GH deficiency is a condition caused by reduced secretion of growth hormone by the somatotrophs of the anterior pituitary, with a consequent decrease in hepatic and tissue production of IGF-1 and impairment of its endocrine, paracrine and autocrine actions. During developmental age, GH is a fundamental determinant of growth velocity, skeletal maturation and acquisition of lean mass; in adulthood, although the goal of linear growth is no longer present, GH remains an important modulator of body composition, lipid and glucose metabolism, cardiovascular function, bone health and psychophysical well-being. As a result, the same deficiency may present with very different phenotypes depending on the time of onset, etiology and possible involvement of other pituitary axes.
From a clinical standpoint, GH deficiency does not correspond to a single pathognomonic sign, but to a coherent set of auxological, biochemical and neuroradiological findings, interpreted in light of the clinical context and pre-test probability. Diagnosis requires caution because GH secretion is intrinsically pulsatile and is influenced by age, puberty, adiposity, sleep, nutrition and comorbidities; moreover, stimulation tests have reproducibility limits and depend on the assay method. Modern management aims to restore the physiology of the signal, treat the underlying cause when possible and prevent long-term complications through structured follow-up, including the transition period from pediatric age to adulthood.
GH deficiency is the most frequent pituitary hormonal deficiency diagnosed in pediatric age among conditions presenting with short stature and reduced growth velocity. Epidemiological estimates vary markedly across registries, geographical areas and diagnostic criteria, precisely because the operational definition depends on dynamic evaluations and on thresholds linked to the test used. European pediatric registries and population-based analyses report prevalences in the order of a few cases per 10,000 children, while annual incidence may fall within similar or lower values, with an apparent male predominance that also reflects patterns of referral and clinical recognition, as well as possible biological differences related to pubertal timing and perception of growth deceleration.
It is useful to distinguish between congenital and acquired deficiency, and between idiopathic and organic forms. Congenital forms include isolated conditions caused by defects in the GH1 gene or in the GHRH receptor, but above all forms included within multiple pituitary hormone deficiencies related to alterations in transcription factors involved in pituitary development. Organic forms include malformations of the hypothalamic-pituitary region and conditions such as pituitary stalk interruption syndrome, in which GH deficiency is very frequent and is often associated, over time, with the progressive appearance of additional pituitary deficiencies. In these settings, epidemiology is not merely a numerical datum, but an indicator of the need for longitudinal surveillance: a child diagnosed with isolated deficiency may evolve toward a combined picture, especially if imaging suggests structural abnormalities.
The main risk factors, from a clinical perspective, are those that increase the probability of organic deficiency or progressive pituitary damage. In pediatric age, these include midline malformations, a history of severe or prolonged neonatal hypoglycemia, cholestatic jaundice and micropenis in males, which may indicate congenital hypopituitarism; furthermore, neurological or visual signs, persistent headache or visual field abnormalities increase the suspicion of sellar or parasellar lesions. In adolescence and adulthood, previous pituitary surgery, cranial radiotherapy, moderate to severe traumatic brain injury, subarachnoid hemorrhage, pituitary apoplexy and infiltrative or inflammatory diseases of the central nervous system become central elements.
A separate chapter concerns conditions that reduce GH secretion without constituting a stable deficiency of pituitary origin. Obesity reduces the GH response to dynamic tests and lowers peak values, making diagnostic overestimation possible if the result is not integrated with clinical probability and with the assessment of IGF-1 and the overall pituitary profile. Chronic systemic diseases, undernutrition, hyperglycemia and hypothyroidism may also interfere with the somatotropic axis, creating “functional” pictures in which correction of the underlying condition modifies GH secretion. For this reason, rather than as a static list, risk factors should be read as a probability gradient that guides the intensity of the diagnostic pathway and interpretation of the tests.
GH deficiency is the final expression of damage or dysfunction of the pituitary somatotropic system, which may originate from developmental abnormalities, acquired structural lesions or functional mechanisms that depress secretion. Under physiological conditions, somatotrophs integrate excitatory and inhibitory stimuli from the hypothalamus, with a central role for signals that modulate the frequency and amplitude of secretory pulses. GH is released in a pulsatile manner, with nocturnal peaks linked to deep sleep and modulations related to exercise, nutritional status and body composition. This temporal profile is essential because the peripheral system, particularly IGF-1 production and activation of intracellular pathways in target cells, responds to the dynamics of the signal as well as to its mean concentration.
