here are a few articles i have found, while not exactly pertaining to males, it is interesting.
Hypothalamic expression of KiSS-1 system and gonadotropin-releasing effects of kisspeptin in different reproductive states of the female Rat.
Roa J, Vigo E, Castellano JM, Navarro VM, Fernández-Fernández R, Casanueva FF, Dieguez C, Aguilar E, Pinilla L, Tena-Sempere M.
Department of Cell Biology, Physiology and Immunology, Faculty of Medicine, University of Córdoba, 14004 Córdoba, Spain.
Kisspeptins, products of the KiSS-1 gene with ability to bind G protein-coupled receptor 54 (GPR54), have been recently identified as major gatekeepers of reproductive function with ability to potently activate the GnRH/LH axis. Yet, despite the diversity of functional states of the female gonadotropic axis, pharmacological characterization of this effect has been mostly conducted in pubertal animals or adult male rodents, whereas similar studies have not been thoroughly conducted in the adult female. In this work, we evaluated maximal LH and FSH secretory responses to kisspeptin-10, as well as changes in sensitivity and hypothalamic expression of KiSS-1 and GPR54 genes, in different physiological and experimental models in the adult female rat. Kisspeptin-10 (1 nmol, intracerebroventricular) was able to elicit robust LH bursts at all phases of the estrous cycle, with maximal responses at estrus; yet, in diestrus LH, responses to kisspeptin were detected at doses as low as 0.1 pmol. In contrast, high doses of kisspeptin only stimulated FSH secretion at diestrus. Removal of ovarian sex steroids did not blunt the ability of kisspeptin to further elicit stimulated LH and FSH secretion, but restoration of maximal responses required replacement with estradiol and progesterone. Finally, despite suppressed basal levels, LH and FSH secretory responses to kisspeptin were preserved in pregnant and lactating females, although the magnitude of LH bursts and the sensitivity to kisspeptin were much higher in pregnant dams. Interestingly, hypothalamic KiSS-1 gene expression significantly increased during pregnancy, whereas GPR54 mRNA levels remained unaltered. In summary, our current data document for the first time the changes in hypothalamic expression of KiSS-1 system and the gonadotropic effects (maximal responses and sensitivity) of kisspeptin in different functional states of the female reproductive axis. The present data may pose interesting implications in light of the potential therapeutic use of kisspeptin analogs in the pharmacological manipulation of the gonadotropic axis in the female.
PMID: 16527840 [PubMed - indexed for MEDLINE]
Novel Role of the Anorexigenic Peptide Neuromedin U in the Control of LH Secretion and its Regulation by Gonadal Hormones and Photoperiod.
Vigo E, Roa J, Pineda R, Castellano JM, Navarro VM, Aguilar E, Pinilla L, Tena-Sempere M.
Physiology Section, University of Cordoba, Cordoba, Spain.
Neuromedin U (NMU) is a widely spread neuropeptide, with predominant expression at the gastrointestinal tract and brain, putatively involved in the regulation of a diversity of biological functions, including food intake, energy balance and circadian rhythms; all closely related to reproduction. Yet, the implication of NMU in the control of the gonadotropic axis remains scarcely studied. We report herein analyses on the hypothalamic expression and function of NMU in different physiological and experimental states of rat reproductive system. Expression of NMU mRNA at the hypothalamus was persistently detected along female postnatal development, with maximum levels in adulthood that fluctuated across the cycle and were modulated by ovarian steroids. Acute central administration of NMU evoked increases of serum LH levels in pubertal female rats, while repeated injection of NMU tended to advance vaginal opening. Likewise, central injection of NMU increased serum LH concentrations in cyclic female rats, with peak responses in estrus. In contrast, NMU significantly inhibited pre-elevated LH secretion in gonadectomized and kisspeptin-treated rats. Finally, in acyclic females due to photoperiodic manipulation (constant light), hypothalamic NMU mRNA levels were markedly depressed but relative LH responses to exogenous NMU were significantly augmented. Altogether, our present data support a predominant stimulatory role of NMU in the control of the female gonadotropic axis, which appears under the influence of developmental, hormonal and photoperiodic cues, and might contribute to the joint regulation of energy balance, biological rhythms and reproduction. Key words: Neuromedin U (NMU), Luteinizing hormone (LH), Neuromedin S (NMS), Estrus cycle, Female rat.
PMID: 17726140 [PubMed - as supplied by publisher]
Effects of single or repeated intravenous administration of kisspeptin upon dynamic LH secretion in conscious male rats.
Tovar S, Vázquez MJ, Navarro VM, Fernández-Fernández R, Castellano JM, Vigo E, Roa J, Casanueva FF, Aguilar E, Pinilla L, Dieguez C, Tena-Sempere M.
Department of Physiology, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain.
