Prolactinomas in male and female patients: a comparative clinicopathologic study.

OBJECTIVE: To explore the basis of the gender-based differences in endocrine and surgical findings in patients with prolactinoma (prolactin cell adenoma) as well as in their clinical outcome. MATERIAL AND METHODS: In young or reproductive-age female patients, older women (beyond 40 years of age), and male patients, we systematically studied the following factors: operative and endocrine features (tumor size, invasiveness, preoperative serum prolactin level, and biochemical outcome), specific biologic variables (mitotic index, MIB-1 labeling index, and p27 immunoreactivity), and hormone receptor status (estrogen and progesterone receptor proteins as well as dopamine D2 receptor messenger RNA). RESULTS: Of the various factors assessed, the preoperative prolactin level and MIB-1 labeling index were lower in young female patients in comparison with older female and particularly male patients. Hormone levels were also positively associated with mitotic activity as well as the MIB-1 labeling index. Although invasion was infrequent in microadenomas of young female patients, no statistically significant differences in tumor size or invasiveness were noted among the three patient groups. Absence of differences in invasiveness may, in part, be explained by artifacts of case selection. CONCLUSION: The basis for the observed differences in proliferative activities in tumors of the three study groups is not readily apparent but may reflect differences in the endocrine milieu or the effect of sex steroid hormone receptors, tumoral vascularity, or specific growth factors.

A retrospective analysis of pituitary apoplexy.

Thirty-seven patients with pituitary apoplexy were analyzed with an emphasis on clinical presentation and visual outcome. Their mean age was 56.6 years, with a male to female ratio of 2:1. Presenting symptoms included headache (95%), vomiting (69%), ocular paresis (78%), and reduction in visual fields (64%) or acuities (52%). Computed tomographic scanning correctly identified pituitary hemorrhage in only 46% of those scanned. Thirty-six patients underwent transsphenoidal decompression. By immunostaining criteria, null-cell adenomas were the most frequent tumor type (50%). Long-term steroid or thyroid hormone replacement therapy was necessary in 82% and 89% of patients, respectively. Long-term desmopressin therapy was required in 11%, and 64% of the male patients required testosterone replacement therapy. Surgery resulted in improvement in visual acuity deficits in 88%, visual field deficits in 95%, and ocular paresis in 100%. Analysis of the degree of improvement in preoperative visual deficits with the timing of the surgery demonstrated that those who underwent surgery within a week of apoplexy had significant recovery in their visual acuities. In the stable, conscious patient with residual vision in each eye, surgical decompression should be performed as soon as possible, because delays beyond 1 week may retard the return of visual function.

Results of surgical treatment for growth hormone-secreting pituitary adenomas.

The results of surgical therapy for acromegaly were reviewed in a series of 175 patients treated between 1972 and 1983. Patients with prior surgery or radiation therapy were excluded from the study. Postoperative radiation therapy was given to 54 patients. The criterion of achieving a postoperative basal or glucose-suppressed growth hormone level of 2 ng/ml or less was used to indicate remission. Utilizing the most recently available growth hormone determinations, 90 (51.7%) of 174 patients were in remission. The actuarial probability of remission at 1 and 5 years after surgery was 48.8% and 62.7%, respectively. Tumor size and the preoperative basal growth hormone level were correlated with outcome. Surgical excision of a pituitary adenoma is the most effective therapy currently available for acromegaly.

Effect of desmopressin on aqueous humor flow in humans.

The rate of aqueous humor flow was studied in 17 human subjects with neurogenic diabetes insipidus. Flow was measured by fluorophotometry on two consecutive afternoons. The first day, subjects used desmopressin to control their diuresis; on the second day, subjects did not use desmopressin and had uncontrolled diuresis. On both days, one eye was treated with the beta-adrenergic antagonist, timolol. With desmopressin, the rate of aqueous humor flow in the untreated eye was 2.53 +/- 0.79 microliters/min (mean +/- standard deviation) and in the timolol-treated eye was 1.69 +/- 0.40 microliters/min. Without desmopressin, the rate of aqueous humor flow in the untreated eye was 2.34 +/- 0.69 microliters/min and in the timolol-treated eye was 1.53 +/- 0.43 microliters/min. Thus, the use of desmopressin was associated with a slightly higher rate of aqueous humor flow in both the normal and the beta-adrenergically inhibited eye (P = .05), and the suppression of aqueous humor flow associated with beta-adrenergic inhibition occurred with and without antidiuretic hormone (P < .001). The observed differences in aqueous humor flow on the two days could have been caused by a direct effect on the eye or to indirect effects, such as the change in plasma osmolality, which changed from 291 +/- 6 mOsm on the desmopressin day to 299 +/- 8 mOsm on the desmopressin-abstention day (P < .001).

