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PubMed1987

Dissociation of adrenarche and gonadarche in precocious puberty and in isolated hypogonadotropic hypogonadism.

Adrenarche is a developmental change of the adrenal gland that results in increased secretion of adrenal androgens. This maturational process generally begins several years before activation of the hypothalamic-pituitary-gonadal axis (gonadarche). To study further the relationship between adrenarche and gonadarche, we examined adrenarche in patients with precocious puberty and in patients with isolated hypogonadotropic hypogonadism. Plasma dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and cortisol were measured basally and during an infusion of ACTH in 50 children with precocious puberty, 5 patients with isolated hypogonadotropic hypogonadism, 7 preadrenarchal children with constitutional short stature, 44 normal pubertal children, and 40 normal adults. Children with precocious puberty did not have a corresponding advance in the timing of adrenarche. Their basal and ACTH-stimulated adrenal androgen levels were markedly lower than those of normal children matched for pubertal stage (P less than 0.05) and were only slightly greater than those reported for normal children of the same age. Similarly, patients with isolated hypogonadotropic hypogonadism and delayed puberty had no corresponding delay of adrenarche. Their adrenal androgen levels were appropriate for chronological age. Thus, these data provide further support for the hypothesis that adrenarche and gonadarche are independent maturational events controlled by separate mechanisms.

Adolescent↗
PubMed1991

Serum melatonin in central precocious puberty is lower than in age-matched prepubertal children.

In children a progressive decrease in nocturnal serum melatonin (MT) has been shown with advancing age, suggesting a reduction in the amplitude of the circadian MT curve with maturation. Whether this alteration of MT levels is related to human sexual maturation or occurs independently remains to be elucidated. Also, the impact of gonadal steroids on the MT rhythm remains an open question. We examined 56 patients (51 females and 5 males) with central precocious puberty (52 idiopathic and 4 neurogenic). Patients were studied before and 3, 6, and 12 months after initiation of GnRH analog treatment. Three hundred and thirty-seven endocrinologically normal subjects (190 males and 147 females) served as controls. In all subjects nocturnal serum MT (blood collection between 2300 and 0100 h) was measured with a highly specific RIA. In young patients, aged 1-5 yr, we found significantly lower MT levels than in age-matched controls. Pubertal patients, aged 5-9 yr, displayed nocturnal MT levels in the same range as control subjects approaching normal pubertal age. In contrast to endocrinologically normal children, there was no age-dependent decrease in nocturnal MT in untreated precocious puberty; rather, it appeared that serum MT had already declined in association with the onset of sexual maturation. Although there was a significant difference in weight between patients and age-matched controls, the low MT values in patients 1-5 yr old were only partly explained by the weight difference (P less than 0.0009); their pubertal status also contributed significantly (P less than 0.006). Pituitary-gonadal suppression induced by long term GnRH analog treatment did not result in a return to prepubertal MT levels; rather, nocturnal MT decreased during therapy. The collected data indicate that nocturnal serum MT levels are related to sexual maturation, since serum MT is similar in precocious puberty and normal pubertal children. Since suppression of the pituitary-gonadal axis did not result in increases in nocturnal MT levels in young patients with precocity (i.e. return to age-appropriate levels), the reduction of nocturnal MT with normal puberty is not likely to be dependent on pubertal gonadotropin or sex steroid milieu.

Aging↗
PubMed1991

Adult height in precocious puberty after long-term treatment with deslorelin.

