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PubMed1980

The prolactin response to metoclopramide in growth hormone deficient adolescent males.

The growth hormone (GH) and prolactin (PRL) responses following administration of 10 mg i.v. metoclopramide (MCP) ('Maxolon'--Beecham Pharmaceuticals) have been examined in thirty adolescent males with short stature and delayed puberty, either of whom have isolated growth hormone deficiency. The results demonstrate that peak GH and PRL levels following stimulation were highly significantly correlated when all subjects were analysed together (r = 0.61, P < 0.001) but when the responses of the GH deficient and non-deficient groups of subjects were analysed separately no significant correlation was obtained (P > 0.1), this reflected the fact that the PRL response to MCP was significantly lower in the GH deficient group (P < 0.0002). In addition two boys who demonstrated biochemical GH deficiency prior to puberty only, showed PRL responses similar to boys with normal GH reserves. The results suggest that the PRL response to MCP may be of value in the assessment of stimulation tests of GH reserve, as well as in the selection of patients for treatment with GH.

Adolescent↗
PubMed1988

The mechanism of the adolescent growth spurt induced by low dose pulsatile GnRH treatment.

We have used GnRH administered in a pulsatile fashion to treat 26 patients (12M:14F) with delayed puberty. Treatment was for a mean of 1.05 years (range, 0.3-1.6). Mean age at the onset of treatment was 16.4 years in the girls (range, 12.7-28.2) and 15.8 years in the boys (range, 13.8-17.8). At different stages of sexual maturation, overnight serum samples for growth hormone (GH) were taken at 15 min intervals between 2000 h and 0600 h. The girls had a peak growth velocity which occurred between breast stages 2 and stage 3 (B2/3). GH secretion (both sum of the GH peaks and area under the GH pulse) increased at B2 and reached a peak at B3. Growth acceleration in the boys started at the attainment of a 9-10 ml testicular volume and reached a peak at 11-15 ml. The boys demonstrated an initial fall in GH secretion with the onset of treatment until the attainment of 9-10 ml testicular volume; peak GH secretion occurred at the attainment of 11-12 ml testicular volume. There was no change in GH pulse frequency during treatment in either sex. These observations and the maintenance of the normal relationship of the growth spurts to the appearance of secondary sexual characteristics are relevant to the mechanisms and timing of the adolescent growth spurts in normal girls and boys.

Circadian Rhythm↗
PubMed1987

Familial transmission of a ring chromosome 21.

A ring chromosome 21 was found in a phenotypically normal mother and her son. The clinical findings in the son were bilateral retention of the testes and a slightly delayed puberty onset. Consequences of a ring formation of a chromosome 21 in phenotypically normal patients are presented and discussed, and the previously reported cases of familially transmitted G-group ring chromosomes are reviewed.

Adolescent↗
PubMed1996

Nocturnal secretory patterns of melatonin, luteinizing hormone, prolactin and cortisol in male patients with gonadotropin-releasing hormone deficiency.

To clarify whether disorders of gonadotropin releasing hormone (GnRH) deficiency are associated with altered melatonin and pituitary hormones secretory patterns, we studied male patients with hypogonadotropic hypogonadism (IGD; n = 6), delayed puberty (DP; n = 7) and age-matched pubertal controls (n = 7). Serum samples for the determination of melatonin, luteinizing hormone (LH), prolactin and cortisol levels were obtained at 15 min intervals from 1900 to 0700 in a controlled light-dark environment, complete bed-rest and fasting with simultaneous sleep recordings. Mean (+/- SD) dark-time melatonin levels were significantly higher in IGD (286 +/- 26 pmol/L) and DP (205 +/- 44 pmol/L) compared with 178 +/- 64 pmol/L in controls (P < 0.003). So were the mean (+/- SD) peak melatonin levels (453 +/- 63, 346 +/- 106 and 292 +/- 96 pmol/L) in IGD, DP and controls, respectively (P < 0.03). Integrated nocturnal melatonin (AUC) values were also higher in IGD and DP (184 +/- 15 and 134 +/- 28 pmol/min/L x 10(3)) compared with 116 +/- 42 pmol/min/L x 10(3) in controls (P < 0.003). The time of onset of the nocturnal melatonin rise was observed earlier in IGD and DP patients as compared to controls. No correlations were found between melatonin and LH levels, between melatonin and prolactin levels, or between melatonin and cortisol levels. These data indicate that melatonin secretion is enhanced in male patients with GnRH deficiency. The lack of correlation between melatonin and LH suggest that circulating gonadal steroids, rather than LH, modulate melatonin secretion in a reverse fashion.