Simultaneous occurrence of primary sclerosing cholangitis and autoimmune chronic active hepatitis in a patient with ulcerative colitis.

The simultaneous occurrence of PSC and autoimmune CAH in a patient with ulcerative colitis is described. Although each disease is a well documented complication of UC, their combination has never been reported. The diagnosis of PSC was based on typical findings on ERCP and liver biopsy and that of CAH was based on typical findings on liver biopsy supported by HLA typings and a remarkable response to a combination of glucocorticoids and azathioprine. The difficulties in establishing the diagnosis and the management of such patients are discussed.

Disease recurrence and rejection following liver transplantation for autoimmune chronic active liver disease.

Autoimmune chronic active liver disease (ACALD), a major indication for liver transplantation, is associated strongly with antigenic determinants HLA-B8 and DR3. A retrospective analysis of 43 patients who underwent OLTx for putative ACALD and who, as well as their tissue organ donors, were typed, was performed. Disease recurrence and graft rejection episodes were determined by chart review and histopathological review of all material available. Disease recurrence was histologically documented in 11 (25.6%) of these 43 cases. Graft rejection episodes occurred in 24 (55.8%). All recurrences were in recipients of HLA-DR3-negative grafts. Nine of the recurrences were in HLA-DR3-positive recipients (odds ratio: 6.14, P less than 0.03). Two of 11 cases of disease recurrence were in recipients who were HLA-DR3-negative. Nine of these 11 had received HLA-DR3-negative grafts. Rejection occurred in 13 HLA-B8-positive recipients, 12 of whom received HLA-B8-negative grafts. Eleven HLA-B8-negative recipients experienced at least one rejection episode and 9 of these had received HLA-B8-negative grafts. Based upon these data we conclude: 1) that recurrence of putative ACALD is more likely to occur in HLA-DR3-positive recipients of HLA-DR3-negative grafts; (2) that recurrences were not seen in recipients of HLA-DR3-positive grafts; (3) that HLA-B8 status does not affect disease recurrence; and (4) that neither the HLA-B8 nor the DR3 status of the graft or recipient has an effect on the observed frequency of rejection.

Free alpha subunit of the pituitary glycoprotein hormones. Measurement in serum and tissue of patients with pituitary tumors.

A solid-phase radioimmunoassay was developed that measures the free alpha subunits of pituitary glycoprotein hormones (alpha PGpHs) and has negligible cross-reactivity with the intact hormones (less than 0.014% for thyroid-stimulating hormone [TSH], less than 0.1% for human chorionic gonadotropin [hCG], 0.8% for luteinizing hormone [LH], and 2.0% for follicle-stimulating hormone [FSH]). The assay is standardized with the alpha subunit of hCG but also reacts well with the alpha subunits of the other glycoprotein hormones (84% for alpha TSH, 77% for alpha FSH, and 64% for alpha LH). Concentrations as low as 0.3 micrograms/L can be reliably measured, and the 97.5% reference range in 27 healthy adults, including postmenopausal females, is less than or equal to 1.2 micrograms/L. Elevated preoperative alpha PGpH concentrations were found in 45 (9.4%) of 479 sera from patients with pituitary adenoma and 3 (4.5%) of 66 patients with nonadenomatous sellar lesions. Postoperative alpha PGpH levels were lower in 30 of 39 adenoma patients and 2 of 3 nonadenoma patients. In five (1%) of the patients with pituitary adenomas, alpha PGpH was the only elevated serum hormone marker. Serum values of alpha PGpH correlate weakly with alpha subunit immunocytochemical staining--95% of those with negative staining have normal alpha PGpH values, but only 18% of those with positive staining have elevated alpha PGpH values.

Reversal of andro-genetic alopecia in a male. A spironolactone effect?

