Malignant testicular tumours

A series of 71 patients with malignant testicular tumours treated primarily by orchiectomy and irradiation is reviewed with respect to pathological and clinical features and modes of treatment.The three-year crude survival rate in 36 patients with seminoma was 86% and in 24 patients with carcinoma it was 41.7%. There were no survivors among patients with choriocarcinoma. Our results are comparable with those of other series.A prospective study is proposed of the value of irradiation and subsequent limited lymph node dissection following orchiectomy in cases of carcinoma of the testis.     

Medical cost of curing childhood acute lymphoblastic leukaemia

Between 1970 and 1979 acute lymphoblastic leukaemia was diagnosed in 378 children at this hospital. The outcome for the 181 survivors was examined six or more years after diagnosis to assess morbidity in an unselected group of long term survivors. One hundred and thirty seven of the survivors were in first remission and probably cured (group I). Forty four (group II) had had one or more relapses, some of whom, who had isolated extramedullary relapses, also have a good chance of cure.In group I 136 patients had prophylactic cranial or craniospinal irradiation, while patients in group II, in addition to having that treatment, received local testicular (17) or craniospinal radiation (seven) for testicular or central nervous system relapse. Eight had additional prophylactic cranial radiotherapy after bone marrow relapse, and six had total body irradiation before bone marrow transplantation. The incidence of clinically important growth and endocrine morbidity was 20% in group I and 68% in group II. The morbidity in patients in group I was mainly attributable to early pubertal maturation. In group II 30 patients had growth failure, of whom 19 had gonadal failure from testicular or total body irradiation, 14 had growth hormone deficiency after doses of cranial irradiation of over 2400 cGy, and 10 had spinal growth impairment after craniospinal irradiation. Two also had early pubertal maturation. Five out of six patients who received total body irradiation had multiple endocrine deficiency. Neuropsychological sequelae of treatment were seen in 40 (42%) of 96 schoolchildren in group I and in 12 (38%) of 32 schoolchildren in group II. Postinfective sequelae of treatment were found in patients in both groups.These results show that the survivors who were in their first remission had a 42% residual morbidity related to treatment compared with an 82% morbidity in the survivors of one or more relapses who had multiple treatments.     

Regulation of testicular steroidogenesis by gonadotropin-releasing hormone agonists and antagonists

Clinical and experimental studies are described on the effects of a gonadotropin-releasing hormone (GnRH) agonist (A) and antagonist (Ant.) on testicular endocrine function. Testicular effects of long-term gonadotropin suppression by GnRH-A were assessed during treatment of prostatic cancer patients. The testis tissue removed after 6 months of A treatment had less than 5% of the testosterone(T)-producing capacity in comparison to testis tissue removed from untreated control patients. However, the LH receptors (R) and responsiveness of T output to LH stimulation in vitro were unchanged. FSH-R decreased by 70%. Hence, despite suppression of gonadotropins and testicular androgen production during long-term GnRH-A treatment the responsiveness to exogenous gonadotropins is maintained. The testicular effects of a gonadotropin suppression induced with GnRH-Ant. and testicular GnRH-R blockade were studied in rats. Besides decreases of gonadotropins and testicular T, systemic Ant. treatment decreased testicular Prl-R, but had no effect on LH-R or FSH-R. Bromocriptine-induced hypoprolactinemia, in contrast, decreased LH-R but had no effect on Prl-R. The results indicate reciprocal regulation of LH-R and Prl-R, and that testicular steroidogenesis and LH-R are under differential regulation, the former by LH, the latter by Prl. In another study, testicular GnRH-R, and consequently the action of a putative testicular GnRH-like factor, were blocked by unilateral intratesticular infusion of Ant. (1 week, Alzet osmotic pumps). The treatment resulted in 90% occupancy of testicular GnRH-R in the Ant.-infused testes, and this was associated with decreased levels of R for LH, FSH and Prl, and of T. The results indicated that the testicular GnRH-R have a physiological function in subtle stimulation of Leydig cell functions.     

Long-term effects of irradiation before adulthood on reproductive function in the male rhesus monkey.

