Onset Of Sexual Development Research Articles

Approach to the Patient: Central Precocious Puberty.

Central precocious puberty (CPP) classically refers to premature activation of the hypothalamic-pituitary-gonadal axis with onset of sexual development before the age of 8 years in girls and 9 years in boys. A decrease in the age of thelarche has been reported over the past several decades; however, the tempo of pubertal progression can be slower and adult height may not be adversely affected in many of the girls who experience thelarche at 6-8 years. Outside of this secular trend in the development itself, the past several decades have also brought about advances in diagnosis and management. This includes the widespread use of an ultrasensitive luteinizing hormone assay, decreasing the need for stimulation testing and a better understanding of the genetics that govern the onset of puberty. Additionally, management of CPP using gonadotropin-releasing hormone analogs (GnRHas) has changed with the advent of new longer-acting formulations. Emerging long-term outcomes of GnRHa administration with regards to obesity, cardiovascular risk factors and fertility are reassuring. Despite these advancements, clinical care in CPP is hampered by the lack of well-designed controlled studies, and management decisions are frequently not supported by clear practice guidelines. Data in boys with CPP are limited and this article focuses on the diagnosis and management of CPP in girls, particularly, in those who present with thelarche at the age of 6-8 years.

Treatment optimization inpubertalchildren with syndrome of biologically inactive growth hormone

Objective — to study the effect of analogues of gonadotropin-releasing hormone (aGRH) in combination with recombinant growth hormone (rGH) on the terminal growth of children with the syndrome of bioinactive growth hormone (GH) during puberty. Materials and methods. The study included 46 children with bioinactive GH and the onset of sexual development at the age from 10 to 12 years, who were divided into 2 groups. Group 1 consisted of 21 patients who received rGH in combination with aGRH. The comparison group (group 2) consisted of 25 children, which were used only rGH. The criterion for the prescription of aGRH therapy was the confirmation of rapid progress of the sexual development with an unsatisfactory growth prognosis. To inhibit the sexual development, an analogue of luliberin — tryptoreline was used. Results and discussion. At the beginning of treatment, the standard deviation (SD) in patients of group 1 was (–2.6 ± 0.6) SD, while in group 2 it was (–2.4 ± 0.7) SD. Against the background of treatment in group 1, SD scores differed significantly from baseline in boys and girls, (p < 0.01 and p < 0.05 respectively), as opposed to SD in group 2, which had no significant differences with baseline values before treatment. The difference in growth between terminal and expected growth (EG) among patients of group 1 in boys was (15.02 ± 0.9) cm, and in girls — (14.55 ± 1.1) cm, which is significantly higher than in patients of group 2 (p < 0.01), where the corresponding difference was (10.32 ± 0.9) cm for boys and (8.2 ± 1.2) cm for girls. Patients who used rGH in combination with aGRH had significantly better terminal growth in comparison with expected growth, in contrast to children taking only rGH. Conclusions. The use of aGRH in combination with rGH is an effective and safe treatmentof patients with the syndrome of bioinactive GH with early onset puberty, which significantly improves the terminal growth of patients regardless of gender, as compared to rGH monotherapy. After withdrawal of aGRHa complete restoration of sexual function occurs.

Functional Analysis of Mating Type Genes and Transcriptome Analysis during Fruiting Body Development of Botrytis cinerea.

ABSTRACTBotrytis cinerea is a plant-pathogenic fungus producing apothecia as sexual fruiting bodies. To study the function of mating type (MAT) genes, single-gene deletion mutants were generated in both genes of the MAT1-1 locus and both genes of the MAT1-2 locus. Deletion mutants in two MAT genes were entirely sterile, while mutants in the other two MAT genes were able to develop stipes but never formed an apothecial disk. Little was known about the reprogramming of gene expression during apothecium development. We analyzed transcriptomes of sclerotia, three stages of apothecium development (primordia, stipes, and apothecial disks), and ascospores by RNA sequencing. Ten secondary metabolite gene clusters were upregulated at the onset of sexual development and downregulated in ascospores released from apothecia. Notably, more than 3,900 genes were differentially expressed in ascospores compared to mature apothecial disks. Among the genes that were upregulated in ascospores were numerous genes encoding virulence factors, which reveals that ascospores are transcriptionally primed for infection prior to their arrival on a host plant. Strikingly, the massive transcriptional changes at the initiation and completion of the sexual cycle often affected clusters of genes, rather than randomly dispersed genes. Thirty-five clusters of genes were jointly upregulated during the onset of sexual reproduction, while 99 clusters of genes (comprising >900 genes) were jointly downregulated in ascospores. These transcriptional changes coincided with changes in expression of genes encoding enzymes participating in chromatin organization, hinting at the occurrence of massive epigenetic regulation of gene expression during sexual reproduction.