Precocious puberty often leads to short adult height. Since the introduction of luteinizing hormone-releasing hormone (LHRH) agonist treatment for LHRH-dependent precocious hormone (LHRH) agonist treatment for LHRH-dependent precocious puberty in 1979, several reports have shown increased predicted height among LHRH agonist-treated children. To determine whether the LHRH agonist deslorelin can normalize the adult height of children with precocious puberty, we are conducting a long-term pilot study involving 161 children. This report describes the first 44 children to have attained final or proximate adult height. These children were 7.1 +/- 1.2 (mean +/- SD) yr old (bone age 11.8 +/- 1.5 yr) and had been in puberty for 3.1 +/- 0.3 yr at the start of treatment. They were treated with deslorelin (4 micrograms/kg/day sc) for 4.1 +/- 1.3 yr and had been withdrawn from treatment for an average of 2.4 yr at the time of this study (age 13.6 +/- 0.9 yr). Fourteen of the 44 children, who had grown less than 0.5 cm during the previous year, were considered to have attained adult height. The other 30 children had achieved 98.6% of predicted mature height (Bayley-Pinneau method) and were considered to be at proximate adult height. The final or proximate adult height of these 44 children averaged -1.1 SD compared to the adult height of the normal population. This height was significantly greater than the pretreatment height (-1.1 vs. -2.0 SD, P less than 0.01), but significantly less than both the predicted height at the end of treatment (-1.1 vs. -0.5 SD, P less than 0.01) and the target height derived from the mean height of the parents adjusted for the sex of the child (-1.1 vs. 0.1 SD, P less than 0.01). The observation that the Bayley-Pinneau height prediction at the end of treatment overestimated the actual adult height emphasizes the importance of using final height data to assess the ultimate impact of LHRH agonist treatment. It also indicates the need for caution when predicting the adult height of children who are still receiving treatment. We conclude that deslorelin has improved the adult height of these patients but has not fully restored height to the patients' genetic potential. We hypothesize that further improvement will be seen in patients who are treated with less delay and at a younger bone age.

Body Height↗
PubMed1991

Luteinizing hormone-releasing hormone (LHRH)-independent precocious puberty unresponsive to LHRH agonist therapy in two girls lacking features of the McCune-Albright syndrome.

Two girls with precocious puberty (chronological age, 1 and 4 yr; bone age, 3 and 6 yr, respectively) were initially given the diagnosis of idiopathic, central precocious puberty and treated with the LHRH agonist deslorelin (D-Trp6-Pro9-NEt-LHRH) for 5 yr. Unlike other girls with central precocious puberty, both had persistently elevated rates of growth and bone maturation, and both menstruated during therapy. One girl had episodic ovarian enlargement and markedly elevated serum estradiol levels due to recurrent unilateral ovarian cysts. Although the bone and skin manifestations of McCune-Albright syndrome were absent, we hypothesize that the underlying defect of McCune-Albright syndrome was expressed in the ovaries, but not in the skin or bones, of these two girls. One of these girls appeared to benefit from the aromatase inhibitor testolactone, which is effective in suppressing precocious puberty in girls with the McCune-Albright syndrome.

Child Development↗
PubMed1993

Treatment of familial male precocious puberty with spironolactone, testolactone, and deslorelin.

Combined antiandrogen (spironolactone) and aromatase inhibitor (testolactone) are effective for the short term treatment of familial male precocious puberty. During this therapy, plasma testosterone levels remain in the adult range, since spironolactone blocks the testosterone receptor without significantly affecting plasma testosterone levels. After our initial 18-month pilot study, we continued to treat eight boys with the combined therapy for 2.0-4.2 yr. During this time all boys exhibited a pubertal rise in gonadotropin secretion and a diminishing response to treatment, which was manifested by the recurrence of clinical features of puberty and an increase in the bone maturation rate (P < 0.05). Addition of the LHRH agonist deslorelin (4 micrograms/kg.day, sc) to the combined therapy decreased peak LH, plasma testosterone, bone maturation rate, and growth velocity (P < 0.05) over the next year. We conclude that the rise in gonadotropin levels during central activation of hypothalamic LHRH secretion in boys with familial male precocious puberty causes a partial escape from the combined effect of spironolactone and testolactone. The addition of deslorelin to the combined therapy appears to restore the control of puberty in this setting.

Age Determination by Skeleton↗
PubMed1993

Serum bioactive gonadotropins during male puberty: a longitudinal study.

