The Clinical and Endocrine Outcome to Trans-

Sphenoidal Microsurgery of Nonsecreting

Pituitary Adenomas
Ronald Comtois, MD, Hugues Beauregard, MD, Maurice Somma, MD,
Omar Serri, MD, PhD, Nahla Ark-Jilwan, MD, and Jules Hardy, MD

From 1962 to 1987,126patients underwent trans-sphenoidal surgery for primary

treatment of pituitary adenomas unassociated with clinical or biochemical evidence
of hormonal overproduction. There were 73 male and 53 female patients (mean age,
50 f 12 years). Before surgery, 56% of the patients (70of 124) had headaches, 74%
(94of 126)had deterioration of vision, and 12% (15of 126)had ophthalmoplegia.
Endocrine evaluation revealed the presence of hypogonadism in 75% (87of 115),
adrenal insufficiency in 36% (46of 126),and hypothyroidism in 18% (21of 122).
Plasma prolactin was increased in 65% (56of 86)with a mean level of 39 k 14 pg/l
(normal, 3 to 20 pg/l). Radiologic enlargement of the sella turcica was documented
in all cases: 67% (84of 126)had enclosed and 33% (42of 126) had invasive
adenomas. After surgery, vision was normalized or improved in 75% (71 of 94)of
the patients. Thyroid, adrenal, and gonadal functions were improved in 14% (three
of 22),41/' (19of 46),11% (ten of 87), were unchanged in 82% (100of 122), 77% (97
of 126),89% (102of 115),and worsened in 15% (19of 22), 8% (ten of 126),3% (102of
115),respectively. Permanent diabetes insipidus occurred in 5% (seven of 126). Two
patients died during the immediate postoperative period. The recurrence rate in
patients with a mean follow-up of 6.4 k 4.2 years was 21% (15 of 71). These data
indicate that trans-sphenoidal microsurgery is an effective and safe initial
treatment for patients with nonsecreting pituitary adenoma and may reverse
hypopituitarism. Cancer 68:860-866,1991.

T UMORS OF THE ANTERIOR PITUITARY gland are not

rare. In the United States, physicians discover about
2500 new cases each year.' Of all hypophyseal tumors,
60% to 75% are adenomas, and of these, almost 18%(238
of 1324) were nonsecreting adenomas in Hardy's series
(personal communication). However, little has been writ-
ten about the effectiveness of trans-sphenoidal surgical
treatment of nonsecreting pituitary adenoma. We report
the outcome of patients with nonsecreting pituitary ade-
noma treated with trans-sphenoidal microsurgery at our
institution.
From the Departments of Medicine and Neurosurgery, Notre-Dame
Hospital, University of MontrCal, MontrCal, Canada.
The authors thank Mrs. Joanne Auclair for her secretarial assistance
and Fran Lowry for editing the manuscript.
Address for reprints: Ronald Comtois, MD, Notre-Dame Hospital,
1560 Sherbrooke East, Montreal, Quebec, Canada H2L 4M1.
Accepted for publication January 16, 1991.
Material and Methods
The records of 126 consecutive patients, who under-
went trans-sphenoidal surgery at Notre-Dame hospital for
the unique initial treatment of nonsecreting pituitary ad-
enoma from 1962 to 1987 were reviewed to evaluate the
effectivenessof this procedure. Trans-sphenoidal surgery
using the surgical microscope and the televised radiofluo-
roscopic control has been described in detail previously.2
Radiation therapy was administered to seven patients only
after a second trans-sphenoidal procedure where a recur-
rence of their adenoma was documented histologically.
Nonsecreting pituitary adenoma was defined as surgi-
cally and histologically proven adenoma without clinical
and biochemical evidence of hormonal overproduction
and without significant immunostaining for growth hor-
mone (GH), prolactin (PRL), adrenocorticotropin
(ACTH), follicle-stimulating hormone (FSH), and lutein-
izing hormone (LH) (when available). In each of the nine
patients with plasma PRL value above 50 pg/l (normal,