Small RNA-mediated regulation of DNA dosage in the ciliate Oxytricha.

Dicer-dependent small noncoding RNAs play important roles in gene regulation in a wide variety of organisms. Endogenous small interfering RNAs (siRNAs) are part of an ancient pathway of transposon control in plants and animals. The ciliate, Oxytricha trifallax, has approximately 16,000 gene-sized chromosomes in its somatic nucleus. Long noncoding RNAs establish high ploidy levels at the onset of sexual development, but the factors that regulate chromosome copy numbers during cell division and growth have been a mystery. We report a novel function of a class of Dicer (Dcl-1)- and RNA-dependent RNA polymerase (RdRP)-dependent endogenous small RNAs in regulating chromosome copy number and gene dosage in O. trifallax. Asexually growing populations express an abundant class of 21-nt sRNAs that map to both coding and noncoding regions of most chromosomes. These sRNAs are bound to chromatin and their levels surprisingly do not correlate with mRNA levels. Instead, the levels of these small RNAs correlate with genomic DNA copy number. Reduced sRNA levels in dcl-1 or rdrp mutants lead to concomitant reduction in chromosome copy number. Furthermore, these cells show no signs of transposon activation, but instead display irregular nuclear architecture and signs of replication stress. In conclusion, Oxytricha Dcl-1 and RdRP-dependent small RNAs that derive from the somatic nucleus contribute to the maintenance of gene dosage, possibly via a role in DNA replication, offering a novel role for these small RNAs in eukaryotes.

Cloning, expression, and polymorphism at the 5ʹ-flanking region of the GnRH gene and their association with laying traits in Muscovy duck (Cairina moschata)

Gonadotropin-releasing hormone (GnRH), a neuropeptide, plays a vital role in the hypothalamus–pituitary–gonadal (HPG) axis. In vertebrates, GnRH is crucial for the onset of sexual development and the entire reproductive process. The purpose of this study was to identify genetic factors associated with egg-laying traits of Muscovy ducks.The full-length cDNA (474 bp) of Muscovy duck GnRH was obtained and characterised. It encodes 92 amino acids containing a 1-amino acid signal peptide cleavage site. Phylogenetic analysis revealed that Muscovy duck GnRH has a close relationship with Anas platyrhynchos GnRH.GnRH showed significantly different expression profiles between 4 developmental periods in the hypothalamus, pituitary, and ovary. The expression of GnRH in the laying period (36 weeks) was higher than at other periods in the three tissues. GnRH was widely expressed in 12 examined tissues of nesting and laying Muscovy ducks. In the hypothalamus, pituitary and gonads, the expression of GnRH was higher than in other tissues.In laying Muscovy ducks, the expression of GnRH in the hypothalamus, pituitary, ovary, muscular stomach, pancreas, heart, duodenum and spleen was significantly higher than in nesting dusks. Differences were detected in the liver and glandular stomach between laying ducks and nesting ducks. Differences between the kidney and lung were not significant.In the pituitary, the GnRH and GnRH receptor (GnRHR) genes shared the same expression profiles during 4 time points. Both genes had the highest expression at 36 weeks of age.A mutation (g.206G > A) in the 5ʹ-flanking region was associated with egg-laying performance. Individuals with genotype GG had better egg-laying performance than the individuals with genotype AA. GnRH may be used as a marker gene for laying performance in the Muscovy duck.

