Pituitary Gigantism Case Study

FROM ANCIENT history throughout the modern age, individuals of extraordinary physical proportions have figured prominently in myths and tales of magic. The concept of superhuman size, whether in the form of Goliath, Hercules, or Bigfoot, has consistently inspired a sense of awe and enthrallment. No less intriguing are the well-documented cases of true gigantism, including that of Robert Wadlow (The Alton Giant) who, at 8 feet 11 inches (272 cm) at his death, remains the tallest person ever recorded (1), and that of SA (Fig. 1), the current tallest living woman at 7 feet 5.5 inches (227 cm). In recent years, scientific breakthroughs regarding the molecular genetic, histologic, and hormonal basis of GH excess have enhanced our understanding of this inherently fascinating disease and have provided important insights into its pathogenesis, prognosis, and the potential for therapeutic intervention.

Gigantism refers to GH excess that occurs during childhood when open epiphyseal growth plates allow for excessive linear growth, whereas acromegaly indicates the same phenomenon occurring in adulthood. Although this review focuses primarily on gigantism, the two disorders may be thought of as existing along a spectrum of GH excess, with principal manifestations determined by the developmental stage during which such excess originates. Supporting this model has been the observation of clinical overlap between the two entities, with approximately 10% of acromegalics exhibiting tall stature (2) and the majority of giants eventually demonstrating features of acromegaly (3). The mean age for the onset of acromegaly is within the 3rd decade of life, whereas gigantism may begin at any age prior to epiphyseal fusion. Even a congenital onset of GH excess has been suggested by linear growth acceleration occurring within the first few months of life in young children with documented gigantism (4–6). The incidence of acromegaly is calculated to be three to four cases per million per year (7), whereas gigantism is extremely rare, with approximately 100 reported cases to date (2), although this is probably an underestimate of the true number.

Etiologies of Gigantism

Excessive GH secretion has several potential causes and may occur in the context of a number of heterogeneous disorders. Among these, a variety of specific pathophysiologic mechanisms have been elucidated or proposed, all of which result in GH excess as the final common abnormality. Cases of GH hypersecretion may be subdivided into two main categories: those originating from a primary pituitary source and those that seem to be caused by increased GHRH secretion or dysregulation. A spectrum of pathologic pituitary morphology exists, ranging from isolated pituitary adenomas typically seen in cases of primary pituitary GH hypersecretion to pituitary hyperplasia, which is usually found in the context of prolonged GHRH excess. Although gigantism typically occurs as an isolated disorder, it may also be a feature of an underlying medical condition such as multiple endocrine neoplasia (MEN) type-1, McCune-Albright syndrome (MAS), neurofibromatosis, or Carney complex. The various etiologies of GH excess along with their associated characteristics are summarized in Table 1 and discussed further.

Table 1.

Causes of excessive GH secretion

Source of GH excess Pathogenetic mechanism Clinical context Associated findings 
Primary pituitary GH excess Gsα mutation Sporadic pituitary adenomas gsp oncogene 
Pituitary adenomas or hyperplasia in association with MAS Café au lait macules, polyostotic fibrous dysplasia, precocious puberty 
Loss of 11q13 heterozygosity Sporadic pituitary adenomas Increased tumor invasiveness 
MEN type 1 Autosomal dominant inheritance, neoplasia of pancreas, pituitary, parathyroids 
Abnormality at 2p16 Carney complex Autosomal dominant inheritance, multiple lentigines myxomas, endocrine neoplasias 
Secondary GH excess Hypothalamic GHRH excess Pituitary hyperplasia Absence of identifiable source of GH or GHRH hypersecretion 
Intracranial tumor secretion of GHRH Gangliocytoma, neurocytoma Close association of tumor neurons with pituitary GH-secreting cells 
Ectopic GHRH excess Carcinoid, pancreatic, bronchial neoplasias Extremely rare cause of gigantism 
Ectopic GH excess Lymphoma One reported case of acromegaly 
Abnormal somatostatin tone Neurofibromatosis with optic gliomas/astrocytomas Infiltration into somatostatinergic pathways 
Source of GH excess Pathogenetic mechanism Clinical context Associated findings 
Primary pituitary GH excess Gsα mutation Sporadic pituitary adenomas gsp oncogene 
Pituitary adenomas or hyperplasia in association with MAS Café au lait macules, polyostotic fibrous dysplasia, precocious puberty 
Loss of 11q13 heterozygosity Sporadic pituitary adenomas Increased tumor invasiveness 
MEN type 1 Autosomal dominant inheritance, neoplasia of pancreas, pituitary, parathyroids 
Abnormality at 2p16 Carney complex Autosomal dominant inheritance, multiple lentigines myxomas, endocrine neoplasias 
Secondary GH excess Hypothalamic GHRH excess Pituitary hyperplasia Absence of identifiable source of GH or GHRH hypersecretion 
Intracranial tumor secretion of GHRH Gangliocytoma, neurocytoma Close association of tumor neurons with pituitary GH-secreting cells 
Ectopic GHRH excess Carcinoid, pancreatic, bronchial neoplasias Extremely rare cause of gigantism 
Ectopic GH excess Lymphoma One reported case of acromegaly 
Abnormal somatostatin tone Neurofibromatosis with optic gliomas/astrocytomas Infiltration into somatostatinergic pathways 

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Primary pituitary GH excess

Many cases of gigantism result from primary GH secretion by pituitary tumors comprised of somatotrophs (GH-secreting cells) or mammosomatotrophs (GH and PRL-secreting cells), either in the form of a pituitary microadenoma or, rarely, macroadenoma (6). The relative contributions of inherent pituitary defects vs. hypothalamic factors in the pathogenesis of pituitary tumors are far from resolved, however. The monoclonal nature of most pituitary adenomas (8), confirmed by X-inactivation studies, has implied that they originate from a single altered cell. The concept of an intrinsic pituitary defect is further supported by the discovery that specific molecular genetic abnormalities seem to form the basis of GH hypersecretion in many cases. In contrast, evidence also exists to suggest an important role for GHRH in disease progression because the number of GHRH messenger RNA transcripts within pituitary adenomas correlates strongly with their clinical behavior (9). The exact functional consequence of locally produced GHRH remains to be clarified, although an autocrine or paracrine role has been suggested by the finding of an elevated plasma GHRH concentration in association with a pituitary somatotroph adenoma, which normalized following surgical removal of the adenoma (10). An approach that integrates the different theories of pituitary adenoma formation has recently been proposed, in which tumor growth ensues via a multistep process. In this model, the initial event consists of genetic transformation of cells, with abnormal growth being subsequently promoted by hypophysiotrophic hormones and other growth factors (11). Identified molecular genetic abnormalities implicated in the pathogenesis of primary pituitary GH excess are discussed below.

