Hau Liu, MD, MBA, MPH; Dena M. Bravata, MD, MS; Ingram Olkin, PhD; Smita Nayak, MD; Brian Roberts, MD; Alan M. Garber, MD, PhD; Andrew R. Hoffman, MD
Acknowledgments: The authors thank Christopher Stave, MLS, Information Services Librarian, Lane Medical Library, Stanford University, for his assistance with the literature review.
Grant Support: Dr. Liu was supported by the U.S. Agency for Healthcare Research and Quality, National Research Service Award, grant number HS000028-19. Dr. Nayak was supported by a U.S. Department of Veterans Affairs Ambulatory Care Fellowship. Drs. Garber and Hoffman were supported in part by the U.S. Department of Veteran Affairs. Dr. Garber was also supported by a grant from the National Institute of Aging (AG17253, Center for Demography and Economics of Health and Aging). Dr. Roberts was supported by a fellowship stipend from Genentech, Inc.
Potential Financial Conflicts of Interest: Consultancies: A.R. Hoffman (Genentech, Teva, LG Life Sciences); Honoraria: A.R. Hoffman (Genentech); Stock ownership or options (other than mutual funds): A.R. Hoffman (Ambrx); Grants received: B. Roberts (Genentech), A.R. Hoffman (Genentech).
Requests for Single Reprints: Hau Liu, MD, MBA, MPH, Stanford University, 117 Encina Commons, Stanford CA, 94305-6019; e-mail, email@example.com.
Current Author Addresses: Drs. Liu, Bravata, and Garber: Stanford University, 117 Encina Commons, Stanford, CA 94305.
Dr. Olkin: Department of Health Research and Policy, Stanford University, Sequoia 126, Stanford, CA, 94305.
Dr. Nayak: University of Pittsburgh, 200 Meyran Avenue, Suite 200, Pittsburgh, PA, 15213.
Dr. Roberts: Stanford University, 300 Pasteur Drive, Stanford, CA 94305.
Dr. Hoffman: Veterans Affairs Palo Alto Health Care System, Endocrinology, 3801 Miranda Avenue, Palo Alto, CA 94304.
Author Contributions: Conception and design: H. Liu, D.M. Bravata, A.M. Garber, A.R. Hoffman.
Analysis and interpretation of the data: H. Liu, D.M. Bravata, I. Olkin, A.M. Garber, A.R. Hoffman.
Drafting of the article: D.M. Bravata.
Critical revision of the article for important intellectual content: H. Liu, D.M. Bravata, I. Olkin, S. Nayak, A.M. Garber, A.R. Hoffman.
Final approval of the article: H. Liu, D.M. Bravata, I. Olkin, S. Nayak, B. Roberts, A.M. Garber, A.R. Hoffman.
Provision of study materials or patients: H. Liu.
Statistical expertise: H. Liu, D.M. Bravata, I. Olkin.
Obtaining of funding: H. Liu.
Administrative, technical, or logistic support: S. Nayak, A.M. Garber.
Collection and assembly of data: H. Liu, S. Nayak, B. Roberts.
Liu H, Bravata DM, Olkin I, Nayak S, Roberts B, Garber AM, Hoffman AR. Systematic Review: The Safety and Efficacy of Growth Hormone in the Healthy Elderly. Ann Intern Med. 2007;146:(2):104-115. doi: 10.7326/0003-4819-146-2-200701160-00005
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Published: Ann Intern Med. 2007;146(2):104-115.
Human growth hormone (GH) is widely used as an antiaging therapy, although its use for this purpose has not been approved by the U.S. Food and Drug Administration and its distribution as an antiaging agent is illegal in the United States.
To evaluate the safety and efficacy of GH therapy in the healthy elderly.
The authors searched MEDLINE and EMBASE databases for English-language studies published through 21 November 2005 by using such terms as growth hormone and aging.
The authors included randomized, controlled trials that compared GH therapy with no GH therapy or GH and lifestyle interventions (exercise with or without diet) with lifestyle interventions alone. Included trials provided GH for 2 weeks or more to community-dwelling participants with a mean age of 50 years or more and a body mass index of 35 kg/m2 or less. The authors excluded studies that evaluated GH as treatment for a specific illness.