Adolescent↗
PubMed1997

Pulsatile patterns of melatonin secretion in patients with gonadotropin-releasing hormone deficiency: effects of testosterone treatment.

Recently, we have demonstrated that male patients with gonadotropin-releasing hormone (GnRH) deficiency had increased nocturnal melatonin secretion that decreased to normal levels during testosterone treatment. The purpose of the current study was to examine if the abnormally increased melatonin levels in these patients were associated with pulsatile secretory patterns, and, if these were modified during testosterone administration. Characteristics of nocturnal melatonin and luteinizing hormone (LH) secretion were compared in six normal young males, six males with idiopathic hypogonadotropic hypogonadism (IGD), and in six males with constitutional delayed puberty (DP). Patients were examined in the untreated state and following the administration of 250 mg testosterone enanthate/month for 4 months. Serum samples for melatonin and LH levels were obtained every 15 min from 19.00 hr to 07.00 hr in a controlled light-dark environment. Pulse detection and pulse characteristics were determined by the program ULTRA. In comparison with normal controls, untreated IGD patients showed significantly higher pulse frequency, lower relative increments and shorter half-life times for melatonin. Similar findings were observed in DP patients, although statistically of borderline significance. Treatment with testosterone normalized melatonin pulse characteristics in both IGD and DP patients. The secretory pattern of LH release in these patients was characterized by significantly higher relative and absolute increments and shorter half-life time without any significant change in the number of LH pulses. Taken together, these data suggest that melatonin is secreted in a pulsatile pattern in normal adult males and in male patients with GnRH deficiency. The abnormally increased nocturnal melatonin secretion observed in these patients may indicate that the pineal pulse generator is expressing an altered activity pattern within its normal capabilities. Testosterone administration normalized melatonin secretory patterns in IGD and DP patients. The lack of relationship between the pulsatile LH and melatonin secretory patterns suggest an independent signal for the nocturnal pulsatile melatonin and LH secretions.

Adolescent↗
PubMed2006

Gender-related differences in urinary 6-sulfatoxymelatonin levels in obese pubertal individuals.

The objective of this study was to measure the urinary excretion of the main melatonin metabolite 6-sulfatoxymelatonin in obese and normal weight (wt) boys and girls. The study included 94 subjects, aged 4-15.7 yr (50 obese and 44 normal wt; 48 boys) classified as: mid-childhood (4-7.99 yr), late-childhood (8-12 yr) and pubertal (10.1-15.7 yr, Tanner II-IV). Normal wt subjects were children with a body mass index (BMI) between the 25th and 75th percentiles, and the group of obese subjects included children whose BMI was above the 97th percentile. A 24-hr urine sample was collected during two intervals: (i) 18:00-08:00 hr, and (ii) 08:00-18:00 hr. Analysis of urinary 6-sulfatoxymelatonin levels was performed by radioimmunoassay. Excretion of 6-sulfatoxymelatonin was expressed as: (i) total amount excreted (microg); (ii) mug excreted per time interval, nocturnal or diurnal; and (iii) the difference between nocturnal and diurnal samples (microg, estimated amplitude). A factorial analysis of variance indicated that nocturnal 6-sulfatoxymelatonin excretion and amplitude were significantly higher in the obese individuals. A significant interaction 'BMI x age' was detected, i.e. the effect of BMI was significant in the pubertal group only. Total, nocturnal and diurnal 6-sulfatoxymelatonin excretion was significantly higher in girls. The increase in 6-sulfatoxymelatonin excretion found in obesity occurred only in boys and at the pubertal age. To what extent this increase in melatonin production contributes to a delayed puberty in some pubertal obese males remains to be established.

Adolescent↗
PubMed1988

Growth and endocrine function after renal transplantation.