Today, many patients, who are often young, undergo total body irradiation (TBI) followed by bone marrow transplantation. This procedure can have serious consequences for fertility, but the long-term intratesticular effects of this treatment in primates have not yet been studied. Testes and epididymides of rhesus monkeys that received doses of 4-8.5 Gy of TBI at 2-4 yr of age were studied 3-8 yr after irradiation. In all irradiated monkeys, at least some seminiferous tubule cross-sections lacked germ cells, indicating extensive stem cell killing that was not completely repaired by enhanced stem cell renewal, even after many years. Testes totally devoid of germ cells were only found in monkeys receiving doses of 8 Gy or higher and in both monkeys that received two fractions of 6 Gy each. By correlating the percentage of repopulated tubules (repopulation index) with testicular weight, it could be deduced that considerable numbers of proliferating immature Sertoli cells were killed by the irradiation. Because of their finite period of proliferation, Sertoli cell numbers did not recover, and potential adult testis size decreased from approximately 23 to 13 g. Most testes showed some dilated seminiferous tubules, indicating obstructed flow of the tubular fluid at some time after irradiation. Also, in 8 of the 29 irradiated monkeys, aberrant, densely packed Sertoli cells were found. The irradiation did not induce stable chromosomal translocations in spermatogonial stem cells. No apparent changes were seen in the epididymides of the irradiated monkeys, and the size of the epididymis adjusted itself to the size of the testis. In the irradiated monkeys, testosterone and estradiol levels were normal, whereas FSH levels were higher and inhibin levels lower when testicular weight and spermatogenic repopulation were low. It is concluded that irradiation before adulthood has considerable long-term effects on the testis. Potential testis size is reduced, repopulation of the seminiferous epithelium is generally not complete, and aberrant Sertoli cells and dilated tubules are formed. The latter two phenomena may have further consequences at still longer intervals after irradiation.     

Analysis of early and late results of progressive Graves-Basedow ophthalmopathy treatment with different methods]

The early (immediately after the end of treatment) and late (from 12 to 91, mean 46.3 months after the end of treatment) results of progressive Graves-Basedow ophthalmopathy treatment were evaluated in 71 patients (57 women and 14 men, aged 25-66, mean 47.3 years). In all patients the thorough ophthalmological evaluation was performed early and late after treatment and the abnormalities found were classified according to Werner's method and Donaldson's ophthalmopathy index. The patients were divided into 7 groups according to different methods of treatment. Groups I-V consisted of 31 patients treated with glucocorticoids or glucocorticoids with azathioprine (Imuran) in the first stage of medication (30 patients). Plasmapheresis (7 patients) or tele-cobalt irradiation (3 patients) was applied as the second stage of treatment when the first stage was ineffective. In one person plasmapheresis and tele-cobalt irradiation was applied without previous glucocorticoid therapy. Two patients were treated successively by glucocorticoids, plasmapheresis and tele-cobalt irradiation. Very good and good late results of treatment were found in 95% of patients out of 22 reexamined persons of groups 1-5. Group 6 consisted of 7 patients treated with cobalt irradiation alone, in all 6 patients evaluated late results were good or very good. Out of 33 patients of group 7 treated by combination of glucocorticoids and telecobalt irradiation 23 were evaluated late and the results were found good or very good in 96%. The results suggest that combined treatment of progressive endocrine ophthalmopathy with glucocorticoids and cobalt irradiation is the most effective method of treatment at present. The affectivity of stage treatment is comparable with combined treatment but lasts longer and usually is more expansive.(ABSTRACT TRUNCATED AT 250 WORDS)     

Possible Role of Hormones in Treatment of Metastatic Testicular Teratomas: Tumour Regression with Medroxyprogesterone Acetate

Three patients in a consecutive series of 16 cases of metastatic mallgnant teratoma testis have shown well-marked tumour regression during hormone treatment. In two cases multiple lung metastases had previously failed to respond to actinomycin D therapy, and following treatment with medroxyprogesterone acetate one patient had well-marked selective tumour regression for nine months while the other is alive, well, and free from disease at seven years. The third case was treated with a combination of actinomycin D and medroxyprogesterone acetate and is alive and disease-free at two years.Attention is drawn to this preliminary study in the hope of stimulating interest in the possible value of hormones, either alone or combined with chemotherapy and irradiation, in the treatment of metastatic testicular teratoma. Multicentre prospective clinical trials are now needed if knowledge is to be advanced in this field.     

