Cushing’s Disease

The clinical diagnosis of Cushing’s syndrome is made when patient presents with central obesity, mooning of face, proximal muscle weakness, striae, hypertension and diabetes. Pigmentation is suggestive of Cushing’s disease (CD). Endogenous hypercortisolemia is diagnosed with 24 hour urinary cortisol or low dose dexamethasone suppression test. Basal ACTH level and pituitary MRI are followed to confirm a pituitary adenoma. Sampling for ACTH from petrosal sinus may be required occasionally.

The choice of therapy is trans-sphenoidal pituitary surgery (TSS). Radiotherapy is used in patients not cured, but takes years to normalise the cortisol values; hence bilateral adrenalectomy is preferred in patients not cured with TSS.

Medical management
The medical treatment is used as temporary measure. The target should be normalization of urinary free cortisol. It is often difficult to predict when a patient will become hypocortisolemic while on medical therapy as the response is not always dose dependent, so replacement with low dose dexamethasone 0.5 mg/d should be strongly considered concurrently.

1. Ketoconazole: First line therapy; inhibits first step (side chain cleavage) in cortisol biosynthesis. It also inhibits ACTH secretion by corticotrophs. It is well tolerated and should be maintained at 600-1000 mg/d. Long term use may cause hepatotoxicity, so liver function should be monitored.

2. Mitotane: Acts on cellular mitochondria to inhibit 11-b hydroxylase. Its metabolites are toxic to adrenal cells causing necrosis. It is effective in maintaining cortisol levels but is not tolerated generally well because of gastrointestinal and neurologic toxicity. It should be considered for patients not controlled on ketoconazole. It is started on 0.5 mg daily in the evening and increased slowly to 3 mg/d, if tolerated.

Aminoglutethimide and metyrapone only partially block conversion of 11-deoxycortisol to cortisol and may be used along with ketoconazole or mitotane.

Follow up
Patients should be followed at three months after radiotherapy completion and an imaging should be obtained which will act as suitable baseline for future reference and repeated whenever indicated. Endocrinologic and visual evaluation should be done yearly. As these patients often have hypopituitarism attributed to disease or treatment, monitoring and appropriate management with hormone replacement therapy is critical so that these patients may live normal life. Hypopituitarism secondary to irradiation develops over a couple of years and should be sought for at follow up evaluations. Hormone replacement therapy should be adjusted as required.

ABSTRACTS

1. The long-term efficacy of conservative surgery and radiotherapy in the control of pituitary adenomas. Brada M, Rajan B, Traish D, Ashley S, Holmes-Sellors PJ, Nussey S, Uttley D. Clin Endocrinol (Oxf)1993;38(6):571-8

OBJECTIVES: We assessed the long-term efficacy and toxicity of conservative surgery and radiotherapy in the control of pituitary adenomas. DESIGN: Retrospective study of patients treated at the Royal Marsden Hospital. PATIENTS: Four hundred and eleven patients with pituitary adenomas treated with conventional external beam radiotherapy at the Royal Marsden Hospital between 1962 and 1986. Two hundred and fifty-two patients had clinically non-functioning pituitary adenomas, 131 had hormone secreting tumours and in 28 patients the secretory status was not known. Three hundred and thirty-eight patients had surgical intervention of whom only 11 had complete tumour excision. All patients received conventional fractionated external beam radiotherapy to a dose of 45-50Gy in 25-30 fractions. MEASUREMENTS: Actuarial progression free survival and overall survival and assessment of toxicity, particularly in terms of vision, requirement for hormone replacement therapy and incidence of second tumours. RESULTS: The actuarial progression free survival was 94% at 10 years and 88% at 20 years for all patients and 97% at 10 years and 92% at 20 years for patients with clinically non-functioning adenomas. Only secretory status was an independent prognostic factor for disease control. The 10 and 20-year survivals for all patients were 77 and 58% respectively. When compared with the normal population the relative risk of death was 1.76 (P < 0.001) and no prognostic factors for survival were identified. The morbidity of radiotherapy was low. Visual deterioration, assumed to be radiation induced, occurred in 1.5% of patients and the risk of second brain tumour was 1.9% at 20 years. Fifty per cent of patients received hormone replacement therapy by 19 years.

