The Downside of Aromatase Inhibition

Side Affects Worth It?

Adolescence is a time of discovery in a man's life; it is a period when one first experiences romantic thoughts, pimples, independence, and begins to understand why people laugh at Dane Cook. (Adulthood is when one wonders why people laugh at Dane Cook.) Physical changes are prominent during adolescence, brought on by surges in various hormones affecting growth and secondary sexual characteristics. Most healthy men remember the awkward occurrence of spontaneous erections during math class, P.E., or in church; many also went through the confusion of adolescent gynecomastia— developing soreness or even visually evident breast tissue under the nipple.

Gynecomastia, or benign (non-cancerous) breast development in the male, occurs when estrogen concentrations are elevated, or the balance between estrogen and androgens is disrupted to favor estrogenic effects in a male. Estrogens are one class of female sex steroid hormones including estrone and the dominant form, estradiol. There are also exogenous estrogens, such as birth control pills or medications to treat menopause.

Estrogens are formed in the body by converting precursor molecules into estrogens, through the actions of the enzyme cluster called aromatase.1 The precursor molecules could be called estrogenic prohormones, but that term is almost never applied, because these precursor molecules are better known for the function they serve as hormones. The immediate precursor molecules to estrone and estradiol are androstenedione and testosterone, respectively. A third estrogen, estriol, is sometimes mentioned; it is physiologically relevant during pregnancy and is not pertinent to estrogen production in man.

Healthy, adolescent boys develop gynecomastia due to the wild swings in androgen concentration they are subjected to as the testes emerge from the hormonally-dormant state of childhood; obese men often develop gynecomastia as a consequence of estrogen excess due to the action of aromatase in adipose (body fat); elderly men, those treated medically for prostate cancer, and men who lose testicular function due to disease or trauma, can develop gynecomastia as androgen (testosterone) levels fall and the relative influence of estrogen grows; certain medications and endocrine disruptors may also stimulate breast development, but those are non-physiologic factors.1,2

Gynecomastia was once common in bodybuilders and other anabolic-steroid (AAS) using men, as the supraphysiologic (way higher than normal body production) doses of testosterone and other AAS supplied aromatase with an equally abundant source of estrogenic precursors.3 Bodybuilders quickly learned that to avoid 'bitch tits,' fat gain, and water retention, doses of aromatizable AAS needed to be kept to a moderate level, and stacked with non-aromatizable AAS, if one wanted to keep a lean physique that wouldn't elicit a suckling response in infants.

Early Generation Drugs

Early generation drugs used to combat the estrogenic side effects seen with AAS use were of limited value and carried additional risks, due to non-specific suppression of steroid production (steroidogenesis). Cytadren® (aminoglutethimide) was used by many elite bodybuilders, especially during pre-competition training, as it provided a dry, hard physique.4

Though Cytadren is capable of reducing estrogen concentration, it does so at an early stage of steroid hormone production. Cytadren interferes with steroidogenesis at two major junctions; it inhibits the formation of pregnenolone from cholesterol (the first step is forming many important steroids), and inhibits aromatase— the conversion of androgens to estrogens.5

Cytadren's first action, inhibiting pregnenolone formation, is dangerous, as it subsequently inhibits the formation of many adrenal steroids, including cortisol. Though known in sports for its role as either a catabolic hormone leading to muscle loss, a stress marker elevated during overtraining/overreaching, or an anti-inflammatory, used to reduce the pain and swelling associated with severe sprains, cortisol is a critical hormone. Some people are born with a condition known as Addison's disease, and are unable to produce cortisol; without hormone (cortisol) replacement treatment, they suffer and die. Cytadren has been implicated as one contributing factor in the premature death of professional bodybuilder Andreas Munzer.

Fortunately, bodybuilders have moved away from the use of Cytadren with rare exception. Other estrogen-controlling drugs emerged, gaining favor due to their lower risk of side effects, low cost, and ease of use. Tamoxifen (Nolvadex®) reduces the effect of estrogen on certain tissues by competing for the receptors that affect the actions of estrogenic hormones, rather than interfering with the aromatase enzyme complex; it does not lower estrogen levels in AAS users, but has been effective in some cases.6,7

During the 1990s, a new class of aromatase inhibitors, developed to aid in the fight against breast cancer, emerged onto the bodybuilding scene. The two most prevalently used in treating or preventing AAS-induced gynecomastia are anastrozole (Arimidex®) and letrozole (Femara®).8,9 With the advent of these two drugs, particularly letrozole, oncologists (cancer doctors) acquired a powerful set of tools that are capable of suppressing estrogen in women down to a nearly undetectable concentration in the blood, and more importantly, in cancerous breast tissue.

