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Andriol for testosterone replacement therapy?

HansNZ

New member
I have been giving some thought to the aging process as well as my sex drive. We all know that when we are elderly our natural testosterone levels drop off. Hormone replacement therapy (especially testosterone) is an avenue that I am positive I will explore. However taking injectable testosterone seems like it could have draw backs. It would shut down what HPTA i'd still have, and there may be potential side-effects.

As a younger person I have also been considering ways of increasing my sex drive and testosterone seems the obvious answer. Long term therapy would not be ideal as it would shut down my HPTA.

A short acting testosterone seems the answer. Something you can take in the morning, get the benefits, and is out of your system by bedtime. Dbol immediately jumps to mind. However I don't think it is ideal to be on a toxic steroid permanently.

The obvious solution is andriol. This has a bad reputation for body building, but for hormone replacement purposes it seems perfect, especially since only a subtle effect is needed. It also seems a good way to increase my sex drive and prevent side-effects of low natural testosterone post cycle while HPTA is recovering.

What do you guys think of this? Any suggestions or info is welcome.
 
Last edited:
For sex drive/ sperm volume/ I prefer Proviron, when recovering.
Here is the latest review on this subject.




NEUROENDOCRINOLOGY

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NEUROENDOCRINE AGING IN MEN
Andropause and Somatopause



Bradley D. Anawalt 1 MD
George R. Merriam 1 2 MD

1 Departments of Medicine (BDA, GRM)
2 Obstetrics and Gynecology (GRM), University of Washington School of Medicine, VA Puget Sound Health Care System, Seattle, Washington




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The authors' work is supported by the Veterans Health Administration and by grants from the National Institute on Aging (R01-AG10943), the National Institute of Mental Health (R01-MH53575), and the National Center for Research Resources (to the University of Washington General Clinical Research Center). GHRH(1-29)NH2 (sermorelin acetate, Geref® ) was donated by Serono Laboratories, Norwell, MA.

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Address reprint requests to
George R. Merriam, MD
Research (A-151)
VA Puget Sound Health Care System
University of Washington School of Medicine
Lakewood, WA 98493



The marked rises in sex steroids and growth hormone that accompany sexual maturation and the pubertal growth spurt in men orchestrate dramatic changes in body composition and functional capacity. Changes in bone density and muscle mass and strength are especially noteworthy. Secretion of androgens and growth hormone reaches a peak in late adolescence and then begins to decrease. The decline in sex steroids is not significant until the fourth decade of life, whereas decreases in growth hormone begin as early as the mid-20s. As these pubertal hormones decline, some of the somatic remodeling induced at puberty also begins to reverse, with a loss of bone and muscle mass and a decline in strength and aerobic capacity, which, at least superficially, resemble the phenotypes of hypogonadism and growth hormone deficiency. Initially clinically silent, these changes lead gradually but progressively to greatly reduced muscle mass (referred to as sarcopenia) and loss of strength and functional capacity to the point at which the risk for falls and fracture or other serious injury when a fall occurs is increased, and the capacity to carry out the tasks necessary for independent living is impaired, a condition called frailty. The increased assistance required by frail elders carries an enormous price tag and has raised the question of whether replacing or stimulating testosterone and growth hormone secretion in older men, therapy already of documented benefit in hypogonadism and adult growth hormone deficiency, could reverse or at least prevent the progression to frailty and prolong the capacity for independent living.

The obvious precedent for trophic hormone supplementation in aging is the use of estrogen replacement in postmenopausal women. The experience with estrogen replacement therapy highlights the potential complexity of what might initially seem a logical suggestion with an apparently simple and compelling rationale. Even after decades of study and large-scale, long-term clinical trials, the definition of which groups should and should not undergo estrogen replacement therapy remains controversial (see the article by Hall elsewhere in this issue). In comparison with the abundant literature on estrogen replacement therapy, there are more reviews of testosterone and growth hormone replacement in normal aging men than there are original studies providing new data, and there are no large, long-term trials with the power to define clinically or economically relevant outcomes and risks for either hormone. Current understanding of androgen and growth hormone in normal aging is based on the imperfect parallel of true hormonal deficiency states, or on studies of relatively small scale (dozens or, at most, a few hundred subjects) and short-term follow-up, with intermediate rather than true final outcomes (bone density instead of fractures, and physical function testing instead of demonstrated prolonged independence or falls). In the year 2001, one can offer only hints and suggestions, not recommendations or consensus guidelines.

Other hormonal systems change in aging men--cortisol secretion may increase with aging, and adrenal androgens decline, a change of some importance in women. The scope of this article does not permit a full discussion of these other processes. The focus here is on possible mechanisms for the age-related declines in gonadal steroids and growth hormone in men, and preliminary studies of the effects of reversing those changes with hormonal interventions.






AGING AND THE MALE GONADAL AXIS
In men, testosterone levels follow a characteristic developmental pattern. Testosterone levels are high at birth and then drop to low levels from infancy through the prepubertal years, peaking with the onset of puberty and reaching a plateau during early adult life. Although older men do not experience as precipitous a decline in sex steroid hormone levels as do women entering menopause, it is now recognized that men have a progressive decrease in free and total testosterone levels after the third decade of life. Because this decline in testosterone levels occurs simultaneously with the decline in strength and muscle mass, bone density, cognitive function, and overall health of aging men, many investigators have attributed a causal effect and describe a syndrome of androgen deficiency of aging males (ADAM) or "andropause." There has been a great deal of interest in testing the hypothesis that supplemental exogenous androgens might benefit older men with low or low-normal serum testosterone levels, even older men without a clear etiology for hypogonadism except the effects of aging. The following discussion excludes men with known hypogonadism owing to testicular or hypothalamic-pituitary disease and focuses on older men who are otherwise healthy and ostensibly eugonadal.

