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To Be or Not To Be… An Anti-Aging Doctor?

E-Newsletter No. 1

Fellow of the American College of Endocrinology
Diplomate American Board of Psychiatry & Neurology
Diplomate National Board of Medical Examiners

Member
American Association of Clinical Endocrinologists
Growth Hormone Research Society  [Click here for information on Human Growth Hormone]
American Society of Andrology

Abstract
Recently the media has shown an interest in anti-aging, the use of growth hormone, sex hormones, and over-the-counter neutraceuticals to treat "the disease of aging." An article in Los Angeles Times, May 8, 2000, "Can Doctors Really Turn Back Time?" cites a "troubling record for Anti-Aging Doctors; nearly 25% of the American Academy of Anti-Aging Medicine (A4M) certified doctors in California have been disciplined at least once by the state medical board, according to board records." Inadequate diagnosis, or treatment, lack of neuroendocrine follow-up, and failure to obviate pre-existing disorders, such as insulin resistance and endothelial dysfunction, prior to instituting hormonal replacement therapy may lead to serious consequences, even death. It is this author’s opinion that the public and the medical profession need to become enlightened about the myth of anti-aging, and to become more discriminative about the standard of care. The management of these patients requires the active input from physicians with expertise in the complex interrelationships between cardiology, immunology, oncology, behavioral medicine and neuroendocrine disorders.

Introduction
Converging forces of cost containment (from medicare to managed care), the changing demographics to a predominantly aging population, and advances in molecular biology commercialized by the pharmaceutical industry making synthetic hormone replacement accessible in an unlimited supply, has created a growing interest in the emerging field of anti-aging medicine. The abundant supply of recombinant DNA origin human growth hormone in combination with recent scientific enthusiasm¹ has prompted its use in the management of aging, even though there is limited long-term efficacy and safety data available from controlled clinical trials.^2,3,4,5

However, extensive clinical experience and available clinical guidelines^6-59 are mutual appropriate foundations for the management of aging in human patients. The issue that medicine is being subjected to multiple pressures, including cost containment, needs to be addressed. These pressures can result in a clinical strategy which is not focused on good clinical care. One scenario is compromised care standards based on the needs of a population but not on the needs of an individual patient. Another scenario is to move outside of the arena of third party reimbursement restrictions into creative endeavors of medical entrepreneurism through the open doors of pseudo-science and financial opportunism.

Anti-Aging Medicine is currently on that threshold. Historically, since the time of the Egyptians, the quest for the "fountain of youth" has been cast in a flood of exaggerated claims and medical entrepreneurism. In other words, just because the public is clamoring for a "cure to aging" doesn’t mean it is all right for you to sell them snake oil. The medical profession is urged to be guided by well-established principles of medical ethics to avoid this image.

1. "Primum non nocere."
2. The interests and benefits of the patient are above those of the physician or caregiver.
3. It is essential to look for and manage preexisting or underlying conditions. It is the best course for our patients and for ourselves.
4. As professionals, you are expected to be compassionate, willing and anxious to help others in need of your expertise and advice, holding their interests above your own. Equally as important, and expected, is that you will recognize your own limitations, and remain within the area of your own unique skills and core competencies.

Is there a cure for aging?
To begin, let us dispel the myth that is being perpetrated upon the public. Is there a single most important drug that could treat aging? Currently, there is no "magic potion," and there is no such thing as a "cure for aging." Rather, the key to anti-aging medicine is that we attend to specific, fundamental, clinical issues.

In fact, the very nature of utilizing what scientific advances have to offer has driven us into many different areas which are components of endocrinology: diabetes mellitus, calcium, bone and mineral disorders, pituitary disorders, diseases of nutrition including obesity and the eating disorders, adrenal disorders, thyroid disease, dyslipidemia and concurrent endothelial dysfunction, hypertension, disorders of sexual and reproductive organs, as well as the merging fields of immunology and neurobiology.

According to the media (newspaper, magazine articles, TV news specials, books to the lay public), hormone replacement therapy, and particularly, supplementing human growth hormone (GH) is the "key to anti-aging."⁶⁰ However, despite its beneficial aspects, such as body composition^61-83 in GH deficient adults, bone mineralization,^61-88 cardiac structure and function,^61-64 lipid and lipoprotein levels,^61-65 and quality of life,^61-64 there are counterbalancing risks such as increased sodium retension,^78-82 reduced concentration of atrial natriuretic peptide seen when GH is given to healthy adults.^83-85 Replacement therapy with GH is associated with significant enhancement of bone turnover.⁶⁷ This usually results in an initial decrease in bone mineralization, follow typically after 12 to 18 months by significant increase.^67,85,86 Increased levels of Lipoprotein(a) after GH replacement have been reported,^87,88 particularly in patients who had elevated levels before treatment began.⁸⁹ Insulin sensitivity is reduced with GH replacement therapy, as GH antagonizes the actions of insulin. ^61,90-95 GH also has potential adverse effects on thyroid function.^61,96-98 There has also been an observation of increased adenomatous polyps developing in the gastrointestinal tract after many years of excessively high GH levels.⁹⁹ To date there is no evidence that GH replacement therapy in adults increase the risk of primary cancer or recurrence of pituitary tumors. This is clearly an issue of great importance. Therefore, long term surveillance of all adults receiving GH is essential. Physicians interested in pursuing a specialty of anti-aging medicine need to familiarize themselves with these issues before they begin treating patients.

Selective Risk Factor Issues
To say we want to focus only on "anti-aging and longevity or life-extension" is to ignore all of the above underlying conditions that are either nascent or clinically present. This superficial pro-active approach can actually cause the patient more harm than simply following a course of benign neglect.

For example, atherosclerosis and coronary artery disease (CAD) commonly begins in the 15-34 year-old age group for both men and women.¹⁰⁰ Along with the traditionally established risk factors of elevation of small dense lipoproteins, lower HDL fractions, obesity, smoking, elevated glycohemoglobin levels and hypertension, we now recognize that homocysteinemia, chlamydial antibodies, and psychoneuroimmunologic factors of hostility, depression and stress are also major contributors to disease of the arterial wall.^101-104

In a recent study by the World Health Organization, cardiovascular disease led the causes of death worldwide.¹⁰⁵ When combined, cardiovascular and cerebrovascular causes represented more than 20% of 50.5 million deaths in 1992. As affluence has increased in industrialized societies, the incidence of cardiovascular disease has also increased. From 1900 to 1950, the incidence of cardiovascular disease increased nearly two-fold within the United States. Thus, it follows that the trend observed in the United States earlier in the twentieth century will be reproduced worldwide in the twenty-first century.

Coronary heart disease (CHD) is the leading cause of death in adult U.S. women. Annually, there are more than 250,000 deaths for CHD. Lack of estrogen has been implicated as a risk factor for coronary artery disease (CAD) since the association between surgical or natural menopausal status and CAD was demonstrated.^106,107

Most of the population-based studies on hormone replacement therapy (HRT) have demonstrated a 30-50% reduction in cardiovascular and all-cause mortality in current users of estrogen. It has been shown repeatedly both in population-based^108,109 and angiographic¹¹⁰ studies that HRT in women with known CAD or with coronary risk factors tend to benefit much more than healthy postmenopausal women without HRT.

After 8.5 years, the Lipid Research Clinic Follow-Up Study found that there was almost a five-fold reduction in death among estrogen users with known CAD at baseline, compared with a two-fold reduction in death among estrogen users without CAD.¹¹¹ The Nurses Health Study (NHS) found that users of HRT who had one or more cardiovascular risk factors had a 50% reduction in all-cause mortality compared with an 11% reduction in HRT users without risk factors¹⁰⁹ in addition, angiographic studies have shown less CAD at baseline in users of HRT¹¹² and lower mortality rates after 10 years of follow-up, with particularly significant findings in women with the more severe CAD at baseline.¹¹⁰ Women who have undergone percutaneous or surgical coronary revascularization also appear to benefit from HRT. Improved long-term survival has been shown for HRT users who have undergone coronary artery bypass grafting¹¹³ or percutaneous transluminal coronary angioplasty (PTCA).¹¹⁴ These studies strongly suggest that HRT may be an important issue for the secondary prevention of CAD or in patients with known coronary risk factors.

Despite these observational study data, prospectively randomized trials to address the effectiveness and safety of HRT for the primary and secondary prevention of CAD in postmenopausal women have just been initiated within the past several years. Results from the primary prevention study (Women’s Health Initiative) is scheduled to be completed in 2005. The results of the secondary prevention study (Heart and Estrogen/Progestin Replacement Study [HERS]) were recently published by Hulley and associates.¹¹⁵

The HERS randomized 2763 postmenopausal women with CHD (younger than 80 years), and intact uteri to either 0.625mg of conjugated equine estrogen plus 2.5mg of medroxy progesterone acetate in one tablet daily or to placebo. The women were followed for an average of 4.1 years, and the primary outcome was the occurrence of nonfatal MI or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, stroke or transient ischemic attack, and peripheral artery disease. Overall, there were no significant differences between groups in the primary or secondary outcomes. The lack of an overall effect occurred despite a net 11% lower LDL cholesterol level and a 10% higher HDL-cholesterol level in the hormone group compared with the placebo group (p<0.001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year one and fewer in years four and five. More women in the hormone group than in the placebo group experienced venous thromboembolic events (including MI) and gallbladder disease.¹¹⁵

Based on this finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, it was not recommended to initiate HRT for secondary prevention of CHD. Hulley et al. suggested that given the favorable pattern of CHD events after several years of treatment, HRT could be appropriate for women currently receiving this treatment to continue.¹¹⁵ While HRT is not recommended for the secondary prevention of ASCVD, no general recommendations can be given relative to primary prevention until the results of The Women’s Health Initiative Study are completed.

In addition, a higher level of plasminogen-activator inhibitor type 1 (PAI-1) an essential inhibitor of fibrinolysis, is found in post-menopausal women.¹¹⁶ Studies have shown that increased plasma levels of PAI-1 are associated with a higher risk of atherosclerosis and subsequent myocardial infarction and stroke.¹¹⁷

Finally, both lipoprotein(a) and homocysteine levels are increased in the plasma of postmenopausal women.¹¹⁸ Each is believed to be an independent risk factor for atherosclerotic disease. Increased plasma homocysteine confers a risk for CHD similar to smoking or hyperlipidemia and powerfully increased the risks associated with smoking and hypertension.¹¹⁹ Of note, oral conjugated estrogen therapy does increase serum triglycerides in a dose-dependent manner, which may be of concern in treating women who already have high levels.¹²⁰

Oral conjugated estrogen, either alone or combined with progestin therapy, reduces plasma PAI-1, lipoprotein(a), and total homocysteine levels.^121-123 Estrogen may also have other lipid-independent cardioprotective effects, including vasodilation, alteration of cholesterol metabolism and deposition, and calcium antagonism.

