February 18, 2026

Green Health Revolution

Natural Health, Harmonious Life

The testobolome in microbial testosterone metabolism and human health

The testobolome in microbial testosterone metabolism and human health

  • Plottel, C. S. & Blaser, M. J. Microbiome and malignancy. Cell Host Microbe 10, 324–335 (2011).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Cojocaru, M. Sex steroid hormones and gut microbiome. J. Clin. Sexol. 2, 73–79 (2019).

    Google Scholar 

  • Singh, V., Mahra, K., Jung, D. & Ho, J. Gut Microbes in Polycystic Ovary Syndrome and Associated Comorbidities; Type 2 Diabetes, Non ‑ Alcoholic Fatty Liver Disease (NAFLD), Cardiovascular Disease (CVD), and the Potential of Microbial Therapeutics. Probiotics Antimicrob. Proteins 16, 1744–1761 (2024).

    CAS 

    Google Scholar 

  • Álvarez-Mercado, A. I., del Valle Cano, A., Fernández, M. F. & Fontana, L. Gut Microbiota and Breast Cancer: The Dual Role of Microbes. Cancers 15, 443 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kunc, M., Gabrych, A. & Witkowski, J. M. Microbiome impact on metabolism and function of sex, thyroid, growth and parathyroid hormones. Acta Biochim. Pol. 63, 189–201 (2016).

    PubMed 
    CAS 

    Google Scholar 

  • Hiort, O. The differential role of androgens in early human sex development. BMC Med. 11, 152 (2013).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Zubeldia-Brenner, L., Roselli, C. E., Recabarren, S. E., Gonzalez Deniselle, M. C. & Lara, H. E. Developmental and Functional Effects of Steroid Hormones on the Neuroendocrine Axis and Spinal Cord. J. Neuroendocrinol. 28, 1–15 (2016).

    Article 

    Google Scholar 

  • Matsuyama, S. & DeFalco, T. Steroid hormone signaling: multifaceted support of testicular function. Front. Cell Dev. Biol. 11, 1–11 (2023).

    Google Scholar 

  • De Loof, A. Ecdysteroids: The overlooked sex steroids of insects? Males: The black box. Insect Sci. 13, 325–338 (2006).

    Article 

    Google Scholar 

  • Tarkowská, D. Plants are capable of synthesizing animal steroid hormones. Molecules 24, 1–13 (2019).

    Article 

    Google Scholar 

  • Hemsell, D. L., Grodin, J. M., Brenner, P. F., Siiteri, P. K. & Macdonald, P. C. Plasma precursors of estrogen. II. Correlation of the extent of conversion of plasma androstenedione to estrone with age. J. Clin. Endocrinol. Metab. 38, 476–479 (1974).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Bracht, J. R. et al. The role of estrogens in the adipose tissue milieu. Ann. N. Y. Acad. Sci. 1461, 127–143 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Gruber, C. J., Tschugguel, W., Schneeberger, C. & Huber, J. C. Production and Actions of Estrogens. N. Engl. J. Med. 346, 340–352 (2002).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Simpson, E. R. Sources of estrogen and their importance. J. Steroid Biochem. Mol. Biol. 86, 225–230 (2003).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Millar, A. C. et al. Predicting low testosterone in aging men: A systematic review. Cmaj 188, E321–E330 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Acevedo-Rodriguez, A. et al. Emerging insights into hypothalamic-pituitary-gonadal axis regulation and interaction with stress signalling. J. Neuroendocrinol. 30, 0–3 (2018).

    Article 
    CAS 

    Google Scholar 

  • Wildt, L. et al. Frequency and Amplitude of Gonadotropin-Releasing Rhesus Monkey. Endocrinology 109, 376–385 (1981).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Magoffin, D. A. Ovarian theca cell. Int. J. Biochem. Cell Biol. 37, 1344–1349 (2005).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Shaw, N. D. et al. Estrogen negative feedback on gonadotropin secretion: Evidence for a direct pituitary effect in women. J. Clin. Endocrinol. Metab. 95, 1955–1961 (2010).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Wen, Q., Cheng, C. Y. & Liu, Y. X. Development, function and fate of fetal Leydig cells. Semin. Cell Dev. Biol. 59, 89–98 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Ramaswamy, S. & Weinbauer, G. F. Endocrine control of spermatogenesis: Role of FSH and LH / testosterone. Spermatogenesis 4, e996025 (2014).

    Article 
    PubMed 

    Google Scholar 

  • Plant, T. M. & Marshall, G. R. The Functional Significance of FSH in Spermatogenesis and the Control of Its Secretion in Male Primates. Endocr. Res. 22, 764–786 (2015).

