Pituitary-gonadal function in Klinefelter syndrome before and during puberty

Serum concentrations of follicle-stimulating hormone, luteinizing hormone, testosterone, and estradiol were determined at intervals before and during puberty in 40 individuals with Klinefelter syndrome (47,XXY karyotype), of whom 27 had been detected in neonatal cytogenetic screening programs. Prior to the appearance of secondary sexual changes, basal serum hormone concentrations and acute responses to stimulation with gonadotropin-releasing hormone and human chorionic gonadotropin were normal. The timing of the onset of clinical puberty was normal. Early pubertal boys showed initial testicular growth and normal serum testosterone levels, while serum follicle-stimulating hormone and estradiol concentrations were significantly elevated. By midpuberty, the Klinefelter subjects were uniformly hypergonadotropic and their testicular growth had ceased. Serum testosterone concentrations after age 15 remained in the low-normal adult range. Serum estradiol levels remained high, irrespective of the presence or absence of gynecomastia. Exaggerated responses to gonadotropin-releasing hormone are seen in pubertal subjects with elevated basal gonadotropin values.     

Evaluation of testicular function following long-term treatment for acute lymphoblastic leukemia

A study of reproductive function was carried out in 31 patients following long-term treatment of acute lymphoblastic leukemia (mean: 4 1/12 years); 17 prepubertal; nine pubertal, and five adults. Spontaneous clinical pubertal development was observed in 4 of 17 prepubertal patients. Serum testosterone response to hCG was normal or increased in the nine prepubertal patients studied. Intratesticular testosterone concentration was normal in 11 out of 12 patients. Only two of 14 prepubertal patients had a reduced number of germ cells. Normal progress of spermatogenesis was seen in six out of seven pubertal patients and only moderate hypospermatogenesis with focal hyalinosis was found in the five adults. Two of them had normal sperm count and one fathered two children. In six out of 14 prepubertal patients unexpected early signs of pubertal stimulation were found. Serum gonadotrophins response to LH-RH was normal in most patients. Testicular infiltration of blastic cells was found in four of 26 biopsies, but only one of 23 patients was without clinical signs of testicular relapse. Computerized axial tomography was normal in 10 out of 13 patients. Bone age was significantly below chronological age in four out of 15 patients. This study suggests that the gonad is moderately injured by long-term antileukemic therapy. In addition, microscopic testicular infiltration is not frequent in subjects without testicular enlargement.     

Accelerated pubertal development in patients with shunted hydrocephalus

OBJECTIVE: To evaluate pubertal development and peripheral concentrations of gonadotrophins and sex hormones in children with shunted hydrocephalus compared with healthy controls. STUDY DESIGN: 114 patients (52 females, 62 males) and 73 healthy controls (35 females, 38 males) aged 5 to 20 years were analysed for stage of puberty, age at menarche, testicular volume, basal serum follicle stimulating hormone (FSH), luteinising hormone (LH), sex hormone binding globulin (SHBG), testosterone and oestradiol concentrations, and free androgen index. RESULTS: Male gonadal and male and female pubic hair development occurred significantly earlier in the patients than in the controls. The mean age at menarche was significantly lower in the female patients than in their controls (11.7 v 13.2 years; p < 0.001), and lower than it had been for their mothers (v 13.1 years; p < 0.001). Relative testicular volume was higher in the male patients than in their controls (1.2 standard deviation score (SDS) v 0.2 SDS; p < 0.001). The prepubertal patients had higher basal LH (0.13 U/l v 0.08 U/l; p < 0.001) and SHBG (132.3 nmol/l v 109.1 nmol/l; p < 0.01) than the controls. Both the prepubertal and pubertal females had significantly higher basal FSH than their controls (1.57 U/l v 1.03 U/l; p < 0.05, and 4.0 U/l v 2.9 U/l; p < 0.01, respectively). CONCLUSIONS: Hydrocephalic children experience accelerated pubertal maturation, reflected in a younger age at menarche in females and an increased testicular volume in males. This may be because of enhanced gonadotrophin secretion, possibly resulting from unphysiological variations in intracranial pressure.     

Accelerated pubertal development in patients with shunted hydrocephalus.

