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Harvey Cushing : the contribution of a gifted doctor to Endocrinology Print E-mail
Written by Ilianna Galli-Vareia   

cushing_devoted_doctor

As far as endocrinology is concerned, Cushing’s contribution is undoubtedly enormous. As a neurosurgeon, he had the chance to study the lesions of the pituitary gland and its various consequences, such as acromegaly or gigantism. However, Harvey Cushing has been mostly linked to the syndrome that bears his name. It was first described in 1932 in his paper “The Basophil Adenomas of the Pituitary Body and their Clinical Manifestations”



Harvey Cushing (April 8, 1869 - October 7, 1932) is a predominant figure, not only in the Neurosurgical field but in the whole medical world. Coming from a family of physicians, he was raised in a highly educational environment, where he was given the chance to develop his learning talents. Later, as an undergraduate at Yale University, as a medical student in Harvard Medical School and, primarily, as a neurosurgeon in Johns Hopkins Hospital, he took the first decisive steps towards his grand career.

cushing_devoted_doctor

Fig 1: Harvey Cushing: A devoted doctor

As far as endocrinology is concerned, Cushing’s contribution is undoubtedly enormous. As a neurosurgeon, he had the chance to study the lesions of the pituitary gland and its various consequences.

 

The pituitary gland is recognized as a part of the endocrine system

The 19th century was marked by the recognition of Hormones and the Endocrine System. Even at the beginning of the 20th century, though, the physiological role of the pituitary gland was largely unknown. There had been a long delay in the understanding of the pituitary, partly because its inaccessibility made it difficult to study. Until the 1600s, the concepts of Galen had persisted. Galen believed that the pituita (from the greek “Πτύω” witch means “to spit” and the Latin “pituita” witch means “Mucus”) secreted waste products from the brain into the nasal cavities.

Pituitary-gland-anatomy

Fig 2: The Pituitary Gland

As the years passed, more evidence came to surface, concerning the actual role of the pituitary. In the 19th century, Cushing himself, along with Crow and Homans performed hypophysectomies on dogs and reported atrophy of the ovaries and uterus in the survivors, while the pups failed to develop sexual characteristics. Ablation of the posterior lobe did not cause these disorders.

Concerning the pituitary gland as a cause of illness in humans, in 1909, Cushing observed that patients improved clinically after partial hypophysectomy, observation which supported the involvement of the pituitary in acromegaly. [1]

 

Cushing and Pituitary Surgery

Cushing was also the pioneer of the pituitary surgery, not only in animals, as mentioned above, but in humans as well. By the time of the first transphenoidal operations, a pituitary tumor had been known to cause acromegaly. Nonetheless, surgical indications for pituitary tumors were at first visual loss and headache. Despite an earlier publication reporting clinical improvement in an acromegalic patient after subtonal hypophysectomy, Cushing indicated in his oration that surgery should only be performed for mass effect (principally headache and visual disturbance). He also implied that pituitary syndromes might also be due to mere hypertrophy or atrophy of the gland, in which cases surgery should not be indicated.

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…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 under-secretion from atrophy, will be found to occur irrespective of tumor growth when examination of the pituitary body becomes a routine measure in the postmortem examination of all cases…When due to tumor, 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 that the hypophysis, and those of a general character from disturbances of metabolism due to alterations of the hypophysis itself.

Several surgical approaches have been introduced through the years by many neurosurgeons. In 1914, Cushing reported his first sublabial transseptal approach using a submucosal dissection. Later, he preferred the midline subfrontal route (Cushing 1932). He believed that the latter improved more reliably the visual field deficits. He wasn’t only a pioneer but a very effective surgeon as well. He managed to have in his operations a mortality rate of 5,6% out of 200 cases, whereas the general mortality rate of such surgeries were almost 10%. [1]


