Excess growth hormone (Growth Hormone, GH) is a pathological condition supported in the great majority of cases by a secreting pituitary tumor, now classified within the category of PitNETs (pituitary neuroendocrine tumors) of the PIT1 lineage. GH acts directly on tissues and, above all, stimulates the production of IGF-1 (insulin-like growth factor 1) at hepatic and peripheral levels, producing a set of somatic, metabolic and organ effects that define a multisystem disease. When hypersecretion begins after fusion of the growth plates, the clinical phenotype is acromegaly, characterized by acral and soft-tissue growth, progressive dysmorphic changes and comorbidities. If GH excess appears before epiphyseal closure, acceleration of linear growth predominates and the condition is referred to as gigantism, often with earlier onset, a more aggressive course and a greater representation of genetic causes.
The clinical relevance of GH excess does not lie only in somatic changes, but also in its impact on the cardiovascular, respiratory, metabolic, osteoarticular and neoplastic systems, as well as on outcomes related to the mass effect of the sellar lesion. A correct assessment therefore requires integration of the pathophysiology of the GH-IGF-1 signal, biochemical criteria for diagnosis and disease control, pituitary imaging, evaluation of comorbidities and a multimodal therapeutic strategy centered on surgery, medical therapy and, in selected cases, radiotherapy.
Acromegaly is a rare disease, with incidence and prevalence varying across studies and registries, influenced by differences in healthcare systems, access to hormonal diagnostics and clinical awareness. A constant feature of its epidemiology is diagnostic delay: the disease evolves slowly, somatic signs are progressive and are often attributed to aging or weight gain, while the comorbidities that emerge (hypertension, diabetes, obstructive sleep apnea syndrome, arthropathy) may be managed for years without being traced back to a unifying cause. This delay increases the probability that the pituitary lesion is a macroadenoma at diagnosis, with therapeutic and prognostic implications.
Pituitary gigantism is much rarer, but clinically crucial because onset in childhood or adolescence entails a greater biological burden of GH and IGF-1 during phases of rapid growth. In this population, the probability of a genetic or syndromic basis is significantly higher than in sporadic adult acromegaly. Mutations in AIP (familial isolated pituitary adenoma, FIPA) and duplications of the Xq26.3 locus involving GPR101 (X-linked acrogigantism, XLAG) are paradigmatic conditions in which the disease begins early, with tumors that are often large, variable response to somatostatin ligands and frequent need for combined approaches. The distinction between sporadic and familial forms is not an academic detail, but guides the screening strategy in relatives, the choice of therapeutic timing and the intensity of follow-up.
Risk factors, understood as conditions that increase the probability of developing GH excess, mostly coincide with genetic and syndromic predispositions. In addition to AIP and XLAG, GH hypersecretion may occur within broader frameworks of predisposition to endocrine or pituitary neoplasms, with implications for surveillance of other districts and for identification of complex phenotypes. In parallel, it should be remembered that some clinical conditions may raise diagnostic suspicion more often than in the general population, not because they cause acromegaly, but because they are frequent associated comorbidities: newly diagnosed or difficult-to-control diabetes mellitus, resistant hypertension, hypertrophic cardiomyopathy or arrhythmias, obstructive sleep apnea syndrome, severe arthropathy and enlargement of the extremities or facial changes reported by the patient or family members.
Overall, the epidemiology of GH excess must be interpreted through a clinical lens: the rarity of the diagnosis does not imply rarity of suspicion, because the disease often hides behind combinations of “common” signs that, when read together, become highly specific. The main epidemiological challenge therefore remains early diagnosis, rather than absolute quantification of cases.
GH excess almost always derives from a secreting pituitary tumor, generally a pure somatotropinoma or a mixed tumor with prolactin co-secretion, classifiable within the PIT1 differentiation lineage. Modern classification emphasizes tumor biology more than size alone: densely or sparsely granulated subtypes, cytokeratin pattern (fibrous bodies), expression of somatostatin receptors (SSTR2 and SSTR5), proliferative markers and genetic context influence clinical aggressiveness and response to medical therapies. This perspective integrates the pathophysiology of secretion with PitNET oncobiology, explaining why patients with similar hormonal levels may have very different courses, comorbidities and sensitivity to treatments.
