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Postnatal profile of plasma leptin concentrations in male and female rats: relation with the maturation of the pituitary-gonadal axis.

Leptin, the ob gene product, has been implicated in the initiation of puberty in mice and humans. However, it is not yet clear whether leptin also plays a pivotal role in promoting sexual maturation in rats. Based on the assumption that circulating leptin levels would increase during the peripubertal period if this hormone triggers puberty, we examined the developmental profile of plasma leptin from neonatal (day 1) through adult (day 85) age in both male and female rats and simultaneously monitored several important indices of pituitary-gonadal function. A significant elevation of plasma leptin during the peripubertal period was not observed in either male or female rats. Although this finding may not support leptin as a humoral factor triggering puberty, we observed a rise in leptin in both sexes from the second postnatal week, which clearly preceded the first significant elevations of luteinizing hormone and gonadal steroids. Therefore, it is still possible that leptin may play a role in promoting sexual maturation in rats of both sexes already from an early postnatal period. It seems that the role for leptin in sexual development is permissive, but not decisive, in rats.

Aging↗

Delayed puberty caused by hyperthyroidism in ram lambs is not a result of suppression in body growth.

Over a period of 8 weeks ram lambs (16 weeks old) were made hyperthyroidal (serum thyroxine approximately equal to 150 ng/ml, compared with control approximately equal to 48 ng/ml) by daily subcutaneous injections of thyroxine or maintained at a constant body weight by restriction of the feed intake. Hyperthyroidal and restricted-intake lambs remained at a constant body weight during the period of treatment whilst control rams gained body weight. Testicular growth was normal in restricted-intake lambs but was suppressed in hyperthyroidal animals. Hyperthyroidism, but not feed restriction, was also associated with decrease in LH pulse frequency (1.3 +/- 0.3/12 h compared with controls 4.8 +/- 0.9/12 h. Hyperthyroidal lambs showed normal LH responses to exogenous LHRH. After cessation of treatment testicular growth continued to be suppressed for up to 16 weeks in previously hyperthyroidic rams; thereafter testes began to increase in size but at 30 weeks after treatment were still smaller than those of control rams. It is concluded that elevated thyroxine concentrations directly influence sexual maturation in ram lambs through actions at hypothalamic and/or higher brain centres which control LH secretion. Transient hyperthyroidism during sexual maturation may cause permanent impairment of sexual development.

Animals↗

Germ cells, gonads and sex reversal in marsupials.

The formation of the testis or ovary is a critical step in development. Alterations in gonadal development during fetal or postnatal life can lead to intersexuality or infertility. Several model systems have been particularly useful in studying gonadal differentiation, the eutherian mammal and amphibia, fish, and birds. However, marsupials provide a unique opportunity to investigate gonadal development and the interactions of genes and hormones in gonadal differentiation and germ cell development in all mammals. On the one hand the genetic mechanisms appear to be identical to those in eutherian mammals, including the testis-determining SRY gene. On the other hand, marsupials retain in part the plasticity of the amphibian gonad to hormonal manipulation. It is possible to induce female to male and also male to female gonadal sex reversal in marsupials by hormonal manipulation, and oestradiol can induce male germ cells to enter meiosis at the time the oogonia do. In addition, in marsupials the development of the scrotum and mammary glands are independent of testicular androgens and instead are controlled by a gene or genes on the X-chromosome. Thus marsupials provide a number of opportunities for manipulating the sexual differentiation of the gonads that are not possible in eutherian mammals and so provide a unique perspective for understanding the common mechanisms controlling sexual development.

Animals↗

Relationship between biological and social aspects of sexual maturity among young Danes.

Representative samples of 286 young Danish women and 336 young men aged 16-20 years were interviewed in 1984-1985 about menarcheal age and age at 1st sexual intercourse. The medium age at menarche was 13.13 years. Altogether 212 (74%) of females and 225 (70%) of males were sexually experienced. Among females the medium age at sexual debut is related to that at menarche in the 4 cohorts investigated where it was possible to estimate both variables. Consequently, the behavioral aspects of sexual maturity among females is heavily influenced by this purely biological index of maturation. Although the median age at 1st sexual intercourse could only be estimated in 3 of the male cohorts an indication of association between the median ages at sexual debut is clear, and they seem to follow the median age of menarche closely. The interrelationship between this biological factor (menarche) and a social event (1st sexual intercourse) indicates a causality in sexual development of young contemporary Danes.

