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  • Updated 08.22.2022
  • Released 04.01.1995
  • Expires For CME 08.22.2025

Acromegaly and gigantism



Acromegaly is a disease characterized by the gradual enlargement of the peaked (acral) parts of the body, including the nose, lips, tongue, lower jaw, hands, and feet and by hyperplastic alterations in the entire osseous system. Gigantism occurs before epiphyseal closure. AIP gene mutations (AIPmut) often predispose to familial isolated pituitary adenomas with clinical features that may negatively impact treatment efficacy. The clinical picture of acromegaly is influenced by many factors, including the levels of growth hormone and insulin-like growth factor, age, tumor size, and delay in diagnosis. Surgical excision of the adenoma by transnasal transsphenoidal approach or by endoscopic endonasal transsphenoidal surgery is recommended. Pegvisomant is a medical therapy that blocks growth hormone action at peripheral receptors, normalizes insulin-like growth factor-1 levels, reduces signs and symptoms, and corrects metabolic defects.

Key points

• Acromegaly is characterized by the gradual enlargement of the acral parts of the body, with hyperplastic alterations in the entire osseous system due to growth hormone excess after epiphyseal closure.

• Gigantism occurs with growth hormone excess before epiphyseal closure.

• Acromegaly is usually diagnosed by increased insulin-like growth factor and growth hormone after an oral glucose tolerance test.

• For the treatment of acromegaly, surgical excision of the responsible pituitary adenoma by the transnasal transsphenoidal approach or by endoscopic endonasal transsphenoidal surgery is recommended. Alternatively, gamma knife therapy is an option.

• Pegvisomant, a growth-hormone-receptor antagonist, reduces signs and symptoms of acromegaly and corrects metabolic defects.

Historical note and terminology

Acromegaly. Acromegaly is a disease characterized by the gradual enlargement of the peripheral (acral) parts of the body including the nose, lips, tongue, lower jaw, hands, and feet and by hyperplastic alterations, particularly in the osseous system.

Acromegaly, the first recognized pituitary syndrome, was described by the French neurologist Pierre Marie (1853-1940) working under Jean-Martin Charcot (1825-1893) at the Salpêtrière Hospital in Paris (117).

Marie realized that many of the arthritic patients had an unusual enlargement of the hands and feet, which inspired the name he gave to this disorder (acromegaly literally means large extremities) (109; 135; 48; 50; 116). Marie's description was based on two cases of his own and five obtained from the literature dating back to 1722. Marie initially attributed the disorder to general nutritional disease but later attributed it to subnormal functioning of the pituitary. However, cases of gigantism and acromegaly were present long before the cases that Marie identified; ancient skeletons with these features have been identified, such as a Fifth Dynasty skeleton at Gyza, Egypt (124) and a Roman skeleton from the Imperial Age (122).

In the 1700s, several famous Irish giants made their living exhibiting themselves in Britain and across Europe. The skeletons of several of them were studied in detail, including Cornelius Magrath (1736-1760), Patrick Cotter (1760-1806), and Charles Byrne (1761-1783). Cornelius Magrath was born in Tipperary, Ireland. In 1752, he traveled to Cork for saltwater treatments to alleviate the pain of his rapid growth. With prodding there, he began exhibiting himself for pay. After touring England, he did short stints throughout Europe, including Germany and Venice, Italy, but while he was in Flanders, his health rapidly began to decline.

He returned to Ireland but died before he reached his 24th birthday. Although he had made friends with medical students from nearby Trinity College in Dublin, they stole his body the day he died. After dissection, his bones were preserved and controversially remain on display at Trinity College, despite numerous efforts to have them properly buried (54). Magrath's skeleton was studied in the late 19th and early 20th centuries, revealing a barrel chest, mild scoliosis, extraordinarily enlarged hands and fingers, and genu valgum (knock knees). The skull showed protrusion of the lower jaw (mandibular prognathism) and an underbite that caused some misalignment between the teeth (malocclusion). The internal view of the skull base showed marked enlargement and erosion of the sella turcica.

In 1895, English-American physician Woods Hutchinson (1962-1930) reported the case of a "French giantess," "Lady Aama," who was to be exhibited in a museum in Iowa City, Iowa in 1893, shortly before her precipitous death from "quick consumption" (tuberculosis).

The pituitary gland was not examined at the time of her autopsy, but the gland was later inferred to have been enlarged based on the enlargement of the pituitary fossa and the destruction of the sella turcica.

Pituitary fossa and frontal sinuses of "Lady Aama"

View of the interior of the cranium, showing the pituitary fossa and frontal sinuses of "Lady Aama." Note the enlargement and destruction of the sella turcica. (Source: Hutchinson W. A case of acromegaly in a giantess. Am J Med...

