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PubMed2003

Pubertal development in patients with McCune-Albright syndrome or pseudohypoparathyroidism.

Gain or loss of function mutations of the GNAS1 gene lead to McCune-Albright syndrome (MAS) or pseudohypoparathyroidism Ia (PHP-Ia), respectively. Patients with MAS, caused by a post-zygotic missense mutation leading to constitutive activation of Gs alpha, suffer from gonadotropin-independent precocious puberty, and delayed or incomplete sexual development and reproductive dysfunction is found in women with PHP-Ia, an inherited disorder caused by deficient expression or function of the Gs alpha protein. In females with MAS, 50% developed precocious puberty by the age of 4 years, the remaining between 4 and 8 years. Peripheral precocious puberty is often atypical and characterized by alternate periods of rapid progression and regression of pubertal development; menstrual bleeding may occur before breast development. Ovarian cyst growth and regression is often described as a sign of ovarian follicle hyperactivation. Notwithstanding this clinical heterogeneity, a subset of patients with MAS develop relentlessly progressive precocious puberty ultimately resulting in premature epiphyseal fusion and reduced adult stature. Long-term information on reproductive function has been obtained in females: some patients had regular menses without ovarian cysts on pelvic US scan, whereas others were oligomenorrheic and showed recurrent ovarian cysts. In males with MAS, precocious puberty occurred in three patients between 4 and 9 years of age. In one patient, long-term follow-up demonstrated normal plasma testosterone and gonadotropin values at the age of 17 years. On testicular sonography, multiple hyperechogeneic spots were found in both testicles (snow-storm appearance). Female patients with PHP-Ia were oligomenorrheic or amenorrheic; more than half had delayed or incomplete sexual development, They were mildly hypoestrogenic with normal to slightly elevated serum gonadotropin levels. These clinical and biochemical findings indicate partial resistance of the theca and granulosa cells of the ovary to gonadotropins due to deficient Gs alpha activity. Responsiveness might be sufficient to promote some degree of follicular development and steroid secretion, but insufficient to induce ovulation

Amenorrhea↗
PubMed2002

The little difference: in vivo analysis of pheromone discrimination in Schizophyllum commune.

The B mating type of Schizophyllum commune is defined by a multi-specific pheromone/receptor system. The interaction of pheromone receptors and their ligands, encoded by the Balpha locus, triggers sexual development. The receptors belong to the family of G protein-coupled seven-transmembrane-domain receptors, while the ligands are small lipopeptide pheromones. A productive interaction is only possible between molecules derived from different specificities. There is no induction of sexual development by pheromones of self-specificity. Since there are nine versions of different specificity for pheromones and receptors in Balpha, this system can be used to study multi-ligand discrimination. We investigated pheromone discrimination using chimeric receptor molecules and the influence of single point mutations on activation profiles of the receptor.

Base Sequence↗
PubMed2005

Evaluation of a two-generation reproduction toxicity study adding endpoints to detect endocrine disrupting activity using vinclozolin.

