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Prospective study on the sexual development of male and female rats perinatally exposed to maternally administered cimetidine.

Cimetidine, a widely prescribed, potent histamine H2-receptor antagonist, is unrelatedly a mild antiandrogen. Since perinatal androgens are essential for normal masculine imprinting, we wanted to determine if maternally administered cimetidine interfered with the offspring's reproductive development. Cimetidine was administered in the mothers' drinking water at several levels reflecting both human and rat therapeutic-like doses from day 17 of gestation through day 7 of lactation. Except for the highest dose of cimetidine (4.0 mg/ml drinking water) the drug had no effect on the dams' food and water consumption or body weight gain. In general, feminine sexual development as measured by pubertal onset, reproductive organ weights and adult estrous cyclicity, was unaffected by perinatal exposure to cimetidine. Similarly, early exposure to the drug had little effect on masculine sexual development. The developmental profile of serum dehydroepiandrosterone, androstenedione, testosterone and 5 alpha-dihydrotestosterone when measured at 1, 4 and 18 weeks of age, was unaffected by perinatal exposure to cimetidine. Furthermore, serum androgen concentrations and seminal vesicle weights following orchiectomy and androgen replacement were the same in control and cimetidine-exposed rats. In contrast, pituitary weights of adult males exposed to maternally administered cimetidine appeared to be insensitive to androgen regulation. However, taken in totality, our results do not support the concept that cimetidine is a reproductive teratogen.

Androgens↗

Differential expression of house-keeping genes of Aspergillus nidulans during sexual development.

The rpl3 gene and the rpl37 gene for Aspergillus nidulans ribosomal protein L3 (RPL3) and RPL37, which were identified as located on chromosome I and chromosome III, respectively, were isolated from chromosome-specific cosmid libraries. The nucleotide sequences of both of the rpl3 gene and the rpl37 gene identified the ORFs of 392 amino acids and 92 amino acids, respectively. Both of the two genes were present in a single copy. The expression of both genes together with two other house-keeping genes, the rps16 gene for RPS16 and the gene for gamma-actin, was analyzed during sexual development. All four genes showed nearly identical expression patterns in that each gene expression reached its maximum after 2 h, decreased thereafter, and increased again after 30-40 h of induction of sexual development.

Actins↗

[Sexual development of the child and the onset of gender identity].

In view of the numerous questions raised by the recently disclosed pedophilia, sexual abuses and prostitution of children, it appeared worthwhile to review the recent studies dealing with the child sexual development and the onset of the gender identity. These studies consist partly in retrospective analysis of pathological situations and partly in the analysis of normal development. It appears that the social and emotional surroundings of the child, provided that they were continuous and devoid of ambiguity, play a prominent role in this process. At present, numerous authors consider that gender identity is achieved at about 2 years of age when the child has a harmonious general development. The family physician and the paediatrician are on the first line to detect potential problems provided that they were aware of the main determinants and symptoms involved.

Child↗

Sister-chromatid exchange (SCE) rate in normal and abnormal sexual development in males and females.

Thirty-three patients with abnormal sexual development (9 male hypogonads, 20 females with primary amenorrhea and 4 cases of ambiguous genitalia), 10 normal males and 8 normal females (below the age of 30 years) were evaluated for SCE/cell and for SCE distribution according to chromosome groups (A to G). Smokers and alcoholics and subjects under medication were excluded from the study. The average rates of SCE/cell in male hypogonads, primary amenorrhea and ambiguous genitalia were 4.23 +/- 1.51, 4.02 +/- 0.90 and 4.33 +/- 1.34, respectively, whereas in normal males and females the average rates were 4.27 +/- 0.69 and 4.49 +/- 0.87, respectively. The SCE data followed a Poisson distribution. Chi-square testing showed a statistically significant difference only in B-group chromosomes when male hypogonads were compared with normal males (p less than 0.02) and females with primary amenorrhea were compared with normal females (p less than 0.02), suggesting the importance of the study of SCE frequency distribution at chromosome group level to bring out the differences otherwise concealed in average rates.

Adult↗

Rapamycin blocks sexual development in fission yeast through inhibition of the cellular function of an FKBP12 homolog.

