Pituitary adenomas:   

 

Dr. A. Vincent Thamburaj,   

Neurosurgeon, Apollo Hospitals,  Chennai , India.

Pituitary adenomas are biologicallly benign tumors originating from adenohypophyseal cells capable of producing various pituitary hormones.  Although Cushing pioneered this particular chapter of neurological surgery, research and treatment of pituitary tumors are still developing.

  

EPIDEMIOLOGY:

 

The peak incidence is in the third and fourth decade. Recent MR evaluation in the general population shows that about 10% of the normal adult population has pituitary abnormalities that are compatible with the diagnosis of asymptomatic pituitary adenomas.

Pituitary adenomas account for about 10-15% of all surgically and histologically diagnosed intracranial neoplasms. Incidence is about 1.5-2/100,000 and they are more common in females. 

PATHOLOGY:

 

Most of them are slow growing and benign; however some grow faster and invade the surrounding structures. They vary in size, endocrine function,

cellular composition, and morphology. They are greyish red and soft, usually well demarcated separated from the adjacent compressed normal gland by

a 'pseudocapsule'. There is no fibrous capsule.

 

Different cell types, and hence the adenomas have different preferential sites.

GH adenomas are seen in the lateral 'wings'.

PRL adenomas can occur anywhere, but mostly in the lateral 'wings'.

ACTH & TSH adenomas occur in the central 'wedge'.

The rarer LH & FSH adenomas have no site preference.

 

CLASSIFICATION: 

Pit.adenoma (H&E): Monotonous proliferation of round cells, arranged in an acinar pattern and in sheets or trabeculae with numerous thin

 walled blood vessels.

Historically, they were classified on the basis of their tinctorial affinity for acidic or basic dyes into acidophilic (secrete growth hormone), basophilic (secrete ACTH), or chromophobic (hormonally inactive) adenomas. This was of no help to an understanding of the cytogenesis or tumor behavior. 

Functional classification: 

Depending on Endocrine activity, they are classified into 

         Prolactinoma 25-50%

         Endocrine-inactive 25-40%

         GH-secreting 20-25%

         ACTH-secreting 5-10%

         TSH – and LH/FSH-secreting < 1%

 

Modern classification (Horvath & Kovacs, 1976) uses the electron microscopy and immunocytochemical analysis of hormones to distinguish: 

Prolactin cell adenomas (Sparsely granulated and Densely granulated)

Growth hormone cell adenomas (Sparsely granulated and Densely granulated)

Plurihormonal adenomas- Mixed prolactin, and growth hormone cell adenomas 

                                    - Acidphilic stem cell adenomas 

                                    - Mammosomatotroph cell adenomas 

ACTH cell adenomas (Sparsely granulated and Densely granulated)

FSH/LH adenomas 

TSH adenomas 

Null cell adenomas (nononcocytic and oncocytic)

Radiological classification: 

The classification introduced by Hardy (1969) and complemented by Wilson (1979) is based on the imaging capabilities of plain skull X-rays and computerized tomography, and cannot exactly define parasellar extension. 

A magnetic resonance imaging and surgical related classification allows a comprehensive morphological differentiation of tumor extension, giving the neurosurgeon more selective criteria for surgical decision making.

Grossly, microadenomas refer to tumors that are less than 1 cm in size.

Macroadenomas represent tumors greater than 1 cm in size, and they may be further classified

 

Stage 1- microadenomas (<1cm) without sella expansion.

 

Stage 2- macroadenomas (>1cm) and may extend above    the sella, without sella expansion.

 

Stage 3- macroadenomas (<1cm) with enlargement and invasion of the floor or suprasellar extension.

 

Stage 4- is destruction of the sella.

 

They may be further classified on the degree of suprasellar extension:

a)      Extension to suprasellar cistern only.

b)      Extension to recesses of the 3rd ventricle.

      c)      Extension to involve the whole 3rd ventricle.

Pit.hyperplasia-

MRI sagittal

Pit.hyperplasia-

MRI.coronal

Pit. microadenoma-MRI.sagittal

Pit.microadenoma-

MRI.coronal

Pit.macroadenoma-MRI.sagittal

Pit.macroadenoma-

MRI.coronal

PATHOGENESIS: 

Two main theories dominate current concepts of the pathogenesis of pituitary tumors (Reichlin, 1991): 

Hypothalamic etiology suggests that adenomas arise as a consequence of target gland feed back or hypothalamic dysregulation. 

