Monitoring Testosterone Anti aging Therapy
Myth: testosterone is associated with prostate cancer risk and will cause prostate cancer. There is, however, a repeated lack of association between testosterone and cancer risk, with studies either yielding a null result or demonstrating an inverse relationship between testosterone and prostate cancer risk. Testosterone is associated with prostate cancer risk, but in the exact opposite relationship that the Myth suggests. Benign prostatic hypertrophy is not eliminated through therapeutic testosterone therapy.
Once any testosterone intervention is initiated, adequate and ongoing follow-up is critical. Starting testosterone therapy is only the first step in a replacement program. Continued monitoring is the hallmark of a truly safe and successful program. With testosterone supplementation, patients must be followed for several possible directly related side effects:
Hemoglobin and hematocrit (H/H) may rise in association with testosterone supplementation. If H/H rises above normal limits, phlebotomy is indicated. The condition of sleep apnea patients may worsen with testosterone therapy, which may be related to a rise in H/H or may occur independently. Patients with known apnea should be followed by the physician who is managing the apnea.
Direct testosterone replacement may result in some degree of testicular atrophy. With testosterone levels supplemented to normal physiologic levels, this occurs in approximately 10%-12% of patients. However, testosterone levels typically return to pretreatment levels when therapy ends; yet, there is a slight chance any suppression of testicular function may not fully resolve.
Acne may occur; with physiologic replacement, this is quite uncommon. Other rare side effects of normal replacement include fluid retention and decline in sperm count.
Patient’s medication list should be reviewed for any potential drug interactions. While there are no true drug/drug reactions associated with testosterone therapy, testosterone levels can affect other drug clearance rates and affect levels of anticoagulants.
An important consideration regarding the side-effect profile of testosterone therapy is the possibility of raising estradiol level, occurring in approximately 10% to 12% of subjects placed on testosterone replacement therapy. Since testosterone is converted to estradiol via an aromatase enzyme, this side effect can be easily mitigated via judicious use of aromatase inhibitors. By inhibiting this enzyme’s function, testosterone levels can be maintained while minimizing any concomitant rise in estradiol level, helping optimize the testosterone-estradiol relationship. Testosterone is aromatized to estradiol by the enzyme aromatase. Estradiol down-regulates testsosterone receptors, increases sex hormone binding globulin (thus decreasing bioavailable testosterone) and diminishes clinical testosterone response. This is of particular importance with maintaining libido and erection quality. Additionally, a rise in extradiol levels may produce nipple tenderness, nipple fullness or even gynecomastia.
A less obvious effect of rising estradiol levels is the “invisible” side effect of a lessened clinical response, despite adequately maintained testosterone levels. For some subjects, no outward side effect may be discernable, but they will report an otherwise unsatisfying clinical result. Tracking pre- and post-therapy estradiol levels allows objective monitoring to minimize this possibility. It may be useful to track testosterone/estradiol ratios, trying to maximize this result for patients who have not had the expected response to testosterone therapy.
The greater the testosterone level; the greater the rate of conversion to estradiol. This relationship is not linear, but shows a geometric increase in estradiol conversion with increase in testosterone levels. This is another important reason to monitor testosterone levels and avoid supra-physiologic peaks between dosing intervals.
Typically, estradiol levels should be maintained within the normal range for men, but if a patient notes side effects before follow-up blood can be drawn, or despite apparently normal estradiol levels, then addressing this issue empirically is appropriate. For patients who have a sub-optimal response to treatment and normal estradiol levels, calculating the testosterone-estradiol ratio and comparing pre- and post-therapy values can be a useful tool in deciding whether or not to institute measures to lower estradiol.
Anastrozole is the most commonly used preparation, administered orally. Anastrozole has a long serum half-life, enabling dosing to be started at approximately two times per week. The typical starting dose of Anastrazole is 0.5 to 1 mg by mouth twice weekly. A newer agent, letrozole, is also available. It may be used in an equivalent fashion to anastrozole, with the conversion rate of anastrozole-to-letrozole being 2.5 to one – i.e. 2.5 mgs of letrozole being the approximate equivalent of 1 mg anastrozole.
