Recovery of hypopituitarism after neurosurgical treatment of pituitary adenomas
01 Oct 1999-The Journal of Clinical Endocrinology and Metabolism (Endocrine Society)-Vol. 84, Iss: 10, pp 3696-3700
TL;DR: Patients with hypopituitarism after neurosurgery should be reassessed after surgery without substitution therapy, because practically half the preoperative pituitary hormone deficiencies recover postoperatively, eliminating the need for life-long substitution therapy.
Abstract: Surgery is the treatment of choice for many pituitary tumors; pituitary function may suffer after operation, but relief of pressure on the normal pituitary may also favor postoperative recovery of hypopituitarism. The aim of this study was to investigate the frequency of new appearance and recovery of hypopituitarism after neurosurgery and try to identify features associated with it. Pre- and postoperative anterior pituitary functions were investigated in 234 patients with pituitary adenomas (56 nonfunctioning, 71 PRL-secreting, 66 GH-secreting, 39 ACTH-secreting, 1 LH/FSH-secreting, and 1 TSH-secreting tumors). Eighty-eight new postoperative pituitary hypofunctions appeared in 52 patients (12 NF, 14 PRL-secreting, 15 GH-secreting, 10 ACTH-secreting, and 1 LH/FSH-secreting adenomas). They corresponded to 27% ACTH deficiencies (in 29 of the 107 patients with normal preoperative ACTH in whom postoperative evaluation was complete), 14.5% (15 of 103) new GH deficiencies, 10.5% (15 of 143; P < 0.0005, significantly less than ACTH deficiency) new TSH deficiencies, 16.5% (20 of 121) new gonadotropin deficiencies, and 13% (9 of 71) new PRL deficiencies. Preoperatively, 93 were deficient in at least 1 pituitary hormone; after surgery, 45 (48%) recovered between 1 and 3 hormones. The 2 patients with LH/FSH- and TSH-secreting macroadenomas did not recover pituitary function. Factors associated with a higher probability of postoperative pituitary function recovery were: no tumor rests on postoperative pituitary imaging (P = 0.001) and no neurosurgical (P = 0.001) or pathological evidence (P = 0.049) of an invasive nature. Tumor size did not differ significantly between those who did and those who did not recover pituitary function after surgery. Even if clear hypofunction is observed at initial work-up, patients should be reassessed after surgery without substitution therapy, because practically half the preoperative pituitary hormone deficiencies recover postoperatively, eliminating the need for life-long substitution therapy.
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TL;DR: There is sufficient evidence that the best and optimal outcome in terms of tumor resection and correction of hormonal oversecretion as well as the lowest rate of complications are obtained in centers of excellence with sufficiently experienced, specialized surgeons and a high patient load.
40 citations
TL;DR: Medical therapy with dopaminergic drugs, somatostatin analogs, or gonadotropin-releasing hormone agonists or antagonists causes mild reduction of tumor size in few patients and, therefore, seems to be of limited value in the therapeutic management of patients with endocrine inactive pituitary adenomas.
Abstract: Endocrine inactive pituitary adenomas represent about one quarter of all pituitary tumors. By immunocytochemistry, most of these tumors are positive for intact gonadotropins and/or their subunits. Clinical presentation is usually secondary to mass effect symptoms, such as visual disturbances, headache, and hypopituitarism. Differential diagnosis is usually accomplished by neuroradiologic studies, even though in selected cases positron emission tomography and/or single photon emission tomography may aid to distinguish pituitary adenomas from other endocrine inactive lesions, such as meningiomas and craniopharyngiomas. Surgical management is usually considered the first choice treatment for patients with endocrine inactive pituitary adenomas because it is very effective in ameliorating symptoms of chiasmal compression and headache. Radical removal of the tumor, however, is difficult to obtain because of the frequent invasiveness into the cavernous sinus. Radiation therapy diminishes the likelihood of tumor recurrence, especially in patients with demonstrable tumor remnants after surgery. Medical therapy with dopaminergic drugs, somatostatin analogs, or gonadotropin-releasing hormone agonists or antagonists causes mild reduction of tumor size in few patients and, therefore, seems to be of limited value in the therapeutic management of patients with endocrine inactive pituitary adenomas.
39 citations
Cites background from "Recovery of hypopituitarism after n..."
...Among 29 patients with preoperative pituitary deficiencies, recovery of one pituitary axis alone occurred in 10 patients (35%), but no patient recovered two or three axes [46]....
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TL;DR: Serial dynamic testing results in a change in classification of GH and ACTH reserve in patients with pituitary disease following transsphenoidal surgery in a relevant proportion of patients.
