The Effect of a Program of Hormone Modulation, Low Glycemic, Nutrition and Exercise Instruction on Select Outcomes Indicative of Disease Risk and Subjective Impression of Quality of Life.

ALAN P. MINTZ, ANTON R. DOTSON, AND JHOANNA MUKAI

ABSTRACT

Substantial benefits of low glycemic nutrition, regular exercise and supplementation of recombinant human growth hormone (G), dehydroepiandrosterone (D), testosterone (T), estrogen (E) and progesterone (P) have been demonstrated independently of one another in controlled clinical trials in diseased and healthy men and women. We collected data retrospectively on 78 men and 29 women enrolled in a comprehensive program utilizing these interventions to see how parameters of disease risk and their subjective sense of quality of life would be altered. While self-directing their nutrition and exercise after detailed instruction, and achieving a substantial rise in levels of the above hormones appropriate for their sex, there were impressive improvements in lipid profiles, bone density, body composition, glucose metabolism, and quality of life outcomes. Side effects were mild and easily controlled.

INTRODUCTION

Testosterone supplementation (T) in men improves strength ⁽¹"⁴⁾ and increases de novo protein synthesis as well as muscle mass ⁵~⁷⁾. T has also been shown to decrease body fat and particularly visceral body fat⁸⁾, increase libido in normal men ^(U)) and increase libido and sexual performance in hypogonadal men^{(n 13)}. Mood is also improved with T in both hypogonadal⁽¹⁴"¹⁵⁾ and older community dwelling men⁽¹⁶⁾ Higher endogenous testosterone has been correlated in. many studies with a reduction in a number of cardiovascular risk factors, among them lower -blood pressure, total cholesterol (TC), LDL-cholesterol (LDL), triglycerides (TG), visceral body fat, waist-hip ratio (WHR), serum insulin, fasting and post-prandial glucose, higher HDL-cholesterol (HDL) and greater insulin sensitivity ⁽¹⁷~²³⁾ In several studies where T has been shown =to increase cardiovascular risk, levels of T achieved were supraphysiologic⁽²⁴²⁸⁾.

Levels   of  dehydroepiandrosterone   sulfate

(DHEAS) correlate inversely with depression⁽²⁹~ ³⁰⁾ and supplementation with DHEA (D) results in improvement³¹³⁵⁾ D also directly stimulates =immune responsiveness in humans³⁶⁾ in animals³⁷⁾and in vitro³⁸³⁹⁾. In men, D has been shown to improve body composition in some studies^(4(M2) but not in others⁽⁴³⁴⁴⁾. DHEAS levels have been shown to correlate inversely with hippocampal atrophy in the elderly⁴⁵⁾ and D was shown in one study to improve memory in depressed patients of middle and older age . Growth hormone deficiency (GHD) is associated with the following, all of which can be significantly reversed with replacement of human growth hormone (G): a decrease in lean body mass⁽⁴⁷~⁵¹⁾, bone density⁵²"⁵⁸, skin thickness⁵⁹, sense of well-being^{60 65)}, rate of wound healing⁶⁶~⁷⁰⁾,immune responsiveness ⁽⁷¹⁷²⁾,and aerobic capacity⁷³⁷⁴. In addition, GHD is associated with an increase in the following,

all of which have been reduced in clinical trials of G: (LDL)⁽⁷⁵⁾, atherosclerosis⁶⁵⁷⁶^, total body fat^{(47 51)} , hospitalization rate and sick days from work⁽⁸³⁾.

The benefits of Estrogen replacement therapy have been well described in terms of reducing risk of coronary disease¹-^{7984 88)}, osteoporosis^{94 97)}, and Alzheimers Disease ⁽⁸⁹~⁹³⁾.

There is evidence that progesterone (P) replacement therapy in both the perimenopausal and post-menopausal periods is effective in reducing risk of osteoporosis through osteoblast stimulation ⁽⁹⁸-¹⁰⁰⁾.

A diet of low glycemic index (LGID) has been shown to lower LDL^{(1M 103)} and TG ^(104105), raise HDL^(105K)7), improve both glycemic control¹⁰²¹⁰⁸ and insulin sensitivity in non-insulin dependent diabetes¹⁰⁹, and reduce coronary artery disease(CAD) risk in women.⁽¹¹⁰⁾

It is certainly no surprise that physical exercise is capable of increasing muscle mass^(ml12), decreasing body fat¹¹¹¹¹³, and lowering the waist-hip ratio (WHR).⁽¹¹³⁾

One well-published risk of GH therapy is an increase in glucose levels with associated insulin resistance/¹¹⁴"¹¹⁸ One recent study showed improvement in insulin sensitivity in obese, insulin resistant individuals using GH along with a low calorie diet compared to a low calorie diet alone¹¹⁹.

