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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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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 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

Homeostasis of bone metabolism and function depends upon bone remodeling, a coordinated, closely coupled process of resorption and formation of new bone. A variety of cell types and functions, hormones (steroid, polypeptide and thyroid hormones), as well as autocrine and paracrine growth factors and cytokines, act in concert to rebuild the skeleton while maintaining its structural and biomechanical properties (1). The two major players involved in bone remodeling, osteoblasts and osteoclasts, are of different origin: osteoblasts derive from pluripotent mesenchymal stem cells of the bone marrow, whereas osteoclasts originate from the hematopoietic granulocyte-macrophage colony-forming units (GM-CFU) (1). Thus, their differentiation to mature bone cells differs substantially with respect to their cytokine requirements and subsequent events of signal transduction.

In addition to their phenotypic markers, collagen type I and alkaline phosphatase, osteoblasts produce a variety of cytokines that are crucial for their maturation, including interleukin 6 (IL-6), IL-11, granulocytemacrophage colony-stimulating factor

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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

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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Armin E Heufelder and Lorenz C Hofbauer

Transport of iodide, an essential constituent of the thyroid hormones T3 and T4, represents the first and main rate-limiting step in thyroid hormone synthesis. The thyroid gland shares its capacity to accumulate iodide (I) with several other tissues, including salivary glands, gastric mucosa, lactating mammary gland, choroid plexus and the ciliary body of the eye. Although the transport systems in extrathyroidal tissues exhibit functional similarities with their thyroid counterpart, they lack the capacities to accumulate I in a TSH-dependent fashion and to organify accumulated I. Its exclusive capacity to efficiently trap and organify I, a scarce trace element in many areas of the world, makes the thyroid gland a highly specialized and truely unique organ. Physiologically, the thyroid gland is capable of concentrating I by 20–40-fold with respect to the concentration of the anion in plasma. Iodide is transported transcellularly from the basolateral to the apical membrane.

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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

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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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,