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. 2022 Nov 10;14(22):4761.
doi: 10.3390/nu14224761.

Biotin Enhances Testosterone Production in Mice and Their Testis-Derived Cells

Kota Shiozawa  1 , Misato Maeda  1 , Hsin-Jung Ho  1 , Tomoko Katsurai  1 , Md Zakir Hossain Howlader  2 , Kimiko Horiuchi  1 , Yumi Sugita  1 , Yusuke Ohsaki  1   3 , Afifah Zahra Agista  1 , Tomoko Goto  1 , Michio Komai  1 , Hitoshi Shirakawa  1   3
Affiliations

Biotin Enhances Testosterone Production in Mice and Their Testis-Derived Cells

Kota Shiozawa et al. Nutrients. .

Abstract

Late-onset hypogonadism, a male age-related syndrome characterized by a decline in testosterone production in the testes, is commonly treated with testosterone replacement therapy, which has adverse side effects. Therefore, an alternative treatment is highly sought. Supplementation of a high dosage of biotin, a water-soluble vitamin that functions as a coenzyme for carboxylases involved in carbohydrate, lipid, and amino acid metabolism, has been shown to influence testis functions. However, the involvement of biotin in testis steroidogenesis has not been well clarified. In this study, we examined the effect of biotin on testosterone levels in mice and testis-derived cells. In mice, intraperitoneal treatment with biotin (1.5 mg/kg body weight) enhanced testosterone levels in the serum and testes, without elevating serum levels of pituitary luteinizing hormone. To investigate the mechanism in which biotin increased the testosterone level, mice testis-derived I-10 cells were used. The cells treated with biotin increased testosterone production in a dose- and time-dependent manner. Biotin treatment elevated intracellular cyclic adenosine monophosphate levels via adenylate cyclase activation, followed by the activation of protein kinase A and testosterone production. These results suggest that biotin may have the potential to improve age-related male syndromes associated with declining testosterone production.

Keywords: adenylate cyclase; biotin; testis; testosterone.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Intraperitoneally administered biotin increases testosterone production in BALB/c mice. Testosterone levels in serum (A) and testis (B), and serum luteinizing hormone levels (C) were measured by ELISA. Data are presented as mean ± standard error (n = 4–7). * p ≤ 0.05, vs. control (Cont.) group, Student’s t-test.
Figure 2
Figure 2
Biotin enhances testosterone production in mouse testis-derived tumor cells. The effect of 24 h of biotin treatment on cell proliferation of I-10 (A) and MA-10 cells (B) were evaluated by WST-1 assay. Testosterone levels in cultured media, as measured by ELISA after 24 h treatment with biotin, are shown for I-10 cells (C) and MA-10 (D). The same was done for progesterone levels in the media after 24 h biotin treatment of I-10 cells (F). (E) Testosterone levels of I-10 cells in a cultured medium after biotin treatment (0, 3, 9, 15, and 24 h) were measured by ELISA. Data are presented as mean ± standard error (n = 3). * p < 0.05, ** p < 0.01 vs. 0 µM biotin group, Tukey–Kramer test.
Figure 3
Figure 3
Biotin stimulates testosterone production via the cAMP/PKA pathway. CREB-mediated reporter activities were measured 3 h after the treatment of forskolin (Fsk), an activator of ADCY, or biotin (A). The testosterone levels in the I-10 cells cultured medium with/without biotin and PKA inhibitor H-89 for 24 h were measured by ELISA (B). cAMP levels in I-10 cell lysate after the treatment of biotin for 1 h were measured by ELISA (C). The testosterone levels in the I-10 cell culture medium with/without biotin, ADCY inhibitor MDL (D) and PDE inhibitor IBMX (F), were measured by ELISA after 24 h of treatment. The testosterone levels of the medium from I-10 cells, transfected with siRNAs targeting Adcy9 or Slc5a6, were also measured (E). Data are presented as mean ± standard error (n = 3). Values with different letters are significantly different at p < 0.05 vs. the 0 µM biotin group, Tukey–Kramer. * p < 0.05, ** p < 0.01 vs. the control (Cont.) or the 0 µM biotin group, Dunnett’s test or Student’s t-test.
Figure 4
Figure 4
Intracellular transport of biotin did not contribute to the enhancement of testosterone levels. The testosterone levels in the I-10 cells cultured medium with/without biotin and pantothenic acid for 24 h were measured by ELISA (A). Free biotin levels in I-10 cell lysates after 24 h of biotin treatment were measured by bioassay using Lactobacillus plantarum (ATCC8014) (B). Data are presented as mean ± standard error (n = 3). Values with different letters are significantly different at p < 0.05 vs. 0 µM biotin group, Tukey–Kramer. * p < 0.05, vs. 0 µM biotin group, Student’s t-test.
Figure 5
Figure 5
The effect of biotin-analogues on testosterone production in I-10 cells, 24 h post-treatment. Shown are the testosterone levels in I-10 cell cultured media, treated with d-desthiobiotin (A), α-lipoic acid (B), or n-valeric acid (C) for 24 h, measured by ELISA. Data are presented as mean ± standard error (n = 3). * p < 0.01, ** p < 0.0 vs. 0 µM group, Tukey–Kramer.
Figure 6
Figure 6
Presumed mechanism of biotin on the enhancement of testosterone production in I-10 cells. 3β-HSD, 3β-hydroxysteroid dehydrogenase; 17β-HSD, 17β-hydroxysteroid dehydrogenase; ADCY, adenylate cyclase; cAMP, 3′, 5′-cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; CYP11A, cytochrome P450 cholesterol side chain cleavage enzyme; PKA, protein kinase A; sER, smooth endoplasmic reticulum; StAR, steroidogenic acute regulatory protein.
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