Acromegaly represents the somatic manifestation of a pathologic excess of growth hormone secretion. When this condition is present in childhood, before the closure of the epiphyses of the long bones, it leads to gigantism. Acromegalic persons and giants have been described in literature and art throughout history. The unfortunate people afflicted with this condition have been held in awe, and enormous strength and physical powers have been attributed to them, although these are rarely present, at least for any extended period of time.
Pierre Marie described acromegaly as a medical syndrome in 1886. The causative role of the pituitary gland was not recognized at that time, however, and the enlarged pituitaries found at autopsy were thought by many to be just another feature of the hypertrophy that affected many parts of the body. By 1900, pathophysiologic correlations by Benda and others had suggested that the hypertrophy or hyperplasia of the pituitary might be the cause of acromegaly, and the adenomatous nature of pituitary enlargement was ultimately documented.
Pathogenesis and Natural History
The vast majority of cases of acromegaly are produced by neoplasms of the somatotropic cells of the anterior pituitary. These tumors appear to arise independently of alterations in other hormones and tropic factors. Some tumors (20 to 30 percent) have the ability to produce excessive amounts of both growth hormone (GH) and prolactin. Acromegaly can also occur as a result of hyperplasia of the somatotropes either independently or in response to excessive amounts of growth-hormone-releasing factor. This latter syndrome has been seen in association with a hypothalamic hamartoma, a pancreatic adenoma, and a mediastinal carcinoid tumour.
Spontaneous remission of acromegaly may occur but is rare and usually is associated with infarction or haemorrhage in the tumour. Spontaneous haemorrhage may also present as pituitary apoplexy, threatening vision and life; fortunately, apoplexy also occurs rarely. Persistent active acromegaly is the usual course associated with a growth-hormone-secreting pituitary tumour. Structural changes occur in the cardiovascular system and are frequently associated with hypertension and severe atherosclerosis. Diabetes mellitus and its many complications are common in these patients. In addition to morphologic changes in soft tissues with enlargement of the digits and loss of dexterity, joints are commonly affected, resulting in severe and progressive osteoarthritis. Early therapy is recommended to forestall these pathophysiologic changes.
Patients with active acromegaly present with a wide spectrum of symptoms and signs. Those who have elevated growth hormone in childhood develop gigantism, with disproportionately long arms and legs and nearly proportional increases in the size of other body parts. The tallest accurately measured acromegalic giant was 2.3 m tall, but others undoubtedly have been taller. Once the epiphyses close, excessive growth hormone produces acromegaly with focal enlargement of bones and soft tissues in various parts of the body. There is thickening of the heel and palm pads and of the soft tissues of the fingers and toes. The facial features become characteristically coarse, and enlargement of the nose and lips occurs. The jaw enlarges, and the teeth become mal occluded. The tongue and heart both enlarge, leading to partial airway obstruction on the one hand and to decreased cardiac output on the other. The scalp may become hypertrophic enough to appear corrugated. There is exuberant enlargement of the air sinuses in the thickened skull, leading to a "beetle brow" appearance. Bone density is generally increased, and joints and costochondral junctions undergo hypertrophy. Later in life, severe degenerative osteoarthritis and spinal stenosis may occur. The ligaments thicken, and median thenar neuropathy from the carpal tunnel syndrome is a common presenting complaint. The generalized effect on the cardiovascular system leads to hypertension.
Abnormalities in glucose metabolism are common, and diabetes mellitus is a frequent finding. Associated hypothyroidism may occur, and a small but significant number of patients (about 5 percent) will have a multiple endocrine neoplasia (MEN) syndrome, most commonly with parathyroid and pancreatic adenomas. These patients with MEN-1 (Wermer's syndrome) may suffer from hypercalcemia and urolithiasis, hyperinsulinemia, and gastric ulcer. Because about 20 percent of acromegalic patients also have hyperprolactinemia, premenopausal women may develop oligo-menorrhea, amenorrhea, and galactorrhea. Other symptoms related to prolactin include loss of libido in both sexes and impotence in men. Large tumors may produce hypopituitarism with fatigue, anaemia, pallor, poor response to stress, and hypogonadotropism.
Compression of the optic apparatus from suprasellar extension of the tumour may lead to photophobia, progressive visual loss (usually a bitemporal hemianopia), and optic atrophy. Sudden loss of vision secondary to apoplexy within the pituitary adenoma (haemorrhage and/or necrosis) may occur. Compression of the cavernous sinus from lateral expansion of the tumour may lead to complaints of trigeminal pain and diplopia. Invasive tumors may produce cerebrospinal rhinorrhea.
Acromegaly undoubtedly has direct effects on the nervous system, perhaps related to abnormalities of peptide neurotransmitters. Acromegalic patients may have a greater than normal incidence of neuropathies and myopathies, epilepsy, dementia, and psychological disturbances. Male to female ratio is 3:2.
The first operation on the pituitary for acromegaly was performed in Vienna in 1908 by Hochenegg using Schloffer's trans-sphenoidal approach. In the United States, the first such operation was performed by Harvey Cushing in 1909. In the first transsphenoidal operation for a pituitary tumour he used a superior transnasal approach, resecting the upper septum and the turbinates. He soon perfected the sublabial rhinoseptal submucosal approach and operated on some 60 acromegalic patients using this method.
