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Clinical Use of Aromatase Inhibitors
By Daniel Gwartney, MD
In men receiving testosterone, or misusing AAS, aromatase inhibitors may prevent, reduce, or treat certain estrogen-related side effects (e.g., gynecomastia).
Contrary to expectations, medical professionals such as physicians and researchers learn from folklore developed within (sub)cultures, or from impassioned pursuits by laymen affected by a specific pathology. For example, there is no ICD-9/10 (International Classification of Diseases) coding for “biceps peak deficiency” or “squatopenia.” Those are matters of choice, not health. Yet, medicine is trailing bodybuilding lore in developing treatments for androgen (testosterone) deficiency or insufficiency due to certain causes. The protocols developed (through trial and error) by drug-enhanced bodybuilders have provided observations upon which treatment of testosterone deficiency due to aging, or other causes that affect the regulatory function of the hypothalamic-pituitary axis, can be guided.
As men age, changes in endocrine and metabolic balance occur that evoke a condition of lessened health, if not outright chronic disease. These changes eventually progress to significantly contribute to recognized chronic disease states (e.g., obesity, metabolic syndrome, cardiovascular disease). The focus of “men’s health” has been on testosterone status, specifically the circulating concentration of total testosterone. While a step forward from the (actually stated but paraphrased here) 1940s-50s stance of the American Medical Association that men should just age and die, and society does not need old men with boners or a young man’s sex drive, there is room (lots of room) for improvement.
Testosterone Insufficiency
The single-minded focus on testosterone has numerous shortcomings; most are outside the scope of this article. One issue that is only recently being addressed is “if and how” to treat men with marginal “normal” testosterone yet complaining of low (subphysiologic) testosterone-related symptoms. This should be defined as “testosterone insufficiency,” much like the accepted vitamin D3 state of insufficiency that precedes full-blown deficiency. The lower cutoff for “normal” peak testosterone is between 280-350 ng/dL, depending upon the guidelines the clinician chooses to follow.1 Remember, it is measured at its highest point of the day – it could be like having your credit score checked right before you take out a big loan, max your credit cards and quit your job.
Most guidelines recommend confirming low testosterone readings with a second test – that is the equivalent of a car dealer checking with a second lender if you get rejected on your first auto loan. So, what about the man who has a total testosterone (never mind that free testosterone correlates better with the signs and symptoms of deficiency) of 360 or even 400, perhaps only on the second blood draw? Keep in mind, the “normal” range extends all the way to 980-1,100 ng/dL, depending upon the lab and method used. The average total testosterone value for healthy, non-obese, young men is 700 ng/dL.2 So a man is considered normal if his testosterone is half the value of the average healthy man. This places him in the bottom 2.5 percent of all men, if the statistical model was valid. There are few people who challenge the “standard of care” reference range. Consider that when hypothalamic-pituitary suppression due to metabolic dysfunction and/or Leydig cell dysfunction is treated, that most men, even older men, respond to the 450-550 ng/dL range or higher.3,4 This level of total testosterone is associated with improved glucose tolerance/insulin resistance, and other metabolic signs in hypogonadal men.5
Most (though thankfully, fewer every year) clinicians view testosterone treatment as “drug seeking” for the purposes of vanity or sexual enhancement. Many seem to get their “professional opinion” from reading the sensationalistic stories online about sports doping rather than medical journals. And the issue of media bias in medical publishing is ignored, despite its clearly evident presence. Certain clinicians are promoting a “better” testosterone status in men who are just barely hanging in the bottom end of the “normal” range. Clomiphene citrate (25-50 mg/day) and hCG (300-500 IU every other day) have become accepted, in part due to their historical use for a similar purpose in fertility treatments for women. Subfertile men, which usually means they have a low sperm count, are being treated similarly.
Aromatase Inhibitors
Another drug class used by bodybuilders has a tougher road to climb to gain clinical acceptance, as it was designed to treat breast cancer, not improve fertility or reproductive function – aromatase inhibitors. Only fairly recently have aromatase inhibitors been reported as effective agents for improving fertility in specific patient groups, such as women suffering from polycystic ovarian syndrome (PCOS).6 The most commonly encountered drugs in this class include anastrozole (Arimidex), letrozole (Femara) and exemestane (Aromasin). The original drug of this class, which lacks specificity and carries a significant risk of serious, even life-threatening side effects is Cytadren (aminoglutethimide), is rarely encountered.
An impressive review of the use of aromatase inhibitors in men with marginal testosterone status was published in the journal Sexual Medicine Reviews.7 The review does suffer, at least in the introduction, from opining in agreement with the disputed, even disproven, association between testosterone replacement therapy and adverse effects on the cardiovascular system and prostate health but is otherwise well done. The review describes the essential role of estrogens in male health and physiology – primarily estradiol, which is the most potent, being the direct metabolite of testosterone when acted upon by the aromatase enzyme complex.
Aromatization is a multistep conversion, rather than a single chemical reaction. Contrary to popular belief, estradiol plays a role in libido, erectile function, bone health, muscle growth, etc., in men. There are rare cases of men who have a genetic aromatase deficiency, and they are described as “eunuchoid” in proportions – eunuchs were servants and slaves that were castrated as children to make them more docile. Men with aromatase deficiency are tall due to a long-delayed closure of the epiphyseal plates in the long bones and they have a low bone density, even osteoporosis at a young age. Changes consistent with the metabolic syndrome (obesity, elevated cholesterol, insulin resistance, etc.) have been described.8
The Role of Estrogens
Sexual maturation (i.e., penis development) of eunuchoid men is normal, but increased testes size is common due to elevated pituitary hormones keeping the testes chronically stimulated. The hormonal values of one affected gentleman provide an example of the relative effect on testosterone and estradiol. This man had a reported total testosterone of 2,015 ng/dL (twice the upper limit of normal), and a combined estradiol and estrone of 7 pg/mL (normal range for estradiol is 10-40 pg/mL, though a value under 15 is usually considered insufficient; estrone is a less potent estrogen formed from androstenedione, an adrenal gland androgen). So, even with a testosterone value consistent with that of men using testosterone for bodybuilding purposes, and extremely low estrogen, this was not a hulking, ripped and muscular Superman with four-hour erections; these men have impaired health and relative frailty compared to “normal” men with higher (but normal) estrogen and lower testosterone. Clearly, estrogens have a role in male health and metabolism.
This review is well referenced, and the topic of aromatase inhibition in adult men can be addressed by relating the highlights of the work. The authors focus on the testosterone/estradiol ratio (T/E2) as the measure of androgen-to-estrogen balance. The T/E2 ratio is given greater regard than the absolute testosterone or estradiol concentrations. In the physiologic range, there is validity to that claim. Fertility researchers have determined that “normal” men have an average T/E2 of ~14, whereas the ratio for subfertile men is half that, or ~7.9 It is interesting that a study of testosterone-deficient men treated with clomiphene demonstrated improvement, with an increase in total testosterone from ~250 ng/dL to ~610 ng/dL, and a correction of the T/E2 ratio from 8.7 to 14.2.10
A more pronounced treatment effect, increase of T/E2 ratio, has been reported with aromatase inhibition therapy in hypogonadal men.11 This is not due to a greater increase in testosterone compared to clomiphene, but rather a 40 to 50 percent reduction in estradiol, resulting in T/E2 ratios greater than 30. Bear in mind, this study included men with low testosterone, so the suppression of the enzyme activity combined with the relatively low testosterone to allow for limited estradiol production. Estradiol concentration in the blood reached a barely sufficient level of ~15 pg/ml. Remember, testosterone is the precursor to estrogen, so low testosterone means less available to interact with the aromatase enzyme complex. Prior aromatase inhibition studies on men with normal testosterone reported testosterone nearly doubled with estradiol falling by about 50 percent, resulting in the T/E2 ratio jumping from ~17 to ~75 in one study; similar results were reported in a second study.12,13 The concentration of estradiol during aromatase inhibition was within the normal range, but just barely.
