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31:26-33, 2007. doi:10.1152/advan.00086.2006 Advan Physiol EducMargaret E. Wierman

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Sex steroid effects at target tissues: mechanisms of action

Margaret E. WiermanUniversity of Colorado at Denver and Health Sciences Center, Aurora;and Veterans Affairs Medical Center, Denver, Colorado

Submitted 24 August 2006; accepted in nal form 22 November 2006

Wierman ME. Sex steroid effects at target tissues: mechanisms of action. AdvPhysiol Educ 31: 26 33, 2007; doi:10.1152/advan.00086.2006.Our understand-ing of the mechanisms of sex hormone action has changed dramatically over thelast 10 years. Estrogens, progestins, and androgens are the steroid hormones thatmodulate reproductive function. Recent data have shown that many other tissuesare targets of sex hormones in addition to classical reproductive organs. This reviewoutlines new advances in our understanding of the spectrum of steroid hormoneligands, newly recognized target tissues, structure-function relationships of steroidreceptors, and, nally, their genomic and nongenomic actions. Sex-based speciceffects are often related to the different steroid hormone mileu in men comparedwith women. Understanding the mechanisms of sex steroid action gives insight intothe differences in normal physiology and disease states.

steroid receptors; genomic and nongenomic actions

SEX STEROID HORMONES , including estrogens, progestins, andandrogens, traditionally have been dened by their role innormal reproductive function. Estradiol and progesterone wereconsidered the major sex hormones produced by the ovary andtestosterone produced by the testis. Steroid hormones, how-ever, are also produced in locally by peripheral conversion intarget tissues such as fat and the liver. These hormones may actin a paracrine manner or circulate to act at target tissues in anendocrine fashion. Recently, researchers have challenged the

classic dogma about how sex hormones work. Informationconcerning their variability in ligand availability, newly rec-ognized alternative forms of sex steroid receptors, previouslyunrecognized targets of steroid hormones, and different modesof genomic and nongenomic actions have altered our knowl-edge of normal physiology. These data have, in turn, given newinsights into pathological states. An understanding of this newinformation can shed light into sex-based differences in diseaseand responses to therapeutic interventions.

Sex Steroid Hormones: Their Role as Reproductive Hormones

Classically, sex steroid hormones have been dened by their

role in normal reproductive function. In the hypothalamic-pituitary-gonadal axis, gonadotropin-releasing hormone is se-creted in an episodic fashion from the hypothalamus to activatethe production of gonadotropins, luteinizing hormone (LH),and follicle-stimulating hormone (FSH) from the anterior pi-tuitary (36, 37) (see Fig. 1). LH and FSH are released in apulsatile manner to act at the gonad to control both gameto-genesis (spermatogenesis or oogenesis) as well as steroidogen-esis. The major sex hormones estradiol, progesterone, and

testosterone are secreted in response to gonadotropins and, inturn, feedback at the level of the hypothalamus and pituitary tocontrol normal reproductive function.

What Are the Relevant Sex Hormone Ligands?

Historically, we were taught that androgens are malehormones and estrogens are female hormones. Most of thephysiological research concerning the roles of androgens inmale reproductive function, however, was performed using thearomatizable androgen testosterone(10). Testosterone and theweaker adrenal prohormones DHEA and dehydroepiandros-terone sulfate can be converted by aromatization into estrogens(Figs. 2 and 3). Common estrogens include estradiol, estrone,and estriol. Progesterone is the natural progestin. Recent stud-ies (7, 19, 34, 40, 44) of naturally occurring mutations in theestrogen receptor (ER) or aromatase deciency in humans aswell as genetic mouse models have reoriented the eld as to thecritical importance of estrogen action in males as well as infemales.

The major estrogens include estradiol, estrone, and estriol.Estradiol is the major estrogen produced by the ovaries, butestrogens are also produced locally in targets such as adipose

tissue. In postmenopausal women, the effects of locally pro-duced androgens and estrogens may explain some of theexcessive risks of combined conjugated estrogen with dailyprogestin hormonal therapy when given broadly to overweightor obese women (40). The major progestin is progesterone,which is made predominantly by the ovaries but also madelocally in tissues. Progestins may have important local effectsto modulate both sexual behavior and neurotransmitter func-tion in the central nervous system (25, 41).

