Influences of anabolic androgens on cardiac growth and metabolism in the rat.

Testosterone, and to a lesser degree methandrostenolone, was shown to influence cardiac growth in immature male rats by affecting protein synthesis and degradation. The nature of cardiac responses to androgen appear to depend on the prevailing experimental conditions. Protein synthesis was inhibited in the castrate rat and was stimulated by subsequent treatment with androgen. Under conditions of induced overgrowth of the ventricles, androgens gave rise to an attenuation of the effects of aortic constriction on ventricular mass and blood pressure involving smaller changes in protein synthesis and proteolysis. Concentrations of testosterone receptors in ventricular cytosol further indicated that the myocardium is more sensitive to androgen action during the prepubertal phase of the life-span. Changes in amount and properties of the receptors showed them to be functional and responsive to castration, aortic constriction, and administration of the androgens. The androgens affected cardiac protein balance by stimulating the incorporation of radiolabelled amino acid into protein in vivo. They also appeared to influence proteolytic processes involving lysosomal hydrolase activities, but their actions were either stimulatory or inhibitory depending on the internal environment. The heart is a target organ for several hormones including androgen, and our findings fortify the notion that hormone action needs to be investigated alone and in association with other endocrines.

Effects of steroids and cyclosporin A on compensatory renal growth and plasma electrolytes in rats.

The uninephrectomized rat presents a reasonable model for the kidney transplant patient and allows for the study of the actions of steroids and immunosuppressive agents under conditions of stimulated renal growth. Following 2 weeks of treatment, neither cyclosporin A nor corticosterone affected the growth of the remaining kidney. The degree of compensatory renal hypertrophy was inhibited to some extent by the administration of prednisone. Renal concentrations of protein and nucleic acids were relatively uninfluenced by these agents, compared with uninephrectomized control values. Testosterone caused little change in renal mass but did incur significant reductions in protein and RNA levels, suggestive of a protein catabolic action. In examining the plasma levels of electrolytes normally handled by the kidney, testosterone also gave rise to losses of plasma potassium and calcium, whereas cyclosporin A administration led to a more pronounced lowering of calcium and magnesium levels. More detailed studies of the actions of these drugs on renal growth and function are desirable in view of their clinical potential and usage.

Embryo resorption following administration of steroidal compounds to rats in mid pregnancy.

In the course of experiments on the effects of anabolic steroids on the myocardium of rat conceptuses, we found that subcutaneous implantation of 10 mg of estradiol, Dianabol or testosterone to rats in mid pregnancy, resulted in embryo resorption. Placental tissue was identified only in estradiol-treated rats which also demonstrated a large amount of serosanguineous fluid that dilated the horns considerably. The yellow nodules of placental attachment sites were represented histologically by cellular and vascular proliferations between the inner and outer layers of the myometrium. The nodular aggregates of cells had variable features according to the steroid administered. Neither decidual cells nor metrial glands that are reported to be the constituents of placental attachment sites were seen in our material. We conclude that anabolic steroids are potent agents for embryo resorption, and that the cells in the nodules of placental attachment sites are likely to be derived from the myometrium.

Gluconeogenesis from threonine in normal and diabetic rats.

L-[U-14C]Threonine was infused at a steady rate to non-anaesthetized rats starved for 1 or 3 days and to diabetic rats starved for 1 day. The rates of turnover of threonine, calculated from the equilibrium specific radioactivity (SA) of plasma threonine, were 5.79 +/- 1.00, 11.67 +/- 1.43 and 13.35 +/- 1.85 mumol/min per kg body wt. in 1-day-starved, 3-day-starved and diabetic rats respectively. The calculated turnover rate of threonine agreed well with the rate expected from the rate of protein turnover reported in the literature. The equilibrium SA of plasma alanine was 5.1-9.8% of that of threonine in the three groups of rats. The equilibrium SA of glucose was 1.42 and 2.90% of that of threonine in 1-day- and 3-day-starved rats respectively. From the non-equilibrium SA of glucose, it is estimated that a higher percentage of 14C atoms is transferred from threonine to glucose in diabetic than in non-diabetic rats. In spite of increases in gluconeogenesis from threonine in long-starved or diabetic rats, we conclude that threonine remains a minor contributor to plasma glucose. Since it is an essential amino acid, its turnover and contribution to the formation of plasma glucose is an index of catabolism and gluconeogenesis from tissue protein.

