Hypopituitarism: Clinical Guidelines

List of Abbreviations

ACTH – adrenocorticotropic hormone

GnRH – gonadotropin-releasing hormone

HP – hypopituitarism

IGHD – isolated growth hormone deficiency

IGF-1 – insulin-like growth factor I

BA – bone age

CDD – constitutional delay of development

CDG – constitutional delay of growth

LH – luteinizing hormone

MPAH – multiple pituitary hormone deficiencies

MRI – magnetic resonance imaging

TSH – thyroid-stimulating hormone

FT4 – free thyroxine

GH – growth hormone

FSH – follicle-stimulating hormone

US – ultrasound examination

hCG – human chorionic gonadotropin

GH-1 – growth hormone gene

Terms and Definitions

Anophthalmia – absence of the eyeballs resulting from agenesis/aplasia of the eye bud.

Astrocytoma – a glial brain tumor arising from astrocytes. The mainstay of treatment for astrocytomas is surgical intervention, followed by chemotherapy and radiation therapy.

Secondary hypogonadism (hypogonadotropic hypogonadism) – a pathological condition caused by the absence or reduction of gonadotropic hormone function (LH and FSH).

Secondary hypocortisolism – a disease caused by the absence or reduction of ACTH secretion.

Secondary hypothyroidism – a disease caused by the absence or reduction of TSH secretion.

Hypothalamic hamartoma – a rare benign tumor of the hypothalamus (morphologically corresponding to a gangliocytoma) manifesting with neurological symptoms, cognitive impairments, and precocious puberty.

Germinoma (dysgerminoma, pinealoma) – a dysontogenetic tumor resulting from impaired tissue differentiation and migration during early embryonic development, typically localized in the deep structures of the brain: pituitary gland, hypothalamus, third ventricle, optic chiasm, pineal gland, and base of the brain, manifesting with neurological symptoms and signs of hypopituitarism.

Hypopituitarism (hypothalamic-pituitary insufficiency) – a disease caused by the absence or reduction of hypothalamic neurohormones, or one or more pituitary hormones. Within hypopituitarism, GH deficiency is the most common, which can be isolated or combined with other trophic hormone deficiencies.

Optic nerve glioma – a slow-growing primary tumor developing from the optic nerve trunk. The main treatment method is surgery, followed by radiotherapy if necessary.

Holoprosencephaly – a severe brain formation disorder characterized by the complete or partial absence of hemisphere cleavage combined with other head and facial malformations. Symptoms of this condition include abnormal facial formation with the development of cyclopia, proboscis (or absence of a nose), cleft lip, and cleft palate.

Craniopharyngioma – a congenital epithelial brain tumor developing from embryonic cells of the hypophyseal duct (Rathke's pouch) and manifesting with visual impairment, headache, hypogonadism, and cranial nerve palsies.

Medulloblastoma – a malignant neuroectodermal tumor of the posterior cranial fossa requiring complex treatment: surgical removal supplemented by radiation and chemotherapy.

Diabetes insipidus – a disease caused by the absence or reduction of vasopressin secretion, characterized by the inability of the kidneys to reabsorb water and concentrate urine, and manifesting with severe thirst and polyuria.

Panhypopituitarism – a disease caused by the absence or reduction of secretion of all hormones produced by the pituitary gland.

GH deficiency (growth hormone deficiency) – isolated growth hormone deficiency.

Ependymoma – a malignant central nervous system tumor that develops from ependymal cells of the brain ventricles and the central canal of the spinal cord, most frequently located in the posterior cranial fossa and primarily treated with combined therapy: surgery supplemented by radiation therapy.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Hypopituitarism (hypothalamic-pituitary insufficiency) is a disease caused by the absence or reduction of hypothalamic neurohormones, or one or more pituitary hormones. Within hypopituitarism, GH deficiency is the most common, which can be isolated or combined with other trophic hormone deficiencies [38].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Hypopituitarism in children can be caused by congenital and acquired factors. Most cases of hypopituitarism result from pathology of the hypothalamus and its stalk, which leads to a deficiency of hypothalamic signals to the pituitary gland.

Etiology of hypopituitarism in children [1].

1. Idiopathic hypopituitarism

1.1 Idiopathic HP

1.2 Neurosecretory dysfunction

2. Congenital hypopituitarism

2.1 Inherited isolated GH deficiency

2.1.1 Growth hormone gene mutations (GH1)

• type IA: GH gene deletion, autosomal recessive inheritance (Illig type of GH deficiency);

• type IB: autosomal recessive inheritance;

• type II: autosomal dominant inheritance;

• type III: X-linked recessive inheritance.

2.1.2 GHRH receptor gene mutations (GHRH-R)

2.2 Inherited multiple pituitary hormone deficiencies

mutations of POU1F1 (PIT1), PROP1, HESX1, LHX3, LHX4, HESX1, Pitx2 genes, etc.

2.3 CNS developmental pathology

2.3.1 Septo-optic dysplasia

2.3.2 Adenohypophyseal hypoplasia, hypoplasia/aplasia of the pituitary stalk, neurohypophyseal ectopia

2.3.3 Empty sella syndrome (including pituitary aplasia)

2.3.4 Single maxillary central incisor syndrome

2.3.5 Cleft palate

2.3.6 Holoprosencephaly

2.3.7 Arachnoid cyst

2.3.8 Congenital hydrocephalus

2.3.9 Other

2.4 Complex congenital hypopituitarism syndromes

2.4.1 Fanconi pancytopenia

2.4.2 Axenfeld-Rieger syndrome

2.4.3 Other

2.5 Prenatal infection

2.5.1 Rubella

2.5.2 Other

3. Acquired hypopituitarism

3.1 Tumors of the hypothalamo-pituitary region

3.1.1 Craniopharyngioma

3.1.2 Germinoma (dysgerminoma, pinealoma)

3.1.3 Hypothalamic hamartoma

3.1.4 Neurofibroma

3.1.5 Pituitary adenoma

3.2 Brain tumors not related to the hypothalamo-pituitary region

3.2.1 Astrocytoma

3.2.2 Ependymoma

3.2.3 Optic nerve glioma

3.2.4 Medulloblastoma

3.2.5 Other

3.3 Treatment for extra-cranial tumors

3.3.1 Lymphoblastic leukemia

3.3.2 Myeloblastic leukemia

3.3.3 Lymphoma

3.3.4 Solid tumor

3.4 Trauma

3.4.1 Traumatic brain injury

3.4.2 Surgical injury to the pituitary stalk

3.5 Infections

3.5.1 Viral and bacterial encephalitis and meningitis

3.5.2 Nonspecific (autoimmune?) hypophysitis

3.6 Infiltrative diseases

3.6.1 Histiocytosis

3.6.2 Sarcoidosis

Congenital hypopituitarism may be caused by mutations in genes that control growth hormone (GH) production, are involved in pituitary development, or are responsible for growth hormone-releasing hormone (GHRH) signaling transduction.

• Hereditary isolated growth hormone deficiency is associated with 5 different variants of genetic defects [2-9] (Table 1, Appendix A3).

• Hereditary multiple pituitary hormone deficiency

In addition to the isolated form, hereditary variants of GH deficiency combined with deficiencies of other anterior pituitary tropic hormones are known. The molecular basis of multiple pituitary hormone deficiency is mutations in genes encoding pituitary transcription factors involved in adenohypophyseal embryogenesis. These genes include: POU1F1 (PIT1), PROP1, HESX1, LHX3, LHX4, Pitx2, OTX2, with pathologies in different genes causing distinct clinical presentations [10, 11-16] (Table 2, Appendix A3).

