Abstract

Testosterone supplement therapy (TST) is the primary treatment for male late‑onset hypogonadism (LOH). However, its indications, potential adverse effects, and long‑term safety remain controversial. Unlike TST, which relies on exogenous testosterone replacement, traditional Chinese medicine (TCM) is guided by the core pathogenesis of LOH-"kidney deficiency with liver constraint, and premature exhaustion of Tiangui"-and emphasizes "tonifying the kidney and soothing the liver" as its fundamental therapeutic principle. This approach demonstrates multi‑level, holistic, and synergistic regulatory advantages. Specifically, Chinese herbs and their bioactive constituents "support the righteous" by restoring testicular microenvironmental homeostasis through regulating redox balance, autophagy, cell cycle, and intrinsic circadian rhythms. On this basis, they "treat the root" by targeting the hypothalamic–pituitary–gonadal (HPG) axis, modulating the expression of testosterone‑biosynthetic enzymes to promote endogenous testosterone recovery, and enhancing androgen receptor (AR) activity in target organs. Meanwhile, they "treat the manifestations" by alleviating core symptoms involving sexual and reproductive function, physical performance and metabolism, and mental and psychological status. Additionally, they "regulate the body" by intervening in systemic states such as glucose and lipid metabolism to facilitate recovery and prevent relapse. This article systematically reviews and elaborates the multi‑target, holistic mechanisms of TCM in LOH and proposes an integrated strategy of "supporting the righteous-treating the root-treating the manifestations-regulating the body", aiming to provide new ideas and references for clinical diagnosis and treatment of LOH.

Keywords: late‑onset hypogonadism; simultaneous treatment of root and manifestations; holistic regulation; exhaustion of Tiangui; kidney deficiency with liver constraint; traditional Chinese medicine

 

 

 

1. Introduction

Male late‑onset hypogonadism (LOH) is associated with a progressive decline in serum testosterone during aging and is accompanied by symptoms and signs involving sexual function, psychological status, and physical performance and metabolism, causing substantial harm to men's physical and mental health [1–2]. Using free testosterone <210 pmol/L together with ≥3 sexual symptoms (decreased libido, reduced morning erections, decreased sexual ability, or reduced sexual activity frequency, etc.) as diagnostic criteria, the estimated prevalence of LOH among elderly men in China is 7.8% [3]. With accelerating population aging, this proportion may increase year by year. Although testosterone supplement therapy (TST) is the mainstay treatment for LOH and has definite efficacy, its adverse effects and safety in clinical use remain controversial [4–5]. In particular, because TST achieves therapeutic effects by exogenous testosterone supplementation, it may bring additional risks when patients have concomitant diseases such as prostate cancer [6]. Therefore, it is urgent to explore alternative therapeutic options that are safer, more effective, and have broader indications.

Holistic regulation is a distinctive advantage of TCM and shows potential value in LOH treatment [7]. The theoretical system, basic research, and clinical practice of TCM mutually corroborate and have progressively elucidated LOH etiology and pathogenesis, therapeutic principles and methods, and the mechanisms of formulas and herbs. "Kidney deficiency with liver constraint, and premature exhaustion of Tiangui" is considered the core pathogenesis of LOH [8–10]. Tiangui is generated from kidney essence and relies on nourishment and regulation by other viscera such as the liver and spleen, thereby maintaining reproduction and growth and development. Some scholars propose that male Tiangui corresponds to the function of the HPG axis and can be regarded as a refined substance integrating functional and material attributes [11], providing a new perspective for understanding LOH via Tiangui theory. In men, the functional attribute of Tiangui mainly promotes and maintains growth and reproductive development; the material attribute includes all substances required to support these functions, such as testosterone, semen, endocrine hormones, and regulatory molecules. Based on this understanding, we propose that during aging, visceral deficiency dominated by kidney‑essence insufficiency, together with functional dysregulation dominated by impaired liver dispersion and dredging, leads to premature exhaustion of Tiangui, resulting in progressive damage to both its functional and material attributes. On the one hand, impairment of the functional attribute leads to core LOH symptoms and signs including decreased sexual function, reduced physical performance, metabolic disorders, and psychological abnormalities; on the other hand, impairment of the material attribute affects synthesis and secretion of testosterone, semen, endocrine hormones, and other substances. This not only explains LOH pathologic changes at the micro level, but also provides quantifiable biological targets for evaluating the efficacy of TCM interventions.

During aging, visceral deficiency dominated by kidney deficiency constitutes the "root" of LOH, while concomitant visceral functional dysregulation underlies diverse clinical symptoms and signs as the "manifestations" [12]. Clinically, TCM interventions that primarily tonify the kidney to replenish visceral deficiency while also regulating visceral function can effectively restore serum testosterone levels and show unique advantages in improving symptoms and signs and quality of life in LOH patients [13–17]. Thus, the characteristics of TCM in LOH treatment lie not only in elevating serum testosterone to address the root, but also in simultaneously improving multi‑system dysfunctions such as sexual function, physical performance, cognition, and mood to address the manifestations-fully reflecting the holistic concept of "seeking the root cause and treating both root and manifestations." Moreover, TCM may rebuild internal homeostasis by targeting intrinsic pathologic changes in LOH, laying a foundation for both testosterone recovery and symptom improvement; this is essentially different from TST, which focuses on exogenous testosterone supplementation and may not fundamentally address intrinsic pathological changes. However, most current basic studies focus on the influence of herbs on specific molecular targets. While these findings reveal multiple internal pathways, they have not yet formed a systematic theoretical framework capable of comprehensively explaining the holistic synergy of TCM. Therefore, integrating multidimensional regulatory pathways and proposing the internal logic of the TCM mechanism of "supporting the righteous-treating the root-treating the manifestations-regulating the body" will help deeply understand the essence of TCM treatment for LOH and has important theoretical and practical significance for clinical application.

 

2. "Supporting the Righteous": Restoring Testicular Microenvironmental Homeostasis

TCM holds that "when righteous qi is preserved within, pathogenic factors cannot invade," and "where pathogenic factors gather, qi must be deficient." With aging, kidney essence gradually declines, Tiangui gradually exhausts, and liver qi easily becomes constrained, leading to a state of deficient righteous qi and, consequently, disturbed internal homeostasis. Modern studies have revealed that the pathological course of LOH at the micro level often manifests as oxidative stress (OS), apoptosis, energy and metabolic imbalance, and circadian rhythm disruption in testicular tissue and Leydig cells [18–19]. Through tonifying the kidney and replenishing essence, soothing the liver and relieving constraint, and related approaches, Chinese herbal interventions "support the righteous" and exert multiple pharmacological effects such as antioxidation, anti‑inflammation, and metabolic regulation, thereby rebuilding internal homeostasis and providing a solid basis for subsequent "treating the root" (restoring testosterone synthesis and AR function) and "treating the manifestations" (improving clinical symptoms) [20].