Effects of prenatal X-irradiation on postnatal testicular development and function in the Wistar rat: development/teratology/behavior/radiation

It is evident that significant permanent tissue hypoplasia can be produced following radiation exposure late in fetal development. Because two organs, brain and testes, are developmentally and functionally interrelated, it was of interest to determine whether fetal testicular hypoplasia was a primary or a secondary effect of fetal brain irradiation. Twenty-four pregnant Wistar strain rats were randomly assigned to one of four groups, and a laparotomy was performed on day 18 of gestation. The fetuses received sham irradiation, whole body irradiation, or only head/thorax or pelvic body irradiation at a dosage level of 1.5 Gy. Mothers were allowed to deliver and raise their offspring until postnatal day 30, when the offspring were weaned. At 60 days of age, 74 male offspring were allowed to mate with colony control females of similar age until successful insemination or until the males reached 90 days of age, when they were killed. Testes were weighed and processed for histologic examination. Direct radiation of testes, due to whole body or pelvic exposure, resulted in testicular growth retardation and significantly reduced spermatogenesis. Breeding activity of the males and the percent of positive inseminations were also slightly reduced. However, a significant percentage of male offspring receiving direct testicular radiation did produce offspring. Head/thorax-only irradiation did not adversely affect testicular growth or spermatogenesis. Therefore, the use of histologic analysis as the sole determinant of infertility may be misleading. This study indicates that testicular growth retardation and an increased infertility rate result from direct prenatal exposure of rat testes to X-radiation and are not necessarily mediated via X-irradiation effects on the central nervous system.     

Reasons for reduced activities of 17 alpha-hydroxylase and C17-C20 lyase in spite of increased contents of cytochrome P-450 in mature rat testis fetally irradiated with 60Co

Pregnant rats received whole body irradiation with 2.6 Gy gamma-ray from a 60Co source at Day 20 of gestation. When pups were 4 months old, activities of electron transport system and steroid monooxygenase in tests were assayed. The content of total cytochrome P-450 in the irradiated testes had increased to 170% of that in non-irradiated rats, but NADPH-cytochrome P-450 reductase activity had reduced to 36% of the control. Also, amounts of cytochrome b5 in testicular microsomal fraction were decreased markedly after irradiation, but no significant change of NADH-cytochrome b5 reductase activity was observed in the treated pups. Because both 17 alpha-hydroxylase and C17-C20 lyase activities tended to be decreased by fetal irradiation, testosterone production from progesterone and 17 alpha-hydroxyprogesterone was reduced to about 30% of the control. From these results, it has been suggested that the testicular cytochrome P-450 is radioresistant but steroid monooxygenase activities are reduced after the fetal irradiation. We propose that the discrepancy arises from the marked decrement of NADPH-cytochrome P-450 reductase activity.     

Catalytic properties of testicular hyaluronidase after gamma-irradiation

The effect of gamma-irradiation on ovine testicular hyaluronidase was studied in aqueous solution. Following irradiation, hyaluronidase is inhibited, and the kinetics of inhibition follow a pattern in which Km and Vmax decline as radiation dose is increased. It was indicated that the binding affinity of the residual activity of hyaluronidase with substrate is enhanced and depends upon radiation damage. Effects of various agents such as pH, salts, PCMB and glutathione on irradiated hyaluronidase have been compared with non-irradiated enzyme. The irradiated hyaluronidase was more sensitive to inhibition by CuSO4 than the non-irradiated enzyme. The residual activity after irradiation is less refractory to FeCl3 inhibition and less sensitive to NaCl stimulation compared to non-irradiated hyaluronidase. pH response curves of ovine testicular hyaluronidase show two maxima which become more evident after irradiation.     

Comment identifier le spermatozoïde vivant?