Impairment of testicular maturation in potassium depleted pre-pubertal rats.

When maintained on a potassium deficient diet 21 day-old weanling rats ceased to grow. At the end of 3 weeks, the testes were small and the diameter of seminiferous tubules was reduced. The reduction of the tubular diameter resulted mainly from a decrease in the number of cells, chiefly spermatids. An occasional tubule contained a few scattered spermatozoa. Ultrastructurally, the cytoplasm of Sertoli cells contained an increased number of lipid droplets as well as phagocytosed degenerative cells. Spermatids, conspicuously fewer in number, showed abnormal forms and did not mature beyond the early acrosomic phase. It appeared then, that potassium deficiency in immature rats not only arrested growth but largely prevented spermatogenesis. This probably resulted from a widespread inhibition of pituitary trophin function. Also, the deleterious effects on spermatids could be due to local lack of potassium which is present in high concentration in normal seminiferous tubular lumen.

Effects of 5 alpha-dihydrotestosterone and methandrostenolone in male guinea pigs.

Young adult guinea pigs were studied 6 and 9 weeks after silastic capsules containing 5 alpha-hydrotestosterone (5 alpha-DHT) and methandrostenolone (Dianabol) were implanted. DHT was more effective in causing testicular atrophy and was apparently more androgenically potent in sustaining the size of the seminal vesicles. Both steroids led to hypertrophy of the masseter muscle and increase in gastrocnemius protein concentration. Cardiac tissue was sensitive to the effects of these steroids, particularly to the larger amounts of absorbed Dianabol, in terms of increases in DNA concentration and transient loss of tissue sodium, potassium, and calcium. All alterations in muscle composition occurred in the total absence of change in tissue water. Hypernatremia and hyperkalemia was present in steroid-treated animals with significant loss of urinary potassium in DHT-treated guinea pigs. Adrenal atrophy and the lowering of circulating cortisol was further indicative of effects upon adrenocortical function and the regulation of electrolyte balance.

Effects of pipecolinomethylhydroxyindane on testicular and adrenocortical function in rats.

Mature and young adult rats were treated with a single dose of 115 mg and 50 mg of pipecolinomethylhydroxyindane (PMHI) maleate per kg of body weight. Large intraperitoneal doses were toxic in mature rats and the growth of younger animals were retarded by the lower subcutaneous dose. In both instances, PMHI caused a rapid reduction in testis weight with arrested spermatogenesis. Atrophic changes to the ventral prostrate and the lowering of blood testosterone levels suggests that the actions of PMHI are not strictly confined to the seminiferous tubules. This was further substantiated by the demonstration of direct inhibition by PMHI of testicular androgenesis in vitro. The actions of PMHI on steroidogenesis may be readily reversible and, compared to tubular actions, are of a minor nature. There were no clear-cut adrenocortical responses to PMHI administration but there was some depression of adrenal gland weight, plasma corticosterone, and aldosterone.

Responses to vasectomy performed at different ages in the rat.

The weights of the liver, heart and kidneys were not influenced by vasectomy at any age whereas rats vasectomized at 50 weeks gained appreciably more (30%) in body weight than their corresponding controls. Significant atrophy of the ventral prostate occurred only in the older group of vasectomized animals but this was accompanied by slight increased in circulating testosterone. Pituitary weight was unaffected by vasectomy, but slight atrophy of the testes in the 50 week old vasectomized rats might suggest the beginnings of decline in gonadal function after vasectomy in the older animals. In addition, the accumulation of lipids in the blood and heart tissue of rats vasectomized at 50 weeks of age indicates that the older animals may be more susceptible to the effects of the surgery than their younger counterparts. There were no marked changes in fasting blood glucose and significant elevation in glucocorticoid status after vasectomy in 10 week old rats was not manifest in the older groups of animals.

