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PubMed1992

Beneficial effects of high daily dose bromocriptine treatment in Cushing's disease.

Treatment with a high daily dose bromocriptine was evaluated in 6 Cushing's disease patients (4 females and 2 males; aged 23 to 56 years). The highest doses administered were 40 mg to patient 1, 55 mg to patient 2, 35 mg to patient 3, 25 mg to patient 4, 25 mg to patient 5, and 17.5 mg to patient 6. The former 3 cases, 2 (patients 1 and 2) of whom were previously reported and further followed up, showed clinical and biochemical improvement with the regimen. Patient 1 who obtained remission with 40 mg/day has been on remission for further 14 months with a total of 36 months. Patient 2, who had a reduction in pituitary tumor size with 35 mg daily, relapsed thereafter. The therapy, however, resolved the paradoxical responses of plasma ACTH and cortisol to arginine. Readministration of bromocriptine resulted into another clinical and biochemical improvement with 45 to 55 mg/day. Patient 3, a relapsed case after a remission with reserpine plus pituitary irradiation, showed an improvement in the 24-h urinary free cortisol excretion with 35 mg/day. Patient 4 was the only case who had a marked decrease in plasma cortisol (basal; 16.3, nadir; 1.9 micrograms/dl) after a single-dose bromocriptine test among the 5 cases tested. The patient had favorable response with 25 mg/day for 2 months but the dose was not increased after an escape. Patient 5 received the drug in 4 occasions, 7.5 to 25 mg/day, in combination with several agents, which failed to induce clinical remission. The last patient did not respond to a maximum dose of 17.5 mg/day. These observations suggest that, regardless of the result of a single-dose bromocriptine test, treatment with a high daily dose of bromocriptine, 35 mg or more, may be necessary to obtain a favorable clinical response and normal cortisol secretion.

Adrenocorticotropic Hormone↗
PubMed1978

Evaluation of the results of trans-sphenoidal surgery in acromegaly by assessment of the growth hormone response to thyrotrophin-releasing hormone.

Eighteen acromegalic patients GH-responsive to TRH were reinvestigated following trans-sphenoidal surgery and radiotherapy. Basal serum GH decreased below 10 microgram/1 in thirteen cases; nine of them became GH-unresponsive to TRH 1 month after operation, and another one following conventional pituitary irradiation. Four of these ten patients also showed a normal GH response to L-Dopa after treatment, and five responded normally to insulin-induced hypoglycaemia; two patients had a normal GH secretory pattern after both these stimuli. No recurrences were observed over a follow-up period of 15-80 months among the ten patients who became GH-unresponsive to TRH following operation, while one of the three subjects still responsive to TRH in spite of normalized basal serum GH concentration relapsed 10 months after surgery. Three patients with normalized TRH test following operation were repeatedly reinvestigated over a 3-6 years period and always found unresponsive. The present study shows that the 'paradoxical' GH responses to TRH and L-Dopa frequently disappear after surgery, that complete normalization of GH secretory pattern may rarely be attained, and that the disappearance of GH response to TRH probably indicates satisfactory treatment of acromegaly. These data suggest that the 'paradoxical' GH responses frequently found in acromegaly are dependent on the adenoma per se and not on hypothalamic dysfunction.

Acromegaly↗
PubMed1998

Treatment of prolactinomas.

The objectives of the treatment of hyperprolactinaemia are to suppress excessive hormone secretion and its clinical consequences, to remove tumour mass, to preserve the residual pituitary function and to prevent disease recurrence or progression. Prior to the advent of pharmacotherapy, therapy usually consisted of surgical resection and/or pituitary irradiation. In microprolactinomas, trans-sphenoidal surgical resection normalizes prolactin (PRL) levels, restores normal menses and produces the disappearance of galactorrhoea in a great majority of patients, but normalization of serum PRL levels varies from 35-70%. In macroprolactinomas, trans-sphenoidal surgery is less successful with only 32% of patients appearing to be cured initially. However, the recurrence rate is 19%, and the long-term cure rate is only 26%. In more than 80% of the patients with microprolactinoma, suppression of PRL levels and tumour shrinkage can be achieved with bromocriptine therapy given at doses of 2.5-5 mg per day. In 5-10% of the patients, the appearance of side-effects (nausea, dizziness and postural hypotension) is a limiting factor in continuing the treatment. Dopaminergic compounds cause notable tumour shrinkage in most macroprolactinomas. Treatment with cabergoline, a selective and long-lasting dopamine 2-receptor agonist at weekly doses of 0.5-2 mg has been shown to be effective both in normalizing PRL levels and in inducing tumour shrinkage. Pharmacotherapy with dopamine (DA) agonists is an appropriate first-line treatment for both micro- and macroprolactinomas. Surgery should be recommended for those patients who are severely intolerant of or resistant to DA agonists.