Loss of normal feedback inhibition by target gland as seen in thyrotrophinomas and gonadotrophinomas, loss of hypothalamic inhibition in prolcatinomas and somatotrophinomas, and excessive secretion of hypo-

physiotropic factors: CRF in ACTH-producing adenomas, GHRH in acromegaly (Ezzat, 1994) and  PRFs in prolactinomas support this theory.  

Oncogene activation theory suggests that adenomas arise as a consequence of activation of oncogenes. A significant proportion of ACTH - producing tumors are monoclonal. 40% of GH-secreting tumors show two different mutations of Gsa gene regulatory protein converting it to an oncogene. The genetic susceptibility to MEN 1 (in PRL-, GH- and ACTH secreting adenomas) is attributed to deletions mapped to a small region within the chromosome band 11q13 and signifies a loss of growth–inhibitory allele. Pituitary tumors develop in transgenic mice carrying the growth inducer SV-40 T antigen, suggesting that an intrinsic genetic defect leads to clonal expansion of a transformed pituitary cell.   

 

CLINICAL FEATURES: 

 

Mass effects: 

Any mass in the sella will compromise the function of neural structures in the vicinity, including the optic nerve, chiasm, and tracts, the hypothalamus, the pituitary gland, the cranial nerves related to the cavernous sinus, the brain itself, and the ventricles.

Symptoms due to mass effect are more likely to appear due to endocrine inactive tumors and sometimes in large, late diagnosed hormone secreting adenomas. 

Visual compromise is to be expected only if the suprasellar tumor exceeds 15mm as measured from the plane of the diaphragma sellae.From subtle compression of the anterior visual pathways to disabling diplopia and headache, the symptoms and signs of pituitary tumors require a thorough ophthalmologic evaluation which can suggest the tumor extensions in relation to the chiasma.

A chiasma situated directly over the sella is present in about 80% of patients, a prefixed chiasm (overlie the tuberculum sella)  in about 10%, and a postfixed chiasma (overlie the dorsum sella) in about 10%. These relationships have a direct bearing on the configuration of the visual field defects resulting from an encroaching pituitary tumor. The resultant field defect can thus be monocular, in postfixed chiasma or in extensive anterior tumor. Involvement of the optic nerve accounts for the scotoma and involvement of the crossing inferior nasal fibers from the opposite optic nerve (von Wilbrand’s knee) results in quadrantic defect. Bitemporal hemianopia uniquely localizes a lesion to the optic chiasm. Due to involvement of crossing fibers of the optic chiasm, the superior temporal quadrants are affected initially, followed by the inferior temporal quadrants. Further damage will affect the non crossing fibers and eventual total blindness and optic nerve atrophy. The optic tracts are more likely to be injured with a pituitary tumor growing posterosuperiorly or with a prefixed optic chiasm with resultant homonymous visual field defect that are typically incomplete and incongruous.

On fundoscopy , papilledema is a rare finding in patients with pituitary adenomas. About 30% of the patients will show temporal pallor.

Rarely, an extremely large pituitary tumor may compress the upper midbrain , resulting in see-saw nystagmus.

 

Distension and distortion of the dura mater and diaphragma sellae sometimes result in headache. 

 

Pituitary dysfunctions may present in many ways: 

·          Somatotroph axis is the most sensitive hormonal axis. Its dysfunction bears clinical significance only in children.

·         Ganodotroph axis, secondary hypogonadism. In women it is the gynecologist who should be able to detect the pituitary origin of the menstrual disturbances.  In men decrease in libido and potency will only occasionally be the presenting symptoms.

·         Thyrotroph axis leads to secondary hypothyrodism.

·         Corticotroph axis with secondary adrenocortical insufficiency.  Adynamia, arterial orthostatic hypotension, and hypokalaemia suggest a secondary adreno-corticotroph insufficiency.

·         Complete anterior pituitary insufficiency. If this is associated with an impairment of the posterior pituitary lobe function (exceptional in pituitary adenomas) the patient is said to have a panhypopituitarism.   

Hypothalamic dysfunction may result in various neurological abnormalities due to its role in consciousness, sleep, emotion, and behavior. Hypothalamus regulates anterior and posterior pituitary function, water balance, and body temperature; its dysfunction results in altered physiological body functions, and endocrinopathies. Diabetes insipidus is clinically characterized by the combination of polydipsia and polyuria associated with low specific gravity (< 1010).  

