Sexual dimorphism in the maturation of the pituitary-gonadal axis, assessed by GnRH agonist challenge.

OBJECTIVE: To assess whether the maturational changes of the pituitary--gonadal axis in a healthy population show gender-specific changes and to establish normative data for the different Tanner stages. DESIGN: Prospective, cross-sectional study. METHODS: The GnRH agonist leuprolide acetate (500 microgram) was administered s.c. to 60 boys and 81 girls (age range, 5--17 years). Serum steroids and gonadotropins were determined at 0 and 24 h and at 0, 3 and 24 h after GnRH agonist challenge respectively, whereas IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3 and sex hormone-binding globulin were measured at baseline. RESULTS: Baseline and peak LH responses to the agonist in late puberty, and basal and peak FSH levels at all Tanner stages, were higher in girls than in boys. Girls showed higher IGF-I levels than boys throughout puberty, sharper decreases in IGFBP-1 and earlier and greater increases in 17-hydroxypregnenolone, dehydroepiandrosterone (DHEA) and DHEA-sulfate. Testosterone responses to the agonist increased during puberty in males, and showed no changes in females. Conversely, estradiol responses rose throughout puberty in females and remained unchanged until late puberty in males. CONCLUSION: Leuprolide acetate stimulates gonadotropin and gonadal steroid secretion during puberty in both sexes and increases FSH levels in prepubertal girls. Pubertal maturation of gonadotrope function is gender specific, as it appears to involve increases in both the releasable and reserve pools of LH in males, and of LH and FSH in females. The earlier increase in Delta(5)-steroids in girls may suggest a sharper rise in ovarian cytochrome P450c17 activity along the Delta(5)-steroid pathway, while the failure of estradiol to increase in response to leuprolide acetate in early pubertal males suggests a late maturation of aromatase activity.     

Comparison of clinical, ultrasonographic, and biochemical differences at the beginning of puberty in healthy girls born either small for gestational age or appropriate for gestational age: preliminary results

CONTEXT: There are limited and controversial data concerning puberty characteristics in girls born small for gestational age (SGA). OBJECTIVE: The objective of the study was to document clinical, ultrasonographic, and biochemical characteristics at the beginning of puberty in matched healthy girls born either SGA or appropriate for gestational age (AGA) recruited from the community. PATIENTS: Inclusion criteria were breast Tanner stage II and a body mass index between the 10th and 95th percentiles. INTERVENTIONS: Recruited subjects underwent a complete physical exam, bone age, and ultrasound measurements of the internal genitalia. Hormonal assessment included fasting early morning dehydroepiandrosterone sulfate, androstenedione, SHBG, inhibin-B, FSH, LH, estradiol (E2), 17-hydroxyprogesterone (17OH Prog), and testosterone. Thereafter, a GnRH agonist test (leuprolide 500 microg, sc) was performed with FSH and LH at time 3 and 24 h for E2, 17OH Prog, and testosterone. RESULTS: Sixty-five girls (35 AGA, 30 SGA) with a mean age of 9.9 +/- 1.03 (7.8-12.5) yr, similar bone age/chronological age (1.02 +/- 0.8 in AGA and 1 +/- 0.76 in SGA), median height of 1.35 +/- 0.06 cm, and similar waist to hip ratio were included. No differences in the presence of pubic hair, axillary hair, apocrine odor, or ultrasound measurements were found. SGA girls had increased baseline E2 as well as stimulated E2 and 17OH Prog. CONCLUSIONS: In a preliminary sample of lean, healthy girls recruited from the community born either SGA or AGA, we observed slight hormonal differences at the beginning of puberty. Longitudinal follow-up of this cohort will allow us to understand whether these differences are maintained and have a clinical impact in their pubertal development.     

Developmentally delimited emergence of more orderly luteinizing hormone and testosterone secretion during late prepuberty in boys

