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Gigantism and Acromegaly Treatment & Management

  • Author: Alicia Diaz-Thomas, MD, MPH; Chief Editor: Stephen Kemp, MD, PhD  more...
 
Updated: Jan 06, 2015
 

Approach Considerations

Most experts define cure, or adequate control, of growth hormone (GH) excess as a glucose-suppressed GH concentration of less than 2 ng/mL, as determined by radioimmunoassay (1 mcg/L by IRMA), and normalization of the serum insulinlike growth factor I (IGF-I) concentration.

However, no single treatment modality consistently achieves control of GH excess. For pituitary adenomas, transsphenoidal surgery is usually considered the first line of treatment, followed by medical therapy for residual disease.[5] Radiation treatment usually is reserved for recalcitrant cases.

Radiotherapy and medical treatment are important because in long-term studies, surgery has been found to cure only approximately 60% of patients with acromegaly.[24] Slow-release formulations of somatostatin are now widely used (including as a primary treatment) and appear to be safe and effective in 50-60% of the patients. A GH-receptor blocking agent, pegvisomant, appears to normalize IGF-I levels in almost all patients.

Guidelines released by the US Endocrine Society in 2014 address important clinical issues regarding the evaluation and management of acromegaly.[25, 26] Recommendations include the following:

  • For most patients with acromegaly, surgical removal of the pituitary gland tumor should be considered the primary treatment
  • An imaging study should be performed at least 12 weeks postsurgery to determine whether any residual tumor tissue is present
  • Patients should be evaluated for any damage caused by the pituitary tumor and for the development of hypopituitarism
  • Medical therapy should be administered only to patients with persistent postoperative disease

The guidelines also address the management of women with acromegaly who are pregnant or trying to conceive.

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Pharmacologic Therapy

The goals of medical therapy for GH excess are as follows:

  • Remove or shrink the pituitary mass
  • Restore GH secretory patterns to normal
  • Restore serum total IGF-I and IGF binding protein 3 (IGFBP-3) levels to normal
  • Retain normal pituitary secretion of other hormones
  • Prevent recurrence of disease

Somatostatin and dopamine analogues and GH receptor antagonists are the mainstays of medical treatment for GH excess and are generally used when primary surgery fails to induce complete remission.

Somatostatin analogues

The most extensively studied and used somatostatin analogue, octreotide, binds to the somatostatin receptor subtypes II and V, inhibiting GH secretion. Octreotide suppresses the serum GH level to less than 2.5 mcg/L in 65% of patients with acromegaly and normalizes circulating IGF-I levels in 70% of patients. Tumor shrinkage, although generally modest, is seen in 20-50% of patients. Consistent GH suppression was achieved with a continuous subcutaneous pump infusion of octreotide in a pubertal boy with pituitary gigantism.

Studies of patients with GH excess for longer than 14 years have demonstrated that the effects of octreotide are well sustained over time. An anaphylactic reaction to octreotide has been described.[27]

Primary treatment with depot octreotide and lanreotide has been found to induce tumor shrinkage in newly diagnosed acromegaly.[6]

Long-acting formulations, including long-acting octreotide, lanreotide, and pasireotide, have been demonstrated to produce consistent GH and IGF-I suppression in patients with acromegaly with once-monthly or biweekly intramuscular depot injections. (Sustained-released preparations have not been formally tested in children with gigantism.)

In 2 Japanese studies, by Shimatsu et al, the sustained-release lanreotide Somatuline Depot (or lanreotide Autogel) was found to control elevated GH and IGF-I levels within the first weeks of treatment, as well as over a long-term period of administration. In an open-label, parallel-group, dose-response study, which included 29 patients with acromegaly and 3 with pituitary gigantism, 5 injections of lanreotide Autogel were administered over a 24-week period, in dosages of 60, 90, or 120 mg.[28]

At week 4, serum GH levels of below 2.5 ng/mL and normalized IGF-I levels were found in 41% and 31% of patients, respectively. At week 24, the investigators found that serum GH levels of below 2.5 ng/mL and normalized IGF-I levels had been attained in 53% and 44% of patients, respectively.[28]

In the second investigation, an open-label, long-term study of 30 patients with acromegaly and 2 with pituitary gigantism, lanreotide Autogel injections were administered every 4 weeks for a period of 52 weeks (13 injections). Patients initially received a 90-mg dose, which was subsequently adjusted based on clinical response. At week 52, serum GH levels of below 2.5 ng/mL and normalized IGF-I levels had been achieved in 47% and 53% of patients, respectively.[28]

Pasireotide’s approval was based on 2 multicenter, phase 3 studies. One in medically naive patients with acromegaly who had prior surgery or in whom surgery was not an option, and the other in patients inadequately controlled on first-generation somatostatin analogs (ie, octreotide, lanreotide). The risk for hyperglycemia needs to be considered with use of pasireotide.[29, 30]

Dopamine-receptor agonists

Dopamine-receptor agonists (eg, bromocriptine, cabergoline) bind to pituitary dopamine type 2 (D2) receptors and suppress GH secretion, although their precise mechanism of action remains unclear.

