Transsphenoidal surgery for acromegaly: endocrinological follow-up of 98 patients

OBJECTIVE: Transsphenoidal surgery is the preferred treatment modality for growth hormone (GH)-secreting pituitary adenomas. In many series, the reported postoperative remission is based mainly on achievement of GH levels less than 2 ng/ml. Strict criteria for insulin-like growth factor I normalization and even lower GH levels (<1 ng/ml) are now suggested to define cure of acromegaly, but the evidence does not yet support such low GH levels in epidemiological follow-up. We analyzed our postoperative results in a large cohort of patients with acromegaly. METHODS: Ninety-eight patients harboring GH-secreting adenomas (46 microadenomas and 52 macroadenomas) underwent transsphenoidal surgery between 1990 and 1999. Ninety-one patients were operated for the first time, and 12 patients underwent reoperations because of previous surgical failure (7 had undergone surgery elsewhere previously). Biochemical remission was defined as a repeated fasting or glucose-suppressed GH level of 2 ng/ml or less, and a normal insulin-like growth factor I level. RESULTS: Remission was achieved in 74% of all patients after one operation, including 84% of patients with microadenomas and 64% of patients with macroadenomas. Seventy-three percent of patients with macroadenomas 11 to 20 mm in size achieved remission, as compared with a 20% remission rate for patients with adenomas larger than 20 mm. Patients with preoperative random GH levels lower than 50 ng/ml had a better outcome (85% remission), whereas GH greater than 50 ng/ml was associated with remission in 30% of the patients. Only one of the patients (8%) with postoperative active disease who underwent a second operation achieved remission. Recurrence was rare (one patient), and all failed surgical attempts could be detected during the immediate postoperative evaluation. CONCLUSION: On the basis of strict postoperative GH and insulin-like growth factor I criteria to define remission, our series demonstrates the efficacy of transsphenoidal surgery for acromegalic patients with microadenomas and noninvasive macroadenomas. However, patients with large adenomas (>20 mm) and preoperative GH greater than 50 ng/ml have a poor prognosis and require adjunctive medical or radiation therapy to control GH hypersecretion.     

Pregnancy following transsphenoidal resection of prolactin-secreting pituitary tumors

This report describes 200 women in the childbearing age group with prolactin-secreting pituitary adenomas treated by transsphenoidal microsurgery. There were 136 patients with microadenomas (10 mm or less in diameter), 30 with macroadenomas, 11 with invasive adenomas, and one with hyperplasia. The overall rate for postoperative normalization of serum prolactin was 57%, and it was 72% for those patients with microadenomas. Pregnancy was desired by 90 women, and 78 (84%) became pregnant, although 10 required postoperative bromocriptine to do so. Serious postoperative complications were rare, and produced no major morbidity. The results of surgery were most favorable in women with microadenomas and preoperative serum prolactin levels of 100 ng/ml or less.     

Changing patterns of insulin-like growth factor-I and glucose-suppressed growth hormone levels after pituitary surgery in patients with acromegaly

