PRL-secreting adenomas are usually diagnosed at the time of puberty or in the post-pubertal period (23,28,38), and clinical manifestations vary in keeping with the age and sex of the child. Pre-pubertal children generally present with a combination of headache, visual disturbances, growth failure, and amenorrhea (Table 1). Growth failure is not, however, a common symptom: 4% of 25 patients in one series (39) and 10% of 20 patients in another series (40) were reported to have short stature at the diagnosis of prolactinoma. In a re-evaluation of the young/adolescent patients with hyperprolactinemia admitted to the University Federico II from January 1st 1995 to December 31st 2004, and recently published (42) short stature was found in 7 of 50 patients (14%), five girls and two boys, and another two, one girl and one boy, had their height below or at the 5° percentile. The height percentiles in the patients with extrasellar/invasive macroprolactinomas were lower than in those bearing smaller tumors (Fig.5). Additionally, all girls present with oligomenorrhea or amenorrhea, most also had galactorrhea; gynecomastia was present in 12 of 21 boys (57.1%) while headache and visual field defects predominate in patients bearing large adenomas (Table 2). Galactorrhea should be carefully investigated by expressing the breast, because teenagers may not spontaneously refer it as a symptom, and frequently it is not spontaneous.

Impairment of other pituitary hormone secretion was found only in a minority of patients of our previous series (27%), and in 5 of them hypopituitarism developed after surgery. In a more recent analysis (41), we can confirm that only the minority of patients bearing large adenomas had severe degree of hypopituitarism while a very few patients with either microadenomas or enclosed macroadenomas had isolated hormone deficiency (Fig.6). Macroadenomas at presentation are more likely in boys than in girls (25,28,39,40). In our series (41), microprolactinoma and enclosed macroadenomas were more frequent in females with a ratio of 1.7:1 while large macroprolactinomas were 2 times more frequent in males (Table 2).

Hyperprolactinemic patients have a decrease of the bone mineral density (BMD), and progressive bone loss has been demonstrated in untreated patients (42,43). Young hyperprolactinemic men were shown to have a more severe impairment of BMD than patients in whom hyperprolactinemia occurred at an older age (44). In 20 patients with diagnosis of hyperprolactinemia during adolescence, we found (45) significantly lower BMD values in adolescents than in young adult patients with hyperprolactinemia. This finding is confirmed in a large cohort of patients (41). In 22 patients all having a diagnosis of prolactinomas before the age of 18 yrs, the bone mineral density (BMD) at lumbar spine was significantly lower than in age-matched controls (Fig.7).

The use of drugs to increase bone mass, such as amino-bisphosponates has not been investigated.

The differential diagnosis of hyperprolactinemia should consider any process interfering with dopamine (DA) synthesis, its transport to the pituitary gland or its action at lactotroph DA-receptors. A single measurement of PRL levels is unreliable since PRL secretion is markedly influenced by physical and emotional stress. In order to obtain a diagnostic value of PRL concentrations, at least 3-6 samples are necessary, and the average value taken into consideration.

In the absence of complications needing immediate surgery, such as visual loss, hydrocephalus, or cerebrospinal fluid leak, pharmacotherapy with dopamine-agonists should be considered the first treatment approach (41). Treatment with dopamine-agonists is effective in normalizing PRL levels and shrinking tumor mass in the majority of adult patients with prolactinoma (41). In children and adolescents, bromocriptine (BRC) has been used successfully by several investigators (39,46-49). In our series, BRC at doses ranging from 2.5-20 mg/day orally, induced normoprolactinemia in 38.5% of patients (39). In the remaining patients, 10 with macro (Fig.8) and 6 with microprolactinoma (Fig.9), PRL levels remained above the normal range despite a progressive increase of the dose of the drug. However, the possibility that some patients were indeed not taken BRC appropriately cannot be ruled out as poor compliance to any chronic treatment is a well known phenomenon in children and adolescents. In addition, some patients required drug discontinuation for intolerable side effects regarding the gastrointestinal tract. Both quinagolide (CV), at doses ranging from 0.075-0.6 mg/day, or cabergoline (CAB), at doses ranging from 0.5-3.5 mg/week orally, two selective DA receptor subtype-2 selective agonists, have been reported to be effective in reducing Prl secretion and tumor size in most adult patients with prolactinoma, even in those previously shown to be poorly responsive or intolerant to BRC (41).