Abstract: The insulin tolerance test (ITT) is considered the gold standard for assessment of GH and ACTH reserve in patients with pituitary disease following pituitary surgery and is usually performed after 6–12 weeks. However, abnormal axes may not be completely recovered by then. The aim of this study was to evaluate dynamic testing 3 and 12 months after transsphenoidal pituitary surgery. Design and patients: Serial dynamic testing was performed in 36 patients (13 women, age 18–78) at 3 and 12 months after transsphenoidal surgery. Results: Compared with 3-month results, median GH peak levels during ITT after 12 months increased by 38% (P!0.05). In patients initially classified as GH deficiency (GHD), median GH peak increased after 12 months by 23% (P!0.05). At 3 and 12 months, 36% (13/36) and 47% (17/36) were GH sufficient respectively. Median cortisol peak levels after 12 months increased by 17% (P!0.01) compared with 3-month ITT. In ACTH-insufficient (AI) patients, peak cortisol levels increased significantly by 12% (P!0.05) at 12 months, and in ACTH-sufficient patients, peak cortisol levels increased significantly by 13% (P!0.05). At 12 months, there was recovery from AI in 11% of the patients, and recovery from GHD in 11% of patients. Conclusions: Serial dynamic testing results in a change in classification by ITT results in a relevant proportion of patients. Dynamic testing should be repeated during follow-up.
36 citations
TL;DR: In this paper, the authors performed the IHT in 25 healthy subjects and in 109 patients with proven or suspected pituitary disorders with serial measurements of serum or plasma cortisol and of plasma ACTH, in order to establish reference levels and to study the dose-response relationship between ACTH and cortisol in this test.
Abstract: OBJECTIVE: The insulin hypoglycaemia test (IHT) is believed to be the most reliable test for evaluating the entire hypothalamo–pituitary–adrenal (HPA) axis. The lower limit for the normal peak serum cortisol response has been reported to be between 500 and 580 nmol/l. Reference levels for a normal plasma ACTH response have not been reported recently.
DESIGN AND PATIENTS: We performed the IHT in 25 healthy subjects and in 109 patients with proven or suspected pituitary disorders with serial measurements of serum or plasma cortisol and of plasma ACTH, in order to establish reference levels and to study the dose–response relationship between ACTH and cortisol in this test. In most patients, other pituitary hormonal axes were evaluated in addition.
RESULTS:With the cortisol kit from Diagnostic Products Corporation (DPC), serum cortisol was about 13% lower than plasma (EDTA) levels with an excellent correlation between serum and plasma (r = 0.976; P < 0.001). In the normals, the lower limit of the cortisol response (mean cortisol peak level minus 2 SD.) was 570 nmol/l for plasma and 500 nmol/l (calculated) for serum, while the lower limit of the ACTH response was 17.6 pmol/l (80 ng/l). In normals, the cortisol response was independent of the magnitude of the ACTH response. Seventeen out of 30 patients with ACTH responses to levels < 8.8 pmol/l (< 40 ng/l) had subnormal cortisol responses. However, 38 of the patients with pituitary disease had normal cortisol responses in spite of subnormal ACTH responses (group 2), while 47 patients had completely normal IHT results (group 1). Patients in group 2 had more often additional pituitary hormone deficiencies than those of group 1. The dose–response relationship between ACTH and cortisol in the patients resembled a dose–response curve that had been set up previously in normal subjects who received incremental doses of subcutaneous human ACTH (1–39).
CONCLUSIONS:The normal increment of plasma ACTH in the IHT is greater than necessary for stimulating serum cortisol to levels > 500 nmol/l. Patients with a subnormal ACTH but normal cortisol response in the IHT have a decreased ACTH secretory reserve. It is unlikely that they are at increased risk of developing an adrenal crisis perioperatively or in other stressful situations unless pituitary function deteriorates. The ACTH-cortisol relationship in the IHT performed in patients with pituirary disease shows no sharp dividing line between normality and disease, and whether a patient needs permanent glucocorticoid substution is a discretionary decision.
36 citations
TL;DR: Assessment of GH secretion is recommended for all patients cured from Cushing's disease, even if not submitted to radiotherapy, as it highlights that even the most favourable therapeutical course, i.e. remission achieved by surgery alone, is accompanied by impaired GH secretion.
