Clin Invest Med 1996; 19 (4): 259-270
(Original manuscript submitted Jan. 8, 1996; received in revised form Mar. 26, 1996; accepted Apr. 1, 1996)
Copyright 1996, Canadian Medical Association
Options: Diagnosis: documenting autonomous growth-hormone hypersecretion and imaging of the pituitary. Treatment: surgical resection, adjunctive therapy with bromocriptine or octreotide and radiation therapy.
Outcomes: Reduction of the morbidity and mortality associated with acromegaly.
Evidence: Review of international literature.
Values: Achievement of consensus among a panel of Canadian endocrinologists.
Benefits, harms and costs: Acromegaly is a chronic debilitating condition that is associated with morbidity and mortality. This consensus statement is designed to improve the diagnosis and management of this rare condition in order to minimize the negative outcomes. Costs were not considered.
Recommendations: The diagnosis of acromegaly is established by documenting autonomous growth-hormone hypersecretion and by imaging the pituitary. Surgical resection is the cornerstone of treatment; however, adjunctive therapy is often needed. Although growth-hormone reduction is often associated with alleviation of symptoms, an attempt should also be made to normalize levels of growth hormone and its target growth factor, insulin-like growth factor-I (IGF-I). Persistent secretion of excess growth hormone and IGF-I may pose significant long-term health risks. A suggested therapeutic algorithm is provided. The ease of administration of bromocriptine should prompt a trial of therapy with this agent. The subcutaneous use of octreotide is of particular benefit to those patients with persistently high levels of growth hormone and IGF-I that cannot be suppressed by other means. Because acromegaly is relatively rare and complex, its diagnosis and treatment require the concerted efforts of an endocrinologist, a neurosurgeon and a radiation oncologist.
Sponsors: A Canadian group of endocrinologists.
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Résumé
Objectif : Dégager au Canada un consensus sur le diagnostic et le traitement de l'acromégalie.
Options : Diagnostic : documentation de l'hypersécrétion de l'hormone de croissance autonome et imagerie de l'hypophyse. Traitement : résection chirurgicale, traitement d'appoint à la bromocriptine ou à l'octréotide et radiothérapie.
Preuves : Réduction de la morbidité et de la mortalité liées à l'acromégalie.
Données probantes : Recension des écrits internationaux.
Valeurs : Dégagement d'un consensus parmi un panel d'endocrinologues canadiens.
Avantages, préjudices et coûts : L'acromégalie est une affection débilitante chronique entraînant la morbidité et la mortalité. Cet énoncé consensuel vise à améliorer le diagnostic et le traitement de cette affection rare afin d'en réduire au minimum les résultats négatifs. Il n'a pas été tenu compte des coûts.
Recommandations : On pose un diagnostic d'acromégalie en documentant l'hypersécrétion d'hormone de croissance autonome et par imagerie de l'hypophyse. Le traitement repose sur la résection chirurgicale, mais il faut souvent un traitement d'appoint. Même si la réduction de l'hormone de croissance est souvent liée à une atténuation des symptômes, il faudrait aussi essayer de normaliser les taux d'hormone de croissance et son facteur de croissance cible, le facteur de croissance I de substances apparentées à l'insuline (IGF-I). Une hypersécrétion persistante d'hormone de croissance et d'IGF-I peut poser d'importants risques à long terme pour la santé. Un algorithme de traitement proposé est fourni. La facilité d'administration de la bromocriptine devrait inciter à essayer un traitement par cet agent. L'utilisation sous-cutanée d'octréotide est particulièrement bénéfique pour les patients dont les taux d'hormone de croissance et d'IGF-I demeurent constamment élevés et ne peuvent être supprimés autrement. Comme l'acromégalie est relativement rare et complexe, il faut les efforts concertés d'un endocrinologue, d'un neurochirurgien et d'un oncologue en radiothérapie pour la diagnostiquer et la traiter.
Commanditaires : Groupe d'endocrinologues du Canada.