GH exerts direct effects through the GH receptor (GHR), activating intracellular pathways such as JAK2-STAT, MAPK and PI3K, with effects on tissue growth, lipolysis, glucose metabolism and endothelial function. However, most chronic somatic effects of GH excess are mediated by IGF-1, produced mainly by the liver but also locally in tissues. IGF-1 acts on tyrosine kinase receptors with mitogenic and antiapoptotic effects, contributing to hypertrophy and hyperplasia of soft tissues, cartilage and some organ compartments. The combination of GH and IGF-1 explains the phenotype: GH promotes insulin resistance and lipolysis, while IGF-1 has insulin-like effects in some contexts, creating a complex balance that varies according to age, adiposity, liver function and global hormonal status.
The difference between acromegaly and gigantism is not only temporal, but biological. During development, open growth plates make longitudinal bone tissue highly responsive to the GH-IGF-1 signal, with acceleration of height growth and increased growth velocity, often accompanied by relative macrocephaly, enlargement of the extremities and visceromegaly. In adults, bone no longer grows in length, but responds with remodeling, thickening and craniofacial changes, while articular cartilage and soft tissues undergo hypertrophy and degeneration. This transition explains why acromegaly is dominated by arthropathy and dysmorphic changes, while gigantism requires urgent assessment also to prevent psychological, orthopedic and cardiometabolic consequences during development.
At the level of organ pathophysiology, chronic excess of GH and IGF-1 induces a cardiovascular picture characterized by myocardial hypertrophy, diastolic abnormalities, possible arrhythmias and valvulopathies, with risk depending substantially on the degree of biochemical control and the presence of traditional risk factors. At the respiratory level, hypertrophy of pharyngeal tissues, macroglossia and modification of the upper airways favor obstructive sleep apnea syndrome. At the metabolic level, GH promotes hepatic and peripheral insulin resistance, increasing the risk of glucose intolerance and diabetes, while changes in lipid profile and body composition are consistent with redistribution of fat and changes in lean mass that are not necessarily favorable in the long term.
Finally, pathophysiology includes the mass effect of the pituitary tumor: headache, visual field defects due to compression of the optic chiasm, hypopituitarism caused by compression of healthy pituitary tissue and, more rarely, pituitary apoplexy. Although these elements are not “mediated” by GH and IGF-1, they are an integral part of the disease burden and influence therapeutic priorities and urgency.
The clinical manifestations of GH excess are the result of a slowly progressive process, often perceived retrospectively rather than recognized in real time. In the clinical history, the patient may report an increase in shoe, ring or glove size, facial changes noticed by family members, increased sweating, fatigue and headache. Very frequently, symptoms related to comorbidities emerge: snoring and daytime sleepiness due to sleep apnea, paresthesias or hand pain due to carpal tunnel syndrome, joint pain and functional limitation, weight gain or difficulty controlling blood glucose, reduced physical performance and sexual dysfunction. The history may include repeated diagnoses of hypertension, heart disease or diabetes despite treatment, suggesting an unidentified endocrine driver.
On physical examination, the most informative signs are the “integrated” ones, meaning combinations of findings that rarely coexist for other causes. The face may show soft-tissue thickening, frontal bossing, increased nasal and lip volume, prognathism and dental diastemata. The extremities appear enlarged, with spade-like hands, thickened and oily skin, and hyperhidrosis. The tongue may be increased in volume, and inspection of the upper airways may suggest a predisposition to obstruction. From an osteoarticular standpoint, acromegalic arthropathy combines signs of hypertrophy and degeneration, with pain, stiffness and reduced range of motion, often disproportionate to age. The spine may show kyphosis or postural abnormalities, and the patient may report low back pain or sciatica.