Patients harboring POU1F1 (PIT1) mutations typically present with severe GH and prolactin deficiency [17-18], whereas the degree of TSH deficiency can be variable.

The most common of all currently known genetic defects underlying congenital hypopituitarism is pathology of PROP1 [19]. Unlike individuals with a POU1F1 (PIT1) defect, patients with a PROP1 mutation have concomitant hypogonadism and hypocortisolism. Hypocortisolism develops gradually and typically manifests no earlier than adolescence, although cases with onset in early childhood may occur [20-21]. About 20% of patients with PROP1 mutations have adenohypophyseal hyperplasia on magnetic resonance imaging (MRI) [22-24], with subsequent involution over the course of life, up to the development of "empty sella" [22, 24-25]. An MRI picture of adenohypophyseal hyperplasia in a child of any age with GH/PRL/TSH deficiency is an indication for molecular diagnostics, primarily analysis of the PROP1 gene [25]. Pathology of the HESX1 gene ("homeobox gene expressed in embryonic stem cells") has been described in children with hypopituitarism combined with septo-optic dysplasia (de Morsier syndrome). De Morsier syndrome implies a triad of congenital anomalies of the midbrain, visual analyzer, and pituitary gland:

- optic nerve and chiasm hypoplasia,

- agenesis/hypoplasia of the septum pellucidum or corpus callosum,

- pituitary hypoplasia and hypopituitarism: ranging from isolated GH deficiency to panhypopituitarism.

At the same time, HESX1 gene mutations are far from being detected in all children with clinical signs of septo-optic dysplasia, indicating the likely involvement of other, as yet unknown genes in the pathogenesis of de Morsier syndrome [16].

Specifically, OTX2 is a transcription factor whose role in the development of the hypothalamo-pituitary system remains largely unclear (it is currently known to influence HESX1 expression); nevertheless, mutations in the gene encoding it (OTX2) have been identified in septo-optic dysplasia. Known OTX2 mutations are associated with hypopituitarism combined with severe ocular pathology—bilateral anophthalmia or microphthalmia [26], psychomotor retardation, seizures, and various MRI anomalies: adenohypophyseal hypoplasia, infundibular hypoplasia (aplasia), and neurohypophyseal ectopia [27-29].

Heterozygous GLI2 mutations have been identified in patients with holoprosencephaly. All of them presented with hypopituitarism combined with craniofacial anomalies of varying severity: proboscis-like nose, cleft soft and hard palate, and a single maxillary central incisor [30-31]. On the other hand, GLI2 mutations associated with hypopituitarism without midline craniofacial anomalies have also been described [32-33].

LHX3 mutations cause deficiencies in tropic hormones, with the exception of ACTH deficiency in the majority of cases, although patients with hypoadrenalism have also been reported [34]. Typically, defects in this gene result in pituitary hypoplasia, while the neurohypopoysis, infundibulum, and midline brain structures remain intact. Most patients have a short neck combined with neck and spinal rigidity, although patients with adequate range of motion have been described [35], and some exhibit sensorineural hearing loss.

Depending on the nature of the LHX4 mutation, hypopituitarism ranges from isolated GH deficiency to panhypopituitarism (most commonly combined GH, TSH, and ACTH deficiency), along with adenohypophyseal hypoplasia—occasionally combined with infundibular hypoplasia and neurohypophyseal ectopia—and corpus callosum hypoplasia [36-37].

Acquired hypopituitarism is most frequently caused by central nervous system tumors of various etiologies, primarily affecting the hypothalamo-pituitary region. Following treatment for such tumors (surgery, radiation therapy, chemotherapy), manifestations of hypopituitarism typically progressive. Craniopharyngioma is the most common tumor of the hypothalamo-pituitary region in childhood [38-40]. Because craniopharyngiomas develop from remnants of Rathke's pouch—which connects the pharynx to the pituitary during embryonic development—the likelihood of hypothalamo-pituitary system involvement is extremely high (endocrine disorders are observed in 32–52% of children before treatment, and low IGF-1 concentrations in 80%). Prior to treatment initiation, 75–100% of children have GH deficiency, 20–70% have hypoadrenalism, 3–30% have hypothyroidism, 8–20% have hyperprolactinemia resulting from pituitary stalk compression, and 10–29% have diabetes insipidus. In adolescents, craniopharyngiomas can cause delayed puberty [41]. Brain MRI, particularly with contrast enhancement, is the most sensitive method for detecting craniopharyngiomas.

Less common causes of hypopituitarism in children include pituitary adenoma, germinoma, and hamartoma.

A number of space-occupying lesions, such as optic nerve gliomas and astrocytomas, are not anatomically connected to the pituitary gland; however, their location in close proximity to the hypothalamo-pituitary region, their progression, or the treatments administered can be complicated by hypopituitarism [42].

High-dose radiation therapy is used to treat patients with medulloblastoma, retinoblastoma, Hodgkin's lymphoma, and acute lymphoblastic leukemia. However, it has been shown that brain irradiation at a dose of 40 Gy and higher causes growth hormone deficiency in virtually 100% of cases [43]. Consequently, GH deficiency in these cases develops as a result of radiation therapy targeting the tumor process. Despite attempts to limit the damaging effects of radiation on surrounding tissues, a portion of the dose inevitably affects the hypothalamo-pituitary region.

In some cases, the development of hypopituitarism (HP) in children is observed after total body irradiation during bone marrow transplantation, or in patients receiving chemotherapy for oncological diseases. Acquired somatotropic insufficiency, regardless of its cause, is in most cases combined with a deficiency of other tropic hormones; however, the «loss» of pituitary hormones does not occur simultaneously, but follows a certain staging. At the same time, GH secretion, being apparently the most sensitive to the damaging factor, is among the first to suffer, and subsequently it may be joined by thyrotroph, gonadotroph, and corticotroph deficiencies. Diabetes insipidus develops much less frequently (in case of damage to hypothalamic nuclei or injury to the pituitary stalk).

1.3 Epidemiology of the Disease or Condition

The frequency of HP in children in various countries ranges from 1:4,000 to 1:10,000 of the pediatric population [38]. According to data as of January 1, 2021, the prevalence of HP in the Russian Federation is 1:8,780 of the pediatric population (11.4:100,000 of the pediatric population) [44]. Boys are affected twice as often as girls.

1.4 Features of Coding the Disease or Condition

E23.0 Hypopituitarism

E23.1 Drug-induced hypopituitarism

E89.3 Hypopituitarism following medical procedures

1.5 Classification of the disease or condition

There is no single classification of HP. Hypopituitarism in children is viewed as a complex of pathogenetically diverse diseases united by common clinical symptoms. HP can be idiopathic (the majority of cases currently) and organic (an etiological factor has been identified), sporadic and familial (hereditary), with an identified or unidentified genetic defect, congenital and acquired. For clinicians, the most convenient and practical classification is based on the etiology of HP.

1.6 Clinical presentation of the disease or condition

The clinical presentation is caused by the deficiency of tropic hormones specific to the individual patient's HP, primarily GH deficiency, which is an obligate component of HP in children.