    Article 

    Google Scholar 

  • Ramaswamy, S., Marshall, G. R., Mcneilly, A. S. & Plant, T. M. Dynamics of the Follicle-Stimulating Hormone (FSH)-inhibin B feedback loop and its role in regulating spermatogenesis in the adult male rhesus monkey (Macaca mulatta) as revealed by unilateral orchidectomy. Endocrinology 141, 18–27 (2000).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • McNeilly, A. S., Crawford, J. L., Taragnat, C., Nicol, L. & McNeilly, J. R. The differential secretion of FSH and LH: regulation through genes, feedback and packaging. Reprod. Suppl. 61, 463–476 (2003).

    PubMed 
    CAS 

    Google Scholar 

  • Barakat, R., Oakley, O., Kim, H., Jin, J. & Ko, C. M. J. Extra-gonadal sites of estrogen biosynthesis and function. BMB Rep. 49, 488–496 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Organski, A. C., Jorgensen, J. S. & Cross, T. W. L. Involving the life inside: The complex interplay between reproductive axis hormones and gut microbiota. Curr. Opin. Endocr. Metab. Res. 20, 100284 (2021).

    Article 
    CAS 

    Google Scholar 

  • Emmerson, E. & Hardman, M. J. The role of estrogen deficiency in skin ageing and wound healing. Biogerontology 13, 3–20 (2012).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Johannsen, T. H. et al. Sex Differences in Reproductive Hormones During Mini-Puberty in Infants With Normal and Disordered Sex Development. J. Clin. Endocrinol. Metab. 103, 3028–3037 (2018).

    Article 
    PubMed 

    Google Scholar 

  • Kuiri-Hänninen, T., Sankilampi, U. & Dunkel, L. Activation of the Hypothalamic- Pituitary-Gonadal Axis in Infancy: Minipuberty. Horm. Res. Paediatr. 82, 73–80 (2014).

    Article 
    PubMed 

    Google Scholar 

  • Cappola, A. R. et al. Hormones and Aging: An Endocrine Society Scientific Statement. J. Clin. Endocrinol. Metab. 108, 1835–1874 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Ibanez, L., Dimartino-Nardi, J., Potau, N. & Saenger, P. Premature Adrenarche — Normal Variant or Forerunner of Adult Disease?. Endocr. Rev. 21, 671–696 (2000).

    PubMed 
    CAS 

    Google Scholar 

  • Hammond, G. L. Diverse roles for sex hormone-binding globulin in reproduction. Biol. Reprod. 85, 431–441 (2011).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Burke, C. W. & Anderson, D. C. Sex-hormone-binding globulin is an oestrogen amplifier. Nature 240, 38–40 (1972).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Baker, M. E. Albumin, steroid hormones and the origin of vertebrates. J. Endocrinol. 175, 121–127 (2002).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Kolátorová, L., Lapčík, O. & Stárka, L. Phytoestrogens and the Intestinal Microbiome. Physiol. Res. 67, S401–S408 (2018).

    Article 
    PubMed 

    Google Scholar 

  • Södergard, R., Bäckström, T., Shanbhag, V. & Carstensen, H. Calculation of free and bound fractions of testosterone and estradiol-17β to human plasma proteins at body temperature. J. Steroid Biochem. 16, 801–810 (1982).

    Article 
    PubMed 

    Google Scholar 

  • Rosner, W. Free estradiol and sex hormone-binding globulin. Steroids 99, 113–116 (2015).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Narinx, N. et al. Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology. Cell. Mol. Life Sci. 79, 1–30 (2022).

    Article 

    Google Scholar 

  • Vermeulen, A. Andropause. Maturitas 34, 5–15 (2000).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Salomonsson, M., Carlsson, B. & Häggblad, J. Equilibrium hormone binding to human estrogen receptors in highly diluted cell extracts is non-cooperative and has a Kd of approximately 10 pM. J. Steroid Biochem. Mol. Biol. 50, 313–318 (1994).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Hammond, G. L. Plasma steroid-binding proteins: Primary gatekeepers of steroid hormone action. J. Endocrinol. 230, R13–R25 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Zhang, D. & Trudeau, V. L. Integration of membrane and nuclear estrogen receptor signaling. Comp. Biochem. Physiol. – A Mol. Integr. Physiol. 144, 306–315 (2006).

    Article 
    PubMed 

    Google Scholar 

  • Davey, R. A. & Grossmann, M. Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clin. Biochem. Rev. 37, 3–15 (2016).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Thomas, P. Membrane androgen receptors unrelated to nuclear steroid receptors. Endocrinology 160, 772–781 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Owen, G. I. & Zelent, A. Origins and evolutionary diversification of the nuclear receptor superfamily. Cell. Mol. Life Sci. 57, 809–827 (2000).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Schiffer, L. et al. Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review. J. Steroid Biochem. Mol. Biol. 194, 105439 (2019).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Raftogianis, R., Creveling, C., Weinshilboum, R. & Weisz, J. Estrogen metabolism by conjugation. J. Natl Cancer Inst. Monogr. 27, 113–124 (2000).