Change in Testosterone/Estradiol Ratio
An issue that has not been adequately explored is the relative change in T/E2 ratio in men on testosterone replacement therapy (TRT) or using anabolic-androgenic steroids (AAS). The reason this is relevant is that the exogenous (pharmaceutical) testosterone suppresses natural testosterone production in the Leydig cells. It is little appreciated that the Leydig cells also produce 20 percent of all circulating estrogens and the majority of the estradiol in men, according to one well-regarded review.14,15 The remainder is produced in other cells, prominently in the fat cell (adipocyte). Leydig cells are fairly resistant to aromatase inhibition when they are not suppressed, because the local concentration of testosterone is up to 600 times that in the blood. In other words, when the testes are not suppressed, they are bathed in so much testosterone that the aromatase inhibitors do not have much effect in that specific tissue. If the Leydig cells are suppressed, then that “reserve” of estradiol production is ablated, and the TRT-treated or AAS-misusing man is at greater risk of an estradiol insufficiency/deficiency. In bodybuilders, this is compounded by the relative lack of adipose tissue, if he maintains a lean physique.
The increase in testosterone seen with aromatase inhibitor use (in drug-free men) is due to the suppressive effect of estradiol on the hypothalamus being lowered significantly. Animal studies suggested that brain aromatase converts testosterone to estradiol locally (at the site of the hypothalamus), but several studies now suggest it is the circulating concentration of estradiol that suppresses the hypothalamus.12,16 Remember, the hypothalamus is like the thermostat for your furnace – it tells the pituitary when to turn the Leydig cells’ production of testosterone up or down. Decreasing estradiol increases the number of times the pituitary gland releases its “go” signal for the Leydig cells, as well as allowing a higher peak of the signal. This results in the increase in testosterone production seen. The androgenic metabolite of testosterone, DHT, has relatively little effect on the hypothalamus or pituitary.17 Estradiol’s effect on the regulatory axis is stated to be 200 times greater.7
Favorable Risk Profile
Aromatase inhibition, in the studies following subfertile men or those with gynecomastia, has demonstrated a favorable risk profile. The drugs, in doses commonly reported to be used by bodybuilders (e.g., anastrozole 1 mg/day; letrozole 2.5 mg/day) have not been associated with adverse events of significance. Reported side effects are generally limited to transient and “mild” increases in liver enzymes, and decreased libido. One concern in chronic use is loss of bone mineral content. Estradiol is the big player in building strong bones, but the general consensus is that there is not a significant decrease in bone mineral content during aromatase inhibition in men. It is possible that adequate TRT or AAS misuse may be protective against this, as well as weight-bearing exercise.
Aromatase inhibitors are being used, off-label, clinically in men with gynecomastia (except when due to anti-androgen drugs used to combat prostate cancer); in hypogonadal men with low LH, including the obese; and in cases of subfertility. Short children are also being treated with aromatase inhibitors to prolong growth (height) by delaying the closure of the growth plates, with reported success.7
As for the use of aromatase inhibition during TRT (or while misusing AAS), there is a large body of anecdotal reports suggesting that aromatase inhibition aids in prolonging the eugonadal effect of long-acting testosterone treatment (e.g., pellet implants, esters); reducing the risk of AAS-related gynecomastia (though extremely high-dose cycles, particularly cycles including nandrolone, can result in breast tenderness or mass even with aromatase inhibition); and improving body composition during cycles with prominent aromatizable AAS content.18
Aromatase inhibitors, specifically anastrozole and letrozole, appear to be relatively safe adjuncts to consider in treating testosterone deficiency or insufficiency when the cause is secondary (related to the hypothalamus and/or pituitary), aging, or a consequence of obesity.19 In men receiving testosterone, or misusing AAS, aromatase inhibitors may prevent, reduce or treat certain estrogen-related side effects (e.g., gynecomastia), but carry the risk of side effects. At this time, the side effects seem relatively benign and resolve once estrogen levels are corrected. As with all medication, aromatase inhibitors should not be used other than when prescribed by one’s personal physician.
DISCUSS ON OUR FORUMSSUBSCRIBE TO MD TODAY
GET OFFICIAL MD STUFFVISIT OUR STORE
SUBSCRIBE TO OUR NEWSLETTER
ALSO, MAKE SURE TO FOLLOW US ON:
FACEBOOKTWITTERINSTAGRAM YOUTUBE
References:
1. Bhasin S, Cunningham GR, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:2536-59.
2. Bhasin S, Pencina M, et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J Clin Endocrinol Metab 2011;96:2430-9.
3. Coviello AD, Matsumoto AM, et al. Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression. J Clin Endocrinol Metab 2005;90:2595-602.
4. Da Ros CT, Averbeck MA. Twenty-five milligrams of clomiphene citrate presents positive effect on treatment of male testosterone deficiency - a prospective study. Int Braz J Urol 2012;38:512-8.
5. Hackett G, Cole N, et al. The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study). Int J Clin Pract 2014;68:203-15.
6. Legro RS, Brzyski RG, et al. Letrozole versus Clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014;371:119-129.
7. Tan RBW, Guay AT, et al. Clinical use of aromatase inhibitors in adult males. Sex Med Rev 2014;2:79-90.
8. Morishima A, Grumbach MM, et al. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 1995;80:3689-98.
9. Pavlovich CP, King P, et al. Evidence of a treatable endocrinopathy in infertile men. J Urol 2001;165:837-41.
10. Shabsigh A, Kang Y, et al. Clomiphene citrate effects on testosterone/estrogen ratio in male hypogonadism. J Sex Med 2005;2:716-21.
11. Gregoriou O, Bakas P, et al. Changes in hormonal profile and seminal parameters with use of aromatase inhibitors in management of infertile men with low testosterone to estradiol ratios. Fertil Steril 2012;98:48-51.
12. Raven G, de Jong FH, et al. In men, peripheral estradiol levels directly reflect the action of estrogens at the hypothalamo-pituitary level to inhibit gonadotropin secretion. J Clin Endocrinol Metab 2006;91:3324-8.
13. T'Sjoen GG, Giagulli VA, et al. Comparative assessment in young and elderly men of the gonadotropin response to aromatase inhibition. J Clin Endocrinol Metab 2005;90:5717-22.
14. Saez JM, Morera AM, et al. Adrenal and testicular contribution to plasma oestrogens. J Endocrinol 1972;55:41-9.
15. Schlegel PN. Aromatase inhibitors for male infertility. Fertil Steril 2012;98:1359-62.
16. Rochira V, Zirilli L, et al. Hypothalamic-pituitary-gonadal axis in two men with aromatase deficiency: evidence that circulating estrogens are required at the hypothalamic level for the integrity of gonadotropin negative feedback. Eur J Endocrinol 2006;155:513-22.
17. DHT does not affect pituitary, reduces aromatase in Leydig cells, and does not reduce T response to hCG. Does suppress hypothalamic GnRH.
18. Rhoden EL, Morgentaler A. Treatment of testosterone-induced gynecomastia with the aromatase inhibitor, anastrozole. Int J Impot Res 2004;16:95-7.
19. Stephens SM, Polotsky AJ. Big enough for an aromatase inhibitor? How adiposity affects male fertility. Semin Reprod Med 2013;31:251-7.