860
No. 4 MICROSURGERY
OF PITUITARY ADENOMAS - Corntois et al. 86 1

3 to 20 pg/l), a negative PRL immunostaining of the ad-
enoma cells was obtained to maintain the diagnosis of
nonsecreting adenoma. In each patient, the basal GH lev-
els were less than 5 pg/l (normal, < 5 pg/l).
Endocrine studies included basal evaluation and dy-
namic testing of the pituitary-gonadal, pituitary-adrenal,
and pituitary-thyroidal axes. An insulin tolerance test was
done by administering intravenous (IV) soluble insulin
(0.05 to 0.2 U/kg) to induce adequate hypoglycemia
(serum glucose, < 2.4 mmol/l and < 50% of the basal
level). Plasma PRL levels were measured in response to
IV thyroid-releasing hormone (TRH, 400 pg) or during
insulin-induced hypoglycemia. The pituitary-gonadal axis
was evaluated by measuring basal serum testosterone and
estradiol- 17B together with the determination of both FSH
and LH after IV gonadotropin-releasing hormone ad-
ministration (100 pg). Serum and urine cortisol were also
measured; oral metyrapone test or cortisol response to
insulin-induced hypoglycemia were used to evaluate the
ACTH reserve. Pituitary-thyroid axis was evaluated by
measuring serum thyroxine (T4)and triiodothyroxine (T3)
together with thyroid-stimulating hormone (TSH) deter-
mination after TRH stimulation. The following criteria
were used to define pituitary hormone deficiency.
A deficiency in gonadotropin secretion in men was di-
agnosed when the plasma testosterone was subnormal
(< 10.5 nmol/l; normal, 10 to 35 nmol/l) and associated
with low or low normal plasma gonadotropin levels
(< 15 IU/l; normal, 3 to 25 IU/l). In premenopausal
women, this was diagnosed when the plasma gonadotro-
pins were low or low normal (< 15 IU/l; normal, 3 to 25
IU/1) together with low estradiol levels (< 110 pmol/l;
normal follicular phase, 220 to 440 pmol/l). In post-
menopausal women, a deficiency of pituitary gonadotro-
pin secretion was diagnosed when the plasma levels of
these hormones were low for age (FSH, < 30 IU/l; LH,
< 30 IU/l; postmenopausal normal, 40 to 140 IU/l) and
associated with hypoestrogenemia.
Deficiency of pituitary ACTH secretion was diagnosed
when urine and plasma cortisol levels were clearly low
(normal, 165 to 695 nmol/l) or when plasma cortisol did
not increase to 540 nmol/l or more during the insulin
tolerance test. In patients tested with metyrapone, ACTH
deficiency was diagnosed when the rise in serum 1 1-deox-
ycortisol was less than 180 nmol/l, and serum cortisol
decreased to less than 160 nmol/l after metyrapone ad-
ministration.
Hypothyroidism was diagnosed when a subnormal
serum T4 level (< 60 nmol/l; normal, 60 to 160 nmol/l),
together with a low level of serum T3 (< 1.2 nmol/l; nor-
mal, 0.8 to 2.7 mmol/l) were associated with a low normal
TSH level (< 5 mU/l; normal, 0 to 5 mU/1) in the absence
of severe nonthyroid illnesses or of medication known to
interfere with thyroid tests.

