Adrenal Archives - GT health

New FDA approval: oral medication for Cushing’s disease

Cushing’s syndrome (CS) is a rare condition. It’s health consequences can be severe, leading to visceral adiposity, muscle weakness, depression, insulin resistance, diabetes, blood clots, reduced immune system, and cardiovascular disease.

A portion of patients diagnosed with CS has Cushing’s disease (CD). In Cushing’s disease, the root cause of hypercortisolism is a pituitary tumor producing excessive ACTH hormone. The preferred treatment is pituitary surgery. Unfortunately, in a small subset of patients, the operation is not successful or indicated.

To address the health concerns for individuals who are not responsive or candidates for pituitary tumor resection, the FDA has now approved a backup treatment via the oral drug Isturisa.

Isturisa, taken twice daily, is a potent inhibitor of 11-β-hydroxylase, a key enzyme in cortisol production. Side effects can include relative adrenal insufficiency, swelling, nausea, vomiting, and headaches. Clinical studies have shown that about 50% of patients respond to therapy.

Isturisa is an excellent addition to the arsenal of combating refractory Cushing’s disease.

Dr. Tashko

Levoketoconazole therapy for Cushing’s syndrome

Cushing’s syndrome is defined by a persistent or cyclical increase in blood cortisol concentrations. The professional diagnosis is based on two or more positive tests: low dose dexamethasone suppression, late-night salivary cortisol, or 24-hour urinary free cortisol.

Surgery is the treatment of choice, which often leads to a permanent cure. However, not infrequently, the source of hypercortisolism cannot be identified, or surgical intervention is not sufficient. In such circumstances, medical therapy is preferred over watchful waiting.

SONICS was a phase 3, open-label, non-randomized clinical trial. Its investigators tested the utility of levoketoconazole in normalizing urinary cortisol levels in 94 adults with uncontrolled Cushing’s syndrome.

After full dose titration and 6-month maintenance therapy, about 30% of patients achieved the desired outcome, as defined by normalized urinary cortisol concentrations. The rate of adverse events was not insignificant: nausea 32%, headaches 28%, study discontinuation 13%, and increased liver enzyme in 11% of participants.

Although the study results are not stupendous, they are meaningful and provide additional options for patients with refractory or uncontrolled Cushing’s syndrome.

Primary hyperaldosteronism in obesity

In this retrospective study, investigators analyzed a group of 400 adults with hypertension due to primary hyperaldosteronism. The study found that obese patients had smaller aldosterone-producing tumors than lower BMI counterparts. It appears that obese individuals had more aggressive – higher functioning – tumors in spite of their smaller size. Adrenalectomy led to a similar clinical outcome – blood pressure improvement – in patients with or without high BMI. Although these results need to be confirmed, it would be useful for endocrinologists, radiologists, and surgeons to be aware of this phenotype.

Right adrenal tumors are frequently missed

A serious article analyzing the prevalence of left-sided vs. right-sided adrenal tumors. Prior observations have consistently shown that left-sided adenomas are more common than right-sided ones, in 2:1 ratio.

Although a reason could be embryological, leading to a greater left adrenal vascularity, innervation, volume and mass; authors suggest that asymmetry could also be due to anatomical locations of the glands.

The left adrenal gland is surrounded by the hypo-attenuated visceral fat, making it easier to be seen by imaging, versus the right gland which is somewhat compressed by the relatively hyper-attenuated liver and kidney.

Authors’ argument is compelling enough that clinicians should be aware of possibly missing right-sided adrenal tumors, especially in the context of hyper-functionality; elevated catecholamines, cortisol, aldosterone and DHEAs.

Late-night salivary cortisol measurements are not consistent in cushing disease

The study reveals that late-night salivary cortisol (LNSC) measures are variable in cushing disease, particularly in those with recurrent or persistent illness. Less variability was seen in new cases of the disease who had not undergone treatment. Hypercortisolemia is expected to be lower in treated vs. untreated patients, thus it is reasonable to suspect similar inconsistencies in LNSC values in those with subtle hypercortisolemia, frequently seen with adrenal adenomas.