The ability of kisspeptins, ligands of the G protein-coupled receptor 54, to potently elicit LH secretion is now undisputed. Yet, most of the pharmacological characterization of their gonadotropin-releasing effects has been conducted after intracerebral administration. In contrast, the effects of peripheral injection of kisspeptin remains less well defined. In this study, dynamic LH secretory responses to iv administration of kisspeptin-10 in different experimental settings are presented, and compared with those evoked by kisspeptin-52, using a protocol of serial blood sampling in conscious, freely moving male rats. LH responsiveness to peripheral administration of kisspeptin appeared extremely sensitive, as doses as low as 0.3 nmol/kg (0.1 microg/rat) evoked robust LH bursts, the magnitude of which was dose-dependent and apparently maximal in response to 3.0 and 30 nmol/kg kisspeptin-10. The ability of kisspeptin-10 to stimulate LH release was fully preserved, and even doubled in terms of relative increases, after short-term fasting despite suppression of prevailing LH levels. Repeated injections of kisspeptin-10 (four boluses, at 75-min intervals) evoked associated LH secretory pulses, the magnitude of which remained constant along the study period. Moreover, in this setting, in vivo LH responses to a terminal injection of GnRH were preserved, whereas basal and depolarization-induced GnRH release ex vivo was significantly enhanced. Finally, iv administration of kisspeptin-52 elicited dynamic LH responses analogous to that of kisspeptin-10; yet, their net magnitude and duration was slightly greater. In summary, we present in this study a series of experiments on the effects of systemic (iv) injection of single or repeated doses of kisspeptin upon dynamic LH secretion in conscious male rats. Aside from potential physiologic relevance, our present data might contribute to setting the basis for the rational therapeutic use of kisspeptin analogs in the pharmacological manipulation of the gonadotropic axis.
PMID: 16513831 [PubMed - indexed for MEDLINE]
Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates.
Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM.
Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
To further study the role of GPR54 signaling in the onset of primate puberty, we used the monkey to examine the ability of kisspeptin-10 to elicit the release of gonadotropin-releasing hormone (GnRH) precociously, and we describe the expression of GPR54 and KiSS-1 in the hypothalamus during the peripubertal period. Agonadal juvenile male monkeys were implanted with a lateral cerebroventricular cannula and a jugular vein catheter. The responsiveness of the juvenile pituitary to endogenous GnRH release was heightened with a chronic pulsatile i.v. infusion of synthetic GnRH before kisspeptin-10 (112-121) injection. Intracerebroventricular (30 microg or 100 microg) or i.v. (100 microg) bolus injections of kisspeptin-10 elicited a robust GnRH discharge, as reflected by luteinizing hormone secretion, which was abolished by pretreatment with a GnRH-receptor antagonist. RNA was isolated from the hypothalamus of agonadal males before (juvenile) and after (pubertal) the pubertal resurgence of pulsatile GnRH release and from juvenile, early pubertal, and midpubertal ovary-intact females. KiSS-1 mRNA levels detected by real-time PCR increased with puberty in both male and female monkeys. In intact females, but not in agonadal males, GPR54 mRNA levels in the hypothalamus increased approximately 3-fold from the juvenile to midpubertal stage. Hybridization histochemistry indicated robust KiSS-1 and GPR54 mRNA expression in the region of the arcuate nucleus. These findings are consistent with the hypothesis that GPR54 signaling by its cognate ligand in the primate hypothalamus may be activated at the end of the juvenile phase of development and may contribute to the pubertal resurgence of pulsatile GnRH release, the central drive for puberty.
Pubertal impairment in Nhlh2"null" mice is associated with hypothalamic and pituitary deficiencies.
Cogliati T, Delgado-Romero P, Norwitz ER, Guduric-Fuchs J, Kaiser UB, Wray S, Kirsch IR.
Genetics Branch, Center for Cancer Research, National Cancer Institute (T.C., P.D-R., I.R.K.), and Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke (S.W.), National Institutes of Health, Bethesda, Maryland 20889; Departments of Obstetrics, Gynecology, and Reproductive Biology (E.R.N.) and Medicine (U.B.K.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Centre for Vision Science, Queen's University Belfast, School of Biomedical Sciences, Belfast, UK, BT12 6BA (J.G).
Pubertal development is impaired in mice lacking the basic helix-loop-helix transcription factor Nhlh2. The mechanisms underlying changes in reproduction in Nhlh2-deficient mice (Nhlh2(-/-)) are unclear. Here we show that hypothalamic gonadotropin-releasing hormone-1 (GnRH-1) content is reduced in adult Nhlh2(-/-) mice as is the number of GnRH-1 neurons localized to mid- and caudal hypothalamic regions. This reduction was detected postnatally after normal migration of GnRH-1 neurons within nasal regions had occurred. Phenotype rescue experiments showed that female Nhlh2(-/-) mice were responsive to estrogen treatment. In contrast, puberty could not be primed in female Nhlh2(-/-) mice with a GnRH-1 regimen. The adenohypophysis of Nhlh2(-/-) mice was hypoplastic although it contained a full complement of the five anterior pituitary cell types. GnRH-1 receptors (GnRHRs) were reduced in Nhlh2(-/-) pituitary gonadotropes as compared to wild type. In vitro assays indicated that Nhlh2 expression is regulated in parallel with GnRHR expression. However, direct transcriptional activity of Nhlh2 on the GnRHR promoter was not found. These results indicate that Nhlh2 plays a role in the development and functional maintenance of the hypothalamic-pituitary-gonadal axis at least at two levels: 1) in the hypothalamus by regulating the number and distribution of GnRH-1 neurons and, 2) in the developing and mature adenohypophysis.
