Modes of action of traditional Chinese medicine for diabetic infertility: from molecular pathways to clinical evidence

Abstract

Diabetes-associated infertility results from interconnected immunometabolic, oxidative, inflammatory, and endocrine disturbances that impair reproductive function in both sexes. Conventional therapies address individual symptoms but often fail to target this systemic, immune-mediated complexity. This narrative review summarizes preclinical and clinical evidence on the role of Traditional Chinese Medicine (TCM) in managing diabetic infertility, with a focus on immune-endocrine interactions, cytokine modulation, and inflammatory signaling. TCM interventions - including single-herb extracts, multi-herb formulations, and non-pharmacological approaches such as acupuncture and mind-body interventions-enhance insulin sensitivity, suppress pro-inflammatory cascades (NF-κB, TNF-α, IL-6), and regulate key immunometabolic pathways such as PI3K/Akt and AMPK. Mechanistic studies have also demonstrated improved nitric oxide bioavailability, endothelial function, and mitochondrial protection in gametogenic cells. They further show stabilization of hypothalamic-pituitary-gonadal and immune signaling, along with modulation of the gut-microbiota-immune axis. These immunomodulatory effects contribute to better spermatogenesis, semen quality, ovulation, endometrial receptivity, implantation, and pregnancy outcomes, particularly in individuals with insulin resistance or polycystic ovary syndrome. Overall, TCM shows promise as an adjunctive immunomodulatory strategy for diabetic infertility, supported by preliminary evidence of reproductive benefits. However, current evidence remains limited, and well-designed multicenter, immunology-informed clinical trials are required to confirm its efficacy.

Introduction

Diabetes and infertility increasingly intersect as major global health concerns, imposing substantial physiological, psychological, and economic burdens. In 2021, an estimated 537 million adults aged 20-79 years were living with diabetes worldwide, a number projected to reach 783 million by 2045 - a 46% increase [1]. Meanwhile, infertility affects approximately 10-15% of couples globally, with male factors contributing to 40-60% of cases [2,3]. Among men with type 2 diabetes mellitus (T2DM), infertility occurs in 35-51%, far exceeding the prevalence in the general population [4].

Diabetic infertility is a multifactorial reproductive disorder arising from chronic hyperglycemia and its downstream metabolic and inflammatory consequences. Persistent hyperglycemia elevates reactive oxygen species (ROS), promotes advanced glycation end-products (AGEs), activates inflammatory cascades, and induces mitochondrial and endoplasmic reticulum (ER) stress [5]. In men, these alterations impair sperm motility, increase DNA fragmentation, and disrupt endocrine homeostasis, often aggravated by immune-mediated testicular injury [6]. In women, insulin resistance (IR), oxidative stress, and hormonal imbalance impair folliculogenesis, reduce endometrial receptivity, and disturb ovulation, frequently presenting as polycystic ovary syndrome (PCOS) [7].

Although diabetic infertility and PCOS share core features such as IR, oxidative stress, and low-grade inflammation, they remain distinct entities. In PCOS, neuroendocrine dysregulation - characterized by elevated gonadotropin-releasing hormone (GnRH) pulse frequency, an increased LH/FSH ratio, and ovarian hyperandrogenism - occurs typically without overt hyperglycemia [8]. By contrast, diabetic infertility results primarily from systemic metabolic dysfunction rather than primary ovarian pathology.

Conventional treatments - including glycemic control, hormone therapy, and assisted reproductive technologies (ART) - address individual symptoms but rarely target the systemic immunometabolic complexity of diabetic infertility. These interventions also impose significant financial, emotional, and physiological burdens [9].

Traditional Chinese Medicine (TCM) provides a holistic, multimodal approach that integrates metabolic, endocrine, inflammatory, and reproductive regulation. Its modalities - including herbal medicine, acupuncture, moxibustion, and lifestyle modification - have demonstrated complementary effects. Herbal formulations improve glycemic control via PI3K/Akt and AMPK pathways and may alleviate reproductive dysfunctions [10,11]. In women with PCOS, TCM reduces insulin and lipid levels, enhances ovulation, and improves pregnancy outcomes with fewer adverse effects than conventional therapies [12]. Acupuncture has been reported to modulate GnRH secretion, increase uterine blood flow, and improve semen quality while lowering miscarriage risk; clinical trials indicate enhanced outcomes when combined with ART [13].

Recent metabolomics-based studies have begun to elucidate the molecular mechanisms underlying TCM efficacy. These analyses show modulation of amino acid metabolism, energy and fatty acid utilization, ketone body turnover, and tricarboxylic acid cycle (TCA) cycle activity following TCM interventions in diabetic models, suggesting a mechanistic link between metabolic restoration and reproductive recovery [14].

Despite these promising findings, current evidence remains fragmented - largely based on small-scale or observational studies - with limited connection between molecular mechanisms and clinical outcomes such as live birth. Encouragingly, a randomized, waitlist-controlled trial is underway to evaluate Chinese herbal medicine for male-factor infertility, reflecting growing recognition of this research gap [15].

To date, no comprehensive review has integrated mechanistic and clinical evidence regarding TCM’s role in diabetic infertility. This review aims to fill that gap by summarizing how diabetes disrupts reproductive function at molecular and systemic levels, critically evaluating TCM-based interventions - including herbal medicine, acupuncture, and lifestyle therapies - and proposing evidence-informed strategies that integrate traditional and conventional approaches to improve fertility outcomes in individuals with diabetes.

Methods

A narrative review design was employed to synthesize experimental and clinical evidence on the therapeutic mechanisms of TCM interventions - including herbal formulations, acupuncture, moxibustion, animal-derived preparations, and mind-body practices - in diabetic infertility. A comprehensive literature search was conducted in PubMed, Scopus, Web of Science, Embase, CNKI, and SinoMed databases for studies published between January 2000 and May 2025. The search strategy combined the following keywords and their synonyms: “Traditional Chinese Medicine”, “herbal medicine”, “acupuncture”, “moxibustion”, “Qigong”, “Tai Chi”, “diabetes mellitus”, and “infertility”. Eligible studies include peer-reviewed preclinical (in vivo/in vitro), clinical (randomized or observational), in silico (network pharmacology), and systematic review or meta-analysis investigations on molecular, physiological, or reproductive effects of TCM in diabetic infertility, either in affected individuals or corresponding animal models. Non-peer-reviewed papers, commentaries, and unrelated studies were excluded. For each study, key data - including study type, model, intervention, and mechanistic outcomes - were extracted and summarized narratively to integrate heterogeneous findings. The collected evidence was qualitatively analyzed to identify recurring molecular and physiological mechanisms linking metabolic regulation, oxidative balance, inflammation, and reproductive function. These insights were synthesized into a conceptual framework illustrates how TCM interventions converge to restore fertility under diabetic conditions.

Diabetes and male infertility

In men, diabetes-mainly through IR and hyperglycemia - induces metabolic and oxidative disturbances along the reproductive axis, ultimately impairing fertility [5]. IR disrupts the hypothalamic-pituitary-gonadal (HPG) axis by reducing GnRH release, lowering pituitary responsiveness, and decreasing LH and FSH secretion. It also impairs Leydig cell function, while hyperinsulinemia further reduces Leydig responsiveness to LH [16]. At the testicular level, altered glucose transporter expression in Sertoli and germ cells limits lactate production, compromising the energy supply required for spermatogenesis [17]. Hyperglycemia activates AGE - receptor for advanced glycation end products (RAGE), polyol, and PKC pathways, which increase mitochondrial reactive ROS, inhibit glycolytic enzymes, and promote oxidative damage to testicular tissue and sperm DNA [16]. These insults, together with ER stress and dysregulated autophagy, weaken the blood-testis barrier (BTB), trigger germ-cell apoptosis, and impair sperm motility and morphology [16]. Mitochondrial dysfunction - manifested as structural abnormalities, membrane potential loss, reduced ATP synthesis, and mitochondrial DNA deletions - further lowers sperm count and motility [18]. MicroRNAs such as miR-30c and miR-141 regulate genes involved in mitochondrial and energy metabolism in Sertoli cells; their dysregulation compromises spermatogenesis [19,20]. Chronic inflammation characterized by elevated TNF-α, IL-1β, and IL-6 suppresses steroidogenic enzyme activity and reduces sperm quality, while endothelial dysfunction and diminished nitric oxide (NO) bioavailability contribute to erectile dysfunction (ED) [21]. Excess ROS damages sperm DNA, lipids, and proteins, leading to fragmentation, lipid peroxidation, and impaired ATP synthesis, all of which reduce motility and fertilization potential [22,23]. ROS overproduction also inhibits the PI3K/Akt/mechanistic target of rapamycin (mTOR) pathway, enhancing autophagy through p62 degradation and nuclear factor erythroid 2-related factor 2 (Nrf2) suppression, thereby weakening antioxidant defenses and disrupting BTB integrity [24]. Oxidative injury induces ER stress, which activates the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α), Inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6) pathways and triggers CHOP-, JNK-, and caspase-12-mediated germ-cell apoptosis. AGE-induced oxidative and ER stress in Leydig cells further impairs steroidogenesis [25]. Additional mechanisms include altered CatSper channel function, which disrupts sperm hyperactivation, and endothelial dysfunction marked by reduced endothelial nitric oxide synthase (eNOS)/NO signaling and elevated endothelin-1 (ET-1), aggravating ED [26]. Diabetes also disturbs zinc homeostasis-essential for antioxidant defense, DNA stability, and sperm maturation-thereby further compromising sperm quality [27]. Together, these neuroendocrine, metabolic, inflammatory, mitochondrial, and vascular disturbances form an interconnected pathophysiological network underlying diabetes-associated male infertility (Figure 1).

Figure 1.

Diabetes-induced mechanisms underlying infertility. Chronic hyperglycemia and glucotoxicity trigger oxidative stress and inflammation, disrupting the HPG axis and damaging reproductive tissues. In females, these changes exacerbate PCOS features, endometrial dysfunction, granulosa cell loss, and oocyte mitochondrial damage, increasing miscarriage risk. In males, metabolic stress impairs Leydig cell steroidogenesis, compromises the blood-testis barrier, and disrupts spermatogenesis, leading to reduced sperm quality and erectile dysfunction. At the molecular level, AGE-RAGE and PKC signaling, ROS accumulation, and NF-κB activation promote inflammation, apoptosis, and autophagy imbalance. IR, insulin resistance; HPG, hypothalamic-pituitary-gonadal; PCOS, polycystic ovary syndrome; BTB, blood-testis barrier; AGE, advanced glycation end product; RAGE, receptor for AGE; PKC, protein kinase C; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species; NF-κB, nuclear factor kappa B; DAG, diacylglycerol; GAP, glyceraldehyde-3-phosphate; mtDNA, mitochondrial DNA; GLUT, glucose transporter; GSK3β, glycogen synthase kinase 3 beta; Cas3, caspase-3.

Diabetes and female infertility

In women, diabetes impairs fertility through central, ovarian, endometrial, and systemic mechanisms. Centrally, insulin deficiency in type 1 diabetes reduces leptin and kisspeptin signaling, disrupting GnRH pulsatility and leading to hypogonadotropic hypogonadism [28-30]. In T2DM, obesity-related IR suppresses leptin signaling and blunts GnRH and LH release, resulting in anovulation. Altered adipokine profiles and mild hypercortisolism further destabilize the HPG axis [8]. At the ovarian level, IR impairs folliculogenesis, oocyte quality, and endometrial receptivity [31]. Hyperinsulinemia overstimulates theca cells, leading to androgen excess typical of PCOS [32]. Baculescu et al. (2025) showed that hyperinsulinemia enhances androgen synthesis, thereby disrupting ovulation and follicular development [33]. Reduced AMP-activated protein kinase (AMPK) activity in granulosa cells lowers mitochondrial efficiency and glucose uptake, limiting the energy available for oocyte maturation [34]. Hyperglycemia-induced upregulation of miR-93 and miR-223 further inhibits AMPK signaling, decreasing oocyte competence [35].

Endometrial dysfunction arises from downregulation of glucose transporter type 4 (GLUT4), which compromises glucose handling and decidualization [31]. Accumulated ROS exacerbate granulosa-cell injury and follicular atresia [36]. Park et al. (2020) reported that oxidative stress activates NF-κB, inducing follicular apoptosis and reducing oocyte viability [37]. Persistent oxidative stress coupled with IL-6-mediated inflammation diminishes endometrial receptivity and contributes to implantation failure [38]. Activation of the AGE-RAGE pathway amplifies oxidative injury. Sopasi et al. demonstrated that this mechanism compromises oocyte integrity and reproductive potential [39].

