GONADOTROPIN-RELEASING HORMONE (LH-RH) AND HUMAN CHORIONIC GONADOTROPIN IN THE TREATMENT OF TWO BOYS WITH HYPOGONADOTROPHIC HYPOGONADISM

Abstract. Two brothers, 16 and 14 years of age, with hypogonadotrophic hypogonadism and anosmia were treated with subcutaneous injections of 200μg 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 a marked development of the secondary sex characteristics was seen.     

尿道下裂伴阴茎发育不良的内分泌改变及治疗

对１８例合并有阴茎发育不良的尿道下裂患儿进行了生殖内分泌测定和绒毛膜促性腺激素（ＨＣＧ）治疗。结果发现黄体生成素（ＬＨ）、促卵泡素（ＦＳＨ）及睾酮（Ｔ）水平与一般尿道下裂患儿差异不大。给予ＨＣＧ治疗后，血清Ｔ明确增加，随之阴茎增长、长粗，未发现明显副作用。治疗结果表明：①ＨＣＧ能有效地刺激这类患儿的睾丸产生Ｔ；②阴茎仅对较高浓度的Ｔ有反应。提示这类患儿阴茎发育不良可能与阴茎对Ｔ的敏感性较低有关。ＨＣＧ治疗不仅有助于改善小阴茎外观而且能为手术创造有利条件。     

Ovarian hyperthecosis in the adolescent patient.

The endocrine findings in two adolescents with hyperthecosis are compared to those in a patient with an androgenic ovarian tumor. In patients with hyperthecosis, luteinizing hormone values were elevated or in the upper normal range, and plasma testosterone and androstenedione values were increased. Following dexamethasone suppression, testosterone and androstenedione values remained elevated, but after administration of human chorionic gonadotropin, they increased further in only one patient. Baseline 17-ketosteroid values were normal, suppressed with dexamethasone, and stimulated to baseline levels following HCG. The patient with a lipoid cell ovarian tumor had low baseline LH levels, and elevated testosterone, androstenedione, and 17-ketosteroid values. Dexamethasone produced little change in urinary or plasma values, but the 17-ketosteroids increased markedly after administration of HCG. The finding of low serum LH values in patients with hirsutism and elevated androgen secretion should alert the clinician to the possibility of a tumor.     

Hormonal replacement therapy with HCG and HU-FSH in thalassaemic patients affected by hypogonadotropic hypogonadism

Gonadotropin (Gn) replacement therapy using HCG plus HU-FSH was administered to 24 patients affected by beta-thalassaemia major with hypogonadotropic hypogonadism aged 18-40 years (25.2 +/- 5.4 yr, m +/- SEM). The age range at the start of treatment was 14.5-24.5 years (16.7 +/- 2.6 yr); the mean duration of Gn treatment was 8.6 +/- 3.9 years (range 1-15.2 yr). Gn therapy was begun with HCG alone, the dosage being initially 500 IU twice a week and then increased to a maximum of 3000 IU twice a week, according to the individual serum testosterone levels obtained. HU-FSH (75 IU twice a week) was added to initiate spermatogenesis in all cases when the HCG-induced testosterone serum levels normalized. The duration of HU-FSH treatment ranged from 1-2 years and then therapy was continued with HCG alone. In nine patients Gn therapy was discontinued after 6-14 years and was replaced by testosterone depot therapy, 75-100 mg i.m. twice a month, for a period ranging from 1-1.5 years. Using Gn therapy, the testosterone levels normalized. The compliant patients obtained good virilization and normal sexual function; testicular volume increased within the normal adult range and spermatogenesis was achieved. When Gn therapy was replaced by testosterone-depot therapy, a marked decrease in testicular volume and sperm count was observed, but the patients complied better and showed a slight increase in coarse hair. In conclusion gonadotropins are an effective replacement therapy for male hypogonadism in thalassaemic patients. If we consider the advantages and disadvantages of this therapy, the former seem to outweigh the latter. Finally, it should be emphasized that physicians caring for these patients must foster compliance during frequent check-ups and examinations.     