Prolactin levels are often adequately suppressed with these agents. However, circulating GH and IGF-I levels rarely normalize with this therapy. Less than 20% of patients achieve GH levels of less than 5 ng/mL, and less than 10% achieve normal IGF-I levels. Tumor shrinkage occurs in a few patients.

Dopamine-receptor agonists are generally used as adjuvant medical treatments for GH excess, and their effectiveness may be added to that of octreotide.

Although long-acting formulations are available, no data about the long-term control of GH and IGF-I with these agents are available.

Bromocriptine

Bromocriptine has an adjunctive role in the treatment of patients with GH excess who fail to achieve a cure by surgical treatment or who are to be treated with radiation. It has limited effectiveness, however, reducing the circulating GH level to less than 5 ng/mL in only 20% of patients with acromegaly and normalizing IGF-I concentration in only 10% of these patients. Shrinkage in tumor size also occurs, albeit in fewer than 20% of patients. Patients in whom prolactin is elevated are more likely to have a favorable response to bromocriptine.

Cabergoline

Cabergoline, another dopamine-receptor agonist, is somewhat more effective than bromocriptine in reducing GH levels, with response rates of 46%. A meta-analysis found that cabergoline used as single-agent therapy in patients with acromegaly normalized IGF-I levels in one third of patients.[31] In those cases in which a somatostatin analogue has failed to control acromegaly, cabergoline adjunction normalized IGF-I levels in about 50% of gases.

GH-receptor antagonists

Tests of pegvisomant (Somavert), a novel hepatic GH-receptor antagonist, demonstrated effective suppression of GH and IGF-I levels in patients with acromegaly due to pituitary tumors or ectopic GHRH hypersecretion.

Normalization of IGF-I levels occurs in as many as 90% of patients treated daily with this drug for 3 months.

In the interim analysis of ACROSTUDY, a global noninterventional surveillance study of 1288 patients with acromegaly treated with pegvisomant for a mean period of 3.7 years (2.1-y mean follow-up), 63.2% of subjects had normal IGF-1 levels at a mean dose of 18 mg/day. The reported incidence of transaminitis, lipodystrophy, and increase in pituitary tumor size was low.[32]

Combination therapy with pegvisomant and cabergoline or somatostatin analogues is also being investigated for efficacy.[33]

Pegvisomant has not been formally tested in children; however, a case study described normalization of IGF-1 in a 12-year-old girl with pituitary gigantism treated with pegvisomant 20 mg/day.[34]

Radiation Therapy

In general, radiation therapy is recommended if GH hypersecretion is not normalized with surgery. Radiation prevents further growth of the tumor in more than 99% of patients after surgical resection.

However, radiation treatment takes to years reduce/normalize GH/IGF-I levels.[35] About 60% of patients have a GH concentration of less than 5 ng/mL 10 years after radiotherapy.

Hypopituitarism is a predictable outcome of radiation treatment, occurring in 40-50% of patients within 10 years after irradiation. Some studies suggest that radiation is associated with the development of secondary tumors.

Newer modalities (eg, stereotactic fractionated radiotherapy, proton beam therapy) may have the advantage of a better target dose-conformation, but long-term outcome data are lacking at this time.[36]

Stereotactic gamma-knife radiosurgery for recurrent or residual pituitary adenomas, when combined with microsurgery, is often effective in controlling pituitary adenoma growth and hormone hypersecretion.[37] Results are influenced by many factors, including adenoma histology, adenoma volume, and radiation dose.

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Transsphenoidal Surgery

The primary goal of surgery is to normalize GH levels. For well-circumscribed pituitary adenomas, transsphenoidal surgery to completely remove the tumor is the treatment of choice, and it may be curative. The procedure can also rapidly improve symptoms caused by mass effect of the pituitary tumor. The following should be kept in mind concerning surgical treatment:

  • The likelihood of a surgical cure greatly depends on the surgeons' expertise and on the size and extension of the mass
  • Intraoperative GH measurements can improve the results of tumor resection
  • Transsphenoidal surgery to resect tumors is as safe in children as it is in adults
  • A transcranial approach is sometimes necessary

As determined by using the GH assays available to date, GH levels should be normalized (< 1 ng/mL for ≥50% of the points measured during the day) in all patients. Because this change is impractical to test, however, GH levels (< 1 ng/mL within 2 h after a glucose load) and serum IGF-I levels (within 2 standard deviations of the reference range adjusted for age, sex, and Tanner stage) are the best measures of a biochemical cure.

A remission rate of 80-85% can be expected for microadenomas and 50-65% for macroadenomas.

The postoperative GH concentration may predict remission rates. According to the results of one study, a postoperative GH concentration of less than 3 ng/dL was associated with a 90% remission rate, which declined to 5% in patients with a postoperative GH concentration of greater than 5 ng/dL.