Testicular sperm extraction (TESE) has been used to retrieve spermatozoa in patients with secretory azoospermia for intracytoplasmic sperm injection (ICSI). However, testicular spermatozoa have poor motility that significantly decreases after cryopreservation and thawing. The major difficulty with testicular spermatozoa is to distinguish between living and dead spermatozoa, as most spermatozoa are immotile. The aim of this study was firstly to report the various methods used to explore spermatozoa vitality. Most tests assess the functional and structural integrity of the sperm membrane, such as staining methods and hypo-osmotic swelling test (HOS-test). We then evaluates the potential of pentoxifylline (PTX), a phosphodiesterase inhibitor of the methylxanthine group, to improve the distinction between living and dead immotile testicular spermatozoa by increasing the number of post-thawed motile spermatozoa. We also analysed the results of 100 ICSI cycles performed with frozen-thawed testicular (n=72) and epididymal (n=28) spermatozoa treated with 3.5 mM PTX. To test the effect of PTX on motility, 14 samples of frozen-thawed testicular spermatozoa from eight patients with secretory azoospermia and six patients with excretory azoospermia were divided into three equal samples: one sample treated with 3.5 mM PTX, one sample initially migrated on two-layer Percoll gradient and then divided into two aliquots (one treated with 3.5 mM PTX, one without treatment), and the last sample without migration and without PTX treatment. The number of motile spermatozoa was evaluated in 10 μL of each sample with an inverted microscope at 15, 30, 60, 120 minutes and 24 hours. We also compared the outcome of ICSI in 100 cycles using frozen-thawed epididymal or testicular spermatozoa between secretory and excretory patients. PTX significantly increased the number of motile frozen-thawed testicular spermatozoa in secretory and excretory azoospermia. In excretory azoospermia, the number of motile spermatozoa was further increased when PTX was associated with migration on Percoll gradient, while PTX alone gave the best results in secretory azoospermia. Fertilization and pregnancy rates as well as embryo quality and division stages were comparable in the two groups. By increasing the number of motile frozen-thawed testicular spermatozoa, PTX improves the selection of living spermatozoa.     

Role of adiponectin as a modulator of testicular function during aging in mice

The mechanisms by which testicular functions decline with aging remain largely speculative. Our recent finding showed the importance of adiponectin in the regulation of testicular functions, whereas its concentration declines during male infertility. Thus, the aim of present study was to explore the potential role of adiponectin during aging. The changes in adiponectin, adiponectin-receptors, and insulin receptor proteins expression in the testis were evaluated and compared with the testicular parameters, mass, and testosterone level in the mice from early post-natal to late senescence period. Further, the current study has examined the effect of exogenous adiponectin treatment on testicular functions in aged mice. The results showed a significant decline in adiponectin/adiponectin-receptors expression simultaneously with a significant decline in testicular mass, insulin receptor expression and testosterone synthesis in the testis of aged mice. Exogenous treatment of adiponectin to aged mice resulted in marked improvements in testicular mass, histological features (cells proliferation), insulin receptor expression, testicular glucose uptake, anti-oxidative enzymes activity and testosterone synthesis as compared with the control. Based on these findings, it may be concluded that a marked decline in adiponectin synthesis and action results in decreased insulin sensitivity (development of insulin resistance) and increased oxidative stress which consequently suppresses testicular functions during aging. This study further showed that treatment with adiponectin ameliorates reduced testicular functions by enhanced expression of insulin receptor in the testis of senescent mice. It is thus hypothesized that systemic adiponectin treatment could be a promising therapeutic strategy for improvement of testosterone production and sperm counts during aging.     

Congenital adrenal hyperplasia in adulthood: do men need to continue treatment?

Due to early diagnosis and appropriate paediatric treatment, internists and endocrinologists are now caring for an increasing number of adult patients with congenital adrenal hyperplasia (CAH). Problems that may be encountered in adult males with CAH are the continuing risk of developing an adrenal crisis and impaired gonadal function due to suppression of the hypothalamic-gonadal axis. Fertility may be further compromised by testicular adrenal rest tumours. Available data suggest that the reversal of infertility is more difficult once testicular nodules have developed. Similar to female CAH patients, male patients may develop adrenal tumours due to inadequate adrenocorticotropic hormone suppression. We therefore recommend continuous treatment of male CAH patients with careful monitoring of clinical and hormonal parameters in order to avoid overtreatment.     

