| disease | Hypopituitarism |
| alias | Pituitary Dwarfism, Pituitary Dwarfism |
Growth hormone deficiency is the most common manifestation of pituitary dysfunction in childhood, representing a prevalent endocrine disorder in pediatrics and a significant cause of growth impairment leading to short stature. Short stature due to pituitary growth hormone deficiency was previously termed pituitary dwarfism, but the use of this term is now discouraged.
bubble_chart Etiology
1. Congenital developmental disorders Pituitary aplasia or hypoplasia often occurs in anencephalic infants, with most cases reported in autopsies. Some may result from hypothalamic developmental defects causing secondary pituitary dysfunction. Children with brain hypoplasia may exhibit pituitary insufficiency. Clinically, growth hormone-releasing hormone stimulation tests can differentiate between hypothalamic and pituitary lesions. Short stature in blind children should prompt consideration of septo-optic dysplasia, optic nerve hypoplasia, or hypoplastic optic discs. Electroencephalography may confirm septal hypoplasia, often accompanied by various endocrine abnormalities. Other manifestations include a single central incisor, nasal septum developmental anomalies with GH deficiency syndrome, and absence of the sella turcica diaphragm, leading to suprasellar subarachnoid herniation into the sella, flattening the pituitary. Skull X-rays may show an empty sella turcica, termed empty sella syndrome.
2. Acquired pituitary hypofunction Various intracranial lesions can lead to anterior pituitary endocrine dysfunction and/or posterior pituitary insufficiency. The most common causes include craniopharyngioma and other hypothalamic tumors such as sarcoidosis, subcutaneous nodules at the skull base, or intracranial hemangiomas. Certain intracranial tumors may cause sella turcica enlargement, clinoid process deformation, or destruction. Calcifications near the sella often indicate craniopharyngioma. Additionally, skull base fractures, hypoxia, or hemorrhagic embolism can injure the pituitary, pituitary stalk, or hypothalamus, leading to growth impairment. Cranial radiotherapy for leukemia, histiocytosis, or tumors of the eyes/ears may also cause hypothalamic-pituitary injury.
3. Idiopathic pituitary hypofunction Children with pituitary hypofunction without identifiable pituitary or hypothalamic lesions but confirmed GH deficiency are classified as idiopathic pituitary hypofunction. This may present as isolated GH deficiency, multiple pituitary hormone deficiencies, or hypothalamic pituitary-releasing hormone secretion defects. Some cases of multiple pituitary hormone deficiency manifest in infancy, while others initially show only GH deficiency before progressing to broader pituitary dysfunction. Most cases are sporadic, though ~5% of isolated GH deficiencies are familial, categorized into the following types based on inheritance patterns and underlying defects:(1) Hereditary GH deficiency type IA; (2) Hereditary hGH deficiency type IB; (3) Hereditary hGH deficiency type II; (4) Hereditary hGH deficiency type III; (5) Familial panhypopituitary dwarfism; (6) Laron dwarfism; (7) Pygmy dwarfism.
4. Growth hormone neurosecretory dysfunction (GHND) Some children exhibit height ≤ -2SD, growth velocity ≤ 4 cm/year, bone age delay ≥ 2 years, and hGH stimulation test peaks ≥ 10 μg/L (10 ng/mL). However, 24-hour or nocturnal hGH secretion profiles reveal low peaks and reduced secretory bursts. Total 24-hour hGH secretion (measured via blood sampling every 20–30 minutes) is diminished, suggesting GHND arises from grade I injury anywhere in the CNS-hypothalamic-pituitary axis, including neurotransmitter dysfunction, reduced GHRH secretion, or increased somatostatin. Recent use of GHRH as a biochemical pharmacologic probe confirms that many classic hGH-deficient children have hypothalamic rather than pituitary defects. GHND patients respond well to hGH therapy.
