| Growth hormone physiology |
> Pulsatile secretion of GH by the anterior pituitary
Normally, somatotroph cells are under the dual control exerted by hypothalamic peptides, including stimulation by growth hormone-releasing hormone (GHRH) and inhibition by somatostatin. Ghrelin, predominantly secreted by the gastric fundus and also expressed in the hypothalamus, provides an additional, poorly understood stimulus of GH secretion.
In healthy individuals, GH is secreted episodically, especially during slow-wave sleep or during exercise. GH exerts multiple effects on metabolism and promotes tissue growth, either directly or indirectly; The indirect actions of GH are mediated by GH induced by the stimulation of insulin-like growth factor 1 (IGF-1), secreted by hepatocytes and muscle and bone cells, among others, acting endocrine or paracrine way. In healthy individuals, GH secretion is under the negative feedback control of circulating IGF-1, mostly of hepatic origin.
Unlike circulating GH, serum IGF-1 levels are stable over a 24-hour period and serve as a measure of GH action. This hormone exerts its action linked to its cognate receptor (GHR), a member of the cytokine receptor superfamily.
GHR exists in a dimeric form before ligand binding. Upon GH binding, GHR undergoes conformational changes that allow the activation of Janus kinase 2 (JAK2), leading to the phosphorylation and activation of several signal transducers and activators of transcription (STAT), including STAT 1, which mediate intracellular GH signaling. Additional GH signaling pathways have been recognized.
IGF-1, secreted in response to the action of GH, mediates its effects by binding to the IGF-1 receptor located on the cell membrane of target cells. Upon ligand binding, the intrinsic tyrosine kinase of the IGF-1 receptor is activated, leading to phosphorylation of several substrates and negative activation of the phosphatidylinositol 3-kinase and Ras-mitogen-activated protein kinase pathways.
| Pathogenesis of acromegaly |
In most cases, acromegaly occurs as a consequence of chronic exposure to excess GH, secreted by a somatotrophic pituitary adenoma in an unregulated manner. These are typically benign tumors and can be classified histologically as densely granulated, sparsely granulated, mixed acidophilic and somatolactotrophic stem cells, and mammosomatotrophic adenomas.
Somatotroph adenomas are usually sporadic. However, familial or syndromic acromegaly occurs in a small minority of patients. They are isolated familial pituitary adenomas, multiple endocrine neoplasia 1 and X-linked acrogigantism, hereditary paraganglioma-pheochromocytoma syndrome, Carney complex, and neurofibromatosis 1.
Exogenous GH, administered in excess, presents with the phenotype of patients with acromegaly. Very rarely, GHRH secretion from an ectopic neuroendocrine tumor or sellar gangliocytoma can drive excess GH from pituitary somatotrophs. Ectopic secretion of GH from islet cell tumors or lymphomas has also been reported.
Somatotrophic pituitary adenomas generally secrete GH autonomously, leading to excess GH and IGF-1. However, silent somatotroph adenomas that are not associated with a hormonal excess syndrome have also been found. In patients whose disease begins before epiphyseal fusion, linear growth is greater, leading to gigantism. In contrast, patients whose tumors occur after epiphyseal maturation develop acromegaly, characterized by typical facial features (frontal bossing, prominent cheeks and nose, thickened lips, prognathism, widely spaced teeth, and macroglossia), acral enlargement, and organomegaly.
On the other hand, chronic excess of GH is associated with multiple manifestations: cardiovascular (hypertension, ventricular hypertrophy, heart failure, arrhythmias), pulmonary (obstructive sleep apnea, neoplastic (colonic polyps and cancer, differentiated thyroid cancer), endocrine and metabolic (insulin resistance and diabetes mellitus, oligomenorrhea), and musculoskeletal (vertebral deformities, osteoarthropathy, carpal tunnel syndrome). About 70% of somatotroph adenomas are macroadenomas, defined (> cm in largest diameter). Pituitary macroadenomas They can exert a mass effect on the normal pituitary gland or surrounding structures, leading to hypopituitarism, headaches, or visual impairment.
| Diagnosis of acromegaly |
In young patients with excessive linear growth during childhood or adolescence, excess GH should be ruled out. Adults who present with acral enlargement or suggestive facial features should be investigated for acromegaly, as well as those who present with a constellation of symptoms, signs, or conditions associated with acromegaly (frequent headaches, excessive sweating, hypertension, sleep apnea, oligomenorrhea, arthralgia, carpal tunnel syndrome and type 2 diabetes mellitus).