Longitudinal height data and physical development were assessed in 45 boys and 34 girls after renal transplantation. All children received alternate day steroids and either azathioprine or cyclosporin A for immunosuppression. There was a significant increase in growth velocity after transplantation in prepubertal children. Growth velocity declined at the expected age of the normal pubertal growth spurt, however, with delay in the appearance of secondary sexual characteristics. Overnight hormone profiles in 17 adolescent subjects with short stature or maturational delay, or both, showed blunting of growth hormone and gonadotrophin pulsatility. It is likely that long term steroid treatment after renal transplantation induces the clinical and endocrine picture of delayed puberty. Failure of growth to accelerate at this time is a cause of short stature, which may have an effect on adult height.

Adolescent↗
PubMed1996

Renovascular and growth effects of childhood sarcoid.

A boy developed early onset sarcoidosis, an extremely rare mimic of juvenile chronic arthritis. Renal granulomas caused severe hypertension and renal impairment, which was controlled by azathioprine and steroids. Severe uveitis caused visual impairment. Impaired growth and delayed puberty, not previously described in childhood sarcoidosis, required growth hormone and testosterone treatment.

Child, Preschool↗
PubMed1984

Galactorrhoea following hypophysectomy in a boy with a prolactinoma.

An 18-year-old boy with delayed puberty was found to have a large prolactinoma. Hypophysectomy led to a fall in serum prolactin concentration, although it remained markedly elevated. The introduction of replacement therapy, including testosterone, resulted in painful swelling of the breasts and galactorrhoea. Bromocriptine therapy resulted in a cessation of galactorrhoea and normalization of serum prolactin concentrations. The absence of galactorrhoea in association with an astronomical concentration of prolactin, and its onset in association with diminished prolactin concentrations following hypophysectomy and the introduction of testosterone therapy, indicate that galactorrhoea requires the presence of high prolactin concentrations to act on mature breast tissue. This would account for the rarity of galactorrhoea in prepubertal children with prolactinomas.

Adenoma, Chromophobe↗
PubMed2003

X chromosome-linked Kallmann syndrome: clinical heterogeneity in three siblings carrying an intragenic deletion of the KAL-1 gene.

Kallmann syndrome (KS) is characterized by the association of hypogonadotropic hypogonadism and anosmia. The gene underlying the X chromosome-linked form of the disease, KAL-1, consists of 14 coding exons. It encodes a glycoprotein, anosmin-1, which is involved in the embryonic migration of GnRH-synthesizing neurons and the differentiation of the olfactory bulbs. We describe herein the clinical heterogeneity in three affected brothers who carry a large deletion (exons 3-13) in KAL-1. All three had a history of hypogonadotropic hypogonadism with delayed puberty. Although brain magnetic resonance imaging showed hypoplastic olfactory bulbs in the three siblings, variable degrees of anosmia/hyposmia were shown by olfactometry. In addition, these brothers had different phenotypic anomalies, i.e. unilateral renal aplasia (siblings B and C), high-arched palate (sibling A), brachymetacarpia (sibling A), mirror movements (siblings A and B), and abnormal eye movements (sibling C). Last but not least, sibling A suffered from a severe congenital hearing impairment, a feature that had been reported in KS but had not yet been ascribed unambiguously to the X-linked form of the disease. The variable phenotype, both qualitatively and quantitatively, in this family further emphasizes the role of putative modifier genes, and/or epigenetic factors, in the expressivity of the X-linked KS.

Adolescent↗
PubMed1984

Effect of testosterone on somatomedin-C concentrations in prepubertal boys.

To investigate the role of testosterone (T) in the pubertal elevation of somatomedin-C (SmC), six prepubertal GH-deficient boys were each given 7-day courses of GH alone (0.05 U/kg X day, im), T alone (T propionate; 25 mg/day, im), and a combination of GH and T at the same dosages. Plasma SmC levels were determined on samples drawn at the start and finish of each period, and each course was separated by a 7-day period. SmC was also measured before and after a course of T propionate (25 mg/day, im) in four GH-sufficient boys with delayed adolescence. In the GH-deficient boys, GH and the combination of GH and T resulted in comparable and significant increments of SmC (mean change, 0.68 U/ml after GH and 0.63 U/ml after the combination of GH and T). T alone caused no change in SmC in the GH-deficient boys (mean change, 0.09 U/ml), but resulted in increases in all four GH-sufficient subjects (mean change, 1.29 U/ml). In a single subject with constitutionally delayed puberty, the integrated 24-h GH concentration rose from 2.8 ng/ml before to 5.8 ng/ml after T therapy. Both the number and amplitude of GH secretory events were greater after therapy. These data show that T stimulates SmC production in prepubertal boys who can secrete GH, but not in those who are GH deficient. We postulate that the effect of T in this regard is due to its effect on pituitary GH secretion. Although the T levels were within the pharmacological range, physiological levels of T (e.g. at puberty) may be responsible for the adolescent SmC increment in men.

