“Doctor, since I was successfully treated for Cushing’s syndrome, I have lost a lot of weight but my abdominal fat will just not go away.” This is a sentence that many endocrinologists frequently hear, and something you, as patients, may also recognize. This article will focus on the long-term effects of pituitary or adrenal Cushing’s on fat (adipose tissue).

Adipose tissue distribution during active Cushing’s syndrome

It is well known that when a patient gets Cushing’s syndrome the distribution of the adipose tissue over the body will change: Fat will accumulate especially around the organs (visceral adipose tissue), and under the skin (subcutaneous adipose tissue) of the abdomen, while the subcutaneous adipose tissue compartments of the extremities (arms and legs) will diminish. This process is irrespective of overall weight gain and results in a centripetal adipose tissue distribution.

Definitions

• visceral adipose tissue: fat that accumulates inside the body, particularly around internal organs
• subcutaneous adipose tissue: fat that accumulates under the skin
• centripetal adipose tissue: the fat, both visceral and subcutaneous that accumulates in the abdominal area
• adipokines: homones secreted by fat tissue including adiponectin, leptin and resistin.

Besides the fact that many people do not think that abdominal fat is very attractive, why should we be concerned about a centripetal adipose tissue distribution?

The answer to this question is quite straightforward: Abdominal fat, and especially visceral adipose tissue, is strongly associated with metabolic diseases like diabetes and cardiovascular diseases of the heart and blood vessels. This can be explained by the fact that adipose tissue is an important endocrine organ. It secrets multiple hormones, called adipokines, which can communicate with the brain, heart, blood vessels, liver, and muscle. These adipokines can be pro-inflammatory or anti-inflammatory, and their balance is crucial to staying healthy. Research in people with normal obesity (caused by an unhealthy diet) has shown that obesity causes adipose tissue dysfunction which leads to dysregulated adipokine production. This leads to the development of a systemic state of low-grade, chronic inflammation which contributes to the development of metabolic and cardiovascular diseases. An adverse adipokine profile has also been shown to be present during Cushing’s syndrome.

Does a centripetal adipose tissue distribution persist after long-term cure of Cushing’s syndrome as patients suggest?

To answer this question we investigated the adipose tissue distribution, adipokine profiles and metabolic risk profiles of 58 patients (both men and women) who had been cured from Cushing’s syndrome (of both pituitary and adrenal origin) for at least 5 years[1]. Each patient underwent an extensive clinical evaluation with measurement of weight, height, blood pressure, heart rate, skin fold thickness and measurement of waist, hip and arm circumferences. Furthermore blood was drawn for determination of laboratory parameters associated with cardiovascular risk and adipokine profiles and a dual-energy X-ray absorptiometry scan was performed. A DEXAscan can accurately measure the percentage of fat and lean body mass in different body compartments. We compared the results of the patients with the results of a healthy control group matched one on one for age, gender and body mass index.

We found that, compared to the matched control subjects, patients in long-term remission of Cushing’s syndrome had:

• a greater waist circumference (the mean (sort of average) difference was 4.6 cm)
• a smaller thigh circumference (mean difference 3.1 cm)
• a higher waist-to-hip ratio
• a higher hip-to-thigh ratio

As measured with DEXA scanning, patients had a higher percentage of abdominal fat mass, and the abdominal fat mass to leg fat mass ratio was greater. Furthermore patients had an adverse adipokine profile, with lower adiponectin levels, higher leptin levels, and higher resistin levels, than control subjects, which is indicative of adipose tissue dysfunction and is associated with low level chronic inflammation. Furthermore patients had higher triglyceride levels (a kind of fat in your blood) and higher levels are associated with increased cardiovascular risk.

We concluded that even after long-term remission, patients who suffered from Cushing’s syndrome in the past continue to have a centripetal adipose tissue distribution and an adverse adipokine profile. Large epidemiological studies suggest that the cardiovascular risk of patients that have been successfully treated for Cushing’s syndrome still seems to be increased (though only mildly) compared to the normal population. The persistent centripetal obesity and adverse adipokine profiles probably contribute to this persistent increased cardiovascular risk.

