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PubMed1998

Expression of androgen receptor mRNA during mouse embryogenesis.

Androgen receptor (AR) is a member of the nuclear receptor superfamily which acts as a ligand-dependent transcription factor (Beato, M., Herrlich, P., Schütz, 1989. Steroid hormone receptors: many actors in search of a plot. Cell 83, 851-857). It plays a pivotal role in sexual development and reproduction (Wilson, J.D., Griffin, J.E., George, F.W., Leshin, M., 1981. The role of gonadal steroids in sexual differentiation. Rec. Prog. Horm. Res. 37, 1-39; Jost, A., 1990. Hormonal control of the masculinization of the body. In: Baulieu, E.E., Kelly, D.A., (Eds.), Hormones, from Molecules to Disease. Chapman and Hall, New York and London, pp. 439-442.). Mutations in the AR sequence cause a number of physiological disorders, such as partial and complete androgen insensitivity syndromes, that lead to abnormal sexual development (Patterson, M.N., McPhaul, M.J., Hughes, I.A., 1994. Androgen insensitivity syndrome. Ballière's Clin. Endocrinol. Metab. 8, 379-404.). There are indications that AR may also have other functions. For example, structural alterations of the AR sequence have been implicated in prostate cancer (Visakorpi, T., Huytinen, E., Koivisto, P., Tanner, M., Keinänen, R., Palmberg, C., Palotie, A., Tammela, T., Isola, J., Kallioniemi, O.-P., 1995. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nature Genet. 9, 401-406.) and in the development of spinal and bulbar muscular atrophy, a neurodegenerative disease (Kennedy, W.R., Alter, M., Sung, J.H., 1968. Progressive proximal spinal and bulbar muscular atrophy of late onset: a sex-linked recessive trait. Neurology 18, 671-680.). Here, we have investigated the spatial and temporal expression of AR during mouse organogenesis by in situ hybridisation. We demonstrate that AR transcripts occur in the developing external genitalia, pituitary, adrenals, kidneys and musculus levator ani, in addition to the known expression sites in the Wolffian ducts and its derivatives and during development of the mammary glands.

Animals↗
PubMed1990

Adenylyl cyclase is dispensable for vegetative cell growth in the fission yeast Schizosaccharomyces pombe.

Disruption of the cyr1 gene of Schizosaccharomyces pombe, which encodes adenylyl cyclase, did not confer lethality to fission yeast cells, although they grew 40% slower than wild-type strains in complete medium. These cells contained no measurable amount of cAMP and no adenylyl cyclase activity. When h+ and h- cyr1 disruptants were mixed, they underwent mating even in rich medium. Propagation of homothallic cyr1 disruptants was difficult, probably because such cells readily mate and produce asci and thus stop growing. A greater than 10-fold increase in the amount of cyr1 mRNA was observed when cloned cyr1+ was introduced into Sch. pombe cells on a multicopy plasmid. The total adenylyl cyclase activity was similarly high in these transformants. However, the level of intracellular cAMP was hardly affected. Evidence suggests that this was not due to increased phosphodiesterase activity. Thus, cAMP level in growing fission yeast cells appears to be regulated not by the amount of adenylyl cyclase protein but by a feedback mechanism at the enzyme level. The cAMP level fell by approximately 50% under nitrogen starvation, which triggers sexual development in Sch. pombe. We suggest that fission yeast controls the level of intracellular cAMP primarily to regulate sexual development rather than to drive or arrest the cell cycle.

Adenylyl Cyclases↗
PubMed2005

A comprehensive survey of the Plasmodium life cycle by genomic, transcriptomic, and proteomic analyses.

Plasmodium berghei and Plasmodium chabaudi are widely used model malaria species. Comparison of their genomes, integrated with proteomic and microarray data, with the genomes of Plasmodium falciparum and Plasmodium yoelii revealed a conserved core of 4500 Plasmodium genes in the central regions of the 14 chromosomes and highlighted genes evolving rapidly because of stage-specific selective pressures. Four strategies for gene expression are apparent during the parasites' life cycle: (i) housekeeping; (ii) host-related; (iii) strategy-specific related to invasion, asexual replication, and sexual development; and (iv) stage-specific. We observed posttranscriptional gene silencing through translational repression of messenger RNA during sexual development, and a 47-base 3' untranslated region motif is implicated in this process.

