Long-term effects on testicular function of high-dose testosterone treatment for excessively tall stature.

High-dose testosterone treatment is applied during puberty to reduce the predicted adult height in excessively tall boys. To date it has remained unclear whether this therapy produces any long-term effects on reproductive functions of the patients. To clarify this question, we performed a follow-up study in 47 tall men, determining seminal and hormonal parameters 10.6 +/- 2.5 years (mean +/- SD) after cessation of therapy. The tall men treated were compared with 123 normal men attending the Institute of Reproductive Medicine as volunteers for various clinical studies. Clinical examination revealed a significantly higher prevalence of varicoceles and history of maldescended testes in the testosterone-treated tall men compared with the controls. Semen analysis revealed significantly lower progressive motility in the tall men compared with the normal men (49.2 +/- 13.4 vs. 54.3 +/- 12.8%). A nonsignificant tendency towards lower sperm concentration (43.8 +/- 35.4 vs. 57.8 +/- 45.6 mL/mL), lower total sperm count (184.4 +/- 158.0 vs. 225.4 +/- 277.5 mL/ejaculate), and reduced normal sperm morphology (27.6 +/- 12.5 vs. 30.9 +/- 13.1%) was evident in the testosterone-treated tall men. Although there was no difference in testicular volume and FSH between the groups, testosterone was lower in the testosterone-treated tall men (19.9 +/- 7.4 vs. 23.9 +/- 7.0 nmol/L). Statistical analysis of the subgroups of testosterone-treated tall men and control men without varicocele and cryptorchidism revealed no differences in any ejaculate parameter. The small difference in semen variables may be explained by a higher prevalence of varicocele and maldescended testes in the testosterone-treated tall men.

The Challenge of Pediatric Hodgkin's Disease-Where is the Balance Between Cure and Long-Term Toxicity?: A report of the West German multicenter studies DAL-HD-78, DAL-HD-82 and DAL-HD-85.

From June 1978 until December 1989 more than 600 children under the age of 16 were treated for Hodgkin's disease in West Germany. In three consecutive multicenter studies (DAL-HD-78, HD-82, HD-85) a combined modality treatment concept was used. The aim of all these studies was to reduce the total dose and the extent of radiotherapy as well as the intensity of chemotherapy. In addition, the invasive abdominal staging procedures and the indications for splenectomy were reappraised, so that the number of laparotomies and splenectomies could be restricted to cases with an high probability of abdominal and/or splenic involvement. Special attention was directed to the effects of radio-and chemotherapy on thyroid and gonadal function as well as the development of secondary malignancies. We conclude, that patients treated for Hodgkin's disease with the combined modality treatment regimen (HD-78, HD-82), which included procarbazine, had a high probability of long term survival in first continuous complete remission (CCR). Omitting procarbazine (HD-85) significantly reduced the number of patients in first CCR in stages IIB to IV demonstrating the efficacy of this drug in the treatment of Hodgkin's disease. On the other hand, procarbazine appeared to be the major gonadotoxic drug causing predominantly testicular injury affecting mainly spermatogenesis. Few secondary malignancies have been observed, until now, however long term follow-up will be needed, to document side effects as well as the efficacy of the different therapeutic regimen.

Case report: Kasabach-Merritt syndrome: a review of the therapeutic options and a case report of successful treatment with radiotherapy and interferon alpha.

