Gigantism and Acromegaly

Gigantism and Acromegaly brings together pituitary experts, taking readers from bench research, to genetic analysis, clinical analysis, and new therapeutic approaches. This book serves as a reference for growth hormone over-secretion and its diagnosis and treatment for endocrinologists, pediatricians, internists, and neurosurgeons, and for geneticists. Pharmaceutical companies may use it as a reference for drug development and research. Students, residents and fellows in medicine and endocrinology and genetics will also find it valuable as it provides a single up-to-date review of the molecular biology of gigantism and acromegaly as well as recommended approaches to evaluation and management.

Acromegaly is a rare pituitary disorder that slowly changes its adult victim’s appearance over time: larger hands and feet, bigger jaw, forehead, nose, and lips. Generally, a benign pituitary tumor is the cause and symptoms of acromegaly can vary from patient to patient, making a diagnosis difficult and prolonging suffering for years. Early detection is key in the management of acromegaly as the pathologic effects of increased growth hormone (GH) production are progressive and can be life-threatening as the result of associated cardiovascular, cerebrovascular, and respiratory disorders and malignancies.

• Accessible, up-to-date overview of the characteristics, state-of-the-art diagnostic procedures, and management of acromegaly and gigantism
• Provides a unique compendium of endocrinology, genetics, clinical diagnosis and therapeutics
• Contains contributions from internationally known experts who have treated patients with acromegaly and gigantism

• Language: English
• Publisher: Academic Press
• Release date: Jun 1, 2021
• ISBN: 9780128145388

Book preview

2016;103(1):5–6.

Chapter 1

History of the identification of gigantism and acromegaly

Liliya Rostomyan, Albert Beckers and Patrick Petrossians,    Service d’Endocrinologie, Domaine Universitaire du Sart Tilman, Université de Liège, Liège, Belgium

Abstract

Giants have always been a source of fascination, not only for the scientific community but also in the general population. Early medical reports included clear cases of acromegaly and acrogigantism. Pierre Marie used the term acromegaly for the first time in 1886 and linked it to a disease with characteristic clinical symptoms. In this chapter, the evolution of the knowledge of acromegaly is presented. Clinical description of individual cases and series of patients made aware of deformation and destruction of the sella, pituitary enlargement, and the presence of pituitary adenoma in acromegaly. Subsequently, the pituitary origin of acromegaly was suspected and supported by histopathological findings. Meanwhile, the etiopathological relation between acromegaly and gigantism was revealed. Indeed, a scientific breakthrough in the study of acromegaly and gigantism occurred during the 20th century when pituitary hormones and their metabolic effects were discovered. Further studies led to the understanding of the molecular basis and the pathophysiology of acromegaly and improved the management of the disease in different subpopulations of the patients.

Keywords

Acromegaly; giants; Marie’s disease; pituitary adenoma; growth hormone; history of medical knowledge

1.1 Historic times

Heroes with large body size and strong features appear in the myths and legends of almost all cultures. One of the oldest mentions of giants can be found in the Old Testament. The biblical Goliath of Gat (the legendary hero of the Philistines) was supposed to measure about 3 m (Fig. 1.1):

… And there came out from the camp of the Philistines a champion named Goliath of Gath, whose height was six cubits and a span …

Sam 17:4, English standard translation

Figure 1.1 David und Goliath. Source: Color lithography by Osmar Schindler, 1888.

A biblical cubit corresponds to 45–57 cm, and a span, 22–28 cm, according to different interpretations. The Jewish scriptures (Torah) in Deuteronomy, the fifth book of the Hebrew Bible, describe King Og the ruler of Bashan, whose height can be estimated as 3.5–4.0 m according to the description of his iron bed:

9 cubits long and 4 cubits wide

Deut. 3:11, English standard translation

Greek mythology describes in detail Giant characters, assigning them different roles. These include the children of Uranus and Gaia (Earth and Sky), predecessors of the Olympian gods, Titans, Cyclops, as well as mortal and deterrent Giants. Similar figures appeared later in many other cosmologies and mythologies like Gog and Magog in British legends, the Irish Fionn mac Cumhaill and the Norse Ymir.

The fossil findings, historical documents, and visual artworks in the museums hint about real historical personages with gigantism and acromegaly in past centuries. The images of the Egyptian pharaoh Akhenaten (Amenhotep IV) from the XVIII dynasty depict signs that could be related to the disease with typical acromegalic facial features, elongated mandible, enlarged lips, and thickened eyebrow arches (Fig. 1.2). However, one could not exclude that these features were the manifestation of a kind of artistic interpretation. Historical facts about the Roman emperor Gaius Julia Vera Maximinus, who ruled in Rome between CE 235 and CE 238, claim that his height was 2.60 m, that he had a large nose and chin, thick eyebrows, and a prominent forehead. Indeed, these features stand out in his images on ancient coins.