This 73-year-old white male has been bald since the age of 28. He developed nonA-nonB-induced liver cirrhosis and had been treated with spironolactone for the last 6 years. For the last 3 months, his hair had started to regrow over the scalp. This might be related to the antiandrogenic effect of spironolactone.

Microcirculatory stasis precedes tissue necrosis in ethanol-induced gastric mucosal injury in the rat.

The relation of blood flow stasis to the development of unequivocal histologic necrosis (loss of parietal cells from the column of contiguous cells) in ethanol-induced gastric mucosal injury was studied in anesthetized rats. The most rapid vascular change that occurred when the gastric mucosa was exposed to 100% ethanol was a severe segmental constriction of the large submucosal venules. At 22 sec, the average venular diameter was 52.2 +/- 6.0% of the original one. This was followed by complete superficial mucosal blood flow stasis at 49 +/- 4 sec and appearance of histologic evidence of necrosis in one of seven rats at 2.5 min, four of six rats at 10 min, and seven of seven rats at 60 min. We conclude that in ethanol-induced gastric mucosal injury, submucosal venular constriction occurs first, followed by cessation of mucosal blood flow to be followed later on with histologic evidence of necrosis.

Diagnosis of pituitary tumors.

In the last two decades, significant strides have been made in the diagnosis and management of pituitary tumors. The identification, isolation, and characterization of the anterior pituitary hormones, the developments of sensitive and specific radioimmunoassays, and the significant advances in neuroradiologic, neurosurgical, and pathologic techniques have led to increasing recognition of pituitary tumors and their clinical syndromes. This article will review the current diagnostic approaches relating to prolactin, growth hormone-, thyrotropin-, and gonadotropin/alpha glycoprotein subunit-secretory, as well as nonsecretory, pituitary tumors.

Assay of somatomedin C by cartridge extraction prior to radioimmunoassay with antiserum developed against synthetic somatomedin C.

The whole molecule of human somatomedin C (SM-C) prepared by the total synthesis method was used as an antigen to produce an antiserum for a radioimmunoassay. Since plasma proteins that bind SM-C interfere with the assay, a method was developed that uses acid dissociation followed by C-2 cartridge extraction to strip SM-C from its binding proteins before assay. This assay has no cross-reactivity with human proinsulin or insulin-like growth factor II (IGF-II). The SM-C values in 339 normal subjects showed age-dependence, increasing from childhood to a peak at age 14 to 16 years and decreasing sharply before adulthood. In adults, the SM-C values decreased gradually with age. All 13 patients with acromegaly who were tested had an increased SM-C value, with no overlap with the normal range. The 12 patients with prolactinoma but non-growth-hormone-producing pituitary tumor had no increase in SM-C. Two children with pituitary deficiency had low SM-C values; one of these children received growth hormone therapy, and his SM-C value increased from undetectable to normal. By three weeks after discontinuation of the therapy, his SM-C value was again undetectable. Of 20 children with short stature and constitutional delay of growth and development, SM-C was below normal in 70 percent and normal in 30 percent. Two patients with malnutrition had below-normal SM-C values.

Comparison of magnetic resonance imaging and computed tomography in the preoperative evaluation of pituitary adenomas.

Twenty surgically verified pituitary adenomas were imaged in a systematic comparative fashion with high field strength magnetic resonance imaging (MRI) and computed tomography (CT) before operation. The study group included 11 microadenomas, 4 macroadenomas, 2 recurrent microadenomas, and 3 recurrent macroadenomas. The MRI and CT examinations were evaluated for lesion detection, pituitary stalk displacement, cavernous sinus displacement or invasion, hemorrhage, cystic degeneration within the adenoma, bony erosion, detection of suprasellar extension, and displacement of suprasellar structures. T1 and T2 relaxation characteristics of the adenomas were evaluated on MRI examinations, and contrast enhancement characteristics were evaluated on CT examinations. MRI was superior to CT for detecting the extrasellar extent of tumor. Within the sella turcica, MRI and CT were equivalent with regard to lesion detection, except for 1 patient in whom CT was able to detect a surgically confirmed 3-mm microadenoma that was not visualized on the MRI examination.

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.

Primary idiopathic hypothalamic hypothyroidism. Report of four cases.