Clinical evaluation must systematically include signs of pituitary mass effect. Targeted questions about reduced peripheral vision, bumping into objects at the sides, blurred vision or diplopia are essential. In macroadenomas, visual field examination and observation of signs of associated hypopituitarism are an integral part of assessment: marked asthenia, cold intolerance, loss of libido, amenorrhea, reduced body hair or symptoms of adrenal insufficiency may coexist, not because of GH excess itself, but because of concomitant pituitary compression or dysfunction.
In gigantism, the clinical history is often dominated by accelerated height growth with increased growth velocity, and physical examination reveals excessive weight and height, enlargement of the extremities, possible prolactin co-secretion with related signs and, in cases of large tumors, neurological or visual signs. Pediatric assessment must always contextualize growth in relation to familial genetic target, bone age and pubertal pattern, because the interaction between GH, puberty and skeletal maturation can mask or amplify hypersecretion.
In summary, the clinical picture of GH excess is a “history of accumulation”: a few isolated signs may be nonspecific, but their coexistence, together with typical comorbidities and a possible sellar mass effect, builds a high pre-test probability pattern that must rapidly lead to biochemical confirmation.
Suspicion of acromegaly should arise when the clinician recognizes a coherent set of somatic and systemic elements, rather than a single marker. A practical criterion is to consider acromegaly whenever progressive phenotypic changes coexist (enlarged hands and feet, facial changes, prognathism, macroglossia) with at least one typical comorbidity: obstructive sleep apnea, difficult-to-control hypertension, diabetes or glucose intolerance, severe arthropathy, carpal tunnel syndrome, profuse sweating and headache. Even in the absence of an overt phenotype, the presence of a pituitary incidentaloma or macroadenoma must always prompt a hormonal profile including IGF-1, because the tumor may be biochemically active before somatic signs are clearly recognizable.
Suspicion is particularly important in some specialist settings. In pulmonology and sleep medicine, patients with severe apnea and macroglossia or with anatomical changes of the upper airways should be evaluated with IGF-1 if other suggestive signs coexist. In diabetology, recently diagnosed diabetes associated with acromegalic features or resistant hypertension deserves screening. In orthopedics and rheumatology, early or disproportionate degenerative arthropathy, with pain and functional limitation, especially when associated with bilateral carpal tunnel syndrome, may be a diagnostic clue. In dentistry and maxillofacial surgery, the finding of progressive malocclusion, diastemata or evolving prognathism is a signal that, if connected to systemic symptoms, may anticipate diagnosis.
For gigantism, suspicion must be even more “aggressive” and early. An increase in growth velocity beyond expected percentiles, especially in childhood, with acceleration not explained by familial pattern, precocious puberty or other causes, requires an endocrinological evaluation oriented toward the GH-IGF-1 axis. In the presence of signs such as enlargement of the extremities, increased sweating, headache, visual disturbances, hyperprolactinemia or a documented pituitary tumor, suspicion becomes a priority. In pediatric cases, a family history of pituitary tumors or gigantism should also direct evaluation toward genetic assessment, because identification of AIP or Xq26.3 alterations has implications for management of the patient and relatives.
In summary, suspecting GH excess means recognizing the “signature” of the disease across its multiple domains: progressive somatic change, typical comorbidities and, when present, signs of pituitary mass effect. This step is decisive because reducing diagnostic delay is the most effective strategy to reduce complications and mortality.
The diagnosis of acromegaly and gigantism is primarily biochemical and requires integration of IGF-1, evaluation of GH secretion and pituitary imaging. The first step, in the presence of clinical suspicion, is measurement of IGF-1 using a validated assay and interpretation according to age and sex. IGF-1 is the marker of choice for screening because it integrates chronic exposure to GH and has lower pulsatile variability. Persistently elevated values above the upper limit of normal, in a coherent clinical context, make the diagnosis highly probable and require confirmation and staging.
Evaluation of GH requires attention to conceptual and analytical limitations: GH is pulsatile, influenced by sleep, exercise, stress, nutritional status and comorbidities, and comparability between laboratory methods is not absolute. For this reason, the most informative test in most cases is assessment of GH suppression after an oral glucose tolerance test (OGTT), because hyperglycemia physiologically suppresses GH. In acromegaly, suppression is inadequate. However, some conditions make interpretation more complex, such as uncontrolled diabetes, liver or kidney disease, pregnancy and oral estrogen therapy, which may alter IGF-1 or GH dynamics. In equivocal cases, repetition of IGF-1 with the same method, optimization of preanalytical conditions and integrated assessment with OGTT and clinical data are essential to avoid overdiagnosis or underdiagnosis.
