Study Examines Therapy Options for Post-adrenalectomy Low Glucocorticoid Levels

Hydrocortisone and prednisone have comparable safety and effectiveness when used as glucocorticoid replacement therapy in patients with adrenal adenoma or Cushing’s disease who underwent adrenalectomy, a new study shows.

The study, “Comparison of hydrocortisone and prednisone in the glucocorticoid replacement therapy post-adrenalectomy of Cushing’s Syndrome,” was published in the journal Oncotarget.

The symptoms of Cushing’s syndrome are related to excessive levels of glucocorticoids in our body. Glucocorticoids are a type of steroid hormones produced by the adrenal gland. Consequently, a procedure called adrenalectomy – removal of the adrenal glands – is usually conducted in patients with Cushing’s syndrome.

Unfortunately, adrenalectomy leads to a sharp drop in hormones that are necessary for our bodies. So, post-adrenalectomy glucocorticoid replacement therapy is required for patients.

Hydrocortisone and prednisone are synthetic glucocorticoids that most often are used for glucocorticoid replacement therapy.

Treatment with either hydrocortisone or prednisone has proven effective in patients with Cushing’s syndrome. However, few studies have compared the two treatments directly to determine if there are significant advantages of one therapy over another.

Chinese researchers set out to compare the effectiveness and safety of hydrocortisone and prednisone treatments in patients with Cushing’s syndrome, up to six months after undergoing adrenalectomy.

Patients were treated with either hydrocortisone or prednisone starting at day two post-adrenalectomy. The withdrawal schedule varied by individual patients.

At baseline, both groups had similar responses to the adrenalectomy, including the correction of hypertension (high blood pressure), hyperglycemia (high blood glucose levels), and hypokalemia (low potassium levels). Furthermore, most patients in both groups lost weight and showed significant improvement, as judged by a subjective evaluation questionnaire.

Hydrocortisone did show a significant advantage over prednisone in the improvement of liver function, but its use also was associated with significant swelling of the lower extremities, as compared to prednisone.

Patients in both groups went on to develop adrenal insufficiency (AI) during glucocorticoid withdrawal. However, there were no significant differences in the AI incidence rate – 35 percent in the hydrocortisone group versus 45 percent in the prednisone group. The severity of A also was not significantly different between the groups.

Furthermore, most of the AI symptoms were relieved by going back to the initial doses of the glucocorticoid replacement.

As there were no significant differences between the two treatments, the findings support “the use of both hydrocortisone and prednisone in the glucocorticoid replacement therapy post-adrenalectomy for patients of adrenal adenoma or Cushing’s disease,” researchers concluded.


Cortisol Modulator Shows Early Signs of Safety, Efficacy in Healthy Volunteers

The glucocorticoid receptor antagonist CORT125134 is safe and has shown preliminary signs of efficacy in healthy volunteers participating in a Phase 1 trial, say researchers in England.

Their study, “Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double-Blind, Randomized, Placebo-Controlled Phase 1 Clinical Study,” appeared in the journal Clinical Pharmacology in Drug Development.”

Cortisol signaling is indirectly controlled by the glucocorticoid receptor (GR). When cortisol binds the GR, the receptor becomes activated and migrates to the nucleus, where it regulates the expression of many genes. This influences a myriad of processes, including inflammation, immune response and brain function.

CORT125134, also known as relacorilant, is being developed by Corcept Therapeutics of Menlo Park, California, for Cushing’s disease patients and others who may benefit from it. The drug is a GR antagonist, blocking the receptor’s activity.

In order to evaluate the safety and tolerability of CORT125134, and learn how it behaves in the body, Corcept researchers conduced a Phase 1 trial in healthy subjects.

The British study, conducted at the Quotient Clinical in Nottingham, included 81 adults who received a single ascending-dose of CORT125134 or placebo, and 48 subjects who received multiple-ascending doses of the drug versus placebo.

Single doses were tested in nine distinct groups. Six tested six different doses of CORT125134, one tested a 150 mg dose in subjects receiving a high-fat meal, and two groups included patients receiving prednisone (a well-known GR activator), prednisone plus Korlym (mifepristone), or prednisone plus CORT125134.

