Acromegaly: Overview and Current Management Options

Abstract

Growth-hormone-producing pituitary adenomas in adults will be the focus of this review acromegaly is a disorder caused by pathologically excess levels of growth hormone (GH), nearly always secondary to a pituitary somatotroph adenoma, which account for 10–20% of all pituitary adenomas. Acromegaly is a pan-systemic disease, including but not limited to effects of excess growth hormone on the cardiovascular, respiratory, gastrointestinal, metabolic, and reproductive systems. This raises the concern for clinicians and patients alike in diagnosing the underlying disease when multiple systems are involved. Numerous organ systems may be differentially affected, and the multiplicity of signs and symptoms possibly overlap with other conditions, with the typically slow progression of the disease, it may take years from the initiation of biochemical GH excess before a diagnosis of acromegaly is made. The goal of effective treatment of acromegaly is to eliminate hypersecretion of GH and normalize the production of IGF-1 while preserving normal pituitary function. Medication, radiotherapy, and surgery, often in combination, and over time, are required to mitigate, reduce, and eliminate the morbidity and excess, premature mortality caused by GH elevation.

1. Introduction

Acromegaly, constructed from the Ancient Greek, ακρον, meaning higher, extreme, or tip, and μεγας, for large or bigger, is an uncommon disorder, with an annual incidence in most countries of roughly 5 cases per million population per year. Due to the insidious nature of the signs and symptoms in patients with acromegaly, the overlap of some features, such as weight gain, hypertension, obesity, arthropathies, glucose intolerance, and metabolic syndrome with other, more common disorders, is felt that the true incidence may be higher. Because of this, the prevalence of acromegaly is thought to be underestimated, with figures ranging from 40 to 130 million cases globally [1]. Based on 2010 regional referral practices in the United Kingdom, Brazil, and Belgium, the prevalence of acromegaly may be as high as 400–1000 individuals per million [2].

2. Pathogenesis

In brief, acromegaly is caused by abnormally elevated levels of growth hormone (GH), which stimulates the synthesis and excess production of insulin-like growth factor 1 (IGF-1), principally from the liver, the small intestines, and within the bones and other tissues in an autocrine/paracrine loop [3, 4].

Under normal conditions, the production and secretion of GH by somatomammotroph cells in the anterior pituitary gland are balanced by stimulatory and inhibitory factors. Growth hormone-releasing hormone (GHRH), produced in the arcuate nucleus of the hypothalamus, is a 44 amino acid peptide that is carried via the hypothalamic-hypophysial portal circulation to the anterior pituitary, where it binds the GHRH receptor and stimulates GH production [5]. GH, a 191 amino acid protein, with a circulatory half-life of several hours, is produced in surges and secreted in a pulsatile manner into the circulation throughout the day and night in a non-circadian pattern, at 3–5 hour intervals [6]. Age, gender, diet, exercise, stress, and other hormones affect GH secretion. Nadirs and zeniths in circulating GH levels may be above or below normal age- and sex-adjusted ranges in both normal patients and those with acromegaly [7].

GH interacts with a cell-surface receptor, the GHR, located in liver, fat, and muscle. Activation of the GHR induces synthesis and secretion of IGF-1 into the systemic circulation [8]. IGF-1 can be produced in local tissues, such as bone, in an autocrine/paracrine fashion. IGF-1 is a 70 amino acid protein with 3 intramolecular sulfide links; in the bloodstream, 98% of IGF-1 is bound to one of six binding proteins (IGF-BPs), which increases IGF-1’s stable and effective half-life, on the order of days to weeks. IGF-1 binds the IGF-1 and insulin receptors, more effectively to the former. IGF-1 receptors are found on cells in skeletal and cardiac muscle, bone, cartilage, kidneys, liver, lung, nerves, skin, and hematopoietic system cells. This explains the myriad effects of the GH system [2, 9, 10].

Negative feedback (inhibition) of the GHRH-GH-IGF-1 axis occurs locally, via somatostatin receptor ligand inhibition, as well as systemically, via elevated levels of IGF-1, which act to decrease GH secretion from somatomammotrophs in the anterior pituitary. In the setting of a GH-secreting adenoma, this negative inhibition is muted or absent. This is discussed in detail in the review by Melmed [8].

There are three ways in which acromegaly may result: primary, extra-pituitary, and excess GHRH [10]. Extra-pituitary GH excess is exceptionally uncommon, seen in rare patients with GH-producing abdominal or pancreatic islet tumors. Iatrogenic administration of GH in excess can be seen. Sustained, pathological elevations of GHRH have been reported in patients with a hypothalamic tumor (e.g., a hamartoma) or a peripheral (non-CNS) neuro-endocrine lesion such as a bronchial carcinoid, small cell lung cancer, or adrenal tumors or thyroid medullary cancers. All these conditions are rare and likely require specialist referral and evaluation, over time.

For this review, however, we will concentrate on approximately 95% of patients in whom acromegaly is caused by an adenoma of the anterior pituitary gland.