CONCLUSION: Conventional external beam radiotherapy as described here combined with conservative surgery is safe and effective in the control of pituitary adenomas. These results should form a baseline for comparison with new treatment strategies.

2. Giant pituitary tumors: a study based on surgical treatment of 118 cases. Goel A, Nadkarni T, Muzumdar D, Desai K, Phalke U, Sharma P. Surg Neurol. 2004 May;61(5):436-45

BACKGROUND: The aim of the study is to analyze the nature, extensions, and dural relationships of hormonally inactive giant pituitary tumors. The relevance of the anatomic relationships to surgery is analyzed. METHODS: There were 118 cases of hormonally inactive pituitary tumors analyzed with the maximum dimension of more than 4 cm. These cases were surgically treated in our neurosurgical department from 1995 to 2002. Depending on the anatomic extensions and the nature of their meningeal coverings, these tumors were divided into 4 grades. The grades reflected an increasing order of invasiveness of adjacent dural and arachnoidal compartments. The strategy and outcome of surgery and radiotherapy was analyzed for these 4 groups. Average duration of follow-up was 31 months. RESULTS: There were 54 giant pituitary tumours, which remained within the confines of sellar dura and under the diaphragma sellae and did not enter into the compartment of cavernous sinus (Grade I). Transgression of the medial wall and invasion into the compartment of the cavernous sinus (Grade II) was seen in 38 cases. Elevation of the dura of the superior wall of the cavernous sinus and extension of this elevation into various compartments of brain (Grade III) was observed in 24 cases. Supradiaphragmatic-subarachnoid extension (Grade IV) was seen in 2 patients. The majority of patients were treated by transsphenoidal route.

CONCLUSIONS: Giant pituitary tumours usually have a meningeal cover and extend into well-defined anatomic pathways. Radical surgery by a transsphenoidal route is indicated and possible in Grade I-III pituitary tumors. Such a strategy offers a reasonable opportunity for recovery in vision and a satisfactory postoperative and long-term outcome. Biopsy of the tumor followed by radiotherapy could be suitable for Grade IV pituitary tumours.

3. Radiotherapy for non-functioning pituitary tumours. Gittoes NJ, Bates AS, Tse W, Bullivant B, Sheppard MC, Clayton RN, Stewart PM Clin Endocrinol (Oxf). 1998:48(3):331-7.

OBJECTIVE: Pituitary radiotherapy (RT) is often used as adjuvant treatment in the post-operative period for patients with clinically non-functioning pituitary tumours (NFTs). There is a distinct lack of objective data, however, describing the efficacy of RT in preventing the regrowth of these tumours. We have therefore determined whether the recurrence rate for NFTs is significantly lower in patients treated with post-operative RT compared with that observed in patients not treated with RT. PATIENTS AND METHODS: A retrospective case notes review was performed on 126 patients with NFTs treated at two institutions in the UK. One hospital routinely administered RT within 12 months of initial pituitary surgery whereas the other used post-operative RT only rarely. The main outcome measure was regrowth of pituitary tumours following surgery in patients who did or did not receive post-operative RT. RESULTS: There was no significant difference between patients who received RT versus those who did not in terms of age, sex, initial tumour size or mode of operation. The actuarial progression-free survival was 93% at both 10 years and at 15 years for the RT treated group, and was 68% and 33%, respectively, for the non-RT-treated group. Using Cox’s model for proportional hazard analysis, we found the only prognostic factor for NFT regrowth was the administration of pituitary RT (P < 0.00005).

CONCLUSIONS: Radiotherapy administered within 12 months of initial pituitary surgery for non-functioning pituitary tumours significantly reduces the risk of tumour regrowth. It remains to be determined whether sequential MRI scanning can help delineate those patients who should receive radiotherapy following pituitary surgery for non-functioning pituitary tumours.

4. Fractionated stereotactically guided radiotherapy and radiosurgery in the treatment of functional and non functional adenomas of the pituitary gland. Milker-Zabel S; Debus J; Thilmann C; Schlegel W; Wannenmacher M. Int J Radiat Oncol Biol Phys 2001 Aug 1;50(5):1279-86.