Beyond ovarian and endometrial impairment, diabetes affects tubal and uterine function through endometriosis progression, pelvic inflammation, and autonomic neuropathy, which together disrupt tubal peristalsis [40]. Diabetic endometrium may also exhibit hyperplasia, abnormal bleeding, edema, and aberrant angiogenesis, increasing the risk of infertility and malignancy [40]. Implantation failure has been linked to abnormal integrin expression, reduced pinopode formation, and dysregulated LIF (leukemia inhibitory factor)/IGF-1 (insulin-like growth factor 1)/Beclin-1 signaling. Maternal hyperinsulinemia also activates the mTOR pathway, impairing decidualization and trophoblast invasion [31]. Additional factors such as excessive AMPK activation in type 1 diabetes, IFN-γ upregulation, and defective spiral-artery remodeling further reduce endometrial receptivity and increase pregnancy loss [41]. Hyperglycemia exerts embryotoxic effects through DNA damage, O-GlcNAcylation, and growth arrest in preimplantation embryos [42]. Also, circadian disruption caused by prediabetes or shift work alters leptin-insulin dynamics, GnRH signaling, and endometrial gene expression, worsening reproductive outcomes [43]. At the clinical level, diabetic neuropathy, vasculopathy, and psychosocial stress contribute to reduced libido and arousal, further decreasing fertility potential [43] (Figure 1).

Principles and applications of TCM in managing diabetic infertility

TCM views diabetic infertility as a manifestation of Yin-Yang imbalance and Qi deficiency, which in biomedical terms correspond to oxidative stress, hormonal dysregulation, and chronic inflammation. Through its herbal and non-herbal modalities (Figure 2), it aims to restore systemic homeostasis and counteract reproductive injury associated with chronic hyperglycemia [12]. Experimental evidence supporting this framework derives from well-established diabetic animal models, including streptozotocin (STZ)-induced β-cell injury, leptin receptor-deficient (db/db) mice, and high-fat diet (HFD) combined with STZ administration to mimic T2DM. For reproductive analogs, letrozole-, dehydroepiandrosterone (DHEA)-, and dihydrotestosterone (DHT)-induced PCOS models have been widely used to investigate ovarian dysfunction under IR conditions. Clinical studies have primarily focused on women with PCOS - with or without IR - and men with T2DM-associated ED, reflecting overlapping yet distinct manifestations of diabetic reproductive impairment.

Figure 2.

Categories of TCM interventions for diabetic infertility. TCM strategies are grouped into individual herbal agents, isolated bioactive compounds, compound herbal formulas, non-herbal modalities, and mind-body practices. TCM, Traditional Chinese Medicine; LWDHD, Liuwei Dihuang Decoction; BYHWD, Buyang Huanwu Decoction; YQYYHXD, Yiqi Yangyin Huoxue Decoction; CGKYR, Chaige Kangyi Recipe; WZYR, Wuzi Yanzong Recipe; MAC, manual acupuncture; EAC, electroacupuncture; L-C therapy, leech-centipede therapy.

Herbal medicine

Herbal medicine represents the core therapeutic approach in managing diabetic infertility. By regulating both glucose metabolism and reproductive hormones, herbal formulations target the metabolic-endocrine interface underlying infertility in diabetes. This dual modulation corrects hyperglycemia-induced oxidative and inflammatory stress while supporting gonadal function, establishing herbal therapy as both a metabolic stabilizer and a fertility restorer within this framework.

Individual herbal agents

As key modulators of metabolic and endocrine balance, several herbs counteract IR and hormonal dysregulation that impair fertility (Table 1). Cinnamon (Cinnamomum spp.) provides the strongest and most consistent evidence linking metabolic regulation to reproductive recovery. In alloxan-induced diabetic rats, cinnamon bark powder (80 mg/kg/day for four weeks) improved glycemic control, enhanced antioxidant defense, and restored sperm motility. In another experiment, the aqueous bark extract (500 mg/kg/day for six weeks) elevated serum testosterone and preserved seminiferous architecture, confirming testicular protection under diabetic stress. A pilot randomized controlled trial (RCT) in forty-five women with PCOS treated with cinnamon powder (1.5 g/day for six months) improved menstrual cyclicity and ovulation despite minimal change in fasting glucose and insulin sensitivity [44-46]. Cinnamon therefore restores reproductive function by improving insulin sensitivity, reducing inflammation, and re-establishing hormonal and oxidative equilibrium.

Table 1.

Main effects and mechanisms of individual botanicals in TCM for diabetic infertility

Herbal species	TCM-based mechanism	Main anti-diabetic effect	Main anti-infertility effect	Study model/population	Key herbal part	Ref.
Cinnamon (Ceylon cinnamon)	Warms & tonifies kidney yang; disperses cold & alleviates pain (abdominal, waist/knees); promotes blood & Qi circulation; warms middle burner & treats cold abdomen/stomach pain; alleviates dysmenorrhea & menstrual pain	↓ FPG/fasting insulin; ↓ HOMA-IR; improved lipids; ↑ glucose uptake; ↑ IRS-1/PI3K interaction; insulin-sensitizing & antioxidant effects; ↓ NF-κB/TNF-α; PI3K/IRS-1 signaling	Women: ↑ menstrual frequency/cyclicity, ↑ ovulation; Men: ↑ sperm count/motility/viability; ↑ testosterone, LH, FSH; ↓ IGF-1/IGFBP-1 (PCOS mice)	Diabetic rats, PCOS women	Bark (inner/outer), whole cinnamon powder, leaf & bud essential oils	[44-46]
Eucommia ulmoides	Nourishes liver & kidneys; strengthens tendons & bones; calms the fetus; relieves lumbar & knee pain; treats osteoporosis; used traditionally for hypertension, hyperglycemia/diabetes, obesity	Improved glucose tolerance & insulin resistance; antioxidant (↑ SOD, GSH-Px; ↓ MDA)	Restored endothelial/EF; ↑ NO/cGMP; Akt-eNOS pathway; penile endothelial integrity	Diabetic Rats	Leaf & bark extract	[57]
Female Ginseng (Angelica sinensis)	Tonifies & invigorates blood; regulates menstruation & relieves menstrual pain (irregular menses, amenorrhea, dysmenorrhea); moistens the intestines to relieve constipation when blood is deficient; disperses cold & harmonizes blood stagnation pains	Improved insulin resistance; ↓ dyslipidemia	Restored estrous cycle; improved ovarian histopathology; hormonal profile regulation	Diabetic rats	Root/Radix (dried root) & root aqueous extract	[48]
Ginger (Zingiber officinale)	Pungent, enters lung, spleen, stomach channels; disperses wind-cold (common cold, chills), warms middle & stops vomiting (especially cold stomach), expels cold phlegm & stops cough; relieves seafood poisoning; strengthens digestion & appetite; dried ginger rescues collapse of yang in severe cold	↓ FBG; ↑ serum insulin; ↑ HOMA-β; antioxidant/anti-inflammatory; ↓ NF-κB/TNF-α; ↑ TAC/SOD/GPx/CAT	↑ sperm count/motility/viability; ↑ testosterone, LH, FSH; preserved seminiferous tubules; anti-apoptotic effects; ↑ PCNA & AR	PCOS mice models	Root/Rhizome	[50,51]
Gynura procumbens	Clears heat & resolves toxicity; stops bleeding & reduces swelling; strengthens & tonifies; expels wind & dampness	Antihyperglycemic effects	Restored spermatogenesis; ↑ testosterone, LH, FSH; ↑ sperm count & morphology; ↑ implantation; ↑ CRISP1, CES5A, ZPBP, PEBP1 → improved sperm maturation, capacitation & sperm-egg interaction	Diabetic rats	Leaf extract (aqueous/ethanolic)	[54-56]
Licorice (Glycyrrhiza glabra)	Tonifies spleen Qi, harmonizes & moderates harsh medicines; clears toxins & alleviates spasms; relieves cough & expels phlegm; protects gastrointestinal lining & treats mild stomach ulceration; diminishes pain & soothes muscle spasm	↑ Insulin; ↓ cholesterol/TG/LDL-C; ↑ HDL-C; antioxidant + anti-inflammatory; ↓ TNF-α/IL-1β/IL-4/IL-6/IL-10; ↑ SOD/CAT/GPx/GSH	Restored folliculogenesis; ↓ cystic/atretic follicles; ↑ corpus luteum; hormonal rebalance; progesterone ↑; androgens ↓	Diabetic rats	Root/Radix (dried root) & root extract	[47]
Pucture-vine (Tribulus terrestris)	Calms liver & anchors yang (for liver-yang rising causing headache, dizziness or vertigo); dredges liver Qi & disperses stagnation (for flank/chest distension, insufficient lactation, irregular menstruation); dispels wind-heat & brightens eyes (for red, swollen, painful eyes with tearing or visual disturbance); dispels wind & stops itching (in skin lesions, urticaria, eczema)	↓ Blood glucose; antioxidant & anti-apoptotic effects (↓ Caspase-3/9, ↑ Bcl-2/Bax)	Mixed clinical results: ↑ IIEF or no benefit, in diabetic rats ↑ sperm count, motility, morphology, testosterone; endothelial NO pathway (↑ eNOS, ↑ NO, ↑ cGMP); androgenic/erectogenic activity; improved smooth muscle/collagen balance	Diabetic Rats, male patients with sexual dysfunction	Aerial parts, fruits, & roots	[58-60]
Saffron (Crocus sativus)	Invigorates blood & dispels stasis; cools blood & clears heat; detoxifies & reduces swelling; calms the mind & relieves melancholy; unblocks channels & alleviates pain	↑ antioxidant enzymes (GSH, GST); ↓ inflammatory cytokines (TNFα, IL-1β, IL-6, IL-18, CRP); ↓ NF-κB/NF-κB p65; ↑ IκB expression	↑ FSH; ↓ LH, testosterone & estrogen; restores ovarian follicle development; improves steroidogenic enzymes; restores estrogen negative feedback	Male patients	Petals	[53]
White tea (Camellia sinensis)	Clears inner heat & detoxifies; moistens lungs & relieves dryness; calms spirit, reduces anxiety; supports memory & protects nerves; helps lower blood pressure & blood lipids; suitable for damp-heat constitutions	Improved glucose tolerance & insulin sensitivity; ↓ lipid/protein oxidation; ↑ FRAP	Restored sperm concentration, motility, viability; normalized morphology; antioxidant effects → testicular/epididymal protection	Male patients	Leaves & young buds/shoots	[49]
Yellow ginger (Dioscorea zingiberensis)	Clears lung heat & relieves cough; promotes diuresis & unblocks urinary strangury; resolves toxicity & reduces swelling; alleviates rheumatic low-back pain; treats early-stage sores/abscesses & pyogenic skin infections; relieves pain from contusions & sprains; treats insect (bee/bug) stings	↓ MDA & 8-OHdG; ↑ SOD; restored GSH/T-GSH, Nrf2-HO-1-NQO1 activation	Improved testicular morphology; ↑ sperm count; ↓ abnormal forms; ↑ ZO-1 → restored BTB	Diabetic mice	Rhizome (underground part)	[52]

Abbreviations: ↑, Increase; ↓, Decrease; TCM, Traditional Chinese Medicine; DZEE, Dioscorea zingiberensis ethanol extract; EULE, Eucommia ulmoides leaf extract; NS, Not specified; RCT, Randomized controlled trial; IIEF, International Index of Erectile Function; LH, Luteinizing hormone; FSH, Follicle-stimulating hormone; CRISP1, Cysteine-rich secretory protein 1; CES5A, Carboxylesterase 5A; ZPBP, Zona pellucida binding protein; PEBP1, Phosphatidylethanolamine-binding protein 1; MDA, Malondialdehyde; 8-OHdG, 8-hydroxy-2’-deoxyguanosine; SOD, Superoxide dismutase; GSH, Glutathione; T-GSH, Total glutathione; Nrf2, Nuclear factor erythroid 2-related factor 2; HO-1, Heme oxygenase 1; NQO1, NAD(P)H quinone oxidoreductase 1; ZO-1, Zonula occludens-1; NO, Nitric oxide; cGMP, Cyclic guanosine monophosphate; Akt, Protein kinase B; eNOS, Endothelial nitric oxide synthase; FPG, Fasting plasma glucose; HOMA-IR, Homeostatic model assessment of insulin resistance; IRS-1, Insulin receptor substrate-1; PI3K, Phosphoinositide 3-kinase; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; TNF-α, Tumor necrosis factor alpha; IGF-1, Insulin-like growth factor 1; IGFBP-1, Insulin-like growth factor-binding protein 1; PCOS, Polycystic ovary syndrome; WEA, Water extract of Angelica sinensis; FRAP, Ferric reducing antioxidant power; TG, Triglyceride; LDL-C, Low-density lipoprotein cholesterol; HDL-C, High-density lipoprotein cholesterol; CAT, Catalase; GPx, Glutathione peroxidase; IL-1β, Interleukin-1 beta; IL-4, Interleukin-4; IL-6, Interleukin-6; IL-10, Interleukin-10; FBG, Fasting blood glucose; HOMA-β, Homeostatic model assessment of β-cell function; PCNA, Proliferating cell nuclear antigen; AR, androgen receptor; TAC, Total antioxidant capacity; GST, Glutathione S-transferase; CRP, C-reactive protein; IκB, Inhibitor of nuclear factor kappa B; BTB, Blood-testis barrier; EF, Erectile function; Bcl-2, B-cell lymphoma 2; Bax, Bcl-2-associated X protein; Caspase-3/9, Cysteine-aspartic proteases 3 and 9.

