Immunoreactive beta-endorphin and adrenocorticotropin in human cerebrospinal fluid.

To elucidate the significance of beta-endorphin in human cerebrospinal fluid (CSF), CSF levels of beta-endorphin-like immunoreactivity (beta-EP-LI) in various diseases were determined by a specific radioimmunoassay and compared with simultaneously determined ACTH-like immunoreactivity (ACTH-LI) levels in CSF. CSF beta-EP-LI and ACTH-LI in the control group, consisting of 5 normal subjects and 19 patients with nonendocrine diseases, were 22.2+/-1.3 and 14.6+/-0.4 fmol/ml, respectively. CSF levels of these peptides in patients with schizophrenia (n = 19) and acromegaly (n = 10) were not significantly different from those in the control group. Patients with Cushing's disease (n = 7) had significantly lower CSF beta-EP-LI and ACTH-LI levels than those in the control group. Four of them showed a parallel increase in CSF beta-EP-LI and CSF ACTH-LI levels after the complete removal of pituitary microadenomas (P < 0.05). Gel chromatography of CSF beta-EP-LI from a normal volunteer, a control patient, and one patient each with catatonia, Nelson's syndrome, Cushing's syndrome (adrenal adenoma), and acromegaly gave similar patterns consisting of three peaks with the elution positions comparable to those of authentic beta-endorphin, beta-lipotropin, and possibly their precursor molecule. Gel chromatographic patterns of CSF beta-EP-LI and ACTH-LI were compared in a normal volunteer. The first peaks of beta-EP-LI and ACTH-LI eluted at the same position and the second peak of ACTH-LI coincided with the elution position of authentic ACTH.CSF beta-EP-LI and ACTH-LI levels determined every 5 min over a period of 80 min in three normal volunteers did not show moment-to-moment variability.A significant correlation (r = 0.75, P < 0.001) was seen between CSF beta-EP-LI and ACTH-LI levels in normal subjects and patients studied (n = 73). This suggests that beta-endorphin and ACTH in human CSF share the common regulatory mechanism in normal and pathologic conditions.

Anterior pituitary function after transsphenoidal selective adenomectomy in patients with Cushing's disease.

The anterior pituitary function in 25 patients with Cushing's disease was assessed before and after transsphenoidal adenomectomy. Pituitary adenoma was detected and removed in 24 cases, resulting in clinical remission in 22. Postoperative hypoadrenocorticism was observed in all of the cases with remission, necessitating substitution of glucocorticoid. One case had a recurrence after a year in remission. Plasma ACTH and cortisol rapidly decreased after surgery and remained at subnormal levels. However, diurnal rhythmicity of ACTH and cortisol appeared in 5 of 9 cases within 6 months after surgery and exhibited normal suppressibility in response to low dose dexamethasone. The impaired ACTH response to hypoglycemia was restored after surgery. The GH response to hypoglycemia and the TSH response to TRH were improved by correction of hypercorticism and became evident over time. These results suggest that preoperative impairment of anterior pituitary hormone secretion is secondary to hyperadrenocorticism and that ACTH hypersecretion by a primary pituitary adenoma is the primary etiology in Cushing's disease. We conclude that transphenoidal pituitary exploration should be considered as a first choice of treatment of Cushing's disease because of its high clinical remission rate in association with normalization of other endocrine functions.

Corticotropin-releasing factor up-regulates its own receptor gene expression in corticotropic adenoma cells in vitro.