Of our 50 cases (41), cabergoline induced normalization of PRL levels in all but 3 cases. Two of the three patients had large extrasellar macroprolactinomas (tumor volume of 4579 mm3 and 1983 mm3 respectively) with baseline PRL levels of 3300 μg/L and 1700 μg/L, respectively that progressively decreased but did not normalize after 2-7 years of treatment period. Tumor shrinkage by 93.2% and 54.5% was obtained in both patients. The latter patient had a microprolactinoma (tumor volume=123.6 mm3) with a baseline PRL levels of 500 μg/L that progressively decreased up to 88 μg/L at the last follow-up after 6 years of treatment and achieved tumor shrinkage by 53.9% (41). Only one case of pituitary apoplexy following cabergoline treatment in a young patient has been reported so far (50). Twelve of our 50 patients (one with enclosed macroprolactinoma and 11 with microprolactinoma) achieved the disappearance of the tumor so that were withdrawn from treatment (51).

In our former series, tumor shrinkage was observed in most patients with macroadenoma and even in some with microprolactinoma (Fig.10). The easy weekly administration makes CAB an excellent therapeutic approach to children/adolescents with prolactinoma.

The clinical manifestations of CD are mostly the consequence of excessive cortisol production. The clinical presentation is highly variable, with signs and symptoms that can range from subtle to obvious (Table 1). The diagnosis is generally delayed since a decrease in growth rate may be the only symptom for a long time. Growth failure in CD may be due to a decrease of free IGF-I levels and/or a direct negative effect of cortisol on the growth plate (54,55). In a series of 50 children with CD, Magiakou et al. (55) found that obesity and growth retardation were the most frequent symptoms (in 90 and 83% of patients, respectively). Weight gain and stunted growth were the most frequent symptoms also in the series by Weber et al. (56) and Devoe et al. (57). The skin of the face is plethoric, and atrophic striae can be found in the abdomen, legs and arms. Muscular weakness, hypertension, and osteoporosis, especially of the spine, are common. Results on BMD or bone metabolism in children with CD have been reported only in some patients in a few studies (56,58). Consistent with the findings in adult patients, marked osteopenia was also found in affected children. The bone loss is more evident in trabecular than in cortical bone (59). As compared to patients with adult-onset disease, those with childhood-onset CD have a similar degree of bone loss at lumbar spine and similar increased bone resorption (60). In a study conducted in 10 patients with childhood-onset and 18 with adulthood-onset Cushing’s disease (CD) Di Somma et al. found that BMD at lumbar spine was significantly lower than in sex and age-matched controls (Fig.11). Osteoporosis was found in 16 patients (57·1%) [8 adolescent (80%) and 8 adult (44·4%) patients] while osteopenia was found in 12 patients (42.8%) [2 adolescent (20%) and 10 adult (55·6%) patients] (60). Additionally, we have recently reported that two years of cortisol normalization improved but did recover bone mass and turnover neither in children nor in adult patients with CD (61). This negative finding suggests that a longer period of time is necessary to restore bone mass after the cure of CD and, thus, other therapeutic approaches may be indicated to limit bone loss and/or accelerate bone recovery in these patients (61).

Hypercortisolism leads to decreased bone formation through direct or indirect inhibition of osteoblast function (62,63), while bone resorption is normal or increased in patients with CD (60,62,64,65). It should also be noted that in children with CD the direct negative effect of hypercortisolism on bone formation is further worsened by concomitant hypogonadism and GH deficiency, both of which are associated with decreased BMD.

Children with CD may also have impaired carbohydrate tolerance, while overt diabetes mellitus is uncommon. Excessive adrenal androgens may cause acne and excessive hair growth, or premature sexual development in the first decade of life. On the other hand, hypercortisolism may cause pubertal delay in adolescent patients. Peculiarly, young patients with CD may present neuropsychiatric symptoms which differ from those of adult patients. Frequently they tend to be obsessive and are high performers at school.

The differential diagnosis of CD includes adrenal tumors, ectopic ACTH production, and ectopic CRH-producing tumors. However, ectopic ACTH secretion is extremely rate in the pediatric age. Among a large series including 306 cases with pediatric and adult Cushing’s syndrome investigated at the St. Bartholomew’s Hospital in London, 32 had ectopic ACTH syndrome of whom only 1 was in the pediatric age (52). This child was discovered as having a bronchial carcinoid tumor approximately 7 yrs after the first diagnosis of CD (56).

In a child/adolescent with suspected CD the diagnosis is based on measurement of basal and stimulated levels of cortisol and ACTH. Measurement of 24-h urinary free cortisol is elevated, and a low dose of dexamethasone (15 μg/Kg) at midnight does not induce suppression of morning serum cortisol concentrations as in normal subjects (52). Loperamide, an opioid agonist, lowers cortisol secretion and has been proposed as a reliable screening test for hypercortisolism in children and adolescents (66). Suppression of the spontaneous circadian variations of serum cortisol is another feature of CD. Suppression of cortisol by more than 50% after high dose dexamethasone (150 μg/Kg) given at midnight will confirm that hypercortisolism is due to an ACTH-secreting pituitary adenoma (66).

