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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 8 3818-3820
Copyright © 2004 by The Endocrine Society

Prepubertal Cushing’s Disease Is More Common in Males, But There Is No Increase in Severity at Diagnosis

Helen L. Storr, Andrea M. Isidori, John P. Monson, G. Michael Besser, Ashley B. Grossman and Martin O. Savage

Department of Endocrinology, St. Bartholomew’s and The Royal London School of Medicine and Dentistry, West Smithfield, London, United Kingdom EC1A 7BE

Address all correspondence and requests for reprints to: Dr. Martin O. Savage, Pediatric Endocrinology Section, Department of Endocrinology, St. Bartholomew’s Hospital, London, United Kingdom EC1A 7BE. E-mail: m.o.savage{at}qmul.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Sex distribution and severity of biochemical indices at the diagnosis of Cushing’s disease (CD) were analyzed in 50 patients (21 males and 29 females; aged ≤30 yr; range, 6.4–30.0 yr). Twenty-five (50%) presented aged 18 yr or younger (17 males and eight females) and 25 aged 18–30 yr (four males and 21 females). CD diagnosed at less than 18 yr occurred predominantly in males, contrasting with 18 yr or older, which was more common in females. The difference between the two groups was significant (P = 0.0003). There was a significant difference ({chi}2) in sex distribution depending on pubertal status (P = 0.0002); in prepubertal patients (n = 11) males predominated (91%) compared with postpubertal patients (n = 27), where females predominated (81%). In patients in puberty (n = 12), there was an equal sex incidence (50% males). In adult patients with CD, males have been reported to have more severe disease. We found no difference in hypercortisolemia or ACTH at diagnosis in males compared with females in the patients less than 18 yr of age [serum 0000 h cortisol, 510.5 ± 75.2 vs. 415.6 ± 63.7 nmol/liter (P = 0.52); plasma ACTH, 48.5 ± 7.9 vs. 42.9 ± 10.9 ng/liter (P = 0.54); percent suppression of serum cortisol during low dose dexamethasone suppression test, 57.2 ± 8.6% vs. 33.5 ± 13.1% (P = 0.14); high dose dexamethasone suppression test, 85.9 ± 3.1% vs. 85.7 ± 4.9% (P = 0.55); percent increase in cortisol after iv CRH, 180.3 ± 15.3% vs. 189.9 ± 20.3% (P = 0.67)]. In conclusion, female preponderance of CD in adult patients was not present in childhood. In patients 18 yr of age or younger, there was no difference in the severity of hypercortisolemia or ACTH at diagnosis between males and females.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PITUITARY-DEPENDENT CUSHING’S disease (CD) is rare in childhood and adolescence (1). In adults, CD has a female preponderance (2, 3). A recent report also suggested sex-related differences in the biochemical and clinical features of adult CD, with increased severity in males (3) and more pronounced elevation of serum cortisol and plasma ACTH levels and a worse postsurgical prognosis.

In the published series of pediatric CD (4, 5, 6, 7), no comment has been made on the sex distribution or the sex variations in biochemical indices at presentation. We have observed that the female preponderance of CD seen in adults may not be present in childhood (1, 8, 9). Consequently, we have analyzed sex distribution, age, and pubertal stage at diagnosis in all the pediatric and adult patients diagnosed in our service at or under the age of 30 yr. We also analyzed the biochemical features in the two sexes at diagnosis in patients less than 18 yr of age.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

All patients (n = 50), aged 30 yr or less, with CD treated at St. Bartholomew’s Hospital (London, UK) during 1983–2003 were reviewed. The group comprised 29 females and 21 males (median age, 18.0 yr; range, 6.4–30.0 yr). Twenty-five patients (17 males and eight females; median age, 13.5 yr; range, 6.4–17.8 yr) were diagnosed at less than 18 yr. They are referred to as the young group. In the adult group (18–30 yr), there were 21 females and four males (median age, 26.0 yr).

Pubertal staging

Puberty was staged according to breast or genital development using Tanner’s criteria (Table 1Go) (10, 11). Prepubertal males had testicular volumes less than 4 ml. Eleven patients (10 males and one female) were prepubertal; 12 patients (six males and six females) were in puberty, i.e. Tanner stages 2–4; 27 patients (five males and 22 females) were postpubertal.


