Estrogenic side effects can refer both to side effects from elevated estrogen levels due to aromatization, and to estrogenic side effects from other causes unrelated to a rise in E2 (Estradiol).
It’s very important to understand this, as estrogenic side effects can arise from various causes.
Most of the estrogenic side effects discussed here can be treated using anti-estrogens.
This will be explained in detail in this blog’s section on Anti-Estrogens.
Here, we will discuss the most common and prominent estrogenic side effects.
The most common and primary cause of gynecomastia is the rise in E2 levels due to the extensive aromatization of androgens like Testosterone, Dianabol (Methandrostenolone), or other aromatizable anabolic steroids.
Secondly, estrogenic side effects can also be caused by compounds that are not estrogenic in nature but 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 primary characteristics of DHT (Dihydrotestosterone) is that the aromatase enzyme does not recognize it as a suitable substrate.
Therefore, Anadrol does not aromatize into Estrogen; instead, it is strongly speculated that Anadrol itself (and/or one or more of its metabolites) acts as an Estrogen at the estrogen receptors in various tissues.
Moving on to other causes of estrogenic side effects, estrogenic effects can occur with the use of xenoestrogens, which will be covered later in this article.
(Xenoestrogens are non-steroidal drugs that are not similar to estrogen but bind to the body’s estrogen receptors).
Finally, estrogenic side effects can be exacerbated by elevated levels of another female ovarian steroid hormone, Progesterone (or the use of Progestins, which are compounds similar to Progesterone).
This can increase the sensitivity of the estrogen receptor to estrogen and further intensify estrogenic side effects.[1]
As a result, an environment is created where even very low levels of estrogen can cause estrogenic side effects.
Gynecomastia (“Gyno”)
Gynecomastia (often shortened to ‘gyno’) refers to the development of female-like breast tissue in males.
Gynecomastia is one of the most common estrogenic side effects of anabolic steroid use and one of the most frequently discussed.
It is also very common in adolescent males and older men over the age of 45. [2],[3],[4]
Gynecomastia is also common in obese men and men with excessively high body fat percentages, as studies have shown that higher body fat levels increase the risk of estrogenic side effects.[5]
While there are several contributing factors to gynecomastia, including human growth hormone, prolactin, progesterone, IGF-1, and estrogen, estrogen tends to be the most critical determining factor, and it must be present at significantly high levels for gynecomastia to develop.
Gynecomastia is a major concern for men, but it is far from a life-threatening estrogenic side effect; it is considered an aesthetically displeasing and unattractive side effect.
Water Retention (Bloating)
The accumulation of water in the body due to high estrogen levels is one of the potentially serious estrogenic side effects, but it also has an aesthetic aspect.
Fluid retention from excessive estrogen levels causes a soft, “puffy” physique that is generally undesirable for athletes and bodybuilders.
The exception is for those who tolerate or even prefer such a physique during bulking and weight gain phases.
The danger of water retention is that as extracellular fluid flows through the circulatory system, blood pressure can rise to dangerous levels, increasing fluid pressure in the arteries and veins.[6]
The estrogenic side effect of water retention stems from estrogen’s ability to stimulate the release of hypothalamic arginine vasopressin (AVP), a hormone directly involved in regulating water influx and efflux to the kidneys.[7]
It is estrogen that is responsible for regulating fluid retention in both men and women.[8]
This is another reason why women naturally have a ‘softer’ look and feel compared to men.
Additionally, water is retained in the subcutaneous tissue under the skin (also known as peripheral water retention).
This is what gives bodybuilders and athletes on high doses of aromatizable anabolic steroids a soft, smooth, and bloated appearance.
Some say that the swollen and bloated look of bodybuilders can be a sign of estrogenic side effects or anabolic steroid use.
Benign Prostatic Hyperplasia and Prostate Cancer
The link between prostate problems in men and estrogen is relatively recent.
For a long time, the prevailing theory was that Dihydrotestosterone (DHT) was the cause of prostate issues.
While this is true, emerging evidence on the influential role of estrogen suggests that DHT (and androgens in general) is only part of the problem.
First, there is a big difference between BPH and prostate cancer, which must be clarified.
BPH stands for Benign Prostatic Hyperplasia, which is the normal, benign enlargement of the prostate, whereas prostate cancer is an actual carcinoma of the prostate.
We must make it clear 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 and does not increase the risk of prostate cancer. [9]
Adding to the confusion between BPH and prostate cancer is the observation that both are indeed androgen-dependent.
This is because, in the absence of androgens, disease progression is significantly reduced or even eliminated (evidence from castration). [10]
However, studies have shown that administering testosterone to TRT patients has no effect on the development of prostate cancer. [11]
Furthermore, the claim that there is an increased risk of developing prostate cancer in anabolic steroid users who use supra-physiological levels of anabolic androgenic steroids is unfounded. [12]
There is also evidence that while testosterone levels are an essential factor in the development of prostate cancer, there is generally no direct link between testosterone levels and prostate cancer. [13]
Let’s return to benign prostatic hyperplasia, which naturally occurs during the initial development of the male prostate.