A two-generation reproduction toxicity study in rats adding extra endpoints to detect endocrine disrupting activity was conducted using vinclozolin by dietary administration at 0, 40, 200, and 1000 ppm, for investigation of its utility. The extra endpoints included anogenital distance (AGD), nipple development, sexual maturation (vaginal opening and preputial separation), estrous cycle, spermatogenesis, sex organ weights, and blood hormone concentrations (thyroid and sex hormones). Hepatic drug-metabolizing enzyme activities were also measured. The results revealed changes due to vinclozolin in the AGD, nipple development, sexual maturation, sex organ weights, and blood sex hormone concentrations in males of both parental animals and offspring, even at the lowest dose of 40 ppm, confirmed by results for the classical endpoints of histopathological examination at 200 ppm and mating at 1000 ppm. The effects on parental males included increased pituitary and testis weights, and decreased epididymis weights at 1000 ppm in both generations, and decreased prostate and epididymis weights at 200 and 1000 ppm and seminal vesicle weights at 1000 ppm in F1 males. Histopathological examination revealed hypertrophy of the basophilic cells in the pituitary at these two doses, and diffuse hyperplasia of the testicular interstitial cells and atrophy of the seminal vesicle mucosa at 1000 ppm in F0 and F1 males. In addition, F1 males demonstrated decrease in prostate fluid at 200 and 1000 ppm. Blood hormone analysis revealed increases in LH, FSH, testosterone, and DHT in F0 and F1 males at 1000 ppm. General toxicological effects included suppressed body weight gain in F0 and F1 females and in F1 males, and reduced food consumption in F0 and F1 females at 1000 ppm. Histopathological examination revealed centrilobular hepatocellular hypertrophy in males at 200 and 1000 ppm and in females at 1000 ppm, increased lipid droplets in the adrenal zona fasciculata and zona glomerulosa in males at 200 and 1000 ppm and in females at 40 ppm and above, and hyperplasia of ovarian interstitial cells and vacuolation of lutein cells in females at 1000 ppm in both generations. Almost all the tissue changes were accompanied by changes in weights. Decreases in T3 and/or T4 were observed in both sexes and generations at 1000 ppm and in F0 females at 200 ppm. However, these were presumed to be secondary to induction of hepatic drug-metabolizing enzymes, activities being increased for a range of enzymes in both sexes and generations at 1000 ppm. Rise in BROD activity was the most prominent, suggesting that vinclozolin mainly induces CYP2B. As for effects on reproductive function, a marked decrease in the fertility index caused by male infertility was observed in F1 animals at 1000 ppm. However, no effects on spermatogenesis were seen in either F0 or F1 males. Since cleft prepuce and penile hypoplasia were observed in infertile males, it is probable that the cause of infertility in F1 males was related to morphological abnormalities in the external genitalia. Vinclozolin did not affect the estrous cycle, mating, fertility, pregnancy, parturition, or nursing behavior in either F0 or F1 females. In offspring, in addition to suppressed body weight gain in F1 males and females at 1000 ppm, neonatal toxicity caused by antiandrogen activity of vinclozolin was observed in F1 and F2 males. Effects included shortened AGD in F1 males at 1000 ppm and in F2 males at 200 and 1000 ppm, and nipple/areola remnants in F1 males at 200 and 1000 ppm and in F2 males at 40 ppm and above. In addition, decreased epididymis weights at weaning and morphological abnormalities of the external genitalia, including cleft prepuce, penile hypoplasia, and vaginal pouch, were seen in F1 and F2 males at 1000 ppm.

Administration, Oral↗
PubMed1993

Oxandrolone in constitutional delay of growth: analysis of the growth patterns up to final stature.

In order to evaluate the effects of low-dosage, 6-12 months course of oxandrolone treatment in constitutional delay of growth, we compared the growth responses on treatment, the pattern of sexual development and pubertal growth events, up to final stature of 11 prepubertal boys, aged 10.6-14.1 yr, with those of 11 prepubertal, age-matched untreated controls. Treatment caused a significant increase of height velocity, from 4 to 9 cm/yr, and a significant acceleration of bone maturation, without affecting the timing of onset of puberty, the progression of sexual development or the onset of pubertal growth spurt. On the other hand, oxandrolone induced an earlier skeletal growth arrest but did not affect the expected final height. Treated boys showed an adult stature not significantly different from that of control subjects. Our data suggest that 6 months-1 year, low dosage oxandrolone treatment in constitutionally delayed growth has no significant effect on the pattern of pubertal growth, nor on the rate of sexual maturation or on final height.

Adolescent↗
PubMed1994

Experimental perturbation of the development of sexual size dimorphism in the mouse skeleton.

