Research Progress On The Regulation Of Reproductive Function By Cistanche
Feb 21, 2023
The clinical practice of TCM has proved that Cistanche can tonify kidney yang, benefit essence, and blood, and moisten the intestinal tract, which is a precious product in tonic Chinese medicine. In recent years, in-depth studies have been conducted on the reproductive pharmacological and toxicological effects of Cistanche cistanche, focusing on its kidney-yang tonifying effects, and the related research results have attracted the widespread attention of TCM researchers. In this paper, we review the effects of Cistanche cistanche extract on the regulation of reproductive function in combination with the analysis of medicinal components. The comprehensive analysis concluded that Cistanche cistanicae extract has a regulatory effect on both female and male reproductive endocrine and can improve reproductive function, which provides a modern life science basis for the classical TCM theory that "Cistanche tonifies kidney yang".
Cistanche deserticola is an endangered species and is a second-class protected plant. Cistanche is also known as Cistanche japonica, Cistanche cistannii, Cistanche cistannii and Cistanche cistannii (in Mongolian). At present, there are 22 species of Cistanche worldwide, and in the desert areas of China, there are four species and one variety of Cistanche, including Cistanche deserticola, Y∙C Ma, C. tibulosa (Schenk) Wight, C. salsa (C. A. Mey) G. Beck, and C. salsa. Cistanches are mostly parasitic on the lateral roots of sand-protecting plants such as Halaxlon ammodendnon, (C∙C∙Meg)∙Bunge, and others. It likes lightly salinated soft sandy areas and is generally suitable for growing in areas with arid climates, low rainfall, high evaporation, long sunshine hours, the large temperature difference between day and night, and extreme growing environment, mainly in Xinjiang, Inner Mongolia, Ningxia, Gansu and other areas in China.
According to Chinese medicine, Cistanches are sweet, salty, and warm in nature. It enters the kidney and large intestine meridians and has the function of tonifying kidney yang, benefiting essence and blood, and moistening the intestine. Modern pharmacological studies have shown that Cistanche has a wide range of effects such as improving reproductive function, protecting the liver, anti-aging, enhancing immunity, and regulating endocrine. At present, several scholars at home and abroad have isolated a variety of compounds from Cistanches using different techniques and conducted comparative analyses, among which the main ones related to reproductive functions are phenylethanoid glycosides (e.g., pineal glycosides, syringeal glycosides), polysaccharides, and leaf ascorbyl glycosides. In this paper, we review the current research progress on the pharmacological and toxicological effects of Cistanche in regulating reproductive function from both male and female aspects, respectively, and the benefits of consuming Cistanche for kidney enhancement in men.
Related studies have shown that men should eat more Cistanche for strengthening and tonifying the kidneys.
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Pharmacological effects of Cistanche on male sexual function
1. Aphrodisiac effect: Cistanches is a valuable Chinese medicine, known as "desert ginseng", and has been the first in the prescriptions for kidney aphrodisiac and strength enhancement for many generations. The aphrodisiac effects of Cistanches have been recorded in ancient medical books. In the Ben Jing, it is written that Cistanches "strengthens yin, benefits essence, and is used for the seven injuries", meaning that it tonifies the kidneys and strengthens yang, and is used for kidney deficiency. Because Cistanches is different from other aphrodisiacs, it does not harm Yin while tonifying the kidney, and even if taken for a long time, it does not cause fire and dryness of the mouth, which has been recorded in the Compendium of Materia Medica as "tonifying without completing, so it has a subdued number". Kidney yang deficiency is one of the important signs in the theoretical system of Chinese medicine, and kidney yang is closely related to reproduction. In recent years, scholars in China have verified the aphrodisiac efficacy of Cistanche with the help of animal experiments.