A high index of suspicion is needed to consider the diagnosis, particularly if the disease is in its early stages. It is common for the interval between the onset of symptoms and diagnosis to be several years. A longer interval between disease onset and diagnosis has been associated with higher overall mortality and a greater number of comorbidities, confirming the importance of early detection.
To detect acromegaly in patients with subtle features, it is useful to analyze current and previous facial features. The use of Machine Learning is being studied , which may allow the early identification of acromegaly, based on the analysis of facial photographs, with a sensitivity of 96% , a specificity of 96%, a positive predictive value of 96% and a negative predictive value of 95%.
Serum IGF-1, measured by immunoassay or liquid chromatography/tandem mass spectrometry, does not show significant diurnal variation, and is the diagnostic test of choice when GH excess is suspected.
In general, when the test is done under conditions of reliability it is accurate; however, repeating it is recommended, particularly when the result is borderline or does not fit the clinical picture. Taking into account that in adulthood, serum IGF-1 levels decrease with advancing age, it is essential that reference intervals are carefully established for patients of different age groups.
Serum IGF-1 levels typically increase during adolescence as well as pregnancy, which could confound test interpretation in these groups. On the other hand, serum IGF-1 levels may be attenuated in patients with acromegaly who present resistance to the action of GH, including those with advanced liver or kidney disease, severe hypothyroidism, malnutrition, anorexia and poorly controlled diabetes mellitus or, in women receiving oral estrogen. Estrogen induces suppressor of cytokine signaling (in hepatocytes, reducing GH-mediated signaling and IGF-1 secretion.
For the diagnosis of acromegaly, it is not recommended to measure serum GH levels in random samples by immunoassay, since it has been associated with biochemical results of surgical or medical treatments. Serum GH levels, measured every 30 minutes for 2 hours after administration of 75 g of oral glucose may be useful in establishing the diagnosis of acromegaly.
In most healthy individuals, GH levels decrease to a nadir below 0.4 µg/L after glucose administration (using sensitive immunoassays). In contrast, patients with acromegaly fail to suppress serum GH levels after oral glucose administration. However, the cut-off point for optimal diagnosis of this test has been a matter of debate. For routine clinical use in the diagnosis of acromegaly, a somewhat higher diagnostic cut-off point (1 µg/L) for nadir GH levels has been suggested, taking into account the more limited precision of some GH immunoassays that are in use today.
Once the diagnosis of acromegaly is confirmed based on the results of endocrine tests, and if a pituitary adenoma (the most common cause of acromegaly) is suspected, magnetic resonance imaging (MRI) should be obtained. If there are contraindications to MRI, a CT scan of the brain can be done (with special attention to the sella turcica). In one study, 3.2% of patients (6 of 190) with acromegaly had no pituitary tumor evident on standard MRI. Among the rare patients with acromegaly without obvious tumor on pituitary MRI, serum GHRH levels and cross-sectional images of the chest and abdomen may be useful in detecting an ectopic source.
| Management of acromegaly |
> Overview
Patients with uncontrolled acromegaly have lower survival, which has been attributed to a higher risk of cardiovascular, cerebrovascular, respiratory and neoplastic diseases. Patients whose disease is controlled, including those with normal serum IGF-1 and low serum GH (random GH level <2.5 µg/L in the old polyclonal immunoassays or a GH level <1.0 µg/L in the newer monoclonal immunoassays), have mortality rates indistinguishable from rates in the general population.