Progestins, as a class, increase LDL and decrease HDL. Accordingly, estrogen’s beneficial effect on LDL and HDL is attenuated with the addition of progestins to HRT.¹²⁴ Micronized progesterone may be less detrimental than other forms of progestins.¹²⁵ Despite the consequences on the lipid profile, observational studies suggest that the cardioprotective effects of postmenopausal estrogen combined with progestins in primary prevention remain.¹²⁶ They do not, however, prove that combined therapy is beneficial. Observational studies are inherently subject to various biases because the investigator has no control over the exposure to the factor of interest and must deal with imperfectly collected or recollected information about the variables of interest. The observational studies of HRT are no different.

When confronted with the choice of using HRT, most women claim that their biggest fear is the possible increased risk of breast cancer. Numerous epidemiologic studies have tried to address this issue with conflicting results, and no one study is definitive. The Nurses’ Health Study¹²⁷ suggested that the relative risk of breast cancer for women currently using estrogen is 1.3, which translates into a 30% increase in risk. Risk was related to the duration of use, with use over 5-10 years being more significant. No increase was found in past users. On the other hand, the Iowa study found that women with a family history of breast cancer who used HRT did not have a significantly increased incidence of breast cancer, even with use of more than five years.¹²⁸ Despite the questionable increased risk, all studies (except one)¹²⁷examining mortality from breast cancer in hormone users have documented lower mortality for women on HRT. This may reflect earlier diagnosis in HRT users who are more likely to have regular mammograms, or that estrogen exposure results in better differentiated tumors that are less aggressive.^128,129

In women with a uterus, more than two decades of evidence have linked the use of unopposed estrogen with adenocarcinoma of the endometrium. A recent meta-analysis estimated this risk to be 2.3 times that of non-users. With 10 or more years of exposure, the relative risk climbed to 9.5 and remained elevated five years after discontinuation.¹³⁰ Adding a progestin negates this risk to that of placebo¹³¹ and should be considered standard in nonhysterectomized women.

Some physicians advocate the addition of androgens to HRT for menopausal women, particularly if they experience diminished libido, cognitive difficulties, or low mood. Small studies have suggested some effect,¹³² but large randomized clinical trials are lacking. Adding an androgen does not diminish the ability of estrogen to relieve vasomotor symptoms or increase bone density.¹³³ In contrast to standard HRT, however, HDL cholesterol decreases with the addition of testosterone, which may have a bearing on long-term cardioprotection in women. Other potent side effects include acne, hirsutism, weight gain, and aggressiveness, although these have mainly been reported in higher doses.

Hormone therapies are often used in patients with prostatic, breast, endometrial, and ovarian cancers. Some data suggests that this approach may be of value in pancreatic cancer, as well. Some in vivo and in vitro experiments indicate that estrogen promotes pancreatic cancer growth.¹³⁴ Androgen receptors have also been found in pancreatic cancers, and testosterone has been found to stimulate pancreatic tumor growth. Nevertheless, the role of both estrogens and androgens in human pancreatic cancer currently remains unclear.^135,136

DHEA also has androgenic effects, particularly in women.¹³⁷ It also may increase the risk of prostate cancer.^137,138 Furthermore, DHEA increases the level of IGF-I. This increases the risk of prostate cancer, female breast and ovarian cancer. According to one prospective study, men with the highest levels of IGF-I had a 4.5 times greater risk of developing prostate cancer. For those over the age of 60, the risk was eight-fold.¹³⁹ IGF-I also stimulates prostate cancer cells to make urokinase-type plasminogen activator (a substance that promotes tumor cell growth).¹⁴⁰ Finally, IGF-I increases tumor growth by supporting angiogenesis.¹⁴¹

Alternatives for women who cannot tolerate or who prefer not to take estrogen are selective estrogen receptor modulators (SERMs) and phytoestrogens. SERMs are a relatively new class of drugs being used for HRT. These drugs bind to the estrogen receptor and have both agonist and antagonist effects, depending on the target organ.¹⁴² Tamoxifen is a first generation SERM that was approved by the FDA in 1969. Because it blocks the effect of estrogen on the breast, it has been used extensively as adjuvant therapy for prevention of receptor-positive breast cancer recurrence. Drawbacks include the onset or worsening of hot flashes, endometrial hyperplasia with the attendant risk of neoplasia, and increased risk of thrombosis.

Raloxifene is a newer generation SERM that has received a lot of attention for use as HRT in postmenopausal women. At a dose of 60mg q.d. raloxifene provides estrogenic effects on the breast and endometrium.^143,144 No studies have documented the vasodilatory effects that estrogen has, or whether a long-term benefit on cardiovascular outcome exists. A direct comparison between raloxifene and estrogen has not been published.

Phytoestrogens are naturally occurring plant-based substances with weak estrogenic effects. The most common forms are isoflavones, found in soybeans and soy products, and lignans, found in flaxseed, vegetables, legumes, and cereals. The clinical importance of the estrogenic effects of the compounds is debated, although more data suggesting some efficacy are accumulating. A recent study found that perimenopausal women given a daily dietary soy supplement had a 45% reduction in daily hot flashes at 12 weeks compared to a 30% reduction in the placebo arm¹⁴⁵. Regarding potential benefits on the lipid profile, a meta-analysis of 38 controlled clinical trials found that the consumption of soy protein rather than animal protein resulted in significant decreased levels of total cholesterol. LDL, and triglycerides.¹⁴⁶ However, a more recent study failed to show a significant impact of medium-term supplementation with 80mg/day of isoflavones on lipid and lipoprotein levels, or on endothelial function in healthy, postmenopausal women.¹⁴⁷ One concern with these compounds is whether high intake may result in endometrial hyperplasia in women with a uterus, similar to the effect of unopposed estrogen.

A longitudinal study established in 1965 for research on heart disease, stroke and cancer among surviving participants in a Hawaiian-based population group for consumption of selected foods examined associations of midlife tofu consumption with brain function and structural changes in later life. In this population, higher midlife tofu consumption was independently associated with indicators of cognitive impairment and brain atrophy in late life.¹⁴⁸

The relationship between the use of estrogen replacement therapy (ERT) and cerebral magnetic resonance imaging (MRI) abnormalities in older women was recently compared in a population-based prospective study (Cardiovascular Health Study). Current ERT users had more clinically significant central atrophy than nonusers, but the implications remained unclear.¹⁴⁹

More data are needed before these compounds can be recommended as a replacement for long-term HRT.

Inflammation, Insulin Resistance and Endothelial Dysfunction
The acute coronary syndrome: unstable angina, myocardial infarction and sudden death occurs from rupture of unstable atheromatous plaques in the wall of coronary arteries. In 70% of cases, before rupture these plaques are obstructing less than 50% of the arterial lumen.¹⁵⁰ The atheromatous plaque becomes unstable because of weakening at the shoulder of its fibrous cap. The weakening of the fibrous plaque is caused by cytokines produced from activated leukocytes (mainly monocytes) within the plaque, and the greater number of leukocytes within the plaque, the greater the possibility of rupture of the plaque.

Rupture of an atheromatous plaque leads to dissection and expansion of the plaque. The blood and clot formation on the plaque may partially obstruct the lumen and cause unstable angina, may completely block the lumen and cause a myocardial infarction, or may embolize and cause an apical infarct.¹⁵¹

The Multiple Risk Factor Intervention Trial showed that an increased basal level of highly sensitive C-reactive protein was associated with a five-fold risk of developing clinical manifestation of coronary artery disease.¹⁵² Other studies have shown significant increases in highly sensitive C-reactive protein levels in women and elderly patients who have had a myocardial infarction and in patients with both stable and unstable angina.^153-155 Furthermore, a recent risk factor assessment showed that an increased highly sensitive C-protein level was a better predictor of occurrence of a myocardial infarction than were serum levels of lipoprotein(a), homocysteine, total cholesterol, fibrinogen and tissue-type plasminogen activator or the ratio of total cholesterol to HDL.¹⁵⁶

In the Physicians Health Study, the predictive value of the increased C-reactive protein level was nullified by taking a buffered aspirin on alternative days.¹⁵⁷ This outcome raises the question of whether the beneficial effect of prophylactic use of aspirin is due to the anti-platelet activity of aspirin, its anti-inflammatory properties, or both. In addition, an analysis of serum from patients in the Cholesterol and Recurrent Events Study showed not only that an increased basal C-reactive protein level was associated with cardiac events, but also that this association was negated in the group that used pravastatin.¹⁵⁸ In addition to its lipid lowering effects, pravastatin is known to be an anti-inflammatory agent.

