Giant Prolactinoma and Effectiveness of Medical Management

ObjectiveTo review our experience with long-term cabergoline and bromocriptine therapy in the treatment of giant prolactinomas.MethodsPatients with giant prolactinomas diagnosed and treated at our center in Mumbai, India, between January 2005 and January 2009 were included. Diagnostic criteria for giant prolactinoma included tumor diameter greater than 40 mm, serum prolactin concentration higher than 1000 ng/mL, and invasive tumor growth pattern with mass effects. Cabergoline was started at a dosage of 0.5 mg weekly and progressively increased as necessary up to 3.5 mg weekly. Patients were followed up with hormone measurements, sellar magnetic resonance imaging, and vision examinations.ResultsThe study group included 10 patients (5 male and 5 female), aged 17 to 50 years (mean, 36.1 years), treated for giant prolactinoma. In 8 patients, cabergoline was first-line therapy. Two patients had previously been prescribed bromocriptine, and this regimen was maintained. Mean serum prolactin concentration before treatment was 10789 ± 14278 ng/mL (range, 1256-43 163 ng/mL; reference range, 5-17 ng/mL). Following treatment, levels normalized in 7 patients within 2 to 18 months (mean, 8.8 months) and decreased in 1 patient to a level 3 to 4 times that of normal. Tumor diameter, which measured from 4 to 7 cm at diagnosis, showed a mean maximal decrease of 49.28 ± 18.27%; response was first noted about 6 months after treatment was begun. Seven patients had visual field defects at diagnosis; vision returned to normal in 3 and improved in 4. Testosterone levels, initially low in all male patients, normalized in 3.ConclusionCabergoline should be first-line therapy for aggressive prolactinomas, even in those patients who present with visual field defects. (Endocr Pract. 2010; 16:42-46)     

Diagnostic Value of Thyrotropin-Releasing-Hormone Stimulation in Patients With Pituitary Tumor

Plasma prolactin response to thyrotropin-releasing-hormone (TRH) stimulation was diminished in 30 patients with prolactinomas and 9 patients with acromegaly who had normal serum prolactin levels. There was no overlap of prolactin responses when compared with 32 control patients. Responses of ten patients with adrenocorticotropin (ACTH)-secreting pituitary tumors were similar to those of controls. Plasma growth hormone concentrations after TRH stimulation changed significantly in 28% of normal control and 20%, 25% and 50% of patients with prolactin-, growth hormone- and ACTH-secreting pituitary tumors, respectively. Our data suggest that the blunted TRH-induced rise in plasma prolactin levels in patients with prolactinomas and those with acromegaly may be related to humoral factor(s) affecting TRH receptor or postreceptor function. Growth hormone responses to TRH are nonspecific and should not be considered a marker for active acromegaly.     

Growth hormone,prolactin, and corticosteroid responses to insulin hypoglycaemia in alcoholics

Plasma growth hormone (GH), prolactin, and corticosteroid responses to insulin-induced hypoglycaemia were studied in 24 men with progressive alcoholism who had been abstinent for two to seven days. Ten normal healthy subjects (five men, five women) served as controls for comparing GH and prolactin responses, while cortisol responses were studied in a further six male controls. Blood samples were taken at intervals after an injection of soluble insulin (0·1 U/kg body weight). All patients developed adequate hypoglycaemia (blood glucose <2·2 mmol/l (<39·6 mg/100 ml)) and nine had impaired GH responses (peak concentration <10 mU/1). Prolactin concentrations fell or remained unchanged in nine patients, eight of whom also had impaired GH responses. In seven patients corticosteroid concentrations decreased from basal concentrations, and six of these patients had impaired GH responses. All three hormone responses were impaired in several patients, and significant correlations were found between the GH and prolactin responses at 45 and 60 minutes. GH response was not correlated with age, duration of drinking, duration of alcoholism, or admitted alcohol intake. GH responses were significantly lower in patients who had the most severe withdrawal symptoms. Our observations of impaired stress responses in some recently abstinent alcoholics may have important implications for the management of alcohol withdrawal syndrome.     