To evaluate the relative changes in serum bioactive (B) and immunoreactive (I) plasma gonadotropin concentrations during pubertal maturation, 28 healthy boys were enrolled at Tanner stage I and followed at 6-month intervals until achievement of Tanner stage V of pubertal maturation. At each visit, a careful interview, complete physical examination, sexual maturation staging, and bone age x-ray study were done, and a blood sample was obtained. Serum concentrations of PRL, dehydroepiandrosterone, and its sulfate, delta 4-androstenedione, estrone, estradiol, and testosterone (T) were determined by RIA. Samples from 20 boys were assayed for I-LH by RIA and for B-LH by the rat interstitial cell testosterone production assay, using 2 standards [Second International Reference Preparation-Human Menopausal Gonadotropin (2nd IRP-hMG) and LER 960]. Samples from 11 boys (3 from LH group and 8 others) were assayed for I-FSH by RIA and B-FSH by the rat Sertoli cell aromatase induction assay. The results were analyzed by regression analysis for B and I LH and FSH by Tanner stages of puberty, and by correlation of B to I LH and FSH as well as B and I LH and FSH to T. The results from both LH standards correlated well to each other (r = 0.967 and 0.882 for B- and I-LH, respectively), and the data are presented for 2nd IRP-hMG standard. In both groups of boys serum T concentrations increased progressively with pubertal development (P < 0.001). The boys bone age, testicular volume, serum T, dehydroepiandrosterone sulfate, dehydroepiandrosterone, delta 4-androstenedione, estrone concentrations correlated well with pubertal maturation, similar to previously published data and indicate that this group of boys had progressed through puberty in the expected normal manner. Mean serum I-LH concentrations increased progressively from Tanner stage I to V of puberty (P < 0.001), and serum B-LH exceeded the increase in serum I-LH levels. Mean serum I-LH concentrations were 2.0 +/- 0.1, 2.9 +/- 0.2, 4.7 +/- 0.4, 6.7 +/- 0.7, and 10.4 +/- 2.0 IU/L 2nd IRP-hMG whereas mean serum B-LH concentrations were 0.8 +/- 0.1, 2.2 +/- 0.2, 5.9 +/- 0.2, 10.3 +/- 1.2, and 22.3 +/- 3.8 IU/L 2nd IRP-hMG for Tanner stages I-V of puberty, respectively. This resulted in a progressive increase of LH B/I ratio with advancing pubertal maturation (P < 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex Hormones↗
PubMed1994

The effects of estrogen priming and puberty on the growth hormone response to standardized treadmill exercise and arginine-insulin in normal girls and boys.

To determine the effects of puberty and estrogen priming on the GH response to standardized treadmill exercise and arginine-insulin in normal boys and girls, we performed tests in 84 normal children (41 girls and 43 boys) representing all stages of puberty. A subset of the prepubertal children received the tests twice, with or without the administration of ethinyl estradiol (40 micrograms/m2 daily) for 2 days before the tests. The peak GH response to the three tests increased significantly with pubertal stage (r = 0.57; P < 0.0001), but did not differ between boys and girls at the same stage. With advancing puberty, the percentage of normal children who failed to attain a GH level greater than 7 micrograms/L during any of the three tests declined from 61% at pubertal stage 1 to 44% at stage 2, 11% at stage 3, and 0% at stages 4 and 5. Administration of estrogen to the prepubertal subjects raised the normal range for the peak GH response to the three tests from 1.9-20.3 to 7.2-40.5 micrograms/L. We conclude that both puberty and estrogen administration significantly increase the peak GH response to exercise, arginine, or insulin in normal subjects. Moreover, the conventional criterion that the peak GH response to three stimulation tests should exceed 7 micrograms/L was applicable in our study only to subjects who had attained pubertal stage 4 or 5 or who had received estrogen administration.

Adolescent↗
PubMed1995

A new constitutively activating point mutation in the luteinizing hormone/choriogonadotropin receptor gene in cases of male-limited precocious puberty.

