Progesterone influence on prostate diseases and prospects in preventing and treating benign prostatic hyperplasia

The prevalence of prostate diseases primarily benign prostatic hyperplasia (BPH) and prostate cancer (PC) has been progressively increasing with age being related to dramatic change in hormonal balance. Researchers and clinicians adhere to traditional understanding in developing BPH pathogenesis underlying no prominent achievements in the disease prevention and treatment. The ongoing search for gaining insights into the mechanisms behind development of these pathologies lies beyond assessing progesterone as one of the key hormones that plays an crucial role in the prostate gland functioning that has not been studied in this regard for many years. Until now, it is believed that progesterone is an exclusively "female hormone", despite that the first line therapy for BPH relies on using drugs lowering activity of enzyme 5α-reductase involved in testosterone-to-dihydrotestosterone transformation, wherein progesterone serves this function in male body under normal in vivo settings. In fact, such drugs are presented by chemical analogues of progesterone bearing minor changes in its molecule structure. In other words, to correct the pathophysiological aspects, it is necessary to proceed from the physiological basics. Presuming this, international research data available on the pathogenesis of BPH and PC as well as the effectiveness for various approaches to pathognomonic therapeutic approaches to prevent them have been analyzed.

1. Cannarella R., Condorelli R.A., Barbagallo F. et al. Endocrinology of the aging prostate: current concepts. Front Endocrinol (Laussane). 2021;12:554078. https://doi.org/10.3389/fendo.2021.554078.

2. Vuichoud C., Loughlin K.R. Benign prostatic hyperplasia: epidemiology, economics and evaluation. Can J Urol. 2015;22(Suppl 1):1–6.

3. Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30. https://doi.org/10.3322/caac.21332.

4. De Santis C.E., Siegel R.L., Sauer A.G. et al. Cancer statistics for African Americans, 2016: progress and opportunities in reducing racial disparities. CA Cancer J Clin. 2016;66(4):290–308. https://doi.org/10.3322/caac.21340.

5. Rohrmann S., Nelson W.G., Rifai N. et al. Serum estrogen, but not testosterone, levels differ between black and white men in a nationally representative sample of Americans. J Clin Endocrinol Metab. 2007;92(7):2519–25. https://doi.org/10.1210/jc.2007-0028.

6. Williams V.L., Awasthi S., Fink A.K. et al. African-American men and prostate cancer-specific mortality: a competing risk analysis of a large institutional cohort, 1989-2015. Cancer Med. 2018;7(5):2160–71. https://doi.org/10.1002/cam4.1451.

7. Kaprin A.D., Alekseev B.Ia., Matveev V.B. et al. Prostate cancer. [Rak predstatel'noj zhelezy. Klinicheskie rekomendacii]. Sovremennaya onkologiya. 2021;23(2):211–47. (In Russ.). https://doi.org/10.26442/18151434.2021.2.200959.

8. Rider J.R., Wilson K.W., Sinnott J.A. et al. Ejaculation frequency and risk of prostate cancer: updated results with an additional decade of follow-up. Eur Urol. 2016;70(6):974–82. https://doi.org/10.1016/j.eururo.2016.03.027.

9. Pernar C.H., Ebot E.M., Wilson K.M., Mucci L.A. The epidemiology of prostate cancer. Cold Spring Harb Perspect Med. 2018;8(12):a030361. https://doi.org/10.1101/cshperspect.a030361.

10. Dedov I.I., Melnichenko G.A., Fadeev V.F. Guide to endocrinology. [Rukovodstvo po endokrinologii]. Moscow: GEOTAR-Media, 2007. 432 p. (In Russ.).

11. Zilber A.P. Sleep apnea syndromes: clinical physiology, treatment, prevention. [Sindromy sonnogo apnoe: klinicheskaya fiziologiya, lechenie, profilaktika]. Petrozavodsk: Izd-vo Petrozavodskogo universiteta, 1994. 184 р. (In Russ.).

12. Al-Shboul O.A., Mustafa A.G., Omar A.A. et al. Effect of progesterone on nitric oxide/cyclic guanosine monophosphate signaling and contraction in gastric smooth muscle cells. Biomed Rep. 2018;9(6):511–6. https://doi.org/10.3892/br.2019.1251.

