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 maturation in girls treated for childhood acute leukaemia

Eleven girlds treated during childhood for acute leukaemia were followed up during their pubertal development. At each examination weight, height, pubertal stage, FSH, LH, oestradiol, testosterone, androstenedione and dehydroepiandrosterone sulphate levels were evaluated. Clinical and endocrinological studies were performed according to age and pubertal stage and compared to those of healthy girls matched for age and pubertal stage. Results showed that pubertal maturation and gonadal function were not affected by oncotherapy; however menarche was attained earlier. Early menarche was explained by the overweight of treated girls during early puberty. No evidence of early hypothalamic activation was found, but endocrine patterns showed a faster hypothalamopituitary-ovarian axis maturation in patients than controls. Cranial irradiation showed no correlation with pubertal onset and age at which menarche was attained. Adolescent menstrual and endocrine patterns were normal.     

HCG stimulation in children with cryptorchidism

Fifty-eight children with cryptorchidism have been given hCG stimulation testing, 31 with bilateral cryptorchidism, 22 with unilateral, and 5 with prior unsuccessful orchiopexy. Hormonal studies were carried out prior to and following stimulation. In bilateral cryptorchidism, bilateral descent was observed in 32 percent of cases and in unilateral, the success rate was 55 percent. From their data, the authors concluded that hCG is not indicated if patients present elevated LH and FSH levels or if the basal T levels are in the pubertal range. In the other subjects, the hCG test will permit the determination of the presence or absence of testosterone production and in some cases it results in testicular descent. Finally, in cases of failure that require surgery, the hCG will stimulate tissue growth enhancing the success of orchiopexy.     

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.     

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.     

Hypergonadotropic Hypogonadism in Newborn Males with Primary Testicular Failure

ABSTRACT. Four infants with genital ambiguity but with apparent testes were given a gonadotropin-releasing hormone (GnRH) test and a human chorionic gonadotropin (hCG) test at age 3–12 days. The results were compared with those from 16 newborn males (aged 2 to 6 days) with minor genital anomalies; 9 with unilateral and 3 with bilateral incomplete testicular descent, 2 with surgically insignificant glandular hypospadias and 2 with penis length <(-2 SD) for gestational age. Treatment with testosterone resulted in clear phallus growth in all four patients. All four patients had elevated basal luteinizing hormone (LH) concentrations as well as an exaggerated LH response to GnRH; three of them also had an exaggerated follicle stimulating hormone (FSH) response. Thus in all patients the etiology of genital ambiguity was considered to be testicular. The testosterone response to hCG was normal in two of the patients but impaired in the other two. The steroidogenic response did not show any specific enzyme defect. We conclude that 1) newborn boys with Leydig cell failure are clearly hypergonadotropic, 2) the GnRH test is a more sensitive indicator of Leydig cell failure neonatally than the hCG test and 3) normal testes greatly inhibit the secretion of both LH and FSH during the first week of life.     

Hypergonadotropic hypogonadism in newborn males with primary testicular failure

Four infants with genital ambiguity but with apparent testes were given a gonadotropin-releasing hormone (GnRH) test and a human chorionic gonadotropin (hCG) test at age 3-12 days. The results were compared with those from 16 newborn males (aged 2 to 6 days) with minor genital anomalies; 9 with unilateral and 3 with bilateral incomplete testicular descent, 2 with surgically insignificant glandular hypospadias and 2 with penis length less than (means-2 SD) for gestational age. Treatment with testosterone resulted in clear phallus growth in all four patients. All four patients had elevated basal luteinizing hormone (LH) concentrations as well as an exaggerated LH response to GnRH; three of them also had an exaggerated follicle stimulating hormone (FSH) response. Thus in all patients the etiology of genital ambiguity was considered to be testicular. The testosterone response to hCG was normal in two of the patients but impaired in the other two. The steroidogenic response did not show any specific enzyme defect. We conclude that newborn boys with Leydig cell failure are clearly hypergonadotropic, the GnRH test is a more sensitive indicator of Leydig cell failure neonatally than the hCG test and normal testes greatly inhibit the secretion of both LH and FSH during the first week of life.     