Short stature and pubertal delay in male adolescents with cystic fibrosis. Androgen treatment

We evaluated the growth rate and pubertal status of 54 adolescent and young adult men with cystic fibrosis and assessed the efficacy of short-term androgen therapy in promoting growth and pubertal development. Thirty-nine percent were below the fifth percentile in height and 8/28 (28%) between the ages of 14 and 18 had delays in pubertal development. Five male adolescents aged 13 years 8 months to 18 years 3 months were treated with testosterone and their conditions were prospectively evaluated. Growth rate increased from an entry mean of 2.2 cm/yr (range 0 to 4 cm/yr) to 7.2 cm/yr (3 to 10 cm/yr). We conclude that a brief course of testosterone appears to be a safe, effective means of improving growth rate in male adolescents with cystic fibrosis with delay of puberty.     

HCG与外用睾酮霜治疗小阴茎的临床疗效观察

目的 探寻临床治疗小阴茎的有效治疗办法及其选择用药的依据.方法 按照小阴茎诊断标准选择病例,分为HCG组(肌注HCG,每次1000IU,每周2次,连用6周)和T组(每日外用睾酮霜2次),并于治疗前后测定阴茎长度、睾丸大小及性激素水平等以观察其疗效及影响.结果 阴茎长度测量:用药前两组阴茎长度比较无显著差异(P>0.05),而用药后两组均有显著增长(P<0.05),但两组用药后增加值比较无显著差异(P>0.05).睾丸体积测量:用药前两组睾丸体积比较无显著差异(P>0.05),但HCG组用药后有显著增长(P<0.05),而睾酮组用药后睾丸体积仪稍有增长(P>0.05).激素水平测定:除HCG组用药前后睾酮水平比较有显著性差异(P<0.05)外,其他各检测指标均无明显变化.疗效:HCG组中7例显效、5例有效、4例无效;T组中6例显效、7例有效、2例无效.两组比较疗效无显著性差异(P>0.05).结论 肌注HCG和外用睾酮霜治疗儿童小阴茎均可使阴茎明显的增长,且对性激素水平无明显干扰,并与患儿年龄大小无关.但外用睾酮霜更为方便实用,在为使睾丸得到同步增长时也可首选HCG治疗.西药治疗无效时应想到雄激素抵抗综合症可能.     

HCG stimulation test in children with abnormal sexual development.

Plasma testosterone was estimated by radioimmunoassay in 60 children with disorders of sexual development before and after stimulation with human chorionic gonadotrophin (HCG). In 21 children the testosterone levels after 3 and 5 daily injections of 1000 units HCG were compared and good correlation was found between the paired results (r =0-93), suggesting that the 5-day HCG test has no advantage over the 3-day test. In 7 boys with apparently normal genital development the increments in plasma testosterone ranged from 2-0 to 8-5 nmol/1 after 3 injections of HCG. 10 boys with anorchia showed little response to HCG stimulation, but in patients with other disorders, such as micropenis (10), cryptorchidism (8), hermaphroditism (3), male pseudohermaphroditism (13), hypospadias (3), and sex chromosome anomalies (6), there was considerable variation in the plasma testosterone level after HCG. In 2 boys with suspected anorchia the results suggested that testes were present and this was confirmed at operation.     

青春期前尿道下裂小儿内分泌变化的研究

对３５例尿道下裂小儿及２０例正常儿作黄体素释放激素（ＬＨ－ＲＨ）兴奋试验和人绒毛膜促性腺激素（ＨＣＧ）试验，应用放射免疫法测定了血清黄体素（ＬＨ）、卵泡刺激素（ＦＳＨ）、及睾酮（Ｔ）浓度。检查结果发现，尿道下裂患儿ＬＨ－ＲＨ刺激后的血清ＬＨ、ＦＳＨ浓度高于正常对照组，而注射ＨＣＧ３天后的血清Ｔ浓度较正常对照组低下。并对以上内分泌异常及其可能在尿道下裂形成过程中的作用进行了讨论     

