Neurosteroids are synthesized de novo and involved in a variety of physiological functions in the central and peripheral nervous systems. Although the steroidogenic acute regulatory protein (StAR) plays an essential role in the steroidogenesis of peripheral endocrine glands, its presence and role in the brain had been previously questioned because of difficulties in detecting it. However, a number of recent studies have confirmed the presence of StAR in rodent and human brains. Moreover, there is evidence suggesting that StAR plays a role in steroidogenesis in the brain, as it does in peripheral endocrine organs. The present review presents data regarding the presence and role of StAR in brain steroidogenesis, demonstrating the essential characteristics of the protein.

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This article reviews the effects of estradiol (E₂), progesterone (P) and P receptor antagonists (PA) on the rhesus macaque endometrium. Ovariectomized macaques can be treated with implants of estradiol (E₂) and P to induce precisely controlled, artificial menstrual cycles. During these cycles, treatment with E₂ alone induces an artificial proliferative phase marked by extensive endometrial epithelial cell proliferation and increased expression of stromal and epithelial estrogen receptor (ER) and P receptor (PR). Androgen receptor (AR) is also upregulated by E₂ but is expressed only by the endometrial stroma. Progesterone acts on the E₂ primed endometrium to induce secretory differentiation and causes suppression of epithelial and stromal ER, epithelial PR, and stromal AR in the functionalis zone. However, epithelial ER and PR are retained in the basalis zone during the secretory phase. When potent P antagonists (PA) are administered acutely at the end of an E₂+P induced cycle, menses typically ensues similar to P withdrawal at the end of the menstrual cycle. When PAs are administered chronically there is significant blockage of all P- dependent effects including upregulation of ER, PR and AR and suppression of glandular secretory function. However, chronic PA administration also inhibits estrogen-dependent endometrial cell proliferation and growth. This endometrial antiproliferative effect is the basis of the clinical use of PA to control various diseases such as endometriosis.

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Estradiol (E) and progesterone (P) act on the primate endometrium to induce dramatic changes in the vascular system during the menstrual cycle. These changes include vessel breakdown and bleeding during menses, heightened angiogenesis during the early proliferative phase, and extensive growth of the spiral arteries in the luteal phase of the cycle. Because steroid hormone action is dependent upon the presence of specific nuclear receptors in target tissues, we used immunocytochemistry with receptor-specific monoclonal antibodies to characterize the spatial and temporal expression of estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), progesterone receptor PR and androgen (A) receptor (AR) in the endometrial vessels of rhesus macaques (Macaca mulatta). The only sex steroid receptor that was present in the endothelium and smooth muscle walls of endometrial vessels was ERβ. ERα, PR, and AR were not detectable in either the endothelium or vascular smooth muscle cells of primate endometrial vessels. However, all of these receptors were strongly expressed by the perivascular stroma, and in these cells, all were modulated by the changes in levels of E and P during the cycle. We concluded that any direct effects of E on endometrial vessels would be mediated by ERβ, and that the actions of P and A, and possibly some of E, were indirectly mediated through perivascular stromal cells.

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Steroid sex hormones (17β-estradiol, testosterone, dihydrotestosterone, and progesterone) and aryl hydrocarbons such as the dioxins regulate epithelial proliferation and secretory protein production and differentiation in their respective target organs in male and female urogenital tracts and mammary glands. Recent evidence has demonstrated that stromal-epithelial interactions are critical for mediating the effects of these molecules on epithelial cells. Our results have indicated that estradiol, testosterone, progesterone, and dioxin regulate epithelial proliferation (stimulation or inhibition) via paracrine mechanisms requiring the appropriate receptor in the stroma. The androgen receptor (AR), estrogen receptor alpha (ERα), progesterone receptor (PR), or aryl hydrocarbon receptor (AhR) in the epithelium are neither necessary nor sufficient for the regulation of epithelial proliferation. Moreover, during prostatic development, signaling through the stromal AR is required to induce prostatic epithelial identity, ductal morphogenesis and glandular differentiation. Epithelial functional differentiation is regulated in the prostate, uterus, and vagina via AR (prostate) and ERα(uterus and vagina). In these organs both epithelial and stromal steroid receptors are required for steroidal regulation of certain aspects of epithelial differentiation such as epithelial secretory protein production in the uterus and epithelial cornification in the vagina and prostate (squamous metaplasia). The mechanistic basis of these stromal-epithelial interactions is poorly understood, but growth factors appear to be mediators of these cell-cell interactions.

