A History of Pituitary Surgery

John A. Jane, Jr., MD, Kamal Thapar, MD, PhD, and Edward R. Laws, Jr., MD

For the last 30 years, the transsphenoidal approach has been the
principal corridor for the treatment of pituitary tumors. However,
transsphenoidal surgery did not reach this position in isolation.
Significant contributions in the field of endocrinology and radiology, not only at the time of the first transsphenoidal operations
but also during its resurgence, allowed the procedure to evolve
and later flourish.
Copyright 2002, Elsevier Science (USA). All rights reserved.

he 20th century gave rise to significant technical advances

T in pituitary surgery. These advances, however, did not occur in isolation. Equally significant progress was made in the
fields of endocrinology and radiology. At the turn of the 19th
century, the burgeoning of these fields allowed surgeons to first
recognize the pituitary as a source of disease. The transsphenoidal corridor was used from the very outset of pituitary tumor
surgery but lost favor in the late 1920s. Further evolution of
endocrinology and radiology allowed transsphenoidal surgery
to re-emerge as the first-line treatment for most pituitary tumors.
For this reason, this discussion of the history of pituitary
surgery attempts to describe the context for two different periods: the turn of the last century, at the beginning of pituitary
surgery, and the late 1960s and early 1970s when transsphenoidal surgery experienced its renaissance. The information is not
altogether new. Excellent historical reviews have been written
on these subjects, reviews essential to the writing of this chapt e r . 109,110,137,167,200

Context of the Birth of Pituitary Surgery

Status

of Endocrinology

Existence of the Endocrine System. The 19th century is

marked by the recognition of hormones and the endocrine
system. In 1855 Claude Bernard emphasized that although the
liver produced an external secretion (bile), it also emitted an
internal secretion directly into the blood stream. 334 In the late
1880s von Meting and Minkowski published findings that are
considered the cornerstone of endocrinology.198 These two scientists observed that diabetes did not follow simple ligation of
the pancreatic duct ligation but would occur if the pancreas
were resected. This experiment proved that the pancreas acted
as a "ductless gland." Bayliss and Starling further elucidated the
Department of Neurosurgery, University of Virginia, Charlottesville,VA,
USA and Division of Neurosurgery, University of Toronto, Toronto, Ontario.
Address reprint requests to Edward R. Laws, Jr., MD, Professor of
Neurosurgery, University of Virginia, Health Sciences Center, Box
800212, Charlottesville, VA 22908; el5g@virginia.edu
Copyright 2002, Elsevier Science (USA). All rights reserved.
doi:l 0.1053/otns.2002.32494

200

concept of the hormone at the turn of the 19th century. 12

Glands were known to secrete hormones into the blood and to
have their effect distant to the site of secretion.
Treatment of other endocrine disorders. The context not only
in which the pituitary gland was first recognized as a source of
disease but also in which pituitary disorders may be treated
surgically is significant. Pathology of other glands was recognized before those of the pituitary. The thyroid was the first
endocrine organ whose hypofunction was recognized to cause a
disease. Building on the observations of William Gull and Emil
Kocher in the 1870s, between 1883 and 1886, Felix Semon and
Sir Victor Horsley proved that hypothyroidism caused myxoedema.68,91,92.1os.lo6dm
The recognition of glandular hypersecretion was recognized
only later. Although the clinical description of Grave's disease
was reported in 1835, it was not until 1886 that Paul Moebius
correlated thyroid hyperactivity with exophthalmic goiter. 141
Successful surgeries on the thyroid for goiter had been described since the early to mid 1800s. 4r,1~
The effect of this recognition was profound. Surgeons realized that if one gland could be the source of disease and amenable to surgery, others, namely the pituitary, might as well.
This point is well illustrated by Cushing's opening statements
in his 1909 American Medical Association oration in which,
before discussing the management of pituitary hyper- or hypofunction, he paid homage to the experimental and clinical work
on the thyroid and parathyroid. 3~
Few chapters in the history of medicine tell a more creditable story
than that which relates our progress toward a better understanding
of the thyroid and parathyroid glands.., whose normal activities
prove to be so essential to the maintenance of physiologic equilibrium. Myxoedema, cretinism, exophthalmic goiter.., have come
to be understandable maladies, definitely amenable to rational
methods of treatment- and organotherapy, when glandular activity
is subnormal, or partial surgical removal to correct functional overactivity.