OBJECT: According to a recent consensus statement on the treatment of acromegaly, its biochemical cure is defined as the normalization of age- and sex-adjusted insulin-like growth factor (IGF)-I levels and the suppression of growth hormone (GH) by glucose to lower than 1 ng/ml. The present study was prompted by the clinical observation that many cases of acromegaly can be considered cured according to one criterion but not others at different moments in a patient's postoperative course. METHODS: Fifty-three patients with acromegaly (30 women and 23 men) harboring nine microadenomas and 44 macroadenomas were evaluated after surgery by assessing age- and sex-adjusted IGF-I levels as well as glucose-suppressed GH levels. Fifty of these patients were studied more than once during follow up. Acromegaly was categorized as cured if the patient's IGF-I level was normal and their glucose-suppressed GH level was lower than 1 ng/ml; the disease was considered to be active if the patient's IGF-I level was high and the GH nadir was higher than 1 ng/ml following administration of glucose. Discordant categories of the disease were found in patients with high IGF-I levels and a GH nadir lower than 1 ng/ml after glucose administration and in those with normal IGF-I levels and a GH nadir higher than 1 ng/ml after glucose intake. At the first postoperative biochemical evaluation (1-3 months), 34% of patients harboring macroadenomas were classified as having been cured of acromegaly, 39% as having the active disease, and 27% as having the discordant form of the disease. When last evaluated (> or = 12 months postoperatively), the percentage of patients with the discordant form dropped to 14% and the proportion of cases cured and active was 44% and 41%, respectively. Of the nine patients with microadenomas, 44.4% were cured of acromegaly, 33.2% had the active disease, and 22% had the discordant variety on first evaluation. Twelve months or longer after transsphenoidal surgery, 55.5% of cases were cured, 11.1% were active, and 33% were discordant. In most cases, the discordant variety developed because of a persistently elevated level of IGF-I, followed by an incompletely suppressed GH level. Nineteen patients (38%) modified their biochemical category. In 15 of these patients this change in category was due to a change in IGF-I levels, becoming normal in 12 patients and rising to above normal range in three. A tumor remnant was demonstrated on magnetic resonance images in only four of these 19 patients. CONCLUSIONS: The authors conclude that the discordance rate between the biochemical markers that define cure in acromegaly is higher than previously reported, and the biochemical status assigned to a patient early in the postoperative course is very likely to change later, particularly when initially discordant.     

Treatment of prolactinoma based on the results of transsphenoidal operations

Ninety-eight patients (16 male, 82 female) with prolactinomas were treated by transsphenoidal operation. The postoperative course was closely related to the tumor size and the preoperative levels of serum prolactin. In 37 (74%) of 50 patients with microadenomas, the levels of serum prolactin returned to normal postoperatively. There were 48 patients with macroadenomas; 27 of these were expansive and 21 were invasive. In 9 (33%) of the 27 patients with expansive macroadenomas, the postoperative levels of prolactin returned to normal; this was not the case in any of the 21 patients with invasive macroadenomas. Of 81 premenopausal women, 35 (43%) resumed normal menstruation postoperatively. All patients with preoperative deficits in the visual field experienced postoperative improvement. There were no postoperative deaths or serious complications in this series. Our data indicate that microprolactinomas are highly curable by transsphenoidal operation alone. In women who plan to have children, prolactinomas should be removed immediately. On the other hand, in patients with macroprolactinomas who manifest high levels of serum prolactin, initial treatment with bromocriptine should be considered because there is little hope for surgical cure and postoperative bromocriptine treatment might be necessary.     

Prolactin-secreting adenomas: the preoperative response to bromocriptine treatment and surgical outcome

Controversy exists regarding the effects of bromocriptine on the success of transsphenoidal surgery for patients with prolactinomas. Various studies on this drug have reported adverse effects, improvement, and no effect upon the subsequent surgical outcome. The authors have retrospectively reviewed the case histories of 55 patients with immunocytochemically confirmed prolactin-secreting pituitary adenomas operated on by a transsphenoidal approach between 1981 and 1985. All patients had received bromocriptine in a variety of doses and for variable durations prior to surgery. Thirty-nine patients were women and 16 were men, with an age range of 8 to 72 years. Basal prolactin levels prior to bromocriptine treatment ranged from 38 to 100 ng/ml in 11 patients, from 101 to 200 ng/ml in 12, and greater than 200 ng/ml in 29. The "cure" rates were 54%, 58%, and 38%, respectively. Thirty-one patients had microadenomas, with a postoperative cure rate of 68%; 12 had diffuse expansive adenomas, with a 17% cure rate; and 12 had grossly invasive tumors, with a 17% cure rate. A response to preoperative bromocriptine therapy was defined as a return of the basal prolactin level to normal: 18 patients were responders and 29 were hyporesponders; in eight the data were not available. The postoperative cure rate was 50% for the responders and 31% for the hyporesponders. Taking into account the distribution of tumor type, there was no actual difference in outcome between the responder and the hyporesponder groups. The total bromocriptine dose received preoperatively was nearly identical for all groups. No significant differences in the frequency or extent of fibrosis, calcification, or prolactin immunoreactivity were observed in the 55 patients when compared with 26 control prolactinomas not treated with bromocriptine. It is concluded that short-term bromocriptine treatment does not adversely affect surgical outcome in any of the prolactin-secreting adenoma groups, nor does response or lack of response to bromocriptine predict surgical outcome.     