    Article 
    CAS 

    Google Scholar 

  • Chouinard, S. et al. Inactivation by UDP-glucuronosyltransferase enzymes: The end of androgen signaling. J. Steroid Biochem. Mol. Biol. 109, 247–253 (2008).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Sten, T. et al. UDP-glucuronosyltransferases (UGTs) 2B7 and UGT2B17 display converse specificity in testosterone and epitestosterone glucuronidation, whereas UGT2A1 conjugates both androgens similarly. Drug Metab. Dispos. 37, 417–423 (2009).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Musey, P. I., Wright, K., Preedy, J. R. K. & Collins, D. C. Formation and metabolism of steroid conjugates: Effect of conjugation on excretion and tissue distribution. Steroid Biochem. 3, 81–131 (1979).

    Google Scholar 

  • Yang, G. et al. Glucuronidation: Driving Factors and Their Impact on Glucuronide Disposition. Drug Metab. Rev. 49, 105–138 (2020).

    Article 

    Google Scholar 

  • Liu, Z., Kanjo, Y. & Mizutani, S. Urinary excretion rates of natural estrogens and androgens from humans, and their occurrence and fate in the environment: A review. Sci. Total Environ. 407, 4975–4985 (2009).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Muir, C., Spironello-Vella, E., Pisani, N. & DeCatanzaro, D. Enzyme immunoassay of 17β-estradiol, estrone conjugates, and testosterone in urinary and fecal samples from male and female mice. Horm. Metab. Res. 33, 653–658 (2001).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Schulze, J. J. & Ekström, L. Editorial: Variation in phase II metabolism of sex steroids – Causes and consequences. Front. Endocrinol. (Lausanne). 6, 2014–2015 (2015).

    Article 

    Google Scholar 

  • Jakobsson, J. et al. Large differences in testosterone excretion in Korean and Swedish men are strongly associated with a UDP-glucuronosyl transferase 2B17 polymorphism. J. Clin. Endocrinol. Metab. 91, 687–693 (2006).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Diviccaro, S. et al. Exploring the impact of the microbiome on neuroactive steroid levels in germ-free animals. Int. J. Mol. Sci. 22, 12551 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Al-Asmakh, M. et al. The gut microbiota and developmental programming of the testis in mice. PLoS One 9, e103809 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Simpson, J. B. et al. Gut microbial β-glucuronidases influence endobiotic homeostasis and are modulated by diverse therapeutics. Cell Host Microbe 32, 925–944.e10 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Hou, L. et al. Ciprofloxacin disrupts testosterone synthesis in mice via downregulating StAR expression through NR4A1 pathway. Ecotoxicol. Environ. Saf. 302, 118511 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Hou, X. et al. Testosterone disruptor effect and gut microbiome perturbation in mice: Early life exposure to doxycycline. Chemosphere 222, 722–731 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Blaser, M. J. & Dominguez-Bello, M. G. The Invisible Extinction. Annu. Rev. Microbiol. 79, 1–15 (2025).

    Article 

    Google Scholar 

  • Tang, L. et al. Inhibition of inosine metabolism of the gut microbiota decreases testosterone secretion in the testis. mSystems 9, 1–15 (2024).

    Article 

    Google Scholar 

  • Pollet, R. M. et al. An Atlas of β-Glucuronidases in the Human Intestinal Microbiome. Structure 25, 967–977.e5 (2017).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Creekmore, B. C. et al. Mouse Gut Microbiome-Encoded β-Glucuronidases Identified Using Metagenome Analysis Guided by Protein Structure. mSystems 4, e00452–19 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cole, C. B., Fuller, R., Mallet, A. K. & Rowland, I. R. The influence of the host on expression of intestinal microbial enzyme activities involved in metabolism of foreign compounds. J. Appl. Bacteriol. 59, 549–553 (1985).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Dabek, M., McCrae, S. I., Stevens, V. J., Duncan, S. H. & Louis, P. Distribution of β-glucosidase and β-glucuronidase activity and of β-glucuronidase gene gus in human colonic bacteria. FEMS Microbiol. Ecol. 66, 487–495 (2008).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Colldén, H. et al. The gut microbiota is a major regulator of androgen metabolism in intestinal contents. Am. J. Physiol. – Endocrinol. Metab. 317, E1182–E1192 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Asano, Y. et al. Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice. Am. J. Physiol. – Gastrointest. Liver Physiol. 303, 1288–1295 (2012).

