Akio Kuwayama

Long Term Results of Transsphenoidal Adenomectomy in Patients with Cushing's Disease

As part of an ongoing series, 100 patients with Cushings 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 Cushings 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 Cushings disease.

Immunoreactive β-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 Cushings 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, Nelsons syndrome, Cushings 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.

Transsphenoidal approach to pituitary adenomas with suprasellar extension

Abstract During the past six years, we have operated upon a total of 59 pituitary adenomas with suprasellar extension. Of 26 patients treated by transsphenoidal operations, 54% (19 of 35 eyes) recovered normal visual acuity; improvement was noted in another 37% (13 of 35 eyes). The visual field was corrected in 84% (41 of 49 eyes). In about 60% (31 of 51 eyes) of the patients who underwent frontal craniotomy, visual improvement occurred. Endocrinologic cure of hypersecreting adenomas with suprasellar extension was difficult, although visual impairment improved. We suggest that in most cases the transsphenoidal approach is the method of choice in pituitary adenomas with suprasellar extension. With this approach there has been excellent visual improvement and fewer operative complications.

Effect of Estrogen on Prolactin mRNA in the Rat Pituitary

The effect of estrogen on prolactin (PRL) synthesis at a single-cell level was studied by in situ hybridization and immunohistochemistry. Long-term estrogen treatment increased PRL-containing cells from 10-20% of total cell population to 80-90%, as revealed by immunohistochemistry. PRL mRNA containing cells also increased in a similar fashion. Moreover, cytoplasmic PRL mRNA expressed as the number of silver grains per cell increased 4- to 5-fold by estrogen. These results suggest that long-term estrogen treatment causes not only PRL cell proliferation but also an increase in PRL mRNA in a single cell.

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.

Morphofunctional study of pituitary adenomas with acromegaly by immunoperoxidase technique and electron microscopy

In attempting to establish a functional classification of acidophilic adenomas of the pituitary gland, immunoperoxidase staining techniques specific for growth hormone (GH), prolactin (PRL), and luteinizing hormone (LH) were carried out. Surgically removed specimens from 24 acromegalic patients were studied. The pathologic observations were then compared with the basal plasma levels of each of the hormones. The existence of GH was demonstrated in all patients. Immunohistologically, GH‐secreting adenomas could be subdivided into three types: Type I had the highest plasma‐GH level (average 121 ng/ml), while the average plasma‐GH levels of types II and III were 103 ng/ml and 73 ng/ml, respectively. This result suggested that the serum‐GH level may correlate with the GH cell population in a tumor. In 13 of the acromegalic patients, immunoenzyme methods were utilized in order to identify prolactin cells. No clear correlation between serum‐PRL levels and the distribution of PRL cells could be demonstrated. A few immunoreactive LH cells were found in 13 patients. These LH cells may be a mixture of normal cells, based on our clinical finding.

Diagnosis, treatment and postoperative results of Cushing's disease

SummaryOne hundred patients with Cushings disease were operated on in Nagoya University Hospital between January 1977 and January 1984. Pituitary adenomas were found and resected in 93 cases and complete clinical remissions were observed in 89 treated by operation alone and in two additional cases by operation followed with radiotherapy. The clinical features, pre-operative endocrine data, radiological findings including high resolution CT with coronal and sagittal reconstructions, data of selective venous sampling, operative findings, tumour pathology, postoperative clinical course, postoperative endocrine results and follow-up findings are presented and discussed.

Increase of β-endorphin in cerebrospinal fluid after removal of ACTH-secreting pituitary adenomas

Abstract &bgr;‐Endorphin and methionine(met)‐enkephalin in cerebrospinal fluid (CSF) were measured before and after removal of an adrenocorticotropic hormone‐(ACTH)‐secreting adenoma in Cushings disease by a sensitive radioimmunoassay and a radio‐receptor assay, respectively. After tumor resection, the level of ACTH in plasma markedly decreased from 82.6 ± 22.7 pg/ml to 16.7 ± 4.1 pg/ml (mean ± S.E., n = 4). It was found that the level of &bgr;‐endorphin in CSF significantly increased from 32.0 ± 4.5 pg/ml to 61.8 ± 10.7 pg/ml (P < 0.05) after tumor resection, while the level of metenkephalin in CSF remained unaltered. This result suggests that hypophysectomy induces an increase of &bgr;‐endorphin in CSF.

