Practice Essentials
Hyposomatotropism is a deficiency in the release of pituitary growth hormone (somatotropin), resulting in short stature. Achievement of final adult height consistent with a child's genetic potential remains the primary therapeutic endpoint for recombinanat human growth hormone (rhGH) therapy in the pediatric population. In addition to its effects on bone mass, GH regulates muscle mass, muscular strength, body composition, lipid and carbohydrate metabolism, and cardiac function. Patients with growth hormone deficiency (GHD) typically have hyperlipidemia, increased body fat, premature atherosclerotic plaques, delayed bone maturation, and impaired cardiac function. [1, 2, 3, 4, 5, 6, 7, 8, 9]
GHD in adults is recognized as a distinct clinical syndrome that encompasses reduced psychological well-being and specific metabolic abnormalities. Such abnormalities, including hypertension, central obesity, insulin resistance, dyslipidemia, and coagulopathy, closely resemble those of metabolic insulin resistance syndrome. [10] The increased rates of cardiovascular morbidity and mortality reinforce the close association between the syndromes. [11]
Recombinant human growth hormone
The commercial introduction of recombinant human growth hormone (rhGH) in 1985 dramatically changed the field of therapy for growth hormone (GH). Since then, rhGH has been administered to tens of thousands of children worldwide, making it one of the most extensively studied therapies in the pediatric pharmacopoeia.
The initial GH replacement therapy limited to GH-deficient patients has evolved into a pharmacologic therapy to include different conditions of non-GH deficient short stature. [12] US Food and Drug Administration (FDA)–approved indications for the administration of rhGH in children include the following:
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Growth failure associated with growth hormone deficiency (GHD)
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Small size for gestational age, with failure to catch up
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Idiopathic short stature
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SHOX gene deficiency
The European Medicines Agency (EMA) has also approved rhGH for all the above indications except idiopathic short stature (ISS) and Noonan syndrome.
While available evidence suggests that long-term GH therapy reduces the adult height deficit in children with ISS, questions remain as to whether the impact of the height gained on physical and psychosocial well-being outweigh the burden for patients and parents, potential adverse effects, cost of therapy, and patients’/parents’ expectations. [12]
Replacement of GH in adults with GHD markedly reduces central obesity and substantially reduces total cholesterol levels but has produced little change in other risk factors, particularly insulin resistance and dyslipidemia. [13] For these patients, concerns are the persistent insulin resistance and dyslipidemia, together with the elevated plasma insulin and lipoprotein(a) levels observed with GH replacement.
The large commercial supply of rhGH fuels research and debate over the proper indications for this potent and expensive therapy. Few disagree that many patients with childhood-onset GHD require continuous GH replacement therapy into adulthood. However, the diagnostic criteria for GHD in patients of any age remain controversial. This ambiguity stems from the wide variability in current tools used to diagnose GHD.
Clinicians and researchers alike will continue to grapple with these dilemmas in the foreseeable future. However, commercial interests and patient advocates continue to pressure the medical community to expand the accepted indications for rhGH. Therefore, the clinician and the clinical researcher must examine published data critically and must educate individual patients and their families about the risk-benefit ratio of rhGH therapy for them.
Diagnosis
The diagnosis of growth hormone (GH) deficiency (GHD), or hyposomatotropism, remains controversial. The diagnosis of GHD is a multifaceted process requiring comprehensive clinical and auxologic assessment combined with biochemical testing of the GH-insulinlike growth factor (IGF) axis and radiologic evaluation. Biochemical testing of the GH-IGF axis includes radioimmunoassays (RIAs) of GH, IGF, and insulinlike growth factor binding proteins (IGFBPs) [14, 15, 16]
Background
Human pituitary-derived growth hormone
In the 1950s, growth hormone isolated from the pituitaries of humans and anthropoid apes was discovered to stimulate growth in children who had growth hormone deficiency. Human pituitary-derived growth hormone (pit-hGH) was purified, and the first patient, a 17-year-old male adolescent with growth hormone deficiency (GHD), was treated successfully with pit-hGH. For many years, pituitary glands harvested from human cadavers provided the only practical source of GH with which to treat GHD. Worldwide, more than 27,000 children with GHD received pit-hGH from the 1950s to the mid 1980s.