Management of prolactinomas associated with very high serum prolactin levels

The authors have reviewed the results of transsphenoidal microsurgical management in 69 patients with prolactin-secreting pituitary adenomas who had preoperative serum prolactin levels over 200 ng/ml. The patients were divided into three groups based on their preoperative serum prolactin levels: over 200 to 500 ng/ml (Group A); over 500 to 1000 ng/ml (Group B); and over 1000 ng/ml (Group C). The percentage of successful treatment ("control rate") was 68%, 30%, and 14%, respectively, in these three groups of patients. Based on these results, the authors offer guidelines for the management of patients with prolactin-secreting pituitary adenomas associated with exceptionally high serum prolactin levels. The surgical control rate of 68% in Group A seems to justify surgery for these patients, while primary medical care with bromocriptine is recommended for most patients with serum prolactin levels over 500 ng/ml.     

Endonasal transsphenoidal approach for pituitary adenomas and other sellar lesions: an assessment of efficacy,safety, and patient impressions

OBJECT: The direct endonasal approach performed with the aid of an operating microscope for removal of pituitary tumors has the potential advantage over the traditional sublabial route of minimizing postoperative rhinological complications, yet maintaining a high degree of efficacy and safety. To assess the effectiveness of this procedure, tumor remission rates and surgical complications were documented, and patients' postoperative complaints were recorded using a questionnaire. METHODS: One hundred consecutive patients underwent 109 endonasal operations for tumor removal. At a median follow-up period of 16 months (range 3-45 months), surgical remission rates were as follows: in 40 patients with endocrine-inactive macroadenomas, 95% for noninvasive and 40% for invasive tumors; in the 20 patients with prolactinomas, 75% for prolactinomas with an initial prolactin (PRL) level lower than 200 ng/ml, 33% for those with a PRL level between 200 and 600 ng/ml, and 0% for those with a PRL level higher than 1400 ng/ml; in the 15 patients with Cushing disease, 73% for microadenomas and 25% for macroadenomas; in the 10 patients with acromegaly, 75% for microadenomas and 50% for macroadenomas; in the five patients with Rathke cleft cysts, 80%; and in the five patients with craniopharyngiomas, 40%. There were seven major surgical complications and no operative deaths. Among the 78 patients who completed questionnaires (response rate 89%), the most common complaints concerned nasal packing (39%), removal of packing (36%), and mouth breathing (35%). At 3 months or longer after surgery, patients quantified sinonasal problems as follows: for facial pain, no problem in 83% and severe difficulty in 4%; for nasal congestion, no problem in 74%, and severe difficulty in 3%; for decreased nasal airflow, no problem in 77% and severe difficulty in 4%; for decreased sense of smell, no problem in 73% and severe difficulty in 4%; and for upper-lip numbness, no problem in 87% and severe difficulty in 1%. Twelve (86%) of 14 patients who had undergone sublabial surgery previously preferred the endonasal approach in terms of pain and ease of recovery. CONCLUSIONS: The direct endonasal route for pituitary tumor removal has efficacy and complication rates comparable to those of the sublabial route. Patients generally recover rapidly from this minimally invasive procedure and have no or minimal sinonasal complaints. For patients requiring a repeated operation, the endonasal route appears to be less painful and easier to recover from than the sublabial route. Given the minimal nasal mucosal dissection required and the frequent patient complaints related to nasal packing, use of packing is no longer used for this procedure.     

