Surgical

Treatment

of Functioning Adenoma

Pituitary

Yukichi YONEMASU, Katsutoshi KITAMURA, Hideho OHTA, Fumio SHIMA, Kazuo KINOSHITA, Masamichi TOMONAGA*, Hiroshi OMA**,Hajime NAWATA**, Ken-ichi KATO**and Hiroshi IBAYASHI**

Department of Neurosurgery,NeurologicalInstitute, Faculty of Medicine, Kyushu Univ The 3rd Department of Internal Medicine, Faculty of Medicine, Kyushu University,Fukuoka, Japan Department of Neurosurgery,Faculty of Medicine, * Fukuoka University,Fukuoka, Japan* Summary Clinical and endocrinological studies in 30 patients with functioning pituitary adenoma were conducted with special reference rendered to the endocrinological results of treat ment. Twenty-one patients were with acromegaly, 5 with Cushing's syndrome and 4 with Forbes-Albright syndrome. In the treatment of patients with acromegaly, early diagnosis (microadenoma) and transsphenoidal removal was emphasized in order to obtain endocrinological cure. In the treatment of advanced tumor or adenoma with marked fibrosis, radical hypophysectomy was recommended to patients with advanced hypertension and/or diabetes mellitus and to patients after climacterium. In patients with pituitary-dependent Cushing's syndrome, even without sellar change and without evidence of pituitary tumor other than endocrinological evidences of pituitary dependency transsphenoidal surgical procedure should be the initial treatment of choice. Forbes-Albright syndrome with or without sellar change or even without visual impairment should also be treated surgically as selective removal of microadenoma may result in cure with restoration of the normal pituitary function. A brief comment was made on the etiology of the pituitary adenoma. The results were ambivalent as to whether hypothalamic or pituitary but, from the clinical point of view, the hypothalamic origin should not be overestimated. In the treatment of the functioning pituitary adenoma transsphenoidal surgical removal should be performed as an initial treatment. Because of its benign and selective nature, endocrinological cure with preservation of normal pituitary function is promised in the cases with microadenoma. Keywords: Functioning pituitary adenoma, acromegaly, Cushing's disease, Forbes-Albrightsyndrome, trans sphenoidalsurgery, microadenoma

Introduction Since the introduction of the operating mi croscope to the transsphenoidal open surgical approach by Hardy,") this procedure has been widely accepted as the surgical procedure of choice in pituitary adenomas,") particularly in

functioning adenomas and a great contribution has been made in understanding the endo crinology and pathology of the pituitary-related disorders. However, the etiological factor in the development of pituitary adenomas remains controversial as to whether primary in the pitu itary gland or hypothalamus."' .17,21) Accord ingly the extent of surgical removal in function

ing adenomas is still under discussion. In the treatment of functioning microadenomas, re moval of the adenoma is generally regarded as a sufficient procedure. The total removal of the anterior lobe of the pituitary gland along with extirpation of the microadenoma is, however, recommended in some European litera tures.4' 9,24, 34) In pituitary adenomas with acromegaly, most of the endocrinological cures were obtained in cases with microadenoma whereas the endo crinological results in cases with so-called invasive adenoma or adenoma with a large suprasellar extension have been unsatisfac tory.' 0.13.21) It is obvious that in the treatment of pituitary adenomas with an endocrine function, an en docrinological cure should also be aimed in addition to improvement of visual disorders, the treatment of which, when present, has been the prime interest of neurosurgeons. The purpose of this communication is to dis cuss the surgical treatment of functioning ade nomas with special reference to the endocrino logical cure from our experiences with various modes of treatment and to make comments on

Table

1

Classification

the etiological factors from the pre and post operative endocrinological studies of our pati ents.

