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Testicular cancers in closely related family members are rare. We herein report the second incidence of pure seminoma occurring in a father and son. The increased risk of malignant tumors developing in the undescended testis is well established. We also describe the second reported incidence of testicular cancers occurring in 2 non-twin brothers, in which 1 of the cancers developed in an undescended testis.
Using differential display RT-PCR, we identified a gene of 2750 bp from human adult testis, named H-Lse, which encoded a putative protein of 523 amino acids and molecular weight of 58 kd with structural characteristics similar to that of mouse lysosome sialic-acid-specific 9-O-acetylesterase. Northern blot analysis showed a widespread distribution of H-Lse in various human tissues with high expression in the testis, prostate, and colon. In situ hybridization results showed that while H-Lse was not detected in embryonic testis, positive signals were found in spermatocytes but not spermatogonia in adult testis of human. The subcellular localization of H-Lse was visualized by green fluorescent protein (GFP) fused to the amino terminus of H-Lse, showing compartmentalization of H-Lse in large dense-core vesicles, presumably lysosomes, in the cytoplasm. The developmentally regulated and spermatogenic stage-specific expression of H-Lse suggests its possible involvement in the development of the testis and/or differentiation of germ cells.
Sperm-egg interaction is a carbohydrate-mediated species-specific event which initiates a signal transduction cascade resulting in the exocytosis of sperm acrosomal contents (i.e., the acrosome reaction). This step is believed to be a prerequisite which enables the acrosome-reacted spermatozoa to penetrate the zona pellucida (ZP) and fertilize the egg. Successful fertilization in the mouse and several other species, including man, involves several sequential steps. These are (1) sperm capacitation in the female genital tract; (2) binding of capacitated spermatozoa to the egg's extracellular coat, the ZP; (3) induction of acrosome reaction (i.e., sperm activation); (4) penetration of the ZP; and (5) fusion of spermatozoon with the egg vitelline membrane. This minireview focuses on the most important aspects of the sperm acrosome, from its formation during sperm development in the testis (spermatogenesis) to its modification in the epididymis and function following sperm-egg interaction. Special emphasis has been given to spermatogenesis, a complex process involving multiple molecular events during mitotic cell division, meiosis, and the process of spermiogenesis. The last event is the final phase when a nondividing round spermatid is transformed into the complex structure of the spermatozoon containing a well-developed acrosome. Our intention is also to briefly discuss the functional significance of the contents of the sperm acrosome during fertilization. It is important to mention that only the carbohydrate-recognizing receptor molecules (glycohydrolases, glycosyltransferases, and/or lectin-like molecules) present on the surface of capacitated spermatozoa are capable of binding to their complementary glycan chains on the ZP. The species-specific binding event starts a calcium-dependent signal transduction pathway resulting in sperm activation. The hydrolytic and proteolytic enzymes released at the site of sperm-zona interaction along with the enhanced thrust of the hyperactivated beat pattern of the bound spermatozoon, are important factors in regulating the penetration of the zona-intact egg.
Sox8, Sox9, and Sox10 constitute subgroup E within the Sox family of transcription factors. Many Sox proteins are essential regulators of development. Sox9, for instance, is required for chondrogenesis and male sex determination; Sox10 plays key roles in neural crest development and peripheral gliogenesis. The function of Sox8 has not been studied so far. Here, we generated mice deficient in this third member of subgroup E. In analogy to the case for the related Sox9 and Sox10, we expected severe developmental defects in these mice. Despite strong expression of Sox8 in many tissues, including neural crest, nervous system, muscle, cartilage, adrenal gland, kidney, and testis, homozygous mice developed normally in utero, were born at Mendelian frequencies, and were viable. A substantial reduction in weight was observed in these mice; however, this reduction was not attributable to significant structural deficits in any of the Sox8-expressing tissues. Because of frequent coexpression with either Sox9 or Sox10, the mild phenotype of Sox8-deficient mice might at least in part be due to functional redundancy between group E Sox proteins.
Aromatase activities and estrogen contents in the gonad of Japanese scallop, Patinopecten yessoensis, were determined during gonadal development and estrogenic cells in the testis were identified immunohistochemically. Ovaries and testes developed rapidly during January and February to reach the mature stage in March and the spawning stage in April. Increases in aromatase activities of the ovary and testis preceded the onset of the ovarian and testicular development. Aromatase activities reached the highest level at the growing stage in February and the mature stage in March, and showed a striking decrease at the spawning stage in April. Contents of ovarian and testicular estradiol-17beta changed similarly to the profile of aromatase activities in the ovary and testis, although estrone showed no change. Immunoreactivities against P450 aromatase and estradiol-17beta were detected in the cells along the inside of the acinar wall of the testis, whereas in the previous reports, the cells are distributed along the outside of the acinar wall in the ovary. This study thus suggests that estrogen is synthesized in the estrogenic cells of the ovary and testis through aromatization by P450 aromatase and that testicular estrogen may play a physiological role in spermatogenesis.