We describe the successful treatment of a neonate with Kasabach-Merritt syndrome who received local irradiation and interferon alpha therapy after failure of corticosteroid treatment. A male neonate, born after an uneventful pregnancy, had a huge haemangioma involving the upper right cervical region as well as severe thrombocytopenia. He was treated with corticosteroids, interferon alpha and radiotherapy. Prednisolone therapy (5 mg kg(-1) day(-1)) was started at 41 days of age. No therapeutic effect was observed after 2 weeks. At this time the tumour size had increased dramatically, platelet counts had decreased progressively and coagulation abnormalities had developed. Because corticosteroid therapy had been ineffective and the child was in a life-threatening condition, irradiation was delivered up to a total dose of 9.5 Gy in five fractions. Simultaneously, prednisolone therapy was slowly decreased and interferon alpha therapy (3 million U m(-2) day(-1)) was started and continued for 6 weeks. After irradiation with 9.5 Gy and beginning interferon alpha therapy, the tumour decreased in size and coagulation parameters normalized within 4 weeks. 6 months later, platelet counts and coagulation parameters were still normal. The tumour had further decreased in size. No acute severe side effects were observed. Radiation therapy combined with interferon alpha treatment is an alternative treatment modality when high dose corticoid steroid therapy has been ineffective in patients with Kasabach-Merritt syndrome, despite the risks of growth delay and secondary malignancy. In children showing no response to corticosteroids, radiotherapy and/or interferon alpha should be considered in Kasabach-Merritt syndrome.

[Diagnosis of hamartoma of the tuber cinereum]. / Zur Kenntnis der Tuber-cinereum-Hamartome.

Hamartomas of the tuber cinereum are tumour-like collections of normal tissue in abnormal location. They are benign lesions with slow or absent growth and without any tendency to neoplastic evolution. Due to their neurosecreting properties they usually cause precocious puberty. Further neuroendocrine disturbances, seizures, or psychoneurological symptoms may be associated in some cases. Cisternography and CT are the most conclusive radiologic procedures in all cases. The typical feature is a well circumscribed round-shaped isodense soft tissue mass without contrast enhancement. Usually the tumour is small, rarely exceeding 2 cm. in diameter. If CT diagnosis is not conclusive, examination in the coronal plane or CT cisternography are recommended. Although CT does not permit a histological diagnosis the clinical and radiological features together are sufficient to make a highly suggestive diagnosis. The treatment of choice is medical therapy. Surgery should be restricted to those tumours which damage surrounding structures by their size and cause other symptoms than precocious puberty.

[Acute focal bacterial nephritis]. / Die akute fokale bakterielle Nephritis (AFBN).

Acute focal bacterial nephritis is a very rare type of infective nephritis. It is characterised by groups of abscesses of 1 to 5 mm. situated in the renal cortex with pus tracking to the papillae. Urography is normal or suggests a non-specific enlargement. On sonography, non-homogeneous foci with reduced echogenicity are observed. Unenhanced CT shows indefinite lesions of reduced density, which do not enhance as much as the surrounding parenchyma after contrast injection. On angiography these areas appear as hypovascular lesions. The disease must be differentiated from a malignant renal tumour and from an acute renal abscess. The clinical findings and the results of sonographic and radiological observations on five patients with acute focal bacterial nephritis are described.

An approach to reduce treatment and invasive staging in childhood Hodgkin's disease: the sequence of the German DAL multicenter studies.

UNLABELLED: From June 1978 through March 1987, 506 children under the age of 16, representing approximatively 70% of the children with Hodgkin's disease in West-Germany entered 3 consecutive multicenter studies at 68 centers. The general objective of these study sequence is to maximize the chance of cure while minimizing radiotherapy and chemotherapy as much as possible in a combined modality treatment concept. The purpose was also to reappraise the need for splenectomy and laparotomy and to define a staging policy which provides adequate evaluation of intraabdominal disease. Study II (HD-82) is described in detail. 203 protocol patients were enrolled between Dec. 1981 and Dec. 1984. Laparotomy was performed in 202 patients, but splenectomy only in 78 (38.4%) using an intraoperative decisional strategy, developed in Study I (HD-78). Patients were stratified according to stage into 3 groups (PS I/IIA, IIB/IIIA and IIIB/IV) receiving 2, 4 or 6 cycles of OPPA/COPP-chemotherapy. Radiotherapy was given only to the involved fields, the dose depending on the extent of chemotherapy (35, 30 or 25 Gy). RESULTS AND CONCLUSIONS: The event-free survival rates after 5 years are 96% (entire group), 99% (stage I/IIA), 96% (stage IIB/IIIA) and 90% (stage IIIB/IV). Thus, only involved field radiotherapy with reduced doses is needed, if a stage-dependent chemotherapy with 2, 4 or 6 cycles of OPPA/COPP is given. The strategy of selective splenectomy has proven very useful. Based on statistical analyses concerning abdominal involvement a clinical decisional strategy for selective laparotomy was developed. Further efforts are needed to reach a stepwise cautious and controlled narrowing-in on the therapy combining the lowest long-term toxicity with the highest chance of cure.

