[Management of true precocious puberty with a delayed-action Gn-RH analog].
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Buserelin↗
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Pubertal development in cystic fibrosis: an overview.
Cystic fibrosis (CF) is an autosomal recessive disease characterized by respiratory and intestinal insufficiencies. It has been reported in the literature that patients with CF show delayed growth and puberty and girls with CF achieve menarche at older age than normal females. Infertility, in both sexes, and menstrual dysfunction, in girls, are common in patients with CF. Previous data suggest that the degree of failure of growth and development is correlated with malnutrition and severity of progressing pulmonary disease. Despite improved nutrition and intensive treatment, patients with CF have delayed puberty and growth pubertal spurt. This maturational lag is accompanied by a significant delay in attaining pubertal levels of insulin-like growth factor-I (IGF-I), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex steroid hormones.
Cystic Fibrosis↗
The consequences of altered somatotropic system on reproduction.
Although the primary control of gonadotropin secretion is by the hypothalamic GnRH and the gonadal function is controlled by the pituitary gonadotropins and prolactin, the emerging evidence suggests a vital role of the somatotropic axis, growth hormone (GH), and insulin-like growth factor-I (IGF-I) in the control of the pituitary and gonadal functions. It has been shown that GH deficiency, GH resistance, and experimental alterations in IGF-I secretion modify folliculogenesis, ovarian maturation, ovulation, and pregnancy, and in the male, GH/IGF-I plays an important role in spermatogenesis and the Leydig cell function. The primary focus of this review is to examine the role of GH/ IGF-I on the onset of puberty, fertility, pituitary, and gonadal endocrine functions. A number of studies have revealed that fertility is affected in GH-deficient dwarf and in IGF-I gene-ablated mice, possibly due to subnormal function of either the pituitary gland or the gonads. In the female GH receptor gene knockout (GHR-KO) mice, there was impairment in follicular development, ovulation rate, sexual maturation, production of and responsiveness to pheromonal signals, and the corpus luteum function. In IGF-I-deficient male GHR-KO mice, puberty is delayed, spermatogenesis is affected, and neuroendocrine-gonadal function is attenuated. Similarly, in some of the human Laron syndrome patients, puberty is delayed due to GH resistance. These data suggest that, in addition to GnRH and gonadotropins, GH/IGF-I influences the pituitary and gonadal functions in animals and humans.
Animals↗
Novel assay for determination of androgen bioactivity in human serum.
We have developed a mammalian cell (COS-1) bioassay, which can measure androgen bioactivity directly from a small amount (10 microL) of human serum. The recombinant assay is based on androgen-dependent interaction between the ligand-binding domain and the N-terminal region of the androgen receptor (AR), which were fused to Gal4 DNA-binding domain of Saccharomyces cerevisiae and transcriptional activation domain of herpes simplex VP16 protein, respectively. The interaction is amplified by coexpression of AR-interacting protein 3 in the cells. The reporter plasmid contains 5 Gal4-binding sites upstream of the luciferase gene; luciferase activity in cell lysates is derived from androgen bioactivity in human serum. Saturating concentration of testosterone in FCS induced more than 700-fold induction in relative luciferase activity. The sensitivity was less than 1.0 nmol/L testosterone in FCS. The intra- and interassay coefficients of variation were 8.3% and 21%, respectively. Interaction between the AR termini was blocked by nonsteroidal antiandrogens, and the assay exhibited minimal cross-reactivity with 17 beta-estradiol. Serum androgen bioactivity was studied in 23 boys (13.9--16.8 yr old) with constitutional delay of puberty and in 9 prepubertal boys with cryptorchidism (1.0--6.4 yr old). Androgen bioactivity was detectable in 15 boys with constitutional delay of puberty and in all boys with cryptorchidism during treatment with human CG (range, 1.0-14.5 nmol/L testosterone equivalents). Serum androgen bioactivity measured by the bioassay correlated strongly with serum testosterone concentration (r = 0.93, P < 0.0001, n = 22) but not to 5 alpha-dihydrotestosterone, dehydroepiandrosterone, or androstenedione levels. We conclude that our novel bioassay enables quantitation of mammalian cell response to bioactive androgens in human serum, even in pediatric patients with relatively low androgen levels.
Adolescent↗
Growth and pubertal development in nephropathic cystinosis.
