Do Anabolic Steroids Make the Prostate Grow?

Researchers in the field of anabolic steroids have been, in my eyes, obsessed with the effects on the prostate for a long time. This is perhaps most evident by looking at the Hershberger assay [1]. Briefly, it is an assay performed on rats in order to arrive at a certain anabolic to androgenic ratio for an anabolic steroid. I’ve covered this assay and the resulting ratio previously in an article dubbed the “The Anabolic to Androgenic Ratio is Worthless and Hinders the Quest for Safer Steroids & SARMs”.

In this assay, growth of the ventral prostate of the rats is used as a marker of androgenic activity. Most importantly, this assay (or slight modifications thereof) has been used for decades and still is used today in the development of SARMs [2]. For some reason I guess it’s very interesting to see what happens to the prostate in rats after administration of anabolic steroids.

Even before this paper it’s clear in the literature that there was a keen interest in effects on the prostate. Notably in the context of prostate cancer [3]. In 1941, a paper demonstrated that a marker of metastatic prostate cancer decreased after castration or estrogen treatment [4]. The latter would’ve severely inhibited endogenous testosterone production, resulting in levels similar or close to those observed after castration. The same paper showed that this marker (prostatic acid phosphatase) increased after daily administration of 25 mg testosterone propionate. Notwithstanding the extremely small sample size (three patients of which only the results of two were shared in the paper’s figures), this paper would be the spark that would dictate a particular train of thought in anabolic steroid research and prostate cancer for many decades to come. A dogma arose which was further fed by troublesome animal experiments and the, otherwise indisputable, role of androgens in the development of the prostate into adulthood.

The dogma would ensure that anyone with prostate cancer, a history of prostate cancer, or at risk of prostate cancer, was denied any prospect of being treated for their testosterone deficiency with testosterone replacement therapy (TRT). Gladly, the tide would turn in 2004 as a result of a publication by the Institute of Medicine [5]. It writes: “In summary, the influence of testosterone on prostate carcinogenesis and other prostate outcomes remains poorly defined, but could greatly influence the risk-benefit ratio for supplementation in both young and elderly populations.”

Since 2004, an increase in new TRT prescriptions can be observed which peaked in 2012-2013 [6]. The decline after 2013 was likely the result of a safety bulletin issued by the Food and Drug Administration (FDA) on January 31, 2014, and subsequently the requirement of the testosterone label to include a possible increased risk of myocardial infarction and stroke on March 3, 2015. Presumably, the publication of the Institute of Medicine was at least partly responsible for the increase observed after 2004. Another milestone paper which might have contributed to a continued increase was one by Morgentaler et al. published in 2009 [7].

The paper was strikingly named “Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth.” It gave a roundhouse kick to the, till then, traditional view of the relationship between testosterone and prostate cancer. The traditional view was pretty straight forward: castration caused regression of prostate cancer and testosterone administration caused more rapid growth. Morgentaler’s saturation model, based on various observations present in the literature, posited that there was a limit to the ability of androgens to stimulate prostate cancer growth. A certain testosterone ceiling concentration was hypothesized above which there was little or no further effect on prostate growth. The underlying mechanism would be a saturation of the androgen receptors in the tissue. At the ceiling concentration these androgen receptors would simply be saturated with androgens, so a further increase would not lead to more androgen receptor activation. Interestingly, the ceiling concentration at which this saturation is thought to take place is low: in the low hypogonadal range.

To date, this hypothesis seems to hold, or at least with short-term TRT [8, 9]. However, due to lack of data, uncertainty remains in the long-term. Hopefully, the TRAVERSE trial—a 5-year double-blinded randomized-controlled trial evaluating the effects of TRT—will provide solid data on this.

Benign prostate growth and anabolic steroid administration

Well, enough about prostate cancer. Part of the reason I discussed that research is that it also carries over to benign growth of the prostate, or “normal” growth of the prostate if you will, as a result of anabolic steroid administration. Perhaps the most interesting question to answer for the audience of this website, is whether or not supraphysiological administration of anabolic steroids increases prostate growth. The short answer is: no, in general, it will not. There’s actually some good research on this, let’s dive in.

A 1995 trial randomized healthy 21 to 39 year-old men to one of three dosages of testosterone cypionate: 100 mg weekly, 250 mg weekly, or 500 mg weekly [10]. They each received 15 injections in total and prostate volume was measured by ultrasound in 5 receiving 100 mg, 6 receiving 250 mg and 9 receiving 500 mg weekly. Prostate volume remained unchanged in all three groups. Moreover, the researchers also measured serum prostate specific antigen (PSA). PSA is a glycoprotein that is produced by the prostate. Notably, its levels can be vastly increased in prostate cancer patients. As such, it’s commonly used to determine the extent of prostate cancer and its response to endocrine treatment. Moreover, it’s also regularly measured for prostate cancer screening purposes. The serum PSA levels correlate well with prostate volume [11, 12], although its correlation is far from perfect. Besides increasing in prostate cancer or benign prostate hyperplasia, PSA can also increase as a result of infection or chronic inflammation [13]. PSA levels also remained unchanged in the three groups receiving testosterone.

Later research from Bhasin’s group demonstrated similar results. Dosages of up to 600 mg testosterone enanthate weekly for 20 weeks had no effect on PSA levels in young men [14] and old men [15]. Another trial from this group also administered dosages up to 600 mg testosterone enanthate weekly for 20 weeks to healthy men aged 18 to 50 years [16]. In addition to PSA levels—which, again, remained unchanged—the researchers also assessed prostate volume. No change in prostate volume could be detected either.