Pit-hGH was a suboptimal therapy for 3 reasons:
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The shortage of pit-hGH limited its use and the dosages administered.
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The biopotency of preparations varied. Strict diagnostic criteria for GHD were used to address these problems (eg, peak plasma immunoreactive GH levels of more than 3.5-5 ng/mL after provocative stimuli).
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Treatment was often interrupted. The mean age for starting treatment with pit-hGH was often 12-13 years (late in childhood), and severe growth failure (height Z score -4 to -6) was required. As a result, pit-hGH therapy was often discontinued when girls attained a height of 60 inches and when boys attained a height of 65 inches.
Nonetheless, pit-hGH had dramatic effects. Among patients with isolated GHD, final height standard deviation scores increased to approximately -2 in boys and -2.5 to -3 in girls. For children with multiple pituitary-hormone deficiencies, height standard deviation scores increased to between -1 and -2.
The number of patients with GHD who were treated with pit-hGH increased from approximately 150 to more than 3000 by 1985. However, in 1985, studies indicated that pit-hGH was the likely source of contaminated material (prions) responsible for Creutzfeldt-Jakob disease (a slowly developing, progressive, fatal neurologic disorder) in 3 young men. [17] As a consequence, production and distribution of pit-hGH for therapy was discontinued.
Since 1985, recombinant DNA–produced human growth hormone has assured a safe and unlimited supply for uninterrupted therapy at doses adequate to restore normal growth.
Pathophysiology
Anatomy
Most of the pituitary gland is dedicated to synthesizing and secreting GH from somatotrophs of the adenohypophysis (anterior pituitary). The adenohypophysis derives from the Rathke pouch, a diverticulum of the primitive oral cavity. The adenohypophysis consists of 3 lobes—namely, the pars distalis, the pars intermedia (which is vestigial in humans), and the pars tuberalis. The pars distalis is the largest lobe and contains most of the somatotrophs. The pituitary gland lies within the sella turcica, covered superiorly by the diaphragma sellae and the optic chiasm. [4]
(See the image below.)
T1-weighted sagittal MRI through the pituitary fossa shows a normal pituitary gland.
Growth hormone
The hypothalamus communicates with the anterior pituitary gland by releasing of hypothalamic peptides, which are subsequently transported in the hypophyseal portal circulation (ie, the blood supply and communication between the hypothalamus and the adenohypophysis). GH is secreted in a pulsatile pattern as a single-chain, 191-amino acid, 22-kDa protein.
Two specific hypothalamic peptides play major regulatory roles in GH secretion: growth hormone-releasing hormone (GHRH) and somatotropin-releasing factor. Amplitudes and frequencies for release of GHRH and somatotropin-releasing factor, as well as GH, differ between boys and girls and may partially account for differences in the phenotypes between the sexes.
Several neurotransmitters and neuropeptides also control GH secretion by directly acting on somatotrophs or by indirectly acting by means of hypothalamic pathways. These neurotransmitters include pituitary adenylate cyclase activating polypeptide (PACAP), galanin, pituitary-specific transcription factor-1 (Pit-1), prophet of Pit-1 (PROP1), HESX1, serotonin, histamine, norepinephrine, dopamine, acetylcholine, gamma-aminobutyric acid, thyrotropin-releasing hormone, vasoactive intestinal peptide, gastrin, neurotensin, substance P, calcitonin, neuropeptide Y, vasopressin, and corticotropin-releasing hormone. [18, 19, 20]
Insulinlike growth factors
Insulinlike growth factors (IGFs) are a family of peptides that partially depend on GH and that mediate many of its anabolic and mitogenic actions.