PMID: 17717072 [PubMed - as supplied by publisher]
A Role for Androgens in Regulating Circadian Behavior and the Suprachiasmatic Nucleus.
Karatsoreos IN, Wang A, Sasanian J, Silver R.
Dept. of Psychology, Columbia University; Dept. of Psychology Barnard College, New York, NY, 10027; Dept. of Anatomy and Cell Biology, Columbia University, New York, NY, 10032.
The suprachiasmatic nucleus (SCN) of the hypothalamus is the locus of a master circadian clock controlling behavioral and physiological rhythms, including rhythmic secretion of gonadal hormones. Gonadectomy (GDX) results in marked alteration of circadian behaviors, including lengthened free-running period, decreased precision of daily onset of running, and elimination of early evening but not late night activity bouts. Androgen replacement restores these responses. These aspects of rhythmicity are thought to be regulated by the brain clock, though the site of androgen action remains unknown. Anatomically, the rodent SCN is composed of a ventrolateral "core" and a dorsomedial "shell", and the present studies show that androgen receptors (AR) are localized to the ventrolateral core SCN. Using a transgenic mouse bearing dual reporter molecules driven by the AR targeted to both membrane and nucleus, we find that projections of AR-containing cells form a dense plexus in the core, with their fibers appearing to exit the SCN dorsally. In a second transgenic strain, in which the retinorecipient gastrin-releasing peptide (GRP) cells express a green-fluorescent protein reporter, we show that GRP cells contain AR. Through immunocytochemistry, we also show that SCN AR cells express FOS following a light pulse. Importantly, GDX reduces the FOS response following a phase shifting light pulse, while androgen replacement restores levels to those in intact animals. Taken together, the results support previous findings of a hypothalamic neuroendocrine feedback loop. As such, the SCN regulates circadian rhythms in gonadal hormone secretion and in turn, androgens act on their receptors within the SCN to alter circadian function.
PMID: 17702841 [PubMed - as supplied by publisher]
Androgen receptor auto-regulates its expression by a negative feedback loop through upregulation of IFI16 protein.
Alimirah F, Chen J, Xin H, Choubey D.
Department of Radiation Oncology, Loyola University Chicago and Edward Hines Jr. VA Hospital, 5th Avenue and Roosevelt Road, Building #1, Mail Code 114B, Hines, IL 60141, USA.
Expression of androgen receptor (AR) in prostate epithelial cells is thought to regulate cell proliferation, differentiation, and survival. However, the molecular mechanisms remain unclear. We report that re-expression of AR in PC-3 human prostate cancer cell line resulted in upregulation of IFI16 protein, a negative regulator of cell growth. We found that the IFI16 protein bound to AR in a ligand-dependent manner and the DNA-binding domain (DBD) of the AR was sufficient to bind IFI16. Furthermore, re-expression of IFI16 protein in LNCaP prostate cancer cells, which do not express IFI16 protein, resulted in downregulation of AR expression and an inhibition of the expression of AR target genes. Our observations identify a role for IFI16 protein in AR-mediated functions.
Androgenic up-regulation of androgen receptor cDNA expression in androgen-independent prostate cancer cells.
Dai JL, Maiorino CA, Gkonos PJ, Burnstein KL.
Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, FL 33101, USA.
The expression of the androgen receptor (AR) gene is regulated by androgens. Although androgens down-regulate AR mRNA in most cell lines and tissues, including the prostate, up-regulation occurs in some tissues. Androgen-mediated reduction in AR mRNA is reproduced in COS1 cells and in the androgen-sensitive human prostate cancer cell line LNCaP when each expresses the AR cDNA. We have previously established that the AR cDNA contains the requisite sequences for this down-regulation. Here we shown that androgen promoted up-regulation of AR mRNA in two androgen-independent human prostate cancer cell lines, PC3 and DU145, when each was transfected with a human AR cDNA. This effect was due to the AR cDNA and not to the heterologous promoter driving AR expression. In addition to up-regulation of AR mRNA, androgen induced comparable increases in AR protein levels in PC3 cells stably expressing an AR cDNA (PC3/AR). Up-regulation of AR in PC3/AR cells was accompanied by failure of these cells to undergo desensitization or inactivation of AR following prolonged (96 h) androgen administration, whereas the same conditions resulted in desensitization of AR transactivation in LNCaP cells and in CVl cells that stably express the AR cDNA. Androgen treatment of PC3/AR cells resulted in induction of an androgen-regulated reporter gene (MMTV-CAT) as well as the native prostate-specific antigen gene, which is silent in untransfected PC3 but is androgen up-regulated in LNCaP and in the prostate. These results suggest that ectopic expression of AR in androgen-independent prostate cancer cell lines establishes both typical and atypical androgenic responses in a target gene-specific manner. Androgenic up-regulation of AR cDNA expression may be due to distinct signaling mechanisms that influence androgen action in androgen-independent prostate cancer cells.
PMID: 8883219 [PubMed - indexed for MEDLINE]