The effect of FSH on the development of the testis in the ram lamb was examined in two experiments where lambs were passively immunized against ovine beta-FSH from birth until 100 or 160 d. In both experiments, immunization resulted in a slower testicular growth relative to that of controls. This effect became apparent at around the start of the period of rapid testicular growth (60-70 d of age) and resulted in testicular weights at the end of treatment ranging from 37 to 51% of those of control groups. Within the testis, this was reflected in shorter seminiferous tubules (48-64% of controls) and in lower numbers of Sertoli cells per testis (57-82%). In the rams immunized until 160 d of age, spermatogenesis had begun and immunization against FSH provoked a lower production of germinal cells which was not solely due to the lower number of Sertoli cells but also due to fewer germinal cells being supported by each Sertoli cell. However, the numbers of A0 spermatogonia per testis and the daily production of the A1 spermatogonia were unaffected by immunization, but the production of the B2 spermatogonia and, as a consequence, of leptotene and pachytene spermatocytes and of round spermatids were all markedly lower (43-47% of controls). These effects were not due to any decreases in the secretion of LH or testosterone as seen in the blood levels of these two hormones. These results show that, in the ram lamb, FSH is essential for normal testicular development and for the establishment of a normal population of Sertoli cells. They also confirm that, once spermatogenesis is established, FSH is necessary for a normal production of germinal cells, with one or more of the divisions between the A1 and B2 spermatogonia being sensitive to suppression of FSH.
85 cases of this syndrom have been published since the original case in 1964. The main clinical symptoms are those of Klinefelter's disease from which it differs by the caryotype only. Azoospermie is the rule. 3 mechanisms can be implicated: Mosaic 46 XX/47 XY with secondary loss of Y chromosome; Translocation of a part of Y chromosome upon an autosome or Y chromosome; Autosomal mutant gene acting upon the masculinizing site of X chromosome and inducing the primitive development of the testis as the short arm and proximal part of the long arm of Y chromosome normally do. These mechanisms perhaps are distinct origins of a syndrom which clinic alone cannot dissociate.
Gonadal protein patterns of the mouse were studied during fetal development by two-dimensional gel electrophoresis. Fetal mice at days 8.5, 10.5, 12.5, and 14.5 post-coitum were analyzed for male or female specific proteins. Although no sex specific proteins were found, several proteins were found which were expressed in significantly different amounts in the two sexes at about the time of gonadal differentiation. Hence, quantitative differences, rather than qualitative ones, could be related to the initiation of testis or ovary development.
A number of genes are known to control the development of the testis but the transcription factor SRY encoded on the Y-chromosome is considered to play the major role in initiating the first step in determining testicular differentiation. Mutations in this gene usually result in gonadal dysgenesis, but it is interesting to note that at least three of these mutations have been found to be familial. Furthermore, fewer than 10% of true hermaphrodites carry an XY karyotype, and so far only two patients have been documented to carry a mutation in the SRY gene. We have identified a familial mutation in the SRY gene involving a previously described locus. The index patient was born with severely ambiguous genitalia and on histological examination the gonads revealed true hermaphroditism, containing ovarian as well as testicular tissue. The father, his three brothers, and his first-born son carry the identical mutation. The severely feminized XY individual was diagnosed shortly after birth, gonadectomized and raised as female. SRY was determined by PCR and subsequently sequenced using cycle sequencing. A previously published point mutation was identified at nucleotide position 680 resulting in a non-conservative exchange of the amino acid iso-leucine at position 90 into methionine. This position represents a mutational 'hot spot', which seems to retain a certain amount of protein activity, enabling normal male development in some individuals. The patient is the third one reported in whom a mutation in the SRY gene results in ovarian-like development. Since ovarian development in XY individuals is extremely rare, its mechanism is of great interest. Further studies in this family might allow the identification of factors initiating and stimulating ovarian development. How far these infantile ovaries would have developed normally, however, is merely speculative.