PURPOSE: We evaluated survival rates and side effects after fractionated stereotactically guided radiotherapy (SCRT) and radiosurgery in patients with pituitary adenoma. METHODS AND MATERIALS: Between 1989 and 1998, 68 patients were treated with FSRT (n = 63) or radiosurgery (n = 5) for pituitary adenomas. Twenty-six had functional and 42 had non functional adenomas. Follow-up included CT/MRI, endocrinologic, and ophthalmologic examinations. Mean follow-up was 38.7 months. Seven patients received radiotherapy as primary treatment and 39 patients received it postoperatively for residual disease. Twenty-two patients were treated for recurrent disease after surgery. Mean total dose was 52.2 Gy for SCRT, and 15 Gy for radiosurgery. RESULTS: Overall local tumour control was 93% (60/65 patients). Forty-three patients had stable disease based on CT/MRI, while 15 had a reduction of tumour volume. After FSRT, 26% with a functional adenoma had a complete remission and 19% had a reduction of hormonal overproduction after 34 months’ mean. Two patients with STH-secreting adenomas had an endocrinologic recurrence, one with an ACTH-secreting adenoma radiologic recurrence, within 54 months. Reduction of visual acuity was seen in 4 patients and partial hypopituitarism in 3 patients. None of the patients developed brain radionecrosis or radiation-induced gliomas.

CONCLUSION: Stereotactically guided radiotherapy is effective and safe in the treatment of pituitary adenomas to improve local control and reduce hormonal overproduction.

5. Stereotactic conformal radiotherapy for pituitary adenomas: technique and preliminary experience. Jalali R; Brada M; Perks JR; Warrington AP; Traish D; Burchell L; McNair H; Thomas DG; Robinson S; Johnston DG. Clin Endocrinol (Oxf) 2000 Jun;52(6):695-702.

OBJECTIVE: Stereotactic conformal radiotherapy (SCRT) is a high precision technique of fractionated radiotherapy which ensures accurate delivery of radiation with reduction in the volume of normal tissue irradiated as compared to conventional external beam radiotherapy. We describe the technique and preliminary experience of SCRT in patients with residual and recurrent pituitary adenomas. PATIENTS AND METHODS: Between February 1995 and March 1999, 22 patients (mean age: 45.3, range: 20-67 years) with residual or recurrent pituitary adenomas (13 non functioning, nine secretory) were treated with SCRT. All were immobilized in a relocatable Gill-Thomas-Cosman (GTC) frame and tumour was localized on a post contrast planning computerized tomography (CT) and MRI scan. The gross tumour volume (GTV) and the critical structures were outlined on contiguous 2-3 mm separated slices. A margin of 5 mm (12 patients) to 10 mm (10 patients) was grown around GTV in three-dimensions (3-D) to generate the planning target volume (PTV). The treatment was delivered by three (five patients) and four (17 patients) maximally separated conformal fixed fields with each field conformed to the shape of the tumour using customized lead alloy blocks (19 patients) or multileaf collimator (three patients). The patients were treated on a 6-MV linear accelerator to a dose of 45 Gy in 25 fractions (18 patients) and 50 Gy in 30 fractions (four patients). RESULTS: The technique of SCRT has become a part of the routine work of the radiotherapy department. The treatment was well tolerated with minimal acute toxicity. One patient developed transient quadrantanopia 2 weeks after treatment with full recovery after a short course of corticosteroids. One patient had a transient visual deterioration 7 months after treatment due to cystic degeneration of the tumour which fully recovered following surgical decompression. Nine of the 15 patients presenting with visual impairment had improvement after treatment and the visual status remained stable in all others. One patient with acromegaly and one with a prolactinoma achieved normalization of elevated hormonal abnormality four and 10 months after SCRT, respectively. The remaining seven patients with a secretory adenoma had declining hormone levels at last follow-up. Newly initiated hormone replacement therapy was required in five patients. At a median follow-up of 9 months (range 1-44 months), the 1 and 2 year actuarial progression free and overall survival were 100%.