Pituitary as Part of the Endocrine System. At the beginning

of the 20th century, the physiological role of the pituitary was
largely unknown. There had been a long delay in the understanding of the pituitary partly because its inaccessibility made
it difficult to study. The concepts of Galen had persisted from
the second century relatively uncontested until the 1600s. Galen argued that the "pituita" (from the Greek ptuo [to spit] and
the Latin pituita [mucus]) secreted waste products from the
brain into the nasal cavities. Two scientists disproved this concept in the 17th century, Conrad Schneider of Wittenberg and
Richard Lower of Oxford. Using anatomical studies, Schneider
and Lower proved that the pituitary was not fluid filled and that
the brain did not communicate with the nasal cavities directly
through the pituitary. 124,177,178
Despite this evidence, significant strides regarding the pituitary remained wanting for another 200 years. In 1886 S.

Operative Techniques in Neurosurgery, Vol 5, No 4 (Month), 2002: pp 200-209

Lothringer and A. Dostoiewsky independently divided the pituitary into chromophobic and chromophilic cells. 45,~23 Six
years later in 1892, Schoenemann further differentiated the
chromophilic cells as staining with either acid dyes (oxyphil,
acidophil, eosinophil, or alpha-cells) or basic dyes (basophil,
cyanophil, or Beta-cells). 179 Even with a better understanding
of pituitary histology, the actual role of the pituitary in human
physiology was not fully appreciated. In fact, some workers
continued to regard it as a vestigial organ as late as 1908.173
Even so, experimental evidence on the possible role of the
pituitary was mounting. In 1892 Guilio Vassale and Ercole
Sacchi reported that ablation of the pituitary disturbed fluid
metabolism. 192 In 1898 Le Comte had noted that the pituitary
enlarged during pregnancy. 24 In 1907 Jacob Erdheim and Emil
Stumme confirmed this finding and also observed that enlarged
eosinophilic ceils of anterior pituitary remained enlarged during lactation. 48 In 1889 Rogowitsch reported that the pituitary
enlarged and the usual number of eosinophilic cells decreased
after experimental thyroidectomy. 166 Later, as a corollary,
Bernhard Aschner reported thyroid atrophy after hypophysectomy of pups. 4 Crowe, Cushing, and Homans also performed
hypophysectomies on dogs and reported atrophy of the ovaries
and uterus in the survivors and failure to develop sexual characteristics in pups. Ablation of the posterior lobe did not cause
these disorders. 26 Finally, Ascoli and Legnani reported adrenal
cortical atrophy after experimental hypophysectomy.5
Pituitary as Source of Disease. Well before the recognition
of a syndrome associated with pituitary disease and before the
first pituitary surgery, anatomists had recognized the ability of
the pituitary gland to expand. On postmortem examinations,
anatomists in the 17th and 18th centuries noted that the pituitary could enlarge and cause blindness, t8,194 Nevertheless, at
the end of the 18th century uncertainty about whether the
pituitary was the seat of disease remained. 8
However, by the end of the 19th century, increasing numbers
of reports began to emerge indicating that the pituitary could
grow as a part of a pathological process. Before Marie's 1886
description and coining of the term acromegaly, Andrea Verga
in 1864 and Vincenzo Brigidi in 1881 had described the clinical
entity and noted an enlarged pituitary. 2~
Verga's postmortem analysis described that the pituitary growth had compressed the optic nerves. Although Verga recognized that the
patient harbored a pituitary tumor, he believed that the tumor
was related to the patient's early loss of menses. Even Pierre
Marie remained uncertain whether the enlarged pituitary in
acromegaly was part of the generalized organomegaly associated with the disease or whether it represented a tumor. He
(and Marineseo) did recognize, however, that a universal finding was an enlarged pituitary that could compress the optic
nerves. 13o
In 1887, Minkowski first suggested that pituitary pathology
was not the result but the cause of acromegaly. 14~After Massalongo proposed that pituitary hyperfunction causes acromegaly
in 1892, in 1900 Benda suggested that the eosinophilic cells he
observed in postmortem examinations were the s o u r c e . 13A32
Cushing's 1909 observations that patients improved clinically
after partial hypophysectomy further supported the pituitary as
the source of acromegaly. 34
At the turn of the 20th century, increasing reports showed
that acromegaly was not the only syndrome associated with
pituitary tumors. Joseph Babinski in 1900 and Alfred Froehlich
in 1901 reported sellar region tumors, likely craniopharyngioA HISTORY OF PITUITARY SURGERY