Radiation therapy for acromegaly also began in 1909 and has been applied with considerable success. Most patients have been treated with conventional photon therapy, currently best delivered by a linear accelerator using multiple ports and appropriate shielding of the eyes. Interstitial radiation by implantation of 198Au or 90y sources has been used in the past, and heavy particle external therapy using neutrons and alpha particles has also been effective. Radiosurgery using stereotactically delivered focal radiation from a Gamma Knife, linear accelerator, or proton beam is also an effective adjunct in the management of acromegaly.
craniotomy in the acromegalic patient is made difficult by the thick cranial bone and exuberant frontal sinuses characteristic of this condition. Large lesions with significant suprasellar or parasellar extension may still require craniotomy if adequate removal of the tumour is to be accomplished. Bronson Ray became extraordinarily skilled in the transfrontal approach and reported his excellent results in a large series of patients. Currently, when craniotomy is indicated, it is usually accomplished by either the transfrontal or the pterional approach, depending on the anatomy of the lesion.
discovery and isolation of somatostatin (growth hormone release-inhibiting factor) gave great promise for medical control of acromegaly. Unfortunately, the effects of this peptide are transient, and the use of somatostatin analogues (e.g., octreotide acetate) for control of excessive GH secretion has numerous problems that often make it impractical. Discovery of the fact that GH release is under significant dopaminergic control has led to the use of the dopamine agonist bromoergocriptine, or bromocriptine, in the management of acromegaly. Approximately 75 percent of patients with active acromegaly, will respond to bromocriptine treatment with a decrease in GH production. Unfortunately, high doses (15 to 40 mg/day) are usually required, and reduction of GH levels to normal is rare. The response to bromocriptine appears to be most dramatic in acromegalic patients who also have hyperprolactinemia. These patients commonly will show shrinkage of the bulk of the tumour after bromocriptine therapy. Although manifestations of the tumour return after bromocriptine therapy is discontinued, continued bromocriptine therapy is thought by many to protect against further growth of the tumour. Tumour shrinkage is less reliable and less dramatic with the use of octreotide, but the tumour shrinks to some degree in up to 20 percent of the patients who respond to the drug with lowered growth hormone levels.
Currently, virtually all acromegalic patients treated surgically are operated on initially with the transsphenoidal microsurgical approach. Criteria for a satisfactory result are clinical improvement in the symptoms and signs of acromegaly and normalization of GH secretion. The latter is measured by a fall in serum GH values to less than 2 ng/ml during a glucose tolerance test. The results are discussed within the limits of these rigid criteria.
Clinical improvement occur in 97 percent of the patients. Endocrinologic success has been more difficult to achieve and is related to the biological and morphologic classification of the tumour and to the preoperative level of GH. Those patients with basal GH values less than 50 ng/ml have the best chance for normalization after surgery. Tumors are classified as microadenomas (less than 10 mm in diameter), diffuse (enclosed) adenomas, and invasive adenomas according to their size and the findings at operation. Those patients with microadenomas have the best prospects for "cure" following surgery. The worst results are in patients with invasive tumors and markedly elevated GH values.
Planned total hypophysectomy is abandoned. Alcohol or Zenker's solution is not in routine use to treat the tumour bed.
When more liberal criteria are used for "cure" (GH less than 10 ng/ml), satisfactory results are obtained in more than 90 percent of patients with microadenoma.
Critical summaries of other forms of primary management are not readily available, but reports have been published of "success" rates of 64 percent for craniotomy, 27 to 41 percent for radioactive implants, 76 to 86 percent for cryotherapy, 88 percent for thermocoagulation, 23 to 81 percent for conventional radiation therapy, and 53 to 91 percent for proton and heavy particle therapy. These reports were summarized by Laws and colleagues in 1982.
Adjunctive Management of Acromegaly
It has been the general policy to recommend postoperative radiation in patients with tumors having suprasellar extension or invasive characteristics. When elevation of postoperative growth hormone levels increases over time, radiation therapy is also usually recommended. Bromocriptine or Sandostatin therapy is considered in cases in which active acromegaly persists despite surgery and radiation therapy and in cases of invasive tumors that appear to remain active or enlarge over time.
Complications of Trans-sphenoidal Surgery for Acromegaly
There have been no operative (30-day) deaths in E. Laws transsphenoidal series, which included 445 acromegalies. Two arterial injuries occurred, one of the carotid artery. which was repaired directly, and one of the anterior cerebral artery, which was clipped. One patient with compromised vision from a large tumour developed further loss of vision, which later recovered. Another patient developed optic nerve type visual loss, which resolved after craniotomy and radiation therapy. Two patients developed cerebrospinal rhinorrhea, which was successfully repaired in each with a second transsphenoidal procedure. Significant intraoperative bleeding occurred in three patients; in two the procedure was abandoned, with later successful surgery in one, and in the third, multiple transfusions allowed completion of the original procedure. Loss of preoperative normal anterior pituitary function occurred in six patients, and permanent diabetes insipidus in four. One patient developed severe sinusitis in the postoperative period, and another developed a nasoseptal perforation. Fortunately, major postoperative complications have been rare