Materials and Methods Clinical and endocrinological studies were made in 30 patients with functioning pituitary adenoma who were evaluated at the Department of Neurosurgery, Kyushu University from 1959 to 1975. These tumors represent 16.8 % of the pituitary adenomas examined by the authors during the same period. Twenty-one patients were with acromegaly ; 5 with Cushing's syndrome; 4 with amenorrhea galactorrhea syndrome. Ten patients with hy persecretion of prolactin without clinical mani festations were not included in this study. The cases are listed in Table 1. Most of the endocrinological evaluations were performed at either the 2nd Department or the 3rd Department of Internal Medicine of our hospital. In recent cases, a serial determination of GH, LH, FSH, TSH and prolactin was done by radioimmunoassay after intravenous in jection of insulin (0.1 U/kg of wt.), LH-RH

of the patients

with

functioning

adenoma

(100 jig), TRH (500 jig) and oral administration of L-dopa (500 mg) and CB-154 (2 Br-alpha ergocryptine) (2.5 mg). Determination of GH in the cerebrospinal fluid was also done in 4 pa tients with acromegaly. In Cushing's disease the pituitary-adrenal function was examined by determination of the serum cortisol level with diurnal changes, the rapid combined test (a combination of the rapid ACTH test and rapid dexamethasone sup pression test)23) and the metyrapone test. In 2 of the recent cases, the serum ACTH level was determined pre and postoperatively. Histological diagnosis was made by hematoxylin-eosin stain, Mallory-Heidenhein azan stain, Masson trichrome stain and phos photungstic acid hematoxylin stain. Particular attention was paid to the fibrosis of the tissue as well as to the cytoplasmic granules. Follow-up studies including endocrinological evaluations were made by questionnaires and/or examinations at the out-patient department.

The results of the endocrinological studies are shown in Table 2. The basal level of serum GH was elevated in all the cases studied ranging from 11 to 137 ng/ml or over. A marked elevation of GH level, two to several times as high as the basal level in response to TRH injection, was noted in the patients with active acromegaly. Suppression of the serum GH level by oral administration of L-dopa was noted in most of the patients exam ined. In all the patient examined, suppression of the serum GH level after oral administration of CB-154 was observed. An excessive increase of prolactin in response to TRH was noted in some patients studied. The details of the en docrinological studies will be published by co authors H.O., K.K. and H.L.

Neuroradiological studies In the plain skull films, a ballooning enlarge ment of the sella turcica was noted in all but two patients. One of these two patients was with destruction of the sella and demineralization of Results the anterior clinoid processes as of the dorsum sellae. In the other patient, only a double floor of Pituitary adenomas with acromegaly the sella was noted. Even in this patient, the tumor involved the whole anterior lobe of the Preoperative clinical and endocrinological studies gland. There was, therefore, no micro The patients with acromegaly are listed in pituitary adenoma in this series. Table 2. Diagnosis was made by clinical manifes The sellae were grouped into four types of tations and elevation of the basal level of serum Vezina and Maltais' classification .33)There were GH and its abnormal responses to various 1 of Type I, 10 of Type II, 8 of Type III and 2 of stimulations. Type IV. Seven patients were males and 15 females, The carotid angiograms revealed an opening ranging in age between 10 to 56 years at the time of the siphon in the majority of the cases. An of admission. One female patient, 10 years of elevation of the horizontal portion of the ante age, initially had gigantism, which gradually rior cerebral artery was noted in 11 out of 17 developed acromegalic manifestations after patients examined with full correspondence to surgical removal of pituitary eosinophilic ade the suprasellar extension confirmed by noma followed by external irradiation. Visual field defect was noted in 11 patients : pneumoencephalography. Pneumoencephalography was performed on bitemporal hemianopia in 8, bitemporal upper 20 patients and suprasellar extension was quadrantanopia in 2 and left nasal lower quad in 12 patients. In 4 out of 6 patients with rantic field defect in 1. Diabetes mellitus was proved large-more than 2-plus-suprasellar extension, verified in 5 patients, 2 of which were refractory the protein content of the CSF was increased, to insulin therapy. Hypertension was noted in 6 measuring 67 to 108 mg/dl. The extent of su patients including the one with gigantism. One prasellar growth is shown in Table 2. One plus patient developed diabetes mellitus and hyper represents less than 5 mm extension of the tension with recurrence of adenoma. tumor from the diaphragm, 2 plus 5 to 15 mm, 3 It should be noted that 19 out of 21 patients more than 15 mm, respectively. This had noticed acromegalic features for more than plus classification corresponds to the Types A, B and 3 years, the longest for 23 years, prior to visiting C as classified by Vezina and Maltais.33> a physician.

