Treatment of delayed puberty and hypogonadism in girls.

The therapeutic management of female delayed puberty depends more on the objectives than on the underlying cause. We will have to consider the development of sex characteristics, the occurrence of menarche and the promotion of growth. In this paper, we will review how girls with delayed puberty of different etiologies can benefit from the following therapeutic alternatives: follow-up without hormonal therapy; administration of growth hormone, anabolic steroids (e.g. oxandrolone) or estrogens and progestogens, and psychological support.     

Ovarian reaction and estrus manifestation in delayed puberty gilts after treatment with equine chorionic gonadotropin

Background

Placental characters vary among Xenarthra, one of four supraordinal clades of Eutheria. Armadillos are known for villous, haemochorial placentas similar to humans. Only the nine-banded armadillo has been well studied so far.

Methods

Placentas of three species of armadillos were investigated by means of histology, immunohistochemistry including proliferation marker, and transmission and scanning electron microscopy.

Results

The gross anatomy differed: Euphractus sexcinctus and Chaetophractus villosus had extended, zonary placentas, whereas Chaetophractus vellerosus had a disk. All taxa had complex villous areas within the maternal blood sinuses of the endometrium. Immunohistochemistry indicated the validity of former interpretations that the endothelium of the sinuses was largely intact. Tips of the villi and the columns entering the maternal tissue possessed trophoblast cell clusters with proliferation activity. Elsewhere, the feto-maternal barrier was syncytial haemochorial with fetal vessels near the surface.

Conclusions

Differences among armadillos occurred in regard to the extension of the placenta, whereas the fine structure was similar. Parallels to the human suggest that armadillos are likely to be useful animal models for human placentation.     

Ovarian activity and uterus organometry in delayed puberty gilts

About 30% of the total number of gilts selected for reproduction at the large breeding farm units in Vojvodina (Republic of Serbia) are culled due to prolonged pre-insemination anoestrus (estrus not detected until 8 mo of age). The aim of this study was to provide the answer to the following question: do the culling gilts reach cyclic ovarian activity at all? One hundred seventy five culled gilts in which external estrus manifestations were not detected by 8 mo of age were sacrificed and their reproductive organs were examined for determination of sexual maturity (ovaries exhibiting pre-ovulatory follicles 8 to 11 mm in diameter, corpora hemorrhagica, corpora lutea and corpora albicantia). Uterine weights and horn length were also determined. Functional ovaries were observed in 107 (61.1%) examined gilts, with 62 animals having one and 45 having two puberty ovarian cycles (57.9% and 42.1%, respectively). Pathomorphological changes which could result in prolonged pre-insemination anoestrus were not observed on the reproductive organs of sexually mature gilts. Our results indicate that most of the culling gilts have reached cyclic ovarian activity. The main reason for culling due to the absence of external estrus manifestations in sexually mature gilts could be inadequate estrus detection technology.     

Nitro(w)-arginine methyl ester treatment delayed the onset of puberty in female rats

It is well documented that nitric oxide (NO) stimulates LHRH, LH and GH release. Present experiments were carried out to analyse whether the blockade of NO generation can affect body growth and puberty onset in female rats. Prepubertal female rats were treated with L-nitro(w) arginine methyl ester (NAME), a blocker of nitric oxide synthase, from day 25 to first estrous (400 or 800 mg/L in drinking water). We measured body growth, age and body weight at vaginal opening and first estrous, and the ovarian and uteri weights and serum LH and FSH concentrations the day of first estrous. Females treated with NAME showed a normal body growth pattern and a delayed puberty. Serum LH concentrations were increased in groups treated with NAME. This stimulatory effect was also observed in 30 and 90 day-old females decapitated 60 min after NAME administration (40 mg/Kg i.p.). We conclude that blockade of NO generation delays puberty in female rats by mechanism(s) other than its effects on LH release.     

Development of biological value of sperm in delayed puberty]

Changes in the biological value of sperm depending on the time of the first ejaculation are presented. A control group included 194 boys with normal puberty in whom a biologic value of sperm was evaluated in dependence of the first ejaculation. In all time points a biological value of sperm was significantly worse in the delayed puberty than that in the control group. Twenty four months following the first ejaculation sperm was not normal in any case whereas in the control group normospermia prevailed in this period of time.     