3' Untranslated Regions↗
PubMed1992

Evidence from mosaic analysis of the masculinizing gene her-1 for cell interactions in C. elegans sex determination.

Sex in Caenorhabditis elegans is determined by a regulatory cascade of seven interacting autosomal genes controlled by three X-linked genes in response to the X chromosome-to-autosome (X/A) ratio. XX animals (high X/A) develop as self-fertile hermaphrodites, and XO animals (low X/A) develop as males. The activity of the first gene in the sex-determining cascade, her-1, is required for male sexual development. XO her-1 loss-of-function mutants develop as self-fertile hermaphrodites, whereas XX her-1 gain-of-function mutants develop as masculinized intersexes. By genetic mosaic analysis using a fused free duplication linking her-1 to a cell-autonomous marker gene, we show here that her-1 expression in a sexually dimorphic cell is neither necessary nor sufficient for that cell to adopt a male fate. Our results suggest that her-1 is expressed in many, possibly all, cells and that its gene product can function non-autonomously through cell interactions to determine male sexual development.

Animals↗
PubMed1984

Thyroid-testis interrelationship during the development and sexual maturity of the rat.

The effects of thyroidectomy and treatment with thyroxine (T4) were studied in immature male rats to evaluate the role of the thyroid in the development of testicular functions. Thyroidectomy inhibited gametogenesis and development of the Leydig cell in these rats. However, the effects could be reversed by administration of 10 micrograms T4 (i.p.) daily for 30 days.

Animals↗
PubMed1985

The pineal and pubertal development.

The pineal gland, through its major secretory product melatonin, influences seasonal breeding in species such as the hamster and the sheep. Recent studies from our laboratory have shown that melatonin also affects sexual development in the rat. A role for melatonin in humans has not yet been found. The laboratory rat is sensitive to daily administration of melatonin at the beginning of sexual maturation. The male rat is most sensitive between day 20 and day 30 of life. Melatonin does not permanently inhibit sexual maturation, since normal but delayed sexual development occurs after 45 days of life whether melatonin administration is discontinued or maintained indefinitely. In female rats, daily injection of melatonin during the prepubertal period delays the vaginal opening and disrupts the normal cyclicity of the first oestrous cycles. In both male and female rats, the inhibitory action of melatonin is highly dependent upon the time of injection, with maximal effects when melatonin is given in the late photoperiod. The inhibitory action of melatonin is most likely exerted at the hypothalamic level, possibly through interference with the control of pulsatile secretion of gonadotropin-releasing hormone. In contrast to some published work, our experiments provide no evidence for modifications of diurnal or nocturnal melatonin secretion during puberty in humans. Our results with the rat indicate that melatonin may be an important factor for the timing of sexual maturation.

Adolescent↗
PubMed2006

Amenorrhea: evaluation and treatment.

A thorough history and physical examination as well as laboratory testing can help narrow the differential diagnosis of amenorrhea. In patients with primary amenorrhea, the presence or absence of sexual development should direct the evaluation. Constitutional delay of growth and puberty commonly causes primary amenorrhea in patients with no sexual development. If the patient has normal pubertal development and a uterus, the most common etiology is congenital outflow tract obstruction with a transverse vaginal septum or imperforate hymen. If the patient has abnormal uterine development, müllerian agenesis is the likely cause and a karyotype analysis should confirm that the patient is 46,XX. If a patient has secondary amenorrhea, pregnancy should be ruled out. The treatment of primary and secondary amenorrhea is based on the causative factor. Treatment goals include prevention of complications such as osteoporosis, endometrial hyperplasia, and heart disease; preservation of fertility; and, in primary amenorrhea, progression of normal pubertal development.

Algorithms↗
PubMed1985

Measures of growth, development, and sexual maturation in mongolian gerbils (Meriones unguiculatus): effects of photic period during ontogeny.