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  		TABLE 1. Clinical features of the young patient group

 
Diagnosis of CD

CD was diagnosed on the basis of a detectable 0900 h plasma ACTH (normal range, 10–50 ng/liter), loss of serum cortisol circadian rhythm (i.e. elevated sleeping 0000 h cortisol, >50 nmol/liter), and failure of serum cortisol to suppress to below 50 nmol/liter during low dose dexamethasone suppression test (0.5 mg every 6 h for 48 h) (12). In addition, the patients had suppression of serum cortisol to less than 50% of baseline in a high dose dexamethasone suppression test (2 mg every 6 h for 48 h) (12), and/or an exaggerated (≥20% of baseline) response of serum cortisol during a human sequence CRH test (100 µg iv) (13). Urinary free cortisol was not routinely measured. All patients had either histological evidence of corticotroph adenoma and/or showed clinical and biochemical remission after surgery and/or pituitary radiotherapy.

Evaluation of severity of CD at diagnosis

The following biochemical indices were evaluated in the young group of patients as a measure of the severity of hypercortisolemia: sleeping serum 0000 h cortisol level (nanomoles per liter), 0900 h plasma ACTH (nanograms per liter), percent rise in serum cortisol from baseline after iv human sequence CRH (100 µg, iv), and percent suppression of serum cortisol from baseline after standard low dose dexamethasone suppression test and high dose dexamethasone suppression test.

Statistical evaluation

Continuous/quantitative data were analyzed using the Mann-Whitney test, whereas discrete/qualitative data were evaluated with the {chi}2 statistics or Fisher’s exact test, as appropriate. Values are stated as the mean ± SEM or SD, as appropriate. The 95% confidence intervals were calculated (mean ± 2 SD) for the biochemical data.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Sex incidence at age of diagnosis

CD occurred predominantly in males in the young patients, whereas females were more common in the adult group [young males, 68% (17 of 25); adult males, 16% (four of 25)]. The difference between the two groups was statistically significant (by Fisher’s exact test, P = 0.0003). In the whole group (n = 50), the mean age of diagnosis was younger in males than in females (males, 14.6 ± 1.3 yr; range, 6.4–29.0 yr; females, 22.1 ± 1.1 yr; range, 10.6–30.0 yr; P = 0.0002; Fig. 1Go). The percentage of female patients compared with males with CD gradually increased with age of onset: 6–9 yr (n = 6), 0%; 10–13 yr (n = 8), 43%; 14–17 yr (n = 11), 46%; 18–21 yr (n = 6), 83%; 22–25 yr (n = 6), 83%; and 26–30 yr (n = 13), 85% (Fig. 2Go).



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  		FIG. 1. Age at diagnosis of patients with CD. The horizontal lines represent the median age of each group.

 


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  		FIG. 2. Sex incidence and age of diagnosis in CD (n = 50).

 
Sex incidence related to puberty

There was a significant difference ({chi}2) between males and females depending on pubertal status (P = 0.0002). Males predominated in the prepubertal group (91%; mean age, 10.2 yr; range, 6.4–13.7 yr), and females predominated in the postpubertal group (81%; mean, 24.5 yr; range, 16.7–30.0 yr). In the patients in puberty there was an equal sex incidence (50% males; mean, 14.9 yr; range, 9.4–17.8 yr).

Severity of CD at diagnosis

Details of the biochemical indices of hypercortisolemia and plasma ACTH in males and females less than 18 yr of age are shown in Table 2Go. No significant difference was found between males and females.


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  		TABLE 2. Biochemical indices of hypercortisolemia at diagnosis in the young patient group (n = 25)

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
ACTH-secreting corticotroph adenomas occur more frequently in females than in males in the adult population, as reported in many published series. We have previously reported a series of 128 patients with ACTH-dependent Cushing’s syndrome, aged 12–77 yr, that included 106 women (83%) (14). Primary adrenal Cushing’s syndrome also occurs 3–4 times more frequently in women than men (13). There are a number of published series of pediatric CD patients, but sex differences in childhood CD have not previously been compared with those in an adult group. Leinung et al. (4) described 22 pediatric patients with CD (<19 yr old) including 12 females (55%), Knappe and Ludecke (5) studied 55 patients (age, 14.4 ± 3.4 yr; range, 4.2–18.9 yr) with an equal ratio of females to males of 1.1:1.0, Massoud et al. (6) studied 23 children, 70% of whom were males, and Devoe et al. (7) described 42 patients (6.5–18 yr), 17 of whom were boys (40%). None of these series specifically investigated the changes in sex incidence with age, and the data are confounded by combining prepubertal, adolescent, and postpubertal patients. Nevertheless, the expected female predominance seen in the adult age group does seem to be absent overall.

Magiakou et al. (15) described a large series of 50 young patients with CD (aged 4–20 yr; 31 females and 19 males), who were divided into prepubertal and pubertal groups The prepubertal group comprised one female and eight males; the pubertal group comprised 30 females and 11 males (15). These data appear to corroborate our findings that prepubertal CD is more common in males, whereas postpubertal CD is more common in females.