Therapeutic indications for delayed puberty and hypogonadism in adolescent boys.

Testosterone and synthetic androgens have formerly been used indiscriminately, but are now applied more selectively. They are the only treatment of primary hypogonadism, but are also useful in gonadotropin deficiency and constitutional delay. 17-Alkylated androgens are no longer used. Oral testosterone undecanoate is not suitable for adolescents because of unreliable absorption. The prototype disorder where replacement is necessary is congenital anorchia. As a physiological replacement, an initial dose of 35 mg/m2 per month for 6 months, followed by 70 mg/m2 for 1 year, and 150 mg/m2 thereafter, is recommended. No general rules can be given for other types of primary hypogonadism. In testicular atrophy after cryptorchidism, defects of testosterone biosynthesis, galactosemia or other causes, it is advisable to carry out periodic testosterone determinations and to wait until the levels drop below normal. Progress has been made in the treatment of gonadotropin deficiency, and pulsatile gonadotropin-releasing hormone (GnRH) has been shown to be effective in the hypothalamic type. Nevertheless, androgens still have a temporary place in this condition. In constitutional delay of growth and adolescence, treatment is not necessary somatically, but there are often psychosocial reasons. Gonadotropins, GnRH or growth hormone (GH)-releasing hormone have been used. Also treatment with human GH is successful in accelerating height velocity. The most simple and economic treatment is still testosterone in a physiological dose for 3-6 months. Oxandrolone or other synthetic androgens have no advantages.     

Genome‐wide association with delayed puberty in swine

An improvement in the proportion of gilts entering the herd that farrow a litter would increase overall herd performance and profitability. A significant proportion (10–30%) of gilts that enter the herd never farrow a litter; reproductive reasons account for approximately a third of gilt removals, with anestrous and failure to conceive the most common reasons for culling. Tools to select gilts for reproductive longevity through genomics or alternative phenotypes would be of great benefit to the producer. Ninety‐one gilts that failed to display behavioral estrus by 240 days (cases) and 127 pubertal littermates (controls) were genotyped with the Illumina Porcine SNP60 Beadchip. One hundred and seventy‐four SNPs with the most significant associations were genotyped in an additional 86 cases and 103 controls. Twelve of these associations were significant in the final analysis. The most significant (P < 1.5 × 10^?14) region associated with failure to attain puberty was on chromosome 4 surrounding the NHLH2 gene. Delayed pubertal development and age at first estrus have been associated with NHLH2 in mice. Because attainment of puberty is a complex trait, identifying genes that affect pubertal age would greatly contribute to our knowledge of reproductive development as well as overall fertility.     

Photoperiodic time measurement is maintained in undernourished lambs with delayed puberty

Beginning at 42 weeks of age undernourished females that had been maintained outdoors were exposed to long days (15L:9D) or short days (9L:15D). After 6 weeks, both groups were placed on short days, and ad-libitum feeding was begun. Rapid 'catch-up' growth occurred similarly in both groups. However, the response to oestradiol negative feedback regulation of LH secretion differed greatly. Short-day lambs remained hyperresponsive to oestradiol inhibition, and circulating LH remained low, a condition that typifies immaturity of the system governing LH secretion. In the females exposed to the long-day-short-day sequence, circulating LH began to increase 10 weeks after the end of long days; this change is characteristic of the neuroendocrine alteration that occurs during puberty. These findings indicate that the growth-retarded lamb can differentiate long days from short days, and can therefore continue to accumulate photoperiod information during prolonged periods of undernutrition.     

