Induction Of Sexual Maturation Research Articles

Discovery and Characterization of Novel Anti-schistosomal Properties of the Anti-anginal Drug, Perhexiline and Its Impact on Schistosoma mansoni Male and Female Reproductive Systems.

BackgroundSchistosomiasis, one of the world’s greatest human neglected tropical diseases, is caused by parasitic trematodes of the genus Schistosoma. A unique feature of schistosome biology is that the induction of sexual maturation as well as the maintenance of the differentiation status of female reproductive organs and egg production, necessary for both disease transmission and pathogenesis, are strictly dependent on the male. The treatment and most control initiatives of schistosomiasis rely today on the long-term application of a single drug, praziquantel (PZQ), mostly by campaigns of mass drug administration. PZQ, while very active on adult parasites, has much lower activity against juvenile worms. Monotherapy also favors the selection of drug resistance and, therefore, new drugs are urgently needed.Methods and FindingsFollowing the screening of a small compound library with an ATP-based luminescent assay on Schistosoma mansoni schistosomula, we here report the identification and characterization of novel antischistosomal properties of the anti-anginal drug perhexiline maleate (PHX). By phenotypic worm survival assays and confocal microscopy studies we show that PHX, in vitro, has a marked lethal effect on all S. mansoni parasite life stages (newly transformed schistosomula, juvenile and adult worms) of the definitive host. We further demonstrate that sub-lethal doses of PHX significantly impair egg production and lipid depletion within the vitellarium of adult female worms. Moreover, we highlighted tegumental damage in adult male worms and remarkable reproductive system alterations in both female and male adult parasites. The in vivo study in S. mansoni-patent mice showed a notable variability of worm burdens in the individual experiments, with an overall minimal schistosomicidal effect upon PHX treatment. The short PHX half-life in mice, together with its very high rodent plasma proteins binding could be the cause of the modest efficacy of PHX in the schistosomiasis murine model.Conclusions/SignificanceOverall, our data indicate that PHX could represent a promising starting point for novel schistosomicidal drug discovery programmes.

Induction of sexual maturation of the female honeycomb grouper, Epinephelus merra, in the non-breeding season by modulating environmental factors with GnRH analogue implantation

Grouper culture assumes importance like any other economically important food fish aquaculture practice in Japan. Regular availability of sexually mature brood stock at appropriate time and stable seed production are considered vital for prolific fish farming. Despite the fact that previous studies have induced sexual maturation and spawning in some grouper species that had ovaries with vitellogenic or full-grown mature oocytes, little attention has been paid to artificial induction of sexual maturation and spawning of immature fish in off-spawning season. Developing such a method will promote grouper aquaculture immensely. In an aim to facilitate such a task, we used one of the popular experimental model fishes, the honeycomb grouper, Epinephelus merra, to induce sexual maturation during non-breeding season by modulating environmental factors with gonadotropin-releasing hormone analogue (GnRHa) implantation using osmotic pump. We performed three different experiments flanking various periods of non-breeding season under artificial/natural photothermal conditions with or without GnRHa implantation. Induction of sexual maturation is scored by the presence of vitellogenic to mature oocytes after various treatments in addition to the data of gonado-somatic index and plasma estradiol levels. Among various treatments, high water temperature with long photoperiod conditions induced sexual maturation in immature groupers during October to December. Implantation of GnRHa to these fishes induced sexual maturation at all periods of non-breeding season tested in this study. In fact some of the fishes belonging to these groups have even spawned during the course of treatment indicating the effectiveness of the treatments. On the other hand, neither GnRHa implantation alone nor exposure to natural photothermal conditions evoked sexual maturation. Likewise, combination of short and long photoperiod with low to high water temperature exposure over the duration period was found to be least effective with or without GnRHa implantation. Similarly, exposure to long photoperiod or high water temperature alone did not induce sexual maturation. Hence, combination of artificial photothermal conditions with GnRHa implantation seems to be a decisive method to induce sexual maturation in immature fish. Based on these results, we demonstrate a superior strategy for successful breeding of sexually immature marine teleost fish during non-breeding season by modulating environmental variables with GnRHa implantation.

