Part 2: The Impact of 6 Key Nutrients on Steroidogenic Pathways

Various foods and nutrients can up- or down-regulate the steroidogenic pathways, resulting in increased or decreased synthesis of steroid hormones (124). This may occur through a variety of mechanisms, including enzymatic induction or inhibition, and positive or negative feedback mechanisms (21)(127). There are six major nutrients, botanicals or exogenous hormones that affect steroidogenic hormone levels in humans, including DHEA, pregnenolone, licorice, saw palmetto, Coleus forskohlii, and zinc. Table 1 lists additional ingredients that may affect the steroidogenic pathways.

DHEA

Exogenous DHEA has been used to improve symptoms of aging, physical and psychological well-being, strength and body composition, and sexual function (103). DHEA may induce or inhibit enzymes involved in regulating the steroidogenic pathways. Specifically, DHEA may induce 17,20 lyase and 5ɑ reductase, while it may also inhibit CYP21, CYP11β1 (117), 3βHSD, and 17βHSD (19). Administration of oral DHEA increases serum DHEA (79)(143)(22)(51), DHEA-S ((22)(45)(48)(51)(55)(70)(85)(130)(143), testosterone (22)(45)(55)(70)(85)(143) androstenedione (18)(22), estradiol (45)(51)(55)(85), estrone (45)(55), and insulin like growth factor-1 (IGF-1)(45). A study with postmenopausal women showed that supplementation over one year with 25 mg of DHEA increases progesterone, DHT, 17-hydroxyprogesterone, allopregnanolone, beta-endorphin, sexual hormone-binding globulin, LH, FSH, growth hormone, and IGF-1 without affecting endometrial thickness (34). Evidence of the effect of DHEA on cortisol levels is conflicting as cortisol may either increase (34)(90), or decrease (35)(117) as a result of DHEA intake. Overall, research supports the use of DHEA to improve cognitive and physical function in older women (55)(143), and in treating hypoadrenalism (69), infertility (11)(97)(109)(137), sexual dysfunction (93), depression (94) and atherosclerosis (73).   

Pregnenolone

Pregnenolone is a precursor to steroid hormones (135). Administration of pregnenolone or its derivatives may result in the inhibition of CYP11A1, STAR (68), 17-hydroxylase, 17,20 lyase (9)(108), and 5ɑ-reductase (9). Pregnenolone administration has led to increased levels of pregnenolone, allopregnanolone, pregnenolone sulfate, DHEAS and progesterone (74). There is evidence that it may also induce CYP3A4 (76).

Pregnenolone is also considered a neurosteroid that increases neuronal activity and may play a major role in neurological conditions (135). In addition to pregnenolone, other steroids including DHEA, progesterone, and their derivatives can act as neurosteroids and are synthesized by steroidogenic enzymes in the brain. They may regulate gene expression through nuclear receptor binding, modulate neurotransmitter release, and regulate GABA, NMDA and sigma-1 receptor activities (138). Pregnenolone, in particular, may improve attention deficits and executive function (62), as well as working memory (100) and functional capacity (75), in patients with schizophrenia. Additionally, it may be used to treat depressive symptoms in bipolar disorder (17), and improve scores for irritability, lethargy/social withdrawal, and short sensory profile in patients with autism (32). Evidence exists for its use in treating manic and depressive symptoms in substance-use disorders (86).

Licorice (Glycyrrhiza glabra)

Licorice has antibacterial, anti-inflammatory, antiviral, antioxidant, and antidiabetic functions (91). Licorice and its flavonoids mainly act as inhibitors of steroidogenic pathway enzymes, specifically 17,20 lyase (23), 3βHSD, 11βHSD (52), 5β (123), and CYP19 (4). Human trials examining the effects of oral licorice supplementation supports its use in alleviating symptoms of menopause including hot flashes (36)(81), increasing muscle mass (60), and reducing total fat, visceral fat, and BMI (71)(125). (6) Licorice administration can decrease testosterone levels (5)(7) and aldosterone (112), but increase deoxycorticosterone, DHEA, and testosterone. (2) Another study showed that DHEAS decreased in men in response to licorice (111). Licorice can increase the urinary cortisol/free cortisone quotient (113). The children of pregnant mothers who had consumed greater than 500 mg per week of glycyrrhizin in licorice during pregnancy has also been linked to higher salivary cortisol concentrations compared with the children of mothers consuming low levels of glycyrrhizin in licorice (less than 250 mg per week) (99). Therefore, high levels of licorice consumption is not recommended during pregnancy due to increased associations with harmful cognitive development in offspring (98). The consumption of licorice may result in side effects of increased blood pressure, possibly as a consequence of an increased cortisone quotient (113).

licorice root in different forms on 4 ceramic white spoons
Licorice and its flavonoids act as inhibitors of certain steroidogenic pathway enzymes.