OBJECTIVE: To evaluate pubertal development and peripheral concentrations of gonadotrophins and sex hormones in children with shunted hydrocephalus compared with healthy controls. STUDY DESIGN: 114 patients (52 females, 62 males) and 73 healthy controls (35 females, 38 males) aged 5 to 20 years were analysed for stage of puberty, age at menarche, testicular volume, basal serum follicle stimulating hormone (FSH), luteinising hormone (LH), sex hormone binding globulin (SHBG), testosterone and oestradiol concentrations, and free androgen index. RESULTS: Male gonadal and male and female pubic hair development occurred significantly earlier in the patients than in the controls. The mean age at menarche was significantly lower in the female patients than in their controls (11.7 v 13.2 years; p < 0.001), and lower than it had been for their mothers (v 13.1 years; p < 0.001). Relative testicular volume was higher in the male patients than in their controls (1.2 standard deviation score (SDS) v 0.2 SDS; p < 0.001). The prepubertal patients had higher basal LH (0.13 U/l v 0.08 U/l; p < 0.001) and SHBG (132.3 nmol/l v 109.1 nmol/l; p < 0.01) than the controls. Both the prepubertal and pubertal females had significantly higher basal FSH than their controls (1.57 U/l v 1.03 U/l; p < 0.05, and 4.0 U/l v 2.9 U/l; p < 0.01, respectively). CONCLUSIONS: Hydrocephalic children experience accelerated pubertal maturation, reflected in a younger age at menarche in females and an increased testicular volume in males. This may be because of enhanced gonadotrophin secretion, possibly resulting from unphysiological variations in intracranial pressure.     

中国九大城市男孩睾丸发育、阴毛发育和首次遗精年龄调查

目的 调查中国九大城市男孩青春发育的平均年龄.方法 采用全国协作性横向调查,于2003-2005年间进行.对象为代表中国东、西、南、北、中部地区的九大城市(包括北京、天津、青岛、上海、武汉、南宁、重庆、广州、福建)城区3-19.83岁的19 054名健康男孩.用睾丸计(Preder orchidometer)测量睾丸容积(ml);通过视诊法进行阴毛发育Tanner分期;发放调查表,由家长和(或)男孩本人填写遗精与否及具体日期.采用概率单位回归法(Probit analysis)计算睾丸发育、阴毛发育和首次遗精的平均年龄及95%可信区间(CI).以睾丸容积4 ml作为青春期启动的标志.将本次调查结果 与国内外文献报道的结果 相比较,并将首次遗精(初遗)年龄与1979年以来进行的五次全国性学生体质健康调查中的相似人群的初遗年龄进行比较.结果 9岁组12.99%的男孩睾丸发育已达4 ml.中国男孩青春期启动的中位年龄是10.55(95% CI 10.27～10.79)岁.阴毛发育Ⅱ期的中位年龄是12.78(95% CI 12.67～12.89)岁,首次遗精的中位年龄是14.05(95% CI 13.80～14.32)岁.1979年以来,中国城区男孩初遗年龄呈现年代提前的变化.结论 中国大城市城区男孩睾丸发育年龄较目前临床所用正常值早,并属当今睾丸青春发育较早、阴毛发育较迟的人群之列;自1979年以来,以呈现首次遗精为特征的性成熟年龄呈年代提前趋势.     

Pubertal development in Swiss boys

Pubertal development between 8 and 18 years is reported in 142 Swiss males of the First Zurich Longitudinal Study (1954-1980). Genital and pubic hair development were rated according to TANNER [14]. Testicular growth was assessed by comparative palpation with the orchiometer of PRADER [10]. The age at which pubertal development was initiated varied between the eighth and the fifteenth year of life. Reaching a testicular volume of 3 ml was found to be the most reliable indicator for the onset of pubertal development. The various pubertal stages of genital and pubic hair development tended to occur at earlier ages in this study than previously reported. This was particularly true for PH6 which was observed in 73% of the boys by age 20. Standard deviations of 1.0 to 1.5 years for the ages at which the pubertal stages were reached reflected the large variations in the timing of pubertal development. The mean duration of genital development was 3.5 +/- 1.1 years, of pubertal penis growth 1.8 +/- 0.7 years, of pubertal testicular growth 3.5 +/- 1.0 years and of pubic hair development 2.7 +/- 1.0 years. Moderate correlations were found between the ages at which genital development, pubic hair development and pubertal testicular growth were initiated. The ages at completion of these pubertal characters and the age at which the peak of the adolescent growth spurt was reached were highly positively correlated with each other. For a given stage of a pubertal character at least 80% of the children were within two successive stages of any other pubertal character, e.g. 87% of the boys were either in G2 or G3 when they reached PH2. No significant relationship between the durations of genital development, pubic hair development and pubertal testicular growth could be established. Likewise no significant relationship could be found between the timing and duration of pubertal development.     