CONCLUSION: Stereotactic conformal radiotherapy is a high precision technique suitable for the treatment of pituitary adenomas requiring radiotherapy. Preliminary results suggest effective tumour control and low toxicity within the range expected for conventional external beam radiotherapy. While the technique is of potential benefit in reducing the volume of normal brain irradiated, the advantages in terms of sustained tumour control and reduced toxicity over conventional radiotherapy need to be demonstrated in long-term prospective studies.

6. Cabergoline in the Treatment of Hyperprolactinemia: A Study in 455 Patients. Verhelst, Abs, Maiter, et al. J Clin Endocrinol Metab 1999; 84(7):2518-22

Cabergoline is a new long-acting dopamine agonist that is very effective and well tolerated in patients with pathological hyperprolactinemia. The aim of this study was to examine, in a very large number of hyperprolactinemic patients, the ability to normalize PRL levels with cabergoline, to determine the effective dose and tolerance, and to assess the effect on clinical symptoms, tumour shrinkage, and visual field abnormalities. We also evaluated the effects of cabergoline in a large subgroup of patients with bromocriptine intolerance or -resistance.

We retrospectively reviewed the files of 455 patients (102 males and 353 females) with pathological hyperprolactinemia treated with cabergoline in 9 Belgian centers. Among these patients, 41% had a microadenoma; 42%, a macroadenoma; 16%, idiopathic hyperprolactinemia; and 1%, an empty sella. The median pretreatment serum PRL level was 124 µg/L (range, 16–26,250 µg/L). A subgroup of 292 patients had previously been treated with bromocriptine, of which 140 showed bromocriptine intolerance and 58 showed bromocriptine resistance.

Treatment with cabergoline normalized serum PRL levels in 86% of all patients: in 92% of 244 patients with idiopathic hyperprolactinemia or a microprolactinoma and in 77% of 181 macroadenomas. Pretreatment visual field abnormalities normalized in 70% of patients, and tumor shrinkage was seen in 67% of cases. Side effects were noted in 13% of patients, but only 3.9% discontinued therapy because of side effects. The median dose of cabergoline at the start of therapy was 1.0 mg/week but could be reduced to 0.5 mg/week once control was achieved. Patients with a macroprolactinoma needed a higher median cabergoline dose, compared with those with idiopathic hyperprolactinemia or a microprolactinoma: 1.0 mg/week vs. 0.5 mg/week, although a large overlap existed between these groups. Twenty-seven women treated with cabergoline became pregnant, and 25 delivered a healthy child. One patient had an intended abortion and another a miscarriage. In the patients with bromocriptine intolerance, normalization of PRL was reached in 84% of cases, whereas in the bromocriptine-resistant patients, PRL could be normalized in 70%.

We confirmed, in a large-scale retrospective study, the high efficacy and tolerability of cabergoline in the treatment of pathological hyperprolactinemia, leaving few patients with unacceptable side effects or inadequate clinical response. Patients with idiopathic hyperprolactinemia or a microprolactinoma, on average, needed only half the dose of cabergoline as those with macroprolactinomas and have a higher chance of obtaining PRL normalization. Cabergoline also normalized PRL in the majority of patients with known bromocriptine intolerance or -resistance. Once PRL secretion was adequately controlled, the dose of cabergoline could often be significantly decreased, which further reduced costs of therapy.

7. Withdrawal of Long-Term Cabergoline Therapy for Tumoural and Non tumoral Hyperprolactinemia. Colao A, Di Sarno, A, Cappabianca, P, et al. NEJM 2003;349:2023-2033