This is necessary for maintaining the prostate in adult men.
Although it is a necessary process, growth stimulation by androgenic anabolic steroids can increase the size of the prostate to uncomfortable levels, causing the aforementioned problems (increased urination frequency, urination difficulty, inflammation, discomfort, etc.).
While androgens like testosterone are known to play a central role, estrogen is known to play an even larger role than androgens in prostate growth. [14]
Estrogen appears to be responsible for increasing the number and proliferation of androgen receptors in the prostate; therefore, even with decreased androgen levels, an increased number of androgen receptors leads to a significant increase in growth rate. [15]
Just as gynecomastia is significantly affected when the ratio of androgens to estrogens shifts towards estrogen, benign prostatic hyperplasia appears to be affected in the same way.
Returning to prostate cancer, there is very strong evidence that estrogen is a potent carcinogen in relation to the prostate, 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 demonstrates that estrogen and testosterone can be used to induce prostate cancer in rodent models and chimeric human tissue transplant models. [16]
Furthermore, various estrogen receptors have been found in the prostate, and estrogen can exacerbate not only BPH, as mentioned earlier, but also malignant prostate cancer through receptor-mediated mechanisms, DNA damage, and the potential mutagenic activity of estrogen and estrogenic compounds. [17]
While all of this seems to paint a very grim picture regarding estrogen and prostate-related side effects, there is a small saving grace for estrogen.
In addition to the negative prostate-related side effects of estrogen, it has also been shown to have beneficial effects that protect the prostate. [18]
On the positive side, stimulation of the estrogen receptor beta can help protect the prostate from inflammation, proliferation, and some carcinogenesis.
The responsibility for the aforementioned negative effects lies with the estrogen receptor alpha.
However, it is safe to conclude that very high levels of estrogen are more harmful than beneficial to the prostate.
This is because elevated PSA levels have been recorded during the administration of anabolic steroids (both mildly and severely estrogenic ones). [19]
Medical References
[1] Insights into the normal mammary gland development in mutant mice with null mutation in the progesterone receptor gene and the in situ localization of the receptor in the mammary gland and the role of estrogen and progesterone. Shyamala G. Trends Endocrinol Metab. 1997 Jan-Feb;8(1):34-9.
[2] Gynaecomastia 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] Disorders of the Testes and 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 (author’s transl). Nippon Naibunpi Gakkai Zasshi 62(1986:18-25)
[6] Salt, hypertension, and edema. Rossler R, Internist (Berl). 1976 Oct;17(10):489-93. Review.
[7] Forsling, M. L., P. Stromberg, and M. Akerlund. Effect of ovarian steroids on vasopressin secretion. J Endocrinol. 95: 147-151, 1982.
[8] Stachenfeld NS. Sex hormone effects on body fluid regulation. Exerc Sports Sci Rev. 2008 Jul;36(3):152-9.
[9] Zhang RT, Kirby R, Chalacombe BJ. Is there a link between BPH 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] Testosterone therapy in men with hypogonadism and prostate cancer risk: a systematic review. Shabsigh R, Crawford ED, Nehra A, Slawin KM. lnt J Impot Res. 2008 Jul 17. [Epub ahead of print]
[12] Long-term psychiatric and medical consequences of anabolic-androgenic steroid abuse: A looming public health problem? Kanayama G, Hudson JI, Pope HG Jr. Drug Alcohol Depend. 2008 Nov 1;98(1-2):1-12. Epub 2008 Jul 2.
[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 2008 Jun 10.
[14] Development and differentiation of the prostate gland by estrogenic regulation. McPherson SJ, Ellem SJ, Risbridger GP. Differentiation. J Cell Biol. 2008 Jul;76(6):660-70. Epub 2008 Jun 28.
[15] Hadley M, Levine J. 2006. Endocrinology. 6th ed. Toronto: Pearson Education, p 403.
[16] Jason L Nelles, Wen-Yang Hu, Gail S Prins. Estrogen action and prostate cancer. Expert Rev Endocrinol Metab. 2011 May; 6(3): 437–451.
[17] Maarten C Bosland, DVSc, PhD. The Role of Estrogen in Prostate Carcinogenesis: A Rationale for Chemoprevention. Rev Urol. 2005; 7(Suppl 3): S4–S10.
[18] G Risbridger, S Ellem et al. Estrogen action on the prostate gland: a critical mix of endocrine and paracrine signaling. J Mol Endocrinol (2007) 39,183–8.
[19] Effect of androgen therapy on prostatic markers in patients on hemodialysis. Teruel JL, Aguilera A, Avila -C, Ortuno J. Scand J Urol Nephrol. 1996 Apr;30(2):129-31.