C-reactive protein is only one marker for inflammation. Other markers of the acute phase response (a general nonspecific response to tissue damage and inflammation) have also been found to be predictive for cardiac events. Such markers include increased serum levels of fibrinogen and soluble intracellular adhesion molecules.¹⁵⁹

There are several possible reasons that inflammation occurs within atheromatous plaques. The first is the presence of insulin resistance, which in itself is an inflammatory state. The second is the presence of hyperglycemia which not only predisposes to infection by decreasing the efficacy of leukocytes, but also allows the formation of advanced glycosylated end products (AGEs). Both insulin resistance and increased AGE levels are associated with endothelial dysfunction, which enhances the ability of leukocytes and bacteria to enter the plaque.¹⁶⁰

Proposed Mechanism for Injury
As previously stated, insulin resistance is thought to be a chronic low-grade inflammatory state, which is an independent risk factor for ischemic heart disease,¹⁶¹ and an increase in many acute phase reactants has been documented in the presence of insulin resistance.¹⁶²  In the acute state, the acute phase response is protective by countering the effects of injury, which improves survival. However, long-term exposure to stressful stimuli such as obesity, lack of exercise, aging, may result in disease instead of repair. For example, with progressive aging, the acute phase response and macrophage cytokine production both increase. In addition, both chronic infections and malignant conditions that stimulate the acute phase response have features of the insulin resistance syndrome (high triglycerides, low HDL, increased fibrinogen, and microalbuminuria). With insulin resistance, the acute phase response changes are small in comparison with those of infection, but the potential damage is greater because of the chronicity of the changes.¹⁶³

Increasing cytokine levels can also reproduce the insulin resistance syndrome. This leads to directing HDL from the liver to the macrophage for use in endothelial cellular repair,¹⁶⁴ increasing fibrinogen levels by increasing the production of PAI-1,^165,166 and stimulating the production of growth hormone and corticotropin-releasing hormone.^167,168 Cytokines, by increasing endothelial permeability, allowing increased migration of macrophages into the subendothelial space, and stimulating smooth muscle proliferation, have a role in the genesis of atherosclerosis; a possible explanation why insulin resistance is an independent risk factor for coronary artery disease.¹⁶⁹ On the basis of the fore-going material, one can hypothesize that the link between inflammation and atherosclerosis is endothelial dysfunction.¹⁷⁰

Protease Inhibitor Side Effects and Insulin Resistance
On a slightly different note, administration of HIV protease inhibitors, while beneficial to AIDS patients, often results in serious side effects. In particular, patients may develop insulin resistance that leads to type 2 diabetes: Murata et al. studied the effects of HIV protease inhibitors indinavir, ritonavir and amprenavir on glucose transport and found that glucose uptake in 3T3-L1 cells via the transporter Glut 4 was severely reduced. Because this transporter is responsible for the insulin-stimulated glucose uptake into muscle and fat, this result suggests a direct connection between protease inhibitors and the development of insulin resistance, and perhaps other disruptions of lipid metabolism.¹⁷¹

In that regard, a three months randomized controlled low-dose trial of the biguanide, metformin, in the treatment of HIV lipodystrophy syndrome was conducted. All patients were receiving protease inhibitors. Reduction of hyperinsulinemia, weight and blood pressure resulted in an improved CAD risk profile. However, patients receiving GH were excluded from this short study. Further studies are necessary to assess directly the effects of metformin on insulin sensitivity in patients with HIV lipodystrophy syndrome using protease inhibitors, and GH.¹⁷²

This new insight is particularly disturbing because it will undoubtedly increase the difficult task of physicians already using GH to manage their HIV or AIDS-related disorders patients.

Insulin Sensitivity and Endothelial Function
Insulin resistance is a multifaceted phenomenon, characterized by decreased rates of insulin-mediated glucose uptake and accompanied by hyperinsulinemia and adverse changes in cardiovascular risk factors, such as high triglyceride levels, low HDL cholesterol levels, and hypertension. The cluster of abnormalities associated with insulin resistance and compensatory hyperinsulinemia has been suggested to increase the risk of cardiovascular disease.^101,102 Since 92% of aging patients with type 2 diabetes are insulin resistant, this presents a major health care problem reflected by the fact that 80% of the aging population die from some form of vascular disease.^173,174

Until recently, the only pharmacological intervention directed at treating insulin resistance was to overwhelm it with sulfonylureas or exogenous insulin. Today, two new classes of agents, biquanides and thiazolidinediones, specifically improve muscle insulin sensitivity and increase insulin-stimulated glucose disposal in skeletal muscle and adipose tissue.^101,102

Insulin resistance (IR) is a common clinical condition. Obesity, type 2 diabetes and essential hypertension are all IR states. It is now well recognized that IR (particularly when associated with central fat distribution) is associated with a cluster of cardiovascular risk factors and a markedly increased risk of macrovascular disease. The risk of death from coronary heart disease in subjects with impaired glucose tolerance (IR) is increased 2-3 fold and can not be accounted for by traditional cardiovascular risk factors. Investigators have recently found that obese and type 2 diabetic subjects display severely impaired endothelial dependent vasodilatation to intra-arterial methacholine chloride but normal endothelium independent vasodilatation to sodium nitroprusside. They found a strong inverse relationship between body fat content or insulin resistance and endothelial dependent vasodilatation. In other studies they assessed in vivo nitric oxide production by measuring nitrate and nitrite (NOX) concentrations in femoral venous blood and calculated NOX flux by multiplying NOX by femoral blood flow. They found that in response to insulin (an endothelium dependent vasodilator) NOX flux was markedly reduced in IR compared to insulin sensitive subjects. More recently they have delineated a potential mechanism for impaired endothelium dependent vasodilatation in IR. Individuals with IR exhibit daylong elevations in circulating free fatty acids (FFA). They have tested whether acute elevation of circulating FFA concentrations can induce endothelial dysfunction in insulin sensitive subjects. To this end, they measured endothelial function before and after an infusion of a lipid emulsion in combination with heparin to raise circulating FFA 2-3 fold above basal levels. They found that FFA elevation cause a rapid and marked impairment in endothelial function. Finally, They have recently tested the ability of reversal of IR with the insulin action enhancers biquanide and troglitazone on endothelial function. Biquanide and/or troglitazone therapy resulted in a 25% improvement in insulin action and a nearly normalization of endothelial function. They conclude that 1) IR is strongly associated with endothelial dysfunction characterized by reduced stimulated NO production, 2) FFA may play a causal role in the induction of endothelial dysfunction in IR. Thus, endothelial dysfunction may be a major contributor to the increased risk of cardiovascular disease in subjects with IR and reversal of IR may have a beneficial effect to reduce that risk. ¹⁷⁵

Psychosocial Factors
A population based study of young men and women aged 18 to 30 over a 10 year period demonstrated a positive graded association between hostility scores at baseline and coronary artery calcification measured using Electron-Beam Computed Tomographic (EBCT) scans 10 years later.¹⁰² Therapy directed at reducing hostility has been shown to reduce the risk of nonfatal reinfarction by more than 50%.¹⁰⁴ An important implication of these findings is that therapy directed at reducing hostility also may have value in preventing the development of subclinical atherosclerosis.

Coronary artery calcification detected by EBCT occurs early in plaque development as part of the inflammatory pathophysiologic cascade of CAD, and is regulated in part by a process similar to bone mineralization. Although not all atherosclerotic segments have detectable calcification, the area of coronary artery calcification quantified on EBCT has a positive relationship with the histopathologic coronary plaque area.¹⁷⁶

The implication is that coronary calcification may be a stronger predictor of angiographic CAD than are standard risk factors,¹⁷⁷ and may be an earlier predictor of coronary events including coronary death, myocardial infarction, or revascularization.^178,179

In terms of psychosocial factors, hostility is considered a personality and character trait with cynicism, mistrust, anger, overt and repressed aggression components.¹⁸⁰ Depression and stress in general have similar characteristics and attitudes.¹⁸¹ Clinical trials are needed to test whether reduction in hostile attitudes and behaviors is an effective means of preventing atherosclerosis and thus ameliorating the burden of coronary disease.

Stress and Immune Function
There is now significant literature showing that psychological stress can down-regulate various aspects of the cellular immune response. It is also established that communication between the central nervous system and the immune system occurs through bi-directional signals linking the nervous, endocrine and immune systems. Psychological stressors affect the immune system by disrupting these networks.

At the molecular level, human immune function is mediated by the release of cytokines, nonantibody messenger molecules from a variety of cells in the immune system, and from other cells, such as endothelial cells. These cytokines subsequently stimulate cellular release of specific compounds involved in the inflammatory response, such as the inflammatory cascade of CAD.¹⁸²

Such biochemical alterations in immune function are, in part, induced by plasma hormone concentration changes elicited by a stressor subsequent to activation of the sympathetic nervous system and the sympathetic-adrenal medullary and hypothalamic-pituitary-adrenal-axes. For example, Beta-adrenergic blocking agents have ameliorated cellular immune and cardiovascular responses to mental stress in humans.^183,184 Thus, the hormonal content of plasma, which in many cases is determined by activity of discrete areas of the brain (for example, the hypothalamus or locus coerulus), can influence the activity of the immune system.^185,186

Information on the impact of stress-induced changes in immune response and in risk for infectious disease is limited. However, data thus far support the hypothesis that the down-regulation or dysregulation of different components of the immune response associated with psychological stressors may have health implications with regard to infectious disease as well as cardiovascular disease.

In addition, it is noteworthy that stress has also been associated with reports of both greater severity and prolongation of disease in patients with infectious diseases as well as other immune-mediated diseases. Stress reduction might also provide significant benefits to these patients.^187-189 Thus, physicians should be encouraged to understand the role of stress in the pathogenesis of aging and the pathogenesis of diseases that accelerate aging such as infections, diabetes, asthma, vascular diseases, rheumatoid arthritis, multiple sclerosis, uveitis, inflammatory bowel disease, psoriasis, and cancer.

Outside of proven clinical interventions, there is good reason to think that promoting behavioral modification to healthy individuals such as certain changes in lifestyle might increase host resistance to illness and disease. These include broadening one’s social involvement (eq., joining social or spiritual groups, having a confidant, spending more time with supportive friends) and being more careful to maintain healthful practices such as proper diet, exercise, and sleep, especially under stressful conditions.¹⁸⁹ This might be the appropriate place to interject the old adage "Physician Heal Thyself!"

Effective Strategies for Intervention
Although there is little data, clinicians may reasonably suspect that the management of aging has become more heterogeneous with dramatic differences in style and approach used by practitioners, whether they be endocrinologists, primary care providers, or allied health professionals. Nevertheless, the rationale for any proposed construct of the management of aging must be approached comprehensively. The overall goal of aging management should be to provide an opportunity for a patient to live out as normal a life expectancy, with minimal complications, as possible. In order to do this, it is critical that we adhere to the fundamental and logical principles of clinical medicine, and not vague claims and inadequate knowledge of pathology that characterizes much of such care recently.

In general, it is essential to emphasize prevention. Atherosclerotic cardiovascular disease (ASCVD) risk assessment should be considered and evaluated. It should also be treated as part of an optimal risk reduction program.¹⁹⁰ Hormone replacement is clearly contraindicated until baseline coronary artery disease (CAD) has been aggressively managed and reduced. Because of its prevalence and occult nature with symptomatology presenting usually only at advanced stages of the disease, physicians are strongly urged to obtain EBCT studies along with studies of other cardiovascular risk factors including lipids, blood pressure, fibrinogen, platelet activity and insulin. The clinician should be aware of these risk factors and treat them by diet, improved glycemic control and drug therapy. Evidence suggests that correction of lipoprotein abnormalities, raised blood pressure (BP) and smoking is beneficial.^{173,174,191-193}

Sedentary Lifestyle
The concept that inactivity leads to an increased risk of ASCVD has become generally accepted by healthcare professionals and the public. It is estimated that 12% of all mortality in the United States may be related to lack of physical exercise.¹⁹⁴ This has led to physical inactivity becoming a major target for preventive medicine. However, no single study provides significant evidence of a causal relationship between physical inactivity and aging.

