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The effect of simultaneous injections of ACTH and methylandrostenediol (MAD), a synthetic androgen, has been studied in the rat. ACTH accelerated the production of cytoplasmic vacuoles by MAD in as much as no such structures were observed in MAD-treated animals at 4 weeks. Adrenal weight was decreased in MAD-treated animals but restored to that of controls by ACTH (MAD plus ACTH group). ACTH by itself did not, however, cause the production of any vacuolar structures nor did it cause any reparation in the number of mitochondrial cristae which were considerably reduced in numbers after MAD plus ACTH.

Female, uninephrectomized rats injected with methylandrostenediol became hypertensive by 4 weeks of treatment. After cessation of treatment, blood pressure continued to rise during the first week but gradually decreased below the borderline of hypertension by 5 weeks. After methylandrostenediol treatment for 4 weeks and after 1 week of recovery, adrenocortical fine structure exhibited a number of abnormalities including reduced numbers of mitochondrial cristae, hypertrophic smooth endoplasmic reticulum, microfilaments and large lipid vacuoles within zona reticularis cells. During an intermediate period of recovery (2 weeks), mitochondrial cristae increased in number, although animals remained hypertensive. After 2 weeks, all of the ultrastructural abnormalities seen at early and intermediate periods of recovery were fully reversed, concomitant with a return of systolic blood pressure to below hypertensive levels.

Two morphologically distinct gonadotrophs have been identified in the anterior pituitary of rats bearing the Snell 494 tumor. Type 1 gonadotrophs first showed ultrastructural alterations at 4 weeks after implantation of the tumor. Numerous large 300 to 600 mmu granules appeared in type 1 cells. The opacity of the granules was variable, and they sometimes contained non-membrane-bounded spherical inclusions. These granules were dispersed among more electron-opaque, 200-mmu granules usually seen in gonadotrophs. A third granule approximately 500 to 600 mmu in diameter was apparently a lysosome-derived structure. Type 2 gonadotrophs first showed changes after 4 weeks, but the alterations were especially prominent by 8 to 10 weeks. No large granules characteristic of type 1 cells were seen in type 2 cells. By 8 to 10 weeks, very few 200-mmu granules were observed in the cytoplasm of type 2 cells. The endoplasmic reticulum was dilated in most type 2 cells; frequently, the cisternae were dilated considerably, forming large lake-like areas. Hypertrophic rough endoplasmic reticulum and the presence of intracisternal granules within cisternae of the rough reticulum suggest that type 2 cells were stimulated by the tumor. Changes in gonadotrophs were undoubtedly produced by the large amount of corticosterone secreted by the tumor. The corticosterone secreted by the tumor. The corticosterone may well act directly on the hypothalamo-hypophyseal axis or it could act indirectly on the ovary; ovarian steroids would then exert a feedback effect. The ovary was atrophic and did not contain maturing Graafian follicles or corpora lutea. In somatotrophs, the number of secretory granules increased, probably reflecting suppression of hormonal release by corticosterone.

Administration of 10 mg of methylandrostenediol for 10 weeks to uninephrectomized, salt drinking, female Sprague Dawley rats caused severe hypertension with extensive renal and cardiovascular damage. The hypertension was accompanied by increased consumption of sodium, high sodium levels in peripheral plasma, decreased weight of the pituitary, thymus, adrenals and ovaries and decreased content of renal renin. Methylandrostenediol treatment also produced impairment of normal adrenal steroidogenesis, reflected in elevated production in vitro of 11-deoxycorticosterone during incubation of adrenal gland homogenates with (14)C-progesterone. Such increased production of deoxycorticosterone is probably responsible for the development of the hypertensive disease. If the methylandrostenediol-treated animals were kept alive for 12 additional weeks after suspension of the treatment with the androgen, the hypertension, as well as the high sodium consumption, high plasma sodium concentrations and low levels of renal renin, persisted to the end of the experiment. The cardiovascular and renal lesions in these animals, killed 12 weeks after suspension of the androgen administration, were similar to those seen in the rats receiving methylandrostenediol but killed at the tenth week of the treatment. Suspension of methylandrostenediol administration, however, resulted in a return to normal weight of the pituitary, thymus, adrenals and ovaries within 12 weeks. Normal amounts of deoxycorticosterone were formed in vitro by the adrenal glands of these rats and the return to normal structure was also confirmed by a electron microscopic study. Thus, contrary to a previous experiment where methylandrostenediol was given for a shorter period of time and the hypertension was reversible, it was shown in this study that metacorticoid hypertension is induced by methylandrostenediol administration, as it is with treatment with deoxycorticosterone. Since adrenal steroidogenesis returned to normal, some other mechanisms must be involved in maintaining the hypertension. It is very likely that these factors are consequent to the extensive and irreversible renal and cardiovascular damage.