3. Pathology of pituitary adenoma formation

3.1 General aspects

Pituitary adenomas are benign tumors that are monoclonal in origin and arise from a lineage of differentiated anterior pituitary cells, including gonadotrophs, corticotrophs, thryotrophs, and somatomammotrophs [8, 11]. In the general population, 5–10% of patients may have an adenoma that can be seen on sellar magnetic resonance (MR) imaging, which has a resolution of roughly 1–3 mm; most of these small tumors do not secrete excess hormone and are called incidentalomas [12, 13]. Tumors less than 10 mm are called microadenomas; tumors bigger than 10 mm are macroadenomas. Somewhere between 0.5 and 2% of the population, increasing with increasing age may have a macroadenoma [13, 14]. Tumors may or may not secrete excess levels of hormone; other tumors may not secrete but do produce hormone within the tumor cells, as revealed by immunohistochemical staining. Non-functional and/or non-secretory tumors are more common than adenomas that secrete hormones, namely GH (acromegaly), adrenocorticotropin-secreting hormone (ACTH), thyroid-stimulating hormone (TSH), or prolactin. Of the latter, prolactinomas are the most common, about 20–30% of all patients with a symptomatic adenoma; while ACTH- and GH-secreting adenomas represent 5–10% of patients. Mixed GH and PRL-secreting adenomas are possible, as well.

3.2 What are the histopathological subtypes of somatotroph adenomas?

Pure-growth hormone-secreting adenomas are divided into two subtypes: densely granulated growth hormone [DGGH] cell adenoma and sparsely granulated growth hormone [SGGH] cell adenoma. There is a key difference between these two adenoma sub-types: whilst there is no difference in survival or cure rate, SGGH cell adenomas are more likely to exhibit locally invasive behaviors [15].

Additionally, GH adenomas may also express prolactin in up to half of a surgical series undertaken, when assessed with immunohistochemical staining [15, 16]. One may subdivide tumor types into mixed GH cell/prolactin cell adenoma, mammosomatroph cell adenoma, and acidophilic stem cell adenoma. In approximately a quarter of acromegalic patients, prolactin is also secreted, and elevated levels are measured in the circulation [17].

3.3 What genetic factors are of importance in acromegaly?

GH-secreting adenomas arise as a consequence of unrestrained somatotroph tumor cell proliferation, with multiple defects, including intrinsic cell-cycle dysfunction, altered autocrine and paracrine factors that influence GH synthesis, and cell growth, see Table 1. Most GH-secreting adenomas arise sporadically and may or may not have somatic genetic alterations. The most common genetic mutation in sporadic GH-secreting adenomas is a dominant (oncogenic) mutation of the gsp or GNAS gene, which triggers the adenylyl cyclase system and acts as if GHRH is permissively activated [15]. Alterations in gsp may be seen in about 30–40% of patients with a sporadic GH-secreting tumor. Other alterations include changes in transcription factors (e.g., CREB), cell cycle control genes, both tumor suppressors and oncogenes (e.g., HRas, CCNB2, CCND1, HMGA2, PFGR4, PTTG, Rb, CDKN1B, among many), which are found in 5–15% of tumors, without a clear cut pattern identified to date. Epigenetic alterations (for example, inactivation of CDKN2A (p16), GADD45, and MEG3) have also been identified as having a role in GH adenomagenesis [19].

Disease	Genetic basis	Comments
Multiple endocrine neoplasia Type I	11q13.1	Rare. Autosomal dominant disorder characterized by varying combinations of tumors of parathyroids, pancreatic islets, duodenal endocrine cells, and the anterior pituitary, with 94% penetrance by age 50
Carney complex Type 2	2p16	Rare.. Associated with skin myxomas 62%, cardiac myxomas 30%, Cushing’s syndrome 31%, and acromegaly 8% of the patients
McCune-Albright syndrome	20q13.32	Associated with pituitary hyperplasia. Rare.; Postzygotic somatic mutation. Classic triad: polyostotic fibrous dysplasia, cafe-au-lait spots with precocious puberty
Familial isolated pituitary adenomas	11q13.2; 20q13.32	Rare. Families where 2 cases develop pituitary adenomas
Familial isolated Somatotropinomas	11q13.2; 20q13.32	Younger patients. Families where 2 cases of acromegaly with no other endocrine symptoms
PRKAR1A mutations	17q24.2	Rare. Phosphorylation mediated by the cAMP/PKA signaling pathway is involved in the regulation of metabolism, cell proliferation, differentiation, and apoptosis
Aryl hydrocarbon Receptor-interacting Protein	11q13.2	Rare. Ligand-activated transcription factor with resulting complex attains binding specificity for its cognate enhancer elements to regulate transcription of a variety of xenobiotic metabolizing enzymes.
X-linked Acrogigantism	Xq26.3	G-protein coupled receptor 101. Expression of GPR101 cells results in a dose-dependent elevation in reporter activity and intracellular cAMP.

Table 1.

Genetic mutations and familial acromegaly in GH-secreting pituitary adenoma.

Note: Adapted, in part, from Cuevas-Ramos et al. [18], the Genetics Home Reference (available at: https://ghr.nlm.nih.gov), and the Online Mendelian Inheritance atlas (available at: omim.org).

Younger age of presentation with macroadenomas associated with higher GH levels and poorer responses to medical treatment with somatostatin receptor ligands. The onset of acromegaly in late adolescence or early adulthood is a severe form of acromegaly seen in familial isolated pituitary adenoma [FIPA] associated with aryl hydrocarbon receptor interacting protein alterations [AIP], found on chromosome 11q13 [2]. Somatotroph adenomas are seen in nearly 80% of AIP mutations; in this cohort, the tumors are noted to be more extensive and locally invasive, frequently require re-operation due to rapid or persistent growth despite medical therapy, often require adjuvant radiotherapy; early use of pegvisomant may be needed [20] (see below).

