Gonadotrophin and Growth Hormone Secretion Throughout Puberty

ABSTRACT. The secretion patterns of gonadotrophin and growth hormone (GH) were investigated in normal healthy children at different stages of pubertal development. The plasma levels of luteinizing hormone (LH) and GH were measured at 10-minute intervals from 12.00 h to 18.00 h and from 24.00 h to 06.00 h using immunoradiometric assays. The levels of follicle-stimulating hormone (FSH) and testosterone were measured hourly. In young prepubertal girls and boys LH was undetectable during the day or night. In children of pubertal chronological age, in whom secondary sexual characteristics had not appeared (stage 1 onset), LH was detectable during the night only. With the progression of puberty there was a gradual increase in the secretion of LH, resulting from increases in both the frequency and amplitude of LH pulses. There was a clear increase in the secretion of FSH during day and night from stage 2 onwards. The secretion of GH also increased with the progression of puberty, due to an increase in pulse amplitude. The increase in GH secretion did not appear to be related to the increase in LH secretion, but rather to changes in the sex steroids.     

Longitudinal gonadal function after bone marrow transplantation for acute lymphoblastic leukemia during childhood

Total body irradiation and high-dose chemotherapy, applied as a preparatory regimen for bone marrow transplantation (BMT) in children with acute lymphoblastic leukemia (ALL), are particularly hazardous to the gonads and, in addition, can impair hypothalamo pituitary-gonadal control. Longitudinal data on pubertal development and gonadal function in these patients are limited. Twenty-one ALL patients (15 males, 6 females) who had successfully undergone allogeneic BMT before puberty (age at BMT: 3.4-12.3 yr) were followed up in University Children's Hospital, Tübingen, Germany over 2 (minimum) to 14 (maximum) years. Tanner development scores, serum testosterone and estradiol, basal follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were analyzed. During pubertal age, the levels of FSH and LH rose consecutively, resulting in noticeably elevated serum concentrations in 100% and 89%, respectively, of boys older than 14 years and in 75% and 75%, respectively, of girls older than 13 years. Nevertheless, pubertal development has been normal in all patients except in one boy and two girls who required substitution with sexual steroids, as timely puberty (i.e. boys < 14 years, girls < 13 years) did not start. In males with normal puberty, testosterone levels, however, were found to be low-normal. In conclusion, after BMT preceded by total body irradiation for childhood ALL, gonadal function is impaired. Even if normal pubertal development occurs, deficiencies in long-term endocrine function cannot be ruled out. In view of the high FSH levels, the prognosis for fertility is doubtful.     

SLEEP-RELATED GONADOTROPIN RHYTHMS IN CHILDREN FOLLOWING TREATMENT OF ACUTE LEUKEMIA: RECOVERY OF THE HYPOTHALAMO-PITUITARY-GONADAL AXIS AFTER CHEMOTHERAPY AND CNS-IRRADIATION

ABSTRACT. Twelve children (5 girls and 7 boys, between the ages of 6 and 20 years) in complete remission from previous ALL who had completed their entire anti-leukemic treatment program and who had been off all chemotherapy for at least one year, were included in a study of sleep-related prolactin and gonadotropin rhythms. All the patients had received prophylactic CNS-irradiation. The patients in early puberty showed a sleep-dependent FSH rhythm. Patients in middle-to-late puberty had sleep-related FSH and LH rhythms, and estradiol and testosterone plasma concentrations were normal for their pubertal stage, suggesting recovery of the hypothalamo-pituitary-gonadal feedback system. We conclude that the neuro-endocrine axis is not permanently injured by CNS-irradiation and anti-leukemic therapy.     

Sleep-related gonadotropin rhythms in children following treatment of acute leukemia: recovery of the hypothalamo-pituitary-gonadal axis after chemotherapy and CNS-irradiation

Twelve children (5 girls and 7 boys, between the ages of 6 and 20 years) in complete remission from previous ALL who had completed their entire anti-leukemic treatment program and who had been off all chemotherapy for at least one year, were included in a study of sleep-related prolactin and gonadotropin rhythms. All the patients had received prophylactic CNS-irradiation. The patients in early puberty showed a sleep-dependent FSH rhythm. Patients in middle-to-late puberty had sleep-related FSH and LH rhythms, and estradiol and testosterone plasma concentrations were normal for their pubertal stage, suggesting recovery of the hypothalamo-pituitary-gonadal feedback system. We conclude that the neuro-endocrine axis is not permanently injured by CNS-irradiation and anti-leukemic therapy.     