Learn about MuscleMeds’ new aromatase inhibitor AROMATEST
Clinical Use of Aromatase Inhibitors
By Daniel Gwartney, MD
In men receiving testosterone, or misusing AAS, aromatase inhibitors may prevent, reduce, or treat certain estrogen-related side effects (e.g., gynecomastia).
Contrary to expectations, medical professionals such as physicians and researchers learn from folklore developed within (sub)cultures, or from impassioned pursuits by laymen affected by a specific pathology. For example, there is no ICD-9/10 (International Classification of Diseases) coding for “biceps peak deficiency” or “squatopenia.” Those are matters of choice, not health. Yet, medicine is trailing bodybuilding lore in developing treatments for androgen (testosterone) deficiency or insufficiency due to certain causes. The protocols developed (through trial and error) by drug-enhanced bodybuilders have provided observations upon which treatment of testosterone deficiency due to aging, or other causes that affect the regulatory function of the hypothalamic-pituitary axis, can be guided.
As men age, changes in endocrine and metabolic balance occur that evoke a condition of lessened health, if not outright chronic disease. These changes eventually progress to significantly contribute to recognized chronic disease states (e.g., obesity, metabolic syndrome, cardiovascular disease). The focus of “men’s health” has been on testosterone status, specifically the circulating concentration of total testosterone. While a step forward from the (actually stated but paraphrased here) 1940s-50s stance of the American Medical Association that men should just age and die, and society does not need old men with boners or a young man’s sex drive, there is room (lots of room) for improvement.
Testosterone Insufficiency
The single-minded focus on testosterone has numerous shortcomings; most are outside the scope of this article. One issue that is only recently being addressed is “if and how” to treat men with marginal “normal” testosterone yet complaining of low (subphysiologic) testosterone-related symptoms. This should be defined as “testosterone insufficiency,” much like the accepted vitamin D3 state of insufficiency that precedes full-blown deficiency. The lower cutoff for “normal” peak testosterone is between 280-350 ng/dL, depending upon the guidelines the clinician chooses to follow.1 Remember, it is measured at its highest point of the day – it could be like having your credit score checked right before you take out a big loan, max your credit cards and quit your job.
Most guidelines recommend confirming low testosterone readings with a second test – that is the equivalent of a car dealer checking with a second lender if you get rejected on your first auto loan. So, what about the man who has a total testosterone (never mind that free testosterone correlates better with the signs and symptoms of deficiency) of 360 or even 400, perhaps only on the second blood draw? Keep in mind, the “normal” range extends all the way to 980-1,100 ng/dL, depending upon the lab and method used. The average total testosterone value for healthy, non-obese, young men is 700 ng/dL.2 So a man is considered normal if his testosterone is half the value of the average healthy man. This places him in the bottom 2.5 percent of all men, if the statistical model was valid. There are few people who challenge the “standard of care” reference range. Consider that when hypothalamic-pituitary suppression due to metabolic dysfunction and/or Leydig cell dysfunction is treated, that most men, even older men, respond to the 450-550 ng/dL range or higher.3,4 This level of total testosterone is associated with improved glucose tolerance/insulin resistance, and other metabolic signs in hypogonadal men.5
Most (though thankfully, fewer every year) clinicians view testosterone treatment as “drug seeking” for the purposes of vanity or sexual enhancement. Many seem to get their “professional opinion” from reading the sensationalistic stories online about sports doping rather than medical journals. And the issue of media bias in medical publishing is ignored, despite its clearly evident presence. Certain clinicians are promoting a “better” testosterone status in men who are just barely hanging in the bottom end of the “normal” range. Clomiphene citrate (25-50 mg/day) and hCG (300-500 IU every other day) have become accepted, in part due to their historical use for a similar purpose in fertility treatments for women. Subfertile men, which usually means they have a low sperm count, are being treated similarly.
Aromatase Inhibitors
Another drug class used by bodybuilders has a tougher road to climb to gain clinical acceptance, as it was designed to treat breast cancer, not improve fertility or reproductive function – aromatase inhibitors. Only fairly recently have aromatase inhibitors been reported as effective agents for improving fertility in specific patient groups, such as women suffering from polycystic ovarian syndrome (PCOS).6 The most commonly encountered drugs in this class include anastrozole (Arimidex), letrozole (Femara) and exemestane (Aromasin). The original drug of this class, which lacks specificity and carries a significant risk of serious, even life-threatening side effects is Cytadren (aminoglutethimide), is rarely encountered.
An impressive review of the use of aromatase inhibitors in men with marginal testosterone status was published in the journal Sexual Medicine Reviews.7 The review does suffer, at least in the introduction, from opining in agreement with the disputed, even disproven, association between testosterone replacement therapy and adverse effects on the cardiovascular system and prostate health but is otherwise well done. The review describes the essential role of estrogens in male health and physiology – primarily estradiol, which is the most potent, being the direct metabolite of testosterone when acted upon by the aromatase enzyme complex.
Aromatization is a multistep conversion, rather than a single chemical reaction. Contrary to popular belief, estradiol plays a role in libido, erectile function, bone health, muscle growth, etc., in men. There are rare cases of men who have a genetic aromatase deficiency, and they are described as “eunuchoid” in proportions – eunuchs were servants and slaves that were castrated as children to make them more docile. Men with aromatase deficiency are tall due to a long-delayed closure of the epiphyseal plates in the long bones and they have a low bone density, even osteoporosis at a young age. Changes consistent with the metabolic syndrome (obesity, elevated cholesterol, insulin resistance, etc.) have been described.8
The Role of Estrogens
Sexual maturation (i.e., penis development) of eunuchoid men is normal, but increased testes size is common due to elevated pituitary hormones keeping the testes chronically stimulated. The hormonal values of one affected gentleman provide an example of the relative effect on testosterone and estradiol. This man had a reported total testosterone of 2,015 ng/dL (twice the upper limit of normal), and a combined estradiol and estrone of 7 pg/mL (normal range for estradiol is 10-40 pg/mL, though a value under 15 is usually considered insufficient; estrone is a less potent estrogen formed from androstenedione, an adrenal gland androgen). So, even with a testosterone value consistent with that of men using testosterone for bodybuilding purposes, and extremely low estrogen, this was not a hulking, ripped and muscular Superman with four-hour erections; these men have impaired health and relative frailty compared to “normal” men with higher (but normal) estrogen and lower testosterone. Clearly, estrogens have a role in male health and metabolism.
This review is well referenced, and the topic of aromatase inhibition in adult men can be addressed by relating the highlights of the work. The authors focus on the testosterone/estradiol ratio (T/E2) as the measure of androgen-to-estrogen balance. The T/E2 ratio is given greater regard than the absolute testosterone or estradiol concentrations. In the physiologic range, there is validity to that claim. Fertility researchers have determined that “normal” men have an average T/E2 of ~14, whereas the ratio for subfertile men is half that, or ~7.9 It is interesting that a study of testosterone-deficient men treated with clomiphene demonstrated improvement, with an increase in total testosterone from ~250 ng/dL to ~610 ng/dL, and a correction of the T/E2 ratio from 8.7 to 14.2.10
A more pronounced treatment effect, increase of T/E2 ratio, has been reported with aromatase inhibition therapy in hypogonadal men.11 This is not due to a greater increase in testosterone compared to clomiphene, but rather a 40 to 50 percent reduction in estradiol, resulting in T/E2 ratios greater than 30. Bear in mind, this study included men with low testosterone, so the suppression of the enzyme activity combined with the relatively low testosterone to allow for limited estradiol production. Estradiol concentration in the blood reached a barely sufficient level of ~15 pg/ml. Remember, testosterone is the precursor to estrogen, so low testosterone means less available to interact with the aromatase enzyme complex. Prior aromatase inhibition studies on men with normal testosterone reported testosterone nearly doubled with estradiol falling by about 50 percent, resulting in the T/E2 ratio jumping from ~17 to ~75 in one study; similar results were reported in a second study.12,13 The concentration of estradiol during aromatase inhibition was within the normal range, but just barely.