13. Alqudah M., Al-Shboul O., Al Dwairi A. et al. Progesterone inhibitory role on gastrointestinal motility. Physiol Res. 2022;71(2):193–8. https://doi.org/10.33549/physiolres.934824.

14. Shackleton C., Malunowicz E. Apparent pregnene hydroxylation deficiency (APDH): seekingthe parentage of an orphan metabolome. Steroids. 2003;68(9):707–17. https://doi.org/10.1016/s0039-128x(03)00115-6.

15. Oettel M., Mukhopadhyay A.K. Progesterone: the forgotten hormone in man. Aging Male. 2004;7(3):236–57. https://doi.org/10.1080/13685530400004199.

16. Fedotcheva T.A. Clinical use of progestins and their mechanisms of action: present and future (review). [Klinicheskoe primenenie progestinov i mekhanizmy ih dejstviya: nastoyashchee i budushchee (obzor)]. Sovremennye tekhnologii v medicine. 2021;13(1):93–108. (In Russ.). https://doi.org/10.17691/stm2021.13.1.11.

17. Graham J.D., Clarcke C.L. Physiological action of progesterone in target tissues. Endocr Rev. 1997;18(4):502–19. https://doi.org/10.1210/edrv.18.4.0308.

18. Kuhl H. Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric. 2005;8 Suppl 1:3–63. https://doi.org/10.1080/13697130500148875.

19. Yakushevskaya O.V. Modern approaches to the appointment of progesterone in the practice of an obstetrician-gynecologist. [Sovremennye podhody k naznacheniyu progesterona v praktike akushera-ginekologa]. Effektivnaya farmakoterapiya. Akusherstvo i ginekologiya. 2012;(4):12–6. (In Russ.).

20. Baranizadeh K., Mahboobian M.M., Amiri I. et al. Effects of progesterone nanoparticles on the sperm capacitation and acrosome reaction in asthenozoospermia men. Andrologia. 2022;54(1):e14258. https://doi.org/10.1111/and.14258.

21. Sutter-Dub M. Rapid non-genomic and genomic responses to progestogens, estrogens, and glucocorticoids in the endocrine pancreatic B cell, the adipocyte and other cell types. Steroids. 2002;67(2):77–93. https://doi.org/10.1016/s0039-128x(01)00142-8.

22. Ghandehari S., Matusov Y., Pepkowitz S. et al. Progesterone in addition to standard of care vs standard of care alone in the treatment of men hospitalized with moderate to severe COVID-19: a randomized, controlled pilot trial. Chest. 2021;160(1):74–84. https://doi.org/10.1016/j.chest.2021.02.024.

23. Beltrame A., Salguero P., Rossi E. et al. Immunometabolic mechanisms underlying the severity of COVID-19. Viral Immunol. 2022;13:1–10. https://doi.org/10.3389/fimmu.2022.834851.

24. Mauvais-Jarvis F., Klein S.L., Levin E.R. Estradiol, progesterone, immunomodulation, and COVID-19 outcomes. Endocrinology. 2020;161(9):bqaa127. https://doi.org/10.1210/endocr/bqaa127.

25. Physicians desk reference. Montvale N.J.: Thomson P.D.R., 2006. 60th ed. 3529 p.

26. Garg D., Ng S.S.M., Baig K.M. et al. Progesterone-mediated non-classical signaling. Trends Endocrinol Metab. 2017;28(9):656–68. https://doi.org/10.1016/j.tem.2017.05.006.

27. Wetendorf M., DeMayo F.J. Progesterone receptor signaling in the initiation of pregnancy and preservation of a healthy uterus. Int J Dev Biol. 2014;58(2–4):95–106. https://doi.org/10.1387/ijdb.140069mw.

28. Valadez-Cosmes P., Vázquez-Martínez E.R., Cerbon M., Camacho-Arroyo I. Membrane progesterone receptors in reproduction and cancer. Mol Cell Endocrinol. 2016;434:166–75. https://doi.org/10.1016/j.mce.2016.06.027.

29. Kolatorova L., Vitku J., Suchopar J. et al. Progesterone: a steroid with wide range of effects in physiology as well as human medicine. Int J Mol Sci. 2022;23(14):7989. https://doi.org/10.3390/ijms23147989.