Assessment of long-term remission of acromegaly following surgery

OBJECT: The criteria for remission of acromegaly following transsphenoidal adenoma resection are in evolution. In the present study the authors evaluate the utility of predicting long-term remission by reference to a single fasting growth hormone (GH) level on the 1st postoperative day. METHODS: A retrospective analysis was conducted on 181 patients with acromegaly who underwent transsphenoidal resection between 1973 and 1990 and completed a 5-year follow-up period. Fasting serum GH levels were obtained in all patients on the 1st postoperative day in the absence of exogenous glucocorticoids. All patients participated in a follow-up evaluation lasting at least 5 years, which included measurements of serum insulin-like growth factor-I (IGF-I) levels as an index of acromegalic activity. Among the 181 patients, GH levels ranged from 0 to 8 ng/ml in 131 (72%) on the 1st postoperative day, suggesting biochemical remission. This group included 107 (84%) of the 127 patients with microadenomas, but only 24 (44%) of the 54 with macroadenomas. Nevertheless, 15 (11%) of the 131 patients who initially had attenuated GH levels displayed recurrent acromegaly within the first 2 years (with elevated levels of IGF-I in all cases, and abnormalities appearing on magnetic resonance images in nine cases). Only one of 116 patients in whom the initial postoperative GH level was lower than 2 ng/ml experienced a recurrence, whereas 14 (93%) of the 15 patients with postoperative GH levels between 2.2 and 8 ng/ml subsequently displayed biochemical evidence of acromegaly. CONCLUSIONS: The findings indicate that a fasting morning serum GH level lower than 2 ng/ml on the 1st postoperative day portends long-term biochemical remission of acromegaly, whereas higher levels are a significant marker for recurrent disease.     

Pathology of invasive pituitary tumors with special reference to functional classification

Pituitary adenomas may remain intrasellar or infiltrate dura and bone. Invasive adenomas are not considered to be malignant; in biological behavior they are between non-infiltrative adenomas and pituitary carcinomas. The latter are defined as tumors with subarachnoid, brain, or systemic metastasis. Invasion may be defined radiologically, operatively, or histologically. On the basis of operatively assessed tumor size and gross invasion of dura and bone as well as immunocytochemical and ultrastructural analysis of 365 pituitary adenomas, the following data were obtained. There were 23 growth hormone (GH)-cell adenomas: 14% microadenomas and 86% macroadenomas; their overall frequency of invasion was 50%. There were 24 prolactin (PRL)-cell adenomas: 33% microadenomas and 67% macroadenomas, with an overall frequency of invasion of 52%. Mixed GH-cell and PRL-cell adenomas were found in 35 cases; 26% were microadenomas and 74% were macroadenomas, and the overall frequency of invasion was 31%. Sixty patients had adrenocorticotropic hormone (ACTH)-cell adenomas (Cushing's disease): 87% microadenomas and 13% macroadenomas; the overall frequency of invasion was 25% (in 8% of microadenomas and 62% of macroadenomas). Twenty patients had ACTH-cell adenomas (Nelson's syndrome): 30% microadenomas and 70% macroadenomas; the overall frequency of invasion in these cases was 50% (in 17% of microadenomas and 64% of macroadenomas). Silent ACTH-cell adenomas, 100% macroadenomas, were found in 11 patients, with an 82% frequency of invasion. There were 32 follicle-stimulating and luteinizing hormone adenomas, all macroadenomas, with a frequency of invasion of 21%. Four patients had thyroid-stimulating hormone adenomas, all macroadenomas, with a 75% frequency of invasion. Null-cell adenomas were found in 93 cases: 2% microadenomas and 98% macroadenomas, with a frequency of invasion of 42%. There were 63 plurihormonal adenomas (GH, PRL, glycoprotein): 25% microadenomas and 75% macroadenomas, with a 50% overall frequency of invasion. Based on this study, and on their usual frequency of occurrence, the estimated rate of gross invasion by pituitary adenomas of all types is approximately 35%. It is concluded that immunocytochemical and ultrastructural characteristics of pituitary adenomas reflect the tendency of these tumors to infiltrate and hence may be of prognostic significance.     