A single point mutation that encodes an aspartic acid (Asp578) to glycine substitution in the LH/CG receptor (LH/CGR) gene, D578G, was recently found in American patients with familial male-limited precocious puberty and in a Japanese patient with a sporadic form of the disorder. Transfection of the mutant, compared to the wild-type, LH/CGR complementary DNA into COS-7 cells results in higher basal cAMP production, but a normal agonist-induced response; the mutation is, therefore, proposed to constitutively activate Leydig cells and elevate serum testosterone, despite low levels of gonadotropin. In the current study we examined two additional Japanese patients with male-limited precocious puberty without a family history of the disease. We describe a heterozygous cytosine (C) to thymine (T) transition at nucleotide 1715 in both; the mutation encodes an alanine to valine substitution in codon 572 of transmembrane helix 6, A572V. Transfected into COS-7 cells, the A572V mutant exhibited the same constitutively high basal cAMP levels and normal agonist-induced cAMP response as the D578G mutant. We conclude that the constitutively higher cAMP levels caused by the A572V mutation led to Leydig cell activation and male-limited precocious puberty, as in the previously described D578G mutation. As the mother of one of the two patients had the same heterozygous mutation, this patient represents the first recognized case of inherited male-limited precocious puberty in the Japanese population. The previously described D578G mutant did not increase basal or agonist-induced inositol phosphate production in transfected COS-7 cells, or the number of LH/CGRs or their affinity for LH/CG. In contrast, transfection of the A572V mutation in COS-7 cells exhibited significantly higher inositol phosphate levels basally and at 10(-11) mol/L hCG, but significantly lower inositol phosphate levels at 10(-7) mol/L hCG. These data suggest that the A572V mutation of the LH/CGR may have effects on the guanine nucleotide binding protein which activates phospholipase C (Gq) coupling and phospholipase-C activation in addition to its effects on Gs coupling and activation of adenylyl cyclase. A572V-transfected cells also exhibited a higher affinity, despite an apparent decrease in the number of binding sites, for [125I]hCG, compared to transfectants with the wild-type LH/CGR. We hypothesize that these differences between the A572V and D578G mutations reflect a greater impact of the A572V mutation on receptor conformation.

Base Sequence↗
PubMed1995

A novel mutation of the luteinizing hormone receptor gene causing male gonadotropin-independent precocious puberty.

Familial male-limited precocious puberty (FMPP) is an autosomal dominant gonadotropin-independent disorder. Affected males generally develop signs of precocious puberty in early childhood. They typically show Leydig cell hyperplasia and increased testosterone production typical for their age, whereas circulating LH concentrations remain prepubertal. Several dominant point mutations of the LH receptor gene were identified in pedigrees with familial male-limited precocious puberty and were shown to cosegregate with the disease. Here we report a novel heterozygote point mutation in the LH receptor gene of a Brazilian boy with gonadotropin-independent precocious puberty. This mutation substitutes alanine 568 with valine at the carboxyterminus of the third cytosolic loop of the LH receptor. The unoccupied mutant receptors confer constitutive activation of adenyl cyclase activity when expressed in COS-7 cells, resulting in 4-fold higher cAMP concentrations over baseline compared with cells expressing an equivalent number of wild-type receptors. The affinity of the mutant receptors to 125I-labeled human LH was not altered compared with the wild type. Mutations of the homologue alanine residue in the alpha 1-adrenergic (in vitro), FSH (in vitro), and TSH (naturally occurring) receptors also result in constitutive adenyl cyclase activation, suggesting that this alanine residue is crucial for signal transduction and a potential site for upregulatory/oncogenic mutations in G-protein coupled receptors.

Alanine↗
PubMed1997

Testosterone treatment in adolescents with delayed puberty: changes in body composition, protein, fat, and glucose metabolism.