Hutchinson commented, anticipating a modern understanding of gigantism as beginning before epiphyseal closure:

The enlargement of the pituitary body would appear to be the principal pathological characteristic of this disease, as it has been found to be present in ten out of the twelve cases, hitherto reported, in which autopsies were held. Its probable size in this case would appear to conform pretty closely to the average hypertrophy reported... What connection, if any, exists between the acromegaly and the giantism? And although the facts at our disposal are so few that any speculation upon the subject must be purely tentative, yet one is tempted to string them together upon some sort of a theory. ... Would it not appear probable that at least one form of giantism is merely acromegaly beginning in foetal or infant life? And that the pituitary body has some title to be regarded as a "growth-centre" for the entire body (85).

By the end of the 19th century, acromegaly was recognized as a multisystem disorder that typically resulted from a tumor or abnormal growth within the anterior pituitary gland, associated with erosion of the sella turcica and abnormal secretory activity of a subset of chromophilic cells (22). Common features included progressive facial and bony deformation, that could then be documented with x-rays (ie, following the report of the discovery of x-rays by German physicist Wilhelm Conrad Röntgen [1845-1923] in December 1895). These findings are well illustrated by a male and female case of acromegaly from the end of the 19th century

and an early x-ray comparison of the hands of an acromegalic man and a large normal man (22).

Comparison of hand x-rays from acromegalic (left) and a normal "large male" (right)

On the left is the hand x-ray of a 38-year-old acromegalic man. "[W]hile the bones of the fingers are apparently of normal length, the fingers, because of the outlines of the soft tissue, appear to be short in proportion to the...

Pituitary surgery rapidly developed in the first decade of the 20th century. In 1906, British neurosurgeon Sir Victor Horsley (1857-1916) reported several successful temporal and frontal transcranial surgeries performed between 1904 and 1906 in 10 patients with acromegaly (84).

British neurosurgeon Sir Victor Horsley (1857-1916)

Photograph by British studio photographer George Charles Beresford (1864-1938). (Courtesy of the Wellcome Collection, London, United Kingdom. Public domain.)

In 1907, Austrian surgeon Hermann Schloffer (1868-1937) successfully resected a pituitary tumor by the transnasal-transsphenoidal route (141; 61; 113; 142).

Austrian surgeon Hermann Schloffer (1868-1937)

In 1907, Schloffer successfully resected a pituitary tumor by the transnasal-transsphenoidal route. (Source: Lindholm J. A century of pituitary surgery: Schloffer's legacy. Neurosurgery 2007;61(4):865-7; discussion 867-8.) (Pub...

In 1908, Austrian surgeon Julius Hochenegg (1859-1940) performed the first transsphenoidal approach for acromegaly (82; 50).

Austrian surgeon Julius von Hochenegg (1859-1940)

Hochenegg performed the first trans-sphenoidal approach for acromegaly in 1908. (Wikimedia Commons from: Haberer v. Sehr verehrter Herr Kollege Hofratvon Hochenegg! Deutsche Zeitschrift für Chirurgie 1929;2:219.)

Shortly thereafter, in 1909, American neurosurgeon Harvey Cushing (1869-1939) performed his first transsphenoidal operation for acromegaly in 1909 but switched to the transcranial route in the late 1920s (50)

American neurosurgeon Harvey Cushing (1869-1939)

(Courtesy of the Wellcome Library. Creative Commons Attribution 4.0 International license [CC BY 4.0].)

As early as 1909, Cushing deduced that the associated eosinophilic pituitary tumors are associated with states of hormonal overproduction and that the hypopituitarism that occurs concomitantly with some eosinophilic and chromophobe adenomas is due to compression of the remaining normal portion of the gland (41).

In the 1920s at the University of California at Berkeley, American anatomist and embryologist Herbert Mclean Evans (1882-1971), in collaboration with zoologist Joseph A Long, found that the injection of anterior pituitary extract caused gigantism in rats (60).

American anatomist and embryologist Herbert Mclean Evans (1882-1971)

The photograph is signed: "To Professor J[ack] C[ecil] Drummond with highest regard, Herbert M. Evans, Berkeley, Calif[ornia], Jan[uary] 11, 1927". Sir Jack Cecil Drummond FRIC, FRS {1891=1952) was a distinguished British bioch...

The impact of species specificity of growth hormone was clarified in 1957, and treatment with human growth hormone proved effective (112).

Pituitary gigantism. Gigantism refers to the increased linear growth in affected children when growth hormone levels are increased before epiphyseal closure. Historically, those affected by gigantism often wound up as sideshow performers in circuses. Some with gigantism and acromegaly were renowned for their superhuman strength and found work as cowboys and professional wrestlers.

In 1900, French internist Émile Charles Achard (1860-1944) reported a man, giant “K,” with gigantism, acromegaly, and diabetes; he stood approximately 6 feet 9 inches tall.

Man with gigantism, acromegaly, and diabetes

Man with gigantism, acromegaly, and diabetes (left), and French internist Émile Charles Achard (1860-1944) (right). The measuring rod is 200 cm (6 feet 7 inches). The man is approximately 6 foot 9 inches tall compared to the sh...