In a retrospective investigation growth and pubertal development were evaluated in 30 patients with nephropathic cystinosis. Growth was investigated during the stage of chronic renal insufficiency as well as after successful kidney transplantation and growth rates were related to kidney function. Pubertal development was evaluated in 17 patients between 12 and 25 years of age. Prepubertal growth rates were stable in a range between -2 and -3 height velocity SDS as long as glomerular filtration rate was above 20ml/min per 1.73m2. A decrease in glomerular filtration rate below this threshold was followed by further decrease in height velocity. After kidney transplantation a significant catch-up growth was seen if immunosuppression was performed with cyclosporine A and low dose prednisolone. This did not occur if conventional therapy with azathioprine and high-dose prednisolone was used. Onset of puberty was delayed in all patients. Gonadotropin and oestradiol levels in female patients showed normal fluctuations according to ovulatory cycles. In male patients after puberty there was an increase in gonadotropin levels above the normal range for adult men while testosterone levels remained in the low normal range. These results indicate that adult men with nephropathic cystinosis may develop hypergonadotropic hypogonadism.
Adolescent↗
The role of mutations affecting gonadotrophin secretion and action in disorders of pubertal development.
A number of mutations that disturb the development and function of the hypothalamic-pituitary-gonadal (HPG) axis and cause disturbances in pubertal development are known today. These mutations have effects at all levels of the HPG axis, from the migration of gonadotrophin releasing hormone (GnRH) neurones from the nasal cavity to the hypothalamus, GnRH secretion, GnRH action, pituitary gonadotroph differentiation, gonadotrophin synthesis and secretion, right through to gonadotrophin action. Most of the mutations are inactivating, thus causing hypogonadism and arrest or delay of pubertal development. One exception is the activating mutations of the LH receptor, which causes the male-limited gonadotrophin-independent precocious puberty. The human mutations and animal models with disrupted function of orthologous genes have clarified the molecular pathogenesis of hypogonadism and disturbances of pubertal development. The correct diagnosis of these disorders using molecular biological techniques is now possible. This allows the selection of specific treatments and correct counselling of the patients and their families.
Adolescent↗
Assessment of complications in children with insulin-dependent diabetes mellitus.
Nineteen children with insulin-dependent diabetes mellitus in the University Department of Paediatrics were assessed for complications of diabetes. 36.8% showed marked growth stunting, and half of the patients who attained puberty had a delayed onset of puberty. 42% showed limited joint mobility. Almost all the patients developed hypertrophic lipodystrophy while only 5 patients developed reversible lipoatrophy. Abnormal nerve conduction velocities were found in all 17 patients tested, with more of sensory nerve involvement. A significant correlation was found between duration of disease and the extent of neuropathy. Evidence of nephropathy was found in 5 patients, 2 of whom showed impaired renal function. One patient had background retinopathy, another had proliferative retinopathy and 2 patients developed cataracts. The high prevalence of microangiopathic complications in these children is probably related to their previous poor diabetic control and it is hoped that with home blood glucose monitoring to improve their control, these complications may be arrested or minimized.
Adolescent↗
Growth, puberty and endocrine function in beta-thalassaemia major.
Although delay in onset of puberty is a common cause of growth failure in adolescent thalassaemic patients, growth retardation could also be due to iron overload, the toxic effects of desferrioxamine, or the development of other endocrinopathies such as GH insufficiency or primary hypothyroidism. Abnormal body proportions with truncal shortening are commonly seen and could be due to the disease itself, iron toxicity, delay in puberty or the toxic effects of desferrioxamine. The absence of a pubertal growth spurt during spontaneous or induced puberty is detrimental to the achievement of a normal final adult height. Low serum IGF-I and normal GH reserve in short thalassaemic children imply that a state of relative GH resistance exists. The rise in IGF-I and improvement in growth with GH therapy suggest that this GH resistance is only partial. Although the results of short-term GH therapy are encouraging, the impact of treatment on final height of non-GH deficient short thalassaemic children remains uncertain. Multiple endocrinopathies, including hypogonadism, hypothyroidism and diabetes mellitus, occur mainly in older patients who tend to have high serum ferritin levels. Prognosis for survival is greatly improved if the serum ferritin is kept below 2000 micrograms/l by regular chelation. Chelation therapy initiated early before the accumulation of a significant iron burden or dosages of desferrioxamine in excess of 50 mg/kg/day should be avoided. Serum ferritin should be checked regularly and the "toxicity index" should be used to monitor chelation therapy. In cases of delayed puberty, sexual development should be induced at an appropriate age.