Testicular function after combination chemotherapy in childhood for acute lymphoblastic leukaemia.

We have assessed testicular function with luteinising hormone-releasing hormone (LH-RH) and human chorionic gonadotrophin stimulation tests in 44 boys previously treated with, or currently receiving, chemotherapy for acute lymphoblastic leukaemia (ALL). At the same time a testicular biopsy was performed in each boy and the morphology was studied. Histologically the chemotherapy appeared to damage the tubular system in particular, and the degree of damage was assessed by estimating the tubular fertility (TF) index which is defined as the percentage of seminiferous tubules containing identifiable spermatogonia. The mean TF index in all 44 biopsies was 51%. Only 2 of the 44 boys showed an absent or blunted testosterone response to human chorionic gonadotrophin. This suggests that Leydig cell function is rarely impaired by such chemotherapy and that most of the boys, similarly treat for ALL, will undergo normal pubertal maturation. Apart from the basal luteinising hormone (LH) levels in the prepubertal group which could not be compared, the median basal serum follicle-stimulating hormone (FSH), LH, and testosterone concentrations, the median peak FSH and LH responses to LH-RH, and the mean plasma testosterone responses to human chorionic gonadotrophin stimulation did not differ between the prepubertal, early pubertal, and late pubertal groups compared with normal boys of similar pubertal maturation. Three of 32 prepubertal ALL boys, and 5 of 12 pubertal ALL boys showed abnormalities of gonadotrophin secretion. The increased frequency of abnormalities of FSH secretion in the pubertal ALL boys compared with the prepubertal ALL boys could not be explained by more severe tubular damage in the former group. We conclude that moderately severe damage to the tubular system of the testis unassociated with Leydig cell impairment may not be detected in the prepubertal boy with current tests of testicular function.     

Spontaneous and GnRH-provoked gonadotropin secretion and testosterone response to human chorionic gonadotropin in adolescent boys with thalassaemia major and delayed puberty

To elucidate whether the cause of sexual maturation arrest in thalassaemia is of gonadal or pituitary etiology, 10 males with thalassaemia and delayed puberty and 10 with constitutional delay of growth and pubertal maturation (CSS) were extensively studied. Their spontaneous nocturnal gonadotropin secretion and gonadotropin response to intravenous 100 micrograms gonadotropin-releasing hormone (GnRH) were evaluated. Circulating testosterone concentration and clinical response were evaluated after 3 days, 4 weeks and 6 months of intramuscular administration of human chorionic gonadotropin (HCG) (2500 U/m2/dose). Thalassaemic boys had significantly lower circulating concentrations of testosterone compared to those with constitutional delay of growth and sexual maturation (CSS) at the same pubertal stage. Short- and long-term testosterone response to administrations of HCG was markedly decreased in thalassaemic boys. After 6 months of HCG administration 50 per cent (5/10) of the boys did not show significant testicular enlargement or genital changes. Despite the low circulating concentrations of testosterone, none of the patients had high basal or exaggerated gonadotropin response to gonadotropin releasing hormone (GnRH) stimulation. Luteinizing hormone (LH) peak responses to GnRH were significantly lower as compared to controls. Follicle-stimulating hormone (FSH) peak responses to GnRH did not differ among the two study groups. The mean nocturnal LH and FSH secretion was significantly decreased in all thalassaemic boys as compared to boys with CSS at the same pubertal stage (testicular volume). These data proved that hypogonadotropic hypogonadism is the main cause of delayed/failed puberty in adolescents with thalassaemia major. MRI studies revealed complete empty sella (n = 5), marked diminution of the pituitary size (n = 5), thinning of the pituitary stalk (n = 3) with its posterior displacement (n = 2), and evidence of iron deposition in the pituitary gland and midbrain (n = 8) in thalassaemic patients, denoting a high incidence of structural abnormalities (atrophy) of the pituitary gland. Moreover, in many of the thalassaemic boys, the defective testosterone response to long-term (6 months) HCG therapy denoted significant testicular atrophy and/or failure secondary to siderosis. It appears that testosterone replacement might be superior to HCG therapy in these patients. This therapy should be introduced at the proper time in these hypogonadal patients to induce their sexual development and to support their linear growth spurt and bone mineral accretion.     