Comparable effects are seen with Glycyrrhiza glabra and Angelica sinensis, which target the ovarian-metabolic axis. In estradiol-induced PCOS rats, Glycyrrhiza extract (100 mg/kg/day for six weeks) normalized sex-steroid profiles and stimulated folliculogenesis, while Angelica sinensis (2-8 g/kg/day for four weeks) in letrozole plus HFD models improved glucose-lipid metabolism, restored ovarian morphology, and rebalanced the gut microbiota [47,48]. These botanicals converge on a gut-ovarian regulatory axis aligning metabolic homeostasis with hormonal equilibrium. Supporting this mechanism, White tea (Camellia sinensis) used as the sole drinking fluid for two months in STZ-diabetic male rats enhanced insulin sensitivity, reduced oxidative stress, and improved sperm motility and viability [49]. These findings suggest that rebalancing metabolic function and oxidative stability is central to restoring fertility under diabetic conditions.

Beyond metabolic regulation, several botanicals directly protect gonadal tissues from hyperglycemic injury. Ginger (Zingiber officinale) (100-400 mg/kg/day for four to eight weeks) increased testosterone, improved sperm viability, and restored ovarian steroidogenic gene expression in diabetic rats [50,51]. Similarly, Dioscorea zingiberensis (125-250 mg/kg/day for ten weeks) activated the Nrf2/HO-1 pathway, reinforced the BTB, and enhanced spermatogenesis [52]. In female PCOS models, Crocus sativus (saffron) petal extract (50-600 mg/kg/day for fifteen days, intraperitoneal) reduced TNF-α, IL-6, and oxidative stress while repairing ovarian histoarchitecture in testosterone-induced mice [53]. These data confirm that oxidative and barrier injuries are reversible through antioxidant and anti-inflammatory mechanisms, reinforcing gametogenic resilience under metabolic stress.

Some herbs primarily enhance male reproductive recovery through interconnected vascular and metabolic mechanisms. Gynura procumbens demonstrates consistent efficacy across preclinical models, where treatment (50-1000 mg/kg/day for two to four weeks) lowered blood glucose, increased sperm count and libido, and improved implantation rates in untreated females [54-56]. Similarly, in STZ-induced diabetic rats, Eucommia ulmoides leaf extract administered for sixteen weeks improved insulin sensitivity and erectile function via activation of NO-cGMP and Akt-eNOS signaling [57]. These findings indicate that vascular remodeling and endothelial repair operate synergistically with metabolic restoration to re-establish male reproductive competence.

Building on this vascular-metabolic interaction, certain herbs further engage androgenic signaling to enhance male reproductive recovery. Tribulus terrestris exemplifies this dual mechanism. In a twelve-week randomized trial involving 180 men, it improved International Index of Erectile Function (IIEF) scores and sexual satisfaction, while a smaller thirty-day study showed no clear advantage over placebo. Complementary preclinical studies demonstrated reduced glucose, higher testosterone, and improved sperm morphology and motility [58-60]. The combined evidence indicates that Tribulus enhances reproductive recovery through dual modulation of androgen signaling and endothelial function. Together, individual herbal agents lay the mechanistic foundation for reversing diabetic infertility through targeted, system-wide regulation (Table S1).

Isolated bioactive compounds

The antidiabetic and fertility-enhancing actions of individual herbs arise from one or more active phytochemicals that have been experimentally validated in diverse infertility models. These bioactive molecules act independently or in concert, engaging overlapping signaling pathways that regulate metabolism, oxidative balance, and gonadal recovery. Through modulation of PI3K/Akt, Nrf2/HO-1, and NF-κB pathways, they collectively restore endocrine and reproductive homeostasis (Table 2).

Table 2.

Main anti-diabetic and reproductive mechanisms of isolated bioactive compounds in diabetic infertility

Bioactive agent	TCM-based mechanism	Main anti-diabetic effect	Main anti-infertility effect	Study model/population	Botanical source	Ref.
Astragaloside IV	Tonifies Qi & raises Yang; strengthens spleen & lung; secures exterior, stops sweating; promotes urination, reduces edema; generates fluids, nourishes Blood; resolves pus, heals sores	↓ Oxidative stress; anti-apoptotic in vivo; pro-apoptotic in vitro KGN cells	Improved ovarian morphology & fertility potential; PPARγ signaling; granulosa cell protection	Diabetic mice; PCOS rats	Dried root (Radix Astragali) of Astragalus membranaceus	[89,90]
Berberine	Clear heat & damp, treat xiao ke (wasting-thirst/diabetes), & resolve damp-heat in the lower jiao linked to reproductive disorders	↓ BMI, FPG, FINS, HOMA-IR; improved lipids; AMPK/PI3K-Akt-GLUT4 activation	↑ Ovulation, pregnancy, live birth; ↓ LH, testosterone; improved ovarian morphology; HPO axis regulation	PCOS rats & women	Rhizome (dried root/rhizome) of Coptis chinensis (Huang Lian), & also from the bark of Phellodendron species (Huang Bai)	[61-67]
Betaine	Tonifies liver & kidney, nourishes yin & essence, brightens eyes; cools blood & stops bleeding; clears heat, generates fluids, harmonizes Stomach; calms Heart & Shen, relieves irritability, stops sweating, alleviates dysentery	↓ ROS, ↓ MDA; ↑ SOD/CAT; improved insulin sensitivity; ↓ TC/TG; antioxidant; PI3K/Akt signaling; osmolyte & methyl donor role	Restored testicular/ovarian morphology; improved estrous cycle, ovulation, embryo development	Diabetic mice, PCOS women	Fruit of Lycium barbarum (Goji), leaves of Spinacia oleracea (spinach), root &/or leaves of Beta vulgaris (beet), various Amaranthus species (amaranth), & the grain of Triticum aestivum (wheat)	[84,86-88,177]
Catalpol	Clears heat & cools the blood; nourishes Yin & replenishes essence; treats heat-entering Ying/Blood, Yin-deficiency signs (dry mouth, night sweats), blood deficiency (anemia), dizziness, tinnitus, soreness of loins & knees	↑ Insulin sensitivity via AMPK/IRS1/GLUT4; ↓ NF-κB; antioxidant; PI3K/Akt/mTOR activation; suppression of RAGE/NOX4/NF-κB	Restored spermatogenesis; ↓ apoptosis; restored sex hormones	Diabetic mice; PCOS rats; PCOS granulosa cells	Root of Rehmannia glutinosa	[91,178,179]
Crocin	Nourishes & invigorates blood; resolves blood stasis; used for pain from stasis, dysmenorrhea, amenorrhea, & emotional depression.	↓ Blood glucose; antioxidant; ↓ oxidative stress	↑ testosterone; ↑ sperm count/motility; improved testis histology; some IVF benefit; antioxidant & anti-apoptotic (↓ Bax/caspase, ↑ Bcl-2)	Diabetic rats, subjects with metabolic syndrome, PCOS rats, diabetic mice	Stigmas of Crocus sativus L. flowers	[85,180,181]
Cryptotanshinone	Same as Salvia miltiorrhiza	↓ HMGB1/TLR4/NF-κB; ↑ GLUT4/PI3K/AKT2 → improved insulin resistance; anti-inflammatory; insulin signaling activation	Restored estrous cycle; improved follicles; ↓ testosterone, LH, estradiol (E2)	Diabetic mice, PCOS rats	Root of Salvia miltiorrhiza (Danshen)	[182,183]
Curcumin	Invigorates blood; promotes Qi; regulates menses; relieves pain; reduces swelling	↓ BMI, FPG, FINS, HOMA-IR; improved lipids; ↑ antioxidant enzymes; PPARγ activation; SIRT1/PGC-1α; anti-inflammatory effects	↓ FAI, ↓ LH/FSH; possible reproductive hormone regulation	PCOS women	Rhizome (underground stem/rootstock) of Curcuma longa	[68,69,184]
DNLP	Nourishing Yin, clearing heat & generating fluids; treating Yin-deficiency manifestations such as dry mouth/throat, thirst, weakness	↓ FBG, ↓ HOMA-IR	↑ Sperm count, motility, viability; improved testicular histology; ↑ PCNA, ↑ SIRT1; anti-apoptotic	Diabetic rats	The root of Astragalus membranaceus & Panax ginseng; stems, leaves, flowers, & roots from Dendrobium nobile	[185]
Ginsenosides (Rg3, Rb1)	Powerfully tonifies Yuan-Qi; strengthens spleen & lung; generates fluids & alleviates thirst; benefits heart-Qi & calms the shen	↓ ROS; improved antioxidant capacity	↓ Granulosa cell apoptosis; restored ovarian reserve; anti-apoptotic (↑ Bcl-2/Bax); mitochondrial protection	KGN cells, diabetic rats	Root of Panax ginseng	[93,94]
GSTT	Same as Tribulus terrestris (see Table 1)	↑ eNOS; ↑ NO/cGMP; endothelial protection; antioxidant, endothelial NO pathway	Improved EF; ↑ ICP; better smooth muscle/collagen balance; ↓ apoptosis	Diabetic rats	Fruits of Tribulus terrestris (puniculate porrect fruit) — the aerial reproductive part of the plant	[79]
Icariin	Tonifies kidney Yang, strengthens bones & sinews, dispels wind-damp, enhances sexual function	Improved glucose homeostasis; antioxidant; anti-apoptotic	Preserved spermatogenesis; improved testis morphology	Diabetic mice	Dried stems & leaves of Epimedium spp	[82]
LBP	Tonifies Liver & Kidney, nourishes Yin & essence, brightens eyes, moistens Lung, promotes fertility	↓ Oxidative stress; ↑ SOD/GSH; ↓ apoptosis; antioxidant, anti-apoptotic (↑ Bcl-2/Bax, ↓ caspase-3)	Preserved spermatogenesis, ↑ sperm quality	Diabetic rats & mice	Dried fruit of Lycium barbarum (wolfberry/goji berry)	[80,81]
Morroniside	Nourishing liver & kidney; arresting seminal emission & sweat; treating kidney-deficiency with symptoms such as dizziness, tinnitus, soreness of loins & knees	PI3K/Akt/mTOR; Nrf2 activation	Improved granulosa cell viability, ↓ apoptosis	PCOS granulosa cells	Fruit (Corni Fructus) of Cornus officinalis	[92]
Pachymic acid	Strengthens spleen, drains damp & promotes urination, calms heart & shen	Improved insulin resistance; anti-inflammatory; HMGB1/RAGE suppression	Improved ovarian function (PCOS)	PCOS rats	Sclerotium of Poria cocos	[95]
PNS	Stops bleeding & disperses blood-stasis; treats bleeding (nose, lung, stomach, urine), trauma bruises, chest/abdominal pain from stasis	↑ SOD; endothelial protection; antioxidant; vascular protection	↑ EF	Diabetic rats	Roots (especially the taproot/rhizome) of the Panax notoginseng	[77]
Puerarin	Releases exterior, relieves muscle stiffness; generates fluids & alleviates thirst; raises Yang & stops diarrhea; promotes eruption in measles	↓ HOMA-IR, FINS, TG/LDL; ↑ HDL; endocrine modulation	↓ LH; ↓ LH/FSH; ↓ testosterone	PCOS women	Root of Pueraria lobata	[72]
Quercetin	Tonifies kidney; nourish yin; clear heat; invigorate blood; & enhance fertility	↓ FBG, ↓ insulin, ↓ HOMA-IR; improved lipid/antioxidant status; ↑ adiponectin; PI3K/Akt activation; antioxidant (↑ SOD, CAT)	↓ testosterone, LH; improved ovarian morphology & folliculogenesis	Diabetic rats, PCOS women	Leaves of Ginkgo biloba, Morus alba, Cuscuta chinensis, Epimedium species, & Sophora japonica	[73,74]
Resveratrol	Clear heat & toxins, invigorate blood, nourish Yin & kidney, tonify Qi & blood, & support reproductive health	↓ FPG; ↓ insulin resistance; restored IGF-1; improved metabolic profile; SIRT2 ↑; glycolysis enzyme regulation; mitochondrial biogenesis	↓ testosterone, ↓ LH; improved folliculogenesis, oocyte/embryo quality, live birth	PCOS women & rats, PCOS granulosa cells	Skin of Vitis vinifera (grape), root of Polygonum cuspidatum (Japanese knotweed), fruit of Morus alba (mulberry), & seeds of Arachis hypogaea (peanut)	[70,71,186-189]
Tanshinones	Invigorates blood & dispels stasis; relieves pain; clears heat & eases irritability; cools blood; reduces swelling & resolves sores; regulates menses	↓ BMI, TG, TC; ↑ HDL; metabolic improvement	↑ Ovulation & pregnancy; ↓ LH, ↓ testosterone; hormonal regulation	PCOS women	Dried root (radix) of Salvia miltiorrhiza (Danshen)	[75,76,190,191]