The main clinical features of somatotropic insufficiency are:

• postnatal growth retardation (height below the 3rd percentile or below 2 standard deviations (< - 2.0 SDS) from the population mean for the corresponding chronological age and sex);

• progressive deceleration of growth velocity.

HEIGHT.

SDS (Standard Deviation Score) is the standard deviation score, an integral indicator used to assess the conformity of a child's individual height to the reference data for the corresponding age and sex. The SDS shows how many standard (sigma) deviations make up the difference between the arithmetic mean and the measured value. The SDS is calculated using the formula:

Height SDS = (x - X) / SD

where x is the child's height,

X is the average height for a given chronological age and sex,

SD is the standard deviation of height for a given chronological age and sex.

or using computer programs.

SDS = - 2 corresponds to the 3rd percentile,

SDS = 0 corresponds to the 50th percentile;

SDS = + 2 corresponds to the 97th percentile.

Postnatal growth in children with HP varies depending on the etiology of the disease. In diseases due to genetic defects, growth retardation can be observed as early as the first months or years of life. Growth retardation due to acquired causes is observed later, usually after 5–7 years. To assess the genetic component, the «genetically programmed height» (GPH) is calculated:

GPH = (father's height + mother's height + 13 cm)/2 ± 10 cm for boys,

GPH = (father's height + mother's height – 13 cm)/2 ± 7 cm for girls.

To assess the indicators of physical development in children, special height-weight curves are used (Fig. 1-4, Appendix G).

GROWTH VELOCITY.

Analysis of growth velocity makes it possible to detect deviation from the growth curve at early stages. To assess growth velocity, data from at least two accurate measurements are required. To minimize calculation errors, it is preferable that the interval between measurements is at least 6 months. Growth velocity is calculated using the formula:

Growth velocity (cm/year) = (height 2 - height 1) / CA 2 – CA 1

height 1 (cm) is the current height measurement,

height 2 (cm) is the preceding height measurement (at least 6 months prior),

CA 1 (years) is the chronological age at the time of height measurement 1,

CA 2 (years) is the chronological age at the time of height measurement 2,

With normal or slightly reduced height, growth velocity is a key indicator of the pathological process. Since the parameter is evaluated in an age-specific aspect, it is preferable to use the growth velocity SDS. Growth velocity and growth velocity SDS are most informative in prepubertal children. In children older than 10–11 years, the evaluation of these indicators can be associated with significant errors due to the rapid dynamics of growth velocity at this age and the varying times of puberty onset.

Body proportions

Somatotropic insufficiency is characterized by proportional body build: arm span equals height, head circumference corresponds to height, and the «upper/lower segment» ratio corresponds to normal values (Table 3, Appendix A3). The assessment of body proportions is carried out for differential diagnosis with various forms of skeletal dysplasias.

Clinical features of hypopituitarism:

➣ Pronounced short stature, progressive deceleration of growth velocity

• Postnatal growth retardation: height below the 3rd percentile or below 2 standard deviations (< – 2.0 SDS) from the population mean for the corresponding chronological age and sex; height more than 1.5 SD below the SDS of the genetically predicted final height

• Progressive deceleration of growth velocity*:

  - in the presence of short stature: growth velocity more than 1 SD below the mean for the given chronological age and sex (at chronological age > 1 year); or a decrease in height SD of more than 0.5 over 1 year in a child older than 2 years;

  - in the absence of short stature: growth velocity over 1 year of observation more than 2 SD below the mean, or growth velocity over 2 years of observation more than 1.5 SD below the mean.

Comments: * - this provision does not apply to prepubertal children with delayed puberty.

➣ Proportional body build

➣ ^*Fine facial features («doll-like face», «cherub» face) combined with a prominent overhanging forehead due to underdevelopment of the facial skeleton bones with satisfactory growth of the neurocranium bones. The following may occur: depressed nasal bridge, small orbits, micrognathia.

➣ ^*Early postnatal symptoms of congenital GH deficiency: fasting hypoglycemia, often pronounced (glucose < 3 mmol/l), prolonged jaundice, neonatal cholestasis.

➣ Delayed bone maturation

➣ ^*Late closure of the anterior fontanelle

➣ ^*Late teething, delayed tooth eruption/replacement. Sometimes - enamel hypoplasia, malocclusion. Frequently - multiple dental caries.

➣ Thin skin

➣ ^*High-pitched voice

➣ Thin, brittle, dry hair

➣ Slow hair and nail growth

➣ ^*Micropenia in boys

➣ Delayed spontaneous puberty in IGHD

^* signs characteristic of congenital GH deficiency.

Comments: patients with HP can vary significantly phenotypically, even within the same genetic defect.

➣ Hypoglycemia

Since GH plays an important role in the regulation of carbohydrate metabolism by activating hepatic glucose production and slowing its peripheral clearance, growth hormone deficiency can lead to the development of hypoglycemia. Hypoglycemia is more characteristic of younger patients, detected in approximately 10% of cases. In the first year of life, the risk of developing hypoglycemia is much higher.

Clinical manifestations of hypoglycemia: increased appetite, pallor, sweating, anxiety, convulsive syndrome, as a rule, observed in the early morning hours, but can also occur during sleep. The risk of neonatal hypoglycemia is higher with concomitant adrenocorticotropic hormone (ACTH) deficiency.

➣ Deficiency of other tropic hormones

Secondary hypothyroidism. Symptoms: bradycardia, hypotension, dry skin, feeling cold, constipation, overweight, sluggishness. Unlike primary hypothyroidism, the clinical symptoms of secondary hypothyroidism are more mild (the frequency of mental deficiency is extremely rare), appear later (usually after 3 years of age), and are combined with deficiencies of other tropic hormones.

Secondary hypocortisolism. Hypocortisolism is the most severe of all pituitary deficiencies, as it can lead to a life-threatening condition. The symptoms of secondary hypocortisolism are usually absent or minimally expressed: weakness, increased fatigue, and a tendency toward hypotension. Skin hyperpigmentation and a craving for salty foods, which are characteristic of primary adrenal insufficiency, are absent in secondary hypocortisolism. In the setting of intercurrent illnesses (infectious diseases, trauma, surgical interventions) and stressful situations, ACTH/cortisol deficiency may trigger an acute adrenal crisis, which can be fatal if adequate therapy is not provided.

Secondary hypogonadism. Gonadotropin deficiency does not manifest in early childhood (except for micropenis) and prepubertal age, since low levels of gonadotropins (luteinizing and follicle-stimulating hormones) are also characteristic of healthy children of this age. Clinical manifestations include the absence of signs of the onset of puberty at a bone age of 13 years in boys and 12 years in girls.

Prolactin deficiency. In children and adolescents, prolactin deficiency has no clinical manifestations.

Antidiuretic hormone (vasopressin) deficiency. Causes the development of central diabetes insipidus, which typically develops as a result of surgical treatment of tumors in the hypothalamo-pituitary region. Clinical and laboratory manifestations include: polyuria, polydipsia, and less commonly, nocturia and enuresis.

➣ Psycho-intellectual development

As a rule, the intellectual development of children with growth hormone deficiency is not significantly impaired. At the same time, specific cognitive disorders may occur due to CNS immaturity, corresponding to the degree of skeletal bone differentiation. These problems are exacerbated by the environment and psychosocial factors caused by short stature.