Previously, we demonstrated decreased protein breakdown and insulin resistance in pubertal adolescents compared with prepubertal children. Puberty-related increases in sex steroids and/or GH could be potentially responsible. In the present study, the effects of 4 months of testosterone enanthate (50 mg in every 2 weeks) on body composition, protein, fat, and glucose metabolism and insulin sensitivity were evaluated in adolescents with delayed puberty. Body composition was assessed by H218O-dilution principle. Protein breakdown, oxidation, and synthesis were measured during primed constant infusion of [1-13C]leucine. Whole-body lipolysis was measured during primed constant infusion of [2H5]glycerol. Insulin action in suppressing proteolysis and lipolysis and stimulating glucose disposal was assessed during a stepwise hyperinsulinemic (10 and 40 mU-m2.min) euglycemic clamp. Fat and glucose oxidation rates were calculated from indirect calorimetry measurements. After 4 months of testosterone treatment, height, weight, and fat free mass (FFM) increased and fat mass, percent body fat, plasma cholesterol, high- and low-density lipoproteins, and leptin levels decreased significantly. Whole-body proteolysis and protein oxidation were lower after testosterone treatment (proteolysis, 0.49 +/- 0.03 vs 0.54 +/- 0.04 g.h.kg FFM, P = 0.032; oxidation, 0.05 +/- 0.01 vs. 0.09 +/- 0.01 g.h.kg FFM, P = 0.015). Protein synthesis was not different, and resting energy expenditure was not different. Total body lipolysis was not affected by testosterone treatment, however, fat oxidation was higher after testosterone (pre-: 2.4 +/- 0.7 vs. post-: 3.5 +/- 0.7 mumol.kg.min, P = 0.031). During the 40 mU.m2.min hyperinsulinemia, insulin sensitivity of glucose metabolism was not affected with testosterone therapy (59.1 +/- 8.8 vs. 57.1 +/- 8.2 mumol.kg.min per muU/mL). However, metabolic clearance rate of insulin was higher posttestosterone (13.6 +/- 1.1 vs. 16.7 +/- 0.8 mL.kg.min, P = 0.004). In conclusion, after 4 months of low-dose testosterone treatment in adolescents with delayed puberty 1) FFM increases and fat mass and leptin levels decrease; 2) postabsorptive proteolysis and protein oxidation decrease; 3) fat oxidation increases; and 4) insulin sensitivity in glucose metabolism does not change, whereas insulin clearance increases. These longitudinal observations are in agreement with our previous cross-sectional studies of puberty and demonstrate sparing of protein breakdown of approximately 1.2 g.kg.day FFM, wasting of fat mass, but no change in insulin sensitivity after short periods of low-dose testosterone supplementation.

Adolescent↗
PubMed1997

Amino acid neurotransmission and initiation of puberty: evidence from nonketotic hyperglycinemia in a female infant and gonadotropin-releasing hormone secretion by rat hypothalamic explants.

The pulse frequency of hypothalamic GnRH secretion increases at the onset of puberty. In rodents and primates, this process involves facilitatory and inhibitory effects mediated through hypothalamic N-methyl-D-aspartic acid (NMDA) and gamma-aminobutyric acid (GABA) receptors, respectively. Precocious puberty was observed in an 11-month-old girl with nonketotic hyperglycinemia. This was thought to result from the effect of high concentrations of glycine (112 micromol/L in cerebrospinal fluid; normal, 3-12) acting on NMDA receptors as a coagonist of glutamate. Regression of pubertal development during anticonvulsive treatment with GABA agonists (loreclezole and vigabatrin) suggested that the stimulatory effects of glycine could be overcome by GABA receptor-mediated inhibition. These two hypotheses were tested in the in vitro model of the explanted hypothalamus from infantile (15-day-old) male rats. Glycine concentrations of 1-10 micromol/L increased the pulse frequency of GnRH secretion. This acceleration was prevented by 7-chlorokynurenic acid, a glycine antagonist at the NMDA receptor complex, and by the GABA agonist loreclezole. In addition, loreclezole and vigabatrin suppressed the developmental increase in the frequency of pulsatile GnRH secretion. The observation of precocious puberty in an infant with hyperglycinemia followed by pubertal regression during GABA agonist therapy and the in vitro findings in hypothalamic explants suggest that stimulatory inputs mediated through NMDA receptors and inhibitory inputs through GABA receptors are involved in the initiation of puberty.

Amino Acid Metabolism, Inborn Errors↗
PubMed1997

Changes in serum immunoreactive and bioactive growth hormone concentrations in boys with advancing puberty and in response to a 20-hour estradiol infusion.