In congenital forms, etiology includes mutations that interfere with GH synthesis, the response to growth hormone-releasing hormone (GHRH) or differentiation of pituitary cell lineages. Alterations in transcription factors that guide gland development may lead to pituitary hypoplasia and a pattern of combined deficiencies, sometimes progressive over time. In these conditions, GH deficiency is often the first deficiency to become clinically evident, but the patient’s pathophysiology cannot be reduced to the somatotropic axis alone, because pituitary architecture and overall secretory capacity are impaired. Malformations of the pituitary stalk and ectopic posterior pituitary may also produce anatomical and functional disconnection, with loss of proper transfer of regulatory signals and vulnerability to progression toward additional deficiencies.
In acquired forms, the most frequent cause is pituitary damage secondary to adenomas and their treatments, or to non-adenomatous lesions of the sellar and parasellar region. The mechanism is often a reduction in functioning somatotroph mass, but alterations in the microenvironment, perfusion and transmission of hypothalamic signals may also contribute. In this context, GH deficiency may coexist with alterations of the corticotropic or thyrotropic axis, which in turn influence metabolism and the clinical perception of symptoms, creating a “summative” phenotype in which it is essential to correctly attribute the portion of clinical burden due to somatotropic deficiency compared with other hormonal deficiencies.
Peripheral pathophysiology derives mainly from reduced IGF-1 action and absence of the direct GH signal on target tissues. In pediatric age, the growth plate requires an adequate hormonal environment to support chondrocyte proliferation and differentiation and to promote bone elongation; deficiency results in reduced growth velocity, delayed bone age and, if prolonged, compromised final height. At the metabolic level, GH exerts a lipolytic effect and contributes to maintaining lean mass; its absence favors an increase in adipose tissue, particularly visceral adiposity, and a reduction in muscle mass, with an impact on physical performance and energy metabolism.
In adults, GH deficiency is associated with an unfavorable body composition profile, lipid alterations with increased LDL cholesterol and reduced HDL in many patients, reduced exercise capacity and changes in quality of life. Bone health is also affected by deficiency: GH and IGF-1 support bone remodeling and formation, and prolonged deficiency may be associated with reduced bone mineral density, especially when gonadotropin deficiency or other risk factors coexist. The overall picture is therefore that of a disease in which a relatively “small” pituitary defect at the anatomical level produces a broad systemic alteration, mediated by the pleiotropic nature of the GH-IGF-1 axis and by its integration with other endocrine axes.
The clinical manifestations of GH deficiency depend critically on age at onset and on the presence or absence of associated pituitary deficiencies. In developmental age, the most informative clinical signal is persistent slowing of growth velocity, often with progressive deviation from expected height percentiles. The history should reconstruct the auxological trajectory over time, including familial target height, growth timing in the first years of life, any height-weight faltering and the presence of systemic symptoms that may indicate chronic disease or malabsorption, because many non-endocrine conditions can mimic growth deceleration. Neonatal history is also relevant, since hypoglycemia, cholestatic jaundice and feeding difficulties may be signs of congenital hypopituitarism, especially if associated with micropenis or cryptorchidism in males.
On pediatric physical examination, in addition to accurate measurement of height and weight with calculation of growth velocity, body proportions, signs of dysmorphism, possible truncal adiposity and assessment of pubertal stage become important. In isolated GH deficiency, an infantile facies and reduced muscle mass may be present, but clinical evaluation must always search for elements that point toward an organic form: headache, vomiting, visual disturbances, focal neurological abnormalities, signs of intracranial hypertension or findings suggestive of a midline malformation. Puberty may be normal in isolated deficiency, but in forms of multiple deficiencies, absent or delayed puberty becomes an integral part of the picture.
In adults, the history focuses on reduced energy, decreased exercise capacity, weight gain with a tendency toward visceral adiposity, reduced strength, worsening psychophysical well-being and sometimes sleep alterations. These symptoms are nonspecific and may overlap with those of hypothyroidism, hypocortisolism or hypogonadism, so clinical assessment must be systematic and aimed at identifying a history of pituitary disease, surgery, radiotherapy, traumatic brain injury or sellar lesions. Physical examination may reveal increased waist circumference, reduced lean mass, drier skin and reduced functional performance, but the absence of specific signs requires suspicion to be based on a coherent clinical context.