We used hydrocortisone acetate to establish an animal model of Yang deficiency in mice and observed the protective effect of Cistanches alba on the function of the kidney and adrenal glands by using the morphological and structural changes of the kidney and adrenal glands as indicators. The results showed that the addition of Cistanche alba to corticosteroids for a longer period of time prevented the atrophy of the adrenal cortex caused by hormone use alone, indicating that Cistanche alba has some protective effect on adrenal function. This suggests that the alcoholic extract of Cistanche cistanche has some protective effect on adrenal gland function. Our experiments showed that the active ingredient of Cistanche tubulosa, Cistanche arborescent, has a tonic effect on the kidney and aphrodisiac. After 14 d of continuous infusion of Cistanche bark extract, the penile erection latency was significantly shortened, the sperm count was significantly increased, the sexual organ coefficient was significantly increased, and the morphological structure of the testes was also significantly improved. Our study further confirmed the tonic effect of Cistanche cistanche in the animal model of "yang deficiency". The results showed that phenylethanoid glycosides extracted from Cistanche tubulosa could promote testosterone synthesis through the CYP450-3β-HSD pathway and upregulate testosterone and its upstream luteinizing hormone (LH) levels. hormone (LH) levels, promote the release of related neurotransmitters and hormones in the body, and improve reproductive dysfunction; at the same time, enhance physical function, resist fatigue, etc., and play an aphrodisiac role. In conclusion, hydrocortisone modeling leads to yang deficiency and yang deficiency symptoms related to reduced adrenal gland function, which further presents a decrease in testicular function and androgen reduction, thus affecting the sexual behavior and function of animals.
2. To investigate the effects of Cistanche on the morphology and histochemistry of testes and epididymis of mice, we selected Kunming male mice and administered Cistanche aqueous decoction [4 g/(kg-d) and 8 g/(kg-d)] by gavage for 3 weeks. The results showed that Cistanche can improve the testicular morphology of mice and induce a strong positive signal for succinate dehydrogenase (SDH) and non-specific esterase (NSE) in testis and epididymis.
3. Pharmacological effects on spermatogenic capacity: Studies have proved that Cistanche cistanche has good protective effects on spermatogenic function and semen quality. Our experimental study concluded that Cistanche phenylethanoid glycosides (PeGs) had significant therapeutic effects on cyclophosphamide-induced spermatogenic disorders in mice, and the mechanism may be related to the upregulation of testosterone levels in testicular tissues. Using a rat sperm peroxidative damage model, we observed that co-incubation of different doses (0.02 g/mL, 0.25 g/mL, 0.5 g/mL raw drug amount) of Cistanche phenylethanolide with sperm suspensions significantly increased total superoxide dismutase enzyme (SOD) activity and decreased malondialdehyde ( malonaldehyde (MDA) content, inhibit sperm membrane lipid peroxidation, exert antioxidant effects, and have obvious protective effects on sperm membrane structure and function. Using a streptozotocin-nicotinamide-induced diabetic rat model, ECH was also found to restore blood testosterone levels and improve reproductive function. Recently, a study concluded that a mixture of Cistanche extract and sea cucumber peptide extract could reduce fatigue in male mice and act as an antioxidant, increase testosterone secretion, and reduce sperm malformation.
4. Reproductive endocrine mechanism of aphrodisiac effect: Hypothalamus is the regulation and control center of the human neuroendocrine system. Cistanche has an adjusting effect on the aging of the hypothalamus and improves nutrition, body mass, endurance, and cold resistance in Yang-deficient animals, which has an obvious aphrodisiac effect on Yang-deficient patients. We used male Wistar rats with body masses of 70-100 g, prepared a model of Yang deficiency by removing both testes, and gave different doses of the alcoholic fraction of Cistanche cistanche aqueous decoction 1.0 g/kg and 3.0 g/kg body mass, respectively, by gavage for 12 d. The results showed that the crude extract of Cistanche cistanche could increase the weight of the seminal vesicles, prostate gland, and other secondary sexual organs, showing androgen-like effects, and no adverse effects on thymus atrophy. The overall effect was better than that of sex hormones. In addition, the ethanolic extract of Cistanche can correct the dysregulation of sex hormones and immune factors in male rats in the model of kidney yang deficiency caused by glucocorticoid overdose, enhance and restore the action of hypothalamic nerve cells, improve immune function, and present a tonic effect on kidney yang. In conclusion, the alcoholic soluble fraction of Cistanche cistanche extract has a mild androgen-like effect, presenting a tonic kidney and yang effect.