    Article 

    Google Scholar 

  • Flores, R. et al. Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: A cross-sectional study. J. Transl. Med. 10, 1–11 (2012).

    Article 

    Google Scholar 

  • Basit, A. et al. Relevance of Human Aldoketoreductases and Microbial b-Glucuronidases in Testosterone Disposition. Drug Metab. Dispos. 51, 427–435 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Wang, Z. et al. Common and unique testosterone and 17 beta-estradiol degradation mechanisms in Comamonas testosteroni JLU460ET by transcriptome analysis. Front. Microbiol. 14, 1–14 (2023).

    Google Scholar 

  • Schulze, J. J. et al. Androgen sulfation in healthy UDP-glucuronosyl transferase 2B17 enzyme-deficient men. J. Clin. Endocrinol. Metab. 96, 3440–3447 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Foster, P. A. & Mueller, J. W. Insights into steroid sulfation and desulfation pathways. J. Mol. Endocrinol. 61, T271–T283 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Ervin, S. M. et al. Structural Insights into Endobiotic Reactivation by Human Gut Microbiome-Encoded Sulfatases. Biochemistry 59, 3939–3950 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Arp, G. et al. Identification of gut bacteria reductases that biotransform steroid hormones. Nat. Commun. 16, 1–14 (2025).

    Article 

    Google Scholar 

  • Doden, H. L. & Ridlon, J. M. Microbial hydroxysteroid dehydrogenases: From alpha to omega. Microorganisms 9, 1–24 (2021).

    Article 

    Google Scholar 

  • Simard, J. et al. Molecular biology of the 3β-hydroxysteroid dehydrogenase/ Δ5-Δ4 isomerase gene family. Endocr. Rev. 26, 525–582 (2005).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Kuiper, G. G. J. M. et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology 139, 4252–4263 (1998).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Huang, S. et al. Pharmacological Activation of Estrogen Receptor Beta Overcomes Tumor Resistance to Immune Checkpoint Blockade Therapy. iScience 23, 101458 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Wang, T. et al. An expanded metabolic pathway for androgen production by commensal bacteria. Nat. Microbiol. 10, 1084–1098 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Schiffer, L., Arlt, W. & Storbeck, K. H. 5α-reduction of epitestosterone is catalysed by human SRD5A1 and SRD5A2 and increases androgen receptor transactivation. J. Steroid Biochem. Mol. Biol. 241, 106516 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Zhang, X. et al. Bacterial cytochrome P450-catalyzed regio- and stereoselective steroid hydroxylation enabled by directed evolution and rational design. Bioresour. Bioprocess. 7, 1–18 (2020).

    Article 

    Google Scholar 

  • Chiang, Y. R., Wei, S. T. S., Wang, P. H., Wu, P. H. & Yu, C. P. Microbial degradation of steroid sex hormones: implications for environmental and ecological studies. Microb. Biotechnol. 13, 926–949 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Ridlon, J. M. et al. Clostridium scindens: A human gut microbe with a high potential to convert glucocorticoids into androgens. J. Lipid Res. 54, 2437–2449 (2013).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Tao, J. et al. Role of intestinal testosterone-degrading bacteria and 3/17β-HSD in the pathogenesis of testosterone deficiency-induced hyperlipidemia in males. npj Biofilms Microbiomes 10, 123 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Wang, P.-H. et al. Bacterial estrogenesis without oxygen: Wood–Ljungdahl pathway likely contributed to the emergence of estrogens in the biosphere. Proc. Natl Acad. Sci. 123, e2422930122 (2025).

    Article 

    Google Scholar 

  • Horinouchi, M., Hayashi, T. & Kudo, T. Steroid degradation in Comamonas testosteroni. J. Steroid Biochem. Mol. Biol. 129, 4–14 (2012).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Wang, P. H. et al. Retroconversion of estrogens into androgens by bacteria via a cobalamin-mediated methylation. Proc. Natl Acad. Sci. USA 117, 1395–1403 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Vom Steeg, L. G. & Klein, S. L. Sex Steroids Mediate Bidirectional Interactions Between Hosts and Microbes. Horm. Behav. 88, 45–51 (2017).