To quantitate changing feedback control in the GnRH-LH/FSH-testosterone axis in male puberty, we here quantitate the orderliness of hormone release patterns using the regularity (pattern-sensitive) statistic, approximate entropy (ApEn), in 46 eugonadal boys representing 6 genitally defined stages of normal puberty. ApEn is a single variable, model-free, and scale-independent barometer of coordinate signaling or integrative regulation within a coupled neuroendocrine axis. Accordingly, we quantitated ApEn of LH profiles obtained by immunofluorometric assay of sera sampled every 20 min for 24 h. LH ApEn declined remarkably between early prepuberty (genital stage I-A: mean bone age, 4.6 +/- 1.6 yr; testis volume, <3 mL for at least 3 succeeding yr) and late prepuberty (genital stage I-C: bone age, 8.7 +/- 1.8 yr; testis volume, <3 mL for up to 1 yr thereafter; P: = 0.00019), which indicates the acquisition of more regular LH release patterns in late prepuberty. Maximal LH orderliness occurred in puberty stage II (bone age, 10.7 +/- 1.0 yr; testis volume, 2.8 +/- 0.4 mL). The LH secretory process was more disorderly in mid- and later puberty (Tanner stages III and IV). Transpubertal variations in testosterone ApEn manifested a similar tempo, i.e. the greatest regularity of testosterone secretion (lowest ApEn) emerged in Tanner genital stage II (P: < 10(-)(7)), with less orderly patterns evident both earlier and later in sexual development. In contrast, FSH ApEn values remained invariant of pubertal status. Analysis of bihormonal coupling using the theoretically related bivariate cross-ApEn statistic disclosed maximal 2-hormone synchrony for LH and testosterone secretion in genital stage II (P: = 0.031), with relative deterioration of coordinate LH and testosterone release patterns both before and after. LH and FSH release became maximally synchronous at the end of prepuberty (genital stage I-C; P: = 0.029), and FSH and testosterone synchrony peaked in pubertal stage III (P: = 0.037). As mean 24-h serum concentrations of LH, FSH, and testosterone rose transpubertally by 35-fold (LH), 68-fold (FSH), and 70-fold (testosterone), respectively, we infer that pubertal developmental stage per se rather than level of hormone output dictates coordinate GnRH-LH/FSH-testosterone secretion. In summary, in eugonadal boys, the regularity of 24-h LH and testosterone secretory patterns undergoes well defined pubertal stage-specific control. No sexually developmentally delimited regulation is inferable for FSH. The concept of temporally biphasic puberty-dependent variations in neurohormone secretory regularity contrasts with the unidirectional rise in daily hormone output. Accordingly, we infer that late prepuberty and early puberty (Tanner genital stages IC and II) embody a physiologically unique sexual developmental window, marked by transiently enhanced LH and testosterone feedback stability in boys. Whether analogous plasticity of hypothalamo-pituitary-gonadal interactions unfolds during female adolescence is not known.     

Leuprolide acetate gonadotrophin response patterns during female puberty

Objective To assess normative data and the usefulness of spontaneous and LHRH analogue‐stimulated serum LH and FSH levels measured by immunoradiometric assays (IRMA) in the evaluation of normal puberty. Design Prospective. Healthy girls in Tanner I and Tanner II from the local community were invited to participate (n = 47). Methods A leuprolide acetate test (500 mcg/m²; sc) was performed. LH and FSH levels were determined using IRMA. Tanner II girls were assessed every 6 months until Tanner V. Girls who progressed from Tanner II to Tanner III in the next 6 months were called Tanner II‐2; otherwise, they were called Tanner II‐1. Results The prepubertal upper limit (CI 95%) was 0·49 IU/l for basal LH and 5·1 IU/l for stimulated LH. Taking into account these LH cut‐off limits, 72·2% and 66·7% of Tanner II‐1 and 41·6% and 41·7% of Tanner II‐2 subjects presented overlapping values for basal and stimulated LH, respectively, as compared with the Tanner I group. The cut‐offs for basal and stimulated LH to predict progression from Tanner II to Tanner III in the next 6 months were a basal LH level ≥0·49 IU/l (Sensitivity = 0·58; 1‐Specificity = 0·33) and a poststimulated LH level ≥4·75 IU/l (Sensitivity = 0·67; 1‐Specificity = 0·44). Conclusion According to an IRMA, the basal and leuprolide acetate gonadotrophin response patterns during the beginning stages of puberty overlapped between Tanner I and Tanner II, and the cut‐offs of basal and stimulated LH levels to predict progress from Tanner II to Tanner III had low sensitivities for the following 6 months.     

Diurnal rhythms of luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol secretion before the onset of female puberty in short children

To investigate hormonal changes before the onset of female puberty, we measured LH and FSH in serum samples drawn every 20 min for 24 h and measured testosterone and estradiol hourly for 24 h. Seventeen girls (13 prepubertal and 4 early pubertal) of short stature, from 5.1-11.4 yr of age, participated in this study. LH and FSH were measured using a time-resolved immunofluorometric assay, and testosterone and estradiol were measured using a sensitivity RIA capable of detecting testosterone and estradiol concentrations of 10 and 2 pg/mL, respectively. Diurnal rhythms of LH, FSH, and testosterone were apparent in all subjects, including those aged 5-6 yr. Serum LH and FSH concentrations showed night-day variation in a pulsatile fashion. The serum testosterone concentration was elevated in the early morning in all subjects. The serum estradiol concentration was elevated in the early morning in 4 of 13 prepubertal subjects and all 4 early pubertal subjects. The diurnal pattern of the serum estradiol concentration was similar to that of the serum testosterone concentration. Mean 24-h LH and testosterone concentrations in prepubertal subjects who did not attain puberty for at least 1 yr were 0.07 U/L and 65 pg/mL, respectively, whereas those in prepubertal subjects who attained puberty within 1 yr (0.14 U/L and 106 pg/mL, respectively) were significantly higher. Furthermore, mean 24-h LH, FSH, testosterone, and estradiol concentrations increased with the onset of puberty. In conclusion, the diurnal rhythms of LH, FSH, and testosterone already exist at 5-6 yr of age, and serum LH and testosterone levels increase before the onset of puberty. These results suggest that preparation for the onset of female puberty may begin in 5- to 6-yr-old girls.     