Acceleration of linear growth during puberty is associated with increased GH secretion, although the relationship between growth and GH is complex. As GH exists as a family of isoforms, some of which may not be identified by immunoassay, there may be alterations in isoform secretion during pubertal maturation that result in increased growth. The changes in serum immunoreactive and bioactive GH concentrations across pubertal maturation were determined in 30 boys, aged 6.5-19.3 yr, with idiopathic short stature or constitutional delay of adolescence. Data were grouped as follows: 1) 6 prepubertal boys with bone age 7 yr or less; 2) 5 prepubertal boys with bone age of more than 7 yr, 3) 10 boys in early puberty; 4) 9 boys with mid- to late puberty. Blood was obtained every 20 min from 2000-0800 h. An equal aliquot of each serum sample was pooled for determination of GH by bio- and immunoassays. The mean serum immunoreactive GH concentration increased from 2.1 +/- 0.3, 1.8 +/- 0.3, and 2.9 +/- 0.5 micrograms/L in groups 1, 2, and 3, respectively, to a peak of 4.6 +/- 0.7 micrograms/L in group 4 (P < 0.05 vs. groups 1-3). The mean serum GH bioactivity was 48 +/- 13 micrograms/L in group 1 and declined to 39 +/- 8 and 31 +/- 3 micrograms/L in groups 2 and 3, increasing to a maximum of 64 +/- 15 micrograms/L in group 4 (P < 0.05 vs. group 3). The ratio of bioactive to immunoreactive GH suggests that the biopotencies of secreted isoforms do not increase during pubertal maturation. The role of E2 in increasing GH secretion was characterized in 8 additional early pubertal boys. Each boy received a saline infusion from 1000-0800 h, followed 1 week later by an infusion of E2 at 4.6 nmol/m2.h. Blood was obtained every 15 min from 2200-0800 h for GH and LH and every 60 min for E2 and testosterone. An equal aliquot of each overnight serum sample was pooled for insulin-like growth factor I (IGF-I) and GH by immuno- and bioassays. The mean serum LH concentration decreased from 5.0 +/- 0.9 to 2.3 +/- 0.6 IU/L (P < 0.01), and the E2 concentration increased from 22 +/- 4 to 81 +/- 26 pmol/L (P < 0.01) during saline and E2 infusions, respectively. Mean serum GH concentrations as measured by immunoassay were similar during both infusions (6.6 +/- 1.4 vs. 9.7 +/- 2.1 micrograms/L; saline vs. E2 infusion, respectively). In contrast, the mean serum GH concentration, as measured by bioassay, decreased from 48 +/- 10 micrograms/L during saline infusion to 16 +/- 3 micrograms/L during E2 infusion (P < 0.05). The mean serum IGF-I concentration also decreased significantly from 116 +/- 17 to 93 +/- 15 micrograms/L (saline vs. E2 infusion, respectively; P < 0.05). Thus, although mean overnight serum GH concentrations increase in late puberty, whether measured by immuno- or bioassay, an acute increase in E2 produces an acute decline in serum GH bioactivity and a lesser decline in the serum IGF-I concentration. These unexpected changes indicate that E2 may affect pubertal growth and GH secretion in a complex or biphasic manner depending on the context in which it is administered.

Adolescent↗
PubMed1998

A unique constitutively activating mutation in third transmembrane helix of luteinizing hormone receptor causes sporadic male gonadotropin-independent precocious puberty.

