Boosting Testosterone via Aromatase Inhibition

Double-dipping is a term used in the business world and refer to situations that provide additional revenue with no additional work. An example of double-dipping is a waste recycler charging a customer to pick up sorted trash (paper, aluminum, etc.) and then selling the materials to a recycling plant for additional income. Though the extra income rarely doubles the amount of money generated, it always improves the company’s bottom line. Wise business operators always look for ways to double-dip. In many cases, the benefits go even further. Consider the waste company— not only have they generated two sources of income from the same operation, but they’ve decreased their cost by not having to pay dump fees for the recycled waste.

Double-Dipping In Bodybuilding
There are rare opportunities for double-dipping in bodybuilding as well. Human growth hormone (GH) offers the double-dipping effects of both burning fat and building lean mass.1,2 Clenbuterol has a mildly anabolic effect, but is also a potent thermogenic agent.3 Clearly, combining both anabolic and lipolytic (fat reducing) effects has made both of these drugs extremely popular among bodybuilders.  There’s another double-dipping opportunity that’s often overlooked. In part, this is due to the relatively new entrance of the latest generation of this class of products. Supply also affects their popularity; as well, they don’t provide as much bang for the buck as anabolic steroids. Regardless, this class of drug is still highly regarded and sought after among more experienced and sophisticated bodybuilders. The class of drug is aromatase inhibitors. Aromatase is a complex of enzymes that convert androgens (testosterone, androstenedione and many anabolic steroids) into estrogenic hormones.4 Estrogens are hormones that impart female sexual characteristics, increase bone density, affect blood clotting and promote fat and water retention. Most bodybuilders are familiar with some of the effects of estrogens, causing bloating or gynecomastia (the development of breast tissue under the male nipple).5,6 There are two primary estrogens, estradiol and estrone, with estradiol (E2) being the more active of the two forms.

Prior to the development of the latest aromatase inhibitors, bodybuilders had few choices for reducing the estrogenic load of a cycle. Often, they tailored their cycles to include both aromatizing and non-aromatizing steroids, tapering down on the amount of the more effective (relative to mass and strength) aromatizing steroids if bloating arose. In preparation for a competition, aromatizing steroids were often removed from the cycle to improve the hardened appearance onstage. If gynecomastia appeared, there were few effective options. Cytadren (aminoglutethimide) is a non-specific inhibitor of steroid formation.7,8 Though it was usually regarded as being a cortisol suppressing agent, it also had moderate anti-aromatase activity at low doses. Nolvadex® (tamoxifen) is a mixed estrogen agonist-antagonist. Though tamoxifen did reduce gynecomastia in some cases, it worsened it in others. Tamoxifen also increases sex hormone binding globin, reducing the bioavailability of steroid hormones; it’s also been noted to increase estrogen levels ironically.9,10 Clomid (clomifene citrate) also works at the level of the estrogen receptor, but its use was usually reserved for restoring natural testosterone production at the end of a cycle.11

Age-Related Testosterone Declines
Though medical science has no interest in bodybuilding, many discoveries relate to the sport. In the matter of aromatase inhibition, breast cancer research has been extremely valuable. Breast cancers are typically responsive to female sex hormones (estrogens and progesterone). Therapies that reduce estrogen levels in the body and especially in tumors, have been actively investigated and developed by the pharmaceutical industry. This has resulted in the development of effective anti-aromatase drugs. Several drugs in this class have been developed, including the most recent generation of aromatase inhibitors, anastrazole and letrozole. Bodybuilders are familiar with anastrazole and letrozole by the trade names Arimidex® and Femara®.12,13 Arimidex is more commonly encountered and has been used with great effectiveness in treating steroid-induced gynecomastia. It’s also believed to provide a tighter, harder appearance. Femara is less commonly encountered but is believed to be slightly more effective for the steroid-using bodybuilder.

