Early Reacting Tissues: The Testes

Abstract

1. The two functions of the testes (spermatogenesis and formation of testosterone by Leydig cells) are under homeostatic control. The luteinizing hormone (LH) formed by the anterior pituitary stimulates the Leydig cells to form testosterone which helps to maintain spermatogenesis, exerts a negative feedback on secretion of LH and has sexual functions. The follicle stimulating hormone (FSH) of the pituitary activates the seminiferous tubule and induces release of an androgen binding protein (ABP) by the Sertoli cells. The latter also secrete inhibin which modulates the secretion of FSH. Sertoli cells also provide a microenvironment for development, maturation and release of germ-cells. 2. Spermatogenesis starts by stem-cells represented by A-dark (Ad) spermatogonia which are dormant reserve cells. They are activated into the proliferating A-pale (Ap) spermatogonia having a long Tc (16 days). They give rise to B-spermatogonia (Tc of 8.3 d) which undergo 4 amplification divisions. Maturation starts by the primary spermatocyte and ends by spermatozoa with two intervening meiotic divisions. The transit time from stem-cells to spermatozoa amounts to 67 days. 3. Spermatogenesis is more sensitive in man than in most animals. The 8-spermatogonia are more radiosensitive than Ap due to a shorter Tc with a smaller proportion of cells in the radioresistant phases of the cell cycle. Ad spermatogonia do not express radiation damage except after activation when they die in mitosis. The radiosensitivity of spermatocytes and spermatids is much lower than that of spermatogonia. 4. After a dose up to 3.0 Gy oligospermia or azospermia develops after 67days(corresponding to the transit time). This may occur earlier after higher doses due to direct killing of spermatocytes and spermatids. A dose of 8.0 Gy produces azospermia in nearly all men. 5. Recovery is very slow in man. It requires more than 6 months after 1.0 Gy and can be delayed for 2 or more years after 6.0 Gy. Even after recovery of the sperm count, infertility or miscarriage may occur due to the production of sperms of low quality or with genetic anomalies. 6. Fractionated irradiation is more effective than single doses principally due to the existence of a large proportion of radioresistant stem-cells. Due to their position in the cell cycle, they are difficult to sterilize by a single dose. This can account for long-lasting azospermia after relatively small daily doses of scattered radiation reaching the testes during pelvic irradiation. It also accounts for the sensitivity of the testes to low dose-rate irradiation and occurrence of testicular dysfunction after years of occupational exposure. 7. Leydig cell function can be monitored by measurement of the testosterone or LH serum levels. The function of Sertoli cells may be estimated directly by measuring the ABP level or indirectly through FSH assay. Both cells are relatively radioresistant in rodents but are more sensitive in man. A dose of 0.10 to 6.0 Gy is followed by an increase in urinary gonadotrophin and elevation of serum LH and FSH levels. The Leydig cells are more sensitive in pubertal rats than adults. This may explain the severe damage following testicular irradiation during childhood which often requires the administration of replacement therapy in order to achieve normal development of puberty. 8. Chemotherapeutic agents can also damage spermatogenesis and Leydig cell function. Phase—specific drugs may kill differentiating spermatogonia with relative sparing of stem -cells. Hence spermatogenesis can recover rapidly. But alkylating agents can injure stem cells and hence damage is more long lasting and can be permanent. A synthetic analogue of the LH-releasing hormone can protect against cyclophosphamide but not radiation damage.