Acromegaly may also present in association with hereditary, autosomal dominant syndromes, multiple endocrine neoplasia type 1 [MEN 1], and Carney Complex [CNC]. MEN1 is caused by a mutation in a tumor suppressor gene located on chromosome 11q13; penetrance is 95% by the age of 55. Roughly 95% of patients have hyperparathyroidism; a pituitary adenoma is seen in 40% or more; and a pancreatic or other foregut tumor is seen in 40% of patients as well. The most common pituitary adenoma is a prolactinoma but somatotropinomas are also seen and may behave more aggressively than sporadic GH-secreting pituitary adenomas; alterations in MEN1 are seen in all MEN1-associated adenomas [21, 22, 23, 24]. Mutations in MEN1 can be seen in about 10% of sporadic tumors, similar to the rates noted above [21].

Mild elevations of IGF-1 in the context of pituitary hyperplasia may be seen in patients with genetic syndromes such as the McCune-Albright syndrome and the Carney complex, which clinically may manifest as a subclinical acromegalic syndrome [2]. Lesions may, on rare occasions, grow large enough to cause mass effect and require surgical debulking [25].

4. What is a typical presentation of a patient with acromegaly?

Patients with acromegaly typically present in the fifth decade of life. While 40% of patients are diagnosed by a primary care physician, many are diagnosed because of presentations that lead them to dentists and oral and maxillofacial surgeons, orthopedic, plastic, and podiatric surgeons. or physiatrists and others because of the variegated nature of symptoms and signs, as outlined above [2]. Traditionally, the most common presenting symptoms are orthodontic ones [overbite], enlargement and coarsening of facial features, inability to wear previously well-fitting rings, and increasing shoe size [9]. However, it is also to be noted that a significant minority of patients may not display clear acromegalic features (Figure 1 and Table 2) [27].

Figure 1.

The acromegaly algorithm. Definitions and notes: SRL: somatostatin receptor ligand, OGTT: oral glucose tolerance test. Algorithm adapted, in part, from Giustina et al. [26] and Capatina and Wass [4].

System	Co-morbidities
Head and neck	Frontal bossing Supraorbital ridge bulging Visual field defects Enlarged nose, tongue and lips Prognathism Mal-occlusion Tongue hypertrophy +/− sleep apnea
Endocrinological	Diabetes, glucosuria, abnormal glucose tolerance test Thyroid gland hypertrophy Galactorrhea Menstrual abnormalities Sexual dysfunction
Cardio-pulmonary	Cardiomegaly Systemic Hypertension Pulmonary Hypertension
Musculoskeletal	Osteoarthritis Carpal tunnel syndrome Enlarged hands Enlarged feet
Gastro-intestinal	Hepatomegaly Nephromegaly Splenomegaly Colonic polyps
Miscellaneous	Skin tags Hyperhidrosis Peripheral neuropathy

Table 2.

Anatomical and physiological disturbances associated with acromegaly.

5. What comorbidities are commonly associated with acromegaly?

The following co-morbidities are common in patients with acromegaly [2]:

• Cardiovascular disease caused by arterial and left ventricular stiffening, with cardiomyopathy. This is the major cause of mortality in acromegalic patients [28]. Cardiomyopathy excess morbidity and premature mortality can be reduced and in some cases, reversed, by successful treatment [29].

• Hypertension is the most relevant negative prognosticator for mortality in acromegaly and occurs in one-third of all patients [9, 10].

• Abnormal glucose regulation is found in up to a third of acromegalic patients and is an independent prognostic factor of more aggressive disease [10].

• Vascular morbidity is enhanced by abnormal glucose regulation and hypertension.

• Obstructive sleep apnea caused by swelling of the nasopharyngeal tissue and macroglossia. It may lead to cor pulmonale and right-sided heart failure, which exacerbates the cardiovascular issues outlined above [30]. Musculoskeletal abnormalities: carpal tunnel syndrome and other neurological entrapment syndromes as well as vertebral fractures in presence of normal bone densitometry.

• Thyroid cancer is the most common cancer associated with acromegaly [2].

• Colonic polyps are much more frequent in both incidence and number and require a minimum of one colonoscopy at diagnosis and closer surveillance based on clinical concern. It is controversial whether there is a clear increase in colon cancer in acromegalic patients [26].

• Mass effect: cranial nerve dysfunction, headache, or visual issues due to optic nerve compression (visual field cuts: most commonly, patients present with superior (bi-)temporal hemianopia, before developing loss in the inferior temporal fields; later still, the nasal fields may be involved, but typically not without temporal field defects; visual acuity losses are not common unless the field cuts are extensive) or cranial neuropathy (causing diplopia or ptosis due to involvement of cranial nerves 3, 6, and 4; and rarely causing pain or sensory problems due to involvement of branches of the trigeminal nerve) and pituitary hormonal dysfunction due to a large tumor (macroadenoma) that compresses the normal anterior gland (see Figure 1).

6. What is the role of radiological imaging in patients with acromegaly?

The current standard for imaging any pituitary adenoma is magnetic resonance (MR) imaging of the brain with fine cuts (1.5 mm intervals or less) of the brain, without and then with contrast. Field strengths of 1.5tesla or higher are optimal. In some cases, with small or difficult-to-visualize tumors, volumetric, breath-held, fine cut images of the sella may be added.