Table

2

Principal

clinical

and

endocrinological

data

in 21 patients

with

acromegaly

*With hypernatremia . **With gigantism. ***With galactorrhea. Histology: U = unverified; E = eosinophilic ; M = mixed; C = chromophobe ; D = diffus type; S = sinusoidal type; P = pleomorphism ; F = fibrosis. Treatment : F = subfrontal ; S = transsphenoidal ; R = irradiation. D.I. = diabetes insipidus. GH = growth hormone ng/ml .

Pathological studies Histological diagnosis was obtained in a total of 17 tumors. In 4 patients, the tumor was not verified. In the patients with acromegaly, the adenoma was of a more or less mixed type of eosinophilic and chromophobe cells. Out of 17 tumors, 11 were eosinophilic ade noma, 2 were chromophobe and 6 were mixed. The cell arrangement was diffuse in 16 tumors, 4 of which demonstrated a sinusoidal pattern in part. The sinusoidal pattern was dominant only in one tumor of mixed cell type. Pleomorphism was noted in 5 tumors of diffuse type, 2 of which were with an invasion of the cellar floor in the plain skull film. A marked fibrosis was noted in 5 eosinophilic tumors and one mixed cell type tumor (Fig. 1). In 4 patients with markedly fibrotic tumors the basal GH levels were only moderately elevated pre operatively ranging from 11 to 89 ng/ml and retained slightly high values after surgical pro cedure. Trea tmen t Until 1970, an intracapsular removal of the tumor by subfrontal approach had been perfor med on 6 patients. Postoperative irradiation was given to 3 patients. Since the introduction of transsphenoidal pro cedure in 1971, the intracapsular removal with preservation of the posterior lobe followed by irradiation has become the procedure of choice for functioning pituitary adenomas. A radical removal of the pituitary gland was not perfor med on any patients with adenoma.

Fig.

1 with

Photomicrograph

of the

tumor

in case

acromegaly.

Degenerative

change

Mallory-Heidenhein

and

fibrosis

azan

stain,

are remarkable, x 80.

14

Twelve patients were operated on by this procedure and irradiation was given to 10 pa tients. Reoperation was performed on two pa tients, due to recurrence of visual disorder in one and development of acromegaly in the other. A subfrontal approach was added in one patient with visual disorder, and transsphenoidal sur gery was repeated on the patient with gigantism and acromegaly. Due to refusal of surgery, 2 patients received only conventional irradiation therapy. The subfrontal procedure was complicated with diabetes insipidus in 3 patients, one of whom was associated with hypernatremia, while hemiparesis due to angiospasm occurred in 2. Seizure disorder developed in 3 patients as late complications. Complications after transsphenoidal surgery were much less frequent than those after sub frontal surgery. Those were one transient diabe tes insipidus, one transient CSF rhinorrhea for two weeks and one rhinorrhea with meningitis for four weeks, which developed after re operation for recurrence. Postoperative clinical and endocrinological stud ies Clinical improvement was obtained in 4 out of 8 subfrontal procedures, in 11 out of 13 trans sphenoidal procedures and in 1 out of 2 irradi ation. Decrease in skin and lip thickness and in finger breadth and joint width was obtained within the immediate postoperative period. Im provement of acromegalic features of the face was minimal. Diabetes mellitus disappeared in 2 out of 5 patients, and in one patient with family history diabetes was well controlled by insulin therapy. Hypertension disappeared in 5 out of 7 patients. Menstruation was maintained in 3 out of 8 preclimacteric female patients. Changes of the pituitary function after the procedure were varied. Improvement was noted in cases with intrasellar tumor. Clinically, about one third of the patients required replacement therapy. As far as the basal level of GH was concerned there was no endocrinological cure in our series (Fig. 2). In most of the cases, basal level of GH decreased but still remained abnormally high. In 14 patients the postoperative basal level of GH was determined within two months after sur gery. Results were : below 20 ng/ml in 4 patients,

plain skull X-ray films, no enlargement of the sella was noted, but a double floor in Case 3 and a sclerotic floor in Case 4 were indicative of pituitary pathology. In no cases was a suprasel lar mass found by pneumoencephalography. Bilateral adrenal hyperplasia was suggested by 131I adosterol adrenal scan in all the 3 cases examined (Fig. 3, right). By the adrenal veno graphy, the diagnosis of bilateral adrenal hyper plasia was made in one patient and unilateral hyperplasia in 3 patients in whom the adrenal venographies were successful only on one side (Fig. 3, left). Fig. 2

Pre

and postoperative

the patients The triangle= = conventional

between

with

basal

levels

of GH in

acromegaly.

transsphenoidal irradiation .