In order to reduce cardiovascular risk it is important to lead a healthy lifestyle with enough exercise and moderate caloric intake. If you smoke it is extremely important to stop smoking because this increases your cardiovascular risk much more than the fact that you had Cushing’s in the past. Furthermore, if you have persisting co-morbidities like diabetes, hypertension or hormonal deficiencies it is very important that they are well controlled with medication. If you do all these things, it is very well possible that, despite the fact that there is persisting centripetal fat and an adverse adipokine profile, your cardiovascular risk is comparable to a healthy person of the same age, gender and BMI.

At present adipokines are only measured for research purposes. In clinical practice they are not (yet) measured to estimate cardiovascular risk as there are no reference values and there is still uncertainty as to the exact function of each adipokine.

So why do some people lose more weight/abdominal fat than others after cure of Cushing’s syndrome?

First of all, of course, an active life style with a moderate caloric intake is important if you want to lose fat, and lifestyle explains a lot of the differences that are seen between patients. However, in our study we investigated whether other patient related parameters (like if they had had Cushing’s syndrome of pituitary or adrenal origin, the treatments they received, the presence of hormonal deficiencies, the use of alcohol and smoking) were associated with a more centripetal adipose tissue distribution. We only found a small association between smoking and a greater waist circumference, and between the use of mineralocorticoid substitution therapy (e.g. fludrocortisone, which is needed if both adrenals have been removed) and a higher abdominal fat percentage.

In contrast to what we found, a more recent study showed that patients who use glucocorticoid replacement therapy (e.g. hydrocortisone) had a higher abdominal fat mass (also assessed by DEXAscanning)[2]. However these patients used a higher average dose of hydrocortisone than our patients do, so this may explain the difference. Furthermore these researchers investigated if genetic differences in sensitivity to cortisol influenced adipose tissue distribution after successful treatment. Cortisol exerts cellular effects through a protein called a glucocorticoid receptor. Studies have shown that some genetic changes (polymorphisms) can make this receptor more or less sensitive to cortisol. These researchers indeed found that patients with glucocorticoid receptors more sensitive to cortisol had a higher abdominal fat mass.

So now what?

More research needs to be done to find out why a centripetal adipose tissue distribution and an adverse adipokine profile persist after cure of Cushing’s syndrome. If the mechanism is understood, hopefully a way to solve this problem can be found (like developing life style interventions or medication). Furthermore, we do not know enough about the cardiovascular health of patients who have been cured of Cushing’s syndrome, especially if it remains increased in all patients or only a subset of patients with persisting co-morbidities such as diabetes or high blood pressure. This should also be investigated.

Conclusion

Patients that suffered from Cushing’s syndrome in the past may still have a centripetal adipose tissue distribution and an adverse adipokine profile compared to healthy controls with the same age, gender and body mass index. A combination of lifestyle, your genetically determined sensitivity to cortisol, and needed hormonal replacement therapy will determine how much abdominal fat you lose after cure of Cushing’s syndrome.

1. Wagenmakers, M., et al., Persistent centripetal fat distribution and metabolic abnormalities in patients in long-term remission of Cushing’s syndrome. Clin Endocrinol (Oxf), 2015. 82(2): p. 180-7.
2. Ragnarsson, O., et al., Body composition and bone mineral density in women with Cushing’s syndrome in remission and the association with common genetic variants influencing glucocorticoid sensitivity. Eur J Endocrinol, 2015. 172(1): p. 1-10.

Author: Dr. Margreet Wagenmakers

Newsletter: Winter, 2015

Editor’s Note: Dr. Margreet Wagenmakers is a Fellow in Endocrinology at the Radboud University Medical Center in Nijmegen, The Netherlands. Under the supervision of Prof. Ad Hermus, Prof. Jan Smit and Dr. Netea Maier, she is completing her PhD on the role of endoscopic transsphenoidal surgery in Cushing’s disease and acromegaly and the long-term effects of Cushing’s syndrome and acromegaly. Her thesis will be titled: “Acromegaly and Cushing’s syndrome: Is Cure Really Cure?” In the future Dr. Wagenmakers hopes be a practicing clinical endocrinologist and to continue research in the long-term effects of especially Cushing’s syndrome.