IN THE NAME OF GOD ACROMEGALY
Growth hormone (GH) • Growth hormone is secreted by somatotrophs. • GH is a protein hormone consisting of a single peptide chain of 191 amino acids. • GH secretion is stimulated by the secretion of Growth Hormone Releasing Hormone (GHRH) by the hypothalamus. • GH secretion is inhibited by the secretion of somatostatin by the hypothalamus. • GH activates a tyrosine kinase receptor.
Physiologic Effects • Somatostatin acts by both endocrine and paracrine pathways to affect its target cells. A majority of the circulating somatostatin appears to come from the pancreas and gastrointestinal tract. • Effects on the Pituitary Gland • Somatostatin was named for its effect of inhibiting secretion of growth hormone from the pituitary gland. Experimentally, all known stimuli for growth hormone secretion are suppressed by somatostatin administration. • Effects on the Pancreas • Somatostatin appears to act primarily in a paracrine manner to inhibit the secretion of both insulin and glucagon. It also has the effect in suppressing pancereatic exocrine secretions, by inhibiting cholecystokinin -stimulated enzyme secretion and secretin-stimulated bicarbonate secretion. • Effects on the Gastrointestinal Tract • Effects on the Nervous System
Although the pituitary tumors associated with acromegaly are nearly always benign, the elevated GH and IGF-I levels lead to a wide range of cardiovascular, respiratory, endocrine, and metabolic morbidities.
Acromegaly is associated with increased morbidity and mortality, As a result, almost all patients should be treated, even those who are asymptomatic and those in whom the disorder does not seem to be progressing.
A number of co -morbidities are present in patients with acromegaly, including arthropathy , hypertension, obstructive sleep apnea (OSA), diabetes, cardiomyopathy, colon polyps, goiter, and headache . Successful treatment of GH/IGF-I hypersecretion will control these comorbidities to varying degrees.
COMPLICATIONS OF ACROMEGALY • Systemic • Cardiovascular • Iscaemic heart disease • Cardiomyopathy • Congestive cardiac failure • Arrythymias • Hypertension • Respiratory • kyphosis • obstructive sleep apnoea • CNS • stroke • Metabolic • Diabetes mellitus • Impaired glucose tolerance (insulin resistance) • Hyperlipidaemia (triglycerides) • Neoplastic • Colorectal • (breast and prostate - uncertain) • Skeletal • Degenerative arthropathy • Calcificdiscopathy • pyrophosphate arthropathy
DIAGNOSIS • Failure of normal suppression of serum growth hormone following administration of oral glucose remains the 'gold-standard' biochemical test. • 75 g of oral glucose is given at 9 am to the fasting patient and plasma glucose and serum GH levels are measured at baseline, 30, 60, 90 and 120 minutes thereafter. • In normal subjects, growth hormone levels suppress to undetectable values (typically <0.2 ng/ml), whilst in acromegaly serum growth hormone remains detectable or in approximately 20% of cases there is a paradoxical increase.
The goals of therapy in acromegaly are to lower the serum insulin-like growth factor-I (IGF-I) concentration to within the reference range for the patient's age and gender and to lower the serum GH concentration to <1 ng/mL (1 mcg/L) as measured by immunoradiometric or chemiluminescent assay after a glucose load.
IGF-1 OR GH The IGF-I criterion is probably better, since some patients who appear to have active disease clinically and by elevated IGF-I concentration have serum GH values that suppress to <1.0 ng/mL .Serum IGF-I concentrations also correlate better than serum GH with insulin sensitivity in patients with acromegaly .
When effective control of GH hypersecretion is achieved, serum GH and IGF-I concentrations decline to normal .the characteristic tissue overgrowth and related symptoms gradually recede, and the metabolic abnormalities, such as diabetes mellitus, improve. Unfortunately, restoration of completely normal GH secretion is not often achieved .
Even if the serum IGF-I returns to normal, bony abnormalities generally do not regress and joint symptoms persist.
MANAGEMENT OF ACROMEGALY • Transsphenoidal surgery • Pituitary Irradiation • Medical therapy • Dopamine agonists • Somatostatin analog • Growth Hormone Antagonists
TRANSSPHENOIDAL SURGERY Selective transsphenoidal surgical resection is the treatment of choice for patients with somatotroph adenomas that are small, large but still resectable, or large and cause visual impairment .