mas, that caused what was later termed dystrophia adiposogenitalis. 7,57 By 1906 Cushing had reported his initial experience with this newly described syndrome. 35
Thus, by the beginning of the 20th century, the field of
endocrinology had been established. More was known about
other glands and their related pathology than the pituitary.
Although some still regarded the pituitary as a vestigial organ,
evidence related the pituitary, in a yet undetermined manner, to
growth, sexual development, thyroid function, lactation, and
the adrenals. Pituitary enlargement was known to compress the
optic nerve, and at least two clinical syndromes associated with
pituitary disease were recognized: acromegaly (growth hormone adenoma) and dystrophia adiposo-genitalis (craniopharyngiomas).

Status of Radiology
During this time, significant advances were also being made in
the field of radiology. Wilhelm Roentgen first reported the
existence of X-rays in 1895.165 The applicability of this new
mode of investigation was quickly appreciated by Harvey Cushing, who in 1897 reported the use of X-ray technology to image
a bullet fragment within the spinal cord of a man with BrownSequard syndrome? ~ In 1899, at the meeting of the Berlin
Society of Psychiatry and Nervous Diseases, the neurologist
Hermann Oppenheim demonstrated that the sella turica was
enlarged in a patient with acromegaly. 135In 1907 Schloffer used
radiography to confirm the sellar pathology before performing
what would be the first transsphenoidal procedure.175
By 1912, Arthur Schuller of Vienna had published the first
textbook of skull radiography and had remarked on the radiographic appearance of patients with sellar tumors. 18o Plain radiographs allowed surgeons to confirm preoperatively what
previously they could only assume. For the first time, surgeons
could see the site of pathology before making the first incision.
This ability increased surgical confidence and emboldened
their pursuit of operative solutions for pituitary tumors. Early
equipment, however, was expensive and unwieldy. Although it
could be used to bolster a clinical diagnosis, it was not used for
intraoperative guidance.

The Birth Of Pituitary Surgery

By the time of the first transsphenoidal operations, a pituitary
tumor was known to cause acromegaly. Nonetheless, surgical
indications for pituitary tumors were first visual loss and headache. Despite a publication in the same year reporting clinical
improvement in an acromegalic patient after subtotal hypophysectomy, Cushing indicated in his oration that surgery should
only be performed for mass effect (principally headache and
visual disturbance). 3s,34 He also implied that pituitary syndromes also might be due to mere hypertrophy or atrophy of
the gland, in which cases surgery would not be indicated. 31
Two conditions, one due to a pathological increased activity of the
pars anterior.., the other due to a diminished activity.., seem
capable of clinical differentiation. The former expresses itself
chiefly as a process of overgrowth . . . . The latter expresses itself... with persistence of infantile sexual characteristics . . . . A tumor of the gland itself.., is naturally the lesion to which one or the
other of these conditions has heretofore been attributed, though it is
probable that over-secretion from simple hypertrophy, or undersecretion from atrophy, will be found to occur irrespective of tu201

TABLE 1. Summary of the Early Transsphenoidal Techniques

Transseptal

Submucosal
dissection

Lateral rhinotomy

Yes

No

Lateral rhinotomy with midline

extension onto forehead
Midline rhinotomy
?
Sublabial
Endonasal, hemitransfixion
Sublabial

Yes

No

Yes
No
Yes
Yes
Yes

Yes
No
No
Yes
Yes

Surgeon (Year) City

Incision

Schloffer (1907)17s Innsbruck

Yon Eiselsberg and
von FrankI-Hochwart (1907)19e Vienna
Kocher (1909)1 ~ Berne
Hirsch (1909)82,8sVienna
Halstead (1910)71'72 Chicago
Hirsch (1911)82.85Vienna
Cushing (1914)36 Baltimore

mour growth when examination of the pituitary body becomes a

routine measure in the postmortem examination of all cases . . . .
When due to tumour, surgery is the treatment that these conditions
demand.., but clinicians and surgeons must clearly distinguish
between the local manifestations of the neoplasm due to involvement of structures in its neighborhood other than the hypophysis,
and those of a general character from disturbances of metabolism
due to alterations of the hypophysis itself.
The goals of surgery were to decompress the tumor; gross total
resection was associated with a high rate of morbidity, a rate
that remained high until the early 1950s when hydrocortisone
and antibiotics became available. 9,2r,4a,46,6s,62 For this reason,
most early reports discuss the surgery as a subtotal or partial
hypophysectomy.3~,34.36,90,175