Epidemiology of Declining Androgen Levels in Aging Men
Most cross-sectional investigations show that circulating total and free testosterone levels are lower in older men than in younger men,[6A] [14] [24] [28] [29] [57] [58] [59A] [79] [85A] although some researchers have found that exceptionally robust older men do not have significantly reduced testosterone levels.[34] [51] [71] Three longitudinal studies have confirmed that total testosterone levels decline with aging.[32] [46] [93] In these longitudinal studies, the rate of decline in total testosterone level ranged from 0.03 to 0.11 ng/mL/yr (0.5% to 1% per year).

The largest longitudinal study of the effects of aging on testosterone levels in healthy men was recently reported.[32] In that study of nearly 900 men followed up over 30 years, serum free and total testosterone levels declined steadily from the third through eighth decades of life (Fig. 1) (Figure Not Available) . The prevalence of hypogonadism (defined as a total testosterone level <3.25 ng/mL, which is in the hypogonadal range of young men) rose from approximately 5% of the cohort in the 20- to 29-year-old group to 20%, 30%, and 50% in the 60 to 69, 70 to 79, and 80 plus year-old groups, respectively. When the free testosterone index (total testosterone/sex hormone-binding globulin) was calculated, the prevalence of hypogonadism was even higher. The decline with age was independent of the effects of chronic illness or medications (including alcohol or tobacco), except for beta-antagonists, which were associated with a trend toward higher serum free and total testosterone levels.

Figure 1. (Figure Not Available) Longitudinal changes in circulating total testosterone and a free testosterone index in healthy men participating in the Baltimore Longitudinal Study on Aging. Each line segment shows the mean and slope of values from a separate cohort of participants, centered on their median age. (From Harman SM, Metter EJ, Tobin JD, et al: Longitudinal effects of aging on serum total and free testosterone levels in healthy men: Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 86:724-731, 2001; with permission.)


Physiology of Aging in the Male Gonadal Axis
The decline in serum testosterone levels in aging men is caused by a dual defect in the hypothalamus and testis. Aging is associated with aberrant secretion of gonadotropin-releasing hormone (GnRH) and a blunted response of the Leydig cell to luteinizing hormone (LH) and human chorionic gonadotropin (hCG).[34] [48] [85] The pituitary is spared; in older men, pituitary gonadotrophs continue to secrete LH normally when stimulated by GnRH.[35] [47] [70] [84] There is an increased sensitivity to androgen negative feedback on LH secretion.[91] Older men lose the circadian rhythmicity in testosterone levels seen in younger men, who have an early morning elevation.[14] As a result of these changes, older men tend to have normal or high-normal serum gonadotropins and low to low-normal testosterone levels when compared with young normal men.

Clinical Consequences of Declining Gonadal Function in Aging Men
The decline in serum testosterone levels has been cited as a potential cause of numerous structural and physiologic changes in older men.[10] [44] [76] These changes include age-related declines in muscle mass and strength, increased fat mass, osteoporosis, decreased libido and sexual function, a decreased sense of well-being, and mood changes such as depression. None of these alterations is specific for testosterone deficiency, and a causal relationship has been difficult to demonstrate.

Body Composition and Strength
Muscle mass and strength decline dramatically in men and women as they age. Skeletal muscle mass decreases approximately 35% to 40% between 20 and 80 years of age, with men experiencing rapid muscle loss between 41 and 60 years of age, and women experiencing rapid loss after age 60.[15] An older cross-sectional study of subjects between 18 and 85 years of age showed that the percentage of body fat doubled from 18% to 36% with aging in men[53] ; however, it is not clear to what degree these changes in body composition and strength are caused by changes in sex steroid hormone levels.

Bone Mineral Density
Bone mineral density (BMD) in men decreases significantly with age, and some epidemiologic studies have shown an association between declining testosterone levels and BMD in older men.[6] [16] [25] [30] [49] This association remains controversial, and several other studies have not shown this linkage.[2] [21] [59] [67] [73] In two studies, serum estrogen levels correlated more strongly with BMD than did testosterone levels.[2] [67] Although the preponderance of the epidemiologic data suggest an association between declining serum androgen levels and BMD in aging men, controversy persists regarding the relative importance of this association in the development of osteoporosis in older men.

Mood and Sexual Function
The relationship between declining testosterone levels and mood and sexual function in older men is even more tenuous. One recent epidemiologic study demonstrated that low androgen levels were associated with a higher prevalence of depression in older men.[8] There are no convincing data associating the decline of sexual function with the age-related decline in serum androgen levels.

Summary of Clinical Effects
Despite the inevitable decline of free and total testosterone levels in men after the third decade of life, it is controversial whether these changes in serum androgen levels cause age-related sarcopenia, osteopenia, or alterations in mood and sexual function. The most germane clinical questions are whether supplemental exogenous androgen therapy is safe in widespread use in otherwise normal older men with low testosterone levels, and whether it confers a significant overall beneficial effect.

