Background on Estrogen Side Effects
Estrogenic side effects can refer to both side effects caused by elevated estrogen levels due to aromatization or estrogenic side effects caused by other causes unrelated to elevated E2 (estradiol).
Because estrogen side effects can have many different causes, it is very important for readers to understand this.
Most of the estrogen side effects discussed here can be treated using anti-estrogens, which will be discussed in detail in the next subsection of this article (Anti-estrogens).
Here we will discuss the most common and prominent estrogen side effects.
The most common and primary cause of gynecomastia is, of course, elevated E2 levels due to the broad aromatizing action of androgens such as testosterone, Dianabol (methandrostenolone), or other aromatizing anabolic steroids.
Secondly, estrogenic side effects can also be caused by compounds that are not estrogenic in nature but tend to bind to estrogen receptors in the body.
A perfect example of this is the anabolic steroid anadrol (oxymetholone), which cannot actually aromatize because it is a DHT derivative, and one of the key characteristics of DHT (dihydrotestosterone) is that the aromatase enzyme does not recognize it as a suitable substrate.
Therefore, it is strongly speculated that anadrol does not aromatize into estrogen, and instead, anadrol itself (and/or one or more of its metabolites) acts as estrogen at estrogen receptors in other tissues.
Moving on to other causes of estrogenic side effects, the use of xenoestrogens can cause estrogenic effects, which we will cover later in this article (xenoestrogens are non-steroidal compounds that are not similar to estrogen but bind to estrogen receptors in the body).
Finally, estrogenic side effects can be exacerbated by elevated levels of another female ovarian steroid hormone, progesterone (or the use of progestins, which are progesterone-like compounds), which can act to increase the sensitivity of estrogen receptors to estrogen and exacerbate estrogenic side effects [1].
The result is an environment where even very low levels of estrogen can cause estrogenic side effects.
Gynecomastia
Gynecomastia (also known as "gyno" for short) is simply the development of female-like breast tissue in men.
Gynecomastia is one of the most common estrogenic side effects of anabolic steroid use, and one of the most commonly discussed estrogenic side effects.
Gynecomastia is also very common in young men during puberty [2][3] and in older men over the age of 45 [4].
Gynecomastia is also common in obese men and men with excessively high body fat, as studies have shown that the higher the body fat percentage, the higher the risk of estrogen side effects [5].
While there are many cogs in the gynecomastia machine, including human growth hormone, prolactin, progesterone, IGF-1, and estrogen, estrogen tends to be the most important causative determinant, and there is an absolute requirement that estrogen must be present and at very high levels for gynecomastia to occur.
Gynecomastia is a condition of great concern among men, but far from being a life-threatening estrogen side effect, it is considered an aesthetically unpleasant and unattractive side effect.
Water retention (bloating)
Water retention due to elevated estrogen levels is one of the potentially serious estrogen side effects, but it also has an element of aesthetic appeal.
Water retention due to excessive estrogen levels causes a soft, "puffy" body shape that is generally undesirable in athletes and bodybuilders, except for those who tolerate or even prefer it during bulking and weight gain phases.
The danger with water retention is that blood pressure can rise to dangerous levels as extracellular water flows through the circulatory system, increasing fluid pressure on the arteries and veins [6].
The estrogenic side effects of water retention stem from estrogen's ability to stimulate the release of hypothalamic arginine vasopressin (AVP), a hormone directly involved in regulating the flow of water into and out of the kidneys [7],
In both men and women, it is estrogen that is responsible for this regulation of fluid retention [8].
So this is another reason why women naturally have a 'softer' look and feel than men.
Water is also retained in the subcutis under the skin (also known as peripheral water retention), which is why bodybuilders and athletes who take high doses of aromatizing anabolic steroids appear soft, smooth, and bloated.
Some people say that the bloated and puffy appearance of bodybuilders can be a sign of estrogenic side effects, or anabolic steroid use.
Benign Prostatic Hyperplasia and Prostate Cancer
The link between estrogen and prostate problems in men is fairly recent, as for a long time the dominant theory was that dihydrotestosterone (DHT) was the culprit in prostate problems.
While this is true, new evidence about the influential role of estrogen makes dihydrotestosterone (and androgens in general) only part of the problem.
First of all, there's a big difference between BPH and prostate cancer that needs to be clarified before we move forward.
BPH is benign prostatic hyperplasia, a normal benign enlargement of the prostate, while prostate cancer is an actual carcinoma of the prostate. We should make it clear to our readers right now that while BPH can be uncomfortable, cause urination problems, and increase the risk of urinary tract infections (and subsequent inflammation), BPH does not lead to prostate cancer, nor does it increase the risk of prostate cancer[9].
.
Adding to the confusion between BPH and prostate cancer, it has been observed that both BPH and prostate cancer are indeed androgen-dependent, as disease progression is significantly reduced and even eliminated in the absence of androgens (as evidenced by castration) [10].
However, studies have shown that administering testosterone to TRT patients has no effect on the development of prostate cancer, and claims of an increased risk of prostate cancer in anabolic steroid users who use anabolic androgenic steroids at supraphysiologic levels are also unsupported [11][12].
There is also evidence that while testosterone levels are a necessary factor in the development of prostate cancer, there is generally no direct link between testosterone levels and prostate cancer [13].
Let's go back to benign prostatic hyperplasia, which is a natural part of early prostate development in men and is necessary for the maintenance of the prostate in adult men.
Although necessary, growth stimulation by androgenic anabolic steroids can increase the size of the prostate to uncomfortable levels and can cause the aforementioned problems such as increased urination frequency, urination problems, inflammation, discomfort, and more.