Puberty in 24 patients with Klinefelter syndrome

Twenty four boys with Klinefelter syndrome, 18 of whom were diagnosed prepubertally, were observed until adulthood. Onset of puberty, as judged from testicular enlargement and pubic hair development, occurred between 11 to 14 years in the above 18 patients. By the age of 17 pubic hair, penile length and height had reached the adult stage in all patients, but arrest of testicular growth was noted at midpuberty, 13 years, with maximal mean (±SD) volume attained being 3.5±1.5 ml. The first conscious ejaculation was reported to have occurred between 13 to 16 years in 10 patients and in the remaining 4 between 17 to 18 years of age. Sperm counts obtained after the age of 18 revealed azospermia or severe oligospermia in all patients except one, who had a sperm count of 30×10⁶/ml. The hypothalamic-pituitary-gonadal axis, assessed by LH-RH and hCG stimulation tests, was found to be normal in prepuberty and during early pubertal stages. From mid-puberty the basal levels of plasma FSH and the response to LH-RH showed a gradual increase above the normal. Towards late puberty (>15 years) basal and peak levels of LH were above normal with a concomitant decrease in the basal level of testosterone and its response to hCG.These findings indicate that during childhood and early puberty function of the hypothalamic-pituitary-gonadal axis is normal in Klinefelter syndrome, allowing the onset of pubertal signs at the appropriate age, and that until late puberty there is a relative preservation of function in the testicular Leydig cells, permitting the normal sequential development of the androgen-dependent pubertal signs. The measurement of testicular testosterone reserve by means of hCG stimulation constitutes a useful aid in determining when and if testosterone replacement therapy should be instituted.     

Age-related change of pulsatile gonadotropin secretion in Turner syndrome

In an attempt to understand the dynamic change of the gonadotropin-releasing hormone-pituitary axis during the transitional stage from prepuberty to puberty, we investigated gonadotropin secretory patterns using a highly sensitive assay system and frequent blood sampling technique in children with Turner syndrome aged 5-17 y. Blood samples were collected every 20 min for 24 h in 16 cases, or every 30 min for 9 h (daytime 5 h, nighttime 4 h) in nine cases. Serum LH and FSH were measured by time-resolved fluoroimmunoassay. A 24-h profile of LH and FSH was analyzed by a computerized pulse detection program (PC-PULSAR). As early as 5 to 6 y of age, mean daytime LH concentration was significantly higher than nighttime concentration and pulsatile LH secretion existed throughout the day and night. At about 9 to 11 y of age, corresponding to the early stage of puberty, a dramatic increase in LH concentration and amplitude was observed, and both concentration and pulse amplitude were much higher during the night than during the day. However, these day-night differences became less clear at ages corresponding to late pubertal stages. Pulse frequency of LH secretion remained almost constant throughout the day and night at all ages investigated. As for FSH concentration, a trend similar to that of LH was observed, although day-night differences and age-related changes were less remarkable. Furthermore, pulsatile FSH secretion was detected in only a small number of the cases. These findings suggest that in Turner syndrome the hypothalamic gonadotropin-releasing hormone oscillator is functioning actively with constant frequency before the onset of puberty.(ABSTRACT TRUNCATED AT 250 WORDS)     

Assessment of the gonadotrophin-gonadal axis in androgen insensitivity syndrome.

