Cushing disease in a patient with nonbullous congenital ichthyosiform erythroderma: lessons in avoiding glucocorticoids in ichthyosis.

Nonbullous congenital ichthyosis erythroderma (CIE) is an autosomal recessive disorder of ineffective keratinization. We present a unique case of a 16-year-old female with CIE who developed Cushing disease (CD) at age 13 with concomitant worsening of her skin disease. After transsphenoidal resection of her pituitary adenoma, she had both resolution of her Cushing symptoms and significantly milder skin manifestations of her CIE. To the best of our knowledge, this is the first reported case of a patient with both CD and CIE, one that is important in demonstrating the role of glucocorticoids in this disorder.

MANAGEMENT OF ENDOCRINE DISEASE: Can we cure Cushing's disease? A personal view.

One of today's challenges in endocrinology is the treatment of Cushing's disease: Although pituitary surgery has the potential to 'cure' the patient and restore a completely normal pituitary adrenal axis, there are immediate failures and late recurrences that will ultimately require alternate therapeutic approaches. Their high number is in direct correlation with their serious limitations and they all appear to be 'default options'. This 'personal view' tries to shed some light on the inescapable difficulties of the current treatments of Cushing's disease and to provide some optimistic view for the future where the pituitary adenoma should be the 'reasonable obsession' of a successful therapeutist.

Preoperative normalization of cortisol levels in Cushing's disease after medical treatment: consequences for somatostatin and dopamine receptor subtype expression and in vitro response to somatostatin analogs and dopamine agonists.

CONTEXT: Corticotroph pituitary adenomas often highly express the dopamine 2 receptor (D2R) and somatostatin receptor subtype 5 (sst5). The sst2 expression is relatively low, likely resulting from downregulating effects of high cortisol levels. This may explain why the sst2-preferring somatostatin analog octreotide, compared with the multi-receptor-targeting somatostatin analog pasireotide, is generally ineffective in Cushing's disease. OBJECTIVE: Our objective was to compare sst and D2R expression levels between adenomas from patients with elevated and normalized preoperative urinary free cortisol excretion. PATIENTS AND DESIGN: Corticotroph adenoma tissue was examined from patients from group 1 (n = 22; elevated preoperative urinary free cortisol) and group 2 (n = 11; mean duration of preoperative normocortisolism 10 weeks). Somatotroph adenoma tissue from 10 acromegalic patients was examined to compare receptor expression profiles. MAIN OUTCOME MEASURES: We evaluated receptor mRNA and protein expression levels and effects of octreotide, pasireotide, and cabergoline on ACTH secretion by cultured human corticotroph adenoma cells. RESULTS: The sst2 mRNA expression in group 2 was 10-fold higher than in group 1 (P < .01), even comparable to that in somatotroph adenomas. There were no statistically significant differences in sst5 and D2R mRNA expression or in sst2, sst5, and D2R protein expression between both groups of corticotroph adenomas. In responders, octreotide (n = 2 out of 4; -30.5% ± 10.4%) was less potent than pasireotide (n = 5 out of 6; -47.0% ± 4.2%) and cabergoline (n = 3 out of 4; -41.9% ± 3.1%) with respect to inhibition of ACTH secretion by adenomas from group 2. CONCLUSIONS: After achieving normocortisolism induced by medical therapy, cortisol-mediated sst2 downregulation on corticotroph adenomas appears to be a reversible process at the mRNA but not at the protein level. Octreotide remains less potent than pasireotide and cabergoline with respect to in vitro inhibition of ACTH secretion. Whether sustained normocortisolism induced by medical therapy induces re-expression of functional sst2 protein in corticotroph adenomas and whether this increases the ACTH-lowering potency of octreotide remains to be established.

Obstructive sleep apnea syndrome causes a pseudo-Cushing's state in Japanese obese patients with type 2 diabetes mellitus.

Activation of the hypothalamic-pituitary-adrenal axis has been reported in some patients with the obstructive sleep apnea syndrome (OSAS). In current study, we investigated whether OSAS affect the screening test for subclinical Cushing's disease using 0.5 mg overnight dexamethasone suppression test (DST) in Japanese obese diabetic patients with OSAS. Among Japanese obese patients with type 2 diabetes mellitus who had been hospitalized in our department, we selected 20 patients with moderate to severe untreated OSAS (apnea-hypoxia index, AHI, of ≥15 events/hour). All patients underwent 0.5 mg DST. The same test was repeated in patients with positive response of it within a few days after continuous positive airway pressure (CPAP) therapy. We found that five patients showed positive response of DST (25%). Three of these patients continued to use CPAP, and they showed normal response of DST after CPAP therapy. Serum cortisol after 0.5 mg DST measured before CPAP therapy correlated significantly with fasting serum cortisol level (r=0.764, p<0.0001), but not with various clinical parameters, including AHI (p=0.784), body mass index (p=0.984), waist circumference (p=0.957), HbA1c (p=0.261), fasting plasma glucose (p=0.420) and HOMA-IR (p=0.500). Our study show that OSAS causes a pseudo-Cushing's syndrome in obese patients with type 2 diabetes mellitus, which phenomena can be reversed by CPAP therapy.