The First Transcranial Surgeries

In 1893 F. T. Paul of Liverpool, along with Caton, published the
first report of a surgical intervention for a pituitary tumor. 21
Although he had planned to reach the tumor via a temporal
craniotomy in this acromegalic patient, he simply performed a
temporal decompression and did not attack the tumor. In London Sir Victor Horsley appears to be the first surgeon to reach
the pituitary successfully. In 1906 he reported his results from
10 such operations, the first of which, reportedly, was performed in 1889. 90
Several transcranial approaches were described. Initially
Horsley approached the pituitary transfrontally, but he ultimately changed to the subtemporal route. 9~ Other surgeons,
however, championed the subfrontal approach. In 1912
McArthur described the fronto-orbital craniotomy with an extradural approach for exposure of the pituitary. 133 Frazier described both an intradural and extradural subfrontal approach
reaching the pituitary through a trajectory that bisected the
midline and sphenoid wing.55, 56 The pterional approach was
developed by Heuer and reported by Dandy in 1918. 40 Cushing
preferred the midline subfrontal route. (Cushing 1932).

Early Transsphenoidal Surgery

Almost two decades passed after Horsley's first transcranial
operation before the first transsphenoidal approaches were described. Within a few years of the first reported transsphenoidal
by Schloffer in 1907,tr5 a flurry of technical variations emerged.
These approaches are discussed from the perspective of contemporary endonasal and sublabial submucosal transseptal
transsphenoidal procedures (Table 1).
Transnasal Approaches. Although transiting the nose, the
first transsphenoidal operation, which was performed by Herman Schloffer of Austria in 1907, was quite unlike those of
202

Bone removal en route to sphenoid

sinus
Septum, superior and middle turbinates,
Left medial orbital wall, maxillary and
ethmoid sinuses
Septum, all turbinates, frontal and
ethmoid sinuses
Septum, vetoer
Left middle turbinate, left ethmoid sinus
Septum, inferior turbinates
Septum
Septum

today, t75 The recipient of the inaugural transsphenoidal procedure was a man with headaches, visual loss, hypopituitarism,
and an enlarged sella turcica on plain radiographs. To access
the sphenoid sinus, Schloffer performed a lateral rhinotomy
and reflected the nose laterally before proceeding to exenterate
most of the remaining endonasal bony structures and to open
the maxillary and ethmoid sinuses. Although symptomatically
improved from the headaches, the patient's vision did not improve. Despite what was initially thought to have been a major
debulking, the patient died within several months of surgery
from obstructive hydrocephalus related to unrecognized and
massive intraventricular extension of the tumor.
In the same year, von Eiselsberg and von Frankl-Hochwart
also performed a similar transnasal transsphenoidal operation
for a patient with hypopituitarism and visual loss. 196The lateral
rhinotomy was extended onto the midtine forehead. Although
the medial orbital wall and maxillary sinuses were not resected,
von Eiselsberg did remove the frontal and ethmoid sinuses.
Ultimately, von Eiselsberg modified this approach and discontinued opening the frontal sinus. 195 Over the next 5 years other
surgeons, including Gods, Proust, and Hochenegg, adapted
this approach for pituitary procedures. 6~
In fact,
Hochenegg was the first surgeon to note symptomatic improvement in an acromegalic patient after transsphenoidal surgery.
In 1909 Kocher initiated the next major advance toward the
operations of today. He was the first surgeon to perform a
transsphenoidal surgery via a transseptal submucosal opening. l~ Like other surgeons, Kocher chose his first operation to
be performed on an acromegalic patient. Although transseptal
and submucosal, the operation was still unlike those performed
today. The septum was approached and removed through an
external midline incision on the bridge of the nose. The frontal,
ethmoidal, and maxillary sinuses, however, were not traversed.
Endonasal submucosal transseptal. In 1910 Hirsch performed the first completely endonasal transsphenoidal procedure. s2 In separate procedures he removed the left middle turbinate and opened the left ethmoidal sinuses before entering
the sphenoid. Although his initial description was neither submucosal nor transseptal, Hirsch ultimately performed the
transsphenoidal approach in a single procedure using a submucosal dissection, s3,s5 This method was not reintroduced and
popularized by others until the late 1980s. 65
Sublabial submucosal transseptal. In Chicago in 1910, Halstead reported the first sublabial approach to the sphenoid, rt,r2
In a multistage operation, Halstead removed both the bony
septum and inferior turbinates. This procedure did not include
a submucosal dissection. Halstead, however, did preserve the
cartilaginous septum, retracting it superiorly.
JANE ET AL