A significant proportion of acromegalic patients who have undergone surgery have been found to have a change in biochemical status upon long-term follow-up. Most of these changes have occurred within the first postoperative year and were more likely to occur if the initial GH postglucose and IGF-I levels were discordant.[38]

If surgery does not normalize GH secretion, options include pituitary radiation and medical therapy.

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Long-Term Monitoring

All patients with a history of GH excess require periodic, lifelong evaluation. In one series, the long-term recurrence rate for GH-secreting adenomas in children was 13.3% after surgery.[39]

IGF-I levels appear to correlate better with clinical activity than do GH levels and should therefore be monitored.

Patients should also be evaluated for severe GH deficiency, which may occur in more than half of all patients treated for acromegaly (even those who have been cured by surgery alone).[40]

Because an association exists between acromegaly and regurgitant valvular heart disease, patients with acromegaly require adequate cardiac evaluation and follow-up to establish whether valvular disease is present and, if so, to determine the extent and progression of valvular involvement.[41]

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Contributor Information and Disclosures
Author

Alicia Diaz-Thomas, MD, MPH Assistant Professor of Pediatrics, University of Tennessee Health Science Center

Alicia Diaz-Thomas, MD, MPH is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society, Tennessee Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi

Disclosure: Nothing to disclose.

Melanie Shim, MD 

Melanie Shim, MD is a member of the following medical societies: American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD Former Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Acknowledgements

Barry B Bercu, MD Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children's Hospital

Barry B Bercu, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Federation for Clinical Research, American Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Pediatric Endocrine Society, Pituitary Society, Society for Pediatric Research, Society forthe Study of Reproduction, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Santiago A Centurion, MD Staff Physician, Department of Dermatology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey

Santiago A Centurion, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, and Sigma Xi

Disclosure: Nothing to disclose.

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS Professor of Medicine (Endocrinology, Adj), Johns Hopkins School of Medicine; Affiliate Research Professor, Bioinformatics and Computational Biology Program, School of Computational Sciences, George Mason University; Principal, C/A Informatics, LLC

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Nutrition, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Informatics Association, American Society for Bone and Mineral Research, International Society for Clinical Densitometry, and The Endocrine Society

Disclosure: Nothing to disclose.

Robert J Ferry Jr, MD Le Bonheur Chair of Excellence in Endocrinology, Professor and Chief, Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, University of Tennessee Health Science Center

Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society

Disclosure: Eli Lilly & Co Grant/research funds Investigator; MacroGenics, Inc Grant/research funds Investigator; Ipsen, SA (formerly Tercica, Inc) Grant/research funds Investigator; NovoNordisk SA Grant/research funds Investigator; Diamyd Grant/research funds Investigator; Bristol-Myers-Squibb Grant/research funds Other; Amylin Other; Pfizer Grant/research funds Other; Takeda Grant/research funds Other

Barry J Goldstein, MD, PhD Director, Division of Endocrinology, Diabetes and Metabolic Diseases, Professor, Department of Internal Medicine, Thomas Jefferson University

Barry J Goldstein, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, and The Endocrine Society

Disclosure: Nothing to disclose.

George T Griffing, MD Professor of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, International Society for Clinical Densitometry, Southern Society for Clinical Investigation, and The Endocrine Society

Disclosure: Nothing to disclose.

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Hasnain M Khandwala, MD, FRCPC Endocrinologist, LMC Endocrinology Centers, Canada

Hasnain M Khandwala, MD, FRCPC is a member of the following medical societies: American Association of Clinical Endocrinologists, American Diabetes Association, Canadian Medical Association, and The Endocrine Society

Disclosure: Nothing to disclose.

Jeffrey J Miller, MD Associate Professor of Dermatology, Pennsylvania State University College of Medicine; Staff Dermatologist, Pennsylvania State Milton S Hershey Medical Center

Jeffrey J Miller, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Association of Professors of Dermatology, North American Hair Research Society, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, New York Academy of Medicine, and Sigma Xi

Disclosure: Nothing to disclose.

Phyllis W Speiser, MD Chief, Division of Pediatric Endocrinology, Steven and Alexandra Cohen Children's Medical Center of New York; Professor of Pediatrics, Hofstra-North Shore LIJ School of Medicine at Hofstra University

Phyllis W Speiser, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Shyam Verma, MBBS, DVD, FAAD Clinical Associate Professor, Department of Dermatology, University of Virginia; Adjunct Associate Professor, Department of Dermatology, State University of New York at Stonybrook, Adjunct Associate Professor, Department of Dermatology, University of Pennsylvania

Shyam Verma, MBBS, DVD, FAAD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Image shows a coauthor of this article with a statue of Robert Wadlow, who was called the Alton giant. The tallest person on record, he was 8 feet 11 inches tall at the time of his death.
A 12-year-old boy with McCune-Albright syndrome. His growth-hormone excess manifested as tall stature, coarse facial features, and macrocephaly.
 
 
 
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