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Prevalence
Although it has been documented from autopsies that pituitary adenomas are found in up to 25% of adults, growth-hormone-secreting adenomas likely represent less than 1% of these adenomas.[1] In a comprehensive survey of a relatively stable population of 3.1 million in the region of Newcastle, England, 164 patients with acromegaly were identified during an 11-year period.[2] A more recent study in Spain confirms these findings[3] and also suggests an annual incidence of 3 per 1 million and a prevalence of about 40 to 60 per 1 million. Thus far, no study has examined the incidence and prevalence of acromegaly in North America. Most experts assume that North American rates are similar to those found in Europe. These data suggest that there are 1500 to 2000 patients with acromegaly in Canada. Because the clinical diagnosis of acromegaly is often missed, its true prevalence is probably underestimated.
The clinical features of acromegaly are caused by prolonged, sustained oversecretion of growth hormone and its target hormone, insulin-like growth factor I (IGF-I). Growth-hormone secretion is subject to dual hypothalamic influence by growth-hormone-releasing hormone (GHRH), which stimulates secretion, and by somatostatin, which inhibits it. Specific receptors for somatostatin (SSTRs) are expressed on somatotrophic adenomas. Earlier studies suggested a relation between the density of somatostatin receptors on growth-hormone tumours and the in-vitro as well as in-vivo secretory response to this somatostatin.[4,5] However, binding sites for somatostatin have also been documented by autoradiography in tumours resistant to the growth-hormone-lowering effects of octreotide.[6] These findings are consistent with differential adenylyl cyclase coupling by the five subtypes of SSTRs and with the heterogenous mRNA expression of SSTRs in pituitary adenomas.[7] As well, expression of somatostatin in growth-hormone tumours appears to be lower than that in normal pituitaries.[8]
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Morphology of growth-hormone tumours
Computed tomography (CT) and magnetic resonance imaging (MRI) of the pituitary allow excellent visualization of the source of this growth-hormone excess. In addition, advances in immunohistochemistry and electron microscopy have resulted in specific identification of the various pituitary tumour-cell types responsible for this condition.[9] Each of the growth-hormone-producing tumour subtypes can now be correlated with a different pattern of hormone secretion and tumour aggressiveness. A precise histologic diagnosis of the subtype of growth-hormone pituitary tumour is of great value in confirming the diagnosis and in predicting the clinical course of the condition.
The differential diagnosis of conditions associated with growth-hormone-producing pituitary lesions is given in Table 1. Primary pituitary tumours account for most cases of acromegaly. These tumours arise from the growth-hormone-secreting cells (somatotrophs), and, under an electron microscope, they appear densely or sparsely granulated. The densely granulated tumours grow slowly and are often associated with an insidious clinical presentation over many years. This type of tumour is seen more commonly in younger patients. The sparsely granulated form, however, usually grows rapidly, causing local invasion, with superior (toward the optic apparatus), lateral (invading the cavernous sinuses) or inferior (eroding through the sphenoid sinuses) extension. About 25% of growth-hormone-secreting pituitary tumours are composed of two different cell types: growth-hormone cells and prolactin cells (mixed adenomas).
The cause of pituitary adenomas remains unknown. Most pituitary tumours arise de novo and are not inherited. Recent evidence suggests that an acquired defect disrupts the signalling pathways in somatic pituitary cells.[10-12] These defects can be traced back to specific genes in the pituitary and are not present in other cells. Nearly 40% of somatotrophic adenomas are associated with a somatic mutation in the membrane coupling Gs protein.[11] This defect results in constitutive adenylate cyclase activity and, hence, increased intracellular cAMP levels. Somatostatin has inhibitory effects on growth-hormone and cAMP production,[6] which supports its use in managing growth-hormone-producing pituitary adenomas. Nevertheless, it appears that multiple disruptions or "hits" may be needed to cause unrestrained cell growth and proliferative autonomy. Although, in culture, many factors stimulate this growth of cells, the event or events that start the process of disordered pituitary cell growth are the subject of intensive research.[13,14]
During the last few years, several reports have described patients with acromegaly and nonpituitary tumours involving the pancreas, lung, breast and ovary. Growth-hormone excess, with its associated features (such as excessive sweating, fatigue and acral enlargement) subsequently resolved after successful surgical removal of these tumours. Although some of these tumours appear to be capable of producing and secreting growth hormone outside the pituitary,[15] most of these nonpituitary tumours secrete GHRH, which can be measured in the blood to confirm the diagnosis.[16] In patients with ectopic GHRH secretion, the pituitary becomes hyperplastic, and CT or MRI may show that it is enlarged.[16] The existence of nonpituitary tumours is an additional reason to conduct a precise histologic examination of all "pituitary tumours" removed from patients suffering from acromegaly.