Factors influencing the outcome of microsurgical transsphenoidal surgery for pituitary adenomas: a study on 184 patients.

OBJECTIVE: Evaluation of factors influencing the outcome of microsurgical transsphenoidal surgery in patients harbouring pituitary adenomas as well as of the efficacy and safety of this procedure. DESIGN: A total of 184 consecutive patients with pituitary adenomas, undergoing microsurgical transsphenoidal resection of their lesions from March 2004 to June 2011, were prospectively studied. Extent of tumour resection and disease remission were defined according to recently established radiological and hormonal consensus criteria. RESULTS: The study included 97 nonfunctioning and 87 functioning adenomas. A gross-total removal, as documented on postoperative imaging, was achieved in 67.4% of all patients. Residual tumour after surgery was detected in 37.1% of patients with nonfunctioning adenomas. The remission rates for patients with functioning adenomas, as documented by the last endocrinological evaluation, were 54.9% for growth hormone-secreting, 69.5% for adrenocorticotropin hormone-secreting, 72.7% for prolactin-secreting and 100% for thyroid-stimulating hormone-secreting, with two recurrences in patients with Cushing's disease. Multivariate analysis showed that factors influencing surgical outcome were cavernous sinus invasion, large tumour diameter (≥25 mm) and reoperation for the nonfunctioning adenomas, and cavernous sinus invasion as well as large tumour diameter (≥25 mm) for the functioning adenomas. In the latter cohort, predictors for endocrinological remission were maximum tumour diameter (≤20 mm) and reoperation. Postoperative complications were present in 3.3% of the cases. One patient developed epistaxis, two hemorrhage at the surgical field, one postoperative rhinorrhea, one postoperative permanent diabetes insipidus and one postoperative panhypopituitarism. CONCLUSIONS: Microsurgical transsphenoidal surgery is an effective and safe treatment in all patients with pituitary adenomas, except for prolactinomas responsive to medical therapy.

Endoscopic transsphenoidal pituitary surgery: a good and safe primary treatment option for Cushing's disease, even in case of macroadenomas or invasive adenomas.

CONTEXT: Although the endoscopic technique of transsphenoidal pituitary surgery (TS) has been widely adopted, reports on its results in Cushing's disease (CD) are still scarce and no studies have investigated long-term recurrence rates. This is the largest endoscopic series published till now. OBJECTIVE: To gain insight into the role of endoscopic TS as a primary treatment option for CD, especially in patients with magnetic resonance imaging (MRI)-negative CD and (invasive) macroadenomas. DESIGN: Retrospective cohort study. PATIENTS AND METHODS: The medical records of 86 patients with CD who underwent endoscopic TS were examined. Data on preoperative and postoperative evaluation, perioperative complications, and follow-up were collected. Remission was defined as disappearance of clinical symptoms with a fasting plasma cortisol level ≤ 50 nmol/l either basal or after 1 mg dexamethasone. RESULTS: The remission rate in different adenoma subclasses varied significantly: 60% in MRI-negative CD (n=20), 83% in microadenomas (n=35), 94% in noninvasive macroadenomas (n=16), and 40% in macroadenomas that invaded the cavernous sinus (n=15). The recurrence rate was 16% after 71 ± 39 months of follow-up (mean ± S.D., range 10-165 months). CONCLUSIONS: Endoscopic TS is a safe and effective treatment for all patients with CD. Recurrence rates after endoscopic TS are comparable with those reported for microscopic TS. Our data suggest that in patients with noninvasive and invasive macroadenomas, the endoscopic technique of TS should be the treatment of choice as remission rates seem to be higher than those reported for microscopic TS, although no comparative study has been performed.

The therapy of Cushing's disease in adults and children: an update.

