HH includes various congenital deficiencies of GnRH production, not involving other pituitary tropins. In Table 2.2, the well-defined syndromes in female subjects are summarized.

The Kallmann syndrome (KS) is the association of isolated hypogonadotropic hypogonadism (HH) and reduced or absent smell sense: the association provides evidence that the dysfunction of GnRH neurons activity is related to their impaired migration during intrauterine life from olfactory area to hypothalamus. The prevalence of Kallmann syndrome is rare (1:50,000 in females) and related to mutations of different genes; it is mainly sporadic; sometimes familiar transmissions X linked or autosomic recessive or autosomic dominant have been documented. Consequently, the phenotype is also variable concerning olfactory ability, secondary sex characteristics development and associated defects. The possibility of a late recovery of hypogonadism has been described in few cases [1].

For the diagnostic workup, it should be kept in mind that the self-evaluation of smell is generally unreliable except in subjects who admit anosmia; so it should be investigated with a selection of essential oils or scented papers or with specific standard kits. In KS the growth is linear, without spurts, exceeding the average for chronological age and inappropriate for bone age, with a prevalent increase of arms and legs, because the physiological pubertal shift between legs and trunk increase doesn’t take place.

Isolated hypogonadism includes various diseases with different stages of pubertal delay without other functional (even if small impairment in olfactory ability is sometimes present) or somatic defects and with normal brain imaging. The underlying genetic mutations are various and overlapping with alterations in genes involved also in KS [2].

The CHARGE syndrome (Coloboma, Heart defects, Choanal atresia, Retarded growth and development, Genital abnormalities, Ear anomalies) is a rare association, mainly sporadic of several anomalies related in more than 60% of cases to CHD7 gene mutation. The hypogonadism may result from the same migration defects of KD and is associated with growth, coloboma of iris and sometimes of retina, choanal atresia, internal and external ear abnormalities, and heart malformations. Cranial nerve defects with problems with breathing and feeding, orofacial clefts, defective sense of smell, vestibular abnormalities, hearing loss, and genital hypoplasia are also common.

The association between hypogonadotropic hypogonadism and leptin deficiency or leptin receptor anomalies entails, in typical forms, obesity and a higher prevalence of infections for an associated T cell functional anomaly; actually leptin mutations have been described even in subjects mildly overweight or normal and with normal immunologic defenses.

Gonadotropin deficiency can be present in congenital diseases involving the production of other pituitary hormones, linked to mutations of genes encoding transcription factors involved in the ontogenesis of pituitary gland or of hypothalamus-pituitary axis. The diagnosis is usually made during infancy and a definite cytogenetic testing is very important in order to plan the follow-up needed to prevent clinical outcomes related to late onset deficiencies [3]. Rare congenital midline cerebral and cranial malformations, i.e., septo-optic dysplasia or absence of septum pellucidum with optic hypoplasia, are associated with endocrine pituitary dysfunction. More frequent is the empty sella syndrome, characterized by cerebrospinal fluid filling the sella; as a result, the pituitary gland is often compressed and flattened. Empty sella may occur as a primary disorder because of an herniation of the arachnoid through a defect in the diaphragma sellae or as a secondary disorder due to damage to the pituitary itself, for instance as long-term consequence of surgery, radiation therapy, or of autoimmune hypophysitis. In most cases empty sella is asymptomatic; in adolescents could be associated with endocrine abnormalities: Gh and gonadotropin deficiency or hyperprolactinemia.

The pituitary gland is characterized by a very high blood flow (0.8 mL/g/min) and therefore is very exposed to overload phenomena especially iron overload. A pituitary injury may arise, in spite of the progress of chelation therapy, as a consequence of iron deposition in reticuloendothelial cells in subjects with hemoglobinopathies (thalassemia, hemolytic or aplastic anemias), who need transfusion therapy (transfusional hemosiderosis). The iron overload increases gradually reducing the pituitary volume and function; chronic hypoxia and ineffective erythropoiesis contribute to the endocrine impairment often involving also the growth hormone production. A significant iron overload in pubertal age is rare in subjects affected by hereditary idiopathic hemochromatosis [4]: in this disease, the deposition is mainly at parenchymal level but very slow and endocrine repercussions appear in older age. The history of relatives affected by the disease, the tiredness, the elevation of liver enzymes and ferritin, and the transferrin saturation of more than 45% address to a more detailed study including genotype.

Neurosarcoidosis and Langerhans cell histiocytosis are uncommon in adolescence; pituitary tuberculous infiltration has been described in adolescents living in other countries. Autoimmune hypophysitis is an inflammation of the pituitary gland due to the attack of T lymphocytes against secreting pituitary cells, sometimes secondary to systemic diseases, infections, or immunomodulating treatments. It occurs more commonly during and shortly after pregnancy, but it is described also in adolescence. Autoimmune damage of the pituitary gland results in the deficiency of various tropins and often diabetes insipidus. Autoantibodies against pituitary (APA), sometimes against hypothalamus (AHA) and thyroid gland, can be detectable. Specific mutation of CTLA-4 gene can predispose to this disease.