Two theories have been proposed regarding the relationship between GH and IGFs: the somatomedin hypothesis and the dual-effector hypothesis. According to the somatomedin hypothesis, IGF mediates all of the anabolic actions of GH. Although this theory is partially correct, GH also has various other independent metabolic actions, such as enhancement of lipolysis, stimulation of amino acid transport in the diaphragm and the heart, and enhancement of hepatic protein synthesis. The attempt to resolve this discrepancy lies in the dual-effector model. According to this theory, GH stimulates precursor cells to differentiate and secrete IGF, which, in turn, exerts mitogenic and stimulatory effects. [15, 21, 22, 23, 24]
Insulinlike growth factor binding proteins
Six high-affinity insulinlike growth factor binding proteins (IGFBPs) bind IGFs in the circulation and tissues, regulating IGF bioavailability to the IGF receptors. Under most conditions, IGFBPs appear to inhibit the action of IGFs by competing with IGF receptors for IGF peptides. However, under specific conditions, several IGFBPs can enhance IGF actions or exert IGF-independent actions.
Relative concentrations of the IGFBPs vary among biologic fluids. IGFBP-3 is the most abundant IGFBP species in human serum and circulates as part of a ternary complex consisting of IGFBP-3, an IGF molecule, and a glycoprotein called the acid-labile subunit. IGFBP-3 is the only IGFBP that clearly demonstrates GH dependence. Therefore, IGFBP-3 is a clinically useful tool for the diagnosis of GHD and the follow-up care of patients.
Sex steroids
Androgens and estrogens substantially contribute to growth during the adolescent growth spurt. Children with GHD lack the normal growth spurt despite adequate amounts of exogenous or endogenous gonadal steroids. The relationship between the sex steroids, GH, and skeletal maturation is not clearly understood. However, GH secretion is lower in frequency and higher in amplitude among males than among females. [25]
Androgen and estrogen receptors have been identified in the hypothalamus and are suspected to play an important regulatory role in the release of somatostatin, the hypothalamic hormone that inhibits GH secretion. Somatostatin regulation is believed to direct the frequency and amplitude of GH secretion. Therefore, it may be one of the sources of the differences between males and females.
Thyroid hormone
Thyroid hormone is essential for postnatal growth. Growth failure, which may be profound, is the most common and prominent manifestation of hypothyroidism. The interrelationships between the thyroid and the pituitary-GH-IGF axis are complex and not yet fully defined. Hypotheses include a direct effect of thyroid hormone on the growth of epiphyseal cartilage and a permissive effect on GH secretion. Proof of the permissive effect on GH secretion derives from studies revealing that spontaneous GH secretion is decreased and that the response to provocative GH testing is blunted in patients with hypothyroidism.
In addition, growth velocity is markedly decreased among rhGH-treated patients with GHD and hypothyroidism until thyroid hormone replacement is begun. Downregulation of GH receptors and decreased production of IGF-1 and IGFBP-3 have been reported in the hypothyroid state. An unexplained relationship exists between the treatment of patients with GHD by using rhGH and the development and unmasking of hypothyroidism.
Etiology
Genetic abnormalities of GH production
A great deal has been learned about the genetic causes of hypopituitarism. By 1979, many families with isolated GHD or diminished production of GH and one or more additional pituitary hormones had been described. The development of a complementary DNA probe for the pit-hGH gene permitted scientists to recognize GH gene deletions in 1981 and placental GH and chorionic somatotropin gene deletions in 1982. The power of polymerase chain reaction (PCR) amplification and DNA sequencing subsequently revealed mutations and small deletions affecting GH in other families with isolated GHD.