Clinical Trials as Topic↗
PubMed1981

Pituitary function in prolactinoma. Effect of surgery and postoperative bromocriptine therapy.

Forty-five women and fifteen men with prolactinomas have been treated surgically. Patients with large tumours received pituitary irradiation and postoperative hyperprolactinaemia was treated with bromocriptine. The patients have been followed-up for 6-36 months following the operation. The tumours were larger and the levels of production higher in men as compared with women. All women had amenorrhoea. Galactorrhoea was present in forty-three women but not in the men. After surgery serum prolactin levels fell significantly in all women but remained above normal in thirty-six; prolactin remained high in twelve men. Bromocriptine effectively decreased the postoperative hyperprolactinaemia. The surgical complications were oculomotor nerve paresis in one woman and one man. After surgery six (23%) women developed impaired GH secretion, six (15%) impaired thyroid function, eight (18%) impaired cortisol secretion and five (17%) impaired LH secretion in isolation or combination which had not been present preoperatively. Three patients relapsed. Fifteen women menstruated after surgery and ten began to do so during the subsequent bromocriptine treatment. Thus, menstruation was restored in all six women with microadenomas in sixteen of twenty patients with intrasellar macroadenomas and three of nineteen patients with suprasellar adenomas. The preoperative LH-reserve proved to be an important prognostic indicator. Nine patients, i.e. 50% of patients desiring fertility became pregnant. In the men gonadal function deteriorated in four patients and did not improve in any without testosterone treatment.

Adenoma↗
PubMed1997

Metastatic prolactinoma: effect of octreotide, cabergoline, carboplatin and etoposide; immunocytochemical analysis of proto-oncogene expression.

A 49-yr-old woman presented with an extensive prolactinoma (serum PRL > 10,000 mU/L, normal range < 450 mU/L). Over a 5-yr period following transsphenoidal surgery and pituitary irradiation, she became increasingly resistant to high doses of bromocriptine and underwent transfrontal surgery followed by stereotactic radiotherapy. In spite of these treatments, serum prolactin estimations rose progressively to > 100,000 mU/L. Magnetic resonance imaging scanning demonstrated a massive cystic tumor invading the temporal lobes, extending into the cervical and thoracic spine, with metastases to cervical lymph nodes. High-dose cabergoline administration resulted in a 30% decrease in serum PRL. Octreotide was administered as a continuous sc infusion with a profound analgesic effect on facial pain but with no effect on tumor progression. She was treated with a course of chemotherapy consisting of carboplatin and etoposide without any noticeable effect. The patient died 6 months following chemotherapy. Immunocytochemical analysis demonstrated positive nuclear staining for WAF-1, Rb protein, c-myc, and p53 both in the original and metastatic tumors. The metastases but not the primary tumor stained for c-jun. Metastatic prolactinoma remains a therapeutic challenge. It is associated with a variable proto-oncogene expression, which may be coincidental or causal. Cabergoline had no advantage over bromocriptine. Octreotide relieved facial pain but did not alter tumor progression. An effective therapy for metastatic prolactinoma remains to be identified.

Antineoplastic Agents, Hormonal↗
PubMed1984

Discordant serum alpha-subunit and FSH concentrations in a woman with a pituitary tumour.

