eMedicine Specialties > Dermatology > Internal Medicine

Acromegaly

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Santiago A Centurion, MD, Staff Physician, Department of Dermatology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey
Contributor Information and Disclosures

Updated: Nov 9, 2009

Introduction

Background

Excess secretion of growth hormone (GH) induces gigantism in prepubertal children and acromegaly in adults. Acromegaly arises from GH-secreting pituitary adenomas. GH is necessary for normal linear growth. GH is not the principal stimulator of growth, but it acts indirectly by stimulating the formation of other hormones. These hormones are termed somatomedins (SMs, ie, somatotropin-mediating hormones) or insulinlike growth factors (IGFs).

Somatomedin C (SM-C; insulinlike growth factor I [IGF-I]), the most important SM in postnatal growth, is produced in the liver, chondrocytes, kidney, muscle, pituitary, and gastrointestinal tract.

Also see eMedicine's endocrinology article, Acromegaly, and pediatrics article, Gigantism and Acromegaly. 

Pathophysiology

GH secretion from the pituitary gland is controlled by a combined hypothalamic regulation. Secretion is stimulated by growth hormone–releasing hormone (GHRH) and inhibited by GH release–inhibitory hormone or somatostatin (also termed somatotropin release–inhibitory factor or SRIF).

Syndromes of excessive secretion of GH or acromegaly are caused 95% of the time by a pituitary adenoma of the somatotrophs. Ectopic GHRH-producing tumors, usually seen in the lung or pancreas, may occasionally be evident elsewhere, such as in duodenum as a neuroendocrine carcinoma.1

Isolated familial somatotropinoma is a rare disease; at least 2 cases of acromegaly or gigantism has been reported in a family that does not exhibit features of Carney complex or multiple endocrine neoplasia type 1.2 It appears to be inherited as an autosomal dominant disease with incomplete penetrance. Although an association exists between the disease and loss of heterozygosity on 11q13, the responsible gene remains unknown.

Approximately 40% of somatotroph tumors have a mutation in the alpha subunit of a stimulatory G protein. Activation of this G protein is associated with binding of guanosine triphosphate (GTP) to the alpha subunit, which allows the alpha subunit to stimulate cyclic adenosine monophosphate (AMP) production. The normal free subunit has intrinsic GTPase activity, which inactivates GTP, preventing continued cyclic AMP stimulation. The mutant alpha subunit in acromegalic patients does not possess GTPase activity; therefore, continued cyclic AMP stimulation results.

GHRH-induced acromegaly is rare but is clinically indistinguishable from acromegaly caused by pituitary adenomas.

High levels of IGF-I are found in acromegaly, and low levels are found in children with GH deficiency. Insulin and IGF-I are similar peptides, and either can bind to IGF-I receptors.

Activation of this receptor leads to the growth and differentiation of many different cell lines, including keratinocytes, fibroblast, and the pilar unit of the skin.

Epidermal growth factor (EGF) and its homologs, transforming growth factor-alpha and amphiregulin, play a pivotal role in the regulation of keratinocyte growth and differentiation. All 3 growth factors stimulate cell growth by activating the epidermal growth factor receptor (EGF-R) that is expressed on keratinocytes in culture and in situ. Active proliferation of keratinocytes is associated with increased expression of the EGF-R and of its ligands (ie, transforming growth factor-alpha and amphiregulin) in the epidermis.

IGF-I and insulin, both of which stimulate keratinocyte growth through the IGF-I receptor, have been identified as primary keratinocyte mitogens. Proliferation induced by insulin and IGF-I requires the presence of other growth factors (notably EGF), and IGF-I stimulates keratinocyte proliferation in the absence of any other polypeptide growth factor at physiologic concentrations, through the IGF-I receptor. Thus, IGF-I is 1 of the factors inducing the growth factor component of the EGF-R–dependent autocrine loop in keratinocytes.

Frequency

United States

Acromegaly is uncommon, with an incidence of 3-4 cases per million per year. This figure easily may be an underestimation because of the insidiousness of this disease.

Mortality/Morbidity

Acromegaly is a severe disease often diagnosed late. Morbidity and mortality rates are high, in particular, because of associated cardiovascular, cerebrovascular, and respiratory disorders and malignancies.

  • Acromegaly is associated with an increase in left ventricular mass, even in the absence of systemic hypertension. Pathologic studies on acromegalic hearts have shown extensive interstitial fibrosis, suggesting the existence of a specific acromegalic cardiomyopathy.
  • Alveolar hypertrophy or hyperplasia is the mechanism for lung growth in this condition.
  • Increased colon and breast cancers have been associated with acromegaly.

Sex

Male-to-female ratio is equal.

Age

Acromegaly occurs most frequently in middle age. The mean age of diagnosis is 40 years in men and 45 years in women.

Clinical

History

Acromegaly symptoms are present many years before the diagnosis is made.

  • Initial symptoms commonly are caused by the tumor and its mass effect (ie, headaches, change in vision).
  • Acromegalic patients often complain of various skin changes.
    • Sponginess and puffiness of hands and feet
    • Increased body hair
    • Excessive sweating
    • Oily skin
    • Increased number of skin tags
    • Thickening of heel pads
    • Hard and thickened nails
    • Coarsening of facial features
    • Noticeably large pores
    • Swollen eyelids
    • Enlargement of the nose
    • Hollow-sounding voice
    • Darkening of the skin (accentuated in intergluteal areas)
  • Other symptoms include the following:
    • Fatigue
    • Back and joint pain
    • Change in glove and shoe sizes
    • Spaces between the teeth
    • Underbite
    • Decreased libido and impotence
    • Polyuria
    • Polydipsia
    • Weakness
    • Sleep apnea
    • Hypersomnolence
    • Galactorrhea
    • Amenorrhea in younger women
    • Depression
    • Arthralgias
    • Muscle weakness
    • Paresthesias

Physical

Involvement of the skin has long been recognized as an important component of acromegaly. Steinberg provided the following description in 1899, "The skin of the palms of hands and soles of the feet is... often spongy and puffy; in the soles of the feet, it swells over the sides when putting the foot to the ground." The skin changes have been considered a classic feature of acromegaly, and as activity of the disease diminishes, the skin changes become stationary and regress.