The pituitary stalk compression syndrome or ‘stalk phenomenon’. 

This is the result of mechanical impairment of the PIF (prolactin inhibiting factor) regulation of PRL secretion.  The regulatory axis can be interrupted at the secreting (hypothalamus) or transportation (pituitary stalk) level of PIF.  This results in loss of inhibition of pituitary PRL secretion with consecutive functional hyperprolactinaemia.  Five to ten fold increase in serum PRL levels a larger pituitary tumor is more likely to be functional, rather than the result of a prolactin cell adenoma. 

 

Compression and invasion of the cavernous sinus results in neurological signs of involvement of neural and vascular intracavernous structures 

·         Oculomotor palsies: especially of the oculomotor and abducent nerves (adenomas with a postero-lateral extensionto the tentorium), as well as of the trochlear nerve;

·         An acute onset of ophthalmoplegia associated with clinical signs of a SAH suggests an acute intratumoral hemorrhage in a pituitary adenoma with parasellar extension. The presurgical duration of the acute ophthalmoplegia is of no prognostic significance, and 70%of them can expect complete recovery. Symptomatic trigeminal neuralgia, especially of the maxillary division is another possible mode of presentation.

·         Retro-orbital pain and occasionally exophthalmos are the result of vascular congestion and occlusion of intracavernous vascular structures. 

Occlusion of the Foramen of Monro with subsequent obstructive hydrocephalus causing signs and symptoms of raised intracranial pressure. 

 

Adjacent brain such as the frontal or temporal lobes may be compressed, resulting in personality problems and seizures. 

Endocrinopathies: 

Depending on their frequency, one may consider four main clinical syndromes of pituitary hormonal oversecretion: 

·         Amenorrhoea-galactorrhoea syndrome (hyperprolactinaemia) in women and impotence and occasional galactorrhoea in men.

·         GH excess (gigantism in children and acromegaly in adults)

·         Hypothalamo-pituitary dependent hypercortisolism (Cushing’s disease)

·         Nelson’s syndrome 

 

Pituitary apoplexy:

       

             Acromegaly

This is an uncommon presentation (1%to 10%) due extensive hemorrhage or ischemic  necrosis (infarction) within a pituitary adenoma that causes a life threatening acute crisis, mimicking SAH, with signs  of meningeal irritation, disturbed consciousness, and opthalmoplegia.

The exact cause is not known. The blood supply of the normal gland has special features with an arterial supply to the median eminence and posterior pituitary and with a portal venous supply to the anterior pituitary from the median eminence and posterior pituitary. This unique anatomy predisposes to apoplexy. Bromocreptine therapy and radiotherapy have been blamed.

Differential Diagnosis:

Due to the intimate relationship of neural, endocrine, vascular, meningeal, and skeletal tissues in the parasellar region, a number of pathological lesions, though rare, must be kept in mind.

They may be neoplastic (Primary pituitary carcinoma, Pituitary metastases (from the breasts and the lungs), optic nerve and hypothalamic gliomas, craniopharyngiomas, hamartomas, histocytosis X, ganglioneuromas etc), non-neoplastic ( Empty sella syndrome, Rathke’s cleft cyst, Epidermal cyst, Mucoceles, Arachnoid cysts), inflammatory disorders (abscesses, sarcoidosis, etc), aneurysms and other vascular malformations. 

Neuroendocrine evaluation: 

In addition to recognizing any hypersecretory syndromes associated with pituitary adenoma, recognition of hypopituitarism prior to surgery is imperative. A screening should include measurement of thyroid, corticosteroid, prolactin, and gonadotropic and somatotrophic hormones.

Deficiency of adrenal, thyroid, and gonadal hormones may be mild.

In selected patients, pituitary hormones should be measured under conditions designed to stimulate their release, tailored to the individual circumstances.

TSH deficiency can be diagnosed by measuring simultaneously basal serum TSH and thyroid hormone levels. A low serum T4 in the presence of an inappropriately low TSH level suggests a central cause of hypothyroidism. To distinguish a hypothalamic from a pituitary defect, the TSH reserve may be assessed by performing a TRH test. In the intact pituitary, TSH and prolactin rise in response to TRH stimulation and growth hormone level falls. TSH over secretion, as in the context of a rare functional tumor, will result in elevated circulating levels of both TSH and T4.