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Clinical presentation
The clinical features of acromegaly are caused by growth-hormone oversecretion and by the compressive effects of an expanding pituitary mass.[17] The compressive effects often include peripheral visual-field impairment and headaches. The long-standing effects of growth-hormone excess include a series of characteristic clinical features (Fig. 1). Although the coarsening of facial features may seem to be obvious in retrospect, only 10% of patients with acromegaly consult a physician for that complaint.[17] Excessive sweating, interruption of menstrual periods, impotence, diabetes mellitus, sleep apnea and skin tags are also common features of the disorder. In two thirds of patients with acromegaly, sleep apnea is obstructive, and in the other third, a central cause is identified,[18] which may be a dysfunction in central somatostatinergic pathways, a putative factor in the control of breathing. It is also common for patients to present with seemingly unrelated complaints such as carpal tunnel syndrome, jaw malocclusion, arthritis or colonic polyps. Adenomatous polyps of the colon appear to be associated with skin tags and may become a significant cause of morbidity and mortality in aging patients with acromegaly.[19]
If left untreated, acromegaly results in disabling arthritis, visual impairment, hypertension, cardiomyopathy, frank diabetes mellitus, sleep apnea and pituitary failure.[20-23] Acromegaly may be associated with an increased risk of cancer of the gastrointestinal tract.[24] Treatment can have a significant effect on the course of the disease and, in many cases, can result in a normal life expectancy.[22] Therefore, it is crucial that appropriate studies are undertaken to establish the diagnosis, find the source of excess growth-hormone production and monitor the success of therapy, once it has been started.
Although some of the earlier studies[25,26] of acromegaly accepted a "normalization" criterion of a growth-hormone value of less than 10 *g/L, most recent studies[27,28] insist that at least 75% of growth-hormone values during a 12-h profile should fall below the limits of assay detection (less than 0.2 *g/L). This normalization criterion agrees more closely with growth-hormone levels found in normal subjects.[29] It should be emphasized that the growth-hormone values discussed in this statement are based on data derived from classic double-antibody immunoassays. With the advent of more sensitive assays, which adopt recombinant growth-hormone standards, stricter criteria (less than 50% of currently accepted values) for normalization of growth-hormone secretion will be required.
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Diagnostic studies
A detailed list of screening and confirmatory tests to establish the diagnosis of acromegaly is given in Table 2. The diagnosis of acromegaly is confirmed by demonstrating excessive, autonomous secretion of growth hormone. Isolated, random sampling of serum growth hormone is inadequate to establish the diagnosis. Since growth-hormone secretion is subject to dual regulation by the hypothalamus, it is pulsatile.[30] GHRH stimulates growth hormone synthesis and release, whereas somatostatin suppresses its release.[29] Somatostatin secretion is also episodic, and it increases during fasting or sleep and in people who are obese. Thus, circulating serum growth-hormone levels may spontaneously reach several times the normal range in healthy individuals, whereas patients with acromegaly may have growth-hormone levels within the normal range. Therefore, to confirm the diagnosis of acromegaly, lack of growth-hormone suppression to less than 2 µg/L after the ingestion of 75 g of glucose (oral glucose tolerance test) must be demonstrated.
