Realized Hope: Leveraging Our Modern Understanding of Human Biology To Fulfill the Decades-old Promise of a Miracle Drug

In 1950, three scientists at the Mayo Clinic were awarded the Nobel Prize for the introduction of “steroid” (glucocorticoid) medicines. From the time the first experimental dose was administered in a clinical trial, the discovery took the medical world by storm. Some of the early patients who received the drug had severe cases of rheumatoid arthritis, and the increase in mobility they experienced after taking steroids was so miraculous that Life Magazine published a feature story on the discovery. Patients literally walked out of their wheelchairs.

More than 70 years after their discovery, steroids remain among the most prescribed drugs in the world. Steroids are extremely effective in treating many inflammatory and immune diseases. They can offer life-changing symptom relief for a range of conditions including rheumatoid arthritis, polymyalgia rheumatica, inflammatory bowel disease, asthma, and allergies. They also are used to prevent organ rejection in transplant patients and as an adjunct to cancer chemotherapy.

It was not long after glucocorticoids were discovered, however, that a dismaying reality became apparent: the miracle drug that offered hope for patients with severely debilitating diseases came with side effects of such magnitude that many patients, such as those featured in Life Magazine, chose to live with their disease rather than take the medicine. The consequences range from the concerning and unpleasant, such as weight gain, mood changes, and sleep disturbances, to the serious and life-threatening, such as psychosis, heart disease, fractures, hypertension, and diabetes.

The dangers of excess glucocorticoids are also revealed in two conditions in which a tumor produces excess steroids. Endogenous Cushing’s syndrome is a rare but extremely serious condition that is caused by a tumor that either directly or indirectly leads to the overproduction of cortisol, the natural glucocorticoid made by the adrenal gland. Cushing’s is characterized by physical changes such as weight gain, a fatty hump between the shoulders, a rounded face, and wide purple stretch marks, and can lead to many of the same issues experienced by patients taking high doses of steroid medicines: diabetes, infection susceptibility, high blood pressure, high cholesterol, fractures, depression, and memory loss. Left untreated the outcomes are often fatal, with a five-year survival rate of fifty percent.

Much more common than endogenous Cushing’s is autonomous cortisol secretion, or ACS, a less severe form of hypercortisolism. ACS is sometimes incorrectly referred to as subclinical Cushing’s syndrome, but it rarely progresses to Cushing’s. The condition is typically diagnosed when an otherwise benign adrenal tumor shows up on a scan for an unrelated health condition and the patient subsequently receives an adequate endocrine workup that identifies the tumor as cortisol-producing. Up to three million Americans may be affected, but as few as three percent of patients with ACS are currently diagnosed. Patients with ACS have many of the same health risks as those with Cushing’s, including higher risks of developing diabetes and experiencing a fracture. Without treatment, the risk of a heart-damaging cardiovascular event, such as heart attack, is increased, and the risk of dying increases with the increasing level of cortisol production.

The 70-year response of the scientific and medical communities to the availability of steroid medicines could be characterized as a “lesser-evil” approach. Many physicians are highly reluctant to prescribe steroids to patients, but without similarly efficacious options, they are left to balance patient pain and suffering against the deleterious side effects of the medicine.

The pharmaceutical industry has taken a different tactic, aiming to set steroids aside for newer treatments, ones that offer much-needed efficacy without the many of the harmful risks. However, many of the newer biologics in the autoimmune space carry their own risks and do not have the same level of efficacy that steroids do for many rheumatologic conditions.

There are even some conditions for which there are no effective treatment options other than steroids. For example, for the millions of adults over 50 years of age around the world who suffer from polymyalgia rheumatica (PMR), glucocorticoids are the treatment of choice. PMR, an autoimmune condition, is characterized by pain and stiffness mainly in the arms and legs that leads to fatigue and impairment of physical function. Patients with PMR often are prescribed steroids for years. While many patients eventually taper completely off steroids, they can continue to suffer health consequences from prolonged steroid exposure. Many subsequently experience disease flares necessitating repeated periods of steroid administration.

Despite the host of issues surrounding steroid medicines, glucocorticoids still occupy a critical role in modern medical care. While traditional thinking has urged a cautious approach to their use, and the pursuit of alternatives, I believe that our modern scientific understanding of human biology equips us to realize the full potential of glucocorticoids while mitigating many of their severe side effects.

Science has shown that certain tissues of the body, such as the kidney, have an enzyme called HSD-2 that works intracellularly to convert cortisol, the naturally occurring steroid, into its inactive form, cortisone. HSD-2 allows the kidney to reduce intracellular levels of cortisol, which can cause salt retention and raise blood pressure. Other tissues, such as the liver, fat, brain, skin, and bone, have a different enzyme, HSD-1, which also works intracellularly to convert cortisone back into active cortisol. HSD-1 and HSD-2 work similarly on cortisol analogues such as prednisolone that are commonly prescribed as steroid medicines. In essence, the peripheral tissues in the body are equipped with a natural function to deactivate and reactivate glucocorticoids at the intracellular level, and it is only active steroids available intracellularly that can act on their receptors to cause undesirable effects.

There is now an opportunity to leverage our understanding of these de- and reactivation processes to intentionally modulate the levels of active steroids that are available intercellularly. Our current understanding indicates that this reactivation of glucocorticoids is responsible for much of steroid toxicity in key tissues. By inhibiting the enzyme involved in the reactivation process, HSD-1, we can limit excess exposure at the intracellular level and thereby potentially mitigate many of the harmful side effects historically associated with steroids. However, intriguingly, HSD-1 does not appear to play as major a role in the immune system, where steroids act to cause their desirable, anti-inflammatory, effects. Therefore, a combination of an effective steroid and a HSD-1 inhibitor may be able to retain the desired efficacy of the steroid while mitigating its dangerous side effects.

In essence, we are expanding the traditional perspective of cortisol as only an endocrine effector, manufactured in one part of the body and transported in its active form to another via the bloodstream, to include the understanding of cortisol as an autocrine effector, a substance that can be activated within a target cell. We shift our focus from consideration of the amount of circulating cortisol and other glucocorticoids to one that focuses on the conversion of inactive steroids to active steroids at the intracellular level.

Seventy-four years ago, patients received hope for a medical miracle. Despite the disappointments which have accompanied that hope, steroids continue to play an important role in the treatment of debilitating symptoms of many autoimmune and other conditions. Now equipped with decades of advances in our understanding of human biology, the time has come to innovate and execute on that promise so that patients and their physicians do not need to balance relief from disease with risk for harm. Now is the time to fulfill the hope of glucocorticoids for patients.

Photo: metamorworks, Getty Images