Forskolin (Coleus forskohlii)

Forskolin, a constituent of Coleus forskohlii, may induce many enzymes of the steroidogenic pathways, including STAR (19), 17-hydroxylase (101), 3βHSD (13), 17βHSD (56), and CYP19 (133). The oral administration of 500 mg (10% extract) per day of forskolin over 12 weeks may weakly increase testosterone levels, but with interindividual variability (37). Forskolin has also been shown to increase cortisol and DHEA secretion, while increasing 3 beta-HSD and P450c17 expression and activity in human adrenocortical cells (13). Forskolin can also induce increases in aldosterone (122). Forskolin may decrease body fat percentage, fat mass and bone mass in conjunction with increased testosterone levels in overweight and obese men (37). It may also mitigate weight gain in women (40) and treat hypertension (46).

Saw Palmetto (Serenoa repens)

Saw palmetto is well known for its inhibition of 5ɑ-reductase(87)(136). This may be of particular importance for reducing the conversion of testosterone to DHT, which is linked to benefits seen in treating benign prostatic hyperplasia (BPH) and lower urinary tract symptoms in a similar manner to the pharmaceutical, finasteride (87). Treatment with saw palmetto has been shown to decrease DHT and epidermal growth factor, and increase testosterone in BPH tissues, suggesting inhibition of 5ɑ-reductase (25). In vitro studies suggest that saw palmetto’s treatment of BPH may be linked to its inhibition of 5ɑ-reductase (88)(134). It has been shown to reduce prostate size and improve urinary flow (104), as well as chronic prostatic inflammation (64). Saw palmetto extract can also increase average and terminal hair count and thus may have potential in treating male pattern baldness with topical (136), or oral administration (102). Evidence also suggests that saw palmetto extract can be used in the treatment of prostatitis (80), sexual dysfunction (121) and polycystic ovarian syndrome (15). Doses of up to 960mg over 18 months have been shown as safe and non-toxic. (8)

Zinc

Zinc has been shown to inhibit 5ɑ-reductase (30)(116)(119) and induce 17-hydroxylase (129) in vitro. In humans, treatment with 10mg of zinc sulfate (43) or 50mg of elemental zinc acetate (72) can lead to increased testosterone, DHT levels, and sperm count (83). Similarly, daily supplementation with 3 mg/kg of body weight of zinc sulfate can prevent decreased testosterone and thyroid hormones associated with exercise in sedentary (58) and athletic men (59). In male patients with end-stage renal disease on hemodialysis, 250mg per day of supplemental zinc sulfate led to an increase in testosterone and luteinizing hormone (47). Higher doses of 50 mg three times per day may lead to nausea, vomiting, gastrointestinal cramping, loss of appetite, diarrhea, headaches, lethargy, anemia, and dizziness (96)(105), while chronic ingestion of greater than 100mg per day over ten years has been associated with a higher incidence of prostatic cancer (67).

Table 1. Natural ingredients that affect steroidogenic pathways

The nutrients presented in this table may up-regulate (induce) or down-regulate (inhibit) steroidogenic pathway enzymes, resulting in increased or decreased levels of specific steroid hormones.