Adolescent↗

Molecular cloning and expression of the osteoclast-stimulating-factor-like gene from the rice field eel.

Sexual development in vertebrates is a complex process. Vertebrates use several mechanisms to determine the development of a male or female organism. The genes for determination of sequential hermaphrodite sex are unknown. We identified a homologue of human osteoclast-stimulating factor (OSF) in the rice field eel, a teleost that undergoes natural sex transformation from female, via intersex, to male during its lifetime. The rice field eel OSF-like gene cDNA encoded a peptide of 214 amino acids that contains a c-Src homology 3 domain, proline-rich region, and ankyrin repeats, suggesting potential involvement in cell signaling. The gene was clustered into the OSF gene group of all the other vertebrates. Although expressed in the three kinds of gonads and in other tissues, OSF-like gene expression in gonads of all the three sexes was restricted to the gonadal germinal epithelium, from where bipotential gonia (oogonia or spermatogonia) will differentiate, suggesting that the OSF-like gene may be involved in sexual differentiation, in addition to its other roles as a regulator in development.

Amino Acid Sequence↗

Delay in the age of balano-preputial skinfold cleavage and alterations in serum profiles of testosterone, 5 alpha-androstane-3 alpha,17 beta-diol, and gonadotropins in adult rats treated during puberty with luteinizing hormone releasing hormone.

Previous work has shown that chronic treatment of intact, immature male rats with luteinizing hormone releasing hormone (LHRH) decreases sex accessory gland weights and results in retardation of the normal developmental increase in the ratio of serum testosterone (T)/5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-Diol) via an apparent enhancement of testicular 5 alpha-reductase or 3 alpha-hydroxysteroid oxidoreductase activities. In the present work, androgen dependent balano-preputial skinfold cleavage was significantly delayed by approximately one week in intact, immature male rats which were treated daily for two weeks with either 1.0 micrograms, 2.5 micrograms or 5.0 micrograms of LHRH during a discrete phase of pubertal development (28-41 days of age). In intact, adult (62 day old) animals which received LHRH treatments during pubertal development, serum T concentrations and sex accessory gland weights were reduced compared to control animal values. Serum 3 alpha-Diol content in the adult rats was either unaltered or increased significantly depending on the LHRH dosage employed during sexual development. Serum luteinizing hormone concentrations were not different between control and LHRH-pretreated adult rats whereas the highest dosage of LHRH employed (5.0 micrograms) during puberty resulted in a significant elevation of adult serum follicle stimulating hormone levels. It is suggested that chronic LHRH treatment of the male rat during puberty results in a perturbation in testicular androgen biosynthetic activities and an impairment of pituitary-testicular hormone feedback mechanisms which persist at least through early adulthood.

Androstane-3,17-diol↗

Müllerian duct agenesis and other congenital anomalies.

The Rokitansky anomalad, although a rare disorder, ranks second as a cause of primary amenorrhea in adolescents. This patient presented with a congenital absence of the vagina and uterus and other associated minor abnormalities. She had primary amenorrhea and asynchronic pubertal development. The syndrome appears to be related to a defect in the paramesonephric ducts with frequent involvement of adjacent structures. This report reviews the syndrome and emphasizes the importance of the chronological sequence of events during female sexual development.

Abnormalities, Multiple↗

Invertebrates may not be so different after all.

Sex determination is widespread, but uses highly varied molecular mechanisms. A possible case of conservation between phyla is that of doublesex (dsx) from Drosophila and mab-3 (male abnormal 3) from Caenorhabditis elegans, genes related in sequence and some elements of function. mab-3 controls multiple aspects of male development, including sense organ formation in the tail and yolk transcription in the intestine, both similar to functions of dsx. Indeed, the male isoform of DSX can replace MAB-3 in C. elegans. Do related genes control sexual development in vertebrates, despite great differences in the biology of sex determination? We have identified several dsx-related genes in mouse and human. One, Dmrt1, appears to play a conserved role in vertebrate male gonad development. In humans, DMRT1 maps to a short interval required for testis differentiation. In all vertebrates examined, including mammals, birds, fish, and reptiles, Dmrt1 is expressed early in the genital ridge, in most cases with higher expression in future male gonads. A null mutation in murine Dmrt1 causes severe defects in testis differentiation, resembling those associated with human deletions removing the gene. Mutant females are unaffected. Other DM domain genes are expressed in embryonic gonad and are currently under study.