Clinical Trials of Androgen Supplementation in Older Men
There are few published clinical trials of the effects of supplemental testosterone in older men with low or low-normal serum testosterone levels. Furthermore, the published trials are small (the largest have about 100 subjects), and most of the studies are relatively short in duration. It is difficult to make comparisons among the published studies because of the variability in the entry criteria for subjects and in the androgen supplementation protocols. With the caveat that more data are needed before definitive conclusions can be drawn, some preliminary observations are possible.

Body Composition and Strength
Short-term studies have shown that exogenous testosterone administration to older men with low or low-normal testosterone levels results in decreases in fat mass, increases in lean body mass, and increases in upper or lower extremity strength.[7] [45] [77] [82] Longer-term studies have shown that these effects persist over continued treatment. Sih and co-workers[65] randomized 32 men aged more than 50 years with low bioavailable testosterone levels (<0.6 ng/mL) to 1 year of treatment with placebo or intramuscular testosterone cypionate, 200 mg every 2 weeks. Grip strength increased significantly in the testosterone-treated group but not in the placebo group. Leptin levels decreased significantly in the testosterone-treated group only, but body composition (lean and fat body mass) did not change in either group. In a 3-year study thus far reported in abstract form, Tenover demonstrated that intramuscular testosterone (150-200 mg every 2 weeks) produced significant increases in lean body mass and handgrip strength in older men with pretreatment testosterone levels less than 3.5 ng/mL.[78]

Snyder and co-workers[69] randomized 108 men aged more than 65 years with total testosterone levels less than 4.75 ng/mL to 3 years of testosterone administration by scrotal patch (6 mg/day) or to a placebo patch. Testosterone treatment increased mean serum total testosterone levels from 3.67 to 6.25 ng/mL. This increase was associated with a significantly decreased fat mass (3 kg) and significantly increased lean body mass (2 kg) in a comparison with the placebo group. Despite the increase in lean body mass, knee extension and flexion strength did not change significantly.

The previous studies show that exogenous testosterone supplementation increases lean body mass and decreases fat mass in older men with low to low-normal serum testosterone levels. The two studies using intramuscular testosterone[65] [78] have demonstrated significant increases in grip strength in the testosterone group when compared with the placebo group, but Snyder's study using testosterone patches did not show differences in lower body strength.[69] The different effects may be explained by a variety of factors, such as differences in the groups studied, differences in the baseline testosterone levels, differences in the route of testosterone administration, or intrinsic differences between the responses of upper and lower extremity muscle groups. It is essential to resolve which factors are most important to the difference in outcomes to be able to study the most important unanswered question: do the favorable changes in body composition and strength translate into clinically relevant outcomes such as an improved ability to live independently?

Bone
The studies by Tenover and Snyder also assessed BMD by dual-energy x-ray absorptiometry (DEXA) scans.[68] [78] In Tenover's study, there was a significant increase in BMD in the group treated with intramuscular testosterone when compared with the placebo group. In the study by Snyder, the testosterone-treated and placebo groups experienced a significant increase in BMD (4%) in a comparison with baseline values, and the change was not significantly different between the two groups. Nevertheless, men with the lowest baseline total testosterone levels (<2 ng/mL) had a larger increase (6%) in BMD, and this response was significantly greater than the response in the placebo group.

There are important differences in the studies by Snyder and Tenover. First, the men recruited into Snyder's study had higher mean baseline total testosterone levels (3.67 ± 0.8 ng/mL) than the men in Tenover's study (in which baseline total testosterone was <3.5 ng/mL). Second, in Snyder's study, both groups were administered supplemental calcium and vitamin D, which were not given in Tenover's study. This may account for the improvement in the placebo group. Third, the route of testosterone administration (patch versus intramuscular) might have resulted in significant differences in net testosterone dosage in the two studies. Despite these differences, the results of both studies are consistent in suggesting that androgen supplementation might increase BMD in older men with low testosterone levels. Although it is reasonable to postulate that the increased BMD might decrease fracture risk, randomized controlled trials are needed to establish this benefit.

Mood and Sexual Function
Data on the effects of supplemental testosterone on mood and sexual function of older men are limited. In Snyder's study, there were no overall differences in a generic health-related, quality-of-life questionnaire, but the placebo group reported a significant decline in self-perceived level of physical functioning during the study, whereas the testosterone patch group did not. There were also no differences in the responses to questionnaires focusing on sexual function.

Side Effects of Androgen Supplementation in Older Men
For androgen supplementation to older men to be a viable clinical intervention, it must be safe to administer. The principal health concerns regarding long-term androgen supplementation include the possibility of increasing prostate disease (prostate cancer or hyperplasia), cardiovascular and lipoprotein effects, hepatotoxicity (with oral preparations only), erythrocytosis, peripheral edema, and sleep apnea.