It was found that by administering anastrozole, estradiol levels were decreased in male subjects. As estradiol levels were reduced, endogenous LH levels rose. As a result, testosterone levels were seen to increase, as shown in the diagram’s middle portion. This effect was seen in both men with idiopathic hypogonadotropic hypogonadism and in normal men The estradiol effect on LH production was elucidated by administering Anastrozole, an aromatase inhibitor, which regulates the conversion of testosterone to estradiol.
Mauras et al, examined this phenomenon and looked at the effect of 0.5 mg versus Anastrozole’s 1 mg per day, given to community dwelling normal men. They found that both 0.5 mg and Anastrozole 1 mg daily dosing was associated with similar declines in estradiol levels, and that both doses were associated with an approximate 50% increase in testosterone levels. The testosterone response was modulated within the normal range, placing men at approximately the 60th – 66thpercentile of testosterone range. This is the same testosterone level reviewed earlier, which was associated with declines in disease risk markers and beneficial clinical outcomes.That same study looked at baseline LH levels and compared them to LH levels after Anastrozole intervention. Baseline LH levels rose from 4 IU/L to approximately 15 IU/L. Peak values increased from approximately 6 IU/L to 10 to 20 IU/L; the frequency of LH pulses went up from baseline as well. One of the main etiologies of the age-related decline in testosterone levels is related to a decline in LH production and LH pulsatility. This Anastrozole study demonstrated a reversal of both of those findings. After intervention with Anastrozole in normal males, estradiol levels fell, testosterone levels increased as did mean LH, the number and amplitude of LH pulses.
In a subsequent study, published in 2004 by Leder, a longer trial clinical was undertaken examining long-term response to Anastrozole as mono-therapy to raise testosterone levels. Researchers noted a prolonged and maintained increase in bioavailable testosterone as well as total testosterone, with no change in dihydrotestosterone values. Regarding total testosterone, pretreatment values averaged approximately 350ng/ml with post treatment values averaging between 550 and 600ng/ml. The same study found a 38% decrease in estradiol and a 50% decrease in estrone.They also demonstrated an approximate 60% – 75% increase in LH production. Noteworthy in these studies is the estradiol level modulation, which has taken place completely within normal laboratory range and equivalent estradiol values, using Quest values demonstrating a fall in estradiol from 25 picogram/ml to approximately 12 picogram/ml. No study results produced estradiol levels below normal or testosterone levels above normal in the studied subjects.
In pharmacokinetic studies, there is an optimal dosing range of HCG. At doses up to 7,000 IU per week, there is a fairly dependable dose response curve. Above 7,000 IU/wk, receptor saturation may occur, and can be associated with a corresponding decline in testosterone response. For some subjects, this receptor saturation may occur at slightly higher or lower HCG doses, making individual monitoring an important follow-up consideration and keeping HCG’s dose response curve in mind. HCG is best dose twice weekly as daily administration is associated with a rapid decline in response and decline in testosterone levels after the first two weeks of therapy, and. weekly dosing is associated with inadequately maintained testosterone levels. Twice weekly dosing then, is associated with well-maintained steady state testosterone levels and this response is preserved over time.
One caveat to treatment of the treatment of andropause symptoms: test first, then treat. In a review of prescriptions filled for all testosterone products in Canada (2007), comparison to national laboratory data showed that family physicians wrote 78.4% of first time prescriptions, and urologists wrote 3%. Thirty-five percent of patients had baseline PSA measurement, but less than 1% received ongoing monitoring. Younger men were more apt to have testosterone levels measured than PSA. The study noted that 28% of prescriptions were filled for women, an off label use for testosterone.
Findings from the literature consistently show improvements in well-being, and specific bone and organ systems studied. The association of low testerstone and MetS is particularly encouraging because of the number of chronic disease involved with the syndrome. Few side effects develop in relationship to the positive outcomes of therapeutic dosing of testerone. Testosterone itself does not prolong the aging process, but men can certainly feel better while growing old.