Though most research on these drugs relates to breast cancer therapy, there have been several interesting studies on aromatase inhibition in human males. One such study was recently published in the Journal of Clinical Endocrinology and Metabolism, reporting some very interesting results.14 There were also several comments in the discussion that hold potential value to bodybuilding, though that aspect wasn’t addressed for obvious reasons. The purpose of this study was to test whether the age-related decline in testosterone is due to an increased suppressive effect of estrogens on the hypothalamic-pituitary axis. To briefly review, natural testosterone production is regulated via a negative-feedback loop, involving the testes and two regions of the brain— the hypothalamus and the pituitary gland. Testosterone production occurs in the testes under the stimulation of a protein hormone released by the pituitary called leutinizing hormone (LH). LH, in turn, is released from the pituitary under stimulation of a hypothalamic hormone called gonadotropin-releasing hormone (GnRH). The hypothalamus is called the master gland because it monitors the body and regulates the activity of the endocrine glands by means of its releasing hormones. In the case of testosterone, when the hypothalamus detects that androgen levels are too high, it temporarily shuts down GnRH release. When GnRH levels drop, the pituitary stops releasing LH and the testes are no longer stimulated to produce testosterone. Once testosterone levels drop, GnRH surges, causing LH and subsequently testosterone levels to pick back up. For reasons not clearly understood, the body isn’t designed to maintain a steady, even level of testosterone. Rather, it produces testosterone in wave-like surges, with peaks and valleys in the blood levels of testosterone. Even more interesting is the fact that the hypothalamus doesn’t only detect testosterone, but also its metabolites estradiol and dihydrotestosterone (DHT).15,16

Altering Ratios
The researchers designed a study whereby they could measure whether older men were more sensitive to estrogen suppression of testosterone production as compared to young adult men. To test this, they measured several hormones, including LH and testosterone (T) in two groups of men, old versus young. It’s known that T production decreases with age, resulting in a 50 percent reduction of bioavailable T.17 It’s believed that this reduction is due to cellular changes in the testes, changes in the regulatory function of the brain and increased negative feedback (or suppression).18 It’s also known that aromatase activity increases with age and overall fat content increases, combining to maintain estrogen levels even in the face of decreasing T levels.19 This results in a markedly lower T:E2 ratio, with E2 representing estradiol levels. This altered ratio is likely responsible for many of the changes experienced by men with age.

Initially, it appeared as though there was little difference between the two groups, as the older and younger men had similar LH and total T values. However, the older men had much higher sex hormone binding globin (SHBG), which traps circulating T, keeping it from being metabolized, but also preventing it from having any biological activity. This resulted in significantly lower free or bioavailable T levels and markedly lower free T:free E2 ratios.14  The subjects were then given 2.5 milligrams per day of letrozole (Femara) for 28 days and retested. The aromatase inhibitor produced “a remarkable and comparable elevation” of both GnRH and T in both groups. Letrozole increased LH and T 339 percent and 146 percent respectively in the younger group; LH and T increased 323 percent and 99 percent in the older group. Letrozole also reduced E2 levels by 46 percent in young men, and 62 percent in the older subjects. SHBG also dropped significantly in both groups, with the T:E2 and free T:free E2 ratios rising sharply in response. Despite the robust response to aromatase inhibition, the study failed to show any evidence of older men experiencing a greater suppressive effect of estrogens on natural testosterone production. In fact, the younger men demonstrated a greater response to aromatase inhibition relative to the suppressive effects of estrogens on the hypothalamus and pituitary gland. While it remains to be seen what accounts for the hormonal changes older men experience, it’s clear that inhibiting aromatase might restore some of the youthful hormonal values.

“Natural” Supraphysiologic Testosterone Levels
Thus far, the study has been valuable in that it clearly demonstrates that healthy men, both young and old, can safely tolerate short-term aromatase inhibition and experience hormonal changes that would be beneficial to those involved in bodybuilding. As noted earlier, there were several comments in the discussion that are worthy of further regard.
One issue that impaired the study, but was very noteworthy was the observation that the effect of letrozole persisted for much longer than anticipated. Subjects were originally scheduled to have a 14-day washout period, where they didn’t receive either drug or placebo before beginning the second phase of the study. However, after the 14-day break, it was discovered that the subjects who received letrozole were still experiencing the effects of the drug with markedly higher T.14 This is somewhat surprising, as letrozole has a half-life of approximately two days, so one would presume 14 days would be sufficient to eliminate the drug from the system.20 It’s possible that the daily dose regimen allowed levels to build up higher than anticipated. In fact, a separate study looking at obese men with low T levels showed that 2.5 mg given three times a week was sufficient to restore normal T levels.21 It’s possible that letrozole wouldn’t need to be dosed daily to provide adequate protection against aromatization.