Animals↗

Precocious puberty.

The child with premature sexual development requires a thorough history, physical, and appropriate laboratory evaluation. The physician and other medical staff should remain sensitive to the family's concerns and the child's emotional adaptation. Counseling and open discussion of the psychosocial and sexual issues may greatly assist both the child and family. Making the correct diagnosis is critical to the selection of the appropriate form of therapy. Fortunately, in most cases in which therapy is warranted, it is extremely effective. In the remaining conditions, promising new forms of therapy are being investigated.

Adolescent↗

[The modelling of the development of Plasmodium yoelli yoelli in different vertebrate hosts].

Outbred mice and inbred BALB/c mice were used for simulating Plasmodium yoelii yoelii (strain 265 BY) development. When the infection is initiated by standardized blood cryosamples and in sporozoite infection in various vertebral hosts the infection develops likewise as regard to parasitemia cyclic recurrences, however, the magnitude of parasitemia peaks, time of their occurrence, its stabilization or attenuation are different, which to a great extent determines the period of gametocyte infectivity. Reproducibility of the models developed is ensured by the use of the same agent strain and host species, standardization of the inoculum type and the following characteristics of the vertebral host: sex, age, source and route of infection, chronobiology of schizogony and gametogony (quantitative and qualitative characteristics), duration of the infection (including a prepatent period) and the number of development peaks. An optimal model of the infection is merozoite infection of mice, when the first peak of gametocytemia is achieved during moderately increased parasitemia, prior to the parasitemia peak. The absence of marked interactions in asexual and sexual development of the parasite, and the coincidence of the parasitemia and gametocytemia peaks (infection models in BALB/c mice and sporozoite infection in mice) restrict substantially model standardization and selection of donors for infecting the carriers.

Animals↗

Sexual maturation and fecundity of wild and domestic Norway rats (Rattus norvegicus).

A population of captive-reared wild Norway rats and two stocks of domestic rats were compared for various parameters of sexual maturation and fecundity. Males did not differ in age at the first appearance of spermatozoa in the testes but wild males were significantly older than Long--Evans and Sprague--Dawley domestic males at first copulation with a hormone-induced oestrous female. Wild females were significantly older than domestic females at the time of vaginal opening, first oestrus and first conception. Stocks did not differ in length of the first oestrous cycle. Wild females produced significantly smaller litters than their domestic counterparts. Domestic rats were significantly heavier than wild rats at the various stages of sexual maturation. The results support the hypothesis that domestication of the rat has been accompanied by genetic and/or environmental changes that accelerate sexual development and improve breeding success under laboratory conditions.

Age Factors↗

Development of selective androgen receptor modulators and their therapeutic applications.

Androgens control a broad range of physiological functions. The androgen receptor (AR), a steroid receptor that mediates the diverse biological actions of androgens, is a ligand inducible transcription factor. Abnormalities in the androgen signaling system result in many disturbances ranging from changes in gender determination and sexual development to psychiatric and emotional disorders. Androgen replacement therapy can improve many clinical conditions including hypogonadism and osteoporosis, but is limited by the lack of efficacious and safe therapeutic agents with easy delivery options. Recent progress in the area of gene regulation by steroid receptors and by selective receptor modulators provides an opportunity to examine if selective androgen receptor modulators (SARMs) could address some of the problems associated with current androgen therapy. Since the composition of the transcriptional initiation complex recruited by liganded AR determines the specificity of gene regulation, synthetic ligands aimed at initiating transcription of tissue and promoter specific genes offers hope for developing better androgen therapy. Establishment of assays that predict synthetic ligand activity is critical for SARM development. Advancement in high throughput compound screening and gene fingerprinting technologies, such as microarrays and proteomics, will facilitate and accelerate identification of effective SARMs.

Androgen Antagonists↗

Delayed reproductive development resulting from aflatoxicosis in juvenile Japanese quail.

