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The Syndromes of Primary Hormone Resistance

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The Syndromes of Primary Hormone Resistance PROGRESS IN ENDOCRINOLOGY AND METABOLISM The Syndromes of Primary Hormone Resistance Guido F. M. Verhoeven and Jean D. Wilson The clinical features. genetics, pathophysiology, and in which the defect resides neither in hormone management of endocrine diseases in which primary deficit nor hormone excess but in the capacity of hormone resistance is the fundamental defect have the tissues to respond to the hormone-so-called been reviewed. Primary hormone resistance has been documented for nearly all hormones-vaso- hormone resistance. The authors hypothesized pressin, parathyroid hormone, growth hormone. that pseudohypoparathyroidism is due to a defi- adrenocorticotropin. thyrotropin. gonadotropins. in- ciency in or interference with some hypothetical sulin, androgens. cortisol. aldosterone. progester- substance with which parathyroid hormone one, thyroid hormones, and vitamin D. A striking reacts. They drew an analogy between the exception is estradiol, a steroid that may be vital for early embryonic development. Most of the hormone syndrome and the Seabright-Bantam rooster in unresponsiveness syndromes represent only partial which female feathering is believed to be due to defects, and it is likely that most such patients go resistance to the action of the male hormone and unrecognized. Therefore, hormone resistance suggested that other types of hormone resistance should be suspected not only when a patient pre- must exist in clinical medicine. In subsequent sents with hypofunction of a particular endocrine system combined with high endogenous hormone studies Albright and his colleagues recognized levels but also whenever apparently normal function the hereditary nature and variability in the of an endocrine system is associated with inappro- disorder.z.3 The suggestion was made that resis- priateJy elevated levels of the corresponding tance to hormone action be termed a “Seabright- hormone. The value of these defects in hormone Bantam syndrome.” responsiveness as a natural laboratory for the study of the normal mechanisms of hormone action is The concept that an endocrinopathy could discussed. result because the tissues cannot respond to normal or increased levels of a hormone has had far-reaching implications for endocrinology. WO TYPES OF ENDEAVOR dominated First, more and more forms of hormone resis- T clinical endocrinology after its birth as a tance have been identified so that by now discipline in the mid 19th century. One involved syndromes have been described in which disease the elucidation of clinical disorders that result results from resistance to any of several from hormonal absence or deficiency. Such stud- hormones.4vs Second, the concept of hormone ies were followed by attempts to characterize resistance has served as a major stimulus for the and synthesize (or extract) the critical hormone study of how hormones act within cells. and administer it to replace the deficit. The Although pseudohypoparathyroidism was de- second involved identification and treatment of scribed before the existence of hormone recep- syndromes of hormone excess. These themes of tors was recognized, the concept that there is a hormone deficit and hormone excess advanced chemical reaction between the hormone and a simultaneously with the development of method- portion of the cell had its inception in the origi- ologies for measurement of hormones in biologic fluids and for the study of the regulation of hormone synthesis, storage, and release in From the Department of Developmental Biology, normal and pathologic states. Thus, for approxi- Catholic University of Leuven. 3000 Leuven. Belgium. and mately 75 yr, clinical endocrinology developed Department of Internal Medicine and the Eugene McDer- mott Centerfor Growth and Development. The University of without any significant insight into the mecha- Texas Southwestern Medical School, Dallas, Tex. nism of action of hormones within target tissues. Received for publication August 25, 1978. The field of endocrinology, basic and clinical, Dr. Verhoeven is Aangesteld Navorser of the Nationaal was ultimately changed by the description in Fonds Voor Wetenschappelijk Onderzoek of Belgium. 1942 of pseudohypoparathyroidism by Fuller Address reprint requests to Jean D. Wilson, Department of Internal Medicine, The University of Texas Southwestern Albright, Charles H. Burnett, Patricia G. Smith, Medical School, Dallas. Tex. 75235. and William Parson.’ This paper demonstrated 0 1979 by Grune & Stratton, Inc. the existence of a third type of endocrine disease 0026-0495/79/2803-0010$05.00/0 Metabolism, Vol. 28, No. 3 (March), 1979 253 254 VERHOEVEN AND WILSON nal Albright paper.’ Each patient with hormone insensitivity of acromegaly;” (2) development of resistance is a natural laboratory for investigat- antibodies that inactivate or block the active ing the mechanism of hormone action, and study hormones such as antibodies to insulin in of such patients has resulted in two significant insulin-treated diabeticsI and antibodies to advances in clinical science: identification of thyroid hormones in certain subjects;14 (3) devel- many specific steps in hormone action and recog- opment of antibodies to hormone receptors as in nition of the remarkable heterogeneity of endo- certain forms of diabetes mellitus;‘5”6 (4) crine disorders. Third, abnormalities of receptors absence of target cells as in Leydig cell agene- are now implicated in the pathogenesis of sis;“*” (5) primary abnormalities of the hormone diseases outside the endocrine domain,6 such as receptor either at the cell surface as in vasopres- myasthenia gravis7 and familial hypercholester- sin-resistant diabetes insipidus” or in the cytosol olemia.8 Finally, description of various syn- as in testicular feminization2’ and (6) disorders dromes of hormone resistance and identification of the post-receptor effector mechanisms within of the biochemical pathophysiology of the target cells as in certain forms of hereditary underlying defects has had important thera- male pseudohermaphroditism.” peutic implications. To design a rational thera- In addition to the primary syndromes, some py, it is necessary to know the exact site in forms of hormone resistance are secondary to cellular metabolism at which the disorder other physiologic derangements. For example, occurs. the angiotensin resistance in the Bartter The presence of hormone resistance does not syndrome is secondary and remote to the necessarily imply an abnormality at the level of underlying principal defect.‘2s23 Thus, the subject the target cell. A variety of pathophysiologic of hormone resistance has become complex. mechanisms known to cause hormone resistance This review is focused on the syndromes in (apparent or real) are summarized in Table 1. which resistance to hormone action is believed to For example, resistance to endogenous hormones be primary to the pathogenesis of the disorder. only can result from the formation of incomplete We have further limited discussion to those or abnormal hormones such as the elevated disorders in which the defect is thought to reside plasma thyrotropin in certain forms of hypothal- at the level of the target cell, either in the amic hypopituitarism,’ the abnormal parathy- receptors themselves or in the post-receptor roid hormone in the syndrome of pseudoidio- effector mechanisms within cells. Exceptions pathic hypoparathyroidism,” and the elevated have been made when discussion of other types immunoreactive insulin in subjects with familial of defects is essential for the consideration of hyperproinsulinemia.” Subjects with such disor- pathophysiology and differential diagnosis. ders respond in a normal fashion to the adminis- These disorders have been subdivided arbitrarily tration of normal hormones. into those involving hormones in which the Individuals with true hormone resistance, in primary receptor mechanism is on the cell contrast, are insensitive to both endogenous and surface, and those involving hormones in which exogenous hormones; such resistance can arise the receptor is intracellular because the mecha- from a variety of causes (Table 1). These include nisms of action are fundamentally different. (1) physiologic antagonism as in the insulin HORMONES WITH CELL SURFACE RECEPTORS Table 1. Pathogenesis of Hormone Resistance The hormones in the first class bind to surface Reststance to Endogenous Hormones Only receptors localized on the cell membrane (Fig. Abnormal hormones I ).24The activity of such hormones is believed to Incompletely cleaved or syntheswed hormones be mediated largely, if not entirely, by so-called Resistance to Endogenous and Exogenous Hormones second messengers, produced by the cell Physlologlc antagonism AntIbodies to hormones membranes. This mechanism applies to some AntibodIes to hormone receptors protein hormones and to the biogenic amines. In Absence of target cells most instances, the second messenger is cyclic Abnormal or absent receptors adenosine 3’,5’monophosphate (CAMP). Cal- Post-receptor-effector defects cium” and other nucleotides such as cyclic PRIMARY HORMONE RESISTANCE 255 and leads to activation or inactivation of various enzymes by phosphorylation. In instances where calcium serves as the second messenger, the mechanism by which it acts to mediate hormonal effects is also unclear.*’ Another type of hormone, i.e., insulin, clearly binds to receptors on the cell membrane, but the mechanism by which this binding is translated into physiologic effects is unknown. TARGET CELL It is evident from the simplified
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