  1. Aiyer, H. S., & Gupta, R. C. (2010). Berries and ellagic acid prevent estrogen-induced mammary tumorigenesis by modulating enzymes of estrogen metabolism. Cancer Prevention Research,3(6), 727-737.
  2. Al-Dujailia, E.A.S., Kenyon, C.J., Nicol, M.R., & Mason, J.I. (2011). Liquorice and glycyrrhetinic acid increase DHEA and deoxycorticosterone levels in vivo and in vitro by inhibiting adrenal SULT2A1 activity. Molecular and Cellular Endocrinology, 336(1–2), 102-109
  3. Allkanjari, O., & Vitalone, A. (2015). What do we know about phytotherapy of benign prostatic hyperplasia? Life Sciences,126, 42-56.
  4. Amaral, C., Toloi, M.R.T., Vasconcelos, L.D., Fonseca, M.J.V., Correia-da-Silva, G., & Teixeira, N. (2017). The role of soybean extracts and isoflavones in hormone-dependent breast cancer: aromatase activity and biological effects. Food & Function, 8(9), 3064-3074.
  5. Armanini, D., Bonanni, G., Mattarello, M.J., Fiore, C., Sartorato, P., & Palermo, M. (2003). Licorice consumption and serum testosterone in healthy man. Experimental and Clinical Endocrinology & Diabetes, 111(6), 341-3.
  6. Armanini, D., De Palo, C.B., Mattarello, M.J., Spinella, P., Zaccaria, M., Ermolao, A., … Karbowiak, I. (2003). Effect of licorice on the reduction of body fat mass in healthy subjects. Journal of Endocrinological Investigation, 26(7), 646-50.
  7. Armanini, D., Mattarello, M.J., Fiore, C., Bonanni, G., Scaroni, C., Sartorato, P., & Palermo, M. (2004). Licorice reduces serum testosterone in healthy women. Steroids, 69(11-12), 763-6.
  8. Avins, A.L., Lee, J.Y., Meyers, C.M., & Barry, M.J. (2013). Safety and toxicity of saw palmetto in the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) Trial. The Journal of Urology, 189(4), 1415–1420.
  9. Banday, A.H., Shameem, S.A., Banday, J.A., & Ganaie, B.A. (2018). Synthesis, 17α-hydroxylase-C17,20-lyase inhibitory and 5AR reductase activity of novel pregnenolone derivatives. Anti-Cancer Agents in Medicinal Chemistry, 18(13), 1919-1926.
  10. Bansal, S. S., Kausar, H., Vadhanam, M. V., Ravoori, S., Pan, J., Rai, S. N., & Gupta, R. C. (2014). Curcumin implants, not curcumin diet, inhibit estrogen-induced mammary carcinogenesis in ACI rats. Cancer Prevention Research,7(4), 456-465.
  11. Barad, D., & Gleicher, N. (2006). Effect of dehydroepiandrosterone on oocyte and embryo yields, embryo grade and cell number in IVF. Human Reproduction, 21(11), 2845-9.
  12. Baravalle, R., Ciaramella, A., Baj, F., Nardo, G. D., & Gilardi, G. (2018). Identification of endocrine disrupting chemicals acting on human aromatase. Biochimica Et Biophysica Acta (BBA) – Proteins and Proteomics,1866(1), 88-96.
  13. Bird, I.M., Imaishi, K., Pasquarette, M.M., Rainey, W.E., & Mason, J.I. (1996). Regulation of 3 beta-hydroxysteroid dehydrogenase expression in human adrenocortical H295R cells. Journal of Endocrinology, 50 Suppl, S165-73.
  14. Bogacz, A., Bartkowiak-Wieczrek, J., Mikołajczak, P., Rakowska-Mrozikiewicz, B., Grześkowiak, E., Wolski, H., . . . Mrozikiewicz, P. (2014). The influence of soybean extract on the expression level of selected drug transporters, transcription factors and cytochrome P450 genes encoding phase I drug-metabolizing enzymes. Polish Gynaecology,85(5).
  15. Bongaard, B.S. (2015). Polycystic ovary syndrome. In V. Maizes, & T. Low Dog (Eds,). Integrative women’s health (289-302). Retrieved from https://books.google.ca/books?hl=en&lr=&id=uveJCgAAQBAJ&oi=fnd&pg=PA289&dq=saw+palmetto+polycystic+ovarian+syndrome&ots=V1VCXdvEiE&sig=S7hDKlx8MXhAvMrHj85d4Bt6whE#v=onepage&q=saw%20palmetto%20polycystic%20ovarian%20syndrome&f=false
  16. Brooks, J. D., & Thompson, L. U. (2005). Mammalian lignans and genistein decrease the activities of aromatase and 17β-hydroxysteroid dehydrogenase in MCF-7 cells. The Journal of Steroid Biochemistry and Molecular Biology,94(5), 461-467.