ENDOCRINOLOGICAL STUDIES IN UNDESCENDED TESTES

Abstract. A cross-sectional study was carried out on 168 boys aged 2.5–16.8 years with unilateral or bilateral testicular maldescent. Urinary excretion of testosterone, Δ₄-androstenedione, LH and FSH was investigated. The results were related to chronological age, bone age and sexual maturation stage. Urinary testosterone excretion was elevated in unilateral and bilateral cases of undescended testis under 9 years of age. The pubertal increase of testosterone excretion seemed to be moderately delayed in the patients. In pubertal stage V the testosterone excretion was normal. The mean testosterone/androstenedione relationship was normal in all age groups up to 14.9 years and increased in patients above this age. After HCG stimulation, the testosterone excretion increased at all ages studied whereas the androstenedione excretion increased only in bilateral cases under 11 years of age. Urinary LH excretion was diminished in bilateral cases aged 6.0–7.9 years and elevated in unilateral cases in pubertal stage V. Urinary FSH excretion was normal below 8 years of age, moderately elevated in bilateral cases aged 8.0–11.9 years and increased in unilateral cases in pubertal stage V. Patients with bilateral anorchia in pubertal stage I, had normal basal testosterone and androstenedione excretion while the LH and FSH levels were increased. The findings in this study indicated that disturbances in the pituitary-gonadal function of cryptorchids might be operative from early childhood and throughout pubertal years.     

Pubertal development in male hypopituitarism

The spontaneous or therapeutically induced pubertal development of 65 male patients with idiopathic hypopituitarism was analysed. Spontaneous puberty occurred in 82% of the patients with prepubertal isolated growth hormone deficiency and in 32.5% of those with impairment in the secretion of more than one pituitary hormone.Out of this group, 36 patients could be studied longitudinally. In 15 patients, the onset of spontaneous puberty was delayed, on average, 3.2 years. It started at a bone age of 10.36±1.25 years and followed a pattern similar to that of normal boys. Testosterone levels at each pubertal stage were not different from those of normal boys. Mean peak height velocity reached 7.27±1.82 cm/year. In 21 patients with gonadotropin deficiency, hCG treatment was started at a chronological age of 19.04±2.17 years and a bone age of 12.94±0.80 years. Plasma testosterone attained normal adult levels in the majority of boys, while the development of sexual characteristics showed a wide variation. Mean growth velocity during the first year of hCG therapy reached 6.11±2.47 cm/year. Partial gonadotropin deficiency was diagnosed in two boys.Although testosterone seems today to be, for practical reasons, the replacement therapy of choice, hCG treatment is an alternative for hypopituitary patients with absent gonadotropin function.Abbreviations IGHD isolated growth hormone deficiency - MPHD multiple pituitary hormone deficiency - hCG human chorionic gonadotropin - hGH human growth hormone - PHV peak height velocity     