To investigate the expression of CRF receptor (CRF-R) in human corticotropic adenoma (hCA) cells, we analyzed messenger RNA (mRNA) levels of type-1 CRF-R (CRF-R1). Adenomas were obtained from 10 patients with Cushing's disease. Northern blot analysis using a rat CRF-R1 complementary RNA probe revealed a main hybridization band of 2.7 kilobases in all the hCAs. The CRF-R1 mRNA level significantly increased after 1 h, reached 15-fold the basal level at 8 h, and remained elevated 24 h after the addition of 10 nmol/L CRF in vitro. Dose dependency of the stimulatory effect of CRF was also demonstrated in hCA cells, whereas CRF down-regulated CRF-R1 mRNA levels in rat anterior pituitary (AP) cells. Treatment with dexamethasone or vasopressin decreased the CRF-R1 mRNA level in hCA cells, as observed in rat AP cells. In conclusion, we detected CRF-R1 mRNA in all hCAs tested. The CRF-R1 mRNA level was up-regulated by CRF itself in cultured hCA cells, in contrast to the down-regulation in rat AP cells.

Thyrotropin-producing microadenoma associated with pituitary resistance to thyroid hormone.

A 21-yr-old female with hyperthyroidism is described. Though her serum-free T3 was 17.8 pmol/L and free T4 was 60.2 pmol/L, TSH was as high as 10.7 mU/L. TRH stimulated an increase in TSH from 10.7-91.7 mU/L. T3 administration in gradually increasing doses of 100, 200, and 400 mg/day resulted in gradual reduction in serum TSH. Cranial computed tomography and magnetic resonance imaging revealed a microadenoma of the pituitary gland. Histology of the surgical specimen showed a TSH-producing adenoma with TSH cell cluster islets and decreased numbers of TSH cells in the nonneoplastic pituitary. Cultured cells from the adenoma secreted TSH spontaneously and in response to TRH. This TRH-stimulated TSH secretion was suppressed by T3 in a dose-dependent manner. One year postoperatively, neither residual tumor nor recurrence were seen by computed tomography and magnetic resonance imaging. However TSH, as well as free T3 or T4, was still high and overresponsive to TRH.

Pituitary adenomas in acromegalic patients: an immunohistochemical and endocrinological study with special reference to prolactin-secreting adenoma.

To establish a functional classification of purification of pituitary adenomas in acromegalic patients, we used immunoperoxidase-staining techniques specific for GH and PRL. Surgical specimens from 55 acromegalic patients were studied. GH was demonstrated in all adenomas and PRL was found in 25 of them (45.5%). Immunohistologically, GH- and PRL-containing adenomas could be divided into 3 types. In type 1 (11 patients), immunoreactive PRL was present in single cells surrounded by immunoreactive GH cells. In type 2 (6 patients), immunoreactive PRL cells formed clusters. In Type 3 (8 patients), immunoreactive PRL and GH cells demonstrated a mosaic pattern, and it was difficult to determine which were in the majority. A double immunostaining method revealed 15 adenomas in which individual cells contained both GH and PRL. Hyperprolactinemia was present in 21 patients, 15 of these had immunoreactive PRL cells (type 1, 4 patients; type 2, 3 patients; type 3, 8 patients). There was no correlation between the size of the adenoma and its type. Endocrinologically, all patients with type 2 and 3 adenomas had an abnormal serum GH response to TRH administration; all type 3 patients had a substantial serum PRL response to TRH administration. Type 3 is considered to be an actively PRL-secreting adenoma, resulting in hyperprolactinemia.

Concomitant secretion of adrenocorticotropin, beta-endorphin, and gamma-melanotropin from perfused pituitary tumor cells of Cushing's disease: effects of lysine vasopressin, rat median eminence extracts, thyrotropin-releasing hormone, and luteinizing hormone-releasing hormone.