The role of estrogen in men is poorly understood by most non-specialists, and not fully understood by any as yet. Bodybuilders were the first adaptors of aromatase inhibitors in men, of course. Word quickly spread about the ability to use doses of the relatively inexpensive and potent testosterone esters beyond limits previously imposed by aromatase-driven, estrogenic side effects.

Aromatase inhibitors were also used during cycles with low potential for estrogenic side effects in the hopes of further honing the 'cuts' and definition. Once research was published demonstrating an elevation in testosterone concentration in non-AAS-using males, both young adults and older adults, many 'drug-free' bodybuilders, athletes, and recreational fitness enthusiasts, began using these drugs.10,11 The misconception was that since these drugs were not controlled substances, not initially placed on the banned substance lists, and used to treat side effects, there was little risk or downside.

What's the Harm?

Truthfully, it is impossible to state whether anyone has been harmed by using aromatase inhibitors for performance- or physique-enhancement; it simply is not tracked. These two drugs are oral (a similar drug, Aromasin®, is injected); they generally do not cause physically perceived, short-term symptoms; and they are rarely used long-term. These factors instill a false sense of security in users.

Yet, there are problems that may arise as a result of aromatase inhibition, particularly aggressive aromatase inhibition that suppresses estrogen concentrations to very low values. Estrogen (primarily estradiol, but let's stay with the generic term estrogen for simplicity's sake) is not a metabolic waste product in men, a primordial remnant of no greater perceived value than the appendix. It is a functioning hormone that is anabolic in some tissues (e.g., bone, fat, breast); a stimulatory hormone (i.e., enhances production of certain circulating proteins in the liver); a metabolic modifier (affects endocrine hormones as well as carrier protein concentrations, such as binding globulins for vitamin D and sex hormones); a neurosteroid affecting neurotransmitter action, behavior, and emotions; an endocrine regulator; and has other functions.

It is irrational to think that there would not be hazards when concentrations are artificially suppressed well below the lowest extreme of the physiologic range, just as occurs when estrogen is elevated past the upper limit of normal. What, then, are some of the possible consequences to creating an estrogen deficiency in adult males?

Again, there is little in the published medical literature regarding aromatase inhibition in males, as there is as yet, no approved clinical indication for prescribing the drugs for men. However, there have been some observations in the limited clinical trials investigating aromatase inhibition in males; further, there are some adverse (harmful) effects that have been noted in female breast cancer patients that are not gender-specific.

Before proceeding further, it must be clear that this article relates to aromatase inhibition in healthy, adult males— including those using AAS; other populations, specifically women, are not addressed. It is worth noting that many of these findings occurred in breast cancer survivors, who may have been on aromatase inhibitors for several years continuously, suppressing circulating estrogen concentration by 98 percent.

Many bodybuilders use anastrozole or letrozole at full doses, seeking near-complete suppression of circulating estrogen. Thankfully, the realization is spreading that the benefits of aromatase inhibition for men, particularly male athletes/bodybuilders, are likely to arise by keeping estrogen within the normal physiologic range. Protocols using every-other-day dosing, one-half, or even one-quarter therapeutic doses are being disseminated in relevant forums.

Clinically, if one were to be prescribed an aromatase inhibitor, serum concentrations of estrogens should be followed to titrate the dosing accordingly, with a watchful eye toward emerging side effects. Unfortunately, aromatase inhibitors are typically obtained through illicit channels and self-administered without any laboratory monitoring or professional guidance.

Side Effects of Aromatase Inhibition

Arthralgia. Joint pain is the most common and relevant short-term side effect of aromatase inhibition. The incidence of arthralgia and musculoskeletal pain in post-menopausal women using aromatase inhibitors is as high as 25 percent.12 Synovial cells, the cells lining joints that produce the synovial fluid that bathes the articulating surfaces, contain a high concentration of aromatase.13 Over-production of estrogen in the synovium is associated with a pro-inflammatory state.14 Imaging studies performed on estrogen-deprived women demonstrate increased fluid surrounding the tendon sheaths, causing pain and limiting mobility (such as occurs with carpal tunnel syndrome).15,16

Fracture. The typical patients receiving aromatase inhibitor therapy are post-menopausal women, a group already at increased risk of bone fracture, due to osteoporosis. However, as estrogen is one of the primary anabolic or strengthening hormones for the bone, it logically follows that decreasing estrogen to near-zero levels would decrease bone re-building and increase fracture risk. In fact, this is seen in breast cancer patients.17

There have not been any cases published in the medical literature of bone density loss or fracture in men using aromatase inhibitors for performance enhancement. One study evaluating the use of anastrozole in elderly men with testosterone deficiency did demonstrate bone loss, suggesting this is an issue relevant to men.18 Of course, another showed no effect, as is the nature of science.10 It appears that this effect would be most pronounced in people with bones that are already compromised (e.g., vitamin D deficiency, anorexics), following prolonged use of aromatase inhibitors. Weight-bearing and contact define most sports, and it would be folly to ignore the potential for serious injury if the skeleton was weakened.