2.1 Restoring Redox Homeostasis

Evidence shows that local OS in the testes can directly inhibit the expression of key proteins such as steroidogenic acute regulatory protein (StAR), thereby impairing testosterone synthesis in Leydig cells [21]. In LOH model rats, decreased activities of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT), together with elevated malondialdehyde (MDA), indicate disrupted redox homeostasis. After intervention with Xiongcan Yishen Formula (雄蚕益肾方), these indicators were effectively reversed and antioxidant capacity was markedly enhanced [22]. In addition, in an H₂O₂‑induced OS injury model of Leydig cells, Xiongcan Yishen Formula significantly upregulated GPx4, GSH, and SOD levels while downregulating ROS and MDA, thereby alleviating oxidative injury and promoting testosterone recovery [23]. Nuclear factor erythroid 2‑related factor 2 (Nrf2), a major regulator of redox homeostasis, affects testosterone synthesis by regulating Leydig cell function [24]. Further mechanistic studies showed that saffron extract alleviated oxidative injury in LOH model mice by activating the PI3K–Akt–Nrf2 signaling pathway, thereby promoting testosterone recovery [19]. Moreover, OS mediated by inhibition of the Keap1/Nrf2/HO‑1 pathway in testes leads to decreased sperm quality in oligoasthenozoospermia model rats [25].

Collectively, these results suggest that Chinese herbs restore redox balance via multiple pathways and, from the perspective of "supporting the righteous," help re‑establish testicular microenvironmental homeostasis in LOH.

2.2 Restoring Cell‑Cycle Homeostasis

During LOH progression, testicular tissue or Leydig cells often exhibit disrupted cell‑cycle homeostasis, manifested as increased cellular senescence and apoptosis. In LOH mouse models, senescence marker SA‑β‑Gal activity is significantly elevated in testicular interstitium, and p21 and p16 expression is markedly increased [19]. Ginsenoside Rg1 reduces the number of senescent Leydig cells in D‑galactose‑induced aging mouse models and downregulates the gene expression of inflammatory factors such as IL‑1, IL‑6, and IL‑8 [26]. The herb pair Dioscorea opposita (Shanyao)–Polygonatum sibiricum (Huangjing) significantly improves apoptosis in rat testicular tissue by regulating the HSP90/p38/NF‑κB pathway [27]. These findings indicate that Chinese herbs can restore cell‑cycle homeostasis by modulating cell‑cycle‑related proteins and inhibiting inflammatory and apoptotic signaling, thereby improving LOH.

2.3 Restoring Autophagy Homeostasis

Systemic metabolic and energy homeostasis depends on mitochondrial function. With aging, Leydig cells undergo degenerative changes accompanied by reduced serum testosterone, and autophagy is significantly impaired, manifested by reduced autophagic structures and downregulated LC3‑II expression [28]. In LOH model rats, PINK1/Parkin‑mediated autophagy is significantly reduced; after Xiongcan Yishen Formula intervention, PINK1 and Parkin protein levels in testicular tissue are significantly increased and Leydig cell autophagy is restored [29]. In a Leydig cell senescence model, Heshouwu Decoction (何首乌饮) enhances autophagy by activating the AMPK–mTOR pathway [30]. In addition, Yijing Capsule (养精胶囊), a kidney‑tonifying formula, significantly upregulates Beclin‑1 and LC3‑II/I in mouse testicular tissue, promotes autophagosome formation, and enhances testosterone synthesis by regulating autophagy homeostasis [31]. These results suggest that Chinese herbs restore Leydig cell autophagy via multi‑target modulation of autophagy‑related pathways, thereby improving LOH.

2.4 Restoring Intrinsic Circadian Rhythm Homeostasis

Testosterone synthesis in Leydig cells is regulated by clock genes [32]. In mouse Leydig cells, the clock gene BMAL1 can inhibit apoptosis [33]. In D‑galactose‑induced LOH rat models, mRNA and protein levels of BMAL1, NR1D1, PER2, and CRY1 in testicular tissue are significantly lower than in normal controls, indicating disrupted local biological rhythms. After Xiongcan Yishen Formula intervention, these clock genes are markedly upregulated, suggesting that herbal treatment can effectively regulate testicular circadian rhythm homeostasis [34]. This indicates that Chinese herbs may improve testosterone synthetic dysfunction due to rhythm disorder by restoring clock gene expression.

 

3. "Treating the Root": Increasing Testosterone Levels and Regulating AR Function in Target Organs

3.1 Modulating the HPG Axis

HPG axis dysfunction is a key pathological basis of LOH, suppressing testosterone synthesis and being closely related to multiple LOH symptoms and signs. The functional and material attributes of Tiangui are highly consistent with the neuroendocrine regulatory network formed by the HPG axis in modern medicine [11]. TCM restores HPG axis function via the combined strategy of tonifying the kidney and soothing the liver to regulate Tiangui: tonifying the kidney consolidates the root and nourishes the source of Tiangui; soothing the liver facilitates qi movement and promotes Tiangui distribution and efficacy. This synergy is regarded as a "treating the root" method for LOH.

Multiple clinical studies show that different formulas regulate HPG axis hormones with different tendencies. Shan Yi et al. [35] reported that Modified Shibao Decoction (加味十宝汤), which primarily tonifies the liver and kidney, significantly increased serum luteinizing hormone (LH), follicle‑stimulating hormone (FSH), free testosterone (FT), and total testosterone (TT) in LOH patients with diabetes of a kidney‑essence deficiency pattern. In contrast, Liu Zhidong et al. [36], Yao Zhemin et al. [14], and Wang Sunya et al. [37] reported that compared with baseline, adding kidney‑tonifying and liver‑soothing formula decoctions, Fufang Xuanju Capsule (复方玄驹胶囊), or Xiongcan Yishen Formula to TST significantly reduced serum LH and FSH while increasing TT. Jia Bo et al. [38] further showed in experimental studies that three active constituents derived from kidney‑tonifying herbs-icariin, acteoside (verbascoside), and ginsenoside Rg1-reduced serum LH and FSH and increased testosterone in LOH model rats. However, a clinical study by Cao Lin et al. [39] showed that after TST combined with the kidney‑tonifying patent medicine Wuzi Yanzong Pill (五子衍宗丸) in LOH patients with type 2 diabetes, LH and FSH did not change significantly.

These findings indicate that herbal regulation of HPG axis hormones may manifest as upregulation, downregulation, or maintenance, reflecting individualization and holistic regulation-likely arising from differences in intrinsic pathological status and syndrome heterogeneity among LOH patients. Notably, most studies lack systematic pre‑intervention assessment of HPG axis functional states. Future research should focus on LOH clinical subtypes, HPG axis states, and TCM syndromes to clarify differential regulatory effects. Overall, these results support, from a modern medical perspective, the scientific connotation and clinical value of TCM pattern differentiation and holistic regulation in modulating HPG axis function during LOH treatment.