Abbreviations: ↑, Increase; ↓, Decrease; LBP, Lycium barbarum polysaccharides; DNLP, Dendrobium nobile Lindl polysaccharides; PNS, Panax notoginseng saponins; GSTT, Tribulus terrestris saponins; EF, erectile function; ICP, Intracavernosal pressure; BMI, body mass index; FINS, fasting insulin; FAI, free androgen index; TC, total cholesterol; TG, triglycerides; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; HMGB1, high mo-bility group box 1; TLR4, toll-like receptor 4; E2, estradiol; CAT, catalase; IGF-1, insulin-like growth factor 1; SIRT2, sirtuin 2; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PPARγ, peroxisome proliferator-activated receptor gamma; KGN cells, human granulosa cell line KGN; PCNA, proliferating cell nuclear antigen; AMPK, AMP-activated protein kinase; GLUT4, Glucose transporter type 4; mTOR, Mechanistic target of rapamycin; RAGE, Receptor for advanced glycation end products; NOX4, NADPH oxidase 4; HPO axis, Hypothalamic-pituitary-ovarian axis; ROS, Reactive oxygen species.

Berberine, an isoquinoline alkaloid from Coptidis Rhizoma, exemplifies this integrative action. In preclinical PCOS models induced by letrozole and HFD, oral berberine (100-400 mg/kg/day for four weeks) activated the PI3K-Akt-GLUT4 axis, enhanced insulin sensitivity, and normalized ovarian morphology. Multiple RCTs involving 80-120 women with PCOS (0.3-0.5 g three times daily for 3-4 months) further demonstrated reduced homeostatic model assessment of insulin resistance (HOMA-IR) and androgen levels, along with improved ovulation and live birth rates compared with placebo or metformin. These consistent findings indicate that metabolic stabilization translates directly into endocrine and fertility recovery [61-67]. Similar cross-pathway effects are observed with polyphenolic compounds, which mitigate oxidative and mitochondrial stress - two hallmarks of reproductive dysfunction. Curcumin (500-1500 mg/day for 6-12 weeks) improved insulin sensitivity and antioxidant capacity in pilot clinical trials involving women with PCOS [68,69]. Resveratrol (20 mg/kg/day in PCOS rats; 400-1500 mg/day in small clinical studies) lowered testosterone, LH, and dehydroepiandrosterone sulfate (DHEAS), while promoting sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (SIRT1/PGC-1α) - mediated mitochondrial biogenesis and improving oocyte quality [70,71]. Likewise, quercetin (30 mg/kg/day in rats; 1 g/day for 12 weeks in PCOS patients) normalized estrous cycles, alleviated insulin resistance, and enhanced ovarian steroidogenesis. Also, Puerarin (150 mg/day for three months) produced similar clinical benefits, improving menstrual regularity and reducing hyperinsulinemia [72-74]. Together, these polyphenols highlight how redox balance and insulin signaling act in concert to restore oocyte quality through mitochondrial repair and metabolic realignment.

Terpenoid derivatives from Salvia miltiorrhiza, particularly tanshinones and cryptotanshinone, extend these protective effects by suppressing high-mobility group box 1/toll-like receptor 4/nuclear factor kappa-B (HMGB1/TLR4/NF-κB) signaling. This inhibition alleviates ovarian inflammation and lipid imbalance, both major contributors to PCOS pathology. In preclinical models, terpenoids restored folliculogenesis and normalized hormonal profiles, while three-month clinical regimens (1 g three times daily; n ≈ 60-90 PCOS patients) improved lipid metabolism and reduced LH, adrenocorticotropic hormone (ACTH), and testosterone levels. These outcomes position terpenoids as dual modulators of inflammation and endocrine balance [75,76]. In male reproductive dysfunction, saponins and vascular regulators play complementary roles by promoting endothelial repair and maintaining erectile function. In diabetic rat models, Tribulus terrestris saponins (40 mg/kg/day for four weeks) enhanced NO-cGMP signaling and cavernosal pressure, Panax notoginseng saponins (50-150 mg/kg/day) improved the Bcl-2/Bax ratio and vascular integrity, and Ganoderma lucidum β-glucans preserved mitochondrial function while reducing fibrosis [77-79]. Clinical observations in men with diabetic ED supported these findings, reporting improved erectile performance and endothelial responsiveness. Maintaining nitric oxide bioavailability and vascular remodeling thus emerges as a fundamental mechanism underlying erectile and testicular recovery in diabetes.

Beyond vascular regulation, polysaccharides and flavonoids protect testicular tissue by preserving mitochondrial stability and antioxidant defense. In STZ-induced diabetic mice, Lycium barbarum polysaccharides (100-200 mg/kg/day for 6-8 weeks) enhanced sperm motility, strengthened the BTB, and prevented germ-cell apoptosis [80,81]. Similarly, icariin (40-80 mg/kg/day for 11 weeks) activated AMPK-Nrf2 signaling to restore BTB integrity, while Dendrobium nobile polysaccharides (400 mg/kg/day for six weeks) elevated SIRT1 and PCNA expression, promoting spermatogenesis [82]. Also, Crocin (15-60 mg/kg/day for 2-4 weeks) reduced ROS and ER stress, restored gonadal morphology, and improved sperm and hormonal parameters in diabetic rodents, whereas betaine (200-800 mg/kg/day in vivo; 5 mM in granulosa and Leydig cell assays) produced comparable antioxidative and steroidogenic benefits [83-88]. These convergent findings emphasize that mitochondrial protection and redox stability are essential to sustaining spermatogenic capacity under diabetic stress.

On the ovarian side, glycosides such as astragaloside IV (20-80 mg/kg/day subcutaneous or 50 mg/kg oral) also support metabolic and reproductive recovery. They improve insulin resistance, restore estrous cycles, and activate PPARγ-dependent autophagy in diabetic female mice and small clinical cohorts [89,90]. Catalpol (50 mg/kg/day for four weeks) and morroniside further strengthen these antioxidative defenses through SIRT1/Nrf2 activation, reducing oxidative injury and apoptosis in ovarian tissues [91,92]. Pachymic acid (8-33 mg/kg/day) suppresses HMGB1/RAGE/NF-κB signaling and normalizes endocrine indices, while ginsenosides Rg3 and Rb1 maintain mitochondrial potential and granulosa-cell viability in both animal and in vitro models [93-95]. Together, these glycosides act through interrelated mechanisms-autophagy induction, oxidative stress reduction, and mitochondrial preservation - to maintain ovarian structure and hormonal balance under diabetic conditions. Overall, these structurally diverse molecules - including alkaloids, polyphenols, terpenoids, saponins, polysaccharides, and glycosides - form an interconnected biochemical network. Acting across metabolic and endocrine pathways, they reestablish vascular, hormonal, and redox stability, thereby defining the molecular framework of fertility restoration in diabetes (Table S2).

Compound herbal formulas

Compound herbal formulas represent the most validated TCM approach for diabetic infertility, acting synergistically across vascular, metabolic, and gonadal axes to restore endothelial integrity, oxidative balance, and hormonal regulation. Restoring vascular health is particularly critical in male diabetic infertility, where endothelial injury and NO depletion drive ED, and herbal prescriptions targeting vascular repair reestablish NO signaling and oxidative stability (Table 3).

Table 3.