TABLE 2. Summary of Pituitary Hormone Discoveries

Hormone

Year isolated

Year radioimmunoassays available

Year
human
sequenced

amino

acid

Luteinizing hormone

1940 Li et al. 118

1966 Midgley 139 1966 Odell et al. 148

1973 Shome & ParlowJ 18 Closse

Follicle stimulating hormone

Prolactin
TSH Thyroid-stimulating
hormone
Adrenocorticotropic
hormone

1949 Li et al. 119

1933 Riddle et al. 162
1937 Lambie

1967 Midgley 138

1971 Hwang et al. 96
1972 Hall r~ Odell 1967147

1974 Shome & Parlow m3

1977 Shome & Parlow ~84
1975 Sairam & Li 17~

1943 Li et al. 117

1972 Riniker et al. le3

Growth hormone

1945 Li et al. 113,116

1965 Imura 97 1968 Berson and

Yallow, ~5 Aubert & Felber, 6
Greenwood 64
1963 Glick et al. 59

et al. 23

Although not his first report of a transsphenoidal procedure,

Cushing reported his first sublabial transseptal approach using
a submucosal dissection in 1914. 36 This was the approach used
by Dott and ultimately taught to Guiot and Hardy, the approach
used when the transsphenoidal approach had its renaissance in
the latter half of the 20th century. 46,67,75
ParanasalApproaches. Various paranasal approaches to the
sella were also described. The sphenoid was also approached
through the palate, 153,1s9 through the ethmoidal sinuses via
medial tarsorrhaphy incisions, 22,t~176
and via the maxillary sinuses.43,111 Reports of these approaches were scattered into the
late 1960s, but they did not gain wide acceptance. 73,98,t4<191

Abandoning the Transsphenoidal Corridor

The sheer number of approaches described attests to the initial
popularity of the transsphenoidal corridor. Nevertheless, the
transsphenoidal approach, both the endonasal transseptal approach of Hirsch and the sublabial transseptal approach of
Cushing, lost favor. This change is primarily attributed to Harvey Cushing who abandoned the technique in 1929 fairly
abruptly in favor of a transcranial approach. 167
Although the reasons underlying his choice are uncertain,
theories have been proposed, lO9,110.167Cushing may have been
dissatisfied with the limited visibility of the transsphenoidal
approach, which caused difficulty with both hemostasis and
gauging the completeness of tumor removal. These problems
led to a relatively high rate of tumor recurrence after transsphenoidal surgery. 81,167Cushing indicated that he believed that the
subfrontal approach more reliably improved visual field deficits. 32
As Rosegay has keenly recounted, 16r in the years preceding
Cushing's change to the subfrontal approach, he repeatedly
confronted tumors that were better suited for the transcranial
route. 29,33,37Cushing bemoaned the difficulty in accurately predicting the tumor type (ie, meningioma vs. adenoma vs. craniopharyngioma) before surgery and consequently which tumors
could be satisfactorily removed transsphenoidally. 29,36Because
he could not accurately predict the diagnosis preoperatively,
Cushing preferred an operation that was suited for any tumor
that he might encounter. 32
The operative mortality rate does not appear to have been a
significant factor. Preliminary operations were associated with
a mortality rate, primarily because of meningitis, as high as
25%. 195 Within a few years, however, the operative mortality
rate was less than 10%, a figure comparable to that of the
transcranial route. 25 Cushing's operative mortality rate for
more than 200 cases was 5.6%. m
Although most neurosurgeons followed Cushing's lead and
A HISTORY OF PITUITARY SURGERY

1969 Li et al 1~5

abandoned the transsphenoidal approach, two notable surgeons remained advocates, Oscar Hirsch and Norman
Dott. 46,82-s5 These surgeons continued to perform the procedure and ultimately taught the technique to those who later
were credited for its renaissance in the late 1960s and early
1970s.