Induction of Sexual Maturation in Wild Female European Eels (Anguilla anguilla) in Darkness and Light

Sexual maturity was induced in wild silver eel females of the European eel (Anguilla anguilla) using a protocol similar to that successfully used for Anguilla japonica. Eels were injected for sixteen weeks with increasing doses of carp pituitary extract (10, 20, 30, and 40 mg CPE/kg body wt) and kept in natural light or completely dark conditions. In both groups, final oocyte maturation and ovulation were induced by injection of 17,20 h-dihydroxy-4-pregnen-3-one (DHP) at 2 mg/g body wt. All sixty eels turned out to be silver and actively migrant (58 in stage V and two in stage IV), showing a particularly high eye index (15.75±1.40), and distributed within three age classes (7-9 years). In the group kept in darkness, one of the four females ovulated 12 h after DHP injection in the thirteenth week. The remaining three females received the final (16th) CPE injection and ovulated 12-36 h after the DHP injection. In the group kept in light, two of the four females received the 16th CPE injection and ovulated 12-36 h after the DHP injection; the remaining two did not ovulate within 36 h post DHP injection. The total number of eggs released by the group kept in darkness (1,485,600) was significantly higher than that of the group kept in light (274,000). There was no mortality during the experiment.

Effects of continuous administration of human chorionic gonadotropin, salmon pituitary extract, and gonadotropin-releasing hormone using osmotic pumps on induction of sexual maturation in male Japanese eel, Anguilla japonica

The purpose of this study was to examine the effects of continuous administration of human chorionic gonadotropin (HCG), salmon pituitary extract (SPE), and gonadotropin-releasing hormone analogue (GnRHa) via an osmotic pump with a long-term sustained hormone-release system on the induction of sexual maturation in male Japanese eels ( Anguilla japonica). Implantation of a single HCG-loaded osmotic pump induced spermatogenesis and increased the gonadosomatic index (GSI) values at 35–42 days postimplantation; GSI values were higher (10.7 ± 1.0) than those of the fish implanted with a cholesterol pellet containing HCG (2.4 ± 0.6). Implantation of an SPE-loaded osmotic pump also stimulated spermatogenesis, although the GSI values were lower than those of the fish implanted with the HCG-loaded osmotic pump. Implantation of a single osmotic pump loaded with various doses of GnRHa (0.94, 1.86, or 3.75 µg/day) did not stimulate spermatogenesis. The GSI values and milt weight of the HCG-administered eels significantly increased at a dosage of 5 IU/day in a dose-dependent manner up to 50 IU/day. Sperm motility was not significantly different among the eels treated with different doses of HCG. Therefore, implantation of a single osmotic pump loaded with HCG (50 IU/day) is a reliable method for inducing spermatogenesis and spermiation in sexually immature Japanese eels.

Estimation of gonadal status of Japanese female eel Anguilla japonica by a single injection of salmon pituitary extract

Cultivated eels often either lack a part of the ovary (abnormal) or do not have any gonadal tissue (completely sterile). These abnormalities may cause a failure of induction of sexual maturation of female eels. In order to effectively induce sexual maturation and obtain good quality eggs, female eels having normal ovaries should be selected before induction of maturation. The present study examined effects of injection of salmon pituitary extract (SPE) on serum estradiol-17β levels to estimate gonadal status of sexually immature Japanese eels. At the initial stage (just prior to SPE injection), serum estradiol-17β levels were low and no significant difference was observed among eels possessing the different gonad types (normal, abnormal, and sterile), suggesting that gonadal status cannot be estimated by the measurement of serum estradiol-17β levels. A single injection of SPE significantly increased serum estradiol-17β levels in eels possessing normal and abnormal ovaries, but not in sterile eels. Serum estradiol-17β levels significantly increased from 24 h and were high on day 3. These data indicate that eels possessing ovaries can be distinguished from sterile eels by measurement of serum estradiol-17β between 1 and 3 days after a single injection of SPE.

The testis histology of artificially maturated European eel (Anguilla anguillaL.) at the end of sexual maturation, and spermatozoa ultrastructure in freshwater rearing

The artificial induction of sexual maturation of European eel males was carried out by using weekly hCG administrations. Histological pictures showed that the testis tissues developed and regressed naturally and no pathological changes took place under the conditions of artificial rearing in freshwater. According to light and electron microscopic investigations the morphology and motility of the spermatozoa of males kept in freshwater proved to be similar to those in seawater. The authors suppose that freshwater rearing of males is not a barrier factor in the artificial propagation of European eels.

Effects of various hormones on the sexual maturity of European eel (Anguilla anguilla L.) females from farm and lakes.