Differences in platelet activation by prolactin and leptin.

Hormones such as prolactin and leptin have recently been recognized as potent platelet aggregation co-activators, and have therefore been postulated as an additional risk factor for both arterial and venous thrombosis. Clinical situations exist that are known to be associated with higher leptin and/or prolactin levels (obesity, pregnancy, prolactinomas and anti-psychotic therapy respectively) and increased venous thrombosis or atherosclerosis risk. Therefore, we compared the impact of both hormones on platelet activation in vitro and in vivo. First, we investigated platelet aggregation and P-selectin expression after stimulation with 1,000 mU/l prolactin or 100 ng/ml leptin in five healthy volunteers in vitro. Prolactin revealed significant higher levels of P-selectin expression and platelet aggregation than leptin in all subjects. We also compared the correlation of prolactin and leptin values with the P-selection expression on platelets. Previously, we detected a significant correlation between prolactin values and ADP-stimulated P-selectin expression on platelets in pregnant women, patients with pituitary tumours, and patients on anti-psychotic therapy. In contrast, leptin did not correlate with P-selectin expression in all subject groups investigated. However, leptin correlated with body mass index in the subjects investigated. Our data indicate that prolactin has a stronger effect on platelet activation as leptin in vitro and in vivo. Moreover, our data suggest that the stronger effect of prolactin on ADP-stimulated platelet aggregation, compared to leptin, depends on higher stimulation of CD62p expression by prolactin.     

Treatment of presumed prolactinoma by transsphenoidal operation: early and late results.

Seventy seven patients who were presumed to have a prolactinoma on the basis of biochemical findings underwent transsphenoidal operation between October 1977 and September 1983. Sixty one patients were found to have a microadenoma, and hyperprolactinaemia was cured in 46 of these, amenorrhoea in 39 (80% of those with the symptom), galactorrhoea in 32 (80%), and infertility in 31 (82%). Four of eight patients found to have a macroadenoma were also satisfactorily treated with surgery. Two patients had a lesion other than a prolactinoma, and in six a tumour could not be found at operation; four of these last eight patients had a normal serum prolactin concentration after operation. Recurrent hyperprolactinaemia was rare, occurring in only three patients in the series overall; among the 32 patients followed up for more than five years only two of the 22 whose operation had initially been successful developed recurrent hyperprolactinaemia.     

Bromocriptine in management of large pituitary tumours.

Bromocriptine has an accepted place in the management of small pituitary tumours that secrete either prolactin or growth hormone. The treatment of large tumours with extrasellar extensions is more difficult, however: though surgery is the standard treatment, it is often unsuccessful in returning excessive hormone secretion to normal and may cause hypopituitarism. A prospective trial was undertaken to assess the frequency with which changes in pituitary function and size of large tumours occurs. Nineteen patients were studied before and during treatment with bromocriptine (7.5 to 60 ml/day) for three to 22 months, using contrast radiology and a detailed assessment of pituitary function. Eighteen patients had hyperprolactinaemia and two of these also had raised concentrations of growth hormones; one patient had an apparently non-functioning tumour. In 12 patients (63%) tumour size decreased with bromocriptine and no tumour enlarged. Nine patients had visual-field defects, which improved in seven, becoming normal in five. Pituitary function improved in nine patients (47%) becoming entirely normal in three. Bromocriptine should be the treatment of choice in patients with large pituitary tumours with extrasellar extensions, provided close supervision is maintained.     

Effects of bromocriptine on pituitary tumour size.