Gonadal function following vasectomy in the rat.

Adult rats were studied at four, eight, and 12 months following vasectomy and sham-operation. The weights of the seminal vesicles, ventral prostate, pituitary, and kidneys were not significantly affected by vasectomy. Testicular endocrine function in vasectotomized rat was transiently stimulated as witnessed by elevation in testicular venous testosterone and androstenedione after four months. There then occurred signs of decline in gametogenic function and atrophy of the testis after 12 months whereas hormonogenesis appeared to remain at normal levels. There was no alteration in the morphology of the epididymis at any of the time intervals of study after vasectomy.

PIP: Possible changes in testicular and accessory sex organ function in rats following vasectomy were observed at regular intervals for periods of 1 year. The intervals of study were 4, 8, and 12 months. Testicualr blood sampels were collected. The left testis was removed for histological examination and the seminal vesicles, prostate, pituitary, and kidneys were excised, cleaned, and weighed. A portion of the epididymis was examined by electron microscopy. The weights of the seminal vesicles, protate, pituitary and kidneys were little effected by the surgery. Testicular endocrine function in vasectomized rats was transiently stimulated as evidence by elevated levels in testicular venous testosterone and androstenedione after 4 months. After 12 months a decline in gametogenic function and atrophy of the testis was seen, while hormone function remained unaltered. The morphology of the epididymis was also unaltered.

Pineal factors in the control of testicular function.

The mammalian pineal gland has become firmly established as a neuroendocrine structure possessing the ability to influence the functions of the sex glands. There is substantial evidence in the literature that pineal factors also affect the activities of other endocrine systems. The pineal gland is thus conceivably far-reaching in its regulatory actions on physiological function, involving actions on the adrenal cortex, the thyroid, and parathyroid glands as well as the gonads of both sexes. The pineal gland of the hamster and the rat responds to environmental influences, particularly changes in length of the daily photoperiod, and in turn exerts regulatory effects on the activity of the testis. This relation is much more sensitive in the hamster where lack of adequate illumination stimulates pineal antigonadal activity to produce inhibition of both testicular gametogenesis and androgenesis. Involvement of the pineal in these responses to darkness or blinding has been clearly demonstrated by the negating effects of its removal. The physiological role of the pineal in regulating seasonal changes in testicular activity and reproductive capacity of the hamster has now been formulated (Reiter, 1973a, 1973b). The laboratory rat, a continuous breeder, is far less sensitive to lack of photic input. Surgical and environmental manipulations involving altered pineal activity invariably lead to less dramatic changes in various parameters of male reproductive function. The evidence would seem to indicate that pineal function in the rat is primarily related to the regulation of testicular endocrine function. Consequently, its physiological role may be associated with seasonal changes in libido in relation to environmental influences, by virtue of the action of pineal factors on androgen status. Spermatogenesis, on the other hand, was unaffected for periods as long as 1 year after the blinding of rats at the time of puberty (Kinson and Liu, 1974). There is evidence that the pineal gland has a part to play in the timing of puberty in the rat and in circadian variations in testosterone levels in the adult animal. Two groups of compounds have been identified as pineal agents and possibly pineal hormones. While the indoles have been more widely investigated as pineal antigonadal factors, the involvement of polypeptides in pineal actions was indicated a decade ago and these compounds are now receiving vigorous attention. Pineal factors influence testicular function by interaction with the neuroendocrine system to affect pituitary gonadotropin secretion. The higher neural centers appear to be responsive to indoles and via the releasing factors give rise to changes in pituitary content and circulating levels of FSH and LH. Prolactin also has been shown to respond to change in ambient lighting and to pinealectomy. Partially purified polypeptide fractions are now claimed to be considerably more potent antigonadotropically than melatonin, the indole most favored as a pineal hormone...