Broadly speaking, therapeutic goals in patients with acromegaly include normalization of GH secretion or (at least) GH action indicated by a normal level of IGF-1 as well as resolution of mass effects induced by the tumor, the symptoms related to acromegaly and the associated comorbidities, all with the objective of mitigating excess mortality while preserving normal pituitary function.
Management options for patients with acromegaly include pituitary surgery, medical treatment, and radiation therapy. Pituitary surgery is the cornerstone of treatment for most patients. In general, medical therapy and radiation therapy represent second- and third-line options, respectively, and are typically recommended for patients who are not in remission postoperatively. Furthermore, preoperative medical therapy may have a role in the management of patients with sleep apnea or heart failure, to reduce perioperative risk.
Some studies have reported that preoperative medical therapy with somatostatin receptor ligands (SLRs) may improve surgical remission rates. However, methodological concerns and low remission rates in patients undergoing surgery without preoperative medical treatment have raised concerns about the generalizability of some of these studies. Some patients may be candidates to be treated in primary care with LRS, such as those with tumors that do not compress the optic apparatus and whose extension into the cavernous sinuses or clivus makes it impossible to be cured by surgery, and also those who refuse or surgery is contraindicated.
Deep Learning and other artificial intelligence technologies may be useful in accurately predicting response to therapy. In addition to tumor-directed treatment and control of GH excess, special attention should be paid to identifying and managing comorbidities associated with acromegaly, which can lead to a deterioration in quality of life (even in patients in remission) and to excess mortality.
To detect such comorbidities, several evaluations have been recommended, such as blood pressure measurements, electrocardiography, echocardiography, sleep apnea testing (sleep study), evaluation of blood glucose and anterior pituitary function, bone mineral density, and morphometry. vertebral (by X-ray), screening colonoscopy and assessment of quality of life.
> Pituitary surgery
Pituitary surgery is usually done transsphenoidally, in most cases using an endoscope, although some surgeons still use an operating microscope. The use of the endoscope may be associated with a higher rate of gross total resection but does not differ in endocrine remission.
Pituitary surgery requires substantial experience to achieve optimal results with respect to endocrine remission and tumor resection, while minimizing perioperative complications, including epistaxis, cerebrospinal fluid leak, tumor bed hemorrhage, meningitis, stroke , diabetes insipidus, hyponatremia and anterior hypopituitarism. Perioperative mortality rates are <1% in expert hands.
When transsphenoidal surgery is performed by experienced surgeons, remission can be achieved in up to 90% of patients with acromegaly caused by tumors <1 cm in maximum diameter (microadenomas). On the contrary, patients with larger tumors (macrodenomas) achieve endocrine remission in 50% to 60% of those operated on transsphenoidally.
In addition to surgical experience and tumor size and invasiveness, serum GH level also predicts the probability of postoperative remission. GH levels in the immediate postoperative period are an important predictor of long-term remission. Patients with pituitary adenomas extending into the cavernous sinuses or clivus or dura mater are significantly less likely to achieve endocrine remission after transsphenoidal surgery and generally require additional treatment. However, subtotal tumor resection (reduction) improves tumor response to LRS treatment.
Transsphenoidal surgery is usually effective in decompressing the optic chiasm, thus improving vision in the majority of patients with visual compromise due to the mass effect exerted by a pituitary adenoma. Several symptoms and comorbidities associated with acromegaly also improve in patients who are in postoperative biochemical remission, as well as organomegaly regresses. However, some comorbidities may persist (hypertension) or even progress (osteoarthropathy) despite achieving biochemical control of GH excess and require additional treatment.
> Medical treatment
Current options for medical treatment of patients with acromegaly include LRS, cabergoline, and pegvisomant. The Food and Drug Administration (FDA) has approved several LRSs and pegvisomant for the treatment of patients with acromegaly. Cabergoline has been used off-label in this patient population.