Prostate Disease
There is no evidence that exogenous testosterone stimulates the development of severe symptomatic prostate hyperplasia, nor does exogenous testosterone seem to increase the risk of clinically significant prostate cancer. Most of the data regarding the effects of exogenous testosterone on the prostate are derived from case-control studies of hypogonadal men receiving androgen replacement therapy, or healthy young men receiving high doses of androgens.[9] [18] [37] [41] Twenty-nine hypogonadal men had low baseline prostate volumes and prostate-specific antigen (PSA) levels, which rose to normal eugonadal levels after treatment with a transdermal testosterone patch for 6 months.[41] A similar result was obtained in a case-control study of hypogonadal men treated with intramuscular, transdermal, or oral preparations of androgens.[9] Young men who chronically used anabolic steroids had similar prostate volumes and PSA levels when compared with age-matched controls.[37] Similarly, healthy young men who were acutely administered dosages of intramuscular testosterone as high as 500 mg weekly for 15 weeks did not have significant changes in PSA.

In older men, the prostatic effects of long-term supplemental testosterone are difficult to assess because of the small number of subjects studied. In Sih's 12-month study of intramuscular testosterone (total number of subjects = 32, cited previously; 17 on active drug), serum PSA levels did not change significantly in the testosterone group when compared with the placebo group, and PSA levels never exceeded the normal range.[65] In Snyder's 3-year study of the testosterone patch, the treated group had a small but statistically significant rise in PSA levels, never exceeding the normal range, whereas the placebo group showed no significant change.[68] [69] Urine flow rates and symptoms of prostatism were similar in the two groups and were unchanged throughout the study. Tenover reported similar results in her 3-year trial of intramuscular testosterone therapy.[78]

In the absence of large clinical trials, the preponderance of the data suggests that exogenous androgens used for supplementation do not cause an increase in prostate disease. It is sensible to advise older men treated with exogenous testosterone about the potential risks of prostate disease and to offer screening with annual digital rectal examination and serum PSA.

Cardiovascular Disease
Because cardiovascular disease is more common in men than women, there has been a longstanding suspicion that exogenous testosterone supplementation may increase the risk of cardiovascular morbidity and mortality in older men; however, epidemiologic studies suggest that testosterone actually has a neutral or favorable effect on cardiovascular disease.[1] Testosterone has multiple effects on cardiovascular risk factors. Exogenous testosterone tends to suppress high-density lipoprotein (HDL) cholesterol levels but also tends to suppress atherogenic lipoprotein (a).[4] [5] [22] In addition, exogenous testosterone decreases visceral adiposity in men,[22] and acts as a coronary vasodilator in men with cardiovascular disease.[90]

There are inadequate data on testosterone and the risk of cardiovascular disease in older men. Nevertheless, based on epidemiologic data and studies of the effects of testosterone on lipids, visceral adiposity, and vascular reactivity, it is likely that exogenous testosterone supplementation is safe in most older men, including those with known established coronary artery disease.

Miscellaneous Side Effects
Androgen-induced erythrocytosis is more common in older men than in younger men. In one long-term study of testosterone replacement in older hypogonadal men, almost 25% of the men experienced clinically significant erythrocytosis during the first year of treatment with intramuscular testosterone, 200 mg every 2 weeks.[31] In Snyder's 3-year study, the group treated with testosterone had a statistically significant increase in hematocrit, and three subjects sustained persistent erythrocytosis. Generally, a reduction in the dose of androgen was sufficient to eliminate this side effect.

Androgen therapy is known to precipitate or worsen sleep apnea, but this complication is rare.[63] There was no worsening of hypopneic or apneic events in Snyder's study.[68] [69]




AGING AND THE SOMATOTROPIC AXIS
Neuroendocrine Regulation of Growth Hormone
Growth hormone, the most abundant pituitary hormone, is a 191 amino acid protein whose secretion depends on hypothalamic stimulation. Three hypothalamic ligand-receptor systems regulate growth hormone synthesis and secretion: (1) somatostatin, an inhibitor of growth hormone secretion; (2) growth hormone-releasing hormone (GHRH), which seems to be the principal growth hormone secretagogue; and (3) ghrelin, discovered in 1999 as the endogenous ligand for a previously characterized growth hormone secretagogue (GHS) receptor, which is distinct from the GHRH receptor[20] [38] (Fig. 2) . All of these substances are brain-gut peptides. Although growth hormone responds primarily or solely to the GHRH and somatostatin secreted into the hypothalamic-pituitary portal system, ghrelin is secreted by the stomach in quantities large enough to activate central GHS receptors, and ghrelin has appetite-stimulating activities that may be distinct from its activities as a regulator of growth hormone.[40] [50] [81] The novel structure of ghrelin, which includes a lipophilic octanoyl side group that is obligatory for biologic activity, also facilitates access to the central nervous system, and it is possible that circulating gastric ghrelin may have a significant role in hypothalamic-pituitary regulation. These peptides, in turn, respond to a variety of higher neuropeptides and neurotransmitters responding to physiologic and pharmacologic stimuli and inhibitors, such as sleep, stress, exercise, food intake, and body composition. Together, they interact to generate a physiologic pattern of pulsatile growth hormone secretion[36] [83] (Fig. 3) (Figure Not Available) . Growth hormone has direct effects, but many of its actions are mediated through stimulating the synthesis of insulin-like growth factor 1 (IGF-1). IGF-1 in the circulation is derived largely from hepatic synthesis, but IGF-1 locally generated in target tissues may be equally important. Two groups have shown that mice with selective hepatic IGF-1 knock-out mutations grow normally except for reduced kidney size.[66] [92]


Figure 2. Neuroendocrine regulation of growth hormone secretion. A convergence of neurotransmitter pathways modulates the secretion of the peptides shown here to generate the observed pattern of episodic growth hormone secretion and the responses to endogenous and exogenous stimuli. For convenience the liver is shown as the major source of circulating IGF-1, although IGF-1 locally generated in many other growth hormone target tissues is of at least equal importance. Ghrelin is secreted by the stomach in concentrations sufficient to exert effects on growth hormone secretion, appetite, and energy balance. Whether ghrelin is also synthesized in the brain is still controversial, and the relative physiological roles of gastric and hypothalamic ghrelin have not yet been clearly defined. GHRH = growth hormone-releasing hormone; SRIF = somatostatin; IGF-1 = insulin-like growth factor 1.