30. Haseroth K., Christ M., Falkenstein E., Wehling M. Aldosterone- and progesterone-membrane-binding proteins: new concepts of nongenomic steroid action. Curr Protein Pept Sci. 2000;1(4):385–401. https://doi.org/10.2174/1389203003381270.

31. Falkenstein E., Heck M., Gerdes D. et al. Specific progesterone binding to a membrane protein and related nongenomic effects on Ca2+-fluxes in sperm. Endocrinology. 1999;140(12):5999–6002. https://doi.org/10.1210/endo.140.12.7304.

32. Falkenstein E., Tillmann H.C., Christ M. et al. Multiple actions of steroid hormones-a focus on rapid, nongenomic effects. Pharmacol Rev. 2000;52(4):513–56. https://doi.org/10.1016/S0031-6997(24)01468-6.

33. Simoncini T., Genazzani A.R. Non-genomic actions of sex steroid hormones. Eur J Endocrinol. 2003;148(3):281–92. https://doi.org/10.1530/eje.0.1480281.

34. Conneely O.M., Lydon J.P. Progesterone receptors in reproduction: functional impact of the A and B isoforms. Steroids. 2000;65(10–11):571–7. https://doi.org/10.1016/s0039-128x(00)00115-x.

35. Cassidenti D.L., Paulson R.J., Serafini P. et al. Effects of sex steroids on skin 5 alpha-reductase activity in vitro. Obstet Gynecol. 1991;78(1):103–7.

36. Hou Z., Huang S., Mei Z. et al. Inhibiting 3βHSD1 to eliminate the oncogenic effects of progesterone in prostate cancer. Cell Rep Med. 2022;3(3):100561. https://doi.org/10.1016/j.xcrm.2022.100561.

37. Chen G., Shi J.-X., Qi M. et al. Effects of progesterone on intestinal inflammatory response, mucosa structure alterations, and apoptosis following traumatic brain injury in male rats. J Surg Res. 2008;147(1):92–8. https://doi.org/10.1016/j.jss.2007.05.029.

38. Nalli A.D., Kumar D.P., Mahavadi S. et al. Hypercontractility of intestinal longitudinal smooth muscle induced by cytokines is mediated by the nuclear factor-κB/AMP-activated kinase/myosin light chain kinase pathway. J Pharmacol Exp Therap. 2014;350(1):89–98. https://doi.org/10.1124/jpet.113.212522.

39. Pang Y., Dong J., Thomas P. Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-α. Am J Physiol Endocrinol Metab. 2015;308(10):E899–E911. https://doi.org/10.1152/ajpendo.00527.2014.

40. Andriole G.L., Humphrey P., Ray P. et al. Effect of the dual 5alpha-reductase inhibitor dutasteride on markers of tumor regression in prostate cancer. J Urol. 2004;172(3):915–9. https://doi.org/10.1097/01.ju.0000136430.37245.b9.

41. Clark R.V., Hermann D.J., Cunningham G.R. et al. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor. J Clin Endocrinol Metab. 2004;89(5):2179–84. https://doi.org/10.1210/jc.2003-030330.

42. McConnell J.D., Wilson J.D., George F.W. et al. Finasteride, an inhibitor of 5 alpha-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia. J Clin Endocrinol Metab. 1992;74(3):505–8. https://doi.org/10.1210/jcem.74.3.1371291.

43. Span P.N., Voller M.C., Smals A.G. et al Selectivity of finasteride as an in vivo inhibitor of 5alpha-reductase isozyme enzymatic activity in the human prostate. J Urol. 1999;161(1):332–7.

44. Wu Y., Godoy A., Azzouni F. et al. Prostate cancer cells differ in testosterone accumulation, dihydrotestosterone conversion, and androgen receptor signaling response to steroid 5α-reductase inhibitors. Prostate. 2013;73(13):1470–82. https://doi.org/10.1002/pros.22694.

45. Lazier C.B., Thomas L.N., Douglas R.C. et al. Dutasteride, the dual 5alpha-reductase inhibitor, inhibits androgen action and promotes cell death in the LNCaP prostate cancer cell line. Prostate. 2004;58(2):130–44. https://doi.org/10.1002/pros.10340.

46. Wu Y., Chhipa R.R., Zhang H., Ip C. The antiandrogenic effect of finasteride against a mutant androgen receptor. Cancer Biol Ther. 2011;11(10):902–9. https://doi.org/10.4161/cbt.11.10.15187.