Over three-fourths of all somatroph adenomas are macroadenomas >1 cm in diameter and are nearly always radiologically detected on MR imaging [31]. In the rare setting in which a fine-cut, high-field sellar MR fails to show an adenoma, a search for an ectopic source of GHRH may need to be done, which is beyond the scope of this review [17].

Somatotroph adenomas, on average, are smaller than most non-functioning or non-secretory macroadenomas; frequently, the tumor will extend into the infrasellar region and involve the sphenoid sinus and clivus [32]. This has been hypothesized based on GH secretion from the presence of normal somatotrophs that tend to be distributed preferentially inferiorly and laterally in the normal pituitary gland, along with the thickening of the diaphragma sella in response to higher GH levels.

7. How is acromegaly diagnosed?

As noted above, neither phenotypic features nor radiological findings comprise distinct, fail-safe diagnostic criteria for acromegaly.

For patients with a suspected pituitary adenoma, biochemical testing is the crux of diagnosis. To evaluate for clinical or sub-clinical acromegaly, one typically measures both GH and IGF-1. The stable plasma levels of IGF-1 correlate with the release of pulsatile GH over 24 h in a log-linear fashion [2]. This pulsatile nature of GH means that isolated, static measures of GH alone cannot be used definitively to make or exclude a diagnosis of acromegaly, since even in the setting of acromegaly, GH secretion remains pulsatile and patients with active disease may have nadir GH levels below the upper limit of normal, just as some normal patients may peak above that limit. Men have random GH levels of <5 ng/mL and women <10 ng/mL as a reference guide in healthy persons. However, as stated above the single, static measure, the IGF-1 level, particularly if it is two times (or higher) than the upper limit of normal for age, sex, and that assay, is the screening test of choice.

If both GH and IGF-1 are markedly elevated, this is pathognomonic for acromegaly, and in the presence of clinical suspicion, an oral glucose tolerance test may not be required [33].

If an oral glucose tolerance test is undertaken, failure of GH to suppress is diagnostic for acromegaly. While the mechanism of glucose-induced GH suppression remains incompletely understood [2] in a healthy person after 100 g of glucose ingestion the GH suppresses to <0–2 ng/mL or undetectable. The high GH nadir value post-oral glucose tolerance test remains the gold standard in the diagnosis of acromegaly.

8. What is the significance of biochemical discordance between GH and IGF-1?

Biochemical discordance between GH and IGF-1 levels is seen in up to one-third of patients with acromegaly; in most patients, the discordance is that of a normal GH and an elevated IGF-1 level. This may be due to polymorphisms of the growth hormone receptor gene [2], which results in increased sensitivity of the receptor to lower GH levels, for example. Additionally, there may be inaccurate laboratory representation of the 24-hour dynamic, pulsatile GH output or technical problems with IGF-1 assays. Growth hormone has a short half-life of 10–20 minutes with IGF-1displaying a longer half-life of hours, of up to a day [7]. Additionally, it has been noted radiotherapy may cause a flat [rather than regular pulsatile] GH secretory pattern [33].

IGF-1, which is synthesized principally in the liver, may be reduced in association with a host of disorders; hepatic failure, renal failure, nutritional [e.g. anorexia], gastrointestinal [e.g. inflammatory bowel disease], endocrine [e.g. hypothyroidism and exogenous estrogens] and metabolic [e.g. type I diabetes mellitus] [2, 33, 34].

9. How is acromegaly monitored?

9.1 Biochemical monitoring of acromegaly

Total IGF-1 levels are noted to reflect GH secretory status accurately. Measurement of free IGF-1 and/or IGF-binding proteins does not provide additional clinical information [33]. The Acromegaly Consensus Group defines ‘controlled GH status’ biochemically, as optimal disease control, in one of three ways: age and gender-matched IGF-1 levels in the normal range; random GH level of <1.0 micrograms/L; or, a nadir GH, after a properly-conducted OGTT, of <0.4 micrograms/L [34]. Both IGF-1 and GH levels correlate proportionally with mortality, with normalization and decrease of IGF-1 and GH resulting in the mortality of patients decreasing to comparable rates of the general population [33, 34]. Specifically, a random serum GH of less than 1 micrograms/L has been shown to be an indicator of successful treatment and better survival outcomes [30].

Patients on somatostatin receptor ligand (SRL) therapy require regular serial IGF-1 levels and correlated with random GH measurements, In SRL therapy there is no role or indication for the oral glucose tolerance test [33]. Of note, patients on GH receptor antagonist therapy only require serial IGF-1 measurements.

9.2 Comorbidity monitoring

The primary endpoint in the treatment of acromegalic complications is biochemical normalization, which correlates directly with the lowering of the associated morbidities [35]. Over the course of treatment and resultant normalization of serum GH and IGF-1, many comorbidities are attenuated – especially cardiovascular disease, hypertension, and diabetes mellitus - and become comparable to that of the general population [17]. Changes related to bone alterations or joint arthropathies are more resistant to change, such that overall quality of life with successful treatment can be difficult to predict. In general, the longer the duration of untreated or incompletely treated disease, the lower the reduction in or amelioration of acromegalic signs and symptoms (Table 3).