We examined, in Mongolian gerbils, the adequacy of two commonly used indices of rate of development, age at eye-opening and age at vaginal introitus, as predictors of biologically important events: initiation of feeding on solid food and age at first parturition. We then enquired as to the interrelationships among body weight, eye-opening, and vaginal introitus in Mongolian gerbils whose rates of development were manipulated by altering the extent of their exposure to illumination during ontogeny. We found that (1) age at vaginal introitus was significantly, but weakly, correlated with age at first parturition (Experiment I); (2) age at eye-opening strongly predicted age of initiation of gnawing on solid food (Experiment II); (3) eye-opening occurred at markedly different ages, but at the same body weight in gerbils reared under 0/24-, 6/18-, 12/12-, and 24/0-hr day-night cycles (Experiment III); and (4) vaginal introitus occurred at both different ages and different body weights in females reared under different day-night cycles (Experiment III).

Animals↗
PubMed1995

Mediastinal teratoma and precocious puberty in a boy with mosaic Klinefelter syndrome.

We describe a boy who developed precocious puberty resulting from chorionic gonadotropin produced by a mediastinal germ cell tumor. Following tumor removal he began spontaneous precocious sexual development which was treated and then arrested spontaneously. Investigation of this arrested puberty established that he had Klinefelter syndrome (KS) mosaicism. He represents the first instance of KS mosaicism reported with a mediastinal germ cell tumor, a neoplasm commonly reported in males with a 47,XXY karyotype. We recommend that all males with KS and early sexual development or with "normal" testicular growth be screened with measurement of germ cell tumor markers including beta-subunit of human chorionic gonadotropin and alpha-fetoprotein.

Child↗
PubMed2004

Ethnic/racial differences in the coming-out process of lesbian, gay, and bisexual youths: a comparison of sexual identity development over time.

This longitudinal report of 145 lesbian, gay, and bisexual (LGB) youths examined ethnic/racial differences in the coming-out process. No significant differences emerged in sexual developmental milestones, sexual orientation, sexual behavior, or sexual identity. However, Black youths reported involvement in fewer gay-related social activities, reported less comfort with others knowing their sexual identity, and disclosed that identity to fewer people than did White youths. Latino youths disclosed to fewer people than did White youths. Analyses of change indicated Black youths had greater increases in positive attitudes toward homosexuality and in certainty in their sexual identity over time than did White youths. These findings support the authors' hypothesis that cultural factors do not impede the formation of identity but may delay identity integration.

Adolescent↗
PubMed1977

Influence of fetal sex on the concentration of amniotic fluid testosterone: antenatal sex determination?

Amniotic fluid testosterone was measured by radioimmunoassay in 226 samples taken between the 12th week of pregnancy and birth. The effect of fetal sex on the level of this androgen was determined and the usefulness of the parameter for predicting fetal sex assessed. Testosterone was measured using an antibody raised in rabbits against testosterone-3-carboxymethyloxime-BSA. The antiserum cross-reacted strongly with 5alpha-dihydrotestosterone so that the values reported were refered to as measuring "immunoreactive testosterone" levels. Male fetal values were highest between the 12th and 15th week of pregnancy reaching a maximum mean of 501 +/- 185 pg/ml gradually falling during the remainder of pregnancy to 281 +/- 74 pg/ml, the difference in values between the first half and the end of pregnancy being highly significant (p less than 0.0005). Female fetal values did not vary significantly during the course of gestation, the minimum mean value being 179 +/- 50 and maximum 253 +/- 98 pg/ml. The fetal amniotic fluid sex difference was highly significant during the first half of pregnancy (p less than 0.0005) and at 12-15 weeks a successful prediction of fetal sex was possible, using testosterone, in 39 out of 41 cases. At birth on the other hand there was no difference between male and female fetal fluid levels. The method can also be used to detect disturbances of intrauterine sexual development as exemplified by the case of a Klinefelter syndrome where female testosterone values were found at the time of sexual differentiation. Thus the measurement of unconjugated testosterone in amniotic fluid would seem to offer not only an addition to chromosomal analysis for prediction of fetal gender but also be a valuable tool for detection of disturbances of intrauterine sexual development i.e. when genetic sex and sex-specific hormone production are discrepant.

