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At the Cutting Edge

Neuroendocrinology 2016;103:7–17 DOI: 10.1159/000371808

The History of Acromegaly

Wouter W. de Herder

Section of Endocrinology, Department of Internal Medicine, Erasmus MC, Rotterdam , The Netherlands

clinical disease with a characteristic clinical picture. He wrote (in French): ‘A condition characterised by hyper-trophy of the hands, feet and the face exists which we pro-pose to be called “acromegaly” which means hypertrophy of the extremities. In reality the extremities are swollen during the disease course and their increase in volume is the most characteristic feature of this disease. Acromeg-aly is different from myxoedema, Paget’s disease or leon-tiasis ossea of Virchow’ [1] .

However, Pierre Marie was not the first physician to give a full record of the clinical picture of acromegaly [2] . Others had preceded him already years before, like the Dutch physician Johannes Wier (1515?–1588) in 1567 ( fig. 2 ). He described (in Latin) a female giant he had seen in one of the earliest medical reports on this disorder: ‘Moreover in this treatise it is not proper that I should pass over a rare and memorable history, worthy of expla-nation. I saw a virgin who, because of the gigantic size of her body, travelled to cities in various regions and in those places exhibited herself in hired buildings to all who paid an offering, from which collections she and her mother sought a livelihood. I also, having entered [to see her], in-quired by diligent questions and I learned from her re-plies and those of her mother that she was born of parents both of whom were of short stature and that none of her ancestors exceeded the ordinary height of men and that this girl from the time of her birth to her twelfth year was of small stature: but at the time when she had reached her fourteenth year and had struggled with her menses for some time, they suddenly ceased and she began to in-crease in size, all of her members proportionately formed so that nothing seemed unusual. Unless I am mistaken, when I saw her she was in the twenty-fifth year from the

Key Words

Acromegaly · Gigantism · Growth hormone · Pituitary surgery

Abstract

Pierre Marie coined the term ‘acromegaly’ in 1886 and linked it to a distinct clinical disease with a characteristic clinical picture. However, Pierre Marie was not the first physician to give a full record of the clinical picture of acromegaly; others had preceded him, like the Dutch physician Johannes Wier. After Marie, pituitary enlargement was noted in almost all patients with acromegaly. Subsequently it was discovered that pituitary hyperfunction caused by a pituitary tumour was indeed the cause of acromegaly. The cause of acromeg-aly could be further determined after the discovery of growth hormone (GH) and insulin-like growth factor I (IGF-I) and af-ter demonstrating an association with GH hypersecretion and elevated circulating IGF-I. From the beginning of the 20th century, acromegaly could be treated by pituitary sur-gery and/or radiotherapy. After 1970, medical therapies were introduced that could control acromegaly. First, dopa-mine agonists were introduced, followed by somatostatin analogues and GH receptor blockers. © 2015 S. Karger AG, Basel

The First Medical Descriptions of Acromegaly and

Gigantism

In 1886, the French neurologist Pierre Marie (1853–1940; fig. 1 ) first coined the term ‘acromegaly’ (initially also known as ‘Marie’s malady’) and linked it to a distinct

Received: October 28, 2014 Accepted after revision: December 25, 2014 Published online: January 5, 2015

Prof. Wouter W. de Herder, MD, PhD Section of Endocrinology, Department of Internal Medicine Erasmus MC, ‘s Gravendijkwal 230 NL–3015 CE Rotterdam (The Netherlands) E-Mail w.w.deherder   @   erasmusmc.nl

© 2015 S. Karger AG, Basel0028–3835/15/1031–0007$39.50/0

www.karger.com/nen

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time she had noticed the cessation of her flowing. Nature required that bloody excrement to nourish and conserve so great a mass. She enjoyed good health in the meantime, her form was not attractive, her temperament was simple and stupid and her whole body was sluggish. The physical qualities which God had infused into her body in the be-ginning, while sufficient for a body of ordinary size, when dispersed afterwards in that vast mass of flesh could not show themselves with the same strength as they would in a body of ordinary size’ [3] . Meanwhile, as shown, Jo-hannes Wier also gave an interesting speculation as to the cause of her amenorrhea.