Acromegalic complications	Evaluation and diagnostic tests
Glucose metabolism Diabetes acromegalic patients	Oral glucose tolerance test Fasting glucose HbA1C C peptide
Cardiovascular system	EKG Holter EKG monitoring Echocardiogram Carotid duplex BP measurement
Respiratory system	Polysomnography Epworth sleep score Chest CT/MR
Gastrointestinal	Colonoscopy
Musculoskeletal	Clinical evaluation X ray and arthroscopy evaluations

Table 3.

Screening of complications of acromegaly.

10. Do acromegalic patients have a higher morbidity and mortality rate than control populations?

If untreated, acromegaly results in significant, excess morbidity and both acromegaly-related and all-cause mortality when compared to control populations, with standardized mortality ratios of 1.5–2.0 [36]. It is disputed in the literature whether patients with acromegaly have an increase in mortality proportionally to higher GH and IGF-1 levels, although the fractional remission rate can be influential [37].

The increase in the mortality of acromegalic patients is multifactorial. First, there is typically a delay in the diagnosis of acromegaly, with an average interval of 5.2 years [2]. This can result in what may be described as a temporal clustering of patients found in a more advanced state of disease, wherein it is harder, or takes longer, to reverse deleterious pathophysiological effects. Second, the mortality in acromegalic patients is primarily due to cardiovascular and pulmonary effects, which may take longer, to reverse [2].

Other causes of the higher mortality may include cranial radiotherapy, which can lead to accelerated cerebrovascular disease in some; and, more frequently, in between 25 and 50% of patients (depending upon the duration of follow-up and the sensitivity of the pituitary hormone assays that are done) iatrogenic hypopituitarism, which is also known to increase morbidity and mortality, even in the face of appropriate replacement [38, 39].

In 2012, the Safety and Appropriateness of Growth Hormone Treatments in Europe [SAGhE] study evaluated the health of nearly 30,000 patients who had been treated with recombinant growth hormone as children in 1980s. Use of GH was proportionally related to increased bone-tumor mortality [osteosarcoma] and a 7-fold increase in mortality secondary to cerebrovascular disease. There was no evidence of increased risk of colon cancer nor an increase in all-type cancer-related mortality [40].

11. Are there treatment algorithms for acromegaly?

In their most recent report, from 2014, the Acromegaly Consensus Group [26] suggested the following treatment options [4, 33]:

• As noted above, the goal of therapy is to achieve biochemical remission and to maintain it, while minimizing the risk of inducing defects in other pituitary hormones or other conditions.

• In surgically-accessible tumors, or those with mass effects causing neurological compromise, trans-sphenoidal surgery is the treatment of choice.

• Medical treatment with somatotropin analogs in surgically-inaccessible somatotroph adenomas without neurological compromise is reasonable. In some cases, pre-surgical treatment in patients with significant soft tissue swelling or potential airway issues somatostatin analogs have been used, although there is no Level I evidence to support their use. In patients in whom residual disease persists after surgery, or there is recurrent disease that is not resectable, medical therapy is warranted to help normal IGF-1 levels.

• The GH receptor antagonist pegvisomant is considered a treatment option if hormone normalization cannot be not achieved with the other therapies noted above.

• Stereotactic radiosurgery can be a useful, adjuvant treatment option, with two long-term and complementary goals: reduction and control of mass effect and lowering or elimination of GH hypersecretion.

12. What options are available for medical treatment?

Medication may be used as the sole first-line therapeutic option, as an adjuvant to surgical resection in selected cases, or after stereotactic radiosurgery or fractionated radiotherapy to reduce GH levels, after which there is an expected delay in GH levels, one that typically takes 2–5 years for radiosurgery and 3–10 years for fractionated radiation [41]. Periodically after radiation (at 6 or 12-month intervals), one may need to withhold medical therapy for several weeks (for short-acting agents) or longer (for longer-acting agents), to determine whether the radiation has been effective, and this appears to be clinically reasonable, with no rebound hormone levels or increase in tumor size [42].

One must recognize that all treatments for acromegaly, however effective, need to be conceived as having helped the patient achieve remission - and that life-long, clinical and biochemical surveillance is required. In this light, the medical treatment of acromegaly is life-long, thereby liable to cumulative side effects, and with varying efficacy with respect to tumor burden and resistance.

12.1 Somatostatin receptor ligands (Octreotide, Lanreotide and Pasireotide)

Somatostatin receptor ligands [SRLs] are the mainstay and first line of medical treatment of acromegaly. The first generation of SRLs, octreotide and lanreotide, target the somatostatin receptor subtype 2 [2]. Somatostatin subtypes 1,2,4,5 are expressed in both arterial and cardiac myocytes: use of SRLs may reduce the cardiovascular co-morbidities, both by effects on GH excess and, to some degree, by improving diastolic function and ejection fraction, with increased exercise capacity [43]. The variable tumor response rate and corresponding reduction in tumor volume is dependent not only on the physiology of somatostatin receptors, but also on E-cadherin, filamin, and β-arrestin expression (Tables 4 and 5) [46].

Acromegaly-associated comorbidity	Incidence, rate per 10,000 persons-years
Arthropathy/synovitis	4.503
Hypertension	3.908
Hypopituitarism	2.267
Osteoarthritis	2.062
Impaired glucose tolerance test and Diabetes	1.931
Colon polyps	1.554
Cardiac dysrhythmias	1.357
Valvular heart disease	1.343
Sleep apnea	1.301
Menstrual abnormality	1.097
Visual field defects	0.644

Table 4.