    Article 
    PubMed 

    Google Scholar 

  • Shin, J. H. et al. Serum level of sex steroid hormone is associated with diversity and profiles of human gut microbiome. Res. Microbiol. 170, 192–201 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Luo, Z. et al. The role of male hormones in bacterial infections: enhancing Staphylococcus aureus virulence through testosterone-induced Agr activation. Arch. Microbiol. 206, 401 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Plotkin, B. J., Roose, R. J., Erikson, Q. & Viselli, S. M. Effect of Androgens and Glucocorticoids on Microbial Growth and Antimicrobial Susceptibility. Curr. Microbiol. 47, 514–520 (2003).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Schmidt, P. J. et al. Pharmacologically Induced Hypogonadism and Sexual Function in Healthy Young Women and Men. Neuropsychopharmacology 34, 565–576 (2009).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Pencina, K. M. et al. Effect of Testosterone Replacement Therapy on Sexual Function and Hypogonadal Symptoms in Men with Hypogonadism. J. Clin. Endocrinol. Metab. 109, 569–580 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Huijben, M. et al. Clomiphene citrate for male infertility: A systematic review and meta-analysis. Andrology 11, 987–996 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Rosenfield, R. L. & Ehrmann, D. A. The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr. Rev. 37, 467–520 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Goodarzi, M. O. et al. Variants in the 5α-reductase type 1 and type 2 genes are associated with polycystic ovary syndrome and the severity of hirsutism in affected women. J. Clin. Endocrinol. Metab. 91, 4085–4091 (2006).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Iftikhar, U. & Choudhry, N. Serum levels of androgens in acne & their role in acne severity. Pak. J. Med. Sci. 35, 146–150 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Xiang, Y. et al. Hyperandrogenism drives ovarian inflammation and pyroptosis: A possible pathogenesis of PCOS follicular dysplasia. Int. Immunopharmacol. 125, 111141 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Bertoldo, M. J. et al. A hyperandrogenic environment causes intrinsic defects that are detrimental to follicular dynamics in a PCOS mouse model. Endocrinology 160, 699–715 (2019).

    Article 
    PubMed 

    Google Scholar 

  • Patel, J., Chaudhary, H., Rajput, K., Parekh, B. & Joshi, R. Assessment of gut microbial β-glucuronidase and β-glucosidase activity in women with polycystic ovary syndrome. Sci. Rep. 13, 1–8 (2023).

    Article 
    CAS 

    Google Scholar 

  • Bhasin, S. et al. Testosterone dose-response relationships in healthy young men. Am. J. Physiol. – Endocrinol. Metab. 281, 1172–1181 (2001).

    Article 

    Google Scholar 

  • Alexander, S. E. et al. Bioavailable testosterone and androgen receptor activation, but not total testosterone, are associated with muscle mass and strength in females. J. Physiol. 0, 1–28 (2024).

    Google Scholar 

  • Tan, W. S. et al. Efficacy and safety of long-acting intramuscular testosterone undecanoate in aging men: A randomised controlled study. BJU Int. 111, 1130–1140 (2013).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Geniole, S. N. et al. Using a Psychopharmacogenetic Approach To Identify the Pathways Through Which—and the People for Whom—Testosterone Promotes Aggression. Psychol. Sci. 30, 481–494 (2019).

    Article 
    PubMed 

    Google Scholar 

  • Chen, C., Decety, J., Huang, P. C., Chen, C. Y. & Cheng, Y. Testosterone administration in females modulates moral judgment and patterns of brain activation and functional connectivity. Hum. Brain Mapp. 37, 3417–3430 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li, D. et al. Gut microbial 3α-hydroxysteroid dehydrogenase promotes depression in males via degrading testosterone. Interdiscip. Med. 3, 1–12 (2025).

    Google Scholar 

  • Sung, H. et al. Differences in cancer rates among adults born between 1920 and 1990 in the USA: an analysis of population-based cancer registry data. Lancet Public Health 9, e583–e593 (2024).

    Article 
    PubMed 

    Google Scholar 

  • Rosenberg, P. S. & Miranda-Filho, A. Cancer Incidence Trends in Successive Social Generations in the US. JAMA Netw. Open 7, E2415731 (2024).

    Google Scholar 

  • Kehm, R. D., Yang, W., Tehranifar, P. & Terry, M. B. 40 years of change in age- And stage-specific cancer incidence rates in US women and men. JNCI Cancer Spectr. 3, 1–7 (2019).

    Article 

    Google Scholar 

  • Rubinstein, M. M., Brown, K. A. & Iyengar, N. M. Targeting obesity-related dysfunction in hormonally driven cancers. Br. J. Cancer 125, 1–15 (2021).

    Article 

    Google Scholar 

  • Freeman, E. W., Sammel, M. D., Lin, H. & Gracia, C. R. Obesity and reproductive hormone levels in the transition to menopause. Menopause 17, 718–726 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Vecchia, C., Brinton, L. A. & McTiernan, A. Menopause, hormone replacement therapy and cancer. Maturitas 39, 97–115 (2001).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Bonelli, L. Hormone replacement therapy in postmenopausal women and risk of breast cancer. Med. Biol. Environ. 26, 27–34 (1998).