Multiple layers of temporal and spatial control regulate accumulation of the fruiting body-specific protein APP in Sordaria macrospora and Neurospora crassa

During fungal fruiting body development, specialized cell types differentiate from vegetative mycelium. We have isolated a protein from the ascomycete Sordaria macrospora that is not present during vegetative growth but accumulates in perithecia. The protein was sequenced by mass spectrometry and the corresponding gene was termed app (abundant perithecial protein). app transcript occurs only after the onset of sexual development; however, the formation of ascospores is not a prerequisite for APP accumulation. The transcript of the Neurospora crassa ortholog is present prior to fertilization, but the protein accumulates only after fertilization. In crosses of N. crassa Δ app strains with the wild type, APP accumulates when the wild type serves as female parent, but not in the reciprocal cross; thus, the presence of a functional female app allele is necessary and sufficient for APP accumulation. These findings highlight multiple layers of temporal and spatial control of gene expression during fungal development.

Final Height in Girls With Central Idiopathic Precocious Puberty Treated With Gonadotropin-Releasing Hormone Analog and Oxandrolone

Central precocious puberty (CPP), the onset of sexual development before age 8 in girls, reflects early activation of the hypothalamic-pituitary-gonadal axis and currently is treated with a gonadotropin-releasing hormone analog (GnRHa). One of the goals of such treatment is to slow bone maturation and thereby increase final adult height. Some patients, however, grow at a less than optimal rate and become short-statured as a result. This open-label study was carried out in 20 girls with CPP who experienced marked growth deceleration (height velocity below the 25th centile for age) during GnRHa treatment. All of them continued to receive 3.75 mg Leuprorelina intramuscularly at monthly intervals. Ten girls (group 1) also received, by mouth, 0.06 mg/kg daily of the androgen oxandrolone (Ox). The remaining 10 girls (group 2) continued to receive only the GnRHa. The groups were matched for chronologic age, bone age, the duration of GnRH analog treatment (averaging 5 years), and the degree of growth deceleration. In both groups, plasma concentrations of luteinizing hormone and follicle-stimulating hormone remained suppressed, rising to appropriate levels within 18 months of the time that GnRHa treatment stopped. Menarche occurred an average of 16 and 18 months after treatment stopped in groups 1 and 2, respectively. Bone age progressed regularly in both groups. When GnRHa treatment began, predicted adult height (PAH) in patients in group 1 did not differ significantly from that recorded at the time Ox was added. At the end of combined treatment, PAH was significantly higher than at the time of diagnosis and at the start of GnRHa therapy. Final height significantly exceeded target height in patients in group 1, was similar to the PAH at the end of treatment, and was significantly higher than when GnRHa treatment began. In patients in group 2, PAH at the start of treatment did not differ significantly from that at the time GnRHA therapy ended. Their final height was similar to the PAH at both the beginning of treatment and its end. Target height was not reached and it significantly exceeded final height. The gap between pretreatment PAH and final height in patients in group 1 differed significantly from that in patients in group 2 (7.8 vs -3.8 cm). The same was the case for the difference between final height and target height (4.6 vs -4.2 cm). No adverse effects were noted in either treatment group. Treatment did not alter circulating levels of insulin-like growth factor I. Adding oxandrolone to GnRHa treatment in girls with idiopathic CPP whose growth has markedly decelerated improves final height without causing significant side effects. In the present study, combined treatment permitted the girls to reach a final height greater than the target height. This was not the case for girls who continued to receive only GnRHa whose final height was lower than target height.