Adolescent↗
Signaling between the pituitary gland and the testes: inverse relationship between serum FSH and inhibin B concentrations in boys in early puberty.
OBJECTIVES: To study the relationship between serum inhibin B and sex steroid concentrations and pituitary FSH responsiveness to GnRH in boys in early puberty, and to examine serum inhibin B levels in prepubertal boys with different timing of the onset of gonadotropin deficiency (GD). DESIGN: Twenty-five boys with constitutional delay of puberty (CDP; 20 in Tanner stage G2 and 5 in G3; age range, 13. 5-16.8 years) and eight prepubertal boys (G1P1) with GD (age range, 10.0-13.2 years) were clinically examined, and serum inhibin B, testosterone and estradiol concentrations were measured from sera obtained immediately before the administration of GnRH (Relefact; 3.5 microgram/kg, maximum 100 microgram i.v.). Thereafter, FSH levels were measured at 30min intervals up to 90min. RESULTS: In the boys with CDP, basal inhibin B and FSH levels did not correlate. However, inhibin B and GnRH-stimulated FSH concentrations (r(S)= -0.43 to -0.45, n=25, P<0.05) and the difference between basal and peak serum FSH levels were inversely related (r(S)= -0.63, n=25, P<0.005). This relationship remained significant in boys at stage G2 (r(S)= -0.66, n=20, P<0.005). Basal testosterone concentrations and GnRH-induced FSH levels did not correlate. Estradiol levels were too low (64% of the boys had estradiol levels below the assay sensitivity) to allow correlation analysis. The boys with GD had low inhibin B concentrations (range, <15.6-53pg/ml); the lowest levels were observed in boys with presumably congenital onset of the disease. Serum inhibin B levels and testis volumes correlated positively (r(S)=0.70, n=8, P=0.07). CONCLUSIONS: These results suggest that, in boys, the reciprocal regulation between inhibin B and FSH is in operation before mid-puberty. Moreover, autonomous inhibin B secretion by the prepubertal human testis is likely to reflect the number of Sertoli cells.
Adolescent↗
Novel treatment of short stature with aromatase inhibitors.
Estrogens have an essential role in the regulation of bone maturation and importantly in the closure of growth plates in both sexes. This prospective, randomized, placebo-controlled study was undertaken to evaluate whether suppression of estrogen synthesis in pubertal boys delays bone maturation and ultimately results in increased adult height. A total of 23 boys with constitutional delay of puberty (CDP) received a conventional, low-dose testosterone treatment for inducing progression of puberty. Eleven of these 23 boys were randomized to receive a specific and potent P450-aromatase inhibitor, letrozole, for suppression of estrogen action, and 12 boys were randomized to receive placebo. Estradiol concentrations in the letrozole-treated boys remained at the pretreatment level during the administration of letrozole, whereas the concentrations increased during the treatment with testosterone alone and during spontaneous progression of puberty. Testosterone concentrations increased in all groups, but during the letrozole treatment, the increase was more than fivefold higher than in the group treated with testosterone alone. The inhibition of estrogen synthesis delayed bone maturation. The slower bone maturation in the boys treated with testosterone and letrozole, despite higher androgen concentrations, than in the boys treated with testosterone indicate that estrogens are more important than androgens in regulation of bone maturation in pubertal boys. During the 18 months follow-up, an increase of 5.1 cm in predicted adult height was observed in the boys who received testosterone and letrozole, but no change was seen in the boys who received testosterone alone or in the untreated boys. This finding indicates that an increase in adult height can be attained in growing adolescent boys by inhibiting of estrogen action.
Adolescent↗
Disturbances of puberty.