BALB/c mice were raised for 30 days under nine treatment regimens to determine their effects on sexual dimorphism for size of the femur and of the body. Treatment groups were divided into three experiments: 1) burrowing in a high litter cage; eight times normal gravity for a total of one hour per day; a voluntary exercise control. 2) Unilateral femoral and sciatic nerve ablation; the opposite unoperated leg. 3) Swimming exercise; anabolic steroid; swimming and anabolic steroid; normal exercise control. Traits measured were body weight gain and thirteen femoral characters: moment at failure, length, cross-sectional area, anteroposterior and lateromedial diameters of the cross section, wall thickness for all four quadrants of the shaft, moments of inertia of the cross section in the anteroposterior and lateromedial directions, deflection of the shaft before failure, and total mineral content. Sexual dimorphism of the traits studied varied significantly with treatment. The greatest dimorphism was seen in the controls and the burrowing group. The least dimorphism was seen in the eight times gravity, the steroid, and the exercise and anabolic steroid groups. Reduction in the extent of sexual dimorphism was not correlated with a reduction in the loading regimen but rather seemed mediated by systemic changes in physiology brought on by several factors. Change in the amount of sexual dimorphism for size from the control reflects change in growth rates for males and females in response to different treatments. Change in growth rates of juvenile males and females will likely result in changes in the size of femoral characters and body weight in the adult. Change in the size of femoral characters affects the strength of the femur. In natural populations, a change in the body size of adult males and females could adversely affect reproductive success in groups that normally exhibit strong dimorphism, and hence, select against any conditions that reduce sexual dimorphism. Ordinarily, a significant change in sexual dimorphism--of the magnitude seen here--through natural selection, would take several generations.

Animals↗
PubMed1975

The effect of danazol in sexual precocity.

The effect of Danazol, a synthetic 2,3 isoxazol derivative of 17 alpha-ethinyl testosterone, was assessed in three girls and two boys with sexual precocity. Progression of sexual development ceased during administration of Danazol; the effect upon growth rate and skeletal maturation was equivocal. Serum estrogen and progesterone concentrations in the girls were lower during treatment; serum testosterone and dehydroepiandrosterone levels in the boys were also lower. Serum and urinary luteinizing hormone concentrations were inconsistently suppressed. No effect upon follicle-stimulating hormone levels could be demonstrated. Although Danazol appears to inhibit sexual development, this study indicates that the pituitary-gonadal axis is not completely suppressed. Growth rate is not reverted to normal, and virilization may occur among girls. Because undesirable side effects may outweight desirable results, careful consideration is recommended before Danazol is prescribed in the management of sexual precocity.

17-Ketosteroids↗
PubMed1995

Testosterone deficiency and extreme retardation of puberty in homozygous sickle-cell disease.

Homozygous sickle-cell (SS) disease is associated with retardation of physical and sexual development but most Jamaican SS children commence their adolescent growth spurt before 16 years of age. Analysis of growth data from children in the Jamaican Cohort Study noted extreme growth retardation, defined as absence of the adolescent growth spurt and pre-pubertal sexual development (Tanner stage 1 or 2) at age 16 years, in 8/52 (15%) SS boys. These and two boys from the general sickle-cell clinic with a similar growth pattern provided a study group of 10 boys who were investigated for a possible endocrine explanation for their extreme retardation of physical maturation. A sub-optimal testosterone response (< 10 nmol/l) to human chorionic gonadotrophin and an exaggerated gonadotrophin response to gonadotrophin hormone releasing hormone was consistent with poor testicular function in 5 boys. Retardation of adolescent growth and development is common in boys with SS disease but, when extreme, requires early investigation to identify potentially correctable mechanisms.

Adolescent↗
PubMed1986

Differences between early- and late-maturing genotypes of the platyfish (Xiphophorus maculatus) in the morphometry of their immunoreactive luteinizing hormone releasing hormone-containing cells: a developmental study.