Treatment of Cushing's Disease by Transsphenoidal Microsurgery

Six patients of ACTH dependant Cushings disease were treated by transsphenoidal resection of pituitary adenomas. Preoperative endocrinological results showed that both plasma ACTH and cortisol were maintained at higher levels and their normal diurnal rhythms were lost. Urinary 17-OHCS excretion was partially suppressed by larger doses of dexamethasone (8 mg). These data was suggestive of pituitary dependent Cushings disease, rather than ectopic ACTH-producing tumors. The sella volume was measured by Di Chiros method and in 3 cases it exceeded minimally above the upper limit of the normal value, but the other 3 showed completely normal sella. Localized bulging of the sella floor was found in 2 cases by midline lateral tomography. In the A-P tomogram asymmetry of the sella floor was found in one case and localized bulging in other 2 cases. Minimal suprasellar expansion of the tumor was found only in one case by midline pneumotomography. Magnified cerebral angiography with subtraction method or computed tomography was not diagnostic to verify pituitary microadenomas. The indication of pituitary surgery had to be decided mainly by endocrinological findings. In only one case the adenoma occupied most of the intrasellar space, but in the other 5 they were microadenomas and 3 of them were buried in the normal glands. Complete resection of the adenoma was attempted, but macroscopically normal tissue was tried to be left as much as possible. Typical Crookes hyaline changes were found in the normal adenohypophysis in one case and immunohistochemical studies using anti-ACTH serum revealed that the Crookes cells are still reactive. After surgery most patients showed decreased plasma ACTH and cortisol levels and substitution therapy of adrenocortical hormones was necessary for the first one or two months. Rapid clinical remission of Cushings syndrome was observed in all but one, who might have residual tumor cells due to technical incompleteness. Successive endocrinological reevaluation showed that pituitary-adrenal function has been normal or subnormal in 5 cases. One showed no significant improvement. None had pan-hypopituitarism nor any serious side effects, such as liquorrhea and continuous diabetes insipidus. Overall results suggest that transsphenoidal resection of pituitary adenomas in Cushings disease should be located in the center of the treatment.

Inhibitory effect of ergot alkaloids on nucleosides transport in cultured bovine anterior pituitary cells

Effect of ergot alkaloids on (3H)-nucleosides uptake by dispersed cells from fresh female bovine anterior pituitary glands was examined, because we had interested in the mechanism of pituitary tumor regression following bromocriptine treatment and considered nucleic acid synthesis as an important process in the metabolism of these cells. The anterior pituitary cells were implanted on culture tubes using D-valine minimal essential medium with serum to suppress the overgrowth of fibroblasts and then maintained in L-valine Dulbeccos modified Eagle medium. (3H)-Uridine uptake by these cells was suppressed by bromocriptine, at-ergocriptine or ergotamine at a concentration varing from 10(-6) M to 10(-5) M, but not 10(-5) M of lergotrile. Among these alkaloids, bromocriptine had most strong inhibitory effect and suppressed the uptake to below 25% of control value at the concentration of 10(-5) M. Bromocriptine also inhibited the uptake of (3H)-thymidine, (3H)-cytidine, (3H)-adenosine or (3H)-guanosine in the same manner as (3H)-uridine. But neither (3H)-uracil, the base of uridine, nor (3H)-galactose uptake by cells was affected by bromocriptine. The incorporation of (3H)-uridine or (3H)-thymidine into TCA-insoluble fraction of the cells was also inhibited by bromocriptine as that in the total cells. It was suspected that bromocriptine acted on distinct transport site of both ribonucleoside and deoxyribonucleoside, because a high concentration (3.3 X 10(-5) M) of radio-inactive thymidine did not modify (3H)-uridine uptake by these cells as well as inhibitory effect of bromocriptine on it. These effect of bromocriptine were not blocked by haloperidol, known as dopamine antagonist, at the same concentration as bromocriptine, and dopamine had no effect on (3H)-uridine uptake by the cells. In addition, by adding 5 X 10(-4) M of dibutyryl cyclic AMP into the medium, the effect of bromocriptine was also not affected. These data suggest that the effect of bromocriptine on nucleoside transport in anterior pituitary cells may be dependent on the other binding site than D-2 dopamine receptor in the anterior pituitary cell membrane.