One man and three women with hypothalamic hypothyroidism are described; they had isolated thyrotropin-releasing hormone deficiency, otherwise normal pituitary function, and no identifiable central nervous system anatomic abnormality. Serum thyrotropin levels were low and thyrotropic response to thyrotropin-releasing hormone was uniformly present, consistent with a hypothalamic cause of hypothyroidism. In two patients, hypothyroidism was transient and spontaneously resolved; in one of them, it was recurrent. Because hypothalamic hypothyroidism is mild and potentially reversible, it is suggested that such patients have follow-up evaluation before therapy is initiated in order to avoid unnecessary treatment.

Laboratory diagnosis of hypopituitarism.

Hypopituitarism can be caused by failure or loss of one or more of the eight identifiable hormones in the anterior lobe of the pituitary gland. The endocrine manifestations of hypopituitarism are related to the type and degree of hormonal deficiency and the stage in life during which the deficiency occurs. In patients with suspected hypopituitarism, the diagnostic approach consists of determining the extent and the cause of the hormonal loss. Specific provocative tests for the diagnosis of hypopituitarism are reviewed in detail in this article.

CT of the sella turcica after transsphenoidal resection of pituitary adenomas.

A retrospective review of 120 patients undergoing transsphenoidal surgery for pituitary adenomas revealed that computed tomography (CT) was less sensitive and less specific than hormonal methods in identifying residual functioning adenomas. However, CT was the only useful method of evaluating nonfunctioning tumors, including pseudo-prolactinomas. Enlargement of the pituitary stalk, when seen on preoperative CT, was 100% predictive of "cure" if the enlargement returned to normal size on a remote follow-up scan (n = 8) and was 100% predictive of residual tumor if the enlargement persisted or evolved (n = 8). Resolution of stalk displacement was the next most reliable predictor of cure (91%, n = 11), but persistent displacement was less reliable than abnormal intrasellar enhancement in predicting the presence of residual tumor (71%, n = 28, vs. 81%, n = 26). Enhancement in the postoperative sella by other than normal pituitary gland was presumed to be due to inflammation in 19% of patients. Inflammatory enhancement was observed in the presence of autograft and homograft muscle plugs and, unlike enhancement due to untreated tumors, was observed to decrease in size and intensity with time. Intrasellar enhancement was an unreliable criterion of success or failure in cases of microadenoma. All 14 patients with functioning adenomas and preoperative parasellar tumor extension had persistent tumor at postoperative evaluation. Of the 47 patients with resected functioning adenomas who had CT scans showing empty or partly empty sellas after operation, 22 (47%) had hormonally detectable residual tumor.

The pathogenesis of acromegaly. Clinical and immunocytochemical analysis in 75 patients.

A series of 75 patients with acromegaly and immunocytochemically characterized pituitary adenomas has been analyzed. Tumors secreting growth hormone (GH) only were found in 21% of cases. The remainder had tumors immunoreactive for more than one pituitary hormone: GH and prolactin in 31%; GH, prolactin, and glycoprotein in 40%; and GH and glycoprotein in 8%. Microadenomas were surgically treated in 17 patients with a success rate of 82%. Overall, normalization of basal GH secretion (to less than or equal to 5 ng/ml) was achieved in 54% of cases. The implications of these findings for the pathogenesis and neurosurgical management of acromegaly are discussed.

Erythrocyte catechol-O-methyltransferase, platelet monoamine oxidase, and platelet phenol sulfotransferase activities in patients with prolactin-secreting pituitary adenomas.

Dopamine is metabolized by oxidative deamination catalyzed by monoamine oxidase, O-methylation catalyzed by catechol-O-methyltransferase, and sulfate conjugation catalyzed by phenol sulfotransferase. This study was performed to determine whether platelet monoamine oxidase, red blood cell catechol-O-methyltransferase and platelet phenol sulfotransferase enzymatic activities in patients with prolactinomas were quantitatively different from the same enzyme activities in blood samples from normal subjects. The mean enzyme activities in blood samples from 22 women with histologically proven prolactinomas were compared to the mean enzyme activities in blood samples from 32 normal women. The blood levels of these 3 enzymatic activities were not significantly different between the two groups (P greater than 0.4). If the regulation of these catecholamine-metabolizing enzyme activities in blood elements reflects the regulation of the enzymes in the hypothalamic-hypophyseal region, these results suggest that a defect in the regulation of dopamine-metabolizing enzymes is not associated with the pathogenesis of prolactinomas.