All patients should undergo pituitary MRI with the administration of gadolinium, but since ACTH-secreting pituitary adenomas are significantly smaller than all other types of adenomas, often having a diameter of 2 mm or less (67), pituitary MRI may fail to visualize the tumor. In most instances the diagnosis of CD can be made by initial clinical and laboratory data (Fig.12). Bilateral inferior petrosal sinus sampling has a high specificity, so that no patient with extra-pituitary Cushing's syndrome runs the risk of being submitted to trans-sphenoidal surgery, but it carries a significant number of false negative results (67). This procedure can also be technically difficult in children, and the risk of morbidity from surgery and/or anesthesia must be considered. Lateralization of the adenoma can be of better help for the surgeon than pituitary scanning (68). Therefore, bilateral venous sampling should only be performed in centers with wide experience in the technical procedure as well as in the interpretation of the results. If a patient without anomalous venous drainage patterns exhibits a lateralizing ACTH gradient of 2:1 or greater (69), removal of the appropriate half of the anterior pituitary gland will be curative in 80% of cases (67). Kunwar and Wilson (67) reported that in the presence of a negative surgical exploration, a guide to the probable location of the adenoma is invaluable, and under the right circumstances, a hemi-hypophysectomy is appropriate and successful in most cases.

Trans-sphenoidal adenomectomy is the treatment of choice for ACTH-secreting adenomas. Surgical excision is successful in the majority of children, with initial remission rates of 70-98% and long-term cure of 50-98% in most studies (28,29,35,55-57,71-75). The success rate decreases when the patients are followed-up for more than 5 years (55-57), and the outcome cannot be predicted either by preoperative or immediate postoperative tests (57). The morbidity is low when the procedure is carried out by an experienced neurosurgeon. In a recent study successful surgery was found in 59% of of 27 patients over a 21-year period, with a higher age favouring cure, as did an identifiable tumour seen at surgery and positive histology (76). Cure was also more likely to be achieved if the surgery is performed by an experienced neurosurgeon, in analogy with other studies performed in acromegaly (77).

Trans-sphenoidal microsurgery is considered successful when it is followed by remission of signs and symptoms of hypercortisolism and by normalization of laboratory values. Surgery is usually followed by adrenal insufficiency and patients require hydrocortisone replacement for 6-12 months. After normalization of cortisol levels, resumption of normal growth or even catch-up growth can be observed. Generally, final height is compromised compared to target height (57,78). Johnston et al. (79) have, however, reported that some children do achieve a normal final stature. However, even if catch-up and favorable long-term growth can be achieved after treatment for Cushing's disease, post-treatment GH deficiency is frequent (80). Lebrethon et al. (80) demonstrated that early hGH replacement may contribute to a favorable outcome on final stature (Fig.13). A re-analysis of this series confirmed that pediatric Cushing’s disease patients achieve a normal final stature provided that replacement therapy including GH is correctly performed (81).

The treatment modality in patients who have relapses after trans-sphenoidal adenomectomy is still controversial. Some authors recommend repeated surgery (55,82), while others favor radiotherapy (83,84). Radiotherapy with or without concomitant mitotane treatment may be indicated in patients with macroadenoma (84). Rarely, surgery may induce panhypopituitarism, or permanent diabetes insipidus (35), while hypothalamic-pituitary dysfunction is an early and frequent complication of radiation (57). Bilateral adrenalectomy may be the last therapeutic option in case of failure of both surgery and radiotherapy. Pharmacotherapy is less successful and only a very few cases have been reported so far. In a 6.2-year-old male patient with severe hypercortisolaemia and life-threatening complications of Cushing's disease not responsive to metyrapone and ketoconazole, low-dose intravenous infusion of etomidate, with dose titration according to serum cortisol levels, induced normalization of cortisol levels in (from 1,250 to 250 nmol/l) within 24 h (85). Greening et al. (85) thus suggested that combined etomidate and hydrocortisone therapy could be a potential safe approach in patients with very severe Cushing’s disease to be treated before bilateral adrenalectomy. To note that pediatric Cushing’s disease patients, in contrast with adult patients, do not completely recover from cognitive function abnormalities despite rapid reversibility of cerebral atrophy (86).

