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PubMed2002

Radiation therapy for Cushing's disease: a review.

Because patients with Cushing's disease have an increased morbidity and an age-corrected mortality, treatment is generally started as soon as possible. The goal of treatment in these patients is to induce remission. Although a variety of treatments are available, pituitary radiation is a good option for aggressive Cushing's disease that fails to respond to surgery, disease that invades the cavernous sinus, and disease that relapses following an initial remission. Conventional radiation therapy, stereotactic radiosurgery, fractionated stereotactic radiation therapy, and brachytherapy with Yttrium-90 (Y 90) and Gold-198 (Au 198) have been used successfully to treat ACTH-secreting pituitary adenomas in specialized centers. Conventional radiation therapy is the most frequently used method of radiation therapy for Cushing's disease. Stereotactic radiosurgery may be used as an alternative in patients with adenomas that are smaller than 30 mm and located at least 3 to 5 mm from the optic chiasm. Fractionated stereotactic radiation therapy is an alternative to radiosurgery while interstitial pituitary irradiation is an alternative to surgical resection in invasive tumors. Hypopituitarism is the most common side effect of pituitary irradiation. This article will review the role of radiation in the primary and secondary treatment in patients with Cushing's disease caused by pituitary adenomas.

Adenoma↗
PubMed1989

Adrenal autotransplantation with attached blood vessels for treatment of Cushing's disease.

A case of Cushing's disease was treated successfully by staged total adrenalectomy, left adrenal autotransplantation with the attached blood vessels and pituitary irradiation. In the first stage the left adrenal gland was removed with its attached blood vessels intact, and adrenal autotransplantation then was performed. An end-to-end anastomosis was made between the adrenal central vein and the right inferior epigastric artery. The anastomosis between the right saphenous vein and the adrenal middle artery was accomplished by intussuscepting the artery into the vein followed by suturing. The second stage operation was total right adrenalectomy. Steroid replacement therapy was stopped 7 days postoperatively and all laboratory studies were normal. Two months after total right adrenalectomy the patient had a sensation of facial fullness. Plasma cortisol and 24-hour urinary 17-hydroxycorticosteroid levels were elevated. Part of the graft was excised with the patient under local anesthesia. The symptoms disappeared and the laboratory studies returned to normal. Pituitary irradiation was administered as supplementary treatment of Cushing's disease. This method for the treatment of Cushing's disease has proved feasible. The inguinal region is the optimal site for adrenal autotransplantation.

Adrenal Glands↗
PubMed2000

Comparison of octreotide acetate LAR and lanreotide SR in patients with acromegaly.

BACKGROUND AND OBJECTIVE: The most effective option for the medical treatment of patients with acromegaly is the use of somatostatin analogues. Long-acting depot formulations for intramuscular injection of two somatostatin analogues have recently become available: octreotide acetate LAR (Sandostatin LAR, Novartis Pharma AG) and lanreotide SR (Somatuline, Ipsen Biotech). We wished to compare efficacy of octreotide LAR and lanreotide SR in acromegalic patients. PATIENTS AND METHODS: A group of 125 patients with acromegaly (67 females; mean age, 47 years; 59 patients had previous pituitary irradiation) from 26 medical centres in France, Spain and Germany were studied. Before the study, all patients had been treated with intramuscular injections of lanreotide SR (mean duration, 26 months) at a dose of 30 mg which was injected every 10 days in 64 and every 14 days in 61 patients, respectively. All patients were switched from lanreotide SR to intramuscular injections of 20 mg of octreotide LAR once monthly for three months. In order to obtain efficacy and safety data of lanreotide SR under study conditions, it was decided to randomly assign at day 1, in a 3 : 1 ratio, the time point of the treatment switch; 27 of the patients were randomly assigned to continue the lanreotide SR treatment for the first 3 months of the study (group A); they were on octreotide LAR 20 mg from month 4-6. The other 98 patients were assigned to be switched to treatment with octreotide LAR 20 mg at day 1 (group B). In group B patients, octreotide LAR treatment was continued until month 6, with an adjustment of the dose based on GH levels obtained at month 3. RESULTS: The mean GH concentration decreased from 9.6 +/- 1.3 mU/l at the last evaluation on lanreotide SR to 6.8 +/- 1.0 mU/l after three injections of octreotide LAR (P < 0.001). The percentages of patients with mean GH values < or = 6.5 mU/l (2.5 microg/l) and < or = 2.6 mU/l (1.0 microg/l) at the last evaluation on lanreotide SR were 54% and 14%, and these values increased after 3 months treatment with octreotide LAR to 68% and 35% (P < 0.001), respectively. IGF-I levels were normal in 48% at the last evaluation on lanreotide SR and in 65% after 3 months on octreotide LAR (P < 0.001). Patients with pre-study pituitary irradiation had lower mean GH and IGF-I concentrations. But the effects of the treatment change did not differ between the irradiated and the nonirradiated patients. In general both drugs were well tolerated. CONCLUSION: Octreotide LAR 20 mg administered once monthly was more effective than lanreotide SR 30 mg administered 2 or 3 times monthly in reducing GH and IGF-I in patients with acromegaly.