Although somatic growth in adults is influenced primarily by growth hormone, the effects of growth hormone are largely mediated through IGF-I, previously known as somatomedin-C. This growth factor is produced in most tissues and also acts locally to regulate cellular growth and differentiation. Circulating IGF-I, however, is mainly hepatic in origin and is dependent on growth hormone. Thus, plasma levels of IGF-I are elevated in virtually all patients with acromegaly.[31] Since IGF-binding proteins may interfere with the accurate measurement of IGF-I, especially in patients receiving treatment,[32] an extraction step is required for removal of the binding proteins. Poorly controlled diabetes mellitus results in impaired hepatic production of IGF-I. Similarly, serum IGF-I levels decline moderately during normal aging and during starvation. IGF-I levels also rise during pregnancy, reaching two to three times the values in women who are not pregnant. With these exceptions, an elevated IGF-I level (more than 333 µg/L in adult subjects) confirms the diagnosis of acromegaly. Furthermore, since blood levels of IGF-I do not fluctuate as rapidly as those of growth hormone, determining serial IGF-I levels may be a practical method of measuring disease activity (or growth-hormone bioactivity) in patients with acromegaly. After a biochemical confirmation of acromegaly, CT or MRI should be used to localize the site of excess hormone secretion. In the absence of a definite pituitary adenoma, an ectopic tumour in the chest, abdomen or pelvis that is the source of GHRH or growth hormone should be considered.
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Treatment objectives
The aims of treatment of acromegaly (Table 3) are to induce a biochemical remission of the hypersomatotropic state with its associated complications and to relieve the compressive effects of a growing pituitary mass. The options for management include drug therapy,[33] surgery[25] and radiation therapy.[26] Regardless of the approach, it is important to recognize that to fulfil these criteria is to effect a cure, and that this often difficult to achieve. Partial fulfilment of the criteria is considered control of the disease.
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Surgery
Transsphenoidal adenomectomy by an experienced neurosurgeon is the primary form of treatment for most patients with acromegaly. A subfrontal approach is sometimes necessary for patients with tumours with suprasellar or parasellar extension. Rapid reduction in growth-hormone levels, with concomitant alleviation of symptoms, can be achieved through surgery. Growth-hormone levels are reduced to less than 5 µg/L in 80% of patients with microadenomas and in 68% of those harbouring macroadenomas after adenomectomy.[34] However, surgical success is closely correlated with the size and degree of invasiveness of the tumour, as well as with surgical expertise. In a world-wide review of 1366 cases of acromegaly treated by trans-sphenoidal surgery, the modest criterion of a growth-hormone level below 10 µg/L was achieved in only 50% of patients.[25] Significant complications, including diabetes insipidus and cerebrospinal fluid leakage, occur in approximately 5% of patients.[25]
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Drug therapy
Many patients report improvement with dopaminergic treatment.[35-39] The mechanism for this effect is unknown, since most of these patients do not have any reduction in growth-hormone or IGF-I levels. A survey of published reports suggests that growth-hormone levels are reduced to 5 µg/L or less in nearly 20% of subjects undergoing dopaminergic treatment. An elevated serum prolactin level portends a favourable response of the growth-hormone level to bromocriptine, the usual dopamine agonist used. IGF-I levels are normalized in only 10% of patients undergoing this form of treatment, and radiographic evidence of a reduction in tumour size is seen in up to 30% of patients.35
Treatment with bromocriptine should be initiated at a dose of 1.25 mg, to be taken in the middle of a bedtime snack. The dose should be increased by 1.25-mg increments weekly until the desired therapeutic end-point is achieved. Once tolerance is achieved, the timing of the doses may be spaced out during the day. A daily dose of up to 40 mg is sometimes needed to control growth-hormone excess,[35,38,39] and optimal growth-hormone suppression often requires administration of the drug three or four times daily.
Data on glucose tolerance are conflicting, showing improvement and deterioration in an equal proportion of subjects. There is no noted correlation between the reduction in growth-hormone levels and the change in glucose tolerance. At the required doses, nausea, gastrointestinal upset and hypotension are the main adverse effects. These side effects may abate with time. Information on the safety and efficacy of bromocriptine to treat acromegaly during pregnancy is limited. However, this agent has not been shown to increase the incidence of congenital malformations or spontaneous abortions in pregnant patients who do not have acromegaly.