Immunoreactive luteinizing hormone releasing hormone (ir-LHRH) containing perikarya, brain nuclei, and pituitary cells were studied during the postnatal development of male sibling platyfish (Xiphophorus maculatus) genetically determined to reach puberty at two different ages using immunocytochemical, cytological, and morphometric methods. Ir-LHRH-containing perikarya first appear in the nucleus olfactoretinalis (NOR) at 5 weeks of age in early maturers and at 11 weeks in late maturers at a maximum number which is similar in both genotypes and remains constant into adulthood. The dimensions of the NOR and its perikarya increase up to the initiation of sexual maturation (gonopodial stage 2) in both genotypes. In the nucleus preopticus periventricularis (NPP), ir-perikarya appear at stage 2 and are maximum in number at maturity (stage 6) when early maturers have 50% more than late maturers. Measurements for the NPP increase between 1 week and stage 6 in both genotypes. In the nucleus lateralis tuberis (NLT), ir-perikarya appear soon after stage 2 in early maturers but are never seen in late maturers. Late maturers also have fewer ir-LHRH containing pituitary cells than early maturers. In both genotypes, measurements for the NLT increase to stage 2 and then decrease to stage 6. During sexual development there are differences between early- and late-maturing genotypes in the morphometry of their LHRH-containing brain centers. The timing of sexual development creates significant differences in the cytological and cytometric characteristics of the three ir-LHRH-containing brain nuclei in fish of the same age but different genotype. Our results also show that for both genotypes there is a positive correlation between the total number of ir-LHRH brain neurons and the total number of ir-pituitary cells and both are lower for late maturers at every age and stage.

Animals↗
PubMedDate not supplied

[Gonadotropic function of the pituitary gland in patients with intersexualism and gonadal dysgenesis].

Radioimmunoassay was used to study the blood content of LH and FSH in 116 patients aged 1 to 36 years with abnormalities of sexual development (false male hermafroditism, false female hermafroditism, true hermafroditism and gonadal dysgenesis). With a view of control the content of gonadotropins was measured in 92 subjects (33 females and 59 males) of the same age. The data were evaluated in accordance with the age and genetic sex of patients. It was shown that in health, the concentration of LH and FSH reflected the process of puberty, permanently growing until 18 years, whereas in patients, the age-related time course was less consistent. Unidirectional changes in the hormonal level (towards its rise) were common to all the forms of abnormal sexual development. In all the examinees, the pattern of changes in gonadotropic activity reflected the features of the formation of the neuroendocrine mechanisms by which the sexual system is controlled in ontogenesis.

Adolescent↗
PubMed1988

Expression of a constitutive form of cytochrome P450 during rat-liver development and sexual maturation.

Cytochrome P450 cDNA clone designated pP450 IGC 1 has been previously isolated from a phenobarbital-induced rat liver cDNA library, characterized and proven to correspond to a constitutive cytochrome P450 sensitive to phenobarbital stimulation. IGC 1 pDNA, as well as a unique synthetic oligonucleotide probe, were used to investigate the mRNA levels at different developmental stages (fetal, male and female rats of various ages) in parallel with the study of the expression of the liver development and male phenotype markers: albumin, alpha-fetoprotein and alpha 2u globulin mRNAs. Cytochrome P450 IGC 1 mRNA responsiveness to phenobarbital administration was studied in animals of both sexes at different developmental stages. P450 IGC 1 mRNA was not detectable in fetuses nor in male or female rat liver before sexual maturation, becoming elevated at 45 days age, increasing up to 3 months and reaching relatively higher levels in the female liver than in the male. The concentrations of P450 IGC 1 mRNA closely paralleled the increases in alpha 2u globulin mRNA in male liver, as analyzed by dot and Northern blot hybridization. However, P450 IGC 1 was markedly induced by phenobarbital already at 20 days age both in males and females while alpha 2u globulin mRNA was not inducible before sexual maturation. It is concluded that the expression of cytochrome P450 IGC 1 mRNA is associated with the sexual maturation being differently modulated in the male and in the female rat liver. This cytochrome P450 isoenzyme may play an important physiological role in sex differential steroid metabolism and susceptibility to cytotoxic and genotoxic agents.

Age Factors↗
PubMed2001

Isolation of a novel gene from Schizosaccharomyces pombe: stm1+ encoding a seven-transmembrane loop protein that may couple with the heterotrimeric Galpha 2 protein, Gpa2.