We have studied a women who presented at the age of 51 with a large FSH and alpha-subunit producing pituitary adenoma. Following insertion of ventriculo-peritoneal shunts and external pituitary irradiation there was no change in the elevated serum concentrations of FSH, and alpha-subunit over a four year period although she developed both ACTH and TSH deficiency. Various drugs, however, did alter the FSH and alpha-subunit concentrations and these changes suggest possible mechanisms controlling FSH secretion. Ethinyloestradiol 0.03 mg daily for three weeks suppressed serum FSH to 77% of the basal level (240 +/- 35 i.u./l to 184 +/- 20 i.u./l) but alpha-subunit rose to 130% of basal level (281 +/- 50 ng/ml to 366 +/- 40 ng/ml). On ethinyloestradiol 0.1 mg daily, FSH suppressed to 17% of basal (40 +/- 11 i.u./l) with no change in alpha-subunit concentration, while on 0.2 mg daily suppression of FSH was similar but alpha-subunit fell to 59% of basal (190 +/- 28 ng/ml). Dexamethasone, 3 mg daily for one week reduced FSH to 53% of the initial concentration and alpha-subunit to 74% while bromocriptine 7.5 mg daily for three months, reduced FSH to 39% and alpha-subunit to 66% of basal. Neither thyroxine, 0.2 mg daily for four weeks, nor an LHRH analogue, (Buserelin, Hoechst) 200 micrograms, three times daily for three months elicited any effect. Chromatography on Sephadex G100 showed that serum FSH and alpha-subunit both had Kav values somewhat lower than those of their standard counterparts (FSH, 0.20 vs 0.25; alpha-subunit 0.35 vs 0.45).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma, Chromophobe↗
PubMed2000

Linear growth and final height after treatment for Cushing's disease in childhood.

Cushing's disease is associated with growth failure in childhood and adolescence. Growth and final height were analyzed in 10 patients who were cured or in remission after treatment of Cushing's disease. Seven males and 3 females, aged 6.8-17.6 yr (bone age, 3.3-15.4 yr), had transsphenoidal surgery, which was combined with pituitary irradiation (4,500 cGy in 25 fractions) in 5 patients. At presentation, 5 patients were prepubertal (males), and 5 were pubertal (2 males and 3 females). The mean height SD score was -2.15 +/-1.26 (range, -0.21 to -4.32) compared with mean target height SD score of -0.43 +/- 0.58. Height velocity in 6 patients was subnormal (0.9-3.8 cm/yr). After treatment, short-term height velocity, over a mean interval of 0.57 yr, in 8 patients not receiving human GH (hGH) therapy, was variable (range, 0.8-7.6 cm/yr). GH stimulation tests (insulin tolerance test/glucagon) in 9 subjects showed peak GH levels of 0.5-20.9 mU/L. Eight were treated with hGH (14 IU/m2 wk), combined in 2 girls and 1 boy with a GnRH analog. After 1 yr of hGH, the mean height SD score had increased from -2.45 +/- 1.0 at initiation of hGH to -2.07 +/- 1.2 (P = 0.01). GH therapy was continued until final height or latest assessment. The mean final height SD score (n = 6) was - 1.24 +/- 1.38, and at the latest assessment the mean height SD score (n = 4) was - 1.52 +/- 1.33. Combining these 2 groups, the mean height so score was -1.36 +/- 1.29. The difference between final or latest height SD score and target height SD score was 0.93 +/- 1.13, i.e. less (P = 0.005) than the difference between height and target height SD score of 1.72 +/- 1.26 at presentation. In conclusion, catch-up and favorable long-term growth was seen after treatment for Cushing's disease. Posttreatment GH deficiency was frequent, and early hGH replacement may have contributed to the encouraging outcome.

Adolescent↗
PubMed1991

[Cushing's disease--pathophysiology and treatment].