Gsα mutations

The heterotrimeric G-proteins play an integral role in postligand signal transduction in many endocrine cells, in which they act by stimulating adenylyl cyclase, resulting in cAMP accumulation and subsequent gene transcription. Activating point mutations of the G-protein stimulatory subunit Gsα are known to form the basis for McCune-Albright syndrome (MAS), a rare disorder characterized by the classic triad of precocious puberty, café au lait spots, and fibrous dysplasia of bone (12). “Constitutive activation” refers to the autonomous and uncontrolled activation of G-protein-mediated cAMP formation that occurs in MAS, resulting in hyperfunction of endocrine and nonendocrine tissues. In some patients with MAS, endocrine abnormalities include gigantism caused by the development of pituitary mammosomatotroph adenomas or hyperplasia. The reported point mutations observed in multiple affected tissues of patients with MAS (13), including those with gigantism (14), involve a single amino acid substitution within codon 201 (exon 8) or codon 227 (exon 9) of the Gsα gene. Interestingly, these same mutations have also been identified in somatotrophs of up to 40% of sporadic GH-secreting pituitary adenomas (15). The resulting oncogene, gsp, is thought to induce tumorigenesis by virtue of persistent activation of adenylyl cyclase with subsequent GH hypersecretion (16). In contrast to tumors without such mutations, gsp-containing pituitary adenomas tend to be smaller, with morphologic characteristics suggestive of slow growth, despite an absence of detectable differences in disease progression between the two groups.

Allelic deletion of the 11q13 locus

Loss of heterozygosity (LOH) at the site of a putative tumor suppressor gene located on chromosome 11q13 represents another molecular genetic abnormality, whose association with pituitary GH excess has been firmly established. First identified within tumors from patients with MEN-1 (17), the genetic mutation was originally believed to be related to the MEN-1 gene and was thought to be the cause of the GH excess in this disease. The recent cloning of the MEN-1 gene, however, has led to the revelation that the affected locus codes for a product that is distinct from the MEN-1 gene. This has been demonstrated by the finding of an intact MEN-1 sequence in individuals from two unrelated kindreds with familial acromegaly/gigantism and 11q13 LOH (18). In addition to familial non-MEN acromegaly/gigantism (19), LOH at 11q13 has also been observed in all types of sporadically occurring pituitary adenomas (20). The exact nature of the encoded product and its role in tumor formation have yet to be clarified. Of note is the fact that LOH at 11q13 and other loci within pituitary adenomas has been correlated with an increased propensity for tumor invasiveness and biological activity (21).

Additional theoretical intrinsic pituitary defects leading to abnormal cell proliferation and excessive GH secretion might result from abnormal activation of the GHRH receptor, somatostatin receptor, pituitary transcription factors, or other growth-related signal peptides. As information regarding the complex developmental cascade of pituitary ontogenesis continues to accumulate, new light will undoubtedly be shed on the underlying mechanisms of both normal and abnormal pituitary cell growth.

Secondary GH excess

Causes of secondary GH excess include those in which there is increased secretion of hypothalamic GHRH, either from an intracranial or ectopic source, and those in which abnormal regulation of the hypothalamic-pituitary GH axis has occurred. Secondary GH excess represents an important, if poorly understood, cause of gigantism. Advances in biochemical detection assays and molecular genetic characterization should allow improved localization of the underlying hormonal abnormality in these cases.

GHRH excess

Hypothalamic GHRH excess or dysregulation has been postulated to be the most common cause of GH hypersecretion in the pediatric population. Although not definitively proven, clinical cases that support this hypothesis include congenital gigantism with massive diffuse pituitary hyperplasia, in which biochemical studies suggested central GHRH hypersecretion (5), as well as a case of mammosomatotroph hyperplasia in which systemic GHRH concentrations were found to be normal (4). The involvement of mammosomatotrophs, frequently a feature of GH excess originating in childhood (22), is further suggestive of early onset increased GHRH exposure because this cell type predominates in fetal life but is rare in the adult. Despite this evidence, the underlying mechanism of the putative abnormality in GHRH action in these cases remains unknown. Theoretical possibilities include an activating mutation in hypothalamic GHRH neurons or a decrease in somatostatin tone (see below). Another form of intracranial GHRH excess occurs in the setting of a neural tumor, such as a gangliocytoma (23, 24) or neurocytoma (25), arising within or in close proximity to the sella. Prolonged tumor secretion of GHRH leads to pituitary hyperplasia with or without adenomatous transformation, resulting in increased levels of GH and other adenohypophyseal peptides. Electron microscopy in such cases has revealed intimate contact between neurons of the tumor and pituitary GH-secreting cells (23). GHRH excess may also originate from an extracranial and ectopic neoplastic source, which represents a well-recognized cause of acromegaly (26), but has only rarely been implicated in cases of GH excess in children (3). Ectopic GHRH-secreting tumors have included carcinoid, pancreatic islet cell, and bronchial neoplasms. Recently, the first reported case of ectopic GH as the cause of acromegaly was identified, in which tumor cells from a malignant lymphoma were found to secrete high levels of pituitary GH (27).

Abnormal Somatostatin tone

Secondary GH excess may also occur from disruption of somatostatin tone. Tumor infiltration into somatostatinergic pathways has been hypothesized to form the basis for GH excess in rare cases of gigantism associated with neurofibromatosis and optic gliomas or astrocytomas (28, 29). Immunocytochemical studies in this setting have demonstrated interruption of somatostatinergic neurons, whereas neuroimaging has revealed diminished magnetic resonance signal intensity in somatostatin-rich areas of the brain (30).