Diagnosis of 5alpha-reductase type 2 deficiency: contribution of anti-Müllerian hormone evaluation

AIM: To evaluate anti-Müllerian hormone (AMH) levels in patients with clinical and molecular diagnosis of 5alpha-reductase 2 deficiency. PATIENTS AND METHODS: Data from 14 patients whose age ranged from 21 days to 29 years were analyzed according to age and pubertal stage. Sexual ambiguity was rated as Prader III in 11 patients. LH, FSH, testosterone (T), dihydrotestosterone (DHT) and AMH serum levels were measured in all but two patients, who had been previously submitted to gonadectomy; T and DHT were also measured in 20 age-matched controls. RESULTS: Gonadotropin levels were normal in all but one patient who retained gonads (six of whom had reached puberty) and T/DHT ratio was elevated in all patients when compared to controls. All prepubertal patients had AMH levels < -1 SD for age, while most pubertal patients had AMH levels compatible with pubertal stage. CONCLUSIONS: Prepubertal patients with 5alpha-reductase 2 deficiency have AMH values in the lower part of the normal range. These data indicate that T does not need to be converted to DHT to inhibit AMH secretion by Sertoli cells.     

Quantitation of urinary gonadotropins in normal children

A simple and improved method for the quantification of urinary LH and FSH was developed. Urinary gonadotropin concentrations were determined by polyclonal double antibody RIA after ammonium sulfate extraction. Urinary LH and FSH concentrated by ammonium sulfate were coeluted with an iodinated LH and FSH tracer. Gel chromatography of the urine revealed that the majority of immunoreactive LH and FSH were eluted coincident with 125I-LH and 125I-FSH. Good correlation was observed between urinary gonadotropin/creatinine ratios in first morning voided and full 24-h urine collections. Age-dependent changes in urinary LH excretion were significant in normal boys and girls 6-17 y of age. Urinary FSH excretion in these children did not change in an age-dependent fashion.     

Normoprolactinemia in boys with marked gynecomastia

Pubertal gynecomastia normally occurs as a transient phenomenon of several months duration, whereas marked pubertal gynecomastia (more than 6 cm in diameter) may persist into aduldhood. In the present study the possible involvement of prolactin (PRL) secretion in the development of marked pubertal gynecomastia was investigated. The diurnal variations of PRL, luteinizing hormone (LH), follicle-stimulating hormone (FSH), as well as the basal values of testosterone (T) and estradiol (E₂) were determined in 5 pubertal boys with marked gynecomastia and in 5 age-matched controls. Mean age of all patients was 14.4 years. The pubertal development was classified as P 3–4.In comparison to controls, boys with marked gynecomastia revealed no differences in basal values of PRL, LH and FSH, as well as in peak values of all hormones during sleep. The response of PRL, LH and FSH to LHRH/TRH stimulation was normal for pubertal age in both groups. In comparison to controls, decreased mean plasma T levels (P<0.05) and slightly increased E₂ levels (P<0.05) were found in boys with marked gynecomastia. The E₂/T ratio was also higher in boys with gynecomastia (P<0.005).These data suggest that prolactin, a hormone which may be increased in galactorrhea, is not involved in the development of marked pubertal gynecomastia in boys. The above findings suggest that slightly elevated day-time E₂ levels may be involved in the development of female-appearing breasts in pubertal boys.     

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.     

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.     