Regulation of secretion of ACTH-, beta-endorphin-, and gamma-melanotropin-like immunoreactivities (ACTH-LI, beta-EP-LI, and gamma-MSH-LI, respectively) was studied by using a perfused Sephadex column containing dispersed pituitary tumor cells obtained from three patients with Cushing's disease. Serial dilution of the perfusion medium gave lines parallel to the standard curve in each RIA for ACTH, beta-EP and gamma-MSH, suggesting that immunoreactive materials in the medium are immunologically indistinguishable from the authentic peptides. Gel exclusion chromatography of the medium revealed the existence of ACTH, beta-lipotropin (beta-LPH), beta-EP, and their possible precursor protein. gamma-MSH-LI consists of a major peak of big gamma-MSH eluted near the elution position of beta-LPH, suggesting the entire or nearly entire N-terminal portion of the precursor molecule. The addition of lysine vasopressin and rat median eminence extracts (MEE) to the perfusion system concomitantly enhanced the release of ACTH-LI, beta-EP-LI, and gamma-MSH-LI, although the dose-response relationship was clear-cut only in the case of MEE. TRH and LRH also elicited the concomitant release of these peptides in one patient, in whom combined administration of TRH and LRH significantly augmented plasma cortisol levels when studied preoperatively. The molar ratio of ACTH-LI to beta-EP-LI was approximately 1.0, whereas gamma-MSH-LI was about one fourth of ACTH-LI when compared on a weight basis. These results indicate that 1) ACTH-producing human pituitary adenomas concomitantly secrete ACTH, beta-LPH, beta-EP, and big gamma-MSH, and 2) lysine vasopressin, MEE, TRH, and LRH act directly on pituitary cells to stimulate the release of these peptides.

Pituitary adenomas that caused Cushing's disease or Nelson's syndrome are not responsive to ovine corticotropin-releasing factor in vitro.

The response of pituitary adenomas obtained surgically from patients with Cushing's disease of Nelson's syndrome to synthetic ovine corticotropin-releasing factor (CRF), vasopressins, somatostatin-28, dexamethasone, 3-isobutylmethylxanthine or high [K+] was examined in vitro by measuring the amount of pro-opiomelanocortin (POMC)-derived peptides secreted into the culture medium. CRF did not stimulate the secretion of adrenocorticotropin-, beta-endorphin-, or gamma 3-melanotropin-like peptides from the pituitary adenomas at concentrations ranging from 1 x 10(-13) M to 1 x 10(-7) M whereas vasopressins, 3-isobutyrl-methylxanthine and high [K+] increased, while somatostatin-28 and dexamethasone suppressed, the secretion of these POMC-derived peptides. These findings suggest that either the pituitary ACTH-producing tumors have lost their receptors to CRF or their post-receptor mechanism to CRF is not functional.

The transsphenoidal removal of nonfunctioning pituitary adenomas with suprasellar extensions: the open sella method and intentionally staged operation.

The surgical treatment of large pituitary adenomas with suprasellar extensions has been controversial. To elucidate the indications for transsphenoidal surgery of large adenomas and to evaluate the techniques for removing the suprasellar portions of the tumors, surgical procedures on 100 consecutive patients with suprasellar extensions of nonfunctioning pituitary adenomas were retrospectively investigated. Patients were followed up for 1 to 12 years (mean, 4.5 yr). One hundred twenty-five transsphenoidal operations were performed on 100 patients. The removal of each suprasellar tumor was facilitated by the placement of a lumbar subarachnoid catheter and the injection of lactated Ringer's solution or saline. This method was used in 77 operations and was effective on 60 of 72 adenomas with < 30-mm suprasellar extensions (Hardy's Grades A, B, and C) but not on those that were fibrous or dumbbell-shaped. The descent of the remaining suprasellar tumor was facilitated by keeping the sella and sellar floor open with an intrasellar drain, and the subsequent removal was achieved with staged transsphenoidal operations. Of nine fibrous or dumbbell-shaped adenomas with 10- to 30-mm suprasellar extensions, gross total removal in eight was achieved by the open sella technique and two-stage transsphenoidal operation, whereas one required transcranial surgery. Adenomas with > 30-mm suprasellar or lateral extensions (Grade D) could not be removed sufficiently by transsphenoidal operations, except one adenoma for which a subtotal removal was achieved in the third staged operation. The disease-free rate 10 years after operation was 74% for all patients: 91% for Grade A, 74% for Grade B, and 61% for Grade C.(ABSTRACT TRUNCATED AT 250 WORDS)

Long term results of transsphenoidal adenomectomy in patients with Cushing's disease.

