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.     

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.     

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.     

Estimation of GnRH pulse amplitude during pubertal development

Fourteen children between 2.5 and 16 years of age were studied to provide a quantitative estimate of the changes in gonadotropin-releasing hormone (GnRH) pulse amplitude in hypophysial portal plasma during puberty. Responses to physiologic doses of synthetic GnRH were measured [induced luteinizing hormone (delta LH) and induced follicle-stimulating hormone (delta FHS)] and compared with spontaneous fluctuations in gonadotropins [spontaneous luteinizing hormone (delta sLH) and spontaneous follicle-stimulating hormone (delta FHS)]. One to four low-dose (0.0125 or 0.025 microgram/kg IV) pulses of GnRH were given every 2 hr between 0800 ad 1600 or 2200 and 0400 hr. Maximal peripheral plasma concentrations of GnRH one min after pulses averaged 107 +/- 25 pg/ml (S.E.) (0.0125 microgram/kg dose) and 218 +/- 33 pg/ml (0.025 microgram/kg dose). In early pubertal children the maximal delta LH was similar to or less than the maximal nocturnal delta sLH (maximum, delta LH 7.0 +/- 0.2 versus maximum delta sLH 7.0 +/- 1.3 mIU/ml in boys, 7.0 +/- 1.2 versus 16.0 +/- 3.0 mIU/ml in girls). Luteinizing hormone (LH) responses were low or undetectable in children whose bone ages were less than 10 years. When discernible, LH pulse frequency was similar during daytime and nighttime sampling periods in early pubertal boys. However, two hourly injections of GnRH given during the day did not simulate the initial nocturnal rise in LH. Overall mean delta FSH and delta sFSH were similar in three prepubertal female patients (3.0 +/- 0.2 versus 2.8 +/- 0.2 mIU/ml). delta FSH was greater than delta sFSH in two patients with gonadal dysgenesis (bone ages, 2.5 and 5 years) and in one prepubertal girl. The gonadotropin responses seen in early pubertal children suggests that the amplitude of nocturnal GnRH pulses is equal to or greater than that previously reported in normal men.     

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.     

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.     

Comparison between spontaneous gonadotropin concentration profiles and gonadotropin response to low-dose gonadotropin-releasing hormone in prepubertal and early pubertal boys and patients with hypogonadotropic hypogonadism: assessment by using ultrasensitive, time-resolved immunofluorometric assay.

To assess whether nocturnal gonadotropin concentration profiles in children could be predicted by measurement of peak gonadotropin levels after gonadotropin-releasing hormone (GnRH) administration, we measured spontaneous gonadotropin levels every 20 min and the gonadotropin responses to low-dose GnRH using an ultrasensitive, time-resolved immunofluorometric assay in 61 boys with short stature and/or delayed puberty. Spontaneous nocturnal LH pulses were observed in 58 out of 61 patients. After GnRH administration in a dose of 25 ng/kg, all of the 61 patients had significant LH and FSH responses, and GnRH-stimulated peak LH and FSH levels were highly correlated with maximal spontaneous nocturnal LH and FSH levels, respectively (r = 0.83 for LH and r = 0.91 for FSH; p less than 0.00001). Analysis of individual subjects revealed that GnRH-stimulated peak LH levels were almost identical to maximal nocturnal LH levels in the subjects whose GnRH-stimulated peak LH levels were between 5 and 10 IU/L, whereas GnRH-stimulated peak LH levels tended to be higher than maximal nocturnal levels in the subjects whose GnRH-stimulated peak LH levels were 5 IU/L or lower. To determine if there were any parameters in the gonadotropin response to GnRH that might be useful in distinguishing early pubertal boys from prepubertal boys, we evaluated the gonadotropin response to GnRH in 44 prepubertal and 10 early pubertal normal short boys. Although maximal nocturnal LH levels did not overlap between prepubertal and pubertal groups, GnRH-stimulated LH peak levels overlapped considerably between the two groups. Even the GnRH-stimulated peak LH to peak FSH ratio overlapped between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Luteinising hormone-releasing hormone nasal spray as therapy for undescended testicle.