Address for reprint requests and other correspondence: M. E. Wierman,111H Endocrinology, Veterans Affairs Medical Center, 1055 Clermont St.,Denver, CO 80220 (e-mail: [email protected]).

The costs of publication of this article were defrayed in part by the paymentof page charges. The article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Adv Physiol Educ 31: 2633, 2007;doi:10.1152/advan.00086.2006.

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Model Systems to Study Steroid Hormone Actions

The complexities of sex hormone action have been eluci-dated by a variety of research approaches and use of differentmodel systems. Initial biochemical reconstitution studies de-ned the structure-function relationships of ligands and theirreceptors and other important proteins involved in transcrip-tional regulation. These type of studies, however, were oftenperformed in nonphysiologically relevant cell systems in anadd-back approach and may not reect the target tissueenvironment. Additional work has been performed in morephysiological relevant tissue specic cell systems but oftenwith immortalized or tumorous tissue. Fewer data have beenderived from primary cultures of cells that are targets of sexsteroid hormones, but when these data are available, they canbe used to conrm or refute data in other systems. Parallelstudies in animal models, primarily in the rodent and primate,have given insights into the mechanisms of sex steroid action.Both transgenic mouse overexpression models as well asknockout models of steroid hormone ligands or receptors haveidentied previously unsuspected targets of sex hormone ac-tion and changed our understanding of normal physiology.Finally, studies in humans, both across normal developmentand with diseased states, have provided important data con-

cerning the potential clinical use of sex hormone agonists andantagonists.

Sex Hormone Targets

Until recently, researchers assumed that the targets for sexhormones were primarily the reproductive organs: the breast,female reproductive tract (uterus and ovary), and male repro-ductive tract (testes and epididymis) (37, 47). Bone was knownto be a target of sex hormones based on the data that gonad-ectomy of either sex resulted in osteoporosis and sex-specichormonal replacement restored bone structure and function(23). An expanded list of sex hormone targets became apparentwhen investigators examined the phenotypes of naturally oc-curring mutations in humans and genetically altered mousemodels. Deciency of aromatase (the enzyme that convertstestosterone to estradiol) or knockout of the ER, progesteronereceptor (PR), or androgen receptor (AR) in mice showedtissue-specic decits (68, 10, 15, 26, 34). Together, thisresearch suggested that sex steroid hormones function in anexpanded list of target tissues (Fig. 4). These include thevascular system, central nervous system, gastrointestinal tract,

immune system, skin, kidney, and lung. An understanding of the tissue-specic roles of gonadal hormones is importantwhen predicting the benets or risks of replacing naturalligands or use of steroid hormone antagonists in humans.

Sex Hormone Actions in the Vasculature

Recent investigation has shown the importance of sex hor-mone action in the vasculature in both sexes (2830). Researchhas documented the presence of ERs, PRs, and ARs in vascularendothelial cells, smooth muscle cells, and cardiomyocytes astargets of sex hormone ligands. Estrogen administration has

Fig. 1. The hypothalamic-pituitary-gonadal axis. GnRH, gonadotropin-releas-ing hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; E,

estrogen; P, progesterone; T, testosterone.

Fig. 2. Sex hormone ligands. Dehydroepiandrosterone, DHEA; dehydroepi-androsterone sulfate, DHEAS.

Fig. 3. Sex hormone ligand prohormones.

Fig. 4. Sex hormone targets. GU, genitourinary system; GI, gastrointestinalsystem.

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27MECHANISMS OF ACTION OF SEX STEROIDS

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been shown to improve vascular reactivity, increase nitricoxide production, decrease free radical production, and preventprogrammed cell death in normal vasculature. In contrast, inthe diseased vessel, a different gene program may be activatedin response to estrogen administration that promotes plaquedestabilization and thrombosis through the activation of met-alloproteinases. Importantly, studies have conrmed that thereis a dose-response relationship to various sex steroid ligands indifferent tissues. These basic studies may give insight into theunexpected toxicities when combined conjugated equine estro-gen and daily progestins were given broadly to postmenopausalwomen in Womens Health Initiative trials (1, 32, 35, 45).