20 to 41 in 7 patients

surgery;

and

the square

over 80 in 3

patients. In 2 patients, the basal level of GH was further determined 23 and 31 months after sur gery and irradiation, and a nearly normal value in the Decrease of the basal GH ation therapy was gradual

Pituitary

further decrease to a GH level was noted. level by mere irradi and temporary.

adenoma with Cushing's syndrome

Preoperative clinical and endoclinological studies Cases are listed in Table 3. Diagnosis of Cushing's syndrome was made by clinical man ifestations and elevation of the basal level of serum cortisol with loss of circadian rhythm and increased excretion of 17-KS and 17-OHCS in urine. Diagnosis of adrenal hyperplasia was made on the basis of the metyrapone test and the rapid combined test in which responses of serum cor tisol to 1 mg of dexamethasone p.o., synthetic ACTH i.v. and 4 mg of dexamethasone p.o. were determined. In 3 recent cases, serum ACTH was determined. In order to diagnose pituitary dependency in Cushing's syndrome, the most reliable findings is by no means a high level of serum ACTH unless an ectopic ACTH secreting tumor is found. Positive metyrapone test was also indicative of pituitary etiology in our series. 2.71Negative re sults in the dexamethasone suppression test and ACTH stimulation test did not totally exclude a possibility

of pituitary

etiology.2,47.231 In the

Pathological studies Basophilic adenoma was verified in 2 patients, Case 3 and 4. The patient of Case 3 underwent a stereotaxic thermocauterization which was fol lowed by a gradual improvement of en docrinological abnormalities, but he finally died of massive duodenal bleeding. It was found at autopsy that the pituitary gland was totally fibrotic except in a tiny area in the anterior and superior aspect where clusters of basophilic adenoma cells were found (Fig. 4). In addition, hyperplasia of the bilateral adrenal cortex was confirmed. The patient of Case 4 was of basophilic mi croadenoma which was surgically removed by transsphenoidal approach (Fig. 5). An encap sulated basophilic adenoma was demonstrated by histological examination. Crookes's de generation was not noted (Fig. 6). In Case 5, the tumor was partially well de marcated under the operating microscope but histological diagnosis was hyperplasia of baso philic cells with Crooke's degeneration. Tumor was not verified in Case 1 and 2 in which the patients underwent a stereotaxic ther mocauterization. The stereotaxic thermocauterization was per formed on 3 patients. In Case 1, this was done for recurrence of Cushing's syndrome after uni lateral adrenalectomy and irradiation to the contralateral adrenal gland. A temporary relief was obtained clinically and this patient had the remaining adrenal removed later. In Case 2, irradiation to the adrenal gland preceded the stereotaxic procedure. in the clinical status was obtained

A fair relief for 4 years

postoperatively and then the disorder recurred. Case 3 was at an advanced stage of the disease

Table

3

Principal

clinical

and endocrinological

data

in 5 patients

with

Cushing's

disease

Histology: U = unverified; B. adenoma = basophilic adenoma; B. Hyperpl. = basophilic hyperplesia. Adrenal scan : Bi. Hyp. =bilateral hyperplasia. Treatment : A = adrenalectomy ; R = irradiation to the pituitary; St = stereotaxic thermocauterization ; AR = irradiation to the adrenal ; Sp = transsphenoidal surgery. 17-KS and 17-OHCS : mg/day. Dexa. Suppr.: with 1 mg dexamethasone. Serum cortisol : µg/dl. Serum ACTH : pg/ml.

Fig. 3 Adrenal venogram and adrenal scan in case 4 with Cushing's disease. Left : Left adrenal venogram showing adrenal hyperplasia. Right : Adrenal scan (posterior view), 8 days after the injection of 131adosterol 600/CI, showing an increased uptake on both sides.

Fig. 4 tained

Photomicrograph at autopsy

of the pituitary

in Case

gland

3 with Cushing's

ob

disease.

Upper: Photomicrograph of the sagittal section of the pituitary gland showing fibrotic change of the whole gland;

arrows

indicate

cells. Mallory-Heidenhein Lower

left : Cluster

Heidenhein Lower

right:

Heidenhein

azan

stain, stain,

of basophilic

stain,

of basophilic

Cluster azan

clusters azan

x 9.

cells.