OBJECTIVE: To study the value of measuring serum luteinising hormone (LH), follicle stimulating hormone (FSH), testosterone, and dihydrotestosterone (DHT) in androgen insensitivity syndrome (AIS). DESIGN: Retrospective study of patients on a nationwide register of AIS. PATIENTS: Sixty one cases of AIS with androgen receptor (AR) dysfunction (abnormalities of the AR gene and/or abnormal AR binding) were divided into three age groups: infants, < 1 year old; children, 1-13 years old; and postpubertal, > 13 years old. MEASUREMENTS: Age, dose of human chorionic gonadotrophin (hCG) stimulation, pre-hCG and post-hCG serum testosterone values, serum DHT values, and serum LH and FSH values before and after LH releasing hormone (LHRH) stimulation. RESULTS: In 23 of 30 infants testosterone was within age related reference ranges; six were above this range. The median testosterone rise following variable dosage of hCG was 9.5 times the basal value. The increment was not related to the hCG dose, age, or basal concentration of testosterone. The median basal and stimulated testosterone:DHT ratios were 2.5 and 6.1, respectively. The median increment in DHT was 2.2-fold. Seventeen of 18 FSH and 11 of 19 LH measurements were within age related ranges in infants; in seven patients LH values were above the range. LHRH stimulation performed in 39 patients showed an exaggerated LH in all age groups. The FSH response was not exaggerated in children. CONCLUSION: Although a positive hCG test excludes biosynthetic defects of testosterone, an inadequate response does not exclude AIS. Basal LH and testosterone may not be raised during early infancy. An LHRH stimulation test might be useful for evaluating cases of suspected AIS presenting in mid-childhood.     

4岁内儿童性早熟57例

目的探讨4岁内儿童性早熟的病因、诊断要点,研究简易的促性腺激素释放激素(GnRH)激发试验的可行性。方法对57例<4岁性早熟患儿的临床资料进行回顾性分析。57例均行GnRH激发试验,对中枢性与部分中枢性组患儿的LH值进行秩和检验。结果本组男3例,女54例。外周性性早熟36例(63.1%);中枢性性早熟(CPP)4例;部分性CPP17例。CPP促黄体生成素(LH)升高为甚,50%峰值落在60~90min,部分性CPP促卵泡生成素(FSH)升高为甚,84.2%峰值落在90~120 min;CPP与部分性CPP 30、60、90、120 min LH比较有显著差异(P均<0.01)。结论<4岁儿童性早熟以女性发病为主,多为外周性性早熟。GnRH激发试验对病因分类很必需,应在0、60、120 min测LH、FSH,以明确CPP和部分性CPP。     

Hormonal profile of puberty in South Australian children II

Serum follicle stimulating hormone (FSH), luteinising hormone (LH) and oestradiol (E₂) concentrations in 117 girls aged 8 to 17.9 years were related to chronological age (CA), bone age (BA), breast development (B1–5+) and pubic hair development (PH1–5+). A progressive rise in serum LH and E₂ was noted in relation to CA, BA and pubertal development. Serum FSH levels reached a peak in mid-puberty and fell thereafter. The FSH/LH ratio decreased with advancing CA and BA. In comparing the data in girls (Part II) with that in boys (Part I) serum FSH and LH levels began to rise earlier in girls and were generally higher than levels seen in boys throughout puberty. Similarly, an earlier rise in serum E₂ in girls compared with T in boys supported the concept of an earlier activation of the female gonad.     

Pubertal development and growth after total-body irradiation and bone marrow transplantation for haematological malignancies

Pubertal development after total-body irradiation (TBI) was investigated in 40 children (21 boys) treated with allogeneic bone marrow transplantation (BMT) for haematological malignancies at a mean age of 11.3 years. The mean age at the last visit was 19.0 years. Twenty-five patients (15 boys) were prepubertal at BMT. Data on secondary sexual characteristics, the pituitary-gonadal axis and longitudinal growth were retrospectively collected from the medical records. In boys not receiving additional testicular irradiation (n = 19), penile growth and pubic hair development was normal and all had serum testosterone levels within the adult range. The majority of them, however, had incidental elevations of LH, suggesting minor Leydig cell damage. Testicular volume at last measurement was small (mean: 10.5 ml) and serum FSH levels were elevated in all boys, with normalisation in only one, suggesting severe impairment of reproductive gonadal function. Of the ten girls who received BMT before puberty, six had a spontaneous onset of puberty and menarche; the four other girls needed hormonal substitution therapy. Recovery of gonadal function after cessation of substitution was seen in one girl, who became pregnant but had a spontaneous abortion. Decrease in height SDS was seen in the majority of patients and was positively correlated with male gender and lower age at the time of BMT. Conclusion Careful monitoring of both gonadal function and growth after bone marrow transplantation and total body irradiation is warranted in order to detect disturbances early and ensure normal pubertal development in children treated for haematological malignancies. Received: 30 December 1998 / Accepted: 15 May 1999     