A rare source of cushing’s syndrome: ovary

Cushing’s syndrome (CS) is a rare illness that leads to visceral adiposity, muscle wasting, insulin resistance, osteoporosis, diabetes, blood clots, high blood pressure, dyslipidemia and frequent infections. Subsequently, affected individuals have increased mortality rates.

The most common cause of the syndrome is a pituitary tumor, otherwise called cushing disease. Although rare, other organs also have the potential of producing excessive cortisol. The article describes a unique case of CS where the source is a right ovarian mass. The selective ovarian and adrenal venous sampling was important in confirming the diagnosis, and eventually driving the therapy.

How to supplement the real adrenal fatigue

Results of the article suggest that longer-acting cortisol-equivalent supplementation is more beneficial than conventional therapy with multiple daily doses of hydrocortisone in adults with adrenal insufficiency. Advantages are reduced body weight, heightened immunity, less recurrent infections, and improved quality of life. A group of 89 participants were followed for 6 months.

Adrenal hormones are useful in sepsis

This is a major trial evaluating the usefulness of hydrocortisone and fludrocortisone during septic shock. About 12,000 patients were followed for 30-120 days. Compared to placebo, high doses of adrenal hormone equivalents improved 90-day death rates significantly. This is a step forward in improving the care of the deadly condition.

Pituitary disorders caused by cancer immunotherapy

Cancer immunotherapy is becoming more common due to its specificity and efficacy. However endocrinopathy is an undesirable byproduct. Ipilimumab, approved for melanoma, has shown to cause pituitary anomalies in 10-15% of patients.

Current report reveals two cases of hypophysitis caused by a different immunotheraputic agent, atezolizumab. Unlike Ipilimumab, atezolizumab seems to have a higher inclination for corticotroph destruction leading to late-onset central adrenal insufficiency.

It is important to be aware of endocrine disorders associated with cancer immunotherapy as early diagnosed and management could be life saving.

The other aldosterone blocker, eplerenone, helps with hypertension

The aim of this review was to determine the effectiveness of eplerenone for reducing blood pressure, its side effect profile, and its impact on clinically meaningful outcomes such as mortality and morbidity.

Clinicians have used eplerenone to treat high blood pressure since 2002. It is important to determine the clinical impact of all antihypertensive medications used in patients to support their continued use in essential hypertension.

The eplerenone dose ranged from 25-400 mg daily. Patients were followed for 8-16 weeks while on therapy. There is currently no evidence that eplerenone has a beneficial effect on life expectancy or complications related to hypertension.

The study finds that eplerenone 50-200 mg/day reduces systolic BP by approximately 9 mmHg and diastolic BP by 4 mmHg compared to taking no medication.

CDSR

Aldosterone vs. renin, a cardiometabolic cat-and-mouse game

Study results are important from several aspects. It confirms prior findings that excess aldosterone increases cardiometabolic sequelae, like cardiovascular events, diabetes, atrial fibrillation and mortality, independent of high blood pressure.

More importantly the study guides us on how to objectively reduce the above risks: the dose of mineralocorticoid receptor antagonists, such as spironolactone or eplerenone, could be adjusted to achieve higher plasma renin activity of ≥1 μg/L/hr.

Plasma renin activity is clinically available and a good biochemical measure of hyperaldosterone end-product, as shown in the figure below.

Adrenal-diabetes connection

Diabetes and prediabetes are the most common endocrine conditions affecting about 38% of the US population. Adrenal tumors on the other hand are relatively rare with prevalence of < 10%. Results of the article suggest that adrenal tumors, even when “benign” or “nonfunctional”, can contribute to the development of diabetes and prediabetes.

Apparently “benign” adrenal masses could be an independent risk factor for glucose dysmetabolism. Should patients with diabetes be screened for such tumors? If present, would surgical or medical intervention reduce this risk?