Two authors independently reviewed articles and abstracted data.
31 articles describing 18 unique study populations met the inclusion criteria. A total of 220 participants who received GH (107 person-years) completed their respective studies. Study participants were elderly (mean age, 69 years [SD, 6]) and overweight (mean body mass index, 28 kg/m2 [SD, 2]). Initial daily GH dose (mean, 14 Âµg per kg of body weight [SD, 7]) and treatment duration (mean, 27 weeks [SD, 16]) varied. In participants treated with GH compared with those not treated with GH, overall fat mass decreased (change in fat mass, âˆ’2.1 kg [95% CI, âˆ’2.8 to âˆ’1.35] and overall lean body mass increased (change in lean body mass, 2.1 kg [CI, 1.3 to 2.9]) (PÂ < 0.001), and their weight did not change significantly (change in weight, 0.1 kg [CI, âˆ’0.7 to 0.8]; PÂ = 0.87). Total cholesterol levels decreased (change in cholesterol, âˆ’0.29 mmol/L [âˆ’11.21 mg/dL]; PÂ = 0.006), although not significantly after adjustment for body composition changes. Other outcomes, including bone density and other serum lipid levels, did not change. Persons treated with GH were significantly more likely to experience soft tissue edema, arthralgias, carpal tunnel syndrome, and gynecomastia and were somewhat more likely to experience the onset of diabetes mellitus and impaired fasting glucose.
Some important outcomes were infrequently or heterogeneously measured and could not be synthesized. Most included studies had small sample sizes.
The literature published on randomized, controlled trials evaluating GH therapy in the healthy elderly is limited but suggests that it is associated with small changes in body composition and increased rates of adverse events. On the basis of this evidence, GH cannot be recommended as an antiaging therapy.
Ronald M. Klatz
President, American Academy of Anti-Aging Medicine (A4M)
January 16, 2007
A4M Official Response Statement, Issued 15 January 2007
The American Academy of Anti-Aging Medicine (A4M; www.worldhealth.net) is a non-profit medical society dedicated to the advancement of technology to detect, prevent, and treat aging related disease and to promote research into methods to retard and optimize the human aging process. A4M is also dedicated to educating physicians, scientists, and members of the public on biomedical sciences, breaking technologies, and anti-aging issues.
The A4M has reviewed the findings of the Liu et al meta-analysis concerning adult growth hormone (GH; HGH) replacement therapy published in the January 15, 2007 issue of the Annals of Internal Medicine, and refutes the paper's findings. Observes Ronald Klatz, M.D., D.O., President of the A4M: "The Liu et al paper is flawed, as it is based on an incomplete compilation of clinical studies of GH replacement in healthy adults. The A4M submits that thousands of published studies on hundreds of thousands of patients have demonstrated the clear benefits of adult GH replacement therapy, when utilized under proper clinical guidelines and at proper physiological dosages. Real-world results must take precedence over academic hypotheses as to benefits and risks."
The A4M finds that the Liu et al paper is flawed for the following reasons.
1. Meta-Analysis Conducted on Incomplete Compilation of GH Therapeutics Studies The Editors of Annals of Internal Medicine state that "The researchers reviewed all clinical trials of GH to determine if it is safe and effective in the healthy elderly. "
However, Liu et al state in the Methods - Study Selection, that "We excluded studies that: Â¡Â evaluated GH as a treatment for a specific illness (for example, adult GH deficiency Â¡Â". To exclude data from studies conducted to treat adult GH deficiency from the meta-analysis flaw the Liu et al review as incomplete. As stated by Savine: "If mean IGF-1 of 300 is mean normal for 20-30 year olds, almost all men and women over the age of 40 have an IGF-1 deficit." [Savine R. et al. Growth hormone replacement for the somatopause. Horm Res 2000;53 Suppl 3:37-4]. It is the position of the A4M that we submit that the empirical data suggests that when treating adult GH deficiency, physicians are treating a documented deficiency disease. In fact, HGH deficiency is associated with significantly decreased longevity in human siblings. Longevity and healthy aging are directly related to GH/IGF-1 levels. [Wuster C, Melchinger U, Eversmann T, Hensen J, Kann P, von zur Muhlen A, Ranke MB, Schmeil H, Steinkamp H, Tuschy U. Reduced incidence of side-effects of growth hormone substitution in 404 patients with hypophyseal insufficiency. Results of a multicenter indications Study. Med Klin 1998 Oct 15;93(10):585-91.]