  • Signs and symptoms of acromegaly include the following:
    • Doughy-feeling skin over face and extremities (one of the earliest signs in acromegaly is swelling of soles and palms)
    • Thick and hard nails
    • Deepening of creases on the forehead and nasolabial folds
    • Noticeably large pores
    • Thick and edematous eyelids
    • Enlargement of lower lip and nose (nose takes on triangular configuration)
    • Wide spacing of the teeth and prognathism
    • Cutis verticis gyrata (ie, furrows resembling gyri of scalp): Acromegaly may be first evident as cutis verticis gyrata.3
    • Small sessile and pedunculated fibromas, ie, skin tags (association between skin tags and polypoid lesions has been described in the literature, but currently, no conclusive studies exist to substantiate this finding)
    • Hypertrichosis in approximately one half of acromegaly patients (hypertrichosis of acromegaly does not affect beard area, as opposed to virilizing disorders)
    • Oily skin (acne is not common)
    • Hyperpigmentation in 40% of patients and acanthosis nigricans in a small percentage (excessive stimulation of keratinocytes and fibroblasts in skin accounts for development of acanthosis nigricans)
    • Excessive eccrine and apocrine sweating
    • Breast tissue becoming atrophic; galactorrhea
    • High blood pressure
    • Mitral valvular regurgitation
  • Acromegaly has been associated with other dermatologic syndromes to include the following:
    • Carney complex (NAME syndrome [nevi, atrial myxoma, myxoid neurofibroma, and ephelides], Carney complex, LAMB syndrome [lentigines, atrial myxoma, mucocutaneous myxomas, and blue nevi]). GH-producing pituitary tumors have been described in individuals with Carney complex (CNC). CNC is a familial multiple neoplasia and lentiginosis syndrome.
      • Manifestations and primary findings in CNC include cardiocutaneous syndrome characterized by pigmented skin lesions and atrial myxomas, lentigines (mucocutaneous), atrial myxomas (may be fatal), mucocutaneous myxomas, blue nevi, congenital melanocytic nevi, and schwannomas.
      • Endocrine abnormalities of CNC include acromegaly, endocrine overactivity, Cushing syndrome, sexual precocity in boys, thyroid hyperplasia, primary pigmented nodular adrenocortical disease, testicular tumors, and uterine myxomas.
    • McCune-Albright syndrome
      • The pathogenetic mechanisms involved in the development of the endocrinopathies are unknown, and 2 hypotheses have arisen. For many years, hypothalamic dysfunction was assumed to be the cause in most cases; an alternate hypothesis postulates that hyperfunctioning endocrine organs work with relative autonomy from hypothalamic control.
      • This syndrome is manifested clinically by the presence of polyostotic fibrous dysplasia of bone, hyperpigmented skin macules, precocious sexual development in children, goiter, hyperthyroidism, acromegaly, Cushing syndrome, hyperprolactinemia, sexual precocity, hyperparathyroidism, and hypophosphatemic hyperphosphaturic rickets.

Causes

  • Several lines of evidence indicate that GH may regulate skin growth and architecture directly and/or indirectly.
  • Ferguson et al4 showed that the mean skin thickness of 22 patients with acromegaly was increased many fold compared to 55 control subjects matched by age. Subsequently, this finding was correlated with changes found on histopathologic specimens.
  • Lobie et al5 have shown immunoreactivity of the GH receptor in neonatal and adult animals in nearly every cell on the skin.
    • The reactivity was localized consistently in the stratum basale and stratum spinosum, with intermittent staining in the stratum granulosum.
    • Intense GH-receptor immunoreactivity was observed in all histologic layers of the lower one third of hair follicles and in hair matrix cells of the dermal papillae.
  • Immunoreactivity also has been detected in sebaceous glands and in fibroblasts of the connective tissue sheath surrounding the follicle.
    • GH-receptor immunoreactivity also is present in the secretory duct and myoepithelial cells of human eccrine sweat glands.
    • Fibroblasts, Schwann cells of peripheral nerve fascicles, skeletal muscle cells, and adipocytes of the dermis also are immunoreactive, as are medial smooth muscle and endothelial cells of arteries.
  • Philpott et al6 showed that physiologic concentrations of IGF-I and insulinlike growth factor II were potent stimulators of hair follicle growth, and in the absence of insulin, hair follicles showed premature entry into a catagenlike state.

More on Acromegaly

Overview: Acromegaly
Differential Diagnoses & Workup: Acromegaly
Treatment & Medication: Acromegaly
Follow-up: Acromegaly
References
[ CLOSE WINDOW ]

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Further Reading

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Keywords

acromegaly, growth hormone, GH, gigantism, GH-secreting pituitary adenomas, somatomedins, SMs, somatotropin-mediating hormones, insulinlike growth factors, IGFs

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Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-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, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

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.

Medical Editor

Shyam Verma, MBBS, DVD, FAAD, Adjunct Clinical Assistant Professor, Department of Dermatology, University of Virginia, State University of New York at Stonybrook, Penn State University
Shyam Verma, MBBS, DVD, FAAD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University 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.

Managing Editor

Jeffrey J Miller, MD, Associate Professor of Dermatology, Penn State University College of Medicine; Staff Dermatologist, Penn 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.

CME Editor

Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital
Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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