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


E-Newsletter No. 1

Physicians -- Click Here for Information on the Fellowship Program

Presentation by Lord Lee-Benner, M.D., F.A.C.E. to the Anti-Aging Panel of the California Society of Plastic Surgeons Annual Meeting, May 27, 2000.

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

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

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 authorís 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.

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 guidelines6-59 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" doesnít 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.

Physicians -- Click Here for Information on the Fellowship Program

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 composition61-83 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-based108,109 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 (Womenís 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 Womenís 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, estrogenís 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 Nursesí 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 oneís 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

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 (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 patientsí 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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