Several constitutively activating mutations have been demonstrated in the sixth transmembrane helix of the human LH receptor (hLHR) in boys with gonadotropin-independent precocious puberty. In the current study, we examined two unrelated Brazilian boys with gonadotropin-independent precocious puberty caused by two different heterozygous activating mutations of the hLHR. Direct sequencing of the entire exon 11 of the hLHR revealed a heterozygous substitution of T for G at nucleotide 1370, that converts Leu 457 to Arg in the third transmembrane helix of the hLHR in one affected boy. His biological parents had a normal hLHR gene sequence, establishing the sporadic nature of this novel Leu457Arg mutation. Human embryonic 293 cells expressing hLHR mutant (L457R) or hLHR wild-type bound CG with high affinity. However, cells expressing hLHR(L457R) exhibited significantly higher basal levels of cAMP (7- to 14-fold) than cells expressing the wild-type receptor, indicating constitutive activation of hLHR(L457R). Basal levels of cAMP in hLHR(L457R)-expressing cells were, nonetheless, not as great as the levels of cAMP produced by hLHR wild-type-expressing cells incubated with a saturating concentration of CG. Furthermore, cells expressing hLHR(L457R) were unresponsive to further stimulation by CG. This finding was confirmed in the patient by lack of an increase in serum testosterone after CG stimulation. These results suggest that the conformation of hLHR(L457R) mutant represents a different activated receptor state (R*) than the agonist-occupied wild-type receptor. We also identified the previously described Ala568Val mutation in the third intracellular loop of the LHR in the other affected African-Brazilian boy and his normal prepubertal sister, suggesting the inherited form of precocious puberty in this boy. We conclude that the third transmembrane helix is a potential area for activating mutations of the hLHR that cause male precocious puberty.

Amino Acid Sequence↗
PubMed1999

Lack of effect of GnRH agonists on final height in girls with advanced puberty: a randomized long-term pilot study.

GnRH agonists improve final height in girls with "true" precocious puberty. To test if a comparable effect can be obtained in older girls, we performed a long-term controlled study in 30 caucasian girls whose puberty started between 8.4 and 10 yr (9.4 +/- 0.1 yr), a variant of normal called "advanced" puberty. At entry into trial, these girls had clinical, biological, and sonographic manifestations of puberty and a bone age greater than 10.9 yr. They were randomized 2:1 to receive 3.75 mg triptorelin im every 4 weeks for 2 yr (n = 20, group I) or no treatment (n = 10, group II). Mean height at inclusion was 135.2 +/- 4.3 cm (+0.6 SDS) in group I, 136.1 +/- 4.2 cm (+0.8 SDS) in group II, with target height 157.6 +/- 4.3 cm (group I) and 157.8 +/- 4.7 cm (group II), and predicted height (Bayley-Pinneau) 154.1 +/- 3.9 cm and 155.2 +/- 3.7 cm. Although GnRH agonists transiently delayed sexual maturation as well as bone age and growth rate, they had no clear-cut long-standing effect, and final height was comparable in treated (157.6 +/- 4.0 cm) and untreated girls (156.1 +/- 5.3 cm) (NS).

Age Determination by Skeleton↗
PubMed2000

Influence of puberty on muscle area and cortical bone area of the forearm in boys and girls.

The aim of the current study is to analyze the interaction of the muscle and bone system (muscle-bone unit) during puberty in males and females by computed tomography of the nondominant forearm. The data presented here are the first results from 318 healthy children (159 boys and 159 girls), aged 6-22 yr, and 336 adults (parents) participating in the DONALD Study (Dortmund Nutritional and Anthropometric Longitudinally Designed Study). Cortical area (CA) of the radius representing bone strength and muscle area (MA) representing muscle strength were measured with peripheral quantitative computed tomography (XCT 2000; Stratec, Pforzheim, Germany). A single slice measurement at a site corresponding to 65% of the ulnar length proximal to the radial endplate was used. MA and CA of the radius have been determined by a built-in software algorithm using density differences. There was a strong correlation between MA (x) and CA (y) in all children, adolescents, and adults (y = 0.019x + 10.93; r2 = 0.77). Before puberty, boys and girls displayed a similar relation between MA and CA. CA in relation to MA was greater in girls than in boys during puberty. Analysis of covariance was performed investigating the dependency of CA on MA, five pubertal stages, sex, and interaction of sex and pubertal stages. MA representing muscle strength was the strongest predictor of CA (P < 0.001) representing bone mass. Pubertal stage (P < 0.001) and interaction of pubertal stage*sex (P = 0.002) also had a significant influence on CA. r2 of the model was 0.85. These data suggest that in pubertal girls and women rather than in pubertal boys and men an additional factor shifts the relationship between MA and CA to higher values of cortical area. The present data confirm previous studies of the influence of puberty and estrogens or related factors on the muscle-bone interaction.