Harvey Cushing's attempt at the first human pituitary transplantation

In 1911, a 48-year old man presented at Johns Hopkins Hospital with bitemporal hemianopsia, hypothermia, hypersomnolence, decreased libido, polydipsia and polyuria. A diagnosis of hypopituitarism followed. The patient was treated with whole gland pituitary extract, which improved his symptoms only temporarily. Harvey Cushing transplanted a pituitary gland obtained from a spontaneously aborted foetus into the cerebral cortex of the patient, resulting to a remarkable  improvement of his somnolence and confusion, whereas his polyuria and polydypsia persisted. A recurrence of symptoms after only 6 weeks prompted Cushing to attempt a second transplant of a foetal pituitary gland, without improvement that time. The patient resumed hormonal supplementation with whole gland pituitary extract, but died a month after the second transplant because of  respiratory complications. [4]


Cushing and Acromegaly-Gigantism

Harvey Cushing wrote about Acromegaly-Gigantism in his “Address on Acromegaly from a Surgical Standpoint” in July 1927. As he said, dividing the two clinical expressions of Hyperpituitarism “it is convenient to divide the cases into two main categories-those in which the disorder has set in during pre-adolesence and those in which it has began to manifest itself in adult life. The former results in Gigantism, the latter in Acromegaly…both of these states in invariably associated with a hyperplasia, or more commonly, with an actual adenoma of the chromophilic elements. He studied closely various cases of both Acromegalic and Gigantic Patients, photos of whom were included in his article.

As an example, we present the case of patient No 26204:

“A Russian tailoress, 23 years of age, unmarried, was admitted to hospital on April 22nd, 1926, with the usual major complaint of severe headaches. She had been known to have acromegaly for a number of years, and on the advice of her physician, she had been given a series or deep x-ray treatments, which had failed to alleviate her discomfort. Meanwhile, her catamenia which had set in at the age of 14 years, continued without interruption, though she had become somewhat masculinised and for her sex, extremely hirsute.


Acromegaly

Fig 3 and 4: Outspoken acromegaly associated with a comparatively small adenoma


She had the typical enlarged extremities, hypertrophic nose, lips, and tongue of fairly advanced case of acromegaly, and the spine showed a well marked kyphosis. Her height was 171 cm. and her weight 84.6 kilograms. The sella turcica was not greatly enlarged and there were no local pressure signs. The basal metabolic rate was +24 per cent, though the thyroid was not palpable. On May 10th, 1926, by the customary transphenoidal route, a fairly radical removal of the glandular contents was accomplished by pituitary rongeurs and "sucker." The tissue showed a typical acidophilic adenoma. Within a week after the operation there had taken place a marked diminution of the puffiness of the hands, the skin having become thinner, softer and more pliant. To this the patient herself first called attention. This change was sufficiently marked to be shown photographically

Acromegaly_hand_

Fig 5 and 6: To show by the pre- and post operative photographs of the patient’s right hand the subsidence of the hyperpituitary oedema


as well as by actual measurement. Meanwhile, she had lost several kilograms in weight and by the time of her discharge on June 3rd her basal metabolic rate had dropped twenty points, to +4 per cent.

She has, at the time of writing, remained free from headaches for a year, and her hands and feet no longer feel stiff and swollen as they formerly did. The basal metabolism remains low.” [2]


Cushing and Cushing’s syndrome-Minnie G

Besides his above-mentioned contribution to endocrinology, Harvey Cushing has been mostly linked to the syndrome that bears his name. It was first described in 1932 in his paper “The Basophil Adenomas of the Pituitary Body and their Clinical Manifestations”. Although this manuscript contains two of Cushing’s own case studies, as well as ten similar cases from the literature of the time, only one patient remains both the archetype of Cushing’s disease and the albatross of medical historians: Minnie G or “Case XLV”.

Minnie_G

Fig 7: Minnie G. at the time of her first consultation with Cushing in 1910.


Minnie G was a 23-year-old patient who was examined in 1910 by Harvey Cushing and triggered his lifelong interest in the syndrome that bears his name. According to his own words, she presented with a “. . . syndrome of painful obesity, hypertrichosis, and amenorrhea with overdevelopment of secondary sexual characteristics accompanying a low grade of hydrocephalus and increased cerebral tension. Pituitary, adrenal, pineal or ovary?