While androgens such as testosterone are known to play a central role, it is estrogen that is known to play an equally large (or even larger) role in prostate growth [14].
Estrogen appears to play a role in increasing the number and proliferation of androgen receptors in the prostate, and thus an increase in the number of androgen receptors, even in the presence of decreased androgen levels, results in a significant increase in growth rate [15].
In the same way that gynecomastia is strongly affected by a change in the androgen:estrogen ratio in favor of estrogen, benign prostatic hyperplasia appears to be affected in this way.
Going back to prostate cancer, there is very strong evidence that estrogen is a potent cancer-causing agent as far as the prostate is concerned, and that high estrogen levels are associated with prostate cancer.
This evidence not only shows changes in estrogen receptor status in advanced prostate cancer, but also shows the use of estrogen as well as testosterone to induce prostate cancer in rodent models and chimeric human tissue transplantation models [16].
In addition, various estrogen receptors have been found in the prostate, and estrogen can not only exacerbate BPH as mentioned earlier, but also exacerbate malignant prostate cancer through receptor-mediated mechanisms, DNA damage, and potential mutagenic activity of estrogens and estrogenic compounds [17].
While all of this seems to paint a very grim picture of estrogen and its prostate-related side effects, estrogen does have a bit of a saving grace.
In addition to the negative prostate-related side effects of estrogen, there is evidence that it also appears to have beneficial effects that protect the prostate [18].
On the positive side, stimulation of estrogen receptor-beta may help protect the prostate from inflammation, proliferation, and some carcinogenesis.
It is the estrogen receptor-alpha that is responsible for the aforementioned negative effects. However, it is safe to conclude that very high levels of estrogen are more harmful to the prostate than beneficial, as elevated PSA levels have been documented during anabolic steroid administration (with both mild and severely estrogenic anabolic steroids) [19].
Medical references
[1] Insights into normal mammary gland development in mutant mice lacking the progesterone receptor and the role of estrogen and progesterone in the in situ localization of the receptor. Shyamala G. Trends Endocrinol Metab. 1997 Jan-Feb;8(1):34-9.
[2] Gynecomastia and breast cancer in men. Niewohner, CB; Schorer, AE (March 2008). BMJ 336(7646): 709-713. doi:10.1136/bmj.39511.493391.BE. PMID 18369226.
[3] Testicular Disorders and the Male Reproductive System Harrison's Principles of Internal Medicine (17th ed.). 340. Fauci, Anthony S.; Eugene Braunwald, Dennis L. Kasper, Stephen L. Hauser, Dan L. Longo, J. Larry Jameson, Kurt J. Isselbacher (2008). New York: McGraw-Hill. ISBN 978-0-07-147693-5.
[4] Gynecomastia: Pathophysiology, Evaluation, and Management. Johnson, RE; Murad, MH (November 2009). Mayo Clinic Proceedings 84 (11): 1010-1015. doi:10.1016/S0025-6196(11)60671-X. PMID 19880691.
[5] Aromatization of androstenedione and 19-nortestosterone in human placenta, liver, and adipose tissue (abstract). Nippon Naibunpi Gakkai Zasshi 62 (1986:18-25)
[6] Salt, hypertension, edema. Rossler R, Internist (Berl). October 1976; 17(10):489-93. review.
[7] Forsling, ML, P. Stromberg, and M. Akerlund. Effects of ovarian steroids on vasopressin secretion. J Endocrinol. 95: 147-151, 1982.
[8] Stachenfeld NS. Effects of sex hormones on fluid regulation. Exerc Sports Sci Rev. 2008 Jul;36(3):152-9.
[9] Zhang RT, Kirby R, Chalacombe BJ. Is there a link between benign prostatic hyperplasia and prostate cancer? Practitioner. 2012 Apr;256(1750):13-6, 2.
[10] Benign hypertrophy and carcinoma of the prostate. Moore RA. Surgery 1944;16:152-67.
[11] Shabsigh R, Crawford ED, Nehra A, Slawin KM. Testosterone treatment and potential prostate cancer risk in men with hypogonadism: a systematic review. lnt J Impot Res. 2008 July 17. [Epub ahead of print].
[12] Kanayama G, Hudson JI, Pope HG Jr. Long-term psychiatric and medical consequences of anabolic-androgenic steroid abuse: A looming public health problem Drug Alcohol Dependence. 2008 Nov 1;98(1-2):1-12. Epub July 2, 2008.
[13] Guilt by association: a historical perspective on Huggins, testosterone therapy, and prostate cancer. Morgentaler A.J Sex Med. 2008 Aug 5(8):1834-40. Epub June 10, 2008.
[14] Estrogen-regulated development and differentiation of the prostate. McPherson SJ, Ellem SJ, Risbridger GP. Differentiation. J Cell Biol. 2008 Jul;76(6):660-70. Epub June 28, 2008.
[15] Hadley M, Levine J. 2006. Endocrinology. 6th ed. Toronto: Pearson Education, 403 pp.
[16] Jason L Nelles, Wen-Yang Hu, Gail S Prins. Estrogen Action and Prostate Cancer. Expert Rev Endocrinol Metab. May 2011; 6(3): 437-451.
[17] Maarten C Bosland, DVSc, PhD. The role of estrogen in prostate cancer development: a rationale for chemoprevention. Urol Pastor. 2005; 7(supply 3): S4-S10.
[18] G Risbridger, S Ellem et al. Estrogen action on the prostate: a critical mix of endocrine and paracrine signaling. J Mol Endocrinol (2007) 39,18388.
[19] Teruel JL, Aguilera A, Avila -C, Ortuno J. Scand J Urol Nephrol. Effects of androgen therapy on prostate markers in hemodialysis patients. 1996 Apr 30(2):129-31.