Mallory

cells.

Mallory

x 400. of basophilic x 800.

and a major surgical procedure was not feasible. On the basis of a temporary effect by irradiation to the pituitary gland, the stereotaxic procedure was performed with a gradual decrease in serum cortisol at 9 a.m. from 31-73 to 16 ug/dl. The patient died of uncontrollable duodenal bleed ing. In Case 4 and 5, the transsphenoidal subtotal removal of the anterior pituitary glands were performed with removal of microadenoma of 4 mm in diameter in Case 4 and adenomatous tissue in Case 5.

Fig. 5

Case

Left :

4 with

Magnified

Cushing's

disease.

operative

view

of

a microad

enoma. Right: Illustration =microadenoma =the

normal

=suction

of the operative view. M herniating out of the gland;

pituitary

gland;

Sp =speculum

P ; S

tube.

An excellent recovery was obtained clinically as well as endocrinologically in Case 4 (Fig. 7). Menstrual periods were resumed and other pituitary function tests showed a low range of the normal, and the rapid combined test was also normalized. Serum ACTH decreased from 400 down to 20 pg/ml. In Case 5, a partially well demarcated adeno matous tissue was removed. No definite tumor tissue was found but basophilic hyperplasia with Crooke's hyaline degeneration. However, clini cal and endocrinological improvements were noted and the basal levels of serum cortisol and ACTH decreased. The patient died of cerebral infarction of undetermined etiology. Autopsy was not permitted. Forbes-Albright syndrome There were 4 cases in our series which fulfilled the criteria of this syndrome (Table 1).Diagnosis was made on the basis of the clinical symptoms, namely, amenorrhea and galactorrhea, and ele vated serum prolactin level. There was no visual problem in 2 patients while transient blurring of vision was observed in one. In the plain skull films, a double floor of the sella turcica without enlargement was noted in 2 patients while slight enlargement was seen in 2. Initially, 3 patients did not want surgical procedure because of undisturbing symptoms and unwillingness to have another child. We

Fig. 6

Photomicrograph

of microadenoma

4 with

Cushing's

Upper

: Photomicrograph

of microadenoma

ing an encapsulated basophilic cell Mallory-Heidenhein azan stain, x 80. Lower

left : Note

around

the tumor.

Mallory-Heidenhein Lower

right:

No

Mallory-Heidenhein

in Case

disease.

a capsule azan Crooke's azan

of connective stain,

tissue

x 400.

degeneration stain,

show tumor.

is noted.

x 800.

were also reluctant to do surgery, except on one patient with slight sellar enlargement. This pa tient, however, refused any further procedures. After two years of follow-up, the patient was seized with a pituitary apoplexy associated with an intracerebral hematoma in the right frontal lobe. By subfrontal approach the intracerebral hematoma was removed and the ruptured ch romophobe adenoma was also removed intrac apsularly elsewhere. Transsphenoidal surgery was performed on one patient and a chromo phobe adenoma extending into the sphenoid sinus was totally removed. Discussion The objectives of therapy in pituitary ade nomas have long been the treatment of visual

Fig. 7

Photographs

of the patient,

Left : Preoperative Right:

Postoperative

photograph 6 months

problems. Particularly, subfrontal surgical pro cedure was indicated to patients with visual field defect and irradiation therapy, either external or internal, was given to patients who were free from visual problems.

Stereotaxic thermocauterization3 5) or cryo coagulation27) was performed on patients with diabetic retinopathy or advanced breast cancer in order to obtain functional ablation of the pituitary gland. These procedures were also ap plied to patients with acromegaly or Cushing's disease.27.36) However, none of the above cited procedures were specific in the treatment of functioning pituitary adenomas and were either insufficient in lowering abnormally high hormone level or excessively destructive as they caused panhy popituitarism, diabetes insipidus and cranial nerve injuries. What are the ideal objectives in the treatment of the functioning adenoma? If defined, they would include the following : 1) Correction of abnormally high hormone level ; 2) Eradi cation of the tumor; 3) Correction of hy popituitarism; and 4) Avoidance of perma

Case

4, with

Cushing's

disease.

of the patient. showing

an excellent

recovery.

