Acromegaly and gigantism are disorders of growth hormone hypersecretion. The most common cause is a growth hormone (GH) secreting adenoma in the pituitary gland. Gigantism occurs when growth hormone hypersecretion occurs before the fusion of the long bone epiphysis and is characterized by tall stature. Acromegaly occurs when GH hypersecretion occurs after the fusion of the epiphysis leading to large extremities and characteristic facies. An elevated insulin-like growth factor-1 (IGF-1) level established the diagnosis. The first line of treatment is surgical excision of the tumor; however, this rarely results in a cure, and further medical treatment with somatostatin analogs or radiation is necessary.
In about 95% cases acromegaly and gigantism are secondary to a GH secreting adenoma in the pituitary gland. Growth hormone-releasing hormone (GHRH) secretion from a hypothalamic adenoma or ectopic GHRH secretion from lung or pancreas neuroendocrine tumors can also cause acromegaly. Rarely, ectopic growth hormone secretion secondary to abdominal and hemopoietic malignancies can cause acromegaly. Genetic syndromes which have been associated with GH hypersecretion are multiple endocrine neoplasia-1 (MEN-1), neurofibromatosis, Carney complex and McCune-Albright syndrome. Familial idiopathic pituitary adenomas (FIPA) which are due to aryl hydrocarbon protein interacting mutations can be associated with familial acromegaly. About 25% of cases with familial acromegaly present as teenagers with gigantism.
The prevalence of acromegaly is 60 per million population, and the incidence is 3 to 4 new cases per year per million population. There is no gender preponderance with equal incidence in males and females. The average age of presentation is 44 years with younger patient tending to have more aggressive disease. About 33% of cases of acromegaly have co-existent hyperprolactinemia.
GH is a 191 amino acid long protein with two disulfide bonds. It is secreted by the somatotroph cells in the anterior pituitary. It circulates for the most part as a 22kD protein and the remaining as a 20kD protein. It is secreted in a pulsatile manner, 4 to 11 pulses in a day. Due to this pulsatile nature of secretion measurement of random GH levels are not useful. Growth hormone-releasing hormone (GHRH) stimulates the release of GH from the pituitary. GHRH containing neurons are mainly seen in the arcuate nucleus and ventromedial nucleus. Somatostatin which is also secreted from the hypothalamus exerts an inhibitory action on the secretion of GH. GHRH and somatostatin also regulate each other's secretion in a paracrine manner. GH stimulates the synthesis of IGF-1 from the liver. IGF-1 is a 70 amino acid protein which is similar to insulin. Besides, post-receptor signaling mechanisms involving tyrosine kinase and insulin receptor substrate-1 (IRS-1) are also similar for IGF-1 and insulin. IGF-1 circulates bound to IGF-1 binding proteins. IGF-1 exerts a negative feedback mechanism through GHRH and somatostatin.
Several other hormones can also modulate the secretion of GH. Thyroid hormone facilitates the expression of the growth hormone gene. Hypothyroidism has been known to be associated with low GH and IGF-1 which are reversible with thyroid hormone replacement therapy. Gonadal hormones can also upregulate the secretion of GH as evident during the onset of puberty. Hypoglycemia decreases the secretion of somatostatin from the hypothalamus and increases the release of GH. Mutations in the somatotrophs is a prerequisite for the abnormal response to GHRH. Point mutations in Arg 201 and Gly227 have been reported which are the sites for adenosine diphosphate (ADP) ribosylation and the binding domain of guanine triphosphate (GTP) respectively result in adenyl cyclase activation similar to GHRH. The tumorigenesis which leads to a monoclonal cell expansion is multifactorial, and the presence of a mutation alone is not enough.
Densely Granulated GH Cell Adenomas
These constitute about 30% of GH secreting pituitary adenomas and are characterized by cells which are similar to somatotrophs and contain numerous large secretory granules. These are slow growing tumors which present in the middle age.
Sparsely Granulated GH Cell Adenomas
These constitute about 30% of GH secreting pituitary adenomas and are characterized by pleomorphic cells with few secretory granules. These are rapidly growing tumors which present with severe disease at a young age.