100

9311 19
80

v)
I-
z
60 70/124
5 1/94

d
LL
0
W
a 40
2z
W
0
K
w
n 20
15/126
10/126
61126

0
VISUAL FIELD
- HEADHACHES VISUAL ACUITY
-I-

OPHTHALMOPLEGIA APOPLEXY CSF

DEFECTS REDUCTION RHINORRHEA

FIG. 1. Presenting neuroanatomic symptoms in 126 patients with nonsecreting pituitary adenoma.
862 CANCERAugust 15 199 1
Antidiuretic hormone secretion was considered defi-
cient in dehydrated patients who had a high volume of
inappropriate low urine osmolality that increased signif-
icantly after vasopressin admini~tration.~
The diagnosis of GH deficiency was based on a peak
GH concentration less than 4 pg/l on two stimulation
tests. However, because only a few patients in this series
have had two provocative tests of GH secretion, the in-
cidence of GH deficiency could not be assessed.
All hormones were measured in duplicate using com-
mercial radioimmunoassay kits obtained from Immu-
nocorp (Montreal, Canada). The interassay coefficients of
variation were all less than 12%. Neuroradiogic studies
included plain radiography of the skull, sellar polyto-
mography, polytomographic pneumoencephalography,
selectivecarotid arteriography, and computed tomography
(CT) with contrast enhancement. Since 1978, magnified
CT reconstructions of the sella region in two planes have
been used for diagnostic scanning assessments. After cor-
relation of the neuroradiologic, operative, and pathologic
findings, the adenomas were classified according to the
amount of sellar destruction (grade) and suprasellar ex-
tension (stage), according to Hardys classification.2
Neuroophthalmologic evaluation included funduscopy.
Visual field and acuity assessments were done before and
a few weeks after surgery. Visual acuity was measured
after refraction. Central and peripheral visual fields were
performed on a Goldmann perimeter. The visual field
was scored by allocating 12.5%for each quadrant of vision.
The final score was obtained by adding the eight per-
centages of both eyes (a normal score was 100%).The
visual acuity score resulted from the mean of visual acuity
assessment of both eyes expressed as a percentage.
The recurrence rate was based on the 71 patients who
were followed for more than 1 year. Before 1978, poly-
tomographic pneumoencephalography and pathologic
findings at surgery confirmed the recurrence of adenoma
in six cases. In eight patients whose follow-up ended before
1978, the absence of recurrence was based on the absence
of symptoms and of sellar polytomographic findings
suggestive of recurrence. Since 1978, the CT scan has been
used for the diagnosis of pituitary adenoma recurrence.
Statistical Analysis
The data are expressed as means & standard deviation
of the means. They were analyzed with Students t test,
the chi-square test, and Pearsons correlation techniques.
Clinical Aspects
Age and sex: The age distributions of the 73 male and
53 female patients did not differ significantly. The age at
diagnosis ranged from 10 to 79 years. The mean age was
49 years for female patients and 5 1 years for male patients;
Vol. 68
79% of the patients were between the ages of 30 and 59
years.
Neuroanatomic symptoms: At the time of the initial
examination, the most frequent symptoms were related
to visual function (Fig. 1). Of the 93 patients who had
visual field defects, 50 (54%)had bitemporal hemianopsia,
17 (1 8%) had lateral hemianopsia, 14 ( 1 5%) had bitem-
poral quadranopsia, seven (8%)had lateral quadranopsia,
and five (5%) had combined abnormalities. Visual acuity
reduction was found in 54%(5 I of 94) of cases. Blindness
of one eye was noticed in 33 patients (65%), and total
blindness was found in three (6%). Other abnormalities
in visual acuity were present in 16 (3 1%).Of the 15 pa-
tients who had an ophthalmoplegia, nine (60%) had a
third nerve cranial palsy, and three (20%)had a fourth or
a sixth cranial nerve palsy.
Fdiy-eight patients had headache. The location was frontal
in 3 1 cases (53%),retroorbital in 13 (22%),temporal in eight
(14%), and other in six (1 1%). At presentation, pituitary
apoplexy occurred in 15 patients (12%) and spontaneous
cerebrospinal fluid rhinorrhea in six (5%).
Endocrine evaluation:At the time of the initial pituitary
function study, 34 (27%)patients had no deficiency, and
14 ( 1 1%) had simultaneous deficiencies in FSH-LH,
ACTH, and TSH. The most common hormone deficiency
present in these patients was FSH-LH. Of the 105 patients
who had gonadal function tests, 87 (75%) had hypogo-
nadism. Forty-six of 126 patients (36%)had adrenal hy-
pofunction, and 22 of 122 (18%) had hypothyroidism.
There were five cases of inappropriate secretion of anti-
diuretic hormone, and two cases of diabetes insipidus
(Fig. 2).
At the time of diagnosis, the plasma PRL ranged from
2 to 75 pg/l. In the 86 cases in which it was measured,
the mean PRL level was 29 k 18 pg/l (normal, 3 to 20
pg/l). The plasma PRL was greater than 20 pg/l in 56
patients (65%)with a mean level of 39 k 14 pg/l. Female
patients had higher PRL level than male patients (37
k 18.7 versus 20 & 17.8 pg/l, P < 0.001). In six of the 13
cases where initial serum PRL was less than 10 pg/l, a
pituitary apoplexy was found during surgery.
Radiologic evaluation: Enlargement of the sella turcica
was documented radiologically in all cases. Eighty-four
patients (67%) had enclosed and 42 (33%) had invasive
adenomas. As summarized in Table 1, all except one case
had a macroadenoma. Mean suprasellar extension was
14 k 6.1 mm.
Results
Surgical Procedures
The 126 patients included in this study underwent a
total of 146 trans-sphenoidal operations, including I3 for
a first and seven for a second recurrence. An adenoma
No. 4 MICROSURGERY
OF PITUITARY
ADENOMAS * Comtois et al. 863