Change in Testosterone/Estradiol Ratio
An issue that has not been adequately explored is the relative change in T/E2 ratio in men on testosterone replacement therapy (TRT) or using anabolic-androgenic steroids (AAS). The reason this is relevant is that the exogenous (pharmaceutical) testosterone suppresses natural testosterone production in the Leydig cells. It is little appreciated that the Leydig cells also produce 20 percent of all circulating estrogens and the majority of the estradiol in men, according to one well-regarded review.14,15 The remainder is produced in other cells, prominently in the fat cell (adipocyte). Leydig cells are fairly resistant to aromatase inhibition when they are not suppressed, because the local concentration of testosterone is up to 600 times that in the blood. In other words, when the testes are not suppressed, they are bathed in so much testosterone that the aromatase inhibitors do not have much effect in that specific tissue. If the Leydig cells are suppressed, then that “reserve” of estradiol production is ablated, and the TRT-treated or AAS-misusing man is at greater risk of an estradiol insufficiency/deficiency. In bodybuilders, this is compounded by the relative lack of adipose tissue, if he maintains a lean physique.
The increase in testosterone seen with aromatase inhibitor use (in drug-free men) is due to the suppressive effect of estradiol on the hypothalamus being lowered significantly. Animal studies suggested that brain aromatase converts testosterone to estradiol locally (at the site of the hypothalamus), but several studies now suggest it is the circulating concentration of estradiol that suppresses the hypothalamus.12,16 Remember, the hypothalamus is like the thermostat for your furnace – it tells the pituitary when to turn the Leydig cells’ production of testosterone up or down. Decreasing estradiol increases the number of times the pituitary gland releases its “go” signal for the Leydig cells, as well as allowing a higher peak of the signal. This results in the increase in testosterone production seen. The androgenic metabolite of testosterone, DHT, has relatively little effect on the hypothalamus or pituitary.17 Estradiol’s effect on the regulatory axis is stated to be 200 times greater.7
Favorable Risk Profile
Aromatase inhibition, in the studies following subfertile men or those with gynecomastia, has demonstrated a favorable risk profile. The drugs, in doses commonly reported to be used by bodybuilders (e.g., anastrozole 1 mg/day; letrozole 2.5 mg/day) have not been associated with adverse events of significance. Reported side effects are generally limited to transient and “mild” increases in liver enzymes, and decreased libido. One concern in chronic use is loss of bone mineral content. Estradiol is the big player in building strong bones, but the general consensus is that there is not a significant decrease in bone mineral content during aromatase inhibition in men. It is possible that adequate TRT or AAS misuse may be protective against this, as well as weight-bearing exercise.
Aromatase inhibitors are being used, off-label, clinically in men with gynecomastia (except when due to anti-androgen drugs used to combat prostate cancer); in hypogonadal men with low LH, including the obese; and in cases of subfertility. Short children are also being treated with aromatase inhibitors to prolong growth (height) by delaying the closure of the growth plates, with reported success.7
As for the use of aromatase inhibition during TRT (or while misusing AAS), there is a large body of anecdotal reports suggesting that aromatase inhibition aids in prolonging the eugonadal effect of long-acting testosterone treatment (e.g., pellet implants, esters); reducing the risk of AAS-related gynecomastia (though extremely high-dose cycles, particularly cycles including nandrolone, can result in breast tenderness or mass even with aromatase inhibition); and improving body composition during cycles with prominent aromatizable AAS content.18
Aromatase inhibitors, specifically anastrozole and letrozole, appear to be relatively safe adjuncts to consider in treating testosterone deficiency or insufficiency when the cause is secondary (related to the hypothalamus and/or pituitary), aging, or a consequence of obesity.19 In men receiving testosterone, or misusing AAS, aromatase inhibitors may prevent, reduce or treat certain estrogen-related side effects (e.g., gynecomastia), but carry the risk of side effects. At this time, the side effects seem relatively benign and resolve once estrogen levels are corrected. As with all medication, aromatase inhibitors should not be used other than when prescribed by one’s personal physician.
DISCUSS ON OUR FORUMS
SUBSCRIBE TO MD TODAY
GET OFFICIAL MD STUFF
VISIT OUR STORE
SUBSCRIBE TO OUR NEWSLETTER
ALSO, MAKE SURE TO FOLLOW US ON:
FACEBOOK
TWITTER
INSTAGRAM
YOUTUBE
References:
1. Bhasin S, Cunningham GR, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:2536-59.
2. Bhasin S, Pencina M, et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J Clin Endocrinol Metab 2011;96:2430-9.
3. Coviello AD, Matsumoto AM, et al. Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression. J Clin Endocrinol Metab 2005;90:2595-602.
4. Da Ros CT, Averbeck MA. Twenty-five milligrams of clomiphene citrate presents positive effect on treatment of male testosterone deficiency - a prospective study. Int Braz J Urol 2012;38:512-8.
5. Hackett G, Cole N, et al. The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study). Int J Clin Pract 2014;68:203-15.
6. Legro RS, Brzyski RG, et al. Letrozole versus Clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014;371:119-129.
7. Tan RBW, Guay AT, et al. Clinical use of aromatase inhibitors in adult males. Sex Med Rev 2014;2:79-90.
8. Morishima A, Grumbach MM, et al. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 1995;80:3689-98.
9. Pavlovich CP, King P, et al. Evidence of a treatable endocrinopathy in infertile men. J Urol 2001;165:837-41.
10. Shabsigh A, Kang Y, et al. Clomiphene citrate effects on testosterone/estrogen ratio in male hypogonadism. J Sex Med 2005;2:716-21.
11. Gregoriou O, Bakas P, et al. Changes in hormonal profile and seminal parameters with use of aromatase inhibitors in management of infertile men with low testosterone to estradiol ratios. Fertil Steril 2012;98:48-51.
12. Raven G, de Jong FH, et al. In men, peripheral estradiol levels directly reflect the action of estrogens at the hypothalamo-pituitary level to inhibit gonadotropin secretion. J Clin Endocrinol Metab 2006;91:3324-8.
13. T'Sjoen GG, Giagulli VA, et al. Comparative assessment in young and elderly men of the gonadotropin response to aromatase inhibition. J Clin Endocrinol Metab 2005;90:5717-22.
14. Saez JM, Morera AM, et al. Adrenal and testicular contribution to plasma oestrogens. J Endocrinol 1972;55:41-9.
15. Schlegel PN. Aromatase inhibitors for male infertility. Fertil Steril 2012;98:1359-62.
16. Rochira V, Zirilli L, et al. Hypothalamic-pituitary-gonadal axis in two men with aromatase deficiency: evidence that circulating estrogens are required at the hypothalamic level for the integrity of gonadotropin negative feedback. Eur J Endocrinol 2006;155:513-22.
17. DHT does not affect pituitary, reduces aromatase in Leydig cells, and does not reduce T response to hCG. Does suppress hypothalamic GnRH.
18. Rhoden EL, Morgentaler A. Treatment of testosterone-induced gynecomastia with the aromatase inhibitor, anastrozole. Int J Impot Res 2004;16:95-7.