Infants with idiopathic pituitary hGH deficiency have normal body length and weight at birth, and some may have a history of breech delivery or postnatal asphyxia. Growth and development in the first year are mostly normal. Approximately half of the cases begin to show slowed growth velocity after one year of age. The other half exhibit gradual growth retardation, with significantly shorter stature compared to peers, becoming more pronounced with age. Pituitary hGH deficiency is mostly manifested as short stature, with length retardation being more severe than weight reduction. The head is round, the face has a "doll-like" appearance, the mandible is underdeveloped, teeth erupt late and are crowded, the neck is short, subcutaneous fat in the chest and abdomen is relatively abundant, hands and feet are small, and the proportions of limbs and trunk are symmetrical. About 10–15% of patients may experience fasting hypoglycemia, but intelligence is normal. The voice is high-pitched, and skin folds appear early. The limbs and trunk are proportionally symmetrical, but hands and feet are small, and the external genitalia often remain juvenile. Due to short stature, psychological effects may arise, leading to personality traits such as introversion and timidity.
In cases of multiple pituitary hormone deficiencies, in addition to GH deficiency, there may also be insufficient secretion of TSH, ACTH, LH, and FSH, leading to dysfunction of the thyroid, adrenal cortex, and gonads. Apart from the manifestations of pituitary dwarfism mentioned above, hypoglycemic symptoms are more severe, and there may be cold intolerance, intellectual retardation, absence of secondary sexual characteristics during puberty, and lack of sexual maturation.
X-ray examination: Long bone X-rays show thinner bone shafts with poor calcification, delayed appearance of ossification centers, and delayed bone age. The anterior fontanelle may close as late as after 2 years of age, and intersutural bones may appear. Skull X-rays may reveal a normal or smaller sella turcica. Intracranial space-occupying sexually transmitted disease lesions may cause skull bone destruction; pituitary tumors may lead to an enlarged sella turcica. If necessary, computed tomography (CT) or magnetic resonance imaging (MRI) can be used to confirm the location of the lesion.
bubble_chart Auxiliary Examination
The baseline value of normal human serum measured by hGH radioimmunoassay is very low, ranging from 0 to 10 μg/L (0 to 10 ng/ml). If the value measured by GH stimulation test is >10 μg/L (10 ng/ml), GH deficiency can be excluded; if it is <10 μg/L (10 ng/ml), further examination is required. First, measure the GH value during sleep, drawing blood within 45–90 minutes after sleep (during deep sleep or under EEG monitoring); or perform an exercise test—after fasting for 3–4 hours, rest quietly for 30 minutes, walk on flat ground for 15 minutes, then run up and down one flight of stairs (about 20 steps) 10–20 times (5 minutes), and immediately draw blood to measure GH. Under the following two conditions, the serum GH concentration in normal children should rise above 10 μg/L (10 ng/ml). If it is <10 μg/L (10 ng/ml), proceed with stimulation tests, such as arginine, insulin, clonidine, dopamine, or glucagon stimulation tests, or a combination of two tests. For patients with reduced pituitary function, severe hypoglycemia may occur during the insulin test, so close observation is necessary. If the hGH stimulation test is normal but clinical suspicion of pituitary dwarfism persists, a 24-hour or 12-hour nocturnal hGH secretion rhythm can be measured; if reduced, consider GHND.
The diagnostic criteria for pituitary hGH deficiency have evolved with the widespread use of hGH therapy. Initially, a post-stimulation hGH peak <5 μg/L (5 ng/ml) was used, later revised to <7 μg/L (7 ng/ml), and now <10 μg/L (10 ng/ml). An hGH peak <5 μg/L (5 ng/ml) indicates complete deficiency, 5–7 μg/L (5–7 ng/ml) indicates partial deficiency, and 7–10 μg/L (7–10 ng/ml) indicates grade I deficiency. If >10 μg/L (10 ng/ml) but the 24-hour GH secretion rate is reduced, it suggests GHND. Hereditary GH deficiency can be diagnosed using an hGH gene probe.
Measuring somatomedin C by radioimmunoassay is also helpful in diagnosing children with GH deficiency. In GH-deficient children, the blood somatomedin concentration significantly increases 12 hours after GH injection.
Hypothyroidism or depression can also lower GH levels, which return to normal after the underlying cause is resolved.