The incidence of co-morbidities associated with acromegaly.

Adapted, in part, from Burton et al. [44]. All incidence rates are based on rate per 10,000 person-years.

Medication	Mechanism of action	Goals of treatment	Comments and FDA.gov guidelines
Octreotide acetate Sandostatin®	SSTR2 RL Long acting octapeptide mimicking somatostatin	To reduce GH and IGF-1 to normal	Begin therapy subcutaneously in an initial dose of 50 mcg three times daily which may be titrated.; GH may reduce to normal range in 50% patients; IGF-1 reduced to normal in 50–60% of patients
Lanreotide acetate Somtuline® depot	SSTR2 RL Synthetic analog of somatostatin	To reduce GH and IGF-1 to normal	Dose range is 60–120 mg every 4 weeks. Recommended starting dose is 90 mg deep subcutaneous route every 4 weeks for 3 months, adjustment based on GH and IGF-1 levels.; After a single injection of Lanreotide, plasma GH levels fall rapidly and are maintained for at least 28 days
Pasireotide diaspartate Signifor®	SSTR5 > SSTR2 > SSTR3 > SSTR1 multireceptor SRL Synthetic analog of somatostatin Binding with high affinity to four of the five SSTRs	To reduce GH and IGF-1 to normal	Indicated in patients with an inadequate response to surgery and/or for whom surgery is not an option. Recommended initial dosage is either 0.6 mg or 0.9 mg by subcutaneous route twice a day. Titrate dosage in response to treatment [reduction in 24-h urinary free cortisol] and symptomatology.
Cabergoline dostinex®	Long acting dopamine receptor agonist with high affinity for D2 receptors	To normalize IGF-I levels Consider for cdenoma co-secreting PRL and GH [45]	Cardiovascular examination prior to therapy commencement to rule out valvulopathy.; Recommended dosage for initiation of therapy is 1.0 mg orally once or twice a week with adjustment until normalization of IGF-1 levels.
Bromocriptine Parlodel®	Ergot derivative with potent dopamine receptor agonist activity	To reduce GH levels; Consider for cdenoma co-secreting PRL and GH	Initial recommended oral dosage is 1.25 mg to 2.5 mg daily, with increments of 2.5 mg biweekly until therapeutic response.; Alone or as adjunctive therapy with pituitary irradiation or surgery, reduces serum growth hormone by 50% or more in approximately half of acromegalic patients treated, although not usually to normal levels
Pegvisomant Somavert®	GH-receptor antagonist Analog of human growth hormone (GH) that has been structurally altered to act as a GH receptor antagonist	To normalize IGF-I levels	Recommended loading dose of 40 mg given subcutaneously with increase every 4–6 weeks; Indicated in patients with an inadequate response to surgery and/or as a second-line treatment in whom the above therapies are contraindicated.

Table 5.

Medical therapy used in acromegaly.

SSTR Somatostatin Receptors, IGF-1 insulin-like growth factor, GH growth hormone PRL prolactin.

As noted above, SRLs are often used after subtotal resection of a somatotroph adenoma (persistent or recurrent disease) and in the latency period while one awaits radiation therapy to reach full effect [1]. Typically, one maintains the patient on the same dose of SRL for 3 months to adequately assess treatment and determine the need to titrate dosing.

Octreotide comes in two forms, a short-acting form, given three times daily, and a long-acting depot. Long-acting octreotide is administered intramuscularly every 4 weeks and normalizes GH and IGF-1 in up to 79% and 68% of patients respectively; roughly 30–40% of patients will see tumor size reductions that are roughly 30–40% of tumor volume [1]. Lanreotide is available as a depot injection, given every 28 days. It is unclear whether there are significant differences in efficacy rates between octreotide and lanreotide concerning achieving biochemical remission [1]. The maximal benefit of SRL therapy may be achieved in the decade after commencement in approximately 70% of patients. SRL therapy is generally well tolerated, with 1 in 10 patients describing transient gastrointestinal symptoms (like diarrhea, abdominal discomfort, nausea, and flatulence) due to the inhibition of pancreatic exocrine secretions [47]. In rare cases (less than 1 in 100 patients), side effects may include glucose intolerance, steatorrhea requiring the introduction of pancreatic enzymes, and hair loss due to thyroid issues [48]. A meta-analysis showed first-generation SRLs to statistically decrease fasting serum insulin, with minor overall clinical impact on acromegaly, irrespective of the use of octreotide or lanreotide [49]. Medical treatment pre-operatively with SRL, as discussed above, has not been demonstrated, in any controlled, randomized, and blinded studies, to improve surgical outcomes or reduce any post-operative complications [8].

The options for patients with resistance to first-generation SRLs include, but are not limited to: higher dosing, combination with pegvisomant and/or cabergoline, and, more recently, the use of pasireotide [46]. Pasireotide is a next-generation SRL with broader somatostatin receptor patterns of interaction with 4 of the 5 SST receptors, particularly somatostatin receptor 5. Pasireotide is given as an intramuscular injection, every 4 weeks. The side effect profile of intramuscular pasireotide is similar to that of first-generation agents, however, a for a higher incidence of hyperglycemia-related adverse events with pasireotide, requiring closer monitoring of the patient’s glycemic status [50].