 

 

High acteoside herb cistanche extract

Click the picture to get more details

 

 

3.2 Promoting the Expression of Testosterone‑Biosynthetic Enzymes

Aging is a key physiological/pathological process leading to decreased testosterone biosynthesis, corresponding to "kidney‑essence deficiency" and "gradual exhaustion of Tiangui" in TCM. Modern studies indicate that compared with young adults (20–30 years), older adults (70–90 years) show significantly reduced expression of key steroidogenic proteins such as StAR and CYP11A1 in testicular tissue [40]. In LOH model rats, multiple key proteins related to testosterone synthesis-including StAR, TSPO, SF‑1, CYP11A1, HSD3B7, and HSD17B4-are downregulated. Pharmacological studies confirmed that Xiongcan Yishen Formula, with kidney‑tonifying and liver‑soothing effects, can upregulate these proteins and restore testosterone levels [34,41]. This supports the therapeutic meaning of "tonifying the kidney and soothing the liver" to nourish Tiangui and restore its material attribute. In addition, ginsenoside Rg1 may promote the gene and protein expression of StAR, 3β‑HSD, and CYP11A1 to some extent by activating the Nrf2 antioxidant pathway [26].

In summary, evidence indicates that "treating the root" with TCM involves not only holistic modulation of the HPG axis, but also targeting key steps of steroidogenesis by upregulating StAR, CYP11A1, and related enzymes to enhance endogenous synthetic capacity.

3.3 Regulating AR Function in Target Organs

The physiological effects of testosterone are mainly mediated by the androgen receptor (AR). AR expression and functional status directly determine testosterone bioefficacy across multiple systems including reproduction, metabolism, skeletal health, and the nervous system. With aging, serum testosterone and testicular AR expression in rats both progressively decline. Although TST alone can effectively maintain serum testosterone in aged rats, it does not significantly improve local testicular AR expression [42]. This suggests that correcting circulating testosterone does not necessarily improve target‑organ testosterone utilization.

TCM shows unique potential in regulating AR function. Classic kidney‑tonifying formulas such as Wuzi Yanzong Pill can significantly upregulate AR expression in the testes of juvenile male rats [43], implying enhanced sensitivity of androgen signaling. In aging models, modified versions such as the Korean herbal formula KH‑204 (modified Ojayeonjonghwan) similarly increase AR expression in testes of aging rats [44], helping explain symptom improvement in LOH. Moreover, in LOH animal models, icariin, acteoside, and ginsenoside Rg1 can upregulate AR mRNA and protein in the testes, epididymis, and seminal vesicles to varying degrees [38], further suggesting multi‑target AR modulation by herbal components.

Nevertheless, whether increased AR expression necessarily translates into enhanced AR activity and sensitivity requires further investigation. Future studies should not be limited to measuring AR gene/protein expression, but should evaluate functional status, including DNA binding to downstream targets, transcriptional activity, and dynamic downstream gene expression. Androgen resistance or reduced AR sensitivity in some target organs contributes to LOH symptoms and may underlie the limited improvement of certain symptoms by TST alone. Whether TCM can restore AR activity/sensitivity is a key future research direction.

Importantly, AR regulation by TCM may involve multiple organs. Within the HPG axis, AR is widely distributed in hypothalamic nuclei [45]. Preliminary evidence shows that total flavonoids from Eucommia ulmoides leaves (杜仲叶总黄酮) can significantly increase AR levels in the hypothalamus and pituitary in a perimenopausal rat model [46]; however, the regulation of hypothalamic/pituitary AR by herbs in LOH models remains unclear. In the reproductive system, the mechanism by which Youjing Zhongzi Decoction (优精种子汤) improves oligoasthenozoospermia may involve AR regulation [47]. Zuogui Wan (左归丸) can significantly enhance AR activity in germ‑cell models [48], supporting a potential mechanism for improving spermatogenesis. In skeletal muscle metabolism, a kidney‑tonifying and spleen‑strengthening formula can increase serum testosterone and specifically promote AR expression in gastrocnemius muscle in an atrophy model, activating MyoD‑related factors to promote proliferation/differentiation and repair muscle injury [49]. In cardiovascular tissues, testosterone and AR promote development and function of cardiovascular and endothelial cells [50–51], and AR‑positive neurons exist in cardiac ganglia in adult and middle‑aged/elderly rats [52]. Whether herbs protect the cardiovascular system via AR modulation requires further validation.

At the same time, herbal regulation of AR appears tissue‑specific and dependent on pathological context. Some evidence suggests that androgen‑like herbs such as Epimedium (淫羊藿), Codonopsis (党参), and Cistanche (肉苁蓉) may upregulate AR in the tumor microenvironment of prostate cancer and promote cancer cell proliferation and progression [53]. In contrast, certain formulas, herb pairs, and active constituents (e.g., Xihuang Pill, Sanleng–Ezhu herb pair, Vaccaria cyclopeptide B) may exert anti‑prostate cancer effects by inhibiting AR activity or blocking AR‑related pathways [54–56]. This indicates bidirectional regulation of AR pathways in prostate cancer contexts. Clinically, for LOH patients with a history of prostate cancer or abnormal prostate‑specific antigen (PSA), herbs with AR agonistic effects should be avoided as much as possible; AR‑inhibitory herbs/formulas may be safer. Strict monitoring, including regular PSA testing and digital rectal examination, is also recommended. Overall, TCM's multi‑pathway, multi‑target modulation of AR expression and function may underpin its holistic regulatory advantages across reproductive, neuroendocrine, metabolic, and motor systems.

 

4. "Treating the Manifestations": Alleviating Core LOH Symptoms

4.1 Improving Sexual and Reproductive Symptoms

Sexual and reproductive symptoms are the most common manifestations in LOH, including decreased libido, erectile dysfunction (ED), and reduced semen quality. TCM holds that the kidney stores essence and governs reproduction, while the liver governs dispersion and "controls the tendons," directly influencing erectile function. Therefore, herbs with kidney‑tonifying and liver‑soothing effects are frequently used clinically [57–59]. For ED improvement, compared with TST alone, combining TST with Jiarong Tablets (佳蓉片), which replenish kidney essence, can reduce Aging Males' Symptoms (AMS) scores, increase serum TT, and improve the International Index of Erectile Function‑5 (IIEF‑5) score [15]. Another clinical study showed that in LOH patients with ED, compared with tadalafil alone, combining tadalafil with Xiongcan Yishen Formula significantly increased IIEF‑5, TT, and FT while lowering AMS [60]. Mechanistic studies suggest that icariin, an active constituent of kidney‑tonifying herbs, improves erectile function in spontaneously hypertensive rats by upregulating Nrf2, HO‑1, DDAH, and PPAR‑γ in corpus cavernosum, inhibiting ADMA, and increasing the P‑eNOS/eNOS ratio [61].

Regarding semen quality and spermatogenesis, Wuzi Yanzong Pill and Jinkui Shenqi Pill (金匮肾气丸) have been confirmed to promote recovery of spermatogenesis [62]. Saffron extract significantly improves semen quality decline in D‑galactose‑induced LOH mice [19]. Several kidney‑tonifying monomers (icariin, acteoside, ginsenoside Rg1) not only restore serum testosterone in LOH model rats but also improve seminiferous tubule lesions and increase spermatogenic cells and sperm counts [38]. Protective mechanisms include: aqueous extract of Cistanche activates Nrf2‑mediated antioxidant pathways to restore antioxidant capacity and increase sperm concentration and motility while reducing deformity rate in cyclophosphamide‑induced testicular injury models [63]; Yishen Zhongzi Formula (益肾种子方) reduces ROS and MDA, increases SOD and CAT, and inhibits OS‑mediated caspase‑3 upregulation to improve testicular/epididymal injury and restore spermatogenic integrity [64]; icariin improves antioxidant status, reduces NOS activity and NO levels, alleviates apoptosis, and repairs testicular function to protect spermatogenesis [65].

