John E. Allison

Part I. Male Pseudohermaphroditism in the Laboratory Norway Rat1

Publisher Summary This chapter presents an analysis of male pseudohermaphroditism in the rat with regard to anatomic, embryologic, genetic, and physiological considerations. The anomaly is transmitted genetically by female carriers to one-half of their male offspring. In addition, one-half of the female offspring of an affected sibship become carriers. Affected males exhibit, in general, a female phenotype characterized by the presence of a blindly ending vaginal recess and mammary line but lack both Mullerian and Wolffian duct systems. Embryologic studies show normal development of Wolffian and Mullerian duct systems up to day 17 in utero, at which time disintegration of these structures takes place. Hence, a male inductor system seems not to be involved, but rather a maintenance factor without which disintegration of the ductal system results. The lack of androgen sensitivity demonstrated in these animals appears to be a reasonable explanation in light of present information. Spermatogenesis does not progress beyond the primary spermatocyte stage in the testes of the pseudohermaphrodite. The interstitial cells show marked proliferation, an indication of gonadotropin stimulation.

Ultrastructural and biochemical characteristics of leydig cells from newborn androgen-insensitive rats

SummaryLeydig cells of the testis of newborn pseudohermaphrodite (tfm) rats have an ultrastructure similar to that of the normal, containing well developed organelles and inclusions. The cytoplasm is filled with smooth endoplasmic reticulum forming a network of interconnected tubules. Lipid droplets are surrounded by cisternae of smooth endoplasmic reticulum and are in close association with pleomorphic mitochondria. Many of the latter are cup-shaped and have tubular cristae and intramitochondrial dense bodies.Essentially, these are characteristics of normal Leydig cells. Accordingly, the production of testosterone by testes from newborn tfm rats is the same as that by testes from normal newborns and adults. However, it is significantly higher than that by testes of tfm adults. Also, the plasma testosterone levels of newborn tfm rats are the same as in the normal newborn, but lower than in normal adults and much lower than in adult tfm animals.Thus, since in the tfm rat the morphology of Leydig cells, androgen production, and maintenance of plasma levels of testosterone are normal in the newborn, but become abnormal with advancing age, it appears that defective androgen action rather than insufficient androgen production is the cause of male pseudohermaphroditism.

Structural and functional abnormality of ectopic testes in rats

Some males of a mutant strain of King-Holtzman rats exhibit an anomalous heritable defect manifested as either unilateral or bilateral ectopic testes. In the adult, these testes contain seemingly immature Sertoli and Leydig cells, seminiferous tubules greatly reduced in diameter, and exhibit arrested spermatogenesis. Thus, the affected testis is essentially sterile. An inability to produce normal amounts of testosterone and androstenedione by these gonads is probably a reflection of changes that have been effected in their Leydig cells. Thus, this study suggests that abnormal function of the Leydig and Sertoli cells and seminiferous tubule failure in these mutant animals result from the physiologically cryptorchid condition.

Androgen receptors in the brain of neonatal normal male and androgen insensitive rats.

Androgen binding was investigated in the cytosol of brains from neonatal normal and tfm rats using sucrose gradient and charcoal assay. The neonatal normal rat brain contains androgen receptors which sediment at 8S in a sucrose gradient at low ionic strength and at 4S in the presence of 0.5M KC1. These receptors have a high affinity (Kd = 1.2 X 10(-9)M) for dihydrotestosterone (DHT), with a binding capacity of 7.3 X 10(-15) moles/mg cytosol protein. By contrast, there is very little, if any, high affinity androgen receptors in the neonatal tfm rat brain. Apparently, metabolism of testosterone does not affect androgen binding in the neonatal rat brain. The presence of these receptors and the occurrence of aromatization in the brain of neonatal rats are discussed in relation to their possible roles in sexual differentiation of the brain.