    Google Scholar 

  • Nelson, H. D. et al. Postmenopausal hormone replacement therapy; scientific review. J. Am. Med. Assoc. 288, 872–881 (2002).

    Article 
    CAS 

    Google Scholar 

  • Lacey, J. V. J. et al. Menopausal Hormone Replacement Therapy and Risk of Ovarian Cancer. J. Am. Med. Assoc. 288, 334–341 (2002).

    Article 
    CAS 

    Google Scholar 

  • Lacey, J. V. J. et al. Endometrial carcinoma risks among menopausal estrogen plus progestin and unopposed estrogen users in a cohort of postmenopausal women. Cancer Epidemiol. Biomark. Prev. 14, 1724–1731 (2005).

    Article 
    CAS 

    Google Scholar 

  • Narod, S. A. Hormone replacement therapy and the risk of breast cancer. Nat. Rev. Clin. Oncol. 8, 669–676 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Swerdloff, R. S., Dudley, R. E., Page, S. T., Wang, C. & Salameh, W. A. Dihydrotestosterone: Biochemistry, physiology, and clinical implications of elevated blood levels. Endocr. Rev. 38, 220–254 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Soory, M. Bacterial steroidogenesis by periodontal pathogens and the effect of bacterial enzymes on steroid conversions by human gingival fibroblasts in culture. J. Periodontal Res. 30, 124–131 (1995).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Cabeza, M. S., Gutiérrez, E. B., García, G. A., Avalos, A. H. & Hernández, M. A. H. Microbial transformations of testosterone to 5α-dihydrotestosterone by two species of Penicillium: P. chrysogenum and P. crustosum. Steroids 64, 379–384 (1999).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Cotton, S., Clayton, C. A. & Tropini, C. Microbial endocrinology: the mechanisms by which the microbiota influences host sex steroids. Trends Microbiol. 31, 1131–1142 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Lanišnik Rižner, T., Stojan, J. & Adamski, J. 17β-hydroxysteroid dehydrogenase from the fungus Cochliobolus lunatus: Structural and functional aspects. Chem. Biol. Interact. 130–132, 793–803 (2001).

    Article 
    PubMed 

    Google Scholar 

  • Zhang, F., Aschenbrenner, D., Yoo, J. Y. & Zuo, T. The gut mycobiome in health, disease, and clinical applications in association with the gut bacterial microbiome assembly. Lancet Microbe 3, e969–e983 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Cuzick, J. et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 11, 1135–1141 (2010).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Ali, S., Buluwela, L. & Coombes, R. C. Antiestrogens and their therapeutic applications in breast cancer and other diseases. Annu. Rev. Med. 62, 217–232 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Riggs, B. L. & Hartmann, L. C. Selective Estrogen-Receptor Modulators — Mechanisms of Action and Application to Clinical Practice. N. Engl. J. Med. 348, 618–629 (2003).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Resnick, S. M. et al. Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment. J. Am. Med. Assoc. 317, 717–727 (2017).

    Article 
    CAS 

    Google Scholar 

  • Heldring, N. et al. Estrogen receptors: How do they signal and what are their targets. Physiol. Rev. 87, 905–931 (2007).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Levin, E. R. Plasma Membrane Estrogen Receptors. Trends Endocrinol. Metab. 20, 477–482 (2009).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Pedram, A., Razandi, M. & Levin, E. R. Nature of functional estrogen receptors at the plasma membrane. Mol. Endocrinol. 20, 1996–2009 (2006).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Toran-Allerand, C. D. et al. ER-X: A novel, plasma membrane-associated, putative estrogen receptor that is regulated during development and after ischemic brain injury. J. Neurosci. 22, 8391–8401 (2002).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Soltysik, K. & Czekaj, P. Membrane estrogen receptors – is it an alternative way of estrogen action?. J. Physiol. Pharmacol. 64, 129–142 (2013).

    PubMed 
    CAS 

    Google Scholar 

  • Qiu, J. et al. Rapid Signaling of Estrogen in Hypothalamic Neurons Involves a Novel G-Protein-Coupled Estrogen Receptor that Activates Protein Kinase C. J. Neurosci. 23, 9529–9540 (2003).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Roepke, T. A., Qiu, J., Bosch, M. A., Rønnekleiv, O. K. & Kelly, M. J. Cross-talk between membrane-initiated and nuclear-initiated oestrogen signalling in the hypothalamus. J. Neuroendocrinol. 21, 263–270 (2009).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Roepke, T. A. et al. Contribution of a membrane estrogen receptor to the estrogenic regulation of body temperature and energy homeostasis. Endocrinology 151, 4926–4937 (2010).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Matthews, J., Celius, T., Halgren, R. & Zacharewski, T. Differential estrogen receptor binding of estrogenic substances: A species comparison. J. Steroid Biochem. Mol. Biol. 74, 223–234 (2000).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Grino, P. B., Griffin, J. E. & Wilson, J. D. Testosterone at high concentrations interacts with the human androgen receptor similarly to dihydrotestosterone. Endocrinology 126, 1165–1172 (1990).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Flores, R. et al. Association of fecal microbial diversity and taxonomy with selected enzymatic functions. PLoS One 7, 1–5 (2012).