In cases of multiple pituitary hormone deficiencies, urinary 17-hydroxycorticosteroids and plasma or urinary cortisol concentrations can be measured. If reduced, it indicates ACTH deficiency. The insulin hypoglycemia test can simultaneously stimulate ACTH release, increasing blood cortisol levels; if no increase occurs, it suggests poor pituitary ACTH reserve. In pituitary TSH deficiency, both serum T4 and TSH concentrations are low. If TSH rises to normal after TRH injection, the lesion is likely in the hypothalamus; if it does not rise, the lesion is in the pituitary. Children with reduced pituitary function also have lower blood TSH and LH concentrations compared to normal peers.
bubble_chart Treatment Measures
Children with pituitary hGH deficiency are now treated with genetically engineered synthetic hGH as a replacement therapy. Treatment should begin as early as possible to allow height growth to catch up to normal levels. There are differing opinions on the dosage and method of hGH administration. Generally, 0.1 mg (0.1 U)/kg is administered subcutaneously once daily, six times a week. Some advocate 0.05–0.1 mg/kg intramuscularly or subcutaneously three times a week. The first year of treatment yields the best results. In Beijing and Shanghai, 80 cases of pituitary dwarfism were treated for one year with Swedish-produced hGH (donated), resulting in height increases of 8–12 cm. Some patients experienced reduced blood thyroxine levels after hGH treatment and required additional thyroid tablet therapy. If pituitary dwarfism is accompanied by ACTH deficiency, corticosteroids are generally not used unless clinical symptoms of adrenal insufficiency (e.g., fatigue) are present. If symptoms occur, a small dose of cortisone acetate may be added. If gonadotropin deficiency is also present, testosterone enanthate (250 mg intramuscularly once a month) can be administered to promote genital development after bone age reaches 12 years.
When hypothalamic lesions cause GHRH deficiency, synthetic GHRH can also be administered intramuscularly or intravenously every 3 hours, though this remains experimental.
Currently, synthetic hGH is not clinically available domestically in China. While a few patients can purchase hGH from abroad for treatment, most still rely on other growth-promoting drugs. Nandrolone phenylpropionate (Durabolin) is commonly used for its protein synthesis-promoting effects, though it has androgenic side effects and accelerates bone age maturation. Improper use may result in shorter final height. The general principle for its use is that the patient’s bone age must lag behind chronological age by at least 3 years to avoid rapid bone age advancement necessitating discontinuation. The recommended dosage is 0.5 mg/kg intramuscularly once a week for 10 doses per course. After discontinuation, bone age is reassessed after six months. If it still lags by more than 3 years, a second course may be administered until the maximum possible height is achieved. Androgens can be added to promote sexual development before or after epiphyseal closure. Beijing Children’s Hospital treated 37 cases of pituitary dwarfism for 1–10 years using nandrolone phenylpropionate (old dosage: 1 mg/kg weekly). Among them, 32 cases treated for one course showed an average growth velocity increase of 5.93 ± 1.78 cm/year (range: 1–9 cm), with bone age advancing by 1.73 ± 0.89 years. One case showed the highest bone age acceleration at 3.5 years in one year. Consequently, the dosage was reduced to 0.5 mg/kg per dose. Two cases treated for 6 and 10 courses reached final heights of 159.5 cm and 157.0 cm, respectively, with bone ages of 16–17 years and unclosed epiphyses.
Additionally, clonidine and other treatments may be tried, showing considerable efficacy in some children. Other testosterone derivatives, such as fluoxymesterone (2.5 mg/m² daily) and oxandrolone (0.1–0.25 mg/kg daily), can also be used. Stanozolol (1 mg orally once daily) has also shown growth-promoting effects in some children.