During the past half century, approximately 50 studies have suggested an association between physical activity and the prevalence or incidence of initial clinical manifestations of CAD, especially myocardial infarction and sudden death.¹⁹⁵ The findings in these studies were too diverse to conclude a concise summary. However, several findings occurred frequently enough to include here: (1) more active people appear to be at lower risk for ASCVD; and (2) moderate amounts of exercise appear to be beneficial.

The evidence indicates exercise probably exerts its beneficial effect through a variety of mechanism: improved myocardial supply/demand relationships; lower plasma triglycerides; raised HDL-cholesterol; reduced BP; and decreased platelet aggregation.¹⁹⁶ Several meta-analysis of randomized trials support a reduction of 20-30% in coronary disease with regular aerobic exercise.^197,198

Obesity
About 30% of the U.S. population is obese (weighting more than 40% of the desired range).^199,200 Epidemiologic studies have observed an increase in morbidity from both CAD and stroke with increasing obesity.^201,202 Obesity is associated with other ASCVD risk factors including low HDL, diabetes, hypertension and increased triglyceride concentrations. It is probable that much of the increased ASCVD risk associated with obesity is mediated by these other metabolic abnormalities.

Visceral or central obesity, which can be quantified by the waist-to-hip ratio (0.9 in men and 0.8 in women) is a common form of obesity associated with the particular metabolic syndrome of insulin resistance, low HDL, elevated triglycerides, LDL subclass pattern B, and hypertension. This cluster of related abnormalities is referred to as Metabolic Syndrome X.  The constellation of lipid abnormalities in Metabolic Syndrome X is designated as the Atherogenic Lipoprotein Phenotype (ALP). ALP has been shown to increase CAD risk.²⁰³ Although no study has specifically examined the effect, or the type of weight loss on CAD events, it is probable that weight reduction will beneficially alter other important risk factors (e.g. lipoprotein abnormalities) that are associated with obesity.

Hypertriglyceridemia
Hypertriglyceridemia (HTG) is a common finding in the insulin resistance syndrome (Metabolic Syndrome X). Many prospective studies have identified HTG as a risk factor in univariate analysis, although after adjustment in multivariate analysis for HDL or APO-B , the association is diminished.^204-210 The status of HTG as a risk factor for CAD remains controversial. High triglycerides are often associated with low HDL-cholesterol concentration, suggesting that this may be responsible for the increase in CAD risk from HTG. At the same time, HTG is also associated with small, dense LDL particles and high APO-B concentrations. Small, dense LDL particles and high APO-B are independent risk factors for CAD.²¹¹

In the Stockholm Ischemic Heart Disease Secondary Prevention Study,²¹² the group treated with clofibrate and nicotinic acid had a significant reduction in the rate of mortality from CAD, which was significantly correlated with the reduction in total triglyceride levels and not with the reduction in cholesterol levels. In The Helsinki Heart Study,²¹³ the reduction in CAD resulting from gemfibrozil therapy was largely localized to the subgroup with a triglyceride level of more than 204mg/dl and a ratio of LDL-cholesterol to HDL-cholesterol of more than 5.

Measuring fasting insulin level, particularly in HTG subjects with obesity and normal fasting glucose levels, should be considered. An elevated fasting insulin level in normoglycemia suggests the need for drug intervention that will increase insulin sensitivity along with reducing triglycerides. Weight reduction, exercise, and balanced diets divided equally into six small feedings per day low in carbohydrates (40% calories) and higher in proteins (40% of calories) should be encouraged. Certainly, when triglycerides are markedly higher (>500mg/dl), fibric acid derivatives, and in nondiabetic, nonhyperinsulinemic patients, nicotinic acid would be useful.

The 1993 National Cholesterol Education Program (NCEP) guidelines⁹ define a favorable triglyceride levels as less than 200mg/dl. Recently, Miller et al. suggested that the NCEP definition of "elevated" triglyceride levels be lowered to reflect the growing concern about the health effects of elevated lipid levels in general.²¹⁴ Their research uncovered three independent predictors of CAD events: diabetes mellitus; low HDL-cholesterol levels (<35mg/dl); and triglyceride levels greater than 100mg/dl. Based upon their retrospective cohort study of 740 heart disease patients, the researchers were convinced that "triglyceride levels previously considered normal are predictive of new CAD events. The cutpoints established by The National Cholesterol Education Program for elevated triglycerides (>200mg/dl) may need to be redefined."

Hormone-Resistant States
The concept of hormone resistance as the cause of endocrinologic dysfunction was first suggested by Fuller Albright and colleagues in 1942 as the mechanism for parathyroid hormone unresponsiveness in pseudohypoparathyroidism.²¹⁵ To date, clinical syndromes of hormone resistance have been described with nearly all hormones.²¹⁶

Extrinsic or secondary defects as a mechanism of hormone resistance result from circulating serum factors, and are reversible following therapeutic perturbations that remove the resistance-causing factor from the blood stream. These defects do no persist in cultural cells. Using insulin resistance as the paradigm, extrinsic factors that reduce insulin action include states of counterregulatory hormone excess, antibodies blocking the insulin receptor, and uremia. That obesity and type II diabetes may be due to extrinsic factors is suggested by improvement and even reversibility of insulin resistance with dietary and pharmacologic interventions.^217,218

Examples of extrinsic (reversible) cellular causes of insulin resistance are: (a) Physiologic states-puberty (perhaps secondary to increased GH secretion), pregnancy, and old age. (b) Abnormal physiologic states-infection, stress, starvation, uremia, cirrhosis, and ketoacidosis. (c) Endocrine causes-glucocorticoids, GH, glucagon, disorders of thyroid function, and hyperparathyroidism.^218-222 (d) Antibodies blocking the insulin receptor.

Reversible forms of GH resistance occurs in the setting of malnutrition, chronic renal failure and diabetes. Also specific binding proteins, the most significant of which is a 150kD GH-dependent ternary complex known as IGF-BP3. The role of IGF-binding proteins is not fully understood, although in most cases, they inhibit IGF action.^220,221

Premature ovarian failure is another syndrome which physicians need to consider. Women with this condition have gonadotropin-resistance ovary syndrome. However, these patients do not undergo physiologic premature menopause because ovarian follicular failure from atresia is not evident in biopsy. The premature ovarian failure in this syndrome is thought to result from defective LH receptors, although verifications of this theory awaits molecular confirmation.²²²

Adult GH Deficiency
The total incidence of adult GH deficiency is not known, but indirect estimates based on the number of patients with pituitary tumors suggest that acquired GH deficiency may affect ten people per million annually. The severity of the condition in these patients is variable.

Most cases of severe GH deficiency acquired in adult life appear to result from pituitary or peripituitary tumors or their treatment.²²³ A number of possible causes of hypopituitarism range from idiopathic to undifferentiated tumors. Of these, benign pituitary adenomas are the most common.²²⁴

Interestingly, the loss of hormones in progressive hypopituitarism follows a characteristic sequence, in which the secretion of GH appears to be particularly sensitive to pituitary disease. Circulating levels of GH are the first to decrease, followed by the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and finally, thyroid-stimulating hormone (TSH) and adrenocorticotrophin (ACTH).²²⁵

Hypopituitarism as a result of pituitary adenoma usually develops slowly, which explains why the symptoms are often vague. The classic finding is the progressive loss of pituitary function in the following order: GH, FSH/LH, TSH and ACTH. However, variations do occur and in some patients isolated GH deficiency is the presenting feature.

Demonstration of abnormally low levels of GH is central to the diagnosis of GH deficiency. For most purposes, assessment by provocation testing is regarded as adequate. The test most commonly used is the GH response to hypoglycemia induced by a standard bolus of insulin (0.15U/kg, insulin tolerance test). Glucagon, GHRH, L DOPA, propranolol, arginine tests are also sometimes used. Maximum response of GH less than 10ng/ml are considered to indicate some degree of GH deficiency.

One problem in assessing adult GH deficiency derives for the lack of consensus on the definitions of complete and partial deficiency. This is illustrated in the literature, where the inclusion criteria for studies in GH-deficient patients vary markedly. In North America, for example, a response of less than 10ng/ml has been taken to indicate GH deficiency, while most Europeans investigators use more conservative values of 3-5ng/ml.²²⁶ The American Association of Clinical Endocrinologists (AACE) Board of Directors has published their most recent systemic review of current data and a summary of guidelines for GH use to clinical endocrinologists.²²⁷The review by Klibanski et al., Endocrine Practice, 1999, seems to indicate a more universal acceptance for the 5ng/ml cutoff.²²⁸

A further problem in defining GH deficiency in adults is the enormous variation in secretion rate of GH associated with normal physiological variables, including age, sex, degree of obesity, food intake, nutritional status, and physical activity. Several activities have shown a natural age-related decrease in GH secretion. ^229-232 Veldhuis and co-workers, for example, estimated reductions in GH secretion of approximately 14% per decade, and approximately 6% for each unit increase in body mass index.²²⁷ In absolute terms 24-hour GH production rates were found to be reduced 50%, either with an increase in age from 21 to 45 years, or with an increase in the body mass index from 21 to 28.

The natural variation of GH status in adults makes it difficult to define the condition of GH deficiency accurately in all but the most extreme cases, in which secretion of GH is virtually undetectable.^232-234 Detailed studies of normal profiles in large numbers of individuals are required to establish adequate reference data to enable the deficient state to be distinguished from normal variations in GH secretion.