  17. Brown, E.S., Park, J., Marx, C.E., Hynan, L.S., Gardner, C., Davila, D., … Holmes, T. (2014). A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. Neuropsychopharmacology, 39(12), 2867-73.
  18. Brown, G.A., Vukovich, M.D., Sharp, R.L., Reifenrath, T.A., Parsons, K.A., & King, D.S. (1985). Effect of oral DHEA on serum testosterone and adaptations to resistance training in young men. The Journal of Applied Physiology, 87(6), 2274-83.
  19. Chen, W., Tsai, S.J., Sheu, H.M., Tsai, J.C., & Zouboulis, C.C. (2010). Testosterone synthesized in cultured human SZ95 sebocytes derives mainly from dehydroepiandrosterone. Experimental Dermatology, 19(5), 470-2.
  20. Cutolo, M., Paolino, S., Sulli, A., Smith, V., Pizzorni, C., & Seriolo, B. (2014). Vitamin D, steroid hormones, and autoimmunity. Annals of the New York Academy of Sciences,1317(1), 39-46.
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  22. Dayal, M., Sammel, M.D., Zhao, J., Hummel, A.C., Vandenbourne, K., & Barnhart, K.T. (2005). Supplementation with DHEA: effect on muscle size, strength, quality of life, and lipids. Journal of Women’s Health, 14(5), 391-400.
  23. Deluca, D., Krazeisen, A., Breitling, R., Prehn, C., Moller, G., & Adamski, J. (2005). Inhibition of 17beta-hydroxysteroid dehydrogenases by phytoestrogens: Comparison with other steroid metabolizing enzymes. Journal of Steroid Biochemistry & Molecular Biology, 93(2005), 285–292.
  24. Dikshit, A., Hales, K., & Hales, D. B. (2017). Whole flaxseed diet alters estrogen metabolism to promote 2-methoxtestradiol-induced apoptosis in hen ovarian cancer. The Journal of Nutritional Biochemistry,42, 117-125.
  25. Di Silverio, F., Monti, S., Sciarra, A., Varasano, P.A., Martini, C., Lanzara, S., & … Toscano, V. (1998). Effects of long-term treatment with Serenoa repens (Permixon) on the concentrations and regional distribution of androgens and epidermal growth factor in benign prostatic hyperplasia. Prostate, 37(2), 77-83.
  26. Drewett, J. G., Adams-Hays, R. L., Ho, B. Y., & Hegge, D. J. (2002). Nitric oxide potently inhibits the rate-limiting enzymatic step in steroidogenesis. Molecular and Cellular Endocrinology,194(1-2), 39-50.
  27. Ducrey, B., Marston, A., Göhring, S., Hartmann, R., & Hostettmann, K. (1997). Inhibition of 5α-reductase and aromatase by the ellagitannins oenothein A and oenothein B from Epilobium species. Planta Medica,63(2), 111-114.
  28. Enyeart, J. A., Liu, H., & Enyeart, J. J. (2009). Curcumin inhibits ACTH- and angiotensin II-stimulated cortisol secretion and Cav3.2 current. Journal of Natural Products,72(8), 1533-1537.
  29. Evans, B. A., Griffiths, K., & Morton, M. S. (1995). Inhibition of 5α-reductase in genital skin fibroblasts and prostate tissue by dietary lignans and isoflavonoids. Journal of Endocrinology,147(2), 295-302.
  30. Fahim, M.S., Wang, M., Sutcu, M.F., & Fahim, Z. (1993). Zinc arginine, a 5 alpha-reductase inhibitor, reduces rat ventral prostate weight and DNA without affecting testicular function. Andrologia, 25(6), 369-75.
  31. Fukuda, K., Ohta, T., Oshima, Y., Ohashi, N., Yoshikawa, M., & Yamazoe, Y. (1997). Specific CYP3 A4 inhibitors in grapefruit juice: Furocoumarin dimers as components of drug interaction. Pharmacogenetics,7(5), 391-396.
  32. Fung, L.K., Libove, R.A., Phillips, J., Haddad, F., & Hardan, A.Y. (2014). Brief report: An open-label study of the neurosteroid pregnenolone in adults with autism spectrum disorder. Journal of Autism and Developmental Disorders, 44(11), 2971–2977.
  33. Gansser, D., & Spiteller, G. (1995). Aromatase inhibitors from Urtica dioica roots. Planta Medica,61(2), 138-140.