Our study showed that cistanche extract pinealiside targets androgen receptor (AR) in the hypothalamus and inhibits its transport from cytoplasm to the nucleus, thus inhibiting the negative feedback of androgens and leading to increased gonadotropin-releasing hormone (GnRH) and LH secretion is increased. Subsequently, LH stimulates CYP11A1, a steroid hormone synthase in the mitochondrial membrane of the testis, to bind to steroidogenic acute regulatory protein (StAR), which together binds to the inner mitochondrial membrane and catalyzes the cleavage of cholesterol side chains to pregnenolone (PREG), a biosynthetic hormone. PREG), which is an important precursor in the biosynthetic pathway for the synthesis of many steroid hormones, including progesterone, dehydroepiandrosterone (DHEA), androstenedione (ADSD), androstenediol (5-AED), testosterone. . The increased testosterone levels further stimulate the transfer of testicular tissue AR from the cytoplasm to the nucleus to regulate gene transcription, which in turn promotes spermatogenesis. In this way, the Cistanche component ECHs may promote the spermatogenesis process in the testis by acting on the hypothalamus to regulate reproductive endocrine secretion. However, according to the above explanation, the specific action of Cistanche extract pineal glycosides on hypothalamic AR receptors, but not in testicular tissues, deserves further attention. On the other hand, as far as the direct action of Cistanche extract on gonadal tissues is concerned, it may be achieved through antioxidant effects, as described earlier. In the case of isolated cultures, the Cistanche extract Cistanoside, which acts as an antioxidant, can directly slow down the damage to spermatogonia in a hypoxic environment; the pinealoside Echinacoside can mediate the endothelium-dependent vasodilatory effect of rat thoracic aortic rings via the nitric oxide (NO)-cGMP pathway. In this way, it is also possible that the pharmacological effects of Cistanche extract do not depend on endocrine regulation at the hypothalamic-pituitary level, but act directly as an antioxidant or vasorelaxant in peripheral tissues.
5. Antagonistic effects on male reproductive toxicity: Experimental studies have shown that C. rebaudiana polysaccharide can reduce testosterone levels and fertility in male mice of the Kunming species, while Cistanche cistanche (drinking tablets, 10 g/kg body mass daily for 20 d) can antagonize its damaging effects on the reproductive system of male rats. We selected adult Balb/C male mice and gavaged them with Radix et Rhizoma Polygoni 30 mg/(kg-d) for 3 weeks to cause a model of hypogonadism, followed by an intervention such as Cistanche decoction equivalent to 10 g/(kg-d) of the raw drug, and also concluded that Cistanche can partially antagonize the reproductive toxicity of Radix et Rhizoma. Aqueous extract of cistanche given by gavage to male Kunming mice at doses of 1.5 g, 3.0 g, or 6.0 g raw drug equivalent/kg body mass antagonized hydroxyurea-induced spermatogenic cell damage and decreased serum LH levels. The components of Cistanche have antagonistic effects against some reproductive toxicants, reflecting protective effects.