A putative seven transmembrane protein gene, stm1(+), which is required for proper recognition of nitrogen starvation signals, was isolated as a multicopy suppressor of a ras1 synthetic lethal mutant in Schizosaccharomyces pombe. Under nitrogen-deficient conditions, transcription of the stm1 gene was induced; deletion of stm1 was associated with early entry into G(1) arrest. Under nutritionally sufficient conditions, overexpression of Stm1 inhibited vegetative cell growth, resulted in decreased intracellular cAMP levels, increased the expression of the meiosis-specific genes ste11, mei2, and mam2, and facilitated sexual development in homothallic cells. However inhibition of vegetative cell growth and reduction of cAMP levels were not observed in a deletion mutant of the heterotrimeric G protein Galpha2 gene, gpa2, that is responsible for regulating intracellular cAMP levels, a key factor in determining the sexual development in S. pombe. Stm1 protein was shown to interact with Gpa2 through its C-terminal transmembrane domains 5-7. Mutation at Lys(199) in the C-terminal domain (stm1(K199A)) abolished the Stm1 overexpression effect on lowering cAMP levels. Induction of ste11, a meiosis-specific gene transcription factor, by Stm1 overexpression was enhanced in gpa2-deleted cells but was absent in a deletion mutant of sty1, a key protein kinase that links mitotic control with environmental signals and induces stress-responsive genes. Moreover, deletion of both stm1 and ras1 caused delayed entry into G(1) arrest in S. pombe when the cells were grown in a nitrogen-deficient medium. Thus we consider that the stm1 gene can function through Gpa2-dependent and/or -independent pathways and may play a role in providing the prerequisite state for entering the pheromone-dependent differentiation cycle in which heterotrimeric Galpha1 protein, Gpa1, and Ras1 play major roles. Stm1 could function as a sentinel molecule sensing the nutritional state of the cells, stopping the proliferative cell cycle, and preparing the cell to enter meiosis under nutritionally deficient conditions.

Adaptation, Biological↗
PubMed1992

A fungal mating type protein that regulates sexual and asexual development contains a POU-related domain.

The A mating type factor of the fungus Coprinus cinereus regulates essential steps in sexual development. Here we describe features of one of the four specificity genes of the A42 factor. By transformation we show that the gene regulates not only sexual development but also asexual sporulation. DNA sequence analysis shows that the gene beta 1-1, encodes a protein with a DNA binding motif and is thus likely to be a transcription factor. The DNA binding domain is an unusual homeodomain with D replacing the normally invariant N in the recognition helix and apparent absence of helix II. The homeodomain is linked to a helical region related to the POUs domain, which is part of a bipartite DNA binding domain of certain animal transcription factors. Like POU factors, the beta 1-1 protein has regions rich in serine, threonine and proline which are possible transactivation domains. Putative dimerization domains and sites for post-translational modification are described.

Amino Acid Sequence↗
PubMed2006

Deletion of the Ttf1 gene in differentiated neurons disrupts female reproduction without impairing basal ganglia function.

Thyroid transcription factor 1 (TTF1) [also known as Nkx2.1 (related to the NK-2 class of homeobox genes) and T/ebp (thyroid-specific enhancer-binding protein)], a homeodomain gene required for basal forebrain morphogenesis, remains expressed in the hypothalamus after birth, suggesting a role in neuroendocrine function. Here, we show an involvement of TTF1 in the control of mammalian puberty and adult reproductive function. Gene expression profiling of the nonhuman primate hypothalamus revealed that TTF1 expression increases at puberty. Mice in which the Ttf1 gene was ablated from differentiated neurons grew normally and had normal basal ganglia/hypothalamic morphology but exhibited delayed puberty, reduced reproductive capacity, and a short reproductive span. These defects were associated with reduced hypothalamic expression of genes required for sexual development and deregulation of a gene involved in restraining puberty. No extrapyramidal impairments associated with basal ganglia dysfunction were apparent. Thus, although TTF1 appears to fulfill only a morphogenic function in the ventral telencephalon, once this function is satisfied in the hypothalamus, TTF1 remains active as part of the transcriptional machinery controlling female sexual development.

Animals↗
PubMed1999

A G protein alpha subunit from Cochliobolus heterostrophus involved in mating and appressorium formation.