Mixed GH Cell and Prolactin Cell Adenoma
These are about 20% of GH secreting pituitary adenomas which are characterized by densely granulated somatotrophs and sparsely granulated lactotrophs. They secrete GH and prolactin.
Acidophilic Stem Cell Adenomas
These are rare tumors and are characterized by giant mitochondria. Clinically these are aggressive tumors which invade the surrounding structures. They also secrete GH and prolactin.
Mammosomatotroph Cell Adenoma
These comprise about 10% of GH secreting pituitary adenomas and are characterized by cells which secrete both GH and prolactin. They commonly occur in children and present with gigantism and hyperprolactinemia.
Plurihormonal Cell Adenomas
As the name suggests, these tumors secrete multiple hormones GH, prolactin, follicle stimulating hormone (FSH), Thyrotropin stimulating hormone (TSH), Adrenocorticotrophic hormone (ACTH), the secondary hormonal products may be silent.
Acromegaly is a very insidious disease where changes occur over many years. Consequently, studies have reported that the diagnosis is often delayed for about nine years on average. Patients may seek care for dental problems, cardiac or rheumatological issues before being referred to endocrinology.
GH secreting pituitary adenomas are often big (> 1 cm) and can have compressive symptoms in the form of visual field deficits, ophthalmoplegia, and headaches which are out of proportion to the size of the tumor. Co-existent hyperprolactinemia can result in galactorrhea and symptoms of hypogonadism (irregular periods in female and decreased libido in males).
Increased size of extremities: Enlargement of the hands and feet is noted secondary to both bony expansion and soft tissue swelling. Patients often appreciate an increase in ring and shoe size. The extremities have a "dough" like consistency due to the soft tissue swelling. There is a decrease in the shoe size and ring size with the treatment of acromegaly due to the resolution of soft tissue swelling; the bony changes, however, are permanent.
Hyperhidrosis and skin tags are present in about 98% of cases of acromegaly; these features are a sensitive sign for the detection of acromegaly. Skin tags are due to the epithelial cell hyperproliferation induced by GH.
Acromegalic facies: Prominent supraorbital ridge, broad nose, acne, large lips, overbite, prognathism, tongue enlargement and coarsening of facial features form the characteristic acromegalic facies. These changes, however, are very subtle and often go unrecognized by family members. Comparison of present and old photographs may show the gradual changes and is an essential part in the assessment of acromegaly.
Musculoskeletal: Generalized weakness and lethargy are common symptoms. Elongation of the jaw can lead to teeth malocclusion, temporomandibular joint pain and also a characteristic interdental separation. Carpal tunnel syndrome is seen about 60% of patients and is secondary to swelling of the median nerve rather than extrinsic compression. Early-onset osteoarthritis due to incongruent articular surfaces in the hips, knees, and spine may be seen. Kyphoscoliosis has also been reported in association with acromegaly.
Gigantism is very rare and should be suspected when the patient's height is 3 standard deviations above normal mean height or 2 standard deviations above the adjusted mean parental height. Since gigantism is associated with various syndromes like neurofibromatosis, Carney complex and McCune Albright syndrome evaluation for neurofibromas, cafe au lait spots, optic gliomas, and skin lentigines should be done.
Biochemical diagnosis: Measurement of IGF-1 level is the initial test for the diagnosis of acromegaly as it is a stable molecule with a half-life of 15 hours. It should be measured in cases where there is clinical suspicion of acromegaly and pituitary masses – normal IGF-1 rules out acromegaly. False positive IGF-1 levels can be seen in pregnancy and adolescence, and false negative levels may be seen with estrogen therapy. Furthermore, hepatic failure, renal failure, hypothyroidism, malnutrition, sepsis, and poorly controlled diabetes mellitus can also influence IGF-1 levels. All cases with elevated IGF-1 levels need to have an oral glucose tolerance test (OGTT) with GH measurement to confirm the diagnosis of acromegaly or gigantism. A GH level of 1 mcg/lt or less 2 hours after a 75 gms of oral glucose tolerance test rules out acromegaly. Plasma glucose needs to be measured before and after the administration of glucose to make sure hyperglycemia has been achieved.