The path to understanding the mechanisms that underlie multiple pituitary hormone deficiency was less straightforward than that regarding single genetic defects. Solutions emerged with the discovery of transcriptional activation factors that direct embryonic development of the anterior pituitary. This story began with the discovery in 1988 of a homeobox protein, called Pit-1, that binds to sequences in the promoter for the GH gene. The story continued with the recognition of many other pituitary and hypothalamic factors that orchestrated pituitary development; 3 main transcriptional factors have been implicated as causes of multiple pituitary hormone deficiency in humans. In chronologic order of their association with human disease, they are Pit-1, PROP1, and HESX1. [19, 20]
The PIT1 gene, located on chromosome 3, is a member of a large family of transcription factor genes responsible for the development and function of somatotrophs and of other neuroendocrine cells of the adenohypophysis. At least 7 point mutations of the PIT1 gene have been associated with hypopituitarism in Dutch, American, Japanese, and Tunisian families.
In 1992, Tatsumi et al described the first human example of pituitary hormone deficiency due to a PIT1 mutation. [26] Two sisters born to parents who were second cousins had profound neonatal hypothyroidism without elevated levels of thyroid-stimulating hormone. One died from aspiration pneumonia at the age of 2 months. The surviving sister also had deficiencies of GH and prolactin. Multiple recessive and dominant types of PIT1 mutations have been recognized over the years. Sporadic cases have also been reported.
The first examples of PROP1 mutations in humans with pituitary hormone deficiencies were reported in early 1998. In humans, the hormonal phenotype involves deficiencies of luteinizing hormone, follicle-stimulating hormone, prolactin, thyroid-stimulating hormone, and GH. Mutations recognized to date involve the paired-like DNA-binding domain encoded by exons 2 and 3 and demonstrate autosomal recessive inheritance. [20]
The HESX1 gene plays an important role in the development of the optic nerves and the anterior pituitary gland. [27] The human gene is located on chromosome 3p21.2. Dattani et al identified the first human patients with a mutation in HESX1 after 135 patients with pituitary disorders were screened. [28]
Developmental malformations
Developmental malformations commonly associated with GHD include anencephaly, holoprosencephaly, and septo-optic dysplasia (de Morsier syndrome). Septo-optic dysplasia, in its complete form, combines hypothalamic insufficiency with hypoplasia (or absence) of the optic chiasm, optic nerves, septum pellucidum, and corpus callosum. Consider this diagnosis in any child with growth failure and impaired vision, especially in one with accompanying nystagmus. HESX1 mutations have been associated with septo-optic dysplasia. [28, 29]
Trauma, infections, tumors, and cranial irradiation
Trauma, infections, sarcoidosis, tumors, and cranial irradiation of the hypothalamus, pituitary stalk, or anterior pituitary may also result in isolated GHD or anterior hypopituitarism.
GHD is most commonly associated with breech delivery, prolonged labor, placental abruption, and other complicated deliveries.
Hypothalamic tumors or pituitary tumors (eg, craniopharyngioma, glioma) are major causes of hypothalamic-pituitary insufficiency.
In rare cases, metastasis from extracranial carcinomas (eg, histiocytosis, germ cell tumor) lead to hypopituitarism.
Craniopharyngiomas and histiocytosis X are major etiologies of pituitary insufficiency. Craniopharyngiomas arise from remnants of the Rathke pouch, which is a diverticulum arising from the roof of the embryologic oral cavity and which gives rise to the anterior pituitary. Most patients present in mid childhood with symptoms of increased intracranial pressure, such as headaches, vomiting, visual field deficits, and oculomotor abnormalities. Short stature often coexists, but this is usually not the first complaint. Most children with craniopharyngiomas have growth failure at the time of presentation. Because of this association, any child in whom GHD is diagnosed should undergo MRI to exclude a brain tumor before the start of GH therapy.
