Therapeutic agent for male hypogonadism, and drug for promoting increase in testosterone level or suppressing onset of male hypogonadism

Abstract

[Problem] To discover a component which effectively contributes to the treatment (suppression) of male hypogonadism, the risk of onset of which increases with age. [Solution] In the present invention, it was examined whether or not coumestrol effectively contributes to the treatment (suppression) of male hypogonadism, by using wild-type mice and ApcMin / + mice that are familial colorectal tumor disease models. The ApcMin / + mice developed hypogonadism with age. In contrast, in mice to which coumestrol had been administered, it was found that the increase in testosterone level with age was promoted and the onset of male hypogonadism was significantly suppressed. In addition, the testosterone increase-promoting effect by coumestrol was observed in the wild-type mice. From the foregoing, it can be said that coumestrol effectively contributes as a component for treating (suppressing) the onset of male hypogonadism and is useful as a therapeutic agent for male hypogonadism (an agent for suppressing male hypogonadism).

Description

Drugs for treating male hypogonadism, drugs for promoting an increase in testosterone levels or suppressing the onset of male hypogonadism

[0001] The present invention relates to a therapeutic agent for male hypogonadism, a drug for promoting an increase in testosterone levels or suppressing the onset of male hypogonadism.

[0002] It is known that the risk of developing male hypogonadism increases with age.

[0003] In recent years, as seen in Patent Document 1 and the like, research has been conducted on therapeutic agents for male hypogonadism.

[0004] Japanese Patent Application Laid-Open No. 2018-199701

[0005] The object of the present invention is to find a component that effectively contributes to the treatment (suppression) of male hypogonadism.

[0006] The present invention provides a therapeutic agent for male hypogonadism containing coumestrol as an active ingredient.

[0007] The present invention also provides a drug for promoting an increase in testosterone levels, which contains coumestrol as an active ingredient.

[0008] Furthermore, the present invention provides a drug for suppressing the onset of male hypogonadism, which contains coumestrol as an active ingredient.

[0009] According to the present invention, coumestrol can promote an increase in testosterone levels and can treat (suppress) male hypogonadism.

[0010] Wild-type mice and Apc Min / ＋ Table showing body weight, testosterone level, testis weight, epididymal fat, and epididymal weight of mice at 12 weeks of age. Min / ＋ Photographs showing mouse testis and epididymis tissues. Graph showing serum testosterone levels in adult men after oral intake of coumestrol-rich soybean sprouts.

[0011] In the present invention, whether coumestrol effectively contributes to the treatment (suppression) of male hypogonadism was examined using wild-type mice and Apc mice, a familial colorectal tumor disease model. Min / ＋ This was investigated using mice.

[0012] Here, coumestrol is a natural organic compound (phytochemical) contained in plants, and it has been confirmed that commercially available bean sprouts (bean sprouts such as soybean sprouts, mung bean sprouts, and black bean sprouts) contain coumestrol. Min / ＋ The mouse is a familial colorectal cancer model mouse with a nonsense mutation at codon 850 of the Apc gene. The Apc gene is a causative gene for familial polyposis coli, which is involved in the early stages of colorectal cancer development. The Apc mouse, developed by Jackson Laboratories (Bar Harbor, Maine, USA), is a mouse model of familial colorectal cancer. Min / ＋ Mice (C57BL / 6J) were used.

[0013] C57BL / 6J mice used in this study were purchased from Japan SLC, Inc. (Shizuoka, Japan) and fed 5L37 LABDIET (Japan SLC, Inc., Shizuoka, Japan) as the standard diet. To prepare the coumestrol-containing diet, soybean sprouts (see JP 2022-58105 A) were grown to be high in coumestrol. These were dried at 80°C for 12 hours, pulverized in a mill, and mixed with the standard diet to achieve a coumestrol concentration of 200 μg / g (coumestrol / diet). This coumestrol-containing diet was prepared by mixing 15% coumestrol powder and 10% potato starch as a binder with the standard diet and drying at 80°C for 10 hours. Mice were fed the coumestrol-containing diet from the 6th week of age and used in the experiments from the 12th week of age.

[0014] Histological observations of the testes and epididymis in this study were performed as follows: Testes were removed from the scrotum, and the weights of the testes, epididymis, and epididymal fat were measured. Testes fixed in Bouin's solution were then cut into 7-μm-thick sections and mounted on silane-coated slides. The slides were then stained with hematoxylin and eosin and observed under a microscope.

[0015] In this study, testosterone levels (serum testosterone levels) were measured by liquid chromatography-tandem mass spectrometry (LC-MS / MS) (Oriental Yeast Co., Ltd., Shiga).

[0016] Data are expressed as mean ± standard deviation, means were compared using Student's t-test, and significance was determined at the P<0.05 level.