In a prospective study designed to assess the influence of bromocriptine on pituitary tumour size 12 patients with pituitary tumours, eight of whom had suprasellar extensions, were treated for three months with 20 mg of bromocriptine daily after a gradual increase to this dose. The group comprised eight women and four men, five with prolactin-secreting adenomas, four with acromegaly, two with functionless adenomas, and one with Nelson''s syndrome. All five patients with prolactin-secreting adenomas showed a reduction in pituitary tumour size as assessed by computerised tomography and metrizamide cisternography accompanied by a fall in prolactin concentrations and clinical and biochemical improvement in their hypopituitarism. One patient in this group had a visual-field defect before treatment, and this resolved. There was no radiological evidence of reduction in tumour size in the remaining seven patients, though this might refect the fairly short duration of treatment, particularly in view of the ancillary evidence of clinical, biochemical, and visual-field improvement in some of the patients. These results emphasise the potential value of bromocriptine in treating patients with large prolactinomas or recurrences of such tumours after previous chiasmal decompression and conventional external megavoltage irradiation on the pituitary.     

Recurrent breast cancer treated with the antioestrogen tamoxifen: correlation between hormonal changes and clinical course.

Forty-five post-menopausal women with recurrent breast cancer were treated with the antioestrogen, tamoxifen, 20 mg twice daily. Clinical assessment after 12 weeks indicated that 18 (40%) showed some remission. Gonadotrophins were suppressed within two weeks to relatively constant concentrations within the post-menopausal range, responses to luteinising hormone-releasing hormone (LH-RH) did not change, and androgen concentrations remained within the normal range in all patients. Oestradiol concentrations rose steadily only in women in whom treatment failed. Serum prolactin concentrations were raised in 18 out of the 44 (41%) patients in whom they were measured; 13 of these did not respond to treatment. Treatment did not change the average prolactin concentration when this was within the normal range, but it significantly reduced prolactin concentrations in hyperprolactinaemic patients--within two weeks (P less than 0-01) in those who responded well and by six weeks (P less than 0-05) in those who showed no remission. Among patients with normal prolactin values the release of prolactin after thyrotrophin-releasing hormone was significantly greater in those with no remission than in those who responded to tamoxifen. Responses in those with hyperprolactinaemia were reduced to about half the control values, and again this change occurred faster in those who were successfully treated. Patients therefore seem to have a better chance of responding to anti-oestrogen treatment if prolactin secretion is low.     

Treatment of prolactinomas with megavoltage radiotherapy.

The outcome of treatment of 36 women with prolactinomas using megavoltage radiotherapy combined with interim dopamine agonists (bromocriptine, lysuride, pergolide) was reviewed; 16 of the women showed radiological evidence of a macroadenoma. The most common presenting symptom was secondary amenorrhoea; 26 of the patients had galactorrhoea. In 29 patients who wished to conceive the ovulation rate (as indicated by circulating progesterone concentrations) was 97% and the successful fertility rate 86%. No patient had enlargement of the tumour during pregnancy and there were no complications of radiotherapy. No further tumour enlargement was detected in serial skull radiographs, and an improvement in size of the fossa was noted in 45% of those assessed. When medical treatment was withdrawn a mean of 4.2 years (range 1-11) after radiotherapy in the 27 patients who had completed their families the serum prolactin concentration had fallen appreciably in 26 of them and later became normal in eight. The incidence of growth hormone deficiency rose from 24% of the whole group before radiotherapy to 79% afterwards. Only one patient required thyroxine, and one was receiving gonadotrophin. No patient became deficient in adrenocorticotrophic hormone. A regimen of megavoltage radiotherapy and interim bromocriptine allows women with prolactinomas safely to undergo pregnancy and results in the long term prospect of tumour shrinkage and control of hyperprolactinaemia.     

Prolactin-secreting pituitary adenomas in males: transsphenoidal microsurgical treatment.

Fifteen male patients with prolactin-secreting pituitary adenomas were studied before and after transsphenoidal microsurgical treatment. Loss of libido and sexual impotence were the most frequent symptoms, being present in 12. Visual defects were present in seven patients, gynecomastia was observed in four and galactorrhea was noted in three. Most of the tumours were large; only one was a microadenoma. Four patients were cured by the operation. In all the other patients the plasma levels of prolactin were significantly lowered and the visual defects corrected or lessened, but sexual impotence was not modified. No important deficiency of the pituitary gland was induced by the operation. The results indicate that in males loss of libido and sexual impotence are frequent and early manifestations of prolactinomas, and that transsphenoidal resection is a safe therapeutic approach.     