    Article 

    Google Scholar 

  • Gloux, K. et al. A metagenomic β-glucuronidase uncovers a core adaptive function of the human intestinal microbiome. Proc. Natl Acad. Sci. USA 108, 4539–4546 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Wang, P., Jia, Y., Wu, R., Chen, Z. & Yan, R. Human gut bacterial β-glucuronidase inhibition: An emerging approach to manage medication therapy. Biochem. Pharmacol. 190, 114566 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Leung, J. W. et al. Expression of bacterial β-glucuronidase in human bile: An in vitro study. Gastrointest. Endosc. 54, 346–350 (2001).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Biernat, K. A. et al. Structure, function, and inhibition of drug reactivating human gut microbial β-glucuronidases. Sci. Rep. 9, 1–15 (2019).

    Article 
    CAS 

    Google Scholar 

  • McBain, A. J. & Macfarlane, G. T. Ecological and physiological studies on large intestinal bacteria in relation to production of hydrolytic and reductive enzymes involved in formation of genotoxic metabolites. J. Med. Microbiol. 47, 407–416 (1998).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Little, M. S. et al. Active site flexibility revealed in crystal structures of Parabacteroides merdae β-glucuronidase from the human gut microbiome. Protein Sci. 27, 2010–2022 (2018).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Michikawa, M. et al. Structural and biochemical characterization of glycoside hydrolase family 79 β-glucuronidase from Acidobacterium capsulatum. J. Biol. Chem. 287, 14069–14077 (2012).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • McIntosh, F. M. et al. Phylogenetic distribution of genes encoding β-glucuronidase activity in human colonic bacteria and the impact of diet on faecal glycosidase activities. Environ. Microbiol. 14, 1876–1887 (2012).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Kisiela, M., Skarka, A., Ebert, B. & Maser, E. Hydroxysteroid dehydrogenases (HSDs) in bacteria – A bioinformatic perspective. J. Steroid Biochem. Mol. Biol. 129, 31–46 (2012).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Harris, S. C. et al. Bile acid oxidation by Eggerthella lenta strains C592 and DSM 2243 T. Gut Microbes 9, 523–539 (2018).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Devlin, A. S. & Fischbach, M. A. A biosynthetic pathway for a prominent class of microbiota-derived bile acids. Nat. Chem. Biol. 11, 685–690 (2015).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Sato, Y. et al. Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians. Nature 599, 458–464 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Edwards, C. A. F. & Orr, J. C. Comparison of the 3α- and 20β-Hydroxysteroid Dehydrogenase Activities of the Cortisone Reductase of Streptomyces hydrogenans. Biochemistry 17, 4370–4376 (1978).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Macdonald, I. A. et al. Metabolism of primary bile acids by Clostridium perfringens. J. Steroid Biochem. 18, 97–104 (1983).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Li, D. et al. Gut-microbiome-expressed 3β-hydroxysteroid dehydrogenase degrades estradiol and is linked to depression in premenopausal females. Cell Metab. 35, 685–694.e5 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Rosa, T. L. S. A. et al. Reductive Power Generated by Mycobacterium leprae Through Cholesterol Oxidation Contributes to Lipid and ATP Synthesis. Front. Cell. Infect. Microbiol. 11, 1–14 (2021).

    Google Scholar 

  • Yu, Y., Liu, C., Wang, B., Li, Y. & Zhang, H. Characterization of 3,17β-hydroxysteroid dehydrogenase in Comamonas testosteroni. Chem. Biol. Interact. 234, 221–228 (2015).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Ye, X. et al. A novel 17β-hydroxysteroid dehydrogenase in Rhodococcus sp P14 transforming 17β-estradiol estrone. Chem. Biol. Interact. 276, 105–112 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Wang, Y. et al. Identification and genome analysis of a novel 17β-estradiol degradation bacterium, Lysinibacillus sphaericus DH-B01. 3 Biotech 10, 1–11 (2020).