Characteristic behavioral features include: an increased need for parental care, difficulties in communicating with peers, reduced self-esteem, and an infantile perception of the surrounding world [45-47].

Disorders of psychosocial adaptation in short stature worsen with age, reaching a maximum during puberty.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis.

The diagnosis of hypopituitarism is established based on the following criteria:

1) patient complaints;

2) anamnesis data;

3) physical examination;

4) laboratory tests;

5) instrumental examinations.

2.1 Complaints and Anamnesis

Comments. Congenital hypopituitarism is characterized by progressive growth retardation starting from an early age. Acquired hypopituitarism is characterized by a sharp decline in growth rate or even growth arrest starting from a certain age prior to which growth velocity was normal. Constitutional delay of growth and puberty is characterized by normal/low-normal growth rates, with the onset of growth retardation or more pronounced growth retardation compared to peers occurring in adolescence.

2.2 Physical Examination

Comments. In children under 2 years of age, height is measured in the supine position. If height is measured in the standing position, 0.7 cm must be added to the obtained value.

In children older than 2 years, height is measured in the standing position. If this procedure is not feasible, height is measured in the supine position, and 0.7 cm must be subtracted from the obtained value.

Calculation of the "lower segment": standing height minus sitting height.

GH deficiency is characterized by marked short stature: height < –2.0 SDS (using the Auxology program [reference data: UK Tanner Whitehouse], download link: https://cloud.mail.ru/public/HmJf/W8zNABGps) for the corresponding chronological age and sex, with proportional body proportions. The difference between the child's height SDS and their target height SDS exceeds 1.5 SDS [38].

In children with acquired forms of GH deficiency, growth retardation (height < -2 SD) may be absent.

Comments. Growth velocity analysis allows the detection of deviation from the growth curve at an early stage. To assess growth velocity, data from at least two accurate measurements are required. To minimize measurement errors, it is preferable that the interval between measurements is at least 6 months. Growth velocity is calculated using the formula:

With normal or slightly reduced height, growth velocity is a key indicator of the pathological process. Since this parameter is evaluated in an age-dependent manner, it is preferable to calculate and use the growth velocity SDS (using the Auxology program [reference data: UK Tanner Whitehouse], download link: https://cloud.mail.ru/public/HmJf/W8zNABGps). Growth velocity and growth velocity SDS are most informative in prepubertal children. In children older than 10-11 years, the evaluation of these parameters may be associated with significant errors due to the rapid dynamics of growth velocity at this age and varying timings of puberty onset.

Comments. GH deficiency is characterized by proportional body build.

Comments. Most patients with GH deficiency have a normal BMI SDS. Extremely low weight due to self-imposed dietary restrictions or comorbid somatic pathology can be the cause of growth and pubertal retardation.

Comments: the scope of investigations/treatment in suspected somatic or osteocartilaginous pathology depends on the clinical presentation of the underlying disease and should be determined by the specialist dealing with the suspected pathology that led to short stature.

2.3 Laboratory Diagnostics

2.3.1 Secondary hypothyroidism

Comments. A low fT4 level documented in at least two blood samples in the presence of normal, low, or moderately elevated TSH is the diagnostic criterion for secondary hypothyroidism.

2.3.2 Secondary hypocortisolism

Comments. The presence of secondary hypocortisolism is confirmed by a low basal cortisol level (below 83 nmol/L) in 2–3 blood samples drawn in the early morning hours (blood collection is performed early in the morning: at 8⁰⁰) against the background of a decreased or normal ACTH level [51–52]. A blood cortisol level > 365 nmol/L rules out hypocortisolism.

Comments. The presence of secondary hypocortisolism is confirmed by a low stimulated cortisol level during the stimulation test with soluble #insulin [human genetically engineered]** (Table 4).

Table 4. Blood cortisol concentration during the stimulation test with soluble #insulin [human genetically engineered]**

2.3.3 Secondary hypogonadism

Recommendations for the diagnosis of secondary hypogonadism in adolescence are outlined below. Recommendations for the diagnosis of secondary hypogonadism during the minipuberty period are detailed in the clinical guidelines "Hypogonadism in Children and Adolescents".

Comments. Secondary hypogonadism is indicated by the following basal levels: in boys: FSH < 1.2 IU/L, LH < 0.6 IU/L, testosterone < 2.0 nmol/L [53–58], in girls: LH < 0.9 IU/L, FSH < 2.5 IU/L, estradiol – undetectable/low [53, 59].

Comments. Secondary hypogonadism is indicated by an Inhibin B level: in boys < 35 pg/mL at puberty stage G1 and < 65 pg/mL at puberty stage G2 [28], in girls < 20 pg/mL [62].

In boys, measuring blood inhibin B levels for the differential diagnosis of hypogonadotropic hypogonadism and constitutional delay of growth and puberty is comparable in sensitivity and specificity to the gonadotropin-releasing hormone analogue test, but is significantly simpler and cheaper than the latter [60].

Comments. Procedure for the GnRH analogue test: baseline serum LH and FSH levels are determined, a short-acting GnRH analogue is administered, and blood LH and FSH levels are measured dynamically during stimulation. GnRH preparations used for the test and blood sampling time points are presented in Table 5.

The instructions for use of #triptorelin 0.1** mg subcutaneously and #buserelin 300 mcg intranasally do not indicate their use as diagnostic tests in the evaluation of suspected reproductive system disorders, but these drugs are used for the aforementioned purpose off-label based on efficacy and safety data obtained from studies [153, 154].

Table 5. Protocols for the gonadotropin-releasing hormone analogue test

Criteria for evaluating the GnRH analogue test: secondary hypogonadism is confirmed by an increase in serum LH < 5 IU/L; secondary hypogonadism is ruled out by an increase in LH > 8 IU/L; if the stimulated LH level is > 5 but < 8 IU/L, additional evaluation and follow-up monitoring are required [58, 63–65].

A ratio of peak gonadotropin levels after GnRH analogue stimulation (LHmax/FSHmax ratio) < 1.0 can serve as an additional criterion confirming the presence of hypogonadotropic hypogonadism in boys.

Clear criteria for evaluating the GnRH analogue test for the differential diagnosis of secondary hypogonadism and constitutional delay of puberty in girls are absent.

The result of the GnRH analogue test may be unreliable at a bone age of less than 11 years in girls and 12 years in boys.

2.3.4 Hypoprolactinemia

Comments. A low prolactin level in multiple blood samples confirms the presence of hypoprolactinemia [38, 48–49].

2.3.5 Central diabetes insipidus

In children with hypopituitarism, diabetes insipidus may be one of the components of the disease.

Comments. Criteria for polyuria are presented in Table 6.

Normally, blood osmolality is 280–300 mOsm/kg, and the osmolality of a nocturnal or most concentrated urine sample is 600–1200 mOsm/kg. With a urine osmolality greater than 650 mOsm/kg or a urine specific gravity greater than 1.015, the presence of diabetes insipidus is unlikely.

Table 6. Polyuria (Diagnosis)

In children and adolescents with polyuria and polydipsia, low urine osmolality (< 300 mOsm/kg) and/or low urine specific gravity (< 1.005) with a concomitantly high serum sodium level (> 145 mmol/L) and/or high blood osmolality (> 300 mOsm/kg) will indicate diabetes insipidus; a decreased serum sodium level (< 135 mmol/L) and/or decreased blood osmolality (< 280 mOsm/kg) indicate a different etiology of polyuria.