Previously described and alternative methods of the induction of sexual maturation in the European eel were investigated. Weekly administrations of a gonadoliberin agonist (nnRH-A=D-Phe6-GnRH-Ea) did not induce statistically significant effect on the gonads of treated eels in none of the dosages used (0.1 microg and 10 microg/fish). Carp pituitary extract and carp pituitary extract together with a dopamine antagonist caused considerable external changes (increase in eye size) and significant gonadal development in two treatment groups: wild and cultivated stocks. The induction of the ovulation by double amount of CP and gonadoliberin agonist with dopamine antagonist mixture was not successful in a wild stock. Fertilisation of stripped eggs of farm eel was attempted unsuccessfully in, due to low egg quality. An advanced phase of the sexual maturation process could be induced in specimen infected by Anguillicola crassus indicating, that nematode infection is not a limiting factor in the artificial propagation of the European eel.

A low-fat, whole-food vegan diet, as well as other strategies that down-regulate IGF-I activity, may slow the human aging process

A considerable amount of evidence is consistent with the proposition that systemic IGF-I activity acts as pacesetter in the aging process. A reduction in IGF-I activity is the common characteristic of rodents whose maximal lifespan has been increased by a wide range of genetic or dietary measures, including caloric restriction. The lifespans of breeds of dogs and strains of rats tend to be inversely proportional to their mature weight and IGF-I levels. The link between IGF-I and aging appears to be evolutionarily conserved; in worms and flies, lifespan is increased by reduction-of-function mutations in signaling intermediates homologous to those which mediate insulin/IGF-I activity in mammals. The fact that an increase in IGF-I activity plays a key role in the induction of sexual maturity, is consistent with a broader role for-IGF-I in aging regulation. If down-regulation of IGF-I activity could indeed slow aging in humans, a range of practical measures for achieving this may be at hand. These include a low-fat, whole-food, vegan diet, exercise training, soluble fiber, insulin sensitizers, appetite suppressants, and agents such as flax lignans, oral estrogen, or tamoxifen that decrease hepatic synthesis of IGF-I. Many of these measures would also be expected to decrease risk for common age-related diseases. Regimens combining several of these approaches might have a sufficient impact on IGF-I activity to achieve a useful retardation of the aging process. However, in light of the fact that IGF-I promotes endothelial production of nitric oxide and may be of especial importance to cerebrovascular health, additional measures for stroke prevention–most notably salt restriction–may be advisable when attempting to down-regulate IGF-I activity as a pro-longevity strategy.

Inhibin B in males with gonadotropin-releasing hormone (GnRH) deficiency: changes in serum concentration after shortterm physiologic GnRH replacement--a clinical research center study.

To examine the role of inhibin B in the feedback regulation of FSH secretion in the human male, we determined serial levels in 18 men with idiopathic hypogonadotropic hypogonadism (IHH) during their initial 8 weeks of GnRH replacement. Pulsatile GnRH was administered every 2 h, with the dose increased at 2-week intervals (5-50 ng/kg/bolus). Every 2 weeks, sera were assayed for inhibin B, FSH, LH, and testosterone. Serial comparisons were performed within the IHH group as well as vs. normal men (n = 20). The baseline inhibin B level in IHH patients averaged 68 +/- 11 pg/mL (mean +/- SEM), significantly less than that in normal men (239 +/- 14 pg/mL; P < 0.001). After 8 weeks of pulsatile GnRH, inhibin B levels in the IHH patients increased significantly to 118 +/- 14 pg/mL (P = 0.003). During GnRH replacement, FSH concentrations correlated negatively with inhibin B concentrations at all doses. Patients previously treated with testosterone began with somewhat lower inhibin B levels but demonstrated a significantly greater increase in serum concentrations than patients who had received prior gonadotropin or GnRH therapy. A history of cryptorchidism did not have a significant impact on inhibin B concentrations before or during GnRH replacement. The low inhibin B levels in IHH men at baseline and their prompt increase in response to pulsatile GnRH suggest acute regulation by gonadotropin stimulation of the testis. The variation in inhibin B levels at baseline and in response to GnRH suggest that prior gonadotropin exposure and seminiferous tubular development also modulate inhibin B secretion. The consistent negative correlation between FSH and inhibin B during the induction of sexual maturation with GnRH supports the role of gonadal inhibin B secretion as an important endocrine regulator of FSH in the human male.

Pituitary and gonadal responsiveness is enhanced during GnRH-induced puberty.

