Human chorionic gonadotropin: a feasible option for treating undescended testes

In order to shed light on the controversy in the literature about the efficacy of medical treatment of undescended testes, HCG was administered to 73 boys. They were seven month to twelve years old and none of them had puberty signs. Cryptorchidism was unilateral in 75.4%; it was bilateral in 24.6%. Children with retractile testes were excluded from the study. The patients received IM HCG 1500 to 2000 IU/sqm twice a week for 5 weeks. Testicular descent was noted in 23.0% of the undescended testes, often in the first 2.5 weeks of therapy. All children were followed up for at least a year and relapse was observed in 8.3%. Clinical signs of testosterone action faded off shortly after the end of injections. No side effects were apparent by the third month after treatment. We conclude that the administration of HCG is worth of a trial before the surgical approach is contemplated in the management of the cryptorchidism.     

Growth effect of human chorionic gonadotrophin in 2-8-year-old boys with undescended testes

Growth-promoting effect of human chorionic gonadotrophin (HCG) was studied in 40 boys of 2-8 years with unilateral undescended testes. A transient acceleration of height and weight increase was noted that exceeded rates found in normal puberty. No significant advance in bone age was noted following treatment. On the basis of this study we conclude that short-term HCG treatment does not change the growth pattern or bone age of 2-8-year-old boys.     

Surgical treatment of undescended testes

The mainstay of therapy for undescended testes is operative treatment within the first years of life in order to avoid ongoing testicular degenerative changes. The surgical therapy for the palpable undescended testis is orchiopexy and when the testis is non-palpable, a supplementary laparoscopic approach. Success of orchiopexy for inguinal testes has been >95% and for abdominal testes >85-90% in most series. Conclusion: Operation within the first year of life is a safe therapy for undescended testes.     

Surgical treatment of undescended testes

Surgical therapy of undescended testes is indicated when the testis is located in any site other than the scrotum, especially after unsuccessful hormonal treatment. If the testis can be palpated pre-operatively, a classical orchiolysis should always be carried out first, followed by orchiopexy.In the Sophia Children's Hospital orchiolysis and orchiopexy are always carried out following the techniques developed by Schoemaker. If the testis is not palpable, laparoscopy should be carried out to determine whether a testicle can be located intra-abdominally. If orchiolysis and orchiopexy would prove inadequate to achieve scrotal fixation due to shortness of the vasa spermatica, autotransplantation with microsurgical techniques can be carried out.     

Pathogenesis and treatment of undescended testes

Impaired intrauterine gonadotropin secretion was the cause of cryptorchidism in 78% of cryptorchid boys studied. On the one hand, this impairement implied the underdevelopment of the epididymis and thus the cryptorchid state of the gonad. On the other hand, the histological alterations of the testis, due to impaired gonadotropin secretion were Leydig cell atrophy and an impairment in the number of the germ cells.The secondary damage, due to the unfavorable position, started during the second year of life. To avoid this damage, early treatment is highly recommended. Hormonal treatment with GnRH is the treatment of first choice. This treatment was successful in 60% of cryptorchid boys. An additional treatment of nonresponders with low doses of hCG increased the overall success rate to 80%. Six months after treatment, 14.5% of those successfully treated suffered a relapse.Abbreviations CR Crown rump length - DHT Dihydrotestosterone - ED Embryonal day - hCG Human chorion gonadotropin - HPG Hypothalamo-pituitary-gonadal axis - LHRH Luteinising hormone-releasing hormone - MIS Müllerian-inhibiting substance - TD Testicular descent     

Prevalence of late orchidopexy is consistent with some undescended testes being acquired

To diagnose the incidence of orchidopexy ersus age over a 15-year period, a study was conducted of all patients discharged from a single institution for orchidopexy with reference to age during operation. The hypothesis drawn was that some boys have acquired UDT and therefore, will present late despite recommendations for early diagnosis and treatment. The study was conducted on patients from Royal Children’s Hospital, Melbourne (1980–94). The results suggested that while the optimal age for management of congenital UDT has been lowered to one to two years of age by under-graduate education, the persistence of a significant number of older children undergoing surgery suggests that some UDT’s are acquired. It also showed that the proportion of orchidopexies performed in infancy increased over the 15-year period while the proportion performed in late childhood remained constant.     

