Elevated E2 During TRT: To Treat or Not To Treat?

TRT may lead to elevations in serum estradiol (E2) and in some cases to levels above the upper limit of normal. The development of nipple or breast tenderness or frank gynecomastia has been reported in association with TRT, and in these cases there is a clear indication for the use of aromatase inhibitors to reduce E2. Some authors recommend with- drawal first of TRT with subsequent resolution of symptoms, followed by the use of aromatase inhibitors together with reinitiation of TRT [113]. Some clinicians, particularly in the antiaging com- munity, advocate the routine use of aromatase inhibitors with TRT even in the absence of symp- toms of estrogen excess. These clinicians believe that maintaining a relatively low estrogen concentration improves male health and the efficacy of TRT.

However, the basis for this belief is uncertain. In one randomized controlled trial, treatment of men with low T with anastrazole normalized T levels, but there was no improvement in symptoms of low T or changes in body composition, muscle strength, or hematocrit [103]. Further studies of this nature are needed. Furthermore, E2 levels in some men treated with aromatase inhibitors decreased below 40 pmol/L, considered the threshold at which there is increased risk of developing osteoporotic changes. Additionally, case reports of men with congenital aromatase deficiency suggest that aromatase inhibition may risk decreasing insulin sensitivity, potentially worsened by TRT [44,45].

The only trials identified in this review that compared the use of TRT with and without an aromatase inhibitor were conducted in men with hyposexuality and seizure disorders. One trial showed a significant benefit in sexual interest from the addition of testolactone therapy [114]. A second trial involving 40 men reported a trend toward improved libido in men treated with T and anastrazole over T alone, although this did not reach statistical significance. Some men in the T-only group reported improvement in libido despite increases in E2 with TRT [115].

The results of these studies should be interpreted with caution as it is not clear how this group compares with the larger group of T-deficient men. These men were all treated with antiepileptic drugs such as phenytoin and carbemazapime, which increase SHBG, likely through induction of hepatic synthesis, and may therefore impact androgen and estrogen concentrations and metabolism. Impotence, decreased libido, and infertility are common and associated with a deficiency in free T despite normal total T levels [116]. E2 levels are increased in hyposexual men with epilepsy compared with men with normal sexual function and with healthy controls [95].

We therefore find no evidence to support the contention that relative reductions in E2 via the use of aromatase inhibitors or other agents in conjunction with TRT offer benefits beyond that offered by TRT alone. Anecdotally, in our practice, there have been rare cases of men who failed to experience symptomatic benefits from TRT and were found to have elevated E2 concentrations. Some of these men have responded to steps to lower E2 concentrations, either by reduction in T dosage or by addition of aromatase. However, these cases are anecdotal, and even if treatment was beneficial, the rarity of such occurrences does not justify the routine use of aromatase inhibitors together with TRT. Moreover, aromatase inhibitors may reduce E2 levels below a crucial threshold for bone health, and dual-energy X-ray absorptiometry (DXA) monitoring should therefore be considered for individuals receiving such therapy.

Nelson Vergel



Estrogens in Men: Clinical Implications for Sexual Function and the Treatment of Testosterone Deficiency Ravi Kacker, MD,* Abdulmaged M. Traish, PhD,† and Abraham Morgentaler, MD* *Beth Israel Deaconess Medical Center, Harvard Medical School, Urology, Boston, MA, USA; †Laboratory for Sexual Medicine Research, Boston University, Boston, MA, USA International Society for Sexual Medicine

Published in Defy Medical Blog
Click here to view full article titled "Testosterone needs estrogen's help to inhibit depression" by Professor Mohamed Kabbaj from Florida State University College of Medicine.


Article commentary by Jasen Bruce

Men and women on testosterone replacement therapy who previously suffered from low testosterone and depression already understand the positive effect that testosterone has on their mood. A study led by Rupert Lanzenberger from the Vienna Medical University Department of Psychiatry and Psychotherapy has demonstrated for the first time worldwide that testosterone increases the number of serotonin transporters (proteins) in the human brain. Serotonin is a neurotransmitter that plays an important role in maintaining positive mood and emotional well-being. There are many more studies which demonstrate the relationship between the sex hormone testosterone, depression, and positive mood. Maintaining adequate levels of testosterone is shown to reduce the occurrence of depression. The presentation titled “Testosterone needs Estrogen's help to inhibit Depression “by Professor Mohamed Kabbaj interestingly shows that both estrogen and testosterone work together to alleviate depression and anxiety. In both men and women, some testosterone converts to estrogen. In men, this is the primary source of estrogen. In women, estrogen is also produced in the ovaries. The article indicates that the actual conversion of testosterone to estrogen in the brain is necessary for anti-depressant and anti-anxiety effects. This research will hopefully help patients suffering from depression obtain better access to hormone testing and proper treatments when certain hormones are found to be too low

The only statement I do not agree with is regarding the “need” to synthesize a drug which acts like testosterone due to the fear of “numerous side effects” associated with testosterone. Of course those of us who read the latest evidence know that the “numerous side effects” result from improper prescribing of testosterone and the lack of proper monitoring. Testosterone replacement therapy correctly administered and monitored by an experienced doctor has very low risk and long term health benefits. Why take a hormone already identical to what the body produces and alter it to produce a drug? I believe the efforts would be better spent educating more doctors on how to properly monitor testosterone replacement therapy after diagnosing low testosterone. Although this study is done on men, we know the effects are equally beneficial in women. Article excerpt: “Maybe in the future, when we are trying to develop an antidepressant that works in low-testosterone males, we can target some of the mechanisms by which testosterone acts, since it has numerous side effects,” he said. Testosterone acts on many receptors and pathways in the brain, so the challenge is to come up with a drug that provides only the effect you want.” Referenced: http://www.defymedical.com/video-education...-rfp69hrv-dpuf

"...the male sex hormone testosterone also affects our mood and emotions, as well as our libido -- and in a positive way."

Published in Defy Medical Blog