de Souza M, Sasso-Cerri E, Cerri PS. Immunohistochemical detection of estrogen receptor beta in alveolar bone cells of estradiol-treated female rats: possible direct action of estrogen on osteoclast life span. J Anat. (2009);215:673–681. doi: 10.1111/j.1469-7580.2009.01158.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Braidman IP, Hainey L, Batra G, Selby PL, Saunders PT, Hoyland JA. Localization of estrogen receptor beta protein expression in adult human bone. J Bone Miner Res. (2001);16:214–220. doi: 10.1359/jbmr.2001.16.2.214. [DOI] [PubMed] [Google Scholar]
  • 46.Bord S, Horner A, Beavan S, Compston J. Estrogen receptors alpha and beta are differentially expressed in developing human bone. J Clin Endocrinol Metab. (2001);86:2309–2314. doi: 10.1210/jcem.86.5.7513. [DOI] [PubMed] [Google Scholar]
  • 47.Karas RH, Patterson BL, Mendelsohn ME. Human vascular smooth muscle cells contain functional estrogen receptor. Circulation. (1994);89:1943–1950. doi: 10.1161/01.CIR.89.5.1943. [DOI] [PubMed] [Google Scholar]
  • 48.Russell KS, Haynes MP, Sinha D, Clerisme E, Bender JR. Human vascular endothelial cells contain membrane binding sites for estradiol, which mediate rapid intracellular signaling. Proc Natl Acad Sci U S A. (2000);97:5930–5935. doi: 10.1073/pnas.97.11.5930. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Broughton BR, Miller AA, Sobey CG. Endothelium-dependent relaxation by G protein-coupled receptor 30 agonists in rat carotid arteries. Am J Physiol Heart Circ Physiol. (2010);298:H1055–1061. doi: 10.1152/ajpheart.00878.2009. [DOI] [PubMed] [Google Scholar]
  • 50.Chakrabarti S, Davidge ST. High glucose-induced oxidative stress alters estrogen effects on ERalpha and ERbeta in human endothelial cells: reversal by AMPK activator. J Steroid Biochem Mol Biol. (2009);117:99–106. doi: 10.1016/j.jsbmb.2009.07.007. [DOI] [PubMed] [Google Scholar]
  • 51.Campbell-Thompson M, Reyher KK, Wilkinson LB. Immunolocalization of estrogen receptor alpha and beta in gastric epithelium and enteric neurons. J Endocrinol. (2001);171:65–73. doi: 10.1677/joe.0.1710065. [DOI] [PubMed] [Google Scholar]
  • 52.Gaudet HM, Cheng SB, Christensen EM, Filardo EJ. The G-protein coupled estrogen receptor, GPER: The inside and inside-out story. Mol Cell Endocrinol. (2015);418:207–219. doi: 10.1016/j.mce.2015.07.016. [DOI] [PubMed] [Google Scholar]
  • 53.Thornton MJ, Taylor AH, Mulligan K, et al. Oestrogen receptor beta is the predominant oestrogen receptor in human scalp skin. Exp Dermatol. (2003);12:181–190. doi: 10.1034/j.1600-0625.2003.120209.x. [DOI] [PubMed] [Google Scholar]
  • 54.El Safoury O, Rashid L, Ibrahim M. A study of androgen and estrogen receptors alpha, beta in skin tags. Indian J Dermatol. (2010);55:20–24. doi: 10.4103/0019-5154.60345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Cesinaro AM, Roncati L, Maiorana A. Estrogen receptor alpha overexpression in multinucleate cell angiohistiocytoma: new insights into the pathogenesis of a reactive process. Am J Dermatopathol. (2010);32:655–659. doi: 10.1097/DAD.0b013e3181d3ca49. [DOI] [PubMed] [Google Scholar]
  • 56.Trejter M, Jopek K, Celichowski P, Tyczewska M, Malendowicz LK, Rucinski M. Expression of estrogen, estrogen related and androgen receptors in adrenal cortex of intact adult male and female rats. Folia Histochem Cytobiol. (2015);53:133–144. doi: 10.5603/FHC.a2015.0012. [DOI] [PubMed] [Google Scholar]
  • 57.Velders M, Schleipen B, Fritzemeier KH, Zierau O, Diel P. Selective estrogen receptor-beta activation stimulates skeletal muscle growth and regeneration. FASEB J. (2012);26:1909–1920. doi: 10.1096/fj.11-194779. [DOI] [PubMed] [Google Scholar]
  • 58.Potier M, Elliot SJ, Tack I, et al. Expression and regulation of estrogen receptors in mesangial cells: influence on matrix metalloproteinase-9. J Am Soc Nephrol. (2001);12:241–251. doi: 10.1681/ASN.V122241. [DOI] [PubMed] [Google Scholar]