Increased LH and FSH secretion after cranial irradiation in boys

The effect of high-dose cranial- and craniospinal irradiation and chemotherapy on the gonadotropin-sex steroid axis was studied during different stages of puberty by measuring pulsatile secretion of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone. The patients were thirteen boys who had been treated for malignant brain tumor residing well away from the hypothalamo-pituitary region. The median time to follow-up was 9 (1–16) years. The onset of puberty was early in the patients, median 10.5 years, compared to the average age for Swedish boys, which is at median 12.4 years. There was, before puberty, no significant difference in LH and FSH secretion between patients and a control group of normal boys. In early, mid- and late stages of puberty, however, LH and FSH secretion was increased in the patients overall, whereas testosterone secretion was maintained within the normal range in spite of signs of gonadotoxocity with small testicular volumes. These results indicate that the vulnerable parts of the gonadotropin releasing hormone (GnRH)-gonadotropin (LH, FSH)-gonadal axis are the regulatory system that determines the timing of pubertal induction and the gonads. The GnRH-LH, FSH-releasing neurons appear relatively resistant to cranial irradiation as they are able to respond with supranormal LH and FSH levels for long periods of time after treatment. Med Ped Oncol 29:280–287, 1997. © 1997 Wiley-Liss, Inc.     

Testicular descent: when to interfere?

Spontaneous descent of testes after birth can occur in up to 70% of cases, yet the factors contributing to it are still controversial. This study aims to evaluate factors contributing to spontaneous descent of palpable undescended testes. Eighty-four newborns with 126 palpable undescended testes (42 unilateral and 42 bilateral) were followed up for a period of one year to study the occurrence and time of testicular descent and its relation to gestational age, birth weight, uni- or bilaterality and levels of FSH, LH and testosterone. A total of 58 testes (46%) descended between 3 and 6 months. Spontaneous descent occurred in 10 premature patients (14 testes 63%) compared to 44 testes of full-term patients (43%). Descent occurred in 14 unilateral undescended testes (33%) compared to 44 (52%) in bilateral cases. In patients with spontaneous testicular descent there was postnatal peak of LH and testosterone at 2 to 3 months of age which returned to basal level at 6 months of age. In patients with permanent undescended testes the peak of LH and testosterone was very low and almost absent in some of them; no significant difference was found between the mean values of FSH in both groups. No spontaneous testicular descent occurred after the 4th month in the full-term group, whereas in the pre-term group spontaneous descent occurred up to 6 months of age. This study concluded that spontaneous descent of palpable undescended testes is closely related to the presence of LH and testosterone surge. Therapy of undescended testes should start at 4 months of age in a full-term baby and at 6 months of age in a pre-term baby.     

Gonadotropin-releasing hormone (LH-RH) and human chorionic gonadotropin in the treatment of two boys with hypogonadotrophic hypogonadism.

Two brothers, 16 and 14 years of age, with hypogonadotrophic hypogonadism and anosmia were treated with subcutaneous injections of 200 microng gonadotropin-releasing hormone at 8-hour intervals for 4 weeks. Serum FSH increased to the range of normal adult men, but serum LH and serum testosterone showed little change and no clinical signs of pubertal development occurred. Thereafter the 2 patients were given HCG for 11 months and a combination of HCG and HMG for a further 3 months. In response to this treatment, the serum testosterone levels increased to the range of normal adult men and marked development of the secondary sex characteristics was seen.     