Indeed, Minnie G, was referred by Dr. DeWitt Stetton from New York and was evaluated for the first time by Cushing in December 1910 at the Johns Hopkins Hospital. Her numerous symptoms included a history of amenorrhea for the past seven years, which appeared together with headache, back pain, and swelling of the feet. At the same time, her vision “began to fail” and she complained of intermittent diplopia. Other striking features included a 20-lb weight gain over a 2-year period, “.... insomnia, tinnitus, extreme dryness of skin, frequent sore throat, shortness of breath, palpitation, purpuric outbreaks, marked constipation, sudden attacks of dizziness with falling, a definite growth of hair and mustache during the past few years with marked falling out of the hair of the scalp. . . . Muscular weakness was . . . extreme and there is much complaint of backache and epigastric pains.”

Mini_G_handwriting_von_Cushing

Fig 8: Cushing’s handwritten note, commenting on Minnie G.’s visual fields. The upper portion reads: ‘‘patient misunderstood what was necessary—speaks English with difficulty [5]


On physical examination, Cushing noted that this patient’s face was “. . . dusky and cyanosed and covered with a fine growth of hair, which is particularly noticeable on forehead and upper lip.

There was also “. . . a definite tendency toward hemophilia. The skin bruises easily and large spontaneous ecchymoses occur frequently. Epistaxis is almost a daily occurrence. Adiposity, particularly limited to the abdomen, is marked and of recent origin. It is very painful and tender (adiposis dolorosa). Plain x-ray films of the sella turcica revealed a “somewhat thinned-out sella of normal configuration, but of small size.

A subtemporal decompression was considered and ultimately performed because some of the symptoms were possibly referable to increased intracranial pressure. A month following the procedure, the patient’s headaches had resolved, her blood pressure had improved, and she had lost 12 lbs. In commenting upon the case of Minnie G., Cushing observed that the patient displayed signs and symptoms similar to those observed by “hypophyseal deficiency” (amenorrhea, adiposity, and short stature). Instead of the “sexual infantilism of reversive type,” which had been associated with cases of hypopituitarism observed by Cushing before that time, however, Minnie G. exhibited “the secondary sexual development, mammary and genital, of a multipara, with unusual and recently acquired hirsuties.

Minnie G. was readmitted to the Peter Bent Brigham Hospital in 1912. At that time her general condition and symptoms were unchanged. Polycythemia and hyper-tension were present. Notes obtained at the time of an additional readmission in 1922, 12 years after the original consultation, refer to signs of spontaneous clinical remis- sion. Her menses had resumed in 1913, but, although she had lost some weight, her general appearance was “much as before.” Cushing concluded that “. . . she seemed at least no worse than in 1912.” The last recorded contact between Cushing and this patient was in 1932, when, on the basis of correspondence, he gathered that she was in “reasonably good health, though some of the stigmata of her malady still persist.[3] 

Discussion

Given the above, it is safe to deduce that Dr. Harvey Cushing was a pioneer in the field of endocrinology. Not only to mention the syndrome that bears his name, he has helped via his talent and ability as a surgeon, as well as a thorough physician, to come to conclusions which lead the way to doctors of the subsequent generations.

 

 

 

References

  1. A History of Pituitary Surgery, J. Jane Jr, MD, K. Thapar MD, PhD, E. Laws Jr, MD, Elsevier Science, 2002
  2. An Address on Acromegaly from a Surgical Standpoint. Harvey Cushing, The British Medical Journal, 1927
  3. Cushing’s case XLV: Minnie G, G. Lanzino MD, N. Maartens MD and E.Laws MD, J Neurosurg 97:231–234, 2002
  4. Harvey Cushing’s Attempt at the First Human Pituitary Transplantation, C. Pendleton, HA. Zaidi, G. Pradilla, AA. Cohen-Gadol, A. Quinones-Hinojosa, Nat. Rev. Endocrinol.  2010 Jan;6(1):48-52.
  5. 5. The Elusive Minnie G: Revisiting Cushing’s case XLV and his early attempts at improving quality of life, C. Pendleton, H. Adams, E. Laws, A. Quinones-Hinojosa, Pituitary, DOI 10.1007/s11102-010-0248-1, Springer Science +Business Media, LLC 2010

 

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