We followed up 21 Cushing's disease patients (16 females and 5 males) aged 15 to 46 years, treated with reserpine (R) plus pituitary irradiation (PI). Mean duration of R administration and mean dose of PI were 24.5 +/- 10.8 (mean +/- SD) months and 54.0 +/- 9.8 Gy, respectively. Of them, four patients did not respond, one who received 66 Gy had brain necrosis and panhypopituitarism, and the other 16 patients (78%, 16/21) achieved initial remission. Of these 16 patients, there were 10 (aged 15 to 46 years) who were irradiated with 50 Gy or less (mean, 45.5 +/- 6.9 Gy), and 7 of them had initial response. As previously demonstrated effectiveness of the present regimen (R plus PI) could be evaluated by subjecting the patients to R-test, higher rate of remission was obtained among R-test responders (J. Clin. Endocrinol. Metab. 41:511, 1975). Eleven of our R-test responders in the present study showed an early onset of remission (6.9 +/- 5.7 months) as compared with 5 R-test non-responders (17.0 +/- 9.1, p less than 0.05). In addition, the response time positively correlated with the ratio of the difference between basal plasma cortisol (11-OHCS) levels before and after midnight administration of 8 mg dexamethasone (delta D8) divided by the difference between 24-h urinary excretion of 17-OHCS for 3 successive days before, during metyrapone (3.0 g/day, 6 divided dose, 2 days) administration and one day after (delta M). The sixteen patients were followed up until 1990 for a mean of 12.4 years (2.2 to 25.2 years). Among them, one died of unrelated illness with this regimen 4 years after achieving remission, 4 relapsed between 5 to 7 years follow-up, and the remaining 11 (52%, 11/21) had long-term remission for a mean of 15.7 +/- 9.0 years (2.2 to 25.2 years). Of them, there were 5 patients who were treated with PI with 50 Gy or less, and had long-term remission (5.8 to 24.4 with a mean of 17.6 +/- 7.6 years). During the long-term follow-up period of these 11 patients, endocrine assessment was carried out while off therapy. Basal urinary excretion of cortisol or 17-OHCS were were normal in all of the 11 patients, and 8 of 9 showed normal diurnal rhythm of plasma cortisol. Nine of 10 patients tested showed normal suppressibility by overnight 1 mg dexamethasone test and 6 of 9 showed normal response to CRH.(ABSTRACT TRUNCATED AT 400 WORDS)

17-Hydroxycorticosteroids↗
PubMed1976

The Jewish Hospital of St. Louis therapeutic grand rounds no. 13. Cushing disease.

Although several effective therapies for Cushing disease have been demonstrated, associated complications, side-effects, and production of adrenal insufficiency indicate the continuing need for a completely satisfactory treatment. Of the surgical approaches to the adrenal gland, total adrenalectomy offers the most predictable amelioration, but is necessitates lifelong replacement and augmentation therapy and can be followed by progressive sella enlargement and hyperpigmentation. Drugs can inhibit adrenal steroid biosynthesis or selectively destroy the zona fasciculata. Inhibitors can be overwhelmed by endogenous ACTH increases, and cause variable electrolyte changes and side-effects. The adrenocorticolytic drug (o,pDDD) is slow in onset, irreversibly destroys adrenocortical reserve, and is poorly tolerated in the gastrointestinal tract. Conventional pituitary irradiation is unpredictably effective in only half of the cases, but is not often followed by the serious neurologic sequelae and hypopitiutarism observed after implantation and heavy particle therapy. Selective hypophysectomy via modern techniques is relatively new, but apparently offers a direct, and possibly, definitive therapeutic option in this disorder.

Adult↗
PubMed1979

The continued importance of adrenalectomy in the treatment of Cushing's disease.

Eighteen patients with pituitary-dependent Cushing's disease have been treated during a ten-year period. Eleven of these received a total of 14 alternative forms of therapy in an attempt to control the clinical manifestations of Cushing's disease prior to adrenalectomy. However, no substantial improvement was noted in these patients, who included four receiving conventional pituitary irradiation, five receiving cyproheptadine, two receiving mitotane, and one each receiving metyrapone and phenytoin. One patient had an attempted transsphenoidal hypophysectomy that could not be accomplished because of hemorrhage. A complete remission of the signs, symptoms, and laboratory abnormalities of Cushing's disease occurred in all 18 patients following bilateral adrenalectomy. There was no operative mortality and morbidity was minimal. This experience confirms that bilateral adrenalectomy is a rapid, safe, and permanent means of reversing hypercortisolism and that it should remain an integral part of the treatment of Cushing's disease.

Adolescent↗
PubMed1995

The need for adjunctive focused radiation therapy in pituitary adenomas.