Aflatoxicosis was induced in young Japanese quail. In the first experiment five replicates of 30 birds per treatment were fed a soy-corn basal ration containing 0, 5, or 10 microgram aflatoxin per gram of feed from 1 to 3 weeks of age. At 3 weeks, the animals were sacrificed and mesurements taken. In the second experiment, 0 to 10 microgram aflatoxin per gram of diet were fed from either 1 to 3 weeks of age or 2 to 4 weeks of age. At 3 weeks of age body weights were significantly (P < .05) reduced and relative liver weights were significantly (P < .05) increased. Testicular weights relative to body weight were depressed by up to 50%. Ovary wet weights, but not relative weights, were reduced. Testicular development (weight) was impaired through 6 weeks of age. Ovarian development, determined both by weight and number of developing follicles, was delayed as long as 3 weeks following withdrawal of aflatoxin from the diet. Radioimmunoassay for circulating androgens revealed that aflatoxin suppressed both the onset of production and the final concentratin of male hormone. The data demonstrate that aflatoxin can exert a deleterious inhibition of sexual development in quail with subsequent impairment of reproductive capacity. These findings raise the implication of potential reproductive failure in economically important species such as broiler breeders.

Aflatoxins↗

True 47,XXX in a patient with premature ovarian failure: the first reported case in Thailand.

A case of triple-X female with premature ovarian failure was reported. The patient was a 23-year-old, single, Thai woman who presented with primary amenorrhea, incomplete development of the secondary sex characteristics, elevated levels of serum gonadotropins, and decreased estrogen concentration. Immunological abnormalities were not identified by antinuclear antibody, rheumatoid factor, antimicrosomal antibody and antithyroglobulin antibody studies. Cyclic estrogen-progestin was given and withdrawal bleeding occurred. The present case represents the utilization of chromosomal analysis in a patient with delayed sexual development, or primary amenorrhea and elevated serum gonadotropin levels.

Adult↗

Sexual maturation of the hypothalamus: pathophysiological aspects and clinical implications.

Sexual maturation in humans begins early in fetal life and culminates in adulthood when the gonads have acquired a full capacity for reproduction. It is remarkable that during this long process, the pituitary gonadal function, hence its hypothalamic control presents an alternative of activation and inhibition periods, during which the interrelations of the 3 components of the hypothalamic-pituitary-gonadal axis change gradually and inversely. The ontogeny of the hypothalamic-pituitary system, the varying activity of the reproductive endocrine system throughout sexual maturation and the developmental changes in the interrelations of the hypothalamic-pituitary-gonadal axis are reviewed: the most striking feature of human sexual development is the long inhibition of hypothalamo-pituitary function during childhood. Much indirect evidence points to the determining role of the CNS in the maturation of hypothalamic function: the occurrence of rhythms of secretion, the amplitude of secretions and peripubertal specific sleep-related nycthemeral rhythm of secretion at the onset of puberty. Despite the reality of a negative feedback control, these changes do occur independently of gonadal secretions since they are observed (qualitatively if not strictly quantitatively) in agonadal children. It is likely that neurotransmitters (dopamine, serotonine) and opiates have an inhibitory effect on Gn-RH release. But we still don't know their evolution during sexual maturation. It does not appear that melatonine plays any determinant role in the onset of human puberty. The clinical implications of our present understanding of the physiological events occurring during sexual maturation are several. Considering the major problems related to abnormal sexual maturation we will discuss successively: (1) diagnosis of hypogonadotrophic hypogonadism in early infancy; (2) differential diagnosis between premature thelarche and true sexual precocity; (3) the usefulness of endocrine investigations in the evaluation of hypothalamic-pituitary function; and (4) the new developments in the treatment of precocious puberty, delayed puberty or hypogonadism.

Adolescent↗

Gene expression and estrogen sensitivity in rat uterus after developmental exposure to the polybrominated diphenylether PBDE 99 and PCB.