Consequences of Prolonged GH Excess

Transgenic mice models with targeted overexpression of GH, GHRH, and insulin-like growth factor (IGF)-I have provided invaluable tools for the exploration of the pathogenetic mechanisms underlying the physiological effects of chronic GH exposure. The first such model, constructed by fusion of the mouse metallothionein-1 gene promoter to the rat GH gene (31), resulted in dramatically accelerated growth in transgenics as compared with control littermates, along with greatly increased circulating GH and tissue GH messenger RNA levels. Subsequently, the role of elevated GHRH in GH hypersecretion was demonstrated by the finding of pituitary hyperplasia and adenomas, increased somatic growth, and elevated plasma GH levels in transgenic mice overexpressing human GHRH (32). The differential effects of chronic GH exposure vs. IGF-I excess have been further investigated by comparing changes exhibited by animals with isolated overexpression of IGF-I with those observed in animals overexpressing GH or GHRH. Anatomical and biochemical changes found to be unique to animals with chronically elevated GH levels have included renal and hepatic enlargement, glomerulosclerosis, skin abnormalities, and elevations of insulin and cholesterol (33). In line with the diverse clinical symptomatology observed in patients with acromegaly, these studies also emphasize the fact that excessive GH exposure has an impact on all tissues in the body.

Clinical Aspects of Gigantism

Unlike GH excess beginning in adulthood, in which an insidious onset and delayed diagnosis are the norm, the presentation of gigantism is usually quite dramatic and the diagnosis is fairly straightforward. The cardinal clinical feature of gigantism is growth acceleration. All growth parameters are affected, although not necessarily symmetrically because mild to moderate obesity is common and macrocephaly has been noted to precede linear and weight acceleration in at least one case (34). Due to the small number of affected patients, there are no precise figures regarding the prevalence of other signs and symptoms of GH excess in children with gigantism. However, a review of clinical case reports reveals several common features among such patients. All have been noted to have coarse facial features and disproportionately large hands and feet with thick fingers and toes. Frontal bossing and a prominent jaw have frequently been present. Organomegaly and deteriorating glucose tolerance were also documented in one patient observed over several years before treatment (29).

In contrast, the myriad signs and symptoms of prolonged GH excess in adults with acromegaly have been well described (35). Enlargement of facial features, excess acral growth and soft tissue swelling are essentially ubiquitous among these patients. Additional common manifestations include headaches, excessive sweating, peripheral neuropathy and arthritis. Frequently associated endocrinopathies include hypogonadism, diabetes, thyromegaly, and galactorrhea. The most common cause of death in acromegaly is from cardiovascular disease (36). Recent observations regarding other consequences of GH toxicity include a potential role for GH in normal and abnormal erythropoiesis (37) and in the pathogenesis of retinopathy (38).

Physical examination of the child presenting with growth acceleration must include a search for evidence of other etiologies of increased growth velocity, such as excessive sex steroid levels, as well as careful attention to the presence of additional physical findings that might suggest an underlying disorder, such as multiple café au lait spots. The differential diagnosis of growth acceleration is contained in Table1 2.

Laboratory findings

An elevated IGF-I on initial screening is suggestive of GH excess, as an excellent linear dose-response correlation between plasma IGF-1 levels and 24-h mean GH secretion have been demonstrated (39). Potential confusion may arise when evaluating normal adolescents because significantly higher IGF-I levels occur during puberty than in adulthood (40), a fact that emphasizes the importance of using age-referenced norms. Although higher concentrations of IGF-I have been reported in children and adolescents with constitutional tall stature (41), no significant differences in neurosecretory dynamics of the GH-IGF-I axis have been found in healthy young adults with heights of more than three sd above the mean as compared with controls (42). The gold standard for making the diagnosis of GH excess is a failure to suppress serum GH levels to less than 5 ng/dL after a 1.75 gm/kg oral glucose challenge (maximum, 75 g). Hyperprolactinemia is an almost invariable finding in GH excess presenting in childhood, undoubtedly related to the fact that mammosomatotrophs are by far the most common type of GH-secreting cells involved in childhood gigantism. The coexistence of both GH and PRL has been clearly demonstrated within the secretory granules contained in the cytoplasm of these cells (22). Although not necessary to make the diagnosis, GH response to additional stimuli such as TRH testing is typically paradoxical. Measurement of serum GHRH levels are useful in differentiating ectopic GHRH excess from other causes of GH hypersecretion. Imaging by magnetic resonance imaging or computed tomography is an essential step in the evaluation following biochemical detection of GH excess.

Psychological aspects of tall stature/gigantism

One need only review the striking positive correlation between stature and financial/professional success in our society to be convinced that “heightism” is a true phenomenon. However, when present to an extreme degree, tallness ceases to be an advantage and may be perceived as a burden, resulting in both physical, as well as psychological, handicaps. This has prompted the pharmacological treatment of constitutionally tall adolescents with sex steroids to accelerate epiphyseal fusion, a practice that has been in existence since the 1950s (43). Whereas tall girls, in particular, often report teasing and social difficulties as a result of their size, these problems generally disappear in adulthood, when the majority of normal tall men and women indicate satisfaction with their stature (44). Because no convincing data indicating lifelong psychopathology as a result of tall stature exists (45), it may be reasonable to pursue counseling as the initial treatment of choice for otherwise healthy tall adolescents with psychosocial difficulties related to their height. In contrast, pathologic tall stature as a result of GH excess obviously results in heights that are far beyond those observed in constitutionally tall individuals. Although no in-depth information regarding the psychological profile of patients with gigantism is available, case series indicate a high incidence of severe depression, social withdrawal, and low self-esteem (3).

Treatment of Gigantism

Several therapeutic modalities have been used in the treatment of GH hypersecretion. The optimal therapy in any given case is dictated by the characteristics of the GH-secreting lesion and other coexisting factors. For well-circumscribed pituitary adenomas, transsphenoidal surgery is the treatment of choice and may be curative (46). Radiation therapy, used as adjunctive or primary treatment, has also been moderately successful in inducing normalization of growth hormone levels (47). Major disadvantages to the use of irradiation exist, however, in the form of delayed efficacy in reducing GH levels and a high incidence of hypopituitarism following treatment.