The above litany of benefits, many of which are attributable to, and overlap among several of the above potential interventions, are demonstrated in controlled clinical trials isolating one intervention and measuring one or more related outcomes. Our practice incorporates all of the above interventions in three categories: LGID, regular exercise and hormone supplementation.

HYPOTHESIS

We hypothesized that applying these three modalities simultaneously to an uncontrolled private patient population where the subject is autonomous and compliance is variable will improve select outcomes of disease risk and in the subjective view of the patient, enhance

quality of life. We further hypothesize that the tendency of G to increase insulin resistance and serum glucose will be offset by the LGID, exercise and perhaps some benefit from testosterone. We collected data on 78 men and 29 women on our program to determine how selected parameters of disease risk were altered. We measured the following outcomes related to disease risk before commencing and after 197 to 274 days on a program: HA1C, TC, LDL, HDL, TG, TC/HDL (CRR), TG/HDL, body fat percentage (%BF), WHR, bone mineral density (BMD), and prostate specific antigen (PSA) in men.

In our practice we have found that quality of life (QOL) issues are at least as important to our patients as longevity. The benefit of an aging control program should also include some means of measuring QOL. Since ones impression of his or her own QOL is largely subjective, a subjective survey would seem appropriate as a means of measuring changes in QOL. We sent a 2- part survey randomly to patients currently on our program and recorded all responses. Part 1 inquired of side effects and part 2 of perceived benefits.

In this paper we report the changes seen in the above-mentioned objective outcomes as well as the results of our side effects and benefits survey given to patients currently on our program.

MATERIALS AND METHODS

All subjects were patients enrolled in the Cenegenics Program between February of 2000 and March of 2001. Data was collected retrospectively on enrolled patients who qualified by having not been on any hormone therapy prior to the trial period, having remained on_a constant set of hormones for the study duration, having not been on any prescription drug known to affect the outcomes being measured, and having had their follow-up blood draws, DEXA scan, and physical measurements taken also during the study period. Most of our patients were disqualified for one or more of these reasons. One

exception to the above criteria was that women previously on estrogens and/or progesterone or progestins were admitted. All subjects had their baseline studies done within the 3 weeks prior to commencing their program. Both baseline and follow-up blood draws were done fasting. Blood testing was routinely performed by Quest Diagnostics in Salt Lake City, Utah, but other commercial labs were sometimes used at the subjects discretion. Normal ranges for the various labs used were identical.

Subjects were initially seen at Cenegenics for a baseline evaluation that included a standard history and physical examination including measurement of WHR, breast and digital rectal examination with stool hemoccult. Pap smears and mammograms were not done but were required to be on record within the past 12 months and annually thereafter for all women on GH or estrogen. % BF, lean body mass and bone density were measured by DEXA scan. Baseline DEXA scanning was done by Cenegenics on a Lunar DPX-IQ Imaging Densitometer. If a follow-up scan was done at a different facility it was disqualified for difference in either technique or precise anatomical location. Baseline blood test results were available at the time of the initial visit. Subjects met for 90 to 120 minutes with a physician for the exam, evaluation of all data and formulation of a hormone program. The physician instructed the subjects on the benefits and risks of each hormone as well as potential side effects and the synergy of nutrition, exercise and hormone supplementation. Initial dosing of hormones was not formula based and was determined solely by the judgment of the physician based on his experience. Each subject met for a similar period of time with a nutritionist for a comprehensive diet analysis, explanation of the physiologic effect of a low glycemic diet, and instruction on healthy and harmful fats. Moderate intake of polyunsaturated and monounsaturated fats were encouraged without a specific requirement in grams or calorie percentage. Patients were encouraged to use green and yellow vegetables (excluding corn, carrots and beets) and the