Ovarian hyperthecosis in the setting of portal hypertension

Hepatocellular dysfunction and perturbed portal hemodynamics alter steroid metabolism. Men with liver disease have gynecomastia, although women similarly affected rarely show virilization. We report a 10-yr-old girl with portal hypertension and shunting associated with precocious puberty and ovarian hyperandrogenism. This was one of premature twin girls; neither had clitoromegaly or genital ambiguity. In one child, neonatal respiratory problems led to umbilical vein catheterization with subsequent development of portal hypertension. Pubic hair was first noted at age 6 yr, breasts at 7 yr, and severe acne and clitoromegaly at 10 yr. Baseline sex hormones were elevated: androstenedione (A), 413 ng/dL; testosterone (T), 226 ng/dL; and estradiol (E2), 160 pg/mL. Liver transaminases were within the normal range, however, the coagulation profile was mildly abnormal. Cosyntropin adrenal stimulation revealed no steroidogenic defect. Dexamethasone suppression reduced A and T slightly. LH-releasing hormone stimulation produced a pubertal rise in LH and FSH. Pelvic sonography showed a large right ovary with numerous follicles. Surgical exploration revealed symmetrically enlarged ovaries with dense capsules. Histology of ovarian wedge resections showed hyperthecosis; immunohistochemistry showed stromal cells expressing steroidogenic enzymes and proteins. One month postoperatively, A and T were unchanged from baseline, whereas E2 decreased to 56 pg/mL. A single dose of depot leuprolide acetate significantly reduced T. Subsequent treatment with oral contraceptives reduced T to 50 ng/dL, and cyclical menses occurred. We conclude that precocious puberty and ovarian hyperthecosis were induced in this young girl by elevated circulating levels of sex hormones, a consequence of portasystemic shunting and impaired hepatic steroid metabolism.     

The early dehydroepiandrosterone sulfate rise of adrenarche and the delay of pubarche indicate primary ovarian failure in Turner syndrome

Pubarche without thelarche has been taken as clinical evidence that adrenarche is independent of gonadarche in females. This study examines whether the course of adrenarche [rise of serum dehydroepiandrosterone sulfate (DHEAS)] and pubarche (Tanner stage PH2) is independent from ovarian function. Serum DHEAS levels (n = 867) were longitudinally measured in 111 girls with Turner syndrome between 1990 and 2002. Of these, 22 had spontaneous puberty onset (Tanner stage B2), and 45 had primary ovarian failure (POF). Serum DHEAS levels were assayed by chemiluminescence and compared with those of healthy girls (n = 322; age range, 3-17 yr in both groups). Between the ages of 7 and 17 yr, girls with Turner syndrome had significantly higher age-related DHEAS levels than normal girls (P 相似文献   

Obesity and sex steroid changes across puberty: evidence for marked hyperandrogenemia in pre- and early pubertal obese girls

CONTEXT: Peripubertal obesity is associated with abnormal sex steroid concentrations, but the timing of onset and degree of these abnormalities remain unclear. OBJECTIVE: The objective of the study was to assess the degree of hyperandrogenemia across puberty in obese girls and assess overnight sex steroid changes in Tanner stage 1-3 girls. DESIGN: This was a cross-sectional analysis. SETTING: The study was conducted at general clinical research centers. SUBJECTS: Thirty normal-weight (body mass index for age < 85%) and 74 obese (body mass index for age >or= 95%) peripubertal girls. INTERVENTION: Blood samples (circa 0500-0700 h) were taken while fasting. Samples from the preceding evening (circa 2300 h) were obtained in 23 Tanner 1-3 girls. MAIN OUTCOME MEASURES: Hormone concentrations stratified by Tanner stage were measured. RESULTS: Compared with normal-weight girls, mean free testosterone (T) was elevated 2- to 9-fold across puberty in obese girls, whereas fasting insulin was 3-fold elevated in obese Tanner 1-3 girls (P < 0.05). Mean LH was lower in obese Tanner 1 and 2 girls (P < 0.05) but not in more mature girls. In a subgroup of normal-weight Tanner 1-3 girls (n = 17), mean progesterone (P) and T increased overnight 2.3- and 2.4-fold, respectively (P 相似文献   