One particularly complex area is the transition phase from pediatric treatment to assessment in adulthood. A patient with GH deficiency diagnosed in pediatric age may not present striking symptoms after completion of growth, but may maintain an unfavorable metabolic and body composition profile; in other cases, especially isolated idiopathic forms, secretion may normalize and continuation of therapy may not be indicated. For this reason, the clinical picture of GH deficiency is not a photograph, but a longitudinal film in which the same diagnosis can change meaning with age, requiring reassessments based on physiology, context and clinical objectives.
Suspicion of GH deficiency should arise from clinical reasoning that integrates auxological data, natural history and pre-test probability. In children, the most robust signal is persistently reduced growth velocity in relation to age and pubertal stage, especially when progressive deviation from the individual trajectory and from percentiles expected in relation to parental height is observed. Suspicion increases if short stature is associated with delayed bone age, relative increase in adiposity and absence of alternative explanations such as chronic gastrointestinal, renal, cardiac or inflammatory diseases. It is equally important to recognize pictures suggesting organic deficiency, in which the diagnostic pathway must be faster and more complete.
In the neonatal period and in the first months of life, suspicion should arise in the presence of recurrent or severe hypoglycemia, prolonged jaundice with cholestasis, poor weight gain and, in males, signs of gonadotropin deficiency such as micropenis or cryptorchidism. These elements may indicate congenital hypopituitarism in which GH deficiency is part of a broader picture, and timeliness is essential to prevent acute complications, especially those related to corticotropic deficiency. In these cases, attention is focused not only on growth but also on metabolic stability and overall endocrine safety in the newborn.
In older children and adolescents, suspicion of GH deficiency becomes particularly strong when headache, visual disturbances, polyuria or polydipsia coexist, or when there are signs of alterations in other pituitary axes, such as excessive growth deceleration associated with central hypothyroidism or unexplained pubertal delay. The presence of midline craniofacial malformations or a history of neurosurgical procedures is also an element that shifts probability toward an organic form and supports early neuroradiological assessment.
In adults, GH deficiency should be suspected primarily in people with known pituitary disease or a history of treatment for sellar and parasellar tumors, because in this setting pre-test probability is high and diagnosis has concrete clinical consequences. In the presence of nonspecific symptoms such as asthenia, increased abdominal adiposity and reduced performance, suspicion becomes stronger when one or more documented pituitary deficiencies, neuroradiological signs of pituitary damage or a history of cranial irradiation coexist. Conversely, in the absence of risk factors and pituitary disease, GH deficiency is unlikely and an approach based only on generic symptoms increases the risk of erroneous diagnoses.
Finally, during the transition from pediatric age to adulthood, suspicion of persistent deficiency must take the original etiology into account. Organic forms and multiple deficiencies have a high probability of persistence, while isolated idiopathic forms often require reassessment. In this phase, suspicion is not linked to height, but to signs of metabolic vulnerability and to the clinical history suggesting a stably impaired somatotropic axis. Correct suspicion is therefore that which arises from the set of data and prepares a rational diagnostic pathway, avoiding both underdiagnosis in high-risk subjects and overdiagnosis in low-probability pictures.
The diagnosis of GH deficiency requires a sequential strategy that starts from clinical probability and leads to robust biochemical demonstration, taking into account the intrinsic limitations of GH measurement. The first step is always definition of the context: age, growth pattern, pubertal status, comorbidities, body composition and presence of pituitary disease or other endocrine deficiencies. In children, accurate auxological assessment and reconstruction of growth velocity are an integral part of the diagnostic process, because the isolated laboratory datum does not replace the biological phenomenon that is being investigated. In adults, diagnosis is not based on symptoms alone, but on the presence of a compatible pituitary context and an appropriate dynamic pathway.
Baseline tests include measurement of IGF-1 and, when useful, IGFBP-3, interpreted in relation to age and sex. A markedly reduced IGF-1 supports suspicion, but is not diagnostic in itself because it can decrease in conditions unrelated to GH deficiency, such as malnutrition, chronic inflammation, hypothyroidism, uncontrolled diabetes and liver failure. It is therefore essential to correct or recognize these confounders before attributing the finding to somatotropic deficiency. In parallel, the profile of the other pituitary axes must be assessed, because the presence of multiple deficiencies increases the probability of GH deficiency and modifies the testing strategy and prognostic meaning.