too
102 115 112 126

100 122 m
80
971126
m
5ff

- NORMALIZED
UNCHANGED
71% WORSENED

60

40

e
20 191122

7/126

0
FSH-LH ACTH TSH ADH
FIG.2. Postoperative pituitary, gonadal, adrenal, thyroidal, and antidiuretic function in 126 patients with nonsecreting adenoma. *The increase
of hypothyroidism incidence after trans-sphenoidal microsurgery is significant (P < 0.0 1).

was documented in each procedure except in four cases, after surgery in the visual field and visual acuity scores
where only necrotic tissue was found. Total resection of (68% versus 87%, P < 0.001; 66% versus 7596, P < 0.01,
the adenoma was done in 102 cases at the first operation, respectively). Fourteen of the 15 cases with ophthalmo-
as judged by the surgeon. plegia recovered completely. One patient with a third cra-
All complications occurring postoperatively, through- nial nerve palsy improved but still was not normalized 1
out the follow-up period (average duration, 6.4 +- 4.2 year after surgery.
years), were compiled. Of the 146 operations evaluated, Thyroid, adrenal, and gonadal functions were nor-
one or more postoperatively complications occurred in malized in 14%(three of 22), 4 1% ( 19 of 46), 1 1% (ten of
42 patients (29%, Table 2). Of two postoperative deaths, 87), unchanged in 82% (100 of 122), 77% (97 of 126),
one was related to surgery; this patient had a postoperative 89% (102 of 1 IS), and worsened in 15%(19 of 122), 8%
cerebrospinal fluid leak followed by intractable meningitis. (ten of 26), 3% (three of 1 1 9 , respectively. There was no
significant change after surgery in the mean quantity of
Pathologic Findings the different hormonal deficiencies (1.3 -+ 1.05 versus 1.2
Of our 126 patients, 88 (70%)had a nononcocytic ad-
enoma, and 30 (24%) an oncocytic adenoma. Four (3%)
had necrotic tissue, and two (1.5%) had ACTH and GH TABLE1. Distribution of Tumor Grade and Stage in I26 Patients
With Nonsecreting Adenoma*
silent adenomas, respectively.
Tumor stage
Clinical and Endocrine Outcome
Tumor grade 0 A B C D Total
After surgery, the neuroanatomic symptoms were im-
Enclosed
proved. Of the 70 patients who complained of headaches I (microadenoma) I - - - - 1
before surgery, 64 (90%)had complete relief. Visual acuity I1 (macroadenoma) 3 15 38 24 3 83
and visual fields were normalized in 18% (17 of 94) and lnvasive
Ill (locally) 2 4 11 4 - 21
44% (52 of I18), improved in 38% (36 of 94) and 38% IV (diffusely) 1 1 1 0 9 - 21
(45 of 1 18), unchanged in 38% (36 of 94) and 18%(21 of
Total 7 20 59 37 3 126
I18), and worsened in 5% (five of 94) and 2% (two of
I 18), respectively. There was a significant improvement * Pituitary adenoma distribution according to Hardys classification.
864 August 15 199 1
CANCER Vol. 68