Note: the terms osmolarity and osmolality are used interchangeably, even though they refer to different units of measurement, since the difference between the values is insignificant, and for very dilute solutions these values are numerically identical.

Almost all medical institutions lack osmometers and calculate osmolarity using formulas:

Urine osmolarity = 33.3 × the last two digits of the urine specific gravity (e.g., 33.3 × 1015 = 499.5 mOsm/L).

Plasma osmolarity = 2 × (K, mmol/L + Na, mmol/L) + glucose, mmol/L + urea, mmol/L + (0.03 × total protein, g/L).

Comments. The test is indicated if:

- there is confirmed hypoosmotic polyuria (urine osmolality < 300 mOsm/kg and/or urine specific gravity < 1.005),

- serum sodium level is < 145 mmol/L,

- blood osmolality is higher than urine osmolality.

Note.

Fluid deprivation test protocol

1. The fluid deprivation test should be performed in an inpatient setting under dynamic monitoring of laboratory and objective parameters and medical supervision.

2. Overnight, the child may consume as much fluid as needed.

3. It is advisable to start the test in the early morning hours. Before starting the test, the child is weighed, pulse and blood pressure are measured, a blood sample is taken to determine sodium levels and/or plasma osmolality, as well as osmolality and/or specific gravity and volume of the first morning urine portion, after which the child stops fluid intake. Everything the child eats during the test should not be high in water and easily digestible carbohydrates (it is advisable to consume boiled eggs, bread, lean meats and fish, and cottage cheese).

4. Every 2 hours, or whenever a urine output exceeding 200 mL is voided, the child must be weighed, plasma sodium and/or plasma osmolality, urine osmolality and/or specific gravity determined, and pulse rate, blood pressure, and overall well-being assessed.

5. The test is terminated if any of the following criteria are met:

   - the patient's weight decreases by 3–5% from baseline,

   - the patient can no longer tolerate thirst,

   - plasma sodium level is > 145 mmol/L and/or plasma osmolality is > 300 mOsm/kg (while serum osmolality exceeds urine osmolality),

   - urine osmolality rises to 700 mOsm/L and/or urine specific gravity to 1.021.

   The final control of laboratory and objective parameters is performed immediately before the end of the test.

6. Upon completion, the patient is allowed to drink a volume of water close to the amount voided during the test.

   If plasma osmolality remains virtually unchanged by the end of the test while urine osmolality increases to 700 mOsm/kg or more (specific gravity > 1.021), diabetes insipidus of any etiology is excluded.

   When the serum sodium level is > 145 mmol/L and/or plasma osmolality is > 300 mOsm/kg, diabetes insipidus is confirmed.

Parameters during the fluid deprivation test

For most patients, restricting fluid intake for 7–8 hours is sufficient; in cases of primary polydipsia, the test may last up to 24 hours.

In infants, a random morning blood osmolality after midnight water cessation > 295 mOsm/kg and/or serum sodium level > 143–145 mmol/L in the presence of low urine osmolality (< 300 mOsm/kg) or a urine-to-blood osmolality ratio < 1 confirms diabetes insipidus [66].

Comments: after confirming the diagnosis of diabetes insipidus, it is necessary to determine its type—central or nephrogenic. Since central diabetes insipidus involves impaired synthesis and/or secretion of vasopressin, treatment with its analogues (replacing the deficient vasopressin) results in improved renal concentrating function, which is reflected by a significant increase in urine concentration—by more than 50%—confirming the diagnosis of central diabetes insipidus [68-71], at least in patients with the "complete" form of diabetes insipidus.

An increase in urine concentration of less than 50% indicates nephrogenic diabetes insipidus.

At the beginning of the test, the patient must completely empty the bladder, then take #desmopressin** (for children older than 10 years: 10 mcg intranasally, or 0.1 mg orally [151, 152], or 60 mcg sublingually [152]; for children under 10 years: 0.05 mg orally [151, 152], or 30 mcg sublingually [152]):

At 2 and 4 hours, urine must be collected to determine its volume and osmolality (or specific gravity).

The patient is allowed to eat and drink, provided that the volume of fluid consumed during the two hours following the end of the test does not exceed the volume of urine voided during the fluid deprivation test.

An increase in urine concentration by more than 50% from baseline indicates central diabetes insipidus, while an increase of less than 50% indicates nephrogenic diabetes insipidus.

Note: for patients with CT or MRI signs of a mass lesion in the hypothalamo-pituitary region, or a history of surgical treatment for a hypothalamo-pituitary tumor, performing the fluid restriction test is not mandatory for diagnosing diabetes insipidus. The presence of clinically overt polyuria, low urine specific gravity in all samples of the Zimnitskiy urine test, and a response to #desmopressin** administration are sufficient (for children older than 10 years: 10 mcg intranasally, or 0.1 mg orally [151, 152], or 60 mcg sublingually [152]; for children under 10 years: 0.05 mg orally [151, 152], or 30 mcg sublingually [152]).

Comments: copeptin is the C-terminal part of the vasopressin precursor, which is stoichiometrically secreted into the blood along with it, but possesses greater stability. Despite the successful use of copeptin and vasopressin levels as markers of renal concentrating capacity in adults demonstrated in several foreign studies [69, 72-75], their role in diagnosing diabetes insipidus in children remains undefined [66].

2.3.6 GH deficiency

Comments: IGF-1 levels exhibit only minor diurnal fluctuations; therefore, a single measurement is an important parameter in the diagnosis of growth hormone deficiency [38, 48-51, 76-82]. IGF-1 concentration depends on age, sex, and pubertal stage, and must be interpreted according to bone age rather than chronological age. In infancy and early childhood (< 5 years), IGF-1 levels are typically low, making it difficult to distinguish between normal and reduced levels in these age groups. During puberty, a normal IGF-1 level strongly indicates the absence of GH deficiency. IGF-1 levels are dependent on the child's nutrition, thyroid status, and the presence of chronic endocrine and non-endocrine diseases. In diagnosing GH deficiency, the measured IGF-1 concentration is used in conjunction with the results of GH stimulation tests [38, 48-51, 76-82].

A normal serum IGF-1 level does not exclude GH deficiency [38, 48-51].

Comments: isolated assessment of a child's physiological growth hormone secretion (single measurement of basal GH levels, determination of nocturnal spontaneous GH secretion, assessment of urinary GH excretion, evaluation of exercise-induced GH secretion) is not a diagnostic criterion for GH deficiency [38, 48-51].

√ The following pharmacological agents are used as provocative stimulants for stimulation tests: #clonidine** (0.15 mg/m², per os);

√ short-acting insulins and their analogues for injection (0.1 IU/kg, IV bolus);

√ #levodopa** per os: 125 mg (for body weight < 15 kg), 250 mg (for body weight 15-35 kg), 500 mg (for body weight > 35 kg);

√ #glucagon** (30 mcg/kg, but not exceeding 1 mg, SC).

LoR CGoE 3Level of Recommendation C (Level of Evidence - 3)

Comments: GH stimulation tests are performed in a hospital setting after overnight fasting by trained personnel in the presence of a physician. The choice of a specific test is determined by the attending physician supervising the examination. Since each test has its own characteristics, it is advisable to consistently use any two specific tests within a single clinic. #Clonidine** testing is recommended as the first test in children with suspected GH deficiency, especially of prepubertal age. All modified tests (2-3 points) are unreliable.

