How did diseases with poorly acting hormones come to be recognized in the first place? And what do these uncommon disorders mean for practitioners?

The idea of a hormone-resistant disease is usually traced to 1942 and Fuller Albright of the Massachusetts General Hospital. In that year, Albright wrote an article titled "Pseudo-hypoparathyroidism—an example of ‘Seabright-Bantam Syndrome.’ Report of three cases" (2; see facsimile reprint in 3). The disease was called "pseudo" because it resembled a known disease—hypoparathyroidism—but the injection of parathyroid hormone into one patient did not produce the expected increases in serum calcium concentration or urinary phosphate excretion.

Albright's report was seen as the first to show the failure of an end-organ response to a hormone. Albright was, in fact, more cautious. He was certainly looking for such a failure and wrote, but only speculatively, that there might be "a deficiency in or interference with some hypothetical substance with which parathyroid hormone reacts." But he also noted that there could be "blood antibodies (‘antihormones’) to the parathyroid hormone" and that "there are probably further possibilities." Perhaps his insight was to regard these patients as fundamentally different from those who did indeed lack hormones.

Albright's 1942 report was not a "bolt from the blue." He had been mulling over problems like this for several years and had already published reports of peculiar cases of rickets resistant to vitamin D [4]. By the early 1940s, he thought that the difficulty in "Tom Thumb," a short-statured adult who worked for a time with P.T. Barnum, was probably "not endocrine but end-organ," that the same was true of women with small breasts (Greif R. Lecture notes on F. Albright's summer course in endocrinology, 1940), and that it explained "the absence of beard in the American Indian" [2]. He even thought of resistance to thyroid hormone and wrote that in patients with a low basal metabolic rate who seemed to need more thyroid hormone than usual, "... the inference is that the low metabolism ... is due to a failure of the body to react in a normal way to the thyroid hormone" [2].

In 1943, Albright wrote to Hermann Zondek that "the concept that there is something wrong with the end-organ is as old as the hills" [5]. Furthermore, Albright was not the only one with this idea. In 1930, Berlin physician Leopold Lichtwitz said, at the end of a discussion on hypothyroidism, that "in some cases of disease due to hormone deficiency the fault may lie in the inability of the tissue to fix the hormone. If this fault concerns parts of the tissues only ... a partial hypothyroidism is possible, even though general hyperthyroidism is present" [6]. And in 1934, Philip Smith, a well-known anatomist-endocrinologist at Columbia University, noted the need to consider "the receptor tissues" in hormone action [7]. The idea was "in the air" in the 1930s; Lichtwitz's comment eerily presaged the patients studied by Brucker-Davis and colleagues.

Another probable influence on Albright's thought is the gradual development of the idea of the tissue receptor in pharmacology. By the 1930s, receptor theory as a mechanism of drug action had been refined and was a powerful stimulus to pharmacologic research [8]. No one knows whether this concept influenced Albright, but it seems likely that it did.

Whence came Albright's "Seabright-Bantam Syndrome," the term he applied to these conditions? Phenotypic sex determination was intensively studied in the 1910s and 1920s; one of the models used was the Sebright bantam rooster, an unusual male bird that had female feathers but crowed and had a normal male comb (Albright consistently misspelled "Sebright" as "Seabright," probably because of previous misspellings). This rooster was extensively discussed in Allen's Sex and Internal Secretions [9], a book that became a bible for endocrinologists in the 1930s and 1940s and one that Albright must have read closely. The conclusion at the time was that the Sebright rooster's testes were normal and that the unusual feathers were due to a genetic defect involving the skin.

Albright took this rooster as a model for the failure of end organs to respond to hormones, and he interpreted the female feathers as the skin's failure to respond to androgen. Thus, he both defined the concept of end-organ resistance with a specific example and recognized that failure to respond need not involve all of the normally responsive organs. Again, there are echoes in the article by Brucker-Davis and colleagues. Ironically, modern studies of this rooster have shown that it has no resistance to androgen; the problem is that the skin converts more testosterone to estradiol than usual [10, 11]. The result is female feathers in an otherwise normal male rooster.

