Germ cell failure and Leydig cell insufficiency in post-pubertal males after autologous bone marrow transplantation with BEAM for lymphoma.
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Germinal epithelium
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Abstract. Male rats treated prenatally with busulfan in order to render them aspermatogenic were treated between 23 and 38 days of age either with testosterone, or flutamide. In such aspermatogenic rats, testosterone supplementation stimulated the growth of accessory sex organs, markedly decreased the secretion of gonadotrophins (by 61% for LH and 83% for FSH), decreased testicular weight (–60%) as well as all parameters relating to testicular histology. Flutamide treatment decreased the weight of accessory sex organs, stimulated the secretion of both LH (+200%) and FSH (+63%) by inhibition of the negative feedback of testosterone; endogenous testosterone secretion was increased by 363%. Testicular weight was increased by 44% and the total volume and the cytoplasmic and nuclear area of Leydig cells were increased by 254 and 28%, respectively, but their number per testis was unchanged. The number of Sertoli cells per testis was increased by 49%, but their nuclear area was not modified. In aspermatogenic prepubertal rats, the large increase in plasma FSH demonstrated that FSH release was partly under the control of inhibin, secreted by Sertoli cells when germinal cells were present. Nevertheless, FSH levels after testosterone (inhibition) or flutamide treatment (stimulation) clearly demonstrated that, in the growing rat, FSH secretion is also partly dependent on the negative feedback of testosterone. In the absence of germ cells, FSH was able to re-initiate Sertoli cells mitoses, but not their functional activity. LH secretion was solely controlled by the negative feedback of androgens and, even in the absence of germinal cells, Leydig cells were able to respond to LH stimulation by an increase in testosterone secretion.
Flutamide
Germinal epithelium
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The effect of differing degrees of destruction of the seminiferous epithelium on serum FSH levels and on Sertoli cell secretory function was studied in adult male rats. Germinal cell aplasia (Sertoli cell-only syndrome, SCO) was induced in male rats by fetal irradiation (250 rads) on day 20 of gestation. Destruction ofthe seminiferous epithelium was induced by treatment with either hydroxyurea (HU) or chronic feeding of a vitamin A-deficient diet (VAD). Serum FSH, LH and testosterone were measured to assess pituitary-testicular interaction, and testicular androgen binding protein (ABP) was measured to evaluate Sertoli cell secretory function in these states. Serum LH was significantly elevated in all three treatment groups, while serum testosterone was significantly lower than normal only in SCO rats. The elevation of LH and the lowered testosterone levels suggest that there is partial Leydig cell failure in rats with germinal cell aplasia induced by fetal irradiation. Significantly elevated levels of serum FSH were seen in all three treatment groups; the degree of elevation was proportional to the severity ofthe induced testicular damage (normal adult males 378 ± 27, HU treated 751 ± 28, VAD 1019 ±49 and SCO rats 1070 ± 54 ng/ml, mean ± SEM). Both the secretion rate of ABP as measured by its accumulation in the testis in the 16 h following efferent duct ligation, and the total amount of ABP both in testis and caput epididymis were markedly decreased in all three treatment groups in proportion to the severity of the induced testicular damage. These findings indicate that Sertoli cell secretory function was impaired as a result of the treatments used to induce testicular damage. The demonstration of impaired Sertoli cell secretory function in association with elevated serum FSH suggests that feedback regulation of FSH may be a function ofthe Sertoli cell.
Androgen-binding protein
Germinal epithelium
Efferent ducts
Testicle
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Introduction. Ghrelin is a hormone which has effects on the secretion of growth hormone, gastrointestinal system, cardiovascular system, cell proliferation and reproductive system. The present study we focused on the relation between ghrelin and GHS-R1a gene expression and the regulation of their expression in the testes of diabetic rats. Material and methods. 40 male Wistar albino rats were divided into four groups: control, and sampled 4, 8 and 12 weeks after induction of diabetes by streptozotocin (STZ) intraperitoneal injection (40 mg/kg). The rats were decapitated under ketamine anesthesia and their testes were removed. Blood was obtained from heart and serum follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels were measured by ELISA. Tissue ghrelin and GHS-R mRNA levels were determined by qRT-PCR, while ghrelin protein expression was studied by immunohistochemistry. Histopathological damage scores were also assessed. Results. Eight weeks after diabetes induction serum FSH level was increased, whereas LH and testosterone concentrations decreased. The ghrelin and GHS-R1a gene expression and ghrelin immunohistochemistry score first tended to increase after first four weeks of diabetes, and then tended to decrease. Ghrelin-immunopositive cells were detected in Leydig cells in all groups of rats, however, not in the germinal epithelium. Congestion of vessels and hemorrhage, formation of the vacuoles in spermatogonia and spermatocytes, desquamation of spermatids in the lumen and disorganization of seminiferous tubule germinal epithelium were observed in testis of all the diabetic rats. In addition, mean testicular biopsy score and mean seminiferous tubule diameter were getting lower in diabetic animals. Conclusion. Our results suggest that diabetes affects ghrelin expression in rat testis.