Results of early treatment of cryptorchidism with human chorionic gonadotropin

One hundred and fifty-three children with common cryptorchidism, 109 unilateral and 44 bilateral, excluding those with associated malformations or abnormalities, were treated at age 6 to 59 months with human chorionic gonadotropin given as nine intramuscular injections on alternate days. Treatment before age 3 years resulted in complete failure in 81%. At 3 to 4 years of age treatment resulted in failure in 55%, but 19% of the patients showed complete testicular descent and 26% showed partial descent. The percent of failures was increased when the dose of human chorionic gonadotropin was lower than 1,000 IU/m2 injection and when the cryptorchid testis was very high. No correlation was found between endocrine data and the clinical results. The plasma testosterone concentration after the third injection of human chorionic gonadotropin was not significantly different in successfully and unsuccessfully treated patients. However, testosterone levels were significantly lower in patients treated at 36 to 59 months of age than in those treated at an earlier age, in contrast to the significantly better clinical results obtained in the older group. Thus human chorionic gonadotropin is not a valuable means of obtaining descent of undescended testes before age 3 years and is of limited usefulness at age 3 to 4 years.     

Nordic consensus on treatment of undescended testes

AIM: To reach consensus among specialists from the Nordic countries on the present state-of-the-art in treatment of undescended testicles. METHODS: A group of specialists in testicular physiology, paediatric surgery/urology, endocrinology, andrology, pathology and anaesthesiology from all the Nordic countries met for two days. Before the meeting, reviews of the literature had been prepared by the participants. RECOMMENDATIONS: The group came to the following unanimous conclusions: (1) In general, hormonal treatment is not recommended, considering the poor immediate results and the possible long term adverse effects on spermatogenesis. Thus, surgery is to be preferred. (2) Orchiopexy should be done between 6 and 12 months of age, or upon diagnosis, if that occurs later. (3) Orchiopexy before age one year should only be done at centres with both paediatric surgeons/urologists and paediatric anaesthesiologists. (4) If a testis is found to be undescended at any age after 6 months, the patient should be referred for surgery--to paediatric rather than general surgeons/urologists if the boy is less than one year old or if he has bilateral or non-palpable testes, or if he has got relapse of cryptorchidism.     

Histopathology of undescended testes

This paper presents a survey of the morphological findings in cryptorchid testes, especially of children. There is no doubt that undescended testes not operated on early in life are seriously damaged. Cryptorchid testes of adults are much smaller than normal. The tubules are atrophic, the germinal epithelium is generally largely absent and the Leydig-cells are vacuolated, and loaded with lipids. Foci of hypoplastic tubules and so-called ring-like tubular structures are frequent.In children the testicular lesions of cryptorchidism are less pronounced than in adults. They are characterized by disturbances in tubular structure and particularly by a diminution of germ cells or, especially in cases of bilateral cryptorchidism, by a complete lack of such elements. These tubular lesions are manifested already in the second year of life. In addition, the interstitial tissue of undescended testes is generally more abundant and Leydig-cells seem to be more atrophic than in normal testes. Some of these lesions found in cryptorchid testes seem to be the result of a malformation rather than of testicular malposition alone.Finally, in patients with cryptorchidism the higher risk of developing a testicular germ cell tumor must be considered. In adults with cryptorchidism so-called atypical germ cells can be demonstrated even if there are no clinical signs of a malignant testicular tumor. Considering the relatively high frequency of malignant germ cell tumors in adults with cryptorchidism, testicular biopsies should be performed if a primary orchidectomy is refused. As testicular tumors may not only develop in the cryptorchid testis but in the descended partner as well, even bilateral testicular biopsies may be indicated.     

Classification and diagnosis of undescended testes

A uniform classification of undescended testes is proposed; diagnosis and treatment, which vary for each condition are outlined lastly, the prognosis which also differs for each type of undescended testes is illustrated by empirical data.     

Undescended testes: Treatment with gonadotropin

The therapeutic success of treatment of testicular maldescent must be judged according to 2 parameters,-I. occurrence of descent, II. fertility. Ad I. Indication for hCG-treatment is always given unless an unequivocal indication for operation exists, i.e. ectopias, accompanying hernias, retention after herniotomy and advanced puberty. The optimal time for treatment is the second year of life. The large European statistics which include the prescrotal but not the retractile testes, unanimously show success rates of 50–55%. In the largest American series which does not include prescrotal testicles, descent was observed in 40% of the bilateral and in 30% of the unilateral cases. Analyzing those cases which did not respond to hormones but had to be operated, in the majority of cases ectopic, not dystopic gonads were found. Ad II. Infertility in testicular maldescent can have two reasons, 1. congenital anomalies of the primordium, 2. acquired damages due to the malposition. The few large prospective studies at hand show fertility in the majority of cases with descent after hCG, but in the minority of those coming down only after additional operation. Obviously the latter group represents a negative selection. Unilateral cases had a higher fertility rate than bilateral ones.     