Context Of The Transsphenoidal Renaissance

Status of Endocrinology
Before the first surgeries for pituitary tumors, experimental
ablative procedures on the pituitary had indicated a possible
role in the function of the gonads, thyroid, mammary glands,
adrenals, and growth. Following the initial pituitary surgeries,
dramatic advances occurred in pituitary endocrinology. By the
rebirth of the transsphenoidal procedure in the late 1960s and
early 1970s, not only had pituitary hormones been isolated and
their physiological roles elucidated, radioimmunoassays had
become available for both diagnosis and posttreatment surveillance (Table 2). The major hypersecretory syndromes were also
described. A brief summary of these events follows.
Recognition of the Remaining Functional Syndromes. In the
first two decades of the 20th century, several reports described
patients with adrenal tumors and clinical signs akin to what was
later termed Cushing's syndrome. 69,88 In 1932 Cushing described the clinical features of hypercortisolism in 12 patients
with basophilic tumors of the pituitary and distinguished patients with adrenal tumors from those with pituitary adenomas. 2s Further advances in understanding Cushing's syndrome
came in 1962, when Liddle et al. confirmed the existence of
ectopic adrenocortitrophic hormone (ACTH) tumors. 12~ Despite these distinctions, most patients were treated with bilateral adrenalectomy. As a consequence of this practice, increasing numbers of patients with Cushing's disease experienced
rapid growth of their unrecognized pituitary adenoma. Nelson
et al. originally described this syndrome in 1960.146
Although currently recognized as the most prevalent hormonally active pituitary tumor, prolactinomas were not recognized as distinct tumors causing a discrete syndrome until
1954. 5~176
The delay partially reflects the "stalk effect"
whereby any macroadenoma causing stalk pressure on the pituitary stalk limits the amount of dopamine reaching the anterior pituitary from the hypothalamus. Although much more
rare, even follicle-stimulating hormone (FSH) adenoma and
thyroid-stimulating hormone (TSH) adenoma syndromes had
been recognized by the early 1970s. 74,2~
20;3

Recognition of Pituitary Hormones. In 1927 Smith and Engle

induced precocious sexual maturity in rats using pituitary
transplants. 186 Although the existence of two different gonadal
hormones governing follicular/Sertoli and lutealFLeydig maturation was postulated as early as 1927, 209 it was not until 1940
that Li, Sampson, and Evans isolated luternizing hormone
(LH). 118Nine years later, the same group isolated FSH. 118,119By
1967 a suitable radioimmunoassay was available for both FSH
a n d LH, 127,138,139,147,148,174,2~ and their amino acid sequence
was described in the early 1970s. 23,182,183
Further evidence of the role of the pituitary in lactation was
found in 1928 when Stricker and Grueter confirmed that anterior pituitary extracts caused lactation in rabbits. 19oAs a corollary to these experiments. Allen and Wiles reported that hypophysectomy halts lactation. 1 In 1933 Oscar Riddle and
coworkers named prolactin, having successfully purified the
hormone from the crop glands of pigeons. 162 Nevertheless,
human prolactin was not isolated and purified successfully
until 1971. 95,112 In the same year, the human prolactin radioimmunoassay became available. 96 Its amino acid sequence was
described in 1977.184
Thyroxin was isolated by Edward Kendall in 1915 and was
produced synthetically by 1933. 8~176In 1922 P. E. Smith and IP
Smith showed that the thyroid atrophy of hypophysectomized
animals, originally reported by Aschner in 1912, could be reversed by injection of anterior pituitary extracts. 4,187 Lambie
and Trikojus isolated TSH in 1937.136 In 1956 von Euler and
Holmgrem provided evidence of a negative feedback loop controlling TSH secretion by showing a decrease in the release of
iodine from the thyroid after thyroxine was injected into the
anterior lobe of the pituitary. ~97 The radioimmunoassay for
TSH was available in 1967] 47 and the amino acid sequence of
human TSH was described in 1975.17~
In 1937 Kendall and coworkers isolated corticosteroid crystals from the adrenal cortex. 1~ In 1943 ACTH was isolated
from sheep pituitary, and a radioimmunoassay for human
ACTH was described between 1965 and 1968. 6,15,64,97 The
amino acid sequence of human corticotropin was reported in
1972.163
In 1921, Herbert Evans and Joseph Long reported that intraperitoneal injection of anterior pituitary extract caused accelerated growth, affected estrous cycles, and caused maturation
in the rat. 49 Growth hormone was isolated from the pituitary in
1945.116 In the 1950s growth hormone was shown to restore
sulphation of cartilage ceils in hypophysectomized rats. 143 In
tissue culture experiments using cartilage cells from hypophysectomized rats, serum restored from rats caused incorporation
of sulphate while growth hormone alone did not. 172 These
investigations indicated that the growth-promoting effects occurred via an intermediary hormone. This "sulfation factor"
was ultimately termed somatomedin. 41 The radioimmunoassay for growth hormone was available in 1963, 59 and the
human amino acid sequence was described between 1969
and 1971.113-115
In addition to the isolation and characterization of pituitary
hormones, during the 1950s and 1960s evidence mounted for
the presence of hypothalamic hormones controlling the pituitary. Preliminary data for a corticotrophin releasing factor
were reported in 1955.169 Between 1960 and 1968, the remaining hypothalamic releasing and inhibiting factors were substantiated.44,1os,134,149
204