Irradiation-induced hypothalamic-pituitary dysfunction is dose related. Low-dose irradiation usually results in isolated GHD, whereas high doses most often result in multiple hormonal deficiencies. One study group reported that 2-5 years after irradiation, 100% of children receiving doses of at least 3000 cGy to the hypothalamic-pituitary axis over 3 weeks had subnormal GH responses to provocative testing. Hypothalamic irradiation also damages the growth plate cartilage and is associated with an increased incidence of precocious puberty (advanced bone age and premature epiphyseal fusion); both of these processes compound the effect on linear growth. [30, 31]
Developmental abnormalities of the pituitary
Congenital absence or hypoplasia of the pituitary has also been identified. Common findings on MRI include an ectopic neurohypophysis, an absent infundibulum, a small adenohypophysis, and absence of the usual high signal intensity (bright spot) in the posterior pituitary as seen on T1-weighted MRIs. [32]
Epidemiology
The prevalence of hyposomatotropism (growth hormone deficiency ) is estimated to be between 1 in 4000 and 1 in 10,000. [33] An estimated 6,000 adults are diagnosed with growth hormone (GH) deficiency every year in the United States. Adult GH deficiency has been estimated to affect 1 in 100,000 people annually, whereas its incidence is approximately 2 cases per 100,000 population when childhood-onset GH deficiency patients are considered. About 15-20% of the cases represent the transition of childhood GH deficiency into adulthood. [28]
A racial ascertainment bias may be noted. Demographic and diagnostic features of GHD in children in the United States reveal that black children with idiopathic GHD are shorter than white children are at the time of diagnosis. The low overall representation of black children in the population with GHD (6%) compared with their representation in the at-risk population (12.9%) also suggests an ascertainment bias between the races.
A male ascertainment bias may be observed. The predominance of GHD diagnosed in boys in the United States and the observation that girls with idiopathic GHD are comparatively shorter than boys at the time of diagnosis suggest a sex-based ascertainment bias.
Mortality in children with growth hormone deficiency is due almost entirely to other pituitary hormone deficiencies. [34]
Prognosis
The prognosis depends on the underlying etiology of growth hormone (GH) deficiency (GHD). Non-adherence to growth hormone therapy (GHT) ican impact treatment success. Several studies have shown that adherence to growth hormone therapy (GHT) is not optimal; however, the exact rate of nonadherence reported varies considerably. There is growing evidence to suggest that shared decision-making may facilitate patient adherence to GHT, which may positively impact treatment outcomes. [35]
Sequelae of hyposomatotropism include the following:
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Behavioral and educational difficulties
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Peripheral vascular disease and reduced myocardial function
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Lean body mass, reduced muscular strength, and reduced exercise capacity
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Reduced thermoregulation
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Abnormal metabolism of thyroid hormone
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Impaired psychosocial well-being
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Decreased bone mineral content
A prospective, multinational, observational study of 9504 GH-treated patients found no significant increase in mortality for GH-treated children with idiopathic GHD, idiopathic short stature, born SGA, Turner syndrome, SHOX deficiency, or history of benign neoplasia. Mortality was elevated for children with prior malignancy and those with underlying serious non-GH-deficient medical conditions. [36]
The overall crude mortality rate for patients with tumor-related, trauma-related, or iatrogenic GHD is 2.7%. Clinicians must be cognizant of the increased incidence of mortality among patients with multiple pituitary hormone insufficiency secondary to adrenal crisis.
Patient Education
Patient education should include the following:
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Offer psychological support to patients and families.
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Discuss the possibility of a delayed onset of puberty.
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Discuss the importance of complying with daily injections.
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Discuss the current understanding of the metabolic actions of GH with patients.
For excellent patient education resources, visit eMedicineHealth's Thyroid and Metabolism Center. Also, see eMedicineHealth's patient education articles Growth Hormone Deficiency, Growth Hormone Deficiency in Children, Growth Failure in Children, Growth Hormone Deficiency Medications, and Growth Hormone Deficiency FAQs.
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T1-weighted sagittal MRI through the pituitary fossa shows a normal pituitary gland.
Tables
Characteristic |
Girls |
Boys |
Mean age at peak height velocity, y |
11.5 |
13 |
Magnitude, cm/y |
8.5 |
9.5 |
Duration, y |
5 |
6 |