No correlation between androgen receptor CAG and GGN repeat length and the degree of genital virilization in females with 21-hydroxylase deficiency.

CONTEXT: In 21-hydroxylase (CYP21A2) deficiency (21OHD), the level of in vitro enzymatic function allows for classification of mutation groups (null, A, B, C) and prediction of disease severity. However, genital virilization in affected females correlates only weakly with CYP21A2 mutation groups, suggesting the influence of genetic modifiers. OBJECTIVE: The objective of the study was to investigate the influence of the polymorphic CAG and GGn repeats of the androgen receptor (AR) gene on the degree of genital virilization in 21OHD females. DESIGN AND PATIENTS: Design of the study was the determination of CYP21A2 genotype, degree of genital virilization (Prader stage), and X-weighted biallelic mean of AR CAG and GGn repeat length in 205 females with 21OHD. OUTCOME MEASUREMENTS: Correlation of AR CAG and GGn repeat lengths with Prader stages using nested stepwise logistic regression analysis was measured. RESULTS: CYP21A2 mutation groups null and A showed significantly higher levels of genital virilization than groups B and C (P < 0.01). However, Prader stages varied considerably within mutation groups: null, Prader I-V (median IV); A, Prader I-V (median IV); B, Prader I-V (median III); C, 0-III (median I). Mean GGn repeat length of patients was not significantly associated with Prader stages, classified as low (0-I), intermediate (II-III), or severe (IV-V) (odds ratio per repeat: 0.98, 95% confidence interval 0.71-1.35). In contrast, patients with Prader 0-I showed a trend toward longer CAG repeats without reaching statistical significance (P = 0.07, odds ratio per repeat: 0.82, 95% confidence interval 0.65-1.02). CONCLUSION: Neither CAG nor GGn repeat lengths are statistically significant modifiers of genital virilization in females with 21OHD.

Long-term results of growth hormone therapy in Turner syndrome.

Short stature is one of the main features of Turner syndrome. Today, most patients are treated with growth hormone (GH) to improve adult height. We have reviewed the literature reporting adult height in patients with Turner syndrome treated with GH alone or in combination with oxandrolone. The reported adult heights as well as the height gain over projected or predicted height are still preliminary and vary considerably among studies. There is some evidence that the age of onset of therapy, dose of GH, duration of GH therapy, target height, time of estrogen substitution, or concurrent treatment with oxandrolone affect adult height. The reported height gains over projected height range from -0.20 to +16.0 cm (median: 5.1 cm) in patients treated with GH and from +0.68 cm to +10.3 (median: 6.40 cm) in patients treated with GH and oxandrolone. Thus, the presently available data are extremely varied and need further detailed analysis after all ongoing clinical trials have published the final results of all patients included in the study.

Final height in children with growth hormone deficiency.