Finally, in the HAARLEM trial, 100 anabolic steroid users were followed over time while they self-administered anabolic steroids [17]. Their mean dosage was 898 mg per week with a median duration of 13 weeks. The users saw their PSA levels increase slightly, but significantly (from 0.71 mcg/L to 0.93 mcg/L), with two subjects having a PSA level above the reference range (>2.0 mcg/L). These results might seem to contradict the earlier research, but this is definitely not necessarily the case. First, the sample size was a lot larger than the other studies which would allow it to detect small changes in PSA which would otherwise go undetected by a lack of statistical power. Second, a lot of the subjects have previous anabolic steroid exposure. As a result, they might recently have experienced a transient period of time in which their testosterone levels were suppressed. This could, potentially, decrease their PSA levels. Subsequently, when they started using anabolic steroids again, this would bounce back to normal.Third, the two people having values above the reference range might be considered expected. Since the reference range covers what would be normal in by far most people, you’ll always find a handful of people which exceed it if you have a large enough sample size. Fourth, previous trials administered only testosterone. The subjects in this trial used a variety of different anabolic steroids which might or might not impact the effect on the prostate slightly differently. Fifth, the previous trials did not last longer than 20 weeks. In the HAARLEM trial, some subjects continued to use anabolic steroids up to a total of 52 weeks. Perhaps a (slight) increase in PSA levels might only become apparent after prolonged usage. It thus might still be possible that anabolic steroid use in high dosages might slightly increase PSA levels even when PSA levels were not ‘recovering’ from a previous state of testosterone deficiency.

Conclusion

The weight of evidence indicates that, at least short-term (20 weeks or less) anabolic steroid use in high dosage has no, or minimal, impact on prostate volume or PSA levels. As it stands, there’s currently no good reason to assume that anabolic steroids, even in high dosages, can cause prostate cancer or benign prostatic hyperplasia [18]. The effect of anabolic steroids on the prostate therefore seems of questionable concern for users. Having said that, evidence of prospective trials that are sufficiently long—and statistically adequately powered— to claim this with high confidence, are lacking.

References

1. Hershberger, L. G., Elva G. Shipley, and Roland K. Meyer. “Myotrophic activity of 19-nortestosterone and other steroids determined by modified levator ani muscle method.” Proceedings of the Society for Experimental Biology and Medicine 83.1 (1953): 175-180.
2. Kim, Juhyun, et al. “The para substituent of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamides is a major structural determinant of in vivo disposition and activity of selective androgen receptor modulators.” Journal of Pharmacology and Experimental Therapeutics 315.1 (2005): 230-239.
3. Morgentaler, Abraham. “Testosterone and prostate cancer: an historical perspective on a modern myth.” European urology 50.5 (2006): 935-939.
4. Ch, Huggins, and C. Hodges. “The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate.” Cancer research (1941).
5. Blazer, Dan G., and Catharyn T. Liverman, eds. “Testosterone and aging: clinical research directions.” (2004).
6. Baillargeon, Jacques, et al. “Testosterone prescribing in the United States, 2002-2016.” Jama 320.2 (2018): 200-202.
7. Morgentaler, Abraham, and Abdulmaged M. Traish. “Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth.” European urology 55.2 (2009): 310-321.
8. Cui, Y., et al. “The effect of testosterone replacement therapy on prostate cancer: a systematic review and meta-analysis.” Prostate cancer and prostatic diseases 17.2 (2014): 132-143.
9. Boyle, Peter, et al. “Endogenous and exogenous testosterone and the risk of prostate cancer and increased prostate-specific antigen (PSA) level: a meta-analysis.” BJU international (2016).
10. Cooper, Christopher S., et al. “Effect of exogenous testosterone on prostate volume, serum and semen prostate specific antigen levels in healthy young men.” The Journal of urology 159.2 (1998): 441-443.
11. Babaian, R. Joseph, Robert B. Evans, and Herbert A. Fritsche. “Prostate‐specific antigen and prostate gland volume: Correlation and clinical application.” Journal of clinical laboratory analysis 4.2 (1990): 135-137.
12. Park, Dong Soo, et al. “Correlation between serum prostate specific antigen level and prostate volume in a community-based cohort: large-scale screening of 35,223 Korean men.” Urology 82.6 (2013): 1394-1399.
13. Jia, Shidong. “Prostate cancer–a biomarker perspective.” Frontiers in endocrinology 3 (2012): 72.
14. Bhasin, Shalender, et al. “Testosterone dose-response relationships in healthy young men.” American Journal of Physiology-Endocrinology And Metabolism (2001).
15. Bhasin, Shalender, et al. “Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle.” The Journal of Clinical Endocrinology & Metabolism 90.2 (2005): 678-688.
16. Bhasin, Shalender, et al. “Effect of testosterone supplementation with and without a dual 5α-reductase inhibitor on fat-free mass in men with suppressed testosterone production: a randomized controlled trial.” Jama 307.9 (2012): 931-939.
17. Smit, Diederik L., et al. “Positive and negative side effects of androgen abuse. The HAARLEM study: A one‐year prospective cohort study in 100 men.” Scandinavian Journal of Medicine & Science in Sports 31.2 (2021): 427-438.
18. Nieschlag, Eberhard, and Elena Vorona. “Medical consequences of doping with anabolic androgenic steroids: effects on reproductive functions.” Eur J Endocrinol 173.2 (2015): 47.

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