Sex Steroid Receptors

Steroid receptors have been cloned and characterized (12).There are two ERs (ER and ER ), two PRs (PRA and PRB),and one AR (see Fig. 5). Sex steroid receptors represent onecategory of nuclear receptors, with the two other categoriesincluding class II receptors (e.g., vitamin D, thyroid hormone,peroxisome proliferator, and retinoid receptors) and orphanreceptors (e.g., steroidogenic factor-1 and estrogen-related re-ceptor). Classically, it was thought that two molecules of eachsteroid receptor bound by the ligand then interacted with targetDNA through palindromic hormone response elements (HREs)to act as transcription factors to control gene expression. Incontrast, class II receptors act as heterodimers with retinoid Xreceptors on direct repeat HREs, whereas orphan receptors actindependent of the ligand as monomers on half-site HREs.

The evolution of this large family of nuclear receptors hasbeen complex with 250 receptors in C. elegans , 21 receptors in Drosophila , and 48 receptors in the human (2, 11). Similarly,the evolution of ligands has diverged across evolution with noligands and 250 orphan receptors in C. elegans , 1 ligand and 20

orphans in Drosophila , and 23 ligands and 25 orphans in thehuman. Future research will dene the functional signicanceof the many orphan receptors and identify their putative li-gands.

After the cloning of sex steroid receptors, it became apparentthat they are modular proteins with distinct functional domains(11, 12) (see Fig. 6). The NH 2 -terminal region contains acti-vation function (AF)-1, a transcriptional activation surface.The midregion of the molecule contains the DNA bindingregion (DBD), followed by a hinge region and then the ligandbinding domain (LBD). Dimerization interfaces are located inthe mid- and COOH-terminal regions. The COOH terminus of the molecule within the LBD contains the AF-2 domain, whichis another transcriptional activation region that is dependent onthe ligand. Biochemical approaches have dissected the struc-ture/function of the steroid receptors, which was conrmedwhen the crystal structure of the various domains with andwithout ligands was solved. Each steroid receptor is activelymodulated by interactions with various steroid agonists com-pared with antagonists and with many other proteins to allowcorrect transcriptional activation or repression.

New Insights Into Transcriptional Control bySteroid Hormones

It was initially shown that promoters of genes regulated bysex hormones contained pallindromic HREs in the 5 ankingregion that acted as binding sites for liganded steroid receptors(5, 11, 12). The ligand (e.g., estradiol) was shown to circulatein the bloodstream, diffuse into cells, and interact with itscognate receptor in the cytoplasm or nucleus to alter theconformational state (Fig. 7, direct). The liganded steroidreceptor was then shown to recognize these HREs on promot-ers of target DNA to directly bind this DNA as a transcriptionfactor and ultimately increase gene expression. However, asmore physiologically relevant gene promoters of sex steroidswere identied, it became apparent that many, if not most,promoters lacked consensus HREs in their 5 anking regions.

Some HREs are in 3 untranslated regions or far distant to thecoding region. In addition, it has become apparent that ligandedsteroid receptors may function in an alternative mechanism thatinvolves protein-protein interactions to either augment or block

Fig. 5. Family of nuclear receptors (NRs).GR, glucocorticoid receptor; ER, estrogenreceptor; PR, progesterone receptor; AR, an-drogen receptor; SR, steroid receptor; HRE,hormone response element; GRE, glucocor-ticoid response element; PRE, progesterone

response element; ERE, estrogen responseelement; VDR, vitamin D receptor; PPAR,peroxisome proliferator-activated receptor;TR, thyroid hormone receptor; FXR, farne-soid X receptor; RXR, retinoid X receptor;LXR, liver X receptor; RAR, retinoic acidreceptor; PXR, pregnane X receptor;NGFI-B, nerve growth factor-induced B;SF-I, steroidogenic factor I; ERR, estrogen-related receptor; RevERB, NR subfamily 1,group D, member 1.