Forty-six patients (28 boys, 18 girls) were treated with growth hormone (GH) for short stature. Twenty-eight patients had total growth hormone deficiency (GHD), 12 partial GHD and 6 patients had short stature without GHD. Brain tumours were the cause of GHD in 8 patients and multiple pituitary hormone deficiency was present in 9 children. All patients received GH with subcutaneous injections only, 6-7 times/week. Mean final height for all patients was -1.11 SDS and was similar in boys (-1.09 SDS) and girls (-1.13 SDS). Target height SDS was -0.80 SDS in 42 patients, comparing favourably with a final height SDS of -1.05. Similar results were obtained in all patient sub-groups. Height velocity during the last year of therapy was between 2.1 and 9.9 cm/year in 34 patients and below 2 cm in 12 patients. As further growth is to be expected, target height will probably be reached by most patients.

Treatment of children with Hodgkin's disease--results of the German Pediatric Oncology Group.

Six hundred sixty-seven children under age 16 were enrolled in 4 consecutive studies in West Germany between 1978 and 1990. These trials were mainly designed to reduce the long-term sequelae of high dose extended-field irradiation as well as the late effects of chemotherapy, in the context of combined modality treatment for all stages. Treatment concepts and results of studies HD-82, HD-85 and HD-87 are presented here. Patients with stages IA/B and IIA were treated with 2 cycles of OPPA (HD-82, n = 100) or OPA without procarbazine (HD-85, n = 53; HD-87, n = 104), followed by involved field irradiation (IFI) using 35 Gy (HD-82, HD-85) or 30 Gy (HD-87). Kaplan-Meier estimates (KME) for event-free survival (survival) at 4.5 years are 99% (100%) in HD-82, 85% (98%) in HD-85 and 88% (100%) in HD-87. Thus, 2 x OPPA is a highly effective chemotherapy eradicating occult microfoci in the non-irradiated adjacent fields, whereas 2 x OPA is less efficacious. Reduction of the radiation dose to 30 Gy (IFI) within the combined modality concept does not affect treatment outcome. About 30% of the boys treated with 2 x OPPA, but none of the girls and none of the boys treated without procarbazine (PC) showed elevated FSH-levels indicating gonadal dysfunction. No secondary leukemias and preleukemias were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pituitary-gonadal function following therapy of testicular relapse in boys with acute lymphoblastic leukemia]. / Die hypophysäre-gonadale Funktion nach Therapie eines Hodenrezidivs bei Jungen mit akuter lymphoblastischer Leukämie.

Testicular function was evaluated in 8 boys with acute lymphoblastic leukemia (ALL) and testicular relapse following another course of intensive chemotherapy with unilateral or bilateral orchidectomy and/or testicular irradiation. LH- and FSH-secretion was studied in all using a standardized LHRH-test. In addition, a HCG-test was performed in 6 boys. In prepuberty, all boys examined showed normal LH- and FSH-values. Beginning at 9 to 10 years, elevated basal and/or stimulated LH- and FSH-values were occasionally noted in contrast to the consistently elevated values after the age of 12. Using the HCG-test, we found a testosterone response only in patients receiving gonadal irradiation of 1 100 and 1 500 rads (2 patients). No response was elicited in those with radiation doses of 2 400 and 3 000 rads. We conclude that high dose gonadal irradiation and chemotherapy cause temporary and possibly permanent impairment of spermatogenesis and Leydig cell function in boys with ALL and testicular relapse.

[Familial hypogonadism with anosmia: Kallmann Syndrome]. / Familiäreer Hypogonadismus mit Anosmie: Kallmann-Syndrom.

The familial occurrence of hypogonadism and anosmia (Kallmann-Syndrome) is reported in a 15 5/12 year old boy and his 20 7/12 year old sister, who in addition has a ventricular septal defect. To establish the diagnosis it is important to examine the patient with hypogonadism for anosmia since voluntary information is rarely obtained. Quite often there are additional, associated anomalies which have to be searched for carefully.

Prediction of growth response in prepubertal children treated with growth hormone for idiopathic growth hormone deficiency.

