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  • Author: Armin E Heufelder x
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Armin E Heufelder

Hypergonadotropic ovarian failure has many etiologies and varied expressions. Its most common and physiological type occurs during menopause, when ovarian function is gradually put to sleep and compensatory efforts of the female pituitary fail to overcome the estrogen deficiency state. Much earlier in life, at puberty, difficulties may arise from the opposite problem, namely a failure of ovarian awakening, maturation and responsiveness to elevated circulating levels of LH and FSH. Despite intact sex determination and anatomically normal internal and external genitalia, affected teenagers may present with variably developed secondary sex characteristics, primary amenorrhea and poorly developed streak ovaries, a rare and mostly sporadic condition termed ovarian dysgenesis (ODG).

Careful examination of the published literature led Simpson and colleagues (1) in 1971 to suspect that some cases of ovarian dysgenesis in individuals with a normal XX karyotype may be caused by autosomal recessive mutations. Subsequently, a population-based study of ODG revealed

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Armin E Heufelder

Graves' ophthalmopathy (GO) is a medically incurable, chronic autoimmune process that affects the retroorbital space and appears to have strong etiological links with autoimmune thyroid disease. The close clinical association between immunogenic hyperthyroidism (Graves' disease), ophthalmopathy and pretibial dermopathy suggests that the antigen responsible for these diverse conditions may be common to the thyroid gland, the retroorbital tissue and the pretibial skin. The varied clinical expressions of GO, including proptosis, extraocular muscle dysfunction, periorbital and lid edema, chemosis and conjunctival congestion, can be explained mechanically by an increase in connective tissue and extraocular muscle volume within the confines of the bony orbits, resulting from the accumulation of collagen, glycosaminoglycans (GAGs) and the attendant edema within these tissues. This process is likely to be driven by T cells that access and infiltrate the orbital space via certain adhesion molecules, and release various cytokines capable of stimulating cell proliferation, GAG synthesis and

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Christine Spitzweg and Armin E Heufelder

Cloning of the ob gene in genetically obese ob/ob mice and of its human homolog has identified leptin, the ob gene product, as an important circulating signal for the regulation of energy balance. Following secretion by differentiated adipocytes, circulating leptin is thought to control body weight by its interaction with leptin-binding sites in the hypothalamus. Intracerebroventricular administration of recombinant leptin induces long-lasting body weight reduction in ob/ob mice by suppressing food intake, and by increasing activity and heat production. Furthermore, leptin appears to be required for induction and maintenance of normal reproductive function. These observations, together with the well-documented close correlation between leptin serum levels and body fat stores in humans, have generated new interest in the central nervous system's pathways that are involved in leptin's action. The hypothalamic peptide neuropeptide Y (NPY), which stimulates food intake, decreases thermogenesis, growth hormone production and fertility, and increases plasma insulin and corticosterone

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Armin E Heufelder and Lorenz C Hofbauer

As a consequence of ongoing environmental pollution, the already long list of environmental agents and toxins that can affect endocrine systems has required many updates during the past 20 years. In addition to chemicals such as the nematocide dibromochloropropane, related compounds and heavy metals, the environmental toxin dichlorodiphenyltrichlorethane (DDT) has been identified as a major damaging factor of the male reproductive tract. Intriguingly, in addition to its well-known estrogenic effects, the capacity of DDT to potently inhibit androgen binding to the androgen receptor and androgen-induced transcriptional activity has only recently been discovered (1) and highlighted (2). In view of the apparent decline in semen quality during the last decades (3, 4), these observations have stimulated considerable debate and concern. Yet another clinical problem frequently encountered by endocrinologists are patients referred by their physicians for evaluation of otherwise unexplained gynecomastia. Although environmental causes such as diets rich in estrogens have been

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Armin E Heufelder and Lorenz C Hofbauer

Human immunodeficiency virus (HIV) infection and the resulting acquired immunodeficiency syndrome (AIDS) may involve, directly or indirectly, virtually every endocrine organ system, including the thyroid gland (1–3). A variety of potential pathogenetic mechanisms may account for thyroid dysfunction in HIV disease. These include alterations of thyroid tissue by hemorrhagic, infectious or neoplastic processes, changes in thyroid hormone secretion or action due to HIV infection, interference with hormone secretion and binding and effects of antibodies, cytokines or other biologically active molecules (Table 1). A further cause of thyroid dysfunction in patients with HIV disease is therapy with drugs that can disturb various endocrine systems and affect thyroid gland integrity or function, as well as hepatic metabolism of thyroid hormones (4). Interpretation of thyroid function tests and thyroid status in patients with HIV infection is complicated further by the well-recognized effects that any acute or chronic illness may have on thyroid function

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Lorenz C Hofbauer and Armin E Heufelder

Progress in biomedical science commonly involves identification of new compounds, the description of novel actions of naturally occurring or exogenously administered agents and clarification of previously unknown interactions underlying physiological or pathophysiological states. Rarer, but none the less exciting are discoveries where two presumably different molecules turn out to be identical. Take bone morphogenesis as a recent example.