Cushing's disease (CD) is a rare endocrine disorder resulting from excessive production of adrenocorticotrophin hormone by a pituitary adenoma. The consequent hypercortisolaemia gives rise to characteristic features of the disease and its morbidities. Treatments aim to restore normal cortisol levels, provide long-term control of the disease and the tumour, and the improvement of patient well-being. The first line of treatment remains transsphenoidal surgery with remission rates of 65-90% in CD secondary to a pituitary microadenoma. Second-line treatment includes repeat surgery, radiotherapy, medical therapy, and bilateral adrenalectomy. The success rate of radiotherapy ranges from 46% to 74% and is probably independent of the mode of delivery of the radiation, but may take several years to become effective. Medical therapy is useful in acutely unwell patients or while awaiting radiotherapy to become effective. The most often-used medical agents include metyrapone and ketoconazole, which inhibit steroidogenesis; less often, centrally-acting drugs or a glucocorticoid receptor blocker are used, but experience with them is more limited. Bilateral adrenalectomy remains an important treatment option to control unresponsive severe hypercortisolism, particularly in patients with severe CD.The management of childhood CD does not differ from adult disease, with transsphenoidal surgery as successful as in adults but radiotherapy is more rapid in onset. Regardless of the age of the patient, Cushing's disease remains a challenge to the physician and requires a multidisciplinary approach to achieve the most desirable outcome.

Recurrence of Cushing's disease after primary transsphenoidal surgery in a university hospital in Korea.

Successful long-term management of patients with Cushing's disease (CD) remains a challenge. To date, studies on the long-term outcome of patients with CD have been conducted mainly in Caucasians. Our objective was to assess the recurrence rate in patients who underwent transsphenoidal surgery (TSS) in the management of CD and to identify predictive markers for the long-term outcomes of CD in Korea. The long-term outcome in 54 patients who underwent TSS for the treatment of CD from 1984 to 2010 was retrospectively reviewed. Recurrence was defined as an elevated serum cortisol or an elevated 24 hour urine free cortisol or a suppressed serum cortisol by dexamethasone higher than 138 nmol/L. Mean age at diagnosis was 35.8 ± 12.8 years and median follow-up duration was 50.7 months. Initial successful TSS was obtained in 38 patients (70.4%). Among these 38 patients, 18 (47.4%) patients had a recurrence of CD. Preoperative serum cortisol level was significantly associated with recurrence. Pathologic confirmation of an adenoma was marginally associated with lower risk of recurrence. Positive results of imaging study and presence of microadenoma were not associated with risk of recurrence. Recurrence rate of CD after initial successful TSS was 32.4% at 5 years and 54.6% at 10 years, respectively. Following initial successful TSS, close long-term endocrine surveillance is mandatory as the recurrence rate increases with time. Preoperative serum cortisol level and pathologic confirmation of an adenoma may have a predictive value for recurrence of CD after TSS.

Outcomes after repeat transsphenoidal surgery for recurrent Cushing's disease.

OBJECTIVE: To systematically analyze patient outcomes after repeat transsphenoidal (TS) surgery for recurrent Cushing's disease. METHODS: We retrospectively reviewed records of all patients with recurrent Cushing's disease who underwent repeat TS surgery for resection of a pituitary corticotroph adenoma at the University of Virginia Medical Center from 1992 to 2006. Remission at follow-up was defined as a normal postoperative 24-hour urine free cortisol, or continued need for glucocorticoid replacement after repeat TS surgery. Recurrence of the disease was defined as an elevated 24-hour urine free cortisol with clinical symptoms consistent with Cushing's disease while not receiving glucocorticoid replacement. Multivariate logistic regression was performed to evaluate the effect of potential predictors on remission. Recurrence rates, subsequent treatments, and the final endocrine status of the patients are presented. RESULTS: We identified 36 patients who underwent repeat TS surgery for recurrent Cushing's disease. The mean age of the patients was 40.3 years (range, 17.1-63.0 yr), and 26 were women. The median time to recurrence after initial successful TS surgery was 36 months (range, 4 mo-16 yr). Remission after repeat TS surgery was observed in 22 (61%) of the 36 patients. During the same time period, of the 338 patients who underwent first-time TS surgery for Cushing's disease, remission was achieved in 289 (85.5%). The odds of failure (to achieve remission) for patients with repeat TS surgery for recurrent Cushing's disease were 3.7 times that of patients undergoing first-time TS surgery (odds ratio, 3.7; 95% confidence interval, 1.8-7.8). Two of the 22 patients with successful repeat TS surgery had a second recurrence at 6 and 11 months, respectively. Complete biochemical and clinical remission after stereotactic radiosurgery, adrenalectomy, and ongoing ketoconazole therapy was achieved in 30 (83.3%) of the 36 patients, and active disease continued in 6 patients (16.7%). CONCLUSION: Although the success of repeat TS surgery for recurrence of Cushing's disease is less than that of initial surgery, a second procedure offers a reasonable possibility of immediate remission. If the operation is not successful, other treatments, including pituitary radiation, medical therapy, and even bilateral adrenalectomy, are required.