Hormonal profile of puberty in South Australian children I

Serum follicle stimulating hormone (FSH), luteinising hormone (LH) and testosterone (T) concentrations in 118 boys aged 8 to 17.9 years were related to chronological age (CA), bone age (BA), genital development (G1–5+), pubic hair development (PH1–5 +) and mean testicular volume (MTV). A progressive rise in serum FSH, LH and T was noted in relation to CA, BA and all pubertal parameters studied. FSH showed an approximate twofold increase, LH an eight to tenfold increase and T a fourfold increase from pre-puberty through to full adult maturity. The FSH/LH ratio decreased with advancing CA, BA and pubertal development.     

Effect of synthetic luteinizing hormone-releasing hormone on the release of gonadotropins in hypophysogonadal disorders of children and adolscents. VII. Constitutional delay of puberty in males.

Serum gonadotropins (LH and FSH) were measured by radioimmunoassay before and after intravenous injection of 0.1 mg/m2 of synthetic luteinizing hormone-releasing hormone in 20 male patients, aged 15 to 18 years, with constitutional delay of puberty. Basal plasma levels of LH and FSH were in the prepubertal range. After administration of LH-RH, the increase in LH was significantly high than in prepubertal control subjects, aged 1 to 13 years; the difference between test patients and pubertal control subjects was not significant. The increase in FSH was in the prepubertal range, significantly lower than that in pubertal control subjects. This discrepancy between LH and FSH responses to LH-RH is similar to that observed in normal boys at the late prepubertal stage and suggests that an elevation of readily releasable pituitary stores of LH correlates with the first step of pubertal onset in males, even if puberty is delayed.     

Induction of puberty in hypogonadal children

Puberty is the transitional period between childhood and adulthood when physical, sexual, and psychosocial maturation occurs. The onset of puberty is controlled by the gonadotropin-releasing hormone (GnRH) neuron and is triggered when inhibition of the neuron is lifted. Subsequently, GnRH induces secretion of other hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which in turn stimulate the gonads. Concurrently, increases in estrogen levels in both boys and girls stimulate growth hormone (GH) and insulin-like growth factor-I (IGF-I) secretion, which are responsible for the pubertal growth spurt. In hypogonadal children, however, hypothalamic/pituitary defects or gonadal diseases preclude the production of these hormones, preventing the onset of puberty. Hormone replacement therapy with either estrogen or testosterone is a viable treatment option for hypogonadal children. These should be administered with consideration of sexual maturation rates, statural and bone growth rates, and occurrence of adverse effects. The merits and disadvantages of various hormone replacement therapies for girls and for boys are discussed.     

The effect of synthetic androgens on the hypothalamic-pituitary-gonadal axis in boys with constitutionally delayed growth.

Serial concentrations of basal serum LH, FSH, testosterone, and LH and FSH responses to intravenous gonadotropin-releasing hormone were measured before and during six months of administration of fluoxymesterone or oxandrolone in 14 boys with constitutionally delayed growth and adolescence, in order to assess the effects of these androgens on maturation of the hypothalamic-pituitary-gonadal axis. Before therapy all boys had normal hormonal responses based on bone age. At the end of six months therapy 10 of the 14 boys had lower LH responses (34 to 89% reduction) to GnRH without consistent changes in FSH responses. With both androgens, there there was significant suppression of both basal serum FSH and testosterone. Eleven boys were restudied six months after completion of therapy; basal serum LH, FSH, and testosterone and responses to GnRH were equal to or greater than pretreatment levels, indicating recovery or progressive maturation of the HPGA. All boys had increased growth velocity and imporved weight gain without excessive bone age advancement; all had improved psychosocial adjustment.     