The greatest progress in recent years in the treatment of GH excess has been within the realm of medical therapy. The development of somatostatin analogs, such as octreotide, represented a major addition to the pharmacological armamentarium for GH hypersecretion. Therapeutic response to octreotide, found to be highly effective in the majority of patients with gigantism or acromegaly, may be predicted by the decrement in serum GH levels after one sc dose (48). The new sustained-release somatostatin analog preparation lanreotide given in the form of an im injection every 2 weeks, has also been shown to be successful in returning GH levels to normal in acromegalic adults with pituitary adenomas (49) as well as in those with ectopic GHRH secretion (50). Although this drug is as yet untested in children, the improved dosing schedule of lanreotide clearly represents a potentially major advance in the treatment of gigantism and disorders of glucose homeostasis in pediatric patients. Side effects of somatostatin analogues consist mainly of mild transient gastrointestinal complaints and an increased risk of gallstones. Additional pharmacological therapy consists of the dopamine agonist bromocriptine, which can provide adjuvant medical treatment of gigantism and has been found to be safe when used in a child for an extended period of time (51). An exciting new therapeutic agent has recently emerged in the form of a competitive GHRH antagonist, which has been shown to effectively suppress GH and IGF-I levels in patients with acromegaly from pituitary somatotrophic tumors as well as ectopic GHRH hypersecretion (52, 53).

Conclusion

In summary, our current understanding of GH excess represents the end result of a unique blend of multidisciplinary investigation. Further illumination regarding the unexplained aspects of this interesting disease undoubtedly will occur as collaborative efforts continue into the new century.

Table 2.

Most common causes of tall stature/growth acceleration

Normal variant 
genetic tall stature 
Endocrine abnormalities 
Precocious puberty 
Hyperthyroidism 
Gigantism 
Exogenous obesity 
Syndromes 
Sotos 
Beckwith-Wiedemann 
Marfan 
Homocystinuria 
Weaver 
Fragile X 
Sex chromosome aneuploidy 
Klinefelter syndrome 
47, XYY 
47, XXX 
Normal variant 
genetic tall stature 
Endocrine abnormalities 
Precocious puberty 
Hyperthyroidism 
Gigantism 
Exogenous obesity 
Syndromes 
Sotos 
Beckwith-Wiedemann 
Marfan 
Homocystinuria 
Weaver 
Fragile X 
Sex chromosome aneuploidy 
Klinefelter syndrome 
47, XYY 
47, XXX 

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2

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Introduction

Interest in the extremes of height stretches back into antiquity, and the occurrence of people with gigantism has contributed to popular myths across many cultures. Even with the recognition that many extreme cases of tall stature are disease manifestations, interest in gigantism has unfortunately remained focused on the visual spectacle, even today. Many forms of short stature are known and screening activities in childhood are geared to identifying these cases for early investigation and intervention (Cheetham & Davies 2014). Overgrowth is less well understood and, particularly if unaccompanied by other syndromic features like developmental delay, its diagnosis may be slower. Societal factors may contribute to this, as tall stature is seen a less ‘undesirable’ physical feature than short stature (Batty et al. 2009). However, increased height also carries risks in terms of disease (Lee et al. 2009), and excessive final adult height carries with it distinct disadvantages, particularly skeletal and orthopedic problems (Hazebroek-Kampschreur et al. 1994, Silventoinen et al. 1999). Surprisingly, the functional and psychological impacts of extreme tall stature have yet to be studied in detail.

Growth and stature are determined by highly complex processes involving genetic and environmental factors, such as endocrine function, nutrition, vitamin status and psychosocial wellbeing (Tanner & O'Keeffe 1962, Mascie-Taylor 1991, Wood et al. 2014). Diseases causing tall stature must be differentiated from other normal variations in height, in which underlying abnormalities are absent. Pathological tall stature can be isolated or syndromic; the latter is usually due to a chromosomal or genetic cause, such as Klinefelter syndrome, Marfan syndrome and Sotos syndrome among others (Davies & Cheetham 2014). Disorders of the growth hormone (GH) axis can lead to abnormal height, the most classical of which is pituitary gigantism, usually due to over-secretion of GH by a pituitary adenoma occurring before epiphyseal closure (Daughaday 1992, Eugster & Pescovitz 1999, Eugster 2000). In recent years a variety of genetic factors that predispose to somatotrope adenomas or hyperplasia have been identified. Mutations in genes such as GNAS and PRKAR1A and particularly AIP are associated with acromegaly and gigantism (Daly et al. 2010a, Xekouki et al. 2010, Stratakis 2015). X-linked acrogigantism (X-LAG) syndrome is associated with a microduplication, including the GPR101 gene, on chromosome Xq26.3 and leads to pituitary hyperplasia and adenomas in children and early onset gigantism beginning usually in the first year of life (Trivellin et al. 2014, Beckers et al. 2015).

Due to its rarity and despite the recent emphasis on pathophysiological causes, the clinical presentation, evolution, complications and responses to treatment of patients with pituitary gigantism have not been studied in a large cohort. To address these issues, we conducted an international collaborative study of the features of patients with pituitary gigantism.

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Methods

This was a study that included patients with pituitary gigantism due to a pituitary adenoma or hyperplasia. The study was performed between 2011 and 2013 at the Department of Endocrinology, Centre Hospitalier Universitaire de Liège, Belgium, in collaboration with 46 other international centers in Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Denmark, India, Italy, Finland, France, Germany, New Zealand, Romania, Russia, Spain, the Netherlands and the United States. This study was approved by the Ethics Committee of CHU de Liège (Belgian clinical trials number: B707201111968). Patients were identified at the participating centers and both historical and current follow-up data were collected; results of previous genetic tests were collected retrospectively, and other genetic analyses were also performed prospectively over the course of the study. Patients consented to the collection and use of clinical data and provided informed consent in their local language for genetic studies.

Eligibility criteria

The diagnosis of pituitary gigantism was defined as current or previous evidence of abnormal, progressive and excessively rapid growth velocity for age (>97th percentile, which corresponds to >+2 s.d.), or a final height >+2 s.d. above the mean for relevant population, associated with elevated GH/insulin-like growth factor 1 (IGF1) and imaging evidence of a pituitary lesion. Details on height sources for the countries are listed in Supplementary Materials and methods, see section on supplementary data given at the end of this article.