The A4M further submits that the Liu et al compilation of studies on which their meta-analysis was conducted, is incomplete. We have compared the Liu et al compilation with the results of MEDLINE literature searches independently conducted by the A4M, and find the following studies absent from the Liu compilation. These missing studies specifically advocate on behalf of the benefits of GH therapeutics in adults:
Northwestern University Feinberg School of Medicine, Chicago, IL USA, April 2006: Dr. Molitch and colleagues found that: "GH therapy offers benefits in body composition, exercise capacity, skeletal integrity, and quality of life measures Â¡Â. The risks of GH treatment are low." [Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Shalet SM, Vance ML; Endocrine Society's Clinical Guidelines Subcommittee; Stephens PA. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2006 May;91(5):1621 -34. Epub 2006 Apr 24. ]
Christie Hospital, Manchester, U,K., April 2002 Ã¾u Dr. Murray and colleagues administered low-dose GH regimen administered to 67 growth- hormone deficient (GHD) adults. Significant improvements in total cholesterol, LDL, triglycerides, and ratio of total cholesterol to HDL were seen. The researchers commented that Â¡Â°Growth hormone deficiency in adult life is associated with a number of adverse biological changes Â¡Â . Most of these changes can be reversed by growth hormone replacement therapy.Â¡Â± [Murray RD, Wieringa GE, Lissett CA, Darzy KH, Smethurst LE, Shalet SM. Low-dose GH replacement improves the adverse lipid profile associated with the adult GH deficiency syndrome. Clin Endocrinol (Oxf). 2002 Apr;56(4):525-32.]
KIGS/KIMS Outcomes Research, Pharmacia AB, Stockholm, Sweden, November 2001 Ã¾u Data concerning visits to the doctor, number of days in hospital, and amount of sick leave were obtained from patients included in KIMS (Pharmacia International Metabolic Database), a large pharmacoepidemiological survey of hypopituitary adults with GHD, for 6 months before GH treatment and for 6-12 months after the start of treatment. Assistance required with normal daily activities was recorded at baseline and after 12 months of GH therapy. Quality of life (QoL) (assessed using a disease-specific questionnaire, QoL-Assessment of GHD in Adults) and satisfaction with physical activity during leisure time were also assessed. For the total group (n = 304), visits to the doctor, number of days in hospital, and amount of sick leave decreased significantly (P < 0.05) after 12 months of GH therapy. Patients also needed less assistance with daily activities, although this was significant (P < 0.01) only for the men. QoL improved after 12 months of GH treatment (P < 0.001), and both the amount of physical activity and the patients' satisfaction with their level of physical activity improved after 12 months (P < 0.001). In conclusion, GH replacement therapy, in previously untreated adults with GHD, produces significant decreases in the use of healthcare resources, which are correlated with improvements in QoL. [Hernberg-Stahl E, Luger A, Abs R, Bengtsson BA, Feldt-Rasmussen U, Wilton P, Westberg B, Monson JP; KIMS International Board., KIMS Study Group. Pharmacia International Metabolic Database, "Healthcare consumption decreases in parallel with improvements in quality of life during GH replacement in hypopituitary adults with GH deficiency," J Clin Endocrinol Metab. 2001 Nov;86(11):5277-81]
II. Benefits and Side Effects of GH Therapeutics The Editors of Annals of Internal Medicine state that "The researchers reviewed all clinical trials of GH to determine if it is safe and effective in the healthy elderly. They found that GH had no important effects on body composition but led to frequent adverse effects."