nent endocrine deficiency and dependency on medication. As a promised procedure which could fulfill these objectives, the subnasal transsphenoidal surgery under microscope and with televised X-ray fluoroscopic control was introduced . Promising results have been reported.', 9,10, 13,21,34) External irradiation has also been reappraised on the basis of direct measurement of various hormones by radioimmunoassay.30,32) Pituitary adenoma with acromegaly From our experience, out of 7 subfrontal procedures only two were free from com plications, while those complications were rather rare in non-functioning chromophobe adenomas. Presumably, this is related to the liability to metabolic derangement due to abnor mally high circulating GH level and to the difficulty in dissecting the tough tumor tissue with fibrosis and to the hypothalamic derange ment caused in an attempt to eradicate the functioning tumor cells. Clinical improvements were obtained in 3 out of 7 and the lowering of

GH was not sufficient as far as judged from the clinical state, although measurement of GH was not available in this group. In comparison with the subfrontal approach, the subnasal transsphenoidal approach is a far more favorable procedure, and, even with the aid of operating microscope, the subfrontal ap proach should be indicated only to patients with huge extensions above the sella or in the frontal or temporal fossa. In most of our cases, a conventional irradi ation therapy was given after surgical removal of the tumor, and in most of the cases the basal level of GH remained moderately high within 3 months after the treatment. In 2 patients, the basal level of GH further decreased 2 to 3 years after the treatment. In 2 patients who were given irradiation therapy alone, one with a high basal level of GH (120 ng/ml) before irradiation re sponded to some extent (84 ng/ml) while the other with a moderately high basal level of GH (31 ng/ml) did poorly. From these results, it may be concluded that the irradiation therapy alone is effective in lowering the basal level of GH slowly with in 6 months to 3 years after the therapy but often is not effective in eradicating the tumor cells. The results were in agreement with others' 0,21,34) and we consider conventional irradiation ther apy as an adjunct of surgical removal. Heavy-particle therapy is certainly another benign and promising treatment according to Kjellberg et al.") and Lawrence et al.,20) but again it requires a relatively long period of time to become effective. Also, because of its un selective nature, it is not recommended to pa tients with suprasellar extension. In addition, its availability is very limited at present. As far as the postoperative basal level of GH is concerned, our results of treatment were by far satisfactory (Fig. 2). The goal of the treatment is set at the basal level of GH below 10 ng/ml by many authors,9,1o,13)and it is below this basal level of GH that metabolic improvements are expectable. One reason why our results were poor, was that our cases were advanced with enlargement of the sella and with suprasellar extension or were of invasive types, and the median duration of acromegaly was much over 6 years ranging from 6 months to 23 years. Another reason is our reluctance of doing a total hypophysectomy.

In fact, most of the ideal therapeutic results were obtained in cases with microadenoma or in trasellar adenoma without sellar enlargement in other series.' 0,13) In none of our cases the tumor was clearly demarcated against the normal pitu itary gland except for the posterior lobe. Accord ingly, a radical hypophysectomy appeared to be rational in order to achieve an ideal lowering of the basal level of GH. A "superradical" pro cedure with an application of protein coagulant in the pituitary fossa should be seriously con sidered in cases with a recurrent tumor or with a tumor demarcated poorly from the dura. We have applied 70 alcohol in an attempt to eradicate the tumor cells in the patient with gigantism and acromegaly at the time of re operation for recurrence, but the basal level of GH remained moderately high in the immediate postoperative month. In this case a pharyngeal hypophysis with adenoma could be responsible for persisting secretion of GH.29) On the other hand, our results indicated that even with these insufficient lowering of the basal level of GH, clinical and metabolic improve ments were obtained in a very good percentage of the cases, and, in addition, only one third of the patients required replacement of hormones. Furthermore, in 3 out of 7 preclimacteric pa tients the menstrual function was maintained. Even with such acceptable clinical results, the life expectancy of these patients with persistent secretion of moderately high GH should be studied for a longer period of time before final decision is made as to whether the treatment should be more radical or not. At present, in the treatment of rather advan ced tumors as in our series, we advocate that radical surgery should be applied to the patients with advanced diabetes mellitus21) and or hyper tension. Radical surgery should also be in dicated reasonably to the patients after climac terium or the patients who could withstand sterility. The results of the endocrinological studies in regard to the hypothalamic regulation of the GH secretion were varying and ambivalent, so were the reports by others.' 1,22) The responses to insulin-induced hy poglycemia were noted in all the active acrome galics, in which the GH-secretory stimuli were mediated via the hypothalamus. The sup pression