Once biochemical evidence has been established, the imaging modality of choice is contrast-enhanced magnetic resonance imaging of the pituitary, aimed at defining size, invasiveness and relationship with the optic chiasm and cavernous structures. In macroadenomas or in the presence of visual symptoms, visual field testing is an essential complement. In parallel, a complete evaluation of pituitary function must always be performed to identify any associated hypopituitarism, which influences perioperative management, therapeutic choice and follow-up. Prolactin co-secretion is frequent in tumor subtypes and must be considered both diagnostically and therapeutically, because it may increase the efficacy of some therapies and modify the clinical profile.
In gigantism, in addition to biochemical confirmation and imaging, assessment must include evaluation of bone age, pubertal status and growth, because “biological time” determines the impact of GH excess. In cases with very early onset or a suggestive phenotype, genetic investigation becomes part of precision diagnostics: identifying AIP or Xq26.3 duplications may explain clinical aggressiveness, guide therapeutic choices and direct family surveillance.
Finally, diagnostic assessment must include systematic evaluation of comorbidities: blood pressure, glucose metabolism, lipid profile, cardiological evaluation when indicated, sleep study for apnea, osteoarticular evaluation and strategies for endoscopic colon screening according to recommendations and individual risk. In this way, diagnosis is not only the label “acromegaly”, but the complete definition of disease burden and therapeutic priorities.
The classification of GH excess must be clinically functional, meaning capable of explaining presentation, probability of control and therapeutic strategy. A first axis distinguishes acromegaly from gigantism according to the state of the growth plates: the same hormonal hypersecretion produces profoundly different somatic consequences before or after epiphyseal closure. This distinction imposes differences in timing of intervention, auxological assessment and psychological and orthopedic management.
A second axis is tumoral and includes size and invasiveness, elements that influence the probability of surgical remission and the risk of post-treatment pituitary deficits. Microadenomas and macroadenomas are not static categories: tumor growth over time interacts with diagnostic delay and PitNET biology. Cavernous sinus invasion, contact with the optic chiasm and tumor consistency are practical determinants of the surgical strategy and of the realistic expectation of biochemical control.
A third axis is histopathological and molecular. Densely granulated somatotropinomas tend, in many contexts, to respond better to somatostatin ligands than sparsely granulated tumors, which are often associated with more aggressive presentations and high hormonal levels. Expression of SSTR2 and SSTR5 provides a biological basis for choosing between first- and second-generation somatostatin analogues, while proliferative markers and some immunohistochemical patterns contribute to defining recurrence risk and the need for closer follow-up. The recent WHO classification has consolidated an approach based on transcription factors and cellular phenotype, offering a more coherent framework linking clinical features, pathology and therapy.
A fourth axis is genetic and distinguishes sporadic forms from familial or syndromic forms. AIP mutations and GPR101 duplications are particularly relevant for early onset and gigantism, but even in adults, the presence of family history or multiple pituitary tumors requires specific assessment. Genetic classification does not replace clinical and tumoral classification, but integrates it, because predisposition may predict larger tumors, more difficult control and the need for combined strategies.
Finally, severity must be defined multidimensionally: not only IGF-1 and GH levels, but also extent of mass effect, burden of comorbidities and degree of functional disability. Two patients with the same IGF-1 may have different prognoses if one has heart disease and severe apnea and the other does not. For this reason, a truly useful classification is one that links tumor biology, biochemical status and global clinical impact, making the choice between surgery, primary or adjuvant medical therapy, radiotherapy and follow-up intensity rational.
