Reviews & Analysis

Bisphosphonates are the drugs most widely used to treat osteoporosis, and can halve the vertebral fracture rate in postmenopausal women. This review details recent work that refines the dosing schedules of established drugs, alendronate and risedronate, and describes two new and potent bisphosphonates, ibandronate and zoledronate.

Disorders of sex development are poorly understood at the molecular level, which reflects in the outdated patient classification still in use. This review focuses on the extreme functional diversity of mutations affecting the main genes of the sex determination pathway (SRY, SOX9 and NR5A1) and the need for improved nomenclature.

Pituitary tumors exhibit variable growth and hormonal behaviors. The pathogenetic mechanisms underlying the neoplastic process include altered hormone regulation, growth factor stimulation, cell-cycle control and cell–stromal interactions due to genetic mutations or epigenetic changes of gene expression. These alterations are targets for the development of novel therapies.

The authors compare the treatment of hyperprolactinemic men and women using dopamine-receptor agonists bromocriptine and the newer drug cabergoline. They describe similarities and differences in treatment responses between genders, the pharmacological profile and safety of the two drugs, and new treatment algorithms in hyperprolactinemic syndromes.

Strategies for assessing and modulating LDL-cholesterol levels are central to preventing coronary artery disease; however, there is currently a great deal of interest in the diagnostic measurement of lipoprotein subclasses, including apolipoprotein B100-containing particles. This Viewpoint examines LDL subclass analysis and asks whether this technique has any clinical relevance.

Pituitary lesions discovered incidentally during a radiologic procedure performed for another reason are common. Pituitary incidentalomas have an autopsy prevalence of approximately 10%. Cost-effective strategies are needed to identify the uncommon lesions likely to cause harm, while avoiding unnecessary risk (and expense) to the majority of individuals with benign incidentalomas.

Two of the genes underlying Kallmann syndrome have been identified. As detailed here, studies of mutations in these genes in human and animal models give insight into the pathogenesis of this syndrome and provide valuable information about the normal development of the reproductive and olfactory systems.

Testosterone use as anabolic therapy is controversial. Here, meta-analyses show that testosterone increases skeletal muscle mass and strength in androgen-deficient young men, older men and men with chronic illness; these data provide a compelling rationale for the development of selective androgen receptor modulators that mimic testosterone's effects without its side effects.

Hereditary disease should be suspected in pheochromocytoma, even when the etiology is apparently sporadic. Mutations have been described inRET, VHL and NF1, as well as in the succinate dehydrogenase genes. The authors discuss the need for genetic screening in possible cases of familial pheochromocytoma and recommend which patients to screen and when.

Currently, surgery is the first-choice therapy for patients with acromegaly; adjuvant therapies include drugs such as somatostatin analogues, dopamine agonists, and a growth-hormone-receptor antagonist. As discussed here, such drugs may sometimes be preferable as primary therapy but there is a pressing need for randomized, controlled trials to establish this.

Ghrelin is produced mostly in the stomach and hypothalamus and has important roles in the release of growth hormone and in control of appetite. This article outlines the many potential clinical applications for ghrelin, which reflect its physiological activities.

The conditions enabling spermatogonial stem cells to be grownin vitro and transplanted in vivo, where they can restore fertility, are now well-established in murine systems. This review describes the features of these cells and their potential use in human cancer treatment, diseases affecting fertility, and potentially in gene therapy.

Strategies that preserve or perhaps increase the β-cell mass in the pancreas could prevent diabetes. There are promising immunomodulatory approaches that include giving at-risk subjects insulin across mucosal barriers, and treating affected patients with monoclonal antibodies that alter immune regulation.

Although medication for Graves' hyperthyroidism can be withdrawn without adverse effects for the patient, the data regarding the optimal duration of therapy are still unsatisfactory. This Viewpoint discusses how long treatment for Graves' disease should be continued and how withdrawal of antithyroid drugs might affect remission and relapse.

Neuroendocrine responses differ markedly in chronic critical illness compared with acute illness, and the chronic response may be harmful. Hyperglycemia is a major risk factor, and control of blood glucose is important. Because hypothalamic–pituitary axes interact during chronic illness, validating new therapies aimed at correcting multiple endocrine pathways seems warranted.

Administration of testosterone to men markedly reduces sperm counts and is a very efficient and well tolerated method of contraception. Combinations with progestogens or with gonadotropin-releasing hormone antagonists are even more effective and suggest that hormonal contraception in men is feasible and may be as effective as the currently used methods.

Thyroid cancer is the commonest endocrine malignancy, and drugs that target protein kinases offer a new approach in combating this and other malignancies. This review describes the various kinase targets in thyroid cancers, and details the inhibitors of the kinases RET and BRAF that are now in clinical trials.

Screening for mutations in theRETproto-oncogene has revolutionized management of multiple endocrine neoplasia type 2 (MEN2), although controversy still exists regarding the timing and extent of surgical intervention. This Viewpoint discusses the relationship between genotype and phenotype in MEN2 and describes strategies to determine the appropriate age for patients to undergo thyroidectomy.