    Article 
    CAS 

    Google Scholar 

  • Wang, P. et al. Characterization of 17β-hydroxysteroid dehydrogenase and regulators involved in estrogen degradation in Pseudomonas putida SJTE-1. Appl. Microbiol. Biotechnol. 103, 2413–2425 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Han, Y., Zhuang, Q. & Ren, R. Approaches for evolutionary, biochemical, and structural analysis of bacterial steroid 5α-reductases. Methods Enzymol. 689, 237–261 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Devendran, S. et al. Clostridium scindens ATCC 35704: Integration of Nutritional Requirements, the Complete Genome Sequence, and Global Transcriptional Responses to Bile Acids. Appl. Environ. Microbiol. 85, e00052–19 (2019).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Häggström, M. & Richfield, D. Diagram of the pathways of human steroidogenesis. WikiJournal Med. 1, 2–5 (2014).

    Article 

    Google Scholar 

  • O’Shaughnessy, P. J., Monteiro, A., Bhattacharya, S., Fraser, M. J. & Fowler, P. A. Steroidogenic enzyme expression in the human fetal liver and potential role in the endocrinology of pregnancy. Mol. Hum. Reprod. 19, 177–187 (2013).

    Article 
    PubMed 

    Google Scholar 

  • Hill, M. et al. Steroid metabolome in fetal and maternal body fluids in human late pregnancy. J. Steroid Biochem. Mol. Biol. 122, 114–132 (2010).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Nassar, G. N. & Leslie, S. W. Physiology, Testosterone. (StatPearls Publishing, Treasure Island (FL), 2025).

  • Roseweir, A. K. & Millar, R. P. The role of kisspeptin in the control of gonadotrophin secretion. Hum. Reprod. Update 15, 203–212 (2009).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Funes, S. et al. The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system. Biochem. Biophys. Res. Commun. 312, 1357–1363 (2003).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Arukwe, A. Steroidogenic acute regulatory (StAR) protein and cholesterol side-chain cleavage (P450scc)-regulated steroidogenesis as an organ-specific molecular and cellular target for endocrine disrupting chemicals in fish. Cell Biol. Toxicol. 24, 527–540 (2008).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Bae, Y. J. et al. Journal of Steroid Biochemistry and Molecular Biology Reference intervals of nine steroid hormones over the life-span analyzed by LC-MS / MS: E ff ect of age, gender, puberty, and oral contraceptives. J. Steroid Biochem. Mol. Biol. 193, 105409 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Igarashi, M. et al. Female-dominant estrogen production in healthy children before adrenarche. Endocr. Connect. 10, 1221–1226 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Wang, Q. et al. Ultrasensitive quantification of serum estrogens in postmenopausal women and older men by liquid chromatography-tandem mass spectrometry. Steroids 96, 140–152 (2015).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Zhou, H. et al. Simultaneous measurement of total Estradiol and Testosterone in human serum by isotope dilution liquid chromatography tandem mass spectrometry. Steroids 409, 5943–5954 (2017).

    CAS 

    Google Scholar 

  • Turpeinen, U., Linko, S., Itkonen, O. & Hämäläinen, E. Determination of testosterone in serum by liquid chromatography-tandem mass spectrometry. Scand. J. Clin. Lab. Invest. 68, 50–57 (2008).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Rothman, M. S. et al. Reexamination of Testosterone, Dihydrotestosterone, Estradiol and Estrone Levels across the Menstrual Cycle and in Postmenopausal Women Measured by Liquid Chromatography Tandem Mass Spectrometry. Steroids 76, 177–182 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Bui, H. N. et al. Serum testosterone levels measured by isotope dilution-liquid chromatography–tandem mass spectrometry in postmenopausal women versus those in women who underwent bilateral oophorectomy. Ann. Clin. Biochem. 47, 248–252 (2010).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Bhasin, S. et al. Reference Ranges for Testosterone in Men Generated Using Liquid Chromatography Tandem Mass Spectrometry in a Community-Based Sample of Healthy Nonobese Young Men in the Framingham Heart Study and Applied to Three Geographically Distinct Cohorts. J. Clin. Endocrinol. Metab. 96, 2430–2439 (2011).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Lood, Y. et al. Determination of testosterone in serum and saliva by liquid chromatography-tandem mass spectrometry: An accurate and sensitive method applied on clinical and forensic samples. J. Pharm. Biomed. Anal. 195, 113823 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Won, E. J. et al. Establishment of Korean Pediatric Reference Intervals for Estradiol using Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry. Clin. Biochem. 113, 52–58 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Labrie, F., Lin, S., Simard, J. & Labrie, C. Role of 17β-Hydroxysteroid Dehydrogenases in Sex Steroid Formation in Peripheral Intracrine Tissues. Trends Endocrinol. Metab. 11, 421–427 (2000).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Fan, L. Q. et al. Regulation of phase I and phase II steroid metabolism enzymes by PPARα activators. Toxicology 204, 109–121 (2004).

    Article 
    PubMed 
    CAS 

    Google Scholar 

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