How did we get from Albright to the present idea of hormonal resistance as a receptor defect? Why did it take almost 50 years? Some of the delay was due to the rarity of the syndromes. Most of the endocrinologic community did not believe in receptors; as a site of endocrine action, the enzyme, not the receptor, was king until the early 1960s. But since then, the major problem has been technical. The techniques of hormonal immunoassay are needed to confirm that resistance exists, and the techniques of molecular biology are needed both to define resistance as receptor-related and to specify the receptor's defect.

Conceptually, the idea of hormonal resistance has several increasingly reductionist stages. The first is Albright's: An organism's hormonal deficiency that fails to respond to exogenous hormone is called "resistance." Next, sensitive immunoassays can show inappropriately high circulating concentrations of a hormone in the face of clinical deficiency; failure to respond to endogenous hormone still defines clinical resistance. Later stages involve studies with tissues rather than organisms or organs: One might show defective specific binding or isolate a defective receptor or its gene. Finally, one might show that a specific mutation actually causes the clinically evident disorder, reversing the reductionist pathway. The idea of thyroid hormone resistance followed this path and can be seen in microcosm in the article by Brucker-Davis and colleagues [1]. The first patient recognized as having resistance to thyroid hormone appeared in 1967; she seemed hypothyroid but had a high serum protein-bound iodine concentration [12]. In the mid-1980s, studies on the specific binding of triiodothyronine were done, but the results were equivocal [13]. Then, in 1986, Weinberger and coworkers [14] in California found that a thyroid hormone receptor was the product of a known human complementary DNA sequence. When Arthur Schneider in Chicago saw this report, he told James Magner, who recognized a long-awaited opportunity to see whether the receptor gene in thyroid-resistant patients was defective. Because his laboratory was not equipped to do the work, Magner in turn spoke with his Chicago colleague Samuel Refetoff, who had described the first patient with resistance to thyroid hormone, and with Bruce Weintraub, Magner's former laboratory director and a co-author of the Brucker-Davis article [1] (Magner J. Personal communication). Both Refetoff and Weintraub thought that the idea was high risk, but by early 1990, both had found a mutation in the thyroid hormone receptor ß [15, 16]. A long list of such mutations now exists, but the total number of patients reported with this disorder is small [12].

Albright's concept has now spread throughout endocrinology; examples are defects in steroid receptors [17, 18] and receptors coupled to G-proteins [19]. Nevertheless, one should not stay only under the reductionist umbrella. A problem might lie in a regulatory component other than a receptor; a receptor defect need not explain resistance [20], and, when it does, it may not explain the actual phenotypes seen in the intact organism [21]. We do not know why the patients studied by Brucker-Davis and colleagues [1] did or did not have learning problems or why some organs are affected more than others. We do not know whether the phenotypic defects occurred primarily in utero or whether the genotype is less relevant in adults. We do not even know the prevalence of thyroid hormone receptor defects in persons with the attention-deficit hyperactivity disorder; the epidemiologic lags behind the molecular. To date, an identified defect cannot reliably predict or fully explain the illness; we need both the clinical and the molecular studies to understand the condition, and we need to recognize our ignorance.

What does all this mean for the practitioner? These disorders are rare. However, they serve as models for understanding physiology, so their value lies perhaps in providing a better understanding of nature and its varied colors rather than in everyday clinical utility. Most internists will simply want to know that these disorders exist and that they should be suspected when the results of the clinical examination and the laboratory tests disagree. In practice, it is worth remembering that the most common cause of a raised serum thyroxine concentration with a normal or elevated serum thyroid-stimulating hormone concentration is not resistance to thyroid hormone but the erratic use of oral thyroxine by a patient with primary hypothyroidism.

Were Albright here today—he would be in his 90s had he lived—he would be both astonished and delighted by what an idea can do. He would have loved what molecular reductionism can show. And he would have gone off to see the next puzzling patient, quoting the work of Brucker-Davis and colleagues to his students as an exaltation, not of larks, but of "Seabright" bantams.