Induction of puberty in boys with delayed adolescence by methandrostenolone

Methandrostenolone administration at a daily dose of 0.03 mg/kg for 3 months was successful in inducing puberty in 9 boys (aged 14 6/12±6/12 years, m±SD) with delayed puberty and studied in the prepubertal stage. One year after initiation of treatment they reached a mid-pubertal stage (testicular volume m±SD 6±2 ml and pubic hair development Tanner stage 3–4). At the same time growth velocity accelerated from 5.3±1.5 to 8.5±3.4 cm/yr and bone age advanced from 10 9/12±9/12 to 13±6/12 years (m±SD).During treatment there was suppression of basal plasma LH and FSH (m±SD) from 1.3±0.3 to 0.5±0.2 mIU/ml (P<0.001) and from 1.4±0.8 to 0.8±0.3 mIU/ml (P<0.05) respectively, and of the LH response to LRH (50 mcg/m², i.v.) from 5.2±1.0 to 1.9±0.6 mIU/ml (P<0.001). After discontinuation of methandrostenolone there was a significant and prolonged elevation of the basal plasma LH (2.0±0.4 mIU/ml) and testosterone levels (from 24±7.7 to 175.6±67.5 ng/dl, P<0.01) and an enhanced LH response to LRH (8.3±2.4 mIU/ml, P<0.05), compared to the pre-treatment levels.Eleven prepubertal boys with constitutional short stature (aged 9 3/12±9/12 years, m±SD) maintained their prepubertal state one year following the same therapeutic regime with methandrostenolone. No significant changes in the basal plasma testosterone and gonadotropin levels, or the responses to LRH, were noted in this group.During treatment a significant increase in growth velocity was noted (from 4.1±1.7 to 9.7±3.0 cm/year, P<0.02), with a subsequent decrease to 5.4±2.9 cm/year (m±SD) which was not significantly different to the pre-treatment value. Bone age advanced from 6 3/12±1 before treatment to 8±1 6/12 years 12 months following methandrostenolone administration.It is concluded that methandrostenolone can induce puberty in boys with delayed puberty if administered in the prepubertal stage, but not in younger prepubertal boys with short stature. The concomitant changes in the basal plasma testosterone and gonadotropin levels, and their response to LRH stimulation, which were found in the boys with delayed puberty indicate that a certain degree of maturation of the hypothalamic pituitary gonadal axis is probably needed to permit induction of puberty by methandrostenolone. The effect of this drug is due in part to its androgenic potency and probably also to its modulation of negative feedback in the hypothalamic-pituitary-gonadal axis, causing a rebound phenomenon following brief suppression.Supported in part by the Harry C. Bernard Fund     

Gonadal function of young patients with beta-thalassemia following bone marrow transplantation

Bone marrow transplantation (BMT) can induce short- and long-term impairment of gonadal function. Patients with beta-thalassemia represent a special group, as their primary diagnosis and its treatment modalities are responsible for gonadal dysfunction. To address the effect of BMT on puberty and gonadal function, we investigated 25 patients (12 males) with thalassemia who received allogenic BMT during childhood or adolescence and at the post-transplant evaluation were at an age that the pubertal process should have started. Pubertal stage by Tanner of breast and pubic hair, as well as testicular volume were assessed pre-BMT once and post-BMT at least twice. Menstrual history was recorded. FSH, LH, testosterone and estradiol levels were also determined. The impact of BMT appears to be different in the two sexes. Males seem to have higher tolerance, as all males who were pubertal at the time of BMT had normal testosterone, and all but one normal gonadotropin levels. From those who were prepubertal at BMT, 62% proceeded to normal pubertal development. Post-menarcheal females seem to be an extremely sensitive group to the deleterious effect of the transplantation process, as 100% of the post-menarcheal females exhibited amenorrhea and elevated gonadotropin levels. These findings are important for pre- and post-BMT counseling.     

Congenital adrenal hypoplasia in a male with gonadotropin deficiency

We report the case of a boy with adrenal insufficiency diagnosed at the age of 2.5 months. He required immediate therapy with corticosteroids. His two brothers and a cousin died in infancy with vomiting and dehydration. Aged 17.5 years (bone age 13 years), he showed no signs of puberty, a testicular volume of 2 ml, an infantile penis, and no axillary or pubic hair. There was no evidence of a pubertal growth spurt. The low plasma levels of cortisol, 17-OHP, delta-4-A, LH and FSH did not increase after stimulation with ACTH or LHRH respectively. Urinary testosterone levels before and after HCG were extremely low. These factors strongly suggest the diagnosis of a sex-linked type of adrenal insufficiency (cytomegalic form), associated with gonadotropin deficiency.     

Endocrinological studies in undescended testes.