Eighteen patients were reviewed 7 to 23 years after prolonged unilateral testicular torsion. They had all undergone surgical untwisting with replacement of the nonviable testis in the scrotum during prepubertal period. Five patients were now married and had fathered one or more children. Thirteen patients were unmarried. There was absence of testis on the affected side in 14 of 18 patients. Four patients had severe testicular atrophy on the affected side (testicular volume less than 1 mL). The contralateral side showed either a normal testicular volume or a compensatory hypertrophy (testicular volume greater than 25 mL). Seminal analysis was done in 13 unmarried men and it was completely normal in 10 patients. Two patients had low sperm density but normal semen volume and motility. One patient had pathologic semen analysis. IgG and IgA specific mixed agglutination reaction (MAR) test did not show evidence of sperm autoantibodies in any patient. Our clinical experience shows that, after prepubertal torsion, the contralateral testis undergoes normal development. Furthermore, torsion in the prepubertal male does not cause autosensitization and diminished fertility in adult life.
Haploinsufficiency of SOX9, which encodes a homeodomain transcription factor, results in Campomelic dysplasia. Classical features of this disorder (e.g. skeletal dysplasia and 46,XY sex reversal) are in concordance with SOX9 expression profiles during human embryonic development. We report the robust expression of SOX9 throughout the pancreas during human embryogenesis, at levels of detection equivalent to the developing skeleton and testis. In the early foetal period, SOX9 expression declines and, in particular, is not apparent within the pancreatic islets. In keeping with this profile, examination of three cases with Campomelic dysplasia revealed abnormal pancreatic morphology. Epithelial cells were less densely packed within the mesenchymal stroma and islets less clearly formed with variable expression of hormone and beta cell markers. Taken together, these data indicate a novel potential role for SOX9 in pancreas development during human embryogenesis and early foetal life.
The mammalian sex-determining gene, SRY, was identified by positional cloning approximately 10 years ago. Since its discovery, intense research into this gene has been directed on two main fronts: elucidation of its function in development of the testis and examination of its singular evolutionary history. The role or SRY as the testis-determining factor (TDF) places it at a crucial point in the highly conserved morphogenetic process of vertebrate gonadogenesis. None of the genes that directly activate SRY nor any of its immediate downstream targets have yet been positively identified. Several genes, however, such as SF1, DAX1, and SOX9, whose spatial and temporal expression profiles overlap with that of SRY, are strongly implicated as co-regulators of gonadogenesis. Molecular genetic manipulation of these genes in mice has shown that they are indispensable to sexual development. Remarkably, its key position in this cascade of gene action has not protected SRY from strong yet poorly understood selective forces that have caused it to evolve rapidly in mammals. The evolution of SRY has been characterized not only by rapid sequence divergence within mammals, but also by structural changes such as intron insertion, gene amplification, and deletion.
Eukaryotic DNA methylation occurs exclusively at the 5'-position of cytosine and has been implicated in the regulation of gene expression. Using high-performance liquid chromatography, the methylation of testis DNA during its development, in different cell populations and during regulation by gonadotropic hormones, were studied. The 5-mC content of testis DNA increased significantly from days 30 to days 150, while in 2-yr-old testis 5-mC content decreased significantly. Among various populations of testicular cells, pachytene spermatocyte DNA contained a significantly high amount of 5-mC when compared to spermatogonia, spermatids and mature sperm DNA. However, the 5-mC content of elongated spermatids was significantly less when compared to the above four fractions. Administration of follicle stimulating hormone to immature rats caused hypomethylation of seminiferous tubular DNA while luteinizing hormone caused similar effects in Leydig cells. These results indicate that in testis, DNA methylation is differentially regulated during development and is controlled by gonadotropic hormones.
A 42 year old (46 XY) subject with 17-ketosteroid reductase deficiency was investigated. The patient reared as female, has developed masculine features (facial hair, male distribution of body hair, male body habitus, acne and clitoridomegaly) at about 15 years of age but never consulted. She married at 22 years and for 20 years thought to have a "normal" female sex life. Only when her 14 year old "niece" was investigated (1) and treated for similar problems she realized hers. She had a small phallus with perineal urethra, vaginal pouch absence of labia minora and undescended testis, no breast development. Baseline peripheral studies showed plasma testosterone (T) in the range of Tanner II stade of puberty (150 ng/dl), elevated delta 4-androstenedione (delta 4) (930 ng/dl) and estrone (E1) (33,5 NG/DL) LEVELS 6--8 times above normal, but subnormal estradiol levels. Increased basal gonadotropins showed an hyper-response to LHRH stimulation. Dynamic tests (ACTH test, Dexamethasone suppression, and hCG stimulation) showed that abnormal delta 4 and E1 were not of adrenal origin. In the spermatic veins delta 4 levels were extremely high (239 micrograms/dl) but T levels low (11.4 micrograms/dl). delta 4/T ratio in the spermatic vein was much higher than in the peripheral blood suggesting intact peripheral conversion of delta 4 to T. After castration all hormone levels returned to the range usually seen in agonadic male or female adults.