Hyperprolactinemia in patients with non-functioning adenoma: analysis of 85 patients treated by transsphenoidal operation

Today, many gynecologists consider that the first choice of the treatment of prolactinomas is bromocriptine therapy. Because bromocriptine not only decreases the levels of serum prolactin but also reduces the tumor size. On the other hand, the patients with non-functioning adenoma sometimes show hyperprolactinemia, probably because PIF (prolactin inhibiting factor) cannot reach the normal prolactin-producing cells of the adenohypophysis. Therefore non-functioning adenoma with elevated serum prolactin levels should be distinguished from prolactinoma. Eighty five patients with non-functioning adenoma were treated with transsphenoidal operation at Hiroshima University Hospital, and Kansai Rosai Hospital from May, 1978 to March, 1981 and at Osaka University Hospital, The Center for Adult Diseases, and Kansai Rosai Hospital from April, 1981 to May, 1986. Non-functioning adenomas were diagnosed by clinical feature, endocrinologic examination, and immunohistochemical study. There were 42 male and 43 female patients, whose age ranged from 17 to 76 years (mean: 49). The most frequent chief complaint was visual disturbance (86%). Amenorrhea-galactorrhea was complained by 9 female patients. However, 7 of them had visual disturbance at the same time. Hyperprolactinemia was seen in 21 patients (30%). The highest serum level of prolactin was 163.2 ng/ml. All of the patients had macroadenomas. There were 2 invasive adenomas and 83 expensive adenomas in them. After operation, cure or improvement of the visual disturbance was noted in almost all the patients. The serum levels of prolactin were normalized in 16 of 17 hyperprolactinemic patients. In conclusion, transsphenoidal operation is the best treatment of non-functioning adenomas. However, it is difficult to decide before operation whether the macroadenoma with serum prolactin level between 100 and 200 ng/ml is non-functioning adenoma or prolactinoma.(ABSTRACT TRUNCATED AT 250 WORDS)     

The neurosurgical management of prolactinomas

BACKGROUND: The objective was to discuss the neurosurgical management of the prolactinomas. METHODS: Five-hundred-fifty patients suffering from prolactinoma were treated with trans-sphenoidal and transcranial approach. The diagnosis of prolactinoma was based on various degree of high level prolactinemia, galactorrhea, gonodal disturbance, neurological examination and radiological findings. In all cases the adenoma was histologically verified. The patients were investigated according to the anatomo-radiological classification of Hardy and Vesina, and the range of preoperative PRL basal levels. RESULTS: Follow-up was ascertained in 81% of patients who were followed for a mean of 7.2 year (1-10 year). While the total removal percentage was 98% in the group with microprolactinoma, this ratio dropped to 63.9% for macroadenomas and 23.5% for giant adenomas. Early improvement of prolactin level ratio was 81.6% in microprolactinomas, 28.3 in macroadenomas and 11.7% in giant adenomas. Hormonal cure was 64.3% in microadenomas, 6.7% in macroadenomas and 0% in giant adenomas. The ratio of hormonal cure was decreasing in patients with high prolactin levels. In the follow-up recurrence of prolactinomas occurred in 39% of the patients. CONCLUSIONS: Medical treatment is the first step in prolactin secreting adenomas. Trans-sphenoidal microsurgery became popular in treatment of prolactinomas because of low operative morbidity and mortality. Patients with recurrence should be evaluated for second step treatment (surgery, bromocriptine, or radiotherapy).     

Cushing's disease and corticotrophic adenoma: results of pituitary microsurgery

Between November 1994 and June 2001, 194 patients with Cushing's disease underwent transsphenoidal surgery: 167 patients had adenomectomy, 14 had ante hypophysectomy, 5 had subtotal hypophysectomy, 4 had hemihypophysectomy 4 had central hypophysectomy. Complications occurred in 18 patients (9.3%), including 4 deaths (three were apparently not related to surgery). Remission of disease was achieved in 162 of 190 (85.3%) patients analyzed. Surgical failures were associated with lack of pituitary adenoma, size of the tumor and invasiveness. Among patients with confirmed adenomas, the rate of remission was significantly higher (p<0.01) in patients with microadenomas (92.6%) than in patients with macroadenomas (66.7%). Reoperation in 6 failures was followed by remission in 4 cases. The overall remission rate was 87.4%. In the 162 patients with immediate success, duration of follow-up was 10.0 +/- 5.9 years (m +/- DS; median=10.0). Recurrence of the disease occurred in 24 (14.8%) of 162 patients at a mean 4.8 years (range: 0.8-12.0 years). Our longest sustained remission is 25.6 years. Actuarial analysis indicates that the probability of a patient remaining well 12 years after surgery is 80.0%. It is 86.2% in microadenomas versus 52.5% in macroadenomas and 94.5% in the patients with postoperative hypocortisolism versus 59.2% in the others.     

