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PubMed2004

Alterations of sex differentiation in males: from candidate genes to diagnosis and treatments.

Sex, that is, whether one is physically male or female, is the basic dichotomy of life. Sex is important not only for reproductive role, but also for physical attributes, personal identity and disease susceptibility. Sex determination is genetically controlled, with the key event in males being the transmission of a Y chromosome from father to offspring. The sex-determining gene on the Y chromosome, SRY, triggers the expression of a repertoire of other genes that cause the undifferentiated gonad to develop as a testis. Hormones secreted by the developing testis cause the internal and external genitalia to masculinize. Testicular development is disrupted by de novo or inherited genetic alterations leading to gonadal dysgenesis. Decreased hormone production from dysgenetic testes disrupts the normal development of the internal and external genitalia. Incomplete masculinization of the genitalia also occurs from hormonal biosynthetic defects or decreased response to hormones from inherited receptor defects. Treatment is tailored to the individual diagnosis and may include removal of dysgenetic gonads, surgical correction of incompletely masculinized genitalia, replacement of deficient hormones, and, in some instances, gender reassignment.

Disorders of Sex Development↗
PubMed1987

Ca2+-binding parvalbumin in rat testis. Characterization, localization, and expression during development.

Parvalbumin, a Ca2+-binding protein, was isolated from rat testis. This is the first demonstration of the protein in endocrine glands. By using a rat parvalbumin cDNA probe, parvalbumin mRNA was demonstrated in the testis, indicating that the protein is synthesized in this tissue and that testis parvalbumin is a product of the same gene as the one encoding for muscle parvalbumin. Parvalbumin was localized by immunohistochemical methods in the Leydig cells and in the acrosome region of maturing spermatids (stages 1-15). The expression of parvalbumin during testis development was followed. High parvalbumin protein and mRNA levels were found at stages of highest Leydig cell activity, i.e. at late fetal stages until birth and again around postnatal day 50. This suggests that parvalbumin may be involved in the production of testosterone in Leydig cells, a process which is highly dependent on calcium.

Acrosome↗
PubMed1999

Cellular immunolocalization of occludin during embryonic and postnatal development of the mouse testis and epididymis.

Cellular junctions in the testis and epididymis play crucial roles for the development and maturation of spermatozoa. In the testis, tight junctions between Sertoli cells form a functional blood testis barrier between 10 and 16 days of age, whereas the tight junctional blood epididymal barrier between adjacent epithelial cells is formed between days 18 and 21. In the present study, occludin, a constituent integral membrane protein of tight junctions, was localized by immunofluorescent confocal microscopy in embryonic (days 13.5-18.5), postnatal (days 5-23) and adult (day 70) mouse testes and epididymides to correlate its expression with the onset of tight junctions and eventual formation of these barriers. At embryonic days 13.5 and 16.5, low diffuse cytoplasmic levels of occludin were observed in cells of the testicular cords. By embryonic day 18.5, the level of occludin was still low but appeared as a filiform-like network streaming toward the center of the cord. At postnatal days 5 and 7 immunostaining became more intense and appeared to outline the periphery of Sertoli cells of seminiferous tubules. Postnatal day 14 marked the appearance of an intense, focal band-like localization of occludin at the base of the tubules, correlating with the appearance of a functional blood-testis barrier. By day 23 and in adults, expression of occludin was noted at the base of the tubule appearing as intense, wavy, discontinuous bands similar in appearance irrespective of the stage of the seminiferous epithelium cycle. In the developing epididymis, intense cytoplasmic immunostaining was present in epithelial cells of many epididymal tubules at embryonic day 13.5. By embryonic day 16.5, intense occludin immunostaining appeared along the lateral plasma membranes of epithelial cells, whereas at embryonic day 18.5, immunostaining was punctate and apically located, suggesting the presence of tight junctions by this age; similar immunostaining was noted at postnatal days 5 and 7. In the adult epididymis, distinct punctate apical staining was observed between adjacent principal cells of all epididymal regions except the proximal initial segment, where occludin was found only in association with narrow cells. These results indicate that in the epididymis, the appearance of occludin at apical sites between adjacent epithelial cells occurs during embryonic development suggesting that tight junctions form earlier than in the testis. While occludin was expressed in a similar pattern between Sertoli cells at all stages of the cycle in the adult testis, its expression in the adult epididymis was cell- and region-specific. Taken together these data suggest that different factors regulate occludin expression in the testis and epididymis.