19. Stephens SM, Polotsky AJ. Big enough for an aromatase inhibitor? How adiposity affects male fertility. Semin Reprod Med 2013;31:251-7.
Learn about MuscleMeds’ new aromatase inhibitor AROMATEST
Click here to view the article.
By Daniel Gwartney, MD
In men receiving testosterone, or misusing AAS, aromatase inhibitors may prevent, reduce, or treat certain estrogen-related side effects (e.g., gynecomastia).
Contrary to expectations, medical professionals such as physicians and researchers learn from folklore developed within (sub)cultures, or from impassioned pursuits by laymen affected by a specific pathology. For example, there is no ICD-9/10 (International Classification of Diseases) coding for “biceps peak deficiency” or “squatopenia.” Those are matters of choice, not health. Yet, medicine is trailing bodybuilding lore in developing treatments for androgen (testosterone) deficiency or insufficiency due to certain causes. The protocols developed (through trial and error) by drug-enhanced bodybuilders have provided observations upon which treatment of testosterone deficiency due to aging, or other causes that affect the regulatory function of the hypothalamic-pituitary axis, can be guided.
As men age, changes in endocrine and metabolic balance occur that evoke a condition of lessened health, if not outright chronic disease. These changes eventually progress to significantly contribute to recognized chronic disease states (e.g., obesity, metabolic syndrome, cardiovascular disease). The focus of “men’s health” has been on testosterone status, specifically the circulating concentration of total testosterone. While a step forward from the (actually stated but paraphrased here) 1940s-50s stance of the American Medical Association that men should just age and die, and society does not need old men with boners or a young man’s sex drive, there is room (lots of room) for improvement.
Testosterone Insufficiency
The single-minded focus on testosterone has numerous shortcomings; most are outside the scope of this article. One issue that is only recently being addressed is “if and how” to treat men with marginal “normal” testosterone yet complaining of low (subphysiologic) testosterone-related symptoms. This should be defined as “testosterone insufficiency,” much like the accepted vitamin D3 state of insufficiency that precedes full-blown deficiency. The lower cutoff for “normal” peak testosterone is between 280-350 ng/dL, depending upon the guidelines the clinician chooses to follow.1 Remember, it is measured at its highest point of the day – it could be like having your credit score checked right before you take out a big loan, max your credit cards and quit your job.
Most guidelines recommend confirming low testosterone readings with a second test – that is the equivalent of a car dealer checking with a second lender if you get rejected on your first auto loan. So, what about the man who has a total testosterone (never mind that free testosterone correlates better with the signs and symptoms of deficiency) of 360 or even 400, perhaps only on the second blood draw? Keep in mind, the “normal” range extends all the way to 980-1,100 ng/dL, depending upon the lab and method used. The average total testosterone value for healthy, non-obese, young men is 700 ng/dL.2 So a man is considered normal if his testosterone is half the value of the average healthy man. This places him in the bottom 2.5 percent of all men, if the statistical model was valid. There are few people who challenge the “standard of care” reference range. Consider that when hypothalamic-pituitary suppression due to metabolic dysfunction and/or Leydig cell dysfunction is treated, that most men, even older men, respond to the 450-550 ng/dL range or higher.3,4 This level of total testosterone is associated with improved glucose tolerance/insulin resistance, and other metabolic signs in hypogonadal men.5
Most (though thankfully, fewer every year) clinicians view testosterone treatment as “drug seeking” for the purposes of vanity or sexual enhancement. Many seem to get their “professional opinion” from reading the sensationalistic stories online about sports doping rather than medical journals. And the issue of media bias in medical publishing is ignored, despite its clearly evident presence. Certain clinicians are promoting a “better” testosterone status in men who are just barely hanging in the bottom end of the “normal” range. Clomiphene citrate (25-50 mg/day) and hCG (300-500 IU every other day) have become accepted, in part due to their historical use for a similar purpose in fertility treatments for women. Subfertile men, which usually means they have a low sperm count, are being treated similarly.
Aromatase Inhibitors
Another drug class used by bodybuilders has a tougher road to climb to gain clinical acceptance, as it was designed to treat breast cancer, not improve fertility or reproductive function – aromatase inhibitors. Only fairly recently have aromatase inhibitors been reported as effective agents for improving fertility in specific patient groups, such as women suffering from polycystic ovarian syndrome (PCOS).6 The most commonly encountered drugs in this class include anastrozole (Arimidex), letrozole (Femara) and exemestane (Aromasin). The original drug of this class, which lacks specificity and carries a significant risk of serious, even life-threatening side effects is Cytadren (aminoglutethimide), is rarely encountered.
An impressive review of the use of aromatase inhibitors in men with marginal testosterone status was published in the journal Sexual Medicine Reviews.7 The review does suffer, at least in the introduction, from opining in agreement with the disputed, even disproven, association between testosterone replacement therapy and adverse effects on the cardiovascular system and prostate health but is otherwise well done. The review describes the essential role of estrogens in male health and physiology – primarily estradiol, which is the most potent, being the direct metabolite of testosterone when acted upon by the aromatase enzyme complex.
Aromatization is a multistep conversion, rather than a single chemical reaction. Contrary to popular belief, estradiol plays a role in libido, erectile function, bone health, muscle growth, etc., in men. There are rare cases of men who have a genetic aromatase deficiency, and they are described as “eunuchoid” in proportions – eunuchs were servants and slaves that were castrated as children to make them more docile. Men with aromatase deficiency are tall due to a long-delayed closure of the epiphyseal plates in the long bones and they have a low bone density, even osteoporosis at a young age. Changes consistent with the metabolic syndrome (obesity, elevated cholesterol, insulin resistance, etc.) have been described.8
The Role of Estrogens
Sexual maturation (i.e., penis development) of eunuchoid men is normal, but increased testes size is common due to elevated pituitary hormones keeping the testes chronically stimulated. The hormonal values of one affected gentleman provide an example of the relative effect on testosterone and estradiol. This man had a reported total testosterone of 2,015 ng/dL (twice the upper limit of normal), and a combined estradiol and estrone of 7 pg/mL (normal range for estradiol is 10-40 pg/mL, though a value under 15 is usually considered insufficient; estrone is a less potent estrogen formed from androstenedione, an adrenal gland androgen). So, even with a testosterone value consistent with that of men using testosterone for bodybuilding purposes, and extremely low estrogen, this was not a hulking, ripped and muscular Superman with four-hour erections; these men have impaired health and relative frailty compared to “normal” men with higher (but normal) estrogen and lower testosterone. Clearly, estrogens have a role in male health and metabolism.
This review is well referenced, and the topic of aromatase inhibition in adult men can be addressed by relating the highlights of the work. The authors focus on the testosterone/estradiol ratio (T/E2) as the measure of androgen-to-estrogen balance. The T/E2 ratio is given greater regard than the absolute testosterone or estradiol concentrations. In the physiologic range, there is validity to that claim. Fertility researchers have determined that “normal” men have an average T/E2 of ~14, whereas the ratio for subfertile men is half that, or ~7.9 It is interesting that a study of testosterone-deficient men treated with clomiphene demonstrated improvement, with an increase in total testosterone from ~250 ng/dL to ~610 ng/dL, and a correction of the T/E2 ratio from 8.7 to 14.2.10
A more pronounced treatment effect, increase of T/E2 ratio, has been reported with aromatase inhibition therapy in hypogonadal men.11 This is not due to a greater increase in testosterone compared to clomiphene, but rather a 40 to 50 percent reduction in estradiol, resulting in T/E2 ratios greater than 30. Bear in mind, this study included men with low testosterone, so the suppression of the enzyme activity combined with the relatively low testosterone to allow for limited estradiol production. Estradiol concentration in the blood reached a barely sufficient level of ~15 pg/ml. Remember, testosterone is the precursor to estrogen, so low testosterone means less available to interact with the aromatase enzyme complex. Prior aromatase inhibition studies on men with normal testosterone reported testosterone nearly doubled with estradiol falling by about 50 percent, resulting in the T/E2 ratio jumping from ~17 to ~75 in one study; similar results were reported in a second study.12,13 The concentration of estradiol during aromatase inhibition was within the normal range, but just barely.