Leydig cell insufficiency after testicular irradiation for acute lymphoblastic leukemia

Leydig cell function in 21 boys with acute lymphoblastic leukemia who had been treated by bilateral direct testicular irradiation (12 X 2 Gy) at 8.4 +/- 0.7 years, was evaluated 3.8 +/- 0.4 years after irradiation. At the time of irradiation all were prepubertal and at evaluation 12 were prepubertal and 9 pubertal. Leydig cell insufficiency, indicated by a low plasma testosterone response to chorionic gonadotrophin and/or an increase in basal level of plasma luteinizing hormone, was observed in 19/21 patients. The children who were the youngest at testicular irradiation were more vulnerable. Spontaneous virilization occurred in 3 of the older children and resulted from compensated Leydig cell dysfunction.     

Testicular dose and associated risk from inverted-Y field irradiation in patients with Hodgkin's disease

This study aims to estimate testicular dose and the associated risks for infertility and hereditary effects from inverted-Y field irradiation Radiotherapy was simulated on a humanoid phantom using a 6 MV photon beam. Testicular dose was measured for various field sizes and tissue thicknesses along beam axis using an ionization chamber. Gonadal dose was reduced by placing lead cups around the testes supplemented by a field edge block. For a tumor dose of 40 Gy, testicular dose was 0.56–6.52 Gy depending upon the field size and the distance from the inferior field edge. The corresponding dose to shielded testes was 0.12–1.96 Gy. The increase of tissue thickness in reased the testicular dose up to 40%. An excess risk of hereditary disorders of (7–391) per 10000 births was calculated. The treatment parameters, the presence of gonad shield and the somatometric characteristics determine whether testicular dose can exceed 1 Gy which allows a complete recovery of spermatogenesis.     

Difference of fertilizing capacity between testicular sperm and vas deferens sperm in Cynops pyrrhogaster

The fertilizing capacity was compared between testicular and vas deferens sperm in Cynops pyrrhogaster. The testicular sperm was not capable of fertilizing jelly eggs. In contrast, the vas deferens sperm was already capable of fertilizing the newt jelly eggs. There was no inhibitory factor for fertilizing jelly eggs in the testis. These results suggest that the testicular sperm is immature as to the fertilizing capacity. The testicular sperm gained the fertilizing capacity for the jelly eggs by treatment with Holtfreter's solution or 1/20 strength Holtfreter's solution. The treatment may promote the step of maturation to achieve the fertilizing capacity. The treated testicular sperm did not fertilize dejellied eggs, although vas deferens sperm fertilized dejellied eggs. Therefore, the maturation state of the treated testicular sperm is different from that of vas deferens sperm. Newt sperm may be matured within the vas deferens, as the newt does not have an organ like the mammalian epididymis.     

Germ Cell Tumors of the Testes

Most malignant testicular neoplasms are of germ cell origin. They are divided into five basic types: seminomas, embryonal carcinomas, teratocarcinomas, adult teratomas and choriocarcinomas. Clinically they may present as an enlarging testicular mass, or with symptoms resulting from metastases or hormonal secretions. The treatment of choice for patients with seminomas is orchiectomy, followed by radiation therapy. This combination results in an 80 to 100 percent five-year survival rate in patients with nonmetastatic or locally metastatic disease. The treatment of nonseminomatous germ cell tumors is more controversial. An aggressive approach, however, with retroperitoneal lymph node dissection and adjuvant chemotherapy has resulted in an overall 78 percent survival rate. Several placental and fetal proteins are secreted by these tumors. Two of these, human chorionic gonadotropin and alpha-fetoprotein, have been shown to be useful for the diagnosis of these neoplasms, for following the disease activity during therapy and for detection of recurrences.     

Dissociation of lutropin-induced loss of testicular lutropin receptors and lutropin-induced desensitization of testosterone synthesis.