For screening patients with suspected GH deficiency, the plasma concentration of IGF-I provides an overall index of GH secretion, and assays of IGF-I are becoming widely used. It is possible that such assays could be useful as a screening test for GH deficiency, as well as for acromegaly. It is important, however, to recognize that the IGF-I concentration is dependent on the nutritional status of the patient. The levels of IGF-I binding protein (IGF-BP3) are GH dependent, and recent work suggests that assessment of the plasma levels of this protein may be more valuable than IGF-I levels in screening for GH deficiency.²³⁵

Another important concern about IGF-I concentration is based upon the widespread practice of non-endocrinologist "anti-aging doctors" to strive toward elevating their patients’ IGF-I levels to 350 to 500ng/l, following the Rudman report.¹ IGF-I is a mitogen for vascular smooth muscle cells (SMC) in vitro and at low doses enhances SMC proliferation in vivo in diabetic rats. IGF-I is also known to have anabolic effects. Treatment with higher infusion rates of IGF-I increased body weight significantly compared to control animals. At high concentrations, IGF-I elicits insulin effects by binding to insulin receptors.²³⁶ In another study, IGF-I was shown to increase aortic-elastogenesis in vivo.²³⁷ This study was done with uninjured aorta. Contradictory results were obtained by the study done on ballon injured aorta. It was then possible to stimulate proliferation of aortic vascular SMC in normal rats with high levels of IGF-I in the circulation.²³⁸

Measurement of urinary GH excretion may also provide a useful screening test. Gerard and Fischer-Wasels have shown that urinary levels of GH reflect circulating levels of the hormone; timed samples follow closely the changes in plasma values. Moreover, the mean of several night samples appears to be valuable in the noninvasive assessment of GH status.²³⁹

A detailed evaluation by a neuroendocrinologist of other pituitary hormones is, of course, also required in adult patients with suspected GH deficiency. Radiologic investigation of the pituitary gland should be performed using either CT or MRI, and assessment of the visual fields is obligatory, as in all patients with suspected pituitary disorders. It is recommended that all adult patients receiving GH therapy be closely supervised by a neuroendocrinologist on an ongoing basis.²⁴⁰

Figure 1.

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References:

1. Rudman D, Feller AG, Nagraj HS, et al. Effects of human growth hormone in men over 60 years-old. New England Journal of Medicine 1990; 323:1-6.
2. Cohn L, Feller AG, Draper MW, et al. Carpal tunnel syndrome and gynecomastia during growth hormone treatment of elderly men with low circulating IGF-I concentrations. Clin Endocrinol 1993; 39:417-425.
3. Rudman D, Shetly KR. Unanswered questions concerning the treatment of hyposomatotropism and hypogonadism in elderly men. J Am Geriatr Soc 1994; 42:522-527.
4. Rudman D, Feller AG, Coln L, et al. Effects of human growth hormone on body composition in elderly men. Horm Res 1991; 36(Suppl 1); 73-8
5. Blackman, MR, Harman SM, Roth J, Shapiro JR: GHRH, GH, and IGF-I Basic and Clinical Advances. New York: Springer-Verlag, 1995.
6. Lee-Benner L: Physician’s Guide to Free Radicals, Immunity and Aging Second Revised Edition, Newport Beach, CA : World Health Foundation Publication, 1990.
7. Growth Hormone Research Society (GRS) Consensus Guidelines for Diagnosis and Treatment of Adults with GH Deficiency. Port Stevens Workshop, Australia, April 14-17, 1997, J Clin Endocrin of Metab, Feb, 1998.
8. American Association of Clinical Endocrinologists (AACE) Clinical Practice Guidelines for Growth Hormone Use in Adults and Children. Endocrine Practice, May/June 1998; 4:165-173.
9. National Cholesterol Education Program Expert Panel. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993; 269:3015-3023.
10. Miller M. Normal triglyceride levels and coronary artery disease events: The Baltimore Coronary Observational Long-term Study. J Am Coll Cardiol 1998; 31:1252-1257.
11. Scance AM, Fless GM. Lippoprotein (a):Heterogeneity and biological relevance. J Clin Invest 1990; 85:1709-1715.
12. Berg K. Twin research in coronary heart disease. In: Gedda L, Parisi P, Nance WE eds. Twin research 3: Epidemiological and Clinical Studies. New York, N.Y.: Alan R., Liss, Inc; 1981:117-130.
13. Lamon-Fava S. the NHLBI twin study: Heritability of apoprotein A-1, B, and the low density lipoprotein subclasses and concordance for lipoprotein (a). Atherosclerosis 1991; 91:97-106.
14. Guyton JR. Relationship of plasma lipoprotein Lp(a) levels to race and to apolipoprotein B. Atherosclerosis 1985-5:265-272.
15. Rosengren A. Lipoprotein (a) and coronary heart disease: A progressive case-control study in a general population sample of middle-aged men. Br Med J 1990; 301:1248-1251.
16. Jauhiainen M. Lipoprotein (a) and coronary heart disease risks, a nested case-control study of the Helsinki Heart Study participants. Atherosclerosis 1991; 89:59-67.
17. Sigurdsson G. Predictive value of apolipoproteins in a prospective survey of coronary artery disease in men. Am J Cardiol 1992; 69:1251-1254.
18. Sandholzer C. Apolipoprotein (a) phenotypes, Lp(a) concentration and plasma lipid levels in relation to coronary heart disease in a Chinese population: Evidence for the role of the apo(a) gene in coronary heart disease. J Clin Invest 1992; 89:1042-1046.
19. Schaefer EJ. Lipoprotein (a) levels and risk of coronary heart disease in men: The Lipid Research Clinics Coronary Primary Prevention Trial. JAMA 1994; 271:999-1003.
20. Rader DJ. Quantitation of plasma apolipoproteins in the primary and secondary prevention of coronary artery disease. Ann Intern Med 1994; 120:1012-1025.
21. Tamura A. Serum lipoprotein (a) concentrations are related to coronary disease progression without new myocardial infarction. Br Heart J 1995; 74:365-369.
22. Terres W. rapid angiographic progression of coronary artery disease in patients with elevated lipoprotein (a). circulation 1995; 91:948-950.
23. Desmarais RL. Elevated serum lipoprotein (a) is a risk factor for clinical recurrence after ballon coronary angioplasty. Circulation 1995; 91:1403-1409.
24. Yamamoto H. Risk factors for restenosis after percutaneoous transluminal coronary angioplasty: Role of lipoprotein (a). Am Heart J 1995; 130:1168-1173.
25. Koltringer P, Jurgens G. A dominant role of lipoprotein (a) in the investigation and evaluation of parameters indicating the development of cervical atherosclerosis. Atherosclerosis 1985; 58:187-198.
26. Murai A. Lp(a) lipoprotein as a risk factor for coronary heart disease and cerebral infarction. Atherosclerosis 1986; 59:199-204.
27. Zenber G. Lipoprotein (a) as a strong indicator for cerebrovascular disease. Stroke 1986; 17:942-945.
28. Molgaard J. Significant association between low-molecular weight apolipoprotein (a) isoforms and intermittent claudication. Atheroscler Thromb 1992; 12:895-901.
29. Valentine Rj. Lp (a) lipoprotein is an independent discriminating risk factor for premature peripheral atherosclerosis among white men. Arch Intern Med 1994; 154:801-806.
30. Cantin B. Lp (a) distribution in a French Canadian population and its relation to intermittent claudication (the Quebec Cardio Vascular Study) Am J Cardiol 1995; 75:1244-1248.
31. Rhoads G.G. Lp (a0 Lipoprotein as a risk factor for myocardial infarction. JAMA 1986; 256:2540-2544.
32. Cantin B, Is lipoprotein (a) an independent risk factor for ischemic heart disease in men? The Quebec Cardiovascular Study. J Am Coll Cardiol 1998; 31:519-525.
33. Thompson GR. Familial hypercholesterolemia regression study. A randomized trial of low density lipoprotein apheresis. Lancet 1995; 345:811-816.
34. Guraber A. Levels of lipoprotein Lp(a) decline with neomycin and niacin treatment. Atherosclerosis 1985; 57:293-301.
35. Selhub J. Vitamin status and intake as primary determinants of homcysteinemia in an elderly population. JAMA 1993; 270:2693-2698.
36. Ubbink JB. Vitamin B₁₂ Vitamin B₆, and folate nutritional status in men with hyperhomoscysteinemia. Am J Clin Nutr 1993; 57:53-57.
37. Rimm EB. Folate and Vitamin B₆ from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998; 279:359-364.
38. Ueland PM. Plasma homcysteine and cardiovascular disease. In: Francis RB. Fr.ed. Atherosclerotic Cardiovascular Disease, Hemostasis and Endothelial Function. NewYork: Marcel Dekker; 1992:183-236.
39. Boushey CJ. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: Probable benefits of increasing folic acid intakes. JAMA 1995; 274:1049-1057.
40. Verhoef P, Stampfer MJ. Prospective studies of homocysteine and cardivascular disease. Nutr Rev 1995; 53:283-288.
41. Bruttstrom L. vitamins as homocysteine-lower agents. J Nutr 1996; 126(suppl); 12765-12805.
42. Jen Heijer M. Hyperhomoscysteinemia as a risk factor for deep vein thrombosis. N Eng J Med 1996; 334:759-762.
43. Stampfer MJ. A prospective study of plasma homocysteine and risk of myocardial infarction in U.S. physicians. JAMA 1992; 268:877-881.
44. Kuller LH, Evans RW. Homocysteine, vitamins and cardiovascular disease. Circulation 1998; 98:196-199.
45. Libby P. Molecular basis of acute coronary syndrome. Circulation 1995; 91:2844-2850.
46. Regenstrom J. Inverse relation between the concentration of low-density lipoprotein, Vitamin E, and severity of coronary artery disease. Am J Clin Nutr 1996; 63:377-385.
47. Niki E. Interaction among vitamin C, vitamin E, and beta-carotene. Am J Clin Nutr 1995; 63:377-385.
48. Stephens NG. Randomized controlled trial of vitamin E in patients with coronary artery disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996; 347:781-786.
49. Boffetta P., Garfin Kel L. Alcohol drinking and mortality among men enrolled in an American cancer Society prospective study. Epidemiology 1990; 1:342-348.
50. Klatsky AL. Risk of Cardiovascular mortality in alcohol drinkers, ex-drinkers and non-drinkers. Am J Cardil 1990; 66:1237-1242.
51. Colditz GA. A prospective assessment of moderate alcohol intake and major chronic diseases. Ann Epidemiol 1990; 1:167-177.
52. Criqui MH. The roles of alcohol in the epidemiology of cardiovascular disease. Acta Med Scand 1987; 7179suppl):73-85.
53. Regan TJ. Alcohol and the cardiovascular system. JAMA 1990; 264:377-381.
54. Gordon T. Alcohol and high density lipoprotein cholesterol. Circulation 1981; 64(suppl 111); 63-67.
55. Miller GJ., Miller N.E. Plasma high-density lipoprotein concentration and development of ischemic heart disease. Lancet 1976; 1:16-19.
56. Meade TW. Effects of changes in smoking and other characteristics of clotting factors and the risk of ischemic heart disease. Lancet 1987, 2:986-988.
57. Renaud S.deLorgeril M. Wine, alcohol, platelets and the French Paradox for coronary heart disease. Lancet 1992; 332:1523-1526.
58. Hertog MGL. Content of potentially anticarcinogenic flavinoids of tea infusions, wines and fruit juices. J Agric Food Chem 1992; 40:2379-2383.
59. Blackburn H. The concept of risk. Pearson TA, Criqui MH, Luepker RV, et al, eds. Primer in Preventive Cardiology, Dallas, Texas: American Heart Association; 1994:25-41.
60. Benedict Carey. Troubling Record for Anti-Aging Doctors. Los Angeles Times; S 7. May 8, 2000.
61. Salomon F, Cuneo RC, Hesp R, Sonksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 1989; 321:1797-1803.
62. Jorgensen JOL, Pedersen SA, Thuesen L, et al. Long-term growth hormone treatment in growth hormone deficient adults. Acta Endocrinol 1991; 125:449-453.
63. Degerblad M, Elgindy N, Hall K, et al. Potent effect of recombinant growth hormone on bone mineral density and body composition in adults with panhypopituitarism. Acta Endocrinol 1992; 126:387-393.
64. Whitehead HM, Boreham C, Mc Ilrath Em, et al. Growth hormone treatment in adults with growth hormone deficiency: results of a 13-month placebo controlled cross-over study. Clin Endocrinol 1992; 36:45-52.
65. Bengtsson B-A, Eden S, Lonn L, et al. Treatment of adults with growth hormone deficiency with recombinant human growth hormone. J Clin Endocrinol Metab 1993 a; 76:309-17.
66. Jorgensen JOL, Thuesen L, Muller J, et al. Three years of growth hormone treatment in growth hormone deficient adults:near normalization of body composition and physical performance. Eur J Endocrinol 1994; 130:224-8.
67. Rosen T, Johannsson G, Halgren P, et al. Beneficial effects of 12 months replacement therapy with recombinant human growth hormone to growth hormone deficient adults. Endocrinol Metab 1994a; 1:55-66.
68. Mardh F, Lundin K, Borg G, et al. Growth hormone replacement therapy in adult hypopituitary patients with growth hormone deficiency: combined data from 12 European placebo-controlled clinical trials. Endocrinol Metab 1994;1 (Suppl A): 43-9.
69. Goodman, H M, Schwartz J. Growth hormone and lipid metabolism. In: Knobil E, Sawyer Wh, eds. Handbook of Physiology. Volume 4. Washington: American Physiological Society, 1974:211-32.
70. Kostyo JL, Nutting DF. Growth hormone and protein metabolism. In: Knobil E, Sawyer WH, eds. Handbook of Physiology. Volume 4. Washington: American Physiological Society, 1974:187-210.
71. Johansson G, Rosen T, Wiren L, et al. Long-term effect of recombinant human growth hormone treatment on adults with growth hormone deficiency. Endocrinol Metab. 1994; 1(Suppl): Abstraact 27.
72. Russell-Jones D, Umpleby M, Hennesy T, et al. Intravenous insulin-like growth factor I (IGF-I) unlike insulin increases whole body protein synthesis in normal volunteers. Diabetes 1993b; 42(Suppl 1): 37A.
73. Russell-Jones DL, Weissberger Aj, Bowes SB, et al. Protein metabolism on growth hormone replacement therapy. Acta Endocrinol 1993a; 128 (Suppl 2): 44-7.
74. Umpleby M, Chubb D, Sonksen PH. The effect of ketone bodies on leucine and alanine metabolism in dogs. Diabetic Med 1986; 3: 375.
75. Jacob R, Barrett E, Pleuve G, et al. Acute effects of insulin-like growth factor I on glucose and amino acid metabolism in the awake fasted rat. J Clin Invest 1989; 83: 1717-23.
76. Fukagawa NK, Minaker KL, Good WR, et al. Acute effects of insulin-like growth factor (IGF) on leucine. Diabetes 1990; 38: (Suppl 1): 12A.
77. Cuneo RC, Salomon F, Wiles Cm, et al. Histology of skeletal muscle in adults with GH deficiency: comparison with normal muscle and response to GH treatment. Horm Res 1992b; 37: 23-8.
78. Whitney JE, Bennet LL, Li CH. Reduction of urinary sodium and potassium produced by hypophyseal growth hormone in normal female rats. Proc Soc Exp Biol Med 1952; 79: 584-7.
79. Herlitz H, Jonsson O, Bengstsson B-A. Effects on recombinant human growth hormone on cellular sodium metabolism. Clin Sci 1994; 86: 233-7.
