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Cushing's - Gender Differences

Guest Rose Marie

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Journal Scan is the clinician's guide to the latest clinical research findings in The Journal of Clinical Endocrinology & Metabolism, JAMA, and The New England Journal of Medicine, among others relating to diabetes, endocrinology, and metabolism. Short summaries of feature articles include links to the article abstracts and full text, when available. (Access to full text usually requires registration at the journal's Web site.)




The Journal of Clinical Endocrinology and Metabolism

April 2003 (Volume 88, Number 4)


Gender-Related Differences in the Presentation and Course of Cushing's Disease

Giraldi FP, Moro M, Cavagnini F; the Study Group on the Hypothalamo-Pituitary-Adrenal Axis of the Italian Society of Endocrinology


by Ashok Balasubramanyam, MD, Kristin M. Richardson


The Journal of Clinical Endocrinology and Metabolism. 2003;88(4):1554-1558


Nearly three quarters of a century since the classic description of the syndrome resulting from a "basophilic adenoma of the pituitary body" by Harvey Cushing, the disease that bears his eponym still continues to fascinate endocrinologists. Progress in understanding its molecular etiology as well as the pathophysiology of its myriad complications has been rather slow, but one would have thought that not much remained to be described about its clinical manifestations. The road to making a diagnosis of Cushing's disease is notoriously rocky, but the journey must always begin with a strong clinical suspicion. Hence, it comes as a nice surprise as well as a welcome addition that Giraldi and colleagues have identified important gender-associated differences in the manifestations of the illness.


The investigators compared clinical features, biochemical parameters, and surgical outcomes in 280 patients with Cushing's disease (233 women, 47 men). They found that men tended to be diagnosed with the illness at a younger age (mean age: late twenties, early thirties, compared with late thirties in women), even though there was no gender difference in the duration of symptoms. Men generally had a more severe form of hypercortisolism, with significantly higher levels of plasma ACTH and urinary free cortisol. End-organ damage was similarly greater in men, who had a greater frequency of osteoporosis, muscle wasting, striae, and nephrolithiasis.


The remainder of the long list of clinical signs of Cushing's disease showed no gender differences, and there were no signs that were more common in women than in men. The analysis also brought out age-related differences in clinical manifestations. Striae were more common in younger patients of either gender, and muscle wasting was more common in younger men than in women and older men. Signs such as striae, muscle atrophy, hypokalemia, moon facies, and hypertension seemed to reflect a greater degree of hypercortisolism, as measured by urine or plasma cortisol levels.


Biochemical testing is the cornerstone of the diagnosis of Cushing's disease, and there were important gender differences here as well. The high-dose dexamethasone suppression test had a much lower diagnostic sensitivity in men (57% vs 82% for women), an important consideration because this test is frequently used to differentiate Cushing's disease from hypercortisolism due to an ectopic ACTH-producing tumor. Fortunately, other tests commonly used for the same purpose -- the ACTH and cortisol responses to CRH stimulation and the ACTH gradient during inferior petrosal sinus sampling -- were equally diagnostic in men and women. Finally, microadenomas were less frequently visualized by radiologic imaging in men.


This useful paper informs us that men tend to have earlier onset and a more severe form of Cushing's disease, and that some standard biochemical tests have significantly lower diagnostic accuracy in men. This may put men at a significant disadvantage with regard to identifying the proper cause of hypercortisolism, since men are more likely than women to have an ectopic ACTH-producing tumor. Hence, the more severe manifestations of Cushing's disease in men, together with the lower diagnostic accuracy of the high-dose dexamethasone test and pituitary imaging, make it even harder to differentiate it from the ectopic ACTH-producing tumor. This is an important cautionary tale to be added to the lore of clinical Cushingology.


? Ashok Balasubramanyam, MD




Gender-related differences in the presentation and course of Cushing's disease.
J Clin Endocrinol Metab 2003 Apr;88(4):1554-8 (ISSN: 0021-972X)
Giraldi FP; Moro M; Cavagnini F

University of Milan, Ospedale San Luca, Istituto Auxologico Italiano, Italy; Collective Name: Study Group on the Hypothalamo-Pituitary-Adrenal Axis of the Italian Society of Endocrinology.

