Pituitary surgery is a distinct subspecialty of neurosurgery in which specific knowledge and interest of pituitary pathophysiology go with precise awareness of basic neurosurgical techniques and associated skills. Nowadays the neurosurgeon has more than one option, including the medical, surgical, and radiotherapeutic ones, alone or in various combinations, in order to manage many of the different pituitary syndromes. The best outcomes for pituitary surgery are obtained in centers where the entire range of pituitary specialties is offered in an environment of effective teamwork. The postoperative management with a long-term patient follow-up in pituitary surgery, perhaps more than other areas of neurosurgery, makes the difference between a satisfactory result and a poor result. It is in such a context that pituitary surgery should be approached today, where the neurosurgeon dealing with techniques, indications, and results resembles a member of an orchestra who is playing a refined instrument. The neurosurgeon must have a keen perception, good instincts, steady hands, and the ability to perform a tailor-made operation for the individual patient and not mass.

Pituitary adenomas are benign tumors arising from adenohypophyseal cells and represent 10–15 % of all intracranial tumors (third most common histotype). They are the most frequent lesions of the sellar region (80 %) with a prevalence of 0.02–0.03 % (200 cases per million of people); about 10 % of population has a hidden adenoma: for this reason we often have a radiological finding of a pituitary tumors (incidentaloma) in asymptomatic patients. The average age at diagnosis is 30–50 years old in 65–70 % of cases and these lesions are more common in women with a ratio of 2:1. Pituitary adenomas are classified into secreting (75 %) and nonfunctioning adenomas; following functional criteria and according to the lesion volume, we have microadenomas (<10 mm in diameter) and macroadenomas (>10 mm in diameter). Macroadenomas grow inside the pituitary fossa and can invade surrounding areas producing mass effect on important neurovascular structures. Secreting adenomas are classified according with endocrinological syndromes caused by the increase of one or more hormones:

PRL-secreting adenomas or prolactinomas cause an amenorrhea-galactorrhea syndrome in child-bearing potential women, while in men they provoke impotence. The high increase of serum prolactin levels is directly responsible for the clinical manifestations. Diagnosis of prolactinoma is confirmed when a radiological finding of sellar lesion goes with a high increase of prolactinemia: a prolactin serum level >150 mcg/L is suggestive of a prolactinoma. On the other hand, a slight elevation in prolactin levels (25–100 mcg/L) can be caused by a functional hyperprolactinemia or a iatrogenic one (reduction of the dopamine-depending inhibitor mechanisms caused by psychotropic drugs, dopamine antagonist, estrogens, or a direct compression on the pituitary stalk). In those cases with an ambiguous diagnosis, it is possible to use functional tests as the TRH or L-DOPA stimulating test; despite these exams are effective, in most cases basal levels of PRL and neuroradiological imaging are sufficient to make a diagnosis once all the other causes of functional or iatrogenic prolactinemia have been excluded [1, 2].

GH-secreting adenomas cause pituitary gigantism during the growth and acromegaly in adults. Acromegaly determines an enlargement of extremities and of somatic characteristics of the face (enlargement of frontal bones, nose, cheekbones, eyebrows, paranasal sinuses, vocal cords, mandible, tongue, lips, and dental diastase) and is associated to systemic complications (cardiovascular, respiratory, metabolic, neoplastic), causing a higher rate of mortality in nontreated patients. As GH secretion is variable during the day, its serum sampling is not a reliable parameter. The IGF-1 serum level is a useful tool when there is the suspect of acromegaly. Another test which can confirm the diagnosis is the lack of suppression of GH levels under serum values of 0.1 ng/ml after OGTT [3–7].

ACTH-secreting adenomas are responsible of Cushing’s disease, whose clinical symptoms are caused by glucocorticoid hormones’ hypersecretion. Weight gain and truncal obesity with supraclavicular and cervical fat depots (“buffalo hump”), rounded “moonlike” facies, thinned skin with purple striae and multiple ecchymoses, acne and hirsutism, and proximal muscle weakness caused by muscle atrophy are the most common clinical characteristics. Hypertension, osteopenia, menstrual irregularities, and neuropsychological disturbances (e.g., depression, irritability, sleep disturbance, cognitive defects, or even frank psychosis) further characterize patients with Cushing’s disease. The diagnosis of Cushing’s disease requires a series of first-line tests, namely, measurement of 24 h urinary free cortisol (UFC) secretion and the evaluation of cortisol serum levels. In patients with discordant test responses, second-line testing may be performed. The dexamethasone-suppressed CRH test and desmopressin stimulation appear the most useful examinations to confirm the pituitary origin of the hypercortisolism [8]. If dynamic testing or pituitary imaging has not yield conclusive etiologic evidence, bilateral inferior petrosal sinus sampling (BIPSS) can be performed. The presence of a center-periphery ACTH gradient higher than 3 confirms the central origin of the disease and the gradient between the two sides can indicate the lateralization of the lesion.