On the other hand, when Cistanche reaches a certain high dose, for male reproduction, in addition to its protective effect, it may have some toxicity. Some studies reported that Cistanche extracts significantly reduced sperm count with some dose dependence, 298.3±48.9 (blank control) vs. 296.6±102.4 (250 mg/kg BW), 236.7±75.1 (500 mg/kg BW), (223.0±48.7) × 106 (1 g/kg BW). However, several studies have recently reported that the results of acute toxicity tests showed that the maximum tolerated doses (MTD) of Cistanche in both female and male mice were >20 g/kg BW, which is 600 times greater than the recommended human dose, indicating that Cistanche cistannii subjects are non-toxic grade substances and does not cause sperm malformation, and to some extent increased the testis/body mass ratio in male mice. However, it is necessary to repeat the experiment to verify whether Cistanche extract affects sperm count and other indices in male mice.
Cistanche is a hot research object in Chinese medicine in recent years, mainly focusing on the modern biological mechanism of the aphrodisiac effect of the kidney. Although the aphrodisiac effect has been studied mainly with the help of male animal models, the function of aphrodisiac effect has been demonstrated not only in males but also in females. Studies on the mechanism of the aphrodisiac effect mainly include studies on the regulation of male endocrine and enhancement of spermatogenic ability, while whether the regulation of female reproductive endocrine depends on similar active ingredients deserves further attention. Although the research on the pharmacological effects of Cistanches is gradually intensifying in recent years, it can be seen from the above review that the mechanism of action involved in its pharmacological effects mainly lies in the phenylethanoid glycoside extracts regulating reproductive endocrine through the targets of the hypothalamus and other tissues, which in turn affects the reproductive function of gonads and plays the role of kidney tonic and aphrodisiac. However, due to the complexity of the pharmacological composition of Cistanche cistanche, the key drug components involved in its classical efficacy are still difficult to identify. In addition, the aphrodisiac effect of phenylethanoid glycosides, a component of Cistanche, is currently recognized to be mainly through the AR receptors in the hypothalamus, which antagonize the feedback inhibitory effect of steroid hormones and increase the secretion of LH and steroid hormones to exert aphrodisiac effects. However, further questions that arise deserve attention, such as why it does not have effects on AR receptors in tissues such as gonads and adrenals, and whether the targets and mechanisms of action are the same in men and women.
Next, there is a need to identify its in vivo targets of action for its key components, such as betaine and phenylethanoid glycosides, the latter including neostigmine (acetonide), pinealoside (echinacoside), and other cistanosides, and to determine their tissue specificity and the mechanisms involved through animal pharmacology experiments. Regarding their cellular targets and mechanisms of action, it is necessary to reveal the relevant molecular targets of action, as well as the functional signaling pathways involved, using tissue-cell models of the hypothalamus, gonads, and adrenal glands for the monomeric compounds of various major components. The discovery of isolated cytological action targets can not only facilitate pharmacological studies at the animal level and drug development using Cistanche as raw material by comparing the differences in targets of cells from different tissue sources, but also systematically reveal the biological mechanism of Cistanche for kidney aphrodisiacs from a theoretical perspective through the integrated analysis of the effects of various components. Recently, it was found that Cistanche cistanche extract has neuroprotective effects and is useful in the prevention and treatment of neurodegenerative diseases, and its relationship with reproductive endocrine regulatory effects also deserves attention.
In conclusion, regarding the modern biological mechanisms of TCM for kidney aphrodisiacs, studies have been conducted mainly using Cistanche cistanche extracts targeting aspects such as reproductive endocrinology and found that its action targets are mainly in the hypothalamus. However, it has recently been found that Cistanche polysaccharide extracts can promote the differentiation of mouse female germinal stem cells in isolation and increase the expression of the meiotic markers Stra8 and Sycp3 in their cells. In this way, the regulatory effect of Cistanche on reproduction may be innovative in terms of new targets and mechanisms, but the existence of the exact targets in the ovary at the level of female germinal stem cells, or even in the ovary or testis for the action of Cistanche, still deserves further study to determine. In conclusion, the systematic study of the reproductive endocrine function of cistanche and the revealing of the modern biological mechanism of its TCM tonic effect is the key to advancing its innovative application in the treatment of diseases related to male and female reproductive function.
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