Dynamic tests are required to diagnose a state of ACTH deficiency as the morning cortisol is persistently low only when ACTH deficiency is very severe. The CRH test will distinguish a hypothalamic CRH deficiency from a pituitary ACTH deficiency. Insulin-induced hypoglycemia and the glucagons test will stimulate the entire hypothalamic-hypophyseal-adrenal axis. The ACTH stimulation test evaluates the capacity of the adrenals to secrete cortisol.

Gondotropin deficiency can be diagnosed by measuring simultaneously basal serum FSH and LH levels and gonadal steroids, estradiol (in premenopausal women), and testosterone in men. In the event of primary gonadal failure, the lack of negative feedback by the gonadal steroids on the hypothalamic GnRH and pituitary LH and FSH secreting cells leads to an elevation of LH and FSH. A low level of circulating gonadal steroids associated with an inappropriately low gonadotropin level suggests a hypothalamic or pituitary disturbance. Lack of response of LH and FSH to GnRH indicates a lesion at the pituitary, rather than the hypothalamic level.

Basal Growth hormone level is often low. Plasma IGF-I level permits a more accurate diagnosis. Stimulatory tests to assess somatotropic function include sleep and exercise studies, insulin-induced hypoglycemia, administration of arginine, L-dopa, clonidine, propranolol, or GHRH.

The diagnosis of vasopressin deficiency may be established by simultaneous measurements of fasting plasma and urine osmolalities and of vasopressin. During a water-deprivation test, the diagnosis of diabetes insipidus is based on the development of abnormally concentrated plasma (osmolality greater than 300 mosm per kg) and urine, which remains dilute (osmolality less than 270 mosm per kg). The urine volume is not reduced. Exogenous vasopressin will correct these abnormalities. 

Neuroimaging: 

Skull X-rays demonstrate the size, shape and morphology of the sella and the sphenoid sinus. 

MRI: Due to its multiplanar and its three-dimensional imaging capability, and due to the vascular imaging possibilities, thin-collimation, high field MRI is able to delineate the tumor anatomy clearly and provide precise information about the fine anatomical structure of the cavernous sinus and the other surrounding anatomical structure, depicting accurately the characteristics of tumor development. MRI also visualizes the major vessels and the proximity of these to the tumor.

Large tumors usually have similar signal intensity to brain on T1 images. The normal pituitary, infundibulum, and cavernous sinuses enhance with GADO. However, in delayed images, the tumor will enhance and the normal pituitaries will washout the contrast before the tumor does.  

CT may be performed if MRI is not available or as a supplement to MRI. CT offers relevant information regarding bony landmarks, intratumoral hemorrhage or calcification. 

MANAGEMENT: 

The objectives of the treatment are a) relief of mass effect, b) correction of endocrinopathies, c) control of tumor growth.

Null cell microadenomas may be observed periodically and does not require any therapy. Macroadenomas, especially with visual problems, need surgery ideally. Large tumors may cause the so called stalk section effect (loss of dopaminergic inhibition to prolactin release) and elevated prolactin levels (<200ng/mL). They must be treated as null cell adenomas. 10% of these tumors will respond to bromocreptine.  In patients with medical conditions that preclude surgery, it is worth a trial. 

Prolactinomas are the commonest pituitary tumors. It has been observed that few microprolactinomas progress to macroadenomas. In contrast, macroadenomas, frequently present in men, may be aggressive and associated with very high prolactin levels. Microadenomas may be treated with bromocreptine or surgical excision; surgery may be a better option if the prolactin level is not significantly high. Surgery is widely employed in large tumors, although there are occasional reports of complete cure of macroadenomas with bromocreptine. 

Growth hormone secreting adenomas usually present early as microadenomas and are best dealt with surgery; post operative radiotherapy and / pharmacotherapy is usually indicated. 

Other rarer tumors (ACTH secreting, TSH secreting, Gonadotroph secreting adenomas) are best treated with surgery. 

Pituitary apoplexy requires intensive therapy with due attention to electrolytes and hormones. Medical management alone may be sufficient in mild cases, but surgery is advised. In some cases, ‘spontaneous cure’ of an adenoma have been reported. In patients who have not been operated, the necrotic material is replaced by an intra and /or suprasellar cyst, empty sella, or squamous metaplasia; chiasmal arachnoiditis is a possibility. 