Change in Testosterone/Estradiol Ratio
An issue that has not been adequately explored is the relative change in T/E2 ratio in men on testosterone replacement therapy (TRT) or using anabolic-androgenic steroids (AAS). The reason this is relevant is that the exogenous (pharmaceutical) testosterone suppresses natural testosterone production in the Leydig cells. It is little appreciated that the Leydig cells also produce 20 percent of all circulating estrogens and the majority of the estradiol in men, according to one well-regarded review.14,15 The remainder is produced in other cells, prominently in the fat cell (adipocyte). Leydig cells are fairly resistant to aromatase inhibition when they are not suppressed, because the local concentration of testosterone is up to 600 times that in the blood. In other words, when the testes are not suppressed, they are bathed in so much testosterone that the aromatase inhibitors do not have much effect in that specific tissue. If the Leydig cells are suppressed, then that “reserve” of estradiol production is ablated, and the TRT-treated or AAS-misusing man is at greater risk of an estradiol insufficiency/deficiency. In bodybuilders, this is compounded by the relative lack of adipose tissue, if he maintains a lean physique.
The increase in testosterone seen with aromatase inhibitor use (in drug-free men) is due to the suppressive effect of estradiol on the hypothalamus being lowered significantly. Animal studies suggested that brain aromatase converts testosterone to estradiol locally (at the site of the hypothalamus), but several studies now suggest it is the circulating concentration of estradiol that suppresses the hypothalamus.12,16 Remember, the hypothalamus is like the thermostat for your furnace – it tells the pituitary when to turn the Leydig cells’ production of testosterone up or down. Decreasing estradiol increases the number of times the pituitary gland releases its “go” signal for the Leydig cells, as well as allowing a higher peak of the signal. This results in the increase in testosterone production seen. The androgenic metabolite of testosterone, DHT, has relatively little effect on the hypothalamus or pituitary.17 Estradiol’s effect on the regulatory axis is stated to be 200 times greater.7
Favorable Risk Profile
Aromatase inhibition, in the studies following subfertile men or those with gynecomastia, has demonstrated a favorable risk profile. The drugs, in doses commonly reported to be used by bodybuilders (e.g., anastrozole 1 mg/day; letrozole 2.5 mg/day) have not been associated with adverse events of significance. Reported side effects are generally limited to transient and “mild” increases in liver enzymes, and decreased libido. One concern in chronic use is loss of bone mineral content. Estradiol is the big player in building strong bones, but the general consensus is that there is not a significant decrease in bone mineral content during aromatase inhibition in men. It is possible that adequate TRT or AAS misuse may be protective against this, as well as weight-bearing exercise.
Aromatase inhibitors are being used, off-label, clinically in men with gynecomastia (except when due to anti-androgen drugs used to combat prostate cancer); in hypogonadal men with low LH, including the obese; and in cases of subfertility. Short children are also being treated with aromatase inhibitors to prolong growth (height) by delaying the closure of the growth plates, with reported success.7
As for the use of aromatase inhibition during TRT (or while misusing AAS), there is a large body of anecdotal reports suggesting that aromatase inhibition aids in prolonging the eugonadal effect of long-acting testosterone treatment (e.g., pellet implants, esters); reducing the risk of AAS-related gynecomastia (though extremely high-dose cycles, particularly cycles including nandrolone, can result in breast tenderness or mass even with aromatase inhibition); and improving body composition during cycles with prominent aromatizable AAS content.18
Aromatase inhibitors, specifically anastrozole and letrozole, appear to be relatively safe adjuncts to consider in treating testosterone deficiency or insufficiency when the cause is secondary (related to the hypothalamus and/or pituitary), aging, or a consequence of obesity.19 In men receiving testosterone, or misusing AAS, aromatase inhibitors may prevent, reduce or treat certain estrogen-related side effects (e.g., gynecomastia), but carry the risk of side effects. At this time, the side effects seem relatively benign and resolve once estrogen levels are corrected. As with all medication, aromatase inhibitors should not be used other than when prescribed by one’s personal physician.
DISCUSS ON OUR FORUMSSUBSCRIBE TO MD TODAY
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SUBSCRIBE TO OUR NEWSLETTER
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References:
1. Bhasin S, Cunningham GR, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:2536-59.
2. Bhasin S, Pencina M, et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J Clin Endocrinol Metab 2011;96:2430-9.
3. Coviello AD, Matsumoto AM, et al. Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression. J Clin Endocrinol Metab 2005;90:2595-602.
4. Da Ros CT, Averbeck MA. Twenty-five milligrams of clomiphene citrate presents positive effect on treatment of male testosterone deficiency - a prospective study. Int Braz J Urol 2012;38:512-8.
5. Hackett G, Cole N, et al. The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study). Int J Clin Pract 2014;68:203-15.
6. Legro RS, Brzyski RG, et al. Letrozole versus Clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014;371:119-129.
7. Tan RBW, Guay AT, et al. Clinical use of aromatase inhibitors in adult males. Sex Med Rev 2014;2:79-90.
8. Morishima A, Grumbach MM, et al. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 1995;80:3689-98.
9. Pavlovich CP, King P, et al. Evidence of a treatable endocrinopathy in infertile men. J Urol 2001;165:837-41.
10. Shabsigh A, Kang Y, et al. Clomiphene citrate effects on testosterone/estrogen ratio in male hypogonadism. J Sex Med 2005;2:716-21.
11. Gregoriou O, Bakas P, et al. Changes in hormonal profile and seminal parameters with use of aromatase inhibitors in management of infertile men with low testosterone to estradiol ratios. Fertil Steril 2012;98:48-51.
12. Raven G, de Jong FH, et al. In men, peripheral estradiol levels directly reflect the action of estrogens at the hypothalamo-pituitary level to inhibit gonadotropin secretion. J Clin Endocrinol Metab 2006;91:3324-8.
13. T'Sjoen GG, Giagulli VA, et al. Comparative assessment in young and elderly men of the gonadotropin response to aromatase inhibition. J Clin Endocrinol Metab 2005;90:5717-22.
14. Saez JM, Morera AM, et al. Adrenal and testicular contribution to plasma oestrogens. J Endocrinol 1972;55:41-9.
15. Schlegel PN. Aromatase inhibitors for male infertility. Fertil Steril 2012;98:1359-62.
16. Rochira V, Zirilli L, et al. Hypothalamic-pituitary-gonadal axis in two men with aromatase deficiency: evidence that circulating estrogens are required at the hypothalamic level for the integrity of gonadotropin negative feedback. Eur J Endocrinol 2006;155:513-22.
17. DHT does not affect pituitary, reduces aromatase in Leydig cells, and does not reduce T response to hCG. Does suppress hypothalamic GnRH.
18. Rhoden EL, Morgentaler A. Treatment of testosterone-induced gynecomastia with the aromatase inhibitor, anastrozole. Int J Impot Res 2004;16:95-7.
19. Stephens SM, Polotsky AJ. Big enough for an aromatase inhibitor? How adiposity affects male fertility. Semin Reprod Med 2013;31:251-7.