In adults, chronic GH hypersecretion causes acromegaly which is characterized by local bone overgrowth, while in children and adolescents it leads to gigantism. The associated secondary hypogonadism delays epiphysial closure, thus allowing continued long bone growth (Fig.14). However, the two disorders may be considered along a spectrum of GH excess, with principal manifestations determined by the developmental stage during which such excess originates (Table 1). Supporting this model has been the observation of clinical overlap between the two entities, with approximately 10% of acromegalics exhibiting tall stature (89), and the majority of giants eventually demonstrating features of acromegaly (90). In contrast with adults where there is an increased prevalence of large bowel polyps and cancer, central or obstructive sleep apnea and cardiomyopathy which are considered major morbidity and mortality factors (91-95), there is no report of similar complications in childhood. In a recent study conducted in six patients with gigantism, Bondanelli et al. showed that 33% of giant patients had left ventricular hypertrophy and inadequate diastolic filling, 16.7% had isolated intraventricular septum thickening and impaired glucose metabolism (96). In acromegaly clinical features develop insidiously and progressively over many years and the average delay between the onset of symptoms and diagnosis is approximately 6 years (97), while the presentation of gigantism is usually dramatic and the diagnosis is straightforward. All growth parameters are affected although not necessarily symmetrically. Mild-to-moderate obesity occurs frequently (88), and macrocephaly has been reported to precede linear and weight acceleration in at least one patient (98). All patients also had coarse facial features, disproportionately large hands and feet with thick fingers and toes, frontal bossing and a prominent jaw (88). In girls menstrual irregularity can be present (99) while glucose intolerance and diabetes mellitus are rare. Only one case of ketoacidosis has been reported so far (100). The diagnosis of acromegaly and gigantism is usually clinical, and can be readily confirmed by measuring GH levels, which in more than 90% of patients are above 10 μg/l (87). The oral glucose tolerance test (OGTT) is the simplest and most specific dynamic test for both the diagnosis and the evaluation of the optimal control of GH excess (87). In healthy subjects, the oGTT (75-100 grams) suppresses GH levels below 1 μg/l after 2 hours, while in patients with GH-secreting adenoma such suppression is lacking, and a paradoxical GH increase is frequently observed. GH excess should be confirmed by elevated circulating IGF-I concentrations for age and gender (101). The assay of IGF-I binding protein-3 is conversely not useful for diagnosis nor for the follow-up of the patients (102,103). The presence of different GH isoforms in patients with gigantism/acromegaly may represent a diagnostic problem (104). A greater sensitivity of the GH assay may facilitate the distinction between patients and normal subjects, as shown by the use of a chemiluminescence GH assay (105). It might help in demonstrating the persistence of GH hypersecretion after surgery or during medical therapy. In case of clinical and laboratory findings suggestive of a GH-producing adenoma, pituitary MRI must be performed to localize and characterize the tumor.

Trans-sphenoidal surgery is the first treatment approach to these tumors. However, since the majority of these adenomas are macroadenomas, which tend to be locally invasive, surgery alone fails to normalize TSH and thyroid hormone levels in most cases. In adults, radiotherapy is recommended as routine adjunctive therapy when surgery has not been curative (125). However, due to the high frequency of post-radiotherapy hypopituitarism, in children pharmacotherapy is the preferred second choice. There is very little success with dopamine agonists for treatment of these tumors (119). In contrast, therapy with somatostatin analogs normalizes TSH levels in the majority of patients, and tumor shrinkage occurs in approximately half of cases (126-129). Chronic treatment with SR-lanreotide reduced plasma TSH and normalized fT4 and fT3 levels, suggesting its use in the long-term medical treatment of these adenomas (129).

The first approach to these adenomas is trans-sphenoidal surgery to remove tumor mass and decompress parasellar structures. As in the other adenoma histotypes, surgery has a low morbidity and leads to an improvement of visual symptoms in the majority of cases. The recent development of the endoscopic endonasal unilateral transsphenoidal approach to the pituitary (133-136), which has the same indications as the conventional transsphenoidal microsurgery, overcomes many of the potential problems tied to the surgical route, thanks to its minimal invasiveness. This procedure encompasses no sublabial aggression nor any fracture of the facial bones with dental or naso-sinusal complications. Furthermore, a wider surgical vision of the operating field is obtained, which potentially improves the likelihood of a better and safer tumor removal. Furthermore, this procedure requires a shorter hospitalization, permits a rapid recovery of the child (137), and allows to maintain the neuroendocrine-pituitary integrity, with ensuing normal growth. This approach can also be safely used for the surgical removal of remnant pituitary tumors (136). After surgery these patients partially recover from hypopituitarism. Postoperative radiotherapy is applied in patients with subtotal tumor removal to prevent tumor re-growth and reduce residual tumors, but is burdened by a high prevalence of panhypopituitarism (138-140). Medical therapy has poor effects on clinically nonfunctioning adenomas (141). Very recently, positive effects of CAB were observed in some patients with α-subunit secreting adenomas, mostly in patients with tumors expressing high number of dopamine D2 receptors (142). A positive response to cabergoline associated with detection of dopamine receptors in vitro has been recently proven in clinically nonfunctioning adenomas (143).

Somatostatin and dopamine agonists have not been tested in children/adolescents with clinically nonfunctioning adenomas.