Octreotide is a synthetic, modified octapeptide analogue of somatostatin. It resists enzymatic degradation and has an extended half life, which lend support to its clinical application for the suppression of growth-hormone hypersecretion.[27,40-44]
Octreotide leads to rapid and significant improvement in most clinical features.[27] Excessive perspiration, soft-tissue swelling, fatigue, arthralgia, acne and headaches are diminished in 50% to 75% of patients with acromegaly treated with octreotide. Headaches are often reported to resolve within minutes of administration, and other symptoms resolve within weeks.[18,27,44,45] Cardiovascular function may improve within 3 months of treatment.[46,47] Mean growth-hormone levels over an 8-h interval decline significantly (by more than 25%) in 70% of subjects, and usually start to decline within 30 min of subcutaneous administration of 100 µg of octreotide.[27] Maximal suppression is reached within 2 h and lasts for 6 h.[27] Mean growth-hormone levels often begin to rise by the 7th hour after drug administration. This phenomenon may necessitate more frequent injections (every 4 to 6 h) or continuous subcutaneous infusion by pump.[48,49] Octreotide effectively suppresses growth-hormone and IGF-I concentrations in patients with acromegaly. Its use is of particular benefit to patients with persistently elevated growth-hormone and IGF-I levels after pituitary surgery or between radiotherapy sessions. It may also constitute primary therapy for those who decline or cannot tolerate surgery or radiation. Treatment should generally be initiated with a 50-µg subcutaneous injection each hour for 8 h. This dosage can be gradually increased by 50-µg increments to achieve maximal growth-hormone and IGF-I suppression. Growth-hormone suppression is best assessed by measuring growth-hormone levels each hour for 8 h after a subcutaneous injection. Since the growth-hormone response is rapid, this assessment can be done at the outset to identify nonresponders. A reduction in growth-hormone levels of more than 25% of baseline for 4 h during the 8-h sampling period is considered a satisfactory response. However, the objective improvement and control of the disease is more closely related to the actual level of growth hormone attained. In the absence of a satisfactory response, the assessment should be repeated at a higher dose.[44] If growth-hormone levels return to baseline before the end of the dosing interval, the frequency of administration can be increased.[28,43,50,51] Patients generally accept only up to four injections a day. If more frequent doses are needed, continuous subcutaneous infusion of 300 µg per day is recommended. Levels of growth hormone and IGF-I should be monitored and the dose titrated to achieve maximal effects with the lowest dose possible.
The following conclusions about octreotide therapy can be drawn from the published studies discussed.
A reduction in the size of the pituitary tumour is seen in 30% to 50% of patients treated with octreotide. Tumour shrinkage is rapid, occurring within weeks, but may be reversed after the drug is discontinued.[27,52] The degree of reduction is usually modest. Although some earlier reports suggested that reduction in the tumour size may facilitate surgical removal and improve outcome,[53] this remains to be resolved.
Transient nausea, abdominal cramps and steatorrhea occur among 75% of patients during the first week of treatment. This effect can be ameliorated by initiating treatment with a low dose of 150 µgµd and gradually increasing the dose to the desired therapeutic level.
Cholelithiasis may result from octreotide use, due to the inhibitory effect of somatostatin on cholecystokinin release and gallbladder responsiveness.[27,54] Asymptomatic gallstones have been reported in 20% to 50% of patients after 6 to 24 months of treatment.55 Patients should have an ultrasonographic examination of the gallbladder before treatment and, if they have symptoms of gallbladder disease, during treatment. The effect on cholelithiasis of diet and of the timing of analogue administration in relation to meals remains to be determined. The long-term use of this agent may require the addition of an anticholelithogenic agent to the regimen, particularly for patients with a history of symptomatic cholecystitis.
In regard to glucose tolerance, the concomitant reduction in growth-hormone hypersecretion and insulin antagonism usually counteracts the potential diabetogenic effect of this analogue. Glycosylated hemoglobin levels remain unaffected in most patients treated.[56]
Patients who benefit particularly from octreotide treatment include (a) those who have tumours sufficiently large to preclude complete removal and in whom tumour shrinkage may facilitate resection, (b) those with with severe cardiovascular or pulmonary complications of acromegaly, in whom preoperative stabilization or improvement is desirable, (c) those who have not achieved sufficient growth-hormone reduction after surgery or radiotherapy, (d) those who cannot tolerate pituitary surgery or who decline radiotherapy and (e) those who require interim treatment after pituitary irradiation.