Table 7. GH stimulation tests used to diagnose growth hormone deficiency in children

Interpretation of GH stimulation test results [48-50]:

√ peak GH concentration upon stimulation < 10.0 ng/mL (in the #glucagon** test < 7 ng/mL) – GH deficiency,

√ peak GH concentration in two GH stimulation tests < 7.0 ng/mL – total GH deficiency,

√ peak GH level in one of the two GH stimulation tests ≥ 7.0 < 10.0 ng/mL – partial GH deficiency,

√ if the peak GH concentration in the first GH stimulation test is > 10.0 ng/mL (for the #glucagon** test > 7 ng/mL), the second test is not performed, and GH deficiency is ruled out.

▪ False-positive results of GH stimulation tests are possible in the presence of [48-50, 83-84]:

√ uncompensated hypothyroidism (primary or secondary),

√ adverse psychosocial developmental factors in the child (poor nutrition, family relationships),

√ obesity,

√ delayed puberty,

√ concomitant therapy (glucocorticoids, neurotropic drugs).

Comments: in these cases, the #glucagon** test is performed (used only in children under 6 years of age). Diagnostic threshold for GH deficiency in the #glucagon** test: < 7 ng/mL [52].

The specifics of the test should be taken into account: first, an increase in blood glucose levels at 30 minutes, followed by hypoglycemia (usually developing after 120 minutes); higher GH values are observed precisely at these time points.

Comments: in adolescents with delayed puberty (boys older than 13 years, girls older than 12 years) to reduce the risk of false-negative results when [48, 50, 86-91]:

- absence of secondary sexual characteristics and/or low testosterone (in boys)/estradiol (in girls) levels,

- moderate growth retardation: height SDS from -2.00 to -2.99,

- skeletal maturation delay of 0-3 years,

- absence of other (non-GH) trophic deficiencies due to a high percentage of false-negative results, the following is advisable [48, 86-91]:

Note: as a rule, the need for sex hormone priming applies to boys, who more frequently than girls experience constitutional growth and puberty delay.

Comments: performing a single GH stimulation test is sufficient if the child obligatorily meets two out of four conditions, Table 8.

Table 8. Conditions allowing the diagnosis of GH deficiency based on a single GH stimulation test

Comments: it is possible to diagnose GH deficiency without performing GH stimulation tests provided that the child strictly meets one of the three conditions, Table 9.

Table 9. Conditions allowing the diagnosis of GH deficiency without performing GH stimulation tests

2.3.7 Re-testing of growth hormone axis

Comments: the purpose of re-testing is to confirm (or rule out) the diagnosis of somatotropic deficiency after achieving final height. Re-diagnosis is performed after a 1-3 month break in somatropin** treatment [93]. The "gold standard" for diagnosing growth hormone deficiency in adults is the insulin tolerance test (ITT) [94-96, 100].

Patients in need of re-testing include [97-99]:

- those with isolated GH deficiency, with a normal IGF-1 level (after somatropin** withdrawal) and without molecular genetic confirmation of the diagnosis;

- those with 1 (other than GH) trophic deficiency with a normal IGF-1 level (after somatropin** withdrawal) and without molecular genetic confirmation of the diagnosis.

Interpretation of re-testing results: the diagnostic criterion for persistent growth hormone deficiency is a maximum stimulated GH concentration of < 5.0 ng/mL [94-96].

2.4 Instrumental Diagnostics

Comments: bone age is usually determined using the Greulich-Pyle method with a radiological atlas (W. Greulich, S. Pyle, 1959) or the Tanner-Whitehouse method (TW20) [102-106]. Bone maturation in GH deficiency in most cases significantly lags behind chronological age (by 2 years or more), and the degree of its delay correlates with the severity and duration of growth hormone deficiency.

In international practice, radiography of the non-dominant hand is used to assess bone maturation [102].

2.5 Other Procedures

Comments: molecular genetic verification of the diagnosis makes it possible to predict the likelihood of developing other trophic deficiencies, ensures early diagnosis and timely initiation of replacement therapy, and determines the scope of investigations during patient follow-up.

In some cases (in young children, when GH stimulation tests and MRI cannot be performed), performing a molecular genetic study without GH stimulation tests may be the only possible method for the timely diagnosis of hypopituitarism.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Treatment prior to hormone replacement therapy

Comments: the absence of intracranial tumor growth or its recurrence for 6-12 months prior to initiating somatropin** treatment (benign tumor) or 24 months (malignant tumor) must be documented. The decision to initiate somatropin** replacement therapy in children with acquired hypopituitarism is made jointly by a pediatric oncologist, pediatric neurosurgeon, pediatric endocrinologist, patient, and their parents/legal representatives.

3.2 Hormone replacement therapy

The goal of hypopituitarism treatment is to maintain hormonal and metabolic status at a normal level for the respective age and sex by compensating for all existing trophic deficiencies.

Comments: hypoprolactinemia does not require compensation [48, 50].

Comments: the goals of somatropin** (recombinant growth hormone) treatment are:

- achieving accelerated growth rates in the first years of treatment and their subsequent normalization;

- ensuring entry into puberty with normal linear growth;

- achieving final growth within or above the genetically predicted range;

- normalization of psychoemotional status and ensuring a satisfactory quality of life;

- normalization of body composition;

- increasing bone mineral density;

- reducing cardiovascular disease risk factors.

• Replacement therapy with somatropin** is strictly not recommended for children with hypopituitarism and:

  - closed growth plates (applies to the pediatric dose);

  - active malignant neoplasms;

  - progressing intracranial tumor growth;

  - hypersensitivity to the drug components due to the high risk of adverse events and/or worsening of the oncological disease course [48, 50].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comments: somatropin** is administered in accordance with the instructions for use of the specific medicinal product, regularly, subcutaneously into the arms and thighs (anterolateral surface) with mandatory alternation.

Comments: long-term domestic and international experience in studying the side effects of somatropin** in children with growth hormone deficiency has demonstrated the safety of this treatment [118, 120-122]. Severe side effects during somatropin** therapy in children are very rare [118, 123]. They include edema, arthralgia, benign intracranial hypertension [124-125], prepubertal gynecomastia, scoliosis, and slipped capital femoral epiphysis [126-127]. As a rule, adverse events are observed within 2 weeks after the initiation of somatropin** therapy.

In case of papilledema, treatment is temporarily discontinued until complete normalization of the funduscopy findings.

Somatropin** therapy does not increase oncological risk in children without additional oncological risk factors; it may have a mild or negligible effect on increasing the incidence or accelerating the development of secondary tumors in patients previously treated for cancer, especially in cases involving cranial irradiation [121, 123, 128-134].

Comments: growth-promoting therapy with somatropin** is discontinued earlier upon reaching the genetically predicted height, but not exceeding 170 cm in girls and 180 cm in boys, or at the request of the patient and their parents/legal representatives who are satisfied with the achieved final height result.

Comments: the criterion for compensation is a mid-normal free T4 level in the blood. TSH levels during levothyroxine sodium** therapy are not assessed during monitoring; a decreased TSH level in patients with hypopituitarism is not a sign of levothyroxine sodium** overdosage.