A Galpha subunit-encoding gene (CGA1) was cloned from Cochliobolus heterostrophus, a heterothallic foliar pathogen of corn. The deduced amino acid sequence showed similarity to Galpha proteins from other filamentous fungi and suggested that CGA1 is a member of the Galphai class. cga1 mutants had reduced ability to form appressoria on glass surfaces and on corn leaves; mutants nevertheless caused lesions on corn plants like those of wild type. cga1 mutants were female sterile; sexual development was completely abolished when the mutant allele was homozygous in a cross. Ascospores produced in crosses heterozygous at Cga1 were all wild type. The signal transduction pathway represented by CGA1 appears to be involved in developmental pathways leading to either appressorium formation or mating; in sexual development CGA1 is required for both fertility and ascospore viability.

Amino Acid Sequence↗
PubMed2003

Pre and postnatal exposure to endosulfan in Wistar rats.

The possible reproductive adverse effects of the pesticide endosulfan on male offspring rats exposed in utero and during lactation were investigated. Dams were treated orally with 0, 0.5 or 1.5 mg of endosulfan/kg 21 days prior to mating, during the mating, pregnancy and lactation. Maternal and reproductive outcome data and male sexual development landmarks (testis descent and preputial separation) were assessed. Reproductive endpoints of the male offspring were examined at adulthood: sex organ weights, daily sperm production, spermatid number, sperm transit, sperm morphology and testosterone level. No signs of maternal toxicity were detected at the dose levels tested. Sexual development landmarks were also unaffected. Moreover, with the exception of a significant increase in the relative epididymis weight seen in the group treated with the lowest dose, we have not found any statistically significant adverse effect in the reproductive endpoints investigated at adulthood. The results of the present study indicate that pre and postnatal exposure to low doses of endosulfan (0.5 and 1.5 mg/kg) do not induce significant adverse effects in the reproductive system of male offspring Wistar rats at adulthood.

Animals↗
PubMed1982

Effect of early pre- and postnatal acquired malnutrition on development and sexual behavior in the rat.

In this paper we attempt to elucidate the effects on the rat offspring of undernourishment during pregnancy and lactation on the following parameters were examined: weight at birth and its evolution over a three-month period, sexual behavior of adult males, vaginal opening and sexual cycle of females, blood sugar, blood proteins, hematocrit, natremia, potassemia, body weight and weight of testicles, seminal vesicles and adrenal glands in males 5 months of age. Our results indicate highly significant decreases in body weight in experimental animals over a period of three months. Vaginal opening in experimental females is significantly delayed and their estrous cycle is shortened. Male sexual behavior shows decreases in neuromotor activity and prolongation of the refractory period in experimental male animals. Of the parameters monitored at 5 months of age, only blood sugar levels were significant decreased in experimental male rats. In view of these results, it can be concluded that in utero and lactation period malnutrition affects fundamental parameters of both development and reproductive function in the offspring.

Adrenal Glands↗
PubMed1989

[Variation in the composition of fatty acids of zeaxanthin and astaxanthin monoesters in the ovary and hepatopancreas of Penaeus schmitti during ovogenesis].

The carotenoid esters of the shrimp, Penaeus schmitti, were investigated by thin layer chromatography and absorption spectrophotometry. Astaxanthin monoester and zeaxanthin monoester were identified in hepatopancreas and ovaries during the sexual development. The nature of fatty acids derived from these natural esters has been determined quantitatively by gas chromatography of their methyl esters. The variations of linkage between fatty acids and carotenoids during ovogenesis are measured. The role of zeaxanthin monoester in carotenoids transfer from hepatopancreas to ovaries during this sexual development, and relations between lipid and carotenoid metabolism are discussed.

Animals↗
PubMed1975

Partial isolation of a pheromone accelerating puberty in female mice.

The sexual development of female mice is accelerated by exposure to an adult male or to male urine. The component of the urine responsible for this effect is androgen-dependent, heat labile, nondialysable, precipitatable with ammonium sulphate, and is not extractable in ether. These results indicate that the pheromone causing accelerated sexual development is associated with a protein component of male urine. Tests of the active fraction after digestion with proteolytic enzymes suggest that the pheromone may be a portion of a protein or a substance bound to a protein.

Adult↗