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Estrogen has crucial roles in the proliferation of cancer cells in reproductive organs such as the breast and uterus. Estrogen-stimulated growth requires two estrogen receptors (ERαand ERβ) which are ligand-dependent transcription factors. High expression of ERs is observed in a large population of breast tumors. In addition, the positive expression of ERs correlates with well-differentiated tumors, a favorable prognosis, and responsiveness to an endocrine therapy with anti-estrogen drugs in patients with breast cancer. Transcription activities of ERs can be regulated by interacting proteins such as coactivators and kinases as well as ligand-binding. Moreover, ER isoforms lacking an ability to transactivate are involved in breast cancer. Downstream target genes of ERs have important roles in mediating the estrogen action in breast cancer. We have isolated and characterized several novel estrogen-responsive genes to clarify the molecular mechanism of the estrogen action in target cells. Among these genes, the estrogen-responsive finger protein (Efp) was found to be highly expressed in breast cancer. Efp as a ubiquitin ligase (E3) is involved in the proteasome-dependent degradation of the 14-3-3σprotein, one of cell cycle brakes, this degradation resulting in the promotion of breast cancer growth. A full understanding of the expression and function of ERs and their target genes could shed light on how estrogen stimulates the initiation and promotion of cancer, providing a new approach to diagnose and treat cancer.

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The adrenocorticotropic hormone (ACTH) acts on adrenocortical cells and promotes steroidogenesis by specific binding to the ACTH (MC-2) receptor (ACTHR). To gain an insight into ACTH action on local steroidogenic organs, we examined the immunohistochemical expression of ACTHR in rat adrenal glands and placentas during the mid-late gestation period. Antibodies against synthetic ACTHR peptides were raised in rabbits, and Western blot analysis showed that the antibody reacted with specific proteins in the rat adrenal glands and placentas. The peroxidase-labeled antibody method revealed that ACTHR was distributed in the plasma membrane and cytoplasm of the parenchymal cells of the adrenocortical zona fasciculata. In the placenta, ACTHR was distributed in the junctional spongiotrophoblasts at day13 of gestation - with a gradual decrease in the staining during the gestational period, whereas ACTHR appeared in the placental labyrinthine cells from days 15 to 19 of gestation. Immunoelectron microscopy revealed that ACTHR was also localized in the ribosomes of the fasciculata cells and the labyrinthine cells. Our findings suggest that ACTHR may play a physiological role in steroidogenesis in the adrenal cortical parenchymal cells as well as in the trophoblasts of rat placentas during mid-late gestation.

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Keratinocyte growth factor (KGF), a mesenchymal cell derived paracrine growth factor that regulates normal epithelial cell proliferation, appears to be an essential mediator of steroids in various reproductive organs. The present study was designed to determine the expression and role of KGF and its receptor (KGFR) in human breast carcinoma tissues by immunohistochemistry. We also compared the results with the expression of estrogen receptor α(ERα), ERβ, the proliferative activity assessed by the labeling index (LI) for the Ki-67 antigen, apoptotic frequency assessed by terminal dUTP nick end-labeling (TUNEL) index, and the expression of Bcl-2. All of KGF-positive cases were ERα- positive (p<0.05), but not that of ERβ, while all of KGFR-positive cases were ERβ-positive (p<0.05), but not that of ERα. The specimens with the coexpression of KGF and KGFR significantly correlated with a lower TUNEL index (p<0.05), but not with Ki-67 LI in breast cancer tissues. Further analysis at the cellular level revealed that Bcl-2 was colocalized in KGFR-positive cells, and these cells were almost negative for TUNEL staining. Bcl-2-positive cells were also associated with ERβ, as expected. Therefore, the results indicate that ERα may be involved in KGF expression, and that the coexpression of KGF and KGFR may play an inhibitory role in the induction of apoptosis possibly through the up-regulation of Bcl-2 expression in human breast cancer.

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The arylhydrocarbon receptor (AhR) is a nuclear transcription factor mediating toxic effects of chemicals such as dioxins. The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a member of polyhalogenated aromatic hydrocarbons family, exerts a wide-variety of toxic effects in a tissue- and species-specific manner including the reproduction process. Recently, AhR-mediated direct effects of TCDD on a cellspecific interaction with ovarian steroids have been shown. However, information regarding the effects of TCDD on the mouse implantation is limited. We therefore examined the expression and localization of AhR in the pregnant mouse uterus from 4 to 10 days of gestation (day 4 to day 10) using immunohistochemistry to investigate the effect of TCDD on uterine tissue during the peri-implantation period. Intense AhR expression was detected in the uterine vasculature throughout the periods examined. We also found that implanted blastocysts and their surrounding luminal epithelia and decidualized stroma expressed AhR on day 5. On days 6 and 7, persistent AhR expression was found in the transitional zone between the invading embryonic tissue and decidual tissue. On days 9 to 10, placental vasculature and spongiotrophoblasts displayed AhR immunoreactivity. The administration of TCDD on day 4 decreased the number of surviving implanted embryos on day 7 in a dose-dependent manner. This effect of TCDD was inhibited by the simultaneous administration of an AhR antagonist, alpha-naphthoflavone (α-NF). The spatio-temporal expression of AhR during the peri-implantation phase of the mouse uterus may indicate functional roles of this orphan receptor in fetomaternal interactions as well as substantiate the risk of exposure to chemicals such as dioxins during the reproductive period.

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