A recent report by Giraldi et al. (3) examined sex-related differences in disease severity in the adult population. In males, CD appeared at a younger age with a more severe clinical presentation, more pronounced elevation of serum cortisol and plasma ACTH levels, and worse postsurgical prognosis (3). In our young patient group, there was no statistically significant difference between indices of hypercortisolemia and ACTH at diagnosis between males and females. We propose that a change in the hormonal milieu in females with increased production of estrogen may be related to the relative increase in CD during and after puberty. The higher incidence of CD in males before puberty has not been described previously, and the cause remains unclear.

In conclusion, in young patients with CD, unlike in adults, there was a male predominance. Sex incidence in prepubertal patients also showed a male predominance, with an equalization of the sex distribution during puberty before the switch to female predominance in adulthood. There was no increase in severity of hypercortisolemia or ACTH levels at diagnosis in male patients with CD compared with females in the young patient group.


   Acknowledgments
 
We are grateful to Janice Thomas for expert statistical advice.


   Footnotes
 
Abbreviation: CD, Cushing’s disease.

Received September 3, 2003.

Accepted May 18, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Savage MO, Besser GM 1996 Cushing’s disease in childhood. Trends Endocrinol Metab 7:213–216[Medline]
  2. Besser GM, Trainer PJ 2002 Cushing’s syndrome. In: Besser GM, Thorner MO, eds. Comp Clin Endocrinol. 3rd ed. Edinburgh: Mosby; 193–202
  3. Giraldi FP, Moro M, Cavagnini F 2003 Gender-related differences in the presentation and course of Cushing’s disease. J Clin Endocrinol Metab 88:1554–1558[Abstract/Free Full Text]
  4. Leinung M, Kane L, Scheithauer B, Carpenter P, Laws ER, Zimmerman D 1995 Long term follow-up of transsphenoidal surgery for the treatment of Cushing’s disease in childhood. J Clin Endocrinol Metab 80:2475–2479[Abstract]
  5. Knappe U, Ludecke D 1996 Transnasal microsurgery in children and adolescents with Cushing’s disease. Neurosurgery 39:484–493[CrossRef][Medline]
  6. Massoud A, Powell M, Williams R, Hindmarsh P, Brook C 1997 Transsphenoidal surgery for pituitary tumours. Arch Dis Child 76:398–404[Abstract/Free Full Text]
  7. Devoe D, Miller WL, Conte F, Kaplan SL, Grumbach MM, Rosenthal FM, Wilson CB, Gitelman SE 1997 Long term outcome in children and adolescents after transsphenoidal surgery for Cushing’s disease. J Clin Endocrinol Metab 82:3196–3202[Abstract/Free Full Text]
  8. Weber A, Trainer PJ, Grossman AB, Afshar, F, Medbak S, Perry LA, Plowman PN, Rees LH, Besser GM, Savage MO 1995 Investigation, management and therapeutic outcome in 12 cases of childhood and adolescent Cushing’s syndrome. Clin Endocrinol (Oxf) 43:19–28[Medline]
  9. Savage MO, Lienhardt A, Lebrethon M-C, Johnston LB, Huebner A, Grossman AB, Afshar F, Plowman PN, Besser GM 2001 Cushing’s disease in childhood: presentation, investigation, treatment and long-term outcome. Horm Res 55(Suppl 1):24–30
  10. Marshall W, Tanner JM 1969 Variation in the pubertal changes in girls. Arch Dis Child 45:291–303
  11. Marshall W, Tanner JM 1970 Variation in the pubertal changes in boys. Arch Dis Child 45:13–23
  12. Newell-Price J, Trainer PJ, Besser GM, Grossman AB 1999 The diagnosis and differential diagnosis of Cushing’s and pseudo-Cushing’s states. Endocr Rev 19:647–672
  13. Newell-Price J, Morris D, Drake W, Korbonits M, Monson JP, Besser GM, Grossman AB 2002 Optimal response criteria for the human corticotropin-releasing hormone test in the differential diagnosis of ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab 87:1640–1645[Abstract/Free Full Text]
  14. Kaltsas GA, Giannulis MG, Newell-Price JDC, Dacie JE, Thakkar C, Afshar F, Monson JP, Grossman AB, Besser GM, Trainer PJ 1999 A critical analysis of the value of simultaneous inferior petrosal sinus sampling in Cushing’s disease and the occult ectopic adrenocorticotropin syndrome. J Clin Endocrinol Metab 84:487–492[Abstract/Free Full Text]
  15. Magiakou MA, Mastorakos G, Oldfield E, Gomez MT, Doppman JL, Cutler GB, Nieman LK, Chrousos GP 1994 Cushing’s syndrome in children and adolescents, presentation, diagnosis and therapy. N Engl J Med 331:629–636[Abstract/Free Full Text]



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