On the other hand, nonfunctioning adenomas do not cause any specific endocrinological syndrome; usually they create deficits due to their mass effect on the surrounding structures, such as optic chiasm or cranial nerves of the cavernous sinus, and with a direct compression on the adenohypophysis provoking hypopituitarism (GH defect and hypogonadism are the most frequent) [9, 10]. The most common problems are the visual deficits caused by the compression of the optic chiasm with a partial or complete bitemporal hemianopia. In 10–15 % of cases, the cavernous sinus is invaded causing palsies of oculomotor nerves or trigeminal neuralgia. Especially with giant adenomas, when temporal or frontal lobe is involved, the mass effect on the brain tissue can lead to specific clinical manifestations such as memory deficits, personality disturbance, and seizures, while an hypothalamic compression can alter electrolytic balance or circadian rhythm. When the ventricular system is implicated, an obstructive hydrocephalus can result.

The anatomo-pathologic examination of pituitary adenomas allows to classify these entities according to their cell coloration, electronic microscope characteristics, or immunohistochemical reactions that recognize hormones produced by adenomas cells, even if the hormonal serum levels are too low to be noticed or hormones are functionally nonactive. As a matter of fact, it has been demonstrated how nonfunctioning adenomas can produce complete glycoproteic hormones (FSH, LH, TSH) or their subunits (alpha subunit, beta-FSH, beta-LH, beta-TSH) [10–12].

A neuroradiological evaluation is a key point for the diagnosis of pituitary adenomas with magnetic resonance imaging as the first choice. Coronal and sagittal images before and after gadolinium (Gd-DTPA) allow to define morphological and volumetric characteristics of the lesion, as its correlation with surrounding structures (suprasellar cistern, optic nerves, medial wall of the cavernous sinus, and internal carotid artery). In case a microadenoma is suspected, it is possible to use thin-slice acquisitions (3 mm) with dynamic sequences. CT scan has a secondary role for the sellar pathology; it can be useful for the preoperative planning of the approach, showing more details of paranasal and nasal cavities with their anatomic variations [13–15].

Therapeutic options available for the treatment of adenomas include medical therapy, surgery, and radiotherapy, but none of them is alone adequate to gain a total control of the disease. So a multidisciplinary approach is requested to choose the best option for the patient.

The normalization of excess hormone secretion, the preservation or restoration of normal pituitary function, the elimination of mass effect with restoration of normal neurological function, the prevention of tumor recurrence, and a complete histologic diagnosis are the multiple goals that therapy for pituitary adenomas is targeted to achieve.

Pituitary apoplexy is a relatively rare condition presenting with sudden headache, abrupt visual loss, ophthalmoplegia, altered level of consciousness, and collapse from acute adrenal insufficiency. It is caused by a hemorrhage in the tumor or by its acute necrosis, with subsequent swelling and frequent spreading into the subarachnoid space, leading to other signs of meningeal irritation; the related acute and severe clinical syndrome demands glucocorticoid replacement and surgical decompression, usually transsphenoidal, if visual loss is severe and progressive [16–19]. If the patient has a mild form of apoplexy and is clinically stable, it is prudent to measure the serum prolactin because some patients with prolactinoma present in this fashion and can be treated successfully with medical therapy.

Progressive mass effect is one more indication for surgical treatment. The compression of surrounding neurovascular structures usually causing visual deficit (due to compression of the optic chiasm) or less frequently cranial nerve palsy (due to compression of cranial nerves inside the cavernous sinus) needs an immediate intervention.

For nonfunctioning adenomas the main goal must be the relief from the mass effect and the recovery of the endocrine functions if altered. Being the medical treatment ineffective, the first choice is surgery [20–22] and the transsphenoidal approach is the most effective. Visual deficits or endocrine dysfunction is an indication for the surgical treatment, while in all other cases, a conservative treatment can be preferred especially for those lesions smaller than 10 mm.

The normalization of the prolactin levels and the restoration from the sexual and gonadic function are the objectives of the treatment for prolactin-secreting adenomas, associated to the control and the reduction of the lesion volume. The first therapeutic option is represented by dopamine-agonist drugs such as cabergoline that in a high percentage of patients is sufficient to obtain the reduction in volume of the lesion and the normalization of the prolactin values [20, 23, 24] The surgical treatment is limited to those cases that develop a resistance, intolerance, or CSF leak after medical treatment, in case of patients with voluminous adenomas with severe neurological deficit or pituitary apoplexy or for patient’s choice [25, 26]. In case of failure of both the medical and the surgical treatment, radiotherapy can be a useful tool.