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the effects of other transcription factors bound to promoter DNA(see Fig. 7, indirect). This alternative process of sex steroid actionhas been shown to be important in the endometrium, where theER modulates the activities of members of the activating protein-1family, including Fos and Jun (8, 18). Similarly, in bone cells,the liganded ER modulates gene function by cross talk withNF- B proteins on relevant target genes (20, 24, 33). Thisadded complexity of the genomic actions of sex hormonesmust be considered when questioning which are the relevanthormonal targets when sex hormones are abolished or replacedin normal physiological and pathophysiological states.

Agonists and Antagonists

Prior work has suggested that naturally occurring or synthe-sized sex hormone ligands acted as pure agonists or antago-nists. Research into the mechanisms of structure-function re-lationships of the ligand-bound steroid receptor has altered thisdogma and now can explain how compounds can be mixedagonist/antagonist or partial agonists (11, 27). Agonists weredened as compounds that act like the natural compound butwith altered receptor afnity or half-life (e.g., phytoestrogensor synthetic estrogens). Antagonists were dened as partial or

mixed (e.g., tamoxifen and raloxifene) or pure (e.g., ICI-182.780). The crystal structure of agonist- versus antagonist-bound ERs demonstrated the distinct differences in how spe-cic ligands t into the LBD pocket of the receptor andtherefore recruit different types of coadapter proteins to in-crease or decrease the efciency of gene transcription (39).

Coregulators Contribute to Genetic Mechanisms of Sex Steroid Actions

In the 1990s, many groups contributed to the insight thatsteroid receptors mediate their transcriptional activities byrecruiting a cohort of docking and adapter proteins. The rstmajor group to be characterized were the members of the p160coactivator family (5, 14, 43). The steroid receptor complex(SRC) family (SRC-1, -2, and -3), cAMP response enhancerprotein binding protein (CBP)/p300, and p300/CBP-associatedfactor were identied as acetyl transferases. In the presence of agonist-bound steroid receptors, these coactivators are re-cruited to the DNA to allow histone acetylation and unwindingof the DNA to promote more efcient gene expression. Sincethat time, a long list of coadaptor proteins have been identiedthat have enzymatic activities including ligases, ATPases, andmethylases as well as proteins that serve as cell cycle regula-tors, RNA helicases, and docking proteins to bridge to basaltranscription factors (see Table 1).

Fig. 6. Modular structure of steroid hormone receptors.N-domain, NH 2 -terminus domain; C, COOH-terminusdomain.

Fig. 7. Transcriptional action by liganded SRs. TF, transcription factor.

Table 1. Diverse functions of coregulators

Function Coregulator

Acetyltransferases SRC/p160, CBP/p300, and pCAFUbiquitin ligases E6-APATPases BRG-1Methylases CARM-1 and PRMT-1RNA transcription SRACell cycle regulators Cdc-25BRNA helicases P72Direct contact with basal

transcription factors TRAP/DRIP/mediator

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When the p160 family of coactivator proteins was investi-gated, it was discovered that they are also modular proteinswith domains that serve specic functions (11, 14, 43) (see Fig.8). The NH 2 terminus contains a basic helix-loop-helix andPer-Arnt-Sim domain that can interact with a coactivator or anATP-chromatin remodeling complex. The steroid interaction(SR) box domain is the region of the molecule that binds tonuclear receptors. It contains an -helix domain with theLXXLL motif, which interacts with the hydrophobic pocket inAF-2 (46). The COOH terminus contains two activation do-mains (AD1 and AD2). AD1 interacts with p300/CBP (withhistone acetylase activity), and AD2 interacts with coactivator-associated arginine methyltransferase 1 (a coadaptor with his-tone methylase activity).