In 1772, the French surgeon Nicolas Saucerotte (1741–1841) gave to the French Academy of Surgery a report on a 39-year-old man with a good clinical description fitting with acromegaly [4, 5] . Other physicians had also given

the disorder different names. In 1822, the French derma-tologist Jean-Louis-Marc Alibert (1768–1837) called it ‘Géant scrofuleux’ [6] . In 1864, the Italian neurologist-psychiatrist Andrea Verga (1811–1895) called it ‘Proso-po-ectasia’ (enlargement of the face; fig. 3 ) [7] . He wrote (in Italian) a report on an acromegalic female he had seen: ‘Since 1860, while visiting the chronic patients admitted to the Church of Santa Maria ai Nuovi Sepolcri, one of the houses subsidiary to the Ospedale Maggiore di Milano, I had been impressed by the look of one patient [Maria B., born in Milan], whose waxen pallor and disproportion-ately large face was almost frightening. The personnel serving in this Hospital must have been similarly im-pressed, as they had nicknamed the woman “big-face”. Seeing that I was staring at her, she told me how she once had not been ugly and looked just like other girls’. This quote from a scientific paper again shows that notwith-standing their intelligence and respectful positions, these investigators-clinicians in the early years were far less sci-entific, critical and careful with respect to their, nowadays completely unacceptable, statements regarding the beau-ty and intelligence of patients suffering from acromegaly or gigantism [8, 9] . In 1862, the patient died at the age of 59 from typhus, and a post-mortem examination was per-formed by Verga. He found a walnut-sized sellar tumour with displacement of the optic nerves. The normal pitu-itary gland was not found. He discussed whether the nor-

Fig. 1. The French neurologist Pierre Marie described acromegaly for the first time in 1886. Collection: W.W. de Herder.

Fig. 2. Dutch stamp (PTT, 1960, creator: Hubert Levigne) depict-ing the Dutch physician Johannes Wier who for the first time gave a clear medical description of a disease which became later known as acromegaly/gigantism. Collection: W.W. de Herder.

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mal pituitary gland had disappeared because of the pres-sure from the tumour or whether the tumour itself was a degeneration of the gland. In 1868, the Italian criminolo-gist Cesare Lombroso (1835–1909) called the disorder ‘macrosomia’ [10–12] . In 1877, the French physician Henri Henrot (1838–1919) published an autopsy report on a patient with gigantism, in whom a sellar tumour was found [13, 14] . In 1877, the Italian physician Vincenzo Brigidi described the case, including the autopsy, of the acromegalic Italian actor Ghirlenzoni ( fig. 4 ) [15] . Vin-cenzo Brigidi wrote (in Italian): ‘... unfortunately, he [Ghirlenzoni] could not speak clearly, on account of the excessive size of his tongue ... the rest of the face had more the appearance of an ape than a man. It was lengthened, with very marked prognathism, flattened and indented laterally, as if the cheeks had been elevated by a blow from the hatchet on each side’ [15] . Ghirlenzoni attempted to drown himself, but was rescued. He was carried to the hospital delirious, lapsed into a coma and died the next day. Vincenzo Brigidi diagnosed the clinical condition as ‘rheumatitis deformans’. At autopsy, he found a hyper-trophied pituitary gland. He also performed the first mi-croscopic examination of a pituitary tumour [15] .

Finally, in 1886, Pierre Marie described two female pa-tients with acromegaly whom he had seen for Jean-Mar-tin Charcot (1825–1893) in the Pitié-Salpêtrière Hospital in Paris. The first case was that of a 37-year-old woman ( fig. 5 ). He wrote (in French): ‘... It was at the age of twen-ty-four, when her menstruation suddenly ceased, that she noticed the sudden increase in her hands. At this time her face also underwent changes … so that when the patient

returned home, none of her relatives could recognize her .... The whole feet are large, including the toes. Though the latter are increased in size, they have preserved their form, there is no true deformity, their appearance is sim-ply that of a very big person .... The tongue is enlarged .... The sight is also slightly defective .... The cranial vertex is of nearly the same size as the end of the chin. The lower jaw is well-developed ...’. He also wrote: ‘The patient’s thirst is intense and in order to satisfy this, it is obliging her to beg tea of her friends. The quantity of urine is enor-mous ...’ [1] . So, did Marie also report diabetes insipidus, or diabetes mellitus here? The second case was that of a 54-year-old woman. Marie wrote (in French): ‘The rims of the orbits are very thick, also the frontal eminences, making between them and the upper border of the malar bone a deep depression, … The nose is large. The lower jaw is very thick …’ [1] .