Congenital hypogonadotropic hypogonadism and micropenis: effect of testosterone treatment on adult penile size why sex reversal is not indicated

Micropenis is commonly due to fetal testosterone deficiency. The clinical management of this form of micropenis has been contentious, with disagreement about the capacity of testosterone treatment to induce a functionally adequate adult penis. As a consequence, some clinicians recommend sex reversal of affected male infants. We studied 8 male subjects with micropenis secondary to congenital pituitary gonadotropin deficiency from infancy or childhood to maturity (ages 18 to 27 years). Four patients were treated with testosterone before 2 years of age (group I) and four between age 6 and 13 years (group II). At presentation, the mean penile length in group I was 1.1 cm (-4 SD; range, 0.5 to 1.5 cm) and in group II it was 2.7 cm (-3.4 SD; range, 1.5 to 3.5 cm). All patients received one or more courses of 3 intramuscular injections of testosterone enanthate (25 or 50 mg) at 4-week intervals in infancy or childhood. At the age of puberty the dose was gradually increased to 200 mg monthly and later to an adult replacement regimen. As adults, both group I and II had attained a mean final penile length of 10.3 cm 2.7 cm with a range of 8 to 14 cm (mean adult stretched penile length for Caucasians is 12.4 2.7 cm). Six of 8 men were sexually active, and all reported normal male gender identity and psychosocial behavior. We conclude that 1 or 2 short courses of testosterone therapy in infancy and childhood augment penile size into the normal range for age in boys with micropenis secondary to fetal testosterone deficiency; replacement therapy at the age of puberty results in an adult size penis within 2 SD of the mean. We found no clinical, psychologic, or physiologic indications to support conversion of affected male infants to girls. Further, the results of this study do not support the notion, derived from data in the rat, that testosterone treatment in infancy or childhood impairs penile growth in adolescence and compromises adult penile length.     

HCG producing malignant teratoma of the testis: a rare cause of precocious isosexual maturation in boys]

Human chorionic gonadotropin (HCG) from a testicular tumor histologically diagnosed from its metastases to be a malignant teratoma induced elevated testosterone levels and subsequent precocious isosexual development in a 12-year-old boy. The endocrinologic consequences of long term ectopic HCG production in the prepubertal male are discussed. The case report illustrates the value of HCG serum levels as a marker for tumor activity.     

Growth and pubertal development in nephropathic cystinosis

In a retrospective investigation growth and pubertal development were evaluated in 30 patients with nephropathic cystinosis. Growth was investigated during the stage of chronic renal insufficiency as well as after successful kidney transplantation and growth rates were related to kidney function. Pubertal development was evaluated in 17 patients between 12 ans 25 years of age. Prepubertal growth rates were stable in a range between –2 and –3 height velocity SDS as long as glomerular filtration rate was above 20ml/min per 1.73m². A decrease in glomerular filtration rate below this threshold was followed by further decrease in height velocity. After kidney transplantation a significant catch-up growth was seen if immunosuppression was performed with cyclosporine A and lowdose prednisolone. This did not occur if conventional therapy with azathioprine and high-dose prednisolone was used. Onset of puberty was delayed in all patients. Gonadotropin and oestradiol levels in female patients showed normal fluctuations according to ovulatory cycles. In male patients after puberty there was an increase in gonadotropin levels above the normal range for adult men while testosterone levels remained in the low normal range. These results indicate that adult men with nephropathic cystinosis may develop hypergonadotropic hypogonadism.     

