Ontogeny of Endocrine Correlation 



609 



cortex, as is reflected respectively in the 

 arrest of the synthesis and storage of thyro- 

 globulin and in the accumulation of adrenal 

 cortical lipids and ascorbic acid. Since these 

 glandular deficiencies are first apparent dur- 

 ing the period of initiation of active histo- 

 genesis of the cell types in the normal 

 anterior pituitary (10 to 13 days) it may be 

 inferred that the anterior pituitary is func- 

 tionally active in the production and release 

 of thyrotrophic and adrenocorticotrophic 

 hormones. 



It is perhaps noteworthy that in the pitui- 

 taryless chick embryos the period of onset 

 of the apparent subnormal hormonal activ- 

 ity of the adrenal cortex and thyroid coin- 

 cides more or less closely with that of the 

 most marked increase in concentration of 

 blood sugar and liver glycogen. Such a 

 correspondence in time seems to suggest that 

 the abnormal accumulation of carbohydrate 

 is somehow brought about by a hormonal 

 imbalance. Whether, however, such imbal- 

 ance can be attributed to (1) the absence 

 of a possible direct-acting or an indirect- 

 acting pituitary principle, (2) a diminished 

 hormonal output of the adrenal cortex and/ 

 or thyroid, or (3) their combined absence 

 remains equivocal. 



Another problem is presented by the ob- 

 servation that almost immediately following 

 this period of correlation of apparent hor- 



* In this study of the mechanisms involved in the 

 production of hypoglycemia in the embryo by in- 

 sulin treatment, Zwilling made the significant dis- 

 covery that the glycogen content of the yolk-sac 

 membrane is greatly increased by the action of in- 

 sulin. This observation, along with others, led to the 

 interpretation that insulin produces its hypogly- 

 cemic effect in the embryo by the inhibition of gly- 

 cogenolysis in the yolk-sac membrane, which as a 

 consequence fails to release glucose in normal quan- 

 tities into the vitelline veins. These experimental 

 studies substantially confirm the concept of Claude 

 Bernard that the yolk-sac membrane ("les parois du 

 sac vitellin") of birds functions as a temporary liver 

 ("foie transitoire") until the embryonic liver is 

 morphologically prepared to assume it [for a his- 

 torical treatment and discussion see Needham 

 ('31)]. Three related questions remain to be an- 

 swered by future research, namely: (1) At what 

 period in development of the chick is the glycogenic 

 function shifted from the yolk-sac membrane to the 

 liver? (2) Is the shift correlated with onset of hor- 

 monal activity? (3) Is there a special period in 

 liver development when the enzymes, such as phos- 

 phorylase and phosphoglucomutase, essential for 

 the formation of glycogen from glucose become 

 active? [According to O'Connor ('53) the initial 

 appearance of glycogen in the liver is associated with 

 changes in enzymatic activity.] 



monal imbalance and high levels of the 

 carbohydrates, i.e., between the twelfth and 

 fourteenth days, the blood sugar level de- 

 clines, whereas liver glycogen continues to 

 increase. Does this hypoglycemic effect in- 

 dicate the onset of some disturbance in the 

 mechanism of conversion of liver glycogen 

 into glucose? If so, is the effect connected 

 with beta cell differentiation which is seem- 

 ingly in progress at this time? Although the 

 specific problems raised by these questions 

 have not been analyzed, the following ob- 

 servations on normal and hormone-treated 

 embryos appear pertinent. (1) The time that 

 the higher rate of increase of blood sugar 

 and liver glycogen begins in the normal 

 chick embryo agrees fairly closely with onset 

 of the hypoglycemic effect in the pituitary- 

 less embryo. (2) The injection of insulin 

 (5 units) into the yolk sac of normal chick 

 embryos on the fifth day produces during 

 succeeding days a diminution in all carbo- 

 hydrate fractions in the embryo proper; how- 

 ever, by the twelfth day, the amount of 

 free sugar and glycogen returns to normal 

 levels (Zwilling, '51)* (3) The injection of 

 cortin (0.02 cc. of adrenal cortical extract) 

 into the yolk sac on the fifth day produces 

 a subsequent rise in blood sugar, which 

 reaches a peak at 10 to 12 days, returning 

 abruptly to normal values by the fourteenth 

 day (Zwilling, '48). These three lines of 

 evidence furnish additional support for the 

 hypothesis that the period between the 

 twelfth and fourteenth days is one of a 

 transitory nature in the development of 

 mechanisms for regulating the quantity of 

 blood sugar by hormonal activity. Whether 

 functional activity of the islets plays a role 

 at this time remains problematical. 



A final problem for brief mention here is 

 posed by the current theory that adrenaline 

 has an accelerating effect, whereas insulin 

 has an inhibiting effect, on sugar formation 

 in the liver. Through such an opposing action 

 these hormones play an important contribu- 

 tory role in the homeostatic regulation of 

 blood sugar. Although the time in ontogeny 

 that such a counter action sets in is un- 

 known, it is of interest to note that adren- 

 aline is present in the adrenal medulla very 

 early in development, and at stages before 

 any sign of functional activity of the islets 

 is manifested. Furthermore, with advance in 

 developmental age adrenaline increases 

 quantitatively, reaching an unusually high 

 concentration in late fetal life (see pp. 590- 

 593). In view of these observations it would 

 be of considerable interest, as a first step in 