Evidence for temporal coupling of growth hormone, prolactin, LH and FSH pulsatility overnight during normal puberty

The patterns of secretion of GH, LH, FSH and prolactin were determined over a single night (20.00-08.00 h; 15-min sampling) in 34 normal subjects (17 male, 17 female, aged 9.1-20.9 years). Plasma GH was measured by an immunoradiometric assay and LH, FSH and prolactin by radioimmunoassay in all samples. Data were analysed by Fourier transformation and cross-correlation after stationarization. The highest mean GH levels were noted in girls at Tanner stage 2/3 and in boys at stages 4/5. Prolactin levels were highest in girls at stage 4/5 and in boys at stage 2/3. LH and FSH showed a progressive rise by puberty stage in both sexes. The dominant pulse periodicities of GH and prolactin were 150-180 min in girls and 180 min in boys. LH and FSH pulse periodicity was around 90 min in early puberty and 180 min in later puberty in both sexes. LH and prolactin pulses showed a phase relationship with GH with a lag of 30-75 min (r = 0.32; P less than 0.001) and 30 min (r = 0.47; P less than 0.0001) respectively. Generally, LH and prolactin pulses were in phase (r = 0.42; P less than 0.0001) and there was a highly significant correlation (r = 0.64; P less than 0.0001) between FSH and LH pulsatility. Whereas mean overnight concentrations and pulse periodicity of the principal pituitary hormones varied between the sexes during early puberty, by the end of puberty a dominant pulse periodicity of around 150-180 min was established and there was remarkable temporal coupling of pulsatility.     

Origin of an ovarian steroid cell tumor causing isosexual pseudoprecocious puberty demonstrated by the expression of adrenal steroidogenic enzymes and adrenocorticotropin receptor

Ovarian steroid cell tumors are rare neoplasms composed of typical steroid hormone-secreting cells. Most ovarian steroid cell tumors, however, cannot be appropriately classified on a morphological basis, because the neoplastic cells closely resemble adrenal cortical cells. Nevertheless, the true adrenal origin of such tumors has been difficult to demonstrate. Here we report a 3-yr-old girl with isosexual pseudoprecocious puberty due to an ovarian steroid tumor whose adrenal cell origin was determined by the presence of messenger ribonucleic acid (mRNA) of adrenal-specific steroidogenic P450 enzymes (P450c11 and P450c21) and ACTH receptor (ACTHR). Her height was +2.3 SD, and she had Tanner stage III breast development, Tanner stage II pubic hair, and a normal clitoris. Bone age was 5 yr. Basal gonadotropin levels were undetectable (<0.6 U/L for LH and <1.0 U/L for FSH) and remained undetectable after stimulation with 100 microg GnRH, i.v. Basal serum testosterone and 17-hydroxyprogesterone levels were slightly elevated, whereas basal serum androstenedione, estradiol, and dehydroepiandrosterone sulfate levels were clearly elevated. Pelvic ultrasound disclosed an enlarged uterus and an adnexal multicystic mass in the right ovary, and pathological studies disclosed an ovarian steroid cell tumor. To establish the cellular origin of the tumor we determined the presence of mRNA for P450c11, P450c21, and ACTHR in tumor tissue and normal adrenal and ovarian tissue. Detection of ACTHR, P450c21, and P450c11 mRNAs isoforms was achieved in tumoral and adrenal control tissue, but not in the ovary control tissue. The RT-PCR products of P450c11 from adrenal control tissue were composed by both BglI-sensitive and -resistant complementary DNAs, indicating the presence of both P450c11AS and P450c11beta, whereas RT-PCR product from the tumor was resistant to BglI digestion, indicating only the presence of P450c11beta. We conclude that the histological origin of so-called adrenal rest tumor could be reliably determined by assessing the expression of specific genes in the tumor as P450c11beta and P450c21. The use ofthese molecular tools will allow a more precise classification of an important subset of the ovarian steroid cell tumors and can help to identify ectopic adrenal tissue in ovary and testis.     