First-generation LRSs (octreotide acetate, octreotide extended-release [LAR], depot lanreotide, oral octreotide) and a second-generation LRS (pasireotide LAR) activate distinct subsets of somatostatin receptors, inhibiting GH secretion. while promoting apoptosis and exerting antiproliferative effects. These agents engage Gi proteins to inhibit adenylate cyclase and calcium while activating potassium channels, causing hyperpolarization of the cell membrane. These events culminate in decreased GH secretion.
Furthermore, LRS activate pertussis toxin G proteins independent of G proteins, leading to the activation of phospholipase C and the generation of inositol 1,4 y5-trisphosphate. Likewise, the tyrosine phosphatases SHP-1 and SHP-2 are activated in response to activation of a subset of different somatostatin receptors, as is the tyrosine kinase Src. Finally, these pathways exert positive regulation of antiproliferative and proapoptotic pathways resulting in antitumor effects. To exert their salutary effects on acromegaly, first-generation LRSs primarily involve SSTR-2 (somatostatin receptor-2) and secondarily SSTR-5.
In a meta-analysis of 90 studies, administration of first-generation LRS normalized IGF-1 and controlled GH in 54% and 55% of 3,787 patients with acromegaly, respectively. No difference in efficacy was found between octreotide LAR and lanreotide depot. First-generation LRS studies in unselected patients have reported somewhat lower efficacy with respect to biochemical control (achieved in about 30% to 40% of patients). Almost 60% of acromegaly patients controlled with first-generation parenteral LRS maintain biochemical control after being switched to oral octreotide. Another meta-analysis of 41 studies with first-generation LRS reported that 53% of 1,685 patients showed some degree of tumor retraction with LRS therapy. Several symptoms and comorbidities associated with acromegaly improve in response to LRS therapy, including headaches, soft tissue swelling, ventricular function, and sleep apnea.
Several factors have been reported as possible predictors of biochemical response to first-generation LRS therapy, including patient age and sex, baseline GH and IGF-1 levels, genetic abnormalities, histopathological and imaging characteristics of the tumor.
In a study of 88 patients treated with depot lanreotide, with a maximum dose for 48 weeks, older age and female sex, an association was found with the biochemical control of GH excess (normal IGF-1 level and GH <2, 5 µg/l). In the same study, lower baseline serum IGF-1 levels were associated with a greater likelihood of achieving biochemical control. Lower serum GH levels at baseline have also been reported to be predictive of IGF-1 normalization in response to LRS therapy but not in all studies.
A minority of patients with acromegaly have germline genetic abnormalities, which may influence response to first-generation LRS therapy. Patients with mutations that inactivate the aryl hydrocarbon receptor activity-modulating protein (AIP) who develop acromegaly exhibit lower GH levels and decreased IGF-1 after LRS administration, but reduction of the tumor. There are also mutations that cause resistance to LRS therapy. Patients with amplification of the GPR101 gene develop early-onset acrogigantism. These patients are unlikely to normalize IGF-1 in response to LRS therapy. Patients with McCune-Albright syndrome may also show little biochemical response to LRS therapy.
Somatic (tumor) mutations in GNAS (guanine nucleotide-bound protein (gsp) are present in 40% of somatotroph adenomas and may predict a favorable GH response to LRS therapy in some but not all studies. In In a meta-analysis, the presence of the gsp mutation was associated with a greater decrease in GH levels during acute octreotide testing (predicting response to long-term LRS treatment).
Densely granulated adenomas represent 30% to 50% of somatotroph tumors and show perinuclear keratin immunoreactivity. These tumors are usually seen in older patients and are typically hypointense on T2-weighted MRI sequences. Patients with this type of adenomas are more likely to respond to treatment with first-generation LRS. In a study of 40 patients treated with octreotide LAR for 28 months, those with densely granulated tumors were significantly more likely to normalize serum IGF-1 and GH levels in response to LRS compared to those with sparsely granulated tumors.