Figure 1.2 Relief of Head of Akhenaten by unknown artist, 18th Dynasty, c. 1350 BCE, Neues Museum, Staatliche Museen, Berlin. Source: Photo © bpk - Photo Agency / Ägyptisches Museum und Papyrussammlung, Staatliche Museen, Berlin.

Historical cases depicted in the visual arts have also been described. In the University Museum of Cultural History in Marburg in the Landgrave’s Castle, a portrait, dated 1583, features a 26-year-old woman with typical signs of acromegaly, who was probably the chambermaid of the second wife of Louis IV, Landgrave of Hesse-Marburg, Barbara Orth (Fig. 1.3). She was named Die große Barb (The big Barb) due to her height reaching 4 ells (a German length measure), the equivalent of 224 cm [1].

Figure 1.3 Die große Barb. Source: Oil on canvas by unknown painter, 16th century. The University Museum of Cultural History in Marburg, Germany.

There are notable giants whose size and feats of strength gained them the attention of kings and brought them to court. For example, the giant William Evans whose height was 2.29 m became a porter to King Charles I. A portrait of Cornish Giant Anthony Payne, who measured 2.24 m and was Sir Bevill Grenville’s bodyguard, was commissioned by King Charles II for his loyalty and bravery at the battle of Lansdowne in which Sir Bevill was killed. King of Prussia Frederick William I, known for his military approach to government, created his own army of giants (Giants from Potsdam) from which he recruited only men with a height exceeding 2 m.

At all times, individuals with outstanding body size and disproportionate features were distinguished by their unusual appearance and attracted the attention of the general public.

For centuries, many people with gigantism caught the spotlight of their contemporaries, becoming objects of popular contemplation, in particular as circus and theater attractions (Fig. 1.4). They wandered around Europe, earning money in performances. Among those were the Irish Cornelius Magrath (2.36 m), Charles Byrne (2.31 m), and Patrick Cotter O'Brien (2.44 m); the Russian Feodor Machnow (2.38 m); and the Chinese Chang Yu Sing (2.44 m). In 1880 the marriage of a couple of two famous circus giants Anna Swan (2.41 m) and Captain Bates (2.36 m) became an almost sensational event in the whole of Europe.

Figure 1.4 Charles Byrne, also known as the Irish Giant (1761–83), presented with the Knipe Brothers who also had gigantism and dwarfs. Three Giants with A Group of Spectators by John Kay in National Portrait Gallery Collection. Source: From Kay’s Originals Volume 1: A series of original portraits and caricature etchings by the late John Kay, with biographical sketches and illustrative anecdotes. Hugh Patton (1837).

1.2 First medical reports

In the past, no one suspected that what they were impressed by was actually a pathological condition that is associated with increased morbidity and mortality. The medical professionals, however, have long had a particular interest in the nature of the excessive stature of those individuals with gigantism. Early description of clinical symptoms and signs of acromegaly including cases with gigantism appeared since the 18th century in medical reports and in notes written by some patients [2,3].

The first medical case report on postmortem examination was done by Andrea Verga in 1864 [4]. He described a woman with what he called prosopectasia (Greek: prosopon—face, ektasis—enlargement), who had dysmorphic facial features. At postmortem examination, he found a destroyed sphenoid bone and displaced optic chiasm by a walnut-sized sellar tumor. A few years later, in 1877 the Italian Vincenzo Brigidi described similar changes, but he supposed that bone disease was the main cause of the disease [5].

The first medically credible recognition as a disease and the use of the term acromegaly (Greek: acro—limb, mega—great) comes from the French neurologist Pierre Marie in 1886 [6] (Fig. 1.5). In his report, Marie presented two cases of acromegaly and their autopsy descriptions. Pierre Marie was the first to question whether the observed pituitary enlargement is primary or secondary to the enlargement of other organs (visceromegaly) and skeletal deformation. In 1887 Oskar Minkowski, describing a case of acromegaly, first suspected the relationship of two elements: enlargement of the pituitary and acromegaly [7], but there was no experimental evidence to support this thesis. The results of autopsy of one of Maries’s cases by Broca demonstrated the enlarged sella [8]. In 1890 José Dantas de Souza-Leite included this case and several other available autopsy results in his thesis, where he definitively demonstrated pituitary enlargement in acromegaly [9]. With the advances in roentgenographic visualization of the bone structures inside the skull, Oppenheim demonstrated in 1901 an enlarged sella on X-ray in a patient with acromegaly [10].