Twenty-two prepubertal children with unilateral cryptorchidism were treated. None had undergone previous medical or surgical to modify the abnormal position of the testes, all of which were located inthe inguinal canal. Treatment was with luteinising hormone-releasing hormone (LH-RH) nasal spray given for 7 days. 9 boys insufflated 100 microgram LH-RH in each nostril 6 times per 24 hours (1200 microgram/24 h); the remaining 13 boys insufflated 500 microgram 12-hourly (1000 microgram/24 h). An LH-RH test (500 microgram IV) was carried out before and after therapy. Full descent of the testis into the scrotum was obtained in 7 out of the 22 cases; in a further 6 cases the testis moved down the inguinal canal. Basal values of luteinising hormone and follicle-stimulating hormone and those for pituitary reserve remained unchanged before and after therapy, and were similar to the values of a control group. No correlation was found between response to therapy and bone age, testosterone level in serum, basal values or pituitary reserve of luteinising hormone or follicle-stimulating hormone.     

The effect of testicular irradiation on Leydig cell function in prepubertal boys with acute lymphoblastic leukaemia.

Testicular function was investigated by the luteinising hormone releasing hormone (LHRH) test and a three day human chorionic gonadotrophin (HCG) test in 11 prepubertal boys with acute lymphoblastic leukaemia (ALL) who had received 2400 rads of fractionated radiation to their testes after relapse at this site. The results were compared with an unirradiated control group. Basal and peak testosterone values after 1000 units of HCG were significantly lower in the irradiated patients than in the control group. Peak follicle stimulating hormone (FSH) values after 100 micrograms LHRH were significantly higher in irradiated boys, but there was no difference in either basal FSH or basal and peak luteinising hormone values. The findings suggest that the ability of the Leydig cell to produce testosterone--as detected by the HCG test--is appreciably reduced after irradiation and that tubular dysfunction in prepubertal boys may sometimes be predicted by a raised FSH response.     

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.     

Endocrine data in cryptorchism]

Endocrine evaluation with LH-RH (0.1 mg/m2) and chorionic gonadotrophin (HCG 3 X 1,500 I.U.) in 154 cryptorchid boys aged 1 month to 15 years showed a decrease of LH pituitary secretion and Leydig-cells response to HCG in prepubertal and early pubertal patients. These deficiencies were positively correlated. Partial and at least transient descent of cryptorchid testis or testes has been obtained in 87 of 265 patients treated with HCG (3 to 9 X 1,500 I.U.). Plasma testosterone after HCG 3 X 1,500 I.U. was less increased in patients whose cryptorchid testis or testes descended after 9 X 1,500 I.U. than in those whose testes remained undescended. These data suggest that a partial, early and transient deficiency of pituitary LH secretion may be responsible for testicular maldescent in part of cryptorchid boys.     

GONADOTROPIN RESPONSIVENESS TO LUTEINIZING HORMONE RELEASING HORMONE IN PREPUBERTAL AND PUBERTAL PATIENTS WITH GROWTH HORMONE DEFICIENCY