Adolescent↗
PubMed1992

Pitfalls in diagnosing impaired growth hormone (GH) secretion: retesting after replacement therapy of 63 patients defined as GH deficient.

Possible causes of error in the diagnosis of isolated GH deficiency are the variability of GH response to repeated tests, the existence of transient GH deficiencies, and the low GH levels found in short statured children with delayed puberty. Sixty-three patients with variously expressed GH deficiency were retested (1 sleep test and 2 pharmacological tests) after 1-3.9 yr of GH therapy (dose, 15 U/m2.week). Forty-eight subjects had arginine, L-dopa, and sleep tests (mean serum GH concentration) twice, while 15 had only arginine and L-dopa tests. All patients were retested 1 month after withdrawal from therapy. The criteria used to subdivide the patients were pubertal development and response to pharmacological and sleep tests at first diagnosis and on retesting. The initial diagnosis in 33 subjects (52.4%) was not confirmed, and 13 (20.6%) were no longer deficient on retesting. The percentage of normalization was high for the sleep test (43.9%), lower for the pharmacological test (24.5%), and lower still (12.9%) for pharmacological and sleep tests considered together. While none of the 28 subjects who remained prepubertal at retesting normalized in any of the tests, 13 of the 35 subjects retested during puberty did. When normalization was observed in pubertal subjects, it occurred predominantly in the sleep test. Growth velocity and height age/bone age increment ratio after the first year of therapy were no different for the groups of subjects classified according to GH secretion on retesting. Our study demonstrates that a number of children diagnosed as GH deficient do not have a true deficiency. However, such a diagnostic error seems to have little effect, at least in the first year of therapy, on the effectiveness of GH treatment.

Adolescent↗
PubMed1996

Testosterone treatment alters melatonin concentrations in male patients with gonadotropin-releasing hormone deficiency.

Recently, we demonstrated that melatonin secretion is increased in untreated male patients with GnRH deficiency. As testosterone (T) can be aromatized to estradiol (E2), and both T and E2 increase during T enanthate treatment, we were interested in determining whether T treatment (when T and E2 levels were well matched with pubertal control values) has an effect on melatonin levels in these patients. We measured nocturnal serum melatonin levels during the administration of 250 mg testosterone enantale/month for 4 months in 12 male patients with idiopathic hypogonadotropic hypogonadism (IGD; n = 6) and delayed puberty (DP; n = 6). Serum samples for melatonin and LH determinations were obtained every 15 min from 1900-0700 h in a controlled light-dark environment. The results of melatonin profiles were compared with the pretreatment values in each group and with values obtained in six normal pubertal male controls. After 4 months of testosterone treatment, all patients attained normal serum testosterone (19.5 +/- 3.7 in IGD vs. 20.8 +/- 4.1 nmol/L in DP) and E2 levels (83 +/- 12 in IGD vs. 84 +/- 9 pmol/L in DP). Serum LH levels were suppressed in all patients during T treatment (0.12 +/- 0.1 in IGD vs. 0.12 +/- 0.2 IU/L in DP). Before T treatment, patient melatonin levels were greater than those in age-matched pubertal controls. Melatonin levels were equal in patients and controls when T and E2 levels were well matched. Mean (+/- SD) dark-time melatonin levels decreased from 286 +/- 23 to 157 +/- 36 pmol/L in IGD and from 217 +/- 32 to 133 +/- 47 pmol/L in DP (vs. 183 +/- 64 pmol/L in controls). The integrated melatonin values decreased to normal (from 184 +/- 16 to 102 +/- 21 in IGD and from 142 +/- 19 to 90 +/- 26 pmol/min.L x 10(3) in DP vs. 119 +/- 61 pmol/min.L x 10(3) in controls). The intraindividual variations in melatonin levels ranged from 7.2-14.5%. These data indicate that male patients with GnRH deficiency have increased nocturnal melatonin secretion. T treatment decreased melatonin secretion to normal levels. The results suggest that in GnRH-deficient male patients, sex steroids, rather than LH, modulate pineal melatonin in a reverse fashion.