A cross-sectional study was carried out on 168 boys aged 2.5-16.8 years with unilateral or bilateral testicular maldescent. Urinary excretion of testosterone, delta4-androstenedione, LH and FSH was investigated. The results were related to chronological age, bone age and sexual maturation stage. Urinary testosterone excretion was elevated in unilateral and bilateral cases of undescended testis under 9 years of age. The pubertal increase of testosterone excretion seemed to be moderately delayed in the patients. In pubertal stage V the testosterone excretion was normal. The mean testosterone/androstenedione relationship was normal in all age groups up to 14.9 years and increased in patients above this age. After HCG stimulation, the testosterone excretion increased at all ages studied whereas the androstenedione excretion increased only in bilateral cases under 11 years of age. Urinary LH excretion was diminished in bilateral cases aged 6.0-7.9 years and elevated in unilateral cases in pubertal stage V. Urinary FSH excretion was normal below 8 years of age, moderately elevated in bilateral cases aged 8.0-11.9 years and increased in unilateral cases in pubertal stage V. Patients with bilateral anorchia in pubertal stage I, had normal basal testosterone and androstenedione excretion while the LH and FSH levels were increased. The findings in this study indicated that disturbances in the pituitary-gonadal function of cryptorchids might be operative from early childhood and throughout pubertal years.     

A patient with Klinefelter's syndrome and thalassemia intermedia

Klinefelter's syndrome (KS) is associated with a wide spectrum of clinical features, such as tall stature, eunuchoid proportions, testes disproportionately small for the level of pubertal development, gynecomastia and behavioral problems. The association of KS with thalassemia intermedia has not been previously reported. A male patient with thalassemia intermedia was diagnosed with KS at the age of 14 years when endocrine evaluation for delayed puberty showed hypergonadotrophic hypogonadism. Thyroid function was normal; however, basal and GnRH-stimulated gonadotropin concentrations were raised while serum testosterone was low. Karyotype analysis revealed KS (47,XXY). Testosterone replacement therapy started soon after diagnosis and now at the age of 20 years the patient's height is 178.3 cm, the U/L ratio is 0.91. Testicular volume is 12 ml (Prader orchidometer) and his pubic hair is stage 4. To our knowledge this is the first case of a patient suffering from KS and thalassemia intermedia reported in the literature.     

Central precocious puberty in 48,XXYY Klinefelter syndrome variant

We report the first case of central precocious puberty in a patient with 48,XXYY Klinefelter syndrome variant. We also report clinical characteristics, growth pattern, endocrine data and pathological testicular findings. The patient did not receive medical care for his precocious pubertal development, because of adequate height prognosis, and reached normal height for both his target height and Klinefelter patients. Since precocious puberty seems to occur in Klinefelter syndrome and its variants, we advise karyotype analysis in boys with mental retardation, gynecomastia, small testes and precocious onset of puberty.     

EFFECT OF OBESITY ON THE HYPOTHALAMO-PITUITARY-GONADAL FUNCTION IN CHILDHOOD

Abstract. In 22 normal and 35 obese boys a gonadal function test (2 000 IU of hCG i. m. daily for three days and assays of plasma testosterone before and after the hCG administration) was carried out. All the "short normal" children and 31 obese subjects underwent the LH-RH test (50 μg i.v.). While basal testosterone was similar in the two groups of children, after hCG testosterone was significantly (p<0.001) lower in the obese boys. In the normal children a significant positive correlation between bone age and basal and after hCG testosterone was demonstrated; this correlation was not found in the obese boys. The pituitary reserve of gonadotrophins did not show significant differences between the two groups of children. Finally a significant positive correlation (p<0.01) between the LH curve area during the LH-RH test and bone age was found only in the normal boys.     

Growth and Maturation in the Male Genitalia From Birth to Adolescence I. Change of Testicular Volume

Testicular volumes of Japanese males from birth to adolescence were studied in cross-sectional series. Maturational events of testicular volumes occurred in the two periods during early infancy and adolescence. The testicular volumes during the first three months of life were slightly greater than later in infancy. Thereafter there was very little increase in testicular volumes from the age 1 to 10 years. After 11 years there was a sudden increase in size. The mean volumes increased from 6.5 cm³ at the age of 11 years to 36.7 cm³ at 14 years. The largest increment was observed between 13 and 14 years of age and between pubic hair stages I and II. Reaching testicular volumes of 6.5 cm³ was found to be a landmark of the earliest sign of puberty. The age at which pubertal development was initiated varied between the ninth and the fourteenth year of life.     

Effect of obesity on the hypothalamo-pituitary-gonadal function in childhood.