Acromegaly↗
PubMed1999

Complete remission of Nelson's syndrome after 1-year treatment with cabergoline.

In this case report we demonstrated that treatment with the long-acting D2 receptor agonist cabergoline for 1 year induced normalization of plasma ACTH levels and disappearance of the pituitary tumor in a patient with Nelson's syndrome. A young man underwent bilateral adrenalectomy and subsequent pituitary irradiation for Cushing's disease after unsuccessful neurosurgical treatment. Thereafter, he was given cortisone acetate replacement at the dose of 62.5 mg a day. Fifteen months after pituitary irradiation, he developed Nelson's syndrome, having skin hyperpigmentation, high plasma ACTH levels (376 ng/l) and a pituitary microadenoma (5 mm) documented at magnetic resonance imaging (MRI) of the pituitary region. After 6 months of cabergoline treatment, given at the dose of 1 mg a week, plasma ACTH levels were significantly decreased (from 376 to 113 ng/l) but they were not normalized. Cabergoline dose was then increased up to 2 mg a week. Six months later plasma ACTH levels were normalized (22 ng/l) and MRI demonstrated the disappearance of the pituitary adenoma. In order to investigate on the direct effect played by cabergoline treatment on the remission of Nelson's syndrome, the treatment was withdrawn. Plasma ACTH levels significantly increased (119 ng/l) after 3 months of treatment withdrawal. At the last follow-up, during cabergoline treatment at the dose of 2 mg/week plasma ACTH levels were normalized (40.4 ng/l). This case demonstrated that cabergoline treatment is able to induce the remission of Nelson's syndrome and may be a valid therapeutic alternative in this syndrome.

Adenoma↗
PubMed1979

Radiation-induced hyperprolactinaemia in a treated acromegalic.

A 31-year-old acromegalic was normoprolactinaemic after partial removal of her pituitary tumour. The post-operative external pituitary irradiation lowered the mean growth hormone (GH) level from 75 mU/1 to less than 1 mU/1 within 2 years. However, at the same time hyperprolactinaemia developed. These changes in the GH and prolactin levels were confirmed 3 and 4 years after irradiation. The cause of the hyperprolactinaemia was radiation-induced hypothalamic damage. Therefore it is suggested that similar damage may occur in patients receiving external pituitary irradiation for 'prolactinomas' and that this mechanism may contribute to the persistent hyperprolactinaemia observed in such patients.

Acromegaly↗
PubMed2003

Clinical laboratory findings and results of therapy in 55 patients with Cushing's syndrome.