Progressive deceleration in growth as an early sign of delayed puberty in boys

OBJECTIVE: To describe the prepubertal growth pattern in boys with delayed puberty. METHODS: Growth curves for height and height velocity covering the age range 4-14 years were constructed on the basis of retrospectively obtained data in 85 boys with delayed puberty, who attained a normal final height. RESULTS: Between the age of 4 and 14 years the height in this cohort progressively deviated from the normal reference. At the age of 4 years, the height SDS was already significantly lower (median -0.8; p < 0.001) and progressively diminished during childhood, resulting in a median height SDS of -1.1 at the age of 12 years (p < 0.001). The median final height of this cohort (-0.4) was not different from their target height (-0.2). The degree of deceleration in growth during childhood was not determined by birth weight or birth height and did not influence final height. The decline of the height velocity with age in this group of boys with delayed puberty was significantly smaller (p < 0.001) than predicted by the model of Rikken and Wit. CONCLUSION: Late-maturing boys often show a prepubertal deceleration in growth that starts at an early age but that does not affect final height.     

Ascertainment and Prevention of Genetic Disease

A genetic register system has been developed for the ascertainment and prevention of genetic disease. Its potential value is illustrated with data collected from 478 families with serious genetic disorders which had been seen during the past five years. Of these 249 were referred specifically for genetic counselling, autosomal dominant disorders accounting for the largest group of families with individuals at high risk of becoming affected. Of 717 individuals at high risk of having affected children (or carrier daughters in the case of X-linked recessive disorders), only 101 were referred specifically for counselling. Many were referred only after the birth of an affected child which might otherwise have been prevented. A genetic register system linked to practitioner, hospital, and health department records could be a valuable means of preventing genetic disease.     

A study of seasonally delayed puberty in the male hare, Lepus Europaeus.

The brown hare, Lepus europaeus, has a mating season which extends from January to September. Adult males exhibit pronounced seasonal changes in the reproductive tract which are associated with changes in LH secretion. Maximum plasma levels of immunoreactive LH occur between March and June and minimal levels in the autumn non-mating period from September to December; this seasonal cycle in gonadotrophin output is reflected by the appropriate changes in the secretion of testosterone from the testes and in the activity of the accessory sex glands. Juvenile animals reach puberty only during the adult mating season, and the age of puberty thus varies with the date of birth. Males born before May reach puberty and become fertile at 3 months of age, while those born from May to July grow to a mature body size during the autumn non-mating season but puberty is delayed for several months. Since some animals experiencing delayed puberty were found to have elevated plasma levels of LH and testosterone, it is concluded that puberty is not completely suppresed by the environmental effects of the autumn, but that the developmental process is prolonged, resulting in the juveniles being synchronized with the adults in their reproductive activity.     

Multinomial Distribution and Ascertainment Models

In this paper general ascertainment models are studied relaxing the strong assumption of complete dominance. Probabilitis of ascertaiment for both the complete and incomplete models depending on family size and register size for two types of affected individuals are derived.     

The hormonal and clinical response of gilts with delayed puberty to GnRH: A preliminary study

Four gilts with delayed puberty were treated with 1 mg of Gn-RH intravenously. Three of the four gilts showed heat after treatment and heats recurred thereafter at normal intervals in these three pigs. All pigs responded with increased blood content of LH after injection of Gn-RH (1.45–6.1 ng/ml). The failure of one pig to exhibit heat after the injection of Gn-RH could not be explained by the resulting LH response.The results of this limited trial indicate that one cause of delayed puberty in gilts may be an insufficient gonadotropic release. Further studies are required to elucidate the reasons for the difference in sexual and ovulatory responsiveness of gilts with delayed puberty to Gn-RH.     

Ascertainment and anticipation in family studies

Many human diseases show anticipation; that is, disease occurs earlier (or with greater severity) in successive generations. In a computer simulation, we assessed the degree of anticipation that one would expect to see in two-generation breast cancer families. Under reasonable assumed distributions for age at cancer onset, number of children, and mortality, we find a consistent earlier mean age at diagnosis in daughters than in mothers, but the same mean age at diagnosis in affected aunts and nieces. We compare these results with published pedigree data for familial breast cancer that show substantial anticipation in affected daughters compared to their mothers. We find that at least some anticipation is expected in human disease families even when the disease is stable and families are ascertained without obvious sampling bias. We further demonstrate that such anticipation is reduced when comparing affected children to the parents' affected siblings.