Abstract: Objective: Impaired GH secretion usually accompanies Cushing’s syndrome and a variable proportion of patients reportedly fail to recover normal GH secretion after successful treatment. This wide variability is most probably due to differences in the treatment (i.e. surgery and/or radiotherapy), timing of patient re-evaluation after surgery and dynamic tests employed to challenge GH secretion, and hinders a precise assessment of risk of GH deficiency after cure. The aim of the present study is to evaluate GH secretory status after long-term cure of Cushing’s disease achieved by surgery alone. Design and methods: We studied 34 patients (27 females and 7 males, age range 21–68 years) formerly affected by Cushing’s disease. Patients were studied 2–20 years (median 3.3 years) following remission of hypercortisolism; all patients underwent transsphenoidal surgery with the removal of an ACTHsecreting adenoma; repeat pituitary surgery for relapse was performed in two patients while bilateral adrenalectomy was necessary in two patients. In all subjects, the GH response to GHRHCarginine stimulation was evaluated. At the time of testing, 13 patients were still on steroid replacement therapy. Results: In long-term surgical remission, 22 patients (65.0%) presented subnormal GH secretion; partial GH deficiency (GH peak !16.5 mg/l) was found in 11 patients and severe GH deficiency (GH peak !9 mg/l) in another 11. Male gender and length of hypercortisolism were risk factors for postsurgical GH deficiency. Conclusions: This study demonstrates the presence of GH deficiency in a high percentage of patients with Cushing’s disease after long-term remission of hypercortisolism obtained by surgery alone. Male gender and length of hypercortisolism are the most significant predictors of postsurgical GH deficiency. This finding is significant as it highlights that even the most favourable therapeutical course, i.e. remission achieved by surgery alone, is accompanied by impaired GH secretion. Assessment of GH secretion is therefore recommended for all patients cured from Cushing’s disease, even if not submitted to radiotherapy. Studies on the clinical impact of GH deficiency and the use of GH replacement therapy seem warranted in patients cured from Cushing’s disease.
35 citations
References
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TL;DR: Preliminary evidence suggests that dopamine agonists may restrain the growth of some functionless tumors; most of these tumors, however, can be satisfactorily debulked using transsphenoidal surgery, although the number of tumors studied is small.
Abstract: The primary aim of this review has been to clarify the tumor shrinking effects of dopamine agonists on pituitary macroadenomas of different cell types. Shrinkage is most dramatic for macroprolactinomas and is due to cell size reduction. Seventy-nine percent of 271 definite macroprolactinomas were reduced in size by at least 25%, and 89% shrank to some degree. Most shrinkage occurs during the first 3 months of treatment, although in a minority shrinkage is delayed. Dopamine agonist resistance during long-term therapy is exceptional. Drug withdrawal nearly always leads to a return of hyperprolactinemia, even after several years treatment, although early tumor reexpansion is unusual. About 10% of true macroprolactinomas do not shrink with dopamine agonists; the molecular mechanisms of such resistance have yet to be determined. Alternative formulations of BC and new dopamine agonists (CV 205-502 and cabergoline) are useful for the minority of patients unable to tolerate oral BC, but do not seem to further improve overall shrinkage rates. The risks of pregnancy have probably been overstated, and BC is suitable primary treatment for women with prolactinomas of all sizes; the drug can be used safely during pregnancy in the event of clinically relevant tumor expansion. The interpretation of different degrees of hyperprolactinemia is discussed and management strategies suggested. Most patients with macroprolactinomas now avoid surgery, but drug-induced, time-dependent tumor fibrosis should be remembered if surgery is contemplated. Nonfunctioning pituitary tumors are mostly of gonadotroph cell origin and may be associated with significant disconnection hyperprolactinaemia. Seventy-six of 84 well-characterized tumors showed no tumor shrinkage during dopamine agonist therapy. Possible explanations include abnormalities of dopamine receptor number and function. Preliminary evidence suggests that dopamine agonists may restrain the growth of some functionless tumors; most of these tumors, however, can be satisfactorily debulked using transsphenoidal surgery. In contrast to macroprolactinomas, other functioning pituitary tumors (GH-, TSH-, and ACTH-secreting) rarely shrink during dopamine agonist therapy, although the number of tumors studied is small.
433 citations
TL;DR: There is a high incidence of anterior pituitary hormone deficiencies in patients treated surgically forpituitary tumours and the incidence increases after external radiotherapy and endocrine testing is recommended on an annual basis.