Amniotic Fluid↗
PubMed2003

Development of sexually abusive behaviour in sexually victimised males: a longitudinal study.

BACKGROUND: Sexual maltreatment is one of the most common forms of child abuse. To identify risk factors for sexually abusive behaviour by adults, we prospectively assessed childhood experiences and personal characteristics of male child victims who became abusers in later life. METHODS: In a longitudinal study (7-19 years duration), we included 224 former male victims of sexual abuse. Risk factors contemporaneous with the abuse, and putative protective influences, were identified from social service and clinical records. Evidence of later criminal acts was obtained from a nationwide search of official records. FINDINGS: Of the 224 former victims, 26 had subsequently committed sexual offences (victim-abusers), in almost all cases with children, mainly outside their families. Risk factors during childhood for later offending included material neglect (odds ratio 3.4, 95% CI 1.2-9.7), lack of supervision (3.0, 1.1-8.3), and sexual abuse by a female person (3.0, 1.1-8.7). Victim-abusers had more frequently witnessed serious intrafamilial violence (3.1, 1.0-10.0). Six (29%) of 21 victim-abusers on whom we had relevant data had been cruel to animals (7.9, 2.0-31.4). No single putative protective factor, nor a composite protective index, significantly reduced the risk of paedophilic behaviour. INTERPRETATION: Most male victims of child sexual abuse do not become paedophiles, but particular experiences and patterns of childhood behaviour are associated with an increased risk of victims becoming abusers in later life. Our findings have implications for the design of selective interventions with a vulnerable subgroup of male victims, aimed at reducing the risk of paedophilic behaviour in later life.

Adolescent↗
PubMed2006

Opposite effects of tor1 and tor2 on nitrogen starvation responses in fission yeast.

The TOR protein kinases exhibit a conserved role in regulating cellular growth and proliferation. In the fission yeast two TOR homologs are present. tor1(+) is required for starvation and stress responses, while tor2(+) is essential. We report here that Tor2 depleted cells show a phenotype very similar to that of wild-type cells starved for nitrogen, including arrest at the G(1) phase of the cell cycle, induction of nitrogen-starvation-specific genes, and entrance into the sexual development pathway. The phenotype of tor2 mutants is in a striking contrast to the failure of tor1 mutants to initiate sexual development or arrest in G(1) under nitrogen starvation conditions. Tsc1 and Tsc2, the genes mutated in the human tuberous sclerosis complex syndrome, negatively regulate the mammalian TOR via inactivation of the GTPase Rheb. We analyzed the genetic relationship between the two TOR genes and the Schizosaccharomyces pombe orthologs of TSC1, TSC2, and Rheb. Our data suggest that like in higher eukaryotes, the Tsc1-2 complex negatively regulates Tor2. In contrast, the Tsc1-2 complex and Tor1 appear to work in parallel, both positively regulating amino acid uptake through the control of expression of amino acid permeases. Additionally, either Tsc1/2 or Tor1 are required for growth on a poor nitrogen source such as proline. Mutants lacking Tsc1 or Tsc2 are highly sensitive to rapamycin under poor nitrogen conditions, suggesting that the function of Tor1 under such conditions is sensitive to rapamycin. We discuss the complex genetic interactions between tor1(+), tor2(+), and tsc1/2(+) and the implications for rapamycin sensitivity in tsc1 or tsc2 mutants.

Amino Acid Transport Systems↗
PubMed1995

Characterization of npf mutants identifying developmental genes in Physarum.