Comments: criteria for compensation include general well-being, normal blood pressure, and the absence of nocturnal hypoglycemia. Blood ACTH and cortisol levels during hydrocortisone** therapy are not assessed. Low ACTH and cortisol levels are not signs of an insufficient hydrocortisone** dose.

Comments: in the presence of gene mutations associated with multiple pituitary hormone deficiency (PROP1, HESX1, LHX3, etc.), if the adolescent (boys older than 12 years, girls older than 11 years) reaches a linear height corresponding to the mid-parental height percentile curve, puberty induction with low doses of sex hormones is possible, regardless of bone age.

Comments: puberty initiation in boys with hypogonadism in cases of late diagnosis and/or pronounced body disproportion using higher doses of #testosterone [esters mixture]** preparations is possible: 125–250 mg once every 21 days intramuscularly [161].

Evidence level 2. Recommendation grade A.

Comments: testosterone levels are assessed 14 days after the regular injection during puberty initiation (testing the maximum testosterone concentration to evaluate the efficacy and safety of therapy) every 6 months throughout the entire period of gradual dose escalation of the testosterone ester mixture. The testosterone level during replacement therapy should remain within the reference interval for the corresponding age.

Upon reaching the full replacement dose of #testosterone** (esters mixture), testosterone levels are assessed 1–2 days before the next injection (testing the trough testosterone concentration before the next injection to evaluate the stability of testosterone levels between injections). The target testosterone values after reaching the full replacement dose are mid-normal values for adult males [136-139].

Assessment of LH and FSH levels during #testosterone** (esters mixture) therapy is not used because it is uninformative.

Erythrocytosis may develop during androgen therapy. The effect is dose-dependent. Currently, data on the adverse effects of testosterone replacement therapy on the cardiovascular system in adolescents are insufficient. It is advisable to evaluate hematocrit before therapy and every 12 months during androgen dose escalation, and every 6 months after reaching the maximum dose [140-141].

There is currently no conclusive evidence that the initiation of androgen therapy in patients with secondary hypogonadism has a negative impact on fertility in adulthood.

In accordance with the instructions, androgens are either not approved for use in individuals under 18 years of age or must be used with caution due to the lack of data on their efficacy and safety. The prescribing of #testosterone** (esters mixture) requires off-label use documentation, obtaining informed consent, and a medical board review prior to administration in individuals under 18 years of age.

Comments: the criterion for the efficacy of #follitropin alfa** preparations is an increase in testicular size and inhibin B levels, although standard values for assessing the concentration of the latter have not been established. Therapy with #human chorionic gonadotropin** and #follitropin alfa** requires high frequency of drug administration and individualized therapy adjustment. In case of an unsatisfactory response, the patient is switched to androgen therapy.

Routine sperm analysis in patients with hypogonadism under 18 years of age is not advisable due to the lack of normative values for this age group.

Comments: the use of transdermal estrogen preparations makes it possible to better mimic the circadian rhythm of estradiol secretion and is preferred due to the absence of the "first-pass" effect through the liver, having a lesser effect on the functional activity of the liver, including the production of procoagulant factors [49, 142]. If transdermal forms cannot be used, therapy with oral #estradiol valerate** preparations is administered [49, 143].

The use of semisynthetic estrogens (17α-ethinylestradiol) as replacement therapy in girls with hypogonadism is highly undesirable [142, 143]. Being a more potent synthetic estrogen, 17α-ethinylestradiol has a more pronounced effect on hepatic protein metabolism and the blood coagulation system, binds less to sex hormone-binding globulin due to the activation of both α- and β-estrogen receptors, and exerts a more active effect on the cartilage tissue of growth plates.

Normally, sexual development in girls continues for 2-3 years. Initiating therapy with low doses of estrogens makes it possible to achieve a good rate of feminization without compromising final height.

Level of evidence validity 5. Level of recommendation consensus C.

Comments. Compensation criteria: normal daily urine output, normal blood sodium and potassium levels.

Surgical treatment

Surgical treatment for children with hypopituitarism is performed in the presence of concomitant surgical pathology.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

No specific rehabilitation measures have been developed for these patients.

5. Prevention and Dispensary Observation

Comments: frequency of medical examination: once every 3 months (for the first 6 months of somatropin** treatment), then once every 6 months.

Anthropometric monitoring parameters include determining the growth response to somatropin treatment: increase in absolute height parameters; height SDS dynamics; growth rate dynamics.

Comments: monitoring includes testing the levels of:

- free thyroxine (FT4) in blood serum;

- total cortisol in the blood (except for patients with diagnosed hypocortisolemia who are receiving glucocorticoid replacement therapy);

- total estradiol (applicable to adolescent girls) / total testosterone (applicable to adolescent boys) in blood serum;

- blood plasma insulin (in overweight adolescents) [145-146];

- insulin-like growth factor I in the blood (the target level during somatropin therapy should not exceed the upper limit of the reference range for the corresponding age and sex) [147-148].

Comments: if symptoms of benign intracranial hypertension appear (headache, nausea, vomiting, visual impairment: diplopia, blurred vision), an ophthalmologic consultation must be performed immediately [117].

Comments: when growth plates are closing, more frequent bone age determination is required—once every 6 months.

6. Organization of Medical Care

Planned hospitalization. Inpatient care, day care.

Indications for hospitalization to a medical organization:

1) comprehensive evaluation upon decompensation of trophic deficiencies;

2) occurrence of adverse events (moderate or mild severity);

3) inadequate growth dynamics;

4) need for adjustment of ongoing therapy.

Emergency hospitalization. Inpatient care.

Indications for hospitalization to a medical organization:

1) adrenal crisis;

2) occurrence of adverse events (severe severity).

Indications for patient discharge from a medical organization:

1) compensation of trophic deficiencies;

2) sustained improvement in condition when the patient can continue treatment in an outpatient clinic or at home without prejudice to health.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

LEADERS:

Valentina Aleksandrovna Peterkova – Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, Scientific Director of the Institute of Pediatric Endocrinology at the Academician I. I. Dedov National Medical Research Center for Endocrinology of the Russian Ministry of Health, Head of the Department of Pediatric Endocrinology and Diabetology at the Institute of Higher and Continuing Professional Education of the Academician I. I. Dedov National Medical Research Center for Endocrinology of the Russian Ministry of Health, Chief freelance pediatric specialist endocrinologist of the Russian Ministry of Health.

Olga B. Bezlepkina – MD, PhD, Professor, Deputy Director of the Center – Director of the Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, Professor at the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

TEXT AUTHORS:

Elena V. Nagaeva – MD, PhD, Head of the Department of Thyroidology, Reproductive and Somatic Development, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, Leading Researcher, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, Associate Professor at the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Tatyana Yu. Shiryaeva – PhD in Medicine, Associate Professor, Leading Researcher at the Department of Thyroidology, Somatic and Reproductive Development, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.

Maria S. Pankratova – PhD in Medicine, Leading Researcher, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, Associate Professor at the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Igor S. Chugunov – Head of the Pediatric Department of Endocrine System Tumors, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, PhD in Medicine.

EXPERTS:

Elena B. Bashnina – MD, PhD, Professor at the Department of Endocrinology named after Academician V.G. Baranov, North-Western State Medical University named after I.I. Mechnikov, Chief freelance pediatric endocrinologist of the North-Western Federal District.