Corticotropin-releasing hormone: a potent androgen secretagogue in girls with hyperandrogenism after precocious pubarche

CRH is an adrenal androgen secretagogue in men and has been proposed as a candidate regulator of adrenarche. CRH also affects androgen production by theca cells and may be involved in the pathogenesis of ovarian hyperandrogenism (OH). Precocious pubarche (PP) in girls can precede adolescent OH, a condition characterized by a high ovarian 17-hydroxyprogesterone (17-OHP) response 24 h after GnRH agonist challenge. In adolescent girls with a history of PP, we assessed the early androgen response to CRH, as well as the CRH effect on the late ovarian response to GnRH agonist. Within a randomized cross-over design, saline or CRH (human CRH 1 microg/kg x h in saline) was infused over 3-h (1100-1400 h) into 12 adolescent girls (age 17+/-2 yr; body mass index 21.4+/-0.9 Kg/m2) who had been pretreated with dexamethasone (1 mg at 0 h) and GnRH agonist (leuprolide acetate 500 microg sc at 0800 h = time 0). All adolescents had hirsutism, irregular menses, hyperandrogenemia, and hyperinsulinemia after PP. Serum LH, FSH, androstenedione, dehydroepiandrosterone (DHEA), and DHEA-sulfate (DHEAS) were measured at time 0, 3, 6, and 24 h, and ACTH and 17-OHP were measured at time 0, 6, and 24 h. ACTH concentrations at the end of saline or CRH infusions were less than 45 pg/mL; neither saline nor CRH infusions evoked early changes in 17-OHP levels. Within 3 h of CRH infusion, DHEAS increased by 46%, on average; androstenedione increased 2.5-fold and DHEA increased 5-fold duringCRH infusion (all P < 0.0001 compared with saline). There was no detectable CRH effect on the responses of LH, FSH, DHEA, DHEAS, 17-OHP, androstenedione, testosterone, and estradiol 24 h after GnRH agonist administration; five of 12 girls had elevated 17-OHP responses suggestive of OH. In conclusion, CRH was found to be a potent adrenal androgen secretagogue in adolescent girls with hyperandrogenism after PP. In this study, CRH failed to detectably affect the ovarian androgen response to gonadotropins.     

ORIGINAL ARTICLE: Leuprolide stimulation testing for the evaluation of early female sexual maturation

Context Low concentrations of serum LH and/or oestradiol (E₂) in girls with early physical signs of precocious puberty pose a diagnostic challenge. Objective To assess the diagnostic value of the leuprolide stimulation test in female precocious puberty. Design Retrospective Chart Review. Setting Outpatient clinic. Patients and intervention Thirty‐nine girls, 6·9 (1·4) years, with premature stage II–III breast development, with or without pubarche, underwent stimulation testing with subcutaneous leuprolide (20 μg/kg) with the following hormonal measurements in serum: FSH, LH, oestradiol at baseline; FSH and LH at 1 and 2 h; oestradiol at 24 h. Twelve girls with isolated pubarche were also tested with leuprolide. Main outcome measure A pubertal hormonal pattern was defined as at least one of the following: a baseline serum level of LH ≥ 0·3 U/l, a baseline oestradiol ≥ 37 pmol/l (10 ng/l), a stimulated (peak) LH ≥ 5·0 U/l, a stimulated oestradiol ≥ 184 pmol/l (50 ng/l) to leuprolide. The hormonal response was related to the clinical course during a period of observation of at least 6 months. Results Following leuprolide stimulation, the hormonal response was concordant with pubertal progression (n = 23) or lack thereof (n = 16) in all children. At baseline, pubertal serum concentrations of LH and/or oestradiol were associated with pubertal progression in all, while serum prepubertal LH and/or oestradiol concentrations were associated with pubertal progression in approximately 50% of the patients. Conclusions In girls with early clinical signs of precocious puberty and low serum concentrations of LH and oestradiol in random samples, the LH and oestradiol responses to leuprolide stimulation accurately predict pubertal progression.     

Serum bioactive follicle-stimulating hormone concentrations from prepuberty to adulthood: a cross-sectional study

