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Management of the undescended testis in relation to the development of cancer.

The undescended testis carries an increased risk of cancer; however, the exact individual risk of a cryptorchist during his life to develop cancer is unknown. The risk of developing cancer can be calculated from three important figures: (a) the number of cryptorchists in the population; (b) the number of malignant testicular tumors found in undescended testicles; and (c) the number of testicular tumors per annum. In the literature, a 48 times increased chance to develop testicular cancer is accepted; it is a high risk which is contrary to the fact that a malignant cryptorchid testis is a very rare disease. Based on the estimated risk for the cryptorchist in the Netherlands to develop testicular cancer, this article criticizes the value of the figures that are generally used to calculate the individual risk; it is concluded that even today the exact risk is unknown. In giving advice concerning the management of undescended testis, one must appreciate not only the supposed cancer risk, but also take into consideration morbidity and mortality after prophylactic orchidectomy and improved cure rates after electively treated testicular tumors.

Adolescent

Effect of thyroid hormone on the pre- and post-natal development of the rat testis.

The relationship between thyroid function and testicular development in the rat was investigated. Hypothyroidism was induced during fetal or post-natal life by adding methimazole (MMI) to the drinking water of pregnant or lactating mothers. A group of newborn rats was treated with MMI and i.p. injections of L-tri-iodothyronine (L-T3). Hypothyroidism was shown by the reduced serum levels of total T3 and of total thyroxine (T4) in pregnant mothers and in pubertal rats. Testes were studied using light microscopy at 18 and 21 days post coitum or during puberty (21, 35 and 50 days after birth); serum levels of gonadotrophins were also evaluated in pubertal rats. Hypothyroidism had no effect on testicular development during fetal life and when induced in newborn rats it was associated at puberty with reduced serum levels of FSH and LH and with delayed maturation of the testis compared with control rats. The delay in maturation consisted of a reduction in the diameter of seminiferous tubules, and a reduction in the number of germ cells per tubule; this was associated with increased degeneration and arrested maturation of germ cells. In addition, Sertoli cells demonstrated retarded development, as indicated by a delay in the appearance of cytoplasmic lipids and in the development of a tubule lumen. Hormonal and morphological abnormalities were absent in rats treated with MMI plus L-T3. In conclusion, hypothyroidism occurring soon after birth caused reduced levels of gonadotrophins in the serum and a delay in pubertal spermatogenesis, possibly due to retarded differentiation of the Sertoli cells.

Animals

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

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

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

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

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

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

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

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

Onset of the response to chorionic gonadotropin in the chick embryo testis.

The stage of development of the chick embryo testis when it begins to respond to gonadotropin stimulation was investigated. The testosterone secretion in vitro, measured by radioimmunoassay, was employed to evaluate the response to hCG in testis from 8 to 16 days of incubation. At 8 to 10 days of the chick embryo development, the testis secreted testosterone, but no increment in the steroid production has been observed after hCG treatment. On the contrary, at 12, 14, and 16 days a clear increase in testosterone secretion has been demonstrated when hCG was added to the culture medium. The absence of hCG response before 12 days of incubation agrees with the hypothesis of an early independence period between testis and adenohypophysis during embryonic development.

Animals

Changes in fine structure accompanying estrogen-induced tumorigenesis of Leydig cells in the mouse testis.

The development of estrogen-induced Leydig cell tumors in cryptorchid BALB/c mice was studied with the electron microscope. Changes in Leydig cell fine structure are apparent by 10 days after the s.c. implantation of a pellet of diethylstibestrol (DES). The smooth endoplasmic reticulum is diminished, and there is an increase in lipid droplets and free polysomes as compared with untreated cryptochid controls. These alterations persist as the Leydig cells proliferate to form focal areas of hyperplasia in the interstitial tissue. During this period of proliferation, activated macrophages containing large residual bodies appear among the Leydig cells. If DES treatment is continued for several months, malignant Leydig cell tumors, result. They are characterized by a nuclear and cytoplasmic pleomorphism of the Leydig cells and a decreased macrophage population. Virus-like particles are rarely seen within the cell during the period of tumorigenesis. Along with the reduction in smooth endoplasmic reticulum in the Leydig cells after DES treatment, evidence from the literature suggests that there is also a decrease in testosterone biosynthesis. However, it is not clear whether these two effect are correlated, since the level of the microsomal enzymes of steroid biosynthesis may vary independently of either the amount of smooth endoplasmic reticulum or the level of androgen secretion. The increase in lipid droplets seen in Leydig cells after DES treatment suggest the accumulation of precursors from the steroid biosynthetic pathway. The macrophages are though to represent scavenger cells, rather than a primary tumor cell population. The paucity of virus-like particles within altered Leydig cells implies that formed virus is not a prerequisite for tumorigenesis.