Immunohistology of aquaporin-1 and stem cell factor-receptor in human undescended testes

Objectives Both aquaporin (AQP) 1 and the stem-cell factor/C-kit system seem to have a definite role in testis function, but very few studies have been reported in humans, especially in the paediatric age group. With the present study we wanted to investigate the expression of these proteins to better delineate their role in normal and pathologic testes.Methods Immunohistology using AQP 1 and C-kit antibodies was performed on paraffin sections of open-testicular biopsies from 32 undescended testes. The testes of cryptorchid patients, with ages ranging from 2 to 15 years, were biopsied during an orchidopexy operation, after obtaining informed consent. Control biopsies, from 8 patients of matched age, were obtained during operations for inguinal hernia or hydrocele, always after obtaining informed consent. Positive results were recorded as diffuse or focal patterns and scored as weak, moderate or strong immunostaining.Results AQP 1 antibody strongly depicted microvessel endothelial cells, but was unlabeled in endotubular and interstitial cell lines, in both control and undescended testes. The C-kit immunostaining in normal testes revealed a diffuse, strong staining in the cytoplasm of spermatogonia and primary spermatocytes. However, in the undescended testes a focal C-kit immunolabelling was weakly recognized in both spermatogonial and immature Sertoli cells.Conclusions These results indicate a direct involvement of AQP 1 in the regulation of fluid transport across the endothelial cell membranes of testicular microvessels. A role of the C-kit receptor protein is also substantiated by its strong expression in the maturing spermatogonia of the normal testes, but was minimally or not recognizable in undescended prepubertal testes.     

Treatment of undescended testes with intranasal application of synthetic LH-RH

The effect of intranasal, synthetic LH-RH (Hoe 471) on undescended testes was investigated in: I. a double blind study comprising 50 patients given either placebo or 0.6 mg LH-RH daily and II. an open study comprising 50 patients with a daily dosage of 1.2 mg LH-RH. In both studies LH-RH was given for 4 weeks. Since some patients had bilateral undescended testes, 116 testes were treated in total. Patients' ages varied between 11/2 and 101/2 years, with a mean of 5 years. Clinical examination before, during and at end of treatment was performed by both the authors independently.In the placebo group, one testicular descent was seen, indicating difficulty in diagnosis. A therapeutic result, i.e. a significant move from the pretreatment location towards the bottom of the scrotum was seen in 60% of the testes, complete descent being seen in about 40%. In a follow-up study 6 months after treatment, in 23 cases with complete descent from a pretreatment inguinal position, relapse was seen in 5 patients (2 were located at scrotal neck, 3 at the pretreatment position i.e. inguinal). The best results were seen on testes located not too far from the scrotal neck, with the higher dosage of LH-RH and in patients less than 6 years of age. No significant hormonal changes (testosterone-,LH-or FSH-levels in peripheral blood) were seen during the study. Side effects were negligible.     

Oxidative,inflammatory and immunologic status in children with undescended testes

Background: In order to better understand the pathogenesis of risk of future sub‐/infertility in children with undescended testes (UDT), we designed this prospective study to examine the oxidative stress, inflammatory response and autoimmunity in children with UDT. We examined the concentrations of malondialdehyde (MDA), interleukin‐6 (IL‐6) and antisperm antibodies (ASA) in children with UDT and healthy controls. Methods: The UDT group consisted of 88 boys (aged 1–14 years, unilateral in 67 and bilateral in 21 cases), and 44 boys with normal descended testes served as a control group. Clinical evaluation revealed no testicular or other system abnormalities. MDA was used as lipid peroxidation index. IL‐6 levels were measured using a commercial enzyme‐linked immunosorbent assay kit. ASA was determined with an anti‐human spermatozoa immunoglobulin G test. Results: Mean age values ± SD were 4.6 ± 3.2 in the UDT group and 4.7 ± 3.4 in the control group (P= 0.872). MDA and IL‐6 results for the UDT and control groups were significantly different (P= 0.003 and P= 0.019, respectively), but those for ASA were not (P= 0.473). The mean MDA and IL‐6 values were significantly higher in bilateral cases than the respective values in the unilateral cases (MDA: 4.03 ± 3.68 vs 3.49 ± 5.22, P= 0.015; IL‐6: 7.70 ± 6.86 vs 3.48 ± 6.50, P= 0.001) (P= 0.015). Conclusion: The results indicate that children with UDT are exposed to high levels of oxidative stress and inflammatory reaction. This could negatively affect the future fertility in these children.     

Ectopic production of human chorionic gonadotropin: A case report

The ectopic production of the β-subunit of human chorionic gonadotropin (hCG) is described in a patient with an anaplastic carcinoma. After chemotherapy the marker decreased in a logarithmic fashion to undetectable levels but the neoplasm progressed and the patient died. The specificity of the β-subunit of hCG is discussed. Discordance of the marker and clinical disease is pointed out, and several possible explanations are outlined. The lack of specificity of the β-subunit of hCG and the discordance that it may exhibit means that its use in diagnosing and following disease progression may be limited.