Considering the presence of polybrominated diphenylethers (PBDEs) in human milk and cord blood, and the estrogenic activity of some congeners, it is conceivable that PBDEs may interact with developing neuroendocrine systems. We investigated effects of 2,2',4,4',5-pentabromo-DE (PBDE 99), a major congener in human milk, on development of brain and reproductive organs, with focus on estrogen target gene expression. Time-pregnant Long Evans rats were subcutaneously injected with PBDE 99 (1 or 10 mg/kg/day), the PCB mixture Aroclor 1254 (10 mg/kg/day), known to interfere with sexual development, or vehicle, from gestational day (GD) 10 to GD 18. In female offspring, anogenital distance was unaffected by PBDE 99 but increased by Aroclor; puberty (vaginal opening) was not significantly changed. Adult PBDE 99-exposed offspring exhibited unchanged uterine weight but increased ovarian weight. Uterine mRNA levels of estrogen target genes were determined by real-time PCR. Progesterone receptor (PR) mRNA was down-regulated at both PBDE 99 doses, estrogen receptor alpha (ER alpha), ER beta and insulin-like growth factor-I (IGF-I) were up-regulated at the lower dose. Aroclor induced different effect patterns. In order to investigate possible changes in sensitivity of target genes to estrogen, some offspring were ovariectomized at 10 weeks of age, s.c. injected with estradiol-17beta (E2, 10 microg/kg) or vehicle at 12 weeks, and sacrificed 6 h later. PBDE 99 dose-dependently reduced the magnitude of IGF-I mRNA induction by E2, and increased the magnitude of ER beta repression. PBDE 99 also influenced baseline levels of PR, IGF-I and ER beta mRNAs in ovariectomized, vehicle-injected controls. These data indicate that developmental exposure to PBDE 99 at doses devoid of general toxicity, affects the regulation of estrogen target genes in uterus. Since PBDE 99 was detected in blood and adipose tissue of adult offspring, these effects may result from interactions with developmental processes, adult functions, or a combination of both.

Adipose Tissue↗

Rat-dietary fructose and the intestinal distribution and growth of Moniliformis (Acanthocephala).

The numbers, distribution in the small intestine, sexual development and growth (dry weight) of 5-week-old Moniliformis dubius (Acanthocephala) were investigated experimentally in adult, female CFHB rats fed on theoretically isoenergetic diets containing known amounts of fructose in combination with either maize-oil fatty acids or maize oil and two concentrations of casein. There was no obvious development of M. dubius when there was no fructose in the host's diet. In contrast, estimated consumption by the host of as little as about 2 g of fructose during the 5-week infection period was accompanied by marked sexual dimorphism and weight gain in most of the M. dubius present. The dry weights of M. dubius of both sexes were positively correlated with fructose concentrations ranging from 0 to 2.5% (w/w) in the diets containing fatty acids. Significant, but not substantial, increases in M. dubius dry weight were observed as the dietary fructose concentration was raised to 12% (w/w). Similar trends were observed when the fructose was offered to the infected rats with maize oil, but in general, fructose added to the fatty-acid based diets supported most M. dubius growth. Differences in the distribution pattern of the worms in rats fed on the fatty-acid or maize-oil based diets were observed and their possible significance is discussed.

Acanthocephala↗

Dietary alpha-linolenic acid deficiency and early uterine development in female rats.

Feeding rats a purified diet containing peanut oil with a low alpha-linolenic acid [18:3(n-3)] content resulted in lower amounts of (n-3) polyunsaturated fatty acids, mainly docosahexaenoic acid [22:6(n-3)], greater amounts of docosapentaenoic acid [22:5(n-6)] in uterus phospholipids, and altered postnatal uterus development when compared with rats fed a diet containing peanut and rapeseed oils. Maximal differences in uterine growth, as measured by uterine weight, protein and DNA content, occurred between d 24 and 30 postpartum and disappeared near the end of sexual development (d 40). The induction of the progesterone receptor was not affected, and serum estradiol concentrations were not significantly reduced in deficient animals. Moreover, growth response of the uterus to low doses of 17 beta-estradiol (less than 5 micrograms/kg) was significantly reduced in ovariectomized animals fed the diet containing only peanut oil. However, the maximal response of the uterus, observed with higher 17 beta-estradiol doses (5-50 micrograms/kg), was not affected. Because the two diets used differed in the content of alpha-linolenic acid, it is likely that alpha-linolenic acid deficiency in animals fed the diet containing only peanut oil was the cause of the affected uterine development.

Animals↗