FKBP12 is a ubiquitous and a highly conserved prolyl isomerase that binds the immunosuppressive drugs FK506 and rapamycin. Members of the FKBP12 family have been implicated in many processes that include intracellular protein folding, transport, and assembly. In the budding yeast Saccharomyces cerevisiae and in human T cells, rapamycin forms a complex with FKBP12 that inhibits cell cycle progression by inhibition of the TOR kinases. We reported previously that rapamycin does not inhibit the vegetative growth of the fission yeast Schizosaccharomyces pombe; however, it specifically inhibits its sexual development. Here we show that disruption of the S. pombe FKBP12 homolog, fkh1(+), at its chromosomal locus results in a mating-deficient phenotype that is highly similar to that obtained by treatment of wild type cells with rapamycin. A screen for fkh1 mutants that can confer rapamycin resistance identified five amino acids in Fkh1 that are critical for the effect of rapamycin in S. pombe. All five amino acids are located in the putative rapamycin binding pocket. Together, our findings indicate that Fkh1 has an important role in sexual development and serves as the target for rapamycin action in S. pombe.

Amino Acid Sequence↗

[The influence of obesity on sexual development in pubertal children].

Serum testosterone and dehydroepiandrosterone sulfate (DHEAS) were measured in obesity and control groups using radioimmunoassay method (RIA). The sexual sign and sexual maturity were measured, too. The results showed that the contents of serum testosterone were 10.36 +/- 5.72 and (8.65 +/- 4.21) nmol/L in males of obesity and control groups respectively (P < 0.01). The levels of serum DHEAS were 8.25 +/- 6.47 and (5.63 +/- 4.98) pmol/L in femals of obesity and control groups, respectively. The length and beadth diameter of testis and length and surround of penis in males in obesity group were significantly higher than in control one (P < 0.01). The first spermatorrhea age of males in obesity group was significantly younger than that in control one (P < 0.01). Menarche age in females of obesity group and the second sexual sign development were earlier than that of control one (P < 0.01). It showed that sexual hormone, sexual development and sexual maturity were significantly higher and earlier in obesity group than those in control one.

Adolescent↗

Secondary sexual development of 'Cape Coloured' girls following kwashiorkor.

This report describes the secondary sexual development of 45 'Cape Coloured' female ex-kwashiorkor patients and 43 female controls. All patients were originally seen between five months and four years four months of age, treated and then followed up for 15 years after discharge. Age at menarche was available on 42 ex-patients and 33 controls, and age at peak height velocity (PHV) was available for 30 ex-patients and 15 controls. Maximum likelihood estimates of the mean age at entry to each pubertal stage were made, age at menarche was obtained directly from the subject records and age at PHV was obtained by fitting a non-linear growth function to the data for each subject. All subjects passed through the sequence of pubertal events in the normal order, i.e., no reversals were observed. Ex-patients were generally delayed in relation to controls but there were no significant differences for ages at entry to any of the pubertal stages. The subjects were combined for comparison to equivalent data on British girls. The South African girls were significantly delayed in the development of pubic hair and menarche but showed no significant differences for age at entry or duration of breast development and PHV. It is suggested that lack of delay in breast development may have selective advantages to females living in situations of chronic malnutrition.

Female↗

Müllerian-inhibiting substance function during mammalian sexual development.

To investigate the role of Müllerian-inhibiting substance (MIS) in mammalian sexual development, we generated MIS-deficient mice. Although MIS-deficient males had testes that were fully descended and produced functional sperm, they also developed female reproductive organs, which interfered with sperm transfer into females, rendering most of these males infertile. Their testes had Leydig cell hyperplasia and, in one instance, neoplasia. The actions of the two primary hormones of male sexual differentiation were genetically eliminated using the testicular feminization (Tfm) mutation in combination with the MIS mutant allele. XY Tfm/MIS double mutants developed as females, with a uterus, coiled oviducts, and no male reproductive organs except undescended dysfunctional testes. These results suggest that eliminating the presumptive female reproductive tract in male fetuses facilitates fertility and that in testes MIS is a negative regulator of Leydig cell proliferation. Eliminating the presumptive male reproductive tract is necessary for proper oviductal morphogenesis during female mouse development.

Androgen-Insensitivity Syndrome↗

Effect of cyclic sound cues on sexual development in nonphotostimulated Japanese quail.

The influence of cyclic ambient sound stimuli on sexual development was studied in nonphotostimulated [6 hr light:18 hr dark (16L:18D)] Japanese quail (Coturnix coturnix japonica). The incidence of accelerated gonadal development was reduced when ambient daily sound stimuli were attenuated by the presence of a white noise mask in the animal quarters. In a second experiment nonphotostimulated (9L:15D) male quail showed a phase-dependent testicular response to a daily 3-hr radio broadcast presented at different portions of the day. The radio sound stimulus induced a higher incidence of accelerated gonadal development when presented 6 hr prior to the photophase than when presented either 3 hr prior to the photophase or when presented coincidently with the photophase onset. In a third experiment locomotion was monitored in nonphotostimulated quail (9L:15D) with a 3-hr radio sound stimulus presented 6 hr prior to photophase onset. The onset of a daily locomotor activity pattern was associated with radio sound in some individuals, but sound-induced locomotion was not consistently associated with sound-induced accelerated gonadal development.