Several multiple regression models have been developed to predict the first-year growth response to human growth hormone (hGH) in children with growth hormone deficiency (GHD). It was the aim of this study to analyse the significance of various growth parameters for a height prediction model. Data from 148 prepubertal children with idiopathic GHD were evaluated. The prediction model was developed by means of univariate and stepwise linear regression analysis and an "all possible" regression approach using Mallow's C(p) statistics. Six out of eight selected variables had a significant influence on the first-year growth rate. The most important parameter was the difference between target height SDS and height SDS at the start of therapy (THSDS-HSDSCO), accounting for 23.95% and 25.74% of the variability. No other single variable or combination of variables was more informative than the variable THSDS-HSDSCO alone. From these data, growth velocity for the first year of hGH treatment was estimated as 1.106 (THSDS-HSDSCO) + 6.8 cm/y +/- 2.2 cm (SE), allowing a prediction for different intervals between THSDS and HSDSCO. This equation was validated in a small group of 18 GHD patients demonstrating a predicted vs. observed first-year growth rate of 9.4 +/- 1.1 vs. 9.5 +/- 2.6 cm/y. We conclude that the difference between THSDS and height SDS at the start of therapy is an important predictor of the first-year growth response in children treated with hGH for idiopathic GHD. Unlike in previous studies, additional parameters did not increase predictability.

Pituitary-gonadal function in boys after high dose testosterone treatment for excessively tall stature.

One hundred excessively tall boys with a height prediction of 205.32 +/- 5.28 cm (mean +/- SD) were treated with 500 mg testosterone oenanthate (TE) every 14 days for a period of 14.96 +/- 5.29 months. Following therapy, the hypothalamo-pituitary-gonadal axis was evaluated, using a standardized GnRH-test at median time intervals of 14 days, 6 weeks, 13 weeks, 6 months and 16 months. Basal and stimulated LH- and FSH-values were not measurable or severely suppressed in all boys 14 days after termination of therapy. Starting at 6 weeks, normalization of pituitary-gonadal function was demonstrated in 93 boys (group 1) with follow-up periods of up to 48 months. Six boys (group 2) developed transitory hypergonadotrophic LH- and FSH-secretory patterns for up to 11 months after the last TE-injection. Testosterone and gonadotrophins were within the normal range in all 6 boys, when prospectively re-evaluated at 12 to 27 months after termination of therapy. During TE-administration, testicular volume was reduced in some, and in most boys did not show the normal enlargement occurring during puberty. However, return to normal testicular size was seen several months after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

[Testicular function after OPA/COMP chemotherapy without procarbazine in boys with Hodgkin's disease. Results in 25 patients of the DAL-HD-85 study]. / Testikuläre Funktion nach OPA/COMP-Chemotherapie ohne Procarbazin bei Jungen mit Morbus Hodgkin. Ergebnisse bei 25 Patienten der Studie DAL-HD-85.

Gonadal function was evaluated in 25 boys treated for Hodgkin's disease according to the DAL-HD-85 protocol with OPA- or OPA/COMP-chemotherapy (vincristine-prednisone-adriamycine/cyclophosphamide-vincristine-m ethotrexate- prednisone). All boys were in first continuous complete remission for 6 to 45 months at chronological ages varying from 14.0 to 18.9 years. Testosterone, basal and GnRH-stimulated LH- and FSH-levels were measured. Gonadal function was normal in 16 patients treated with 2 cycles of OPA-chemotherapy in Hodgkin stages I-IIA. 9 patients were treated with 2 OPA- and 2 or 4 COMP-cycles of chemotherapy and had received mean cyclophosphamide doses ranging from 2004 to 3722 mg/m2. Again, no major testicular damage was noted, though some patients had increased stimulated LH-levels possibly indicating compensated Leydig cell-insufficiency. Our results demonstrate, that testicular function is not severely affected when patients are treated for Hodgkin's disease without procarbazine even if cyclophosphamide is given in cumulative doses below 3800 mg/m2. The previously documented severe testicular damage in boys treated according to the DAL-studies HD-78 and HD-82 is thus a result of the gonadotoxic action of procarbazine.