Abstract: The development of anterior pituitary hormone deficiencies has been studied in a group of 165 patients who underwent external radiotherapy for tumours of the pituitary or closely related anatomical sites, and who have been observed for up to 10 years. One hundred and forty had undergone pituitary surgery before radiotherapy. All patients received external radiotherapy by a three-field technique, giving 3750-4250 cGy in 15 or 16 fractions over 20-22 days. A combined test of anterior pituitary function using insulin hypoglycaemia or glucagon stimulation in conjunction with thyrotrophin and gonadotrophin releasing hormone tests and basal estimations of prolactin, thyroid hormones and testosterone or oestradiol was performed before radiotherapy. This was repeated six and 12 months later and subsequently annually. Before radiotherapy, 18 per cent of patients had normal growth hormone secretion, 21 per cent had normal gonadotrophin secretion, 57 per cent had normal corticotrophin reserve and 80 per cent had normal thyrotrophin secretion. Life table analysis demonstrated increasing incidences of all anterior pituitary hormone deficiencies with time: by five years all patients were growth hormone deficient, 91 per cent were gonadotrophin deficient, 77 per cent were corticotrophin deficient and 42 per cent were thyrotrophin deficient. At eight years, respective incidences of deficiencies were 100, 96, 84 and 49 per cent. Radiation-induced hyperprolactinaemia was seen in 73 patients; mean serum prolactin concentration rose from 227 +/- 11 mU/l to a peak of 369 +/- 60 mU/l at two years and subsequently declined towards the basal value. The primary diagnosis, patient age, sex, irradiated tissue volume and previous surgery were examined as variables that might influence the rate of development of anterior pituitary hormone deficiencies, but none of these factors had a significant effect. The radiation induced hyperprolactinaemia was however more marked in female patients. Although anterior pituitary hormone deficiencies most commonly developed in the order growth hormone, gonadotrophin, corticotrophin, thyrotrophin (61 per cent of patients), other sequences were evident. Most notably corticotrophin deficiency occurred before gonadotrophin deficiency. There is a high incidence of anterior pituitary hormone deficiencies in patients treated surgically for pituitary tumours and the incidence increases after external radiotherapy. Deficiencies may occur in an unpredictable sequence and endocrine testing is recommended on an annual basis.
419 citations
TL;DR: It is suggested that compression of the portal circulation is a possible mechanism for hypopituitarism in this setting and significant improvement in pituitsary function may occur after surgical adenomectomy for nonsecreting pituitary tumors.
Abstract: Detailed pituitary function studies were conducted on 26 patients with large nonfunctioning pituitary adenomas before and 2-3 months after transsphenoidal adenomectomy. Basal serum PRL, GH, TSH, LH, FSH, and ACTH levels were measured, and dynamic studies of their secretion were made. Preoperatively, GH deficiency was found in all 26 patients (100%), hypogonadism in 25 patients (96%), hypothyroidism in 21 patients (81%), and adrenal insufficiency in 16 patients (62%). Serum PRL levels were low (1.5-4 ng/ml) in 5 patients, normal (5-20 ng/ml) in 9 patients, and mildly elevated (21-53 ng/ml) in the remaining 12 patients. After selective adenomectomy, variable improvement in pituitary function occurred in 17 patients, worsening in 1 patient, and persistence of hypopituitarism in 8 patients. After surgery, normal thyroid function was documented in 12 of the 21 patients (57%) who were hypothyroid preoperatively. Similarly, 6 of the 16 patients (38%) with adrenal insufficiency recovered normal adrenal function, and 8 of the 25 patients (32%) with hypogonadism recovered normal gonadal function. GH deficiency persisted in all but 4 patients (15%). Serum PRL levels decreased in all patients, and only 5 had midly elevated levels after surgery. The presence of a normal or mildly elevated serum PRL level before surgery in these patients was of value in predicting possible recovery of pituitary function after surgery; none of the 5 patients with low preoperative serum PRL levels had any improvement in pituitary function after surgery. A rise in serum TSH levels after TRH administration before surgery also was helpful in predicting possible recovery from hypopituitarism. Most patients who had a rise in serum TSH level in response to TRH stimulation preoperatively recovered some pituitary function after adenomectomy. In contrast, no improvement in pituitary function occurred in patients who had blunted responses to TRH preoperatively. Improvement in pituitary function occurred more often in patients with tumors measuring 25 mm or less than in those with larger tumors. In conclusion, significant improvement in pituitary function may occur after surgical adenomectomy for nonsecreting pituitary tumors. A rise in serum TSH levels in response to TRH stimulation preoperatively suggested the presence of viable pituitary tissue in these patients with hypopituitarism. The presence of a normal or mildly elevated serum PRL level before surgery also suggested the presence of functioning pituitary lactotrophs. These observations suggest that compression of the portal circulation is a possible mechanism for hypopituitarism in this setting.(ABSTRACT TRUNCATED AT 400 WORDS)
271 citations
TL;DR: Data indicate that trans‐sphenoidal microsurgery is an effective and safe initial treatment for patients with nonsecreting pituitary adenoma and may reverse hypopituitarism.