4.2 Improving Physical Performance and Metabolic Symptoms

LOH commonly features decreased energy, reduced muscle strength, increased body fat, and dysregulated glucose/lipid metabolism. TCM attributes these symptoms to "kidney‑essence deficiency." The kidney governs bones and generates marrow; deficiency leads to insufficient "sea of marrow" and poor nourishment of tendons and bones, resulting in fatigue and weakness. Decline of kidney yang fails to warm and transform the spleen, leading to phlegm‑damp accumulation and obesity and metabolic disorders. Clinical studies show that herbal interventions tailored to different syndromes can improve physical and metabolic symptoms. In LOH patients with combined yin‑yang deficiency pattern, Erxian Decoction (二仙汤) significantly decreased physical/vascular symptom scores within the PADAM symptom scale [17]. Another study found that Shibao Decoction (十宝汤) significantly increased whole‑body and appendicular skeletal muscle mass indices and reduced insulin resistance in LOH patients with kidney‑essence deficiency [16].

4.3 Improving Mental and Psychological Symptoms

Among male disorders, LOH patients are prone to anxiety and depression [66]. A systematic review suggested that TCM is superior to Western medicine (testosterone undecanoate) in improving mental/psychological scores [7]. Zhang Qi et al. [67] proposed that LOH with depression is closely related to dysfunction of the "kidney–liver–Tiangui" axis: kidney deficiency with depleted essence and declining Tiangui leads to insufficient nourishment of the spirit as an initiating factor; impaired liver dispersion and Tiangui dysregulation with liver qi stagnation drives progression. They advocate tonifying the kidney and replenishing essence, soothing the liver and relieving constraint, and regulating Tiangui. Clinically, Erxian Decoction significantly reduced mental/psychological symptoms in PADAM scores after treatment [17], reflecting the positive role of the kidney‑tonifying and liver‑soothing approach.

 

5. "Regulating the Body": Regulating Glucose and Lipid Metabolism to Prevent Disease

LOH is closely related to metabolic disorders such as obesity, hyperlipidemia, and hyperglycemia, and the two often intertwine to form a vicious cycle [68–70]. This not only further suppresses testosterone but may also induce and aggravate LOH symptoms, promoting disease progression and affecting treatment outcomes [71–72]. TCM attributes abnormal glucose/lipid metabolism to dysfunction of the liver, spleen, kidney, and other viscera [73–76]. Therefore, clinical interventions via liver‑soothing, spleen‑strengthening, and kidney‑tonifying methods can regulate glucose/lipid metabolism and body weight, achieving dual goals of preventing LOH occurrence and reducing recurrence ("treating disease before it arises" and "promoting recovery and preventing relapse").

 

Table 1. Core mechanisms and supporting evidence for Chinese herbal formulas, herb pairs, and active ingredients in the treatment of LOH

Abbreviations: LOH, late-onset hypogonadism; OS, oxidative stress; HPG axis, hypothalamic–pituitary–gonadal axis; ROS, reactive oxygen species; MDA, malondialdehyde; SOD, superoxide dismutase; CAT, catalase; GSH, glutathione; GPx4, glutathione peroxidase 4; AR, androgen receptor.

(A) "Supporting the righteous" (restoring testicular microenvironmental homeostasis)

Level of action	Pathway / target	TCM therapeutic strategy	Dosage form, dose, and duration (as reported)	Key effects	Representative formula / active ingredient	Evidence type	Refs
Restore redox homeostasis	Antioxidant defense (GPx4, GSH, SOD, CAT), ROS/MDA	Tonify kidney illegiblesyndromeitemillegible syndrome itemillegiblesyndromeitem	Xiongcan Yishen Formula (雄蚕益肾方) 10.4, 20.8, 41.6 g/kg; 1×/day; 28 days	↑ GPx4, GSH, SOD, CAT activity; ↓ ROS, MDA; restoration of redox balance; enhanced antioxidant capacity	Xiongcan Yishen Formula	Animal experiment	[22–23]
Restore redox homeostasis	PI3K–Akt–Nrf2 signaling	-	Saffron extract 10, 20 mg/kg; 1×/day; 30 days	Activation of PI3K–Akt–Nrf2 pathway; improved oxidative injury; ↑ testosterone (T) recovery (implied by study aim)	Saffron extract	Animal + cell experiments	[19]
Restore cell-cycle stability	Senescence/inflammation markers (IL‑1, IL‑6, IL‑8)	-	Ginsenoside Rg1 (intraperitoneal) 40 mg/kg; 1×/day; 26 days	↓ IL‑1/IL‑6/IL‑8 gene expression; reduced senescent Leydig cells (anti‑senescence)	Ginsenoside Rg1	Animal + cell experiments	[26]
Restore cell-cycle stability	HSP90/p38/NF‑κB pathway	-	Shanyao–Huangjing herb pair (山药–黄精) (group 1: 2.5 g/kg Shanyao decoction + 2.5 g/kg Huangjing decoction; group 2: 5 g/kg Shanyao + 2.5 g/kg Huangjing; group 3: 2.5 g/kg Shanyao + 5 g/kg Huangjing); 1×/day; 21 days	Regulated HSP90/p38/NF‑κB; improved apoptosis in rat testis (anti‑apoptosis)	Shanyao–Huangjing herb pair	Animal experiment	[27]
Restore autophagy homeostasis	PINK1/Parkin‑mediated mitophagy	-	Xiongcan Yishen Formula 10.4, 20.8, 41.6 g/kg; 1×/day; 28 days	↑ PINK1 and Parkin protein levels; restoration of Leydig‑cell mitophagy/autophagy	Xiongcan Yishen Formula	Animal experiment	[29]
Restore autophagy homeostasis	AMPK–mTOR pathway	Tonify kidney and replenish essence	Heshouwu Decoction (何首乌饮) 6.13 g/kg; 2×/day; staged dosing; 90 days	Activated AMPK–mTOR pathway; enhanced Leydig‑cell autophagy capacity	Heshouwu Decoction	Cell experiment	[30]
Restore autophagy homeostasis	Beclin‑1; LC3‑II/I	Tonify kidney	Yijing Capsule (养精胶囊) 0.315, 0.63, 1.26 g/kg; 1×/day; 28 days	↑ Beclin‑1 and LC3‑II/I; promoted autophagosome formation; enhanced testosterone synthesis capacity (via autophagy regulation)	Yijing Capsule	Animal experiment	[31]
Restore circadian rhythm homeostasis	Clock genes BMAL1, NR1D1, PER2, CRY1	-	Xiongcan Yishen Formula 10.4, 20.8, 41.6 g/kg; 2×/day; 28 days	↑ mRNA and protein of BMAL1/NR1D1/PER2/CRY1; restored testicular circadian rhythm; improved steroidogenesis dysfunction linked to rhythm disorder	Xiongcan Yishen Formula	Animal experiment	[34]