In this study, 55 patients with Cushing's syndrome (CS) (50 female, 5 male; mean age 34 +/- 12.3 yr) who attended our clinics between the years 1983 and 2000 were retrospectively evaluated for clinical and laboratory features and modalities and results of therapy, due to a few similar studies over the last ten years. Cushing's disease was diagnosed in 39 patients (71%), adrenal adenoma in 13 patients (23.6%) and adrenal carcinoma in 3 patients (5.5%). Centripedal obesity, moon face, hypertension, hirsutism and purplish stria were the most frequent findings. Loss of normal serum F circadian rhythm was found in all patients with CS. The overnight 1 mg oral dexamethasone suppression test and low-dose dexamethasone suppression test (LDDST) yielded 100% and 100% diagnostic sensitivity for CS, respectively. Sensitivity and specivity of the high-dose dexamethasone suppression test (HDDST) in distinguishing Cushing's disease was found to be 82% and 100%, respectively. All of the patients with adrenal CS were not suppressed with HDDST. Sellar CT and/or MRI accurately identified the tumor in 58% of these patients. Recurrence was observed in 3 (11%) of the 28 patients with Cushing's disease, treated by transsphenoidal adenomectomy. Recurrence was diagnosed 1.5, 3 and 6 yr after the operation in these 3 patients. One patient had residue tumor. In our case series, bilateral adrenalectomy plus pituitary irradiation achieved the highest remission rate (100%) in Cushing's disease. In 2 out of 4 patients (50%) treated by left adrenalectomy associated with pituitary irradiation, recurrence was observed. Panhypopituitarism due to tumor apoplexy was observed in one of the patients with Cushing's disease. All of the patients with adrenal CS, the tumor was accurately localized with imaging methods before the operation. The appropriate operative procedure resulted in complete remission in patients with adrenal adenoma. Consequently, Cushing's disease was the most common form of CS. The overnight 1 mg oral DST and 24-h urine free F excretion (UFC) as screening tests, 2-day LDDST as diagnostic test and 2-day HDDST as differential diagnostic test were good studies. More successful outcomes have been achieved in treatment of Cushing's disease with the development of pituitary surgery in the recent years, as well as in our case series. Surgery is also curative for adrenal adenoma patients. Survival remains poor among carcinoma patients.

Adrenalectomy↗
PubMed2005

Fractionated proton beam irradiation of pituitary adenomas.

PURPOSE: Various radiation techniques and modalities have been used to treat pituitary adenomas. This report details our experience with proton treatment of these tumors. METHODS AND MATERIALS: Forty-seven patients with pituitary adenomas treated with protons, who had at least 6 months of follow-up, were included in this analysis. Forty-two patients underwent a prior surgical resection; 5 were treated with primary radiation. Approximately half the tumors were functional. The median dose was 54 cobalt-gray equivalent. RESULTS: Tumor stabilization occurred in all 41 patients available for follow-up imaging; 10 patients had no residual tumor, and 3 had greater than 50% reduction in tumor size. Seventeen patients with functional adenomas had normalized or decreased hormone levels; progression occurred in 3 patients. Six patients have died; 2 deaths were attributed to functional progression. Complications included temporal lobe necrosis in 1 patient, new significant visual deficits in 3 patients, and incident hypopituitarism in 11 patients. CONCLUSION: Fractionated conformal proton-beam irradiation achieved effective radiologic, endocrinological, and symptomatic control of pituitary adenomas. Significant morbidity was uncommon, with the exception of postradiation hypopituitarism, which we attribute in part to concomitant risk factors for hypopituitarism present in our patient population.

Adenoma↗
PubMed1981

Familial Cushing Disease.

A 28-year-old woman and her niece presented with manifestations of the Cushing syndrome. Endocrine studies, including small-and large-dose dexamethasone-suppression test confirmed the diagnosis of pituitary ACTH excess. The first patient had a sella of normal size and went into clinical and hormonal remission after external pituitary irradiation, and she has remained well of follow-up for 9 years. The niece had an enlarged sella turcica on tomography and is receiving a course of external pituitary irradiation.

Adult↗
PubMed2001

Cushing's disease in childhood: presentation, investigation, treatment and long-term outcome.