In Physarum polycephalum, uninucleate haploid amoebae develop into macroscopic multinucleate plasmodia. Wild-type, sexual development is triggered when two amoebae carrying different alleles of matA fuse to form a zygote which develops into a diploid plasmodium. Mutations in the matA genetic region give rise to apogamic strains in which a single haploid amoeba can develop into a haploid plasmodium. An essential stage in both sexual and apogamic plasmodium formation is an extended cell cycle in uninucleate cells, which ends with the formation of a binucleate cell by mitosis without cytokinesis. Using a 'brute force' screening method, we have isolated mutants blocked in apogamic plasmodium development. Genetic analysis showed that the mutations we have identified were unlinked to matA, unlike mutations previously identified following an enrichment step. Most of the loci revealed by our screen were represented by only one allele, indicating that further screening should lead to the identification of additional genes required for plasmodium development. Phenotypic analysis showed that different mutants were blocked at different stages of plasmodium formation. Some of the mutations blocking apogamic development at an early stage, close to the start of the long cell cycle, failed to block sexual development in zygotes homozygous for the mutation. Since the two modes of plasmodium formation differ only in the initiation of development, these mutations presumably interfere with the initiation process. In the remaining mutants, in which both sexual and apogamic development were blocked, development first became abnormal towards the end of the long cell cycle. This suggested that the wild-type gene products were required by this time and was consistent with previous evidence that many changes in cellular organization and gene expression occur during the long cell cycle. Each of these mutants showed a different terminal phenotype and some aspects of plasmodium development occurred normally although others were blocked, suggesting that development involves multiple pathways rather than a dependent sequence of events. Phenotypic analysis of double mutants supported this conclusion and also revealed epistatic interactions, presumably due to blocks in the same pathway. In several of the mutants, terminally differentiated cells died by an apoptosis-like mechanism; since this was never observed in vegetative cells, it was presumably triggered by the failure of development. Phenotypic analyses of additional mutants will extend our understanding of the pathways involved in plasmodium development.

Animals↗
PubMed2006

Effects of nitrate and atrazine on larval development and sexual differentiation in the northern leopard frog Rana pipiens.

Pollution from agrochemicals may be contributing to the global decline in amphibian populations. Environmentally relevant concentrations of nitrate and/or atrazine on anuran development and gonadal differentiation were tested. Four replicates of 20 tadpoles per tank (80/treatment) were exposed from Taylor-Kollros stage 2 to 3 to stage 23 to 34 to either 10 mg/L nitrate, 10 microg/L atrazine, a combined exposure of 10 mg/L nitrate plus 10 microg/L atrazine, or untreated controls. No treatment-dependent effects on weight, snout-vent or hind limb length, or time to forelimb emergence were observed. The proportions of females increased in all treatments compared to the controls, especially in the combined treatment (chi2 = 17.90, df = 6, p = 0.0065, combined = 66.4% female, control = 41% female). The frequency of intersex was low in all treatments. No treatment-related effects on the total number of spermatogenic cells were observed, but the ratio of cell types differed in that testes from animals in the treated groups exhibited more spermatogonia, fewer spermatocytes, and more spermatids than the control (significantly different, Kruskal-Wallis, p < 0.05). Ovaries from animals treated with nitrate or atrazine exhibited larger immature (previtellogenic) and mature (vitellogenic) follicles, but ovaries from the combined treatment had larger immature follicles only. Testicular oocytes were observed in the nitrate-only and atrazine-only treatments, and the control treatment, but not the combined treatment. Overall, this study has demonstrated changes in sex ratios that are more marked in response to combined nitrate/atrazine exposure than with these chemicals alone. Histological evidence suggests that premature maturation of gonad may occur as a result of nitrate and/or atrazine exposure during larval development.

Animals↗
PubMed2001

[Differential diagnosis and treatment of girls with 46XY-karyotype and androgen insensitivity syndrome].

The importance of the secretion and action of androgens during the critical period of male sexual development is exemplified in patients with androgen insensitivity syndrome. Their karyotype is always 46XY. In 2 sisters, aged 11 and 13 years, the androgen insensitivity syndrome was diagnosed based on an androgen receptor gene mutation. Ambiguous genital development of a new-born was shown to be due to a lack of testosterone production, based on a luteinizing hormone receptor gene mutation. Finally, in a phenotypically female new-born a gene mutation of 17-beta hydroxysteroid dehydrogenase type 3 was found to be responsible for insufficient testosterone synthesis during embryonic development. The presentation of a patient, and specifically a neonate, with abnormal genital development represents a difficult diagnostic and therapeutic challenge. Referral to a centre with experience in the diagnosis and management of disorders of sexual development is advised where the emphasis should be on psychological and genetic counselling.

17-Hydroxysteroid Dehydrogenases↗