---

(B) "Treating the root" (restoring endogenous testosterone synthesis and upstream regulation)

Level of action	Pathway / target	TCM therapeutic strategy	Dosage form, dose, and duration (as reported)	Key effects	Representative formula / active ingredient	Evidence type	Refs
Modulate HPG axis	Serum LH, FSH (and clinical status improvement)	Tonify liver and kidney; replenish deficiency	Modified Shibao Decoction (加味十宝汤) 1 dose/day, taken in morning and evening; 12 weeks	↑ LH, FSH (and clinical condition improved)	Modified Shibao Decoction	Single‑center, randomized, double‑blind clinical trial	[35]
Modulate HPG axis	Serum LH, FSH, TT	Tonify kidney and soothe liver	Kidney‑tonifying & liver‑soothing formula 1 dose/day, taken morning and evening; 3 months	↓ LH, FSH; ↑ TT	Kidney‑tonifying & liver‑soothing formula (复方/汤剂)	Single‑center, randomized, double‑blind clinical trial	[14,36–38] (as shown in table)
Modulate HPG axis	Serum LH, FSH, testosterone	Tonify kidney andother,illegibleand other, illegibleandother,illegible	Icariin + Acteoside + Ginsenoside Rg1 each 200 mg/kg; 1×/day; 60 days	↓ LH, FSH; ↑ testosterone	Icariin; Acteoside; Ginsenoside Rg1	Animal experiment	[38]
Upregulate testosterone biosynthesis	StAR, TSPO, SF‑1, CYP11A1, HSD3B7, HSD17B4	Tonify kidney and soothe liver	Xiongcan Yishen Formula 10.4, 20.8, 41.6 g/kg; 2×/day; 28 days	↑ StAR/TSPO/SF‑1/CYP11A1/HSD3B7/HSD17B4; ↑ testosterone	Xiongcan Yishen Formula	Animal experiment	[34,41]
Upregulate testosterone biosynthesis	StAR, 3β‑HSD, P450scc (CYP11A1)	-	Ginsenoside Rg1 (intraperitoneal) 40 mg/kg; 1×/day; 26 days	↑ StAR, 3β‑HSD, P450scc (gene/protein); reduced senescent Leydig cells	Ginsenoside Rg1	Animal + cell experiments	[26]

Clinical studies show that after 6 months of treatment with Wuzi Yanzong Pill combined with testosterone undecanoate in LOH patients with type 2 diabetes, BMI, waist circumference, fasting blood glucose, 2‑hour postprandial glucose, HbA1c, insulin resistance index, total cholesterol, LDL‑C, HDL‑C, and triglycerides were significantly improved compared with baseline and compared with the testosterone‑only group [39]. Another clinical study showed that a kidney‑tonifying and spleen‑strengthening formula effectively regulated lipid metabolism, improved insulin resistance, and lowered blood glucose in type 2 diabetes patients with dyslipidemia of a spleen–kidney deficiency pattern [77]. These findings suggest that, on the basis of TST, syndrome‑differentiated herbal intervention can improve metabolic disorders and thereby enhance overall efficacy in LOH patients with metabolic syndrome.

Mechanistically, the method of strengthening the spleen, soothing the liver, and resolving turbidity may improve glucose/lipid disorders and insulin resistance in type 2 diabetes model rats by upregulating hepatic IRS‑1 and GLUT‑4 proteins [78]. Zishen Qinggan Formula (滋肾清肝方) may reduce lipid synthesis by inhibiting fatty acid synthase and regulate NF‑κB signaling to improve glucose/lipid metabolism [79]. Astragalus polysaccharides may reduce hepatic lipid deposition and lower blood glucose by inhibiting the Wnt1 pathway in diabetic rats [80]. These molecular findings provide scientific rationale for integrated Chinese–Western management of LOH.

 

6. Conclusions and Perspectives

TCM treatment of LOH is characterized by multi‑pathway and multi‑level actions. After herbal intervention, LOH model rats show comprehensive improvements in testicular interstitium, sperm counts, mitochondrial injury, and histological and ultrastructural changes [81–82]. Network pharmacology suggests that Jiarong Tablets may treat LOH by targeting testosterone‑biosynthetic enzymes in Leydig cells, oxidative stress, apoptosis, and other pathways [20]. Similarly, saffron extract helps restore redox homeostasis while also inhibiting apoptosis [19]. These findings indicate that TCM can achieve holistic intervention through synergistic strategies of "supporting the righteous," "treating the root," and "treating the manifestations." Given the close pathological relationship between metabolic syndrome and LOH, TCM's regulation of glucose/lipid metabolism confers dual advantages of "treating disease before it arises" and "promoting recovery and preventing relapse," further expanding its clinical value. Future clinical practice should emphasize comorbidity management of LOH and metabolic diseases, especially in high‑risk populations such as obesity and metabolic syndrome, and scientifically evaluate clinical benefits. Exploring the optimal timing of intervention based on TCM preventive principles is also practically meaningful.

In terms of therapeutic connotation, "supporting the righteous," "treating the root," and "treating the manifestations" constitute an organic whole. "Supporting the righteous" focuses on rebuilding the testicular microenvironment by restoring redox balance, cell‑cycle homeostasis, autophagy, and circadian rhythms, thereby providing internal保障 and laying the foundation for "treating the root" and "treating the manifestations." "Treating the root" emphasizes restoring testosterone biosynthesis and physiological efficacy by tonifying the kidney and soothing the liver to regulate Tiangui, rebuilding HPG axis homeostasis, enhancing steroidogenesis, and improving AR functional status to increase testosterone utilization efficiency. "Treating the manifestations" focuses on relieving core symptoms-improvement in sexual function, physical capacity, and mood can enhance adherence and optimize metabolic feedback, thereby reinforcing the "root" basis. Finally, by regulating systemic states such as glucose/lipid metabolism, TCM helps reduce LOH occurrence and recurrence risk. Current abundant preclinical evidence and limited clinical trials provide preliminary support across "supporting the righteous," "treating the root," "treating the manifestations," and "regulating the body," and offer references for syndrome‑based prescribing. Specifically, for combined yin‑yang deficiency patterns, Erxian Decoction, Jiarong Tablets, or herbs such as Epimedium, Cistanche, and Polygonatum may be selected; for kidney‑essence deficiency patterns, Shibao Decoction, Wuzi Yanzong Pill, Heshouwu Decoction, Zuogui Wan, or herbs such as Dioscorea, Polygonatum, and prepared Rehmannia may be used; for kidney deficiency with liver constraint patterns, Xiongcan Yishen Formula, Shugan Yiyang Capsules (疏肝益阳胶囊), or herbs such as goji berry, white peony, and tribulus may be considered. Nevertheless, the strength of clinical evidence remains limited-sample sizes are often small, studies are mostly single‑center, and populations are often complex (LOH with comorbidities), making the true effect difficult to estimate accurately. Future trials should adopt rigorous designs with large sample sizes, multicenter, double‑blind, placebo‑controlled methods to clarify independent efficacy and safety.