Reduction in size of prolactin-secreting tumours in men treated with pergolide.

The effect of pergolide mesylate was studied in two previously untreated men with large prolactinomas and exceptionally high prolactin concentrations. The study was designed to determine whether pergolide would be effective in alleviating symptoms, correcting hormonal abnormalities and shrinking the tumour. Starting with 50 micrograms daily the dose of pergolide was slowly increased over 10 weeks to 1 mg once daily, when repeat assessment was performed. Both patients reported complete relief of symptoms, with no side effects. Serum prolactin concentration was suppressed to normal in both subjects, and evidence to suggest tumour shrinkage was observed. Pergolide appears to be effective treatment for men with large prolactinomas.     

Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and soluble interleukin-2 receptor (sIL-2R) concentrations in peripheral blood as markers of pituitary tumours

Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and soluble interleukin-2 receptor (sIL-2R) are important cytokines. They are secreted by normal pituitary glands and those with all types of adenomas and may be involved in pituitary tissue growth. The peripheral blood concentrations of VEGF, bFGF and sIL-2R in nineteen patients (17-70 years) with pituitary tumours and ten healthy subjects (23-34 years) were studied. Hypersecretion of prolactin (five cases), human growth hormone (four cases), and thyroid stimulating hormone (one case) was recorded in some patients, and the remaining subjects were diagnosed as having nonfunctional pituitary tumours. Increased peripheral blood plasma levels of VEGF (310.82 +/- 59.17 pg/ml) compared with controls (40.32 +/- 11.80 pg/ml; p < 0.01), as well as bFGF (87.27 +/- 7.58 pg/ml) versus controls (11.14 +/- 2.43 pg/ml; p < 0.001) were recorded. The levels of sIL-2R did not differ between the pituitary tumour patients (4,490.58 +/- 581.50 pg/ml) and control subjects (3,617.01 +/- 1,397.18 pg/ml; p > 0.05). The concentrations of VEGF and bFGF in the peripheral blood are useful additional markers of the presence of tumours.     

How often should patients be reviewed after treatment with iodine-131 for thyrotoxicosis?

Six to 18 years after treatment with iodine-131 for thyrotoxicosis 69 euthyroid patients with raised serum thyrotrophin (TSH) concentrations (mean 25.0 +/- SE 2.0 mU/l) and 61 with normal concentrations (mean 4.0 +/- 0.2 mU/l) were included in a prospective five-year follow-up study beginning in 1972. During this period 13 patients from the original group with raised serum TSH concentrations became hypothyroid. In contrast it was five years before hypothyroidism developed in a single patient from the group with normal serum TSH concentrations in 1972, although raised concentrations were recorded in 19 of these patients during the study.     

Positive Prolactin Response to Bromocriptine in 2 Patients with Cabergoline-Resistant Prolactinomas

ObjectiveTo describe a positive prolactin response to bromocriptine treatment in 2 patients with cabergolineresistant prolactinomas.MethodsWe report the patients’ clinical presentations, laboratory test results, imaging findings, and clinical courses.ResultsPatient 1 had a 5-mm pituitary microadenoma that was initially diagnosed at age 30 years. After initial diagnosis, she was treated with transvaginal bromocriptine for 9 years and then subsequently went untreated for 2 years. After developing symptoms of amenorrhea, decreased libido, and hyperprolactinemia, oral cabergoline, 0.5 mg twice weekly, was initiated. Her prolactin concentration remained elevated at 80 ng/mL while taking cabergoline. Her prolactin concentration decreased to 13 ng/mL after her regimen was switched to bromocriptine, 5 mg daily. Patient 2 had a 17-mm pituitary macroadenoma that was initially diagnosed at age 15 years. Oral cabergoline was started at 0.5 mg twice weekly and increased to 1 mg 3 times weekly when prolactin levels continued to rise to 340 ng/mL over 18 months. After visual field defects developed, transsphenoidal surgery was performed. One year after surgery, magnetic resonance imaging showed a 6-to 7-mm pituitary adenoma, and there was a gradual rise in serum prolactin. Her serum prolactin concentration continued to rise to 212 ng/mL with increasing tumor size over 3 years. Cabergoline was discontinued and oral bromocriptine was initiated at a dosage of 10 mg daily. After 4.5 months of bromocriptine therapy, her serum prolactin concentration decreased to 133 ng/mL. However, after 2 months, the macroadenoma continued to increase in size and a visual field defect developed, so another transsphenoidal operation was performed.ConclusionsAlthough cabergoline is generally preferred to bromocriptine for the treatment of patients with prolactinomas because of its better tolerance profile and greater effectiveness, in patients with cabergoline-resistant prolactinomas, a bromocriptine trial should be considered a safe, relatively inexpensive, and well-tolerated alternative. (Endocr Pract. 2011;17:e55-e58)     

