|Men’s Bioidentical Hormone Restoration|
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Thinking Ahead of the Curve for Men’s Bioidentical Hormone Restoration Therapy (BHRT)
Why must aging men, men with low testosterone, or men with prostate cancer simply have to accept the loss of libido, energy, risk-taking, sleep and muscle mass to fight depression and the inevitability of man breasts and snoring that comes with changes in the hormone balance? Why should hormone supplementation be statically dosed? T.S. Wiley thinks that replicating the youthful hormone regime to restore lust and love, sleep, muscle mass, and bone health, and to counter depression along with the other effects of low testosterone and dehydroepiandrosterone ( DHEA) is more than important, it’s achievable. This challenges decades of medical thinking.
Once more Wiley goes where no regimen for replacing men’s hormones has gone before... to rhythmic, youthful physiologic dosing of testosterone and DHEA for men. Who says men have a cycle or that they would benefit from a rhythm? Wiley does.
In men four hormones significantly decrease with age: testosterone, estradiol, (DHEA)/ DHEA sulfate (DHEA-S), and growth hormone (GH). A longitudinal study showed that mean total testosterone levels decreased by 30 percent between the ages of 25 and 75 and mean free-testosterone levels decreased by as much as 50 percent. This decline in testosterone is secondary to a decrease in the number of testicular Leydig cells, a decrease in testicular perfusion, and changes in the hypothalamic-pituitary axis. Serum estradiol also decreases in aging men, likely due to a decrease in available testosterone to be aromatized to estradiol. Serum levels of the adrenal androgens, DHEA and DHEA-S, decline most dramatically as men age; however, the clinical significance of this change is unclear. Lastly, the GH/insulin-like growth factor 1 (IGF-1) axis also declines with age.
Age-related decreases in hormone levels lead to a number of negative impacts on men’s lives. Andropause is defined as an age-related decline in serum testosterone levels in older men to below the normal range in young men, which is associated with a clinical syndrome consistent with androgen deficiency. The syndrome may include decreased muscle strength and/or endurance, decreased pubic and increased axillary hair, reduced physical function, diminished libido, fatigue, depressed mood, decreased generalized well-being, hot flashes, osteoporosis/osteopenia, and anemia. Andropause is being recognized increasingly in the geriatric, endocrinology, and primary care literature as a syndrome of aging men.
Office screening tools, such as the Androgen Deficiency in Aging Males (ADAM) questionnaire, have been developed to determine which older men should have testosterone testing performed. If the ADAM questionnaire is positive, bioavailable or free testosterone is low, and, if there are no specific contraindications, it has been recommended that men should be treated with replacement testosterone therapy. An estimated 2 million to 6 million American men have low testosterone. Other trials have explored the benefit of GH replacement. A 1990 study showed that replacement of GH in aged men for 6 months improved lean body mass and decreased body fat, but a more recent study, looking at replacement of both GH and sex steroids, demonstrated unacceptable adverse effects, including the development of diabetes mellitus.
It is well known that sex steroids influence bone metabolism, but the mechanism is not completely understood. Both estrogen and androgen receptors are present in bone. A complex relationship exists between sex hormones and other hormones, including IGF-1 and 25-OH vitamin D.
Until the 1990s, it was thought that androgens alone modulated skeletal health in men. Then, in 1994, Smith et al. reported a young male with a homozygous estrogen-receptor gene mutation, causing estrogen resistance, with normal testosterone levels and osteoporosis. Several case reports followed of men with aromatase deficiency and osteopenia that were successfully treated with estrogen therapy. A large cohort study, the Rancho Bernardo Study, reported that, of all sex hormones, estrogen was most strongly associated with bone mineral density (BMD) in both men and women, although testosterone was also associated with BMD. By blocking testosterone and estrogen in elderly men via leuprolide injection and selectively replacing testosterone, estrogen, both, or neither, researchers found that estrogen played a significant role in bone resorption, and testosterone had a smaller role that was not significant. The relationship between sex steroids and bone growth/turnover is an ongoing area of research.
Does supplementation with testosterone increase the risk of developing prostate cancer? The discussion below reviews current treatment approaches and the growing body of research designed to answer this question.
Prostate cancer cells rely on androgens, male hormones that include testosterone, to survive and grow. A landmark paper by Huggins and Hodges, published in 1941, has become the reference study used to justify the refusal of testosterone supplementation in men with prostate cancer or who are at risk. This study, which included only eight patients with advanced prostate cancer, won the authors the Nobel Prize. Three patients received testosterone after castration, which resulted in a rise in prostatic acid phosphatase. Elevated prostatic acid phosphatase levels may indicate the presence of prostate cancer. When testosterone supplementation was stopped, their acid phosphatase levels declined. One patient had an initial decline in acid phosphatase, followed by a rise that was presumed to be due to adrenal testosterone.
