Gender-Specific Differences in Clinical Profile and Biochemical Parameters in Patients with Cushing’s Disease: A Single Center Experience

Abstract

Cushing's disease (CD) is remarkably prevalent among females; however, more severe clinical presentation and adverse outcomes have been found in males. The purpose of this study was to investigate the overall clinical profile and biochemical parameters in patients with CD to identify the gender differences. Here we describe our series of CD patients referred to our medical center during 2012-2013. Among 73 cases, females presented a marked preponderance compared to males. Males had significantly higher ACTH, BMI, HbA1c, systolic blood pressure, and hemoglobin than females. For the first time, the incidence of fatty liver and hepatic function was also shown to be elevated in males. Multiple linear regression analysis was performed to further investigate the correlation of risk factors with hypokalemia, HbA1c, and systolic blood pressure. Gender and serum cortisol were associated with hypokalemia. Age, gender, and serum cortisol were significantly associated with HbA1c. Additionally, only gender was significantly associated with systolic blood pressure. Regarding clinical presentation, purple striae seemed to occur more frequently in males than in females. Thus, more severe clinical presentation, biochemical parameters, and complications were found in males than in females. Clinical professionals should pay more attention to the diagnosis and management of males with CD.

Sex Differences in Presentation but Not in Outcome for ACTH-Dependent Cushing's Syndrome

“…A major strength of this study is that it includes a large cohort from two centers and focuses on a broad spectrum of potential differences between sexes, thereby allowing a more accurate description and clear understanding of the clinical picture of ACTH-dependent Cushing's syndrome based on sex, than previous cohort studies. The differences in biochemistry and morbidity found in this study are largely in line with previous studies: higher plasma ACTH (9, 12–14), more often anemia (16) and osteoporosis (with fractures) (8, 11–13). The lack of difference in etiology and pituitary tumor size was in agreement with some studies (9, 12), but not with others (8, 11).…”

“…Interestingly, the female preponderance is not yet present in prepubertal cases, suggesting that males are diagnosed with Cushing's syndrome at a younger age (9, 10). This is confirmed by some studies in adults with Cushing's syndrome (11, 12), but rejected by others (13, 14). Some cohort studies have reported males to have more severe clinical presentation (higher body mass index and waist circumference, reduced libido and sexual dysfunction, more striae, myopathy, and hypokalemia), biochemical parameters (higher ACTH, serum cortisol, and urinary free cortisol [UFC] concentrations), complications at diagnosis (higher HbA1c concentrations, more often hypertension, anemia, spine osteoporosis with vertebral fractures, rib fractures, and hypercoagulable state), and worse outcome after surgery (more often anemia, lower cortisol normalization rate, and higher recurrence rate), than females (8, 9, 11–16).…”

Sexual Dimorphism in Cellular and Molecular Features in Human ACTH-Secreting Pituitary Adenomas

“…From a clinical viewpoint, in addition to clear preference for the female sex [2], clinical presentation and course differ between men and women with Cushing's disease. In fact, our first report on gender-dependent differences among these patients [3] was subsequently confirmed by other investigators [6][7][8][9]. Male patients with Cushing's disease usually present at a younger age, with more severe hypercortisolism and pronounced clinical features; hypogonadism induced by cortisol excess appears an important contributor to some clinical signs in males [8,39,40].…”

“…Male patients with Cushing's disease usually present at a younger age, with more severe hypercortisolism and pronounced clinical features; hypogonadism induced by cortisol excess appears an important contributor to some clinical signs in males [8,39,40]. As regards hormonal secretion, urinary free cortisol levels are higher in male patients with Cushing's disease [3,6] as occurs in normal adult men [41,42]; plasma ACTH concentrations follow the same pattern as higher levels have been observed in male patients [3,6,7,9], as well as in normal men [42,43]. Comparison of responses to diagnostic tests revealed that men with Cushing's disease are less likely to inhibit with the high dose dexamethasone test [3,7,8] and less likely to present positive pituitary magnetic resonance imaging [3,6]; in fact, inferior petrosal sinus sampling was required more frequently in men than women to confirm the pituitary lesion [44].…”

“…ACTH-secreting pituitary adenomas, i.e., Cushing's disease, are known to occur far more frequently in women than in men [1,2] and, as we first showed some years ago [3], give rise to a somewhat different clinical course in the two sexes. In fact, men with Cushing's disease are more likely to be younger, exhibit a more severe clinical presentation and a less favourable response to surgical as well as medical treatment [3][4][5][6][7][8][9]. Furthermore, recently identified somatic mutations in the deubiquitinases USP8 and USP48 occurs with greater frequency in women than men with Cushing's…”