As part of an ongoing series, 100 patients with Cushing's disease underwent transsphenoidal operations. Pituitary adenomas were confirmed in 93 patients, and initial remission was achieved in 86 (92%) of them. Hypercortisolemia was not corrected in 7 patients, and in 4 this was due to invasive adenomas. These patients were subjected to irradiation, medical treatment, or both after operation. Only 7 of the 100 patients had no pituitary adenoma found at operation, and they obtained no clinical remission even after partial or subtotal hypophysectomy. Follow-up review, with an emphasis on endocrinological studies, was performed on these patients for a mean period of 38 months. Seventy-eight patients were in long term remission after operation and had restoration of noncorticotropic hormone secretion as well as pituitary-adrenal function. Recurrence was noted in 8 patients after 19 to 82 months in remission. In all of these patients, pituitary adenomas were verified by reoperation and no case of corticotrophic cell hyperplasia was noted. We conclude that late recurrence of Cushing's disease may occur after adenoma removal and is due to the regrowth of adenoma cells left behind in the peritumoral tissue at the first operation. In view of the overall remission rate, transsphenoidal adenomectomy is considered a highly effective treatment for Cushing's disease.

Difficulty in differentiating thyrotropin secreting pituitary microadenoma from pituitary-selective thyroid hormone resistance accompanied by pituitary incidentaloma.

A 33-year-old woman with inappropriate secretion of TSH and a 2-mm pituitary microadenoma is described. She had a high serum free T4 concentration (31 pmol/L) with an inappropriately nonsuppressible serum TSH concentration (0.93 mU/L). The alpha/TSH molar ratio was 2.3 and magnetic resonance imaging with gadolinium enhancement identified an area of low signal intensity in the left lateral pituitary gland. However, TSH secretion was not completely autonomous. There was a significant response to exogenous TRH stimulation and suppression by T3 administration. Therefore, it was difficult to rule out a nonfunctioning pituitary adenoma with concomitant pituitary selective thyroid hormone resistance syndrome. A 2-mm microadenoma was excised via transsphenoidal surgery. The tumor cells were immunoreactive to antisera to alpha-subunit and minimally immunoreactive to antisera to TSHbeta. The patient's thyroid function normalized after surgery without medication. Because the adenoma could become large and intractable if the patient was treated inadequately, early diagnosis and treatment are important in patients with TSH secreting adenomas.

Detection of mRNA of prolactin and ACTH in clinically nonfunctioning pituitary adenomas.

Clinically nonfunctioning pituitary adenomas have been thought to synthesize some pituitary hormones as shown by studies involving cell culture, immunocytochemistry, or measurement of hormone levels in tumor homogenates. Nevertheless, they are not associated with hypersecretion of pituitary hormones. To further clarify hormone synthesis in such pituitary adenomas, the presence of messenger ribonucleic acid (mRNA) of prolactin (PRL) growth hormone, and adrenocorticotropic hormone (ACTH) in the cytoplasm of 16 nonfunctioning adenomas was determined by means of a hybridization technique, and compared to the immunocytochemical findings. In three adenomas (19%) PRL mRNA was detected and in one case (6%) ACTH mRNA was detected. The hybridization technique appears to be more sensitive than immunohistochemistry for detection of specific mRNA's in assigning the hormone synthesis potential to clinically nonfunctioning tumors. The results suggest that PRL and ACTH are synthesized in some cases of clinically nonfunctioning pituitary adenomas and that hybridization techniques are useful to investigate hormone synthesis in pituitary adenomas. The ability to demonstrate PRL mRNA in tumor tissues allowed differentiation between hyperprolactinemia caused by synthesis of PRL in the tumor and that due to hypersecretion from the adjacent normal pituitary.

Prolactin gene expression in human growth hormone-secreting pituitary adenomas.