Microprolactinomas in males treated by transsphenoidal surgery

Summary ¶Objective. To support the opinion that transsphenoidal surgery can be an effective alternative to medical treatment for microprolactinomas in men. Design. Clinical study with retrospective data analysis. Patients and methods. Of 46 men who were operated on for prolactinoma in the Department of Neurosurgery of the University of Vienna General Hospital between 1985 and 2000 a microadenoma was detected 11 times (24%). Results. Median patient age was 41 years (range 32 to 54 years). Symptoms were of endocrine nature in all patients with erectile dysfunction, infertility and gynaecomastia being the initial complaints and having lasted for a median of 13 months (range 7–68 months). Preoperative median serum prolactin (PRL) was elevated to 120ng/ml (range 41–1000ng/ml). Radiography by MRI revealed microadenomas with a median diameter of 8mm (range 4–10mm). All patients were operated on via the transsphenoidal approach. Endocrine cure as defined by a serum PRL <25ng/ml was achieved in 8 of 11 patients (73%) after a median follow-up of 7 years (range 2–13 years). In none of the 3 patients with preoperative serum PRL levels >150ng/ml was a normoprolactinaemia obtained after surgery: 2 require further dopamine-agonist therapy after surgery, 1 after late follow-up.Surgery and medical treatment could restore potency and libido in all but 1 patient, 2 of 3 patients remain infertile. Conclusion. Prolactinomas in males are potentially curable by surgery if detected at an early stage. They most commonly present with insidious signs and symptoms of endocrine disturbances such as loss of libido, impotence and sterility. We stress the importance of early determination of serum prolactin and high resolution magnetic resonance tomography of the sella in male patients with hyperprolactinaemia as this may prevent the possible progression to larger tumours which are rarely curable by surgery and necessitate life-long medical therapy.Published online October 13, 2003     

Effects of open-heart surgery on renal function in patients with chronic renal failure--is hemodialysis during cardiopulmonary bypass really required?]

In 300 consecutive adult patients who underwent open-heart surgery in our department, 16 patients (ischemic heart disease in 8 patients, valvular heart disease in 7 and congenital heart disease in 1) were preoperatively complicated with chronic renal failure (CRF); creatinine clearance (Ccr) < 40 ml/min and serum creatinine (Scr) > 1.6 mg/dl. The effects of open-heart surgery on renal function were studied in these CRF patients who were divided into the following 3 groups according to their preoperative Ccr values: Group 1 (6 patients), 30 < Ccr < 40 ml/min; Group 2 (5 patients), 20 < Ccr < 30 ml/min; and Group 3 (5 patients, 4 of whom were on dialysis preoperatively), Ccr < 10 ml/min. In addition, Group C (38 patients, Ccr > 50 ml/min) was set up as normal controls. Instead of hemodialysis, the extracorporeal ultrafiltration method (ECUM) was employed for all patients during the cardiopulmonary bypass (CPB). The Ccr in Group 1 showed the lowest value of 24.2 +/- 12.0 ml/min on postoperative day (POD) 0 which then recovered to the preoperative level on POD 1. This quick recovery of the Ccr in Group 1 was similar to that in Group C. In contrast, the Ccr in Group 2 showed the lowest value of 13.0 +/- 6.0 ml/min on POD 1, followed by a delayed recovery that did not reach the preoperative level until POD 5. The Ccr in Group 3 was quite low (< 5 ml/min) throughout the test period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biochemical remission and recurrence rate of secreting pituitary adenomas after transsphenoidal adenomectomy: long-term endocrinologic follow-up results