Acoustic Stimulation↗

Sexual development of patients with isochromosomes for the long arm of the X chromosome.

The sexual development of 14 girls with non-mosaic monocentric 46,X,iXq karyotype was studied. Seven out of eight girls were found to have immature secondary sexual characteristics and amenorrhoea, a finding greatly contrasting with that in Triplo-X girls. The relative ineffectiveness of the isochromosome Xq in maintaining fertility may be due to the absence of one short arm, which probably also carries a gonadal determinant. Alternatively, the presence of two inactivation sites on one isochromosome may render the gonadal determinants inactive at an important stage in gonadal development.

Adolescent↗

The effects of immunization against luteinizing hormone-releasing hormone on performance, sexual development, and levels of boar taint-related compounds in intact male pigs.

The effect of a newly developed anti-LH-RH vaccine on the performance, sexual development, and incidence of boar taint-related compounds was investigated in young intact male pigs. At 29 kg BW, 40 crossbred intact males and 20 castrates were allocated to three groups. Castrates and half of the intact males were untreated. The remaining intact males were immunized against LH-RH at 29 kg and again at 89 kg BW. All pigs were slaughtered at 105 kg BW. Compared with control intact males, feed efficiency in castrates was decreased by 10%, muscle content was reduced by 5%, and carcass fat content was increased by 26%. Growth performance and carcass traits did not differ significantly between immunized and control intact males. Genital tract weight, measured at slaughter, was decreased (P < or = .002) by immunization. Plasma testosterone concentrations were not significantly affected at 89 kg BW, whereas they were sevenfold lower (P < .001) in immunized than in control intact males at 105 kg BW. Fat androsterone levels, measured at slaughter, were substantially reduced (P < .001) from .66 +/- .07 microgram/g in control to .21 +/- .01 microgram/g in immunized intact males. Rates of testicular steroid biosynthesis, measured in vitro, were decreased by immunocastration. Fat skatole levels were very low and did not differ significantly between the three groups. The present results demonstrate that anti-LHRH immunization was effective in reducing the level of androstenone, a boar taint-related compound, although having a limited effect on the performance of the animals.

Adipose Tissue↗

Puberty without gonadotropins. A unique mechanism of sexual development.

Recent evidence suggests that a group of children exists in whom premature sexual maturation occurs in the absence of pubertal levels of gonadotropins; that is, they have gonadotropin-independent precocious puberty. We compared six boys and one girl with this disorder with four boys and five girls with central precocious puberty, in which there is a pubertal pattern of gonadotropin release. The two groups were similar in age of onset, degree of sexual development, growth velocity, and rate of skeletal maturation. A family history of precocity was noted in four of the boys with gonadotropin-independent precocity, and the girl had McCune-Albright syndrome. Children with central precocious puberty demonstrated a pulsatile release of gonadotropins, pubertal responses to luteinizing hormone-releasing hormone, and complete suppression of gonadarche after exposure to an analogue of luteinizing hormone-releasing hormone (LHRHa). In contrast, children with gonadotropin-independent precocity demonstrated an absence of gonadotropin pulsations, variable responses to luteinizing hormone-releasing hormone, lack of suppression of puberty in response to LHRHa, and cyclic steroidogenesis. Tissue from testicular biopsies performed in five of six boys with gonadotropin-independent precocity showed a range from incipient pubertal development of the tubules with proliferation of Leydig cells to the appearance of normal adult testes. We conclude that gonadotropin-independent precocious puberty is a distinct syndrome, of unknown cause, that may be familial and may have been responsible for many previously reported cases of precocious puberty.

Child↗

Growth and sexual development before and after sex steroid therapy in patients with thalassemia major.