Acromegaly and the Pituitary

In 1886, Pierre Marie was not yet aware of any pitu-itary pathology in patients with acromegaly. In the fol-lowing years, he and his collaborators, the Brazilian neu-rologist José Dantas (de) Souza-Leite (1859–1925) and the Rumanian neurologist Gheorghe Marinescu (1863–1938) significantly contributed to the further knowledge on the clinical features and pathology of acromegaly by publishing many research papers [16–21] . Several au-thors had reported on the coexistence of sellar or pituitary enlargement in patients with acromegaly. However, it

Fig. 3. Skull of a 59-year-old female patient who suffered from ‘prosopectasia’ (acro-megaly) who was described by the Italian neurologist and psychiatrist Andrea Verga in 1864. Note the enlargement and destruc-tion of the sella turcica. [7] .

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was not clear whether this was the cause or the conse-quence of the disease. For a long period of time it was de-bated whether acromegaly and gigantism were due to (1) pituitary hypersecretion, (2) pituitary insufficiency, (3) no causative relationship with the pituitary at all, or (4) a disorder involved in nutrition. The famous Scottish sur-geon John Hunter (1728–1793) could have been the first to describe pituitary enlargement in gigantism/acromeg-aly, if only he would have opened the skull of the giant Charles Byrne of Littlebridge (Ireland; also known as Pat-rick O’Brien, 1761–1783, 2.31 m, 7 ft 7 in; fig. 6 ) whose remains came into Hunter’s possession after the death of the giant [22] . But, as stated by the American neurosur-geon Harvey W. Cushing (1869–1939), ‘his [John Hunt-er’s] passion as a collector exceeded his thirst for knowl-edge’ [23] . It was only until 1909, when Harvey Cushing together with the Scottish anatomist and curator of the John Hunter museum in London (UK), Sir Arthur Keith (1866–1955), opened the skull of Charles Byrne and dem-onstrated that the giant’s sella turcica was enlarged [23–27] . In 1887, the Lithuanian endocrinologist-diabetolo-gist Oskar Minkowski (1858–1931) reported that pitu-itary enlargement was found in all post-mortem studies of patients with acromegaly [28] . In 1892, the Italian phy-sician Roberto Massalongo could correlate acromegaly to increased pituitary function by demonstrating that a pi-tuitary tumour from a patient with acromegaly contained specific granulated cells [29] . By 1900, the German pa-thologist-physiologist-microbiologist Carl Benda (1857–1932) could determine from a series of normal and patho-logic pituitaries, that acromegaly is associated with an eo-sinophilic pituitary tumour [30, 31] . Finally, at the end of the 19th century, the relationship between a pituitary hy-perfunction-hypertrophy, or a hyperfunctioning pitu-itary tumour and acromegaly was clearly established and confirmed by many investigators [30–34] .

Acromegaly and Gigantism

Initially, it was also believed that acromegaly and gi-gantism were two totally different diseases. Pierre Marie [18–24] , his Brazilian intern José Dantas (de) Souza-Leite [16] and the French neurologist Georges Guinon (1859–1932) [35] were convinced that acromegaly and gigan-tism were two entirely different disorders. Gigantism was considered as an exaggerated variant of normal develop-ment, whereas acromegaly was considered as a patholog-ical condition. However, in 1884, Christian F. Fritsche (1821–1898) and the German pathologist T.A. Edwin

Fig. 4. Skeleton of the 64-year-old Italian actor Ghirlenzoni who suffered from ‘rheumatitis deformans’ (acromegaly) and who committed suicide in 1875 [15] .