In addition to coactivators, corepressors have been charac-terized. Small modulator of repression of thyroid hormone(SMRT) and nuclear component of repression (NCOR) are theprototypes for this class of proteins (14, 16, 17, 42). Antago-nist-bound sex steroid receptors or agonist-bound thyroid hor-mone receptors recruit these corepressors rather than coactiva-tors. These corepressors then activate a family of histone

deacytelases (HDACs), which result in chromosomal deacyte-lation and failure to recruit the basal transcription machineryand inhibition of gene expression. This is in contrast to the

effects with coactivator recruitment in the presence of agonists,which results in efcient transcriptional activation (Fig. 9).The prototype corepressors, SMRT and NCOR, are also

modular proteins (11, 17) (see Fig. 10). Each contains multiplerepression domains (RD1, -2, and -3) that repress transcriptionby recruitment of HDACs either directly or indirectly. Steroidreceptor interaction domains (RID1 and RID2) are the sites of binding to steroid receptors through a recognition sequencecalled the CoRNR box (IXXI/VI with an extended sequence).A deacetylase activation domain region in the corepressors isimportant for the activation of HDAC3.

This process of sex steroid-mediated transcriptional activationor repression is quite complex at the molecular level. In additionto many proteins directly or indirectly binding liganded steroid

receptors, each protein may be posttranslationally altered topromote or prevent histone modication and chromosomalremodeling (14, 21, 43). Does this newly identied cohort of coadaptor proteins play a specic role in physiology or dis-ease? These studies are ongoing, but there are a few examplesof cell-specic patterns of coadaptor gene expression. Forexample, SRC-2 appears to have specic roles in the endome-

Fig. 8. Structural domains of p160 coactivators. bHLH, basic helix-loop-helix;PAS, Per-Arnt-Sim; HAT, histone acetylase; CARM, coactivator-associatedarginine methyltransferase; HMT, histone methyltransferase.

Fig. 9. Recruitment of coactivators or corepressors mediatestranscriptional activation or repression. SRC, SR complex;CBP, CREB binding protein; pCAF, p300/CBP-associated fac-tor; TFII-B, transcription factor; TBP, transcription bindingprotein; RNA pol, RNA polymerase.

Fig. 10. Structural domains of corepressors. SMRT, small modulator of repression of thyroid hormone; NCOR, nuclear component of repression;mRPD3, mouse RPD histone acetylase.

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trium apart from the other SRC family members (31, 42).Investigators are examining changes in the expression of co-adaptor proteins in disease progression. For example, tamox-ifen is an antagonist in breast cancer cells in the presence of corepressors (13). Studies have shown that tamoxifen-resistantMCF-7 breast cancer cells have decreased levels of the core-pressor NCOR. Theoretically, lack of corepressor protein ex-pression may allow coactivators to be recruited to antagonist-bound steroid receptors and convert the antagonist to an ago-nist effect. Samples from breast cancers are under analysis todetermine if alterations in coadaptor expression may underlythe loss of clinical responses to selective ER modulator drugs.

Nongenomic Actions of Sex Steroids

In addition to the classic genomic effects of sex steroids,recent data have shown the importance of acute nongenomiceffects (4, 9, 11, 22, 29, 38, 45) (Fig. 11 and Table 2). Sexsteroids may act in a variety of ways to modulate cellularactivity (4). Studies have provided evidence of actions of estrogens and progestins to directly alter plasma membraneuidity; however, at micromolar concentrations. Research inthe central nervous system and vascular systems has shown theability of steroids to interact at the plasma membrane withnon-nuclear receptors such as ion channels and G protein-coupled receptors (GPCRs). In these systems, the effects areinsensitive to antagonists. An explosion of research is dissect-

ing the relevant effects of membrane-bound steroid receptors,which only represent 2% of the steroid receptor pool but canimpact on physiological processes. Potentially relevant mem-brane-bound steroid receptors have been shown for ER , ER ,PR, and AR. In addition, ligand-bound steroid receptors can bemodied whether in the plasma, cytoplasmic, or nuclear com-partments by alterations in intracellular signaling cascades,which alter serine or threonine phosphorylation on these re-ceptors and indirectly alter cellular function (3, 9, 21). Theseeffects are mediated by the NH 2 terminus of the steroidreceptor molecule and often involve AF-1 (4, 11) (see Fig. 6).

Nongenomic Effects of Estrogen Via GPCRs

In vascular cells, estrogen may interact with plasma-boundGPCRs to induce acute effects on intracellular signaling

Fig. 11. Membrane versus nuclear signaling by sex SRs.[Republished, with permission, from Lorenzo (24).]