Imaging: Pituitary Magnetic resonance imaging (MRI) is the preferred imaging modality for the diagnosis of acromegaly. The size, extent of the tumor, optic chiasmal compression, and cavernous sinus invasion can all be assessed on the MRI scan. Visual field testing is to be done in all cases where the tumor is in contact with the optic chiasma on the MRI scan.
Other tests: Prolactin levels need to be assessed especially in the presence of galactorrhea or symptoms of hypogonadism. Anterior pituitary hormonal assessment needs to be done based on the clinical picture. Rarely, in the presence of a normal pituitary and biochemically confirmed acromegaly GHRH levels and imaging of the chest and abdomen need to be done to evaluate ectopic GH or GHRH secretion.
The aims of treatment in acromegaly are:
There are three main modalities available for the treatment of acromegaly each with its advantages and disadvantages, surgery, medical therapy, and radiation. The decision to use these modalities is made on a case by case basis.
Surgical excision of the tumor is the preferred initial treatment unless the patient is deemed unfit for surgery. Surgery is also the preferred modality in recurrence as long as the tumor remains accessible. The transsphenoidal approach involves accessing the tumor by getting to the sphenoid sinus either through a nasal or sublabial approach and removing the sellar floor. Even tumors with suprasellar extension can be removed with this approach. Endoscopic transsphenoidal resection has better tumor clearance, decreased morbidity, and complications as compared to microscopic approach. Post-surgical complications include diabetes insipidus and anterior pituitary deficiencies.
IGF-1 and GH levels need to be measured 12 weeks after surgery. The goal is normalization of IGF-1 and an undetectable GH level.
Various medical therapies are available for the management of acromegaly. They are used in the treatment of persistent disease after surgery.
Radiation is often used as an adjunct for the treatment of persistent disease after surgery; rarely it may be used as a first-line treatment in patients unfit for surgery. Two commonly used radiation therapy modalities are external irradiation and stereotactic single high dose irradiation.
Acromegaloidism: This is a condition where the patients have acromegaloid facial features or tall stature, however, laboratory assessment of GH and IGF-1 are normal. Imaging of pituitary in these cases is unremarkable.
Soto's syndrome: This is a congenital overgrowth syndrome characterized by tall stature, acromegaloid facies, intellectual disabilities, macrocephaly, and advanced bone age. Other clinical features include neonatal hypotonia, congenital heart defects, strabismus, scoliosis and a predisposition to cancer. Soto syndrome is due to haploinsufficiency of NSD1 gene on chromosome 5. Laboratory assessment of IGF-1 and GH are normal. Genetic studies are needed to differentiate it from acromegaly.
Obstructive Sleep Apnea (OSA)
The prevalence of sleep apnea is 70% in patients with acromegaly. Prognathism, enlarged tongue and soft tissue accumulation in the upper airways all predispose to having OSA. Clinical assessment (Epworth score) and if needed polysomnography should be done and baseline and repeated every year. Surgical correction of prognathism may help, and referral to the maxillofacial surgeon should be considered.
Around 75% of patients with acromegaly are affected with arthropathy. Both small and large joints are affected. Bony expansion and soft tissue swelling can lead to nerve entrapment. Early diagnosis and aggressive treatment of acromegaly are essential to prevent arthropathy as these changes are irreversible.
Colon length is increased in acromegaly, and so are the mucosal folds. There is an increased prevalence of colonic polyps with acromegaly; however, the risk of colon cancer may or may not be increased. Patients should get a colonoscopy at baseline and every 5 years.
Hypopituitarism can occur as a result of surgery of radiation. Annual assessment of pituitary hormones and replace hormones as needed.
The management of acromegaly and gigantism is with a multidisciplinary team that includes an endocrinologist, neurosurgeon, internist, cardiologist, rheumatologist, pulmonologist and oncologist. Untreated acromegaly has increased mortality as compared to the general population. The major contributors to mortality are cardiovascular disease (60%), respiratory disease (25%) and malignancies (15%). Mortality rates are similar to the general population in patients with controlled GH secretion. Besides, the level of GH presence of cardiac disease is an important prognostic indicator. Presence of cardiac disease at diagnosis has a 100% mortality rate at 15 years. The mortality rate of patients with acromegaly and diabetes at 20 years is 80%.
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