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Klebs (1834–1913) [36] , supported by the work published in 1872 by the Austrian anatomist Karl Langer, Ritter von Edenberg (1819–1887) [37] , concluded that, in contrast to gigantism, which they considered as a congenital dis-order, acromegaly was an acquired variety of gigantism occurring at a later age when growth is completed.

In 1894, the Austrian internist Maximilian Sternberg (1863–1934) concluded that there were many similarities between acromegaly and gigantism [38] . However, in 1897 he changed his view and agreed with Pierre Marie and others that both disorders were different [39] . In 1891, the Scottish physician Daniel John Cunningham (1850–1909) pointed to the connection between acro-megaly and gigantism. He did so after having studied the skeleton of the Irish giant Cornelius Magrath (1736–1760, 2.26 m, 7 ft 5 in) from Tipperary. This skeleton is in the possession of Trinity college, Dublin [40–42] ( fig. 7 ). In

1893, the American neurologist Charles L. Dana (1852–1935) [43] and, in 1895, the English-born physician Woods Hutchinson (1862–1930) [44] concluded the same. In 1895, the French physician and pathologist Éd-ouard Brissaud (1852–1909) and the French neurologist Henry Meige (1866–1940) described the case report of the French acromegalic giant Jean-Pierre Mazas (1847–1901, 2.30 m, 7 ft 6½ in). They also concluded that acro-megaly and gigantism coexisted in the same person [45, 46] . Jean-Pierre Mazas was also known as ‘the giant of Montastruc’ from Monastruc, Haute-Garonne, France ( fig.  8 ). Édouard Brissaud and Henry Meige were, like Pierre Marie, both pupils of Jean-Martin Charcot at the Pitié-Salpêtrière Hospital in Paris. It gradually became evident that both disorders had the same pathogenetic mechanism but were different as to the age of onset. Gi-gantism would occur much earlier in life, when the skel-

Fig. 5. A 37-year-old woman with acromegaly who was described by Pierre Marie in 1886 [1] .

Fig. 6. The acromegalic Irish giant Charles Byrne, later also known as ‘Patrick O’Brien’ (2.31 m, 7 ft 7 in) next to his normal-sized tai-lor William Ranken. Etching (1803) by John Kay (1742–1826). Collection: W.W. de Herder.

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eton still had the potency to grow, a developmental phase we now call pre-pubertal [45–47] .

Finally, the cause of acromegaly and gigantism, a pitu-itary adenoma hyper-secreting growth hormone (GH), became known in the early years of the 20th century [48] . But even in the 21st century, scientific interest into gigan-tism (and Charles Byrne) has led to new discoveries. In 2010, Harvinder S. Chahal et al. [49] from the UK extract-ed DNA from a tooth of the skeleton of the Irish giant Charles Byrne in the Hunterian Museum at the Royal Col-lege of Surgeons in London and identified a germline mu-tation in the aryl hydrocarbon-interacting protein gene (AIP). Four contemporary Northern Irish families who presented with gigantism, acromegaly, or prolactinoma had the same mutation and haplotype associated with the mutated gene. Using coalescent theory, they came to the conclusion that these persons shared a common ancestor who lived about 57–66 generations earlier [49, 50] .

Four years earlier, Vierimaa et al. [51] from Finland discovered that AIP mutations accounted for 16% of pa-tients diagnosed with GH-secreting pituitary adenomas. AIP is a typical example of a low-penetrance tumour sus-ceptibility gene. More recently, it has been demonstrated that pituitary adenomas in patients with AIP mutations show clinical features that may negatively impact treat-ment outcomes. Furthermore, there is a predisposition for aggressive pituitary tumours in AIP mutation-posi-tive young patients with acromegaly, or gigantism [52] . Recently, microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism has been found. These microduplications are generated during chromo-some replication and contain 4 protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients’ pituitary lesions. This pediatric disorder was named X-linked acrogigantism (X-LAG) [53] . Interestingly, al-

Fig. 7. The skull of the Irish giant Cornelius Magrath (2.26 m, 7 ft 5 in). Note the enlargement and destruction of the sella turcica [40–42] .