Patient disposition

Patient information (demographics, medical and familial history, genetics, clinical examination, laboratory investigations, radiology, disease status during follow-up, treatment modalities and response to therapy) were systematically collected in each study center, recorded in the case report form and transmitted anonymized to the coordinating center. All patients with pituitary causes of gigantism diagnosed at any time at the participating centers were valid for inclusion. Overall, 229 patients were enrolled; 21 cases were ineligible and excluded (Klinefelter's syndrome (n=5), constitutional tall stature (n=3), Sotos syndrome (n=2), obesity (n=2), ectopic growth hormone-releasing hormone (GHRH) secretion (n=1) and tall stature of unknown etiology without GH axis excess (n=8)). The final study population consisted of 208 patients diagnosed with pituitary gigantism (Supplementary Figure 1, see section on supplementary data given at the end of this article).

Study measures

Height was expressed as Z-scores above the mean value of height of the reference population. The mid-parental height (MPH) was defined as the average of the parents’ heights −6.5 cm for girls and +6.5 cm for boys. The difference of the final height from MPH was used to determine the variance from target stature.

The age at disease onset was derived from existing patient case files and following consultation with the patient and family. The age at diagnosis was assessed as the age at which a first definitive diagnosis of a pituitary gigantism was recorded in the case notes. Pituitary tumors were classified as per the local radiology reports according to the maximal diameter on magnetic resonance imaging or computerized tomography as microadenomas (<10 mm) and macroadenomas (≥10 mm); the latter included giant adenomas (those measuring ≥40 mm). Invasion of surrounding structures and extrasellar expansion was evaluated by neuroimaging and at surgical intervention.

Therapeutic modalities were assessed and details collected; a total treatment score was calculated as the sum of the use of somatostatin analogues (SSA), pegvisomant, dopamine agonists (DA), each individual surgery and radiotherapy (each was allocated one point). The multimodal treatment approach was considered with ≥3 modalities. Long-term disease control criteria (≥12 months of follow-up) were shrinkage or stable size of pituitary adenoma, the absence of clinical activity, an age/sex-appropriate IGF1 that was ≤upper limit of normal (ULN) for the assay used at the individual clinical center and a GH level <1 ng/ml at last follow-up (pegvisomant-treated patients were assessed on IGF1 only).

Statistics

Statistical analysis (statistical computing and graphics) was performed using STATISTICA, version 10 (StatSoft, Tulsa, OK, USA), and R package, version 2.15.1 (R Core Team, Vienna, Austria). Absolute numbers and percentages were used to describe qualitative and categorical data. Continuous data did not fit parameterized distributions, therefore they were represented as medians and interquartile ranges (IQR) and non-parametric statistical tests were used for the analysis (Spearman's R and χ2) tests for the association between variables and Mann–Whitney U and Kruskal–Wallis tests for comparison of independent subgroups). A P-value of <0.05 was designated as the level of statistical significance.

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Results

Characteristics at diagnosis

The pituitary gigantism population consisted of 208 patients, the majority of whom were male (n=163; 78%) (Table 1). Patients were diagnosed across a number of decades: 1950s (1%), 1960s (1%), 1970s (3%), 1980s (13%), 1990s (20%), 2000s (42%) and current decade, 2010s (20%). The median height Z-score was +3.1 (2.5; 4.0), the median age at height measurement was 29 (21; 37) years, and the majority of patients (84.1%) had reached their final height at a median age of 20 (18; 22) years. The median age at the onset of rapid growth was 13 (9; 15) years overall and was significantly younger in females than in males (11 (3; 14) vs 13 (10; 15) years, respectively; P=0.003). There was a median delay of 5.3 (2; 11) years between first symptom onset and pituitary adenoma diagnosis; this delay was significantly shorter in females than males (2.5 (1; 6) vs 6.2 (3; 12) years, respectively; P=0.03). Overall, 42.4% of patients were aged ≤19 years at diagnosis and significantly more female patients fell in this age group (P=0.004).

The most frequent first clinical sign was increased growth (∼75% of patients), followed by acral enlargement and facial changes (37%), headache (23%) and visual field defects (12%). Pubertal delay occurred in ∼29% of males and females.

Nine cases of pituitary apoplexy were reported at baseline and seven patients had diffuse pituitary hyperplasia (radiological or surgical); the remainder had pituitary adenomas. Patients with diffuse pituitary hyperplasia presented in childhood/adolescence and were generally younger at first symptoms and had a higher height Z-score at diagnosis than the remainder of the gigantism cohort; these differences were not statistically significant. Pituitary tumors were predominantly macroadenomas (84.3%), with 15% of those being ‘giant’ adenomas. Extrasellar extension and invasion occurred in most cases (89% and 64% of macroadenomas, respectively). Radiological characteristics did not differ between males and females.

Despite the relatively young age of the patients, acromegalic features were present in almost all males (92%) and females (94%) at diagnosis (Supplementary Table 1, see section on supplementary data given at the end of this article). The median shoe sizes at diagnosis were 15.0 (13.0; 17.0) in males and 11.5 (10.5; 14.5) in females (European (EU) sizing, 48 (46.0; 50.0) and 42 (41.0; 45.0) in males and females respectively). Among 156 cases that had cardiac assessments reported, cardiac disease had already been diagnosed in 36.5% at baseline, mainly left ventricular hypertrophy (21%) and diastolic dysfunction (10%).

Females exhibited higher median GH levels at diagnosis than males (62.3 (27.8; 95.0) vs 29 (12.3; 64.0) ng/ml, respectively; P=0.009), but IGF1 levels were similar between genders. Co-secretion of prolactin occurred in 34% overall and was more frequent in patients with invasive macroadenomas with extrasellar extension. At diagnosis, 25% of patients had a deficit in ≥1 axis; among those aged ≤19, hypopituitarism at baseline was seen in 18.3%.