The Rathke’s pouch is embryologically an ectodermic evagination at the roof of the developing mouth that gives rise to the anterior pituitary; its posterior wall remains as intermediate lobe of the gland. Fluid-filled cysts can arise from the expansion of remnants of this formation. They are generally asymptomatic, but sometimes exert compression on adjacent pituitary tissue and distortion of the pituitary stalk. Arachnoid cysts are probably derived by congenital splitting of the arachnoid layer with accumulation of CSF within this potential space and usually located in the middle cranial fossa. The majority of arachnoid cysts are asymptomatic, but sometimes their gradual enlargement produces a mass effect resulting in either direct neurological or endocrine dysfunction or distortion of normal CSF pathways.

A chronic obstructive hydrocephalus may be derived from a congenital stenosis at or below the level of the aqueduct of Sylvius, connecting the third to fourth ventricle (often on genetic basis), or from compression gradually exerted by a colloid or an arachnoid cyst on the third ventricle located on the diencephalon of the forebrain between the right and left thalamus. It may cause a distension of the periventricular or medial basal hypothalamus disrupting the physiological release of GnRH; sometimes hypothyroidism and anomalies of Gh secretion are associated. In congenital aqueduct stenosis, the presence of symptoms of increased intracranial pressure (headache, nausea, vomiting, papilledema) is very rare and the situation is mainly asymptomatic.

Considering the tumors affecting the hypothalamic-pituitary region, craniopharyngioma is a dysontogenic lesion arising, near the pituitary stalk, from the epithelial nests of craniopharyngeal duct or of Rathke’s pouch. The prevalence is about 1:50,000 subjects. It is a capsulated tumor, with slow evolution but with a tendency to invade surrounding structures and to recur after resection. At the beginning of its growth symptoms are uncommon, so the diagnosis is often delayed when the pressure on the optic tract or on the pituitary gland causes impaired vision, growth and pubertal delay, obesity, insipid diabetes or when an intracranial hypertension has been established. Vomiting in the morning and pathological rate of growth are generally the early manifestations of the disease [5]. Pituicytoma arising from pituitary parenchyma or germinoma and teratoma growing from germ cells inclusions can also involve the sella region as well as neoplastic lesions coming from adjacent structures.

Traumatic brain injuries can lead to acute endocrine changes but also both temporary and permanent alterations of pituitary function in the long term: the most common are Gh deficiency and alterations of puberty. We estimate that 3 months after the trauma about 35% of children and adolescents display pituitary secretion abnormalities and 30% after 12 months. A spontaneous recovery is possible, but permanent deficiencies have been documented [6]. A deficiency in gonadotropin secretion can be the long-term effect of treatments (mainly radiation) of leukemia and brain tumors even if therapeutic procedures with less impact on endocrine function are increasingly under study.

An hyperprolactinemia is infrequently a cause of delayed puberty. A prolactin excess can be related to a PRL secreting (or Gh secreting) adenoma or to other intracranial pathologies (chordoma or other neoplasia) causing a pituitary stalk interruption or dislocation (pseudo-prolactinoma). The compression on the stalk may impair the function of TIDA (TuberoInfundibular DopAmine) neurons that physiologically inhibit the secretory activity of PRL cells. An hyperprolactinemia can also be associated to hormone deficiencies secondary to pathologies damaging the hypothalamus-pituitary region, as already mentioned. A prolactin excess related to primary hypothyroidism, linked to TSH secreting cells hyperplasia, has also been described. Increased prolactin concentrations as a consequence of drug intake, especially psychiatric drugs (Table 2.3), are more frequent; so a pharmacological anamnesis is always mandatory.

In subjects with prolactinoma, the history and the symptomatology can be insignificant: the linear growth is generally normal, neurological symptoms mostly absent, and galactorrhea is rare in this age group.

Isolated Gh deficiency (IGD) can be acquired (as result of trauma, infection, radiation therapy, or tumor growth), or congenital on genetic basis: the genes coding for Gh (Gh1), its receptor (GhRHR) and Ghrelin receptor (GhSR) are the most commonly involved; less often mutations of transcription factors active in pituitary development are involved. However, known mutations explain only a small percentage of clinical cases (several GD are diagnosed as idiopathic); moreover, genotype–phenotype correlation is not univocal and is variable over time. Subjects with GD may present with insufficient growth velocity and delayed growth spurt, considering their chronological age. Slow tooth eruption and poor nail growth can be present in the history. In subjects with previous diagnosis of IGD and under treatment the pubertal timing is generally normal.