Pituitary Dysfunction as a Cause of Cardiovascular Disease.

The hypothalamic-pituitary axis is responsible for the neuroendocrine control of several organ systems. The anterior pituitary directly affects the functions of the thyroid gland, the adrenal glands, and gonads, and regulates growth and milk production. The posterior hypophysis, through nerve connections with the hypothalamic nuclei, releases vasopressin and oxytocin responsible for water balance and social bonding, sexual reproduction and childbirth, respectively. Pituitary gland hormonal excess or deficiency results in dysregulation of metabolic pathways and mechanisms that are important for the homeostasis of the organism and are associated with increased morbidity and mortality. Cardiovascular (CV) disorders are common in pituitary disease and have a significant impact on survival. Hormonal imbalance is associated with CV complications either through direct effects on the heart structure and function and vasculature or indirectly by altering the metabolic profile. Optimal endocrine control can prevent or reverse CV defects and preserve survival and quality of life. In this review, we discuss the effects of pituitary hormone excess and deficiency on the CV system. Specifically, we assess the impact of Somatotroph, Corticotroph, Gonadotroph, and Lactotroph anterior pituitary axes on the CV system. The effect of posterior pituitary function on the CV system is also explored.

Thyroid and bone.

The hypothalamic-pituitary-thyroid axis plays a key role in skeletal development, acquisition of peak bone mass and regulation of adult bone turnover. Euthyroid status is essential for maintenance of optimal bone mineralization and strength. In population studies, hypothyroidism and hyperthyroidism have both been associated with an increased risk of fracture. Furthermore, recent studies in healthy euthyroid post-menopausal women indicate that thyroid status in the upper normal range is also associated with low bone mineral density and an increased risk of non-vertebral fracture. Studies in mutant mice have demonstrated that thyroid hormone receptor α is the major mediator of T3 action in bone and that thyroid hormones exert anabolic actions during growth but have catabolic effects on the adult skeleton. Nevertheless, TSH has also been proposed to be a direct negative regulator of bone turnover, although the relative importance of T3 and TSH actions in the skeleton has yet to be clarified.

Pediatric aspects in Graves' orbitopathy.

Although pediatric Graves' disease is an uncommon condition, children have about the same (or slightly increased) risk as adults to develop Graves' ophthalmopathy (GO) once they have contracted Graves' hyperthyroidism. GO occurs in the same proportion between sexes but with a milder clinical presentation compared with adults. Lid lag, soft tissue involvement and proptosis are the commonest manifestations, whereas restricted eye muscle motility, severe strabismus and optic neuropathy are practically absent. Genetic, immunologic and environmental factors may be associated with the different appearance of GO in children and adolescents. Interestingly, manifestation of GO begins to resemble the adult findings more closely when adolescence approaches. This could be explained by increasing smoking prevalence with age as long as smoking is a proven to be a risk factor for GO, and the odds increase significantly with increasing severity of GO. Management of hyperthyroidism is essential for the control of complications and seems to offer improvement of eye changes upon restoration of euthyroidism. Antithyroid drugs are the first choice treatment. Lasting remission rates though are achieved in less than 30% of cases. Long periods of therapy are needed and risk for side effects (often serious) increases. In resistant or severe cases early radical treatment with surgery or radioiodine is needed. Both can be equally effective and safe in selected cases. Identification of subjects prone to relapses is critical for optimal management. Regarding treatment of thyroid eye disease in childhood, most physicians who are dealing with such cases prefer a 'wait-and-see' policy. Pharmacological intervention, predominantly with steroids, is considered appropriate in case of deterioration or no improvement of eye changes when the patient has become euthyroid. It has been shown that somatostatin analogs (SM-as) might be of therapeutic value in the treatment of active eye disease in adults. Newer generations of SM-as that target a wider range of somatostatin receptors may show markedly superior results in the treatment of ophthalmopathy. Surgical orbital decompression is hardly ever necessary due to the mild nature of the disease, while retrobulbar irradiation, which has been proved beneficial in adults, has no place in the treatment of juvenile GO, in view of the theoretical risk of tumor induction.

Bone signaling pathways and treatment of osteoporosis.

Osteoporotic fractures are a major healthcare burden costing over US$50 billion/per year. Bone turnover is a continuous process regulated by the coupled activities of osteocytes, osteoclasts and osteoblasts that maintain bone mass and strength. Osteoclastic bone resorption is regulated by the RANKL/osteoprotegerin/RANK pathway, while osteoblastic bone formation is controlled by canonical Wnt signaling. Antiresorptive bisphosphonates remain the mainstay of treatment but recombinant parathyroid hormone is increasingly being used as an anabolic agent. Nevertheless, these drugs are limited by patient compliance, efficacy and cost. Cathepsin K inhibitors and RANKL antibodies have been developed as new antiresorptive drugs, while short-acting calcilytics and antibodies to Dickkopf-1 and sclerostin are promising anabolics. The recent identification of adipocytes and duodenal enterochromaffin cells as novel regulators of bone mass represent exciting opportunities for future drug development.