A fundamental role of these substances in biology is determined by the fact that they are polycyclic. This leads us to consider the role of the ring itself in reactivity, as shown by a study of the steroids in opposition to the fatty acids. In the fatty acids, the bonds between carbons as present in the aliphatic chain, insure a high reciprocal mobility between these carbons. As a result, the entire aliphatic chain is highly flexible. On the other hand, rigidity is characteristic for all the rings, and is increased by the polycycling of the molecules. The constituents of the molecules are kept in fixed reciprocal positions. While, in the fatty acids, the flexibility of the chain permits the energetic centers to take different relative positions among themselves toward other molecules, the rigidity of the polycyclic molecules maintains the energetic centers of the cycle, or those attached to it, in the same relative position. This fundamental characteristic of the cyclic molecules appears to be an important factor in determining the biological role of the various agents which have such cycles in their molecules.

In the case of steroids, this attribute acquires special importance. An understanding of the different biological activities of steroids can be obtained by an analysis of the forces resulting from this characteristic composition. Besides the energetic centers or formations attached to it, two energetic centers appear as part of the steroid nucleus itself. One is at C3 and the other center is represented by the cyclopentanic group. The fact that these centers are maintained in fixed relative position through the rigidity of this polycyclic nucleus has resulted in an important property of the nucleus itself which becomes translated into a dipolarity of the molecule. The study of these two energetic centers has advanced our knowledge of the role of steroids.

The study of the polar groups bound to C3 of the polycycle skeleton of steroids has permitted us to recognize the conditions which induce stronger activity for these polar groups, conditions which are usually fulfilled in the naturally occurring members. It could thus be seen that the reactivity of an oxygen bound to C3 is increased if another double bond present in the cycle is parallel to the double bond through which the oxygen is bound to C3. A double bond between C4 and C5, as shown in Figure 64 (a), fulfills such a condition. A similar influence is exerted mdirectly by a double bond between Cc and C7 (b) which, through induction, will influence the parallel C4 and C5 bond and further the double bond of the oxygen. This explains the influence exerted by the double bond present between C1 and C2 (c), as in the synthetic, prednisolone. Further enhancement of reactivity would be obtained with a third double bond added between C6 and C7. The parallelism between three double bonds (d) would produce an increased reactivity.

Influence exerted upon the oxygen bond at C3

Fig. 64. Influence exerted upon the oxygen bond at C3 by the position of the double bond in the cycles 1 and 2 of the cyclopentanephenanthrene molecule. A parallelism between the double bond of oxygen and that present between C4 and C6 increases the energetic character of the carbonyl (a). A similar influence but less active, is exerted by the double bond between C6 and C7. A double bond added between C1 and C3 (c) increases the activity. Still more activity would result from a third double bond added between C6 and C7 (d).

For the hydroxyl, a similar enhanced reactivity is induced by double bonding of the carbon to which the hydroxyl is attached with a double bond for the C3 C4 or C2 C3, as shown in Figure 65 (a and b). A similar condition is fulfilled if a double bond is present in the molecule parallel to any of these bonds, as seen in Figure 65 (c) where the double bond is between C5 and C6. An enhanced reactivity of these compounds would be obtained with one double bond between C3 and C4 and another between C5 and C6 (d).

The influence exerted upon the hydroxyl bond at C1

Fig. 65. The influence exerted upon the hydroxyl bond at C1 by a double bond in the cycle 1 and 2 of the phenanthrene is increased if the double bond is adjacent or parallel to the bonds of C3, bearing the hydroxyl.

We will come back to this important intervention of the double bonds in cyclic molecules.

The energetic property of the cyclopentane group appears to be correlated with its odd number of carbons. The alternate succession of carbons with positive and negative characters resulting from the induction effect causes two carbons of this cycle to have the same sign. This "twin formation" induces a special molecular reactivity related to the pentanic cycle of the steroid molecule. (Note 9)

The special reactivity seen for C3 of the cyclopentanophenanthrene molecule can be explained through a hypothesis covering the origin of these substances. Although the origin of a cholesterol molecule through a cyclization of squalene (35) appears plausible, this seems less probable for the corticoids. We have tried to connect their origin to arachidonic acid.

Several considerations such as the high levels of arachidonic acid and corticoids in the adrenals, and the reduction of the former when an important amount of the latter is excreted (Note 10), seem to establish a correlation between these substances. According to our hypothesis, the steroids with a two carbon chain at C17, as seen present in the corticoids and luteoids, would result from a cyclization of the arachidonic molecule. (Note 11) This would explain the special reactivity of C3, which would correspond to C9 of the arachidonic acid bound in this molecule by a double bond.

A study of the different steroids under this energetic aspect has permitted us to understand their physiologic properties.

With the C3 having a hydroxyl or an oxygen as polar group in almost all the steroids, the variety of the biological properties would be related to the different conditions at the other extremity of the molecule, principally at C17, which result from the special energetic conditions prevalent at this region of the molecule. The simplest steroids are those having a polar group represented by an OH or O fixed at C17. Such naturally occurring steroids have properties related to secondary sex characteristics. We will discuss them briefly here.