The degree of T elevation experienced by the younger and older men was quite pronounced. In fact, both groups ended up with T levels at or above the upper limit of normal for young men.14 This would suggest that suppressing aromatase could allow a steroid-free bodybuilder to experience “natural” supraphysiologic testosterone levels. This would be roughly equivalent to receiving 250 to 300 milligrams of testosterone enanthate per week.
Though the goal of aromatase inhibition is to reduce estrogen conversion of androgens, it’s not necessary to completely remove estrogens from the body. There are case reports of men and women who were born without any aromatase activity due to genetic mutation. These individuals are not particularly robust specimens. They are typically very tall (due to a failure to close the growth plates of the bone), have fragile skeletons due to low bone mineral density and in the case of males, are fully mature sexually. Females experience pubertal failure with virilization (male characteristics— facial hair, clitoromegaly, etc). Males also have macroorchidism, a term describing abnormally large testes. Thus, complete suppression of aromatase would not be of benefit to the bodybuilder long term. Fortunately, the degree of suppression appeared to be only partial in the letrozole study. Both groups still retained approximately 40 to 50 percent of their original estrogen levels, though it remains to be seen if such values would lead to an increased risk of osteoporosis.

Reducing Side Effects, Increasing Testosterone
The authors compared the results of other aromatase inhibition studies in males, using either anastrazole (Arimidex) or letrozole (Femara).14 The estrogen-reducing effect seen in this study is in agreement with other letrozole studies. While anastrazole also has a potent estrogen lowering effect, its potency is less than that of letrozole. Comparing several studies, using different dosing schedules, it appears that letrozole is capable of lowering estrogen levels 40 to 60 percent, while anastrazole (commonly dosed at one milligram per day) lowered estrogen 30 to 50 percent. It’s important to note that these figures represent blood levels and there’s some debate as to the importance of tissue levels, rather than circulating levels of estrogen. Even in that regard, letrozole is considered superior. Also discussed were the comparable results between letrozole and clomiphene citrate (Clomid).23 Clomid is used at the end of cycles to aid in restoring natural testosterone production. In considering this comment, and the fact that Femara (letrozole) is used in some fertility drug protocols, it appears that letrozole could be used in place of Clomid for off-cycle recovery.11 This would be particularly beneficial when used along with human chorionic gonadotropin (hCG), as hCG is known to raise estrogen levels in men, even as they are attempting to restore their testosterone producing ability.24

An unrelated study suggested another mechanism whereby aromatase inhibition helps resolve feminizing side effects. In studying the cellular effects of aromatase inhibitors versus tamoxifen on breast cancer cells, it was determined that aromatase inhibition led to a reduction of progesterone receptors in the tissue.25 In contrast, tamoxifen increased progesterone receptor density. Progesterone is another female steroid hormone, and is believed by some to be due for the uncommon cases of nandrolone-induced gynecomastia.26 It remains unclear as to why older men suffer the hormonal changes associated with age. Certainly, it is known that older men have a higher aromatase activity and greater fat mass leading to higher estrogen levels, higher SHBG leading to lower bioavailability of T, functional and cellular changes in the testes and brain leading to less orderly signaling and lower T response, and a greater degree of inhibition by DHT and T. Though enhanced estrogenic suppression of the hypothalamus and pituitary isn’t the culprit causing older men to have lower testosterone and free T:free E2 ratios, by suppressing estrogen formation through aromatase inhibition, many of the changes are corrected. For the bodybuilder, this is of significant note, as it proves once again the utility of this class of drug for the steroid using bodybuilder and offers the non-steroid using bodybuilder an option to consider for increasing testosterone to mildly supraphysiologic levels. Aromatase inhibitors are on the banned substance list for the IOC (Olympics), so competitive athletes need to be aware of organizational restrictions.

Aromatase inhibitors give bodybuilders a chance to double-dip as the drug reduces estrogenic side effects and increases testosterone levels. By reducing SHBG, testosterone and other steroids would have a greater bioavailability though they would clear the system more quickly. Gynecomastia, water retention and fat accumulation could be more easily controlled.
While these effects are clearly attractive to bodybuilders, they also hold value to aging men. Hopefully, in the interest of the growing aging population, further research will be conducted to investigate the role of this class of drugs in combating the ravages of aging and age-associated diseases.

References
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