While concerns about TST adverse effects persist, the safety of herbal clinical applications should not be overlooked. Herbal toxicity is often related to improper dosage, non‑standard decoction methods, unreasonable use, and unclear mechanisms [83]. Therefore, LOH clinical practice should emphasize accurate syndrome differentiation, standardize dosing and preparation methods, and rationally combine herbs to minimize safety risks. Existing evidence suggests that inappropriate use of certain herbs such as Evodia, Polygonum multiflorum (He Shou Wu), Bupleurum (Chai Hu), and Toosendan (Chuan Lian Zi) may increase the risk of drug‑induced liver injury in susceptible populations (e.g., those with hepatic/renal insufficiency) [84–85]. For patients with abnormal PSA levels or prostate cancer, extra caution is needed with AR‑agonistic herbs such as Epimedium, Codonopsis, and Cistanche. Comprehensive baseline evaluation-including liver and kidney function and PSA-is therefore particularly important.

In summary, guided by the core pathogenesis of "kidney deficiency with liver constraint and premature exhaustion of Tiangui," the holistic regulatory role of TCM in LOH is realized through synergistic interventions across four dimensions-"supporting the righteous-treating the root-treating the manifestations-regulating the body"-forming a multi‑level and full‑course therapeutic network. Mechanistically, herbs rebuild physiological balance of the testicular microenvironment by regulating oxidative stress, maintaining cellular homeostasis, and improving autophagy; on this basis, they regulate HPG axis function and restore expression of testosterone‑biosynthetic enzymes to recover endogenous testosterone, and modulate AR activity via multi‑pathway, multi‑target mechanisms to improve androgen utilization and physiological efficacy. Meanwhile, symptom‑targeted interventions achieve "treatment of root and manifestations" and "supporting the righteous while dispelling pathogenic factors." Finally, by intervening in systemic states such as glucose/lipid metabolism, TCM facilitates recovery and prevents relapse, embodying the essence of holistic regulation and preventive medicine, and highlighting its distinctive advantages compared with TST alone-thereby providing practical references for the clinical application of TCM in LOH.

 

 

 

References

 