BACKGROUND: Whether the withdrawal of treatment in patients with non tumoural hyperprolactinemia, microprolactinomas, or macroprolactinomas is safe and effective has been unclear. We performed an observational, prospective study of cabergoline (a dopamine-receptor agonist) withdrawal in such patients. METHODS: The study population included 200 patients — 25 patients with non tumoural hyperprolactinemia, 105 with microprolactinomas, and 70 with macroprolactinomas. Withdrawal of cabergoline was considered if prolactin levels were normal, magnetic resonance imaging (MRI) showed no tumour (or tumour reduction of 50 percent or more, with the tumour at a distance of more than 5 mm from the optic chiasm, and no invasion of the cavernous sinuses or other critical areas), and if follow-up after withdrawal could be continued for at least 24 months. RESULTS: Recurrence rates two to five years after the withdrawal of cabergoline were 24 percent in patients with non tumoural hyperprolactinemia, 31 percent in patients with microprolactinomas, and 36 percent in patients; with macroprolactinomas. Renewed tumour growth did not occur in any patient; in 10 female patients (22 percent) and 7 male patients (39 percent) with recurrent hyperprolactinemia, gonadal dysfunction redeveloped. In all diagnostic groups, prolactin levels at the time of recurrence were significantly lower than at diagnosis (P<0.001). The Kaplan–Meier estimated rate of recurrence at five years was higher among patients with macroprolactinomas and those with microprolactinomas who had small remnant tumours visible on MRI at the time of treatment withdrawal than among patients whose MRI scans showed no evidence of tumor at the time of withdrawal (patients with macroprolactinomas, 78 percent vs. 33 percent, P=0.001; patients with microprolactinomas, 42 percent vs. 26 percent, P=0.02).

CONCLUSIONS: Cabergoline can be safely withdrawn in patients with normalized prolactin levels and no evidence of tumor. However, because the length of follow-up in our study was insufficient to rule out a delayed increase in the size of the tumor, we suggest that patients be closely monitored, particularly those with macroprolactinomas, in whom renewed growth of the tumor may compromise vision.

8. Long-Term Mortality after Transsphenoidal Surgery and Adjunctive Therapy for Acromegaly. Swearingen B, Barker F, Katznelson L, et al. Clin Endocrinol Metab, 83(10), 3419-3426

To analyze the long term outcome after multimodality therapy for acromegaly, a retrospective review was performed on 162 patients who underwent transsphenoidal surgery at Massachusetts General Hospital between 1978 and 1996. The surgical cure rate for microadenomas was 91%, that for macroadenomas was 48%, and it was 57% overall. The surgical cure rate was significantly dependent on tumour size, but was not dependent on age or sex. An improvement in the surgical cure rate was noted over the course of the review, from 45% before 1987 to 73% since 1991. Long term follow-up was obtained in 99% of U.S. residents (149 of 151), with a mean follow-up period of 7.8 yr. Adjuvant radiation and/or pharmacological therapy was given to 61 patients. Of the entire group, 83% (124 of 149) were in biochemical remission as determined by normalization of serum insulin-like growth factor I levels or by GH suppression after oral glucose tolerance testing at last contact or at death. The recurrence rate was 6% at 10 yr and 10% at 15 yr after surgery in those patients who initially met the criteria for surgical cure. The 10-yr survival rate was 88%, and there were 12 deaths at postoperative intervals of 2–12 yr, with the most common cause of death being cardiovascular disease. A Cox proportional hazards model showed that patient-years with persistent disease carried a 3.5-fold [95% confidence interval (CI), 1.0–12; P = 0.02] relative mortality risk compared to those patient-years in remission. A Poisson person-years regression analysis showed no significant difference in survival between those 86 patients cured at operation and an age- and sex-matched sample from the U.S. population [standardized mortality ratio (SMR), 0.84; 95% CI, 0.3–2.2; P = 0.35]. A similar analysis on the entire group of 149 patients showed no significant difference in survival from that in a control sample (SMR, 1.16; 95% CI, 0.66–2.0; P = 0.3). Mortality risk for patient-years with persistent active disease after unsuccessful treatment vs. that in the U.S. population sample remained increased (SMR, 1.8; 95% CI, 0.9–3.6; P = .05). This analysis suggests that the decreased survival previously reported to be associated with acromegaly can be normalized by successful surgical and adjunctive therapy.

9. Conventional Pituitary Irradiation Is Effective In Lowering Serum Growth Hormone And Insulin-Like Growth Factor-I In Patients With Acromegaly. Jenkins P, Bates P, Carson M, et al J. Clin Endocrinol Metab 2006 (in press)

