Changing concepts of active androgens in blood.

We have provided a brief historical review of developments in our understanding of the endocrine mechanisms underlying the expression of androgen action in women. An alternative to the free hormone concept is considered which proposes that, at least in some target cells, androgens bound to SHBG are the biologically relevant molecules. In nearly every instance, the changes in blood levels of SHBG that have been observed are consistent with this idea. At present there are only bits of direct evidence to support the hypothetical mechanism proposed. As already mentioned, control of androgen action at the level of cellular uptake would provide obvious advantages as well as a potential mechanism to explain the antagonism between androgens and oestrogens which is still a mystery. It is important to note that the proposed mechanism is not obligatory for androgen or other steroid hormone action. Synthetic steroids which do not bind to SHBG or CBG clearly can gain access to target cells by simple diffusion and bind to intracellular receptors. Compounds such as methyltestosterone and dexamethasone are metabolized much more slowly than their natural counterparts and therefore are cleared slowly from the circulation. It is possible that the well-known difficulties in selecting appropriate therapeutic regimens with such compounds is related to the fact that they bypass an important regulatory step in steroid hormone action-modulated entry into target cells. Hopefully, the recent development of powerful new tools of molecular endocrinology will hasten the answer to the question: What is the active androgen in blood?