Estrogens inf luence the differentiation and maintenance of reproductive tissues and affect lipid metabolism and bone remodeling. Two estrogen receptors (ERs) have been identified to date, ER␣ and ER␤. We previously generated and studied knockout mice lacking estrogen receptor ␣ and reported severe reproductive and behavioral phenotypes including complete infertility of both male and female mice and absence of breast tissue development. Here we describe the generation of mice lacking estrogen receptor ␤ Estrogens are critical to the functioning and maintenance of a diverse array of tissues and physiological systems in mammals. The actions of estrogen on such classical targets as the reproductive tract, gonads, mammary tissue, and hypothalamic͞pituitary axis have been well characterized. A role in nonreproductive tissues, such as maintenance of bone mineral density and cardiovascular health in women, also has been described (1, 2). The physiological responses to estrogen are known to be mediated within specific tissues by at least two estrogen receptors (ERs), ER␣ and ER␤ (3-5). The ERs are a class I member of the nuclear hormone receptor family and act as ligand-activated nuclear transcription factors (6). Studies of the receptors' tissue distribution and expression pattern indicate that ER␣ has a broad expression pattern, whereas ER␤ has a more focused pattern with high levels in the ovary, prostate, epididymis, lung, and hypothalamus (7,8). However, the exact physiological responses attributable to each receptor are unknown. We previously described the pleiotropic effects of disruption of the ER␣ gene in ER␣ knockout mice (␣ERKO), including absence of breast development in females and infertility caused by reproductive tract and gonadal and behavioral abnormalities in both sexes (9-13). Here, we describe the generation of mice homozygous for a disruption of the ER␤ gene; initial characterizations indicate that the ER␤ Ϫ͞Ϫ mice exhibit phenotypes that are distinct from those of the ␣ERKO mice.

Estrogens influence many physiological processes in mammals, including but not limited to reproduction, cardiovascular health, bone integrity, cognition, and behavior. Given this widespread role for estrogen in human physiology, it is not surprising that estrogen is also implicated in the development or progression of numerous diseases, which include but are not limited to various types of cancer (breast, ovarian, colorectal, prostate, endometrial), osteoporosis, neurodegenerative diseases, cardiovascular disease, insulin resistance, lupus erythematosus, endometriosis, and obesity. In many of these diseases, estrogen mediates its effects through the estrogen receptor (ER), which serves as the basis for many therapeutic interventions. This Review will describe diseases in which estrogen, through the ER, plays a role in the development or severity of disease.

The steroid hormone 17␤-estradiol (E 2 ) is a key regulator of growth, differentiation, and function in a wide array of target tissues, including the male and female reproductive tracts, mammary gland, and skeletal and cardiovascular systems. The predominant biological effects of E 2 are mediated through two distinct intracellular receptors, ER␣ 1 and ER␤, each encoded by unique genes (1) but possessing the hallmark modular structure of functional domains characteristic of the steroid/thyroid hormone superfamily of nuclear receptors (introduced in the Minireview Prologue (54)). Certain functional domains of the ER␣ and ER␤ exhibit a high degree of homology, namely the DNA-and ligand-binding domains, at 97 and 60%, respectively, whereas considerable divergence is apparent in the N terminus (18% homology). Hence, ER␣ and ER␤ interact with identical DNA response elements and exhibit a similar binding affinity profile for an array of endogenous, synthetic, and naturally occurring estrogens when assayed in vitro (2). In vitro studies also suggest the two receptors may play redundant roles in estrogen signaling; however, tissue localization studies have revealed distinct expression patterns for each receptor that suggest otherwise. Whereas ER␣ is the predominant subtype expressed in the breast, uterus, cervix, vagina, and several additional target organs, ER␤ exhibits a more limited expression pattern and is primarily detected in the ovary, prostate, testis, spleen, lung, hypothalamus, and thymus (3). Regional expression differences of the two receptors have been identified in the brain (4). Further evidence of distinct biological functions for the ERs is revealed by the contrasting phenotypes observed in the individual lines of ER knockout mice, the ␣ERKO and ␤ERKO, which exhibit phenotypes that generally mirror the respective ER expression patterns (5). The most striking phenotypes in the female ␣ERKO mice include estrogen insensitivity (leading to hypoplasia) in the reproductive tract, hypergonadotropic hypergonadism, lack of pubertal mammary gland development, and excess adipose tissue, whereas in the male, testicular degeneration and epididymal dysfunction are major factors (5). These phenotypes combined with severe deficits in sexual behavior result in complete infertility in both sexes of the ␣ERKO. In contrast, ␤ERKO males are fertile and to date show no obvious phenotypes; however, ␤ERKO females exhibit inefficient ovarian function and subfertility. Interestingly, compound knockout mice (␣␤ERKO) exhibit phenotypes that most heavily resemble those of the ␣ERKO, with the exception of the ovarian phenotype, characterized by progressive germ cell loss accompanied by redifferentiation of the surrounding somatic cells, suggesting a requisite role for both ER forms in this tissue (6, 7).With the cloning of the first ER cDNA 15 years ago has come an immense appreciation of the complex molecular mechanisms underlying the diverse physiological actions of E 2 and the multitude of synthetic ER ligands. This minireview wi...