We hypothesized that the hypothalamic gonadotropin-releasing hormone (GnRH) signal that initiates sexual maturation is further amplified at both the pituitary and gonadal levels during puberty. To test this theory, six GnRH-deficient men were monitored during administration of exogenous GnRH at a physiological frequency for greater than or equal to 9 mo. GnRH doses were progressively increased until normal testosterone (T) concentrations and secondary sexual development were achieved. This "optimized" dose of GnRH was then sustained for at least 6 mo to allow maturation of the hypothalamic-pituitary-gonadal axis. The GnRH dose was then progressively decreased to a level that had been unable to stimulate normal T secretion before sexual maturation. Changes in pituitary responsiveness were analyzed in four of the six men by comparing gonadotropin responses to identical doses of GnRH before and after sexual maturation. Mean serum luteinizing hormone and follicle-stimulating hormone levels as well as luteinizing hormone pulse amplitudes were greater after the induction of sexual maturation than before despite identical doses of GnRH. Both pituitary and gonadal responsiveness was then analyzed in the remaining two subjects by choosing periods of evaluation where endogenous gonadotropin levels were matched before and after the period of sexual maturation. Serum T concentrations were greater after sexual maturation than before despite equivalent gonadotropin input to the testes and LH pulse amplitudes. Thus the testicular responsiveness to gonadotropins increased during sexual maturation. After initiation of puberty by GnRH secretion, amplification at both the pituitary and gonadal levels contributes to sexual maturation in the human.

Reproduction of Penaeus kerathurus using eyestalk ablation

In a preliminary experiment on the induction of sexual maturity in Penaeus kerathurus by unilateral eyestalk ablation, spawning was obtained in 94% of the females treated. The time necessary to reach the spawning stage appeared to be closely related to the stage of natural physiological development of the gonads and the length of the photoperiod, the period between ablation and spawning decreasing from 69 days for females treated in November to about 10 days for females treated at the beginning of their natural reproductive period in May/June. Spawning after treatment was repeated up to eight times, sometimes at intervals of less than 10 days, without showing a decrease in the amount of fertile spawn. The mean number of fertile eggs per spawn was 78.400, which is not significantly different from the corresponding mean obtained previously after thermal stimulation of almost mature breeders; the hatching percentage, 67%, was also similar. Often only the anterior and median lobes of the ovaries are included in the spawning process. The discharged spawn is nearly always completely free of matrix material. It is anticipated that induction by eyestalk ablation could allow a considerable extension of the growing season and of the area suitable for culture.

La maturation sexuelle chez les m�les d'Octopus vulgaris (Cephalopoda: Octopoda), en relation avec le r�flexe photo-sexuel

The role of light in induction of sexual maturation in male Octopus vulgaris has been studied on experimentals reared in the laboratory. Experiments were carried out during January, February and March, the time of the year when females do not breed or are just beginning to breed. Males (20 to 500 g) were artificially illuminated for 8 or 16 h/day or kept in complete darkness. Their gonads were compared with those of wild specimens killed a few hours after capture. In the Mediterranean Sea, under natural conditions, O. vulgaris males of less than 150 g never display sexual maturity; under our experimental conditions, young males from 70 g onwards, illuminated 16 h daily, show gonad development. Males of over 150 g, illuminated 16 h daily, have a larger number of spermatophores than wild specimens of individuals illuminated 8 h daily. O. vulgaris reared in complete darkness are sexually more mature than wild individuals. An hypothesis on induction of sexual maturation in the Cephalopoda is proposed.

HEREDITARY ISOLATED SOMATOTROPIN DEFICIENCY: EFFECTS OF HUMAN GROWTH HORMONE ADMINISTRATION

The clinical and laboratory appraisal of a familial isolated growth hormone deficiency is reported. The lack of consanguinity and the absence of other short members in the family speak for the occurrence of a mutation in the father which he then transmitted as a dominant trait to four of his seven children. Growth hormone administration not only resulted in an increase in linear growth in those members of the family whose epiphyses were not closed, but also the rapid appearance of secondary sexual characteristics in the 18-year-old sexually infantile female and an increase of body hair and libido in both the father and the 21-year-old sexually mature, staturally retarded sister. These observations strengthen the contention that the diagnosis of hypopituitarism cannot be excluded on the basis of eventual sexual development in individuals whose statural growth is retarded. It is concluded that induction of sexual maturation during growth hormone therapy is not related to increased pituitary gonadotropin release. Growth hormone administration appeared to have no effect on thyroid function or on adrenal responsiveness to administered ACTH and metyrapone. An antiinsulinogenic effect of growth hormone was demonstrated during both oral and intravenous glucose tolerance tests.