Biochemical confirmation is based on stimulation tests, chosen according to age, risk profile and contraindications. The insulin tolerance test has historically been considered a reference for evaluation of GH deficiency in adults and in the appropriate setting, because it induces hypoglycemia and activates a robust hypothalamic-pituitary stimulus; however, it requires a controlled setting and has contraindications, particularly in patients with ischemic heart disease, epilepsy or increased risk of adverse events. Glucagon is a widely used alternative when insulin testing is not feasible; in this case as well, interpretation must consider that adiposity and pre-test probability influence peak values. In some settings, other pharmacological stimuli are used, and in pediatric age two tests are often required in the absence of an evident organic etiology, precisely to increase diagnostic reliability in a condition with broad physiological variability.
In pediatric age, interpretation of tests must integrate pubertal stage and, when appropriate, the effect of steroid “priming” in peripubertal subjects, because the GH response is modulated by gonadal status and a non-contextualized test may produce false positives. Moreover, test reproducibility is not perfect and cut-offs are not universal, since they vary according to the analytical method and guideline recommendations. For this reason, the most solid diagnosis is one derived from consistency among auxology, IGF-1, test response and, when present, evidence of a pituitary lesion or genetic basis.
Neuroradiology, particularly hypothalamic-pituitary magnetic resonance imaging, is a crucial step when suspicion of an organic form is significant, when other pituitary deficiencies are present or when onset is early. Imaging allows identification of pituitary hypoplasia, stalk abnormalities, ectopic posterior pituitary, sellar or parasellar masses and signs of postsurgical or post-radiation outcomes. In a relevant number of idiopathic pediatric cases, imaging may be normal, but the presence of structural findings increases the probability of deficiency persistence and requires closer endocrinological follow-up.
During the transition period, a key element of the diagnostic pathway is reassessment of GH secretion after treatment withdrawal, once longitudinal growth has been completed. This step distinguishes transient forms from persistent ones and makes it possible to avoid unnecessary treatments, while maintaining therapy in subjects in whom deficiency persists and has metabolic and quality-of-life implications. Overall, diagnosis of GH deficiency is a process that must be rigorous, probabilistic and multidimensional, because the simple dichotomy “positive or negative test” does not adequately describe the biological complexity of the somatotropic axis.
Classification of GH deficiency is a clinical tool used to predict natural history, select the most appropriate investigations and define realistic therapeutic goals. A first fundamental distinction is between isolated deficiency and deficiency included in multiple hypopituitarism. In isolated deficiency, the alteration mainly involves the somatotropic axis and the presentation may be dominated by reduced growth velocity in children or by body composition alterations in adults; in multiple deficiencies, by contrast, GH deficiency is often accompanied by thyrotropic, corticotropic or gonadotropic deficiency, with clinical consequences that may be more urgent and that modify interpretation of symptoms and laboratory data.
A second axis of classification concerns etiology: idiopathic and organic forms. Organic forms include tumors, malformations, infiltrative lesions or treatment sequelae, and generally have a higher probability of persistence and progression toward multiple deficiencies. Idiopathic forms are often diagnosed on the basis of auxology and dynamic tests with normal imaging, but they represent a heterogeneous group that includes cases with unrecognized genetic bases and cases in which the phenotype is influenced by physiological variables such as adiposity, pubertal maturation and nutritional status. In these patients, diagnostic caution and reassessment over time are particularly important.
Classification by age at onset distinguishes congenital forms, often evident already in the neonatal period or in the first years of life, from acquired forms that appear after a period of normal growth and development. This distinction has profound clinical implications: a deficiency present during childhood directly influences height and skeletal development, while a deficiency arising in adulthood manifests mainly through metabolic and functional changes. Furthermore, in the transition phase, deficiency is defined as “persistent” when the deficiency is confirmed after treatment withdrawal and dynamic reassessment, in contrast to “transient” forms that do not require continuation of treatment.
The severity of deficiency cannot be defined only by the peak value during tests, because this datum is influenced by methodology and confounders. In clinical practice, severity is estimated by integrating several dimensions: the extent of auxological impairment in the child, degree of IGF-1 reduction, presence of an organic lesion, number of associated pituitary deficiencies and clinical impact. In some organic forms with multiple deficiencies, GH deficiency may be considered highly probable even before multiple tests, while in low-probability pictures the pathway must be more rigorous to avoid overdiagnosis.