In 22 normal and 35 obese boys a gonadal function test (2000 IU of hCG i.m. daily for three days and assays of plasma testosterone before and after the hCG administration) was carried out. All the "short normal" children and 31 obese subjects underwent the LH-RH test (50 microng i.v.). While basal testosterone was similar in the two groups of children, after hCG testosterone was significantly (p less than 0.001) lower in the obese boys, In the normal children a significant positive correlation between bone age and basal and after hCG testosterone was demonstrated; this correlation was not found in the obese boys. The pituitary reserve of gonadotrophins did not show significant differences between the two groups of children. Finally a significant positive correlation (p less than 0.01) between the LH curve area during the LH-RH test and bone age was found only in the normal boys.     

Pubertal development in the Prader-Labhart-Willi syndrome.

The sexual maturation in the Prader-Labhart-Willi (PLW) syndrome was investigated in 14 patients, 10 females and 4 males. A wide variability in the pattern of pubertal development was found including delayed puberty in 5 patients and normal puberty in 4 patients; sexual precocity was also observed in 5 patients, true precocious puberty in one patient and incomplete sexual precocity in the form of precocious pubarche in 4 patients. In 5 patients, 3 of them with precocious pubarche, the appearance of the pubertal signs was followed by a delay or arrest in their future development. An LH-RH stimulation test was performed in 11 patients. In the 6 patients who eventually developed normal puberty, the basal levels and the peak responses of both LH and FSH were within the range of those observed in normal controls of the same pubertal stage. In 4 patients showing marked delay or arrest of puberty, the basal levels were normal or low and the responses of LH and FSH to LH-RH were blunted. Priming with repeated LH-RH stimulation in one of the male patients led to an augmented LH response, suggesting a hypothalamic hypogonadotrophism. It is concluded that the lack of uniformity in the pattern of sexual maturation in the PLW syndrome is due to a variability in the location and extent of a hypothalamic lesion, which may comprise an active process continuing beyond the perinatal period.     

PUBERTAL DEVELOPMENT IN THE PRADER-LABHART-WILLI SYNDROME

ABSTRACT. The sexual maturation in the Prader-Labhart-Willi (PLW) syndrome was investigated in 14 patients, 10 females and 4 males. A wide variability in the pattern of pubertal development was found including delayed puberty in 5 patients and normal puberty in 4 patients; sexual precocity was also observed in 5 patients, true precocious puberty in one patient and incomplete sexual precocity in the form of precocious pubarche in 4 patients. In 5 patients, 3 of them with precocious pubarche, the appearance of the pubertal signs was followed by a delay or arrest in their future development. An LH-RH stimulation test was performed in 11 patients. In the 6 patients who eventually developed normal puberty, the basal levels and the peak responses of both LH and FSH were within the range of those observed in normal controls of the same pubertal stage. In 4 patients showing marked delay or arrest of puberty, the basal levels were normal or low and the responses of LH and FSH to LH-RH were blunted. Priming with repeated LH-RH stimulation in one of the male patients led to an augmented LH response, suggesting a hypothalamic hypogonadotrophism. It is concluded that the lack of uniformity in the pattern of sexual maturation in the PLW syndrome is due to a variability in the location and extent of a hypothalamic lesion, which may comprise an active process continuing beyond the perinatal period.     

A mixed-longitudinal study on the pattern of pubertal growth: relationship to socioeconomic status and caloric-intake--IV

The pubertal growth pattern was observed on 791 girls belonging to upper and low SES. These girls ranged between 7-16 years. The effect of calorie intake on the pubertal growth was also ascertained. The development of breast was first to appear at the age of 8.25 years. It was followed by pubic and axillary hair development. The mean age of menarche was 12 years and 12.8 years for USES and LSES, respectively. The onset of menarche, breast and pubic hair was significantly delayed in LSES girls by 0.8 years. Menarche was found to correlate better with breast development than pubic or axillary hair. The girls on adequate calories showed early onset of breast, pubic hair and axillary hair development and of menarche. Similarly, these girls attained mature stage (adult) of these variables earlier compared to those who were on inadequate calories. However, intermittent developmental stages of pubic hair and axillary hair showed no consistency with intake of calories. The girls on inadequate calories showed approximately one year late onset of breast and pubic hair development. The present observations suggest that the onset of puberty is strongly influenced by environment but its attainment is under the genetical control.