Aging↗
PubMed2002

Post-natal development of the rat testis: steroid hormone receptor distribution and extracellular matrix deposition.

The control of testicular development and differentiation depends on hormones and a variety of cell-cell interactions mediated mainly by paracrine factors. In the second and third weeks of post-natal development important changes take place in the rat testis, e.g. the tubular lumen starts to open on post-natal day 10, the blood-testis barrier starts to form on day 15, and Sertoli cell proliferation ceases on day 15. In the present study the expression in different testicular compartments of the androgen receptor (AR), progesterone receptor (PR), and extracellular matrix proteins such as laminin, entactin-1 (nidogen-1) and fibronectin, during post-natal development was examined using immunohistochemistry and semiquantitative image analysis. An intratubular AR peak on days 14-17, an increase in intratubular PR expression on days 14-16, and an increase in peritubular entactin-1 expression during the second and third weeks post-partum are demonstrated. These results suggest that a variety of changes occur at the cellular level during this period when certain milestones of testicular development occur, substantiating the hypothesis of a particular role for paracrine interactions during the development of the rat testis.

Aging↗
PubMed1984

Changing concepts in the treatment of nonseminomatous germ cell tumors of the testis.

The development of effective chemotherapy for advanced nonseminomatous germ cell tumors of the testis has changed dramatically the outlook for this once uniformly fatal disease. We reviewed our experience with changing modalities of therapy during a 7-year period in the treatment of 152 patients with all stages of testis tumor. Survival rates have increased from 84 per cent for patients with stage A, B1 or B2 tumors treated with sandwich irradiation therapy and retroperitoneal lymph node dissection to 100 per cent for patients with node dissection with or without chemotherapy. Survival rates continuously free of disease for patients with advanced (stage B3 or C) disease have increased from 53 per cent in 1975 to 1977 to 82 per cent by the addition of platinum-based polychemotherapy and judicious lymphadenectomy. A unified plan of management for patients with low stage and advanced stage nonseminomatous testicular tumors has evolved.

Antineoplastic Agents↗
PubMed1995

Ontogenesis of somatic and germ cells in sheep fetal testis.

Testicular development of sheep fetuses was studied between day 42 of gestation and birth. Testis mass and the total number of testicular cells increased curvilinearly with fetal age and a positive linear relationship was established between the logarithmic values of age and testis mass, sex cord total length, total number of Sertoli cells, germ cells and Leydig cells per testis. The mean number of gonocytes per unit length of sex cord, the Sertoli cell nuclear cross-sectional area and the Leydig cell cross-sectional area decreased linearly with age between day 42 of gestation and birth. Hypophysectomy and hemicastration were performed to study the regulation of testicular cell divisions during fetal life and to determine whether they were under pituitary control and whether a feedback mechanism was present. Hypophysectomy at day 100 or 110 of gestation nonsignificantly decreased (0.05 < P < 0.01) the testis mass, total length of sex cords and total number of Sertoli cells and significantly decreased (P < 0.05) the cross-sectional area of Leydig cells and nuclei of Sertoli cells. Sex cord diameter and total number of gonocytes were unaltered. Hemicastration at day 110 of gestation significantly increased (P < 0.05) the total number of Leydig cells per testis without changing any other testicular parameter. In male sheep fetuses, the proliferation of testicular somatic and germ cells occurs throughout testicular fetal growth at a higher rate before day 100 of gestation than later, but without any differentiation. Mitotic divisions of Sertoli cells are more numerous before birth than afterwards. Before birth, the proliferation of gonocytes is not under pituitary control.

Animals↗
PubMed1981

Germ cell kinetics in the neonatal rabbit testis.

Germ cells in the developing rabbit testis were found to undergo several distinct changes in the first two weeks after birth. Mitotic activity, which had been high in the late fetal period, reached a peak on the day before birth, then diminished steadily and ceased entirely after five days of age. Extensive germ cell degeneration occurred in the first week after birth resulting in accumulation of pools of degenerating germ cells in the central portions of the cells at various stages of preleptotene could be found in squash preparations. This corresponded to the time when germ cells in the rabbit ovary enter and proceed through meiotic prophase. There was no evidence of entry into leptotene or later stages of meiosis in the neonatal testis. The findings suggest that a similar stimulus for entry into meiosis may exist in both sexes, but a blockage occurs in the male.

Animals↗
PubMed1998

[The development of the horse testis].