Adolescent↗
PubMed2005

Haploinsufficiency of chicken ovalbumin upstream promoter transcription factor II in female reproduction.

The chicken ovalbumin upstream promoter transcription factor II, COUP-TFII, is a member of the orphan nuclear receptor transcription factor family. Genetic ablation of COUP-TFII results in early embryonic lethality and demonstrates that this gene is required for cardiac and vascular development. Expression of COUP-TFII persists throughout postnatal life in various tissues including the female reproductive tract. However, the physiological function of COUP-TFII in female reproduction has not been extensively analyzed. Here, we provide phenotypic evidences that haploinsufficiency of COUP-TFII in mice demonstrates an important role of COUP-TFII for normal female reproduction. COUP-TFII +/- females show significantly reduced fecundity, irregular estrus cycles, delayed puberty, and retarded postnatal growth. Analysis of the reduced fertility revealed that although ovarian function was normal with respect to ovulation, the ovaries have reduced ability to synthesize progesterone in response to exogenous gonadotropins. This reduction is due to the reduction of the expression of steroidogenic enzymes important for progesterone synthesis and the reduction of vascularization in COUP-TFII heterozygotes. Analysis of uterine function demonstrated a reduced response to an experimentally induced decidual cell reaction indicating that the ability of the uterus to support embryo implantation was reduced. Taken together, our data show global impact of gene dosage effects of COUP-TFII on female postnatal life and indicates requirement of COUP-TFII in normal female reproduction, in particular for uterine endometrial functions during the peri-implantation period.

Animals↗
PubMedDate not supplied

Clinical evaluation in isolated hypogonadotrophic hypogonadism (Kallmann syndrome).

OBJECTIVE: To describe the clinical features, laboratory investigation and treatment of Kallmann syndrome. DESIGN: A retrospective study of patients treated in the Endocrine Clinic of the Royal Children's Hospital and St Vincent's Hospital, Melbourne, between 1984 and 1996. RESULTS: Eleven males and 5 females with Kallmann syndrome are described. Their ages at presentation ranged from one week to 21 years. Presenting symptoms were micropenis, small testes, anosmia and delayed puberty. Fifty-six percent (9/16) had a family history of either anosmia or infertility. The features of Kallmann syndrome are variable. We have described unilateral renal aplasia, coloboma of iris, deafness, midline anomalies, oculomotor apraxia and Moebius anomalad as features that were associated with Kallmann syndrome in our group of subjects. One patient diagnosed as having X-linked Kallmann syndrome has previously been shown to have a specific mutation in an intronic sequence adjacent to exon 6. Most patients showed low serum levels of basal gonadotrophins, testosterone or oestrogen, and had a poor response to LHRH stimulation, but two patients showed a pubertal response to LHRH stimulation, and may have a variant form of Kallmann syndrome. Treatment given to these patients included exogenous testosterone or oestrogen for induction of puberty, with appropriate pubertal progress occurring in each patient. CONCLUSION: The manifestations of Kallmann syndrome vary, depending upon the degree of LHRH deficiency. Therapy should combine exogenous sex hormone replacement and psychological support, with long-term follow-up to ensure maintenance of normal sexual function, normal bone mass and psychosocial outcome, with fertility induction when indicated.

Adolescent↗
PubMed2002

Hypogonadotrophic hypogonadism associated with prelingual deafness due to a connexin 26 gene mutation.