When there is a deficiency of multiple pituitary tropic hormones, the corresponding hormones should be supplemented. For example, if blood TSH is low or clinical symptoms appear, thyroid hormone can be used, with the dose varying by age, typically 7.5 μg/kg per day. The dosage of desiccated thyroid tablets is 20–40 mg/d. The combined use of thyroid hormone and hGH has a synergistic effect on promoting growth. Regarding corticosteroids, they should only be administered when laboratory tests confirm ACTH deficiency and clinical symptoms such as weakness or hypoglycemia are present. The dosage should be conservative; for example, the daily dose of hydrocortisone is 7.5–10 mg. During hGH treatment, if corticosteroid deficiency persists until bone age exceeds a certain threshold during puberty, gonadotropins can be added. For boys, human chorionic gonadotropin (hCG) can be administered intramuscularly at 1000–1500 units per dose, three times a week, for six months, followed by observation of developmental progress. Alternatively, testosterone enanthate 250 mg can be injected intramuscularly once a month. For girls, ethinylestradiol 0.02 mg can be taken orally once daily until secondary sexual characteristics develop, after which cyclic hormonal therapy can be initiated.
Intracranial tumors should be considered for surgical treatment.
Nowadays, most treatments use genetically engineered human growth hormone, and if started early, many patients can achieve normal height. However, treatment remains challenging for some patients with hereditary hGH-N gene deficiency or growth hormone insensitivity.
There are many causes of growth disorders, and the following diseases need to be differentiated from GH-deficient dwarfism. Classification by body type makes differentiation relatively straightforward.
1. Disproportionate dwarfism: Including cretinism, achondroplasia, and dwarfism with various deformities, these are relatively easy to differentiate. The characteristics of these diseases include disproportionate body proportions, especially an upper-to-lower body ratio that does not match the age, with most cases showing a higher upper-to-lower body ratio compared to normal values for the same age. Some children may also have intellectual disabilities, abnormal skeletal X-ray findings, and low blood thyroid hormone levels.
2. Dwarfism with normal body proportions and normal growth rate: These are normal children. Their growth rate is essentially normal, with proportionate body types, but their average height deviates by more than two standard deviations. The causes include: ① Familial short stature: Due to short parental height, determined by genetic factors. ② Constitutional delayed adolescence: More common in boys, with slow growth during the pre-pubertal period (not growth stagnation). The onset of puberty may be delayed by 3–5 years compared to normal children, and bone age may also be correspondingly delayed, but height normalizes after puberty. ③ Low birth weight dwarfism: Apart from low birth weight and short stature, other body proportions and bone age are close to normal. Growth rate is at the lower limit of normal, and some may have heights below the third percentile. Serum growth hormone levels in these cases are normal.
3. Dwarfism with normal body proportions but reduced growth rate: This type most requires differentiation from pituitary hGH deficiency. Common diseases include:
(1) Environmental and psychological factors causing dwarfism, also known as emotional deprivation dwarfism: Psychological depression and long-term emotional低落 can lead to growth retardation, which closely resembles reduced pituitary function. This is a reversible decrease in hGH secretion. Blood GH and somatomedin levels are low, and the response to GH stimulation tests is also reduced, with delayed puberty. The exact reason why emotional and psychological depression affects growth remains unclear. Careful observation of affected children may reveal certain abnormal psychological manifestations, such as voracious appetite, enuresis, insomnia, spasmodic crying, susceptibility to spleen qi, or extreme docility or defiance. Intelligence is often at the lower end of normal. Some cases may involve family-related unhappiness, but the cause of emotional depression is often unclear. However, changing the living environment can lead to significant improvement and rapid growth. Diagnosis should be made cautiously, excluding organic diseases such as intracranial tumors.
(2) Primary ovarian dysgenesis (Turner syndrome): In girls with short stature, the possibility of missing or partially missing X chromosomes should be considered, known as primary ovarian dysgenesis. Clinical karyotypes include 45,XO; 45,XO/46,XX mosaicism; 46,XXp- (short arm deletion of X), among others. Clinical features include short stature, neck webbing, cubitus valgus, low hairline, absence of secondary sexual characteristics, primary amenorrhea, underdeveloped female genitalia, and sometimes intellectual disability and visceral deformities. In girls with short stature and lack of secondary sexual development, cell chromatin and chromosome tests should be performed for confirmation.
(3) Dwarfism caused by other endocrine diseases: Conditions such as hypercortisolism, congenital adrenal hyperplasia, and precocious puberty can all present with dwarfism, but each has its own clinical manifestations, making differentiation easier.