Table 1

Clinical characteristics of patients with pituitary gigantism

Treatment and follow-up

Treatment regimens differed among centers due to the availability of medical therapies (Fig. 1). The median period of follow-up on treatment was 10.4 years (4; 20) overall. Initial surgery in 177 patients was associated with control in 15%. Among 40 cases that were then re-operated, 7.5% of those were controlled. Postoperative SSA were used in 66.7% (n=118) of the patients and disease control was achieved in 34% (n=40). A further 26% (n=54) of the patients received primary SSA treatment, but only 7% (n=4) of these were controlled. Pegvisomant was used preoperatively either alone (n=1) or in combination with SSA or DA (n=8); control was achieved in four cases. Pegvisomant was administered after surgery with SSA and/or DA in 28 patients; control was achieved in 53.5% (n=15) of these cases. A total of 63 patients were irradiated (two had primary radiotherapy) with control in 43% (median follow-up: 168 months (62; 235)); 56.5% of these also had received an SSA during follow-up. The median number of treatment modalities was 2 (1; 3). Overall, disease control was achieved in 45.6% of the patients. The median duration of follow-up post-treatment was 7 years (3; 17), and in those followed up for ≥12 months, disease control was achieved in 39.5% of cases. There was a significant correlation between larger tumor diameter and a greater number of treatment modalities (r=0.18, P=0.02). Macroadenomas required significantly more treatment modalities than microadenomas (≥3 modalities in 50% vs 19% respectively; P=0.009). Median maximal tumor diameter was smaller in patients who were controlled (19 (11; 25) vs 27 mm (17.0; 37.5) in uncontrolled cases; P=0.0003). However, there was better control at the last follow-up in those patients with tumors diagnosed at the age of ≤19 years than in older patients (58.5% vs 36.4% respectively; P=0.02). Maximal tumor diameter at diagnosis was correlated with GH (but not IGF1) levels (r=0.34, P=0.002) at diagnosis.

Figure 1

Schematic representation of treatments used in the management of patients with pituitary gigantism. Numbers in parentheses indicate the number of patients. RadioThx, radiotherapy; DA, dopamine agonists; SSA, somatostatin analogues; PegV, pegvisomant.

During follow-up, pituitary apoplexy occurred in nine patients. Hypopituitarism rose from 25% at baseline to 64% at the last follow-up. The proportions of patients with deficits in the various pituitary axes at the last follow-up were as follows: gonadal 62%, adrenal 47%, thyroid 41%, GH 10% and diabetes insipidus 8%. Among the patients with hypopituitarism, 92.6% had undergone surgery and 46% had received radiotherapy. In those aged ≤19 years at diagnosis, hypopituitarism was present at diagnosis in 18.3% and in 66% after treatment, with a deficiency of three pituitary axes in 29% and panhypopituitarism in 3%. The presence of hypopituitarism at the last follow-up was significantly related to larger tumor size (30 mm (20; 39) vs 15.5 mm (10; 25); P=0.006) but not to duration or control of the disease.

Seven patients (3.4%) died during follow-up; causes of death were thrombosis/embolism (n=2), hemorrhage, myocardial infarction, tumor progression, accident and suicide (n=1 each).

Growth responses

The height of each patient expressed in Z-scores above the mean and their age at the last measurement are shown in Fig. 2. The median height Z-score at diagnosis was higher in those who were still growing than those who had attained their final height (+4.1 s.d. (2.8; 5.7) and +2.9 s.d. (2.5; 3.8) respectively; P=0.004).

Figure 2

Age and Z-score for height of patients at the last follow-up. Of the total population of 208 patients, 57 patients had an absolute height >200 cm at the last measurement (eight are still growing) and the tallest patient was 247 cm. Of those who were controlled before the end of the linear growth, 11 had a height at the last follow-up of <+2 s.d. (seven of these later had a disease recurrence).

Excess GH/IGF1 secretion was controlled before the end of linear growth in 20.8% of the total group; in 11 of these cases, hormonal control led to a normalization of the growth pattern and a height at last follow-up that was <+2 s.d. (Fig. 2). Hormonal control at ≤19 years of age was associated with an earlier halting of linear growth than in those controlled after that age (P=0.0052). Overall, patients’ final height exceeded their MPH by a median difference of 20 cm (15; 24) and no gender differences were seen.

Height Z-score and the difference from MPH correlated significantly with tumor size (r=0.2, P=0.03) and GH (but not IGF1) at diagnosis (r=0.29, P=0.0001). Height Z-scores were also significantly greater in those who were younger both at first symptoms (r=−0.3, P=0.01) and at the start of rapid growth (r=−0.19, P=0.01). The difference of final height from MPH depended on age when first control was achieved (r=0.23, P=0.02), being significantly lower in those with disease control aged ≤19 years than thereafter (10.9% (7.7; 13.8) vs 12.7% (9.32; 16.3) respectively; P=0.044). Median excess over MPH was greater in patients with hypogonadism or pubertal delay than in those with normal gonadal status (12.8% (8.8; 16.3) vs 10.7% (8.5; 13.3) respectively; P=0.04).

Genetic studies

In the study population, 143 pituitary gigantism patients consented to genetic testing (AIP, MEN1, PRKAR1A, GNAS1, Xq26.3 duplication) and 46% had genetic causes or inherited syndromes (Fig. 3). In total, 29% of the patients were positive for AIP mutations. There were 28 familial isolated pituitary adenoma (FIPA) patients (23 males) of whom 18 had AIP mutations. Four members of two FIPA families had Xq26.3 microduplications and X-LAG syndrome, as did a further ten sporadic cases. In addition, seven McCune-Albright syndrome, two familial Carney Complex and one MEN1 gigantism case were observed; 54% of the patients had no genetic cause identified.

Figure 3

Genetic results in the study population. Numbers for each sector show the number of patients in the subgroup and its prevalence in the total group. AIP+, AIP mutation affected; Genetically –, genetically negative testing; MAS, McCune-Albright Syndrome; X-LAG, X-linked acrogigantism syndrome.

As compared with the AIP mutation-positive patients, those with no detected genetic cause were significantly more likely to be female, were older at first symptoms and at diagnosis (fewer cases were aged ≤19 years) and had a longer disease latency, with higher GH/IGF1 levels, more frequent multimodal therapy and poorer overall control rates (Fig. 4; Table 2). X-LAG cases were predominantly female and significantly younger at onset but had similar tumor size and lower rates of invasion and extension as AIP mutation-positive cases (Fig. 4; Table 2).

Figure 4

Comparisons of characteristics among genetically distinct groups of pituitary gigantism patients (genetically negative, AIP-mutation positive (AIP+) and X-linked acrogigantism syndrome (X-LAG)) showing statistically distinct patterns of age at first symptoms (A), age at diagnosis (B) and no intergroup difference in terms of maximal tumor diameter at diagnosis (C). (D) demonstrates the female and male predominance of X-LAG and AIP+ related gigantism cases; the genetically negative group was also male predominant although less markedly so than the AIP+ group.