Germinal epithelium
Seminiferous tubule
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Germinal epithelium
Total body irradiation
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SUMMARY Eighteen men (mean age 27, range 18‐30 years) treated for Hodgkin's disease with 6‐8 courses of MVPP (Mustine, Vinblastine, Procarbazine and Prednisolone) have had Leydig cell function assessed by their steroidogenic responses to stimulation by a single bolus dose of HCG (1000 units intramuscularly). Normal age‐matched men ( n = 16) acted as controls. Baseline immunoreactive FSH was markedly raised in the patients (mean 18.1 ± SD 6‐9 vs 2.0 ± 1.5 IU/1, P < 0‐0001) reflecting damage to the germinal epithelium. Immunoreactive LH was also greater in patients (10‐3 + 3‐9 IU/1) than in controls (3‐9+1‐9 IU/1, P <00001). There were no differences between the baseline testosterone, androstenedione, oestradiol, oestrone and sex hormone binding globulin (SHBG) concentrations. The testosterone/SHBG ratios were similar in the two groups and there was no correlation between baseline LH and testosterone concentrations or testosterone/SHBG ratios. Testosterone, androstenedione, oestradiol and oestrone secretion in response to HCG stimulation were similar at 24 h and 96 h in both groups. In order to explain the paradox of elevated immunoreactive LH in the face of normal testicular steroidogenesis in such patients, LH biological activity (B) as well as LH immunoreactivity (I) and FSH and testosterone were estimated in a second similar group of patients ( n = 17, mean age 27, range 17‐43 years) and in a further age‐matched control group ( n = 17). Bioactive and immunoreactive LH levels were significantly increased (P< 0‐005 and P < 0‐001, respectively) in the patient group. However, the biological: immunological (B:I) LH ratios were found to be similar in the patients (2.7 ± 0.6, mean ± SD) and controls (2.8 ± 0.7). There was a significant correlation between immunoreactive LH and FSH concentrations in the patient group (r = 0‐65, P <001), but not in the controls. In conclusion Leydig cell function, as judged by the steroidogenic responses to HCG stimulation, is normal in patients with chemotherapy‐induced spermatogenic damage. The biological activity of LH is not changed, but there is a resetting of the LHLeydig cell axis
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Although di-n-butyl phthalate (DBP) induces germ cell apoptosis, the underlying mechanism is not yet clear in quail. In this study, prepubertal quails were given a single dose of 500mg kg-1 DBP by gavage and were then killed 3, 6 and 24h after treatment. There was a significant reduction in intratesticular testosterone (ITT) concentrations and testicular steroidogenic enzyme mRNA expression and a significant increase in germ cell apoptosis in DBP-treated compared with control quails at all time points. Maximum apoptosis was detected 6h after treatment and the maximum reduction in testosterone concentrations was at 3h. To investigate whether DBP suppressed testicular steroidogenesis by affecting the hypothalamic-pituitary-testicular axis, we analysed pituitary LH subunit β (Lhb) mRNA expression and serum LH concentrations. At all time points, pituitary Lhb expression and serum LH concentrations were significantly decreased following DBP treatment. The present observations suggest the possibility that DBP blocked LH secretion from the hypothalamus and/or pituitary, thereby decreasing LH stimulation of Leydig cells and reducing ITT concentrations. DBP-induced decreases in ITT concentrations may cause changes to the physical structure of Sertoli cells, which, in turn, may induce germ cell apoptosis.