Main effects and mechanisms of compound herbal formulas in diabetic infertility

Herbal compound	TCM-based mechanism	Main anti-diabetic effect	Main anti-infertility effect	Study model/population	Herbal composition	Ref.
ABR+SV	Regulates blood-stasis; strengthens liver & kidney; relieves lumbar-knee soreness & weakness; moves blood & resolves menstrual disorders; promotes lactation	↓ Blood glucose; ↑ insulin/glucagon	Improved EF; improved penile histology; ↑ eNOS; ↓ VEGFA/ACE; ↓ Caspase-3	Diabetic rats with ED	Achyranthes bidentata Blume (ABR) 15 g, Gypsophila vaccaria (L.) Sm. (SV) 10 g	[112]
BSHXD	Tonifies kidney, strengthens sinews & bones; activates blood & stops pain. Used for post-injury weakness of kidney/Yin: loins/knees soreness & weakness, especially lower back; tongue pale, white coating; pulse thin & weak	↑ PI3K/AKT signaling	↑ ICP; improved EF; ↓ apoptosis & fibrosis; anti-apoptotic; anti-fibrotic	Diabetic rats with ED	Rehmannia glutinosa (Gaertn.) DC. (Shudi) 15 g, Cornus officinalis Siebold & Zucc. (Shanzhuyu) 12 g, Dioscorea oppositifolia L. (Shanyao) 12 g, Paeonia lactiflora Pall. (Baishao) 12 g, Ligusticum chuanxiong Hort. (Chuanxiong) 10 g, Angelica sinensis (Oliv.) Diels (Danggui) 10 g, Cuscuta chinensis Lam. (Tusizi) 15 g, Eucommia ulmoides Oliv. (Duzhong) 15 g, Psoralea corylifolia L. (Buguzhi) 12 g, Carthamus tinctorius L. (Honghua) 10 g	[111]
BSHZF	Strengthens spleen & kidney, transforms turbidity & clears toxins; used for PCOS with kidney deficiency + phlegm-dampness, & chronic renal failure with spleen-kidney weakness & damp-turbid accumulation	↓ FBG; ↓ FINS; improved insulin resistance; gut microbiota modulation	↓ testosterone; improved ovarian morphology; improved estrous cycle; ↑ SCFA bacteria; ↓ LPS/TNF-α	PCOS rats	Cuscuta chinensis Lam. (Tusizi) 15 g, Lycium barbarum L. (Gouqizi) 15 g, Pinellia ternata (Thunb.) Makino, praeparata cum alumine (Qing Banxia) 8 g, Angelica sinensis (Oliv.) Diels (Danggui) 15 g, Poria cocos (Schw.) Wolf (Fuling) 15 g, Salvia miltiorrhiza Bunge (Danshen) 20 g, Cyperus rotundus L. (Xiangfu) 10 g, Ligusticum chuanxiong Hort. (Chuanxiong) 10 g, Paeonia lactiflora Pall. (Baishao) 15 g, Glycyrrhiza uralensis Fisch. (Gancao) 6 g, Citrus reticulata Blanco (Qingpi) 6 g, Coix lacryma-jobi L. var. ma-yuen (Roman.) Stapf (Yiren) 20 g, Plantago asiatica L. (Cheqianzi) 10 g, Platycodon grandiflorus (Jacq.) A.DC. (Jiegeng) 10 g, Patrinia scabiosifolia Fisch. ex Trevir. (Baijiangcao) 20 g, Benincasa hispida (Thunb.) Cogn., exocarpium (Dongguapi) 30 g	[127]
Bushen-based decoctions	Tonifies the kidney (Yin or Yang) & strengthens bones & marrow; used in patterns of Kidney-deficiency with Blood-stasis to treat osteoporosis, lumbar-knee weakness, diminished ovarian reserve, & menopausal syndrome	Improved insulin resistance; ↓ BMI; ↓ glucose/lipids	↑ Pregnancy; improved perfusion & receptivity; ↓ LH/testosterone; hormonal modulation; improved ovarian blood flow	PCOS women	Bushen Quyu Huatan decoction, Bushen Jianpi decoction, Shugan Bushen decoction, Bushen Huoxue Cupailuan decoction, Bushen Huoxue Culuan Prescription, Bushen Tiaochong decoction, Bushen Huatan fang	[125,126]
BYHWD	Tonifies Qi & activates blood; treats hemiplegia, mouth-&-eye deviation, speech impairment post-stroke; improves neurological recovery in cerebral small vessel disease & peripheral nerve injury; addresses conditions of Qi-deficiency with blood-stasis.	NS	↑ EF; ↑ IIEF-5; ↑ QoL; hormonal rebalance; endothelial & oxidative stress regulation	Diabetic patients with ED	Astragalus membranaceus (Fisch.) Bunge (Huangqi), Angelica sinensis (Oliv.) Diels (Danggui), Paeonia lactiflora Pall. (Red Peony, Paeoniae Radix Rubra), Ligusticum chuanxiong Hort. (Chuanxiong), Prunus persica (L.) Batsch (Peach Kernel, Taoren), Carthamus tinctorius L. (Safflower, Honghua), Pheretima aspergillum (E. Perrier) (Earthworm, Dilong)	[99]
CFDT/CFDTD/MCDD	Dries damp; transforms phlegm; moves Qi; treats phlegm-dampness syndrome with irregular menstruation, PCOS; obesity, vaginal discharge; alleviates abdominal distension; improves insulin resistance & follicular development.	↓ HOMA-IR; ↓ FBG; improved insulin signaling; ↓ inflammation; PI3K/AKT activation; ASK1/JNK inhibition; NF-κB modulation	↑ Pregnancy & ovulation; improved receptivity & ovarian morphology	Patients with delayed menstruatio; PCOS women	Atractylodes lancea (Thunb.) DC. (Cangzhu), Cyperus rotundus L. (Xiangfu), Citrus reticulata Blanco, pericarpium (Chenpi), Pinellia ternata (Thunb.) Makino, praeparata (Banxia), Poria cocos (Schw.) Wolf (Fuling), Glycyrrhiza uralensis Fisch. (Gancao), Citrus aurantium L. (Zhiqiao), Magnolia officinalis Rehder & E.H.Wilson (Houpo), Arisaema heterophyllum Blume, praeparata (Tiannanxing), Alisma orientale (Sam.) Juz. (Zexie).	[115-117,136-138,192]
CGKYR	Modern formulation without classical TCM basis	↓ Insulin resistance; PI3K/Akt activation; ↓ NF-κB	Improved decidualization; improved endometrium; better pregnancy outcomes; IL-6/STAT3 pathway; Th17/Treg balance; trophoblast invasion	RPL patients with insulin resistance	Bupleurum chinense DC. (Chaihu), Scutellaria baicalensis Georgi (Huangqin), Citrus aurantium L. (Zhike), Pueraria lobata (Willd.) Ohwi (Gegen), Codonopsis pilosula (Franch.) Nannf. (Dangshen), Zingiber officinale Roscoe (Shengjiang), Atractylodes lancea (Thunb.) DC. (Cangzhu), Paeonia lactiflora Pall. (Baishao), Pinellia ternata (Thunb.) Makino (Banxia), Cinnamomum cassia (L.) J.Presl (Rougui), Alisma orientale (Sam.) Juz. (Zexie)	[139]
Cuscuta-Salvia herb pair	Nourishes liver & kidney Yin; secures essence; activates blood to remove stasis; treats kidney-deficiency symptoms such as weak, sore loins/knees, tinnitus, dizziness; regulates menstruation, alleviates abnormal uterine bleeding & miscarriage threats; clears blood stasis & promotes menstrual flow	Regulated PI3K-Akt, MAPK; IL-6, AKT1, VEGFA targets	Improved ovarian morphology; improved follicle development	PCOS mice	Semen Cuscutae + Radix Salviae	[128]
DXP/Xiaoyao-based	Soothes liver qi; strengthens spleen; nourishes blood; treats liver-Qi stagnation with spleen deficiency: depression, emotional disturbance, functional dyspepsia, menstrual irregularity, post-stroke mood disorders	↓ FINS; ↓ HOMA-IR; improved insulin resistance	Ovulation; ↑ pregnancy rates; anti-inflammatory; metabolic modulation	PCOS women	Astragalus membranaceus (Fisch.) Bunge (Huangqi) 120 g, Angelica sinensis (Oliv.) Diels (Danggui) 6 g, Paeonia lactiflora Pall. (Chishao) 4.5 g, Pheretima aspergillum (Dilong) 3 g, Ligusticum chuanxiong Hort. (Chuanxiong) 3 g, Carthamus tinctorius L. (Honghua) 3 g, Prunus persica L. (Taoren) 3 g	[130,131]
DZSD	Modern formulation without classical TCM basis	↓ Insulin resistance (HOMA-IR); ↓ plasma cardiotrophin-1; improved glucose-lipid metabolism; insulin-sensitizing; anti-inflammatory effects	Improved ovulation; ↑ clinical & biochemical pregnancy; improved menstrual cycle & hormone; modulation of HPO axis; endocrine regulation	PCOS women	Atractylodes chinensis (Cangzhu) 12 g, Pinellia ternata (Banxia) 12 g, Angelica sinensis (Danggui) 12 g, Atractylodes macrocephala (Baizhu) 10 g, Poria cocos (Fuling) 10 g, Alisma orientale (Zexie) 10 g, Ligusticum chuanxiong (Chuanxiong) 10 g, Cyperus rotundus (Xiangfu) 9 g, Glycyrrhiza uralensis (Gancao) 9 g	[129]
FXJC	Modern formulation without classical TCM basis	↓ AGEs; ↓ Ang II; RAAS modulation; endothelial protection	Improved EF; synergy with tadalafil	Diabetic patients with ED	Curculigo orchioides Gaertn. (Xianmao), Cynomorium songaricum Rupr. (Suoyang), Epimedium brevicornu Maxim. (Yinyanghuo), Psoralea corylifolia L. (Buguzhi)	[109,110]
GFW	Tonifies kidney & liver Yin; used for kidney-Yin deficiency with symptoms: weak, sore loins & knees; tinnitus; night sweats; dry mouth/throat; seminal leakage; internal heat signs; red tongue, thin rapid pulse.	↓ HOMA-IR; ↓ TNF-α; ↓ IL-6; PI3K/AKT/mTOR regulation	↓ testosterone, ↓ LH; improved ovulation & ovarian morphology; gut microbiota-inflammation axis	PCOS rats	Cinnamomum cassia (Ramulus Cinnamomi/Guizhi) 15 g, Poria cocos (Fuling) 15 g, Semen Persicae (Taoren) 15 g, Paeonia lactiflora (Chishao) 15 g, Cortex Moutan (Mudanpi) 15 g	[118,119]
GHYSJ	Nourishing kidney essence & replenishing Qi & Yin; treating dizziness, memory loss, insomnia, fatigue & weakness	↓ FBG; ↓ ROS/MDA; ↑ Nrf2/HO-1, GPX4; antioxidant; anti-ferroptosis	↑ Sperm count; ↑ motility; ↑ testosterone	Diabetic rats	Panax ginseng C.A. Mey. (Renshen), Astragalus membranaceus (Fisch.) Bunge (Huangqi), Epimedium brevicornu Maxim. (Yinyanghuo), Polygonatum sibiricum Redouté (Huangjing), Lycium barbarum L. (Gouqi), Cuscuta chinensis Lam. (Tusizi), Ligustrum lucidum W.T. Aiton (Nvzhenzi), Lonicera japonica Thunb. (Jinyinhua), Paeonia lactiflora Pall. (Baishao), Rosa laevigata Michx. (Jinyingzi), Glycyrrhiza uralensis Fisch. (Gancao).	[143]
Ginger + Cinnamon combo	Warms middle burner & disperses cold; warms stomach & relieves gastric pain; promotes digestion; warms meridians & stops pain in cold patterns.	Synergistic ↓ glucose; ↑ insulin; antioxidant; ↑ SIRT1; ↓ NF-κB/TNF-α	Synergistic ↑ sperm count, motility, testosterone; anti-apoptotic	Diabetic rats	Ginger (Zingiber officinale) 1 g/L, Cinnamon (Cinnamomum zeylanicum) 1 g/L	[144,145]
HXTLQWD	Activates blood & dredges the collaterals; dispels blood stasis & calms wind; used for patterns of collateral obstruction with stasis-related pain or numbness	Antioxidative stress (↓ PKC)	Improved EF (human & animal); endothelial rescue; NO pathway	Diabetic rats & patients with ED	Astragalus membranaceus (Fisch.) Bunge (Huangqi), Angelica sinensis (Oliv.) Diels (Danggui), Ligusticum chuanxiong Hort. (Chuanxiong), Salvia miltiorrhiza Bunge (Danshen), Paeonia lactiflora Pall. (Baishao), Carthamus tinctorius L. (Honghua), Prunus persica (L.) Batsch (Taoren)	[107,108]
Kuntai capsule	Nourishes Yin & clears heat; calms the mind & relieves irritability; tonifies heart & kidney; treats menopausal symptoms, diminished ovarian reserve/ovarian insufficiency; regulates reproductive hormones & enhances ovarian & uterine health	↓ BMI; ↓ FPG; ↓ insulin resistance; improved lipids; insulin sensitizing	↓ LH; ↓ testosterone	PCOS women	Rehmannia glutinosa, Coptis chinensis, Paeonia (Paeonia lactiflora/Paeonia alba), Scutellaria baicalensis, Equus asinus (donkey-hide gelatin, Ejiao), & Poria cocos	[124]
LDP	Tonifies liver-Yin & kidney-Yin; used for Yin-deficiency signal patterns: weak, sore loins & knees; tinnitus; night sweats; dry throat/mouth; frequent/clear urination; dizziness & fatigue	↓ HOMA-IR; improved glucose-lipid metabolism; PI3K/AKT inhibition; FoxO1a activation	↑ Pregnancy rate; improved ovarian morphology	PCOS women & rats	Rehmanniae Radix Praeparata: Corni Fructus: Dioscoreae Rhizoma: Alismatis Rhizoma: Moutan Cortex: Poria cocos = 8:4:4:3:3:3 (by weight)	[120,121,123]
QLST capsule	Clears heat & drains dampness; resolves blood-Stasis; used in TCM for chronic prostatitis & prostate hyperplasia with damp-heat & stasis: frequent/urgent urination, dribbling, perineal or lower abdominal discomfort	↓ MDA; ↓ ET-1; ↑ NO; ↑ SOD; ↑ GSH; antioxidative stress; NO pathway	Improved EF	Diabetic patients with ED	Hedyotis diffusa Willd. (Baihuasheshecao), Scutellaria baicalensis Georgi (Huangqin), Plantago asiatica L. (Cheqianzi), Polygonum cuspidatum Siebold & Zucc. (Huzhang), Curcuma longa L. (Jianghuang), Glycyrrhiza uralensis Fisch. (Gancao)	[103,106]
RR-CO	Nourishes kidney-Yin & liver-Yin; treats kidney-yin deficiency with loins/knees soreness & weakness; used for tinnitus, frequency of urination, seminal emission, & other symptoms of Yin deficiency	↓ FBG; ↑ GLP-1; improved gut microbiota	Improved sperm/testis morphology; ↑ testosterone; gut-testis axis regulation; GLP-1R upregulation	Diabetic mice	Rehmannia glutinosa (Gaertn.) DC. 25 g, Cornus officinalis Siebold & Zucc. 15 g	[122]
STP	Tonifies kidney-essence & secures the fetus; used for threatened or recurrent miscarriage with kidney deficiency signs; sense of lower abdominal dragging, weak loins & knees, dizziness, tinnitus	Improved insulin resistance; antioxidant; anti-inflammatory	↑ Progesterone; improved endometrial blood flow; ↑ pregnancy; progestogenic effects	Recurrent spontaneous abortion women	Semen Cuscutae (Tu Si Zi) 20 g, Dipsacus asper (Xu Duan) 30 g, Ligustrum lucidum (Nu Zhen Zi) 10 g, Parasitic Loranthus (Sang Ji Sheng) 20 g, Colla Corii Asini (Ass-hide Gelatin) 30 g	[135]
TJTLD	Modern formulation without classical TCM basis	↑ eNOS; inhibition of RhoA/ROCK	Improved EF; ↑ sexual hormones; endothelial rescue via NO pathway	Diabetic rats with ED	Epimedium brevicornu Maxim. 15 g, Rehmannia glutinosa (Gaertn.) DC. 10 g, Hirudo nipponica Whitman 10 g, Cyathula officinalis K.C.Kuan 10 g	[105]
WYZR	Nourishes kidney jing; secures seminal emission; strengthens loins & knees; treats impotence, premature ejaculation, dribbling urine, & male sterility	↓ Blood glucose, ↓ ER stress	Preserved spermatogenesis; ↓ DNA oxidative damage; improved sperm quality; NO-cGMP activation; ↓ caspase-3 (anti-apoptotic); hormone regulation	PCOS rats, Diabetic mice & rats	Lycium barbarum (Fructus Lycii, Gouqizi), Cuscuta chinensis (Semen Cuscutae, Tusizi), Rubus idaeus (Fructus Rubi, Fupenzi), Schisandra chinensis (Fructus Schisandrae, Wuweizi), Plantago asiatica (Semen Plantaginis, Cheqianzi)	[140-142]
Yiyuan qiwei Pill	Modern formulation without classical TCM basis	NS	↑ nNOS activity; ↑ EF; reduced corpus cavernosum damage; NO-cGMP activation; endothelial repair	Diabetic rats with ED	Rehmannia glutinosa Praeparata (Shudihuang) 25 g, Cistanche deserticola (Roucongrong) 20 g, Cornu Cervi (LuRong) 20 g, Rehmannia glutinosa (Shengdi) 15 g, Eucommia ulmoides (Duzhong) 15 g, Cuscuta chinensis (Tusizi) 15 g, Psoralea corylifolia (Buguzhi) 15 g, Cynomorium songaricum (Suoyang) 15 g, Lycium barbarum (Gouqizi) 15 g, Epimedium brevicornu (Yinyanghuo) 15 g, Panax ginseng (Renshen) 15 g, Achyranthes bidentata var. (Niuxi) 15 g, Asparagus cochinchinensis (Tian dong) 15 g, Hippocampus (Seahorse) 1 pair, Bombyx mori larva (Can’e) 10 g, Pantala flavescens (Qingting) 9 g, Nine-aroma insect (Jiuxiangchong) 9 g, Amber (HuPo) 8 g, Syzygium aromaticum (Dingxiang) 8 g, Amomum villosum (Sharen) 8 g, Costus root (Mu Xiang) 9 g	[104]
Yougui pill/Yougui Wan	Warms kidney-Yang; restores Ming-men fire; fortifies essence & blood; treats impotence, low sperm count, cold limbs, lumbar-knee weakness; reverses menopausal atrophy; enhances immune function; reduces glucocorticoid-induced apoptosis	Antioxidant	Improved EF vs placebo; ↑ testosterone; Nrf2-HO-1 activation; anti-oxidative stress	Diabetic rats with ED; ED patients; female rats with sexual dysfunction	Radix Rehmanniae Praeparata (Shu Di Huang), Radix Aconiti Lateralis Praeparata (Fu Zi), Cinnamomi Cortex (Rou Gui), Rhizoma Dioscoreae (Shan Yao), Fructus Corni (Shan Zhu Yu), Semen Cuscutae (Tu Si Zi), Fructus Lycii (Gou Qi), Cervi Cornus Colla (Lu Jiao Jiao), Eucommiae Cortex (Du Zhong), Radix Angelicae Sinensis (Dang Gui)	[100-102,193]
YQYYHXD	Tonifies Qi & nourishes Yin; activates blood circulation; used for Qi-Yin deficiency with blood stasis pattern (e.g. in type II diabetes to reduce proteinuria, improve renal function; in IPF to lower fibrosis; in ischemic stroke to ameliorate symptoms)	Adjunct glycemic support	↑ Testosterone; ↓ LH, ↓ estradiol; improved EF; HPG-axis balance	Diabetic patients with ED	Astragalus membranaceus, Pseudostellaria heterophylla, Rehmannia glutinosa, Cornus officinalis, Dioscorea opposita (or oppositifolia), Epimedium brevicornu, Ligusticum chuanxiong, Carthamus tinctorius, Paeonia lactiflora, Cyathula officinalis, Ophiopogon japonicus, Cuscuta chinensis	[98]
YSHXD	Tonifies kidney & nourishes essence; invigorates Blood & dispels stasis; strengthens sinews/bones & relieves lumbar-knee soreness; indicated for Kidney-deficiency with Blood-stasis patterns (e.g., post-trauma convalescence, chronic lumbago/weakness)	NS	Improved EF (↑ IIEF-5, EQS); ↓ ET-1; ↑ NO; antioxidative stress; endothelial protection	ED patients	Rheum palmatum (Rhei Radix et Rhizoma, Da Huang), Angelica sinensis (Angelica sinensis Radix, Dang Gui), Achyranthes bidentata (Achyranthes bidentata Radix, Niu Xi), Salvia miltiorrhiza (Salvia miltiorrhiza Radix et Rhizoma, Dan Shen), Panax notoginseng (Notoginseng Radix et Rhizoma, San Qi), Carthamus tinctorius (Carthami Flos, Hong Hua), Astragalus membranaceus (Astragali Radix, Huang Qi)	[96,97]
ZYP	Modern formulation without classical TCM basis	Improved insulin resistance; ↓ oxidative stress; anti-inflammatory; antioxidant	↑ Implantation; ↑ pregnancy; ↑ live birth; improved endometrium	Infertile & PCOS women	Cortex, Morindae Officinalis Radix, Cervi Cornu Degelatinatum, Codonopsis Radix, Atractylodis Macrocephalae Rhizoma, Asini Corii Colla, Lycii Fructus, Rehmanniae Radix Praeparata, Polygoni Multiflori Radix Praeparata, Artemisiae Argyi Folium, Amomi Fructus.	[132-134]
ZYZY	Modern formulation without classical TCM basis	NS	Improved EF; synergy with sildenafil; sexual confidence; QoL improvement	Diabetic patients with ED	Rehmannia glutinosa (Gaertn.) DC. 20 g, Reynoutria multiflora (Thunb.) Moldenke 18 g, Lycium barbarum L. 18 g, Dioscorea oppositifolia L. 15 g, Broussonetia papyrifera (L.) L’Hér. Ex Vent. 15 g, Dendrobium nobile Lindl. 15 g, Ligustrum lucidum W.T.Aiton 15 g, Epimedium brevicornu Maxim. 10 g, Cuscuta chinensis Lam. 10 g, Cervus nippon Temminck 10 g, Rosa laevigata Michx. 10 g, Albizia julibrissin Durazz 8 g	[113,114]