  • 59.Le May C, Chu K, Hu M, et al. Estrogens protect pancreatic beta-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice. Proc Natl Acad Sci U S A. (2006);103:9232–9237. doi: 10.1073/pnas.0602956103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Liu S, Le May C, Wong WP, et al. Importance of extranuclear estrogen receptor-alpha and membrane G protein-coupled estrogen receptor in pancreatic islet survival. Diabetes. (2009);58:2292–2302. doi: 10.2337/db09-0257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Gao H, Bryzgalova G, Hedman E, et al. Long-term administration of estradiol decreases expression of hepatic lipogenic genes and improves insulin sensitivity in ob/ob mice: a possible mechanism is through direct regulation of signal transducer and activator of transcription 3. Mol Endocrinol. (2006);20:1287–1299. doi: 10.1210/me.2006-0012. [DOI] [PubMed] [Google Scholar]
  • 62.Reue K, Dwyer JR. Lipin proteins and metabolic homeostasis. J Lipid Res. (2009);50:S109–S114. doi: 10.1194/jlr.R800052-JLR200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Miller WR. Aromatase activity in breast tissue. J Steroid Biochem Mol Biol. (1991);39:783–790. doi: 10.1016/0960-0760(91)90026-2. [DOI] [PubMed] [Google Scholar]
  • 64.Sasano H, Uzuki M, Sawai T, et al. Aromatase in human bone tissue. J Bone Miner Res. (1997);12:1416–1423. doi: 10.1359/jbmr.1997.12.9.1416. [DOI] [PubMed] [Google Scholar]
  • 65.Shozu M, Simpson ER. Aromatase expression of human osteoblast-like cells. Mol Cell Endocrinol. (1998);139:117–129. doi: 10.1016/S0303-7207(98)00069-0. [DOI] [PubMed] [Google Scholar]
  • 66.Zhong M, Carney DH, Boyan BD, Schwartz Z. 17beta-Estradiol regulates rat growth plate chondrocyte apoptosis through a mitochondrial pathway not involving nitric oxide or MAPKs. Endocrinology. (2011);152:82–92. doi: 10.1210/en.2010-0509. [DOI] [PubMed] [Google Scholar]
  • 67.Slominski A, Wortsman J. Neuroendocrinology of the skin. Endocr Rev. (2000);21:457–487. doi: 10.1210/edrv.21.5.0410. [DOI] [PubMed] [Google Scholar]
  • 68.Brincat MP. Hormone replacement therapy and the skin. Maturitas. (2000);35:107–117. doi: 10.1016/S0378-5122(00)00097-9. [DOI] [PubMed] [Google Scholar]
  • 69.Harada N. A unique aromatase (P-450AROM) mRNA formed by alternative use of tissue-specific exons 1 in human skin fibroblasts. Biochem Biophys Res Commun. (1992);189:1001–1007. doi: 10.1016/0006-291X(92)92303-F. [DOI] [PubMed] [Google Scholar]
  • 70.Emoto N, Ling N, Baird A. Growth factor-mediated regulation of aromatase activity in human skin fibroblasts. Proc Soc Exp Biol Med. (1991);196:351–358. doi: 10.3181/00379727-196-43200. [DOI] [PubMed] [Google Scholar]
  • 71.Barros RP, Gustafsson JÅ. Estrogen receptors and the metabolic network. Cell Metab. (2011);14:289–299. doi: 10.1016/j.cmet.2011.08.005. [DOI] [PubMed] [Google Scholar]
  • 72.Parthasarathy C, Renuka VN, Balasubramanian K. Sex steroids enhance insulin receptors and glucose oxidation in Chang liver cells. Clin Chim Acta. (2009);399:49–53. doi: 10.1016/j.cca.2008.09.011. [DOI] [PubMed] [Google Scholar]
  • 73.Klair JS, Yang JD, Abdelmalek MF, et al. A longer duration of estrogen deficiency increases fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease. Hepatology. (2016);64:85–91. doi: 10.1002/hep.28514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Iavarone M, Lampertico P, Seletti C, et al. The clinical and pathogenetic significance of estrogen receptor-beta expression in chronic liver diseases and liver carcinoma. Cancer. (2003);98:529–534. doi: 10.1002/cncr.11528. [DOI] [PubMed] [Google Scholar]
  • 75.Marzioni M, Torrice A, Saccomanno S, et al. An oestrogen receptor beta-selective agonist exerts antineoplastic effects in experimental intrahepatic cholangiocarcinoma. Dig Liver Dis. (2012);44:134–142. doi: 10.1016/j.dld.2011.06.014. [DOI] [PubMed] [Google Scholar]