Finally, a useful functional classification concerns the availability of residual pituitary tissue and the possibility of evolution. In conditions such as stalk abnormalities or mutations of pituitary development genes, the natural history may include late appearance of additional deficiencies, requiring a dynamic perspective. Classifying therefore means recognizing that GH deficiency is not always a definitive and immutable diagnosis, but often a node within an endocrine network that requires monitoring over time and revision of strategies according to clinical evolution.
Treatment of GH deficiency is based mainly on replacement therapy with recombinant growth hormone, with different objectives depending on age. In children, the central goal is to normalize growth velocity and optimize final height, while preserving harmonious progression of development and skeletal maturation. In adults, the purpose is not linear growth, but correction of alterations in body composition, metabolism and quality of life, and prevention of long-term consequences on bone and cardiovascular risk, within an overall framework of hypopituitarism management when present.
In pediatric age, GH therapy requires planning that takes etiology, severity of deficiency, age at initiation and pubertal stage into account. Response to therapy is greater when treatment begins early and adherence is good, while diagnostic delays and irregularity of administrations reduce height gain. Practical management includes progressive dose adjustment and regular monitoring of growth, bone age and clinical signs, with the aim of avoiding both undertreatment and excesses that may undesirably accelerate skeletal maturation or increase the risk of adverse events. In the presence of multiple deficiencies, safety requires corticotropic and thyrotropic deficiencies to be recognized and adequately treated, because GH therapy may modify glucocorticoid metabolism and thyroid homeostasis, making integrated endocrinological supervision necessary.
In adult deficiency, guidelines recommend indicating therapy after appropriate diagnostic confirmation, especially in subjects with high clinical probability, and starting with relatively low doses, titrating according to clinical response and IGF-1 levels, with particular caution in older age and in the presence of obesity or altered glucose metabolism. The objective is to obtain an IGF-1 profile within the expected range for age and sex, avoiding high levels that increase the likelihood of side effects. In patients with multiple pituitary deficiencies, GH therapy becomes part of a replacement mosaic that includes cortisol, thyroxine and, when indicated, sex steroids, and must be coordinated because correction of one axis may modify the requirements of the others.
During the transition period, therapeutic choice depends on persistence of the deficiency. In subjects with an organic form or multiple deficiencies, the probability of persistence is high and continuation of therapy may be indicated to support full acquisition of bone mass, a favorable body profile and a better metabolic transition toward adulthood. In isolated idiopathic forms, by contrast, reassessment after GH withdrawal and completion of growth is often necessary, because a non-negligible proportion of patients no longer present persistent deficiency. The therapeutic decision in this phase must therefore be physiopathologically grounded and personalized.
An emerging chapter concerns long-acting GH formulations, developed to reduce injection frequency and improve adherence. These options may be useful in selected patients, but require careful monitoring because they modify the temporal profile of the signal and the interpretation of IGF-1 levels, in addition to requiring specific evaluations of long-term efficacy and safety. In any case, treatment of GH deficiency is not an isolated act, but a pathway that must combine clinical objectives, safety, adherence and periodic review of the indication according to the patient’s evolution.
Follow-up of GH deficiency is essential because response to therapy and risk profile change over time and because the somatotropic axis interacts with many physiological systems. In treated children, monitoring is based on accurate and frequent auxological measurements, with assessment of growth velocity and its course in relation to the expected target. Periodic review of bone age makes it possible to evaluate skeletal maturation and correctly interpret height gain in relation to the remaining growth window. Inadequate growth does not automatically imply GH inefficacy, because it may depend on poor adherence, non-optimal dose, an alternative diagnosis or concomitant conditions such as hypothyroidism, celiac disease or chronic diseases; for this reason, follow-up must be clinically reasoned and not reduced to automatic dose adjustment.
Biochemical monitoring includes assessment of IGF-1 as an indicator of biological exposure to GH, interpreting it in context and without considering it a perfect surrogate of clinical efficacy. In patients with multiple deficiencies, surveillance of the other axes is fundamental: GH therapy may reduce cortisol availability in patients with borderline corticotropic reserve and may modify peripheral conversion of thyroid hormones, making reassessment of replacement with glucocorticoids or levothyroxine necessary when present. This aspect is particularly relevant at treatment initiation and during significant dose changes.