Growth, sexual development, and hypothalamic-pituitary-gonadal function were evaluated in 23 patients with thalassemia major (14 female and nine male) aged 13 to 29 years. Five women (group 1) with hemoglobin levels of less than 7 g/dL, which were maintained by transfusions during childhood, did not spontaneously enter puberty. They had evidence of severe hypothalamic-pituitary dysfunction. Maintaining hemoglobin levels of about 8 g/dL resulted in spontaneous onset of puberty in seven of nine female patients (group 2), but had no such ameliorative effect on the nine male patients. In the latter, peak luteinizing hormone (LH) responses to gonadotropin releasing hormone correlated with bone age. Treatment with testosterone produced inconsistent partial inhibition of LH and follicle-stimulating hormone (FSH) responses to stimulation. After discontinuation of testosterone treatment, a rebound of basal testosterone, LH, and FSH levels was observed, but this was not sustained. These findings are compatible either with dysfunction of hypothalamic maturation or with partial pituitary dysfunction. Four of the group 1 females and six of the males treated with appropriate sex hormones showed satisfactory pubertal progression. Acceleration in linear growth was observed in four of the male patients whose epiphyses were still open. Treatment was well tolerated in all patients.

Adolescent↗

Health, growth and sexual development of teenagers exposed in utero to medroxyprogesterone acetate.

General health, growth and sexual development were evaluated in 74 teenage boys and 98 girls who had been exposed to medroxyprogesterone acetate (MPA) in utero, and 385 boys and 448 girls not exposed. In this 17-year prospective study, the ascertainment of the end points was 'double blind' in that neither the interviewer nor the subject was aware of our interest in MPA. On average, girls exposed to MPA reported reaching the menarche 4 months earlier than the comparison group. This difference disappeared, however, in a multiple regression analysis taking into account social class, the mother's age at menarche and height of the girl's mother and father. Boys exposed to MPA reported their growth spurt to have occurred an average of 6 months earlier and voices to have broken 5 months earlier than unexposed boys. Again, the differences between them and the comparison group disappeared after controlling for confounding variables. There were no significant differences between the MPA-exposed and comparison groups in a wide variety of indices of health reported by the teenagers' mothers. These findings are consistent with the hypothesis that intrauterine exposure to MPA, in the doses used for pregnancy maintenance or for contraception, poses no threat to the long-term health and development of the progeny.

Adolescent↗

HCG stimulation test in children with abnormal sexual development.

Plasma testosterone was estimated by radioimmunoassay in 60 children with disorders of sexual development before and after stimulation with human chorionic gonadotrophin (HCG). In 21 children the testosterone levels after 3 and 5 daily injections of 1000 units HCG were compared and good correlation was found between the paired results (r =0-93), suggesting that the 5-day HCG test has no advantage over the 3-day test. In 7 boys with apparently normal genital development the increments in plasma testosterone ranged from 2-0 to 8-5 nmol/1 after 3 injections of HCG. 10 boys with anorchia showed little response to HCG stimulation, but in patients with other disorders, such as micropenis (10), cryptorchidism (8), hermaphroditism (3), male pseudohermaphroditism (13), hypospadias (3), and sex chromosome anomalies (6), there was considerable variation in the plasma testosterone level after HCG. In 2 boys with suspected anorchia the results suggested that testes were present and this was confirmed at operation.

Adolescent↗

Sexual development and free-running period in quail kept in constant darkness.

In Japanese quail (Coturnix coturnix japonica) sexual development may occur in total darkness (DD). Linked to sexual maturation, variations of the rhythm of feeding activity were observed: in DD, the amount of activity increased and the period of the free-running rhythm lengthened. During the first weeks in DD all the quails presented a free-running period less than 24 hr (22.3 +/- 0.5 hr; N = 50). At the end of the experiment, the more a bird was mature, the greater the lengthening of its period. In DD, testosterone implants in castrated male quails can mimic these modifications but we failed to find any correlation between the number of implants (i.e., the level of testosterone) and the extent of the lengthening.

Activity Cycles↗

The effect of preweaning undernutrition upon the sexual development of male mice.

Sexual maturation was evaluated in male mice subjected to preweaning undernutrition by separating pups from their mothers. Underfed and normally fed males were sacrificed at 20, 30, 40, 50 and 60 days of age. From 20 to 60 days, body and organ weights (testes, seminal vesicle) were lower in underfed males. Plasma testosterone levels were lowered in undernourished males at 20 and 30 days of age, and thereafter they were not significantly different from controls. First fertile matings, which occurred between 36 and 46 days (mean age: 40.6 +/- 0.6) in controls, were delayed in underfed males and occurred between 42 and 58 days (mean age: 48 +/- 1.7). The mean body weight, at the time of first fertile matings, was significantly different in controls (29.5 +/- 0.5 g, range 25.9-32.4) and in undernourished males (24.3 +/- 0.3 g, range: 22.0-25.6). Testicular weight and plasma testosterone concentrations were also significantly lower in underfed males, at the time of first fertile matings. The data lead to the conclusion that puberty did not occur at the same body weight in normal and undernourished male mice.

Aging↗