In Mediterranean countries, almost half the incidence of non-syndromic congenital hearing loss is caused by mutations in the gap junction (GJ) connexin 26 gene (GJB2/DFNB1 locus). In this form of deafness the cochlear defect is usually isolated. We describe here the first case of hypogonadotrophic hypogonadism in association with this particular cochlear defect. The male patient had moderate deafness inherited from his deaf parents. All family members had a homozygous 35delG mutation in the connexin 26 gene. This mutation accounts for 70% of all connexin 26 gene mutations. The patient was referred to a paediatric endocrinology unit at 11 years of age for moderate growth retardation. Growth rate was normal until 11 years. The patient then presented delayed puberty (testicular volume 4 ml, penis length 4 cm) and did not undergo the usual pubertal growth spurt. LH and FSH secretory responses to GnRH at the age of 14.5 years (bone age 13.5 years), were: LH baseline level 1.1 IU/l, peak 34 IU/l; FSH baseline level 1.8 IU/l, peak 5.7 IU/l. Testosterone concentration was <0.11 ng/ml. From 11 to 14 years old, testosterone concentration ranged from 0.11 to 0.2 ng/ml. Anti-Mullerian hormone (AMH) level was 38.6 ng/ml (normal for Tanner stage I), cortisol 109 ng/ml, and ACTH 37 pg/ml., Karyotype was 46 XY. On MRI analysis, the anterior pituitary and olfactory bulbs were normal. These data were consistent with partial hypogonadotrophic hypogonadism of hypothalamic origin, and the patient was treated with testosterone. This report supports the possible involvement of connexins in puberty initiation. Connexins may play a part in the co-ordination and synchronisation of GnRH release.

Adolescent↗
PubMed2002

Basal ultrasensitive LH assay: a useful tool in the early diagnosis of male pubertal delay?

The aim of this study was to evaluate the usefulness of basal measurements of gonadotropins in distinguishing between constitutionally delayed puberty (DP) and hypogonadotropic hypogonadism (HH), comparing its diagnostic efficiency with that of the dynamic GnRH infusion test (0.83 microg/min during 120 min). We studied 20 males, chronological age (CA) 14-18 years, with a final diagnosis of DP (n = 8), partial HH (n = 5) and complete HH (n = 7), confirmed by follow-up. We also evaluated basal samples of ultrasensitive LH and FSH in 117 healthy control males (CA 2-19 yr), classified according to Tanner stage. In the control group, ROC plot analysis showed a cutoff to differentiate prepuberty from puberty of 0.65 IU/l for LH (sensitivity: 91%, specificity: 98%). Differences were found (p < 0.05) in basal LH and in maximal responses to GnRH in complete HH in relation to DP and partial HH. The diagnostic efficiency of the GnRH infusion test was 85%. For basal LH, a cut-off limit of 0.65 IU/l showed a diagnostic efficiency of 85% for complete HH and 100% for partial HH and DP. We conclude that, in our experience, basal LH levels above 0.65 IU/l measured by ultrasensitive assay would rule out a complete deficiency. It was not possible to differentiate DP from partial HH, either in basal samples or with the infusion test.

Adolescent↗
PubMed2002

Anorexia nervosa in female adolescents: endocrine and bone mineral density disturbances.

Anorexia nervosa (AN) is a chronic childhood psychiatric illness that involves a reduction in caloric intake, loss of weight and amenorrhea, either primary or secondary. The diagnostic criteria for AN have been established by the American Psychiatric Association. The prevalence of this disease amongst adolescents and young adults is between 0.5 and 1% and the incidence of new cases per year is approximately 5-10/100,000 between 15 and 19 years of age.A number of endocrine and metabolic disturbances have been described in patients with AN including amenorrhea-oligomenorrhea, delayed puberty, hypothyroidism, hypercortisolism, IGF-I deficiency, electrolyte abnormalities, hypoglycemia and hypophosphatemia, among others. In addition to prolonged amenorrhea, osteopenia and osteoporosis are the most frequent complications leading to clinically relevant fractures and increased fracture risk throughout life. Patients exhibit an alteration in the hypothalamic-pituitary-gonadal axis, which is responsible for the menstrual disorders. The increase in gonadotropin secretion that can be observed after ponderal recuperation suggests that malnutrition could be the most important mechanism involved in the decrease in gonadotropin secretion. The loss of fat tissue as a consequence of nutrient restriction has been associated with hypoleptinemia and abnormal secretion of peptides implicated in food control (neuropeptide Y, melanocortins and corticotropin-releasing factor, among others).A review of the endocrine abnormalities, disturbances in neurotransmitters, as well as a detailed analysis of bone markers and bone mineral density in patients with AN is described.

Adolescent↗