Treatment of GH excess is typically multimodal and aims to achieve biochemical control (normalization of IGF-1 and adequate GH suppression according to shared criteria), reduction or stabilization of tumor mass, improvement of comorbidities and reduction of mortality. The choice of therapeutic sequence depends on tumor size and invasiveness, availability and surgical expertise, the patient’s clinical profile and specific objectives, including management of gigantism in pediatric age, where rapid control is often a priority to prevent excessive growth and organ damage during development.
Transsphenoidal surgery represents the first-line therapy in most cases, especially when the tumor is resectable and when signs of chiasmal compression are present. The probability of remission depends on size, cavernous invasion and the possibility of complete resection, as well as on the experience of the center. Surgery, when effective, offers rapid control and reduces the need for chronic therapies. However, a significant proportion of patients requires adjuvant treatment for biochemical persistence or residual tumor, making it essential to plan from the outset a pathway that includes medical therapy and, in selected cases, radiotherapy.
Medical therapy includes three main classes. Somatostatin receptor ligands (SSA) are often the cornerstone: they reduce GH secretion and may reduce tumor volume, with efficacy influenced by receptor expression and tumor subtype. Octreotide LAR and lanreotide autogel are established options; in selected patients, a ligand with greater affinity for SSTR5 such as pasireotide may be considered, taking into account its metabolic tolerability profile, particularly the risk of worsening glycemic control. Dopamine agonists, especially cabergoline, may be useful in mild forms, in the presence of prolactin co-secretion or as add-on therapy when IGF-1 is modestly elevated. Pegvisomant, a GH receptor antagonist, blocks the peripheral action of GH and normalizes IGF-1 in a high proportion of patients, proving particularly useful when the main goal is biochemical normalization and metabolic control; however, it requires hepatic monitoring and careful surveillance of tumor mass because it does not directly reduce GH secretion and, in some contexts, volumetric stability must be documented over time.
Therapeutic combinations are frequent and rational: SSA plus cabergoline to enhance control in forms that do not respond completely, SSA plus pegvisomant to achieve IGF-1 normalization while reducing dosages and improving the metabolic profile, and personalized strategies based on biochemical response, imaging and tolerability. In some patients, medical therapy may be used as primary treatment when surgery is expected to have low yield, when comorbidities increase operative risk or when this reflects the patient’s informed preference. In the presence of large tumors, an approach with preoperative medical therapy may be considered in expert centers to improve clinical conditions and sometimes reduce volume, while maintaining the most effective long-term strategy as the goal.
Radiotherapy, including stereotactic radiosurgery when appropriate, is reserved for residual tumors not controlled with surgery and medical therapy or for forms with more aggressive behavior. Its main limitation is the latency of hormonal control and the risk of hypopituitarism over time, which requires prolonged endocrine follow-up. In gigantism, management may be particularly complex because of biological aggressiveness, genetic predisposition and the objective of rapid control; here, integration of early surgery, intensive medical therapy and, rarely, radiotherapy must be assessed case by case in referral centers.
In parallel with control of the GH-IGF-1 axis, it is essential to actively treat comorbidities: management of diabetes and hypertension, treatment of sleep apnea, interventions for pain and joint disability, and surveillance plans for colon neoplastic risk according to the individual profile. Effective treatment of GH excess improves many comorbidities, but does not always normalize them completely, especially when the disease has been long-standing, which is why therapy must be conceived as an integrated pathway rather than a single intervention.
Follow-up of acromegaly and gigantism must be structured to meet three needs: confirming stable biochemical control, monitoring tumor mass and managing long-term comorbidities and complications. Biochemical control is based mainly on IGF-1, interpreted according to age and sex and measured with methods that are consistent over time, alongside GH evaluations according to clinical indications and shared criteria. After surgery, the timing of reassessment must consider the dynamics of IGF-1 normalization and the possible discrepancy between GH and IGF-1 in the early phases; after medical therapy, monitoring is aimed at optimizing dose, assessing adherence and identifying non-responders or partial responders who benefit from combinations.