Figure 3. (Figure Not Available) Patterns of growth hormone secretion in healthy younger and older men and women. Older subjects show a reduction in pulse amplitude and in the fraction of growth hormone secreted during sleep, with little change in pulse frequency. L = large GH pulses; S = small pulses, according to the authors' criteria. (From Ho KKY, Evans WS, Blizzard RM, et al: Effects of sex and age on the 24-hour profile of growth hormone secretion in man: Importance of endogenous estradiol concentrations. J Clin Endocrinol Metab 64:51-58, 1987; with permission.)


Physiologic Changes of Growth Hormone in Aging
Growth hormone secretion peaks around the time of the pubertal growth spurt and then declines steadily and progressively with aging in men and women (Fig. 3) (Figure Not Available) ,[36] with a commensurate steady decline in IGF-1. This decrease is steep enough that normal IGF-1 levels in older men often fall below the normal range for young men, and most, but not all, clinical laboratories now provide age- and gender-appropriate normal ranges. There is a particular decline in nocturnal, sleep-related growth hormone secretion such that older adults secrete only slightly greater growth hormone during sleep than during waking hours.[36] [86] Although testosterone generally stimulates growth hormone secretion, perhaps via conversion to estrogens, the age-related decline in growth hormone is at least partially independent of sex steroid changes and cannot be fully reversed by sex steroid treatment.[20] In men, the decline in growth hormone is not explained by the decline in testosterone levels.

Numerous possible mechanisms could underlie this decline. Possible explanations include decrements in GHRH or ghrelin secretion; an increase in somatostatin, in part related to increased adiposity; declining pituitary responses to GHRH or ghrelin; or increased sensitivity to IGF-1 negative feedback. The last of these mechanisms is not supported by studies by Chapman and co-workers,[17] who administered graded IGF-1 infusions to healthy younger and older subjects and found similar dose-response curves for the inhibition of growth hormone secretion.

Studies of growth hormone responses to GHRH in aging have produced variable results. The authors found that growth hormone remained highly responsive in a group of healthy lean older adults,[56] but other researchers have demonstrated reduced responses, possibly related to higher body fat and increased somatostatin secretion in the older subjects. Ghigo and colleagues[3] [26] have shown that the growth hormone response to the combination of GHRH and arginine (a presumed inhibitor of somatostatin) does not decline with aging, a result compatible with increased somatostatin in more obese older men. In an elegant series of experiments, Russell-Aulet and colleagues[62] administered graded infusions of a GHRH antagonist and showed that less antagonist was needed to block growth hormone secretion in older than in younger men, a result compatible with reduced GHRH secretion in aging. There are no published studies of changes in ghrelin secretion with aging. The effects of ghrelin or its mimetics on growth hormone are similar to the effects of GHRH, with generally reduced responses in older men that are boosted by coadministration of arginine.[3] [27] The central mechanisms of the age-related decrease in growth hormone in men are likely to be multifactorial, with a decrease in GHRH and, except in healthy lean subjects, an increase in somatostatin secretion.

Clinical Consequences of Reduced Growth Hormone Secretion in Aging
The age-related changes in growth hormone are of clinical interest because they are accompanied by changes in body composition and physical and psychologic function that are strongly reminiscent of the changes seen in adult patients with frank growth hormone deficiency, as described in detail elsewhere in this issue (see the article by Stavrou and Kleinberg). These changes include reductions in lean body mass and muscle strength and an increase in body fat, especially in the abdominovisceral compartment. Memory and cognitive function gradually deteriorate. Deep (stage 3 and 4) sleep also decreases markedly with aging, in parallel with the decrease in nighttime growth hormone secretion, and sleep disorders become a significant clinical problem in old age. Although these changes show only an association and not causality, they have led to speculation that growth hormone or its secretagogues may promote sleep and vice versa.

Most of these changes are the same ones noted earlier to parallel the age-related decline in testosterone secretion. Given the similarities in phenotype, it is not generally possible to single out which hormonal change (if either) is primarily related to the alterations in body composition and function.

Growth Hormone Treatment in Normal Aging
As is true for the age-related changes that evoke similarities with male hypogonadism, the similarities with the phenotype of adult growth hormone deficiency and the success of growth hormone treatment in reversing many structural and functional abnormalities in that condition have led to speculation that the age-related decline in growth hormone is also a hormone deficiency syndrome, and that reversing the decline by administering growth hormone or stimulating its secretion would confer clinical benefits. This interest has spread beyond the scientific and medical communities. Dietary supplements claiming to provide or stimulate growth hormone secretion have found a substantial popular market, and a number of life-extension clinics provide physician-prescribed growth hormone for off-label use. The title of one popular work, Grow Young With HGH,[37A] suggests (incorrectly) that this prospect has already been validated.