Korlym is a medicine approved for Cushing’s  patients with high blood sugar levels due to high cortisol in circulation. But the drug targets the progesterone receptor and is associated with side effects like pregnancy termination and irregular vaginal bleeding.

Multiple doses, given for up to 14 days, were tested in four additional cohorts. Researchers observed that CORT125134 was rapidly absorbed and eliminated, presenting a suitable profile for once-daily dosing.

Efficacy was determined by CORT125134’s ability to counteract the effects of prednisone. In addition, a single dose of 500 mg or multiple dosing with 250 mg had similar effects as those seen with 600 mg of Korlym — the therapeutic dose used for Cushing’s treatments.

Most common treatment-related adverse events reported in the single-ascending dose part of the study were nausea, vomiting and thirst; most were mild. In those given multiple-ascending doses, adverse events included mild musculoskeletal and connective tissue disorders, as well as gastrointestinal system disorders.

Multiple 500 mg doses exceeded the maximum tolerated dose, as it led to musculoskeletal symptoms that forced researchers to stop treatment.

“This first-in-human study has demonstrated that CORT125134 is well tolerated following single doses up to 500 mg and repeated doses up to 250 mg once daily for 14 days,” researchers wrote. “Pharmacological activity was confirmed following the administration of a single 500-mg dose and daily administration of 250 mg.”

Corcept is now enrolling participants into a Phase 2 open-label trial (NCT02804750) to evaluate CORT125134 in patients with Cushing’s syndrome. This trial is being conducted in the United States and Europe and will include 80 participants. Top-line results are expected in the first quarter of 2018.


Hydrocortisone Dosing for Adrenal Insufficiency

In a randomized crossover study, higher doses resulted in modestly higher blood pressure.

No universally accepted glucocorticoid replacement dose exists for patients with adrenal insufficiency. When hydrocortisone is used, divided doses often are given to mimic natural diurnal variation (higher dose early, lower dose later). In this double-blind crossover study, researchers compared the blood pressure effects of higher and lower hydrocortisone doses in 46 Dutch patients with secondary adrenal insufficiency. Each patient received courses of high-dose and low-dose hydrocortisone (10 weeks each, in random order), according to a dosing protocol. For example, a 70-kg patient received 15 mg daily during the low-dose phase (7.5 mg, 5.0 mg, and 2.5 mg before breakfast, lunch, and dinner, respectively), and twice these amounts during the high-dose phase.

Mean blood pressure was significantly higher at the end of the high-dose phase, compared with the low-dose phase (systolic/diastolic difference, 5/2 mm Hg). Plasma renin and aldosterone levels were lower with high-dose than with low-dose hydrocortisone, presumably reflecting hydrocortisone’s mineralocorticoid activity.


Although the higher blood pressure with high-dose hydrocortisone was modest, it conceivably could be consequential over many years of treatment. However, these researchers have published quality-of-life outcomes from this study elsewhere (Neuroendocrinology 2016; 103:771), and those outcomes generally were better with high-dose than with low-dose therapy. This study was too brief to be definitive, but it does highlight potential tradeoffs involved in glucocorticoid dosing for adrenal insufficiency. Whether the findings apply to patients with primary adrenal insufficiency is unclear.


  • Disclosures for Allan S. Brett, MD at time of publication Nothing to disclose



Cushing’s Syndrome and Skin Problems

By Afsaneh Khetrapal, BSc (Hons)

Cushing’s Syndrome (sometimes called hypercortisolism) is a hormonal disease caused by an abnormally high level of the hormone cortisol in the body. This may arise because of an endogenous or exogenous source of cortisol. Endogenous causes include the elevated production of cortisol by the adrenal glands, while exogenous causes include the excessive use of cortisol or other similar steroid (glucocorticoid) hormones over a prolonged period of time.

The adrenal glands are situated just above each kidney, and form part of the endocrine system. They have numerous functions such as the production of hormones called catecholamines, which includes epinephrine and norepinephrine. Interestingly, the outer layer (cortex) of the adrenal glands has the distinct responsibility of producing cortisol. This hormone is best known for its crucial role in the bodily response to stress.