BACKGROUND: There has been recent controversy as to the effectiveness of conventional pituitary irradiation in reducing circulating growth hormone (GH) levels to < 2.5 ng/ml and/or normalization of serum IGF-I. OBJECTIVES: To determine the effects of conventional pituitary irradiation on: (i) lowering of serum GH and IGF-I levels; (ii) the proportion of patients who achieve a GH level < 2.5 ng/ml and a normal age-corrected IGF-I and the time taken to achieve this; and (iii) the incidence of hypopituitarism and other adverse effects. DESIGN: Retrospective data collection from 14 centers throughout the United Kingdom. PATIENTS: 1840 patients with acromegaly of whom 884 had received conventional pituitary irradiation. MEASUREMENTS: Circulating GH and IGF-I levels and pituitary function at intervals after irradiation. RESULTS: Mean GH levels declined from 13.5 to 5.3 ng/ml at 2 yr post irradiation, to 2.0 ng/ml by 10 yr and to 1.1 ng/ml at 20 yr. 22% of patients achieved a level < 2.5 ng/ml by 2 yr, 60% by 10 yr and 77% by 20 yr. The interval to achieve this depended on the pre-irradiation GH level. IGF-I levels fell in parallel to those of GH with 63% of patients having a normal level by 10 yr. The proportions of patients with new pituitary hormone deficiencies 10 yr after irradiation were 18% for LH/FSH, 15% for ACTH and 27% for TSH. No other side effects were noted.

CONCLUSIONS: In this, the largest series reported, conventional pituitary irradiation is shown to be an effective and safe means of reducing both serum GH and IGF-I concentrations in patients with acromegaly.

10. Treatment of Acromegaly with the Growth Hormone–Receptor Antagonist Pegvisomant. Trainer P, Drake W, Katznelson L, et al. N Engl J Med, 2000, 342: 1171-77

BACKGROUND: Patients with acromegaly are treated with surgery, radiation therapy, and drugs to reduce hypersecretion of growth hormone, but the treatments may be ineffective and have adverse effects. Pegvisomant is a genetically engineered growth hormone–receptor antagonist that blocks the action of growth hormone. METHODS: We conducted a 12-week, randomized, double-blind study of three different daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo, given subcutaneously, in 112 patients with acromegaly.

RESULTS: The mean (±SD) serum concentration of insulin-like growth factor I (IGF-I) decreased from base line by 4.0±16.8 percent in the placebo group, 26.7± 27.9 percent in the group that received 10 mg of pegvisomant per day, 50.1±26.7 percent in the group that received 15 mg of pegvisomant per day, and 62.5±21.3 percent in the group that received 20 mg of pegvisomant per day (P<0.001 for the comparison of each pegvisomant group with placebo), and the concentrations became normal in 10 percent, 54 percent, 81 percent, and 89 percent of patients, respectively (P<0.001 for each comparison with placebo). Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in ring size, soft-tissue swelling, the degree of excessive perspiration, and fatigue. The score for total symptoms and signs of acromegaly decreased significantly in all groups receiving pegvisomant (P < 0.05). The incidence of adverse effects was similar in all groups.

CONCLUSIONS: On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone–receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement.

11. Diagnosis and Management of Cushing’s Syndrome: Results of an Italian Multicentre Study. Invitti C, Giraldi F, Martin M J. Clin Endocrinol Metab 1999, 84, 440–448