The initiation and progress of puberty requires progressive pulsatile stimulation of the pituitary by GnRH and of the gonads by LH and FSH. Gonadal maturation continues throughout childhood and is not confined to puberty. We have discussed the events of normal puberty and emphasized the consonance of the acquisition of different components of sexual maturation, including growth acceleration. Departure from this consonance is a sign of abnormality. The method by which constitutional delay of growth and puberty can be distinguished from gonadotrophin deficiency has been discussed as well as the treatment options for both conditions. We have emphasized the significance of pulsatile gonadotrophin secretion and how the development of a multicystic ovarian morphology on ultrasound can be used as a non-invasive assessment of gonadotrophin pulsatility in girls. Pulsatile GnRH therapy mimics normal puberty. The converse of suppressing the clinical signs of central precocious puberty can be achieved by abolishing gonadotrophin pulsatility with GnRH analogue therapy. We now recognize qualitative pulse abnormalities of gonadotrophin secretion which occur in isolated premature thelarche and in some cases of delayed puberty. Although clinical assessment remains the key to the diagnosis of disorders of puberty, studies of gonadotrophin pulsatility have aided our understanding and treatment of these conditions.
Adolescent↗
Genetics of hypogonadotropic hypogonadism.
Determining the physiologic influences that modulate GnRH secretion, the prime initiator of reproductive function in the human, is fundamental not only to our understanding of the rare condition of congenital idiopathic hypogonadotropic hypogonadism (IHH), but also common disorders such as constitutional delay of puberty and hypothalamic amenorrhea. IHH is characterized by low levels of sex steroids and gonadotropins, normal findings on radiographic imaging of the hypothalamic-pituitary regions, and normal baseline and reserve testing of the remainder of the hypothalamic-pituitary axes. Failure of the normal pattern of episodic GnRH secretion results in delay of puberty and infertility. IHH is characterized by rich clinical and genetic heterogeneity, variable modes of inheritance, and association with other anomalies. To date, 4 genes have been identified as causes of IHH in the human; KAL [the gene for X-linked Kallmann syndrome (IHH and anosmia)], DAX1 [the gene for X-linked adrenal hypoplasia congenita (IHH and adrenal insufficiency)], GNRHR (the GnRH receptor), and PC1 (the gene for prohormone convertase 1, causing a syndrome of IHH and defects in prohormone processing). As these mutations account for less than 20% of all IHH cases, discovery of additional gene mutations will continue to advance our understanding of this intriguing syndrome.
Aspartic Acid Endopeptidases↗
Activation of AMPA receptors inhibits prolactin and estradiol secretion and delays the onset of puberty in female rats.
Previous experiments have evidenced the neuroendocrine role of AMPA receptors. Present studies were carried out to obtain information on the role of these receptors in the control of the onset of puberty. To this end, female rats were i.c.v. injected with vehicle or AMPA (agonist of AMPA receptors: 0.1 or 0.5 nmol/day) between 26 and 30 days (Experiment 1), or 30 and 34 days (Experiment 2) of age. Serum concentrations of PRL, LH and estradiol were measured before drug administration, 10 min after the last injection, at vaginal opening (VO) and at first estrus (FE) presentation. In both experiments, AMPA administration inhibited PRL and estradiol secretion without affecting LH release. When AMPA was administered between 26 and 30 days a significant delay in the day of vaginal opening was observed. These results confirmed the inhibitory effect of AMPA on PRL secretion and suggests a role of AMPA receptors in the control of puberty onset.
Age Factors↗
The effect of asthma and its treatment on growth.
Asthma has little, if any, significant effect on attained adult height. Untreated asthma results in a delay of puberty by approximately 1.3 years, and pubertal delay is likely to explain the majority of apparent growth failure in asthmatics. All currently available inhaled corticosteroids (ICS) result in growth suppression at conventional doses (400 microg/day of beclomethasone dipropionate equivalent), but the growth suppressive effects are relatively short lived, after which growth reverts to pretreatment levels. Younger, prepubertal children, appear more sensitive to the growth suppressive effects of ICS. Asthmatic children receiving conventional doses of ICS (400 microg/day of BDP equivalent) will attain an adult height indistinguishable from their predicted adult height (based on their mid parental height), and no different from non-asthmatics. Adult height could possibly be decreased in severe asthmatics, but this is unlikely to be greater than a 1.2 cm decrement. Recent longitudinal studies offer reassurance that at conventional doses ICS do not have significant long term effects on growth, and that their benefits consistently outweigh their side effects.
Administration, Inhalation↗
Sexual development of the fetus and pubertal child.