Other histopathological characteristics and molecular tumor markers have been identified, proposed as possible predictors of response to LRS. Ki-67 is a nuclear protein expressed in cells that are not in the resting phase. A lower Ki-67 index (Ki-67 <2.3%) may predict a greater response to first-generation LRS. Furthermore, higher expression of SSTR-2 has been associated with a greater likelihood of achieving biochemical control in patients with acromegaly in response to LRS therapy. A higher ratio between SSTR-2 and SSTR-5 expression has been associated with better biochemical response to first-generation LRS therapy.
Among patients without germline AIP mutations, higher AIP expression in somatotroph tumor cells has been associated with greater likelihood of achieving biochemical control in first-generation LRS therapy. It has been suggested that SSTR-2 expression, AIP expression and the Ki-67 index can independently predict the biochemical response to LRS therapy. Lower expression of β-arrestin, a protein that negatively regulates SSTR-2-mediated signaling, has been associated with a higher response rate to LRS therapy.
Furthermore, higher expression of E-cadherin, a cell adhesion protein, has been associated with a higher likelihood of achieving biochemical control outcomes with LRS therapy. Similarly, increased expression of ZAC1, a zinc finger transcription factor that appears to be one of the intracellular signaling mediators of octreotide action, has been associated with increased biochemical response to first-generation LRS therapy. . Increased expression of the Raf kinase inhibitor protein, which mediates SSTR-mediated signaling, has been associated with a better response to LRS therapy in acromegaly.
Imaging characteristics on MR may also predict response to first-generation LRSs. T2 hypointense adenomas make up 40% of somatotroph adenomas and are generally densely granulated. T2 hypointense tumors are more likely to have a good biochemical response to LRS therapy. In a recent study, peak pixel intensity (image texture) predicted normalization of serum IGF-1 in first-generation LRS therapy.
Pasireotide LAR is a second-generation LRS with expanded specificity SSTRs (engaging SSTR-1, 2, 3, and 5). It is probably more effective than first-generation LRS in controlling GH secretion.
About 20% of patients with acromegaly who are not controlled with first-generation LRS can achieve biochemical control with pasireotide LAR. Whether expression of SSTR-5 or SSTR-2 predicts response to pasireotide LAR therapy is debatable. On the other hand, T2 signal intensity on MRI can predict the response to pasireotide LAR. All LRSs share a similar potential for gastrointestinal adverse effects (diarrhea, abdominal pain, cholelithiasis), alopecia, and sinus bradycardia. However, LAR pasireotide is more likely to induce hyperglycemia or diabetes mellitus than first generation, perhaps as a consequence of SSTR-5 activation resulting in decreased insulin and incretin secretion.
Cabergoline is a selective D2 agonist at dopamine receptors approved by the FDA for the treatment of patients with hyperprolactinemia. It is used off-label in patients with acromegaly. A meta-analysis of 9 studies reported that cabergoline normalized IGF-1 and controlled GH, 34% and 48%, respectively (of 149 patients). Lower baseline serum IGF-1 levels and anterior sella radiotherapy predicted a good biochemical response to cabergoline therapy. In the same meta-analysis (5 studies) of data on patients inadequately controlled with LRS, additional therapy with cabergoline resulted in normalization of IGF-1 in 52% of 77 patients. Lower baseline serum IGF-1 levels predicted a greater likelihood of biochemical response to cabergoline. Associated adverse effects include nausea, vomiting, orthostatic dizziness, headache, nasal congestion, constipation, and digital vasospasm.
In patients with Parkinson’s disease, treatment with cabergoline at high doses (3 to 7 mg/day) was associated with cardiac valvular disease, probably as a result of activation of 5-hydroxytryptamine subtype 2B receptors. In acromegaly, doses higher than those used in hyperprolactinemic patients but lower than those used in patients with Parkinson’s disease are usually used. The risk of valvular heart disease in patients with hyperprolactinemia appears to be low. However, the risk of valvular disease in patients with acromegaly receiving cabergoline remains unclear. It is advisable to perform periodic echocardiography in patients receiving >2 mg/week of cabergoline. However, the cost-effectiveness of this strategy has not been established.
