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The undervalued endocrine system

Insulin, tamoxifen, EPO – just a few examples of life-saving, blockbuster drugs from endocrinology research.

“Hormones are responsible for homeostasis, maintaining our internal environment,” says Professor Saffron Whitehead, Department of Basic Medical Sciences, St George’s University of London, “so they regulate every system in the body.” This puts endocrinology, the study of hormones, at the center of life sciences.

Everything makes hormones

Just look at the breakthroughs in the field in the last 20 years, says Whitehead, coauthor of Endocrinology: An Integrated Approach, and Clinical Endocrinology. We’ve discovered so many new hormones and tissues that produce them that she says, “I think we’ll find that everything makes hormones.” Examples are leptin (an adipokine) from fat and myostatin (a myokine) from muscle.

“The human genome sequence,” says Whitehead, “is contributing to the rapid identification of hormones and their functions. Leptin, myostatin, and now osteocalcin, for instance, are all implicated in regulating energy stores, obesity and diabetes.

Despite their central function, hormones are somewhat neglected, says Whitehead. We hear about athletes boosting performance with erythropoetin (EPO), which promotes red blood cell production, but in clinical settings, hormones are often overlooked. Doctors treating depression or high blood pressure, for example, might not consider the link between such conditions and high levels of the stress hormone cortisol. Better training, says Whitehead, would help clinicians be more aware of how integral hormones are to health.

Potential for translation

Hormone research has an impressive translation record. For instance, the discovery of osteoprotegerin in the late 1990s led to an osteoporosis treatment in the 2000s. Many hormone-based drugs are easily administered by simple injection. The classic example is insulin.

But despite nine decades of treating diabetes with insulin, we are still learning about the condition, in part through studies on endocrine connections. Professor Karin Dahlman-Wright worked on metabolic diseases at Pharmacia and Upjohn before moving to the Department of Bioscience at Karolinska Institute in 2000 to work on estrogen signaling, focusing on breast cancer and type 2 diabetes. A major advance in breast cancer treatment has been identifying tumors with high levels of estrogen receptors that respond to anti-estrogens like tamoxifen. Studies on knockout mice and observations of humans, including on anti-estrogens, show a link between estrogen and metabolism, cardiovascular disease, obesity, and type 2 diabetes.

“Estrogen improves the conditions of type 2 diabetes,” says Dahlman-Wright, “so estrogen therapy might provide therapeutic opportunities for diabetes, assuming it could be made selective, to avoid side effects.”

This is the double-edged sword of hormones: they influence multiple conditions, making them and their receptors useful drugs and drug targets. But they affect many tissues, leading to unwanted side effects. “We don’t know how to make estrogen act only on particular tissues,” says Dahlman-Wright. “If we could make a drug tissue specific, like estrogenic only in the liver or muscle, that would be an enormous breakthrough.”

An approach that Dahlman-Wright’s group takes to understand the tissue specificity of hormones like estrogen is studying proteins that interact with hormone receptors. “The receptors are found in many tissues,” says Dahlman-Wright, “so maybe the key to controlling responses is identifying tissue-specific proteins that modulate the receptor’s function.” These could be therapeutic targets, she says.

Future directions for endocrinology

Dahlman-Wright uses high-throughput methods to study links between estrogen and diseases such as breast cancer and diabetes. A current unmet need, she says, is “understanding molecular mechanisms of metabolic disease”. What genetic variants, what epigenetic modifications are involved in their development? What factors in the environment modulate individual sensitivity to disease and which of these can we influence?

Her group is investigating how hormones and lifestyle changes affect epigenetics such as DNA methylation (see “The Epigenetic Effects of Exercise,” page 26). Epigenetic signatures, protein markers, and genetic variants related to diabetes, she says, could be used to match patients to effective treatments, or predict disease so we can prevent or delay its onset.

Other possibilities for new endocrinology applications, says Saffron Whitehead, include hormonal control of appetite, for obesity. The hormone kisspeptin, whimsically named for Hershey’s kisses, is being tested as a therapy for reproductive disorders. Treatment of endocrine deficiencies could be transformed by coaxing stem cells into thyroid, pancreatic, and other hormone-secreting tissues. Endocrinology is a field to watch, with every tissue, organ system, and human condition affected by hormones: “They really come into every branch of medicine,” says Whitehead.

 

 

 

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