In children and adolescents, follow-up must include active surveillance for rare but clinically important adverse events. Symptoms such as severe headache, visual disturbances or persistent nausea require attention because of the risk of intracranial hypertension, while hip pain or limping requires orthopedic evaluation to exclude slipped capital femoral epiphysis. Progression of scoliosis, especially in predisposed patients, must also be monitored pragmatically, distinguishing acceleration related to growth from true structural worsening. Metabolic assessment, including blood glucose and lipid profile, is useful particularly in patients with adiposity or a family history of diabetes, because GH can influence insulin sensitivity in a dose-dependent manner.
In adults, follow-up combines clinical and instrumental parameters: changes in body composition, waist circumference, blood pressure, lipid profile and subjective well-being, together with IGF-1 for dose titration. Some patients may experience fluid retention, edema, arthralgias or paresthesias, especially in the initial phases or with rapid dose increases; these signs support more gradual titration. Bone health requires specific attention, especially in subjects with prolonged deficiency, associated hypogonadism or fracture risk factors: bone densitometry may be indicated within an individualized surveillance plan.
During transition, follow-up includes reassessment of the indication: after GH withdrawal and completion of growth, controlled repetition of dynamic tests in appropriate subjects makes it possible to distinguish persistent deficiency from normalization of secretion. In patients with high pre-test probability, such as those with organic lesions or multiple deficiencies, reassessment may be more targeted and follow-up should focus on bone mass, metabolism and quality-of-life objectives. At all ages, the quality of follow-up depends on continuity of care and on the ability to integrate clinical findings, laboratory results and imaging within a coherent and adaptive pathway.
The prognosis of GH deficiency is generally favorable when diagnosis is correct and treatment is appropriately established, but it varies substantially according to etiology and the presence of associated pituitary deficiencies. In children with isolated deficiency treated early, the growth outcome may be very good, with recovery of growth velocity and improvement in final height, although with variability linked to age at initiation, severity, adherence and pubertal context. In organic forms, prognosis also depends on the underlying disease and its treatment, and GH deficiency may be only one element of a more complex picture requiring multidisciplinary surveillance.
A clinically relevant complication of untreated or late-treated deficiency in pediatric age is the loss of growth opportunity, with impairment of final height and potential psychological and social consequences. In multiple deficiencies, the greatest risk is not only height, but the possibility that other deficiencies, especially corticotropic deficiency, remain unrecognized and lead to acute events. For this reason, prognosis cannot be assessed by isolating GH from the rest of the pituitary profile, especially in congenital forms and structural abnormalities.
In adults, GH deficiency is associated with an unfavorable metabolic and cardiovascular profile in many patients, with increased visceral adiposity, lipid alterations and reduced exercise capacity. Replacement therapy may improve several of these aspects, but prognosis depends on integration with management of other risk factors, correction of other endocrine deficiencies and lifestyle. Bone health may also be compromised by prolonged deficiency, especially when associated with hypogonadism or central hypothyroidism; in these cases, the risk of reduced bone mineral density and skeletal fragility requires specific long-term attention.
Complications related to GH therapy are generally infrequent and often manageable with dose adjustments, but some deserve particular attention because of their clinical impact. In pediatric age, intracranial hypertension and slipped capital femoral epiphysis are rare but important events that require early recognition. In adults, fluid retention, edema, arthralgias and alterations in glucose tolerance may emerge especially with high initial doses or rapid titration, making a cautious and progressive approach preferable. In patients with a history of intracranial neoplasms or radiotherapy, management must be coordinated with oncological and neuroradiological surveillance, because safety with respect to the underlying disease remains the priority.
A central prognostic theme is transition: persistence of deficiency in adulthood is not uniform and depends on etiology. Organic forms and multiple deficiencies tend to persist, while some isolated idiopathic forms may normalize; functional prognosis and the need for long-term therapy therefore depend on correct reassessment and on the ability to identify those who truly benefit from continuation. In summary, GH deficiency is a treatable condition with a good prognosis, but it requires rigorous diagnosis, structured follow-up and a systemic view that considers comorbidities, other pituitary axes and the natural history of the causal disease.