For GH adenomas the surgical treatment is the option of choice with a normalization of GH and IGF-1 achieved in 44–76 % of cases. In the last decade, the preoperative treatment with somatostatin analogues or GH receptor antagonists (Pegvisomant) has been proposed as an alternative or a complement to surgery. The use of dopamine agonists is reserved for those cases in which the GH secretion is associated to high levels of prolactin [27–30].

The objective of the treatment in Cushing’s disease is the normalization of the ACTH and cortisol levels and the option of choice is the surgical treatment via a transsphenoidal approach.

Pre- and postoperative pharmacological treatment and different drugs have been attempted and new agents are under investigation.

Stereotactic radiotherapy is used to treat recurrent adenomas or residual tumor after surgery. In case of all these options are not successful for the disease control, adrenalectomy is the last choice to solve the hypercortisolism.

As for the other secreting adenomas, the treatment of TSH adenomas must be direct to the mass effect relief and the hypersecretion normalization.

Transsphenoidal approach is the first option; the postoperative treatment with dopamine agonists and radiotherapy is reserved for those patients with residual tumor or still elevated levels of TSH.

Pituitary surgery was developed and has advanced on the basis of repeated innovations and exchanges between Europe and the USA. Starting with the British experience of Horsley in 1889, who performed the first operation on a pituitary tumor [31, 32], followed by Paul, a general surgeon in 1893, with a temporal decompression in an acromegalic patient [33, 34], we arrive to 1907 when with the Viennese surgeon Schloffer we had the first transsphenoidal approach [35]. Based on anatomic studies of the Italian physician Giordano [36, 37], who had analyzed the Egyptian technique used to extract cerebral tissue transnasally in the mummification process by means of special hooked instruments, without disfiguring the face, Schloffer performed a lateral rhinotomy, reflecting the nose to the right, removing the turbinates, and opening the maxillary, ethmoid, and sphenoid sinuses, before reaching the sella. In the same year, von Eiselsberg [38], in Vienna, performed a similar, if even more extended, procedure. Since then the evolution of the transsphenoidal technique had numerous contributions by eminent figures in the history of neurosurgery, such as Kocher, Kanavel, Hirsch, Hajek, and Kilian [39–46], that posed the basis for the sublabial approach performed by Cushing first and Halstead later, respectively, in 1909 and in 1910 [47–50]. After this initial enthusiasm for the transsphenoidal approach, Cushing himself abandoned this procedure [40, 51, 52] for the transcranial approach proposed by Dandy [53] who, in 1918, presented his experience in about 20 cases operated on through an intracranial intradural approach to the chiasm. A similar way had been originally used by Heuer in 1914, who described a frontotemporal route to the pituitary along the sylvian fissure [54, 55]. The two main transcranial options, subfrontal and frontotemporal, are still used today, together with more recent skull base approaches. The late 1920s to the 1960s was a relatively dark period for transsphenoidal surgery; the only one who kept this technique alive was Dott, neurosurgeon of the Royal Infirmary at Edinburgh and Cushing’s pupil [40, 56], who taught the method to Guiot, laying the groundwork for the modern transsphenoidal surgery, formally started with Hardy in the late 1960s and 1970s with the introduction of the microscope [57]. Since then, the transsphenoidal approach was largely used and developed thanks to the efforts of eminent neurosurgeons such as Laws in the USA and Fahlbush in Europe. A new milestone in the evolution of this technique was the introduction of the endoscope [58]. Used for the first time by Guiot in 1963 [59] as an adjunct to the microscope to expand the field of vision (endoscope-assisted microneurosurgery), it had then been abandoned for years because it still was technically insufficient. The endoscope has come into regular use as a stand-alone visualizing and operating tool (pure endoscopic transsphenoidal surgery), thanks primarily to the work of Jho and Carrau in Pittsburgh, USA [60, 61], and of the group of Naples, Italy [62, 63]; these groups standardized an endonasal anterior sphenoidotomy approach to the sella, without the use of the operating microscope or of a transsphenoidal retractor. In the recent year the evolution of the endoscopic endonasal transsphenoidal approach allowed to remove giant and invasive adenomas by this procedure. The extended approach to the suprasellar region [64–66] as well as to the cavernous sinus [67, 68] has been recorded from several groups around the world.