12.2 Growth hormone receptor antagonist (Pegvisomant)

Pegvisomant is a mutated analog of human growth hormone, with highly selective ligand affinity for growth hormone receptor binding sites 2 and 5. When it binds to the GH receptor, it prevents functionally correct receptor dimerization [51]. Pegvisomant is administered subcutaneously once daily.

The ACROSTUDY showed pegvisomant to be an effective, single medical treatment option for patients with acromegaly, with approximately two-thirds (65.8%) of subjects achieving and maintaining IGF-1 normalization at 5-year follow-up [43, 52]. Serum IGF-1 concentrations show a dose-dependent decrease, with 75% of the final maximal reduction occurring within the first 2 weeks of administration [51]. As would be expected in an agent that lowers IGF-1 by blocking the GH receptor, many patients will have a compensatory rise in the GH level. The most common side effects include liver enzyme abnormalities in 2.5% of patients, administration site reactions in the form of lipodystrophy in 2.3%, and a comparable rate of tumor growth in 10 of 710 patients who were on pegvisomant alone [49].

In general, pegvisomant is reserved for patients with persistently elevated IGF-1 levels despite maximizing other treatment modalities [1, 2]. It may also be used in conjunction with an SRL, or even cabergoline or bromocriptine, especially in patients that have elevated levels of GH and prolactin (mixed somatomammotropinomas) [8]. Pegvisomant is significantly more expensive than most SLRs. Given the expense, it has been suggested that at least a 2/3rds reduction in actual cost would make pegvisomant more cost effective relative to the other medical agents, certainly to become a widely used first line medication [9].

12.3 DAs: dopamine agonist (cabergoline)

Dopamine agonists, such as cabergoline or bromocriptine, decrease GH (and prolactin) secretion. Typically, they are used as complementary, adjuvant therapy with SRLs, since monotherapy with DA is effective in roughly 10% of patients or fewer [8]. Oral dopamine agonists, as noted above, may be useful in patients whose tumors secrete both prolactin and GH [43].

DAs are generally not used in patients with Parkinson’s Disease patients. An association between long-term, high-dose therapy and clinically relevant cardiac valvular disease remains controversial and uncertain [8].

13. What are the surgical options in acromegaly?

Surgical resection is the first-line, gold standard, and the most efficacious treatment option for patients with microadenomas and macroadenomas without extracellular invasion [1, 9, 42, 53]. Both the microsurgical transsphenoidal and endonasal, endoscopic transsphenoidal routes are utilized to access pituitary adenomas. Surgical resection results in both a rapid reduction of the tumor mass effect on surrounding structures (cranial nerve palsies and optic chiasm) and a reduction in hormonal secreting tumor bulk, with normalization of IGF-1 levels in 6–12 weeks after total resection (recognizing the half-life of IGF-1).

After surgery, biochemical normalization is seen in 50–95% of patients. Tumor volume and invasion of parasellar structures (bone, dura, or cavernous sinus walls or contents) as the best predictors of both the limits of resection and of hormone normalization [54]. Thus, hormone control rates are lower in patients with macroadenomas when compared to those with microadenomas; and patients in whom the bone, dura, or cavernous sinus are invaded, have continued reductions in surgical remission rates associated with lower control rates [42]. Even with large and invasive tumors, remission rates in patients where trans-sphenoidal surgery is combined, deliberately, with adjunctive multimodal therapy, long-term remission rates can exceed 80% [55].

In cases with residual disease, medication [usually SRLs] or postoperative radiation therapy is recommended [56]. The complication rate for transsphenoidal surgery is surgeon experience dependent, usually quoted as less than 5% and this includes infection (sinusitis; less commonly, meningitis), hyponatremia, CSF leak, anterior pituitary hormone deficiencies, diabetes insipidus, cranial neuropathies, and vision perturbations.

Cranial approaches are rarely needed and are generally reserved for patients with large tumors that invade the intracranial spaces and cause neurological compromise. The craniotomy is done to achieve maximal, safe resection as part of a multi-modality approach that will likely also include medication and radiation to achieve long-term mass and hormone control.

14. What is the role of radiation therapy in acromegaly?

Conventional radiotherapy is delivered as single beams of high-energy radiation in fractionated, daily doses given over 5–6 weeks, typically for a cumulative dose in the range of 50 Gy [53, 57]. The risk of adverse effects is proportional to the daily fractionated dose and the maximal dose. At present, most centers use conformal techniques of intensity-modulated radiation therapy [IMRT] to reduce the radiation dose to normal intracranial structures. IMRT may be considered a safe alternative option for residual or recurrent tumors close to the optic chiasm [within 2 mm] [42].

The pre-radiotherapy levels of GH and IGF-1 are the most important factors in the eventual success of radiation therapy in acromegaly [30]. In patients undergoing IMRT, the higher the pre-treatment GH and IGF-1 levels (off medication), the longer it takes to achieve remission and the lower the overall success remission rate with radiation alone [57]. Although the greatest reduction in GH levels after IMRT is in the first 24–36 months, it may take a decade or longer to achieve biochemical remission and normalization of IGF-1 levels [57]. As one may conceive, this long latency period means that radiation is not a first-line treatment option for patients with acromegaly, for the reasons discussed above. Depending upon how long (years versus decades) and how extensively one screens patients for hypopituitarism after radiation, anterior hormone deficiency ranges from 25% to as high as 80% in some studies [1, 35, 51, 57]. Other delayed deficits of radiation therapy include visual deficits (approximately 5%), radiation necrosis (on the order of 1%), and an increase in cerebrovascular disease since the large cerebral vessels at the base of the skull are included in the field [57].