[1] 中国老年保健协会生长发育和性腺疾病专业委员会. 男性迟发性性腺功能减退症的诊疗指南[J]. 中华医学杂志, 2025, 105 (9):650-660.
[2] 男性迟发性性腺功能减退症中西医结合诊疗与健康管理专家共识[J]. 中华男科学杂志, 2024, 30 (10):942-952.
[3] Liu YJ, Shen XB, Yu N, et al. Prevalence of late-onset hypogonadism among middle-aged and elderly males in China: results from a national survey[J]. Asian J Androl, 2021, 23 (2):170-177.
[4] Santos MRD, Bhasin S. Benefits and Risks of Testosterone Treatment in Men with Age-Related Decline in Testosterone[J]. Annu Rev Med, 2021, 72:75-91.
[5] Snyder P. Testosterone treatment of late-onset hypogonadism - benefits and risks[J]. Rev Endocr Metab Disord, 2022, 23 (6):1151-1157.
[6] Miranda EP, Torres LO. Late-onset hypogonadism: Prostate safety[J]. Andrology, 2020, 8 (6):1606-1613.
[7] 司红梅, 于旭东, 商建伟, 等. 中医药治疗迟发性性腺功能减退症的系统评价与Meta分析[J]. 中国实验方剂学杂志, 2021, 27 (3):191-197.
[8] 吴悔, 宁港, 李波男, 等. 从"天癸-肝肾"论治男性迟发性性腺功能减退症[J]. 湖南中医药大学学报, 2023, 43 (2):354-358.
[9] 吴悔, 宁港, 李波男, 等. 基于"天癸失于时序"论治男性迟发性性腺功能减退症[J]. 北京中医药大学学报, 2024, 47 (11):1501-1505.
[10] 赵志伟, 李玉坤, 刘大胜, 等. 中医"九法五径"临证法则治疗男性迟发性性腺功能减退症思路探析[J]. 中国性科学, 2025, 34 (9):77-82.
[11] 苏亮, 曹䶮, 朱健, 等. 从男性迟发性性腺功能减退症探析男性"天癸"内涵[J]. 中国中医基础医学杂志, 2022, 28 (11):1791-1793.
[12] 吴悔, 宁港, 李波男, 等. 男性迟发性性腺功能减退临床辨治思路及预防调护策略[J]. 中华男科学杂志, 2025, 31 (8):757-760.
[13] Zhang H, Deng S, Liu L, et al. Clinical efficacy of Chinese traditional herbal medicine (Fufang Xuanju capsule) on males of late-onset hypogonadism presenting with sexual dysfunction[J]. Medicine (Baltimore), 2025, 104 (1):e41160.
[14] 姚哲敏, 黄双双, 单云峰. 复方玄驹胶囊治疗男性迟发性性腺功能减退临床研究[J]. 新中医, 2023, 55 (15):105-109.
[15] 吴猛, 郝宝金, 梁威宁, 等. 佳蓉片联合十一酸睾酮胶丸治疗迟发性性腺功能减退症的多中心临床疗效观察[J]. 中华男科学杂志, 2020, 26 (4):346-350.
[16] 陈少康, 单意, 史振滏, 等. 十宝汤治疗肾精亏虚型迟发性性腺功能减退的临床研究[J]. 中华男科学杂志, 2025, 31 (7):630-636.
[17] 张奇峰, 张焱, 丁毅. 二仙汤治疗肾阴阳两虚型男性迟发性性腺功能减退症临床研究[J]. 南京中医药大学学报, 2018, 34 (3):269-272.
[18] 袁书凝, 韦妮妮, 杨晓玉, 等. 睾丸氧化应激与男性迟发性性腺功能减退症[J]. 国际生殖健康/计划生育杂志, 2025, 44 (4):311-315.
[19] Liu H, Guo Z, Zang Z, et al. Saffron extract alleviates D-gal-induced late-onset hypogonadism by activating the PI3K-Akt-Nrf2 signaling pathway[J]. J Ethnopharmacol, 2025, 340:119273.
[20] 胡瑞, 吴悔, 李波男, 等. 基于网络药理学方法探讨佳蓉片治疗男性迟发性性腺功能减退症的可能机制[J]. 中华男科学杂志, 2022, 28 (10):915-925.
[21] 吴冰燕, 曹原, 刘思丽, 等. 氧化应激对公鸡睾丸组织结构及睾酮合成相关基因表达的影响[J]. 农业生物技术学报, 2024, 32 (3):605-616.
[22] 唐雪, 李波男, 周海亮, 等. 雄蚕益肾方对迟发性性腺功能减退症大鼠睾丸组织形态学改变及抗氧化作用研究[J]. 湖南中医药大学学报, 2020, 40 (8):951-956.
[23] 彭阿建, 宁港, 吴悔, 等. 雄蚕益肾方对小鼠睾丸间质细胞氧化应激损伤后铁死亡的影响[J]. 中华男科学杂志, 2024, 30 (7):640-647.
[24] 吴悔, 宁港, 李波男, 等. Nrf2 对睾丸微环境的影响及其在男性疾病中的研究进展(英文)[J]. Journal of Chinese Pharmaceutical Sciences, 2023, 32 (7):513-526.
[25] 毕佳杰, 马婧, 李波, 等. 百合育子方对少弱精子症大鼠睾丸锌稳态,CFTR 和 Keap1/Nrf2/HO-1 信号通路影响[J]. 中国中西医结合杂志, 2024, 44 (2):193-201.
[26] 向叶舟, 汪子铃, 肖含先之, 等. 人参皂苷Rg1拮抗D-半乳糖致睾丸间质细胞雄激素分泌障碍的机制研究[J]. 中国细胞生物学学报, 2021, 43 (7):1437-1445.
[27] 王成立, 王子晗, 刘嘉. 山药-黄精药对通过调控 HSP90/p38/NF-κB 改善大鼠少弱精子症[J]. 药物评价研究, 2025, 48 (11):3073-3087.
[28] 李维仁, 侯垒, 崔功静, 等. 老年大鼠睾丸间质细胞自噬的变化[J]. 中国男科学杂志, 2013, 27 (7):3-7,12.
[29] 周兴, 唐雪, 吴霞, 等. 雄蚕益肾方通过 PINK1/Parkin 通路介导 LOH 大鼠睾丸间质细胞线粒体自噬研究[J]. 中华男科学杂志, 2020, 26 (12):1129-1134.
[30] 李朝英, 李思睿, 张伟, 等. 补肾中药通过 AMPK-mTOR 通路提高肾精亏虚大鼠睾丸间质细胞自噬能力[J]. 河北大学学报(自然科学版), 2024, 44 (6):633-642.
[31] 金亦涵, 邢栋, 孙大林, 等. 养精胶囊通过调节自噬提高睾丸间质细胞睾酮合成功能的研究[J]. 中国男科学杂志, 2023, 37 (6):39-43,77.
[32] 高磊, 洪金, 张丽萍, 等. 生物钟基因调控牦牛睾酮分泌的机制研究[J]. 西北农林科技大学学报(自然科学版), 2023, 51 (3):9-18,28.
[33] 丁赫, 郭乐薇, 徐高青, 等. BMAL1 对小鼠睾丸间质细胞凋亡的影响[J]. 中国畜牧杂志, 2019, 55 (6):63-67.
[34] 吴悔, 宁港, 李波男, 等. 雄蚕益肾方对雄性迟发性性腺功能减退大鼠睾丸组织生物钟基因表达的影响[J]. 中华男科学杂志, 2023, 29 (1):76-82.
[35] 单意, 陈少康, 史振滏, 等. 加味十宝汤对肾精亏虚型男性迟发性性腺功能减退症合并糖尿病患者血清性激素水平的影响[J]. 中国实验方剂学杂志, 2025, 31 (1):227-233.
[36] 刘志东, 温庆辉, 缪海婷. 补肾疏肝法治疗男性迟发性性腺功能减退症的疗效及对 IGF-1,INSL3 的影响[J]. 现代中西医结合杂志, 2024, 33 (3):361-364.
[37] 王孙亚, 李望辉, 宾东华, 等. 雄蚕益肾方联合小剂量睾酮补充治疗男性迟发性性腺功能减退症临床观察[J]. 湖南中医药大学学报, 2018, 38 (8):903-907.
[38] 贾波, 尹漾阳, 姚俊波, 等. 中药单体对迟发性性腺功能减退模型大鼠的疗效与作用机制研究[J]. 中国性科学, 2025, 34 (01):129-133.
[39] 曹琳, 赵晓丽, 谢绍锋, 等. 五子衍宗丸联合十一酸睾酮胶丸治疗男性 2 型糖尿病合并迟发性性腺功能减退症 42 例[J]. 西部中医药, 2019, 32 (12):73-76.
[40] 李维仁, 韩勃萱, 刘涛, 等. 老年人睾丸间质细胞结构及 StAR 和 P450scc 蛋白表达的变化[J]. 北京大学学报(医学版), 2011, 43 (4):505-508.
[41] 周兴, 李波男, 周海亮, 等. 雄蚕益肾方对LOH大鼠Leydig细胞胆固醇转运蛋白,睾酮合成酶和SF-1表达的影响[J]. 中华男科学杂志, 2020, 26 (3):258-264.
[42] 牛晓振, 郑军华, 耿江, 等. 男性更年期综合征患者性腺轴功能变化及其与代谢综合征的关系的动物性实验研究[J]. 临床与病理杂志, 2015, 35 (4):603-608.