Treatment should be initiated at 50 µg subcutaneously every 8 h for the first week, followed by 100 µg subcutaneously every 8 h thereafter. If growth hormone or IGF-I levels remain elevated, the dose given every 8 h should be titrated upward every 1 to 2 wk by 50 µg. The dose interval should be shortened to every 4 to 6 h if growth-hormone levels rise significantly before the end of the 8-h dose interval. Consideration should be given to administration by continuous subcutaneous infusion pump for responsive subjects who require frequent drug administration.
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Radiotherapy
This adjunctive therapeutic option is usually reserved for patients for whom surgery or drug therapy has failed to control acromegaly.[26,57] There are three techniques for the irradiation of pituitary tumours. The first, conventional external irradiation with a total dose of 4500 rads (given over 3 weeks of therapy), results in reduction in growth-hormone levels in most patients. Growth-hormone levels decline by approximately 15% per year, with values of less than 5 µg/L being reached by 40% of patients after 5 years and in 70% of subjects after 10 years. Tumour growth is arrested and the size of the tumour subsequently reduced. Adverse effects include transient hair loss and, rarely, visual loss.[26,58-60] The most common and troublesome complication is late-onset, irreversible hypopituitarism. Although this complication occurs no more often in patients with acromegaly than in patients with non-growth-hormone adenomas, it does develop in nearly 50% to 60% of subjects.[26,58-60] It is documented more often among patients who have undergone pituitary surgery.[57] The second method, high-particle (alpha- and proton-beam) irradiation, delivers high doses to the tumour bed and is associated with more rapid action than conventional treatment. Third, interstitial irradiation with radioactive seeds is offered in some specialized centres.[58] All forms of irradiation achieve very comparable net results, which are limited mainly by their slow onset.[57]
External-beam megavoltage (4500 rads) irradiation is still the most widely used means of controlling the disease for patients in whom other treatment options have failed or are impossible. If drug therapy is also being given, it needs to be interrupted periodically between radiation doses to assess the effectiveness of radiotherapy.
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Monitoring of therapy
The effects should be monitored in all patients after surgery, and monitoring should be repeated annually (Table 4). More frequent monitoring may be necessary after the institution of adjunctive therapy.
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Conclusions
Acromegaly is often a chronic debilitating condition which, if left uncontrolled, is associated with morbidity and mortality. The diagnosis is established by documenting autonomous growth-hormone hypersecretion and by imaging the pituitary. Since it is usually caused by a pituitary adenoma, surgical resection of the responsible adenoma is the cornerstone of management. Adjunctive therapy is often necessary, however, because complete resection is often impossible. Although the reduction in growth-hormone levels after surgery is often associated with alleviation of symptoms, an attempt should also be made to normalize levels of growth hormone and IGF-I. Persistent excess secretion of growth hormone and IGF-I may pose significant long-term cumulative risks of hypertension, cardiomyopathy, diabetes mellitus and disabling arthritis. A suggested therapeutic algorithm is shown in Fig. 2. The ease of administration of bromocriptine should prompt a trial of therapy with this agent. The subcutaneous use of octreotide is of particular benefit to those patients with persistently high levels of growth hormone and IGF-I after pituitary surgery or during the periods between radiotherapy sessions. Octreotide administration may also constitute primary therapy for those who decline or cannot tolerate surgery or radiation therapy. When the drug therapy is used, the dose of the agent should be titrated to achieve maximal effects with the lowest dose possible.
In the case of acromegaly caused by ectopic GHRH production, surgical resection of the responsible tumour is usually required. This can be followed by the adjunctive administration of octreotide.
Because acromegaly is relative rare and hormonal testing is complex, an endocrinologist must be actively involved in supervising the work-up of patients and the progress of therapy. Depending on the therapeutic methods chosen, the involvement of a neurosurgeon with expertise in transsphenoidal hypophysectomy and of a radiation oncologist is vitally important in the management of patients with acromegaly.
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References