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Acromegaly

Image: “Image from page 818 of ‘Physiology and biochemistry in modern medicine’ (1918), A, To show the appearance before the onset of acromegalic symptoms; B, The ap-pearance after seventeen years of the disease.” by Internet Archive Book Images. License: No known copyright restrictions


Definition and Overview of Acromegaly

Description

Acromegaly is a condition in which an adenoma within the pituitary gland produces excess growth hormone. Acromegaly is characterized by enlarged extremities and facial features, as well as joint pain and a protruding lower jaw. If the hormone-producing adenoma occurs in childhood, prior to growth plate fusion, the condition is referred to as gigantism.

Synonyms: acromegaly (ancient Greek for ‘extreme’ and ‘large’), gigantism, Pierre Marie’s disease.

Epidemiology of Acromegaly

In the United States, acromegaly has a prevalence of approximately 20,000 patients, and approximately 1,000–2,000 new cases of acromegaly are diagnosed each year. 

The median age of diagnosis of acromegaly is approximately 40 years. Even with advanced medicine, a lag of 9-10 years between the onset of acromegaly and its diagnosis is common. 

Life expectancy is shortened by about 10 years in patients with acromegaly due to malignant tumors. No significant differences in its incidence have been found between men and women. 

Etiology and Pathogenesis of Acromegaly

Growth hormone (GH) in acromegaly

Note: GH = growth hormone = somatotropic hormone = STH

GH is a peptide hormone produced in the adenohypophysis and secreted predominantly during sleep and during puberty. Production of GH is also affected by nutrition. GH has insulin-antagonistic, growth-stimulating, and anabolic (i.e.↑ intracellular integration of amino acids, ↑ protein synthesis) effects. The effects of GH are indirect and mediated via insulin-like growth factor (IGF-1) synthesis in the liver. Levels of GH increase during:

  • Hypoglycemia
  • Stress
  • Physical exertion

Note:

  1. GH is responsible for cell growth and mechanical signal propagation in the locomotor system and in connective tissue.
  2. GH increases gluconeogenesis in the liver and stimulates glucagon secretion.

Hormonal regulation

  • The hypothalamus produces GH-releasing hormone (GHRH), also known as somatoliberin; GHRH ⇒ stimulation of GH production.
  • The hypothalamus synthesizes GH-inhibiting hormone (GHIH), also known as somatostatin; GHIH ⇒ inhibition of GH production.
  • GH acts peripherally via IGF-1 produced in the liver. In acromegaly, there is no negative feedback mechanism for GH. For more information on feedback mechanisms, read the Hypothalamus Pituitary Adrenal Axis article.

GH-producing hypophyseal adenoma

GH overproduction in acromegaly is typically caused by a monoclonal pituitary adenoma. GH-producing tumors constitute 20% of all hypophyseal adenomas. In rare cases, acromegaly is induced by a decrease in somatotropin (GHIH) synthesis or an excess of GHRH. Undue secretion of GH leads to enlarged organs and extremities underlying the characteristic facial appearance.

Overproduction of GH in childhood, prior to growth plate fusion, results in a similar condition called gigantism. Afflicted patients are typically 6’6” tall. The characteristic malocclusion and enlargement of the temporomandibular joint are the domain of orthodontists and dentists, who are the primary consultants specializing in these abnormalities. 

Symptoms and Clinical Presentation of Acromegaly

Clinical symptoms of acromegaly are attributed to elevated stimulation of endochondral and appositional bone growth, increased stimulation of skin and skin appendages, and organ growth.

Children (before growth plate fusion) Adults (after growth plate fusion)
Hypophyseal gigantism > 6’6” Acromegaly, visceromegaly

Typical characteristics and symptoms of acromegaly

Facial aspect of a patient with acromegaly

Image: Facial aspect of a patient with acromegaly. By Openi, License: CC BY 2.0

  • Visceromegaly (visible organ enlargement, e.g., goiter formation)
  • Enlargement of osseous extremities
hand of a person with acromegaly (B) and a healthy woman (A)

Image: Hand of a healthy woman (A) and a person with acromegaly (B). By Openi, License: CC BY 2.0

  • Thickening of the dermis (pachydermia): hypesthesia, paresthesia
  • Macroglossia: enlargement of the tongue with dysphonia
  • Enlarged nose
  • Formation of supraorbital bulges
  • Separation of the teeth and broadened interdental grooves
  • Headache, fatigue, bone pain, increased perspiration

Note: Important anamnestic questions: Does your wedding band still fit? Has your shoe or hat size changed?