Surgery: 

Sir Victor Horsley (1889) was the first to perform pituitary surgery.  He attempted to remove a pituitary adenoma via the transcranial approach. Schloffer (1907) reported on the first successful transsphenoidal operation for a pituitary tumor, via a lateral rhinotomy. Kocher (1909) modified the superior nasal procedure, and was the first to use a submucosal approach. Hirsch (1909-1910) entered the sella through a transseptal approach using a nasal speculum.

Cushing (1910) ingeniously combined the advantages of previous techniques and developed the basic oronasal midline rhinoseptal transsphenoidal approach. Frazier (1912) used the intracranial transfrontal approach to the pituitary.  This approach was then adopted even by Cushing himself, as the transsphenoidal operation showed a higher incidence of recurrence. Dott (1925) believed in Cushing’s transsphenoidal approach and consistently used it throughout his career. In the sixties Guiot continued Dott’s tradition and taught Derome and Hardy. Hardy (1962) reintroduced the procedure in North America, and refined the technique using the operating microscope and televised radiofluroscopic control.  

Preoperative cortisol, thyroid, and electrolytes levels are mandatory. Preexisting hypothyroidism may manifest acutely during early postoperative period. Reestablishment requires approximately one week of treatment prior to an elective procedure. Concomitant cortisol deficiency must be treated prior to initiating thyroid therapy to avoid an adrenal crisis. 

Transsphenoidal surgery: About 90% of pituitary tumors are amenable to this approach and is preferred regardless of the size. Extensive lateral extension of the tumor may warrant a craniotomy for a radical excision. Many of these will herniated into the enlarged sella once the sellar component has been evacuated. Extended procedures may give access to anterior skull base, clivus, and cavernous sinus inferolaterally.

    

 

 

Pit.adenoma-preop-CT (contrast)

Pit.adenoma-postop-CT(contrast)

Acute oronaso/paranasal infections may be treated prior to the procedure. Transcranial approach is occasionally used if transsphenoidal surgery is contraindicated ( when there is evidence of sinusitis and unacceptable visual loss) or as a second step in the combined transsphenoidal- tanscranial approach in large (giant) adenomas.

Of late, Endoscopy is increasingly used in transsphenoidal excision and it facilitates better clearance of the tumor and is less invasive than a routine transsphenoidal procedure.

Perioperative glucocorticoid is administered to all patients. Dose regimen is tailored to the individual patient’s needs. The stress of surgery may provoke an acute crisis in those without sufficient reserve and should be considered in those with unexplained alteration in mental status postoperatively. Urine volume and serum electrolytes must be monitored. Loss of vision may alert the surgeon of an evolving hemorrhage. 

Operative morbidity includes CSF leakage (4.4%), Meningitis (1%), Sinusitis (5%), Hypopituitarism (4%), SIHADH (3.5%). Incidence of Diabetes insipidus has been reported to be 1.7% to 18%.

Transient DI is common following manipulation of the normal posterior pituitary. DI may be transient or permanent but only the permanent type is regarded as a complication, and it is rare, with a reported incidence of 0.5 to 15%.Intraopertive CSF leak had a high association with postoperative diabetes insipidus. Transient DI is thought to be caused by temporary dysfunction of vasopressin-producing neurons as a result of surgical trauma and occurs in 10 to 60% of reported cases Usually only 20% of patients require treatment with desmopressin.

Typically, SIADH occurs 5 to 7 days postsurgery. One of the explanations for this phenomenon has been the release of stored ADH from the damaged posterior pituitary nerve terminals, and require fluid restriction.

A CSF leak may occur intra- or postoperatively and entails the risk of meningitis, which is a potentially fatal complication.

The reported incidence of CSF fistulas after transsphenoidal surgery is 1 to 4% and the incidence of meningitis is 0.8 to 2%. A CSF leak that is recognized intraoperatively can be repaired by packing the sella and the sphenoid sinus with fat or muscle.  Meningitis may also occur without a postoperative CSF leak. Although a small percentage of these will resolve spontaneously, many will require operative repair. Prophylactic antibiotic drugs are used by most surgeons in an attempt to prevent meningitis but the effectiveness of these prophylactic medications has never been proven.

Vascular injury occurring during transsphenoidal surgery is a rare yet potentially fatal complication and includes carotid artery (CA) rupture, CA cavernous fistulas, traumatic aneurysms, subarachnoid hemorrhage, CA vasospasm, and stroke.  Postoperative hemorrhage from the cavernous sinus, CA, or tumor bed can occur, causing visual deterioration or hypothalamic injury. Incidence of injury varies from 0.4 to 1.4%.