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The effect of [D-Trp6]LHRH, a potent agonist of LHRH, on pituitary-testicular responses was investigated in male rhesus monkeys. Acute administration of 5, 25, or 500 μg [D-Trp6]LHRH produced dose-related increases in serum testosterone and bioassayable LH levels. The administration of 500 μg [D-Trp6]LHRH twice weekly for 12 weeks led to a 75% decrease in the LH responses to successive doses of this peptide; testosterone responses in these animals were unchanged, however. The lack of any change in the motility or sperm number in semen obtained by electroejaculation suggested that there was no effect on spermatogenesis during the twice weekly administration. These animals were then treated with [D-Trp6]LHRH (500 μg daily) for 16 weeks. This caused dramatic decreases in the LH responses to the agonist in all four animals. The testosterone response was reduced in two and abolished in two animals. These latter two animals also lost their electroejaculatory response. During the recovery period following the cessation of treatment, these two animals produced ejaculates with no sperm, indicating that a transient period of azoospermia was achieved. The results of these studies suggest that 1) the responsiveness of the pituitary is more susceptible to desensitization by [D-Trp6] LHRH than that of the testes; and 2) even though chronic administration of [D-Trp6]LHRH suppressed the pituitary-Leydig cell axis in all monkeys, seminiferous tubular function was reduced only in those animals with very low androgen levels.
Testicle
Electroejaculation
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Summary The sex‐reversed X/X Sxr mouse is phenotypically male but lacks germ cells. This provides the opportunity to examine Leydig cell function in the absence of a normal germinal epithelium and without experimental manipulation of the testis. Serum testosterone was lower in Sxr males compared to normal (X/Y) males but there was no significant difference in intratesticular testosterone levels. Serum immunoactive and bioactive luteinizing hormone levels were not significantly different between the two groups. Injection of human chorionic gonadotrophin (hCG) increased intratesticular testosterone in Sxr males more than in normal males although there was no difference in serum testosterone levels. These differences in circulating and intratesticular testosterone levels may be related to reduced blood flow through the Sxr testis. Both basal and hCG‐stimulated androgen production by whole testes in vitro were not significantly different between normal and Sxr males. Androgen production per Leydig cell, however, was significantly reduced in cells from Sxr males; this difference was apparent under basal conditions and following stimulation with hCG, dibutyryl cyclic AMP, 22R‐hydroxycholesterol or pregnenolone. Results show that in the absence of a normal germinal epithelium there is a decrease in the steroidogenic capacity of the Leydig cells although steroidogenesis by the whole testis is not impaired significantly.
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Basal (medicine)
Human chorionic gonadotropin
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Treatments given for childhood malignancies can alter gonadal function by several mechanisms: (1) cranial irradiation may cause either gonadotrophin deficiency or premature puberty. (2) Irradiation of the testes can induce germinal epithelium dysfunction even if the dose delivered is very low; Leydig cell failure occurs beyond 5-6 Gy and ovarian insufficiency beyond 6-7 Gy. (3) Chemotherapy is considerably more toxic for the germinal epithelium of the testes than for the ovaries; alkylating agents are especially toxic. Analysis of the consequences of preparation for bone marrow transplantation by chemotherapy or total body irradiation will be required when longer follow-up are available.
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Total body irradiation
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Testicular function was studied in ten men, aged between 17 and 36 years, who had received irradiation for a nephroblastoma during childhood. The dose of scattered irradiation to the testes ranged from 268 to 983 rad. Eight subjects had either oligo- or azoospermia (0 to 5.6 million/ml), seven of whom had an elevated serum follicle-stimulating hormone (FSH) level. One subject showed evidence of Leydig cell dysfunction with a raised serum luteinizing hormone level (LH) and a low plasma testosterone concentration. A second group of eight prepubertal males, aged between 8 and 14 years, were studied. These had also been irradiated for abdominal malignancies during childhood and received a similar dose of irradiation to the testis as the first group studied. The plasma testosterone levels were within the normal range for prepubertal boys in all eight. The mean gonadotrophin levels were not significantly different from the mean levels of normal prepubertal males. Thus irradiation-induced damage to the germinal epithelium in prepubertal boys produces raised FSH levels after puberty but not before it. We conclude, therefore, that inhibition has a minor role in the control of the prepubertal hypothalamic-pituitary testicular axis and its contribution to gonadal control of gonadotrophin secretion changes with sexual maturation.
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