To elucidate the mechanism of hyperprolactinemia often observed in patients with growth hormone (GH)-secreting pituitary adenomas, the presence of immunoreactive prolactin (ir-PRL) and prolactin (PRL) messenger ribonucleic acid (mRNA) in the tumor tissue was examined by immunohistochemistry and cytoplasmic dot hybridization. Hyperprolactinemia was observed in three of 18 patients with GH-secreting adenoma. The tumor tissue was demonstrated to contain ir-PRL in nine patients and PRL mRNA in 13. The presence of ir-PRL in the tumor tissue was always associated with positive PRL mRNA, indicating production of PRL in GH-secreting tumors. Among the three patients with hyperprolactinemia, both ir-PRL and PRL mRNA was revealed in the tumor tissue of one, PRL mRNA but not ir-PRL was detected in the adenoma tissue of another, and neither PRL mRNA nor ir-PRL was found in the tumor tissue of the third. The association of hyperprolactinemia with the presence of both ir-PRL and PRL mRNA or PRL mRNA alone is indicative of PRL production and secretion. However, the absence of ir-PRL and PRL mRNA in the tumor tissue may indicate that hyperprolactinemia is caused by the suppression of PRL inhibitory factor due to hypothalamic dysfunction by the tumor mass. Thus, the study of PRL gene expression and immunohistochemistry in GH-secreting adenomas is valuable to understanding the pathophysiology of pituitary tumors.

Pro-opiomelanocortin gene expression in silent corticotroph-cell adenoma and Cushing's disease.

The silent corticotroph-cell adenoma (SCCA) is characterized by the presence of immunoreactive adrenocorticotropic hormone (ACTH) in the tumor tissue in patients without symptoms of Cushing's disease. To elucidate the pathophysiology of SCCA, the expression of pro-opiomelanocortin (a ACTH precursor) genes was studied in a patient with SCCA and in three patients with Cushing's disease. Pro-opiomelanocortin messenger ribonucleic acid (mRNA) was found in the SCCA tissue to a greater degree than in the adenomas of the patients with Cushing's disease. Northern blot analysis revealed that the size of pro-opiomelanocortin mRNA present in the SCCA tissue was indistinguishable from that in the adenomas associated with Cushing's disease. A ribonuclease mapping study indicated that there were no point mutations in the coding sequence of pro-opiomelanocortin mRNA present in the SCCA tissue. Because of the presence of pro-opiomelanocortin mRNA and immunoreactive ACTH in the adenoma tissue, it is proposed that translation of the mRNA and subsequent accumulation of ACTH precursor occurred in the SCCA. Thus, the absence of Cushing's disease symptoms in this SCCA could not be caused by abnormality in the coding sequence of the pro-opiomelanocortin gene or in ribonucleic acid processing. The occurrence of abnormality at or after the translational steps was strongly suggested.

Endocrinological evaluation of ACTH-secreting pituitary microadenomas: their location and alpha-melanocyte stimulating hormone immunoreactivity.

It has been hypothesized by Lamberts and coworkers in their analysis of 15 cases that adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas may be derived from either the anterior lobe or the intermediate lobe. The intermediate lobe type of Cushing's disease is thought to be controlled through a hypothalamic pathway and is characterized by hyperprolactinemia; suppressibility of cortisol with bromocriptine, and lower sensitivity to dexamethasone. The authors investigated the validity of this hypothesis in 125 cases of ACTH-secreting pituitary microadenomas by analyzing the endocrine findings, the locations of the microadenomas, and alpha-melanocyte stimulating hormone (alpha-MSH) immunoreactivity in the adenoma cells. No significant differences in the basal hormone levels, cortisol suppressibility with bromocriptine, sensitivity to dexamethasone, and recurrence rate were observed between patients with the microadenoma adjacent to the posterior lobe (considered typical of the intermediate lobe-derived tumor) or those with the microadenoma located in the anterior lobe. The locations of the microadenoma were not correlated with alpha-MSH immunoreactivity in the adenoma cells. No significant differences in endocrine findings were noticed between adenomas positive or negative for alpha-MSH. Thus, Cushing's disease cannot be simply divided into either the anterior lobe type or the intermediate lobe type by endocrinological evaluation as described by Lamberts, et al.