Table 2

Comparisons of characteristics between X-linked acrogigantism (X-LAG) syndrome group, AIP mutation positive (AIPmut) patients and genetically negative patients

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Discussion

In this study we report the clinical and genetic characteristics of 208 patients with pituitary gigantism due to GH hypersecretion. This, the first extensive series of patients with radiologically and hormonally proven pituitary gigantism, provides insights into the disease profile of this rare disorder. Genetic or familial disease was seen in 46% of the cases tested. Of the tested cases, 29% had AIP mutations or deletions. Previous studies have noted that AIP mutations are associated with gigantism, either sporadic, within individual FIPA kindreds or in large historical studies (Naves et al. 2007, Jennings et al. 2009, Daly et al. 2010a, Chahal et al. 2011). This high frequency of AIP mutations among pituitary gigantism patients is logical, given that AIP mutations are characteristically common among children and young adults and most frequently lead to somatotropinomas (Stratakis et al. 2010, Tichomirowa et al. 2011). X-LAG syndrome is a recently described form of pituitary gigantism due to chromosome Xq26.3 microduplications (Trivellin et al. 2014, Beckers et al. 2015) and constituted 10% of the genetically studied cases in the current study. X-LAG syndrome has a particularly early age at onset, can present sporadically or as FIPA and predominantly affects females. We found no microduplication on Xq26.3 in any case diagnosed aged >5 years in our series, whereas the youngest AIP positive patient was 8 years old at diagnosis. Other genetic causes occurred less frequently; McCune-Albright Syndrome (MAS), Carney complex and MEN1 comprised 7% of gigantism overall. Although pituitary gigantism can occur in both genders, it predominantly affects males (78%). This is likely due to male predominance among AIP-mutated gigantism cases, as we reported previously in acromegaly (Daly et al. 2010b). This gender imbalance may have a number of causes, including unknown genetic factors. Likely contributors to the imbalance include the typical onset of AIP mutation-related somatotropinomas during puberty when GH excess coincides with the longer period of prepubertal growth and the greater pubertal peak growth velocity in males (Rogol et al. 2002). This could serve to augment the usual height difference between males and females at the end of puberty and push more males than females into the gigantism height range. As AIP mutation-related adenomas are usually large, concomitant impingement on normal pituitary tissue could lead to hypogonadism, thereby further prolonging the time to final epiphyseal closure in males. Among patients without AIP mutations, the gender balance was heterogeneous: X-LAG syndrome cases are mainly female (Trivellin et al. 2014, Beckers et al. 2015), whereas cases that were negative on genetic testing were predominantly male but less markedly so than the AIP-mutated group. The genetically negative group comprised more than half of all cases studied. The clinical phenotype of patients with AIP mutations or X-LAG syndrome has shown to be aggressive (Daly et al. 2010a, Beckers et al. 2015). In this study we noted that genetically unexplained pituitary gigantism patients are even more aggressive (e.g., invasion, hormone levels, lower control rates) than AIP mutation cases. This group may be a priority for further genomic pathophysiologic studies.

An important question regarding pituitary gigantism is whether earlier diagnosis and control of GH/IGF1 secretion can influence final height. As this study included patients with gigantism diagnosed at any time during their growth (not only on final adult height >+2 s.d.), we were able to address whether early recognition could limit excessive linear growth. In the group overall, the height at last follow-up was clearly in excess of MPH (11.6%; absolute difference, 20 cm) in both males and females. The median age at which linear growth ceased was 23 years, which is later than in the general population – 20 years (Deaton 2007). This delay permitted a longer period of growth before epiphyseal closure, a factor that was exacerbated in those with concomitant hypogonadism who had a greater final height. We found that a greater final height Z-score was determined by earlier age of onset, larger tumor size and greater GH excess. Moreover, these three features were interconnected, with younger patients developing larger tumors and higher GH secretion. Importantly, the age at which GH control was achieved had an important effect on final height. When control was achieved during the period of usual linear growth (≤19 years), the final height was lower, with a decrease in the difference between MPH and final height. These findings strongly suggest that an earlier diagnosis and a more rapid achievement of hormonal control can help reduce final height in pituitary gigantism patients. The delay between first symptoms of increased growth being noticed for the first time and the diagnosis of a pituitary adenoma relies on a number of factors. Not only is good awareness of the clinical features of excessive growth (including accompanying signs/symptoms) important in the general population but also the urgency of seeking and obtaining both general and specialized medical input depends on the patients and families and the attitude and efficiency of the health system. Access to expert diagnostics and treatment is not uniform, and particularly in economically disadvantaged regions, such access may be extremely difficult to obtain. Although these represent significant challenges, this study provides scientific evidence to support improvements in disease awareness and to improve the efficiency of current diagnostic and treatment networks.

In three-quarters of the cases abnormal growth was the first sign/symptom reported, and it was generally established by late prepubertal childhood or early adolescence (median 13 years). We found that signs/symptoms were noted significantly earlier in females than in males, which led to an earlier diagnosis and shorter latency period before diagnosis. A number of factors may have contributed to this earlier diagnosis. Disease onset overlapped with the earlier pubertal growth spurt in females. The superposition of abnormal acromegaly symptoms on top of accelerated vertical growth may have led to patients seeking medical attention earlier. In addition, tall stature even in healthy girls has long been viewed as less socially desirable (Lee & Howell 2006), possibly contributing to an earlier recourse to medical investigation by parents and doctors. However, despite the shorter latency period in females, the difference between final height and MPH did not differ between males and females. This was probably due to the similar duration between the time of diagnosis and the time of hormonal control in the two gender groups. This highlights that earlier recognition and diagnosis needs to be accompanied by rapid therapeutic intervention to control GH/IGF1 to influence final height.