At physiologically appropriate levels, cortisol is vital in maintaining normal sleep-wake cycles, and acts to increase blood sugar levels. It suppresses the immune system, regulates the effect of insulin on the metabolism of fats, proteins, and carbohydrates, and help with the homeostasis of water in the body.

Exogenous corticosteroids can also lead to Cushing’s syndrome, when they are used as a form of long-term treatment for various medical conditions. In fact, the long-term use of steroid medication is the most common reason for the development of Cushing’s syndrome.

Prednisolone is the most commonly prescribed steroid medicine. It belongs to a class of medicine that is sometimes used to treat conditions such as certain forms of arthritis and cancer. Other uses include the rapid and effective reduction of inflammation in conditions such as asthma and multiple sclerosis (MS), as well as the treatment of autoimmune conditions such as lupus erythematosus, and rheumatoid arthritis.

Overall, Cushing’s syndrome is quite uncommon and affects approximately 1 in 50,000 people. Most of them are adults between the ages of 20 and 50.  Women are 3 times more commonly affected than men. Additionally, patients who are obese, or those who have type 2 diabetes with poorly controlled blood sugar and blood pressure show a greater predisposition to the disorder.

Symptoms of Cushing’s syndrome

There are numerous symptoms associated with Cushing’s syndrome, which range from muscle weakness, hypertension, curvature of the spine (kyphosis), osteoporosis, and depression, to fatigue Specific symptoms which pertain to the skin are as follows:

  • Thinning of the skin and other mucous membranes: the skin becomes dry and bruises easily. Cortisol causes the breakdown of some dermal proteins along with the weakening of small blood vessels. In fact, the skin may become so weak as to develop a shiny, paper-thin quality which allows it to be torn easily.
  • Increased susceptibility of skin to infections
  • Poor wound healing  of bruises, cuts, and scratches
  • Spots appear on the upper body, that is, on the face, chest or shoulders
  • Darkened skin which is seen on the neck
  • Wide, red-purple streaks (at least half an inch wide) called striae which are most common on the sides of the torso, the lower abdomen, thighs, buttocks, arms, and breasts, or in areas of weight gain. The accumulation of fat caused by Cushing’s syndrome stretches the skin which is already thin and weakened due to cortisol action, causing it to hemorrhage and stretch permanently, healing by fibrosis.
  • Acne: this can develop in patients of all ages.
  • Swollen ankles: this is caused by the accumulation of fluid, called edema.
  • Hyperhidrosis (excessive sweating)

Reviewed by Dr Liji Thomas, MD


Long-term Cognitive Effects of Glucocorticoid Excess in Cushing’s Syndrome

Psychoneuroendocrinology. 2016 Mar;65:26-33. doi: 10.1016/j.psyneuen.2015.11.020. Epub 2015 Nov 30.

Forget H1, Lacroix A2, Bourdeau I2, Cohen H3.



We previously found that patients with Cushing’s syndrome (CS) scored lower than controls in several domains of cognitive function and that correction of hypercortisolism is not necessarily correlated with short-term improvement in intellectual performance. Here, we examined the long-term outcome in patients treated for CS by assessing the extent to which the detrimental effects of glucocorticoid (GC) excess on cognition can be reversed three years after corrective surgery.


A battery of neuropsychological tests, including tests of attention, visuospatial processing, learning and memory, and executive functioning were administered pre-treatment and 12, 24 and 36 months post-treatment.


We included 18 patients with endogenous CS recruited before surgical treatment and 18 controls matched for age, sex and education.


CS patients performed worse than controls on tests of attention, executive functioning and nonverbal aspects of memory. Moreover, at 36 months following eucortisolism, executive function performance and, to a lesser extent, attention tasks showed limited change compared to pre-treatment testing.


Chronic hypercortisolism is accompanied by a deleterious impact on aspects of cognitive function. This negative effect on attention, executive performance and nonverbal memory seen in patients with CS suggests a differential effect of excess GCs upon different brain areas and networks. This influence persists years after the return to normal cortisol secretion levels.

Copyright © 2015 Elsevier Ltd. All rights reserved.


Attention; Cognitive functions; Endogenous Cushing’s syndrome; Glucocorticoids; Hypercortisolism; Memory

[PubMed – in process]


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