lower glycemic fruits as sole sources of carbohydrate. Sugars and starches were strongly discouraged. A calculation of daily protein requirement based on lean body mass and activity level was performed. Emphasis was placed on motivating the patient through education rather than imposing strict dietary rules. An evaluation was made of physical restrictions and/or disability, followed by the recommendation of a specific exercise plan. The subjects then met for 15 to 30 minutes with a registered nurse who instructed them on the administration of all prescribed hormones including self-injection. Subjects were encouraged to call in to speak with the physician, nurse or nutritionist at any time they had questions, doubts or symptoms. The first follow-up blood draw was scheduled 6 weeks after the initial visit. Subjects reviewed the results in a teleconference with their physician and dose was adjusted in an effort to attain or maintain the serum level in the "Cenegenics Optimal Range" (COR). The COR was arbitrarily chosen by the following guidelines: Estradiol: mid-range for the early follicular phase; Progesterone: upper normal for the follicular phase yet below normal for the luteal phase; T: upper 40% of the normal range for men (not age defined); IGF-1: upper 40% of the normal range for men and women for the age bracket of 39 to 54; DHEAS: upper 30% of the normal range for a young adult. The only drug therapy used to effect hormone levels was anastrozole, an aromatase inhibitor, used for men whose estradiol rose above the normal range with the administration of T. The dose of anastrozole was estimated with the goal of keeping estradiol levels in the upper Vz of the normal range for men. Subsequent blood draws were scheduled approximately 12 weeks after the first follow-up blood draw.

For data collection and reporting, the subjects were divided into five groups: Men on androgens (A) (D orally and T as testosterone cypionate by weekly IM injection), men on A plus G (recombinant human growth hormone by subcutaneous injection 6 mornings per week), women on A (D orally and T as

compounded transdermal testosterone cream or gel) plus hormone replacement therapy (HRT) (oral progesterone plus ttansdermal Estradiol, or Triest [estradiol, estriol, estrone] or Biest [estradiol, estriol]), women on A plus G, and women on A plus HRT plus G. Patients were assigned to a particular group based on their personal selection of a hormone program after consulting with the physician. Doses are not reported. Since the patients were managed according to their serum level for each hormone, the dose varied widely. The intent of the study was not to correlate the outcomes to a specific dose, but to correlate the outcomes with the change in serum level in the context of the program. The average study period was defined as the number of days from the first day of hormone therapy to the date of the last blood draw within the first 9 months of the patients program. Since the data was collected retrospectively and the timing of the blood draw was strongly influenced by patient preference, the average study period varied for each group. It ranged from 197 to 274 days. The average study period for each group is shown in Table 1.

table 1: average study interval by group in days

Men on A Men on A+G Women on A+G+HRT Women on A+HRT Women on A+G

A (men): androgens (T.cypionate); G: growth hormone A (women): androgens (DHEAitransdermal T); HRT: estradiol+progesterone

RESULTS

Table 2 shows the change in serum hormone levels as well as the change in PSA for both groups of men — those on A, and those on A plus G. Estradiol level was not shown in these men because it was kept in the normal range with the use of anastrozole.

The change in levels of the various administered hormones for women are shown in Tables 3 and 4. Estradiol and progesterone levels were not followed in women who were not taking them. The normal range of testosterone, free testosterone, DHEAS and insulin-like growth factor-1 (IGF-1) were different for those aged 50 and over versus those under 50.

TABLE 2: BASELINE AND POST-TREATMENT SERUM LEVELS OF SELECT HORMONES AND PSA

IN MEN ON A AND MEN ON A+G

TT: total testosterone; Free T: free testosterone; DHEAS: dehydroepiandrosterone-sulfate; IGF-1: insulin-like growth factor-1; PSA: prostatic specific antigen; DHT: dihydrotestosterone; A: androgens (T. cypionate); G: growth hormone.

TABLE 3:   BASELINE AND POST-TREATMENT SERUM LEVELS OF SELECT HORMONES IN WOMEN ON A+G+HRT AND WOMEN ON A+HRT ONLY.

E: estradiol; P: progesterone; TT: total testosterone; Free T: free testosterone; DHEAS: dehydroepiandrosterone-sulfate; IGF-1: insulin-like growth factor-1; A: androgens (DHEA +_ transdermal T); G: growth hormone; HRT: estradiol + progesterone

The change in levels of the various administered hormones for women are shown in Tables 3 and 4. Estradiol and progesterone levels were not followed in women who were not taking them. The normal range of testosterone, free testosterone, DHEAS and insulin-like growth factor-1 (IGF-1) were different for those aged 50 and over versus those under 50.

Table 5 shows the change in HA 1C for all the groups. In addition, calculations were done to show the change in all men and all women, regardless of which hormone program they were on.

We also calculated the change for all subjects, for all men and for all women, separating these three categories further into those receiving or not receiving G.