by L-dopa

noted

in patients

examined

also was an indication of the hypothalamic con trol. Bromocryptine (CB 154), a dopaminergic receptor stimulant, suppressed the GH sec retion, and the TRH injection stimulated the GH secretion in all the active acromegalics stud ied, while, in the normal subjects, the responses to these stimuli were reverse. Apparently, the mechanism of the GH sec retion in acromegaly is different from that in the normal subjects. Although it is beyond the scope of this com munication to discuss the issue in detail as to whether the hypothalamus or the pituitary gland is the primary site of the derangement, the issue has a certain therapeutic implication. Our data and the reports have been contradictory' ` 11,13,14,18,22,35) and solution to the problem may not be available until determination of the GH releasing and inhibiting hormones is established. On the other hand, the endocrinological studies before and after removal of microadenoma favor the autonomous function of the ade noma, 10.13,14>and the accumulation of such studies on the patients with microadenoma trea ted successfully without recurrence is valuable for better understanding of the etiology of the functioning pituitary adenoma. Here is another reason why an early diagnosis and treatment should be stressed. Cushing's disease In the treatment of Cushing's syndrome, our experiences, though limited in number, deserve special comments in view of reappraisal of pitu itary origin of this syndrome. It is well known that the majority of Cushing's original patients had pituitary adenomas with adrenal hypertrophy presenting remarkable clinical features due to hypercorticism.3) How ever, because most of the patients found sub sequently did not have sellar enlargement, pituitary-dependent Cushing's syndrome has been considered to be a rather rare condition, and, on the basis of the hypothalamic pathology as seen in such cases and the hypothalamic regulation of ACTH secretion, the hypothalamic origin of pituitary dependent Cushing's syn drome has been emphasized. In addition, the primary adrenal pathology was found to be responsible for the syndrome in many cases, subsequently the target organ in the treatment has become primarily the adrenal

gland and the pituitary origin seemed to have been ignored until recently. Particularly in Japan, there have been few reports on the treatment of Cushing's disease by hypophysectomy, and bilateral adrenalectomy has been regarded as the treatment of choice for Cushing's syndrome except in cases with an ectopic ACTH secreting tumor. In recent years, there have been increasing reports on the treatment of pituitary-dependent Cushing's syndrome (Cushing's disease) by the stereotaxic or surgical hypophysectomy in the European and North American literatures. Clinical studies indicate that 60 to 90 % of the cases of Cushing's syndrome are due to adrenal hyperplasia with pituitary adenoma (70 %) and with basophilic hyperplasia (30 %)2.25)and the condition is curable by either removal of the adenoma or hypophysectomy.4,7,13,17,29) Also remarkable on one hand is the progress of evaluation of pituitary dependency in Cushing's syndrome since the advent of radioim munoassay, particularly of ACTH. The radio isotopic scanning and angiography on the other hand have enabled us to make the diagnosis of adrenal hyperplasia with reliable accuracy. Since 1960, we have treated 5 patients with various modes of hypophysectomy. All the pa tients responded more or less to the treatment. Conventional irradiation resulted in only a slight and temporary lowering of the serum ACTH level. Apparently, as reported by others, basophilic adenoma is refractory to conven tional irradiation. Stereotaxic thermocauter ization was performed on 3 patients with a gradual fall in the ACTH levels, and was fol lowed by recurrence in 2 to 4 years in 2 patients. One patient died of duodenal bleeding 2 months after hypophysectomy. At autopsy a nearly com plete fibrosis of the pituitary gland was observed but there was a tiny cluster of basophilic cells. These cells could have been responsible for the persistent slight elevation of serum ACTH in this patient, and would have grown resulting in recurrence, should the patient have survived. Recurrence in 2 other patients may also be attributed to an incomplete eradication of baso philic cells or tumor as was found in Case 3. Apparently, it was not the selection of the target organ that was responsible for the un favorable results in these patients but the in adequacy of the procedure performed.