Fig. 8. The acromegalic French giant Jean-Pierre Mazas, also known as ‘the giant of Montastruc’ (2.30 m, 7 ft 6½ in) [46] .

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ready in 1912, Harvey Cushing in his monograph The Pituitary Body and Its Disorders [54] had hinted at ‘Men-delian tendencies’ in 2 patients with familial gigantism (case XIII, surgical No. 27784, pp 89–92 and case XXXI, surgical No. 27011½, pp 158–162).

Pituitary Surgery

In 1892, the Italian pathologists Giulio Vassale (1862–1913) and Ercole Sacchi destroyed the pituitary using electric and chemical cauterization (via the transpalatal route) in cats [55] . They concluded that complete pitu-itary resection was invariably fatal, and later in 1894 they stated: ‘... the pituitary ... is vital to the organism. Its func-tion consists in the elaboration and endocrine secretion of a special product, necessary to the body’ [56] . Their work formed the basis of the hypophysectomy studies in dogs performed in the early 1900s by the Rumanian phys-iologist Nicolae C. Paulescu (1869–1931) [57] . His meth-odologies were successively adapted by the Austrian physiologist Bernhard Aschner (1883–1960) [58–61] , the British surgeons Handelsmann and Sir Victor A.H. Hors-ley (1857–1916) [62] as well as by Harvey Cushing [54] . These experimental studies also contributed to the under-standing of the pituitary in the regulation of thyroid, go-nadal, and metabolic function and growth. Harvey Cush-ing also introduced the terminologies ‘hyperpituitarism’

and ‘hypopituitarism’ and described some of their clinical features, including acromegaly, as well as the potential role of (neuro)surgery in these cases [54] .

Pituitary Surgery for Acromegaly

The first unsuccessful pituitary tumour removal using a temporal craniotomy in a male human patient with ac-romegaly and severe headaches was attempted in 1893 by the British neurosurgeons Sir Richard Caton (1842–1926) and Frank Thomas Paul (1851–1941). Unfortunately, the tumour was never reached successfully, but the patient improved from the subtemporal decompression [63] . Sir Victor Horsley reported several successful temporal and frontal transcranial surgeries performed in 10 patients with acromegaly between 1904 and 1906 [64] . In 1907, the Austrian surgeon Hermann Schloffer (1868–1937) re-ported the successful resection of a pituitary tumour via the transnasal-transsphenoidal route [65] . One year later, the Austrian surgeon Julius (von) Hochenegg (1859–1940; fig. 9 ) performed the first transsphenoidal approach for acromegaly [66] . His reputation reached across the At-lantic. The New York Times of May 10, 1908 reported: ‘ACROMEGALY CURED; Successful Operation Per-formed by Prof. Hochenegg of Vienna. Berlin, May 9. American surgeons, who by the reluctant consent of their European confrères are now ranked at the top of their pro-

Fig. 9. The Austrian surgeon Julius (von) Hochenegg who performed the first trans-sphenoidal approach for acromegaly in 1908. Collection: W.W. de Herder. Fig. 10. The French radiotherapist Antoine Béclère, a pioneer in the field of pituitary radiotherapy. Collection: W.W. de Herder.

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fession, will be interested in the brilliant achievement re-ported at last week’s surgical congress in Berlin by Prof. Hochenegg of Vienna. The professor told how he oper-ated successfully in a case of acromegaly, a disease which causes strange and enormous enlargements of the bones of the hands, feet, and face. The patient on whom the op-eration was performed was a young girl. She showed the usual symptoms of brain tumours and a marked distur-bance of her vision. The diagnosis having been confirmed by means of X-rays, Prof. Hochenegg moved the girl’s nose to one side, cut through the thin floor of the skull, and then removed the tumour from the hypophysis or gland-like body that is suspended like a cherry from the base of the brain. The difficulty in reaching the acromega-lian tumour is such that surgeons have been rather shy of operating for the disease. It is said, too, that none of the operations reported prior to last week was successful; but the Vienna girl left the hospital 6 weeks after Prof. Ho-chenegg’s operation with her health fully restored. Acro-megaly is not infrequently encountered in the United States, but heretofore, the Germans say, it has baffled American surgical skill’.