Cushing's disease (CD) presents a marked female preponderance, but whether this skewed gender distribution has any relevance to the presentation and outcome of CD is not known. The aim of the present study was the comparison of clinical features, biochemical indices of hypercortisolism, and surgical outcome among male and female patients with CD. The study population comprised 280 patients with CD (233 females, 47 males) collected by the Italian multicentre study. Epidemiological data, frequency of clinical signs and symptoms, urinary free cortisol (UFC), plasma ACTH and cortisol levels, responses to dynamic testing, and surgical outcome were compared in female and male patients. Male patients with CD presented at a younger age, compared with females (30.5 +/- 1.93 vs. 37.1 +/- 0.86 yr, P
Major Subject Heading(s) Minor Subject Heading(s) CAS Registry / EC Numbers

[*]Cushing Syndrome [diagnosis] [physiopathology]  

[*]Sex Characteristics

[*]Adenoma [diagnosis] [surgery]


[*]Age Factors


[*]Corticotropin-Releasing Hormone [diagnostic use]

[*]Corticotropin [blood]

[*]Cushing Syndrome [epidemiology]

[*]Dexamethasone [administration & dosage] [diagnostic use]

[*]Glucocorticoids, Synthetic [administration & dosage] [diagnostic use]

[*]Hydrocortisone [blood] [urine]

[*]Italy [epidemiology]

[*]Pituitary Neoplasms [diagnosis] [surgery]  


[*]0 (Glucocorticoids, Synthetic)

[*]50-02-2 (Dexamethasone)

[*]50-23-7 (Hydrocortisone)

[*]9002-60-2 (Corticotropin)

[*]9015-71-8 (Corticotropin-Releasing Hormone)

Indexing Check Tags: Comparative Study; Female; Human; Male
Language: English
MEDLINE Indexing Date: 200305
Publication Type: Owner: NLM; Status: Completed
Publication Type: Journal Article
PreMedline Identifier: 0012679438
Unique NLM Identifier: 22566140
Journal Code: AIM; IM
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Guest Lynne Clemens

Funny how they didn't mention how men were also diagnosed because they take men's illness more seriously.  Must've been written by a guy.

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Guest Rose Marie

You know Lynne, they actually do. I bought the AACE 2003 meeting tape on adreanal disorders where Dr. Young from Mayo spoke and he mentioned that half of ACTH dependent Cushings in men is caused by ACTH-ectopic sources. ?He also mentioned that the high dose dex test was not reliable in differentiating between ectopic and pituitary disease and recommended it not be done. If this is true, then the high cortisols from the ectopic sources make these patients acutely ill. Still with his particular case he was presenting, the patient had symptoms for 4 years before becoming clinical, and even then, he mentioned that he really didn't have a buffalo hump (and his cortisols were in the 700s.)


According to the above study, the hypercatabolic symptoms are directly related to the higher UFC, plasma ACTH and cortisol concentrations. In other words, the patients who had the muscle atrophy, hypokalemia, ecchymoses, and hypertension had higher cortisol levels. Very high cortisol levels are discussed to be associated with severe clinical manifestations such as psychosis, peritonitis, and infections. The paper goes on to say that their findings indicate that the degree of hypercortioslism also accounts for the progressive appearance of more common symptoms of Cushings.


They also elude to steriod induced osteoporosis and diabetes is not related to the degree of hypercortisolism, but to other factors. They also discuss the direct link to high ACTH to psychiatric disturbances.


They have a wonderful chart about symptoms.

Women first, then men

Obesity 86.2/85.1

Moon facies 81.1/89.4

Hypertension 67.4/68.1

Buffalo hump 53.6/51.1

Purple striae 50.6/72.3

Impaired glucose tolerance/diabetes 45.4/42.8

Muscle atrophy 45.5/63.8

Psychiatric disturbances 34.3/25.5

Osteoporosis 31.6/46.8

Ecchymosis 32.2/21.3

Acne 27.5/19.1

Hypokalemia 21.8/32.6

Nephrolitiasis 6.4/21.3


Me thinks some medical books need to be updated.

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