Long-term growth hormone responses to nonspecific hypothalamic hormones in acromegalic patients.

Nonspecific hypothalamic hormones such as thyrotropin-releasing hormone or luteinizing hormone-releasing hormone, or both, elicited abnormal growth hormone responses in 73 of 108 (67.6%) acromegalic patients. After transsphenoidal adenomectomy, the provocative tests using these hormones were repeated in 26 patients with abnormal preoperative growth hormone responses to study variations in these responses during a 1-8-year observation period (average duration, 4 years). After surgery, 7 of the 26 patients regained normal basal growth hormone levels (less than 5 ng/mL) and manifested normal responses to the hypothalamic hormones. During the postoperative observation period, their basal growth hormone levels remained normal as did their responses to provocation with hypothalamic hormones, confirming that the adenoma had been completely resected. Eight other patients demonstrated normal growth hormone levels after surgery; however, they continued to have abnormal responses to provocation with hypothalamic hormones, suggesting the presence of residual adenomatous tissue in the gland. These patients manifested no marked increase in basal or peak growth hormone levels during the follow-up period (from less than 1 to less than 7.5 years) and they were all in clinical remission without any other treatment. Only one incompletely adenomectomized patient who had received no additional treatment experienced regrowth of the tumor. The main factor affecting the surgical results appears to be the preoperative basal growth hormone level, because abnormal growth hormone secretion ceased in all patients who had manifested preoperative levels below 45 ng/mL. Technical refinements of the operative procedure are another important factor in the postoperative outcome. Peritumoral tissue resection after simple selective adenomectomy is mandatory for better surgical results. Our studies indicate that fairly good results can be obtained without risk of the recurrence of the tumor or regrowth, when postoperative growth hormone levels are below 5 ng/mL and that the results are not affected by the postoperative growth hormone responses to provocation with hypothalamic hormones.

Elevation of plasma atrial natriuretic peptide in a neurosurgical patient with the syndrome of inappropriate secretion of antidiuretic hormone--case report.

The authors describe a case of subarachnoid hemorrhage with hyponatremia accompanied by elevation of plasma atrial natriuretic peptide (ANP). The early phase of hyponatremia was classified as the syndrome of inappropriate secretion of antidiuretic hormone (ADH) due to subarachnoid hemorrhage. However, in the later phase, hyponatremia and natriuresis were accompanied by suppression of ADH while plasma ANP remained elevated. The patient was effectively treated with demeclocycline and hypertonic saline. The significance of ANP in the pathophysiology of increased natriuresis is discussed.

Cervical flexion myelopathy associated with cervical spina bifida occulta--case report.

A 16-year-old boy presented with segmental muscular atrophy of the bilateral distal upper extremities. Cervical spine x-ray films showed occult spina bifida from C-1 to T-1 associated with an abnormal long club-like bone located parallel to the epidural space between C-5 and C-7. In neck flexion, the cervical spinal cord was stretched and compressed to the posterior aspect of the vertebral body. Moreover, the dorsally placed abnormal bone migrated ventrally, indenting the dorsal portion of the spinal cord. This is quite an unusual case of so-called "flexion myelopathy," aggravated by the abnormal bone located dorsally.

[Cerebral vasospasm and vasoactive amines (author's transl)].

The management of patients with ruptured intracranial aneurysm is complicated by an apparently irreducible and unmanageable morbidity that can be traced directly to cerebral vasoconstriction. Technical skills required to attack aneurysms successfully have been mastered by many surgeons. Vasospasm, on the other hand, remains a challenge and has yet to respond to any practical modality of treatment. Spasm of the basilar artery in the dog was induced by the injection of blood into the cisterna magna, and documented by means of vertebral angiography. The author, also, described the modification of experimental cerebral vasospasm by the administration of reserpine to deplete platelets of serotonin as well as other vasoactive amines such as histamine and catecholamines.

