Review Articles in 2006

Osteoporosis is an increasingly prevalent condition that, currently, is underdiagnosed and thus undertreated, so that improved screening and preventative dietary and lifestyle changes are needed. For more-severe cases, there are also several drug classes available or in development that work in different ways; these are detailed in this Review.

Many hormones use G-protein-coupled receptors and G proteins in the target cell to transduce their signals. A range of disease-causing mutations have been characterized that mimic states of hormone deficiency or excess. This Review describes these mutations, and their resultant clinical and biochemical features.

Ectonucleotide pyrophosphatase phosphodiesterase 1 (E-NPP1) inhibits the insulin receptor. E-NPP1 mutations are associated with type 2 diabetes, and E-NPP1 expression is increased in nonobese, nondiabetic insulin-resistant subjects; E-NPP1 might therefore act as a marker for at-risk individuals and reveal new targets for prevention and treatment of diabetes and cardiovascular disease.

Many of the genes involved in development of adrenocortical tumors have been identified, and their effects on well-known signaling pathways (for example those involving cyclic AMP or β-catenin and Wnt) have been investigated. These advances have important implications for understanding disease development, identifying molecular markers and designing new therapeutic strategies for adrenocortical tumors.

Most tissues express glucocorticoid receptors but tissue-specific modulation of this receptor affects homeostasis, immune responses and cell differentiation mediated by glucocorticoids. This Review describes the mechanisms involved—including nucleocytoplasmic shuttling, degradation and gene polymorphisms—and details the effects on the metabolic syndrome.

Oxyntomodulin and peptide tyrosine–tyrosine are gut hormones that act as satiety signals and decrease food intake; oxyntomodulin may also increase energy expenditure. Studies in humans show these effects in normal-weight and overweight volunteers; these peptides and their derivatives are, therefore, potential therapies for conditions such as obesity.

Excess local tissue production of prolactin may be associated with development and progression of breast and prostate cancers. Pure prolactin-receptor antagonists, such as described here, block prolactin signaling, and may provide a novel therapeutic approach to these cancers, as well as a means of treating drug-resistant forms of hyperprolactinemia.

This Review details treatment of prolactinomas that do not respond to dopamine agonists. Cabergoline is the most effective agonist and options include maximizing the dose and changing agonists. Trans-sphenoidal surgery is an option if medical therapy is ineffective. Radiation therapy is reserved for invasive tumors that do not respond to medical or surgical therapy.

Multiple endocrine neoplasia type 1 can be caused by mutations in the gene encoding menin. By interacting with both transcription factors and histone-protein modifying factors, menin can activate or repress gene expression, and—as detailed here—specific pathways affected by menin have been identified. This offers hope for new screening and therapeutic strategies.

Not only the levels, but also the function and components of HDL-cholesterol appear to play a role in atherosclerosis. Levels of anti-oxidants and pro-oxidants can vary in HDL-cholesterol, as can its effects on LDL-induced inflammation. This Review describes recent progress that might lead to new therapeutic approaches.

Thyroid hormone transport across the plasma membrane is essential for hormone functions. As detailed here, novel mutations in monocarboxylate transporter 8 reveal important roles in thyroid hormone access to the brain and might explain the pathogenesis of Allan–Herndon–Dudley syndrome, which is now known to feature thyroid hormone resistance.

In many countries, the clinical profile of primary hyperparathyroidism has changed to one with few of the disease's “classical” features. Although the reason for this change is unknown, various organs remain targets of the hyperparathyroid process. NIH treatment guidelines were recently updated, as the need for surgery in all patients remains controversial.

Many chronic diseases produce a condition called cachexia, which involves anorexia, decreased lean body mass and increased energy expenditure, worsening the prognosis for the underlying disease. This article describes a promising new approach to treating cachexia, targeting a key appetite-regulating center in the hypothalamus called the melanocortin system.

The level of insulin-like growth factor 1 (IGF-I) is influenced by many factors but, as detailed here, IGF-I measurements are useful to screen for growth hormone deficiencies in children and young adults. IGF-I levels are an excellent diagnostic test for acromegaly but are also useful to assess disease severity and the response to treatment.

This Review examines the biochemistry that underlies the behaviors of obesity, in particular the relationship between hyperinsulinemia and leptin resistance. Hyperinsulinemia promotes the behaviors of increased calorie intake, decreased exercise and altered hedonic reward responses to food that are associated with the current obesity epidemic.

Partly because of increased use of sonography, thyroid nodules are now detected more frequently but are usually asymptomatic. Very few thyroid nodules are malignant, and so management is particularly important but remains controversial. This Review details the various options available, and assesses the indications for each one.

This Review describes the many clinical, endocrine and genetic abnormalities that cause growth hormone (GH) insensitivity disorders, listing all the known GH-receptor mutations and describing the current therapy with insulin-like growth factor 1 (IGF1) and a novel therapy using complexes of IGF1 and IGF-binding protein 3.

This Review summarizes the data showing that adipocytes express the specific receptors for nearly all known pituitary hormones and hypothalamic releasing factors. The existence of a hypothalamic–pituitary–adipose axis is therefore most likely. The name “adipotropins” is suggested to characterize pituitary hormones and hypothalamic releasing factors that act directly on adipocytes.

At the molecular level, puberty remains an enigmatic process. This article details the discovery of a novel pathway involving GPR54 and its ligand, kisspeptin-1, in control of the gonadotropin-releasing-hormone pulsatility that characterizes sexual maturation and the female estrus cycle. These findings have clear implications for treatment of reproductive disorders.

As detailed in this Review, leptin seems to act primarily in states of energy deficiency, and common forms of obesity are characterized by leptin resistance. Clinical trials have shown leptin to be effective in subjects with relative or complete leptin deficiency.