The aim of the study was to answer the open questions concerning the development of the horse's testis. This study revealed that the seminiferous tubules originate from the sex cords of the coelomic epithelium and Leydig cells from the proximal part of mesonephric nephrons, whereas the rete and the ductuli efferentes derive from intermediate and distal parts of the mesonephric tubules. During the development the Leydig cells undergo an enormous proliferation due to the PMSG secretion in the mare. The proliferation of these cells prevent the deep penetration of the rete into the medulla and is therefore the reason for the reduced extension of the rete and mediastinum testis in the stallion, although 80% of these cells degenerate in the last third of pregnancy. The growth of the seminiferous tubules during sexual maturity reduces the rete to the extremitas capitata of the testis.

Animals↗
PubMed1978

Genetic aspects of the hormonal regulation of some testis enzymes during pubertal development of the rat.

Using a rat model, it was shown that the synthesis of certain testis enzymes during pubertal development is under hormonal control, which acts as regulatory mechanism for gene expression during eukaryotic differentiation. Esterase activity and its electrophoretic banding pattern can be specifically induced by human chorionic gonadotrophin (HCG). Alcohol dehydrogenase and 3beta-hydroxysteroid dehydrogenase are independently induced by HCG, and are apparently coded for by 2 different genetic cistrons.

3-Hydroxysteroid Dehydrogenases↗
PubMed1977

The effect of 5-bromodeoxyuridine on the postnatal development of the rat testis.

The effects of 5-bromodeoxyuridine (BrdU) on postnatal testicular development were studied in rats treated on the second, third and fourth days of life. Testes were removed for study at 5, 15 and 35 days of age. Body weights and diameters of seminiferous cords and tubules were significantly less in the treated than control animals. At 15 days of age fewer pachytene spermatocytes were present in treated animals. At 35 days of age the testes of treated animals contained fewer canalized cords. Spermatids exhibited an altered distribution of chromatin material, contained less agranular endoplasmic reticulum and fewer mitochondria, and had not yet developed tails. Sertoli cells and Leydig cells of treated animals contained less agranular endoplasmic reticulum and more lipid droplets than the normal.

Age Factors↗
PubMedDate not supplied

LH/hCG receptors and stimulation of testosterone biosynthesis in the rat testis: changes during foetal development in vivo and in vitro.

The development of gonadotropin receptors to LH/hCG in the foetal rat testis from 14 to 20 days of gestation was monitored by quantitative binding assays using [125I]hCG and compared to testosterone secretion under basal and stimulated conditions in vitro. Specific hCG binding was first detected on day 15. Thereafter the binding increased gradually with advancement in gestational age and correlated with LH-stimulated secretion of testosterone in vitro. On day 18 of gestation the KA was 0.82 x 10(10) M-1 and the binding capacity was 0.57 fmoles per testis. No binding was detectable in the female gonads at this age. The differentiation of hCG receptors obtained in vitro was very low, although it was sufficient to give a full response to LH with testosterone biosynthesis. The results of the present study suggest that functional receptors do not appear before the capacity to synthesize testosterone is expressed and that their appearance is not dependent on factors extrinsic to the testis. However, additional factors could be necessary for a full development of the receptors.

Animals↗
PubMed1981

Importance of the episodic nature of luteinizing hormone secretion for normal development of the bovine testis during puberty: interference with oestradiol-17 beta.

An experiment was conducted to determine the importance of episodic LH secretion during pubertal development in beef bulls. Testicular growth, LH secretory patterns and serum testosterone concentrations were monitored in control bulls, and bulls implanted with one or two oestradiol-filled capsules from 26 to 38 weeks of age. Control but not oestradiol-treated bulls showed normal testicular growth and episodic LH secretory patterns. Serum LH and testosterone responses of 38-week-old control and oestradiol-treated bulls to an intravenous challenge of 5 micrograms LH releasing hormone indicated normal pituitary responsiveness, but steroidogenic responsiveness had not yet developed in oestradiol-treated bulls. Removal of the capsules at 38 weeks of age resulted in a normal episodic release pattern for LH, with concomitant growth of the underdeveloped tests up to 44 weeks of age. Serum concentrations of LH and testosterone were within the range of normal, adult values by 42 weeks of age. These results suggest that oestradiol can interfere with episodic LH secretion and normal pubertal development in beef bulls, and furthermore that episodic LH secretion is commensurate with the establishment of normal development of the bovine testis during puberty.

Animals↗
PubMedDate not supplied

Expression and localization of total Akt1 and phosphorylated Akt1 in the rat seminiferous epithelium.