Animals

5 Alpha- and 5 beta-reductases for 4-ene-3-ketosteroids and 17 beta-ol-dehydrogenase in epididymis and testis of golden hamster during sexual development.

Homogenates of the epididymis, testis and seminal vesicle from 15, 25, 35 and 60-day old golden hamsters were incubated with [3H]4-androstene-3,17-dione and NADPH and enzyme activity was estimated. In the testis, activities of 5 alpha- and 5 beta-reductases were the highest (32 +/- 4 and 68 +/- 13 (SD) nmol/100 mg protein/h, respectively) at 25 days of age, moderately high at 35 days and very low (1-3 and 5-6, nmol/100 mg protein/h, respectively) at 15 and 60 days. In the epididymis, 5 alpha-reductase activities increased with age during sexual development by up to 50-fold and reached the maximum value (40 +/- 11 nmol/100 mg protein/h) at 60 days. The 5 alpha-reductase activities in the seminal vesicle were found to be relatively low (0.5-1 nmol/100 mg protein/h), compared with those in the epididymis and testis. Activities of 5 beta-reductase in the epididymis and seminal vesicle were very low (0.1-0.5 nmol/100 mg protein/h) at all ages. These results indicate the existence of a marked, but transient, increase in 5 alpha- and 5 beta-reductase activities during immature period in the testis of golden hamster. In the epididymis, however, 5 alpha-reductase activity increases with age during sexual maturation, while 5 beta-reductase activity is almost undetectable at all ages.

17-Hydroxysteroid Dehydrogenases

Expression of a candidate sex-determining gene during mouse testis differentiation.

The development of a eutherian mammal as a male is a consequence of testis formation in the embryo, which is thought to be initiated by a gene on the Y chromosome. In the absence of this gene, ovaries are formed and female characteristics develop. Sex determination therefore hinges on the action of this testis-determining gene, known as Tdy in mice and TDF in humans. In the past, several genes proposed as candidates for Tdy/TDF have subsequently been dismissed on the grounds of inappropriate location or expression. We have recently described a candidate for Tdy, which maps to the minimum sex-determining region of the mouse Y chromosome. To examine further the involvement of this gene, Sry, in testis development, we have studied its expression in detail. Fetal expression of Sry is limited to the period in which testes begin to form. This expression is confined to gonadal tissue and does not require the presence of germ cells. Our observations strongly support a primary role for Sry in mouse sex determination.

Animals

Loose connective tissue of rat rete testis. Fine structure, postnatal development and effect of efferent duct ligation.

Fine structure, postnatal development and reaction to efferent duct ligation of the loose connective tissue of the rat rete testis were studied by light and electron microscopy. The loose connective tissue of adult rats consists of elongate fibroblasts in a homogenous ground substance, together with some Leydig cells, lymphocytes, macrophages and mast cells. During postnatal development this tissue increases in amount, while the interstitial areolar tissue decreases. The "looseness" of the tissue becomes more evident between days 22 and 27, and may reflect an increase in hydration. Efferent duct ligation for 15 min to five days has no effect on the histological appearance of the tissue.

Animals

Cytoplasmic filaments in fetal and neonatal pig testis.

Leydig cells in developing fetal pig testis contained during the fetal regressive phase large accumulations of intermediate filaments. Before and after this period these filaments were arranged in a criss-cross fashion. In the pig as well as in the dog testis these filaments have been characterized as vimentin. Within the vimentin aggregates occasionally a weak positive actin reaction was seen in pig but not in dog Leydig cells. Microfilaments were hardly observed. Most Sertoli cells contained a layer of actin microfilaments close to the basal cell membrane. In the lower cell compartment and around the nucleus (intermediate) vimentin filaments could be observed in a criss-cross configuration.

Aging