Harvey Cushing performed his first transsphenoidal operation for acromegaly in 1909 but abandoned it in the late 1920s in favour of the transcranial route. Most neu-rosurgeons followed him. However, the Czech-born ear, nose and throat surgeon Oskar Hirsch (1877–1965) and the Scottish neurosurgeon Norman McOmish Dott (1897–1973) continued to advocate the transsphenoidal approach and this technique revived in the 1960s [67] .

Modern advances in the development of pituitary sur-gery came with the adaptation of the surgical microscope and televised fluoroscopy by the Canadian neurosurgeon Jules Hardy (1932) followed by the development of endo-scopic techniques [68, 69] . The origin of intraoperative MRI for neurosurgery was the Magnetic Resonance Ther-apy Unit at Brigham and Women’s Hospital in Boston, Mass., USA [70] and was further developed in Germany for application in pituitary surgery [71] .

Pituitary Radiotherapy for Acromegaly

In 1909, the French radiotherapist Antoine Béclère (1856–1939; fig.  10 ) first reported that some local tu-mour-related symptoms (headaches, visual disturbanc-es) were improved by repeated radiotherapy in a young female with acromegaly/gigantism [72] . Simultaneously, similar results were reported by another French radio-therapist, A. Gramenga [73] . During the early 1900s, ra-

diotherapy continued to be the first choice therapy for acromegaly, especially since at that time pituitary surgery was associated with high intra- and post-operative mor-bidities and mortality. Over time, dosing schedules and dose intervals changed. In 1953, the International Com-mission on Radiological Units and Measurements intro-duced the concept of absorbed dose and defined its unit: the rad. After 1960, the SI unit for absorbed dose was called gray. Besides fractionation, also the radiation sources changed with the introduction of linear accelera-tors in the 1960s. Initial techniques involved the two lat-eral opposed field technique, which was replaced by the three-field technique and this was replaced by non-co-planar 3D stereotactic radiation techniques in the 1990s. Other developments involved proton beam radiosurgery first introduced in 1951 by the Swedish neurosurgeon Lars Leksell (1907–1986) [74] and gamma knife technol-ogy [75] . Nowadays, pituitary radiotherapy only plays a minor role in the treatment of acromegaly and gigan-tism.

Biochemical Diagnosis of Acromegaly and Other

Pituitary Conditions

GH was isolated and its molecular structure was deter-mined in 1945 by the Chinese-born American chemist Cho(h) Hao Li (1913–1987) in the laboratory of the American anatomist and embryologist Herbert McLean Evans (1882–1971) [76] .

The British (neuro-)endocrinologist Geoffrey W. Har-ris (1913–1971; fig. 11 ) demonstrated that pituitary secre-tion was controlled by the hypothalamus via releasing factors that were transported from the hypothalamus to the pituitary by the portal blood via the pituitary stalk [77] . In the 1950s-1970s, the research groups of the Pol-ish-American physiologist Andrew V. Schally (1926) and the French-American physiologist Roger C.L. Guillemin (1924) identified several hypothalamic factors, including GH-releasing hormone and somatostatin. The Nobel Prize in Physiology or Medicine 1977 was divided be-tween Rosalyn Yalow (1921–2011) ‘for the development of radioimmunoassays of peptide hormones’ and the oth-er half jointly to Roger Guillemin and Andrew Schally ‘for their discoveries concerning the peptide hormone pro-duction of the brain’ [78–80] . The American endocrinol-ogists William D. Salmon Jr. (1927–2009) and William Daughaday (1918–2013) demonstrated that sulphate up-take into cartilage from hypophysectomised rats could not be influenced directly by GH, but the addition of se-