In pituitary adenomas radiation therapy regardless of the technique should be limited to surgical failures. The delayed onset of beneficial effects and the high rate of pituitary insufficiency have to be weighed against the good surgical and/or medical results in the treatment of these tumours. Unfortunately surgical outcome is almost invariably correlated with invasive growth. Invasiveness is statistically significantly correlated with tumour size, as well as with high proliferation rates, which can be measured by immunohistological methods such as mAB KI-67. Owing to the good results of medical treatment, radiation therapy is usually unnecessary in prolactinomas. Patients with persistent hypersecretion of growth hormone after unsuccessful surgery may represent the ideal candidates for radiation therapy, whereas patients with persistent Cushing's disease need cure for hypercortisolism without delay. In patients with residual tumour due to non functioning adenomas, radiation therapy should only be given if the proliferation rate is high.

Adenoma↗
PubMed1996

Persistent and recurrent hypercortisolism after transsphenoidal surgery for Cushing's disease.

After transnasal operations in Cushing's syndrome persisting hypercortisolism either due to negative pituitary exploration or due to subtotal tumor removal, and recurrence of the disease after successful surgery still are challenging. We report on the therapeutic failures among 310 consecutive patients who underwent primary transsphenoidal microsurgery for Cushing's disease. In 287 patients an ACTH-producing pituitary adenoma could be detected (finding rate: 92.6%). In 264 cases remission of hypercortisolism could be attained (remission rate with adenoma 92.0%, for the whole series of primary operations 85.2%). In 23 patients no adenoma could be found despite extensive pituitary exploration (7.4%). Here, we will focus on the management of the 23/287 patients with persistent hypercortisolism after transnasal tumor operation (8.0%) and those 29 cases of the 264 patients with a remission who developed a recurrence of hypercortisolism (11.0%). In recurrent hypercortisolism we recommend transsphenoidal reoperation even when no tumor is visible in MRI. Seventeen of 24 reoperations in recurrent Cushing's disease were successful (70.8%). In persistent hypercortisolism we perform a reoperation during the same hospital stay. Nine of 16 early reoperations led to remission of hypercortisolism (56.3%). If transsphenoidal reoperation fails we indicate radiation therapy of different modalities depending on the extension and location of the tumor remnants. Bilateral adrenalectomy is proposed by us only if all other therapeutic measures failed.

Adrenalectomy↗
PubMed1990

Neurological and behavioral sequelae following different approaches to craniopharyngioma. Long-term follow-up review and therapeutic guidelines.

The criteria by which the operative approaches to craniopharyngioma are chosen are still controversial. The authors performed a retrospective analysis in 32 patients with craniopharyngioma who were surgically treated. Results of neurological and psychological tests administered during the follow-up period were correlated with the surgical approach. On the basis of these preliminary data and a maximum follow-up period of 10 years, the authors conclude that the subfrontal approach to the craniopharyngioma and partial removal of its solid part appears to be associated with a lower morbidity rate and minor frontal lobe disorders.

Adolescent↗
PubMed1996

Complications in paediatric craniopharyngioma treatment.

Forty-eight consecutive children treated for craniopharyngioma at the Juan P. Garrahan National Paediatric Hospital (Buenos Aires, Argentina) from 1988 to 1994 are described. Complications of patients undergoing total resection alone and those undergoing subtotal or partial resection plus radiotherapy were compared. Survival time and quality of life proved more satisfactory in the former group, as there were no recurrences. In contrast, among the latter patients, 53% suffered relapses. Endocrinological complications were similar in the two groups. Postsurgical subdural haematomas were quite frequent and eight patients required treatment for intracranial hypertension. Vascular complications, though less common, led to high morbidity and mortality. There was a considerable incidence of shunt malfunction (80%), arguing against placement of a preoperative shunt, which tended besides to foster postsurgical subdural haematomas.

Adolescent↗
PubMed1986

Craniopharyngioma in Finland. A study of 123 cases.

We report on 123 patients with craniopharyngioma diagnosed in Finland from 1951 to 1982. 45 patients were under 16 years of age at the time of diagnosis and 78 over 16 years. The age-distribution had peaks at 11-20 years and at 41-50 years. 115 patients were operated on; operation was radical in 67 cases (58%). Surgical mortality was 13%. The number of radical operations increased and surgical mortality decreased after 1970. Recurrence developed in 26 patients (21%), 11 after a radical and 15 after a non-radical operation. Recurrence-free survival, 10-year survival and life expectancy were best after radical operation. We consider that radical operation is the best treatment. For patients with a non-radical operation or with recurrence modern radiotherapy gives long-lasting relief.

Adolescent↗