Table 2. Nongenomic actions of sex steroids

Nonreceptor-mediated actions at theplasma membrane

Membrane uidity: ligand atmillimolar concentrations

Steroid activation of non-nuclearreceptors at the plasmamembrane

Ion channels and G protein-coupled receptors:insensitivity to antagonists

Rapid signaling through membrane-bound steroid receptors

2% of pool, estrogen receptor- or - , or progesteronereceptor

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through cAMP and can be blocked by pertussis toxin (4, 22)(Fig. 12). This signaling can modify Src, which phosphorylatesthe EGF receptor (EGFR) and releases metalloproteinases,which trigger the release of heparin-bound EGF ligand toactive EGF to augment the tyrosine receptor kinase EGFR.These steps can be blocked with protein phosphatase 2 orCRM-197 (see Fig. 12). Ligand-stimulated EGFR interactswith the docking proteins of Sos and Shc to eventuate in theactivation of the Ras/Raf/MEK/ERK signaling system. Thiscomplex modulation of multiple intracellular signaling sys-tems can then have both acute, nongenomic effects orchronically modify gene expression. Each cell or target of

sex steroid action may have a different complement of membrane receptors and responses to ligands to mediatecell-specic effects in normal physiology and altered com-plements in disease states.

Summary

Thus, our current understanding of tissue-specic effectsof sex steroids has evolved over the past decade. In address-ing a potential sex-based or target-specic response, onemust account rst for ligand availability, i.e., estrogen,progestin, or androgen. Then, one must ask what are thesteroid receptor expression proles for that tissue. In eachcell, the promoter-specic response is dened by the pro-

moter organization. New research is characterizing the com-plement of coregulators in normal cells and disease states.The nal word is out on whether there are cell-speciccoregulators. In addition, it is hypothesized that the com-plement of proteins or their activation state is altered in thetransition from normal to disease states. Finally, the infor-mation concerning the role of sex steroids to act in anongenomic fashion, cross talking with membrane receptorsand multiple intracellular signaling pathways, suggests thatour true understanding of sex steroid effects is still notcomplete. We await with excitement the further unravelingof the complexities of sex steroid action in normal physiol-

ogy and disease states and the insight this research willprovide to new therapeutic options in the future.

REFERENCES

1. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA,Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R,Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J,Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L,LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J,Margolis K, Ockene J, OSullivan MJ, Phillips L, Prentice RL,Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefanick ML, VanHorn L, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S.Effects of conjugated equine estrogen in postmenopausal women withhysterectomy: the Womens Health Initiative randomized controlled trial. JAMA 291: 17011712, 2004.

2. Baulieu EE, Atger M, Best-Belpomme M, Corvol P, Courvalin JC,Mester J, Milgrom E, Robel P, Rochefort H, De Catalogne D. Steroidhormone receptors. Vitam Horm 33: 649736, 1975.

3. Bjornstrom L, Sjoberg M. Mechanisms of estrogen receptor signaling:convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 19: 833842, 2005.

4. Cato AC, Nestl A, Mink S. Rapid actions of steroid receptors in cellularsignaling pathways. Sci STKE 2002: RE9, 2002.

5. Conneely OM. Perspective: female steroid hormone action. Endocrinol-ogy 142: 21942199, 2001.

6. Conneely OM, Lydon JP. Progesterone receptors in reproduction: func-tional impact of the A and B isoforms. Steroids 65: 571577, 2000.

7. Couse JF, Korach KS. Estrogen receptor null mice: what have we learnedand where will they lead us? Endocr Rev 20: 358417, 1999.

8. Curtis SH, Korach KS. Steroid receptor knockout models: phenotypesand responses illustrate interactions between receptor signaling pathwaysin vivo. Adv Pharmacol 47: 357380, 2000.

9. Driggers PH, Segars JH. Estrogen action and cytoplasmic signalingpathways. Part II: the role of growth factors and phosphorylation inestrogen signaling. Trends Endocrinol Metab 13: 422427, 2002.