15. What is the role of stereotactic radiosurgery (SRS) in acromegaly?

Stereotactic radiosurgery (SRS) has emerged as a useful, adjuvant treatment modality option for well-selected patients with residual tumors after surgery and some on medical treatment. Typically, to be a candidate, the tumor needs to be at least 2 mm from the optic nerve, chiasm, or radiation; this may be the lower limit for frame-based methods – it may be greater than 2 mm when treating with frameless techniques, since the former may have slightly better accuracy, because the head is fixed rigidly during treatment [1, 42, 53]. SRS consists of multiple, low-energy beams forming a dosimetric map around the target, with a suprathreshold integral dose, but sharp radioactivity falls off beyond the target [57]. There are several brands of SRS that differ in the method used, including Gamma Knife® (Elekta, Stockholm, Sweden), which uses a cobalt-60 source to generate gamma rays; Cyberknife® (Accuray, Sunnyvale, CA), a linear particle accelerator that generates 6MV x-ray irradiation); or proton-beam radiosurgery.

SRS is usually administered as an outpatient, one-day, single-dose treatment. Over the long-term of 3–5 years, SRS may be more cost-effective than the life-long medical treatment options of SRLs and GHRAs [1]. The mean radiation dose to the margin of the pituitary adenoma in most patients is 16-20Gy, striving to at least achieve 15Gy to the equivalent of the 50% local isodose line (the outer aspect of the tumor, with doses increasing inside the mass of the tumor to essentially twice the 50% isodose) [57, 58]. One strives to minimize the dose to normal, para sellar structures, especially the optic apparatus, trying to keep the dose to 9Gy or less, if possible [53]. IMRT and SRS have comparable incidences of hormone normalization and hypopituitarism, although SRS tends to effect biochemical remission faster, typically in 2–5 years in 70–80% of those patients treated with SRS, compared to 3–10 years for IMRT [42, 53].

There are several key points to consider:

• The greater the maximal radiation dose (that can be delivered safely) significantly predicts hormonal remission. Interestingly, the marginal radiation dose is not prognostically significant [53].

• The radiation dose to the pituitary stalk directly correlates to the degree of hypopituitarism [42].

• Mass control means the tumor stays the same size as well as, in many patients, becoming smaller. However, not all tumors get smaller, even if the tumor cells no longer secrete or die. It is therefore important to recognize that in some patients, hormone normalization is not directly associated with a reduction in the tumor size post-radiation. In this setting, neuroimaging may be misleading; biochemical monitoring of IGF-1 is the crux of long-term follow-up [35, 57].

• Some small, non-controlled, retrospective studies in which somatostatin analogs were given at the time of radiation, suggested that concurrent use may decrease the efficacy of radiation by decreasing the proliferation rate of the adenoma, as indicated by lower GH levels [35, 53]. Some advocate holding off on medical therapy for 1–2 months and 1–3 months after radiation, to take advantage of any DNA damage that radiation may cause to proliferating tumor cells. This remains an unclear area.

• Compared to radiation therapy, SRS has a shorter mean remission time, of 3.3 years, with late-onset hypopituitarism (more than 5 years later), which may affect up to 50% of patients [1, 42]. The second most common adverse effect is optic neuropathy, which occurs in fewer than 1% of patients [57].

16. Conclusion

This paper reviews the current management options for the management of acromegaly, including the various options of medical treatment, radiation therapy, and surgical options.

Learning objectives

Identify the clinical and biochemical features of acromegaly.

Discuss the treatment options for patients with acromegaly to compare and understand the risks and rationale of each treatment strategy.

Understand the accompanying comorbidities of acromegaly requiring long-term surveillance and treatment.

Key points

In approximately 95% of patients, acromegaly is caused by a somatotroph adenoma, with excess secretion of growth hormone after epiphyseal plate closure resulting in symptoms and signs due to hypertrophic changes in bones, muscles, joints, and soft tissues without changes in height. Before epiphyseal plate closure this results in excessive vertical and appendicular growth in children and adolescents.

In <5% of the patient population, acromegaly is secondary to ectopic growth hormone releasing hormone (GHRH) or a growth hormone-secreting neuroendocrine tumor.

• Acromegaly is characterized by chronically elevated growth hormone [GH] and insulin-like growth factor-1 [IGF-1] serum levels.

• On presentation, acromegalic patients may have involvement of multiple systems: cardiovascular, respiratory, metabolic, bones, and joints, resulting in elevated morbidity and premature mortality rates compared to age- and sex-matched patients without acromegaly.

• For most patients, trans-nasal surgical resection of the adenoma is the preferred option, due to its ability to effect rapid and lasting biochemical cure, with long-term (5+ years) remission rates of 80–90% in microadenomas, with decreasing surgical efficacy as tumors increase in size and extent of parasellar invasion of the bone, dura, cavernous and paranasal air sinuses, and intracranial spaces.

• Other therapeutic options for acromegaly include lifelong medical treatments with one or more of a variety of agents, including somatostatin ligand receptors, growth hormone receptor antagonists, and dopamine agonists. For some patients, especially those with invasive tumors and those who have incomplete responses to medical treatment, radiotherapy may be useful. Both stereotactic radiosurgery and fractionated radiation therapy can treat both the mass effect and reduce and, possibly, eliminate the hypersecretory states.