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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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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,

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Lorenz C Hofbauer and Armin E Heufelder

Melatonin (N-acetyl-5-methoxytryptamine) represents the predominant hormone synthesized by the pineal gland, which is located at the posterior aspect of the third ventricle. Melatonin synthesis is mainly controlled by the light/dark environment. Retinal perception of light inhibits synthesis of melatonin, while darkness stimulates its production upon postsynaptic activation ofβ-adrenergic receptors. Owing to its nocturnal surge of synthesis, melatonin has gained popularity as the "hormone of darkness". Physiological roles of melatonin have been linked, among others, to modulation of the hypothalamic–pituitary–gonadal axis, onset of puberty and seasonal patterns of reproduction and breeding. Altered melatonin synthesis has been reported in a variety of disorders, including amenorrhea of anorectic and excessively exercising women, delayed onset of puberty, winter depression, asomnia, and jet lag (1). Further, lack of appropriate melatonin synthesis has been associated with sudden infant death syndrome, certain forms of breast cancer, premature ageing and cataract formation (1). Recently, novel actions of

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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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Lorenz C Hofbauer and Armin E Heufelder

The cell largely depends upon the actions of autocrine and paracrine peptide growth factors. After binding to, and activating, their respective serin/threonine or tyrosine kinase receptors, a diverse network of local growth factors orchestrates cellular proliferation and differentiation. Members of the transforming growth factor β (TGF-β) superfamily, usually disulfide-linked homodimers, play a crucial role in embryogenesis and growth as well as in reproductive and immune functions. These members (TGF-β, activin, bone morphogenetic proteins) exclusively bind to extracellularly located serin/threonine kinase receptors. Bone morphogenetic proteins (BMPs), originally identified by, and named after, their osteoinductive ability, constitute a major subgroup of the TGF-β superfamily (1, 2). Members of the BMPs have been implicated recently in early embryogenesis (3) and in shifting bone marrow stroma-residing pluripotent osteoprogenitor cells from the adipocyte to the osteoblast differentiation pathway (4). Although there is a steadily growing literature in bone cell biology on the cellular phenomena induced,

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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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Armin E Heufelder and Lorenz C Hofbauer

Serum levels of calcium and phosphate, two essential ions for the maintenance of bone metabolism, are mainly controlled by parathyroid hormone (PTH), calcitonin and vitamin D upon activation of their respective receptors in kidneys, gut and bone. Synthesis and secretion of the peptide hormone PTH is inversely correlated with the serum level of ionized calcium: sensing of appropriately high serum ionized calcium levels by parathyroid cells suppresses PTH release and results in calcium deposition into bone. In contrast, hypocalcaemia leads to a counter-regulatory PTH surge that enhances the absorption of calcium by kidneys and gut, thus promoting mobilization of calcium from bone (1). In addition, vitamin D directly inhibits transcription of PTH. In the setting of primary hyperparathyroidism this tightly regulated feedback loop gets out of control. As a result of an altered set point, excessive secretion of PTH occurs despite the presence of hypercalcaemia. Consequently, the above-mentioned calcium-sparing mechanisms

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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