Transsphenoidal surgery was performed on two patients. In Case 4, the removal of the microadenoma with subtotal anterior hy pophysectomy resulted in an excellent recovery with normalization of the endocrine disorders. In Case 5, lowering of the serum ACTH level was gradual after subtotal removal of the ante rior pituitary gland including a partially de marcated adenoma-like tissue. Histological examination disclosed the tissue to be basophilic hyperplasia with Crooke's degeneration. In this case, the hypothalamic dysregulation could be a possible etiologic factor which would justify a radical anterior hypophysectomy. Presence of a highly set circadian rhythm of the serum cortisol level in this patient may substantiate this specu lation, but the results of endocrinological studies in other patients such as loss of circadian rhythm, ineffective suppression by L-dopa did not favor a hypothalamic control of ACTH secretion in Cushing's disease. Successful treat ment with removal of the microadenoma in Case 4 implied a pituitary origin of the syndrome with autonomous functions of adenoma. Reports on the recurrence have been rare after trans sphenoidal or transethomoidal total hypo physectomy or even after removal of micro adenoma',',' 1,17,29) after which procedure recurrence should have been inevitable if the hypothalamus was primary in etiology. This also is true in the treatment of Nelson's syndrome. There have been reports on the suc cessful treatment by a selective removal of aden oma with preservation of the normal pituitary function and recurrence has been rarely reported in these cases.' 13) This fact and the similarities in the pathologi cal and electron microscopic findings of adeno mas found in Nelson's syndrome and Cushing's disease substantiate the speculation that Nelson's syndrome may primarily well be Cushing's disease. More than one etiology may be possible. A hypothalamic derangement may be responsible for the initiation of development of adenoma or adenomatous hyperplasia. There are, however, ample evidences which favor a pituitary etio logy.' 7) From our results, it may be concluded that in pituitary-dependent Cushing's syndrome trans sphenoidal removal of microadenoma, when present and even without sellar enlargement, or

hypophysectomy should be the initial treatment of choice. There is a good chance of cure of the disorder with restoration of the normal pituitary function. It should also be emphasized that even if hypopituitarism develops after surgery it is more benign and more easily controllable con dition than the adrenal insufficiency which is often life threatening and inevitable after bilater al total adrenalectomy.2) Forbes-Albright syndrome From our limited experience, we would like to comment only on the indication of therapy of this condition. We have been rather reluctant to give any surgical procedure or irradiation to those patients with minimal distress until we encountered the patient of Case 3 in whom a pituitary apoplexy developed after two years of observation. Increasing evidences indicated that about one-third of chromophobe adenomas were associated with hypersecretion of prolactin with infrequent galactorrhea. Forbes-Albright syndrome with or without sellar enlargement may appear at an early stage of chromophobe adenoma. It should be the ideal stage for treat ment in order to preserve the normal pituitary function. Follow-up studies of non-treated pituitary adenomas31> justified early treatment from the fact that about 80 % of the patients developed compression signs later. Because of its benign nature, transsphenoidal surgery is the most ideal procedure. Conclusion In the treatment of the functioning pituitary adenoma, transsphenoidal microsurgical pro cedure is the treatment of choice, because of its benign and selective nature. In advanced tumor and fibrotic tumor with acromegaly, subtotal removal of the tumor rarely resulted in an endocrinological cure and radical hypophysectomy is recommended to the patients with advanced hypertension and/or diabetes mellitus and to the patients after cli macterium. In the patients with pituitary-dependent Cushing's syndrome, the primary treatment should be directed to the pituitary gland even without the neuroradiological evidences of pitu itary adenoma. Transsphenoidal removal of

microadenoma may result in an endocrinologi cal cure with the normal pituitary function. Forbes-Albright syndrome without visual manifestation should be regarded to be at an ideal stage for treatment of pituitary chromo phobe adenoma (microadenoma) and an en docrinological cure with restoration of the nor mal pituitary function may be obtained by transsphenoidal removal of microadenoma.

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Acknowledgements The authors are greatful to Drs. A. Shirouzu, T. Nakashima, K. Inoue and T. Omae, the 2nd Department of Internal Medicine, and Dr. N. Watanabe, Department of Pediatrics, and staff of Department of Radiology (Director : Dr. K. Matsuura), Kyushu University Hospital, for their clinical, radiological and endocrinological evaluation of the patients, and also to Drs. S. Toyoshima and M. Enjoji, the 2nd Department of Pathology, Kyushu University, for autopsy study of patients with Cushing's disease.

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