Despite the breadth and persistence of this interest, controlled studies of the effects of growth hormone in aging are limited. In a 1990 study on which much of the popular interest is based, Rudman and colleagues[60] reported the effects of 6 months of treatment with placebo or growth hormone in 21 men aged more than 60 years. The dose was chosen to bring circulating IGF-1 levels to the middle of the normal range for healthy men in their twenties. Subjects receiving growth hormone showed a 90% increase in lean body mass, a 14% reduction in body fat, and a 7% increase in skin thickness. A small (2%, p = 0.04) increase in vertebral--but not femoral or radial--BMD was reported. This finding was unusual in that most studies of growth hormone in adults with growth hormone deficiency do not show increased BMD until at least 1 year of therapy. The changes in body composition persisted over a year of growth hormone treatment.[61] No effects on strength or physical function were reported. In a study of combined treatment with growth hormone and IGF-1 in women, Thompson and co-workers[80] reported similar changes in soft-tissue body composition. Recent studies using growth hormone[12] [13] or GHRH[42] [64] reported in abstract form confirm these increases in lean body mass and decreases in body fat in men and women. As is true in growth hormone treatment of adult growth hormone deficiency, the authors' studies using a 6-month intervention with GHRH show that these effects are more pronounced in men than in women, particularly when women receiving estrogen replacement therapy are studied.[43] Although estrogen seems to blunt many of the actions of growth hormone, testosterone injections do not seem to impair growth hormone effects in older men, and the two treatments may have additive effects (see below).

Strength and Functional Performance
The effects on lean body mass encourage the hope that growth hormone treatment may also improve muscle strength and functional performance, but the results thus far have been disappointing and inconclusive. In a relatively large study, Papadakis and colleagues[54] treated 52 men aged 70 to 85 years with placebo or growth hormone for 6 months. There was a 13% reduction in fat mass and a 4% increase in lean body mass in the treatment group, effects consistent with earlier studies; however, there was no effect of growth hormone on knee or handgrip strength or endurance. The weight of this negative result is undercut somewhat by the vigorous functional status of the treatment group at baseline; subjects were close to the top of the range of some of the tests used, even before treatment. This "ceiling effect" made it difficult to see further improvements with growth hormone treatment.

In a separate study, Taaffe and co-workers[74] showed that exercise training improved strength and exercise capacity, but growth hormone treatment did not further augment this effect. In studies of the effects of 5 to 6 months of treatment with placebo or GHRH, the authors examined the effects on strength and physical function using tests that replicated activities of daily living in a standardized fashion. A preliminary analysis of these measurements did not show an improvement with treatment in this measure of physical functional performance.[87] A study using growth hormone in higher effective doses, also reported thus far in abstract form, found a small but significant 3.2% increase in aerobic capacity (MVO2 ) after 6 months of treatment.[23] Given the wide variety of tests used, it is difficult to compare these disparate results directly. There is no current consensus on whether the increase in lean body mass produced by growth hormone or growth hormone secretagogues is accompanied by improvements in strength, endurance, or physical functional performance.

Mood, Cognition, and Sleep
There are even fewer reports on the effects of growth hormone or growth hormone secretagogues on psychologic function or affect. Several tests of cognition and mood were included in the study by Papadakis and colleagues,[54] with no consistent growth hormone treatment effect. In a preliminary report, 5 months of GHRH treatment improved performance when compared with placebo on several measures, including digit-symbol substitution, finding `A's, and single-dual tasks, tests that are responsive to changes in psychomotor and perceptual processing speed.[86] [88] This tentative finding requires confirmation.

Sleep disorders are common and are a major problem in aging. In younger men, nocturnal growth hormone secretion is closely linked to deep (stage 3 and 4) slow-wave sleep. Both stages of sleep decrease with aging, and a small number of preliminary studies have suggested that growth hormone may not only be stimulated by slow-wave sleep but may, in turn, promote restful sleep. Acute or short-term interventions with GHRH or with ghrelin mimetics have enhanced sleep in several settings.[11] [86] The authors' ongoing 5-month intervention with GHRH includes an assessment of effects on sleep and simultaneous growth hormone secretion.

Side Effects and Risks of Growth Hormone Treatment in Aging
Side effects of growth hormone treatment in normal aging must be considered in a different way from side effects in established growth hormone deficiency. Aging is not a disease, and despite the apparently unfavorable changes in body composition and functional capacity, at this early stage of knowledge one must be sensitive to the possibility that at least some of these changes are adaptive responses to other age-related processes, and that pushing growth hormone above the age-appropriate normal range may have as many risks, both acute and delayed, as benefits. The acute side effects of growth hormone are largely hormonal. The most worrisome long-term potential side effect is the risk of cancer.

The acute side effects of growth hormone treatment in normal aging are similar to the side effects encountered in growth hormone replacement in adults with growth hormone deficiency--that is, fluid retention, with peripheral edema, arthralgias, and carpal tunnel syndrome (see the article by Stavrou and Kleinberg elsewhere in this issue). Although Rudman and colleagues reported no significant side effects using growth hormone doses sufficient to restore IGF-1 levels to those of young adults, subsequent investigators encountered frequent side effects with similar growth hormone doses.[33] Several subjects showed increased fasting glucose levels, with values in three men rising above the normal range. These hormonal effects have uniformly responded completely to dose reductions, and most recent studies have used lower growth hormone doses that elevate IGF-1 into the lower part of the young adult normal range.