Optic nerve injury occurred is caused by a misdirected approach and contusion of the optic nerve. Other possible causes of injury include vasospasm, a postoperative hematoma, or devascularization of the optic apparatus. Delayed visual deterioration can also occur with the empty sella syndrome.

Injuries to the cranial nerves (excluding the second cranial nerve) usually occur as a result of exploration of the cavernous sinus for tumor, and the nerve most commonly injured is the sixth cranial nerve. The reported incidence is 0.4 to 1.9% and the injury may be temporary or permanent.

Problems related to the nasal aspects of the operation are rarely fatal but may produce significant discomfort and distress, and include sinusitis (1--15%), septal perforations (0.3--0%), and epistaxis (0.4--4.3%). Nasal septal perforation can lead to chronic infection and may require secondary surgical repair. Nasal tip deformities or a saddle nose may occur when the nasal spine or cartilage is too aggressively removed. Postoperative sinusitis may require additional medical or surgical treatment. 

Epistaxis is rare and can be treated with nasal packing, cautery, or ligation/embolization of the internal maxillary artery. Delayed massive epistaxis is a rare but significant complication of transsphenoidal surgery. Injury to branches of the external carotid artery, along with injury to the internal carotid artery, should be suspected in patients who present with delayed epistaxis after transsphenoidal surgery. Angiography performed in patients with refractory bleeding should include selective external carotid injections. Epistaxis that is refractory to anterior and posterior nasal packing may be effectively treated with endovascular embolization.

Anosmia and hyponosmia is a frequent and under recognized minor complication. Fibrosis of neuroepithelium, poor aeration of olfactory receptors, and sinusitis likely contribute.

Prior to discharge, A.M cortisol will determine the need for long term cortisol replacement. Thyroid levels may be done after a month since autonomous thyroid function may persist for sometime. Post operative imaging is best done after 3 months to decide on further therapy. 

Outcome: Immediate improvement in vision may occur, with significant improvement usually within 2 weeks. The improvement may continue for up to 12 months. 

Radiotherapy: 

The goal of post operative radiotherapy is to delay the recurrence, especially in large and invasive lesions. Several studies suggest improved tumor control with the combination of surgery and radiotherapy.

The combination of surgical decompression followed by radiotherapy in the dosage range of 4500-5000 cGy over 25 fractions yields tumor control rates (>90%) in giant pituitary adenomas similar to those of smaller pituitary adenomas.

In general, all large tumors, especially with cavernous sinus involvement, and those who have failed surgical or medical therapy are considered for post operative radiotherapy. With functioning tumors, evaluation of post operative endocrine status may indicate the effectiveness of surgical removal.

Primary radiotherapy is occasionally employed in the elderly and high risk patients. Primary radiotherapy alone offers a 50% recurrence rate with a 75% local control rate following salvage.

Adverse effects of radiotherapy range from mild to severe. There is a significant risk of worsening preexisting hypopituitarism (25% to 100% among various series). Visual impairment may result as a result of empty sella syndrome, treatment failure, or direct damage to optic pathways( especially when the daily dose is >220cGy).

Stereotactic radiosurgery: Backlund and Rahn (1969) introduced stereotactic pituitary irradiation using radiosurgery with the Leksell Gamma Unit. This offers an alternative to those who do not require decompression of optic pathways or more rapid hormone correction, and in those where surgery has failed. Ideally, the tumor must be more than 2mm from the optic pathways. From the available studies, the optimum dose has not been established; the tumor control is excellent (>90%), and the endocrinopathy control is suboptimal. Long term studies are awaited. 

Pharmacotherapy: 

Quadri and Besser (1972) reported described his experimental and clinical report on the effects of bromocriptine in prolactnomas. Liuzzi (1974) reported on GH suppression in acromegaly by oral bromocriptine. Tolis (1986) described the therapeutic efficacy of a somatostatin analogue in acromegaly. 