SERUM PROLACTIN, FSH AND LH DURING PUBERTY IN GIRLS AND BOYS

ABSTRACT. Serum prolactin, follicle-stimulating hormone and luteinizing hormone were determined in 200 girls and 80 boys. The boys have been examined on three occasions at one-year intervals and the girls twice at 1.5-year intervals. In girls, serum FSH rapidly increased in the youngest age groups (7.5–11.5 years), whereas in boys, the increase took place later and the first significant increase was seen between age groups 9.5 and 12.5 years. In girls, a rise in serum LH took place later than that of FSH (between 10.5 and 11.5 years), and LH peaked at 13.0–13.5 years. In boys, the timing in the changes of serum LH closely resembled that of FSH. The girls displayed a significant increase in serum prolactin between 7.5 and 8.5 years, and this was followed by a slow progressive increase. In the group of boys, serum prolactin did not show any significant changes. In girls, there was a correlation between serum LH and body weight, as well as calculated fat amount and body fat percentage early in puberty. There was no correlation between serum LH and chronological or bone age in this age group, which suggests that the correlation found is not due to age-related parallel phenomena.     

Serum prolactin, FSH and LH during puberty in girls and boys.

Serum prolactin, follicle-stimulating hormone and luteinizing hormone were determined in 200 girls and 80 boys. The boys have been examined on three occasions at one-year intervals and the girls twice at 1.5-year intervals. In girls, serum FSH rapidly increased in the youngest age groups (7.5-11.5 years), whereas in boys, the increase took place later and the first significant increase was seen between age groups 9.5 and 12.5 years. In girls, a rise in serum LH took place later than that of FSH (between 10.5 and 11.5 years), and LH peaked at 13.0-13.5 years. In boys, the timing in the changes of serum LH closely resembled that of FSH. The girls displayed a significant increase in serum prolactin between 7.5 and 8.5 years, and this was followed by a slow progressive increase. In the group of boys, serum prolactin did not show any significant changes. In girls, there was a correlation between serum LH and body weight, as well as calculated fat amount and body fat percentage early in puberty. There was no correlation between serum LH and chronological or bone age in this age group, which suggests that the correlation found is not due to age-related parallel phenomena.     

Prognostic values of the determination of sleep-related gonadotropin rhythm in delayed puberty

Sleep-related gonadotropin rhythms are specific for puberty. Sleep-dependent increases of prolactin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were studied in 6 boys and 1 girl with constitutional delay of growth and puberty. The purpose of this study was to determine whether gonadotropin rhythms occur in the same hormonal sequence in children with constitutional delay of puberty as in normal children. At the onset of puberty a sleep-related FSH increase was detectable, followed by LH-rhythms 1 to 2 years later. The findings of a sleep-dependent FSH increase excludes a hypogonadotropic hypogonadism and triggers the development of secondary sex characteristics.     

Pulsatile secretion of LH and FSH in prepubertal and early pubertal boys revealed by ultrasensitive time-resolved immunofluorometric assays

Pulsatile secretion of LH and FSH was examined in 10 prepubertal (aged 4.5-12.9 y) and seven early pubertal (aged 12.8-14.5 y) boys with ultrasensitive (0.019 and 0.014 IU/L) time-resolved immunofluorometric assays. Plasma LH and FSH levels were measured every 15 or 20 min for 6 h during the day and night. The lowest mean LH level in a prepubertal boy was 0.02 IU/L and in eight other prepubertal boys mean LH levels were less than 0.4 IU/L. In early pubertal boys the mean LH levels ranged from 0.3 to 6.5 IU/L. The difference in mean FSH level between prepubertal (0.61 IU/L) and early pubertal boys (1.85 IU/L) was smaller than the difference in LH level. All boys had significant LH and FSH pulses. The LH interpulse interval was 135 +/- 86 min (mean +/- SD) and 76 +/- 65 min for the prepubertal and pubertal boys, respectively (p less than 0.01). For FSH, the respective values were 150 +/- 122 and 221 +/- 157 min (p = NS). The mean LH pulse amplitudes were 11-fold greater in the early pubertal boys than in the prepubertal boys, whereas the mean FSH pulse amplitudes were similar between the two groups. The present method shows that the mean LH levels in prepubertal boys are much lower, and the increase during puberty larger, than previously reported. The increase is apparently due to increased pulse frequency and amplitude. The increase in mean FSH level is smaller and evidently not caused by an increase in pulse frequency or pulse amplitude.