The Prolactin per Unit Tumor Volume Ratio Accurately Distinguishes Prolactinomas From Secondary Hyperprolactinemia due to Stalk Effect

ObjectiveThe prolactin levels alone are insufficient to distinguish between some cases of prolactinomas and stalk effect. We aimed to formally characterize the relationship between serum prolactin and prolactinoma volume, determine a cutoff for prolactin/mm³ that accurately distinguishes prolactinomas from stalk effect, and validate this cutoff in a cohort selected to include ambiguous prolactin values ranging from 50 to 150 ng/mL.MethodsWe used the Research Patient Data Registry and transsphenoidal surgery database in our institution to retrospectively identify adult patients with clinically nonfunctioning (NF) tumors (primary analysis, n = 279; validation cohort, n = 10) and prolactinomas (primary analysis, n = 94; validation cohort, n = 18). Solid tumor volumes were measured by Visage 7 software, and cystic foci within tumors were excluded.ResultsProlactin levels were significantly correlated with prolactinoma volume (r² = 0.801) but were not a relevant predictor of NF tumor size (r² = 0.015). The prolactin/mm³ values did not overlap between NF tumors (median, 0.016; interquartile range, 0.009-0.028) and prolactinomas (median, 0.551; interquartile range, 0.265-0.845) (P < .0001). A cutoff of 0.065 ng/mL)/mm³ correctly discriminated between prolactinomas and NF tumors in all 401 patients in the primary analysis and validation cohort.ConclusionThe prolactin/volume ratio correctly distinguished all prolactinomas from stalk effect in this study, including a validation cohort specifically chosen for potential ambiguity. To our knowledge, this study is the first formal volumetric analysis of prolactin secretion in pituitary adenomas, and our results suggest that the measurement of prolactin/mm³ is a valuable tool to better characterize challenging cases of primary tumoral secretion versus secondary hyperprolactinemia due to stalk effect.     

A follow-up study of 85 patients with Graves' disease in remission who developed undetectable serum thyroid-stimulating hormone concentrations using sensitive TSH assays.

Eighty-five patients with Graves' disease in clinical remission after treatment for over 1 year by methimazole therapy (36 patients, group A) or subtotal thyroidectomy (49 patients, group B) who became undetectable for serum thyrotropin levels (TSH less than 0.05 mU/l), were further followed for 1 year or more. Eight patients in group A (22%) and 7 patients in group B (14%) relapsed. Eleven patients in group A (30%) and 5 patients in group B (10%) had fluctuating patterns of free T4 in the upper normal to slightly supranormal range indicative of subclinical hyperthyroidism. The remaining patients continued to have undetectable TSH levels or restored normal TSH levels and normal thyroid hormone concentrations in sera. The results of the present study indicate that the occurrence of undetectable serum TSH concentrations in Graves' disease patients previously treated with methimazole or surgery are not necessarily predictive of clinical relapse because the eventual outcome is variable.     

Effectiveness of pergolide mesylate in long term treatment of hyperprolactinaemia.