In principle, treatments with GHRH or ghrelin-like growth hormone secretagogues should offer a more physiologic approach to growth hormone enhancement, recreating a pulsatile rather than a prolonged elevation in growth hormone and retaining the capability for negative feedback inhibition of growth hormone by rising levels of IGF-1. In practice, the authors have found side effects of GHRH treatment to be less frequent and milder, but similar in character, to those reported with growth hormone interventions. Because GHRH stimulates a lesser increase in IGF-1 levels than that reported in most growth hormone intervention studies, it is not clear whether this more favorable side-effect profile represents a qualitative difference or just a lower effective growth hormone dose.

Severe and Long-Term Side Effects
Growth hormone and IGF-1 are growth factors and can promote the growth of certain tumor cell lines. In their review of growth hormone treatment of adult growth hormone deficiency syndrome in this issue, Stavrou and Kleinberg discuss the potential risks of cancers related to long-term growth hormone treatment. Although several growth hormone and growth hormone secretagogue studies include the participation of a safety monitoring board, cancers may be delayed in appearance well beyond the end of the study. Considering the age of the subjects, it is not surprising that cancers have developed in several participants in the authors' and other studies during or following their participation. There is no evidence that the risk of cancer is increased over background rates, but these small, short-term studies lack the statistical power to make any conclusive statement about cancer risk. Men treated with growth hormone or growth hormone secretagogues should receive age-appropriate cancer screening, and the presence of any malignancy should be considered a contraindication to growth hormone treatment.

The increased mortality reported in critically ill hospitalized patients given high doses of growth hormone[75] has not been observed in any studies using the lower doses of growth hormone tested in otherwise healthy older adults and is probably not a significant concern.

Animal studies have called into question in a more general way the fundamental working hypothesis underlying all of these studies, namely, that increasing growth hormone secretion and IGF-1 should be considered a net benefit. In rodents, caloric restriction, which lowers IGF-1, has been associated with an increased life span in numerous experiments. Mice with growth hormone resistance and profoundly reduced IGF-1 levels seem healthy and have a consistently increased life expectancy.[19] The parallel between these results and human senescence is not clear, but these experiments should at least raise caution about promoting growth hormone treatment before appropriate clinical trials have been completed.

Growth Hormone and Exercise
Nonpharmacologic interventions to promote health seem equally promising, particularly regular exercise conditioning. Vigorous regular exercise has repeatedly been shown to increase lean body mass, muscle strength, and aerobic capacity in older and young men.[55] A general discussion of exercise programs in aging is outside the scope of this article, but certain aspects should be mentioned because of the links between exercise and growth hormone. Vigorous exercise acutely stimulates growth hormone secretion and is sometimes used as a first screening test for growth hormone deficiency in children.

The growth hormone response to exercise decreases with aging--even in highly conditioned athletes--but is retained in older adults.[39] This observation led to speculation that some of the effects of exercise might be mediated via effects on growth hormone and IGF-1, a theory that has been disproved. Although exercise stimulates an acute rise in growth hormone secretion, subsequent overnight growth hormone secretion is inhibited.[52] In older adults, three periods or even intensive five periods of weekly exercise do not elevate serum levels of IGF-1.[89] The effects of exercise seem to be separable from those of growth hormone.

Given the apparent difference in mechanism, the authors studied whether a combined intervention with exercise and GHRH might provide additive or even synergistic effects. Over a 6-month intervention, subjects undergoing aerobic exercise conditioning alone showed no changes in IGF-1 levels, and subjects given GHRH and exercise instruction who then discontinued GHRH had no greater IGF-1 effect than with GHRH alone and returned to baseline values when GHRH was stopped.[42] Effects of the combined intervention on lean and fat mass were greater than the effects with either alone. Effects on strength and physical function are still being analyzed. Exercise has the added benefit of reducing the insulin resistance often encountered with growth hormone or GHRH treatment.[64]




COMBINED INTERVENTIONS WITH GROWTH HORMONE AND ANDROGENS
Given the finding that androgens and growth hormone both increase muscle mass and decrease body fat but work by different mechanisms, it is remarkable that there have been few studies of combined interventions with growth hormone and testosterone. A recently completed Johns Hopkins-National Institute on Aging study examined the effects of 6 months of treatment with placebo, growth hormone, testosterone, or the two trophic hormones together in healthy older men (as well as the combination of growth hormone and estrogen patch hormone replacement therapy in women). Results are reported to date in a series of abstracts.[12] [13] [23] [33] [80] Growth hormone was initially given in the same doses used by Rudman and colleagues but was reduced by one-third on average because of side effects. Testosterone was given as intramuscular injections at 2-week intervals.