A receptor assay using [125I]bTSH-binding to guinea-pig testis membrane was developed. Unlabelled hCG and FSH inhibited [125I]bTSH binding. In patients with Graves' disease and in untreated hyperthyroid patients, almost all long-acting thyroid stimulators and thyroid-stimulating antibodies, respectively did not inhibit [125I]bTSH binding, which on the other hand was inhibited by thyroid stimulation blocking antibodies in patients with primary hypothyroidism. When the inhibitory effect on the binding of [125I]hCG and 125I-synthetic alpha-subunit peptide (alpha 26-46) of hCG to testis membrane was examined, bTSH resulted in a significant inhibition. However, all three kinds of TSH receptor antibodies had no inhibitory effect. This study demonstrated 1. interaction of alpha-subunit of TSH and hCG with the testicular receptor; 2. binding of thyroid stimulation-blocking antibody and lack of binding of thyroid-stimulating antibody to the testicular TSH receptor in spite of binding of these TSH receptor antibodies to the thyroidal TSH receptor, and 3. lack of binding of thyroid-stimulating antibody and thyroid stimulation-blocking antibody to the testicular gonadotropin receptor.
A reliable and uniform vascular perfusion fixation method for the testis has been developed by using an initial washout solution containing a vasodilator and an anticoagulant. This is followed by a brief fixation with a sodium phosphate buffered formaldehyde-glutaraldehyde solution of conventional strenght, and then a second more concentrated aldehyde fixative solution containing picric acid. The method takes into account some of the unique features of the vascular supply of the male genital tract for its favorable perfusion and fixation. The advantages of this method are: (1) consistently favorable preservation of the testis; (2) simple and inexpensive apparatus; and (3) stable and relatively innocuous stock solutions.
The transcription factors SF-1 and WT1 play pivotal roles in mammalian gonadal development and sexual differentiation. In human embryos, both SF-1 and WT1 are expressed when the indifferent gonadal ridge first forms at 32 days post-ovulation. As the sex cords develop - providing morphological evidence of testis differentiation - SF-1 localises predominantly to developing Sertoli cells in the sex cords, whereas WT1 retains a broader pattern of expression. Later, SF-1 localises predominantly to steroidogenic Leydig cells, and WT1 localises to the sex cords. In the ovary, SF-1 and WT1 transcripts persist in the gonadal ridge from the earliest developmental stages throughout the critical period of sex determination. These studies, which delineate for the first time the sequential expression profiles of SF-1 and WT1 during human gonadal development, provide a framework for understanding human sex reversal phenotypes associated with their mutations.
The onset and localization of P450(17-alpha)-hydroxylase (P450(17-alpha)) and P450 aromatase (P450arom) mRNA expression were studied in the gonads of chicken embryos at Days 4-9 of incubation by in situ hybridization analysis, and expression of both mRNAs was measured in the ovary and testis of the chicken after sexual differentiation by Northern and slot-blot analysis and was related to changes in concentration of 17-beta-estradiol (E2) in the gonad. In situ hybridization analysis showed the first detection of P450(17-alpha) mRNA at Days 5-6 of incubation in the genetic male and female gonads and the first detection of P450arom at Day 6.5 of incubation in the female gonad but none was detected in the male gonad. Both mRNAs were observed in the medullary cords of the gonad. Slot-blot analysis demonstrated that levels of P450(17-alpha) mRNA in the ovary remained high during the period between Day 10 of incubation and 7 days of posthatching, while those in the testis remained low at Days 10-14 of incubation but increased at Day 16 of incubation up to posthatching days. Levels of P450arom mRNA in the left ovary were invariably higher than those of the right ovary and testis throughout the period between Day 10 of incubation and 7 days of posthatching. These results suggest that expression of P450arom mRNA occurring in the genetic female gonad around Day 6 is associated, at least in a part, with sexual differentiation toward femaleness by increasing E2 production which may promote cellular proliferation of the left gonad. In contrast, in the genetic male gonad marked expression of P450(17-alpha) mRNA with little expression of P450arom mRNA may lead to production of androgen which promotes the gonadal development to the testis.