Mammalian bone comprises the body's largest site of connective tissue accumulation, which mainly consists of extracellular matrix proteins impregnated by minerals. Type I collagen fibers account for approximately 90% of its extracellular matrix proteins, whereas the remainder includes osteocalcin, osteopontin, osteonectin, fibronectin, thrombospondin and various glycosaminoglycans, in addition to a long list of paracrine or autocrine growth factors. The dynamic balance

Division of Endocrinology, Medizinische Klinik, Klinikum Innenstadt, Ludwig-Maximilians-Universität, München, Germany between local synthesis, deposition and degradation of bone extracellular matrix components plays a crucial role in the body's attempt to adapt

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Lorenz C Hofbauer and Armin E Heufelder

Liddle's syndrome (pseudoaldosteronism) represents an inherited, autosomal dominant form of severe hypokalaemic hypertension which clinically resembles primary hyperaldosteronism. Urine assessment in patients with Liddle's syndrome reveals excessive renal sodium absorption and concomitant potassium wasting (1). However, in contrast to primary hyperaldosteronism, serum and urine aldosterone levels are suppressed in patients with this disorder. Further, Liddle's syndrome is frequently refractory to sodium restriction and various regimens of antihypertensive drugs (1). Diuretics acting on the distal tubule, such as triamterene and amiloride, may be effective in controlling the profound hypertension and marked potassium loss in patients with Liddle's syndrome if dietary sodium intake is restricted, while aldosterone antagonists are ineffective. In his original description, Liddle (2) hypothesized that the crucial mechanism in this disorder was that 'the renal tubules transport ions with such abnormal facility that the end result simulates that of a mineralocorticoid excess'. Complete recovery of signs and symptoms in

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Lorenz C Hofbauer and Armin E Heufelder

Osteocalcin, a polypeptide composed of 49 amino acids, represents one of the most abundant non-collagenous proteins in bone tissue. In bone, osteocalcin is mainly synthesized by osteoblasts as they mature and become capable of mineralization (1). Of the three genes encoding osteocalcin, osteocalcin gene 1 (OG1) and 2 (OG2) are exclusively expressed in bone, whereas osteocalcin-related gene (ORG) is solely detected in the kidney (2). Various hormone-responsive elements for 1,25-dihydroxyvitamin D, retinoid acid analogues, glucocorticosteroids, thyroid hormone, cyclic AMP, as well as growth factors and cytokines have been located within the promoter region of osteocalcin, suggesting that osteocalcin gene expression is modulated by multiple factors (3,4). Proposed functions of osteocalcin include those of a bone adhesion molecule and chemotactic agent, a signal transducer, and a regulator of osteoclast differentiation, bone mineralization, and bone remodelling (5). Although several molecular and structural details of osteocalcin have been delineated during the last decade,

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Armin E Heufelder and Peter C Scriba

Heufelder AE, Scriba PC. Characterization of adhesion receptors on cultured microvascular endothelial cells derived from the retroorbital connective tissue of patients with Graves' ophthalmopathy. Eur J Endocrinol 1996:134:51–60

T lymphocytes have been demonstrated recently to play an important role in the pathogenesis and propagation of Graves' ophthalmopathy (GO). Recruitment of T cells to the retroorbital tissue in GO involves the activation of certain adhesion molecules both in the vascular endothelium and in the extravascular connective tissue within the retroorbital space. To characterize the interactions between orbital endothelial cells (OECs) and circulating T cells in vitro, we designed a two-step immunopurification procedure with bead-immobilized Ulex europaeus I lectin and anti-human endothelial cell antigen (CD3I) monoclonal antibody for rapid and reproducible isolation of highly pure microvascular endothelial cell populations from small quantities of retroorbital connective tissue. Endothelial origin of the resulting cell populations was confirmed by positive immunoreactivity for von Willebrand factor. CD 3 I and thrombomodulin. Under baseline conditions, GO-OECs, but not normal OECs, expressed intercellular adhesion molecule 1 (ICAM-1) and CD44 immunoreactivity but no immunoreactivity for endothelial leukocyte adhesion molecule I (ELAM-1) and vascular cell adhesion molecule I (VCAM-1) was detected. Exposure of GO-OEC and normal OEC monolayers to interferon γ, interleukin 1 α and tumor necrosis factor α resulted in marked up-regulation of immunoreactivity for ICAM-1 and in induction of ELAM-1 and VCAM-1. Blocking experiments using monoclonal antibodies directed against various adhesion molecules demonstrated that interactions between matched activated T lymphocytes and OECs were mediated by integrin-dependent ICAM-1/leukocyte function-associated antigen 1 (LFA-1): VCAM-1/very late antigen 4 (VLA-4)) and integrin-independent (CD44) pathways, and revealed marked differences when comparing GO-OECs and normal OECs. In conclusion, the availability of OECs from affected retroorbital tissue of patients with GO provides a valuable tool for studying further the mechanisms responsible for orbit-specific lymphocyte recruitment in GO.

Armin E Heufelder, Molecular Thyroid Research Unit, Medizinische Klinik, Klinikum Innenstadt, Ziemssenstrasse 1, 80336 München, Germany

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Lorenz C Hofbauer and Armin E Heufelder

Medical terminology provides many terms for diseases of yet unknown etiology, including idiopathic, essential, or cryptogenic. Fortunately, some of them at some point in time need to be renamed, when their true identity becomes better known. Idiopathic acquired hypoparathyroidism might be such an example. This disorder, characterized by decreased levels of intact parathyroid hormone, usually affects children in their first decade of life, with a female preponderance, and eventually leads to hypocalcemia and hyperphosphatemia. Clinically, individuals with acquired hypoparathyroidism may display neuromuscular signs and symptoms of persistent hypocalcemia, including episodes of tetany, calcification of the basal ganglia, increased prevalence of seizures, mental retardation, and papilledema, as well as cataract formation and dental abnormalities (1).

In search of an autoimmune etiology of acquired hypoparathyroidism (AH), investigators have rounded up several suspects during recent years. First, autoantibodies directed against parathyroid tissues have been detected in some individuals with AH (1, 2). Second,