Libido and sexual function. A decreased libido is commonly reported by women receiving aromatase inhibitors.17,19 Additionally, vaginal dryness, pain and decreased sexual function/response often co-exist. There has been no data collected in estrogen-deprived men, but anecdotal reports of decreased libido have been expressed. This is consistent with observations seen in men with a genetic aromatase deficiency.20

Cardiovascular Risk. Estrogen plays a role in cholesterol metabolism, and estrogen deprivation may increase the risk for heart attack or stroke by possibly raising total cholesterol and LDL (bad) cholesterol, though this response is not uniform.17 Estrogen also protects against unhealthy changes in the electrical pulse controlling the heart beat, as well as protecting against hypertrophy (an enlarged heart).21,22 Estrogen deprivation may affect the blood supply, function, and structure of the heart in a negative manner.

Mental changes. Estrogens are neurosteroids, so it is no surprise that changing concentrations severely could affect a person's memory, math and verbal skills, emotions, personality, and mood.17,23 This area is poorly understood, particularly in men.

Kidney Disease. Much was made in the press recently about findings that some AAS-using men developed a type of kidney disease called sclerosing glomerulonephritis.24 A similar condition was diagnosed in a women receiving anastrozole.25 Though the association is weak at this time, considering that most men using anastrozole also used AAS, the potential compounded increase in risk is something to acknowledge.

Eyes. Retinal hemorrhages (bleeding) have been noted in women treated with aromatase inhibitors.26 The exact cause is unknown, but may be due to damage to small vessels in the eye, or retraction of the fragile retina, due to changes in the fluid of the eye.27 Complete blockage of the artery that feeds the eye has also been reported.28

Liver. Many proteins secreted by the liver, including IGF-1, are reduced with estrogen deprivation in men.29 Two case of hepatitis/hepatotoxicity have also been reported.30,31

The list above identifies some known and suspected adverse effects that are associated with the use of aromatase inhibitors. Much of the information comes from women being treated for breast cancer, but the physiology behind the injury is similar between men and women. Some effects may be gender-specific (e.g., mood changes) or predisposed to vulnerable populations (e.g., osteoporotic post-menopausal women), but this should not dissuade the intelligent person from considering the above when evaluating the pros and cons of using aromatase inhibitors.

There is likely a great deal that remains unknown about suppressing a hormone that acts on nearly every tissue in the body. Even less is known about the impact on the health or function in men, due to the gender bias in estrogen-related research. Many bodybuilders have found that using aromatase inhibitors provides them with the benefits of reduced body fat, as well as protection against gynecomastia and other estrogen-related side effects. Performance athletes have not been as enthusiastic about the use of this class of drug. Estrogen deprivation is reported to reduce the anabolic effect of some AAS, reduce exercise tolerance due to joint and tendon pain, and decrease libido.

It is likely that aromatase inhibition will find a defined role in men's health. As for the bodybuilder, his goal of maximizing definition may justify (for him) the short-term use of aromatase inhibitors. For athletes and fitness buffs, aromatase inhibition may offer some benefit if it is used to partially suppress estrogen production. However, this would need to be monitored and directed by someone skilled in the field in order to prevent a decrease in performance, adverse effects on health, or decline in quality of life. Despite being viewed as mild and safe drugs, the information above should clearly enlighten the audience of potential risks involved with aromatase inhibition.

References:

1. Gooren LJ, Toorians AW. Significance of oestrogens in male (patho)physiology. Ann Endocrinol, (Paris) 2003 Apr;64(2):126-35.

2. Johnson RE, Murad MH. Gynecomastia: pathophysiology, evaluation, and management. Mayo Clin Proc, 2009 Nov;84(11):1010-5.

3. Evans NA. Gym and tonic: a profile of 100 male steroid users. Br J Sports Med, 1997 Mar;31(1):54-8.

4. Mareck U, Sigmund G, et al. Identification of the aromatase inhibitor aminoglutethimide in urine by gas chromatography/mass spectrometry. Rapid Commun Mass Spectrom, 2002;16(24):2209-14.

5. Santen RJ, Misbin RI. Aminoglutethimide: review of pharmacology and clinical use. Pharmacotherapy, 1981 Sep-Oct;1(2):95-120.

6. de Luis DA, Aller R, et al. [Anabolic steroids and gynecomastia. Review of the literature] – article in Spanish. An Med Interna, 2001 Sep;18(9):489-91.