Significance of the Status of Endocrinology. By the early

1970s, all of the major hypersecretory syndromes were recognized. Endocrinologists understood the major pituitary axes
and could measure the levels of the major pituitary hormones
using radioimmunoassays. Radioimmunoassays could not only
diagnose pituitary adenomas earlier in their course but could
assess the efficacy of therapy. No longer was relief of symptoms
and visual improvement the only gauge of a given therapy.
Hormonal normalization and preservation of pituitary function
could be quantified. Although various medications had been
studied and reported, most endocrinologists recognized that
effective medical therapy for pituitary tumors was lacking. 151
Status of Radiology
Major advances occurred in the field of radiology during the
20th century. After the development of plain radiography, the
next major advance in neuroradiology came in 1918 and 1919
when Walter Dandy of Baltimore introduced ventriculography
and encephalography, respectively. 39,4~These diagnostic tools
were not without faults. Ventriculography required a surgical
procedure, and encephalography was dangerous in patients
with high intracranial pressure. Still, preoperative encephalography more accurately indicated the size and extent of sellar
lesions than plain radiography and was used regularly. 55,56,75,79
Further progress in the diagnosis of intracranial pathology
came in the late 1920s when Egas Moniz introduced cerebral
angiography.~42 The technique of percutaneous carotid angiography, introduced in 1936, allowed the procedure to gain wider
acceptance. 122 Although not universally used preoperatively,
angiography allowed surgeons to understand the position of
the carotid arteries within the siphon as well as the working
distance between them. Despite its clinical rarity, angiography
could also exclude an aneurysm mimicking a pituitary tumor.
After the introduction of linear tomography in 1931, polytomography was developed in the 1950s and was used increasingly in the early 1960s. 121 Anterior and lateral polytomograms
of the sella and sphenoid sinus improved surgeons' understanding of bone thickness and asymmetries that would be encountered intraoperatively within the sphenoid sinus.t~
Imaging studies began to be used intraoperatively as well. In
1962, Hardy described his use of intraoperative radiofluoroscopy for image guidance. 75 By 1965 Hardy and Wigser had
reported the utility of intraoperative air encephalography to
gauge the extent of tumor removal, r9 Intraoperative imaging
allowed surgeons to correlate their anatomical findings with
imaging in real time, thereby increasing the safety of surgery.
Thus, in the late 1960s and early 1970s when the transsphenoidal technique was being reviewed for pituitary adenomas,
the radiological techniques available to most surgeons included
plain radiography, videofluoroscopy, encephalography, angiography, and polytomography. These were significant advances compared to the plain radiography available to surgeons
who first operated on the pituitary. Nevertheless, there were
limitations. These images did not provide a direct view of the
pituitary gland itself. Surgeons were still unable to visualize the
precise anatomy and intracranial extensions of a tumor. The
diagnosis of hypersecretory syndromes because of microadenomas relied heavily on the expertise of endocrinologists. No
imaging study could direct the surgeon regarding the laterality
of these tumors. Also, none of these imaging modalities were
JANE ET AL

suited for routine postoperative assessment of the extent of

tumor removal or for surveillance of recurrence.