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Disruption of the estrogen receptor in humans need not be lethal. Estrogen is important for bone maturation and mineralization in men as well as women.

Precise control of transcriptional programmes underlying metazoan development is modulated by enzymatically active co-regulatory complexes, coupled with epigenetic strategies. One thing that remains unclear is how specific members of histone modification enzyme families, such as histone methyltransferases and demethylases, are used in vivo to simultaneously orchestrate distinct developmental gene activation and repression programmes. Here, we report that the histone lysine demethylase, LSD1--a component of the CoREST-CtBP co-repressor complex--is required for late cell-lineage determination and differentiation during pituitary organogenesis. LSD1 seems to act primarily on target gene activation programmes, as well as in gene repression programmes, on the basis of recruitment of distinct LSD1-containing co-activator or co-repressor complexes. LSD1-dependent gene repression programmes can be extended late in development with the induced expression of ZEB1, a Krüppel-like repressor that can act as a molecular beacon for recruitment of the LSD1-containing CoREST-CtBP co-repressor complex, causing repression of an additional cohort of genes, such as Gh, which previously required LSD1 for activation. These findings suggest that temporal patterns of expression of specific components of LSD1 complexes modulate gene regulatory programmes in many mammalian organs.

Oestrogen is considered to be the 'female' hormone, whereas testosterone is considered the 'male' hormone. However, both hormones are present in both sexes. Thus sexual distinctions are not qualitative differences, but rather result from quantitative divergence in hormone concentrations and differential expressions of steroid hormone receptors. In males, oestrogen is present in low concentrations in blood, but can be extraordinarily high in semen, and as high as 250 pg ml −1 in rete testis fluids 1,2 , which is higher than serum oestradiol in the female 3 . It is well known that male reproductive tissues express oestrogen receptors [4][5][6][7] , but the role of oestrogen in male reproduction has remained unclear. Here we provide evidence of a physiological role for oestrogen in male reproductive organs. We show that oestrogen regulates the reabsorption of luminal fluid in the head of the epididymis. Disruption of this essential function causes sperm to enter the epididymis diluted, rather than concentrated, resulting in infertility. This finding raises further concern over the potential direct effects of environmental oestrogens on male reproduction and reported declines in human sperm counts 8,9 .Classic cellular responses to the hormone oestrogen are mediated through nuclear oestrogen receptors (ER), which function as ligand-dependent transcription factors. Efferent ductules of the testis are known to express high amounts of ER-α 10,11 , higher even than uterine tissue, and both the α and β forms of ER are present in efferent ductules and the epididymis 10 . These ductules form a series of small tubules that transport sperm from the testis to the epididymis 12 . In humans, one third of the epididymal head consists of efferent ductules 13 . In addition to ciliated cells that stir the luminal fluid, their epithelia contain nonciliated cells that resemble proximal tubule cells in the kidney. The non-ciliated cells have a reabsorptive function that results in the uptake of water, ions and proteins from the ductal lumen 12,14 . Ductules in the rat reabsorb nearly 90% of the rete testis fluid, coupling water and active ion transport in an electroneutral environment, in which Na + and water are reabsorbed at equal rates, thereby increasing the concentration of sperm as they enter the Correspondence and requests for materials should be addressed to R.A.H. (r-hess@uiuc.edu). 15,16 . This method of concentrating sperm improves their survival and maturation during epididymal storage and ensures that a large number of sperm are released upon ejaculation, increasing the randomness of fertilization and providing genetic variation 14 . These data and the observation that efferent ductules contain the highest concentrations of ER in the male led us to hypothesize that oestrogen participates in the regulation of fluid reabsorption in the male reproductive tract. HHS Public AccessTo test this hypothesis, we used the ER-α gene knockout mouse (ERKO) 17,18 . The ERKO male is infertile 18 , but its testes appear normal un...

The mechanisms through which estrogen regulates gonadotropin-releasing hormone (GnRH) neurons to control mammalian ovulation are unknown. We found that estrogen positive feedback to generate the preovulatory gonadotropin surge was normal in estrogen receptor beta knockout (ERbeta) mutant mice, but absent in ERalpha mutant mice. An ERalpha-selective compound was sufficient to generate positive feedback in wild-type mice. As GnRH neurons do not express ERalpha, estrogen positive feedback upon GnRH neurons must be indirect in nature. To establish the cell type responsible, we generated a neuron-specific ERalpha mutant mouse line. These mice failed to exhibit estrogen positive feedback, demonstrating that neurons expressing ERalpha are critical. We then used a GnRH neuron-specific Pseudorabies virus (PRV) tracing approach to show that the ERalpha-expressing neurons innervating GnRH neurons are located within rostral periventricular regions of the hypothalamus. These studies demonstrate that ovulation is driven by estrogen actions upon ERalpha-expressing neuronal afferents to GnRH neurons.