The review by Goldman et al.() is a strong restatement of the free hormone hypothesis (FHH) with its contingent focus on measurement of so-called “free” testosterone (FT). The FHH has even been recently described as a “central dogma of endocrinology”(), reminiscent of the hubris of Crick’s () central dogma of molecular biology stated as a unidirectional information transfer from DNA to RNA to protein, which proved neither a dogma (an unassailable proposition) nor universally correct. The review provides an outstandingly clear and encyclopedic summation of what is and is not known of the molecular mechanisms of testosterone binding to circulating binding proteins. On the other hand, its coverage of FT measurement and its interpretation are both more selective and tendentious. Above all the review’s overall focus on means rather than ends, on how to do it rather than why, the review belies why the application of FT measurements remain contentious so that less expert readers may wonder what controversy there is that the authors hint at fleetingly. Despite being extant for decades, the use of FT measurement has barely been stated in a testable form and virtually never directly tested as a refutable hypothesis. Rather by inference and repetition as if it is self-evident, it has become entrenched as an enthusiastically wielded yet largely untested concept that goes from one paper to the next without ever seeming to pass through a questioning mind. The FHH originated in a now obsolete s pharmacology theory of adverse drug reactions by which such interaction was attributed to mutual displacement of drugs bound to circulating binding proteins (). That now discarded speculative concept () has been superseded by physiological drug interaction mechanisms, such as molecular receptor binding, cytochrome P induction/inhibition, P-glycoprotein, and ion channel blockade (). Contemporaneously, the s provided fertile ground for introducing the concept of “free” hormones into Endocrinology. The revolutionary invention of radioimmunoassay introduced the notions of free and bound hormones in immunoassay and also hormone receptor theory, both deriving from the biochemical theory of equilibrium binding equations. Although pharmacological theories evolved, FHH persisted in Endocrinology making a remarkable transit from a simple, illustrative heuristic to quasi-axiomatic status without ever undergoing critical empirical testing. Regardless of its flimsy basis, invoking FT has flourished as a panchreston (explain-all), a final arbiter to resolve uncertainty about androgen status. This reached a farcical zenith in papers glorifying FT calculation as by the “Law of Mass Action,” an affectation comparable with describing measuring weight on a miscalibrated scale according to the “Law of Gravity.” In that sense the review is a welcome restatement of a hypothesis whose quasi-axiomatic status has granted it a free pass from engaging with logic or evidence in its application. To provide a more nuanced picture, an alternative view that FT represents a muddled and misleading concept, an explanatory fiction that provides false reassurance in men’s reproductive health care, is outlined briefly.

The fatal flaw of FHH theory, not addressed in the review, is its lack of a coherent physiological basis for interpretation of FT. Although the review notes the evidence refuting each of the three key assumptions of interpreting FT—that only unbound testosterone is able to enter tissues to exert androgenic effects, that testosterone bound to circulating proteins constitutes an inert buffer, and that the same mechanisms operate equally in all tissue capillaries—it …