The past 45 yr’ experience with Cushing’s syndrome (CS) has led to the awareness of its complex nature and, by the same token, brought about an increase in the diagnostic and therapeutic dilemmas. We carried out a retrospective multicentre study on the diagnostic work-up and treatment in 426 patients with CS, subdivided as follows: 288 with Cushing’s disease (CD), 80 with an adrenal adenoma, 24 with an adrenal carcinoma, 25 with ectopic ACTH and/or CRH secretion, and 9 with ACTH-independent nodular adrenal hyperplasia. Normal urinary free cortisol (UFC) values among multiple collections were recorded in about 10% of patients with CS. In 28% of patients with ACTH-independent CS, basal ACTH concentrations were within the normal range but did not respond to CRH stimulation. Measurement of ACTH levels by immu-noradiometric assay, rather than by RIA, offered a greater chance of recognizing patients with ACTH-independent CS or ectopic secretion. A 50% increase in ACTH or cortisol levels after CRH yielded a diagnostic accuracy of 86% and 61%, respectively, in the differential diagnosis of ACTH-dependent CS. An 80% decrease in cortisol levels after 8 mg dexamethasone overnight, or in UFC values after the classical 2-day administration, excluded an ectopic secretion but carried a low negative predictive value given the high number of non suppressors among patients with CD. Pituitary imaging identified an adenoma in 61% of patients with CD. At inferior petrosal sinus sampling, an ACTH centre: periphery gradient after CRH less than 3, correctly classified all patients with ectopic secretion but misdiagnosed 15% of 76 patients with CD. Transsphenoidal pituitary surgery, the standard therapy for CD, resulted in complete remission (appearance of clinical signs of adrenal insufficiency associated with low/normal UFC excretion and, when available, low/normal morning plasma ACTH and cortisol levels) in 69% of patients. The overall relapse rate after pituitary surgery was 17%. The probability of relapse-free survival, as assessed by Kaplan-Meier analysis, was 95% at 12 months, 84% at 2 yr, and 80% at 3 yr. Risk of relapse was significantly correlated with postoperative baseline plasma ACTH and cortisol peak after CRH. No relapses were observed among patients who did not respond to CRH. Other therapeutic approaches for CD, such as pituitary irradiation and medical therapy, resulted in normalization of cortisol secretion in about half of treated cases. In summary, an accurate selection of the available diagnostic tools leads to the correct diagnosis in the majority of patients with CS. The therapeutic options for CD, adrenal carcinoma, and ectopic secretion are, as yet, not fully satisfactory. The high incidence of relapse after pituitary surgery calls for a prolonged follow-up.

12. Clinical and Endocrine Responses to Pituitary Radiotherapy in Pediatric Cushing’s Disease: An Effective Second-Line Treatment. Storr H, Plowman P, Carroll P, et al J. Clin Endocrinol Metab 2003, 88; 34-37

Transsphenoidal surgery (TSS) is considered first-line treatment for Cushing’s disease (CD). Options for treatment of postoperative persisting hypercortisolemia are pituitary radiotherapy (RT), repeat TSS, or bilateral adrenalectomy. From 1983 to 2001, we treated 18 pediatric patients (age, 6.4–17.8 yr) with CD. All underwent TSS, and 11 were cured (postoperative serum cortisol, <50 nM). Seven (39%) had 0900-h serum cortisol of 269–900 nM during the immediate postoperative period (2–20 d), indicating lack of cure. These patients (6 males and 1 female; mean age, 12.8 yr; range, 6.4–17.8 yr; 4 prepubertal; 3 pubertal) received external beam RT to the pituitary gland, using a 6-MV linear accelerator, with a dose of 45 Gy in 25 fractions over 35 d. Until the RT became effective, hypercortisolemia was controlled with ketoconazole (dose, 200–600 mg/d) (n = 4) and metyrapone (750 mg–3 g/d) ± aminoglutethimide (1 g/d) or o’p’DDD (mitotane, 3 mg/d) (n = 3). All patients were cured after pituitary RT. The mean interval from RT to cure (mean serum cortisol on 5-point day curve, <150 nM) was 0.94 yr (0.25–2.86 yr). Recovery of pituitary-adrenal function (mean cortisol, 150–300 nM) occurred at mean 1.16 yr (0.40–2.86 yr) post RT. At 2 yr post RT, puberty occurred early in one male patient (age, 9.8 yr) but was normal in the others. GH secretion was assessed at 0.6–2.5 yr post RT in all patients: six had GH deficiency (peak on glucagon/insulin provocation, <1.0–17.9 mU/liter) and received human GH replacement. Follow-up of pituitary function 7.6 and 9.5 yr post RT in two patients showed normal gonadotropin secretion and recovery of GH peak to 29.7 and 19.2 mU/liter. The seven patients were followed for mean 6.9 yr (1.4–12.0 yr), with no evidence of recurrence of CD. In conclusion, pituitary RT is an effective and relatively rapid-onset treatment for pediatric CD after failure of TSS. GH deficiency occurred in 86% patients. Long-term follow-up suggests some recovery of GH secretion and preservation of other anterior pituitary function.

13. Cerebrovascular mortality in patients with pituitary adenoma. Brada M; Ashley S; Ford D; Traish D; Burchell L; Rajan B. Clin Endocrinol (Oxf) 2002 Dec;57(6):713-7.