80. Biglieri EG, Wathington CD, Forsham PH. Sodium retention with human growth hormone and its subfractions. J Clin Endocrinol Metab 1961; 21: 361-70.
81. Ludens JH, Bach RR, Williamson HE. Characteristics of the antinatriuretic action of growth hormone. Proc Doc Exp Biol Med 1969; 130: 1156-8.
82. Cuneo RC, Solomon F, Wilmshurst P, et al. Cardiovascular effects of growth hormone treatment in growth hormone-deficient adults: Stimulation of the renin-aldosterone system. Clin Sci 1991a; 81: 587-92.
83. Herlitz H, Jonsson O, Bengtsson B-A. Effect of recombinant human growth hormone on cellular sodium metabolism. Clin Sci 1994; 86: 233-7.
84. Ho KY, Weissberger AJ. The antinatriuretic action of biosynthetic human growth hormone in man involves activation of the renin-angiotensin system. Metabolism 1990; 39: 133-7.
85. Moller J, Jorgensen JOL, Moller N, Hansen KW, Pedersen EB, Christiansen JS. Expansion of extracellular volume and suppression of atrial natriuretic peptide after growth hormone administration in normal men. J Clin Endocrinol metab 1991; 72: 768-72.
86. Vandeweghe M, Taelman P, kaufman J-M. Short and long-term effects of growth hormone treatment on bone turnover and bone mineral content in adult growth hormone-deficient males. Clin Endocrinol 1993; 39: 409-15.
87. Eden S, Wiklund O, Oscarsson J, Rosen T, Bengtsson B-A. Growth hormone treatment of growth hormone-deficient adults results in a marked increase in Lp(a) and HDL cholesterol concentrations. Arterioscler Thromb 1993; 13: 296-301.
88. Olivecrona H, Ericsson S, Berglund L, Angelin B, Increased concentrations of serum lipoprotein (a) in response to growth hormone treatment. BMJ 1993; 306:1726-7.
89. Modigliani E, Kerchouni R, Uzzan B, Valensi P, Chanson P, Caron J. Modification of blood lipids and lipoproteins after human growth hormone treatment in adults with growth hormone deficiency: a preliminary report. Endocrinol metab 1994: 1(Supple A): 31-5.
90. Bratusch-Marrain PR, Smith D, DeFronzo RA. The effect of growth hormone on glucose metabolism and insulin secretion in man. J Clin Endocrinol Metab 1982; 55:973-82.
91. Sherwin RS, Schulman GA, Hendler R, Walesky M, Belous A, Tamborlane W. Effect of growth hormone on oral glucose tolerance and circulating metabolic fuels in man. Diabetologia 1983; 24: 155-61.
92. Fowelin J, Attvall S, von Schenck H, Smith U, Lager I. Characterization of the insulin-antagonistic effect of growth hormone in man. Diabetogia 1991; 34: 500-6.
93. Karnieli E, Laron Z, Richer N, Singer P, Wasserman M, Meyerovitch Y et al. Insulin resistance in GH-deficient adult patients treated with human growth hormone: evidence for a postbinding defect in vivo. In: Laron Z, Butenandt O, eds. Growth hormone replacement therapy in adults: pros and cons. Tel Avis/London: Freund Publishing House, 1993: 41-9.
94. Weaver JU, Monson JP, Noonan K, Edwards A, Evans K, Cunningham J. the effect of growth hormone on insulin sensitivity and central fat in growth hormone deficient adults. Endocrinol Metab 1994; 1 (Suppl) : Abstract 14.
95. Fowelin J, Attvall S, Lager I, Bengtsson B-A. Effects of treatment with recombinant human growth hormone on insulin sensitivity and glucose metabolism in adults with growth hormone deficiency. Metabolism 1993; 42: 1443-7.
96. Sato T, Suzuki Y, Taketani T, Ishiguro K, Masuyama T, Takata I et al. Enhanced peripheral conversion of thyroxine to triiodothyronine during hGH therapy in GH deficient children. J Clin Endocrinol Metab 1977; 45: 324-9.
97. Grunfeld C, Sherman BM, Cavalieri RR. The acute effects of human growth hormone on thyroid function in normal men. J Clin Endocrinol Metab 1988; 67: 1111-4.
98. Jorgensen JOL, Pedersen SA, Laurberg P, Weeke J, Skakkebaek NE, Christiansen JS, Effects of growth hormone therapy on thyroid function of growth hormone-deficient adults with and without concomitant thyroxine-substituted central hypothyroidism. J Clin Endocrinol Metab 1989b; 69: 1127-32.
99. Bengtssob B-A. Acromegaly and neoplasia. J Pediatr Endocrinol 1993; 6: 73-8.
100. Strong JP. The Prevalence and Extent of Atherosclerosis in Adolescents and Young Adults. JAMA 1999; 281: 727-735.
101. Howard BV, Howard WJ. Dyslipidemia in non-insulin-dependent diabetes mellitus. Endocr Rev 1994; 15:263-74.
102. Millar JS, Packard CJ. Heterogeneity of apolipoprotein B-100-containing lipoproteins: what we have learned from kinetic studies. Curr Opin Lipidol 1998; 9:197-202.
103. Irilbarren C., Sidney S., Bidd D., et al. Association of Hostility with Coronary Artery Calcification in Young Adults. The CARDIA Study. JAMA, 2000; 283:2546-2551.
104. Friedman M, Thoresen CE, Gill JJ, et al. Alteration of Type A Behavior and Its Effects on Cardiac Recurrences in Post Myocardial Infarction Patients. Am Heart J. 1986; 112:653-665.
105. Murray CJ, Lopez AD: Mortality by cause for eight regions of the world: Global burden of disease study. Lancet 1997; 349: 1269-1276.
106. Wuerst JH, Jr., et al. The degree of coronary atherosclerosis in bilaterally oophorectomized women. Circulation 1953; 7: 801.
107. Kerner DJ, Kannel WB. Patterns of coronary heart disease morbidity and mortality in the sexes: 26-year follow-up of the Framingham population. Am Heart J 1986; 113: 383-390.
108. Bush TL, et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: Results from the Lipid Research Clinics Program follow-up study. Circulation 1987; 75: 1102-1109.
109. Grodstein F, et al. Postmenopausal hormone therapy and mortality. N Engl J Med 1997; 336: 1769-1775.
110. Sullivan JM, et al. Estrogen replacement and coronary artery disease: Effect on survival in postmenopausal women. Arch Int Med 1988; 108: 358-363.
111. Bush TL, et al. Cardiovascular and noncontraceptive use of estrogen in women: Results from the Lipid Research Clinic Program Follow-Up Study. Circulation 1987; 75: 1102-1109.
112. Gruchow HW, et al. Postmenopausal use of estrogen and occlusion of coronary arteries. Am heart J 1988; 115: 954-936.
113. Sullivan JM, et al. Effects on survival of estrogen and occlusion of coronary artery bypass grafting. Am J Cardiol 1997; 79: 847-850.
114. Kim SC, et al. Estrogen improves long-term outcome after coronary angioplasty. Circulation 1995; 92 (suppl I): I-674.
115. Hulley S, et al. For the Heart and Estrogen/progestin Replacement Study research group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in post-menopausal women. JAMA 1998; 280: 605-613.
116. Gebara OC, et al. Association between increased estrogen status and increased fibrinolytic potential in the Framingham Offspring Study. Circulation 1995; 91: 1952-1958.
117. Juhan-Vague I, et al. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. Circulation 1996; 94: 2057-2063.
118. Wouters MG, et al. Plasma homocysteine and menopausal status. Eur J Clin Invest 1995: 25: 801-805.
119. Graham IM, et al. Plasma homocvsteine as a risk factor for vascular disease: The European Concerted Action Project. JAMA 1997; 227: 1775-1781.
120. Walsh BW, et al. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991; 325: 1196-1204.
121. Koh KK, et al. Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women. N Engl J Med 1997; 336: 683-690.
122. Espeland MA, et al. Effect of postmenopausal hormone therapy on lipoprotein(a) concentration. Circulation 1998; 69: 876-882.
123. Mijatovic V, et al. Postmenopausal oral 17B -estradiol continuously combined with dydrogesterone reduces fasting serum homocysteine levels. Fertil Steril 1998; 69: 876-882.
124. Stampfer MJ, et al. Pstmenopausal estrogen therapy and cardiovascular disease: Ten-year follow-up from the Nurses’ Health Study. N Engl J Med 1991; 325: 756-762.
125. The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995; 273: 199-208.
126. Grodstein F, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996; 335: 453-461.
127. Colditz GA, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995; 332: 1589-1593.
128. Sellers TA, et al. The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer. Ann Intern Med 1997; 127: 973-980.
129. Bonnier P, et al. Clinical and biologic prognostic factors in breast cancer diagnosed during postmenopausal hormone replacement therapy. Obstet Gynecol 1995; 85: 11-17.
130. Grady D, et al. Hormone replacement therapy and endometrial cancer risk: A meta-analysis. Obstet Gynecol 1995; 85: 304-313.
131. The Writing Group for PEPI trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women: The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA 1996; 275: 370-375.
132. Davis NB, et al. Testosterone enhances estradiol’s effects on postmenopausal bone density and sexuality. Maturitas 195; 21: 227-236.
133. Watts NB, et al. Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause. Obstet Gynecol 1995; 85: 529-537.
134. Andren-Sandberg A, Backman PL: Hormonal therapy and immunotherapy, in Howard JM, Idezuki Y, Ihse I, Prinz RA (eds): Surgical Diseases of the Pancreas ed 3. Baltimore, Williams and Wilkins, 1998, pp. 613-622.
135. Wong A, Chan A, Arthur K: Tamoxifen therapy in unresectable adenocarcinoma of the pancreas. Cancer Treat Rep 1987; 71: 749-750.
136. Bakkevold KE, Pettersen A, Arnesjo B, Espehaug B: Tamoxifen therapy in unresectable adenocarcinoma of the pancreas and papilla of Vater. Br J Surg 1990; 77: 725-730.
137. Morales AJ, et al. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 1994; 76: 1360-1367.
138. Jones JA, et al. Use of DHEA in a patient with advanced prostate cancer: A case report and review. Urology 1997; 50: 784-788.
139. Chan JM, et al. Plasma insulin-like growth factor-1 and prostate cancer risk: A prospective study. Science 1998; 279: 563-566.
140. Miyake H, et al. Elevation of serum levels of urokinase-type plasminogen activator and its receptor in associated with disease progression and prognosis in patients with prostate cancer. Prostate 1999; 39: 123-129.
141. Nakao-Hayashi J, et al. Stimulatory effects of insulin and insulin-like growth factor 1 on migration and tube formation by vascular endothelial cells. Atherosclerosis 1992; 92: 141-149.
142. Khovidhunkit W, Shoback DM. Clinical effects of raloxifene hydrochloride in women. Ann Intern Med 1999; 130: 431-439.
143. Delmas PD, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997; 337:1641-1647.
144. Ettinger B, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) investigators. JAMA 1999; 282: 637-645.
145. Albertazzi P, et al. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 1998; 91: 6-11.
146. Anderson JW, et al. Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 1995; 333: 276-282.
147. Leon A, Simmons et al. Lipid Research Department, St. Vincent’s Hospital, darlinghurst NSW 2010, Australia. 200; 85: 1297-1301.
148. White, LR, et al. Brain Aging and Midlife Tofu Consumption. J Am Col Nutrition.2000; 19: 242-255.
149. Luoto R, et al. Estrogen Replacement Therapy and MRI-Demonstrated Cerebral Infarcts, White Matter changes, and Brain Atrophy in Older Women: The Cardiovascular Health Dtudy. J Amer Geriatrics Society, 200; 48: 467-472.
150. Falk E, Shah PK, Fuster V. coronary plaque disruption. Circulation 1995; 92: 657-671.
151. Davies MJ. Acute coronary thrombosis-the role of plaque disruption and its initiation and prevention. Eur Heart J. 1995, 16(Suppl L): 3-7.
152. Kuller LH, tracy Rp, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study: Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1996; 144: 537-547.
153. Tracy RP, Lemaitre RN, Psaty BM, et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly: results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arteriosler Thromb Vasc Biol. 1997; 17: 1121-1127.
154. Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998; 98: 731-733.
155. Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB (European Concerted Action on Thrombosis and Disabilitites Angina Pectoris Study Group). Production of C-reactive protein and risk of coronary events in stable and unstable angina. Lancet 1997; 349: 462-466.
156. Ridker PM. Evaluating novel cardiovascular risk factors: can we better predict heart attacks? Ann Intern Med. 1999: 130: 933-937.
157. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men [published erratum appears in N Engl J Med. 1997; 337:356]. N Engl J Med 1997; 336: 973-979.