Figure 1.5 Pierre Marie (1853–1940). Source: Photograph by Eugéne Pirou, Collection of portraits in Bibliothéque interuniversitaire de santé, Paris, France.

Over the next years, there were several more reports of similar cases. In light of earlier studies and his own observations, the Italian doctor Roberto Massalongo suggested that acromegaly and gigantism are part of the same pathological process caused by pituitary hypertrophy [11]. Finally, Brissaud and Meige claimed that gigantism and acromegaly are the same diseases, and gigantism is the acromegaly of the young [12]. Several detailed reports of acromegaly and gigantism cases ensued in the monograph by Launois and Roy, describing large pituitary lesions [13].

Further evidence for the pituitary etiology of the disease was obtained with a thorough examination of the skull of the giant Charles Byrne by Harvey Cushing showing the deformation and destruction of the sella turcica [14]. In 1909 Harvey Cushing performed partial hypophysectomy in a patient with acromegaly and concluded that pituitary surgery leads to remission of disease symptoms [15].

1.3 The discovery of the role of growth hormone

Many histopathological studies reported pathological changes in the pituitary, like the description of eosinophilic cells’ accumulation in the pituitary by Benda in 1900 [16]. In 1927 Cushing and Davidoff clearly established that acromegaly was the result of an eosinophil pituitary adenoma [17].

In 1921 Evans and Long demonstrated the presence of a growth-stimulating factor in the pituitary. In their experiment on rats, intraperitoneal administration of an extract of the anterior pituitary to animals caused changes similar to acromegaly [18]. These findings supported the idea that the cause of acromegaly is pituitary hyperfunction. Over the next 35 years, many studies followed, giving indirect evidence on the substance which stimulated growth. Thus the administration of an extract from the anterior pituitary gland of acromegaly patients was able to outline its metabolic activity and effects, in particular the induction of bone growth [19,20]. It was not until 1950 that Li and Papkoff, in California, and Raben, in Massachusetts, isolated human growth hormone (GH) from pituitaries collected at autopsy [21,22]. Five years later, with the advent of biochemical analysis with radioimmunoassay techniques, the GH serum concentrations were measured, and elevated GH levels in acromegaly patients was confirmed [23,24].

Along with the isolation of GH, there have been reports of a secondary substance that mediated the effects of GH. In their studies, Salmon and Daughaday showed that GH requires another compound for its action on skeletal tissue, in particular for the GH-dependent incorporation of sulfate into chondroitin sulfate [25]. This substance was initially called the sulfation factor. Furthermore, the elevated activity of this compound was also observed in serums of patients with active acromegaly, whereas its level generally came back to the normal ranges when the disease became inactive [26]. Subsequent studies expanded the effects of this GH-dependent plasma factor beyond cartilage sulfation and other metabolic actions were discovered. Due to its intrinsic insulin-like biological effects that could not be inhibited by antiinsulin antibodies, it was termed nonsuppressible insulin-like activity [27]. In 1972 it was considered a key mediator of GH action and the term somatomedin was proposed [28]. Purification and measurements of serum concentration of the basic peptide (somatomedin C) by radioimmunoassay followed, permitting a more accurate assessment of its activity in different clinical conditions, in particular acromegaly [29]. In 1978 when Rinderknecht and Humbel demonstrated that active somatomedins from human plasma display structural homology with proinsulin, they were finally renamed to insulin-like growth factors.

1.4 The discovery of hypothalamic regulation

In the late 1940s British physiologist and neuroendocrinologist Geoffrey Harris’ early research led to the concept of the neurohumoral regulation of the anterior pituitary by hypothalamus [30]. Further research included identification of the hypothalamic releasing factors released into the hypophyseal portal system by two groups, those of Drs. Andrew Schally and Roger Guillemin. Somatostatin was isolated, characterized, and sequenced in 1973 [31], while growth hormone–releasing hormone (GHRH) which was one of the first hypothalamic hormones to be sought [32,33] had to wait until 1982 to be discovered in a pancreatic tumor from an acromegalic patient [34–38]. Since then, exceptional cases of acromegaly have been reported due to hypothalamic or ectopic GHRH secreting tumors (gangliogliomas, pancreatic, and lung tumors), which constitute approximately less than 2% of all acromegaly cases