Twenty five patients with hyperprolactinaemia were treated with pergolide mesylate, a new dopamine receptor agonist. Twenty three received treatment for six to 20 months, and in all serum prolactin concentrations were considerably reduced. In most patients prolactin concentrations were maintained in the normal range by a low, once daily dose of pergolide and reversal of associated reproductive disorders was observed. Tumour volume as assessed by computed tomography decreased considerably during treatment in three out of four patients with a pituitary tumour. The drug was well tolerated. Side effects were similar to those of bromocriptine, but four out of eight patients who had been forced to stop taking bromocriptine because of untoward effects were subsequently able to tolerate treatment with pergolide. Pergolide mesylate promises to be a useful addition to the currently available long acting dopamine agonists in the management of hyperprolactinaemia.     

CT abnormalities of the pituitary in hyperprolactinaemic women with normal or equivocal sellae radiologically.

Sixteen young women with hyperprolactinaemia and normal or equivocal sella in radiographs underwent computed tomography using a Siemens Somatom II. In all but one case an abnormality was found. The sella was full in seven and partially empty in nine. A tumour was visible in six of the full and in four of the partially empty sellae. All but one of the 10 tumours was unilateral, and in seven the pituitary stalk was deviated away from the tumour. After administration of intravenous contrast (Urografin) four tumours showed diffuse enhancement, four ring enhancement, and two enhanced less than adjacent normal pituitary tissue. Two of the tumours have been subsequently shown histologically to be prolactinomas. Prolactin response to thyrotrophin-releasing hormone predicted a tumour in seven out of eight with visible tumours but also in three out of four without visible tumours; using metoclopramide, a tumour was predicted in six out of seven with tumours, but again in three out of four without visible tumours. Such results question the value of dynamic tests for the discrimination of tumours. We conclude that practically all women with sustained hyperprolactinaemia and a normal or equivocal sella radiologically have pituitary disease.     

Development of pituitary adenoma in women with hyperprolactinaemia: clinical,endocrine, and radiological characteristics.

Sixty eight women referred for treatment of hyperprolactinaemia entered a three year follow up study to determine the clinical and endocrine course of the disease and its association with microadenoma of the pituitary. Details recorded before treatment included medical history, gonadotrophin and ovarian hormonal concentrations, and release of prolactin in response to protirelin (thyrotrophin releasing hormone), benserazide, cimetidine, and nomifensine. Sellar tomography was then performed yearly for three years in all women, 54 of them also undergoing computed coronal and sagittal tomography. At baseline evaluation 27 women showed radiological evidence of pituitary adenoma; at the end of the follow up period the number had increased to 41. Amenorrhoea, steady and raised serum prolactin concentrations, a low ratio of luteinising hormone to follicle stimulating hormone, a longer duration of disease, and low serum progesterone concentrations were more common in women with a final diagnosis of pituitary adenoma than in those whose sella remained normal. Tests for release of prolactin had yielded abnormal results from the outset in all 41 women with radiological evidence of pituitary adenoma and in about half of those whose sella had remained radiologically normal. Response to medical treatment (metergoline in 20 patients, bromocriptine in 21) was similar and showed no difference between patients with tumorous and non-tumorous hyperprolactinaemia. These findings suggest that a large proportion of women with hyperprolactinaemia may harbour a prolactin secreting pituitary adenoma which becomes apparent over a relatively short period. Amenorrhoea and steady and raised serum prolactin concentrations are more common in these women. Tests for release of prolactin are of predictive value in identifying women who will develop a pituitary adenoma.     

Results of combined therapy in patients with nonseminomatous testicular tumors

The results of multidrug therapy of 44 male patients with non-seminomatous testicular tumours are discussed. The diagnosed tumours were of all stages of the clinical advances and were treated with combined chemotherapy (surgery and PVP regimen). Thirty two patients (73%) are followed up between 7 and 103 months and survived, complete remission is noted in 29 patients (66%) including 6 patients who survived over 5 years. Symptoms of the tumour are found in 3 patients. Twelve patients (27%) died. The treatment did not produce life-threatening complications. The obtained results have been compared with those reported by other authors.