However, once again, the A4M submits that the Liu et al study neglected to include in its meta-analysis several key studies finding that GH therapy in adults is beneficial and tolerated without side effects, as follows:
Research Centre for Endocrinology and Metabolism, University Hospital, Goteborg, Sweden, October 2001: In this 1-center study, including 118 consecutive adults (70 men and 48 women; mean age, 49.3 yr; range, 22-74 yr) with adult-onset GH deficiency, the effects of 5 yr of GH replacement on body composition, bone mass, and metabolic indices were determined. The mean initial GH dose was 0.98 mg/d. The dose was gradually lowered, and after 5 yr the mean dose was 0.48 mg/d. The mean IGF-I SD score increased from -1.73 at baseline to 1.66 at study end. A sustained increase in lean body mass and a decrease in body fat were observed. The GH treatment increased total body bone mineral content as well as lumbar (L2-L4) and femur neck bone mineral contents. BMD in lumbar spine (L2-L4) and femur neck were increased and normalized at study end. Total cholesterol and low density lipoprotein cholesterol decreased, and high density lipoprotein cholesterol increased. At 5 yr, serum concentrations of triglycerides and hemoglobin A(1c) were reduced compared with baseline values. In conclusion, 5 yr of GH substitution in GH-deficient adults is safe and well tolerated. The effects on body composition, bone mass, and metabolic indices were sustained. The effects on body composition and low density lipoprotein cholesterol were seen after 1 yr, whereas the effects on bone mass, triglycerides, and hemoglobin A(1c) were first observed after years of treatment. [Gotherstrom G, Vensson J, Koranyi J, Alpsten M, Bosaeus I, Bengtsson B, Johannsson G, "A prospective study of 5 years of GH replacement therapy in GH-deficient adults: sustained effects on body composition, bone mass, and metabolic indices," J Clin Endocrinol Metab. 2001 Oct;86(10):4657-65]
Department of Medical Sciences, University Hospital, Uppsala, Sweden, October 2001: The safety and effects of a fixed low dose of growth hormone (GH), 0.17 mg/day was evaluated for 3 months, on glucose metabolism, serum lipids, body composition and cardiac function in 53 GH deficient adults aged 18-78 years. At 3 months, serum levels of insulin- like growth factor (IGF)-I, IGF binding protein (IGFBP)-3 and lipoprotein (a) and lean body mass were increased (P<0.05). Total and low density lipoprotein cholesterol levels and fat mass were reduced (P<0.05). There was an increase in the serum glucose value at 120 min after an oral glucose tolerance test performed at 3 months (P<0.05), no other changes in glucose metabolism or in cardiac function were noted. Side-effects were few and mild. This fixed low-dose regime resulted in improvements in body composition and lipid profile, without causing serious side effects. This is therefore a valid method to institute GH replacement in adults. [Gillberg P, Bramnert M, Thoren M, Werner S, Johannsson G, "Commencing growth hormone replacement in adults with a fixed low dose. Effects on serum lipoproteins, glucose metabolism, body composition, and cardiovascular function," Growth Horm IGF Res. 2001 Oct;11(5):273-81]
Department of Diabetes & Endocrinology, Royal Liverpool University Hospital,, UK, June 2001: Dr. Ahmad and colleagues found that: "Low-dose GHR improves body composition and QoL as early as 1 month after commencement and the beneficial effects continue at 3 months. Most importantly, these changes occur in the absence of side-effects. We therefore suggest the use of low-dose GH therapy." [Ahmad AM, Hopkins MT, Thomas J, Ibrahim H, Fraser WD, Vora JP. Body composition and quality of life in adults with growth hormone deficiency; effects of low-dose growth hormone replacement. Clin Endocrinol (Oxf). 2001 Jun;54(6):709-17.]
In the anti-aging clinical setting, adult GH replacement therapy employs doses of GH that are 1/3 of that used in the individual studies analyzed by Liu et al, which utilized doses at 1/3 to 1/2 that used in the pediatric setting for the treatment of dwarfism. The attenuated low-dose therapies have been proven effective in more than ten years of application by physician members of the A4M. The side effect profile does not apply to clinical treatment where low doses are used initially and doses are slowly ramped up and decreased if side effects occur. Significant side effects are rarely seen in clinical practice. Also, when the same total dose is divided daily over a week-long period (instead of administering 3 days a week) side effects are diminished or absent. If side effects do occur, it has been clinically demonstrated that they disappear with cessation of treatment. When the proper dosing customized to the anti-aging patient is reached, and coupled with regular laboratory testing and clinical examination, our member physicians are able to limit adverse effects of GH replacement therapy in adult patients.