Since 1941, doctors have based treatment of prostate cancer on depriving patients of androgens, either by castration or chemical methods, on the conclusions of this study. For most patients, this hormone deprivation therapy causes tumors to shrink, sometimes dramatically. However, it is never a cure. Tumors eventually regrow into a stronger form, becoming resistant to this and other forms of treatment. Seeking the reason why this therapy eventually fails, a research study looked to a key player: the androgen receptors on prostate cancer cells.
Using a large database, researchers searched for variations of the nucleic acid RNA that prostate cells use to create androgen receptors, eventually identifying seven RNA sequences different from the "normal" androgen receptor already known to scientists. They found cells isolated from 124 prostate cancer patients, they found over-production of these outlaw variants in prostate cancer cells taken from patients whose disease had become resistant to hormone deprivation therapy. One variation—known as AR-V7, was also prevalent in a select group of patients who had never taken hormone therapy, but whose cancer aggressively regrew after surgery to remove their tumors. Unlike cells with other androgen receptors, those with only AR-V7 receptors acted as if they were continually receiving androgens—turning on at least 20 genes that rely on androgens for activation—even though no androgens were present.
The results suggest that androgen deprivation therapy (ADT) might encourage prostate cancer cells to overproduce the AR-V7 receptors over time, leading them to survive and grow aggressively even without androgens. In some patients, AR-V7 receptors might already be prevalent even without hormone therapy, predisposing them to an already-aggressive form of prostate cancer that won't respond as well to hormone deprivation therapy.
Men who show an increasing PSA after surgery but without signs of metastases are offered a variety of options for treatment, including radiation, prostatectomy, observation or androgen deprivation therapy (ADT). Unfortunately virtually all patients treated with ADT progress to metastatic disease. Men with prostate cancer who are being treated with ADT increase their risk of developing bone- and heart-related side effects compared to patients who do not take these medications, according to a new study. ADT can cause a variety of side effects including skeletal and cardiovascular complications, sexual dysfunction, periodontal disease, and mood disorders.
Bone and heart complications are among the most serious side effects associated with ADT, but the actual risk patients have of developing these effects is unknown. The study revealed that men treated with ADT for prostate cancer had an increased risk of bone fractures and heart-related death, although the absolute risk for both was still low. For bone fractures, there was a 23 percent increased risk compared to prostate cancer patients who did not undergo the treatment. The absolute risk of fracture among ADT-exposed men was still only 7.2 per 100 person years. For heart-related death, the increased risk among ADT-exposed men was 17 percent higher compared to other prostate cancer patients. However, because the baseline risk is low, the increase translated to additional one-to-two deaths per 1,000 men who received ADT. Two large studies also documented significant increases in diabetes risk associated with the therapy.
The role of testosterone supplementation in treating prostate cancer has been receiving more recent attention by researchers. Although primary prostate surgery or radiotherapy is successful in many cases of prostate cancer, some patients will suffer a recurrence of the disease, which is most often first detected by a measurable Prostate-Specific-Antigen (PSA) blood test. This so-called biochemical recurrence affects 30 percent to 40 percent of patients after surgery. One risk factor for recurrence, the presence of cancer potentially outside the prostate after surgery, will affect about a third of men. Wiley is tracking the men who have had prostate cancer who are using the Wiley Protocol to provide data on this issue.
The Wiley Protocol for Men™ rhythm is based on four-day sun cycles and magnetism, not moon rhythms and light, as is the Wiley Protocol for Women™. Scientifically, the sun rotates faster at its equator than at its poles. This period of actual rotation is approximately 25 days at the equator and 35 days at the poles. However, due to our constantly changing vantage point from the earth as it orbits the sun, the apparent rotation of the Sun at its equator is about 28 days. This is a geocentric perspective. A 28 day hormone cycle for men is based on this equatorial rotational period. Changes in the Sun's magnetic field are carried outward through the heliosphere by the solar wind. The solar wind takes about 8 days to reach the earth. So, there is an eight day cycle of magnetism overlapping the four day cycle that changes as the “orange wedge” of the rotating sun changes its face toward the earth.
Testosterone and DHEA are used with the rhythm of the sun cycles; DHEA is only applied in the morning when men’s androgens normally peak. DHEA provokes an androgen receptor more quickly, lowering estrogen reception. Dose elevations occur every four days rather than every three days to allow DHEA to create more receptors for testosterone. Biomimetic rhythmic, cyclical hormone replacement can restore quality of life. What’s more, the protocol may provide a youthful, anti-aging hormone regime that puts life in men’s years as well as years in men’s lives.