Galina A. Galkina – MD, PhD, Head of the Pediatric Endocrinology Department, Research Institute of Obstetrics and Pediatrics, Rostov State Medical University of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Rostov Region, Chief freelance pediatric endocrinologist of the Southern Federal District.

Aleksey V. Kiyaev – MD, PhD, Professor at the Department of Hospital Pediatrics, Ural State Medical University of the Russian Ministry of Health, Head of the Center for Pediatric Endocrinology, Regional Children's Clinical Hospital, Chief freelance pediatric endocrinologist of the Sverdlovsk Region, Chief freelance pediatric endocrinologist of the Ural Federal District.

Anna A. Kolodkina – Head of the Department of Hereditary Diseases and Early Childhood Endocrinopathies, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, PhD in Medicine.

Irina B. Kostrova – Head of the Department of Pediatric Endocrinology, Children's Republican Clinical Hospital named after N.M. Kuraev, Chief freelance pediatric endocrinologist of the Republic of Dagestan, Chief freelance pediatric endocrinologist of the North Caucasian Federal District.

Elena E. Petryaykina – MD, PhD, Director of the Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of Moscow, Chief freelance pediatric endocrinologist of the Central Federal District.

Lyubov N. Samsonova – MD, PhD, Head of the Department of Pediatric Endocrinology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health.

Tatyana E. Taranushenko – MD, PhD, Head of the Department of Pediatrics, Institute of Postgraduate Education, Krasnoyarsk State Medical University named after Professor V.F. Voйно-Yasenetsky of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Krasnoyarsk Territory, Chief freelance pediatric endocrinologist of the Siberian Federal District.

Anatoly N. Tyulpakov – MD, PhD, Associate Professor, Head of the Department of Endocrine Disease Genetics, Research Centre for Medical Genetics named after Academician N.P. Bochkov of the Ministry of Science and Higher Education of Russia, pediatric endocrinologist at the Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

Olga A. Chikulaeva – PhD in Medicine, Leading Researcher at the Department of Thyroidology, Somatic and Reproductive Development, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, Associate Professor at the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Conflict of interest: the authors of the clinical guidelines declare no conflict of interest. For the final edition and quality control, the guidelines were re-evaluated by the members of the working group, who concluded that all comments and feedback from experts have been taken into account, and the risk of bias in the development of the guidelines has been minimized.

Appendix A2. Methodology for Developing Clinical Guidelines

The guidelines presented herein are based on a systematic literature review performed by the group members. Articles published up to 2024 were submitted for review. The experts within the group reviewed these data as well as selected articles with the highest level of evidence.

Target audience for these clinical guidelines:

1. Pediatric endocrinologists;

2. Pediatricians;

3. Endocrinologists;

4. General practitioners (family physicians);

5. Neonatologists;

6. Oncologists;

7. Neurosurgeons.

Table 10. Level of Evidence (LoE) rating scale for diagnostic methods (diagnostic interventions)

Table 11. Level of Evidence (LoE) rating scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, rehabilitative)

Table 12. Grade of Recommendation (GoR) rating scale for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, rehabilitative)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Decree of the Government of the Russian Federation No. 1416 dated November 26, 2018 (as amended on February 15, 2023) "On the Procedure for Organizing the Provision of Medicines to Persons with Hemophilia, Cystic Fibrosis, Pituitary Dwarfism, Gaucher Disease, Malignant Neoplasms of Lymphoid, Hematopoietic and Related Tissues, Multiple Sclerosis, Hemolytic-Uremic Syndrome, Systemic-Onset Juvenile Idiopathic Arthritis, Mucopolysaccharidosis Types I, II and VI, Unspecified Aplastic Anemia, Hereditary Deficiencies of Factor II (Fibrinogen), Factor VII (Labile), Factor X (Stuart-Prower), Persons after Organ and/or Tissue Transplantation, and on Declaring Certain Acts of the Government of the Russian Federation Invalid" (together with the "Rules for Organizing the Provision of Medicines to Persons with Hemophilia, Cystic Fibrosis, Pituitary Dwarfism, Gaucher Disease, Malignant Neoplasms of Lymphoid, Hematopoietic and Related Tissues, Multiple Sclerosis, Hemolytic-Uremic Syndrome, Systemic-Onset Juvenile Idiopathic Arthritis, Mucopolysaccharidosis Types I, II and VI, Unspecified Aplastic Anemia, Hereditary Deficiencies of Factor II (Fibrinogen), Factor VII (Labile), Factor X (Stuart-Prower), Persons after Organ and/or Tissue Transplantation", and the "Rules for Maintaining the Federal Register of Persons with Hemophilia, Cystic Fibrosis, Pituitary Dwarfism, Gaucher Disease, Malignant Neoplasms of Lymphoid, Hematopoietic and Related Tissues, Multiple Sclerosis, Hemolytic-Uremic Syndrome, Systemic-Onset Juvenile Idiopathic Arthritis, Mucopolysaccharidosis Types I, II and VI, Unspecified Aplastic Anemia, Hereditary Deficiencies of Factor II (Fibrinogen), Factor VII (Labile), Factor X (Stuart-Prower), Persons after Organ and/or Tissue Transplantation").

2. Order of the Ministry of Health of the Russian Federation No. 583n dated October 29, 2024 'On approval of the Procedure for the provision of medical care in the profile of "pediatric endocrinology".'

Table 1. Gene defects causing isolated growth hormone deficiency

Table 2. Gene defects causing multiple adenohypophyseal hormone deficiency

Table 3. Normal upper-to-lower segment ratios (Kaplan S., 1989)

Comments: when assessing body proportions in children with significant bone maturation delay, it is recommended to use the child's «bone age».

Appendix B. Physician Action Algorithms

1. Growth hormone deficiency diagnostic algorithm

Appendix C. Patient Information

Hypopituitarism is a condition caused by the absence or decreased secretion of one or more pituitary hormones. Growth hormone deficiency is the most frequent component of hypopituitarism, which can be isolated or combined with impaired function of the thyroid gland, adrenal glands, ovaries/testes, or diabetes insipidus. Hypopituitarism in children can be caused by congenital and acquired factors. In most cases, growth retardation and reduced growth velocity are observed. The prevalence of hypopituitarism in children is 1 in 6,000–10,000 children. Growth retardation can be a consequence of many causes: intrauterine growth restriction, osteochondral developmental anomalies, underlying somatic disease (kidney, heart, lung, gastrointestinal, or hematopoietic system disorders) or endocrine disease (hypothyroidism, diabetes mellitus, congenital adrenal hyperplasia, hypercortisolism), as well as syndromic disorders (Turner syndrome, Silver-Russell syndrome, Noonan syndrome, etc.), malnutrition, and psycho-emotional factors.

After ruling out all possible causes of short stature, GH stimulation tests are performed in a hospital setting to diagnose the presence or absence of growth hormone deficiency. Once growth hormone deficiency is confirmed, the child is prescribed replacement therapy with recombinant growth hormone administered as daily subcutaneous evening injections at home. Successful treatment requires regular visits to the attending physician and strict compliance with all recommendations. Under these conditions, the child can reach the target height of their biological parents.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1.

Title: Growth and weight percentile curves.

Source: CDC. SOURCE: Developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion http://www.cdc.gov/growthcharts.

Type: rating scale.

Purpose: assessment of physical development in children and adolescents.

Figure 1. Growth and weight percentile curves (boys, 0–36 months)