[0017] The results of this study are shown in Figure 1.

[0018] The body weight of wild-type mice fed the standard diet was 28.6±1.24 g, while that of wild-type mice fed the coumestrol-containing diet was 25.6±0.97 g, a slight but significant decrease in body weight.

[0019] In addition, the body weight was measured at 12 weeks after birth, and the weight of Apc Min / ＋ In mice, it was 18.8±1.78g, and in Apc Min / ＋ It was observed that mice lost significant weight, but the Apc mice fed the coumestrol-containing diet Min / ＋ In mice, the mean values ​​were 24.5±2.42g, and in Apc mice fed a diet containing coumestrol Min / ＋ In mice, Apc fed a standard diet Min / ＋ Significant weight recovery was observed in mice.

[0020] In wild-type mice fed the standard diet, the testis weight was 0.09±0.01 g and the epididymal weight was 0.012±0.0007 g, while in wild-type mice fed the coumestrol-containing diet, the testis weight was 0.09±0.01 g and the epididymal weight was 0.012±0.0007 g, and no significant differences were observed in testis or epididymal weight.

[0021] However, Apc fed standard bait Min / ＋ In mice, testis weight was 0.04 ± 0.03 g, epididymal weight was 0.006 ± 0.0014 g, and Apc Min / ＋ The mice had significantly reduced testis and epididymis weights, and Apc Min / ＋When the testicular and epididymal tissues of the mice were examined, hypogonadism was observed as shown in Figure 2A and B. However, the Apc mice given coumestrol showed no significant changes in their gonadism. Min / ＋ In mice, the testis weight was 0.08±0.02 g and the epididymal weight was 0.010±0.0011 g. As shown in Figure 2C and D, the Apc Min / ＋ In mice, Apc fed a standard diet Min / ＋ It was observed that mice recovered from hypogonadism significantly better than mice.

[0022] Furthermore, histological observations revealed that Apc fed with coumestrol-containing diets Min / ＋ In mice, Apc fed a standard diet Min / ＋ A significant recovery of spermatogenesis from hypogonadism was observed in mice compared with control mice.

[0023] Furthermore, testosterone levels were 283.0±51.0 pg / mL in wild-type mice fed a standard diet, and 283.0±51.0 pg / mL in Apc mice fed a standard diet. Min / ＋ In Apc mice fed the coumestrol-containing diet, the mean values ​​were 17.0±6.6pg / mL, whereas in wild-type mice fed the coumestrol-containing diet, the mean values ​​were 2780.4±1971.7pg / mL. Min / ＋ In mice, it was 973.3±785.7pg / mL.

[0024] Thus, wild-type mice and Apc mice fed a diet containing coumestrol Min / ＋ In mice, wild-type mice and Apc mice fed a standard diet were Min / ＋ A significantly higher testosterone level was observed in the rats than in the rats.

[0025] We also investigated serum testosterone levels after adult males orally ingested soybean sprouts high in coumestrol. Soybean sprouts (see JP 2022-58105A) were grown to be high in coumestrol, dried at 80°C for 12 hours, then milled into powder. The powder, containing 10-20 mg of coumestrol per 100 g, was packed into capsules of 250-300 mg each, and 10 capsules were orally ingested daily at any time.

[0026] The results are shown in Figure 3. Human testosterone levels (serum testosterone levels) were measured using a Testosterone High Sensitivity ELISA kit, Human ADI-900-176 (Cosmo Bio Co., Ltd.). In the figure, p indicates the significance level.

[0027] As shown in Figure 3, it was confirmed that oral intake for three months significantly increased blood testosterone levels in adult men, just as in mice.

[0028] As explained above, Apc fed standard diet Min / ＋ Mice developed hypogonadism with age, whereas Apc mice fed a diet containing coumestrol Min / ＋ In mice, it was found that the increase in testosterone levels was promoted and the onset of hypogonadism was significantly suppressed.

[0029] It was also found that oral intake of bean sprout powder containing coumestrol significantly increased blood testosterone levels in adult men.

[0030] From these findings, it can be said that coumestrol promotes an increase in testosterone levels and effectively contributes as an ingredient to treat (suppress) the onset of male hypogonadism, and is useful as a therapeutic agent for male hypogonadism (agent for suppressing male hypogonadism).

[0031] In addition, coumestrol can suppress the aging phenomenon caused by the decline of testosterone due to aging by increasing testosterone. Furthermore, by increasing testosterone, coumestrol is expected to suppress depression and other conditions.

Claims

1. A drug for treating male hypogonadism containing coumestrol as the active ingredient.

2. A drug containing coumestrol as an active ingredient to promote an increase in testosterone levels.

3. A drug containing coumestrol as an active ingredient for suppressing the onset of male hypogonadism.

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