  • 76.Colciago A, Celotti F, Pravettoni A, Mornati O, Martini L, Negri-Cesi P. Dimorphic expression of testosterone metabolizing enzymes in the hypothalamic area of developing rats. Brain Res Dev Brain Res. (2005);155:107–116. doi: 10.1016/j.devbrainres.2004.12.003. [DOI] [PubMed] [Google Scholar]
  • 77.Rettberg JR, Yao J, Brinton RD. Estrogen: a master regulator of bioenergetic systems in the brain and body. Front Neuroendocrinol. (2014);35:8–30. doi: 10.1016/j.yfrne.2013.08.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Kaludjerovic J, Ward WE. Ward, The Interplay between Estrogen and Fetal Adrenal Cortex. J Nutr Metab. (2012);2012:837901. doi: 10.1155/2012/837901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Alonso-Magdalena P, Ropero AB, Carrera MP, et al. Pancreatic insulin content regulation by the estrogen receptor ER alpha. PLoS One. (2008);3:e2069. doi: 10.1371/journal.pone.0002069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Yuchi Y, Cai Y, Legein B, et al. Estrogen Receptor alpha Regulates beta-Cell Formation During Pancreas Development and Following Injury. Diabetes. (2015);64:3218–3228. doi: 10.2337/db14-1798. [DOI] [PubMed] [Google Scholar]
  • 81.Pedram A, Razandi M, O’Mahony F, Lubahn D, Levin ER. Estrogen receptor-beta prevents cardiac fibrosis. Mol Endocrinol. (2010);24:2152–2165. doi: 10.1210/me.2010-0154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Novensà L, Novella S, Medina P, et al. Aging negatively affects estrogens-mediated effects on nitric oxide bioavailability by shifting ERalpha/ERbeta balance in female mice. PLoS One. (2011);6:e25335. doi: 10.1371/journal.pone.0025335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Prossnitz ER, Maggiolini M. Mechanisms of estrogen signaling and gene expression via GPR30. Mol Cell Endocrinol. (2009);308:32–38. doi: 10.1016/j.mce.2009.03.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Lowe DA, Baltgalvis KA, Greising SM. Mechanisms behind estrogen's beneficial effect on muscle strength in females. Exerc Sport Sci Rev. (2010);38:61–67. doi: 10.1097/JES.0b013e3181d496bc. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Enns DL, Tiidus PM. The influence of estrogen on skeletal muscle: sex matters. Sports Med. (2010);40:41–58. doi: 10.2165/11319760-000000000-00000. [DOI] [PubMed] [Google Scholar]
  • 86.Antus B, Hamar P, Kokeny G, et al. Estradiol is nephroprotective in the rat remnant kidney. Nephrol Dial Transplant. (2003);18:54–61. doi: 10.1093/ndt/18.1.54. [DOI] [PubMed] [Google Scholar]
  • 87.Wada-Hiraike O, Imamov O, Hiraike H, et al. Role of estrogen receptor beta in colonic epithelium. Proc Natl Acad Sci U S A. (2006);103:2959–2964. doi: 10.1073/pnas.0511271103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Shen L, Turner JR. Role of epithelial cells in initiation and propagation of intestinal inflammation. Eliminating the static: tight junction dynamics exposed. Am J Physiol Gastrointest Liver Physiol. (2006);290:G577–G582. doi: 10.1152/ajpgi.00439.2005. [DOI] [PubMed] [Google Scholar]
  • 89.Straub RH. The complex role of estrogens in inflammation. Endocr Rev. (2007);28:521–574. doi: 10.1210/er.2007-0001. [DOI] [PubMed] [Google Scholar]
  • 90.Phiel KL, Henderson RA, Adelman SJ, Elloso MM. Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations. Immunol Lett. (2005);97:107–113. doi: 10.1016/j.imlet.2004.10.007. [DOI] [PubMed] [Google Scholar]
  • 91.Kouro T, Medina KL, Oritani K, Kincade PW. Characteristics of early murine B-lymphocyte precursors and their direct sensitivity to negative regulators. Blood. (2001);97:2708–2715. doi: 10.1182/blood.V97.9.2708. [DOI] [PubMed] [Google Scholar]
  • 92.Masuzawa T, Miyaura C, Onoe Y, et al. Estrogen deficiency stimulates B lymphopoiesis in mouse bone marrow. J Clin Invest. (1994);94:1090–1097. doi: 10.1172/JCI117424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.Wilson CA, Mrose SA, Thomas DW. Enhanced production of B lymphocytes after castration. Blood. (1995);85:1535–1539. [PubMed] [Google Scholar]