Serum bioactive (B) LH concentrations increase with each pubertal stage and exceed immunoreactive (I) measurements in boys and girls throughout puberty. These results have been attributed to increased GnRH secretion and/or sex steroid modulation. FSH secretion is likewise affected by these factors. We, therefore, tested the hypothesis that serum B-FSH concentrations would increase with each stage of puberty in boys and girls. In this study we compared the serum concentrations of B-FSH, I-FSH, and sex steroids and stages of puberty (determined according to Tanner) in 111 sera obtained from boys and girls from 6-18 yr of age with the results obtained from 6 young men under the age of 35 yr and 13 cycling women (studied during the follicular, periovulatory, and luteal phases of their menstrual cycles). The serum I-FSH, testosterone (T), and estradiol (E2) concentrations were determined by RIAs, and B-FSH was determined by the rat Sertoli cell aromatase induction assay. The results were analyzed by one-way analysis of variance followed by Scheffe's test for each gender and two-way analysis of variance followed by Student-Newman-Keuls test for comparison of the results between sexes. In boys the mean serum T concentrations increased progressively with each stage of pubertal development up to Tanner stage 4 (P less than 0.01). The mean serum I-FSH concentration at Tanner stage 1 was 0.7 +/- 0.1 ng/mL (hFSH-3) and did not change significantly until Tanner stage 4, when it was increased to 3.7 +/- 1.0 ng/mL (P less than 0.05). The mean serum I-FSH concentrations for Tanner stage 5 and adult men were not statistically different, but were lower than in Tanner stage 4. Mean serum B-FSH concentrations measured with the same standard were 1.9 +/- 0.4, 3.1 +/- 0.4, 2.7 +/- 0.4, 4.2 +/- 1.4, and 3.6 +/- 0.3 ng/mL in Tanner stages 1-5, respectively. These were not significantly different. In girls the mean serum E2 concentrations increased progressively between the Tanner stages (P less than 0.00005, by two-way analysis of variance). Mean serum I-FSH levels did not change significantly with the achievement of different pubertal stages. The mean B-FSH concentrations were 2.7 +/- 0.4, 2.8 +/- 0.5, 3.8 +/- 0.8, 2.8 +/- 0.7, and 3.9 +/- 0.6 ng/mL at Tanner stages 1-5, respectively, and were, likewise, not statistically significantly different. In adult women the mean serum B-FSH concentrations during the follicular phase of the menstrual cycle were not significantly different from pubertal values.(ABSTRACT TRUNCATED AT 400 WORDS)     

Androgen receptor gene CAG repeat polymorphism in the development of ovarian hyperandrogenism

Ovarian hyperandrogenism, a key feature of polycystic ovary syndrome, is preceded by precocious pubarche (PP) (pubic hair < 8 yr) in some populations. We hypothesized that this earlier presentation may relate to increased androgen sensitivity, indicated by androgen receptor gene CAG repeat length. This polymorphism was genotyped in 181 Barcelona girls (age, 10.9 yr; range, 4-19 yr) who had presented with PP, and in 124 Barcelona control girls. PP girls had shorter mean CAG number than Barcelona controls (PP vs. controls: mean, range: 21.3, 7-31 repeats vs. 22.0, 15-32, P = 0.003) and greater proportion of short alleles 20 repeats or less (37.0% vs. 24.6%, P = 0.002). Among post-menarcheal PP girls (n = 69), shorter CAG number (biallelic mean 相似文献   

Serum luteinizing hormone concentrations increase 100-fold in females from 7 years to adulthood, as measured by time-resolved immunofluorometric assay

The increases in serum immunoreactive (RIA) LH and FSH concentrations during puberty are small and of limited value in the evaluation of pubertal development. We, therefore, used highly sensitive time-resolved immunofluorometric assays to evaluate the changes in LH and FSH during female puberty. The sensitivity of the LH assay was 0.02 IU/L, and that of the FSH assay was 0.01 IU/L. Fifty normal premenarcheal girls, 7-12 yr old, 15 postmenarcheal girls, 16 to 17 yr old, and 15 adult women, 24-29 yr old, were studied. In postmenarcheal women, the blood samples were taken on cycle days 4-7. Serum estradiol concentrations were measured by RIA, and pubertal stages were graded. Serum LH levels in prepubertal girls were very low; the mean concentration was 0.05 IU/L. All girls less than 10 yr of age had serum LH concentrations below 0.2 IU/L, while FSH levels varied from 0.3-2.0 IU/L. The earliest significant changes in serum LH, FSH, and estradiol levels took place simultaneously at 9-10 yr of age. The increase in serum FSH was gradual, but the increase in serum LH was sudden and very steep, coinciding with the increase in serum estradiol and the onset of physical puberty. The increase in the mean LH concentrations between the 7-yr-old and the adult group was 116-fold, that for estradiol was 12-fold, and that for FSH was 6.7-fold. These results suggest that the increase in serum LH is important at the onset of puberty, and LH concentrations are a sensitive indicator of pubertal development.     

Precocious puberty in girls: pituitary height as an index of hypothalamo-pituitary activation.