7. Spano F, Ryan WG. Tamoxifen for gynecomastia induced by anabolic steroids? N Engl J Med, 1984 Sep 27;311(13):861-2.

8. Llewellyn W. Arimidex (anastrozole). Anabolics, 2005. Body of Science Publication, Jupiter, FL;2005:232.

9. Llewellyn W. Femara (letrozole). Anabolics, 2005. Body of Science Publication, Jupiter, FL;2005:243.

10. Leder BZ, Finkelstein JS. Effect of aromatase inhibition on bone metabolism in elderly hypogonadal men. Osteoporos Int, 2005 Dec;16(12):1487-94.

11. Handelsman DJ. Indirect androgen doping by oestrogen blockade in sports. Br J Pharmacol, 2008 Jun;154(3):598-605.

12. Winters L, Habin K, et al. Aromatase inhibitors and musculoskeletal pain in patients with breast cancer. Clin J Oncol Nurs, 2007;11(3):433-9.

13. Le Bail J, Liagre B, et al. Aromatase in synovial cells from postmenopausal women. Steroids, 2001 Oct;66(10):749-57.

14. Schmidt M, Weidler C, et al. Androgen conversion in osteoarthritis and rheumatoid arthritis synoviocytes--androstenedione and testosterone inhibit estrogen formation and favor production of more potent 5alpha-reduced androgens. Arthritis Res Ther, 2005;7(5):R938-48.

15. Morales L, Pans S, et al. Importance of synovial fluid retention and thickening in patients with severe musculoskeletal pains treated with letrozole or exemestane: a case series describing the impact of symptoms, clinical findings and magnetic resonance imaging [abstract 4056]. Breast Cancer Res Treat, 2006;100(1).

16. Thorne C. Management of arthralgias associated with aromatase inhibitor therapy. Curr Oncol, 2007 December;14(1):S11-9.

17. Hong S, Didwania A, et al. The expanding use of third-generation aromatase inhibitors: what the general internist needs to know. J Gen Intern Med, 2009 Nov;24 Suppl 2:S383-8.

18. Burnett-Bowie SA, McKay EA, et al. Effects of aromatase inhibition on bone mineral density and bone turnover in older men with low testosterone levels. J Clin Endocrinol Metab, 2009 Dec;94(12):4785-92.

19. Cella D, Fallowfield L, et al. Quality of life of postmenopausal women in the ATAC ("Arimidex", tamoxifen, alone or in combination) trial after completion of 5 years' adjuvant treatment for early breast cancer. Breast Cancer Res Treat, 2006 Dec;100(3):273-84.

20. Carani C, Rochira V, et al. Role of oestrogen in male sexual behaviour: insights from the natural model of aromatase deficiency. Clin Endocrinol (Oxf), 1999 Oct;51(4):517-24.

21. Atsma F, van der Schouw YT, et al. Lifetime endogenous estrogen exposure and electrocardiographic frontal T axis changes in postmenopausal women. Maturitas, 2009 Aug 20;63(4):347-51.

22. Donaldson C, Eder S, et al. Estrogen attenuates left ventricular and cardiomyocyte hypertrophy by an estrogen receptor-dependent pathway that increases calcineurin degradation. Circ Res, 2009 Jan 30;104(2):265-75.

23. Blaustein JD. The year in neuroendocrinology. Mol Endocrinol 2010 Jan;24(1):252-60.

24. Dotinga R. Long-term use can lead to severe kidney scarring, new research shows. Medline Plus, 29 October 2009. Available at: http://www.nlm.nih.gov/medlineplus/news/fullstory_91224.html, accessed January 19, 2009.

25. Kalender ME, Sevinc A, et al. Anastrozole-associated sclerosing glomerulonephritis in a patient with breast cancer. Oncology, 2007;73(5-6):415-8.

26. Eisner A, Falardeau J, et al. Retinal hemorrhages in anastrozole users. Optom Vis Sci, 2008 May;85(5):301-8.

27. Eisner A, Thielman EJ, et al. Vitreo-retinal traction and anastrozole use. Breast Cancer Res Treat, 2009 Sep;117(1):9-16.

28. Karagoz B, Ayata A, et al. Hemicentral retinal artery occlusion in a breast cancer patient using anastrozole. Onkologie, 2009 Jul;32(7):421-3.

29. Mauras N, O'Brien KO, et al. Estrogen suppression in males: metabolic effects. J Clin Endocrinol Metab, 2000 Jul;85(7):2370-7.

30. de la Cruz L, Romero-Vazquez J, et al. Severe acute hepatitis in a patient treated with anastrozole. Lancet, 2007 Jan 6;369(9555):23-4.

31. Zapata E, Zubiaurre L, et al. Anastrozole-induced hepatotoxicity. Eur J Gastroenterol Hepatol 2006 Nov;18(11):1233-4.