Research Progress On Promoting Testosterone Secretion Of Leydig Cells By Aphrodisiac Traditional Chinese Medicine

Abstract: Testosterone synthesis is related to male reproductive function and aging. Leydig cells are the central place for the synthesis and secretion of testosterone. Various enzymes and transcription factors are involved in the process of testosterone synthesis. Warming and tonifying kidney-yang traditional Chinese medicine and its main active ingredients, including epimedium, dodder, and cistanche, have been proven to regulate reproductive endocrine levels, improve oxidative stress, inhibit inflammation, regulate testosterone synthesis-related enzyme mRNA and protein expression, and affect testosterone synthesis and secretion. Combined with the literature, the main factors affecting the synthesis and secretion of testosterone in Leydig cells, and the research on the regulation of testosterone synthesis and secretion by warming and tonifying kidney yang Chinese medicine are reviewed.

Cistanche, Epemedium Herbal Supplement for stimulate Testosterone synthesis

Keywords: Leydig cells; testosterone; androgen; epimedium; warming and tonifying kidney yang

Testosterone is an important androgen in the body. Studies have shown that 95% of the testosterone in the human body is synthesized and secreted by the Leydig cell (LC), and a small amount of testosterone is also secreted by organs such as the adrenal gland, kidney, and ovary. Testosterone can affect target organs through the androgen receptor, and the androgen receptor is widely distributed in the corresponding tissue cells of the reproductive system, nervous system, and circulatory system. The activity is of great significance [1]. Abnormal testosterone synthesis and secretion can cause hypogonadism, etc., and increase the risk of type 2 diabetes and cardiovascular disease, and has obvious links with obesity and metabolic syndrome, and can also induce osteoporosis, depression and polycystic ovary Syndrome etc. Therefore, it is important to maintain a physiological level of testosterone.

During the development of LC from fetus to adult, it presents typical curve characteristics. Fetal Leydig cells (FLC) can produce high levels of androgen necessary for the differentiation of male characteristics during fetal development. Postpartum testosterone decreases with the number of FLC. It reaches its nadir in the early postpartum period. With the development of LC, testosterone gradually increases to high levels from puberty until old age [2]. The differentiation cycle of LC and the changes in the synthesis and secretion of testosterone, that is, the cycle changes of male development and aging, may be related to the "Tiangui" mentioned in "Ancient Innocence". The middle-aged and elderly people often show kidney deficiency syndrome due to "Tian Gui Jie", and the deficiency of kidney essence is more prominent in the disease state. Traditional Chinese medicine for warming and tonifying kidney yang is an effective natural medicine for improving kidney yang deficiency syndrome. This paper focuses on the review of the promotion of testosterone production in Leydig cells by warming and tonifying kidney-yang traditional Chinese medicine.

1 The synthesis process of testosterone and the regulation factors of its secretion

1. 1 Biochemical process of testosterone synthesis The raw material for testosterone synthesis is cholesterol, which enters the inner mitochondrial membrane through the outer mitochondrial membrane under the regulation of the steroidogenic acute regulatory protein (StAR). effect. After cholesterol is transported to the inner mitochondrial membrane, the cholesterol side chain cleavage enzyme P450scc encoded by cytochrome P450 family 11 subfamily A member 1 (CYP11A1) cleaves the side chain of cholesterol into pregnenolone (pregnenolone, PREG) , into testosterone via the Δ5 or Δ4 pathway. The Δ5 pathway is also called the classical pathway, that is, PREG is converted into 17α-hydroxypregnenolone (17α-hydroxypregnenolone, 17OH-PREG), then converted into dehydroepiandrosterone (DHEA), and then converted into androstenedione (androstenedione). ), and finally catalyzed by 3β-hydroxysteroid dehydrogenase (3β-hydroxysteroid dehydrogenase, 3β-HSD) into testosterone. Δ4 pathway, that is, PREG is catalyzed by 3βHSD in the mitochondria and endoplasmic reticulum to convert progesterone (progesterone), and progesterone is converted into progesterone by cytochrome P450 steroid 17-α-monooxygenase (cytochrome P450 steroid 17- α-monooxygenase, CYP17A1) encoded P450c17α hydroxylase into 17α-hydroxyprogesterone (17-α-hydroxyprogesterone), into androstenedione and finally into testosterone [2-5].

