Premature ovarian failure (POF) syndrome, an early decline of ovarian function in women, is frequently associated with X chromosome abnormalities ranging from various Xq deletions to complete loss of one of the X chromosomes. However, the genetic locus responsible for the POF remains unknown, and no candidate gene has been identified. Using the Cre͞LoxP system, we have disrupted the mouse X chromosome androgen receptor (Ar) gene. Female AR ؊/؊ mice appeared normal but developed the POF phenotype with aberrant ovarian gene expression. Eight-week-old female AR ؊/؊ mice are fertile, but they have lower follicle numbers and impaired mammary development, and they produce only half of the normal number of pups per litter. Forty-week-old AR ؊/؊ mice are infertile because of complete loss of follicles. Genome-wide microarray analysis of mRNA from AR ؊/؊ ovaries revealed that a number of major regulators of folliculogenesis were under transcriptional control by AR. Our findings suggest that AR function is required for normal female reproduction, particularly folliculogenesis, and that AR is a potential therapeutic target in POF syndrome.male hormone ͉ nuclear receptor ͉ female physiology ͉ folliculogenesis ͉ kit ligand

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Androgen receptor (AR) mediates diverse androgen actions, particularly reproductive processes in males and females. AR-mediated androgen signaling is considered to also control metabolic processes; however, the molecular basis remains elusive. In the present study, we explored the molecular mechanism of late-onset obesity in male AR null mutant (ARKO) mice. We determined that the obesity was caused by a hypercorticoid state. The negative feedback system regulating glucocorticoid production was impaired in ARKO mice. Male and female ARKO mice exhibited hypertrophic adrenal glands and glucocorticoid overproduction, presumably due to high levels of adrenal corticotropic hormone. The pituitary glands of the ARKO males had increased expression of proopiomelanocortin and decreased expression of the glucocorticoid receptor (GR). There were no overt structural abnormalities and no alteration in the distribution of cell types in the pituitaries of male ARKO mice. Additionally, there was normal production of the other hormones within the glucocorticoid feedback system in both the pituitary and hypothalamus. In a cell line derived from pituitary glands, GR expression was under the positive control of the activated AR. Thus, this study suggests that the activated AR supports the negative feedback regulation of glucocorticoid production via up-regulation of GR expression in the pituitary gland.Sex steroid hormones exert a wide variety of biological actions. They are also involved in pathological events, such as the development of hormone-dependent cancers in reproductive organs (5,37). In vertebrates, sex hormones play a pivotal role in male reproductive function and metabolic control. Most sex steroid actions are mediated through transcriptional control of target genes by nuclear receptors (NRs). NRs form a gene superfamily and act as transcriptional factors (9,20). Sex hormone receptors have been shown to transactivate particular sets of target genes in a hormone-dependent manner through direct DNA binding to specific elements in target gene promoters. Hormone receptors activated by hormone binding recruit a number of coregulator-coregulator complexes for transactivation (28). These complexes then affect transcription through chromatin remodeling (12,17,22) and histone modification (1, 7). Hormone binding to the receptors may also transrepress target genes. The mechanisms of hormone-dependent transrepression of steroid receptors likely involve proteinprotein interactions and are thus more diverse than that of transactivation (8,10,13,21).The molecular mechanisms behind the regulation of gene transcription by hormones and their NRs are complicated.Gene disruption studies have clarified the role of various NRs in steroid hormone action. By combining a Cre-loxP system with a canonical gene disruption approach, we succeeded in disrupting the androgen receptor (AR) on the X chromosome in mice in a manner that did not result in male infertility (14). Male AR null mutant (ARKO) mice exhibit abnormalities typical of testicular fem...

Injection of the melanocortin-3/4 receptor agonist melanotan-II (MTII) into the nucleus of the solitary tract (NTS) produces rapid and sustained reduction of food intake. Melanocortin-4 receptors (MC4Rs) are expressed by vagal afferent endings in the NTS, but it is not known whether these endings participate in MTII-induced reduction of food intake. In experiments described here, we evaluated the contribution of central vagal afferent endings in MTII-induced reduction of food intake. Examination of rat hindbrain sections revealed that neuronal processes expressing immunoreactivity for the endogenous MC4R agonist ␣-melanoctyte-stimulating hormone course parallel and wrap around anterogradely labeled vagal afferent endings in the NTS and thus are aptly positioned to activate vagal afferent MC4Rs. Furthermore, MTII and endogenous MC4R agonists increased protein kinase A (PKA)-catalyzed phosphorylation of synapsin I in vagal afferent endings, an effect known to increase synaptic strength by enhancing neurotransmitter release in other neural systems. Hindbrain injection of a PKA inhibitor, KT5720, significantly attenuated MTII-induced reduction of food intake and the increase in synapsin I phosphorylation. Finally, unilateral nodose ganglion removal, resulting in degeneration of vagal afferent endings in the ipsilateral NTS, abolished MTII-induced synapsin I phosphorylation ipsilateral to nodose ganglion removal. Moreover, reduction of food intake following MTII injection into the NTS ipsilateral to nodose ganglion removal was significantly attenuated, whereas the response to MTII was not diminished when injected into the contralateral NTS. Altogether, our results suggest that reduction of food intake following hindbrain MC4R activation is mediated by central vagal afferent endings.

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We report a fetal autopsy case that was diagnosed with a mole coexistent with a live fetus at an early gestation and finally showed coexisting true hermaphroditism of 46,XX/46,XY mosaicism and partial hydatidiform mole, developing metastatic gestational trophoblastic tumors in the lungs of the mother. A 23-year-old Japanese female had a mole coexistent with a fetus and showed a high chorionic gonadotropin titer in urine and serum at 10 weeks of gestation. The fetus was interrupted for gestational toxicosis and genital bleeding at 20 weeks of gestation. A chromosome analysis demonstrated 46,XX and 46,XY mosaicism in both umbilical cord blood and mole samples. Intrapelvic organs contained a testis in the one gonad, and an ovotestis in the other gonad microscopically. The testis had seminiferous tubules containing primitive germ cells, immature Sertoli cells, and cytomegalic Leydig cells. The ovary in the ovotestis had numerous primitive germ cells and a few stromal cells. Cortical cytomegaly and medullary neuroblastoma in situ were seen in the adrenals. The placenta showed focal villous hydrops and focal trophoblast hyperplasia. The patient presented multiple metastatic pulmonary tumors at 1 month after the interruption, and was treated with chemotherapy for the clinical diagnosis of gestational trophoblastic tumor metastases. She responded well and is alive without any symptoms.