Impulse control disorders have been reported in hyperprolactinemic patients receiving cabergoline therapy, presumably as a consequence of activation of the D2 receptor in the mesolimbic dopamine pathway.
Pegvisomant is a GH analog that carries several amino acid substitutions and functions as a GHR antagonist. Several multidetector polyethylene glycol fractions have been covalently linked to pegvisomant to prolong its half-life in the systemic circulation. Pegvisomant binds to GHR with high affinity but does not activate positive signaling through the JAK/STAT pathway. It is effective in inhibiting the action of GH and normalizes IGF-1 in 89% to 97% of patients with acromegaly. In post-marketing studies, pegvisomant therapy led to normalization of IGF-1 in up to 75% of patients. It is possible that inappropriate dose titration or adherence to therapy could have resulted in reduced efficacy of pegvisomant in real-world settings.
Better glycemic control was observed in patients who switched from LRS therapy to pegvisomant, due to inhibition of GH action and lack of suppression of insulin or incretin secretion. Patients with lower body mass index or serum IGF-1 at baseline appear more likely to normalize IGF-1 with pegvisomant monotherapy. Patients with diabetes mellitus may be less likely to achieve IGF-1 normalization with pegvisomant, which may reflect the effects of insulin on GHR expression in hepatocytes.
Pegvisomant has been administered as adjunctive therapy to patients who partially respond to LRS and is an effective treatment option in this population. Patients with lower body mass index or serum IGF-1 levels at baseline may require lower doses of pegvisomant to normalize serum IGF-1, in combination therapy. Associated adverse effects of pegvisomant include transaminitis, rash, and injection site reactions. Transaminitis is reversible with dose reduction or drug discontinuation but hepatic failure has not been reported.
An increase in the size of somatotroph adenomas has also been reported in patients treated with pegvisomant (3.2% of 936 patients). In some cases, this increase may have been a consequence of discontinuation of LRS treatment or simply due to the natural history of more aggressive pituitary adenomas. It is advisable to periodically monitor the images.
Other treatments in research and development are: paltusotine (an orally active non-peptide LRS), somatoprim (an LRS involving SSTR-2, 4 and 5), CAM2029 (liquid crystal formulation of octreotide depot) and, an antisense oligonucleotide directed to the mRNA that encodes the GHR.
> Radiotherapy
In general, radiotherapy is recommended for those who are not in postoperative remission and do not show a good response or tolerance to medical treatment. It also allows controlling tumor growth in patients with pituitary adenomas that do not respond adequately to surgery and medical treatment. It can be administered in conventional fractionated form or as stereotactic radiation. The latter can be administered in a single session (“radiosurgery”) in patients with smaller tumors, distant from the optic apparatus.
Biochemical control can be achieved in up to 60% of patients with acromegaly after several years, so it is necessary to apply provisional medical treatment until the healthy effects appear. In a recent retrospective analysis of 352 patients from the German Acromegaly Registry, endocrine remission was anticipated in patients who received stereotactic radiotherapy. However, the proportion of patients achieving endocrine remission at 10 years after radiotherapy was not different from that achieved by fractionated radiotherapy.
More than 90% of acromegaly patients who receive radiotherapy achieve tumor control. Adverse effects associated with radiation include: anterior hypopituitarism (40% to 50% of patients at 5 years), cranial optic or other neuropathies (1% to 2%). Other less common effects are: necrosis of the temporal lobe, stroke and secondary tumors.
The development of anterior pituitary hormone insufficiency may be less common after administration of stereotactic radiosurgery compared with fractionated techniques. However, long-term data are needed to determine whether these rare long-term adverse effects may also occur after stereotactic radiation therapy because new radiation therapy techniques minimize exposure of healthy brain structures to radiation.