BACKGROUND: Transsphenoidal surgery is safe and effective in patients with secreting pituitary adenomas; however, variable outcomes have been reported according to the different criteria used to define the biochemical remission of hormone hypersecretion. We report the long-term endocrinologic follow-up results of a large cohort of patients who underwent TSS for secreting pituitary adenomas according to the most recent stringent criteria of cure. METHODS: Two hundred ten consecutive patients were operated on by TSS between 1995 and 2004 for a secreting pituitary adenoma (65 PRL-, 109 GH-, and 36 ACTH-secreting adenomas) and were considered for the study. RESULTS: The overall remission rate was 65% for the whole series, being 64%, 61%, and 75% for PRL-, GH-, and ACTH-secreting adenomas, respectively. Eighty-six percent of microadenomas and 53% of macroadenomas were cured by surgery. Remission rates were significantly higher in GH- and ACTH-secreting pituitary macroadenomas than in macroprolactinomas. At a median follow-up of 56 months, tumor recurrence was 0%, 11%, and 14% for GH-, ACTH-, and PRL-secreting tumors. Tumor size, cavernous sinus invasion, and high hormone levels were negatively correlated to the outcome. CONCLUSION: Transsphenoidal surgery remains an effective treatment for secreting pituitary tumors according to the most recent criteria of cure. Patients with PRL- or ACTH-secreting adenomas may recur after apparently successful surgery, thereby justifying long-term careful endocrinologic follow-up.     

Transsphenoidal surgery for acromegaly: predicting remission with early postoperative growth hormone assays

Background

Early detection of residual disease may benefit management strategies in patients undergoing transsphenoidal surgery for acromegaly. This requires establishing objective thresholds for early postoperative growth hormone (GH) assays, and incorporating these parameters into a scale for outcome prediction.

Method

We analyzed a database containing the records of 86 patients who had undergone gross total transsphenoidal resection of GH-secreting pituitary adenomas. Early postoperative biochemical testing included a morning fasting basal GH assay on the first postoperative day (POD1) and a second GH assay following suppression with 100 g of oral glucose on the seventh postoperative day (POD7). Remission was defined as a normal IGF-1 with either a GH nadir <0.4 ng/ml following suppression with oral glucose or a basal fasting GH <1 ng/ml on follow-up dated >3 months after surgery. Receiver operator characteristic (ROC) curves identified optimal thresholds for all biochemical parameters. Logistic regression analysis assessed the statistical significance of factors associated with cure. A point system was developed, employing regression coefficients obtained from the multivariate statistical model to quantify the impact of each predictor on cure.

Results

Remission was achieved in 34.6 % of patients and was associated with smaller, non-invasive tumors with lower preoperative, POD1 and POD7 GH levels. Optimal thresholds obtained from the ROC analysis suggested that lower POD1 and POD7 GH values provided good sensitivity and specificity for cure, despite modest predictive values. The model with the best ability to predict outcome included size, POD1 GH and POD7 GH levels, with a score of ≥95 demonstrating high specificity for prediction of remission.

Conclusion

Early postoperative GH assays are highly sensitivity and specific. The scoring system that we propose provided excellent predictive value and requires further validation in larger cohorts and in different populations. The model may help guide the intensity of follow-up and enable early identification of residual disease.     

Prolactin reduction after combined therapy for prolactin macroadenomas

The ability of surgery or bromocriptine to produce endocrine control of a prolactin macroadenoma decreases as the prolactin level increases. Guidelines for the use of multimodality therapy have not been developed for tumors associated with markedly elevated prolactin levels. We reviewed the records of 21 patients with prolactin levels greater than 200 ng/ml treated by transsphenoidal surgery and postoperative radiotherapy with or without a dopamine agonist. Values before and after treatment were available for 19 patients (13 men and 6 women). The mean basal prolactin level before treatment for the entire group was 2410 ng/ml. Surgery and radiotherapy resulted in a 90% reduction and serum prolactin levels within normal limits in 0 of 7 patients, versus the combination of surgery, radiotherapy, and dopamine agonist, which resulted in a 99.5% reduction and values within the normal range in 12 of 12 patients. Spontaneous physiological improvement was not often observed. One woman and two men were able subsequently to have children. A plan for these patients is discussed.     