The pituitary heights in 47 girls having breast development before 8 yr were measured by magnetic resonance imaging and compared to the normal values for age and to clinical and laboratory data. They were classified into 3 groups: 1) premature thelarche (PT), isolated breast development with plasma estradiol less than 74 pmol/L (8 cases); 2) mild form of central precocious puberty (CPP1) with an LH/FSH peak ratio after the LH-releasing hormone test less than 1 (22 cases); 3) classical form of CPP (CPP2) with an LH/FSH peak ratio greater than 1 (17 cases). All girls with CPP had breast and pubic hair development before 8 yr, accelerated growth velocity, and no intracranial lesion. The mean ages at breast development [7.2 +/- 0.4 (SE), 6.5 +/- 0.4, and 7.2 +/- 0.3 yr] and the mean times between breast development and magnetic resonance imaging evaluation (0.8 +/- 0.1, 0.8 +/- 0.2, and 0.9 +/- 0.1 yr) were similar in the 3 groups. The mean pituitary heights were 4.9 +/- 0.2 in PT, 5.1 +/- 0.2 in CPP1, and 6.2 +/- 0.2 mm in CPP2. They were not significantly different in PT and CPP1 but were significantly greater in CPP2 than in PT (P < 0.001) or CPP1 (P < 0.001). Individual values of pituitary height were compared to those of age-matched girls: they were greater than or equal to mean +/- 2 SD in 8% of PT, 32% of CPP1, and 70% of CPP2. In the CPP group, the pituitary height was correlated with the LH/FSH peak ratio [correlation coefficient (r = 0.52, P < 0.01] and plasma estradiol (r = 0.60, P < 0.01). Four patients with high pituitary height despite LH/FSH peak ratios less than 1 had an increase of their breast development within 1 yr. We conclude that the pituitary height is normal for age in girls with premature thelarche or a mild form of CPP. Conversely, pituitary height is in the pubertal range in girls with the classical form of CPP. Its correlation with LH/FSH peak ratio suggests that pituitary height reflects changes in the degree of hypothalamo-pituitary activation and may provide an indication of its future development. It may therefore help in decisions on LH-releasing hormone analog therapy in certain cases.     

Diagnostic value of fluorometric assays in the evaluation of precocious puberty.

To establish normative data and determine the value of fluorometric AutoDELFIA assays (Wallac Oy) in the investigation of precocious puberty, we determined serum levels of LH, FSH, testosterone, and estradiol under basal and GnRH-stimulated conditions in 277 normal subjects at various pubertal stages and in 77 patients with precocious puberty. A substantial overlap was observed in basal and GnRH-stimulated gonadotropin levels in normal individuals of both sexes with pubertal Tanner stages 1 and 2. The 95th percentile of the normal prepubertal population was the cut-off limit between prepubertal and pubertal levels. These limits were 0.6 IU/L in both sexes for basal LH, 9.6 IU/L in boys and 6.9 IU/L in girls for peak LH after GnRH stimulation, 19 ng/dL in boys for basal testosterone, and 13.6 pg/mL in girls for basal estradiol. Basal and peak LH exceeding these limits were considered positive tests for the diagnosis of gonadotropin-dependent precocious puberty. According to these criteria, the sensitivities of basal and peak LH for the latter diagnosis were 71.4% and 100% in boys, and 62.7% and 92.2% in girls. The specificity and positive predicted value were 100% in both sexes for basal and peak LH levels. The negative predicted values for basal and peak LH were 62.5% and 100% in boys, and 40.6% and 76.5% in girls. Basal and GnRH-stimulated FSH levels overlapped among the various pubertal stages in normal subjects and were, in general, not helpful in the differential diagnosis of precocious puberty. In conclusion, basal LH levels were sufficient to establish the diagnosis of gonadotropin-dependent precocious puberty in 71.4% of boys and 62.7% of girls. In the remaining patients, a GnRH stimulation test was still necessary to confirm this diagnosis. Finally, suppressed LH and FSH levels after GnRH stimulation indicate gonadotropin-independent sexual steroid production.     

Changes in serum inhibin B during normal male puberty

OBJECTIVE: In adult men, inhibin B (InhB) regulates FSH secretion by a negative feedback. The aims of this study were to evaluate the changes of InhB during puberty in the male and the relationship between InhB and FSH, LH, testosterone and testicular volume. DESIGN: Cross-sectional study. METHODS: InhB was measured using a two-site ELISA in 100 healthy boys subdivided by their pubertal development according to Tanner into five groups of 20. RESULTS: During puberty we observed an increase of InhB level (G1 = 84.3 pg/ml, G3 = 132.2 pg/ml, G5 = 206.1 pg/ml). In G1, InhB correlated positively with FSH (P = 0.0001), LH (P = 0.005), testosterone (P = 0.001) and testicular volume (P = 0.007); in G5, InhB correlated inversely with FSH (P = 0.001) and LH (P = 0.045) and directly with testicular volume (P = 0.013). The multivariate analysis demonstrated that: in G1, FSH is the most important, and testosterone the second most significant, stimulus for InhB increase; in G2 only FSH has a positive effect on InhB variation; in G3 only mean testicular volume fits the model (G1-G3: InhB dependent variable); considering the FSH dependent variable, in G4, InhB is the most important stimulus for FSH decrease and mean testicular volume is a secondary directly proportional variable; in G5, only InhB shows a significant inverse relationship with FSH. CONCLUSIONS: During puberty there is a regular increase of InhB. In the first phases of gonadal maturation, InhB and FSH correlate positively, while in mid-late stages the relationship is inverse. We found that in mid-puberty (G3-G4), the serum concentration of InhB increases, as its inverse relationship with FSH is being established and hence spermatogenesis.     

