Experimental evidence has been presented showing that the thymus gland of the rat enlarges rapidly in those animals surviving double suprarenalectomy. The enlargement has been observed to follow bilateral ablation with such constancy that it may be said to occur in all rats which survive double suprarenalectomy in good condition for from 3 to 5 weeks. The thymus enlarges even though the animal loses some weight after operation. Our data, though inconclusive, would seem to indicate a sex difference, the secondary hyperplasia of the thymus being more marked in the female than in the male. This difference, we believe, may shed some light on the mechanism of thymus enlargement following double suprarenalectomy. In the rat there is a definite sex difference in the weight of the suprarenals (20), the glands being much larger in the female than in the male. This weight difference becomes greater as the rat grows, and it appears at an early period of life; indeed, it is obvious at about 35 days of age, in spite of the fact that sexual maturity is seldom attained before 60 to 90 days. This difference in the suprarenals is independent of pregnancy. It is highly probable that the suprarenal glands stand in closer relation to the sex organs of the females than in the male, and that removal of these glands disrupts the sex interrelationships between gonads, suprarenals, and thymus, this disturbance being more definitely expressed in the female than in the male.
The great majority of the rats were operated on when they were between 6 and 7 months of age; that is, after thymus involution would normally have set in. Thymuses examined when they had reached their largest size resembled both grossly and microscopically the growing thymuses of much younger animals, the only evidence of previous involutionary change being the presence of thickening of the vessels. We assume, therefore, from indirect, but statistical data, that regeneration of the involuted thymus must have taken place. The regeneration following bilateral ablation describes a curve which reaches its height between the 3rd and 5th weeks after operation. After the height of enlargement is attained, there is a gradual decline in the size of the gland, but involutionary changes may be retarded for months. Pregnancy prior to suprarenalectomy does not prevent thymus regeneration following this operation. Thymic enlargement does not ordinarily take place following a unilateral ablation. Severe chronic infections may sometimes bring about such a pronounced pathological involution of the thymus that the hyperplasia may be prevented.
There can as yet be only speculation as to the mechanism involved in the regeneration of the thymus which follows suprarenalectomy. This secondary thymic hyperplasia may be one manifestation of the generalized lymphoid hyperplasia that follows sublethal but sufficient suprarenal injury, and which is characterized by the appearance of prominent lymphoid foci in the various organs, particularly in the thyroid, a generalized hyperplasia of the lymph nodes and bone marrow, and the appearance of a lymphocytosis in the blood. The evidence at present available would suggest that both the thymic and general lymphoid hyperplasia may be effected through the gonads and parasex tissues and that the thymus especially regenerates because of a disruption of the interrelations between the interrenal gland, the gonads, and the thymus.
The close association between the gonads and the suprarenals (21) is well known. The latter undergo enlargement in pregnancy, ovulation, and castration, and the ovaries hypertrophy after suprarenalectomy. Tumors of the suprarenals are associated frequently with sex perversion and precocity both in the male and female. The interrelation between the gonads and thymus is classical, castration before puberty delaying thymus involution for a long time.
A number of diseases present thymus enlargement among the major pathological findings at autopsy. The most outstanding of these are Addison's disease, status lymphaticus, and Graves' disease. It is now generally recognized that the suprarenal glands play an important r61e in the etiology both of Addison's disease and status lymphaticus. Whether the interrenal or the chromophil system is primarily involved or whether disturbances in function of both systems are at the basis of these diseases is still undetermined. The newer evidence, including our own work on lymphoid regeneration following suprarenalectomy supports the view that the lymphoid hyperplasia occurring in both Addison's disease and status lymphaticus is dependent upon insufficiency of the interrenal system (suprarenal cortex). While anatomical studies have not disclosed any constant lesions in the suprarenals in Graves' disease, evidence is being accumulated which would indicate that functionally these glands also play an important if not a primary role in the production of the clinical syndrome of Graves' disease (14, 18, 19). We are of the belief that the persistence of the thymus which occurs in status lymphaticus, and the regeneration which occurs in Addison's and Graves' diseases, are brought about by the same disturbances in glandular interrelations which bring about regeneration of the thymus in the experimental animal after suprarenalectomy.