The Transsphenoidal Renaissance

Intracranial Surgery for Pituitary Tumors
Before the 1950s pituitary insufficiency posed a major concern
because surgeons could not replace steroids perioperatively.
Because of the associated risk of mortality, reports preceding
the introduction of steroids suggested that gross total resection
of pituitary tumors, regardless of route, should not be attempted. 9,.2,61,62 After the introduction of hydrocortisone in
1950, more radical resections could be accomplished with a
lower rate of morbidity. 2~ By the late 1960s, a shift in therapeutic goals was evident. More surgeons were advocating
radical excision of pituitary tumors, ls8 Despite the more
radical tumor removals, the rate of operative mortality related to intracranial adenoma surgery had fallen from a little
over 10% to as low as 1.2%. 9,61,62,89,131,155,158-161,188The realization that surgery could be performed safely engendered a
new enthusiasm for pituitary pathology.

Hypophysectomy
A significant impetus to find safe and effective routes to the
pituitary developed as surgeons in the earl?, 1950s became
aware of the role of hypophysectomy in the treatment of hormonally active carcinomas and diabetic retinopathy. 9<t25,t2<152
Initially transcranial approaches were employed. However, because the patients were ill, surgeons sought other, less invasive
methods for pituitary ablation. These less invasive techniques
were employed by numerous neurosurgeons during the 1950s
and 1960s and included radioactive pituitary implants, cryohypophysectomy, and radiofrequency thermal hypophysectomy. tT,Sb54,t57,2~176176 Although effective, these treatments were associated with a risk of CSF rhinorrhea and
cranial nerve injury in as many as 30% of patients. ~99,2~
In the early 1960s neurosurgeons began to return to the
transsphenoidal approach to accomplish the hypophysectomy. 11,19,r5,78,164 The approach proved to be well tolerated
by the generally sick population of patients and provided an
effective hypophysectomy with a low incidence of morbidity.
These experiences played a significant role in the rise of the
transsphenoida] hypophysectomy for pituitary tumors. Surgeons appreciated the utility of this approach and the ease with
which the sella could be exposed. Enthusiasm mounted for
performing the transsphenoidal approach not just for cancer
and diabetic retinopathy but also for tumors.

The Return of the Transsphenoidal Technique

A few neurosurgeons, notably Oscar Hirsch and Norman Dott,
had continued to perform the transsphenoidal technique for
pituitary adenomas after its general abandonment. Gerard
Guiot of Paris learned the technique from Norman Dott in the
mid-1950s. By the end of that decade, he had reported the
outcomes of his first 18 patients. 66,67Guiot, however, improved
Dott's technique by using intraoperative fluoroscopy. 6r This
innovation, still used by most transsphenoidal surgeons, improved the surgeon's ability to confirm the surgical trajectory,
relating exposed anatomical structures to those seen radiographically. Jules Hardy of Montreal learned the technique
A HISTORY OF PITUITARY SURGERY

from Guiot and offered significant improvements. Although

not the first surgeon to use the operating microscope in transsphenoidal surgery. Hardy popularized its utility for selective
adenomectomy in the late 1960s. l~,~8,76-r8,~xra64The once dark
and deep corridor was finally not only illuminated but also
magnified.
By the early 1970s, the operative indications for pituitary
tumors were changing. Although most operative indications
were mass effect, an increasing number of patients were being
treated purely on the basis of endocrinological diagnosis. 10,99,128Hardy's concept of selective adenomectomy marked
a maj or change in the operative indications for transsphenoidal
surgery. Despite a normal-appearing sella on preoperative imaging, Hardy was able to confirm the presence and ultimately
cure patients with hyperfunctioning pituitary tumors, rr,r8 This
change was partially possible by the use of radioimmunoassays
that could confirm the diagnosis of pituitary-related pathology
and was bolstered by subsequent advances in radiology that
have permitted the diagnosis of progressively smaller tumors. It
is important, however, to recognize that the rebirth of the transsphenoidal procedure began before the introduction of computed tomography to clinical medicine in 19742,93 and well
before the introduction of magnetic resonance imaging. 38,168
By 1973 transsphenoidal surgery was considered first-line
therapy for all pituitary adenomas, with the exception of ACTH
microadenomas. T M Until the early 1970s, the distinction of
Cushing's disease from Cushing's syndrome was important, not
only because the pituitary adenoma would be excised, but because the pituitary could be radiated prophylactically to prevent Nelson's syndrome. T M Not until 1978 was the selective
removal of ACTH microadenomas shown to be possible and
effective. ~6,1rl,~r6 The transsphenoidal technique had reached
its fruition.

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