  • 94.Salem ML. Estrogen, a double-edged sword: modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production. Curr Drug Targets Inflamm Allergy. (2004);3:97–104. doi: 10.2174/1568010043483944. [DOI] [PubMed] [Google Scholar]
  • 95.Härkönen PL, Väänänen HK. Monocyte-macrophage system as a target for estrogen and selective estrogen receptor modulators. Ann N Y Acad Sci. (2006);1089:218–227. doi: 10.1196/annals.1386.045. [DOI] [PubMed] [Google Scholar]
  • 96.Komi J, Lassila O. Nonsteroidal anti-estrogens inhibit the functional differentiation of human monocytederived dendritic cells. Blood. (2000);95:2875–2882. [PubMed] [Google Scholar]
  • 97.Mao A, Paharkova-Vatchkova V, Hardy J, Miller MM, Kovats S. Estrogen selectively promotes the differentiation of dendritic cells with characteristics of Langerhans cells. J Immunol. (2005);175:5146–5151. doi: 10.4049/jimmunol.175.8.5146. [DOI] [PubMed] [Google Scholar]
  • 98.Mor G, Sapi E, Abrahams VM, et al. Interaction of the estrogen receptors with the Fas ligand promoter in human monocytes. J Immunol. (2003);170:114–122. doi: 10.4049/jimmunol.170.1.114. [DOI] [PubMed] [Google Scholar]
  • 99.Jung C, Hugot JP, Barreau F. Peyer's Patches: The Immune Sensors of the Intestine. Int J Inflam. (2010);2010:823710. doi: 10.4061/2010/823710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.Lycke NY, Bemark M. The role of Peyer's patches in synchronizing gut IgA responses. Front Immunol. (2012);3:329. doi: 10.3389/fimmu.2012.00329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101.Mkaddem SB, Christou I, Rossato E, Berthelot L, Lehuen A, Monteiro RC. IgA, IgA receptors, and their anti-inflammatory properties. Curr Top Microbiol Immunol. (2014);382:221–235. doi: 10.1007/978-3-319-07911-0_10. [DOI] [PubMed] [Google Scholar]
  • 102.Singh K, Chang C, Gershwin ME. IgA deficiency and autoimmunity. Autoimmun Rev. (2014);13:163–177. doi: 10.1016/j.autrev.2013.10.005. [DOI] [PubMed] [Google Scholar]
  • 103.Kwa M, Plottel CS, Blaser MJ, Adams S. The Intestinal Microbiome and Estrogen Receptor-Positive Female Breast Cancer. J Natl Cancer Inst. (2016);108 doi: 10.1093/jnci/djw029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104.Relman DA. Gut microbiota: How to build healthy growth-promoting gut communities. Nat Rev Gastroenterol Hepatol. (2016);13:379–380. doi: 10.1038/nrgastro.2016.74. [DOI] [PubMed] [Google Scholar]
  • 105.Wischmeyer PE, McDonald D, Knight R. Role of the microbiome, probiotics, and 'dysbiosis therapy' in critical illness. Curr Opin Crit Care. (2016);22:347–353. doi: 10.1097/MCC.0000000000000321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106.Nishijima S, Suda W, Oshima K, et al. The gut microbiome of healthy Japanese and its microbial and functional uniqueness. DNA Res. (2016);23:125–133. doi: 10.1093/dnares/dsw002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107.Highet AR, Berry AM, Bettelheim KA, Goldwater PN. Gut microbiome in sudden infant death syndrome (SIDS) differs from that in healthy comparison babies and offers an explanation for the risk factor of prone position. Int J Med Microbiol. (2014);304:735–741. doi: 10.1016/j.ijmm.2014.05.007. [DOI] [PubMed] [Google Scholar]
  • 108.Tuddenham S, Sears CL. The intestinal microbiome and health. Curr Opin Infect Dis. (2015);28:464–470. doi: 10.1097/QCO.0000000000000196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 109.Fourie NH, Wang D, Abey SK, et al. The microbiome of the oral mucosa in irritable bowel syndrome. Gut Microbes. (2016);2016:1–16. doi: 10.1080/19490976.2016.1162363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 110.Hernandez CJ, Guss JD, Luna M, Goldring SR. Links Between the Microbiome and Bone. J Bone Miner Res. (2016) doi: 10.1002/jbmr.2887. [Epub ahead of print] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 