Serum inhibin A and inhibin B in healthy prepubertal, pubertal, and adolescent girls and adult women: relation to age, stage of puberty, menstrual cycle, follicle-stimulating hormone, luteinizing hormone, and estradiol levels

Biochemical assessment of gonadal function during maturation in girls and in adult women can be troublesome. With the recent advent of specific assays for the gonadal peptides inhibin A and inhibin B, it might be possible to achieve a clearer picture of events. We therefore determined serum levels of inhibin A, inhibin B, FSH, LH and estradiol in a cross-sectional study of 403 healthy schoolgirls (aged 6 -20 yr) in relation to age and stage of puberty and in 181 healthy nonpregnant women (aged 20-32 yr) in relation to stage of the menstrual cycle. In addition, inhibin A and inhibin B were measured daily throughout the menstrual cycle in 10 healthy adult women. Levels of inhibin B are low or undetectable in prepubertal girls (median, 26.5 pg/mL; 95% prediction interval, <20-100 pg/mL), increase sharply through pubertal stage II to peak in stage III (median, 84 pg/mL; 95% prediction interval, 28-227 pg/mL) and thereafter decline through pubertal stages IV and V. These changes presumably reflect increasing ovarian stimulation through early puberty, resulting in an increased number of developing follicles, follicles reaching a later stage of development before undergoing atresia, or both. Declining levels in late puberty and adulthood probably reflect the onset of the menstrual cycle and the subsequent appearance of the luteal phase, where inhibin B levels are low. Inhibin A levels are undetectable or very low in early puberty (median, <7 pg/mL; 95% prediction interval, <7-14) pg/mL), increasing gradually through pubertal stages to reach their highest values in adult women (median, 21.5 pg/mL; 95% prediction interval, <7-129 pg/mL). Levels of inhibin A greater than 19 pg/mL are only seen in postmenarcheal girls in puberty and in adult women, again consistent with inhibin A being primarily produced by the corpus luteum. Determining cut-off levels of serum inhibin B regarding whether a girl had entered puberty resulted in similar (low) sensitivities and specificities as those found for cut-off levels of LH or estradiol due to the large overlap between serum values in Tanner stages I and II. Correlations between inhibin A and inhibin B and FSH, LH, and estradiol within pubertal stages are presented. In early puberty both inhibin A and inhibin B correlated positively with LH and FSH. In late puberty inhibin A correlated negatively with FSH and did not correlate with LH; inhibin B still correlated positively with both FSH and LH, now most strongly with FSH. In adult women during the menstrual cycle, serum inhibin B levels increased during the follicular phase, indicating the greatest production by follicles in early stages of development. In contrast, serum inhibin A levels peaked during the luteal phase, indicating the greatest production by the corpus luteum. In conclusion, serum inhibin A and inhibin B levels in normal puberty in girls show consistency with our knowledge of the manner in which these hormones are secreted within the menstrual cycle in adult women. The presented reference values may be of use in the clinical evaluation of pubertal development in girls.     

Hyperandrogenism and hyperinsulinism in children of women with polycystic ovary syndrome: a controlled study

OBJECTIVE: Hyperandrogenia and insulin resistance are heritable family traits, likely to cluster in children of polycystic ovary syndrome (PCOS) mothers. DESIGN: We performed a case control study of PCOS children (n = 32) compared with children from control women (n = 38) for reproductive and metabolic abnormalities, stratifying results by three Tanner stage groupings. The children underwent history and physical examinations, a 3-h timed urine collection, a 2-h oral glucose tolerance test, and abdominal ultrasound examination (females only). Serum was obtained in older children (age > 8 yr) who consented. RESULTS: Urine LH levels were significantly lower in the Tanner IV-V PCOS girls compared with controls (P = 0.04). Urine testosterone levels were significantly elevated in Tanner II-III PCOS boys compared with controls (P = 0.007). There were no significant differences in dehydroepiandrosterone levels. We validated the correlation between salivary and serum levels of insulin (insulin areas under the curve) in an adult population [n =30, Pearson correlation coefficient (r) = 0.67; P < 0.0001], which also replicated in the children (2-h insulin r = 0.57; P = 0.0004). Mean area under the curve salivary insulin levels were significantly higher in the Tanner IV-V PCOS girls in the later stages of puberty when compared with controls (3625 +/- 1372 vs. 1766 +/- 621 min x muU/ml, 95% confidence interval 475-3242; P < 0.02). CONCLUSIONS: Hyperinsulinism may be a familial characteristic of PCOS children (or at least girls) but does not appear until the later stages of puberty. Other reproductive abnormalities that characterize PCOS may develop later.