Seventeen patients with Cushing's disease (CD) were treated from 1978 to 2000. There were 11 males and 6 females aged 6.8-18.8 years (mean age 13.0 +/- 5.9 years). Presenting features were: weight gain (100%); growth failure (71%); hirsutism (53%); striae (53%); hypertension (47%). Mean age of patients with striae was 15.2 +/- 2.3 years, without striae 10.3 +/- 3.3 years. Median height SDS was -1.81 (range -0.28 to -4.17), 53% having height SDS < -1.8. The height velocity in 6 subjects was subnormal (0.9-3.8 cm/year). Median BMI SDS was 2.29 (range 1.72-5.06). Cushing's disease was confirmed by detectable serum ACTH, median 28 ng/l (range 12-99, NR <10-50) (n = 15); loss of cortisol circadian rhythm values at midnight ranging from 216 to 1,080 nmol/l (NR <50) (n = 15); lack of cortisol suppression (NV < 50 nmol/l) during low-dose dexamethasone suppression test (LDDST) (0.5 mg 6-hourly x 8) (n = 14); and >50% suppression of cortisol compared with the basal value during high-dose dexamethasone suppression test (HDDST) (2 mg 6-hourly x 8) (n = 14). A CRH test (1 microg/kg i.v.) showed an increase of cortisol from 12 to 217% (median 73.5%) (n = 16). Pituitary imaging (CT/MRI) showed an image consistent with microadenoma in 6/17 patients, but there was concordance between pituitary imaging and surgical findings in 1/11 patients (9%). Inferior petrosal sinus sampling (IPSS) for ACTH after CRH was performed in 11 subjects (age 10.7-18.8 years). Central to peripheral ACTH ratios were >2 (2.5-157.2) in 10/11 patients. The inter-petrosal sinus ACTH gradient was >1.4 in 10 patients (2.1-20.8), indicating lateralization of ACTH secretion. In 10 patients (91%), the side of the tumour on IPSS was predictive of findings at surgery. Therapy consisted of transsphenoidal microadenomectomy (TSS) in 16 patients and bilateral adrenalectomy (1978) in 1. Following TSS alone, 7 patients were cured (cortisol <50 nmol/l) and 2 were in remission (cortisol <300 nmol/l), i.e. 56%. Seven had persisting hypercortisolaemia and underwent pituitary irradiation (4,500 cGy). Therapeutic outcome for a median of 8 years (0.5-24 years) resulted in cure of CD in 14/17 patients (82%) and remission in 1. Linear growth after TSS +/- pituitary irradiation in 10 subjects showed no short-term catch-up growth, with peak growth hormone (GH) 0.5-20.9 mU/l to insulin tolerance test (ITT)/glucagon. Eight patients were treated with human growth hormone (hGH) (14 U/m(2)/week) combined in 3 with GnRH analogue. The mean final (n = 6) or latest (n = 4) height SDS was -1.36. The difference between final/latest height SDS and target height SDS was 0.93 +/- 1.13, i.e. less (p = 0.005) than the difference between height SDS and target height SDS at presentation, i.e. 1.72 +/- 1.26, indicating long-term catch-up growth.

Adolescent↗
PubMed1989

Repeat transsphenoidal surgery for Cushing's disease.