The relationship between changes in testicular lutropin receptors, as measured by specific binding of 125I-labeled human chorionic gonadotropin, and testosterone synthesis in response to lutropin (testicular responsiveness) was studied in intact and hypophysectomized rats. Administration of a single 200-microgram dose of ovine lutropin to intact rats results at 3 days in a 58% decrease in lutropin receptors associated with a parallel decrease in testicular responsiveness. A single 30-microgram dose of lutropin to intact rats resulted in a comparable decrease in lutropin receptors with a transient increase in testicular responsiveness. Rats receiving twice-daily injections of 15 microgram lutropin for 10 days exhibited a 48% decrease in lutropin receptors by day 3 which persisted during the 10-day treatment period, but was accompanied by a progressive increase in testicular responsiveness to lutropin. Hypophysectomy resulted in an 80% loss of receptors and a 72% loss in responsiveness 7 days after surgery. Daily treatment with lutropin initiated immediately following surgery resulted in a further dose-dependent decrease in lutropin receptors and a dose-dependent increase in testicular responsiveness. Loss of lutropin receptors was not due to occupancy of the receptor by exogenous lutropin. These studies demonstrate a dissociation between the negative regulation of lutropin receptors and testicular responsiveness to lutropin. Furthermore, the studies in hypophysectomized rats indicate that lutropin is the only hormone essential for maintenance of steroidogenesis and that this is independent of lutropin receptor concentration.     

Biosynthesis and localization of lactate dehydrogenase X in pachytene spermatocytes and spermatids of mouse testes

The presence and biosynthesis of the testis-specific isozyme of lactate dehydrogenase (LDH-X) in cells at various stages of spermatogenesis have been examined. Enrichment of testicular cells in various stages of spermatogenesis has been achieved by two methods: (1) cell separation by velocity sedimentation in the Elutriator rotor and (2) γ irradiation of testes to eliminate specific classes of testicular cells. Separation of cells from immature mice indicated that cells prior to the midpachytene stage contain no LDH-X. Measurement of LDH-X levels in cells separated from adult mice and in testicular homogenates prepared at various times after irradiation indicated that the highest level of LDH-X per cell (normalized for DNA content) was in spermatids. Synthesis of LDH-X was determined, after in vivo injection of [³H]valine, by measurement of the radioactivity in LDH-X precipitated with specific antiserum. After irradiation, the rate of LDH-X synthesis remained constant, despite the loss of early primary spermatocytes. In separated cells, the rate of LDH-X synthesis was highest in late pachytene spermatocytes, lower in round spermatids, and even lower, but still significant, in elongated spermatids. Therefore, the synthesis of LDH-X begins at a specific point during spermatogenesis, the midpachytene stage of spermatocyte development, and continues throughout spermatid differentiation.     

Carcinoma in situ of the testis: aneuploid cells in semen

The content of cellular DNA in ejaculates from eight patients with carcinoma in situ of the testis and 26 controls without evidence of testicular neoplasia was studied by flow cytometry. An aneuploid cell population with a ploidy value similar to that found for carcinoma in situ cells was detected in seminal fluid from four of the eight men with carcinoma in situ but in none of the controls. One year after orchidectomy or local irradiation in these four men no aneuploid cells were found in the semen.These findings show that a detectable proportion of malignant germ cells may be released into the seminal fluid of patients with carcinoma in situ of the testis. Analysis of seminal fluid may therefore aid in screening for early neoplasia of the testis.     

Increased rat testicular heme oxygenase activity associated with depressed microsomal heme and cytochrome P-450 levels after repeated administration of human chorionic gonadotropin

Repeated administration of human chorionic gonadotropin to rats results in a maximal depression of testicular microsomal heme and cytochrome P-450 levels at 24 h, followed by increases that plateau at pretreatment levels by day six. Associated with the depressed levels of microsomal heme and cytochrome P-450 is an increase of testicular microsomal heme oxygenase activity at 12-24 h. Testicular mitochondrial delta-aminolevulinic acid synthase activity was increased at 24 h, and remained elevated throughout the 9-day treatment period. Pretreatment with 1,4,6-androstatrien-3,17-dione, an aromatase inhibitor, failed to prevent the depression of testicular microsomal heme or cytochrome P-450 or increased heme oxygenase activity caused by repeated administration of human chorionic gonadotropin, and administration of estradiol benzoate failed to alter testicular microsomal heme oxygenase activity suggesting that these parameters were not related to altered testicular estrogen content caused by increased aromatase activity. These results suggest that increased testicular heme oxygenase activity is associated with decreased microsomal heme and cytochrome P-450 content during human chorionic gonadotropin-induced desensitization.