ABSTRACT. Gonadotropin response to 100 μg/m² LHRH was determined in 31 patients with growth hormone deficiency. According to their bone ages the patients were divided into a "prepubertal" ( n =18) and a "pubertal" ( n =13) group. The results were compared with the LHRH tests from 16 healthy prepubertal boys and girls and 32 healthy adult probands, respectively. The maximum increment of LH and FSH was evaluated. In the "prepubertal" group five patients had an insufficient rise of LH and FSH, four of them having additional anterior pituitary hormone deficiencies. In the "pubertal" group nine patients were found to be gonadotropin deficient, all of them had additional hormone deficiencies, TSH being the most frequently affected hormone. Only one of 14 gonadotropin-deficient patients had no other than growth hormone deficiency in addition. An isolated decreased FSH increment without LH deficiency was found in 6 male and 2 female patients and is not thought to be of diagnostic value. No influence of growth hormone treatment or growth velocity on the gonadotropin responsiveness was found. Patients with an additional thyreotropic defect could be classified as pituitary or hypothalamic disorder due to their reaction in the TRH test. These groups could not be differentiated by a single bolus LHRH test, indicating the need of prolonged stimulation to recover the pituitary hyporesponsiveness. Due to methodological problems the diagnosis of gonadotropin deficiency in an individual patient of the prepubertal age group might be questioned. However, a normal gonadotropin response to LHRH can be expected in prepubertal patients with growth hormone deficiency and may indicate a normal gonadotropin function.     

The relation between the secretion of growth hormone (GH), somatomedin C/IGF I (IGF I) and steroids before and after the onset of puberty in patients of small stature

Somatomedin C/IGF I, dehydroepiandrosterone sulfate (DHAS), testosterone (T) or estradiol (E2) have been measured in 154 patients of a previous study in which growth hormone (GH) responses to classical pharmacologic stimuli and spontaneous growth hormone secretion during sleep were compared in short children before and at the beginning of puberty. Five groups were identified: Group I, normal growth hormone secreting children; group II, completely growth hormone deficient; group III, partially growth hormone deficient; group IV, with normal sleep secretion and low responses to stimuli; group V, with the reverse situation. The somatomedin C/IGF I levels were widely dispersed. In group I, the mean +/- SEM levels of somatomedin C/IGF I were 0.77 +/- 0.047 U/ml before puberty and 1.36 +/- 0.142 U/ml in early pubertal patients, with a relation to age (r = 0.52, p less than 0.001). The difference between prepubertal and pubertal patients was significant. In groups II to V, there was no pubertal rise of somatomedin C/IGF I. In group II, the mean IGF I level was 0.48 +/- 0.05 U/ml, significantly lower than in prepubertal patients of group I. In groups III, IV and V, it was 0.7 +/- 0.069 U/ml, 0.8 +/- 0.059 U/ml, and 0.73 +/- 0.059 U/ml respectively, not different from prepubertal patients of group I, but significantly lower than in early pubertal patients of the same group. In prepubertal patients, somatomedin C/IGF I was slightly but highly significantly correlated to growth hormone sleep secretion (r = 0.27, p less than 0.001) and to dehydroepiandrosterone sulfate (r = 0.36, p less than 0.001), but growth hormone and dehydroepiandrosterone sulfate were not correlated with each other.(ABSTRACT TRUNCATED AT 250 WORDS)     

Two-year results of treatment with depot leuprolide acetate for central precocious puberty.

We report results from 2 years of therapy with the long-acting form of the gonadotropin-releasing hormone (GnRH) analog leuprolide acetate, which was previously reported in short-term trials to be efficacious in the treatment of central precocious puberty. Thirteen girls and two boys, aged 1.9 to 9.7 years, who satisfied clinical criteria including GnRH-stimulated luteinizing hormone (LH) greater than 10 IU/L (mean radioimmunoassay LH, 29.1 +/- 5.54 IU/L), received depot leuprolide, 6 to 15 mg intramuscularly every 4 weeks. Estradiol (or testosterone), insulin-like growth factor I, and GnRH-stimulated gonadotropins were obtained at baseline, at 2 months, and at 6-month intervals with bone age determinations. Pubertal progression ceased in all patients, and menses did not occur. Mean increase in height during therapy was 5.77 +/- 2.0 cm/yr. Predicted adult height increased over baseline by 5.52 +/- 1.16 cm at 18 months. Mean estradiol values in the girls declined from 3.3 +/- 0.6 to 0.60 +/- 0.03 ng/dl, with no overlap of baseline and treatment values. The mean basal LH value was unchanged by therapy; mean basal and peak LH values for all follow-up GnRH stimulation tests were 4.05 +/- 0.57 and 4.95 +/- 0.70 IU/L, respectively. Basal and peak follicle-stimulating hormone (FSH) values were suppressed from 4.10 +/- 0.62 and 10.06 +/- 1.34 IU/L, respectively, to generally undetectable levels (< 1). Comparison with untreated control patients suggested that basal LH did not completely return to prepubertal levels, whereas FSH levels were suppressed below prepubertal levels. Estradiol, FSH, and LH levels reached their nadir by 2 months; in contrast, mean serum levels of insulin-like growth factor I progressively declined from +0.57 +/- 0.19 SD score to -0.06 +/- 0.22 SD score at 24 months. Two girls were withdrawn from the study because of reactions at injection sites, with apparent sterile abscess formation in one patient. This study provides evidence that (1) long-term treatment with depot leuprolide is characterized by immediate and sustained laboratory and clinical suppression, (2) GnRH-stimulated LH and random FSH and estradiol concentrations are useful laboratory measures of efficacy, and (3) the progressive increase in predicted adult height is temporally associated with decreased serum levels of insulin-like growth factor I and striking deceleration of bone age advancement.     