The disorders of sexual differentiation and maturation are a fascinating study in physiology. The interaction of chromosomes, regulation of transcription, as well as hormone production and action are far from being completely understood. Aberrations anywhere along these systems can cause abnormal sexual development. It is important for the practicing obstetrician and gynecologist to be cognizant of these conditions and include them in differential diagnoses so that removal of dysgenetic gonads is not delayed, inappropriate sexual assignment is not announced, and the treatment of TS or other sexually immature girls is not handled hastily.
Adolescent↗
Is complete catch-up possible for stunted malnourished children?
Although malnourished children are stunted, their bone maturity is usually retarded to a comparable degree. This is seen in impoverished societies as well as in diseases such as coeliac disease, inflammatory bowel disease and hormonal deficiency. When these children are followed to adulthood they normally have some degree of spontaneous catch-up. With a change in environment, through adoption, emigration or with treatment of the disease there is usually definite catch-up growth, although it is often not to the NCHS standards. If puberty is delayed and/or growth continues into the early or mid twenties, then an acceptable final adult height is achieved. However, there may be a limitation imposed on an individual's maximum height by genetic imprinting in very early development. This may be the case where full catch-up appears to have taken place but is followed by an advanced puberty and early cessation of growth (Proos, Hofvander & Tuvemo, 1991a). The data from US slaves and cases of hormonal replacement, where treatment was initiated after age 18, each show that, if the circumstances of children in the Third World change, almost complete reversal of stunting is possible. The children can reach their own height potentials. Total reversal to affluent societal norms would probably require cross-generational catch-up. The most obvious reason why catch-up is not seen regularly is that an appropriate diet is not available over a sufficient period of time. We do not know the optimum ingredients for such a diet. Sulphur has been neglected as an essential nutrient; its economy should be examined in relation to skeletal growth in stunted populations.
Adolescent↗
The N-methyl-D-aspartate receptor antagonist MK-801 delays the onset of puberty and may acutely block the first spontaneous LH surge and ovulation in the rat.
The physiological role of activated hypothalamic N-methyl-D-aspartate (NMDA) receptors during the final phase of female sexual maturation was explored in the rat. The effects of administration of the specific non-competitive receptor antagonist MK-801 on the occurrence of first ovulation and on LH secretion were studied. Injections of MK-801 (0.1-0.2 mg/kg body wt, s.c.) were given once or twice daily, starting at 28 or 35 days of age and continuing up to the day of first ovulation, resulted in a significant delay of this ovulation. Rats that were treated daily with 0.2 mg MK-801/kg, starting on days 30 or 34 and continuing up to day 38, but not including the day of first pro-oestrus, also showed retarded first ovulation. No decrease in serum LH concentration, compared with control rats, could be detected in these rats. Acute treatment with MK-801 (one or two injections of 0.2, or one injection of 0.5 mg/kg) given at 11.30 h (and 16.00 h) on the day of first pro-oestrus produced partial (1 x 0.2 mg/kg) or complete (2 x 0.2 and 1 x 0.5 mg/kg) blockade of first ovulation; blocked rats ovulated 1 day later. Serum LH concentrations at 16.00 h on the day of pro-oestrus were significantly decreased in all MK-801-treated groups compared with saline-injected control rats. At 19.00 and 22.00 h LH concentrations remained low in all non-ovulating MK-801-treated rats, but increased in the MK-801-treated rats and ovulated.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Caloric balance, brain to body ratio, and the timing of menarche.
Caloric availability regulates female reproductive function. Menses do not normally occur until the amount of stored fat is sufficient to meet the nutritional requirements of pregnancy. Unusual energy drains such as heavy exercise cause a reversible cessation of menses. The brain appears to monitor the balance between the availability of calories and their utilization, and reproduction is suppressed when the balance is unfavorable. We postulate that the juvenile human brain, with its unique metabolic requirements, constitutes an important energy drain in the premenarchal girl, and that caloric utilization by the brain may explain the delay of reproductive competence in man. It follows that the changing energy requirements of the brain relative to the body during normal premenarchal growth may play a key role in the timing of menarche. Pathological examples of altered brain to body ratios support this hypothesis: an increase of the brain to body ratio has been observed to delay menarche, a decrease of the brain to body ratio to advance menarche. We explore several clinical implications of this hypothesis and present suggestions for its experimental evaluation.
Adolescent↗