158. Ridker PM, Rifai N, Pleffer MA, et al. (Cholesterol and Recurrent Events [CARE] Investigators). Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation 1998; 98: 839-844.
159. Ernst E, Resch Fl. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med. 1993; 118: 956-963.
160. Vlassara H, Bucala R, Striker L. Pathogenic effects of advanced glycosylation: biochemical, biologic, and clinical implications for diabetes and aging. Lab Invest 1994; 70: 138-151.
161. Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996; 334: 952-957.
162. Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia 1997; 40: 1286-1292.
163. McMillan DE. Increased levels of acute-phase serum proteins in diabetes. Metabolism 1989; 38: 1042-1046.
164. Steel DM, Whitehead AS. The major acute phase reactants: C-reactive protein, serum amyloid P component and serum amyloid A protein. Immunol Today 1994; 15: 81-88.
165. Yudkin JS. Coronary heart disease in diabetes mellitus: three new risk factors and a unifying hypothesis. J Intern Med 1995; 238: 21-30.
166. Ganda OP, Arkin CF. Hyperfibrinogenemia: an important risk factor for vascular complications in diabetes. Diabetes Care 1992; 15: 1245-1250.
167. Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine. Adv Immunol 1993; 54: 1-78.
168. Jaattela M. Biologic activities and mechanisms of action of tumor necrosis factor-alpha/cachectin. Lab Invest 1991; 64: 724-742.
169. Yokota T, Hansoon GK. Immunological mechanisms in atherosclerosis. J Intern Med 1995; 238: 479-489.
170. Vallance P, Collier J, Bhagat K. Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link? Lancet 1997; 349: 1391-1392.
171. Murata H, et al. Protease Inhibitors Side Effects. J Bio Chem 2000; 275(27): 20251-20254.
172. Hadigan C, Corcoran C, Basgoz N, et al. Metformin in the treatment of HIV Lipodystrophy Syndrome. JAMA 2000; 284: 472-477.
173. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Eng J Med 1993; 329: 986-997.
174. Getz Gj. Report on the workshop on diabetes and mechansims of atherogenesis. September 17^th and 18^th, 1992, Bethesda, MD. Atheroscler Thromb 1993: 13: 459-464.
175. Baron, AD. Insulin Resistance and Vascular Biology. Satellite Symposium of the Amer Assoc Clin Endocrin Ann Meeting, May 17, 2000. Atlanta, GA.
176. Rumberger JA, Sheedy PFll, Breen JF, et al. Electron Beam Computed Tomography and Coronary Artery Disease. Mayo Clinic Proc. 1996; 71:369-371.
177. Kennedy J, Shavelle R, Wang S, et al. Coronary Calcium and Standard Risk Factors in Symptomatic Patients referred for Coronary Angiography. Am Heart J. 1998; 135:696-702.
178. Secci A, Wong N, Rang W, et al. Electron Beam computed Tomographic Coronary Calcium as a Predictor of Coronary Events. Circulation, 1997; 96:112-129.
179. Lahad A, Heckbert SR, Koepsell TD, et al. Hostility, Aggression and the Risk of Non-fatal Myocardial Infarction in Postmenopausal Women. J Psychosom Res. 1997; 43:183-195.
180. Williams JE. Anger Proneness Predicts Coronary Heart Disease Risk: Prospective Analysis from the Atherosclerotic Risk in Communities (ARIC). Study. Circulation 2000 May 2; 101:2034-9.
181. Frasure-Smith. Social Support, Depression, and Mortality during the First Year after Myocardial Infarction. Circulation 2000 April 25; 101: 1919-24.
182. Rabin, BS. Stress, Immune Function and Health: the Connection. New York, NY; Wiley-Liss & Sons Inc,; 1999
183. Bachen EA, Manuck SB, Cohen S, et al. Adrenergic Blockade Ameliorates Cellular Immune Responses to Mental Stress in Humans. Psychosom Med. 1995; 57:366-372.
184. Benschop RJ, Nieuwenhuis EES, Tromp EAM, et al. Effects of Beta-adrenergicBlockade on Immunologic and Cardiovascular Changes Induced by Mental Stress. Circulation. 1994; 89:762-769.
185. Wetmore L, Nance DM. Differential and Sex-Specific Effects of Kainic and Domoic Acid Lesions in the Lateral Septal Areas of Rats on Immune Function and Body Et. Regulation. Exp Neurol. 1991; 113:226-236.
186. Rassnick S, Sued AF, Rabin BS. Locus Coerulu Stimulation by Corticotropin-releasing Hormone Suppresses Invitro Cellular Immune Responses. J Neurosci. 1994; 14:6033-6040.
187. Cohen S, Doyle WJ, Skoner DP, et al. Social Ties and Susceptibility to the Common cold. JAMA. 1997; 277:1940-1944.
188. Fratiglioni L. Influence of Social Network on Occurrence of Dementia: a Community-Based Longitudinal Study. Lancet 2000 April 15; 355:1315-9.
189. Berkman L F. Which Influences Cognitive Function: Living Alone or Being Alone? Lancet 2000 April 15; 355:1291-2.
190. Stamler J, Daviglus ML, Garside DB, et al. Relationship of Baseline Serum Cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and longevity. JAMA, 2000; 284: 311-318.
191. Haffner SM, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J med 1998; 339: 229-234.
192. Pyorala K, et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. Diabetes Care 1997; 20: 614-620.
193. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837-853.
194. Pate RR, et al. Physical activity and public health. A recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. JAMA 1995; 273: 402-407.
195. Powell KE, et al. Physical activity and the incidence of coronary heart disease. Ann rev Public Health 1987; 8: 253-287.
196. NIH Consensus Development Panel on Physical Activity and Cardiovascular Health. Physical activity and cardiovascular health. JAMA 1996; 276: 241-246.
197. O’Connor GT, et al. An overview of randomized trials of rehabilitation with exercise after myocardial infarction. Circulation 1989; 80: 234-244.
198. Oldridge NB, et al. Cardiac rehabilitation after myocardial infarction. Combined experience of randomized clinical trials. JAMA 1988; 260: 945-950.
199. Williamson DF, et al. The 10-year incidence of overweight and major weight gains in U.S. adults. Arch Intern Med 1990; 150: 665-672.
200. Harlan WR, et al. Secular trends in body mass in the United States, 1960-1980. Am J Epidemiol 1988; 128: 1065-1074.
201. Berg FM. Health Risks of Obesity; 1993 Special Report. Hettinger ND, Obesity & Health, 1992.
202. Manson JE, et al. A prospective study of obesity and risk of coronary heart disease in women. N Engl J Med 1990; 322: 882-889.
203. Havek RJ, Rapaport E. Management of primary hyperlipidemia. N Engl J Med 1995; 332: 1491-1498.
204. Hulley SB, et al. Epidemiology as a guide to clinical decisions: The association between triglyceride and coronary heart disease. N Engl J Med 1980; 302: 1383-1389.
205. Nestel PJ. Is serum triglyceride and independent predictor of coronary artery disease? Pract Cardiol 1987; 13(8): 96-101.
206. Austin MA. Plasma triglyceride as a risk factor for coronary heart disease: The epidemiologic evidence and beyond. Am J Epidemiol 1989; 129: 249-259.
207. Wilhelmssen L, et al. Multivariate analysis of risk factors for coronary heart disease. Circularion 1973; 48: 905-908.
208. Salonen JT, Puska P. Relationship of serum cholesterol and triglycerides to the risk of acute myocardial infarction, cerebral stroke and death in eastern Finnish male population. Int J Epidemiol 1983: 12:26-31.
209. Cambien F, et al. Is the level of serum triglyceride a significant predictor of coronary death in "normocholesterolemic" subjects? A Paris prospective study. Am J Epidemiol 1986; 124: 624-632.
210. Pocock SJ, et al. Concentrations of high density lipoprotein cholesterol, triglycerides, and total cholesterol in ischaemic heart disease. Br Med J 1989; 298: 998-1002.
211. Austin MA, et al. Low density lipoprotein subclass patterns and risk of myocardial infarction. JAMA 1988; 260: 1917-1921.
212. Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm Ischemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta med Scand 1988; 223: 405-418.
213. Manninen V, et al. Lipid alterations and a decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA 1988; 260: 641-651.
214. Miller M, et al. Normal triglyceride levels and coronary artery disease events: the Baltimore Coronary Observational Long-term Study. J Am Coll Cardiol 1998; 31: 1252-1257.
215. Albright F, Burnett Ch, Smith PH, et al. Pseudohypoparathyroidism: an example of "Seabright-Bantam Syndrome." Endocrinol 1942; 922-932.
216. Geffner, ME. Hormone-Resistant States, in Lavin N:Manual of Endocrinology and Metabolism, ed 3. Boston: Little, Brown and Co, 1994, p 7.
217. Taylor SI. Molecular mechanisms of insulin resistance: Lessons from patients with mutations in the insulin receptor gene. Diabetes 1992; 41: 1473-1490.
218. Geffner, ME, Golde DW. Selective insulin action on skin, ovary, and heart in insulin-resistant states. Diabetes Care 1988; 11: 500-505.
219. Usala SJ, Weintraub BD. Thyroid Hormone Resistance Syndrome. Trends Endocrinol Metab. 1991; 2: 140-144.
220. Van Dop C. Pseudohypoparathyroidism: Clinical and molecular aspects. Semin Nephrol 1989; 9: 168-178.
221. Le Roith D, et al. Insulinlike growth factors and their receptors as growth regulators in normal physiology and pathologic states. Trends Endocrinol Metab 1991; 2: 134-139.
222. Mc Kusick VA. Mapping the genes for hormones and growth factors and the mutations causing disorders of growth. Growth Genet Horm 1989; 5: 1-10.
223. Sonksen PH. Replacement therapy in hypothalamopituitary insufficiency after childhood: Management in the adult. Horm Res 1990; 33 (Suppl 4): 45-51.
224. Rosen T, Bengtsson B-A. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990; 336: 285-8.
225. Besser GM, Cudworth AG, eds. Clinical Endocrinology, an illustrated text. London. Gower Medical Publishing, 1987.
226. Growth Hormone Research Society (GRS) Consensus Guidelines for Diagnosis and Treatment of Adults with GH Deficiency. Port Stephens Workshop, Australia. April 14-17, 1997. J Clin Endocrinol Metab. 1998; 83: 379-381.
227. Gharib H, Saenger PH, Zimmerman D. AACE Clinical Practice Guidelines for Growth Hormone use in adults and children. Endocrin Practice, May/June 1998; 4: 165-173.
228. Klibanski A, Clemmons DR, Christiansen J, et al. Growth Hormone Replacement Therapy for Growth Hormone Deficiency in adults: the changing Role of Growth Hormone Therapy, March/April 1999; Vol 5, No. 2: 88-96.
229. Carlson HE, Gillin JC, Gorden P, Snyder F. Absence of sleep-related growth hormone peaks in aged and normal subjects and in acromegaly. J Clin Endocrinol Metab 1972; 34: 1102-5.
230. Finkelstein JW, Roffwarg HP, Boyar RM, Kream J, Hellman L. Age-related change in the twenty-four-hour spontaneous secretion of growth hormone. J Clin Endocrinol Metab 1972; 35: 665-70.
231. Bazzarre TL, Johanson AJ, Huseman CA, Varma MM, Blizzard, RM. Human growth hormone changes with age. In: Growth hormone and related peptides: Proceedings of the Third International Symposium. Excerpta Med Int Congr Ser 1976; 381: 261-70.
232. Rudman D, Kutner MH, Rogers CM, Lubin MF, Fleming GA, Bain RP. Impaired growth hormone secretion in the adult population. J Clin Invest 1981; 67: 1361-9.
233. Iranmanesh A, Lizarralde G, Veldhuis JD. Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men. J Clin Endocrinol Metab 1991; 73: 1081-8.
234. Ross RJM, Buchanan CR. Growth hormone secretion: its regulation and the influence of nutritional factors. Nutr Res Rev 1990; 3: 143-62.
235. Blum WF, Ranke MB, Keitzmann K, Gauggel E, Zeisel HJ, Bierich JR. A specific radioimmunology for the growth hormone dependent somatomedin binding protein: its use for diagnosis of growth hormone deficiency. J Clin Endocrinol Metab 1990; 70: 1292-8.
236. King GL, Goodman AD, Buzney S, et al. Receptors and growth promoting effects of insulin and insulin-like growth factor on cells from bovin retinal capillaries and aorta. J Clin Invest 1985; 75: 1028-1036.
237. Bornfeldt KE, Skottner A, Arnqvist HJ. In-vivo regulation of messenger RNA encoding insulin-like growth factor-I (IGF_I) and its receptor by diabetes, insulin, and IGF-I in rat muscle. J Endocrinol 1992; 135: 203-211.
238. Chen Y, Capron JO, Magnusson LA, et al. Insulin-like growth factor-1 stimulates vascular smooth muscle cell proliferation in rat aorta in vivo. Growth hormone and IGF Research 1998; 8: 299-303.
239. Girard J, Fischer-Wasels Th. Measurement of urinary growth hormone. Horm Res 1990; 33 (Suppl 4): 12-18.
240. Korenman, SG. ed. Neuroendocrinology and Pituitary Disease (Atlas of Clinical Endocrinology, Vol 4). Philadelphia: Current Medicine, 2000.

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