The psychosocial impact of Klinefelter syndrome--a 10 year review

OBJECTIVE: To describe psychosocial morbidity in a cohort of young males with hypogonadism due to Klinefelter syndrome, to document the effect of androgen replacement on behaviour, to underline issues confronting clinicians involved in treatment of this condition and to demonstrate a need for a structured program for prospective intervention for this group. We also compare this group to young men with hypogonadotrophic hypogonadism. DESIGN: A retrospective audit of patients with Klinefelter and Kallmann syndromes, presenting for medical assessment from 1994-2004. PATIENTS: Postpubertal males with Klinefelter syndrome (n = 32) and Kallmann syndrome (n = 19) were audited by chart review for psychosocial comorbidities, pubertal management, and the need for exogenous testosterone. RESULTS: Seventeen of 32 postpubertal patients with Klinefelter syndrome required testosterone therapy while 11 were documented to have serum testosterone in the normal adult range. All patients with Kallmann syndrome required long term testosterone treatment. Significant psychosocial and behavioural problems were present in 22/32 of patients with Klinefelter syndrome, including seven who were testosterone replete, with an identifiable pattern of disorder, including marked lack of insight, poor judgement and impaired ability to learn from adverse experience. Use of long term replacement testosterone treatment reduced episodes of behavioural indiscretion. Of those patients with Kallmann syndrome, 5/19 reported mild depressive symptoms only, all resolving with testosterone replacement. CONCLUSION: Inadequately treated hypogonadism in Klinefelter syndrome increases recognized psychosocial morbidity. There is a need for prospectively planned and timed support for young men with Klinefelter syndrome, to ameliorate current poor psychosocial outcomes.     

Precocious Puberty in A Seven-Year-Old Boy due to Human Chorionic Gonadotropin Producing Pineal Tumor Detected by Nuclear Magnetic Resonance Computed Tomographic Scanning

We report a 7-year-old boy who developed incomplete sexual precocity due to a human chorionic gonadotropin (HCG)-producing tumor in the pineal region. The patient presented enlarged testes (3times2x2 cm) bilaterally, enlarged penis, pubic hair development of Tanner Stage 111, advanced bone age and growth spurt. Initial hormonal studies showed an adult male level of testosterone (13 ng/ml) and a high level of HCG as well as HCG-β subunit. A high basal level of LH, probably due to immunocross-reactivity with HCG, and low basal level of FSH, probably suppressed by testosterone, did not respond to LH-RH infusion. Search for the site of HCG production failed at the initial workup, but calcification without definite signs of tumor in the pineal region was found by conventional brain CT scan. Because of subsequent progression of clinical and laboratory findings of sexual precocity, nuclear magnetic resonance computed tomographic (NMR-CT) scan was performed, which confirmed the presence of a pineal tumor three months later. The patient was treated with 4,500 rad. of radiation therapy, and responded dramatically to this regimen. He has been followed for more than two years without any signs of recurrence. We have reported here a very rare case of incomplete sexual precocity due to an HCG-producing intracranial tumor in the pineal region. An NMR-CT scan is a very useful tool for the diagnosis of some types of pineal tumor, such as germinoma, which are highly radiosensitive.     

Pubertal androgen therapy in boys

Anabolic-androgenic steroids (AAS) are necessary for normal male sexual differentiation and development and pubertal development. Androgen therapy is appropriate for boys with delayed development (constitutional delay of growth and puberty, CDGP) as well as those with primary or secondary hypogonadism. The principal goal is to restore the serum testosterone (T) level to the normal range at each stage of adolescent development and then to the normal adult range if the hypogonadism is permanent. In addition the levels of dihydrotestosterone and estradiol should also be within the normal range. One should be able to do that with a wide variety of androgen preparations-injectable, implantable, and cutaneous patches or gels. However, during the transition from prepubertal to adult it is difficult to reliably deliver the relatively small doses of T necessary for adolescent development using any of the cutaneous preparations. Androgen therapy should permit normal linear growth (including the adolescent growth spurt), adolescent sexual development, and the attainment of normal body composition including lean body mass, bone and the appropriate regional distribution of body fat as well as the psychological development appropriate for the stage of adolescent development.     