Possible complications of acromegaly

  • Cessation of residual adenohypophysis function overgrowth symptoms 
  • Visual field disturbances (bitemporal hemianopsia due to compression of optic chiasm)
Pituitary macroadenoma with suprasellar extension, compressing the optic chiasm

Image: Pituitary macroadenoma with suprasellar extension, compressing the optic chiasm. By Openi, License: CC-BY 2.0

  • Carpal tunnel syndrome due to connective tissue hyperplasia

Secondary complications in acromegaly

  • Sleep apnea (> 90% of patients are affected)
  • Diabetes mellitus
  • Secondary hypogonadism (women: secondary amenorrhea and menstrual cycle disturbances; men: loss of libido and potency), hyperprolactinemia, erectile dysfunction
  • Hypertension (30% of patients)
  • Spinal column and joint complaints
  • Increased incidence of colon and breast cancers

Diagnosis of Acromegaly

Acromegaly should be diagnosed as quickly as possible

Early detection can minimize the patient’s suffering and consequences. When acromegaly is suspected, ask the patient for an older picture, such as an old driver’s license, and compare facial features.

Laboratory studies

The secretion of GH varies by the time of the day. Therefore, single observations of GH are not useful for the diagnosis of acromegaly. The easiest diagnostic test is the oral glucose tolerance test (OGTT) with a parallel observation of serum GH. In acromegaly, GH levels are not suppressed to <1 μg/L.

Furthermore, hormone analysis will reveal pathologically high levels of IGF-1 and GH. Bound IGF-1 has a serum half-life of up to 18 hrs, which indicates that serum observation is sufficiently meaningful.

To exclude the presence of other hormone-producing adenomas of the adenohypophysis, levels of luteinizing hormone/follicle-stimulating hormone (LH/FSH), thyroid-stimulating hormone (TSH), prolactin, and adrenocorticotropic hormone (ACTH) are also tested. Complete or partial hypopituitarism is often observed in parallel with acromegaly.

Pathology

Microscopically, the tumors in acromegaly can be differentiated into sparsely-granulated (aggressive) and densely-granulated (less aggressive) types. In one-third of acromegaly cases, elevated secretion of prolactin (monomorphic, mono-cellular, mixed cell adenomas) is also observed.

Radiologic procedures

Sagittal MRI brain with enlarged pituitary and suprasellar cyst

Image: Pituitary macroadenoma with suprasellar extension, compressing the optic chiasm. By Openi, License: CC-BY 2.0

Patients with acromegaly show an enlarged sella turcica on skull X-ray, the nasal sinuses, and the heart. MRI is indicated for tumor screening.

Differential Diagnoses of Acromegaly

Diseases similar to acromegaly

GH disturbance without adenoma Hereditary acromegaly Further differential diagnoses
Pituitary hyperplasia MEN-1 syndrome Constitutional tallness
Ectopic/paraneoplastic GH-/GHRH-formation McCune-Albright syndrome Acromegaloid
Familial acromegaly Primary hypertrophic osteoarthropathy or pachydermoperiostosis
Carney complex

Treatment of Acromegaly

Surgical treatment

Trans-sphenoidal adenoidectomy via endonasal access is the current standard of care. This surgery is curative, resulting in an immediate decline in GH levels following complete tumor excision.

Note: GH levels declining below 2 µg/L indicate cure.

Final evidence suggesting successful tumor removal and cure in acromegaly is obtained several weeks after the surgery based on a renewed endocrinologic examination.

Radiation therapy

Inoperable tumors or incomplete resection warrant stereotactic radiosurgery, proton therapy, and conventional radiation therapy. The effect of radiation, however, is often not immediate but occurs after several years under specific circumstances. Furthermore, one must consider the risk of anterior pituitary insufficiency.

Therapeutic medication

Pharmacologic intervention is indicated for patients with inoperable acromegaly and refractory to transient radiotherapy. If the patient’s tumor is large, preoperative pharmacologic treatment may be useful to induce tumor shrinkage and improve the patient’s general constitution. All medications aim to inhibit GH secretion:

Drug group Effect Examples
Dopamine D2-receptor agonists Inhibition of GH production by the pituitary adenoma Bromocriptine, Cabergoline
GH receptor antagonists Normalization of the elevated IGF-1 level Pegvisomant
Somatostatin analogs Decreased size of the adenoma, normalized GH levels Octreotide, Lanreotide

Prognosis of Acromegaly

Lowered life expectancy 

The life expectancy of patients with acromegaly is shortened by approximately 10 years due to secondary complications. Lethality is twice as high and up to 4-fold higher than healthy individuals. The primary reasons for decreased life expectancy are usually hypertension, cardiovascular disease, and diabetes mellitus.

An Acromegaly Case Report

A 45-year-old man presented with the typical changes of acromegaly (i.e. enlarged nose, ears, lips, tongue, fingers, and toes). Endocrinology tests showed pathologically elevated GH levels; he was diagnosed with acromegaly. Subsequent magnetic resonance imaging (MRI) showed a small pituitary tumor with little contrast uptake, which suggested a GH-releasing adenoma.

The tumor was surgically removed by gaining access through the right nasal cavity and the sphenoidal sinus using a surgical microscope and endoscope. After the operation, GH levels returned to normal. A post-surgical MRI showed complete removal of adenoma with adequate visualization of the normal pituitary gland. Postoperative hormone tests revealed normal functioning of the remaining pituitary gland without the need for hormone replacement. Acromegaly was cured with surgical intervention alone.

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