Reviews & Analysis

Elevated levels of growth hormone (GH) and insulin-like growth factor 1 (IGF1) in conditions such as acromegaly have been implicated in increased cardiovascular risk. The authors of this Viewpoint argue, however, that hormone deficiency might pose a greater risk than hormone excess, and ask the question—what levels of GH and IGF1 can be considered 'safe'?

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.

Ovarian hyperstimulation syndrome (OHSS) is a complication of pregnancy caused by an excessive response to follicle-stimulating hormone (FSH). OHSS can arise spontaneously or after exogenous FSH administration duringin vitrofertilization procedures. Novel genetic predictors of OHSS, including mutations and polymorphisms of the FSH receptor, are described in this Viewpoint.

Prader–Willi syndrome (PWS) is associated with uncontrolled appetite and morbid obesity. Management of PWS is particularly challenging and requires the involvement of both the family and health-care providers, as well as the affected individual. In this Viewpoint the efficacy of the strategies currently used to control obesity in PWS is discussed.

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.

Experimental studies have implicated GH in the initiation and/or promotion of tumorigenesis, suggesting that patients treated with GH might be at increased risk of cancer. In this Viewpoint, the author reviews several cohort studies and finds that GH therapy could be associated with an elevated incidence of cancer, particularly of the colon.

Although there is some evidence that high levels of GH might cause cancer, patients with acromegaly do not have an increased cancer incidence. This Viewpoint argues, therefore, that GH replacement therapy is not associated with an increased risk of malignancy and that the benefits of treatment probably outweigh the perceived risks.

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.

Gene expression profiling techniques have revolutionized molecular biology, allowing researchers to analyze the expression of thousands of genes in a single assay. This Viewpoint asks whether microarray technology can also be applied to clinical practice, and focuses on the diagnosis, prognosis and risk stratification of thyroid carcinoma.

FDA regulation of levothyroxine formulations aims to ensure consistent drug content and bioavailability of brand name and generic products. This Viewpoint suggests that the pharmacokinetic measure of therapeutic equivalence in current use—measurement of total T₄levels in the blood—might not be sufficiently reliable to achieve these goals.