Abbreviations: ↑, Increase; ↓, Decrease; WYZR, Wuzi Yanzong recipe; YSHXD, Yishen Huoxue Decoction; YQYYHXD, Yiqi Yangyin Huoxue Decoction; BYHWD, Buyang Huanwu Decoction; EF, Erectile function; QoL, Quality of life; nNOS, Neuronal nitric oxide synthase; TJTLD, Tianjing Tongluo Decoction; BMI, Body mass index; IR, Insulin resistance; CFDT, Cangfu Daotan Decoction; CFDTD, Cangfu Daotan Decoction (variant); MCDD, Modified Cangfu Daotan Decoction; AKT1, RAC-alpha serine/threonine-protein kinase 1; VEGFA, Vascular endothelial growth factor A; HXTLQWD, Huoxue Tongluo Qiwei Decoction; GFW, Guizhi Fuling Wan; FXJC, Fufang Xuanju Capsule; AGEs, Advanced glycation end products; Ang II, Angiotensin II; RAAS, Renin-angiotensin-aldosterone system; QLST, Qianlie Shutong Capsule; LDP, Liuwei Dihuang Pill; ICP, Intracavernosal pressure; PNS, Panax notoginseng saponins; ABR+SV, Achyranthes bidentata root + Semen vaccariae; BSHXD, Bushen Huoxue Decoction; BSHZF, Bu Shen Hua Zhuo formula; GHYSJ, Guhan Yangsheng Jing; ROS, Reactive oxygen species; GPX4, Glutathione peroxidase 4; DZSD, Danxi Zhishitan Decoction; CT-1, Cardiotrophin-1; CGKYR, Chaige Kangyi Recipe; STAT3, Signal transducer and activator of transcription 3; Th17/Treg, T-helper 17 cells/Regulatory T cells; DXP, Danzhi Xiaoyao Pill; SIRT1, Sirtuin 1; RR-CO, Radix Rehmanniae - Cornus Officinalis; GLP-1, Glucagon-like peptide-1; GLP-1R, Glucagon-like peptide-1 receptor; STP, Shoutai Pill; ZYP, Zishen Yutai Pill; ZYZY, Ziyin Zhuangyang Capsule; ACE, Angiotensin-converting enzyme; ASK1, Apoptosis signal-regulating kinase 1; JNK, c-Jun N-terminal kinase; MAPK, Mitogen-activated protein kinase; ET-1, Endothelin-1; PKC, Protein kinase C; RhoA, Ras homolog family member A; ROCK, Rho-associated protein kinase; AKT2, RAC-beta serine/threonine-protein kinase 2; SCFA, Short-chain fatty acids; LPS, Lipopolysaccharide; HPG axis, Hypothalamic-pituitary-gonadal axis; FoxO1a, Forkhead box O1; IIEF-5, International Index of Erectile Function-5; EQS, Erection Quality Score; ED, Erectile dysfunction.

In controlled clinical studies, oral Yishen Huoxue Decoction (12 weeks) improved erectile-function scores, raised NO and superoxide dismutase (SOD), and lowered endothelin-1 and malondialdehyde (MDA) levels in men with diabetic ED. Also, corroborative preclinical findings showed enhanced penile eNOS/cGMP signaling and improved blood flow, confirming NO-mediated endothelial recovery [96,97]. Yiqi Yangyin Huoxue Decoction, in men with T2DM-ED, increased IIEF-5 scores and testosterone while lowering LH and E₂, suggesting improved erectile function via hormonal regulation [98]. Likewise, a four-month controlled clinical trial involving seventy diabetic men found that Buyang Huanwu Decoction enhanced erectile tone and testosterone, while complementary animal models demonstrated eNOS-cGMP activation and reduced cavernosal apoptosis, indicating that microvascular remodeling underlies its clinical efficacy [99]. These convergent clinical and experimental data indicate that vascular formulas act primarily through NO-eNOS preservation and microcirculatory repair to reverse endothelial dysfunction.

Further evidence from both pilot clinical and preclinical studies supports the vascular-restorative role of antioxidant-activating formulas. Oral Yougui Pill (9g for eight weeks) achieved efficacy comparable to tadalafil but with fewer side effects, while diabetic rat models showed activation of Nrf2-HO-1 signaling and reduced endothelial apoptosis, linking antioxidant defense to vascular recovery [100-102]. Similarly, Qianlie Shutong Capsule (with α-lipoic acid) improved endothelial integrity and NO bioavailability in middle-aged men after eight weeks, and preclinical analogs such as Yiyuan Qiwei Pills and Tianjing Tongluo Decoction enhanced eNOS expression and normalized sex-hormone profiles in diabetic rats [103-106]. The consistent upregulation of NO-related pathways across these formulations underscores endothelial activation and redox stabilization as shared mechanisms driving functional recovery.