Age Variations in the Concentration of Non-Protein Nitrogen, Creatinine and Urea in Blood of Infants and Children

Non-protein nitrogen as well as serum urea and creatinine concentrations were determined in 113 healthy children ranging in age from newborn to six years. The results were compared with those from corresponding analyses of adult blood.
NPN and creatinine levels at birth were found to approximate those in adults but to decrease within five or six days to values significantly lower than the adult ones. This confirmed reports published much earlier. It was found, in addition, that at an age between about five and seven months the NPN concentration rose rather abruptly to the adult range. The question as to whether this phenomenon resulted from the child's natural development or whether it stemmed from the increased protein intake, is discussed.
The serum concentration of urea at birth was found to be significantly lower than the adult value. That this was attributable to a low urea concentration in the maternal blood is a possibility which cannot be ruled out. As with NPN and creatinine, the concentration of urea increased to the adult range at an age of five to seven months.
The normal means and concentration ranges for NPN, creatinine, and urea-N in blood from children of different age groups are tabulated.     

Plasma testosterone and βHCG levels in the first twently-four hours of life in neonates with cryptorchidism

We determined serum concentrations of HCG and testosterone by specific radioimmunoassays in eight cryptorchid and 13 normal newborns in the first 24h of life.Mean serum HCG concentration in the cryptorchid infants (18.9±9.7 miu/ml) did not differ significantly from the control group (26.7±7.6 miu/ml). Mean serum testosterone level in the cryptorchid newborns (271±27 ng/dl) also did not differ significantly from the control group (333±30 ng/dl).These data suggest that HCG and testosterone concentrations on the first day of life are of the same magnitude in normal and cryptorchid infants.     

Serum complement levels in infancy: age related changes

Levels of eight complement components and two control proteins, were determined on cord serum from normal full term neonates and serum from healthy infants aged 1 and 6 months. For all proteins, the levels were below the adult normal at birth and rose toward the adult range by age 6 months. In a second group of 271 patients, ages 1-36 months, serum Clq and properdin levels were measured. For both proteins, the mean values in early infancy were more than two SD below the adult range and did not reach the adult range until 18-21 months of age. The Clq concentration was more variable than that for any other component studied. In infants from 11 months-3 yr of age, Clq levels correlated with serum IgG levels, but properdin levels did not.     

Leydig cell damage after testicular irradiation for lymphoblastic leukaemia

The effect of testicular irradiation on Leydig cell function has been studied in a group of boys irradiated between 1 and 5 years earlier for a testicular relapse of acute lymphoblastic leukaemia. Six of the seven boys irradiated during prepubertal life had an absent testosterone response to HCG stimulation. Two of the four boys irradiated during puberty had an appropriate basal testosterone level, but the testosterone response to HCG stimulation was subnormal in three of the four. Abnormalities in gonadotrophin secretion consistent with testicular damage were noted in nine of the 11 boys. Evidence of severe Leydig cell damage was present irrespective of whether the boys were studied within 1 year or between 3 and 5 years after irradiation, suggesting that recovery is unlikely. Androgen replacement therapy has been started in four boys and will be required by the majority of the remainder to undergo normal pubertal development.     

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.     

Testicular function following combination chemotherapy with cis-platin, vinblastine, and bleomycin

Recovery of the pituitary-gonadal axis following treatment with vinblastine, bleomycin, cis-platin +/- doxorubicin (VBP +/- A) is assessed retrospectively in 18 men with germinal neoplasms. One patient also received VP-16-213. In the first year after completing treatment all men demonstrated elevated follicle stimulating hormone (FSH) and luteinizing hormone (LH) values with concomitant azoospermia. Of the 11 men evaluated at least 24 months from completion of therapy, seven (64%) had recovery of both FSH and LH to normal or near normal levels. Spermatogenesis was present in five of six (83%) men providing semen samples and who were at least 2 years from stopping VBP. Five of seven (71%) men who were within 24 months of therapy were azoospermic. Regardless of the time of evaluation, most men (94%) had normal serum testosterone. Patients receiving maintenance vinblastine had more prolonged elevation of serum gonadotropins. We conclude that some men have evidence of recovery of fertility beginning two years after VBP +/- A. In addition to germinal epithelium destruction, transient Leydig cell dysfunction occurs but is not accompanied by clinical findings of hypogonadism.