It is the position of the A4M that the side effect profile of GH therapy is nominal when the dosage is properly determined and monitored by a qualified endocrinologist or anti-aging physician. Laboratory testing is essential to the safe and scientific application of anti-aging hormone replacement therapy. Safe optimization of essential hormone levels in the deficient and symptomatic patient is the goal of anti-aging endocrinology. This requires careful monitoring of bio-available hormone levels. This also requires establishment of baseline laboratory data and regular analysis on at least a semi-annual basis in order to achieve the safest and most effective hormonal balance at the lowest possible dose.
To deny the benefit of HGH and other essential hormonal regulators of metabolism in deficient patients based on age may be considered a heinous act of malpractice which will prove to be erroneous and short-sighted in the years to come, and may in fact lead to unnecessary morbidity in the form of diminished healthspans, as well as excess mortality in the form of reduced lifespans. In the future, the replacement of essential hormones that decline with age may be seen as important as insulin replacement in diabetics today.
Anti-aging medicine is a medical specialty founded on the application of advanced scientific and medical technologies for the early detection, prevention, treatment, and reversal of age-related dysfunction, disorders, and diseases. It is a healthcare model promoting innovative science and research to prolong the healthy human lifepan. Anti-aging medicine is based on principles of sound and responsible medical care that are consistent with those applied in other preventive health specialties. The safety and clinical value of GH replacement in aging adults is proven to decrease weight and body fat mass; increase lean body mass; increase exercise capacity; increase muscle mass and strength; improve cardiac performance; improve bone density and decrease fracture rate; improve poor sleep; and improve an impaired sense of well being. As the master regulating hormone, HGH is a pacemaker for all the other rejuvenative (anti-aging) hormones such as estrogen, testosterone, DHEA, and melatonin, and as a result is an essential component of physiologic replacement therapy.
In conclusion, it is the position of the A4M that adult GH replacement therapy is safe and efficacious when administered judiciously by a qualified endocrinologist or anti-aging physician. Thousands of controlled research studies conducted over the course of the past fifteen years document the safety and efficacy of adult GH replacement therapy. HGH has an extensive history of rigorous scientific trials and practical clinical application. The American Association of Clinical Endocrinologists has stated that: "The usefulness of GH treatment in adults who have completed their statural growth is based on the roles of GH in: increasing bone density; increasing lean tissue; decreasing adipose tissue; bolstering cardiac contractility; improving mood and motivation; increasing exercise capacity." [AACE Guidelines for Growth Hormone Use, Endocrine Practice 4(3):165-173]. Many clinical studies have demonstrated the value of HGH replacement in healthy adults, associated with negligible side effects, when acquired from a reliable, safe, approved pharmaceutical supplier and administered judiciously by a qualified physician.
The A4M believes that the disabilities associated with normal aging are caused by physiological dysfunction which in many cases are ameliorable to medical treatment, such that the human lifespan can be increased, and the quality of one's life enhanced as one grows chronologically older. A4M seeks to disseminate information concerning innovative science and research as well as treatment modalities designed to prolong the human lifespan. Although A4M seeks to disseminate information on many types of medical treatments, it does not promote or endorse any specific treatment nor does it sell or endorse any commercial product.
Wee Shiong Lim
Tan Tock Seng hospital
January 29, 2007
Growth hormone in the elderly: more answers than questions
The meticulous work of Liu et al (1) in assimilating the hitherto available evidence regarding the safety and efficacy of growth hormone (GH) in the healthy elderly is to be applauded. The systematic review confirmed the initial impressions of earlier small isolated studies that GH therapy in the absence of a deficiency state confers little clinical benefit (other than minimal alterations in body composition), and is associated with increased rates of adverse effects. It also raises the novel possibility of a gender difference in GH dosage requirements, response and side effects.
The authors rightly excluded studies that evaluated GH as a treatment for a specific illness. In particular, the state of adult GH deficiency (GHD) should be distinguished from the age-related decline in GH that occurs with somatopause. Adult GHD is a well recognized clinical syndrome that often occurs in the context of pituitary/peri-pituitary pathology; as defined by strict hormonal criteria, adult-onset idiopathic GH deficiency is very rare (2). By excluding this distinct group of GH-deficient patients from the analysis, the authors provide proof-of concept evidence that the magnitude of benefit seen in adult GHD is not replicated in the context of somatopause. The lack of statistical homogeneity among included studies further supports this point.