Both preclinical and small clinical data further demonstrate the capacity of Huoxue Tongluo Qiwei Decoction to preserve endothelial ultrastructure and increase intracavernosal pressure following eight weeks of therapy, directly mapping microstructural repair to hemodynamic improvement [107,108]. In combined interventions, Fufang Xuanju Capsule with tadalafil produced superior erectile and vascular outcomes compared to tadalafil alone, consistent with inhibition of AGEs and Ang II signaling [109,110]. Complementary preclinical studies on Bushen Huoxue Decoction and Achyranthes bidentata plus Semen vaccariae Granules confirmed enhanced NO-cGMP signaling, improved vascular elasticity, and reduced apoptosis under hyperglycemic stress [111,112]. Moreover, RCTs of Ziyin Zhuangyang Capsule (Shisanwei) reported improved erectile scores, normalized testosterone, and elevated NO, suggesting dual restoration of endothelial and androgenic function [113,114]. Collectively, these findings support that vascular-targeted herbal prescriptions rebuild endothelial tone and restore erectile performance through overlapping antioxidative and NO-mediated mechanisms.

Beyond vascular repair, compound formulas that regulate metabolic and ovarian axes play a pivotal role in restoring female fertility disrupted by diabetes and PCOS. Cangfu Daotan Decoction, tested in both preclinical models and small clinical cohorts (~3 months), improved insulin sensitivity, suppressed ASK1/JNK and NF-κB/LCN-2 signaling, and restored folliculogenesis and uterine perfusion [115-117]. Guizhi Fuling Pill acted through PI3K/Akt/mTOR activation, lowering TNF-α and IL-6 while protecting granulosa cells from apoptosis, and preclinical results indicated improved IR and ovarian morphology [118,119]. In human RCTs involving 80-120 participants (8-12 weeks), Liuwei Dihuang Pill enhanced IRS-1/FoxO1a signaling and improved ovulation and pregnancy rates, while the Rehmanniae glutinosa-Cornus officinalis herb pair increased GLP-1 secretion and enriched butyrate-producing gut microbiota, linking metabolic-microbial modulation with reproductive improvement [120-123]. These findings collectively highlight metabolic-hormonal crosstalk as a major determinant of ovarian repair.

Further evidence from a double-blind RCT (1.2 g/day for three months) showed that Kuntai Capsule lowers body mass index (BMI), fasting insulin, and testosterone while improving ovulation, providing robust clinical validation of its endocrine and metabolic regulatory effects [124]. In obese PCOS women, Bushen Quyu Huatan and Bushen Tiaochong Decoctions modulated leptin/adiponectin balance and improved ovarian perfusion, yielding pregnancy rates above 70% [125,126]. In STZ-induced diabetic rat models, Bu Shen Hua Zhuo Formula inhibited TLR4/NF-κB signaling and remodeled gut microbiota toward short-chain-fatty-acid producers, linking inflammation control to ovarian restoration [127]. Similarly, Danxi Zhishitan Decoction improved ovarian function and insulin sensitivity under metabolic stress, while Cuscuta-Salvia Formula activated PI3K-Akt/MAPK signaling to sustain granulosa-cell viability and enhance endometrial receptivity [128,129]. Danzhi Xiaoyao regimens further normalized ovulation by modulating inflammatory and hypothalamic-pituitary signaling [130,131]. These interrelated mechanisms demonstrate how adipokine regulation, microbial rebalancing, and neuroendocrine stability collectively restore ovarian function under diabetic stress.

Formulas promoting uterine receptivity and implantation complete this therapeutic cascade. In two multicenter RCTs enrolling over two thousand IVF patients, Zishen Yutai Pill (5 g TID) significantly improved implantation and live-birth rates without added adverse effects [132-134]. In PCOS women with kidney-deficiency syndrome, combining Zishen Yutai Pill with Bushen Tiaojing Decoction for three cycles improved ovulation (90%) and pregnancy rates (76%), while reducing LH and testosterone levels [134]. A systematic meta-analysis of twelve RCTs confirmed that Shoutai Pill reduced miscarriage and increased live-birth rates [135]. Similarly, Modified Cangfu Daotan Decoction and Bu Shen Hua Zhuo Formula promoted follicular maturation and endometrial receptivity via metabolic-microbiome crosstalk [127,136-138]. In IR contexts, Chaige Kangyi Recipe improved endometrial receptivity through IL-6/vascular endothelial growth factor (VEGF) modulation, aligning angiogenesis with implantation success [139]. These uterine-targeted regimens demonstrate that local vascular, endocrine, and immune mechanisms cooperate to enhance conception and early gestational stability.

At the gonadal level, herbal combinations preserve spermatogenic function and testicular microcirculation under oxidative stress. In preclinical diabetic models, Wuzi Yanzong Recipe reduced ER stress and germ-cell apoptosis, activated NO-cGMP signaling, and maintained testicular structure, while aging models confirmed its capacity to prevent seminiferous degeneration [140-142]. Guhan Yangsheng Jing limited ferroptosis by restoring GPX4/xCT expression and reducing lipid peroxidation, linking mitochondrial protection to sperm viability [143]. The Radix rehmanniae-Cornus officinalis pair further increased GLP-1-mediated gut-testis communication, improving spermatogenesis through metabolic repair [122]. Similarly, the Ginger-Cinnamon combination reduced oxidative and inflammatory injury in diabetic rat testes, improving sperm motility and testosterone levels [144,145]. Collectively, these findings indicate that gonadal-protective formulas sustain spermatogenic integrity and redox equilibrium under metabolic stress (Table S3).

Non-herbal TCM modalities

Acupuncture

Acupuncture modulates neuroendocrine and metabolic signaling across the hypothalamic-pituitary-ovarian (HPO) and insulin pathways, integrating systemic and reproductive regulation, which is relevant to diabetic and PCOS-related infertility.

In women with PCOS, RCTs (8-12 weeks) consistently reported improved insulin sensitivity, lower BMI and HOMA-IR, and reduced LH and testosterone with normalization of the LH/FSH ratio [146-148]. These outcomes indicate restored hypothalamic-pituitary feedback and endocrine homeostasis. Corresponding reproductive improvements-enhanced follicular growth, greater endometrial thickness, and higher ovulation and pregnancy rates-confirm that hormonal normalization translates into measurable fertility gains.

Combined protocols pairing electroacupuncture (EA) with Chinese herbal medicine or clomiphene citrate achieved superior ovulation and conception rates compared with single therapy [149], illustrating how neuromodulatory stimulation enhances ovarian responsiveness when integrated with pharmacologic or herbal regimens. In obese women, 12-week abdominal acupuncture achieved metabolic and menstrual benefits comparable to metformin [150], supporting its potential as a non-pharmacologic insulin sensitizer. Animal studies using letrozole-, DHEA-, or DHT-induced PCOS models showed that low-frequency EA restored estrous cyclicity and ovarian morphology, improved glucose uptake, and normalized gonadotropins through modulation of GnRH, insulin receptor, and connexin-43 expression [151]. These mechanisms link autonomic regulation with ovarian recovery. When combined with metformin, EA further improved glucose tolerance and ovarian structure, underscoring its dual metabolic-reproductive role. Microbiome analyses also revealed increased Agathobacter and decreased Erysipelatoclostridium after EA [152], suggesting that gut-brain-ovarian signaling may partly mediate its systemic effects. Overall, acupuncture synchronizes central endocrine control with peripheral metabolic and ovarian signaling, providing a mechanistic rationale for its adjunctive use in diabetic and PCOS-associated infertility (Tables 4 and S4).

Table 4.

Effects of non-herbal TCM modalities in diabetic infertility

TCM modality	TCM-based mechanism	Main anti-diabetic effect	Main anti-infertility effect	Study model/population	Intervention component	Ref.
EAC	Modern technique without classical TCM basis	↓ BMI, ↓ fasting insulin, ↓ HOMA-IR; ↑ ISI; improved insulin sensitivity & glucose tolerance	Restored estrous cyclicity & ovarian morphology; ↓ LH, ↓ testosterone; ↑ E2, FSH, SHBG; ↑ ovulation & pregnancy	PCOS rats & women	Needling at ST29 (Guilai) & SP6 (Sanyinjiao)/(≈2-10 Hz)	[151,194,195]
Leech-Centipede granules	Breaks up blood stasis & opens collaterals; used for menstruation blocked by blood stasis, trauma bruising, & painful numbness in limbs	↓ Blood glucose; ↑ insulin & glucagon; antioxidant (↑ SOD, ↓ MDA); ↓ NF-κB/ICAM-1/LOX-1; endothelial protection	↑ EF; improved endothelial morphology & penile hemodynamics; endothelial protection	Diabetic rats with ED	Hirudo spp. (leech, whole dried body), Scolopendra spp. (centipede, whole dried body)	[156]
MAC	Elevates Qi; opens the collaterals & relaxes sinews; treats low back/leg pain; numbness; stiffness in joints; clears meridian blockages caused by cold-damp or blood-stasis	Improved insulin sensitivity; ↓ HOMA-IR, FBG, fasting & 2 h insulin; ↓ BMI & WHR; improved glucolipid metabolism; regulation of HPO axis; metabolic modulation; possible gut microbiota effects; neuroendocrine stress regulation	↑ Ovulation & pregnancy rates; improved menstrual regularity; ↓ LH, ↓ testosterone, ↓ LH/FSH; ↑ E2; improved endometrial thickness & ovarian histology; hormonal balancing compared to OCP; improved ovarian/endometrial environment	PCOS women	Needling at RN4 (Guanyuan), EX-CA1 (Zigong), ST29 (Guilai), ST36 (Zusanli), SP6 (Sanyinjiao), RN6 (Qihai), RN12 (Zhongwan), ST25 (Tianshu), KI3 (Taixi), KI6 (Zhaohai), LR3 (Taichong), SP10 (Xuehai), PC6 (Neiguan), DU20 (Baihui)	[196,197]
MAC + moxibustion	Warm meridians; stimulate qi & blood flow; dispel cold & damp; relieve joint & low back pain, numbness; improve digestion; ease menstrual discomfort	↓ BMI; ↓ fasting insulin; improved insulin resistance; endocrine regulation	↑ Pregnancy & ovulation; ↓ miscarriage; ↓ LH, ↓ LH/FSH; ↓ Testosterone; generally mild AEs	PCOS women	Needling at RN4 (Guanyuan), EX-CA1 (Zigong), ST29 (Guilai), ST36 (Zusanli), SP6 (Sanyinjiao), RN6 (Qihai), RN12 (Zhongwan), ST25 (Tianshu), KI3 (Taixi), KI6 (Zhaohai), LR3 (Taichong), SP10 (Xuehai), PC6 (Neiguan), DU20 (Baihui), SP9 (Yinlingquan), GB26 (Daimai), SP3 (Taibai), Qihai, PiShu, ShenShu, TianShu, BL32 (Ciliao), BL20 (Pishu), BL23 (Shenshu)	[155]

Abbreviations: ↑, Increase; ↓, Decrease; EAC, electroacupuncture; MAC, manual acupuncture; ISI, insulin sensitivity index; AEs, adverse events; OCP, oral contraceptive pill; WHR, waist-to-hip ratio; 2h-PBG, 2-hour postprandial blood glucose; ICAM-1, intercellular adhesion molecule 1; LOX-1, lectin-like oxidized low-density lipoprotein receptor-1; SHBG, Sex hormone-binding globulin; RN, EX-CA, ST, SP, KI, LR, PC, DU, GB, BL: Standard WHO acupuncture meridian point prefixes (e.g., RN = Ren, ST = Stomach, SP = Spleen, KI = Kidney, LR = Liver, PC = Pericardium, DU = Governing vessel, GB = Gallbladder, BL = Bladder).

Moxibustion

Moxibustion, a thermal therapy employing Artemisia vulgaris, promotes reproductive recovery under metabolic stress through vascular and inflammatory regulation. In PCOS rat models, it preserved granulosa-cell integrity, enhanced ovarian blood flow, and modulated gut-metabolite interactions by suppressing TNF-α, IL-6, and NF-κB activity-evidence of restored ovarian microcirculation and reduced cytokine-driven atresia [153]. Small RCTs (6-12 weeks, n = 60-100) mirrored these effects in humans, reporting improved ovulation, menstrual regularity, and pregnancy rates, particularly when moxibustion was combined with acupuncture or herbal therapy [154,155]. These combined protocols also increased integrin αvβ3 and VEGF expression, improving uterine perfusion and endometrial receptivity. Such findings suggest that moxibustion restores fertility by rebalancing ovarian and uterine vascular dynamics through coordinated anti-inflammatory and pro-angiogenic mechanisms, offering a simple, low-cost adjunct for metabolic infertility (Tables 4 and S4).