Akt1 is a survival factor that is believed to play a role in the transcriptional modulation of a subset of genes associated with cell growth, proliferation, and apoptosis. We have explored in detail the expression of total Akt1 and phosphorylated Akt1 in the developing and adult rat testis. Throughout testis postnatal development, the expression of total Akt1 protein exhibited a mainly cytoplasmic localization within both the germ cells and the supporting Sertoli cells. In contrast, phosphorylated Akt1 staining demonstrated a mainly nuclear localization within germ cells. In the developmental sequence of germ cells, phosphorylated Akt1 stained the nuclei of spermatogonia, spermatocytes, and round spermatids. During spermiogenesis, phosphorylated Akt1 staining decreased in the nucleus and became localized to a bright spot at the base of the nucleus in elongate spermatids. Of interest, total Akt1 was found to localize to the perinuclear region of germ cells and the supranuclear region of Sertoli cells, depending on fixation. Further analysis demonstrated this staining to be associated with the Golgi complex in both germ and Sertoli cells.

Aging↗
PubMed1996

The rat thymus contains a heparin-binding factor that modulates steroidogenesis in the testis.

Thymus development and function are under the influence of hormones secreted by the gonads and pituitary. On the other hand, thymus is crucial for the development of reproductive capacities in female and male rats and we have shown that a factor derived from the prepubertal rat thymus has antigonadotropic effect in ovarian and testis cells in vitro. In the present paper we show that the rat thymic factor which modulates gonadotropin action in the gonads is an heparin-binding factor. This capacity was also used as a useful tool to obtain this activity from semipure extracts. An acetone extract was prepared from 15 day old male rats and subjected to molecular filtration chromatography. The activity, of those fractions was investigated in a testis cells bioassay, by measuring testosterone secretion under basal and hCG-stimulation. Active fraction were processed in an heparin-Sepharose affinity column. We found that fractions that eluted with 0.6 and 2M NaCl/10mM Tris had biological specific activity. The electrophoretic procedure showed that the apparent molecular weight of the Heparin Sephadex binding factor is 60 kDa. Since this factor was obtained from a protein peak that eluted in the volume of carbonic anhidrase a dimerization process could be involved. Present results show that the rat thymus has an heparin-binding factor that interacts with hCG in testis cells. This factor could play an interesting role in the mutual influence between thymus and gonads.

Animals↗
PubMed2005

The undescended testis.

Testicular development is determined by the influence of the SRY gene on the Y chromosome of the fetus. This influences the germ cells to produce testosterone and Mullerian inhibiting substance which control descent of the testis. Maldescent of the testis occurs in 0.8% of boys. Current best advice is to perform orchidopexy before the age of two years, therefore a programme for examination by skilled healthcare workers should be established in the first year of life. Indications for surgery include a possible beneficial effect on fertility, malignant potential particularly if intra-abdominal, torsion or trauma and social considerations. Hormonal treatment in the first three months of life is recommended by some. Laparoscopy is the optimum method for evaluating and managing the intra-abdominal testis.

Cryptorchidism↗
PubMed1987

Expression of hsp70-related gene in developing and degenerating rat testis.

Rat testes contain highly elevated levels of 2.5 kb RNA transcribed from a heat shock (hsp70) related gene. In the present paper northern blot analysis was used to follow the changes in the 2.5 kb transcript level during the postnatal development of rat testis and during the degeneration of the seminiferous epithelium in adult rats caused by experimental cryptorchidism. The 2.5 kb transcript was undetectable in newborn rats until the 3rd week of life. The level of the transcript reached a maximum at the 4th week and remained unchanged from that point on. Two days after the surgical translocation of the testes from the scrotum into the abdominal cavity the level of 2.5 kb transcript rapidly declined. Presented results strongly suggest that the hsp 70-like gene coding for the 2.5 kb RNA is specifically expressed in germinal cells, most probably in the spermatocytes.

Animals↗
PubMedDate not supplied

PDGF and the testis.

Testicular development is controlled by a complex hierarchy of gene regulatory proteins, growth factors, cell adhesion molecules, signaling molecules and hormones that interact, often acting within short time windows, via reciprocal control relationships. The identification in the testis of platelet-derived growth factor (PDGF), a key regulator of connective tissue cells in embryogenesis and pathogenesis, has focused attention on the role of this growth factor in testicular pathophysiology. This review summarizes recent advances in the study of the actions of PDGF in the male gonad, and attempts to incorporate complex in vitro and in vivo experimental data into a model that might clarify the role played by PDGF in the mammalian testis.

Aging↗