Prolactinoma treatment status in the cabergoline era

The aim of our study is to report the most adequate therapy for prolactinoma in the cabergoline era. From 2003 to 2009, 27 patients with prolactinoma were treated at our hospital. Patients are categorized into 2 groups. The Cabergoline Group: Cabergoline was administered for 5 years and discontinued. Using this protocol, the case with normal prolactin level in addition to having no visible tumor more than 24 months after the discontinuation of cabergoline was judged as cured. The Operation Group: Transsphenoidal surgery (TSS) was performed first. In the Cabergoline group, 12 cases were cured with 5 years cabergoline treatment (Cure) and 6 cases were not cured (Not cure). We compared the pretreatment prolactin level, the normalization of the serum level of prolactin, the degree of invasiveness on MRI, regression of the tumor during treatment on MRI, max dose of cabergoline, degree of pituitary hormone replacement, frequency of pregnancy, and follow up periods between the Cabergoline-cure group, the Cabergoline-not-cure group, and the Operation group. Normalization rate in serum level of prolactin and cure rate were 91% and 63% in the Cabergoline group. Pretreatment prolactine level and the frequency of tumor invasiveness on initial MRI were significantly higher in the Cabergoline-not-cure group compared to the Cabergoline-cure group. All of the five woman accompanied with pregnancy after the treatment belonged to the Cabergoline-cure group. In the Operation group, all 4 cases achieved normalization of serum prolactin level without visible tumor and with normal pituitary function. Cabergoline for prolactinoma is effective, but the cure rate by continuous usage of cabergoline for 5 years was 67%. The factors that cabergoline and / or TSS can cure prolactinoma are non-invasive tumor and prolactin level under 200 ng/mL at pretreatment.     

Clinically non functioning pituitary adenomas and gonadotroph-cell adenomas

Clinically non-functioning pituitary adenomas and gonadotroph-cell adenomas are relatively common: microadenomas (< 1cm) are usually pituitary incidentalomas while most macroadenomas are revealed by mass effect and/or hypopituitarism. They are rarely associated with high gonadotropin (Luteinizing hormone, LH; Follicle-stimulating hormone FSH) levels while increased alpha-subunit levels are more frequent. Immunocytochemistry of pituitary tumor confirms the diagnosis of clinically non-functioning or gonadotroph-cell adenoma. Pituitary MRI follow-up seems to be indicated for microadenoma. Treatment of macroadenoma with visual field defect or hypopituitarism is transphenoidal surgery, but cure is rarely obtained and tumor recurrence is significant during follow-up. Therefore postoperative treatment (pituitary radiotherapy or medical treatment with dopamine agonists or somatostatin analogs) should be discussed against close follow-up with repeated MRI scans.     

Preoperative short-term administration of octreotide for facilitating transsphenoidal removal of invasive growth hormone-secreting macroadenomas

The somatostatin analog octreotide was administered prior to transsphenoidal surgery in three patients with tumors that extended to the suprasellar space and one side of the cavernous sinus. Octreotide, 100 micrograms twice a day, was subcutaneously injected for 2 weeks. Octreotide administration reduced the serum growth hormone (GH) levels in these patients from 82 to 22 ng/ml, from 148 to 12 ng/ml, and from 129 to 9 ng/ml. The tumor size shrank by about 50%, and the suprasellar extension disappeared in two patients. The main tumor was sharply dissected from the normal pituitary gland at surgery. Intracavernous portions were removed using a curette. Postoperatively, GH levels were less than 5 ng/ml in two patients, and 8.5 ng/ml in one patient. Follow-up magnetic resonance imaging revealed a small residual tumor in one side of the cavernous sinus in all patients. Follow-up GH levels were less than 5 ng/ml in one patient, and less than 2 ng/ml in two patients treated with bromocriptine. Preoperative administration of octreotide for 2 weeks reduced tumor volume and allowed near-total surgical resection of invasive macroadenomas without compromising the treatment course. Residual tumor due to intracavernous extension can be managed with bromocriptine or gamma knife radiosurgery.