Leech-Centipede granules

Leech-Centipede Granules (LCG), derived from Hirudo and Scolopendra, exhibit vasoprotective activity in diabetic ED, a key vascular cause of male infertility. In STZ-diabetic rats (4-6 weeks, oral), LCG upregulated eNOS-cGMP signaling, enhanced cavernosal blood flow, and reduced fibrosis [156]. Concomitant downregulation of LOX-1, PKCβ, TNF-α, and IL-6, along with lower collagen deposition, indicated integrated antioxidant and anti-inflammatory remodeling of the endothelium. These molecular and histological changes restore erectile capacity under hyperglycemic stress, identifying LCG as a mechanistically coherent but still preclinical candidate for vascular repair in diabetic infertility (Tables 4 and S4).

Mind-body practices

Mind-body exercises such as Tai Chi and Qigong engage shared metabolic, vascular, and neuroendocrine pathways relevant to both diabetes and infertility.

A meta-analysis of RCTs in T2DM showed significant reductions in fasting glucose and HOMA-IR, confirming improvements in insulin signaling and glycemic regulation [157]. Another systematic review of RCTs in inflammatory conditions showed reduced C-reactive protein (CRP), IL-6, and TNF-α levels with enhanced antioxidant enzyme activity, suggesting systemic anti-inflammatory and redox stabilization [158]. Similarly, a meta-analysis of Tai Chi and Qigong in hypertension found increased nitric oxide and reduced ET-1, indicating endothelial repair and vascular relaxation [159]. Neuroendocrine trials support these mechanisms: a Tai Chi RCT in older women normalized cortisol and improved heart-rate variability, implying stabilization of HPG balance [160]. These physiological effects mirror PCOS pathology, where oxidative stress and gut dysbiosis impair steroidogenesis and ovulation [161,162]. Consistently, a meta-analysis of mind-body interventions (mainly Tai Chi and Qigong) in women with PCOS showed reductions in BMI, testosterone, and insulin resistance, alongside improved quality-of-life scores [163]. In men, a single-arm study of 92 infertile participants found that a three-month Qigong program improved sperm concentration and motility, achieving a 27% spontaneous pregnancy rate - demonstrating direct reproductive benefit via metabolic and vascular repair [164].

Overall, Tai Chi and Qigong act as low-cost, non-pharmacologic interventions that enhance glycemic control, vascular homeostasis, and endocrine stability, highlighting their potential as adjunctive therapies for diabetic infertility.

Challenges of TCM in managing diabetic infertility

Despite promising evidence, translating this approach into standardized care for diabetic infertility faced several challenges. The first involves variability in quality and authenticity among multi-herb formulations. DNA-metabarcoding studies revealed species substitution and adulteration, while ongoing surveillance continues to identify heavy-metal and microbial contamination-issues that complicate dosage determination and reduce reproducibility [165]. Although the European Medicines Agency-Herbal Medicinal Products Committee (EMA-HMPC) guidelines specify standards for identity testing, chemical markers, and contaminant limits, their implementation remains inconsistent across regions and product categories [166]. The second challenge relates to the limited clinical evidence base (Table 5). Despite the Consolidated Standards of Reporting Trials for Chinese Herbal Medicine 2017 (CONSORT-CHM 2017) framework, RCTs involving herbal medicine and acupuncture continue to show heterogeneity in syndrome differentiation, small sample sizes, incomplete reporting, and inadequate blinding-factors that weaken effect estimates [167,168]. A third concern involves herb-drug interactions, which present potential risks in diabetes management. For example, goldenseal reduced metformin exposure by approximately 25% in controlled trials, whereas berberine co-administration enhanced glycemic lowering. These findings highlighted both potential benefits and risks, emphasizing the need for prospective pharmacokinetic monitoring [169]. Safety and pharmacovigilance represent another key priority, especially among reproductive-age populations. Known toxicities such as aristolochic acid-induced nephropathy and urothelial cancer underscore the importance of validated sourcing and continuous post-marketing surveillance [170]. Finally, regulatory heterogeneity-ranging from the EU registration system to WHO-documented regional frameworks - continues to hinder international comparability and the integration of clinical trials [171,172]. These barriers explain the scarcity of adequately powered studies specifically addressing diabetic infertility and highlight essential priorities: adopting pharmacopoeial-grade standardized products, designing CONSORT-compliant RCTs with core fertility outcomes, predefining herb-drug interaction monitoring, and implementing transparent multi-region pharmacovigilance systems.

Table 5.

Summary of clinical studies evaluating TCM interventions for diabetic infertility

Intervention	Study type	Number	Population summary	Fertility endpoints
Berberine	5 RCTs + 1 prospective cohort	1,682	Women with PCOS ± IR	Pregnancy rate, ovulation rate, menstrual regularity, hormones, metabolic indices
Cinnamon supplements	RDBPCT	45	Women with PCOS	Menstrual cyclicity, ovulation rate
Tribulus terrestris	2 RDBPCTs	210	Men with mild to moderate ED	Sexual function (IIEF scores, satisfaction, desire)
Curcumin	3 RDBPCTs	192	Overweight/obese women with PCOS	Hormonal and metabolic indicators related to fertility (LH, LH/FSH, testosterone, IR)
Modified Yougui Pill	RCT	74	Women with PCOS	LH, LH/FSH, testosterone, E2, menstrual and ovulatory function
Puerarin	RCT	51	Obese and non-obese women with PCOS	Menstrual regularity, testosterone, SHBG
Quercetin	RDBPCT	84	Women with PCOS	testosterone, LH, SHBG
Resveratrol	2 RCTs + 1 meta-analysis of 4 RCTs	300	Women with PCOS	Oocyte/embryo quality, pregnancy rate, sex hormones
Tanshinone	4 RCTs	≈ 220	Women with PCOS with hyperandrogenism or metabolic disorders	Testosterone, LH, ACTH, GH, ovulatory function
Bushen Quyu Huatan Decoction	RCT	148	Women with PCOS-related infertility	Pregnancy rate, ovulation rate, LH, LH/FSH, testosterone
Bushen Tiaochong Decoction	RCT	147	Obese women with PCOS	E2, LH, FSH, LH/FSH, endometrial receptivity
BYHWD	RCT	70	Men with diabetic ED	IIEF-5, sexual and life quality
CFDT	6 RCTs	≈ 440	Women with PCOS or infertility	Pregnancy rate, ovulation rate, endometrial thickness, LH, FSH, testosterone
DXP	RCT	60	Women with PCOS	Ovulation rate, pregnancy rate, LH, testosterone
Xiao Yao San	Meta-analysis of 19 RCTs	1,588	Women with PCOS	Pregnancy rate, ovulation rate, LH/FSH, testosterone, E2
DZSD	RCT	92	Women with PCOS	Pregnancy rate, ovulation rate, LH, FSH, E2
FXJC + LDP	RCT	60	Men with T2DM-ED	IIEF-5, erectile function
FXJC	RCT	80	Men with T2DM-ED	IIEF-5, erectile hardness, satisfaction
HXTLQWD	RCT	66	Men with T2DM-ED	IIEF-5, erectile function
Kuntai Capsule	RDBPCT	100	Women with PCOS	LH, LH/FSH, testosterone, menstrual regularity
LDP + Xiaoyao San	Observational study	16	Women with PCOS	Ovulation rate, pregnancy rate, LH, LH/FSH, testosterone
QLST	2 RCTs	136	Men with T2DM-ED	IIEF-5, erectile function
STP	Meta-analysis of 12 RCTs	916	Pregnant women with URSA	Early pregnancy loss, live birth rate
Yougui Pill	RCT	42	Men with T2DM-ED	IIEF-5, erectile function
YSHXD	2 RCTs	200	Men with T2DM-ED	IIEF-5, EQS, erectile function
ZYP	3 RCTs	2,425	Women with infertility due to PCOS or decreased ovarian reserve, including IVF/IUI patients	Pregnancy rate, live birth, ovulation rate, implantation, LH, FSH, E2, testosterone, ovarian and endometrial indices
ZYZY	2 RCTs	180	Men with T2DM-ED	IIEF-5, erectile function, sexual satisfaction
EAC	RCT	84	Women with PCOS	Testosterone, menstrual frequency
MAC	2 RCTs (sham-controlled)	170	Women with PCOS-related infertility	Pregnancy rate, ovulation rate, LH, FSH, testosterone, LH/FSH
MAC + moxibustion	Meta-analysis of 25 RCTs	1,991	Women with PCOS	Pregnancy rate, ovulation rate, miscarriage rate, sex hormones

Abbreviations: RDBPCT, Randomized Double-Blind Placebo-Controlled Trial; ACTH, Adrenocorticotropic Hormone; GH, Growth Hormone.

Future opportunities: epigenetics, artificial intelligence (AI), and standardization

Emerging research provides new directions for advancing this field in diabetic infertility. Epigenetic studies in T2DM have revealed reproducible DNA methylation and chromatin patterns associated with insulin signaling and inflammation, offering mechanistic targets and potential biomarkers for future trials [173]. Human and animal data indicate that glycemic control mitigates oocyte-level epigenetic damage, whereas maternal diabetes induces heritable methylation changes that influence fertility outcomes [174]. At the endometrial level, epigenetic regulation of AGE-RAGE signaling and impaired embryo-endometrium communication highlightthe need for disease-specific reproductive endpoints in upcoming studies [40]. AI applications may accelerate these advances by integrating clinical, omics, and pharmacological data to identify bioactive compounds, optimize formulations, and improve product quality control. However, challenges such as inconsistent datasets, limited model interpretability, and the absence of prospective validation still restrict broader implementation [175]. Among emerging innovations, standardization offers the most immediate translational benefit. International frameworks - including ISO/TC 249, EMA/HMPC, and WHO regulatory guidelines - provide harmonized criteria for herbal identity, marker compounds, and contaminant thresholds. Aligning future research with these standards will facilitate multicenter collaboration and enhance consistency in reporting fertility outcomes such as ovulation, menstrual regularity, and pregnancy rates [172,176].

Conclusion

This narrative review evaluated the therapeutic potential of TCM in managing diabetes-related infertility - a disorder characterized by intertwined metabolic, oxidative, inflammatory, and hormonal disturbances that impair the HPG axis and reproductive tissues. Evidence from preclinical and clinical studies indicates that interventions based on this system - including isolated compounds, multi-herb formulations, and non-herbal modalities such as acupuncture - enhance fertility by improving insulin sensitivity, reducing oxidative stress, regulating hormonal balance, and preserving mitochondrial and gonadal function (Figure 3). Clinical findings have shown improved sperm quality and sexual function in diabetic men, alongside enhanced ovulation and pregnancy rates in women with IR or PCOS. Among isolated compounds, berberine, resveratrol, and quercetin demonstrate consistent though preliminary human evidence, while most other agents remain supported mainly by preclinical data. Nevertheless, small sample sizes, heterogeneous formulations, and limited reporting of definitive endpoints-particularly live birth-restrict translational certainty. Safety concerns, including herb-drug interactions and variability in product quality, further emphasize the need for stringent regulatory and pharmacovigilance oversight. Future research should prioritize large, multicenter RCTs employing standardized formulations, validated products, core fertility outcomes, and structured safety monitoring. Integrating omics technologies and AI-based analytical approaches may further elucidate underlying mechanisms and support precision applications. Despite current limitations, TCM offers a scientifically grounded, holistic, and multi-target framework that complements conventional therapies and represents a promising direction for restoring fertility in diabetes.

Figure 3.

Integrated mechanistic framework of TCM restoring metabolic and reproductive balance in diabetic infertility. Diverse TCM modalities converge on shared metabolic, antioxidant, vascular, gonadal, and neuroendocrine pathways, collectively enhancing insulin sensitivity, alleviating oxidative and inflammatory stress, and restoring reproductive function.

Disclosure of conflict of interest

None.