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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↗

[Sexual development in obese women].

By means of an interview and the questionnaire "Heterosexual Development of Women" [HDW] the authors subjected to sexuological examination 129 obese women aged 20-50 years with a body mass index above 25. As regards the time when overweight developed 29 women developed obesity during the prepubertal period and in 100 of the women obesity developed during adolescence and later. It was revealed that the sexual development of obese women was normal. The mean values in the HDW questionnaire in both subgroups with a different period of development of overweight were all within the normal range.

Adult↗

[Sexual development and levels of plasma testosterone in the light type of cockerel].

The concentration of testosterone in blood plasma during the ontogenetic development of cockerels was studied in relation to the development of spermatogenic part of gonads. On the basis of the results, sexual development of cockerels can be divided into three stages. The first stage (from hatching to the age of eight to nine weeks) was characterized by a slow increase in gonad weight, by low concentration of plasma testosterone (0.4-2.0 nmol/l) and by the occurrence of spermatogonia in testes. In the course of the second stage (from the age of nine to 16 weeks) a rapid increase in the weight of testes and testosterone concentration was observed. At the end of this stage all phases of spermatogenic cycle were observed in gonads; the testosterone levels averaged to 10 nmol/l. In the course of this stage all cockerels reached sexual maturity; large individual differences in spermatogenesis development were observed. The third stage (16 weeks of age and more) was characterized by an intensive spermatogenesis, further increase in gonad weight and by typical variations of the plasma testosterone levels. The concentration of the circulating testosterone increased before the onset of the final stages of the spermatogenic cycle.

Animals↗

Secondary sexual development in rural and urban South African black children.

The timing and duration of secondary sexual development in two samples of rural and urban South African black children were investigated using the Tanner staging techniques and compared to similar data from Switzerland and England. In general rural black children were consistently delayed in the age at which they entered the events of puberty, and took longer to pass through each of the stages. Urban black children, from good socioeconomic backgrounds, were advanced in relation to their rural peers and slightly ahead of the European samples. There were no significant differences in the sequence of events. Estimates of testicular volume on the well-off urban boys demonstrated that they exhibited similar volumes to European boys at similar ages. It is suggested that the British clinical longitudinal growth standards could be effectively used to sensitively monitor the growth and maturation of black urban children from good socioeconomic backgrounds.

Adolescent↗

A novel cyclic AMP metabolism exhibited by giant cells and its possible role in the sexual development of Dictyostelium discoideum.

In Dictyostelium discoideum cyclic AMP (cAMP) metabolism during macrocyst development, i.e., the sexual cycle of this organism, and in giant cells, i.e., fusion products from opposite mating-type cells, was investigated. The pattern of change in cAMP levels during macrocyst development differed considerably from that observed during fruiting-body formation, i.e., the asexual cycle. Giant cells produced and excreted considerable amounts of cAMP. Adenylate cyclase activity catalyzing cAMP production in giant cells was comparable to that of unfused cells. However, the activity of membrane-bound phosphodiesterase in giant cells was extremely low, and no extracellular phosphodiesterase was excreted. A phosphodiesterase inhibitory protein was secreted in excess by giant cells.

3',5'-Cyclic-AMP Phosphodiesterases↗

Effects of prenatal testosterone propionate on the sexual development of male and female rats: a dose-response study.

Testosterone plays a major role in male sexual development. Exposure of females to testosterone in utero can induce masculine characteristics such as anovulation, increased anogenital distance (AGD), absence of nipples, retention of male-like tissues, and agenesis of the lower vagina. In addition, high levels of androgens during fetal development can lead to toxic effects such as reduced litter size and viability. The study of the effects of testosterone administration during sexual differentiation provides a foundation for understanding the effects of environmental androgens on fetuses, a sensitive subpopulation. In the current study, we investigated the ability of a range of concentrations of testosterone propionate (TP) administered prenatally to masculinize female and alter male offspring, and measured maternal and fetal T levels. Pregnant Sprague-Dawley rats were dosed by sc injection on gestational day (GD) 14-19 (GD 1= day of plug) with either corn oil (vehicle; 0.1 ml/rat) or with 0.1 ml of TP solution at 0.1, 0.5, 1, 2, 5, or 10 mg/0.1 ml. Parturition was delayed at 2, 5, and 10 mg TP, litter size was reduced at 5 and 10 mg TP, and pup weight was significantly reduced in both sexes at 0.5 mg TP and higher doses. Viability of offspring was unaffected at any dosage level. Androgenic effects seen at 0.5 mg TP in females included increased AGD at weaning and adulthood, reduced number of areolas and nipples, cleft phallus, small vaginal orifice, and presence of prostate tissue. This dose of TP elevated maternal T levels 10x but had no effect on fetal T levels. At 1 mg TP and above, female AGD on postnatal day (PND) 2 (or postcoital day 24 [gestation length = 22(1/2)]) was increased; areolas and nipples were virtually eliminated; levator ani muscle, bulbourethral glands, and seminal vesicles (2 mg TP and above) were present; none of the females developed a vaginal orifice and many females in the 1 and 2 mg TP dose groups developed a greatly distended, fluid-filled uterus after puberty. Maternal T levels at 1 mg TP were elevated 30x, and female fetal T levels showed an 80% increase. Male offspring displayed a reduced AGD and body weight on PND 2 at 0.5 mg TP and higher doses. These effects were not evident by weaning and male offspring displayed no malformations. We conclude that gestational administration of 0.5 and 1 mg TP masculinizes female offspring without greatly affecting pup viability or pregnancy of the dam. This study provides a useful model for in utero testing of environmental androgens for their potential to induce developmental abnormalities.