Radiological monitoring with pituitary magnetic resonance imaging is essential to document residual tumor, stability or progression, with frequency adjusted according to invasiveness, behavior and type of therapy. In patients treated with pegvisomant, volumetric surveillance is particularly important because the therapy acts downstream of GH and biochemical control may coexist with the need to confirm tumor stability. Ophthalmological evaluation and visual field testing must be repeated when there is chiasmal risk or symptoms, while the status of the other pituitary axes must be monitored over time, especially after surgery and radiotherapy, to identify hypopituitarism early and establish appropriate replacement therapy.
Surveillance of comorbidities is a parallel and continuous axis. Blood pressure, glucose metabolism and lipid profile should be reassessed regularly, because improvement after hormonal control may be partial and dependent on the previous duration of disease. Evaluation of obstructive sleep apnea syndrome should be repeated when indicated, since reduction of soft tissues after treatment may improve the respiratory picture, but does not always eliminate the need for specific therapy. From an osteoarticular standpoint, acromegalic arthropathy may persist even after biochemical control, requiring a pathway for pain management, physiotherapy and, in selected cases, orthopedic interventions.
A relevant component of follow-up concerns colon screening and surveillance. The association between acromegaly and colorectal neoplasms or polyps is supported by epidemiological evidence and meta-analyses, and recommendations converge on the need for colonoscopy and personalized surveillance strategies based on endoscopic findings and individual risk factors. Follow-up must also include attention to possible thyroid neoplasms, nodularity and other risk domains discussed in the literature, integrating surveillance within the overall clinical context.
In gigantism, follow-up must include auxological and pubertal monitoring, assessment of growth and bone age, in addition to the classic parameters. Early control of IGF-1 and growth is essential to prevent irreversible excessive height and reduce psychosocial impact. In genetic cases, family surveillance and counseling must be part of the pathway, because management of the individual patient often fits within a broader context of predisposition.
The prognosis of acromegaly is strongly dependent on the degree of biochemical control and management of comorbidities. In periods when control was less achievable, mortality was increased mainly due to cardiovascular and respiratory causes. With modern strategies, prognosis approaches that of the general population when IGF-1 is normalized, GH is adequately controlled and comorbidities are effectively treated. This makes prognosis a dynamic concept: it is not determined only by the presence of the diagnosis, but by the trajectory of control over time and the quality of follow-up.
Complications can be divided into three main domains. The first is related to the mass effect of the PitNET: chiasmal compression with visual field defects, headache, hypopituitarism from compression and, more rarely, pituitary apoplexy. Even after treatment, residual tumors may require prolonged surveillance and additional therapies. The second domain concerns the systemic complications of GH-IGF-1 excess: hypertension, metabolic dysfunction up to diabetes, sleep apnea, heart disease with hypertrophy and possible arrhythmias and valvulopathies, visceromegaly and skin changes with hyperhidrosis and thickening. The third domain includes osteoarticular and neuromuscular complications: degenerative arthropathy with pain and disability, carpal tunnel syndrome and peripheral neuropathies, spinal changes and reduced quality of life.
An area of particular clinical interest is the risk of neoplasms, especially colorectal neoplasms. Evidence indicates an increased risk of polyps and colon cancer in acromegaly, with a consequent need for endoscopic screening and surveillance. The proposed pathophysiology includes proliferative effects mediated by IGF-1 and alterations in the metabolic and inflammatory microenvironment, but individual risk also depends on disease duration and biochemical control, as well as on risk factors in the general population. This implies that secondary prevention, through appropriate colonoscopy programs, is an integral part of long-term prognosis.
In gigantism, complications include a greater burden of effects from early and intense exposure to GH and IGF-1, with impacts on growth, the cardiovascular system and metabolism during critical phases of development. Genetic forms may present more aggressive and difficult-to-control tumors, making prognosis more variable. However, here too, prognosis improves substantially when hormonal control is achieved early, growth is stabilized and comorbidities are followed continuously.
In conclusion, acromegaly and gigantism are conditions in which prognosis depends above all on timely diagnosis, sustained biochemical control, personalized therapeutic strategy and integrated management of comorbidities and complications. The clinical objective is not only to “normalize a value”, but to reduce the multisystem burden of the disease and prevent irreversible damage, with follow-up that accompanies the patient over the long term.