111.Weaver CM. Diet, gut microbiome, and bone health. Curr Osteoporos Rep. (2015);13:25–130. doi: 10.1007/s11914-015-0257-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 112.Fernandez-Feo M, Wei G, Blumenkranz G, et al. The cultivable human oral gluten-degrading microbiome and its potential implications in coeliac disease and gluten sensitivity. Clin Microbiol Infect. (2013);19:E386–E394. doi: 10.1111/1469-0691.12249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 113.Zhao Z, Sakai T. Characteristic features of ghrelin cells in the gastrointestinal tract and the regulation of stomach ghrelin expression and production. World J Gastroenterol. (2008);14:6306–6311. doi: 10.3748/wjg.14.6306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 114.Lyons PM, Truswell AS, Mira M, Vizzard J, Abraham SF. Reduction of food intake in the ovulatory phase of the menstrual cycle. Am J Clin Nutr. (1989);49:1164–1168. doi: 10.1093/ajcn/49.6.1164. [DOI] [PubMed] [Google Scholar]
  • 115.Mela V, Vargas A, Meza C, Kachani M, Wagner EJ. Modulatory influences of estradiol and other anorexigenic hormones on metabotropic, Gi/o-coupled receptor function in the hypothalamic control of energy homeostasis. J Steroid Biochem Mol Biol. (2016);160:15–26. doi: 10.1016/j.jsbmb.2015.07.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116.Blaut M. Gut microbiota and energy balance: role in obesity. Proc Nutr Soc. (2015);74:227–234. doi: 10.1017/S0029665114001700. [DOI] [PubMed] [Google Scholar]
  • 117.Obremski K, Poniatowska-Broniek G. Zearalenone induces apoptosis and inhibits proliferation in porcine ileal Peyer's patch lymphocytes. Pol J Vet Sci. (2015);18:153–161. doi: 10.1515/pjvs-2015-0020. [DOI] [PubMed] [Google Scholar]
  • 118.Matthews J, Wihlén B, Tujague M, Wan J, Ström A, Gustafsson JA. Estrogen receptor (ER) beta modulates ERalpha-mediated transcriptional activation by altering the recruitment of c-Fos and c-Jun to estrogen-responsive promoters. Mol Endocrinol. (2006);20:534–543. doi: 10.1210/me.2005-0140. [DOI] [PubMed] [Google Scholar]
  • 119.Matthews J, Gustafsson JA. Estrogen signaling: a subtle balance between ER alpha and ER beta. Mol Interv. (2003);3:281–292. doi: 10.1124/mi.3.5.281. [DOI] [PubMed] [Google Scholar]
  • 120.Matthews J, Gustafsson JA. Estrogen receptor and aryl hydrocarbon receptor signaling pathways. Nucl Recept Signal. (2006);4:e016. doi: 10.1621/nrs.04016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 121.Liu MM, Albanese C, Anderson CM, et al. Opposing action of estrogen receptors alpha and beta on cyclin D1 gene expression. J Biol Chem. (2002);277:24353–24360. doi: 10.1074/jbc.M201829200. [DOI] [PubMed] [Google Scholar]
  • 122.D’Errico I, Moschetta A. Nuclear receptors, intestinal architecture and colon cancer: an intriguing link. Cell Mol Life Sci. (2008);65:1523–1543. doi: 10.1007/s00018-008-7552-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 123.Butcher D, Hassanein K, Dudgeon M, Rhodes J, Holmes FF. Female gender is a major determinant of changing subsite distribution of colorectal cancer with age. Cancer. (1985);56:714–716. doi: 10.1002/1097-0142(19850801)56:3<714::aid-cncr2820560345>3.0.co;2-d. [DOI] [PubMed] [Google Scholar]
  • 124.Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, et al. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med. (2004);350:991–1004. doi: 10.1056/NEJMoa032071. [DOI] [PubMed] [Google Scholar]
  • 125.Caiazza F, Ryan EJ, Doherty G, Winter DC, Sheahan K. Estrogen receptors and their implications in colorectal carcinogenesis. Front Oncol. (2015);5:19. doi: 10.3389/fonc.2015.00019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 126.Plottel CS, Blaser MJ. Microbiome and malignancy. Cell Host Microbe. (2011);10:324–335. doi: 10.1016/j.chom.2011.10.003. [DOI] [PMC free article] [PubMed] [Google Scholar]

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