Transsphenoidal resection of adrenocorticotrophic hormone (ACTH)-producing pituitary adenomas has the potential of curing most patients with Cushing's disease. However, transsphenoidal exploration of the pituitary is not always curative, and patients who have remission of hypercortisolism following surgery occasionally develop a recurrence. Whether repeat pituitary surgery should be performed for recurrent or persistent Cushing's disease has not been evaluated previously. To determine the efficacy of transsphenoidal surgery in recurrent or persistent Cushing's disease, we performed transsphenoidal surgery in 31 patients (22 women and nine men) who had previously undergone a transsphenoidal operation and two female patients who had had previous pituitary irradiation only. In 24 (73%) of the 33 patients, remission of hypercortisolism was achieved by surgery. Although preoperative computerized tomography (CT) scanning identified an adenoma in only three of the 33 patients, in 20 patients a discrete adenoma was identified at pituitary exploration. The incidence of hypercortisolism was greatest if an adenoma was identified at surgery and the patient received selective adenomectomy (19, or 95% of 20 patients), if there was evidence at surgery or by preoperative CT scanning that the previous surgical exposure of the pituitary was incomplete (seven, or 78% of nine patients), if an adenoma was seen on preoperative CT scanning (three of three patients), or if the patient had had prior pituitary irradiation without surgery (two of two patients). In contrast, only five (42%) of 12 patients who received subtotal or total hypophysectomy had remission of hypercortisolim. Surgically induced hypopituitarism occurred in six (50%) of these 12 patients, but in only one (5%) of the 20 patients who underwent selective adenomectomy. Three (13%) of the 24 patients who were in remission from hypercortisolims following repeat surgery developed recurrent hypercortisolism 10 to 47 months postoperatively. Repeat transsphenoidal exploration of the pituitary and treatment limited to selective adenomectomy should be considered in patients with hypercortisolism despite previous pituitary treatment. If an adenoma is identified during surgery, the chance of remission of Cushing's disease is high and the risk of hypopituitarism is low; however, if no adenoma can be found and partial or complete hypophysectomy is performed, remission of hypercortisolism is less likely and the risk of hypopituitarism is about 50%.

Adenoma↗
PubMed1989

Repeat megavoltage irradiation of pituitary and suprasellar tumors.

From 1965 to 1984, ten patients with suprasellar or pituitary tumors received repeat courses of radiation therapy at the Joint Radiation Oncology Center of the University of Pittsburgh. The radiation doses varied between 36.00 to 53.65 Gy for the first treatment course and from 35.00 to 49.60 Gy for retreatment. Six patients were treated for pituitary tumors, two for germinoma, one for optic glioma, and one for craniopharyngioma. One died of disease progression 19 years after a second course of radiation. Two patients were dead of intercurrent disease 0.2 and 1.5 years after repeat radiation. The remainder are free of disease progression 1.6 to 20.5 years after repeat irradiation. Optic neuropathy developed in one patient 1.3 years following a second course of treatment to 40 Gy in 20 fractions administered 7.5 years after initial treatment to 46 Gy in 23 fractions. Neither the Nominal Standard Dose nor the Neuret formula provided an adequate estimate of the repair of radiation. An estimation that 40% of the original radiation dose effect is still present appears to be a reasonable "rule of thumb" guideline to account for prior radiotherapy.

Adolescent↗
PubMed1989

[Pituitary radiotherapy of Cushing's disease (an analysis of 22 cases and literatures review)].

22 patients with Cushing's disease were treated in our hospital from 1976 to 1983. 18 patients were treated by adrenal surgery combined with pituitary irradiation, while 4 patients by radiotherapy of pituitary alone. Overall effective rate was 94%, 82% of patients were able to return to work. Adrenal resection followed by radiation of the pituitary had a relapse rate of 9.1%. The relapse rate was increased to 85.7%, if post-operative radiation was not given. The authors proposed that for young patients with mild disease, radiotherapy alone for pituitary yields good results. As post-operative radiotherapy radiation should be started 2 weeks to 2 months after adrenal operation. Two opposing lateral preauricular portals together with one prefrontal midline portal are preferable and can effectively reduce the dose to the normal brain, the recommended dose is DT 40-50 Gy.

Adolescent↗
PubMed1989

Prolactinomas presenting as primary amenorrhoea and delayed or arrested puberty: response to medical therapy.