OBJECTIVE: To assess cerebrovascular mortality in a UK cohort of patients with pituitary adenoma known to have increased incidence of cerebrovascular accidents (CVA). METHODS: A total of 334 patients treated at the Royal Marsden Hospital (RMH) between 1962 and 1986 with surgery and postoperative radiotherapy were followed up via the NHS Central Register (NHSCR) to identify deaths and emigrations. The causes of death were assessed by NHSCR-based death certificates and coded according to the 9th revision of ICD. Follow-up was censored at age 85, on emigration or cancellation of NHSCR. Thirteen patients could not be traced. A total of 4982 person-years was accumulated in the cohort. Expected numbers of deaths were computed from the national age-, sex- and period-specific mortality rates for England and Wales. RESULTS: In the pituitary adenoma cohort, 128 deaths were observed compared to 80.9 expected [relative risk (RR) of death 1.58 (95% CI: 1.32-1.90)]. There were 33 cerebrovascular deaths compared with 8.04 expected (RR 4.11, 95% CI 2.84-5.75). Three deaths were from subarachnoid haemorrhage compared to 0.54 expected (RR 5.51, 95% CI 1.14-16.09). There was an increased cerebrovascular mortality in women (RR 6.93, 95% CI 4.29-10.60) compared to men (RR 2.4, 95% CI 1.24-4.20; P = 0.002) and in patients having debulking surgery (RR 5.19, 95% CI 3.50-7.42) compared to biopsy/no surgery (RR 1.33, 95% CI 0.27-3.88; P = 0.02). The RR in patients with nonsecretory tumours was 3.65 (95% CI 2.26-5.58), compared with 5.23 (95% CI 2.25-10.30) in secretory tumours (P = 0.4). The effect of age at radiotherapy was not significant (P = 0.4).

CONCLUSION: Patients with pituitary adenoma treated with surgery and radiotherapy have an increased risk of cerebrovascular mortality compared to the general population, which mirrors the increased incidence of CVA. The possible risk factors include hypopituitarism, radiotherapy and extent of surgery but none are at present proven causes. The evaluation of new treatment strategies should not only assess intermediate end-points of tumour and endocrine control but should concentrate on long-term survival with particular emphasis on CVA incidence and mortality.

14. Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma: update after an additional 10 years. Minniti G; Traish D; Ashley S; Gonsalves A; Brada M. J Clin Endocrinol Metab 2005 Feb;90(2):800-4.

We assessed the risk of second brain tumours in a cohort of patients with pituitary adenoma treated with conservative surgery and external beam radiotherapy. Four hundred and twenty-six patients (United Kingdom residents) with pituitary adenomas received radiotherapy at the Royal Marsden Hospital (RMH) between 1962 and 1994. They were followed up for 5749 person-years. The cumulative incidence of second intracranial tumours and systemic malignancy was compared with population incidence rates through the Thames Cancer Registry and the National Health Service Central Register (previously OPCS) to record death and the potential causes. Eleven patients developed a second brain tumour, including five meningiomas, four high grade astrocytomas, one meningeal sarcoma, and one primitive neuroectodermal tumour. The cumulative risk of second brain tumours was 2.0% [95% confidence interval (CI), 0.9-4.4%] at 10 yr and 2.4% (95% CI, 1.2-5.0%) at 20 yr, measured from the date of radiotherapy. The relative risk of second brain tumour compared with the incidence in the normal population was 10.5 (95% CI, 4.3-16.7). The relative risk was 7.0 for neuroepithelial and 24.3 for meningeal tumours. The relative risks were 24.2 (95% CI, 4.8-43.5), 2.9 (95% CI, 0-8.5), and 28.6 (95% CI, 0.6-56.6) during the intervals 5-9, 10-19, and more than 20 yr after radiotherapy (four cases occurred >20 yr after treatment). There was no evidence of excess risk of second systemic malignancy. An additional 10-yr update confirmed our previous report of an increased risk of second brain tumours in patients with pituitary adenoma treated with surgery and radiotherapy. The 2.4% risk at 20 yr remains low and should not preclude the use of radiotherapy as an effective treatment option. However, an increased risk of second brain tumours continues beyond 20 and 30 yr after treatment.