Histrelin Hydrogel Implant ??? Valera

Valera Pharmaceuticals, formerly Hydro Med Sciences, is developing a once-yearly Histrelin Hydrogel Implant [Histrelin implant, LHRH-Hydrogel implant, RL 0903, SPD 424, Vantas], a subcutaneous (s.c.) reservoir device capable of long-term delivery of histrelin at constant release rates for the treatment of prostate cancer. Histrelin is a luteinising hormone-releasing hormone agonist (LHRH). A different formulation of the LHRH implant is currently in development for the treatment of central precocious puberty (CPP). On 4 September 2003, Hydro Med Sciences announced that it had changed its name to Valera Pharmaceuticals. Shire Pharmaceuticals had an option to market and distribute the histrelin implant outside the US, but in a realigned agreement announced in January 2002, Shire stated that HydroMed (now Valera) would be responsible for concluding the phase III studies, filing for regulatory approval and producing the implant, while also gaining marketing rights in the US. Shire has no further involvement in development, but retains an option to market and distribute the product outside the US. The product is available for rest-of-the-world licensing through Valera Pharmaceuticals' business development division. Paladin Labs has received the exclusive rights for the sale and marketing of histrelin hydrogel implant in Canada. Valera Pharmaceuticals will have the responsibility for manufacturing and completing development of the product. In July 2004, Paladin announced it had filed for regulatory approval with Health Canada for the treatment of prostate cancer. Phase III trials have been conducted and initially involved two open-labelled, randomised, parallel studies that compared the hydrogel implant with the active comparators, leuprorelin acetate 22.5 mg depot (TAP Pharmaceutical's Lupron Depot) and a 3-month implant of goserelin acetate (Astra Zeneca's Zoladex). However, because of financial constraints, HydroMed discontinued recruitment in a phase II European study and could not rationalise keeping the comparator arm of the phase III study. The US FDA then gave permission to continue the US part of the programme without the comparator arm, but with appropriate increases in the patient sample size. Patient enrolment in the phase III trial (US and Canada) was completed in July 2002. Valera Pharmaceuticals believes the product may have advantages over standard prostate cancer treatments including reduced costly surgical procedures, lower dosing, increased patient compliance and peace-of-mind, as well as potentially less cost to the patient. The phase III studies were completed in the second half of 2003.CPP arises from the increased release by the pituitary gland hormone gonadotropins and is characterised by an early onset of sexual development in pre-adolescents. Currently, the treatment of CPP involves injections of synthetic gonadotropic hormone-releasing factor agonists such as Supprelin (histrelin acetate) and TAP Pharmaceutical's Lupron Depot-Red (leuprolide acetate) every 28 days, a potentially painful procedure. This treatment inhibits pituitary release of gonadotropins. Valera's histrelin implant is a compact, removable subcutaneous implant that can be applied under a local anaesthetic in doctor's surgery.

Stimulated growth hormone (GH) secretion in children with delays in pubertal development before and after the onset of puberty: relationship with peripheral plasma GH-releasing hormone and somatostatin levels.

A reduced GH secretion has often been shown in prepubertal children with delays in pubertal development. In order to study the mechanism underlying this finding, we evaluated peripheral circulating levels of GH, GHRH, and somatostatin (SRIH) before and after the onset of sexual development in a group of eight late maturing children (six boys, two girls), comparing the results with those obtained in two groups of five prepubertal and four pubertal short children with familial short stature. GH was measured by a two-site immunoradiometric assay. Both GHRH and SRIH were assayed by specific RIAs after an acetone-petrolether extraction from plasma. Our data showed a significant increase (P less than 0.001) in GH, GHRH, and SRIH levels (peak vs. basal values) in response to L-dopa administration in all groups. In pubertal children with delays in pubertal development GH and GHRH peak values (15.8 +/- 2.2 micrograms/L and 120 +/- 18 pg/mL, respectively) were significantly greater (P less than 0.001) than in the same subjects before puberty (8.2 +/- 0.9 micrograms/L and 79 +/- 9 pg/mL, respectively), whereas SRIH peak values did not significantly change (41 +/- 6 vs. 41 +/- 5 pg/mL; P = NS). Furthermore, prepubertal subjects with delays in pubertal development showed GH and GHRH peak values lower (P less than 0.001) than those of prepubertal subjects with FSS (13.3 +/- 1.8 micrograms/L and 120 +/- 13 pg/mL, respectively), whereas no statistical difference was present between the two groups of subjects after pubertal development (18.2 +/- 2.9 micrograms/L and 128 +/- 11 pg/mL, respectively). In conclusion, these findings support the assumption that in late maturing subjects during prepubertal period the decreased GH secretion may be ascribed to a reduced GHRH secretion, reversible with the onset of puberty, without change in circulating SRIH levels.