Adolescent↗
PubMed2001

Sex-dependent variations and timing of thyroid growth during puberty.

Marked changes in thyroid function occur during puberty as an adaptation to body and sexual development. Characteristics of thyroid growth were investigated in 259 healthy adolescents (110 girls and 149 boys), aged 11--17 yr, in an urban area of Switzerland with sufficient iodine supply. The thyroid volume determined by ultrasonography was correlated with chronological age, body weight, body height, cervical circumference, body mass index, and body surface area (BSA). Iodide concentration was measured in urine. The increase in thyroid volume mainly occurred between 11--15 yr (age at maximum thyroid growth rate, 12.5 yr) and was best correlated with BSA in both genders (girls, r(2) = 0.38; boys, r(2) = 0.49). The BSA-related thyroid growth was almost constant throughout puberty in boys and similar in girls up to menarche, but 14.5% larger in girls after menarche (P < 0.01). Percentiles of thyroid volume were lower than WHO reference values despite low normal urinary iodide concentration (median, 0.75 micromol/L). These findings suggest that physiological thyroid growth during puberty is mainly influenced by growth factors involved in somatic development and further modulated by sex steroid secretion profiles. The thyroid growth spurt coinciding with menarche in girls may contribute to a higher incidence of goiter during mid- to late puberty.

Adolescent↗
PubMed2002

Sertoli-Leydig cell tumor of the ovary, a rare cause of precocious puberty in a 12-month-old infant.

We report a 12-month-old infant who presented with a 4-month history of isosexual precocious puberty secondary to an estrogenizing Sertoli-Leydig cell tumor of the ovary. Total serum immunoreactive inhibin and subunits A and B were markedly elevated before surgical resection and subsequently decreased 7 wk later into the normal prepubertal range. Twenty weeks following surgical removal, the patient presented again with central precocious puberty; inhibin B levels were raised on this occasion, a luteinizing releasing hormone stimulation test confirmed central precocious puberty. This is the youngest reported occurrence of this rare sex cord stromal neoplasm. The prognosis of this extremely rare tumor presenting at this early juvenile stage is uncertain. This report illustrates the usefulness of serum inhibin as a tumor marker during therapeutic suppression with leuprorelin acetate for central precocious puberty. Analysis of genomic and tumor DNA revealed a normal nucleotide sequence for the LH receptor and the Galpha(s) gene. To understand the molecular pathogenesis of this tumor we analyzed mRNA levels for the inhibin A and B subunits, FSH receptor, LH receptor aromatase, steroidogenic factor-1 and the ER beta genes. Molecular characterization reveals the presence of genes specific for granulosa and Leydig cells; the relative expression of these genes, in addition to its histologic characteristics, suggests that this tumor may result from a dysdifferentiation of a primordial follicle.

Androstenedione↗
PubMed2005

Effects of environmental agents on the attainment of puberty: considerations when assessing exposure to environmental chemicals in the National Children's Study.

The apparent decline in the age at puberty in the United States raises a general level of concern because of the potential clinical and social consequences of such an event. Nutritional status, genetic predisposition (race/ethnicity), and environmental chemicals are associated with altered age at puberty. The Exposure to Chemical Agents Working Group of the National Children's Study (NCS) presents an approach to assess exposure for chemicals that may affect the age of maturity in children. The process involves conducting the assessment by life stages (i.e., in utero, postnatal, peripubertal), adopting a general categorization of the environmental chemicals by biologic persistence, and collecting and storing biologic specimens that are most likely to yield meaningful information. The analysis of environmental samples and use of questionnaire data are essential in the assessment of chemicals that cannot be measured in biologic specimens, and they can assist in the evaluation of exposure to nonpersistent chemicals. Food and dietary data may be used to determine the extent to which nutrients and chemicals from this pathway contribute to the variance in the timing of puberty. Additional research is necessary in several of these areas and is ongoing. The NCS is uniquely poised to evaluate the effects of environmental chemicals on the age at puberty, and the above approach will allow the NCS to accomplish this task.

Adolescent↗