MALE PSEUDOHERMAPHRODITISM DUE TO DEFICIENCY OF TESTICULAR 17-KETOSTEROID REDUCTASE

ABSTRACT. A 12.9 year-old girl, genotypically 46, XY, and considered to have a testicular feminization syndrome, developed signs of virilization and gynaecomastia. Very high androstenedione concentrations (10-fold the mean of the reference interval in boys) in relation to low normal testosterone in peripheral serum indicated a 17-ketosteroid reductase deficiency. In addition to androstenedione, the basal peripheral levels of 17-hydroxyprogesterone and estrone were increased, being 5- and 3-fold the mean of the reference interval, respectively, whereas pregnenolone, progesterone, dehydroepiandrosterone, 5α-dihydrotestosterone and estradiol concentrations were within pubertal stage-appropriate reference intervals. The total spermatic vein serum steroid concentrations were about 5-fold the mean in old men, and androstenedione, estrone and dehydroepiandrosterone were particularly elevated, whereas estradiol was normal and testosterone subnormal by a factor of 1/8. In the testis tissue, the concentration of androstenedione was extremely high, whereas that of testosterone tended to be relatively low. Our patient was obviously producing testicular steroids at her maximal rate, because no response to hCG administration was observed. This state was assiociated with a high-normal circulating LH concentration. The concentration of testicular LH/hCG receptors was only one-fifth of that seen in old men, which may have resulted from receptor down-regulation associated with a high degree of stimulation.     

Central precocious puberty and growth hormone deficiency in a boy with Prader-Willi syndrome

In Prader-Willi syndrome (PWS) hypothalamic dysfunction is the cause of hormonal disturbances, such as growth hormone deficiency (GHD), hypogonadism, and delayed or incomplete puberty. Only a few cases of central precocious puberty (CPP) have been reported. We describe an 8.8-year-old PWS boy, with microdeletion of chromosome 15q, who developed CPP. On admission, height was 131.1 cm (+0.17 SD), BMI 26.2 kg/m², pubic hair (Ph) 2, and testis 4.5 ml. We found increased growth velocity (7 cm/year), high testosterone levels, pubertal response to GnRH test, and advanced bone age (10.6 years). An evaluation of growth hormone (GH) secretion revealed a deficiency. Pituitary MRI was normal. LHRH analogue therapy (Leuproreline 3.75 mg/28 days i.m.) was started at 8.9 years and discontinued at 11.3 years, when the patient had bone age of 13 years. During therapy, growth velocity, testosterone, FSH, and LH peak decreased significantly, with no pubertal progression. Growth hormone therapy (0.24 mg/kg/week) was started at 9.5 years and discontinued at 15.3 years because the patient had bone age of 17 years. After interrupting LHRH therapy the patient demonstrated spontaneous pubertal progression with pubertal gonadotropin and testosterone. At 16.3 years, height was 170 cm (−0.48 SDS), BMI 36.3 kg/m², Ph 4, testis volume 10 ml and there was a combined hypothalamic and peripheral hypogonadism hormonal pattern (normal LH even with low testosterone and undetectable inhibin B with high FSH). To our knowledge this is the fourth male patient with genetically-confirmed PWS demonstrating CPP and GHD and the first with a long follow-up to young adulthood.     

Response to LH-RH and HCG in two brothers with the Reifenstein syndrome.

Two brothers with Reifenstein syndrome underwent LH-RH and HCG tests at various ages ranging from 13 to 17 years. We found that at age 13 the plasma LH and FSH response to one LH-RH injection was normal. After the age of 14, the basal plasma concentration of LH and FSH and their response to LH-RH became elevated. Concomitantly the plasma testosterone levels rose to abnormal levels. These findings are compatible with progressive development of primary gonadal dysfunction and with peripheral insensitivity to testosterone.     

Treatment of persistent pubertal gynecomastia with dihydrotestosterone heptanoate

Four boys with persistent pubertal gynecomastia were given intramuscular dihydrotestosterone heptanoate (DHT-hp) at 2 to 4-week intervals for 16 weeks. By the end of treatment, breast size in all four boys had decreased 67% to 78%. Initial plasma levels of gonadotropins, estradiol, testosterone, and dihydrotestosterone (DHT) were normal. Mean plasma DHT concentration rose with the injections of DHT-hp, and remained elevated throughout the treatment period. Estradiol, LH, FSH, and testosterone decreased during treatment, as did 24-hour urinary LH and FSH. No regrowth of breast tissue was observed 6 to 15 months after treatment, although hormone concentrations had returned to near pretreatment values by 2 months after the last injection. DHT-hp has potential to be an effective medical therapy for persistent pubertal gynecomastia.