[Hyponatremia with high plasma ANP level--report of two cases with emphasis on the pathophysiology of cerebral salt wasting].

Two cases of hyponatremia with intracranial lesions are reported with emphasis on diagnostic value of measurement of antidiuretic hormone (ADH) and atrial natriuretic polypeptide (ANP). Case 1. A 77-year-old female was transferred to our hospital for further care of vegetative state after subarachnoid bleeding on May 23, 1986. She was operated by neck clipping of rt-IC bifurcation aneurysm and lt-internal carotid-posterior communicating aneurysm at another hospital. On admission, computed tomography showed diffuse low density at bilateral thalamus and centrum semiovale. Biochemical analysis revealed hyponatremia (120 mEq/t) with increased natriuresis. Endocrinological date revealed normal plasma ADH and high plasma ANP levels. Patient was treated with infusion of 1% NaCl. Case 2. A 65-year-old male was admitted to our department because of gradual impairment of consciousness and generalized convulsion. Computed tomography showed small low density area at rt-thalamus and lt-cerebellar hemisphere. Biochemical date revealed severe hyponatremia (91 mEq/t) with normal plasma level of ADH and high plasma ANP. He was treated with infusion of 3% NaCl and hyponatremia was improved. The hyponatremia is frequently associated with intracranial disorders such as brain tumor, subarachnoid hemorrhage and head injury. Originally, hyponatremia with natriuresis was thought to be caused by salt wasting. This syndrome was defined as the inability to prevent salt loss in the urine due to undefined natriuretic factor in the brain. However, since 1957, because of introduction of concept of SIADH, it has generally become accepted that patients with natriuresis had SIADH. (ABSTRACT TRUNCATED AT 250 WORDS)

[Size reduction of a nonfunctioning pituitary adenoma after bromocriptine therapy: case report].

Bromocriptine therapy may cause regression of prolactinomas and GH producing adenomas, but there is only few reports about the effect of bromocriptine against nonfunctioning pituitary adenomas and there is no reports about its histopathological changes. We report a nonfunctioning pituitary adenoma, which remarkably regressed during and following bromocriptine therapy. A 47-year-old man developed blurred vision on January 20, 1981. He was pointed out of bitemporal hemianopsia and of his left palor optic fundus. His endocrinological condition was panhypopituitarism and no hypersecreting hormones were found. Cranial computerized axial tomography showed huge dumbbell shaped high density mass extending from the enlarged intrasellar area to the floor of the third ventricle. On treatment with bromocriptine, 5 mg daily for 3 days, his visual acuity and field was remarkably improved. Treatment was continued with gradually increased doses of bromocriptine to 15 mg and so, remarkable shrinkage of tumor size about 50% was seen by computerized axial tomography by a month. In addition, by eight months, the tumor reduced to 22%. Transsphenoidal surgery revealed centrally necrotic tumor mass surrounded by peripheral fibrous one. Because of fibrous and hemorrhagic tumour, we could not remove it totally. The pathological specimen was examined by light and transmission electron microscopy. The tumor was diffuse-type chromophobe adenoma partially intersected by hypertrophied fibrous interstitial materials. Some tumor cells were stained faintly eosinophilic. The cytoplasms were shrunken and the tumor cells were clumped. The immunostaining of tumor was negative to all anterior pituitary hormones. The intracytoplasmic organellae, for example, rough endoplasmic reticulum, Golgi apparatus, were scanty but prominant deformed mitochondria and small secretary granules (the size of about 90-150 nm) were found by transmission electron microscope. We think that the tumor cells had various responsiveness to this drug and the one extreme was destruction of the nucleus, the irreversible change, and the other extreme was some cytoplasmic reduction, the reversible change. The histopathological changes were almost the same as those of prolactinomas treated with bromocriptine. In conclusion, the mechanism of shrinkage of nonfunctioning pituitary adenomas treated with bromocriptine is unclear but it is worth while treating inoperable or recurrent large nonfunctioning pituitary adenomas with bromocriptine.