10. Eddy EM, Washburn TF, Bunch DO, Goulding EH, Gladen BC,Lubahn DB, Korach KS. Targeted disruption of the estrogen receptorgene in male mice causes alteration of spermatogenesis and infertility. Endocrinology 137: 47964805, 1996.

11. Edwards DP. Regulation of signal transduction pathways by estrogen andprogesterone. Annu Rev Physiol 67: 335376, 2005.

12. Fuller PJ. The steroid receptor superfamily: mechanisms of diversity.FASEB J 5: 30923099, 1991.

13. Graham JD, Bain DL, Richer JK, Jackson TA, Tung L, Horwitz KB.Thoughts on tamoxifen resistant breast cancer. Are coregulators the

Fig. 12. Nongenomic effects of estrogen action via G protein-coupled receptors (GPCRs). E 2 , estradiol; MMP, metalloproteinase; HB-EGF, heparin-bound EGF;Sos, GTP exchange factor; Grb2, adaptor; Shc, adaptor; Ras, small G protein; Raf, Ser/Thr protein kinase; PP2, protein phosphatase 2. [Modied and corrected,with permission, from Cato et al. (4).]

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9/9

answer or just a red herring? J Steroid Biochem Mol Biol 74: 255259,2000.

14. Hermanson O, Glass CK, Rosenfeld MG. Nuclear receptor coregulators:multiple modes of modication. Trends Endocrinol Metab 13: 5560,2002.

15. Hewitt SC, Korach KS. Oestrogen receptor knockout mice: roles foroestrogen receptors alpha and beta in reproductive tissues. Reproduction125: 143149, 2003.

16. Hu X, Lazar MA. Transcriptional repression by nuclear hormone recep-tors. Trends Endocrinol Metab 11: 610, 2000.17. Huang EY, Zhang J, Miska EA, Guenther MG, Kouzarides T, Lazar

MA. Nuclear receptor corepressors partner with class II histone deacety-lases in a Sin3-independent repression pathway. Genes Dev 14: 4554,2000.

18. Klotz DM, Hewitt SC, Korach KS, Diaugustine RP. Activation of auterine insulin-like growth factor I signaling pathway by clinical andenvironmental estrogens: requirement of estrogen receptor-alpha. Endo-crinology 141: 34303439, 2000.

19. Korach KS, Couse JF, Curtis SW, Washburn TF, Lindzey J, KimbroKS, Eddy EM, Migliaccio S, Snedeker SM, Lubahn DB, SchombergDW, Smith EP. Estrogen receptor gene disruption: molecular character-ization and experimental and clinical phenotypes. Recent Prog Horm Res51: 158186, 1996.

20. Kurebayashi S, Miyashita Y, Hirose T, Kasayama S, Akira S, Kishi-moto T. Characterization of mechanisms of interleukin-6 gene repressionby estrogen receptor. J Steroid Biochem Mol Biol 60: 1117, 1997.

21. Lange CA. Making sense of cross-talk between steroid hormone receptorsand intracellular signaling pathways: who will have the last word? Mol Endocrinol 18: 269278, 2004.

22. Levin ER. Integration of the extranuclear and nuclear actions of estrogen. Mol Endocrinol 19: 19511959, 2005.

23. Lindsay R. Hormones and bone health in postmenopausal women. En-docrine 24: 223230, 2004.

24. Lorenzo J. A new hypothesis for how sex steroid hormones regulate bonemass. J Clin Invest 111: 16411643, 2003.

25. Mani SK, Blaustein JD, OMalley BW. Progesterone receptor functionfrom a behavioral perspective. Horm Behav 31: 244255, 1997.

26. Matsumoto T, Takeyama K, Sato T, Kato S. Study of androgen receptorfunctions by genetic models. J Biochem (Tokyo) 138: 105110, 2005.

27. McDonnell DP, Clemm DL, Hermann T, Goldman ME, Pike JW.Analysis of estrogen receptor function in vitro reveals three distinct classes

of antiestrogens. Mol Endocrinol 9: 659 669, 1995.28. Mendelsohn ME. Genomic and nongenomic effects of estrogen in thevasculature. Am J Cardiol 90: 3F6F, 2002.

29. Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovas-cular gender differences. Science 308: 15831587, 2005.

30. Mendelsohn ME, Karas RH. The protective effects of estrogen on thecardiovascular system. N Engl J Med 340: 18011811, 1999.

31. Mukherjee A, Soyal SM, Fernandez-Valdivia R, Gehin M, ChambonP, Demayo FJ, Lydon JP, OMalley BW. Steroid receptor coactivator 2is critical for progesterone-dependent uterine function and mammarymorphogenesis in the mouse. Mol Cell Biol 26: 65716583, 2006.

32. Prentice RL, Pettinger M, Anderson GL. Statistical issues arising in theWomens Health Initiative. Biometrics 61: 841911, 2005.

33. Raisz LG. Pathogenesis of osteoporosis: concepts, conicts, and pros-pects. J Clin Invest 115: 33183325, 2005.

34. Robertson KM, ODonnell L, Jones ME, Meachem SJ, Boon WC,Fisher CR, Graves KH, McLachlan RI, Simpson ER. Impairment of spermatogenesis in mice lacking a functional aromatase (cyp 19) gene.Proc Natl Acad Sci USA 96: 79867991, 1999.

35. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C,Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC,Kotchen JM, Ockene J. Risks and benets of estrogen plus progestin inhealthy postmenopausal women: principal results from the WomensHealth Initiative randomized controlled trial. JAMA 288: 321333, 2002.

36. Santoro N, Butler JP, Filicori M, Crowley WF Jr. Alterations of thehypothalamic GnRH interpulse interval sequence over the normal men-strual cycle. Am J Physiol Endocrinol Metab 255: E696E701, 1988.

37. Santoro N, Filicori M, Crowley WF Jr. Hypogonadotropic disorders inmen and women: diagnosis and therapy with pulsatile gonadotropin-releasing hormone. Endocr Rev 7: 1123, 1986.

38. Segars JH, Driggers PH. Estrogen action and cytoplasmic signalingcascades. Part I: membrane-associated signaling complexes. Trends En-docrinol Metab 13: 349354, 2002.

39. Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA,Greene GL. The structural basis of estrogen receptor/coactivator recog-nition and the antagonism of this interaction by tamoxifen. Cell 95:

927937, 1998.40. Simpson ER, Clyne C, Rubin G, Boon WC, Robertson K, Britt K,Speed C, Jones M. Aromatasea brief overview. Annu Rev Physiol 64:93127, 2002.

41. Singh SR, Briski KP. Central GABAA but not GABAB receptorsmediate suppressive effects of caudal hindbrain glucoprivation on theluteinizing hormone surge in steroid-primed, ovariectomized female rats. J Neuroendocrinol 17: 407412, 2005.

42. Smith CL, Nawaz Z, OMalley BW. Coactivator and corepressor regu-lation of the agonist/antagonist activity of the mixed antiestrogen, 4-hy-droxytamoxifen. Mol Endocrinol 11: 657666, 1997.

43. Smith CL, OMalley BW. Coregulator function: a key to understandingtissue specicity of selective receptor modulators. Endocr Rev 25: 4571,2004.

44. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B,Williams TC, Lubahn DB, Korach KS. Estrogen resistance caused by amutation in the estrogen-receptor gene in a man. N Engl J Med 331:

10561061, 1994.45. Turgeon JL, Carr MC, Maki PM, Mendelsohn ME, Wise PM. Com-

plex actions of sex steroids in adipose tissue, the cardiovascular system,and brain: insights from basic science and clinical studies. Endocr Rev 27:575605, 2006.

46. Webb P, Valentine C, Nguyen P, Price RH Jr, Marimuthu A, WestBL, Baxter JD, Kushner PJ. ERbeta binds N-CoR in the presence of estrogens via an LXXLL-like motif in the N-CoR C-terminus. Nucl Recept 1: 4, 2003.

47. Whitcomb RW, Crowley WF Jr. Male hypogonadotropic hypogonad-ism. Endocrinol Metab Clin North Am 22: 125143, 1993.

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