TABLE2. Postoperative Complications of Trans-Sphenoidal Surgery jective loss of vision and often loss of Most of
in 126 Patients With Nonsecreting Adenorna* these tumors occurred in middle-aged patients. Gonad-
Complications No. of cases otropins are impaired in most cases. However, our data
challenge the conventional order of appearance of target
Patients requiring gland failure. I Adrenal hypofunction was found more
9

transfusion 16 (12.7)*
Hyponatrernia 12 (9.5)
Diabetes insipidus,
permanent 7 (5.6)
Septa1 perforation 7 (5.6)
Cerebral fluid leak 6 (4.8)
Cranial nerve palsy 2 (1.6)
Graft site infection 2 (1.6)
Meningitis 2 (1.6)
Death 2 (1.6)
Sinusitis 2 (1.6)
Stornatitis l(0.8)
Graft site hernatorna 1 (0.8)
* Percentages are given in parentheses to facilitate comparison with
other published data.
+_ 1.19). Only the incidence of hypothyroidism was mod-
ified significantly (increased) after trans-sphenoidal mi-
crosurgery (P< 0.01) (Fig. 2). During the postoperative
period, transient diabetes insipidus occurred in 30% (38
of 126) of cases; permanent diabetes insipidus occurred
in 5% (seven of 126).
Long- Term Follow-Up Review
Seventy-one patients had a follow-up of 1 year or more.
Based on clinical and radiologic data, the recurrence rate
was 21% (15 of 71) with a mean follow-up of 6.4 k 4.2
years (range, 1 to 16 years; Fig. 3). There was no statis-
tically significant difference in duration of follow-up be-
tween patients with recurrent disease (6.3 +- 2.9 years)
and those without recurrence (6.4 k 4.6 years). Figuw 4
illustrates the I5 patients who had a recurrence. Of these,
seven (46%) had a second recurrence 7.6 k 4 years after
the first one. This high second recurrence rate occurred
after a more aggressive second surgery followed by radia-
tion therapy in five of these seven patients. In the eight
cases who did not have a second recurrence, radiation
therapy was given in only two cases.
Recurrence was observed more frequently with invasive
tumor. Thirty-three percent (eight of 24) of the invasive
adenomas (tumor Grades 111and IV) recurred versus 15%
(seven of 47) of the enclosed adenomas (P< 0.05). There
was no relationship between recurrence and age, sex, su-
prasellar extension, and hormonal deficiency.
Discussion
In our series, a typical clinical syndrome could be de-
scribed for the patient harboring a nonsecreting pituitary
adenoma. In agreement with previous studies, the lesion
usually was large enough to produce subjective and ob-
frequently (36%) than hypothyroidism ( 18%).
Plasma PRL was elevated abnormally in most of our
patients (65%). Hyperprolactinemia associated with pi-
tuitary macroadenomas may be caused by the secretion
of prolactin from the tumor. Alternatively, it may result
from the compression of the pituitary stalk or the hypo-
thalamus with consequent reduction of the delivery of
factors that normally inhibit PRL secretion from the pi-
tuitary. Our results strongly suggest that the adenoma
causes hyperprolactinemia by affecting stalk pressure for
two reasons. The first is that the plasma PRL level never
exceeded 75 pg/l. The second is that the characteristics
of these adenomas agreed with those in another study.
These authors studied the relationship between mean
pretreatment levels of serum PRL and the presence of
positive immunostaining for PRL in the pituitary tumors
of 55 patients. They suggested that a macroadenoma
causes hyperprolactinemia by stalk compression when the
serum PRL level is under 125 ,ug/l. By contrast, a low
PRL level was found in 13 of our patients. Of these, six
instances of pituitary apoplexy were observed, suggesting
extensive pituitary damage.
The percentage of surgically related complications
(29%) and deaths (1.3%) in this series of 126 patients cor-
relates with values in other large ~ e r i e s . ~ . ~Postsurgical
*-~
improvement in visual field defects and visual acuity oc-
curred in 82%and 56% of cases, respectively. These results
compare favorably with other pituitary adenoma operative
series, both trans-sphenoidal and transcranial.16 We were
also impressed by the high proportion of ophthalmoplegia
normalization (14 of 15) occurring usually a few days
after surgery. This disagrees with the findings of others,17
who reported that, in 17 of 20 surgical patients, extra-
ocular muscle palsy worsened after treatment, even though
the surgery was followed by radiation therapy in 17 cases.
In most of our patients, hormonal status was not af-
fected by the surgery. By contrast, Arafah reported in a
series of 25 patients with nonsecreting adenoma that, after
surgery, 12 of 2 1 recovered a normal thyroid function,
and six of 16 and eight of 25 had, respectively, normal-
ization of their adrenal and gonadal functions. However,
the definition of hypothyroidism in that study did not
consider the functional thyroid hormone changes related
to hypoadrenalism. Consequently, normalization of ad-
renal status by medication or surgery could normalize the
thyroid hormone levels and be erroneously interpreted as
a hypothyroidism normalization directly related to the
surgery. Furthermore, the long-term outcome was not re-
ported. It is conceivable that a conservative surgical pro-
No. 4 MICROSURGERY
OF PITUITARY
ADENOMAS - Comtois et al. 865