Fourteen patients presented with arrested pubertal development associated with prolactin-secreting pituitary tumours; serum prolactin ranged from 4000-104,300 mU/l in the ten females and 920-68,000 in four males. Skull X-ray showed a markedly expanded pituitary fossa in eight patients. CT scan and/or air encephalography showed macroadenomas in nine, of whom seven had large suprasellar extensions to their tumours, yet only five had complained of headache and only two had visual field defects. All were treated with bromocriptine (7.5-60 mg/day) which lowered prolactin substantially in all and into the normal range in 11 (range less than 60-3090, median 105 mU/l). Puberty thereafter progressed spontaneously in 13, but in one patient, whose prolactin did not suppress completely, menarche could be induced only with clomiphene. Anterior pituitary function improved on bromocriptine. In seven patients with macroadenomas, tumour shrinkage into the pituitary fossa was complete and in two others incomplete shrinkage was followed by transsphenoidal hypophysectomy. Seven patients received pituitary irradiation, six after bromocriptine-induced shrinkage and one after transsphenoidal surgery. At follow-up 6 months to 10 years (median 5 years) after presentation, ten remain on bromocriptine with a suppressed serum prolactin, one has a normal prolactin after surgery, and three are off bromocriptine with residual hyperprolactinaemia (418-4680 mU/l). To date, four females have become pregnant and one male has fathered two children. Prolactinomas are an important, albeit rare, cause of arrested puberty and should therefore be sought. Most patients respond well to bromocriptine, with or without pituitary irradiation.

Adolescent↗
PubMed1994

[Thyroid-stimulating hormone-secreting pituitary adenoma].

A 40-year-old male patient with a 2 years history of recurring hyperthyroidism is presented with clinical hyperthyroidism and diffuse goiter. Despite thyreostatic treatment and surgical thyroid ablation the hyperthyroidism recurred. The patient had laboratory evidence of hyperthyroidism and his serum TSH was persistently and enormously elevated (T4:214 nmol/l, T3:6.9 nmol/l, TSH:218 mIU/l)> Computed tomography and magnetic resonance imaging confirmed a pituitary mass of 7 cm in a-p diameter, with supra-, parasellar and sphenoidal extension. The pituitary adenoma was partially resected by transsphenoidal surgery, which failed to result in a substantial decrease in the serum thyrotropin level. Pituitary irradiation and a long-term somatostatin analog octreotide treatment (300-600 micrograms/die) combined with bromocriptine therapy resulted in a significant, but still incomplete suppression of thyrotropin secretion (TSH level about 15 mIU/l) and persisting mild hyperthyroidism. The size of the adenoma was unchanged during the two years of highdose octreotide treatment period. According to our best knowledge this is the first reported case of a thyrotropin-secreting pituitary adenoma in Hungary.

Adult↗
PubMed1976

Pituitary hormone responses to hypothalamic releasing hormones in acromegaly.

The pituitary reserve of GH, prolactin, TSH, LH, and FSH has been studied in a group of 13 acromegalic patients with the aim of evaluating the pituitary function and the activity of the disease. Plasma GH, TSH and polactin were determined after thyrotrophin releasing hormone (TRH) administration, plasma gonadotrophins and GH after luteinizing hormone releasing hormone (LH-RH) administration. The plasma TSH response to TRH was generally blunted in the patients treated with pituitary irradiation; however, none of the patients with diminished TSH reserve had signs of hypothyroidism. Six acromegalics showed prolactin basal levels higher than controls; none had galactorrhoea; 4 of them complained of impairment of the gonadal function. The prolactin response to TRH was variable and not related to prolactin basal levels. A subnormal LH reserve after LH-RH stimulation was observed in 5 out of 10 patients; 4 of them had also clinical signs of hypogonadism. A normal FSH response to LH-RH was present in all patients. A non-specific GH response to TRH and/or LH--RH was obtained in about half of the acromegalics studied. The GH responsiveness to TRH and/or LH-RH was not related to the activity of the disease or to a specific derangement of the hypothalamo-pituitary function. A concordant response was observed only between GH and prolactin response to TRH; the highest prolactin responses to TRH were obtained in the GH responsive patients. Each patient showed a constant GH pattern of response on repeated testing. Even after pituitary irradiation the pattern of GH response was unchanged in spite of lowered GH plasma levels.

Acromegaly↗