Influence of testosterone and/or luteinizing hormone releasing hormone analogue on precocious sexual development in the juvenile rainbow trout.

The influence of testosterone, luteinizing hormone releasing hormone (LHRH) agonist and combinations of these hormones on gonadotropic hormone (GtH) levels in the sexually immature trout was investigated. Both the steroid and releasing hormone preparations, testosterone in Silastic capsules and cholesterol-pelleted LHRH-A, were formulated for sustained release and long-term biological action following a single hormone implantation. Marked increases in pituitary GtH followed testosterone and/or testosterone and LHRH analogue treatment combined, but the low pituitary GtH level in controls remained unchanged after LHRH analogue administration alone. Plasma GtH titers increased with time after testosterone treatment, indicating a positive steroid feedback effect by androgen on GtH in the juvenile rainbow trout. When combined with testosterone treatment, LHRH analogue augmented plasma GtH levels compared to fish receiving testosterone treatment alone. In males the elevated plasma GtH levels were associated with testes stimulation and onset of spermatogenesis; in females, however, no significant stimulation of the ovaries was observed. It can be concluded from these studies that the testosterone stimulus is sufficient to induce onset of sexual development in immature males but not females. Whereas LHRH analogue releases GtH from the testosterone-primed trout pituitary, LHRH treatment alone under these conditions fails to stimulate the juvenile trout reproductive system.

Transient partial hGH deficiency in prepubertal children with delay of growth.

The hGH response to an ornithin or an insulin test was measured in 105 children from 11-18 yr old with delay of growth more than 2 SD. Besides 74 subjects with normal values and 7 with complete lack of response, 24 subjects exhibited a partial rise of GH. Most of the latter had decreasing growth rate and no sign of puberty. Out of 15 assessed for GH function after onset of puberty, 14 showed a normal response accompanying a markedly increased growth velocity. Four other subjects with partial response who were receiving sexual hormones for 48 hr before the second test showed a normal response also. An exogenous hGH treatment administered in two of these patients resulted in a marked and sustained growth increase far before entering puberty. The findings that plasma GH responses to stimulation tests is reduced in some children with decreasing growth rate before puberty and return to normal after onset of sexual development, would suggest a transient and functional defect in growth hormone secretion and the physiologic role of sexual hormones on GH release mechanism at that period of life.

Effect of androgenic and anabolic compounds on pseudocholinesterase activity in the liver and serum of the rat.

ABSTRACT Immature male and female rats have a similar basal level of pseudocholinesterase activity in the liver and serum. In male rats pseudocholinesterase activity declines sharply with the onset of sexual maturity, between the fourth and the fifth week, after which it remains more or less constant. In female rats, also coinciding with the onset of sexual development, the activity starts to rise between five and six weeks and then increases gradually up to twenty weeks. Castration of male rats results in an increase of the enzyme activity to the basal level, whereas subsequent injection of testosterone-propionate brings about a fall to the level found in adult male rats. Three androgenic/anabolic steroids were compared for their effects on pseudocholinesterase activities in liver and serum of male castrates, viz. testosterone-propionate, testosterone-phenyl-propionate and nor-testosterone-phenyl-propionate, the latter known to possess a relatively high anabolic potency. This was confirmed in our experiments by direct protein determinations in liver and serum and by levator ani muscle/seminal vesicle ratios. At a dose of 1 mg daily for ten days, the former two substances had a similar considerable effect on pseudocholinesterase activity, whereas the effect of the nor-derivative was much smaller. A response similar to that of one milligram of testosterone-propionate was only obtained with 4 mg of the nor-derivative. At that dose level the androgenic effect of the nor-derivative on the seminal vesicles is somewhat less than that of 1 mg testosterone-propionate daily. It is concluded that the cholinesterase activity lowering effect of the compounds investigated is correlated with their androgenic rather than with their anabolic potencies.