10

0 NO RECURRENCE 56 patlents
W RECURRENCE 15 patients

0
1 3 4 7 8 9 10
n11 12 13 14 15 16

YEARS OF FOLLOW-UP
FIG.3. Incidence of recurrences after a follow-up of more than I year (6.4 +- 4.2 years) in 71 patients who underwent trans-sphenoidal surgery as
the unique initial treatment of nonsecreting adenoma. Recurrence status was defined according to clinical and radiologic findings.

cedure would leave an increased amount of normal pi-
tuitary cells in place and probably also more adenoma
cells. Consequently, a higher recurrence rate could result.
In our study, the recurrence rate after trans-sphenoidal
surgery as the unique initial treatment was 21% after a
mean follow-up of 6.4 k 4.2 years. The recurrence rate
RECURRENCE RATE
71 PATIENTS
in other series ranged from 22% to 7 1%4-6,8*12,'3,15-18after
surgical treatment alone. In this study, the strongest prog-
nostic factor appeared to be the invasiveness of the tumor.
The recurrence rate was not associated with the volume
of the adenoma. This could be because pituitary adenomas
that invade the bone may be more aggressive than those
that expand and induce only compression. An alternative
explanation is that complete surgical removal is more dif-
ficult in invasive than in enclosed adenomas.
The course of recurrent adenomas should be consid-
ered. Seven of the 15 recurrent patients had a second re-

I currence, despite radiation therapy after the first recur-

rence in five and a more aggressive second surgery in all.
There was a higher second recurrence rate in patients re-
ceiving radiation therapy (five of seven) after the first re-
NO RECURRENCE RECURRENCE
56 15 currence compared with those who did not receive this
(7 9 % ) therapy (two of eight). However, no serious conclusion
can be drawn about the difference in the prognosis of
these two groups of patients because radiation therapy
might be given more frequently in patients with a higher
NO RECURRENCE RECURRENCE risk of a second recurrence. Nevertheless, it seems likely
8 7 that some nonsecreting adenomas have, by themselves, a
(53%) (47%)
greater tendency to recur.
FIG. 4. Recurrence rate in 7 1 patients who underwent trans-sphenoidal After postoperative irradiation, recurrence rates vaned
surgery as the unique initial treatment of nonsecreting adenoma, and in from 8%to 21%,5-8,14-'5,18.'9 and this is generally consid-
15 of them who had a recurrence and thereafter were treated by surgery.
Radiation therapy was performed in five of the seven cases with a second ered lower than after surgery alone. However, radiation
recurrence and in two of eight without this event. therapy may produce more adverse sequelae. Radiation
866 CANCER
August I5 199 1
necrosis involving the hypothalamus and optic apparatus
in patients who receive pituitary radiation, although rare,
may be unfortunate. Furthermore, according to Snyder
et al.,*O deficiencies of adrenal, thyroid, and gonadal func-
tion occurred after a mean follow-up of 5 years in 13%,
1370, and 0% of patients who had pituitary surgery alone
and in 67%, 5570,and 67% of patients who had postop-
erative radiation therapy.
In conclusion, trans-sphenoidal selective microsurgical
adenomectomy should be considered the method of
choice for the initial management of nonsecreting pitu-
itary adenomas.
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