It is unfortunate that the heterogeneity of outcome measures precluded the pooling of results for functional outcomes. Nonetheless, evidence suggests that the improvement in body composition does not translate into clinically meaningful functional improvement (3). It is also doubtful if GH supplementation would yield any benefit above and beyond that seen with resistance training in the elderly (4).
Another unaddressed issue, due to the relatively short duration of included studies (mean: 26.6 weeks), is the long-term safety of GH therapy. While the dosing in standard GH therapy does not commonly approach the levels commonly seen in acromegaly, there are concerns that the chronically elevated GH state (relative to the "physiological" age- related decline in GH) may predispose to co-morbidities associated with GH excess states including hypertension, diabetes mellitus, dyslipidemia and malignancy (5).
Taken together, the current body of evidence and a realistic appraisal of erstwhile unanswered questions (such as optimal dosing and duration, relative efficacy between different GH and GH-secretagogue formulations, and long-term benefits and side effects of chronic GH administration) do not support the clinical utility of GH as the proverbial fountain of youth to retard the aging process in the healthy elderly.
1. Liu H, Bravata DM, Olkin I, Nayak S, Roberts B, Garber AM, et al. Systematic review: The safety and efficacy of growth hormone in the healthy elderly. Ann Intern Med. 2007;146:104-15.
2. Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Shalet SM, Vance ML. Evaluation and treatment of adult growth hormone deficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2006;91:1621-34.
3. Blackman MR, Sorkin JD, Munzer T, Bellantoni MF, Busby-Whitehead J, Stevens TE, et al. Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA. 2002;288:2282-92.
4. Taaffe DR, Pruitt L, Reim J, Hintz RL, Butterfield G, Hoffman AR, et al. Effect of recombinant human growth hormone on the muscle strength response to resistance exercise in elderly men. J Clin Endocrinol Metab. 1994;79:1361-6.
5. Vance ML. Growth hormone for the elderly? N Engl J Med 1990;323:52 -4.
Universidad Nacional AutÃ²noma de Mexico
February 15, 2007
I offer the following comments regarding the interesting article by Liu et al (1)concerning the antiaging therapy. After a systematic review in 31 articles related with the treatment of 220 participants( healthy elderly ),these authors concluded that growth hormone(GH)therapy can not be recommended as an antiaging therapy. On the contrary, other authors(2,3)consider that the GH replacement therapy is vital in helping prevent the aging process. There are 3 therapeutic methods used up to date against aging (4 ):1)exogenous GH, 2)exogenous growth hormone- releasing hormone(GHRH),and 3)secretagogue products. Besides these,we have reported a 82-year-old man who suffered previously of type 2 diabetes, arterial hypertension, stroke and aging (4). After omental transplantation on the optic chiasma,the carotid bifurcation and the anterior perforated space, this patient experienced rejuvenation at least 10 years.The postoperative picture is recorded on 4 videotape. For these reasons,we believe that ischemic neurons and/or in ischemic penumbra in the arcuate nucleus and adjacent zones,are responsibles of the aging process. Because, by contrast, its revascularization produce rejuvenation due to secretion of GHRH by residual neurons in the producing hypothalamic nuclei of GHRH. Therefore, aging process is a disease.
<P>1.Liu H,Bravata DM,Olkin I,et al. Systematic review : The safety and efficacy of growth hormone in the healthy elderly.Ann Intern Med 2007;146(2):104-115.
<P>2.Kerckoff H.Manejo de la somatotropina sinthtica como terapia anti-envejecimiento. Rev Climaterio 2004; 7(42):245-249. www.revistasmedicasmexicanas.com.mx
<P>3.Verhoeven HC. Growth hormone replaceme! Nt therapy:Is it safe ?. The Aging Male 2005;8(2):121-122 (abstract) .
<P>4.Rafael H. Rejuvenation after omental transplantation on the optic chiasma and arotid bifurcation. Case Rep Clin Pract Rev 2006;7:48-51. www.crcpr-online.com
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