Learn about MuscleMeds’ new aromatase inhibitor AROMATEST
Clinical Use of Aromatase Inhibitors
By Daniel Gwartney, MD
In men receiving testosterone, or misusing AAS, aromatase inhibitors may prevent, reduce, or treat certain estrogen-related side effects (e.g., gynecomastia).
Contrary to expectations, medical professionals such as physicians and researchers learn from folklore developed within (sub)cultures, or from impassioned pursuits by laymen affected by a specific pathology. For example, there is no ICD-9/10 (International Classification of Diseases) coding for “biceps peak deficiency” or “squatopenia.” Those are matters of choice, not health. Yet, medicine is trailing bodybuilding lore in developing treatments for androgen (testosterone) deficiency or insufficiency due to certain causes. The protocols developed (through trial and error) by drug-enhanced bodybuilders have provided observations upon which treatment of testosterone deficiency due to aging, or other causes that affect the regulatory function of the hypothalamic-pituitary axis, can be guided.
As men age, changes in endocrine and metabolic balance occur that evoke a condition of lessened health, if not outright chronic disease. These changes eventually progress to significantly contribute to recognized chronic disease states (e.g., obesity, metabolic syndrome, cardiovascular disease). The focus of “men’s health” has been on testosterone status, specifically the circulating concentration of total testosterone. While a step forward from the (actually stated but paraphrased here) 1940s-50s stance of the American Medical Association that men should just age and die, and society does not need old men with boners or a young man’s sex drive, there is room (lots of room) for improvement.
Testosterone Insufficiency
The single-minded focus on testosterone has numerous shortcomings; most are outside the scope of this article. One issue that is only recently being addressed is “if and how” to treat men with marginal “normal” testosterone yet complaining of low (subphysiologic) testosterone-related symptoms. This should be defined as “testosterone insufficiency,” much like the accepted vitamin D3 state of insufficiency that precedes full-blown deficiency. The lower cutoff for “normal” peak testosterone is between 280-350 ng/dL, depending upon the guidelines the clinician chooses to follow.1 Remember, it is measured at its highest point of the day – it could be like having your credit score checked right before you take out a big loan, max your credit cards and quit your job.
Most guidelines recommend confirming low testosterone readings with a second test – that is the equivalent of a car dealer checking with a second lender if you get rejected on your first auto loan. So, what about the man who has a total testosterone (never mind that free testosterone correlates better with the signs and symptoms of deficiency) of 360 or even 400, perhaps only on the second blood draw? Keep in mind, the “normal” range extends all the way to 980-1,100 ng/dL, depending upon the lab and method used. The average total testosterone value for healthy, non-obese, young men is 700 ng/dL.2 So a man is considered normal if his testosterone is half the value of the average healthy man. This places him in the bottom 2.5 percent of all men, if the statistical model was valid. There are few people who challenge the “standard of care” reference range. Consider that when hypothalamic-pituitary suppression due to metabolic dysfunction and/or Leydig cell dysfunction is treated, that most men, even older men, respond to the 450-550 ng/dL range or higher.3,4 This level of total testosterone is associated with improved glucose tolerance/insulin resistance, and other metabolic signs in hypogonadal men.5
Most (though thankfully, fewer every year) clinicians view testosterone treatment as “drug seeking” for the purposes of vanity or sexual enhancement. Many seem to get their “professional opinion” from reading the sensationalistic stories online about sports doping rather than medical journals. And the issue of media bias in medical publishing is ignored, despite its clearly evident presence. Certain clinicians are promoting a “better” testosterone status in men who are just barely hanging in the bottom end of the “normal” range. Clomiphene citrate (25-50 mg/day) and hCG (300-500 IU every other day) have become accepted, in part due to their historical use for a similar purpose in fertility treatments for women. Subfertile men, which usually means they have a low sperm count, are being treated similarly.
Aromatase Inhibitors
Another drug class used by bodybuilders has a tougher road to climb to gain clinical acceptance, as it was designed to treat breast cancer, not improve fertility or reproductive function – aromatase inhibitors. Only fairly recently have aromatase inhibitors been reported as effective agents for improving fertility in specific patient groups, such as women suffering from polycystic ovarian syndrome (PCOS).6 The most commonly encountered drugs in this class include anastrozole (Arimidex), letrozole (Femara) and exemestane (Aromasin). The original drug of this class, which lacks specificity and carries a significant risk of serious, even life-threatening side effects is Cytadren (aminoglutethimide), is rarely encountered.
An impressive review of the use of aromatase inhibitors in men with marginal testosterone status was published in the journal Sexual Medicine Reviews.7 The review does suffer, at least in the introduction, from opining in agreement with the disputed, even disproven, association between testosterone replacement therapy and adverse effects on the cardiovascular system and prostate health but is otherwise well done. The review describes the essential role of estrogens in male health and physiology – primarily estradiol, which is the most potent, being the direct metabolite of testosterone when acted upon by the aromatase enzyme complex.
Aromatization is a multistep conversion, rather than a single chemical reaction. Contrary to popular belief, estradiol plays a role in libido, erectile function, bone health, muscle growth, etc., in men. There are rare cases of men who have a genetic aromatase deficiency, and they are described as “eunuchoid” in proportions – eunuchs were servants and slaves that were castrated as children to make them more docile. Men with aromatase deficiency are tall due to a long-delayed closure of the epiphyseal plates in the long bones and they have a low bone density, even osteoporosis at a young age. Changes consistent with the metabolic syndrome (obesity, elevated cholesterol, insulin resistance, etc.) have been described.8
The Role of Estrogens
Sexual maturation (i.e., penis development) of eunuchoid men is normal, but increased testes size is common due to elevated pituitary hormones keeping the testes chronically stimulated. The hormonal values of one affected gentleman provide an example of the relative effect on testosterone and estradiol. This man had a reported total testosterone of 2,015 ng/dL (twice the upper limit of normal), and a combined estradiol and estrone of 7 pg/mL (normal range for estradiol is 10-40 pg/mL, though a value under 15 is usually considered insufficient; estrone is a less potent estrogen formed from androstenedione, an adrenal gland androgen). So, even with a testosterone value consistent with that of men using testosterone for bodybuilding purposes, and extremely low estrogen, this was not a hulking, ripped and muscular Superman with four-hour erections; these men have impaired health and relative frailty compared to “normal” men with higher (but normal) estrogen and lower testosterone. Clearly, estrogens have a role in male health and metabolism.
This review is well referenced, and the topic of aromatase inhibition in adult men can be addressed by relating the highlights of the work. The authors focus on the testosterone/estradiol ratio (T/E2) as the measure of androgen-to-estrogen balance. The T/E2 ratio is given greater regard than the absolute testosterone or estradiol concentrations. In the physiologic range, there is validity to that claim. Fertility researchers have determined that “normal” men have an average T/E2 of ~14, whereas the ratio for subfertile men is half that, or ~7.9 It is interesting that a study of testosterone-deficient men treated with clomiphene demonstrated improvement, with an increase in total testosterone from ~250 ng/dL to ~610 ng/dL, and a correction of the T/E2 ratio from 8.7 to 14.2.10
A more pronounced treatment effect, increase of T/E2 ratio, has been reported with aromatase inhibition therapy in hypogonadal men.11 This is not due to a greater increase in testosterone compared to clomiphene, but rather a 40 to 50 percent reduction in estradiol, resulting in T/E2 ratios greater than 30. Bear in mind, this study included men with low testosterone, so the suppression of the enzyme activity combined with the relatively low testosterone to allow for limited estradiol production. Estradiol concentration in the blood reached a barely sufficient level of ~15 pg/ml. Remember, testosterone is the precursor to estrogen, so low testosterone means less available to interact with the aromatase enzyme complex. Prior aromatase inhibition studies on men with normal testosterone reported testosterone nearly doubled with estradiol falling by about 50 percent, resulting in the T/E2 ratio jumping from ~17 to ~75 in one study; similar results were reported in a second study.12,13 The concentration of estradiol during aromatase inhibition was within the normal range, but just barely.