Consistent with the findings in other studies, growth hormone induced a rise in IGF-1, a reduction in body fat, and an increase in lean body mass. Testosterone did not increase IGF-1 and did not blunt the rise induced by growth hormone. The combination of growth hormone plus testosterone had a greater effect on lean body mass (8.3%) than did growth hormone (5.7%) or testosterone (3.1%) alone as assessed by whole-body DEXA scanning. Combination treatment also enhanced the reduction in body fat (21%) when compared with growth hormone (13%) or testosterone (6%) alone. Body composition effects were of lesser magnitude in women, were not enhanced, and, in some cases, were reduced by hormone replacement therapy. Effects on strength or functional performance were also studied but have not yet been reported.

Side effects in men were primarily caused by growth hormone treatment and included edema, arthralgias, and carpal tunnel syndrome, all of which responded to dose reduction. Glucose levels increased, in one subject to diabetic levels. Testosterone did not cause an increase in prostate symptoms or in PSA levels, and there was no apparent interaction with growth hormone side effects, although the number of subjects was small.




SUMMARY
Aging is accompanied by gradual but progressive reductions in the secretion of testosterone and growth hormone in men, and by alterations in body composition and functional capacity that, to some degree, undo the effects of puberty. Preventing or reversing these changes with the use of trophic factors, including androgens, growth hormone, and growth hormone secretagogues, is an appealing prospect, but documenting the effectiveness of these interventions and their benefits and risks has proven to be a difficult undertaking that is far from complete. Small-scale clinical studies have shown that it is practicable to boost growth hormone and IGF-1 levels for periods of up to 12 months, and testosterone for up to 36 months, to reverse at least some age-related changes in body composition. Information regarding the effects of these interventions on strength, exercise capacity, and the ability to perform activities of daily living is still sparse, and additional reports from recently completed or currently ongoing clinical trials will not provide sufficient data to make firm conclusions.

From the limited information currently available, androgen supplementation may be of benefit in some men aged more than 65 years, particularly in men with low serum testosterone levels (<2 ng/mL). In this group, supplemental androgen therapy would be expected to increase lean body mass, bone mass, and possibly strength. In older men with testosterone levels between 2 and 3.5 ng/mL, some benefit might result from androgen supplementation, but it is not yet clear whether the benefits outweigh the risks. For men in this category, one might consider a 6- to 12-month trial of therapy after a full discussion and explicit consent, followed by a reassessment of the value of ongoing treatment.

The even more limited data on growth hormone or growth hormone secretagogue interventions in aging do not support their general clinical use in healthy older men. Growth hormone is much more expensive than testosterone and is not covered by insurance for off-label uses. Patients who persistently seek a trial of therapy should be encouraged to enroll in a study if one is locally available.

All of the growth hormone studies reported to date have focused, generally for reasons of safety, on healthy and robust groups of older subjects, men in whom the need for intervention is least compelling and in whom the functional effects of treatment may be the most difficult to observe. Phase II studies of intermediate size and duration examining prefrail groups of elderly who are at greater risk for functional loss and who stand to benefit the most from either preventive or restorative interventions are underway but are limited to the intermediate outcomes of body composition, strength, and function.

Trials designed to assess clinically relevant final outcomes, such as falls, fractures, and institutionalization, are of necessity large-scale, long-term, and expensive. Support for larger phase III studies of growth hormone is unlikely to be forthcoming until the phase II studies are completed and show further promise. A multicenter clinical trial of testosterone is currently being planned under the joint sponsorship of the National Institute on Aging, the Veterans Health Administration, and industry, aimed at assessing the effects of testosterone on the risk for falls and fractures. The results of this trial and other large clinical trials should help to better define the balance of benefits and risks of trophic factor intervention in normal older men.

ACKNOWLEDGMENTS
The authors thank their colleagues at the University of Washington who collaborated on the studies discussed in this review and who provided helpful suggestions and critiques, particularly William Bremner, MD, PhD, David Cummings, MD, Alvin Matsumoto, MD, Karen Moe, PhD, Robert Schwartz, MD, and Michael Vitiello, PhD. They are also grateful for the assistance of the study coordinators and technicians who made these studies possible, including Suzanne Barsness, RN, Colleen Carney, RN, Monica Kletke, BA, and Lynna Smith, ARNP, and the expert and dedicated staffs of the University of Washington Clinical Research Center and the VA Clinical Studies Unit.

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Andriol really has too short a half life to be very effective for what you want. Something like Androderm, Androgel or Oxandrin would give you what you want and not shut down HTPA. This just my personal xp. My test levels were actually higher taking 20mg Oxandrin once a day in the morning or a 5mg Androderm patch put on before bed than when I was prescribed 200mg of test cyp/week. I think AS that mimics your bodies own diurnal hormone secretion of test like I mentioned above really maximize what your own body produces even if you have low test levels normally.
 
Dianabol ART Program

hansnz: Somone else did indeed have your idea: I'm on my own customized Dianabol ART [Androgen Replacement Therapy] Program since 1.5 months ago :)

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To see my entire story please visit the following forums - they're mirrors of each other exept for the first which is another short summary also with links to the two main forum posts. I cannot post the links but you can just copy-paste the titles into Google to find the threads:

Think Steroids: A long term unconventional HRT-TRT regimen with Dianabol

Longecity Forum: Hypogonadotropic Hypogonadism
(My username is Isochroma-Reborn on Longecity)

And my report on how and why the intranasal route is so critical to a correct mind cure of low-Testosterone symptoms:

TESTOSTERONE NATION: Insufflation (Snorting) Dbol: Trip Report
 
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