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I'm interested in learning how creatine increases DHT levels in the context of 5α-reductase inhibitors (5ARIs).

A study (doi: 10.1016/j.urology.2013.02.045) found that 5ARI-induced DHT deficiency inhibited "autophagy and promoted apoptosis of smooth muscle cells in corpus cavernosum". The article concludes that DHT plays an important role in regulating erectile function. Creatine was shown NOT to increase testosterone levels in the same study that marked a sharp increase in DHT. I don't know if this means creatine produces testosterone which is all subsequently converted or if it facilitates 5ARI's enzymatic activity in some way. The study did not say, and this is what I'm trying to find out. If it's the latter, then in combined use with 5ARIs creatine should lead to less free testosterone (leftover from competitive inhibition) = less estrogen converted as an end result.

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  • $\begingroup$ For putative connection to Lion's mane mushrooms, see e.g. reddit.com/r/Nootropics/comments/d8hdyx/… $\endgroup$
    – Karsten
    Commented Apr 10, 2022 at 3:54
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    $\begingroup$ @KarstenTheis in that same thread "I've posted this on another thread already: The unsaturated fatty acids should be the cause of the 5α-reductase inhibiton of LM (and other mushrooms). Linoleic acid is found in LM and is a 5α-reductase inhibitor. Vitamin B2 (riboflavin) is also found in LM and has 5α-reductase inhibiton effects. Chart about the 5ari effects of different mushrooms. Source" $\endgroup$
    – rhourus
    Commented Apr 10, 2022 at 5:52

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How does creatine increase dihydrotestosterone (DHT) levels?

To my knowledge, It is yet to know. I don't know anyone have clear path to explain this phenomenon. It has been found that three weeks of creatine monohydrate supplementation affects dihydrotestosterone (DHT) to Testosterone (T) ratio in college-aged $(\pu{18.7 \pm 0.53 years})$ rugby players (Ref.1).

Accordingly, these volunteering subjects loaded with creatine ($\pu{25 g}$ creatine plus $\pu{25 g}$ glucose per day) or placebo ($\pu{50 g}$ glucose per day) for 7 days followed by 14 days of maintenance (test subjects: $\pu{5 g}$ creatine plus $\pu{25 g}$ glucose per day or placebo: $\pu{30 g}$ glucose per day). The levels of DHT and T were measured after 7 days and 21 days (after 14 day meaintenance).

After 7 days of creatine loading, or a further 14 days of creatine maintenance dose, serum T levels did not change. However, levels of DHT increased by 56% after 7 days of creatine loading and remained 40% above baseline after 14 days maintenance $(P \lt 0.001)$. The ratio of DHT:T also increased by 36% after 7 days creatine supplementation and remained elevated by 22% after the maintenance dose $(P \lt 0.01)$.

However, these results have not been explained by the authors, and as recent reveiw pointed out that these results have not been replicated either (Ref.2). Further, considering creatine is endogenously formed from reactions involving the amino acids, arginine, glycine, and methionine in the kidneys and liver, and exogenously obtained from meat and/or as a dietary supplement one may come to conclude that it may have studied extensively. However, according to PubMed (archive of biomedical and life sciences journal literature at the U.S. National Institutes of Health’s National Library of Medicine) there are over 500 peer-refereed publications involving various aspects of creatine supplementation as of 2021 (Ref.2). Thus, creatine might not be extensively studied in all the aspects it might have created including elevation of DHT in the presence of $5\alpha$-reductase Inhibitors.

One posibility is creatine may act as $5\alpha$-reductase stimulant (opposit of inhibition) so that it may compete with $5\alpha$-reductase Inhibitor sites. Yet, that won't explain why serum levels of T is not changing but significant increase in levels of DHT as also obereved in rats (Ref.3).

The best explanation would have been creatine may alternate the fate of DHT (which includes several enzymes), increasing its time of existence:

Fate of DHT


References:

  1. Johann van der Merwe, Naomi E. Brooks, Kathryn H. Myburgh, "Three Weeks of Creatine Monohydrate Supplementation Affects Dihydrotestosterone to Testosterone Ratio in College-Aged Rugby Players," Clin. J. Sport Med. 2009, 19(5), 399-404 (DOI: 10.1097/JSM.0b013e3181b8b52f).
  2. Jose Antonio, Darren G. Candow, Scott C. Forbes, Bruno Gualano, Andrew R. Jagim, Richard B. Kreider, Eric S. Rawson, Abbie E. Smith-Ryan, Trisha A. VanDusseldorp, Darryn S. Willoughby, and Tim N. Ziegenfuss, "Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show?," Journal of the International Society of Sports Nutrition 2021, 18(13), 17 pages (DOI: https://doi.org/10.1186/s12970-021-00412-w).
  3. Min-Guan Zhang, Xian-Jin Wang, Zhou-Jun Shen, and Ping-Jin Gao, "Long-term Oral Administration of $5\alpha$-reductase Inhibitor Attenuates Erectile Function by Inhibiting Autophagy and Promoting Apoptosis of Smooth Muscle Cells in Corpus Cavernosum of Aged Rats," Urology 2013, 82(3), 743.e9-743.e15 (DOI: https://doi.org/10.1016/j.urology.2013.02.045).
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