His hands were dramatically larger than those of a normal man, but the fingers were proportionately widened and appeared stubby, and the soft tissue was thickened. An extraordinary pituitary tumor was discovered at autopsy.

Another man with gigantism was (Joseph) Édouard Beaupré (1881-1904), Canada's tallest man. His height increased rapidly from age 3 years to around 21 years. His final height was variously given as from 2.40 meters (7 feet 10.5 inches) to 2.52 meters (8 feet 3 inches) with a weight of 166 to 170 kg (365-375 pounds). He was exceptionally strong and worked as a cowboy and as a sideshow performer. From age 17 (1897), he toured as “The Willow Bunch Giant” in circus side shows and at fairs throughout Canada and the United States. He was able to lift a horse weighing 363 kg (800 pounds) to shoulder height by crouching under it and extending his legs but he injured his back in an attempt to lift 408 kg (900 pounds). He died in 1904 at age 23 while he was performing at the “World’s Fair” held in St Louis, Missouri. The cause of death was pulmonary hemorrhage as a result of tuberculosis. After death, his body was displayed for money by a funeral parlor and then a museum before inclusion in the collection of the department of anatomy at the University of Montreal. A skull x-ray in 1967 showed an enlarged sella tursica (measuring 1.6 × 1.2 cm, or 0.6 × 0.5 inches) and overgrowth of the frontal bones (16; 17). Following a legal action, his body was returned to his relatives in 1989 and then cremated to prevent further exploitation and exposition.

John Aasen (1890-1938), also known as the “Minneapolis giant”, was an American silent film actor and sideshow performer who was one of the tallest actors in history. By 1917, he began his career as a circus sideshow performer who was known as “Johnny the Gent.” He started his acting career in 1922 and acquired a new nickname of “Harold Lloyd Giant”. Aasen is shown in this photograph standing next to a normal-sized man. Aasen's height has variously been reported from 2.68 meters to 2.74 meters (8 feet 9.7 inches to 8 feet 11.5 inches). Aasen never underwent pituitary surgery nor was he treated with pituitary radiotherapy. Just before his death, at age 46, he was measured during a medical evaluation at 7 feet 0.9 inches, but by this time he had lost some height due to aging and could not stand completely straight anymore. He died at age 48 from pneumonia. In June 2008, Loma Linda University confirmed that the 7-foot-2.4-inch (219 cm) skeleton they had in their collection was his.

American actor John Aasen suffered from gigantism

John Aasen (1890-1938), also known as the “Minneapolis giant”, was an American silent film actor and sideshow performer who was one of the tallest actors in history. (Picture from the collection of Wouter W de Herder. Source: (...

The tallest man who ever lived for whom there is irrefutable evidence was the American giant Robert Pershing Wadlow (1918-1940), also known as the Alton Giant and the Giant of Illinois. Wadlow reached 2.72 meters (8 feet 11.1 inches) in height, weighed 199 kg (439 pounds), and had a U.S. shoe size of 37 AA at the time of his death at age 22. His great size and his continued growth in adulthood were due to hyperplasia of his pituitary gland. He required leg braces to walk and had little feeling in his legs and feet. He became a celebrity after his 1936 U.S. tour, at age 18, with the Ringling Brothers Circus, with appearances at Madison Square Garden and the Boston Garden. During his circus appearances, he always appeared in the center ring (never in the sideshow), always wearing his regular clothes, and consistently refusing the circus's request that he wear a top hat and tails. In 1938, he began a promotional tour with the International Shoe Company, which provided him with free shoes. Wadlow considered himself as a celebrity who worked in advertising, not as a freak who was being exhibited. He possessed great physical strength until shortly before his death. He died of sepsis that resulted from an infection of his ankle brought on by chafing from a faulty brace.

American giant Robert Wadlow, the tallest man who ever lived

Front of a postcard of Robert Wadlow (left) with his average-size father (right). Robert Wadlow (1918-1940) was 2.72 meters (8 feet 11.1 inches) in height, weighed 199 kg (439 pounds), and had a U.S. shoe size of 37 AA at the t...

Perhaps the most famous acromegalic giant, certainly within living memory, was André René Roussimoff (1946-1993), better known as André the Giant. Roussimoff worked as a professional wrestler and actor. He was diagnosed with gigantism and acromegaly when he was in his mid-20s and wrestling professionally in Japan. By the late 1980s, Roussimoff was 7 foot 4 inches tall (224 cm) and then weighed 520 pounds, a result of gigantism caused by excess growth hormone, which later resulted in acromegaly. By this point, the features of acromegaly had become much more apparent. In 1988, he defeated Hulk Hogan (Terry Eugene Bollea) to win the World Wrestling Federation's World Heavyweight Championship. Outside of wrestling, he was best known for appearing as Fezzik the Giant in The Princess Bride, a 1987 American fantasy adventure comedy film. He declined medical treatment for his acromegaly that may have prolonged his life because he was worried it would adversely affect his professional wrestling career. He died of congestive heart failure at age 46. At that time, he wore a size 24 shoe and weighed 555 pounds.