Nocturnal integrated gonadotropin concentrations in evaluating pubertal transition in girls

We assessed the utility of measuring the physiological levels of gonadotropins as a diagnostic tool for pubertal onset in girls. Two methods of gonadotropin measurements were compared: the standard frequent sampling method, in which blood samples were drawn every 20 min, and the multiple integrated sampling method, in which samples were obtained continuously at 30 min intervals by a withdrawal pump. The two methods were examined simultaneously overnight in a group of eight girls at different stages of puberty. The following parameters of both LH and FSH secretion, calculated by PULSAR program, were highly correlated between these methods: area under the curve (AUC), mean levels, mean from smoothed baseline and mean peak height. The diagnostic value of multiple integrated sampling of gonadotropins (performed over 6 h) was then assessed in five prepubertal girls and six girls at early puberty (Tanner stages 2 and 3), in whom peak gonadotropins levels in response to GnRH stimulation test were in the prepubertal range. Several parameters of LH (but none of FSH) were significantly higher (p<0.05) in early pubertal compared to prepubertal girls: AUC (5.61 +/- 2.40 vs 2.39 +/- 1.41), mean levels (0.52 +/- 0.21 vs 0.23 +/- 0.14), smoothed mean level (0.43 +/- 0.18 vs 0.18 +/- 0.11) and peak area (0.27 +/- 0.08 vs 0.11 +/- 0.06). We conclude that the technically simple method of multiple integrated sampling is useful in detecting pubertal transition and is superior to the GnRH-stimulation test. This method can be used in selective cases when the stimulation test yields equivocal results.     

Leptin levels in boys with pubertal gynecomastia

BACKGROUND: It has been reported that there is a relationship between circulating leptin and sex steroid hormones and leptin is able to stimulate estrogen secretion by increasing aromatase activity in adipose stromal cells and breast tissue. Leptin receptors have been also shown in mammary epithelial cells and it has been suggested that leptin is involved in the control of the proliferation of both normal and malignant breast cells. AIM: To investigate circulating leptin levels in boys with pubertal gynecomastia. METHODS: Twenty boys with pubertal gynecomastia who were in early puberty and had no obesity, and 20 healthy individuals matched for age, pubertal stage and body mass index (BMI) with the study group, were enrolled in the study. Body weight, height and left midarm circumference (MAC) and left arm triceps skinfold thickness (TSF) were measured and BMI was calculated. A fasting blood sample was collected and routine hormonal parameters including prolactin, beta-human chorionic gonadotropin (betaHCG), total and free testosterone, estradiol, luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, androstenedione (AS) and dehydroepiandrosterone sulfate (DHEAS) levels were studied. Serum leptin levels were analyzed using radioimmunoassay. RESULTS: The mean ages of the study and control group were not different (13.9 +/- 0.89 and 14.2 +/- 0.66, respectively). No significant difference was found for BMI, MAC and TSF values between the two groups. There was no significant difference for hormonal parameters including FSH, LH, total and free testosterone, estradiol, AS, DHEAS and estradiol/total testosterone ratio between boys with pubertal gynecomastia and the controls. Serum leptin levels were found significantly higher in the study group compared with the healthy controls (5.58 +/- 0.81 and 2.39 +/- 0.29 ng/ml, respectively; p <0.001). No correlation could be determined between serum leptin levels and hormonal parameters. CONCLUSION: The presence of higher leptin levels in boys with pubertal gynecomastia indicates that leptin may be involved in the pathogenesis of pubertal gynecomastia. The role of circulating leptin in pubertal gynecomastia is probably related to increase in estrogen and/or estrogen/ androgen ratio by the stimulating effect of leptin on aromatase enzyme activity in both adipose and breast tissues, or a direct growth stimulating effect of leptin on mammary epithelial cells, or increase in sensitivity of breast epithelial cells to estrogen with inducing functional activation of estrogen receptors by leptin in breast tissue.     