Abstract: From 1962 to 1987, 126 patients underwent trans-sphenoidal surgery for primary treatment of pituitary adenomas unassociated with clinical or biochemical evidence of hormonal overproduction. There were 73 male and 53 female patients (mean age, 50 +/- 12 years). Before surgery, 56% of the patients (70 of 124) had headaches, 74% (94 of 126) had deterioration of vision, and 12% (15 of 126) had ophthalmoplegia. Endocrine evaluation revealed the presence of hypogonadism in 75% (87 of 115), adrenal insufficiency in 36% (46 of 126), and hypothyroidism in 18% (21 of 122). Plasma prolactin was increased in 65% (56 of 86) with a mean level of 39 +/- 14 micrograms/l (normal, 3 to 20 micrograms/l). Radiologic enlargement of the sella turcica was documented in all cases: 67% (84 of 126) had enclosed and 33% (42 of 126) had invasive adenomas. After surgery, vision was normalized or improved in 75% (71 of 94) of the patients. Thyroid, adrenal, and gonadal functions were improved in 14% (three of 22), 41% (19 of 46), 11% (ten of 87), were unchanged in 82% (100 of 122), 77% (97 of 126), 89% (102 of 115), and worsened in 15% (19 of 22), 8% (ten of 126), 3% (102 of 115), respectively. Permanent diabetes insipidus occurred in 5% (seven of 126). Two patients died during the immediate postoperative period. The recurrence rate in patients with a mean follow-up of 6.4 +/- 4.2 years was 21% (15 of 71). These data indicate that trans-sphenoidal microsurgery is an effective and safe initial treatment for patients with nonsecreting pituitary adenoma and may reverse hypopituitarism.
244 citations
TL;DR: The results of transsphenoidal pituitary surgery for acromegaly were analyzed to assess the longer‐term outcome for patients not offered further treatment when post‐operative levels of GH < 5 mU/l were achieved.
Abstract: OBJECTIVE Previous studies of surgical treatment for acromegaly have used varied criteria for ‘cure’, but elevated GH levels are considered to be associated with continuing disease activity. We wished to analyse the results of transsphenoidal pituitary surgery for acromegaly and assess the longer-term outcome for patients not offered further treatment when post-operative levels of GH < 5 mU/l were achieved.
DESIGN We studied a retrospective group of patients who underwent transsphenoidal surgery for acromegaly at St Bartholomew’s Hospital between 1985 and 1993.
PATIENTS One hundred consecutive patients (53 male, mean age 46 years, range 18–68 years) undergoing transsphenoidal surgery for acromegaly were assessed. The patients were followed for a mean of 3.8 years (range 0.5–8 years) after operation.
MEASUREMENTS GH levels are represented as a mean value from a four-point day curve taken at 0830, 1300, 1700 and 1900h. ACTH reserve was assessed basally and, if this was normal, with the insulin tolerance or glucagon tests. TSH, T4, PRL, LH, FSH, testosterone or oestradiol and plasma and urine osmolality were also measured.
RESULTS Post-operatively, 42% of patients achieved a mean GH level of 100 mU/l achieved post-operative GH values < 5mU/l. In addition, tumour size influenced the outcome of surgery with 61% of patients with a microadenoma but only 23% of patients with a macroadenoma achieving post-operative GH levels of < 5 mU/l. Of the 42 patients considered in remission postoperatively (mean GH < 5 mU/l), 32 were available for long-term follow-up and were not offered any further treatment: only one of these has shown evidence of mild biochemical recurrence after a mean follow-up of 3.8 years (range 0.5–8). There were no peri-operative deaths. Two patients required surgical repair for CSF leaks and there were eight documented cases of meningitis. Permanent diabetes insipidus was noted in eight patients post-operatively. New anterior pituitary deficiency occurred in 21% of patients following surgery; 73% had unaltered pituitary function and in 6% recovery of partial hypopituitarism was noted.
CONCLUSIONS The stated outcome of surgery depends on the criteria adopted. Safe GH levels (mean levels < 5 mU/l) can be achieved in 42% of an unselected series of patients with acromegaly and if the tumour is a microadenoma this figure rises to 61%. Based on the current evidence it is safe not to offer further treatment to those patients in whom post-operative GH < 5 mU/l are achieved.
199 citations