Enzymes play an important role in the synthesis of testosterone. Cytochrome P450 (cytochrome P450, CYP450) and hydroxysteroid dehydrogenase (hydroxysteroid dehydrogenase, HSD) are essential enzymes for all steroid synthesis. CYP450 is an important catalyst in the metabolism of steroids, P450scc encoded by CYP11A1 is the rate-limiting enzyme for steroid synthesis, and CYP17A1 encodes P450c17 enzyme, which simultaneously exhibits 17α hydroxylase activity and 17, 20 lyase activity. In addition, P450 oxidoreductase (cytochrome P450 oxidoreductase, POR) auxiliary protein also participates in each step of CYP17A1 catalysis, and cytochrome b5 (cytochrome b5, CYB5A) participates in the process of CYP17A1 as a redox donor [6], enhancing its reaction rate. In addition, ferredoxin 1 (ferredoxin 1, FDX1) and ferredoxin reductase (ferredoxin reductase, FDXR) can promote the reaction of cytochrome P450 [7]. 17β-Hydroxysteroid dehydrogenases (17β-HSDs) are a class of oxidoreductases, among which 17βHSD2, 17β-HSD3, 17β-HSD4, AKR1C3, etc. It plays a key role in steroid metabolism [8]. Cytoplasmic sulfonase (sulfotransferase 2A1, SULT2A1) can sulfate DHEA and transport it into the circulation. Due to the lack of SULT2A1 in the testis, testosterone synthesis in the testis is converted from DHEA to testosterone through the Δ5 pathway. The conversion of testosterone into dihydrotestosterone by 5α-reductase (SRD5A) can produce a stronger effect [9].

Some transcription factors can regulate steroid synthesis by regulating the gene expression of steroid synthase and protein, such as P450scc, P450c17, 3β-HSD, StAR and high-density lipoprotein receptor (Scavenger receptor BI, SRBI), including steroidogenic factor (steroidogenic factor -1, SF-1), Nur77 receptors, peroxisome proliferator-activated receptor γ, aryl hydrocarbon receptors, cyclic adenosine monophosphate (cyclic adenosine monophosphate, cAMP) response element binding protein and GATA factors. In addition, nuclear factor κB (nuclear factor kappa-B, NF-κB), arachidonic acid, phosphatase, transforming growth factor α, etc. can all affect the synthesis of testosterone [10].

1. 2 Factors regulating testosterone synthesis and secretion LC

The secretion of testosterone is regulated by the hypothalamus-adenophysis, the hypothalamus secretes gonadotrophin-releasing hormone (GnRH), and regulates the follicle-stimulating hormone (Follicle-stimulating Hormone, FSH) and luteinizing hormone (Luteinizing Hormone) of the pituitary gland. , LH). FSH acts on Sertoli cells to secrete androgen-binding protein, and LH acts on LC to regulate androgen synthesis. It binds to receptors on the surface membrane of LC cells, and then couples to G protein to activate adenylate cyclase. Adenylyl cyclase converts adenosine triphosphate to

cAMP, thereby activating cAMP-dependent protein kinase A (protein kinase A, PKA). PKA promotes the expression of steroidogenic enzymes such as StAR through the phosphorylation of specific serine and threonine residues. cAMP and Ca2 + are second messengers of the LH pathway, Ca

2 + can activate cAMP in turn[5]. In addition, thyroid hormone (T3) has a direct stimulating effect on testosterone production, and hormones and cytokines such as stem cell factor, Mullerian inhibitor, INSL3 and IGF-I also affect the synthesis and secretion of testosterone [11].

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