[43] He M, Wang L, Chen Y, et al. Effect of Wuziyanzong pill on levels of sex hormones, and expressions of nuclear-associated antigen Ki-67 and androgen receptor in testes of young rats[J]. J Tradit Chin Med, 2016, 36 (6):743-748.
[44] Choi SW, Jeon SH, Kwon EB, et al. Effect of Korean Herbal Formula (Modified Ojayeonjonghwan) on Androgen Receptor Expression in an Aging Rat Model of Late Onset Hypogonadism[J]. World J Mens Health, 2019, 37 (1):105-112.
[45] 刘晓柳, 李光千, 赵小明. 雄性大鼠下丘脑雄激素受体蛋白及其 mRNA 表达的探讨[J]. 神经解剖学杂志, 2003, (4):423-426.
[46] 田硕, 白明, 苗明三. 杜仲叶总黄酮对围绝经期大鼠模型的影响[J]. 中华中医药杂志, 2018, 33 (12):5386-5391.
[47] 吴岩橙, 滕凤猛, 卢阳, 等. 基于网络药理学和分子对接技术对优精种子汤治疗少弱精子症的作用靶点及分子机制研究[J]. 中国临床研究, 2025, 38 (3):445-451.
[48] Bao B, Yang Z, Deng S, et al. Zuogui Wan improves spermatogenesis of GC1-spg cells through modulating AR-related pathways[J]. Andrologia, 2022, 54 (6):e14407.
[49] 常岑, 金晔华, 张超超, 等. 基于雄激素-雄激素受体通路探析补肾健脾方改善骨骼肌萎缩的机制[J]. 时珍国医国药, 2018, 29 (12):2907-2909.
[50] 陈玉慧, 李学伟, 马继登. 睾酮及其受体对心血管发育和功能的影响[J]. 中国生物化学与分子生物学报, 2021, 37 (11):1423-1431.
[51] 邹和德, 陈文康, 赵家有. 男性雄激素影响血管内皮细胞机制的研究进展[J]. 中国现代医学杂志, 2024, 34 (7):55-59.
[52] 刘晓柳, 吴秀卿, 李光千, 等. 中老年雄性大鼠心内神经节雄激素受体及其 mRNA 的表达变化[J]. 神经解剖学杂志, 2006, (1):85-88.
[53] Zhang Z, Ip S, Cho WC, et al. Evaluation of the effects of androgenic Chinese herbal medicines on androgen receptors and tumor growth in experimental prostate cancer models[J]. J Ethnopharmacol, 2020, 260:113058.
[54] 吴丽通, 洪志明, 袁金筠, 等. 三棱-莪术药对通过相须配伍协同调控 AR/FOXA1 信号轴及肿瘤相关巨噬细胞 M2 极化增强抗前列腺癌作用研究[J]. 中国中药杂志, 2026, 51 (3):799-810.
[55] 戴新军, 龙衍, 邹博, 等. 基于 AR/mTOR 信号通路探讨西黄丸对前列腺癌 LNCaP 细胞增殖,凋亡影响的实验研究[J]. 中国中药杂志, 2023, 48 (15):4147-4155.
[56] 牟睿宇, 廖洋, 贾春鑫, 等. 王不留行环肽 B 逆转前列腺癌 C4-2 细胞激素非依赖性生长及作用机制[J]. 中草药, 2024, 55 (17):5898-5904.
[57] 李波男, 周青, 何清湖, 等. 基于数据挖掘探讨谭新华治疗勃起功能障碍用药规律[J]. 中国中医药信息杂志, 2023, 30 (8):23-28.
[58] 王耀武, 周馨, 朱智, 等. 基于数据挖掘探讨中医药治疗勃起功能障碍的临床运用现况及规律[J]. 中国性科学, 2023, 32 (1):5-10.
[59] 王彪, 林群芳, 杨扬, 等. 谭新华运用子类中药治疗男性不育症经验[J]. 上海中医药杂志, 2024, 58 (10):48-50,62.
[60] 王孙亚, 李望辉, 周兴, 等. 雄蚕益肾方联合小剂量他达拉非治疗男性迟发性性腺功能减退症伴男性勃起功能障碍的临床研究[J]. 中国性科学, 2019, 28 (6):19-22.
[61] 杨焜木, 杨志惠, 姜睿. 淫羊藿苷上调 NRF2 改善 SHR 大鼠勃起功能[J]. 中华男科学杂志, 2021, 27 (2):106-113.
[62] 张树成, 贺斌, 王尚明, 等. 五子衍宗丸和金匮肾气丸对动物生精功能影响的比较研究[J]. 中国计划生育学杂志, 2009, 17 (7):401-404.
[63] 夏伦斌, 蒋平, 何燕飞, 等. 肉苁蓉水提物对环磷酰胺致小鼠睾丸损伤的保护作用及其机制初探[J]. 中华男科学杂志, 2022, 28 (9):771-778.
[64] 韩强, 曾银, 王任远, 等. 基于氧化及 Caspase-3 凋亡探讨益肾种子方防治大鼠睾丸损伤机制研究[J]. 中国中西医结合杂志, 2023, 43 (9):1095-1099.
[65] 吴瑶, 时姗姗, 柳海燕, 等. 淫羊藿苷改善白消安联合环磷酰胺诱导的雄性小鼠生殖功能损伤的作用研究[J]. 中华男科学杂志, 2025, 31 (1):25-33.
[66] 袁亦铭, 方冬, 张志超, 等. 男科门诊常见疾病患者抑郁焦虑患病特点的单中心大样本调查研究[J]. 临床泌尿外科杂志, 2016, 31 (4):303-307.
[67] 张琪, 曹得中, 罗成龙, 等. 基于"肾肝-天癸"论治男性迟发性性腺功能减退症合并抑郁症[J]. 北京中医药, 2025, 44 (9):1173-1176.
[68] 黄崇兵, 王思宏, 倪孝兵, 等. 老年男性 2 型糖尿病患者血清睾酮与体重指数的相关性研究[J]. 中国处方药, 2024, 22 (6):171-173.
[69] 曹庆, 田艳霜, 明明, 等. 男性 2 型糖尿病患者腹型肥胖与性激素之间的相关性分析[J]. 大连医科大学学报, 2023, 45 (5):421-426.
[70] 白小岗, 李霞, 贾爱华, 等. 2 型糖尿病男性患者性激素水平与体重指数,糖脂代谢及胰岛素抵抗相关性分析[J]. 陕西医学杂志, 2022, 51 (9):1086-1089.
[71] 冯隽龙, 李海松, 孙松, 等. 转录组学联合网络药理学探究高血压通过cGMP/PKG信号通路诱导勃起功能障碍的机制[J]. 中华男科学杂志, 2024, 30 (9):771-781.
[72] 尹利军, 杨亚南, 林小晶, 等. 雄激素及其受体在有氧运动改善肥胖及肥胖相关疾病症状和血糖血脂中的作用[J]. 中国运动医学杂志, 2020, 39 (7):552-561.
[73] 杨瑞娟, 李晓波, 白红霞, 等. 基于"清浊相干"理论探析运枢化浊法治疗 2 型糖尿病合并高脂血症思路[J]. 江西中医药, 2025, 56 (9):13-15.
[74] 刘乃华, 林传权, 高永, 等. 脾功能本质与"从脾论治"治法方药研究的探索与展望[J]. 广州中医药大学学报, 2024, 41 (10):2608-2614.
[75] 孙贵炎, 苏嘉楠, 安继仁, 等. 基于"精不正化"理论探讨糖尿病前期的中医药干预[J]. 中华中医药学刊, 2023, 41 (4):177-179.
[76] 马艺鑫, 宁顺宇, 吕晓明, 等. 基于"肝脾相关"理论探讨疏肝健脾法调控肠道微生态防治糖脂代谢性疾病[J]. 时珍国医国药, 2020, 31 (10):2450-2452.
[77] 潘梓珊, 李东玲, 冯敏瑶, 等. 补肾健脾方治疗 2 型糖尿病合并血脂异常患者的疗效及对脂联素的影响研究[J]. 广州中医药大学学报, 2024, 41 (1):54-61.
[78] 姜玉华, 陈曦, 张冰晗, 等. 健脾疏肝消浊法对 2 型糖尿病大鼠糖脂代谢及 GLUT-4,IRS-1 表达的影响[J]. 时珍国医国药, 2025, 36 (6):1040-1044.
[79] 王景存, 田春雨, 张帆, 等. 基于转录组学探讨滋肾清肝方改善 2 型糖尿病糖,脂代谢的作用机制[J]. 中国实验方剂学杂志, 2024, 30 (8):109-117.
[80] 武洁, 刘旭光, 冯晓辞, 等. 黄芪多糖调控 Wnt1 信号对糖尿病大鼠糖脂代谢紊乱影响机制研究[J]. 辽宁中医药大学学报, 2024, 26 (11):43-51.
[81] 田园园, 李波男, 周海亮, 等. 佳蓉片对LOH大鼠睾丸形态结构与功能改善作用研究[J]. 中华男科学杂志, 2020, 26 (3):237-241.
[82] 周兴, 周青, 何清湖. 雄蚕益肾方对迟发性性腺功能低下症大鼠睾丸组织病理变化与超微结构的影响[J]. 湖南中医药大学学报, 2017, 37 (6):586-590.
[83] 李娆娆, 张志杰, 王祝举, 等. 近 60 年中药毒副作用及不良反应文献分析[J]. 中国实验方剂学杂志, 2010, 16 (15):213-216,221.
[84] 陈洋, 董嘉皓, 李斐, 等. 吴茱萸毒性概述与思考[J]. 时珍国医国药, 2017, 28 (9):2215-2217.
[85] 吴豪 , 钟荣玲, 夏智, 等. 潜在肝毒性中药的成分研究进展 [J]. 中国中药杂志 , 2016, 41 (17):3209-3217.