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rum from normal rats, or serum from hypophysect-omised rats treated with GH resulted in increased sul-phate uptake [81] . This concept of a circulating ‘sulpha-tion factor’ that was induced by GH and that mediated the effects of GH in peripheral tissues was named the ‘so-matomedin hypothesis’ in the 1970s [82] . Somatomedin C was shown to mediate GH action. In 1979, a radio-immunoassay for this peptide had been developed for monitoring disease activity in acromegaly [83] . The Swiss endocrinologist E. Rudolf Froesch (1929–2014) and his colleagues had observed that a significant proportion of serum insulin-like activity was not suppressed by anti-insulin antibodies [84] . This ‘nonsuppressible insulin-like activity’ was due to insulin-like growth factors (IGFs) I and II. In the 1980s, it was shown that somatomedin-C and IGF-I were two names for the same peptide [85, 86] . The great majority of circulating IGF-I is bound to one of six binding proteins (IGFBP), named IGFBP-3. These binding proteins were identified in the 1980s–1990s with a prominent role for the research groups of the Australian scientist Robert C. Baxter and British scientist Jeffrey M.P. Holly [87, 88] .

The Czech-American scientist Ladislav Krulich (1925–2005), together with the research group of the American scientist Samuel M. McCann (1925–2006), discovered a hypothalamic factor that inhibited the secretion of GH in 1968 [89] . In 1973, the Canadian scientist Paul Brazeau

and collaborators in the research group of Roger Guille-min could successfully isolate a hormone from sheep hy-pothalami which could inhibit the release of GH and which was named somatostatin [90] .

In the 21st century, biochemical screening for acro-megaly/gigantism is performed using IGF-I assays, con-firmation of the diagnosis is made by a non-suppressible GH after an oral glucose load and some also monitor IGFBP-3 levels.

Medical Therapies for Acromegaly

After the discovery that pituitary secretion of GH and prolactin was under the influence of dopaminergic path-ways, dopamine agonists were introduced as medical therapies for acromegaly. In the 1970s, G. Michael Besser (1936) started using the dopamine agonist Bromocriptine (CB-154) for controlling active acromegaly [91] Later, other dopamine agonists, like Quinagolide (CV 205–502) [92] and Cabergoline [93] , proved to be more effective than Bromocriptine in controlling the pathologic GH hy-persecretion.

After the identification of the GH release-inhibiting hypothalamic peptide somatostatin by Roger Guillemin and Paul Brazeau, it soon became clear that this peptide displayed a much wider activity of hormone release-in-hibiting actions [94] . In 1978, the American endocrinolo-gist Wylie W. Vale (1941–2012) and his colleagues re-ported on a short octapeptide somatostatin analog with full somatostatin biological activity [95] . A new molecule, Octreotide (SMS 201–995), was developed by the Swiss chemist Wilfried Bauer and collaborators [96] . In 1988, Octreotide was registered by the Food and Drug Admin-istration (FDA) for the treatment of acromegaly [97] . Re-cently, Pasireotide (SOM230), a multi-ligand somatosta-tin analog, has demonstrated superior efficacy over Oc-treotide in acromegaly [90] .

In the early 1990s, the research group of the American molecular biologist John Kopchick (1950) was working on the development of GH receptor antagonists [98] . The mechanism by which these GH antagonists act is by failing to induce ‘proper = functional’ GH receptor di-merization. This finally led to the development of a pe-gylated (to increase the drug’s half-life in the circulation) GH receptor antagonist initially named B2036 PEG [98] . This new drug, later named Pegvisomant, proved to be very successful in the treatment of acromegaly and is currently used as monotherapy or in combination with other drugs for the treatment of refractory acromegaly

Fig. 11. The British (neuro-)endocrinologist Geoffrey W. Harris, a pioneer in the field of neuroendocrinology. Collection: W.W. de Herder.

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[99–101] . In the 21st century, it is possible to control the pathologic GH secretion in >90% of patients with acro-megaly or gigantism with drugs. New developments in this field are the development of receptor-specific and/or multiligand somatostatin analogs, chimeric drugs with affinities to both somatostatin and dopamine recep-tor subtypes and super-long acting somatostatin ana-logs.

Disclosure Statement

No funding was acquired for this work. The author has no con-flicts of interest with regard to this paper.

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