Pituitary-gonadal axis in male undermasculinisation.

AIMS: To study the value of assessing serum concentrations of luteinising hormone (LH), follicle stimulating hormone (FSH), testosterone, and dihydrotestosterone (DHT) in patients with male undermasculinisation not caused by androgen insensitivity. METHODS: A retrospective study of a register of cases of male undermasculinisation (20 with abnormal testes, eight with 5alpha-reductase deficiency, three with testosterone biosynthetic defects, seven with Drash syndrome, and 210 undiagnosed). RESULTS: A human chorionic gonadotropin (hCG) stimulation test was performed in 66 of 185 children with male undermasculinisation. In 41 of 66 patients the dose of hCG was either 1000 U or 1500 U on three consecutive days. The rise in testosterone was related to basal serum testosterone and was not significantly different between the two groups. Testosterone:DHT ratio in patients with 5alpha-reductase deficiency was 12.5-72.8. During early infancy, baseline concentrations of LH and FSH were often within normal reference ranges. In patients with abnormal testes, median pre-LHRH (luteinising hormone releasing hormone) concentrations of LH and FSH were 2 and 6.4 U/l, respectively, and post-LHRH concentrations were 21 and 28 U/l. An exaggerated response to LHRH stimulation was observed during mid-childhood in children where the diagnosis was not clear and in all children with abnormal testes. CONCLUSIONS: The testosterone:DHT ratio following hCG stimulation is more reliable than the basal testosterone:DHT ratio in identifying 5alpha-reductase deficiency. During infancy, the LHRH stimulation test may be more reliable in identifying cases of male undermasculinisation due to abnormal testes than basal gonadotrophin concentrations.     

Premature thelarche--natural history and sex hormone secretion in 68 girls

Data obtained during long-term follow-up of 68 girls with premature thelarche were analysed. In 85% onset was before the age of 2 years, in 30.8% being present at birth. In 44.1% there was a regression after 3 2/12 +/- 2 8/12 years (SD). Basal levels of plasma FSH and response to LH-RH were significantly higher than prepubertal controls (1.93 +/- 1.56 vs. 0.8 +/- 0.1 mU/ml and peaks 12.3 +/- 5.4 vs. 7.9 +/- 1.0 mU/ml respectively; p less than 0.001). Twenty-seven of 52 patients tested had increased plasma estradiol and in 27 of 40 patients tested, urocytograms or vaginal smear showed estrogenization. Basal levels of LH and response to LH-RH were prepubertal. The girls with premature thelarche were significantly taller than normal controls of the same age (p less than 0.001). These results suggest that premature thelarche is an incomplete form of precocious sexual development probably due to derangement in the maturation of the hypothalamo-pituitary-gonadal axis which results in a higher than normal secretion of FSH, as well as a defect in the peripheral sensitivity to the sex hormones.     

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.