Despite the young age at disease onset, pituitary adenomas were already large and most had extension and invasion at diagnosis. Elevated levels of GH and IGF1 (with prolactin co-secretion in one-third of cases) were seen at diagnosis and underpin the early and profound overgrowth seen among pituitary gigantism sufferers. Patients required multimodal treatment, with repeated surgeries and frequent use of radiotherapy. As the study was international and retrospective, not all modalities were uniformly available in all countries, particularly medical therapies like pegvisomant and SSA. Previous reports of individual cases or small series of pituitary gigantism have noted challenging disease control that required pegvisomant (Rix et al. 2005, Goldenberg et al. 2008). More uniform early recourse to medical therapies in patients not controlled by surgery alone could theoretically improve the poor responses seen in the current cohort. However, certain genetic forms of gigantism, such as AIP mutations and X-LAG syndrome, are poorly responsive to traditional SSA, further complicating the management (Daly et al. 2010b, Beckers et al. 2015). Radiotherapy has a relatively slow onset of effect and may not be sufficient alone following failed surgery, as in the setting of pituitary gigantism in which the window to provide effective therapy and to restrain overgrowth is quite narrow. Given these challenges, it would appear ideal that patients with suspected pituitary gigantism be referred to experienced centers with available multimodal therapy as soon as possible to improve chances of earlier effective disease control.

The clinical presentation included many typical disease features of adult acromegaly despite the relatively young age of the patients (Supplementary Table 1). The range of signs/symptoms was mainly influenced by the duration of GH/IGF1 hypersecretion and the delay in diagnosis. These included glucose metabolism disorders, arterial hypertension and heart disease, which are more typical of an older age group. Taking into account the poor hormonal control rate, it was not surprising that clinical symptom rates were not greatly ameliorated by surgery or on medical treatment (Supplementary Table 1). Moreover, hypopituitarism was diagnosed frequently in our cohort – probably due to high prevalence of macroadenomas – and rose from 25% of patients at baseline to 64% at the last follow-up due to cumulative effects of treatment (i.e., surgery and radiotherapy). Given the young age of disease-associated comorbidities, relatively low control of GH/IGF1 and the high rate of hypopituitarism, pituitary gigantism patients have significant morbidity. The impact of this morbidity on the lifespan as compared with what is established in adult acromegaly is unknown (Biermasz 2014). In our group, seven patients died, all relatively young, but specific studies are required to better assess the effects of disease burden on mortality. In addition, the impact of the often dramatic physical overgrowth on quality of life in pituitary gigantism patients should be addressed.

Height is highly variable across human populations due to a variety of factors, including complex genetic influences (Silventoinen 2003, Wood et al. 2014). In addition, secular trends in anthropomorphic measures, including height, in national or regional sub-populations can lead to rapid changes over a few generations due to factors like improved nutrition (Hesse et al. 2003, Marques-Vidal et al. 2008, Jordan et al. 2012, Avila et al. 2013). For this reason, the diagnosis of abnormal height must be made based on appropriate population norms, which ideally are country specific and regularly updated. We chose such normal datasets for the current study, which allowed us to classify patients with gigantism according to Z-scores for height based on their own country of origin.

This is the first study to describe the clinical, genetic and therapeutic features of pituitary gigantism in a large international cohort. However, there are some limitations. This was an analysis conducted among patients with variable disease duration and treatment history, which could impact analyses of disease control. Changes in the availability of modalities across time and across geographic regions are an unavoidable issue in studies of this type and must be borne in mind. The methodology of the study was based on definitive measures to a large extent to make the analyses and conclusions more robust. However, certain aspects, such as the age at the onset of rapid growth, may suffer from imperfect recall. Similarly, the multicenter nature of the study has implications for hormonal and radiological assessments due to heterogeneity of testing kits and normal ranges and neuroradiological equipment and results. In such a rare condition, it is not feasible for an academic (i.e., noncommercial) study to recruit large numbers of patients at the same disease stage and receive the same diagnostic and therapeutic workup measured centrally in the same laboratory and by the same neuroradiologists. We recognize the important variability in hormonal measurement in the GH/IGF1 axis depending on standards and methods used, and the variability of normal values over time and among laboratories always requires caution (Clemmons 2011). As a follow-up study, we will examine the pituitary tumor characteristics of gigantism patients using the same neuroradiological methods and interpretation, albeit in a small subset of the larger study group. Although this is the most extensive genetic study of patients with pituitary gigantism to date, only half of the patients consented to and underwent genetic testing; the final proportions of different genetic causes (and patients with unknown causes) could therefore vary from those we report here.

Pituitary gigantism patients are predominantly males diagnosed at a young age with macroadenomas, but females have their first symptoms and are diagnosed earlier than males. AIP mutations/deletions and X-LAG syndrome account for about 40% of the patients tested. However, a genetic cause remains to be found in more than half of the pituitary gigantism patients and these patients had aggressive disease features. Final height in gigantism was determined by an earlier age of onset, larger tumor size and greater GH excess; control of GH excess at a younger age led to a decreased final height. Treatment in patients with pituitary gigantism was complex and multimodal therapy was frequently needed. Pituitary gigantism is a challenging condition, and improved management to permit rapid diagnosis and treatment would likely be aided by greater general awareness of the condition, its genetic pathophysiology and the vital role of multidisciplinary surgical and medical teams.

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Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

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Funding

This study was supported by an educational grant from the JABBS Foundation (UK Charity Number: 1128402) and from the Fonds d'Investissement de Recherche Scientifique of the Centre Hospitalier Universitaire de Liège, to A Beckers. This study is based in part on confidential data provided by Eurostat, the statistical office of the European Union: European Health Interview Survey (EHIS) 1 microdata. The responsibility for all conclusions drawn from the data lies entirely with the authors.

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Acknowledgements

We would like to thank the following for contributing individual patient details: Daniel L Metzger, Hamilton Raúl Cassinelli, Satinath Mukhopadhyay, Natalia Strebkova, Monica Tome Garcia, Jens Otto Lunde Jorgensen, Jacob Dal, Annamaria Colao, Ismene Bilbao, Jose Ignacio Labarta Aizpun, Klaus Von Werder, Ann McCormack, Nadia Mazerkina, Dominique Maiter, France Devuyst, Marie-Christine Vantyghem, Alexander Dreval, Simona Juliette Mogos, Diego Ferone, Elena Nazzari, Vincent Rohmer, Patrice Rodien, Francoise Borson-Chazot and Sandrine Laboureau-Soares Barbosa. We also acknoledge the help of Nucleo de Apoio a Pesquisa from Instituto Sabin-Brasilia and CNPq, Brazil.

  • Revision received 14 July 2015
  • Accepted 16 July 2015
  • Made available online as an Accepted Preprint 17 July 2015
  • © 2015 Society for Endocrinology

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