Prolactinomas respond best to pharmacotherapy. Bromocreptine, a dopamine agonist that suppresses prolactin production and release by the stimulation of dopamine receptors, has been proven safe and effective. Most patients respond to 2.5 mg three times daily; some large tumors may require up to 15 to 20mg daily. However, in certain cases, the dose may be decreased after achievement of adequate suppression. Surgery may be considered if adequate response is not achieved in three months. Following surgery, the hyperprolactinemia is often more responsive, requiring lower doses. Withdrawal of the drug results in recurrence in most patients. Some microadenomas do not recur.

Following adequate therapy, prolactin levels are usually lowered by over 80%; larger tumors may take longer. Menstruation begins within 6 months and in men, elevations in testosterone levels precede the normalization of semen analysis by several months. In most, a progressive in tumor over several years is observed; in some it may be dramatic and takes only days/weeks. Bromocreptine therapy induces cell shrinkage, and degenerative, necrotic, and fibrotic changes in the tumor. These changes are reversed after bromocreptine withdrawal.

Pregnant women with microprolactinomas rarely develop tumor expansion. However, in pregnant women with macroprolactinomas, the risk is about 15%, during all trimesters. Although surgery is recommended prior to conception, bromocreptine is an effective alternative, with no increased risk of congenital anomalies, spontaneous abortion, or multiple births.

Significant side effects include malaise, nausea, vomiting, and postural hypotension. Less commonly, headache, abdominal cramps, constipation, nasal congestion, and depression have been described. Rarely, CSF rihnorrhea  can occur.  The tumor may become fibrous and cause difficulty in surgery, if required. 

Pergolide is another equally effective dopaminergic agent and may be used in those who do not tolerate bromocreptine. Long acting, cabergoline, an ergoline derivative can be given biweekly. CV 205-502 (quinagolide), a nonergot dopamine agonist, is another long acting, effective agent. 

GH secreting adenomas exhibit a moderate growth and often present as macroadenomas. Most of them have mixed GH and prolactin hypersecretion. GH secretion is variable, and depends on activity. GH over-secretion results in elevated IGF-I levels that are fairly stable and better indicator.

Surgery is the best option, even in microadenomas.

Persistent elevation of GH or IGF-I levels requires pharmacotherapy or radiotherapy.

Somatostatin suppresses GH release from the pituitary and GHRH release from the hypothalamus. Octreotide, a short acting analogue, contains the active sequence of somatostatin. It is administered 50 to 100mg subcutaneously every 8 hours. The dose is gradually increased until adequate suppression. The majority  will need 300 to 600mg per day. The maximum recommended dose is 1500mg per day. About 80% of patients experience clinical improvement. Normally, IGF-I levels fall within a week. Plasma prolactin levels in mixed tumors are suppressed in about 50% of cases. The tumor is softened and facilitates surgery.

Several side effects have been reported. A transient decrease in gastrointestinal motility and slowed absorption occur in most patients. Steatorrheam, presumably due to a reduction in pancreatic enzymes is less frequent. Cholelithiasis due to suppression of cholecystokinin resulting in decrease bile flow is a concern. Gallstone formation occurs in about 50% pf patients on long term octreotide.

Lanreotide is a slow-release formutation somatostatin analogue. 

Dopamine agonists, such as bromocreptine, stimulate GH secretion in normal individuals. In contrast, in acromegalic patients, they suppress GH secretion in at least 50% through a PRL-dependent D-receptor mechanism. They are primarily effective in GH-secreting tumors that also secrete prolactin. Up to 20 to 30mg may be needed. Tumor reduction does not occur.

Few patients who do not respond to either octreotide or bromocreptine alone, respond to a combination of the two. 

ACTH-secreting pituitary adenomas are usually small and amenable for surgery alone. Macroadenomas are frequently invasive, requiring post surgical radiotherapy. Preoperatively and during the months required for radiotherapy to become effective, hypercortisolism needs to be controlled by medical therapy. Adrenolytic agent, mitotane is initiated at a dose of 0.5gms/day and increased to 4gm/day. Dexamethasone replacement therapy should be started to avoid adrenal insufficiency. Mineralocorticoids is usually not required. 20% of the patients may not respond and require an adrenal enzyme inhibitor, such as, aminoglutethimide, metyrapone, and ketoconazole,that usually controls the disease. 

TSH-secreting adenomas are rare and invasive macroadenomas. Octreotide and lanreotide has been a useful adjunctive therapy while awaiting radiotherapy effect. Preliminary reports of recent studies on pharmocotherapy of the GnRH antagonist Nal-Glu GnRH in gonadotroph-secreting adenomas have shown encouraging results.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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