Change in Testosterone/Estradiol Ratio
An issue that has not been adequately explored is the relative change in T/E2 ratio in men on testosterone replacement therapy (TRT) or using anabolic-androgenic steroids (AAS). The reason this is relevant is that the exogenous (pharmaceutical) testosterone suppresses natural testosterone production in the Leydig cells. It is little appreciated that the Leydig cells also produce 20 percent of all circulating estrogens and the majority of the estradiol in men, according to one well-regarded review.14,15 The remainder is produced in other cells, prominently in the fat cell (adipocyte). Leydig cells are fairly resistant to aromatase inhibition when they are not suppressed, because the local concentration of testosterone is up to 600 times that in the blood. In other words, when the testes are not suppressed, they are bathed in so much testosterone that the aromatase inhibitors do not have much effect in that specific tissue. If the Leydig cells are suppressed, then that “reserve” of estradiol production is ablated, and the TRT-treated or AAS-misusing man is at greater risk of an estradiol insufficiency/deficiency. In bodybuilders, this is compounded by the relative lack of adipose tissue, if he maintains a lean physique.
The increase in testosterone seen with aromatase inhibitor use (in drug-free men) is due to the suppressive effect of estradiol on the hypothalamus being lowered significantly. Animal studies suggested that brain aromatase converts testosterone to estradiol locally (at the site of the hypothalamus), but several studies now suggest it is the circulating concentration of estradiol that suppresses the hypothalamus.12,16 Remember, the hypothalamus is like the thermostat for your furnace – it tells the pituitary when to turn the Leydig cells’ production of testosterone up or down. Decreasing estradiol increases the number of times the pituitary gland releases its “go” signal for the Leydig cells, as well as allowing a higher peak of the signal. This results in the increase in testosterone production seen. The androgenic metabolite of testosterone, DHT, has relatively little effect on the hypothalamus or pituitary.17 Estradiol’s effect on the regulatory axis is stated to be 200 times greater.7
Favorable Risk Profile
Aromatase inhibition, in the studies following subfertile men or those with gynecomastia, has demonstrated a favorable risk profile. The drugs, in doses commonly reported to be used by bodybuilders (e.g., anastrozole 1 mg/day; letrozole 2.5 mg/day) have not been associated with adverse events of significance. Reported side effects are generally limited to transient and “mild” increases in liver enzymes, and decreased libido. One concern in chronic use is loss of bone mineral content. Estradiol is the big player in building strong bones, but the general consensus is that there is not a significant decrease in bone mineral content during aromatase inhibition in men. It is possible that adequate TRT or AAS misuse may be protective against this, as well as weight-bearing exercise.
Aromatase inhibitors are being used, off-label, clinically in men with gynecomastia (except when due to anti-androgen drugs used to combat prostate cancer); in hypogonadal men with low LH, including the obese; and in cases of subfertility. Short children are also being treated with aromatase inhibitors to prolong growth (height) by delaying the closure of the growth plates, with reported success.7
As for the use of aromatase inhibition during TRT (or while misusing AAS), there is a large body of anecdotal reports suggesting that aromatase inhibition aids in prolonging the eugonadal effect of long-acting testosterone treatment (e.g., pellet implants, esters); reducing the risk of AAS-related gynecomastia (though extremely high-dose cycles, particularly cycles including nandrolone, can result in breast tenderness or mass even with aromatase inhibition); and improving body composition during cycles with prominent aromatizable AAS content.18
Aromatase inhibitors, specifically anastrozole and letrozole, appear to be relatively safe adjuncts to consider in treating testosterone deficiency or insufficiency when the cause is secondary (related to the hypothalamus and/or pituitary), aging, or a consequence of obesity.19 In men receiving testosterone, or misusing AAS, aromatase inhibitors may prevent, reduce or treat certain estrogen-related side effects (e.g., gynecomastia), but carry the risk of side effects. At this time, the side effects seem relatively benign and resolve once estrogen levels are corrected. As with all medication, aromatase inhibitors should not be used other than when prescribed by one’s personal physician.
DISCUSS ON OUR FORUMS
SUBSCRIBE TO MD TODAY
GET OFFICIAL MD STUFF
VISIT OUR STORE
SUBSCRIBE TO OUR NEWSLETTER
ALSO, MAKE SURE TO FOLLOW US ON:
YOUTUBE
References:
1. Bhasin S, Cunningham GR, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:2536-59.
2. Bhasin S, Pencina M, et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J Clin Endocrinol Metab 2011;96:2430-9.
3. Coviello AD, Matsumoto AM, et al. Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression. J Clin Endocrinol Metab 2005;90:2595-602.
4. Da Ros CT, Averbeck MA. Twenty-five milligrams of clomiphene citrate presents positive effect on treatment of male testosterone deficiency - a prospective study. Int Braz J Urol 2012;38:512-8.
5. Hackett G, Cole N, et al. The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study). Int J Clin Pract 2014;68:203-15.
6. Legro RS, Brzyski RG, et al. Letrozole versus Clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014;371:119-129.
7. Tan RBW, Guay AT, et al. Clinical use of aromatase inhibitors in adult males. Sex Med Rev 2014;2:79-90.
8. Morishima A, Grumbach MM, et al. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 1995;80:3689-98.
9. Pavlovich CP, King P, et al. Evidence of a treatable endocrinopathy in infertile men. J Urol 2001;165:837-41.
10. Shabsigh A, Kang Y, et al. Clomiphene citrate effects on testosterone/estrogen ratio in male hypogonadism. J Sex Med 2005;2:716-21.
11. Gregoriou O, Bakas P, et al. Changes in hormonal profile and seminal parameters with use of aromatase inhibitors in management of infertile men with low testosterone to estradiol ratios. Fertil Steril 2012;98:48-51.
12. Raven G, de Jong FH, et al. In men, peripheral estradiol levels directly reflect the action of estrogens at the hypothalamo-pituitary level to inhibit gonadotropin secretion. J Clin Endocrinol Metab 2006;91:3324-8.
13. T'Sjoen GG, Giagulli VA, et al. Comparative assessment in young and elderly men of the gonadotropin response to aromatase inhibition. J Clin Endocrinol Metab 2005;90:5717-22.
14. Saez JM, Morera AM, et al. Adrenal and testicular contribution to plasma oestrogens. J Endocrinol 1972;55:41-9.
15. Schlegel PN. Aromatase inhibitors for male infertility. Fertil Steril 2012;98:1359-62.
16. Rochira V, Zirilli L, et al. Hypothalamic-pituitary-gonadal axis in two men with aromatase deficiency: evidence that circulating estrogens are required at the hypothalamic level for the integrity of gonadotropin negative feedback. Eur J Endocrinol 2006;155:513-22.
17. DHT does not affect pituitary, reduces aromatase in Leydig cells, and does not reduce T response to hCG. Does suppress hypothalamic GnRH.
18. Rhoden EL, Morgentaler A. Treatment of testosterone-induced gynecomastia with the aromatase inhibitor, anastrozole. Int J Impot Res 2004;16:95-7.
19. Stephens SM, Polotsky AJ. Big enough for an aromatase inhibitor? How adiposity affects male fertility. Semin Reprod Med 2013;31:251-7.
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