Abnormalities, Drug-Induced↗

A mutation in the cAMP signaling pathway affects sexual development of Dictyostelium discoideum.

Amoebae of cellular slime molds have two developmental modes, asexual fruiting body formation and sexual macrocyst formation. How developmental choice is made is an interesting subject of wide importance. Light exposure and dry conditions are favorable for asexual development, while conditions of darkness and high humidity are so for sexual development. In Dictyostelium discoideum, the latter conditions enhance zygote formation, which determines the fate of surrounding cells for sexual development. Here, a mutant (TMC1) defective in the post-fusion aggregation of cells during sexual development is described. This mutant is also aggregationless in asexual development, and the level of cyclic adenosine monophosphate (cAMP) receptor is reduced. Correspondingly, a series of existing mutants with defects in cAMP signaling pathways showed the same sexual phenotype as TMC1. These results suggest that molecular mechanisms of development are shared by the two alternative developmental modes.

Animals↗

Hormones and psycho-sexual development in young men following chronic heroin use.

Sixteen former addicts who began heroin use during early puberty were compared with seventeen current heroin users and ten drug-free control subjects with respect to psycho-sexual development and pituitary gonadal hormone levels. Plasma testosterone and luteinizing hormone (LH) levels did not differ between the former addicts and normal control subjects, but were significantly suppressed in the current heroin users. Measures of sexual behavior and physical development did not differ significantly between the three subject groups. Recurrent heroin use during early puberty did not significantly disrupt pubertal development in males. It is postulated that tolerance to opiate induced suppression of pituitary gonadal hormones occurs in pre-pubescent as well as post-pubescent males.

Adolescent↗

c-Jun and RACK1 homologues regulate a control point for sexual development in Aspergillus nidulans.

Amino acid limitation results in impaired sexual fruit body formation in filamentous fungi such as Aspergillus nidulans. The starvation signal is perceived by the cross-pathway regulatory network controlling the biosynthesis of translational precursors and results in increased expression of a transcriptional activator encoded by a c-Jun homologue. In the presence of amino acids, the gene product of the mammalian RACK1 homologue cpcB is required to repress the network. Growth under amino acid starvation conditions permits the initiation of the sexual developmental programme of the fungus, but blocks fruit body formation before completion of meiosis. Accordingly, arrest at this defined control point results in microcleistothecia filled with hyphae. Addition of amino acids results in release of the block and completion of development to mature ascospores. The same developmental block is induced by either overexpression of c-Jun homologues or deletion of the RACK1 homologue cpcB of A. nidulans in the presence of amino acids. Therefore, the amino acid starvation signal regulates sexual development through the network that also controls the amino acid biosynthetic genes. Expression of the RACK1 gene suppresses the block in development caused by a deletion of cpcB. These data illuminate a connection between metabolism and sexual development in filamentous fungi.

Amino Acids↗

Adrenocortical function in children with precocious sexual development during treatment with cyproterone acetate.

Adrenal function was studied in thirty-two children with precocious sexual development who were being treated with cyproterone acetate (CPA) at doses ranging from 68 to 175 mg. m2. day for periods lasting from 2 to 79 months. In eighteen children the adrenocortical function evaluation was made before and during CPA treatment. In these eighteen patients, the mean basal plasma cortisol level during the morning hours was 11.2 +/- 4.6 micrograms/dl (m +/- SD) before treatment and fell significantly to 7.2 +/- 4.1 micrograms/dl (P less than 0.02) during therapy. In fifteen patients tested during insulin hypoglycaemia the cortisol peak fell from 21.6 +/- 5.5 micrograms/dl before treatment to 16.7 +/- 6.8 micrograms/dl (P less than 0.05) during CPA therapy. There was a significant inverse correlation between this peak and the dose of CPA but no correlation was found between the cortisol response and duration of treatment. In eight of twenty patients tested, urinary free cortisol levels were undetectable during treatment. No change in basal plasma ACTH levels were demonstrated using standard radioimmunoassay techniques. In the patient receiving the highest dose of CPA and showing complete suppression of the adrenal axis, prolonged stimulation with ACTH-Depot demonstrated a responsive adrenal gland. Addition of a replacement dose of cortisol to the CPA treatment led to the rapid development of the typical signs of Cushing's syndrome. It was concluded that despite the evidence of adrenal suppression by CPA, cortisol supplementation is not necessary and may not even be contraindicated.

Adrenal Cortex↗

Chronic intermittent immobilization of male rats throughout sexual development: a stress protocol.

A stress protocol--6 h of daily immobilization--was applied throughout male rat sexual development. Immobilization caused a small reduction in food intake and body weight gain whereas pair-fed animals had a marginal decrease only in body weight gain. Stress, confirmed by increased plasma adrenocorticotrophic hormone (ACTH) and corticosterone, caused a decrease in plasma luteinizing hormone (LH) after 15 and 60 days of immobilization and in plasma testosterone after 60 days, but produced an opposite androgenic response in pubertal animals (15 days of immobilization). A persumed sympathetic over-stimulation is suggested to account for increased testosterone levels in pubertal stressed rats.

Adrenocorticotropic Hormone↗

[Abnormalities of sexual development in Puerto Rico: status report].

Puerto Rico presents the highest incidence in the world of anomalous sexual development. The authors have collected over 3100 cases in the past 19 years. Clinical and laboratory studies suggest possible estrogenic contamination of meats and poultry products. Variation in diet provides protection to a significant number of patients. The possibility of mycotic contamination of food employed in animal husbandry by Fusarium sp., and mycotoxins capable of estrogenic effects have been suggested in a preliminary study. Private and government investigators are active in the study of the condition, but more fiscalizing action is needed. A detailed study of food components for possible contaminants determination is considered mandatory.

Adolescent↗