It is time to rethink our assumptions about the role of ADT and of testosterone supplementation. We know that cancer of the prostate, at least early in its progression, is usually dependent on testosterone and appears to regress with castration. However, some animal and cell line models show accelerated growth of cancer in the presence of low testosterone. A strong case can be made that in fact it is low levels of testosterone that are indicative of the potential for prostate cancer. Prostate cancer is a disease of older men; young men with high testosterone on the whole do not develop prostate cancer. Prostate cancer is an age-dependent cancer. Data correlating prostate cancer with high testosterone levels are scarce. Low testosterone levels are associated with high grade prostate cancer and a poor prognosis. There is evidence that prostate cancer cell lines show apoptis with high levels of testosterone.
Longitudinal studies show no association between baseline serum testosterone and the risk of prostate cancer. In a 2008 study published in the Journal of the National Cancer Institute, a collaborative analysis was performed of the existing worldwide epidemiologic data to examine the association of testosterone and other sex hormones in serum with the risk of prostate cancer in a uniform manner and to provide more precise estimates of risks. In this collaborative analysis of the worldwide data on endogenous hormones and prostate cancer risk, serum concentrations of sex hormones were not associated with the risk of prostate cancer. (Prostate Cancer Collaborative Group).
A 2009 literature search was performed of English language publications on testosterone administration in men with a known history of prostate cancer and investigation of the effects of androgen concentrations on prostate parameters, especially prostate specific antigen and published in Urology. Although it is clear that prostate cancer is exquisitely sensitive to changes in serum testosterone at low concentrations, there is considerable evidence that prostate cancer growth becomes androgen indifferent at higher concentrations. No controlled studies have been performed to date to document the safety of testosterone therapy in men with prostate cancer; however, the limited available evidence suggests that such treatment may not pose an undue risk of prostate cancer recurrence or progression.
Another literature review published in Frontiers of Hormone Research (2009) concluded that numerous smaller clinical trials as well as population-based longitudinal studies consistently fail to support the historical idea that testosterone therapy poses an increased risk of prostate cancer or exacerbation of symptoms due to benign prostatic hyperplasia. The authors postulated that the lack of prostate risk despite increased serum testosterone appears to be explained by data showing that exogenous testosterone does not raise intraprostatic concentrations of testosterone or dihydrotestosterone (DHT), suggesting a saturation model. There is mounting evidence that low serum testosterone is associated with greater prostate cancer risk, and more worrisome features of prostate cancer. The study concluded that the available evidence strongly suggests that testosterone therapy is safe for the prostate.
In 1989, Sonnenschein determined that testosterone does not directly stimulate prostate tumor growth at physiologic levels and that high levels of testosterone are directly inhibitory and shut off proliferation of prostate tumor cells. At least 21 studies suggest that low levels of testosterone are associated with prostate cancer. One model used to explain this is the saturation model, which indicates that the most likely mechanism for this loss of androgen sensitivity at higher testosterone concentrations is the finite prostate canceracity of the androgen receptor to bind androgen. This saturation model explains why serum testosterone appears unrelated to prostate cancer risk in the general population and why testosterone administration in men with metastatic prostate cancer causes rapid progression in castrated but not hormonally intact men. Worrisome features of prostate cancer such as high Gleason score, extraprostate cancersular disease and biochemical recurrence after surgery have been reported in association with low but not high testosterone. An earlier study (Meikle, 1982) reported that a familial risk of prostate cancer is associated with low testosterone levels.
There is additional evidence in research on DHT that low levels of testosterone cause cancer. The finasteride (Proscar) Prostate Cancer Prevention Trial generated controversy when a small increase in prostate cancer risk in patients who used finasteride, which blocks DHT, was interpreted as an indicator that use of the drug creates the same hormonal tissue environment as prostate cancer. DHT levels are lower in prostate cancer and are decreased in the advanced stages of prostate cancer. There is an inverse relationship between DHT levels and PSA numbers. In a 1995 study, the androgen-induced bell-shaped growth response in LNCaP cancer cells represented the manifestation of two different cellular events in dose-related manner: cellular proliferation at low DHT concentrations and increased production of PSA at high DHT concentrations with an accompanying decline in cell proliferation. Tsihlias (1999) looked at the mechanism by which high levels of DHT inhibited LNCaP cancer cell growth and determined that it was not cell death but G1 arrest that was involved.
Research suggests it is low-dose testosterone that stimulates proliferation of prostate cancer cells, reversing the atrophy and aptosis resulting from castration levels. High-dose testosterone, by contrast, inhibits growth by inducing differentiation. Wiley’s experimental protocol will explore this relationship further.
Wiley’s Protocol for Men is the wave of the future. As patients become aware of this option, they will have a choice about aging: well and slowly.