Transsphenoidal surgery is the treatment of choice for intrasellar microadenomas, noninvasive macroadenomas (i.e. those without cavernous sinus or bone invasion), and when the tumor is causing compression symptoms. In patients with intrasellar microadenomas, surgical removal provides biochemical control with normalization of IGF-I in 75–95% of patients. approximately 40–60%of macroadenomas are unlikely to be controlled with surgery alone.
a tumor at least 2 cm in diameter is associated with a greatly reduced success rate, Expertise in surgical management of acromegaly is very important neurosurgeon conducting at least 50 pituitary operations per year.
Surgery may also be considered for large adenomas that are not entirely accessible surgically (eg, tumors with cavernous sinus extension), with the goal of removing a sufficient mass of tissue to increase the options for subsequent adjuvant therapy. In this setting,perioperative medical therapy is typically used .
Contraindications to surgery include patient refusal, severe cardiomyopathy or respiratory disease, or the lack of an available skilled surgeon.
When transsphenoidal surgery is performed by the most experienced pituitary neurosurgeons, GH secretion falls to normal in about 80 to 90 percent of patients with microadenomas and pituitary secretion of other hormones is preserved.The success rate is lower in patients with macroadenomas and/or higher preoperative serum GH concentrations .
Serum GH concentrations typically fall to normal within one to two hours, depending upon the degree of elevation, after transsphenoidal surgery. Serum IGF-I concentrations often fall to normal in 7 to 10 days, but can remain high for several months before declining to normal.
There is a rapid diuresis, and soft tissue swelling and hyperglycemia can diminish remarkably in a few days. Vision, if impaired, and headaches can also improve in days and cartilaginous overgrowth in some joints diminishes. Sleep apnea also improves after transsphenoidal surgery.
Surgical cure goal is a serum IGF-I concentration normal for age and gender and a serum GH concentration less than 1 ng/mL or lower by immunoradiometric or chemiluminescent assay.
Recurrence Approximately 3 to 10 percent of patients in whom the operation is initially successful, as determined by normal basal and normal post-glucose serum GH concentrations, have a recurrence several years or more after surgery, probably due to incomplete adenoma resection. patients with even subtle abnormalities in post-suppression GH levels may have additional evidence of enhanced GH secretion and a greater risk of disease recurrence .
Long-term deficiency of one or more pituitary hormones has been reported in up to 70 percent of patients .Patients with acromegaly treated with both surgery and radiation are particularly prone to develop pituitary deficiency, Inappropriate glucocorticoid replacement for ACTH deficiency may also be an adverse determinant of long-term mortality in these patients.
MEDICAL THERAPY Several medications are now available for treating acromegaly, including some that inhibit GH secretion and one that inhibits its action. Pharmacologic treatment is used when surgery alone has not reduced serum GH and IGF-I to normal. Its role as primary therapy has not been clearly established .
Somatostatin receptor ligands As first-line therapy when there is a low probability of a surgical cure. After surgery has failed to achieve biochemical control. Before surgery to improve severe comorbidities that prevent or could complicate immediate surgery. To provide disease control, or partial control, in the time between administration of radiation therapy and the onset of maximum benefit attained from radiation therapy.
Somatostatin analogs Octreotide and lanreotide are analogs of somatostatin (growth hormone-inhibitory hormone) that inhibit GH secretion more effectively than native somatostatin because of their greater potency and longer plasma half-life (two hours versus two minutes).
Efficacy should be judged by normalization of the serum GH and IGF-I concentrations, which should eventually be followed by regression of the soft tissue manifestations of acromegaly and by shrinkage of adenoma size.
Octreotide - lanreotide Normalization of serum IGF-I concentration with somatostatin analogs occurs in 40 to 75 percent of patients. Somatostatin analog therapy leads to a reduction in adenoma size of about 20 to 50 percent in approximately 30 percent of patients .
pasireotide drug pasireotide LAR shows superior efficacy compared to Sandostatin® LAR® in Phase III trial of patients with acromegaly. Patients on pasireotide (SOM230) LAR were 63% more likely to achieve full biochemical control than those on Sandostatin LAR.
Therapy is associated with an improvement in the following clinical manifestations: • Soft tissue swelling, carpal tunnel syndrome, and snoring. • Insulin sensitivity – In diabetic patients treated with insulin, the insulin dose may need to be reduced substantially. • Sleep apnea also may improve over 2 to 12 months. • Left ventricular mass decreases and left ventricular function improves concomitantly with the fall of serum GH and IGF-I levels .
In a study published after the systematic review of 99 patients with acromegaly who received somatostatin analogs as primary therapy, 45 percent had normalization of serum IGF-I concentrations, and 44 percent had a significant degree (>50 percent reduction in size) of tumor shrinkage .