VIth ICA - Symposium - Testicular Toxicology (1996)
Richard Sharpe (UK) introduced the potential of environmental chemicals to have hormonal effects in the male, as exemplified by DDE, the metabolite of DDT and a potent androgen receptor antagonist, and by environmental estrogens. The estrogen receptor (ERa) is expressed in the rat fetal Leydig cell, not in the seminiferous tubule, and may be the site at which exogenous estrogens interfere with T production. For example, if pregnant rats are given estrogens on day 17, when testosterone production is at its maximum, 17a-hydroxylase levels are specifically reduced without change in Leydig cell numbers. This effect is associated with a reduction in expression of steroidogenic (transcription) factor-1 indicating that estrogen brings about a reduction in the transcription of 17a-hydroxylase. ERa is also expressed in the Leydig cells of the adult but to a lesser extent than in the fetus and is one site of action of DES and tamoxifen. Treatment of adult rats with aromatase inhibitor (Anastrozole) leads paradoxically to an apparent decrease in Leydig cell numbers. Neonatal treatment with DES reduces adult testis size and daily sperm production in some phenotypes whereas in others it may lead to Sertoli cell-only testes and complete atrophy. Finally, Dr. Sharpe indicated that the efferent ducts are an important site at which estrogens may regulate fluid resorption.
HO Adami (Sweden) reviewed the rapid and variable increases in the incidence of testicular cancer and explored some of the possible causal factors. Drawing on data from some 34,000 cases registered in nine cancer registries in countries around the Baltic Sea, he described a 10 fold variation in the incidence between countries, the lower rates being in Finland and the Baltic countries and the highest in Denmark. In general, there was a doubling every 15-20 years, which is unusual in cancer incidence. Men born around 1960 experience about a 5 fold increased risk compared to those born at the turn of the century. In East Germany, Poland, and Finland, the comparison was about 7 fold increased risk. Peak incidence occurred in the age range 25-35 years. It was concluded that major etiologic factors operated early in life, perhaps even in utero. Testicular cancer is seen more on the right side and cryptorchidism carries a 5-10 fold increased risk. Ethnicity is important as exemplified by the considerable higher incidence among the high risk white versus the low risk black US population. Other potential factors were considered to be: ionizing radiation and environmental estrogens; and some pesticides. Finally, a case-control study was undertaken to abstract data from birth records of men born at different locations in Sweden between 1920 and 1978 with follow up to 1994 to look for perinatal factors in risk patterns. Birth weight, placental weight and neonatal jaundice were apparently involved.
The third speaker, E. Clegg (USA) described a prospective human study planned to predict the relationships between various measurements of sperm production and function and male fertility. A total of 210 couples were recruited who were discontinuing contraception in order to achieve a pregnancy. The mean age of the men was 32.3 years and of the women 30.6 years; the female age limit was 38 years and 52.5% were nulliparous. The men provided two semen samples after 36-48 hour abstinence which were analyzed for volume, sperm concentration, motility and morphology by both WHO and strict criteria. Pregnancy occurrence, time to conception, and incidences of clinical occult pregnancy loss were recorded. Overall, 116 (58%) achieved pregnancy during the first 3 cycles and 163 (82%) during the 12 month study period. Pregnancy loss rates varied between 29 and 33% during cycles 1-3. In relating the various semen parameters with pregnancy outcome, preliminary analysis suggests that the percentage and total number of spermatozoa with normal morphology by strict criteria were highly predictive of fertility. Adding percent normal morphology to percent motile significantly increased the predictive value. There was widespread belief that the data from this study, once fully analyzed, will be invaluable in identifying the sperm function measurements predictive of fertility.
Geoffrey Waites, Switzerland