  34. Genazzani, A.D., Stomati, M., Bernardi, F., Pieri, M., Rovati, L., & Genazzani, A.R. (2003). Long-term low-dose dehydroepiandrosterone oral supplementation in early and late postmenopausal women modulates endocrine parameters and synthesis of neuroactive steroids. Fertility and Sterility, 80(6), 1495-501.
  35. Genazzani, A.R., Pluchino, N., Begliuomini, S., Stomati, M., Bernardi, F., Pieri, M., … Luisi, M. (2006). Long-term low-dose oral administration of dehydroepiandrosterone modulates adrenal response to adrenocorticotropic hormone in early and late postmenopausal women. Gynecological Endocrinology, 22(11), 627-35.
  36. Ghazanfarpour, M., Sadeghi, R., Abdolahian, S., & Latifnejad Roudsari, R. (2016). The efficacy of Iranian herbal medicines in alleviating hot flashes: A systematic review. International Journal of Reproductive BioMedicine, 14(3), 155–166.
  37. Godard, M.P., Johnson, B.A., & Richmond, S.R. (2005). Body composition and hormonal adaptations associated with forskolin consumption in overweight and obese men. Obesity Research, 13(8), 1335-43.
  38. Goodin, M., Bray, B., & Rosengren, R. (2006). Sex- and strain-dependent effects of epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) in the mouse. Food and Chemical Toxicology,44(9), 1496-1504.
  39. Gumy, C., Thurnbichler, C., Aubry, E. M., Balazs, Z., Pfisterer, P., Baumgartner, L., . . . Rollinger, J. M. (2009). Inhibition of 11β-hydroxysteroid dehydrogenase type 1 by plant extracts used as traditional antidiabetic medicines. Fitoterapia,80(3), 200-205.
  40. Henderson, S., Magu, B., Rasmussen, C., Lancaster, S., Kerksick, C., Smith, P., … Kreider, R.B. (2005). Effects of coleus forskohlii supplementation on body composition and hematological profiles in mildly overweight women. Journal of the International Society of Sports Nutrition, 2, 54-62.
  41. Hiipakka, R. A., Zhang, H., Dai, W., Dai, Q., & Liao, S. (2002). Structure–activity relationships for inhibition of human 5α-reductases by polyphenols. Biochemical Pharmacology, 63(6), 1165-1176.
  42. Horn, T. L., Reichert, M. A., Bliss, R. L., & Malejka-Giganti, D. (2002). Modulations of P450 mRNA in liver and mammary gland and P450 activities and metabolism of estrogen in liver by treatment of rats with indole-3-carbinol. Biochemical Pharmacology,64(3), 393-404.
  43. Hunt, C.D., Johnson, P.E., Herbel, J., & Mullen, L.K. (1992). Effects of dietary zinc depletion on seminal volume and zinc loss, serum testosterone concentrations, and sperm morphology in young men. American Journal of Clinical Nutrition, 56(1), 148-57.
  44. Iehlé, C., Délos, S., Guirou, O., Tate, R., Raynaud, J., & Martin, P. (1995). Human prostatic steroid 5α-reductase isoforms—A comparative study of selective inhibitors. The Journal of Steroid Biochemistry and Molecular Biology,54(5-6), 273-279.
  45. Igwebuike, A., Irving, B.A., Bigelow, M.L., Short, K.R., McConnell, J.P., & Nair, K.S. (2008). Lack of dehydroepiandrosterone effect on a combined endurance and resistance exercise program in postmenopausal women. The Journal of Clinical Endocrinology and Metabolism, 93(2), 534-8.
  46. Jagtap, M., Chandola, H.M., & Ravishankar, B. (2011). Clinical efficacy of Coleus forskohlii (Willd.) Briq. (Makandi) in hypertension of geriatric population. Ayu, 32(1), 59-65.
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  48. Jedrzejuk, D., Medras, M., Milewicz, A., & Demissie, M. (2003). Dehydroepiandrosterone replacement in healthy men with age-related decline of DHEA-S: effects on fat distribution, insulin sensitivity and lipid metabolism. Aging Male, 6(3), 151-6.
  49. Jonas, A., Rosenblat, G., Krapf, D., Bitterman, W., & Neeman, I. (1998). Cactus flower extracts may prove beneficial in benign prostatic hyperplasia due to inhibition of 5α reductase activity, aromatase activity and lipid peroxidation. Urological Research,26(4), 265-270.
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